PHD Thesis On Vascular en Dot Helium

Safety and Efficacy of
Radial Artery Conduits
for Coronary Artery Bypass Surgery
A thesis submitted for the degree of
DOCTOR OF PHILOSOPHY
by
PERMYOS RUENGSAKULRACH
M.D., FRCST
Cardiac Surgery Department

University of Melbourne
Austin & Repatriation Medical Centre
Heidelberg, Victoria 3084
AUSTRALIA
June 2001
“There is no privileged territory. In the abysses of our inner world
everything has a meaning. We cannot choose only those things that please us,
according to the dictates of our feelings, our imagination, the scientific and
philosophical form of our mind. A difficult or obscure subject must not be
neglected just because it is difficult and obscure. All methods should be
employed. The qualitative is as true as the quantitative. The relations that can be
expressed in mathematical terms do not posses greater reality than those that
cannot be so expressed. Darwin, Claude Bernard, and Pasteur, whose discoveries
could not be described in algebraic formulas, were as great scientists as Newton
and Einstein. Reality is not necessarily clear and simple. It is not even sure that
we are always able to understand it.”
Alexis Carrel
Man, The Unknown
Harper & Brothers Publishers, New York and London, 1935
2
To My parents:
Mr. Chue Kieo Hao
Mrs. Sujitra Mahatthanaphanit
Patients and volunteers

Supervisors and colleagues
without you
this thesis would not exist
3
Abstract
Coronary artery bypass grafting (CABG) is the most common cardiac

surgical operation performed in western countries, and is also increasingly being
performed in developing countries. However the long-term results of CABG using
the saphenous vein graft have not been satisfactory. Surgeons have therefore been
seeking a better conduit. The radial artery (RA) is a potentially suitable alternative
conduit and has to date provided good early results. This thesis investigates the
utility of the RA as a coronary artery bypass graft from a number of perspectives.
It demonstrates the safety of RA harvesting by examining hand collateral
circulation using anatomical dissection, physical examination using the modified
Allen test, measuring digital blood pressure, and examining the flow velocity in
the digital artery using Doppler ultrasound. Anatomical examinations revealed
consistent continuity between the RA and ulnar artery in the hand through either
superficial or deep palmar arches. The modified Allen test was found to be useful
as a screening test compared with the Doppler dynamic test and digital blood
pressure index. A histological comparison was made between pre-existing intimal
disease in the RA compared with that in the standard conduit the internal thoracic
artery (ITA). The RA showed a higher prevalence and degree of intimal disease
than ITA. Risk factors for intimal hyperplasia in the RA were age, diabetes,
smoking and peripheral vascular disease. The only predictor for medial
calcification was age. Ultrasound was used to examine the RA preoperatively and
found to be useful in detecting a significant degree of calcification. However it
was not useful to determine the severity of intimal disease in the RA. A cohort of
patients who received the RA or the right ITA as a second graft in addition to the
left ITA had improved survival rates at median 3 years follow-up compared with
patients who received a saphenous vein grafts as a second graft. Early graft
patency in a prospective randomized controlled trial, The Australian Radial Artery
Study Trial, also showed excellent patency of the radial graft. These findings have
led me to the conclusion that the RA is a safe and effective alternative conduit for
CABG. To demonstrate more clearly, long-term angiographic follow-up is
required.
Declaration
The studies described in this thesis have not previously been submitted for a
degree at this or any other university or tertiary institution. The studies undertaken
and their interpretation are my own original work, except where due
acknowledgement has been made.
I also declare that the sum total of the words in this thesis, exclusive of
tables, figures, bibliography and appendix is less than 100,000 words.
Permyos Ruengsakulrach
Cardiac Surgery Department
Austin & Repatriation Medical Centre
The University of Melbourne
Heidelberg, Victoria, 3084
AUSTRALIA
v
Acknowledgements
This work was undertaken in the Cardiac Surgery Department of the Austin
& Repatriation Medical Centre and was supervised by Professor Brian Buxton
and Professor Roger Sinclair.
These research projects and thesis would not have been possible without the
support and assistance of many people. My deepest debt of gratitude is to
Professor Brian Buxton who first kindled my interest in the radial artery (RA) for
use as a bypass conduit for coronary artery surgery and provided me with the
opportunity to undertake this series of studies. His excellent supervision and
constant encouragement have enabled me to overcome the many challenges I
faced as an overseas student studying English as a second language and as a
young Fellow in cardiac surgery research. He willingly shared his immense
knowledge of coronary artery surgery and provided invaluable advice on the
presentation of every chapter of this thesis. For all of these reasons, I owe a great
deal to him.
Special mention must be made of Professor Roger Sinclair for his expert
supervision and guidance in histopathology, and the energy and time he spent
reviewing the first draft of this thesis; Dr. Ian Gordon for his invaluable advice on
research methodology, statistical analysis; the research nurses (Ms. Louise
Greene, Ms. Kathy Cowie, and Ms. Meg Storer) for their help with patient
enrolment and data collection; Ms. Sue Merritt and Dr. Tania Lewis for their
expertise in English expression; Ms. Beth Croce for her medical illustrations; and
the Austin & Repatriation Medical Centre Library staff for their assistance and
support.
I would like to thank Dr. Norman Eizenberg and Professor Marius Fahrer,
Department of Anatomy and Cell Biology, The University of Melbourne for
guiding and supporting the anatomical work in Chapter 2; Mr. Paul Martinello for
his expert technical assistance in establishing morphometric analysis in Chapter 4.
vi
I also acknowledge Dr. Mark Brooks, Department of Radiology and Dr. David
Hare, Department of Cardiology, Austin & Repatriation Medical Centre for their
advice and assistance with the ultrasound work in Chapters 5 and 7.
I also gratefully acknowledge Dr. Stan Bennett from the Australian Institute
of Health and Welfare for conducting the matching process using the National
Death Index and thus enabling me to perform an accurate survival study in
Chapter 8. In addition, I would like to thank Dr. John Fuller, Cardiology
Department, Epworth Hospital for providing me with a data set for the survival
analysis, and cardiac surgeons at the Austin & Repatriation Medical Centre (Drs.
Alexander Rosalion, George Matalanis, Jai Raman) and the Epworth Hospital
(Professor Donald Esmore, Professor James Tatoulis, and Drs. John Goldblatt,
Serge Lubicz, Peter Skillington, Alistair Royse, Ian Nixon, Anthony Wilson,
Robin Brown, Jacob Goldstein, and Mr. Marc Rabinov) for their cooperation and
help. The randomized elective coronary angiography for the semi-quantitative and
quantitative angiography, providing an early insight into the RA graft patency,
was supplied by the Australian Radial Artery Study Group at the Austin &
Repatriation Medical Centre, The University of Melbourne. I also owe a great
deal to a number of cardiac surgeons previously employed at the Austin &
Repatriation Medical Centre who are now practicing overseas including Professor
Masashi Komeda, Professor and Chairman Department of Cardiovascular
Surgery, Graduate School of Medicine, Kyoto University, Japan and Mr. Jullien
Gaer, Consultant Cardiac Surgeon, Harefield Hospital, London, United Kingdom.
Finally I would like to thank the patients and volunteers, without whose co-
operation these studies would not have been possible.
vii
Publications and Communications
Journal Publications:
Ruengsakulrach P., Eizenberg N., Fahrer C., Fahrer M., Buxton B. Surgical
implications of variations in hand collateral circulation: Anatomy revisited. J
Thorac Cardiovasc Surg 2001;122(4):682-686.
Ruengsakulrach P., Buxton B., Eizenberg N., Fahrer M. Anatomical assessment

of hand circulation in harvesting the radial artery. J Thorac Cardiovasc Surg
2001;122(1):178-180.
Ruengsakulrach P., Brooks M., Sinclair R., Hare DL., Gordon I., Buxton B.
Prevalence and prediction of calcification and plaques in radial artery grafts by
ultrasound. J Thorac Cardiovasc Surg 2001;122(2):398-399.
Ruengsakulrach P., Brooks M., Hare DL., Gordon I., Buxton B. Preoperative
assessment of hand collateral circulation by Doppler ultrasound and modified
Allen test. J Thorac Cardiovasc Surg 2001;121(3):526-531.
Ruengsakulrach P., Sinclair R., Gordon I., Buxton B. Predictors of severe intimal
disease in radial arteries for use in coronary artery surgery (abstract) The Journal
of Heart Failure 2000; 6(1):86.
Ruengsakulrach P., Brooks M., Hare DL., Grant AM., Koutrouza N, Buxton B.
Evaluating the safety of radial artery removal: Allen Test versus Doppler
ultrasound (abstract). Aust NZ J Med 2000;30(1):184.
Ruengsakulrach P., Brooks M., Hare DL., Grant AM., Koutrouza N., Buxton B. Is
Doppler ultrasound useful for assessing the radial artery before coronary artery
surgery? (abstract). Aust NZ J Med 2000;30(1):176.
Buxton B., Ruengsakulrach P., Komeda M., Hare DL. Safety of removing the
viii
radial artery: Allen test versus thumb systolic blood pressure index (abstract).
Aust NZ J Med 2000;30(1):177.
Ruengsakulrach P., Komeda M., Raman J., Windsor M., Sinclair R., Buxton B.
Comparative histopathology of the radial artery versus the internal thoracic
arteries (abstract). Aust NZ J Med 1999;29(1): 111.
Ruengsakulrach P., Sinclair R., Komeda M., Raman J., Gordon I., Buxton B.
Comparative histopathology of the radial and internal thoracic arteries and risk
factors for development of intimal hyperplasia and atherosclerosis Circulation
1999;100(suppl II):II-139 – II-144.
Comparative histopathology of the radial and internal thoracic arteries. (abstract)
Circulation 1998 (suppl): I-457.
Ruengsakulrach P., Sinclair R., Gordon I., Buxton B. Histopathology of the radial
artery: a conduit for coronary artery bypass grafting (abstract). Asia Pacific Heart
J 1999; 8(1): 59-59.
Buxton B., Gaer J., Komeda M., Ruengsakulrach P. The road to complete arterial
grafting for coronary artery disease. Int J Cardiol 1997; 62(Suppl 1): S65-S70.
ix
Manuscripts under review
Ruengsakulrach P., Fuller J., Rosalion A., Matalanis G., Raman J., Gordon I.,
Goldblatt J., Tatoulis J., Buxton B.
Improved survival in coronary artery bypass grafting using the radial artery.
Ultrasound intima-media thickness does not predict histological intimal disease in
arteries.
Comparison of ultrasound and histopathology for detecting calcification in the
distal and proximal segments of radial artery grafts.
Buxton B., Ruengsakulrach P., Gordon I., Komeda M., Raman J., Greene L.,
Wilson G., Hare DL.
Safety of removing the radial artery: Allen test versus digital brachial systolic
blood pressure index.
x
Prizes and awards:
Finalist of 2000 TAG Young Achievers Award

Ruengsakulrach P., Buxton B., Fuller J., Rosalion A., Gordon I.
Is the radial artery improving survival in coronary artery bypass grafting?
Presented at
The 15th Annual Inter Annual Scientific Congress, Cardio-Thoracic Section,
Royal Australasian College of Surgeons, October 26-29, 2000.
Brisbane, Queensland, Australia.
Travel Award 2000

Ruengsakulrach P., Brooks M., Hare DL., Gordon I., Buxton B.
Doppler ultrasound validates the use of the Allen test before radial artery
harvesting.
Presented at
The 8th Annual Meeting of the Asian Society for Cardiovascular Surgery
(ASCVS), September 6-8 , 2000.
Fukuoka, Japan.
1998 TAG Young Achievers Award

Ruengsakulrach P., Sinclair R., Gordon I., Buxton B.
Histopathology of the radial artery: A conduit for coronary artery bypass grafting.
Presented at
The 13th Inter Annual Scientific Congress, Cardio-Thoracic Section, Royal
Australasian College of Surgeons, November 5-8, 1998.
Brisbane, Queensland, Australia.
Finalist of 1998 Ralph Reader Prize Presentation

Ruengsakulrach P., Komeda M., Raman J., Windsor M., Sinclair R., Buxton B.
Comparative histopathology of the radial artery versus the internal thoracic artery.
Presented at
The 46th Annual Scientific Meeting of the Cardiac Society of Australia and New
Zealand, August 2-5, 1998.
Perth, Western Australia, Australia.
Finalist of 1998 Viven Thomas Young Investigator Award
Comparative histopathology of the radial and internal thoracic arteries and risk
factors for development intimal hyperplasia and atherosclerosis.
Presented at
The 71st Scientific Sessions, American Heart Association, November 8-11, 1998.
Dallas, Texas, USA.
xii
Communications Presented at Scientific Meetings:

Predictors of Severe Intimal Disease in Radial Arteries for Use in Coronary
Artery Surgery.
Presented at
The 7th World Congress on Heart Failure – Mechanism and Management,
Vancouver, B.C., Canada. 9-12 July, 2000.
Ruengsakulrach P., Eizenberg N., Fahrer C., Fahrer M., Buxton B.

Does the Radial Artery Always Communicate with the Ulnar Artery in the Hand?
Presented at
The Annual Meeting of the Society of Cardiothoracic Surgeons of Great Britain
and Ireland, London, England, 13 March, 2000.
Ruengsakulrach P., Brooks M., Sinclair R., Hare DL., Buxton B.

The Use of Ultrasound for Assessing the Radial Artery before Coronary Artery
Surgery.
Presented at
The 14th Biennial Asian Congress on Thoracic & Cardiovascular Surgery, Lahore,
Pakistan, 2 December, 1999.
Ruengsakulrach P., Brooks M., Hare DL., Grant AM., Koutrouza N., Buxton B.
Evaluating the Safety of RA Removal: Allen Test versus Doppler Ultrasound.
Presented at
Zealand, Wellington, New Zealand, August, 1999.
xiii
Ruengsakulrach P., Brooks M., Sinclair R., Grant AM., Koutrouza N., Hare DL.,
Buxton B.
Is Doppler Ultrasound Useful for Assessing the Radial Artery before Coronary
Artery Surgery? (Poster Presentation).
Presented at
Buxton B., Ruengsakulrach P., Komeda M., Hare DL.

Safety of Removing the Radial Artery: Allen test versus Thumb Systolic Blood
Pressure Index (Poster Presentation).
Presented at

Predictors of Severe Intimal Disease in Radial Arteries.
Presented at
The First Virtual Congress of Cardiology, Argentine federation of Cardiology,
1999 (on the Internet) at http://pcvc.sminter.com.ar/cvirtual/ingreso/ingreeng.htm
xiv
Table of Contents
Abstract ...............................................................................................................................iv
Declaration .......................................................................................................................... v
Acknowledgements .............................................................................................................vi
Publications and Communications.................................................................................... viii
Preface..............................................................................................................................xvi
Chapter 1 Introduction ........................................................................................................ 1
Chapter 2 Surgical Anatomy and Variations of the Arterial System of the Upper Extremity
.................................................................................................................................. 60
Chapter 3 Vascular Histology and Histopathology ........................................................... 98
Chapter 4 Comparative Histopathology of the Radial Artery versus the Internal Thoracic
Artery and Clinical Predictors for Development of Intimal Hyperplasia and
Atherosclerosis ....................................................................................................... 111
Chapter 5 The Use of Ultrasound for Assessing the Radial Artery before Coronary Artery
Bypass Grafting ...................................................................................................... 146
Chapter 6 Preoperative Assessment of Hand Circulation by Doppler Ultrasound and

Modified Allen Test ................................................................................................. 178
Chapter 7 Evaluating the Safety of Radial Artery Removal: Allen Test versus Digital
Brachial Systolic Blood Pressure Index using Photoplethysmography .................. 194
Chapter 8 Survival after Coronary Artery Bypass Grafting: Comparison of the Internal
Thoracic Artery, Radial Artery and Saphenous Vein as the Second Graft of Choice
................................................................................................................................ 211
Chapter 9 Semi-quantitative and Quantitative Coronary Angiography of the Radial Artery,

Internal Thoracic Artery and Saphenous Vein in an Elective Cohort ..................... 229
Chapter 10 Summary...................................................................................................... 289
Chapter 11 Future ........................................................................................................... 294
Bibliography .................................................................................................................... 289

Preface
The prevention and treatment of coronary heart disease is one of the largest
challenges facing the medical profession in the developed world. For instance, in
1996, approximately 200,000 patients presented with coronary artery disease in
the United State alone. One of the increasingly common treatment modalities for
ischemic heart disease is coronary artery bypass grafting.
An ageing population and the use of angioplasty have resulted in an

increasing number of patients requiring multivessel grafting. Until recently, the
current practice for multivessel grafting involved using a single internal thoracic
artery in combination with the saphenous vein graft. However, while this
approach has proven beneficial in the short-term, the long-term outcomes of this
operation have been disappointing. In particular, early death, myocardial
infarction and recurrent angina have been linked with saphenous vein graft failure
and the progression of native coronary artery disease. In contrast with the poor
results associated with saphenous vein grafting, the internal thoracic artery has
shown excellent long-term results with a graft patency at 10-years of about 95%.
As a consequence, surgeons have begun to explore the use of bilateral, sequential
and composite internal thoracic artery grafts.
Furthermore, in an attempt to avoid the complications associated with

saphenous vein graft failure and to improve long-term survival, some surgeons
have abandoned the saphenous vein in favour of complete arterial grafting. The
shift towards complete arterial grafting has been hampered, however, by the
limited number of conduits available. Increasingly, then, surgeons concerned with
finding suitable alternative conduits for grafting have been experimenting with the
use of arteries other than the internal thoracic artery. However, most of these have
demonstrated limitations, such as, difficulty in harvesting (the splenic artery and
the right gastroepliploic artery) and inadequate vessel length and diameter (the
inferior epigastric artery). In contrast, an alternative conduit that has a number of
xvi
favorable characteristics for bypass grafting is the radial artery.
When the radial artery was initially used in the early 1970s it was soon
abandoned due to a high graft failure rate. However, this occurred at a time when
there was no knowledge of the importance of the endothelium in controlling graft
function. The subsequent discovery that some of the radial artery grafts from the
1970s were patent 15 years later prompted the reevaluation of the radial artery as
a conduit for coronary artery bypass grafting. New studies using the radial artery
produced suprisingly good patency rates. It was suggested that the improvement
may have been the result of the use of calcium channel blockers to control
vasospasm.
Although some studies have suggested that the patency rates of radial artery
grafts are better than those of the saphenous vein and approach those of the
internal thoracic artery, a number of questions remain unanswered. In particular,
the feasibility, safety and efficacy of using the radial artery as a coronary artery
bypass graft needs to be objectively assessed before it can be confidently used
routinely in bypass procedures.
xvii
Chapter 1
Introduction
(a) The History of the Development of Coronary Artery Surgery and

The Role of the RA as A Conduit for Coronary Artery Bypass
Grafting
Introduction
Extracardiac Operations for Angina

Observations and Hypotheses
Sympathectomy
Thyroidectomy
Indirect Coronary Revascularization

Pericardiectomy, pericardial abrasion, cardiopericardiopexy, Cardiomyopexy
Redirection of venous drainage of the heart
Increasing left heart blood volume
Increasing coronary collaterals
Increasing pulmonary collaterals
Transmyocardial laser revascularization
Direct Coronary Revascularization

Venous conduits
Arterial conduits
The Role of the RA as a Bypass Graft

Early patency
Conclusion
Expanded Use of Arterial Grafting
Vasoreactivity of Vascular Grafts
(b) Hypotheses and Specific Aims

First hypothesis: Suitability
Second hypothesis: Safety
Third hypothesis: Efficacy
Background 57
(a) The History of the Development of Coronary Artery Surgery and

The Role of the RA Graft as a Conduit for Coronary Artery
Bypass Grafting
“Only the man who is familiar with the art and science of the past is
competent to aid in its progress in the future”
Theodor Billroth
Introduction
The history of cardiac surgery provides interesting insights into the

development of contemporary surgical procedures. Furthermore, an historical
approach may also open up future directions for cardiac surgery. The development
of coronary artery surgery has not always progressed in a linear fashion. For
example, some major advances have been made by revisiting previous techniques
and approaches. Thus, although early surgical attempts to treat ischemic heart
disease either failed or achieved marginal results, these pioneering techniques
foreshadowed later developments in contemporary cardiac surgery. In the
discussion that follows I will outline some of the major techniques developed to
treat ischemic heart disease. These techniques are divided into three groups,
namely, extracardiac operations for angina, indirect coronary revascularization,
and direct coronary revascularization. This will be followed by discussion of the
history of the use of the radial artery (RA) as a bypass graft.
While the development of techniques for managing ischemic heart disease

also has not always followed a smooth, chronological path, it can be seen as
progressing through several reasonably distinct stages ¾ from the development of
palliative techniques for the treatment of ischemia and its symptoms, through use
of both indirect and direct methods of revascularizing the myocardium, to present
day direct coronary artery grafting. I have included an overview of the history of
surgery for ischemic heart disease because I believe this history places my own
2
Background 57
work in an appropriate historical context. It also provides many useful examples

of the ingenuity, tenacity and work needed to achieve progress in a difficult field.
Extracardiac Operations for Angina

Observations and Concepts
In the late 19th and early 20th centuries, a number of extracardiac

approaches to the treatment of angina emerged. Interestingly, the idea of surgical
revascularization was first suggested as early as 1880 when Langer observed the
interconnections within the coronary system, and between coronary vessels and
surrounding extracardiac structures such as the diaphragm, bronchi, and the
pericardium.1 In 1898, Pratt suggested that coronary sinus blood flow could be
reversed by the insertion of an artery into the myocardial venous system thereby
enhancing myocardial blood flow.2 Much of the early surgical treatment of
ischemic heart disease however, was primarily concerned with relieving the
discomfort of angina rather than with revascularizing the myocardium. In 1899 for
example, Parisian Professor of Physiology, Charles Emile Francois Franck,
suggested treating angina by performing sympathetic ganglionectomy of the upper
thoracic ganglia to divide the afferent pain fibres.3 Another palliative approach for
treating angina, namely thyroidectomy, emerged from Kocher’s observation in
1902 that a patient with angina became asymptomatic after total thyroidectomy.4
Finally, Wearn, who had found connections between the cardiac chambers and the
myocardial sinusoids, suggested in 1928 that “ if coronary flow was occluded,
1
Langer. Sitzungsberichte Akad Wiss Wien 1880; 82:25-29.
2
Pratt. Am J Physiol 1898; 1:86-89.
3
Francois-Franck. Bull Acad Med Paris 1899; 41:565-94.
4
Kocher. Mitt Grenzgeb Med Chir 1901; 1:1-13.
3
Background 57
flow in the thebesian vessels could be reversed, thus supplying blood from the
ventricular cavities to the myocardium”.5
Sympathectomy
The first operation for ischemic heart disease in humans was carried out by
Charles Mayo in 1913 and involved cervical sympathectomy.6 The idea of
cervico-thoracic sympathectomy for angina pectoris was put to clinical trial on
April 2, 1916, by Thomas Jonnesco of Bucharest. After performing bilateral
extirpation of the cervical sympathetic trunk and the first dorsal ganglion he found
that the procedure eliminated the symptoms of angina.7 The sympathetic
denervation of the heart provided a reasonable result in terms of diminishing the
symptoms of angina, and was also thought to produce coronary vasodilatation.
This procedure was carried out fairly widely for a number of decades. Surgeons
differed as to how the procedure should be performed and how extensive it should
be. The Jonnesco-type sympathectomy was criticized by Danielopolu (Director of
the Second Medical Clinic at the University of Bucharest) on the grounds that it
produced an irreversible deterioration in cardiac function. He therefore directed
his surgical colleague, Hristide, to cut the posterior roots of the upper thoracic
spinal nerves, thereby dividing only the sensory fibres. Danielopolu later declared
cervicothoracic sympathectomy to be disastrous from a therapeutic point of view,
and concluded that the removal of the stellate ganglion was incompatible with life.
Several other techniques of cardiac denervation emerged in this period

including paravertebral alcohol injection (destruction of the upper thoracic
sympathetic ganglion by alcohol injection), posterior rhizotomy (section of the
upper five thoracic posterior nerve-roots on both sides), ganglionectomy (removal
5
Wearn. J Exp Med 1928; 47:273-291.
6
Mayo. Arch Surg 1925; 10:531-43.
7
Jonnesco. Bull Acad Med Paris 1920; 84:93-102.
4
Background 57
of the inferior cervical and upper three thoracic sympathetic ganglion)8 and
cardiac irradiation.9 The extensive operation and lack of complete relief from
angina made them somewhat questionable in patients with significant coronary
artery disease.
Thyroidectomy
The premise behind use of thyroidectomy for the treatment of angina was
that it reduced the cardiac workload by lowering the metabolic rate so that the
demands on the myocardium are reduced. It had been observed that some patients
developed congestive heart failure or angina when the classic signs of
exophthalmic goiter appeared, and that their cardiac symptoms occasionally
improved after remission from thyrotoxicosis. In 1926, Boas performed the first
subtotal thyroidectomy on a patient with angina. Unfortunately, it was not
successful.10 Later, Blumgart observed temporary improvement of cardiac
symptoms when patients with no evidence of thyroid toxicity were subjected to
subtotal thyroidectomy, consequently total thyroidectomy was recommended.11
Harold Rosenblum and Levine reported a reduction in congestive heart failure and
angina in hyperthyroid patients following thyroidectomy arguing that the result
obtained in one patient whose thyroid was found to be normal suggested that this
procedure might prove useful in the treatment of a variety of heart disorders.12
The first total thyroidectomy in such patients was performed by Elliott Cutler on
8
White, Smithwick and Simeone. The autonomic nervous system 1952.
9
Mueller, Rosengart and Isom. Ann Thorac Surg 1997; 63:869-78., Sussman. Am J
Roentgenol 1930; 24:163-168.
10
Mueller, Rosengart and Isom. Ann Thorac Surg 1997; 63:869-78.
11
Blumgart, Levine and Berlin. Arch Int Med 1933; 51:866-717, Blumgart, Riseman,
Davis and DD. Arch Int Med 1933; 52:165-225.
12
Rosenblum and Levine. Am J Med Sc 1933; 185:219-33.
5
Background 57
December 14, 1932.13 He also performed subtotal thyroidectomies in several

patients in order to relieve angina, and found that their symptoms improved.
However, while it provided symptomatic relief in 80% of patients, it often
resulted in them being transformed physiologically and psychologically into a
vegetative state. Eventually, the operation was modified to only a simple ligation
of the superior and inferior thyroid arteries. Some authorities declared that
improvement was not maintained. In 1947, Bourne stated that total thyroidectomy
was still the best method of decreasing the motor activity of the heart.14 Patients
were obtained relief for five years after the operation. As the mortality was as high
as 9 % and improvement was not necessarily maintained, White, Smithwick and
Simeone in 1952 considered the operation to be unjustifiable for treatment of
cardiac pain.15 The development of antithyroid drugs and radioactive iodine was a
valuable adjunct to the treatment of cardiac pain without the risk of surgery. In
1948, Blumgart reported using iatrogenically induced hypothyroidism employing
radioactive iodine131 for the treatment of angina. This was effective in about 50%
of cases. By this time, the induction of hypothyroidism had fallen into disrepute
and the results of various operative efforts to increase myocardial circulation were
judged to be promising.
Indirect Coronary Revascularization

Pericardectomy, pericardial abrasion, cardiopericardiopexy, cardiomyopexy
In 1930, Claude Beck championed early attempts at increasing the blood

supply to the myocardium by inducing pericardial scarring and thereby
encouraging neovascularization.16 Support for this approach came from the
13
Cutler and Levine. Presse Med 1934; 42:937-40.
14
Bourne. British Surgical Practice 1947.
15
White, Smithwick and Simeone. The autonomic nervous system 1952.
16
Beck and Griswold. Arch Surg 1930; 1064-1071.
6
Background 57
research of AR Moritz who in 1932, injected carbon particles into the coronary
arteries of cadaver hearts and analyzed the extensive network of collaterals
between vascular territories, as well as the vascularization of pericardial
adhesions.17 Moritz also noted the enhanced anastomoses between the coronary
arteries and extracardiac structures in humans dying of pericarditis, as well as the
vascular anastomoses between pericardial fat pads and branches of the aorta.
Beginning in 1932 with animals and in 1935 with human experiments, Beck
developed two procedures, namely cardiopericardiopexy or pericardial poudrage
and cardiomyopexy.18 The first procedure involved inducing pericarditis by
mechanical abrasion to the epicardium. The second operation consisted of
epicardial abrasion, inducing pericarditis by instillation of powdered bone into the
pericardial space (poudrage) and suturing a pectoralis major muscle graft
(cardiomyopexy) onto the epicardium.19 He performed a cardiomyopexy on a
patient on February 13, 1935, the first such operation in a human. The patient had
no angina seven months after the operation. By 1936 Beck reported that six of
eleven very ill patients so treated were living.20 The latter procedure lead to the
search for ever-better means of inducing vascular pericardial adhesion by
chemical irritants such as sodium morrhuate, sand, and talc, as well as the search
for appropriate vascular organs to contact with the abraded epicardium.21 British
surgeon, Laurence O’Shaughnessy performed the first cardioomentopexy on
17
Moritz, Hudson and Orgain. J Exp Med 1932; 56:927-931.
18
Beck, Tichy and Moritz. Proc Soc Exp Biol Med 1935; 32:759-761.
19
Beck. Ann Surg 1935; 102:801-813.
20
Beck. J Thorac Surg 1936; 5:604-11.
21
Harken, Balck, Dickson and Wilson. Circulation 1955; 12:955-962, Heinbecker and
Barton. J Thorac Surg 1939; 9:431, Kline, Stearn, Bloomer and Leibow. Am J Pathol 1956;
32:663-693, Thompson. Proc Soc Exp Biol Med 1939; 40:260-261, Thompson and Raisbeck.
Ann Int Med 1942; 16:495, Thompson and Raisbeck. Ann Int Med 1949; 31:1010, Vineberg.
Prog Cardiovasc Dis 1962; 4:391-418.
7
Background 57
October 2, 1936. He also performed cardiopneumopexy in August 1937. He

reported in the summary that all fourteen survivors were better for six months or
more, that those who had been bedridden were walking about, and that those who
had been unable to work had returned to work. There was only one fatality.22
Several other operations (cardiojejunopexy, cardiogastropexy, cardiolienopexy)
and revascularization of the heart by tubed pedicle graft of skin and subcutaneous
tissue were also developed.23
Redirection of venous drainage of the heart
In 1934, Robertson while experimenting on dogs, ligated the great cardiac

vein. This procedure raised the venous pressure and redirected the blood flow in
thebesian vessels from the chambers back into the myocardium. Louis Gross in
1936 at Mt. Sinai Hospital in New York demonstrated the benefit of partial
coronary sinus ligation in dogs who had been subjected to ligation of the anterior
descending coronary artery. Compared with a control group these dogs showed a
decreased rate of infarction and increased survival.24 On April 14, 1939 Mercier
Fauteux of Montreal first used Gross’ technique of great cardiac vein ligation on a
human subject. The outcome was positive with the patient being free from angina
for two years.25 Five additional patients were treated similarly. Fauteux and his
group also experimented with pericoronary neurectomy and reported good results
22
O'Shaughnessy. Br J Surg 1936; 23:665-670, O'Shaughnessy. Practitioner 1938;
140:603-18.
23
Key, Kergin, Martineau and Leckey. J Thorac Surg 1954; 28:320-330, Moran,
Neumann, von Wendel, et al. Plast Reconstr Surg 1952; 10:295.
24
Gross, Blum and Silverman. J Exper Med 1937; 65:91-108.
25
Fauteux and Palmer. Can Med Assoc J 1941; 45:295-299.
8
Background 57
combining coronary vein ligation with pericoronary neurectomy.26 However, great

cardiac vein ligation was discontinued after extensive experimental study.27
Robert and colleagues in 1943 carried out the first experimental coronary sinus
arterialization using brachiocephalic, subclavian, and innominate arterial grafts
placed through glass tubes.28 In 1953, Bailey and colleagues reported their and Dr
Claude Beck’s experience of coronary sinus arterialization using the jugular vein,
anastomosed between the descending aorta and coronary sinus, and proximal
partial occlusion of the coronary sinus in 18 patients.29 The anastomosis could not
be performed in two patients, and the operative mortality rate was 11.1%, with
one patient having empyema thoracis, two having thrombosed anastomosis, one
dying six months after surgery, and another four with graft thrombosis. Only
seven patients improved their symptoms.
Although Beck had initially concluded that coronary sinus ligation was not
justified for clinical use, by 1954 he was employing it routinely along with
pericardial poudrage and mediastinal grafting. This triple tiered technique became
known as the Beck I operation.30 Results of the Beck I procedure were reported in
1955. In summary, 90% of patients had a definite improvement in angina and half
had no residual angina at all; 90% returned to work, with 35% of all patients
having no work limitation and 55% having some limitation; and the mortality rate
of 6.6% was attributed primarily to the severity of the underlying disease.31 The
26
Fauteux. Ann Surg 1946; 124:1041-46, Fauteux. Am Heart J 1946; 31:260-69, Fauteux
and Swenson. Arch Surg 1946; 53:169-81.
27
Siderys, Grice, Shumacker and Riberi. Surg Gynec & Obst 1956; 102:18-26.
28
Roberts, Browne and Roberts. Fed Proc 1943; 2:90.
29
Bailey, Truex and Angulo. J Thorac Surg 1953; 25:143-72.
30
Beck and Leighninger. JAMA 1954; 156:1226-1233.
31
Beck and Leighninger. JAMA 1955; 159:1264-71.
9
Background 57
Beck procedure continued to be used by Beck and many other cardiac surgeons,
and, with modifications became the most common operation for coronary disease
until the era of aortocoronary bypass surgery. In 1946, Beck also began to
experiment with coronary sinus arterialization in dogs using either common
carotid or intercostal arteries, or a free autologous jugular vein graft. In January
1948 he commenced using this technique clinically. The operation involved the
interposition of an autogenous systemic arterial graft between the descending
thoracic aorta and the coronary sinus, and operative constriction of the coronary
sinus a few weeks afterwards. This procedure became known as the Beck II
operation, which involved a staged procedure consisting of coronary sinus
arterialization followed by partial sinus ligation. However, due to the invasiveness
of the procedure it was not widely used.32
Increasing left heart volume
In 1939, Lillehei created a surgical communication between the pulmonary

artery and left atrium in patients in an effort to increase left heart volume and thus
antegrade coronary artery blood flow. However, this right to left shunt caused
major physiological problems and thus was not suitable for clinical use.33
Increasing coronary collaterals
Also in 1939, Fieschi suggested that the bilateral ligation of the distal
internal thoracic arteries would shunt flow through branches of the
pericardiophrenic arteries back through the heart via vascular anastomoses within
the epicardium.34 Fieschi and colleagues reported their results in 1942. Battezzati
and colleagues reintroduced this procedure in 1955. Few surgeons however were
32
Beck. J Thorac Surg 1958; 36:329-51, Beck, Stanton, Batinchok and Leiter. JAMA
1948; 137:436-42.
33
Mueller, Rosengart and Isom. Ann Thorac Surg 1997; 63:869-78.
34
Fieschi. Arch Ital Chir 1942; 63:305-310.
10
Background 57
convinced that this was a rational approach to the problem.35 It was shown that
ligation of such small vessels did not affect the arterial pressure in the vessels
proximal to the obstruction indicating that the concept was flawed.
Increasing pulmonary collaterals
In 1956, Kline and associates occluded the left pulmonary artery in dogs in
order to increase the bronchial artery collateral flow. He then sutured parts of the
lung to epicardium denuded by silver nitrate.36 In 1957, Kownacki increased
pulmonary collateral flow to the heart by ligating the lingular vein and then
suturing the lingula to the epicardium.37 Unfortunately, the increasing myocardial
supply through such collaterals was minimal.
Transmyocardial revascularization
The concept of transmyocardial revascularization was based on knowledge

of the myocardial sinusoids and the thebesian system. Goldman and colleagues in
1955 made a tunnel in the myocardium using a carotid arterial graft (U shape or
straight graft) and a polyethylene tube in order to direct blood from the heart
chamber to the myocardium in dogs. After ligating the anterior descending artery,
significant reductions in the number of myocardial infarctions as well as improved
survival rates were reported.38 Massimo and Boffi in 1956 used a T-shaped
polyethylene tube, 4 mm in diameter, inserted in such a way that the horizontal
branch was imbedded inside the ventricular wall (subendocardial layer) with the
vertical branch opened to the ventricle. Favorable results were produced using this
35
Battezzati, Tagliaferro and De Marchi. Minerva Med 1955; 46:1178-88, Smol'iannikov
and Likhachev. Grudn Khir 1964; 6:99-102.
36
Kline, Stearn, Bloomer and Leibow. Am J Pathol 1956; 32:663-693.
37
Kownacki, Kownacki, Kennel, Imbriglia and Martin. A M A Arch Surg 1958; 76:106-
12.
38
Goldman, Greenstone, Preuss, Strauss and Chang. J Thorac Surg 1956; 31:364-74.
11
Background 57
technique.39 Sen and colleagues, in 1965, tried to recreate the reptilian myocardial
vascular pattern in the mammalian animal. They simply acupunctured the
myocardium and demonstrated a reduction in infarction size and an increased
survival rate.40 However this concept of direct myocardial revascularization from
the ventricle was criticized by surgeons who argued that flow from the ventricular
cavity to the myocardium during systolic contraction was impossible.41 Although
the development of coronary artery surgery resulted in a decline in interest in
indirect coronary revascularization, there has recently been a return to
microcirculatory approaches for the treatment of ischemic heart disease with a
number of surgical teams using lasers to produce multiple small sinusoids in the
myocardium. Mirhoseini and colleagues conducted a series of animal experiments
using lasers to create tunnels in the myocardium.42 Subsequently, transmyocardial
laser was clinically employed in 1983.43 Gene therapy has also been used as an
adjunct to transmyocardial laser therapy in order to increase angiogenesis.44
While there have been some promising initial results, the mechanism by which
transmyocardial laser revascularization works is not understood and there is
39
Massimo and Boffi. J Thorac Surg 1957; 34:257-64.
40
Sen, Udwadia and Kinare. J Thorac Cardiovasc Surg 1965; 50:181-9.
41
Pifarre, Jasuja, Lynch and Neville. J Thorac Cardiovasc Surg 1969; 58:424-31, Pifarre,
Wilson, LaRossa and Hufnagel. J Thorac Surg 1968; 55:309-319.
42
Mirhoseini and Cayton. Journal of Microsurgery 1981; 2:253-60, Mirhoseini,
Muckerheide and Cayton. Lasers Surg Med 1982; 2:187-98.
43
Masayoshi, Kazuta, Hiroyuki, et al. Nippon Geka Gakkai Zasshi 1985; 86:1203-7.,
Mirhoseini, Fisher and Cayton. Lasers Surg Med 1983; 3:241-5, Okada. Nippon Geka Gakkai
Zasshi 1996; 97:234-9., Okada. Ann Thorac Cardiovasc Surg 1998; 4:119-24.
44
Hughes, Annex, Yin, et al. Cardiovasc Res 1999; 44:81-90., Sayeed-Shah, Mann,
Martin, et al. J Thorac Cardiovasc Surg 1998; 116:763-9.
12
Background 57
considerable debate over which aspects of the process are responsible for the
clinical effects that have been measured.45
Direct Coronary Revascularization
The idea of operating directly on the coronary arteries was conceived as

early as the first decade of the twentieth century when Alexis Carrel’s
experiments grafting both arteries and veins in animals paved the way for the
development of direct coronary artery bypass grafting in humans. He developed a
technique of vascular anastomosis (applicable to either small or large arteries and
veins) which achieved a watertight suture without narrowing the caliber of the
vessel.46 His experimental results of anastomosing the innominate artery of one
dog into the distal coronary artery of another were reported in 1910. He also
performed the first coronary artery bypass using a free carotid artery graft
45
Aaberge, Nordstrand, Dragsund, et al. J Am Coll Cardiol 2000; 35:1170-7., Allen,
Dowling, DelRossi, et al. J Thorac Cardiovasc Surg 2000; 119:540-9., Allen, Dowling, Fudge, et
al. N Engl J Med 1999; 341:1029-36., Burkhoff, Schmidt, Schulman, et al. Lancet 1999;
354:885-90., Chu, Giaid, Kuang, et al. Ann Thorac Surg 1999; 68:301-7; discussion 307-8.,
Cooley, Frazier, Kadipasaoglu, et al. J Thorac Cardiovasc Surg 1996; 111:791-7; discussion 797-
9., Cooley, Frazier, Kadipasaoglu, et al. Tex Heart Inst J 1994; 21:220-4., Frazier, Cooley,
Kadipasaoglu, et al. Circulation 1995; 92:II58-65., Frazier, March and Horvath. N Engl J Med
1999; 341:1021-8., Hirsch, Thompson, Arora, et al. Ann Thorac Surg 1999; 68:460-8; discussion
468-9., Horvath, Chiu, Maun, et al. Ann Thorac Surg 1999; 68:825-9., Horvath, Cohn, Cooley, et
al. J Thorac Cardiovasc Surg 1997; 113:645-53; discussion 653-4., Hughes, Kypson, Annex, et al.
Ann Thorac Surg 2000; 70:504-9., Li, Chiba, Kimura, et al. Eur J Cardiothorac Surg 2001;
19:156-163., Lutter, Martin, Dern, et al. Eur J Cardiothorac Surg 2000; 18:38-45., Malekan,
Reynolds, Narula, et al. Circulation 1998; 98:II62-5; discussion II66., Oesterle, Sanborn, Ali, et
al. Lancet 2000; 356:1705-10., Ozaki, Meyns, Racz, et al. Eur J Cardiothorac Surg 2000; 18:404-
10., Reuthebuch, Podzuweit, Thomas, et al. Eur J Cardiothorac Surg 1999; 16:144-9., Rimoldi,
Burns, Rosen, et al. Circulation 1999; 100:II134-8., Schneider, Diegeler, Krakor, et al. Eur J
Cardiothorac Surg 2001; 19:164-169.
46
Carrel. Lyon Med 1902; 98:850.
13
Background 57
anastomosed between the descending thoracic aorta and left coronary artery.47 In
addition, he first performed vein bypass grafting by anastomosing a vein into a
transected aorta.48 At this time, this operation was performed with difficulty and
carried a high mortality rate. In 1912, Carrel was awarded the Nobel Prize in
Medicine or Physiology for his work on transplantation and vascular grafting.
The first report of direct implantation of vessels into the myocardium of a

human was by Griffith and Bates in 1938. They repaired an accidentally
perforated left ventricle with pectoral muscle and sutured the branches of the
internal thoracic artery into the myocardium.
The idea of direct coronary revascularization was also included the

endarterectomy technique which was expanded after successful endarterectomy
for the occlusive disease of the abdominal aorta and its branches. Absolon and
colleagues and May performed experimental endarterectomy in dogs.49 The first
successful coronary artery endarterectomy in human was performed by Bailey and
colleagues on Oct 26, 1956 without cardiopulmonary bypass.50 The coronary
endarterectomy had been used in several centres for a period of time.51
Nevertheless, the mortality rate was high, due mainly to dissection of the distal
47
Carrel. Ann Surg 1910; 52:83-95.
48
Carrel. J Exp Med 1912; 15:389-92.
49
Abosolon, Aust, Varco and Lillehei. Surg Gynecol Obstet 1956; 103:180-185., May.
Am J Surg 1957; 93:969-973.
50
Bailey, May and Lemon. JAMA 1957; 164:641-646.
51
Cannon, Longmire and Kattus. Surgery 1959; 46:197-210., Effler, Groves, Sones and
Shirey. J Thorac Cardiovasc Surg 1964; 53:93-101., Effler, Groves, Suarez and Favaloro. J
Thorac Cardiovasc Surg 1967; 53:93-101, Longmire, Cannon and Kattus. N Engl J Med 1958;
259:993-999., Senning. J Thorac Cardiovasc Surg 1961; 41:542-549.
14
Background 57
portion of the coronary artery or occlusion of important side branches, and

procedure was used less frequent.52
Venous conduits
It was not until 1940, however, that Carrel’s ideas were developed further
when the Canadian surgeon, Gordon Murray, began experimenting with direct
coronary artery anastomoses, including the use of venous interposition homografts
using sutures.53 A major development during this period was the prevention of
clotting and thrombosis of the graft by the anticoagulant “heparin”, research
pioneered by Murray.54 The technique of repair of blood vessels, grafts in blood
vessels, and surgery of blood vessels was developed by Carrel during the period
of the First World War and shortly afterwards, however success was minimal due
to the incidence of clotting and thrombosis, which formed the need for an
anticoagulant. A number of important surgeons had tried with some success, to
alleviate cases where gangrene was inevitable as the result of plugging of great
blood vessels by thrombus. Dr. Einer Key of Sweden, Dr. Meyer and Dr.
Trendelenburg in Germany, Dr. Evarts Graham in America and others approached
this subject with great boldness and performed feats in vascular surgery which
were previously unknown at that time. Many attempts were made to prevent
clotting. Key along with others advocated the use of sodium citrate. However, due
to its toxicity, it could only be used during operations in the operative field and
could not be administered systemically, which posed a perplexing and
fundamental problem.
52
Favaloro. Circulation 1972; 46:1197-207.
53
Murray. Canad M Asso J 1952; 67:100, Murray, Hilario, Porcheron and Roschau.
Angiology 1953; 526-31, Murray, Porcheron, Hilario and Roschau. Canad M Ass J 1954; 71:594-
97.
54
Murray. Medicine in the Making 1960.
15
Background 57
Hirudin, extracted from the leech, was recognized as the most effective
anticoagulant. It was applied to the affected area in patients. Attempts were made
to introduce it beneath the skin, but the substance was so toxic that it was not
suitable for this form of application. Searching for a more effective method,
Murray learned of a substance, heparin, originally an extract of liver (hepar =
liver), which had been discovered in Professor Howell’s laboratory in
Philadelphia. Heparin was reported to work well as an anticoagulant, but was
noted for its toxicity to animals, and therefore had not been used on humans.
Murray continued with his investigation believing that heparin toxicity may be
due to impurities. He did not receive support from his colleagues and indeed many
senior surgeons objected to his research interests. To overcome these objections,
he had to undertake research during his “off-duty” hours and at night.
Murray firstly studied the process of blood clotting under the microscope by
mixing blood with a small quantity of heparin solution. The blood on the slide
remained dispersed. The cells did not agglutinate into clumps and there were no
visible changes in arrangement. He showed that the substance neutralized a
prothrombin, thus making it an antiprothrombin. This prevented the protein part
of the blood, fibrinogen, from forming a solid matrix. His experiments showed
that heparin had this effect in animals, but toxicity still existed. Control
experiments were performed for comparison, so that the effect of giving heparin
under standard conditions could be observed. Simultaneously, purification of the
substance was being conducted by the Chemistry section of the Department of
Physiology. Murray determined the dosage necessary to get the required effect
experimentally and clinically. He performed many experiments to study a delivery
method, the maintenance level and the necessary duration of administration of
heparin. He then performed a simple division across a fairly large artery, such as
the carotid artery and immediately sutured it. This produced a roughened and
damaged area in the vessel which, if left to itself would have become plugged
with thrombus. On the injection of heparin, however, the clotting was prevented
and the vessel healed perfectly and within about three days further heparin was
unnecessary.
16
Background 57
Following this, Murray engaged in work which was to be of great

significance in its application to clinical surgery. A portion of an artery was
removed and the gap was bridged by grafting a piece of vein from an animal. His
sceptical colleagues on the hospital staff considered this concept ridiculous,
stating that no vein could withstand arterial blood pressure and that obviously the
experiment could not succeed. This particular experiment had been performed by
French surgeons in the 1880’s, but all such grafts had failed because of plugging
with thrombus. Now, with the use of heparin, which was becoming more purified
with the diligence and efforts of the chemists, these vessels were kept patent so
that what had never been possible before, was now accomplished. Observations
were made of changes in the vein under arterial pressure. Changes such as those
occurring during healing were studied at short intervals and continued until the
vessel was restored to a normal functioning structure, replacing the original artery.
It was upon these experiments and their results, made possible by the use of
heparin that the subsequent popularity of vascular surgery was to rest, as was its
wide application in a great variety of human injuries and diseases including the
repair of many congenital defects in the vessels, repair of degenerated conditions
in vessels, even in the aorta, and in cerebral and coronary arteries. Murray was
invited on many occasions to address the leading national and international
surgical bodies in the United States. He was also invited to give the Hunterian
Lecture in 1939 before the Royal College of Surgeons in London, England. He
also introduced the “direct attack” concept on another process occurring in the
blood ¾ thrombosis ¾ against which it was not known whether heparin was
effective. At intervals he received some technical assistance through the
Department of Surgery, but his own work was undertaken without remuneration
and his own funds went into expenses involved in the experimental work. In the
meantime the chemists, Drs. Charles and Scott, had worked valiantly to produce
the improved heparin. The expense soon became a burden on the department. Mr.
J. S. MacLean, a close friend, had watched with much interest the various
experimental problems resolved, and generously provided funds to cover the
further expenses.
Murray had already received an intravenous injection of a small dose of
17
Background 57
heparin without ill effects, so it was decided to use it clinically. The toxic effects
of heparin in humans were still evident in the early stages of research, however
they were soon eliminated. Heparin began to be used clinically for pulmonary
embolism, thrombophlebitis and coronary thrombosis. Murray also performed
end-to-end suture of severely injured vessels at the elbow region in a car accident
patient as well as performing the first successful graft placed in the arterial system
of a human being. The patient was a newspaper boy who had inadvertently driven
a knife into his groin region, dividing the main femoral artery. He had collapsed,
whilst in the hospital, a surgeon exposed the area and tied off both ends of this
great vessel according to the orthodox method at the time. This stopped the
hemorrhage but within a few hours it became evident that while the patient was
stable, the circulation to the leg was inadequate. Dr. Burns Plewes, who had
performed the operation, was aware of Dr. Murray’s experimental work, and with
great resolve removed the patient from his own hospital and rushed him to the
General Hospital. Murray was unable to get the two ends of vessels together
without tension therefore he dissected out a vein in the region of the operative
field, removing a length sufficient to bridge the gap in the main artery. As the
venous system has a series of valves at short intervals, the graft had to be turned
end to end, so that the valves would stay open and not impede the circulation. He
grafted the vein by suturing the two ends of the divided artery, bridging a gap of
about two and a half inches. After injecting heparin solution the circulation was
restored. The patient made an excellent recovery with normal circulation in the
extremity, and under observation for many years everything continued to be
normal. There were to be further improvements in the grafting of vessels. It was
demonstrated, for example, that a portion of an artery would work as well as a
vein graft in some conditions, and better in others. In subsequent years vascular
surgery progressed steadily, until the aorta itself was being operated upon, most
commonly for aneurysm. His first, and one of the earliest in the abdominal aorta
was a homologous graft of aorta removed at postmortem. Subsequently, many
grafts were performed and eventually this type of surgery spread to all the large
medical centres. All of this success in surgery depended on the development of his
anticoagulant.
18
Background 57
Gordon Murray also was interested in heart disease. During early year of his
practice, hearing of the activity in surgical treatment of heart disease in Cleveland,
he visited Dr. Elliott Cutler and his assistant at that time, Dr. Claude Beck. Dr.
Cutler, later Professor of Surgery at Harvard, was working on the problem of
mitral stenosis which was one of the commonest forms of acquired heart disease.
He was also working with a large group of patients suffering from coronary heart
disease. It is curious to think that before 1912, when Herrick of Chicago described
coronary disease, such a diagnosis had never been made.
In the 1950s cardiopulmonary bypass techniques were developed that paved

the way for the more precise techniques later performed on the nonbeating heart.
In this same period the systemic hypothermia technique was developed. In 1953
Gibbon perfected the first effective heart-lung bypass machine, using a screen
oxygenator.55 In 1959, Dubost and colleagues became the first to perform a
coronary operation in a human using cardiopulmonary bypass when they carried
out a coronary ostial reconstruction on a patient with syphilitic aortitis.56 An
effective heart-lung bypass was available by the mid-1950s, but would not be used
routinely in operations for ischemic heart disease until the late 1960s.57 Another
landmark event in coronary surgery was the development of coronary
angiography by Sones and colleagues, who in 1958 conducted the first selective
injection of contrast media into coronary arteries.58 This development allowed for
precise definition of anatomic obstruction and laid the foundation for direct
bypass surgery.
55
Gibbon. Minn Med 1954; 37:171-85, Gibbon. Am J Surg 1978; 135:608-19, Hill. Ann
Thorac Surg 1982; 34:337-41.
56
Dubost, Blondeau and Piwinica. Surgery 1960; 48:540-7.
57
Spencer, Yong and Prachuabmoh. J Cardiovasc Surg 1964; 5:292-97.
58
Sones and Shivey. Mod Conc Cardiovasc Dis 1962; 31:725-35, Sones, Shivey, Proudfit
and Westcott. Circulation 1959; 20:773.
19
Background 57
Reverse saphenous vein grafting techniques from the ascending aorta to a

coronary artery were first tried in an animal experiment by DeBakey and Henley
in 1961. These grafts functioned in 50% of dogs. The saphenous vein was first
used in a human for coronary artery bypass grafting by David Sabiston, Jr, on
April 4, 1962 at Johns Hopkins.59 The patient however suffered a stroke two days
after surgery and died, and this was not published until 1974. The world’s second
human vein bypass graft operation, and the first successful one, was performed by
Garrett, Dennis and DeBakey at Methodist Hospital in Houston on November 23,
1964, on a 42-year-old man. The vein graft to the left anterior descending artery
remained patent for seven years after surgery.60 Unfortunately, the patient died the
following year from an occlusion in the grafted vessel distal to the insertion of the
patent vein graft. This was not reported until 1973. In 1967, Rene Favaloro
popularized the use of the saphenous vein as an autologous vein conduit.61
Initially, the saphenous vein was employed using an end-to-end distal
anastomosis, with the proximal end of the right coronary artery ligated. Later,
Favaloro and his team performed vein bypass grafting with an end-to-side distal
anastomosis with the proximal end sutured to the ascending aorta. This became
the standard coronary artery operation. Johnson in Milwaukee also deserves credit
for early use of the saphenous vein. In 1969 he reported to the American Surgical
Association a mortality rate of 2% on the left coronary artery bypass operation in
301 patients.62 Consequently, the vein bypass procedure became the standard
operation throughout the world. Between 1967 and 1971, Favaloro and his
colleagues at the Cleveland Clinic performed 3,185 saphenous vein grafts in 2,201
patients.
59
Sabiston. Johns Hopkins Med J 1974; 134:314.
60
Garrett, Dennis and DeBakey. JAMA 1973; 223:792-94.
61
Favaloro. Ann Thorac Surg 1968; 5 334-39.
62
Johnson, Flemma and Lepley. Ann Thorac Surg 1970; 9:436-44, Johnson, Flemma,
Lepley and Ellison. Annals of Surgery 1969; 170:460-70.
20
Background 57
While the saphenous vein was the primary vessel used for grafting, surgeons
also experimented with a number of other venous conduits. In 1969, Kakkar
reported the first use of an arm vein for grafting.63 Cephalic veins were used as
bypass grafts in seven patients with arterial disease of the lower extremity, and all
were found to be patent with no dilatation of the graft after 4-12 months.
Schulman and Badhay used 68 arm veins in femoropopliteal grafting and reported
in 1982 that most of the conduits rapidly developed intimal hyperplasia and
occluded.64 The few that were still patent had elongated and had become
aneurysmal. Jarvinen and colleagues, in 1984, reported their experiences with the
arm veins as aortocoronary bypass grafts in 15 patients. A total of 34 anastomoses
were performed with 16 arm vein grafts and they found a patency rate of 87% at
mean follow-up of 1.4 years.65 Stoney and colleagues reported in 1984 arm vein
graft patency of only 57% at 2 years follow-up by angiography in 28 of 59
patients.66 The probable reason for the poor performance of the arm vein as a graft
is that the velocity of blood flow from the upper extremity is approximately one-
half that of the lower extremity flow, and that arm veins have only one half the
tensile strength of leg veins. Thus, powerful arterial hemodynamic forces, along
with the degradation of wall elastin, cause the vein to elongate and become
tortuous and aneurysmal soon after implantation.67 This is associated with a low
flow velocity and predisposition to atherosclerosis. Consequently, reports of
suboptimal results from use of arm veins in comparison with those of internal
63
Kakkar. Surg Gynecol Obstet 1969; 128:551-6.
64
Schulman and Badhey. Surgery 1982; 92:1032-41.
65
Jarvinen, Harjula, Mattila, Valle and Harjola. J Cardiovasc Surg 1984; 25:344-7.
66
Stoney, Alford, Burrus, et al. J Thorac Cardiovas Surg 1984; 88:522-6.
67
Dobrin, Schwarcz and Baker. Surgery 1988; 104:568-71, Norman, Lansing and Yared.
Journal of the Kentucky Medical Association 1991; 89:67-70.
21
Background 57
thoracic artery and saphenous vein grafts led to the abandonment of the arm vein
as a bypass graft.
In 1975, Crosby and Carver reported using the lesser saphenous vein as an
alternative venous conduit for aortocoronary bypass in three patients.68 Following
Crosby’s report, other researches also experimented with using the lesser
saphenous vein. However, these studies were limited by small patient samples and
lacked long-term follow-up. While patency of the lesser saphenous vein
theoretically should have been similar to that of the great saphenous vein, the
small numbers of patients receiving lesser saphenous graft made it hard to draw
conclusions.69
In 1974, three large clinical trials: Veterans Administrative (VA)

Cooperative Study (1972-1974), European Coronary Surgery Survey (ECSS)
(1973-1976) and Coronary Artery Surgery Survey (CASS) (1975-1979), were
initiated comparing surgical versus medical treatment of ischemic heart disease.70
The VA study demonstrated improved survival only for patients with significant
left main artery disease. Survival in the high-risk subgroup was 87% for the
surgically treated patients and 74% for those treated medically, a highly
significant difference after four years of follow-up. However, exclusion of the left
main artery disease group reduced the difference to a non-significant (84% for
surgery versus 79% for medical treatment) result. Among patients not in the high-
risk subgroup, survival at four years (with left main artery excluded) was 93% for
those treated surgically and 96% for those treated medically. For all patients, the
68
Crosby and Craver. Ann Thorac Surg 1975; 20:703-5.
69
Grimball, Bradham and Locklair. Journal - South Carolina Medical Association 1989;
85:226-7, Raess, Mahomed, Brown and King. Ann Thorac Surg 1986; 41:334-6, Salerno and
Charrette. Ann Thorac Surg 1978; 25:457-8.
70
Fisher and Davis. Circulation 1985; 72:V110-6.
22
Background 57
rates were 85% and 86% respectively.71 The surgical advantage for patients with
impaired left ventricular ejection fraction was significant at 5 years (P = 0.03) and
8 years (P = 0.05) but appeared to have diminished at 10 years (P = 0.15).72 The
benefits of CABG on survival, symptom control and postinfarction mortality were
transient and lasted less than 11 years. The benefits began to diminish after 5
years, when graft closure accelerated.73 The overall 22-year cumulative survival
rates were 25% and 20% in the medical and surgical cohorts (P = 0.24).74
The ECSS study demonstrated a significantly higher survival rate (P =

0.0001) in the surgical group (92.4±2.7%) than in the medical group (83.1±3.9%)
at the 5 years follow-up interval. However, during the subsequent seven years, the
survival rate in the surgical group decreased more rapidly.75
In the CASS study, CABG benefited patients with left main coronary artery
disease or left main equivalent (combined proximal LAD and proximal left
circumflex artery), patients with poor left ventricular function and patients with
normal left ventricular function with at least 1.00 mm of ischemic ST-segment
depression or low exercise capacity.76 The indexes of quality of life such as
71
Detre, Murphy and Hultgren. Lancet 1977; 2:1243-5, Detre and Peduzzi. Controlled
ClinTrials 1982; 3:355-64.
72
Scott, Deupree, Sharma and Luchi. Circulation 1994; 90:II120-3.
73
The VA Coronary Artery Bypass Surgery Group. Circulation 1992; 86:121-30.
74
Peduzzi, Kamina and Detre. Am J Cardiol 1998; 81:1393-9.
75
Varnauskas. Circulation 1985; 72:V90-101., Varnauskas. N Engl J Med 1988; 319:332-
7.
76
Alderman, Fisher, Litwin, et al. Circulation 1983; 68:785-95, Caracciolo, Davis, Sopko,
et al. Circulation 1995; 91:2325-34, Caracciolo, Davis, Sopko, et al. Circulation 1995; 91:2335-
44, Chaitman, Fisher, Bourassa, et al. Am J Cardiol 1981; 48:765-77, Passamani, Davis, Gillespie
23
Background 57
angina relief, increased activity and reduction in use of anginal medications

initially appeared superior in patients assigned to surgery than medical treatment,
however by 10 years these advantages were much less apparent.77 The
significance of the CASS study was hampered by the fact that (1) the CASS
randomized study applied to only a small minority of patients with coronary artery
disease78; (2) 37% of the medical group had undergone CABG because of
increasing chest pain during 10 years follow-up which created a bias against
surgical treatment.79
Thus, while these studies showed encouraging results, at least in the short
term, overall they supported the use of surgical revascularization for coronary
artery disease.80 These early series mostly employed saphenous vein grafting. It
and Killip. N Engl J Med 1985; 312:1665-71, Weiner, Ryan, McCabe, et al. Am J Cardiol 1987;
60:262-6.
77
Alderman, Bourassa, Cohen, et al. Circulation 1990; 82:1629-46, Chaitman, Ryan,
Kronmal, et al. J Am Coll Cardiol 1990; 16:1071-8, Killip. Zeitschrift fur Kardiologie 1985;
74:79-85, Myers, Gersh, Fisher, et al. Ann Thorac Surg 1987; 44:471-86, Myers, Schaff, Fisher,
et al. J Thorac Cardiovas Surg 1988; 95:382-9, Myers, Schaff, Gersh, et al. J Thorac Cardiovas
Surg 1989; 97:487-95, Rogers, Coggin, Gersh, et al. Circulation 1990; 82:1647-58.
78
CASS Principal Investigators and their Associates. Circulation 1983; 68:951-60, CASS
Principal Investigators and their Associated. Circulation 1983; 68:939-50, CASS Principal
Investigators and their Associated. J Am Coll Cardiol 1984; 3:114-28, CASS Principal
Investigators and their Associated. N Engl J Med 1984; 310:750-8.
79
Alderman, Bourassa, Cohen, et al. Circulation 1990; 82:1629-46, Peduzzi, Detre, Wittes
and Holford. J Thorac Cardiovasc Surg 1991; 101:481-7., Rogers, Coggin, Gersh, et al.
Circulation 1990; 82:1647-58, Weinstein and Levin. J Thorac Cardiovas Surg 1985; 90:541-8.
80
Bonow and Epstein. Circulation 1985; 72:V23-30, Davis, Fisher and Pettinger.
Circulation 1985; 72:V117-22., Fisher and Davis. Circulation 1985; 72:V110-6.
24
Background 57
later became apparent that one of important risk factors for death and
postoperative angina was the use of only vein graft.81
Arterial conduits
Internal Thoracic Artery

In 1945, Vineberg developed a technique subsequently known as the
Vineberg procedure.82 This involved implanting the internal thoracic artery (ITA)
and other vessels into the myocardium in order to augment its blood supply.
While this technique should be included in the indirect vascularization category, it
was an important precursor to CABG as it was the first time the ITA had been
used to revascularize the myocardium. Vineberg and Miller implanted the distal
end of ITA into a myocardial tunnel (5 cm) in the anterolateral wall of the left
ventricle between the left anterior descending artery and the circumflex coronary
artery to create new coronary collaterals.83 They cut the sixth intercostal branches
to permit side flow and pulling the ITA through the tunnel and fixing it at its distal
end. Some year later, it was shown collaterals developed between the ITA and
coronary artery. The ITA was also patent as long as 17 years later.84 More than
5,000 of these operations were performed between 1950 and 1970, with at least
subjective improvement of angina in many patients. Vineberg also described the
use of the right gastroepiploic artery for his operation if the ITA was not suitable.
In 1957, Smith and colleagues modified the Vineberg procedure. They used the
saphenous vein and nylon tubes anastomosed to the descending aorta, made
81
Cameron, Davis and Rogers. J Am Coll Cardiol 1995; 26:895-9.
82
Vineberg. Canad M Ass J 1941; 45:295-98, Vineberg. Canad M A J 1958; 78:871-79,
Vineberg and Buller. J Thorac Surg 1955; 30:411-31, Vineberg, Munro, Cohen and Buller. J
Thorac Surg 1955; 29:1-36, Vineburg. Ann Thorac Surg 1964; 159:185-207.
83
Vineberg and Miller. Surg Forum 1950; 5:294-299.
84
Vineberg. JAMA 1975; 234:693-694.
25
Background 57
multiple holes in the graft and then placed into the myocardial tunnel.85 Sabiston,
Fauteux and Blalock used the carotid artery as a modified Vineberg procedure.86
In 1954, Murray reported the successful experimental use of arterial

conduits (axillary or carotid arteries) placed from ascending aorta to the coronary
arteries by direct anastomosis in five dogs.87 Murray was interested in the fact that
the heart lies in its pericardial cavity unattached to anything except through the
narrow pedicle at its base, at which point the great vessels enter and leave. He
began experiments trying to reproduce the conditions that in theory might
augment circulation to the heart. In animals, grafts of surrounding vascular tissue
carrying a good supply were stitched on to the heart in various positions. The
effects of the grafts were tested, after varying lengths of time, by the original
coronary arteries being tied off one at the time in order to see if the grafts were
supplying sufficient nutrition to the heart. Using this procedure on an animal, he
was able to create sufficient circulation to the heart from other sources. He
commented, “the ITA, which runs over the top of the heart, seems particularly
suitable for the source of such grafts”. A portion of the muscle in which the ITA
ran, and even the bare artery itself, was transplanted into the wall of the heart, in
the hope of giving it increased circulation. In addition, foreign bodies were placed
in the sac around the heart, in expectation that they might provide a vascular
source through adhesions, which would improve cardiac circulation. In years to
come many of these techniques were perfected, and have been used clinically
resulting in considerable improvement in patient outcomes.
However, the first successful anastomosis of the ITA to the left anterior
descending (LAD) was performed in 1953 by Russian surgeon, Vladimir P.
85
Smith, Beasley, Hodes, et al. Surg Gynecol Obstet 1957; 104:263-268.
86
Sabiston, Fauteux and Blalock. Ann Surg 1957; 145:927-942.
87
Murray, Hilario, Porcheron and Roschau. Angiology 1953; 526-31, Murray, Porcheron,
Hilario and Roschau. Canad M Ass J 1954; 71:594-97.
26
Background 57
Demikhov in animals.88 Robert H. Goetz performed the first successful human

CABG, on May 2, 1960, anastomosing the right ITA to the right coronary artery
using a tantalum ring. An angiogram at 14 days postoperatively demonstrated a
patent anastomosis and the patient remained free of angina pectoris for one year.89
Demikhov’s experimental work paved the way for the work of another prominent
Russian surgeon, Vasilii I. Kolessov who, in 1964, performed the first sutured
ITA to coronary artery anastomosis in a human subject.90
In 1968 a number of surgical teams began performing ITA grafting.

However, despite occasional reports of successful ITA-to-LAD grafting, from the
early seventies to the eighties, the saphenous vein was, for the most part, the
conduit of choice for CABG. The ITA was used in less than 15% of coronary
artery bypass procedures as late as 1981.91 The main reasons for this situation
were: (1) the abundant supply of veins; (2) the fact that the saphenous vein is easy
to harvest and suture; and (3) the superior flow rates of the saphenous vein
compared to the ITA.
During the 1980s, there was a shift to arterial revascularization due to an

increasing awareness of the problems involved with long-term vein graft patency
and an accumulation of data demonstrating the excellent patency rates of ITA
88
Demikhov. , Demikhov. Eksp Khir Anesteziol 1969; 14:3-8.
89
Goetz, Rohman, Haller, Dee and Rosenak. J Thorac Cardiovasc Surg 1961; 41:378-96,
Konstantinov. Ann Thorac Surg 2000; 69:1966-72.
90
Kolesov. Klin Med 1966; 44:7-12, Kolesov. Kardiologiia 1967; 7:20-5, Kolesov.
Vestnik Khirurgii Imeni i - i - Grekova 1978; 121:3-7, Kolesov. Vestnik Khirurgii Imeni i - i -
Grekova 1982; 128:49-53, Kolesov and Potashov. Eksperimentalnaia Khirurgiia i Anesteziologiia
1965; 10:3-8.
91
Miller, Hessell, Winterscheid, Merendino and Dillard. J Thorac Cardiovas Surg 1977;
73:75-83, Miller, Ivey, Bailey, Johnson and Hessel. J Thorac Cardiovas Surg 1981; 81:423-7.
27
Background 57
grafts. The occlusion rate of the saphenous vein was 12-20% in the first year.92
The annual closure rate was 2-4% during the first 4-5 years93 while the yearly
occlusion rates doubled to 4-8% between 5 and 10 years. Approximate 50% of
saphenous veins were occluded at 10 years.94 These results clearly demonstrated a
higher failure rate than those of the ITA. In 1983, Campeau and colleagues found
that only 30% of vein grafts were in a satisfactory condition 10 years
postoperatively.95 Meanwhile, Okies and associates found that the 10-year
survival and patency rates were significantly better in those patients who had
received an ITA rather than only saphenous vein grafts.96 In 1986, Loop and
associates reported better survival rates for patients who had received both ITA
grafts and saphenous vein grafts than those who were given vein grafts only.97
More recently, a number of studies also have shown that, compared with vein
grafts, ITA grafting to the LAD results in a better survival rate, less recurrent
angina, and a higher long term graft patency.98 While previously being used only
92
FitzGibbon, Leach, Keon, Burton and Kafka. J Thorac Cardiovas Surg 1986; 91:773-8,
Grondin, Lesperance, Bourassa, et al. J Thorac Cardiovas Surg 1974; 67:1-6.
93
Grondin, Campeau, Lesperance, et al. J Thorac Cardiovas Surg 1979; 77:24-31.
94
Grondin, Campeau, Lesperance, Enjalbert and Bourassa. Circulation 1984; 70:I208-12.
95
Bourassa, Campeau, Lesperance and Solymoss. Cardiology 1986; 73:259-68, Campeau,
Enjalbert, Lesperance and Bourassa. Canadian Journal of Surgery 1985; 28:496-8, Campeau,
Enjalbert, Lesperance, et al. Circulation 1983; 68:II1-7, Grondin, Campeau, Lesperance, Enjalbert
and Bourassa. Circulation 1984; 70:I208-12.
96
Okies, Page, Bigelow, Krause and Salomon. Circulation 1984; 70:I213-21.
97
Loop, Lytle, Cosgrove, et al. N Engl J Med 1986; 314:1-6.
98
Cameron, Davis, Green, Myers and Pettinger. Circulation 1988; 77:815-9, Lytle, Loop,
Taylor, et al. J Thorac Cardiovas Surg 1992; 103:831-40, Lytle, McElroy, McCarthy, et al. J
Thorac Cardiovas Surg 1994; 107:675-82; discussion 682-3, Zeff, Kongtahworn, Iannone, et al.
Ann Thorac Surg 1988; 45:533-6.
28
Background 57
in younger patients, complete arterial grafting is now used in patients of all ages
with most surgeons now viewing arterial bypasses, in particular single left internal
thoracic arteries, as the graft of choice especially when attached to the left anterior
descending coronary artery.
In studies of long-term graft patency, the ITA, when compared with

saphenous vein grafts, has been demonstrated to be the far superior conduit for
coronary artery bypass surgery. At 10 years, ITA grafts have been shown to have
up to 90% patency, in comparison to vein grafts with 25-50% patency. The lower
percentage in veins is largely explained by the fact that saphenous vein grafts tend
to develop late postoperative atherosclerosis while internal thoracic arteries
remain relatively free of disease.
These facts, along with the increased number of repeat coronary bypass
procedures being performed, and the limited availability of the ITA, have resulted
in a number of surgeons experimenting with the use of other arteries for coronary
artery bypass grafting.
Radial artery
The RA initially was used as a conduit for coronary artery bypass grafting
by Carpentier and associates in 1973.99 In contrast to other arterial conduits, the
RA appeared to offer a highly promising alternative for a number of technical
reasons. It is similar in length and size to the internal thoracic artery, its diameter
is closer to the size of the coronary artery than that of the saphenous vein graft, it
is easily harvested, and rarely affected by atherosclerosis. However, despite these
potential advantages, Curtis and colleagues reported in 1975 that the failure rate of
RA grafts in a group of 79 patients was 64.7% at 6 to 12 months after
operation.100 This represented a significantly higher failure rate than that of the
99
Carpentier, Guermonprez, Deloche, Frechette and DuBost. Ann Thorac Surg 1973;
16:111-21.
100
Curtis, Stoney, Alford, Burrus and Thomas. Ann Thorac Surg 1975; 20:628-35.
29
Background 57
saphenous vein and ITA grafts used in the same patients. Furthermore, one of the
histologically normal RA grafts removed at reoperation revealed marked
concentric intimal hyperplasia. This shed considerable doubt upon the viability of
the RA as an alternative graft. In 1976 Chiu suggested that the thick-walled RA
appeared to depend more on vasa vasorum for its integrity than the thin-walled
vein.101 The vasa vasorum of free RA graft, which disrupted at both ends, cannot
regenerate readily from the adjacent tissue and may have been more vulnerable to
intimal hyperplasia and occlusion than either vein grafts or ITA grafts. In 1976
Fisk and colleagues reported results from 48 RA grafts. After 1 to 24 weeks, only
50% of RA grafts were patent compared with 77% of saphenous vein grafts.102
These authors suggested that the RA should not be used. As a result of these poor
results the RA fell out of favor, and only recently has been rediscovered as a
viable conduit.
The early 1990s witnessed a revival of interest in the RA. During this
period, Carpentier and associates were contacted by a patient who had been part
of their trial conducted in the 1970s. This patient’s RA graft was thought to have
occluded soon after surgery. However, to their surprise, an angiogram 18 years
later indicated that the RA was in fact patent and free from disease. This discovery
led to Acar and colleagues to reinvestigate the use of the RA for CABG.103
Other Arterial Conduits

Over the past decade or so, surgeons have experimented with other arterial
conduits such as the right gastroepiploic artery and the inferior epigastric artery.
In 1987 Pym, Suma, Attum and Carter reported using the right gastroepiploic
101
Chiu. Ann Thorac Surg 1976; 22:520-3.
102
Fisk, Brooks, Callaghan and Dvorkin. Ann Thorac Surg 1976; 21:513-8.
103
Acar, Farge, Chardigny, et al. Archives des Maladies du Coeur et des Vaisseaux 1993;
86:1683-9, Acar, Jebara, Portoghese, et al. Ann Thorac Surg 1992; 54:652-9; discussion 659-60.
30
Background 57
artery (RGEA) as a bypass conduit.104 Anatomical Studies demonstrated the

constant presence of a direct intramural anastomotic circulation between the right
105
and left gastroepiploic arteries and showed that size of the RGEA was
106
appropriate for grafting. Histopathologic studies showed mild intimal
hyperplasia in the RGEA.107 Immunocytochemical and ultrastructural examination
revealed similarity of smooth muscle and endothelial cells in the gastroepiploic
artery and the ITA.108 Although there are differences in vasoreactivity between the
RGEA and ITA109, the gastroepiploic artery is now an established alternative to
the ITA. Although little is known about its long-term patency, studies have shown
that it has an excellent short to mid-term patency.110 In Suma’s series the early
104
Attum. Tex Heart Inst J 1987; 14:289-292, Carter. Aust NZ J Surg 1987; 57:317-321,
Pym, Brown, Charrette, Parker and West. J Thorac Cardiovas Surg 1987; 94:256-9, Suma,
Fukumoto and Takeuchi. Ann Thorac Surg 1987; 44:394-7, Suma, Takeuchi and Hirota. Ann
Thorac Surg 1989; 47:712-5.
105
Dei Poli, Albertino, Spalluto, et al. Panminerva Med 1990; 32:61-4.
106
Hannoun, Le Breton, Bors, et al. Anat Clin 1984; 5:265-71., Saito, Suma, Terada, et al.
Ann Thorac Surg 1992; 53:266-8., Samoilenko, Koltashov and Shalbakin. Grud
Serdechnososudistaia Khir 1990:29-33., Suma, Fukumoto and Takeuchi. Ann Thorac Surg 1987;
44:394-7.
107
Malhotra, Bedi, Bazaz, Jain and Trehan. Ann Thorac Surg 1996; 61:124-7, Suma and
Takanashi. Ann Thorac Surg 1990; 50:413-6, van Son, Smedts, Vincent, van Lier and Kubat. J
Thorac Cardiovasc Surg 1990; 99:703-7., van Son, Smedts, Yang, et al. Ann Thorac Surg 1997;
63:709-15.
108
Sasaguri, Hosoda, Tahara, et al. Nippon Kyobu Geka Gakkai Zasshi - Journal of the
Japanese Association for Thoracic Surgery 1993; 41:1188-93.
109
Buikema, Grandjean, van den Broek, et al. Circulation 1992; 86:II205-9, Dignan, Yeh,
Dyke, et al. J Thorac Cardiovas Surg 1992; 103:116-22; discussion 122-3.
110
Isomura, Hisatomi, Hirano, et al. J Thorac Cardiovas Surg 1993; 105:1088-94,
Kusukawa, Hirota, Kawamura, et al. Circulation 1989; 80:I135-40, Lytle, Cosgrove, Ratliff and
31
Background 57
patency rate of the RGEA was 94% (253/268) and the late (2-5 years) patency
was 94% (47/50). In 1994, Grandjean and colleagues reported the results of the
RGEA in combination with one or both ITAs in 300 patients.111 Hospital
mortality was 3.3%. Two of these patients had an infarct in the area revascularized
by the gastroepiploic artery. There were no deaths at mean follow-up of 14
months (0.5 to 39 months). One patient with an occluded RGEA graft underwent
reoperation using right ITA. The other had percutaneous transluminal coronary
angioplasty of the right coronary artery after occlusion of the RGEA. Elective re-
catheterisation was performed in 88 patients at 1 to 25 months after operation
(mean 10 months). Patency in RGEA grafts increased steadily from 77% in the
first semester of the study to 95% in the fourth semester which then equaled the
patency of the ITA grafts (97%), which was constant. In 1995, Bergsma and
colleagues reported the results of arterial grafting using RGEA and bilateral ITAs
in 256 patients.112 Seven-year actuarial survival was 91.1%. The cumulative
probability of event-free survival for myocardial infarction, re-intervention and
angina pectoris at 7 years was 97.3%, 95.4%, and 85.4%, respectively. They also
found 85.4% freedom from angina pectoris after 7 years, which is lower than the
results of studies in which vein grafts, single ITA grafts or double ITA grafts were
used. In 1995, Jegaden and colleagues reported the results of use of the RGEA
grafting to bypass the right coronary artery trunk or branches in 400 patients
Loop. J Thorac Cardiovasc Surg 1989; 97:826-31., Manapat, McCarthy, Lytle, et al. Circulation
1994; 90:II144-7, Mills and Everson. Ann Thorac Surg 1989; 47:706-11, Mills, Hockmuth,
Everson and Robart. J Thorac Cardiovas Surg 1993; 106:579-85; discussion 586, Nakao and
Kawaue. J Thorac Cardiovasc Surg 1993; 106:149-53., Pym, Brown, Pearson and Parker.
Circulation 1995; 92:II45-9, Suma, Amano, Horii, et al. Eur J Cardiothorac Surg 1996; 10:6-10;
discussion 11., Suma, Wanibuchi, Furuta, et al. Eur J Cardiothorac Surg 1991; 5:244-7, Suma,
Wanibuchi, Furuta and Takeuchi. J Thorac Cardiovas Surg 1991; 101:121-5, Takayama, Suma,
Wanibuchi, et al. Circulation 1992; 86:II217-23.
111
Grandjean, Boonstra, den Heyer and Ebels. J Thorac Cardiovasc Surg 1994; 107:1309-
15; discussion 1315-6.
112
Bergsma, Grandjean, Voors, et al. Circulation 1998; 97:2402-5.
32
Background 57
(mean age 59 ± 9 years).113 The RGEA was used alone in six patients, associated
with one ITA in 111 patients (two arterial grafts, 2.2 ± 0.4 anastomoses) and with
both ITAs in 283 patients (three arterial grafts, 3.4 ± 0.6 anastomoses). No vein
graft was used. Early (15th postoperative day) angiographic study of the RGEA
graft was performed in 104 patients; the patency rate was 92%. Anomalies of
RGEA grafts were three occlusions, five stenoses, three with competitive flow and
none had a string or slender sign. The 2- and 4-year actuarial survival rate was
96.7 ± 1.9%. The rate of late cardiac events was 2% patient/year; angioplasty for
right gastroepiploic graft failure was required in four patients. In 1996,
Voutilainen and colleagues reported a 5-year angiographic follow-up study of
RGEA grafts in 31 consecutive patients who underwent coronary artery surgery
between March 1987 and May 1990.114 The 5-year patency of RGEA grafts was
82.1% with a 95% confidence interval of 63.1% to 93.9%. The 5-year patency of
the left ITA was 90.3% and for the right ITA 94.4%. This result was superior to
the 66.7% patency of venous grafts. In 2000, Suma reported that the cumulative
patency rate of RGEA graft, estimated by the Kaplan-Meier method, was 96.6% at
1 month, 91.4% at 1 year, 80.5% at 5 years, and 62.5% at 10 years.115 Although
acceptable results for the RGEA have been reported, there are severe
complications and morbidity directly related to use of this graft: coronary artery
steal syndrome116, pancreatitis117, gastric perforation118, splenic injury requiring
splenectomy119, diaphragmatic hernia120 and intraabdominal abscess.121
113
Jegaden, Eker, Montagna, et al. Eur J Cardiothorac Surg 1995; 9:575-80; discussion
581.
114
Voutilainen, Verkkala, Jarvinen and Keto. Ann Thorac Surg 1996; 62:501-5.
115
Suma, Isomura, Horii and Sato. J Thorac Cardiovasc Surg 2000; 120:496-8.
116
Kawasuji, Takemura, Sakakibara and Watanabe. Eur J Cardiothorac Surg 1997; 11:790-
2., Kawasuji, Tekemura, Sakakibara, Matsui and Watanabe. Ann Thorac Surg 1994; 57:1645-7.
117
Manapat, McCarthy, Lytle, et al. Circulation 1994; 90:II144-7.
33
Background 57
The inferior epigastric artery was first used by Puig in 1990.122 Its role as an
arterial alternative has been less popular however because it tends to become
narrower at its distal end, does not always yield an adequate length of viable
conduit, and is extremely muscular and therefore prone to vasospasm.
Nevertheless, early studies indicate that this vessel may produce an early patency
rate of more than 70%.123 Other conduits that have been employed as coronary
artery bypass grafts include the left gastroepiploic artery124, splenic artery125,
lateral costal artery126, ulnar artery127, intercostal artery128, lateral femoral
118
Hayashi and Kawaue. Nippon Kyobu Geka Gakkai Zasshi 1993; 41:1086-8.,
Tsuneyoshi, Minami, Nakayama and Sakaguchi. Jpn J Thorac Cardiovasc Surg 1998; 46:719-23.,
Witkop, Dillemans, Grandjean, Bams and Ebels. Ann Thorac Surg 1994; 58:1170-1.
119
Perrault, Carrier, Hebert, et al. Ann Thorac Surg 1993; 56:1082-4, Tavilla, Berreklouw
and Schonberger. J Cardiovasc Surg (Torino) 1995; 36:257-60.
120
Pasic, Carrel, Von Segesser and Turina. J Thorac Cardiovas Surg 1994; 108:189-91,
Verhofste and Tam. Ann Thorac Surg 1995; 60:458-9.
121
Lloyd, Ascione, Gupta and Angelini. Eur J Cardiothorac Surg 1999; 16:371-3.
122
Puig, Ciongoli, Cividanes, et al. Arquivos Brasileiros de Cardiologia 1988; 50:259-61,
Puig, Ciongolli, Cividanes, et al. J Thorac Cardiovas Surg 1990; 99:251-5.
123
Manapat, McCarthy, Lytle, et al. Circulation 1994; 90:II144-7, Puig, Sousa, Cividanes,
et al. Eur J Cardiothorac Surg 1997; 11:243-7, Watanabe, Misaki, Yamamoto, et al. Kyobu Geka
1994; 47:89-93; discussion 94-7.
124
Buffolo, Maluf, Barone, Andrade and Gallucci. Arq Bras Cardiol 1987; 48:167-71.
125
Edwards, Blakeley and Lewis. J Thorac Cardiovas Surg 1973; 65:272-5, Edwards,
Lewis, Blakeley and Napolitano. Ann Thorac Surg 1973; 15:35-40, Kolesov, Romankova,
Volodkivich and Dulaev. Vestnik Khirurgii Imeni i - i - Grekova 1975; 114:9-14.
126
Hartman, Mawulawde, Dervan and Anagnostopoulos. Ann Thorac Surg 1990; 49:816-
8.
34
Background 57
circumflex artery129 and left gastric artery.130 The shortage of viable conduits also
has led to the use of preserved blood vessels and synthetic vascular prostheses,
however they are associated with poor long-term patency.131
Expanded use of arterial grafting
As a result of the excellent ITA graft patency, surgeons around the world
have experimented in increasing the number of grafted coronary arteries with one
ITA or using both left and right ITA and combined arterial grafting.132
Sequential techniques
Sequential techniques have been used in both ITA and saphenous vein grafts
and also other arterial conduits. Some risks are involved in surgical techniques.133
The sequential technique originally was used in saphenous vein grafts134, first
127
Buxton, Chan, Dixit, et al. Ann Thorac Surg 1998; 65:1020-4.
128
Dandolu, Furukawa and Valluvan. J Invest Surg 1998; 11:373-9.
129
Sato, Terada, Moriki, et al. Kyobu Geka 1999; 52:814-7.
130
van Aarnhem, Schreur, Firouzi and Jansen. Ann Thorac Surg 2001; 71:1013-4.
131
Chard, Johnson, Nunn and Cartmill. J Thorac Cardiovas Surg 1987; 94:132-4, Hartman,
Vlay, Dervan, et al. Clin Cardiol 1991; 14:75-8, Sapsford, Oakley and Talbot. J Thorac
Cardiovas Surg 1981; 81:860-4.
132
Tector. Ann Thorac Surg 1986; 42:S22-7., Tector, Amundsen, Schmahl, Kress and
Peter. Ann Thorac Surg 1994; 57:33-8; discussion 39., Tector, Schmahl, Crouch, Canino and
Heckel. Eur Heart J 1989; 10:71-7.
133
Grondin and Limet. Ann Thorac Surg 1977; 23:1-8.
134
Grow and Brantigan. J Thorac Cardiovasc Surg 1975; 69:188-9., Hutchins and Bulkley.
J Thorac Cardiovasc Surg 1977; 73:660-7., Loop. Ann Thorac Surg 1974; 17:637-8.
35
Background 57
reported for the ITA in 1983 by Kabbani135 and McBride.136 In 1981, Crosby and
colleagues reported a prospective analysis of the angiographic and operative
anatomic and reconstructive variables that influenced vein graft patency in 50
consecutive patients.137 Postoperative restudy showed that 18 of the 168 grafts
performed were occluded due to venous disease, inadequate run-off, or sequential
design error. Simple vein grafts had a 96% patency while sequential grafts had
80%. When design error for sequential grafts was eliminated, the sequential
patency rate rose to 88%. In 1986, Keiser and colleagues studied sequential
anastomosis grafts with a follow up time of 13 years.138 They concentrated
specifically on 212 “double” grafts with 100% selective angiographic follow-up -
90% at 1-year and 44% at 5 years after operation. Four hundred and twenty four
control single grafts were studied similarly. The patency rates of side-to-side
anastomoses were much better than those of end-to-side anastomoses, whether
sequential or control single grafts. Considering specifically diagonal coronary
artery - left anterior descending coronary artery sequential grafts, the combined
patency of all sequential anastomoses theoretically exceeds that of a comparable
number of single grafts at all times of study, but the differences are small. In
1984, Tector and colleagues reported the results of sequential ITA grafts in 29
patients.139 The left ITA was anastomosed side-to-side to the diagonal and end-to-
side to the left anterior descending coronary artery (LAD) in 24 patients, side-to-
side to the proximal LAD and end-to-side to the distal LAD for proximal and mid
vessel obstruction in four patients, and in one patient the left ITA was grafted
135
Kabbani, Hanna, Bashour, Crew and Ellertson. J Thorac Cardiovas Surg 1983; 86:697-
702.
136
McBride and Barner. J Thorac Cardiovas Surg 1983; 86:703-5.
137
Crosby, Wellons, Taylor, et al. Annals of Surgery 1981; 193:743-51.
138
Kieser, FitzGibbon and Keon. J Thorac Cardiovas Surg 1986; 91:767-72.
139
Tector, Schmahl, Canino, Kallies and Sanfilippo. Circulation 1984; 70:I222-5.
36
Background 57
side-to-side to the first marginal branch of the circumflex artery and end-to-side to
the second marginal branch. There were no operative deaths but one patient died
10 months after surgery from viral pneumonia. There was no evidence of left
ventricular failure. None of the patients suffered perioperative myocardial
infarction or return of their angina. Eleven patients underwent postoperative stress
tests and the results were all negative. Graft visualization in three patients showed
patent grafts without kinking or narrowing. In 1986, Orszulak and colleagues
compared efficacy of sequential anastomoses of the ITA to the left anterior
descending and diagonal coronary arteries in 40 patients and sequential saphenous
vein grafts in 58 patients.140 Treatment with dipyridamole (starting 48 hours
before operation) and aspirin (added 7 hours after operation) was given to the 40
patients with ITA grafts and to 32 of the 58 patients in the saphenous vein group.
After the bypass procedure, mean blood flows were as follows: 68 ml/min in
patients with ITA grafts, 73 ml/min in patients who received saphenous vein
grafts and a placebo, and 99 ml/min in those who received saphenous vein grafts,
aspirin, and dipyridamole. Early patency of sequential ITA grafts to the diagonal
and left anterior descending coronary arteries was comparable to that of sequential
saphenous vein grafts. In 1995, van Brussel and colleagues reviewed 428
consecutive patients who underwent isolated venous coronary artery bypass graft
surgery.141 Follow-up was 99.8% complete and averaged 15.4 years for the
survivors. They found that revascularization with sequential grafts only, and
obesity at operation were incremental risk factors for acute myocardial infarction
using the Cox regression model.142 In 2000, Dion and colleagues reported the
graft patency in the first consecutive 500 patients receiving at least one sequential
ITA who had a late angiographic restudy at a mean interval of 7.4 (range 1-12.2)
140
Orszulak, Schaff, Chesebro and Holmes. Mayo Clin Proc 1986; 61:3-8.
141
van Brussel, Plokker, Voors, et al. Eur Heart J 1995; 16:1200-6.
142
van Brussel, Ernst, Ernst, et al. InterJ Cardiol 1997; 58:119-26, van Brussel, Plokker,
Voors, et al. Eur Heart J 1995; 16:1200-6, van Brussel, Plokker, Voors, et al. J Thorac Cardiovas
Surg 1996; 112:69-78.
37
Background 57
years.143 The patency rate of the sequential ITA was 96.1%. There was no
significant difference between the patency of the proximal and the distal
sequential ITA anastomoses. The sequential anastomoses constructed in the length
tend to remain more patent than the diamond-shaped ones: 97.2% vs. 91.5%
(P=0.004). In 2001, Dion and colleagues reviewed the same group of patients and
found a significant difference between the saphenous vein graft patency and
intactness of sequential versus single anastomoses: 76% versus 60% and 64.5%
versus 44.4% at 5 and 10 years, respectively.144 There was no significant
difference in either patency or intactness between right ITA and sequential
saphenous grafts anastomosed to the right coronary artery: 83.4% versus 75.2%
and 77.8% versus 62.4%, respectively. The same was true for the anastomoses to
the “remote area” (distal circumflex, distal right coronary artery). Therefore
complementary sequential saphenous grafting still deserves consideration in some
patients below 70 years of age, particularly for those with disease in the “remote
area”.
Bilateral internal thoracic artery

The first report of the use of bilateral ITA was by Suzuki in 1973.145 In
1985, Barner and colleagues reported their 12 years’ experience of 1,000 isolated
coronary bypass patients with at least one ITA, and 103 of them had bilateral ITA
grafts.146 There were 1,158 ITA and 1,395 vein grafts anastomoses, for a total of
2,556 grafts (2.5 per patient). The followed up time was 1 to 12 years (mean 6.3
years). Graft patency was assessed by 1,029 follow-up catheterisations in 519
patients. The patency rate of the left ITA was 96.4% at 1 year, 88.1% at 5 years,
and 88.1% at 10 years. That of the right ITA was 92.8% (P = not significant) at 1
143
Dion, Glineur, Derouck, et al. Eur J Cardiothorac Surg 2000; 17:407-14.
144
Dion, Glineur, Derouck, et al. J Thorac Cardiovasc Surg 2001; 122:296-304.
145
Suzuki, Kay and Hardy. Circulation 1973; 48:III190-7.
146
Barner, Standeven and Reese. J Thorac Cardiovasc Surg 1985; 90:668-75.
38
Background 57
year, 84.6% (P = not significant) at 5 years, and at 10 years the numbers were too
small to be meaningful. Comparison of patency rates for all ITA grafts with vein
grafts gave 1 year graft patency rates of 95.7% versus 93.4% (P< 0.025), 5 year
rates of 87.9% versus 74.0% (P< 0.001) and 10 year rates of 83.0% versus 41.0%
(P<0.001). Morbidity and mortality for patients having ITA grafting are
comparable to those of patients having saphenous vein bypass only.
The concern in using the bilateral ITA is the risk of sternal ischemia and
infection.147 In 1992, Carrier and colleagues evaluate the effect of median
sternotomy and ITA dissection on sternal vascular supply. Sternal bone
tomography was performed at 7 days and one month after cardiac operation in 67
patients.148 After median sternotomy without single or bilateral ITA grafts, the
average hypoperfusion ratio was 4 ± 1% compared with 13 ± 3% after single ITA
grafts and 24 ± 6% after bilateral ITA grafts (P < 0.0001). Diabetic patients
without ITA, with single ITA, and with bilateral ITAs showed hypoperfusion
areas of 5 ± 3%, 15 ± 5%, and 23 ± 9%, respectively, a result similar to that of
non-diabetic patients. One month after operation the hypoperfusion area decreased
to 2% ± 2% (P < 0.05) in restudied patients. The risk of sternal complication is
higher in obese patients.149 The benefit of right ITA in elderly patients is
147
Aarnio, Kettunen and Harjula. Scand J Thorac Cardiovasc Surg 1991; 25:175-8.,
Arnold. J Thorac Cardiovasc Surg 1972; 64:596-610., Cosgrove, Loop, Lytle, et al. Circulation
1985; 72:II170-4., Cosgrove, Lytle, Loop, et al. J Thorac Cardiovasc Surg 1988; 95:850-6.,
Galbut, Traad, Dorman, et al. Ann Thorac Surg 1990; 49:195-201., Grossi, Esposito, Harris, et al.
J Thorac Cardiovasc Surg 1991; 102:342-6; discussion 346-7., He, Ryan, Acuff, et al. J Thorac
Cardiovasc Surg 1994; 107:196-202., Kouchoukos, Wareing, Murphy, Pelate and Marshall. Ann
Thorac Surg 1990; 49:210-7; discussion 217-9., Lytle, Cosgrove, Loop, et al. Circulation 1986;
74:III37-41., Uva, Braunberger, Fisher, et al. Ann Thorac Surg 1998; 66:2051-5., Zacharias and
Habib. Chest 1996; 110:1173-8.
148
Carrier, Gregoire, Tronc, et al. Ann Thorac Surg 1992; 53:115-9., Carrier, Gregoire,
Tronc, et al. Ann Thorac Surg 1993; 55:803-4.
149
He, Ryan, Acuff, et al. J Thorac Cardiovas Surg 1994; 107:196-202.
39
Background 57
questionable. In 1986, Lytle and colleagues reviewed the first 500 patients (420
men, 80 women, mean age 55 years, range 24 to 78) undergoing bilateral ITA
grafting.150 The major complications did not correlate with gender, diabetes,
number of grafts or preoperative left ventricular function but were associated with
increasing age (P = 0.0001) and previous cardiac surgery (P = 0.009). The
complications were decreased by the use of cardioplegia (P = 0.002). In 1994, He
and colleagues examined the risk of death in 512 elderly patients (70 years and
older) undergoing ITA grafting.151 The operative mortality in these patients was
7.62% (39 of 512), significantly higher than that (1.97% [60 of 3,047]; P <
0.0001) in younger patients (i.e. under 70 years old). Of 53 variables examined,
using univariate analysis, nine preoperative variables (age, smoking history,
congestive heart failure, myocardial infarction, New York Heart Association
functional class, ejection fraction, left main artery disease, stenosis of the left
anterior descending artery and re-operation), three intraoperative variables
(emergency operation, bilateral ITA and right ITA), and nine postoperative
variables were significantly associated with the higher mortality (P< 0.05). The
significant preoperative and intraoperative variables and variables that exhibiting
a tendency for correlation (P<0.2) to mortality were included in a stepwise
multiple logistic regression. The regression analysis demonstrated that right ITA,
re-operation, history of myocardial infarction, age, left main artery disease,
history of smoking and postoperative complications are the risk factors for the
elderly undergoing ITA grafting. In 1996, a prospective multicentre study
comprising 1830 patients in 10 units over a 4-month period were undertaken: 960
underwent coronary artery bypass grafting and 870 other procedures.152
According to the Centers for Disease Control and Prevention definitions, 2.3% of
patients (42/1830) acquired a deep sternal wound infection. Independent risk
factors for deep sternal wound infection were obesity, coronary artery bypass
150
Lytle, Cosgrove, Loop, et al. Circulation 1986; 74:III37-41.
151
He, Acuff, Ryan and Mack. Ann Thorac Surg 1994; 57:1453-60; discussion 1460-1.
152
J Thorac Cardiovasc Surg 1996; 111:1200-7.
40
Background 57
grafting, reoperation, and postoperative inotropic support. Independent risk factors

after coronary artery bypass grafting were obesity, bilateral ITA grafting,
reoperation, and postoperative inotropic support.
In 1998, Buxton and colleagues demonstrated the benefit of the use of

bilateral ITA.153 Two thousand eight hundred and twenty six patients (age 62 ± 9
years [mean ± 1 SD], 2350 men, mean follow-up 52 months) who underwent
surgery with ITAs, supplemented by saphenous vein grafts were reviewed. Single
ITA grafting (n = 1557) was compared with double (n = 1269) using the Cox
proportional hazards model. Significant predictors of all-cause mortality were as
follows: (1) peripheral vascular disease, rate ratio (RR) = 2.4 (1.7 to 3.4 [95%
CI]); (2) prior myocardial infarction, RR = 2.1 (1.5 to 3.1); (3) severe left
ventricular dysfunction, RR = 3.9 (2.6 to 5.9) and moderate left ventricular
dysfunction, RR = 2.0 (1.5 to 2.6); (4) age ³ 70 years, RR = 3.4 (2.4 to 4.8), and
age 60 to 69 years, RR = 1.7 (1.3 to 2.4); (5) diabetes mellitus, RR = 1.7 (1.3 to
2.4); (6) carotid disease, RR = 1.7 (1.2 to 2.4); and (7) single ITA (versus bilateral
ITA), RR = 1.4 (1.1 to 1.8). Single ITA was also a predictor of all-cause
mortality, late myocardial infarction, or late reoperation (RR = 1.3 [1.1 to 1.6]).
In 1999, Lytle and colleagues reviewed a group of patients who had

undergone elective primary isolated coronary bypass grafting and received either
single (8123 patients) or bilateral ITA grafts (2001 patients), with or without
additional vein grafts with a mean follow-up of 10 years.154 In-hospital mortality
was 0.7% for both the bilateral and single ITA groups. Survival rates for the
bilateral ITA group were 94%, 84% and 67%, and for the single ITA group 92%,
79% and 64% at 5, 10, and 15 postoperative years respectively (P<0.001). Death,
reoperation, and percutaneous transluminal coronary angioplasty were more
frequent for patients undergoing single rather than bilateral ITA grafting. This
153
Buxton, Komeda, Fuller and Gordon. Circulation 1998; 98:II1-6.
154
Lytle, Blackstone, Loop, et al. J Thorac Cardiovas Surg 1999; 117:855-72.
41
Background 57
observation remained true despite multiple adjustments for patient selection,

sampling, and length of follow-up.
Skeletonized internal thoracic artery

The first report of skeletonized ITA was by Keeley in 1987.155 In 1992,
Parish and colleagues investigated chest wall blood flow in a canine model
measured with radioactive microspheres. Chest wall blood flow was significantly
decreased from preharvest levels after ITA harvesting regardless of the technique
used. Tissue blood flows decreased to 46.9%, 22.1% and 41.2% of baseline values
for the manubrium (P < 0.01), sternum (P < 0.001) and ribs (P < 0.05),
respectively. Residual sternal blood flow on the side of the skeletonized vessel
was significantly greater than on the side of the pedicle graft (2.60 ± 0.68 versus
1.27 ± 0.27 cm3/min/100 gm, P < 0.001). In 1999, Calafiore and colleagues
reported results of 1,146 patients who underwent isolated CABG using bilateral
ITAs, 304 receiving pedicled grafts (group A, October 1991 through May 1994)
and 842 skeletonized conduits (group B, June 1994 through June 1998).156 Group
B had a higher incidence of patients with diabetes (223 versus 40, P < 0.001).
Seventy-one patients in group A and 133 (15.8%) in group B underwent
postoperative angiography. The patency rate was similar, both early (100% in
group A versus 98.6% in group B, not significant) and late (98.6% in group A
versus 98.4% in group B, not significant). In 1999, Gaudino and colleagues
compared the morphology of ITA harvesting by skeletonized and pedicled
techniques in 40 consecutive patients undergoing coronary artery bypass. They
were randomized to receive a skeletonized (n = 22) or a pedicled (n = 18) ITA
graft. There was no difference in endothelium integrity in both groups.
Composite T or Y graft
This technique has allowed surgeons to expand the use of the ITA and also
benefit patients with an aorta disease. Mills introduced the concept of connecting
155
Keeley. Ann Thorac Surg 1987; 44:324-5.
156
Calafiore, Vitolla, Iaco, et al. Ann Thorac Surg 1999; 67:1637-42.
42
Background 57
one ITA to the other in 1982. In 1986, Tector and Sauvage published articles
about this technique.157 In 1994, Tector reported early results in 486 patients
undergoing total coronary artery revascularization using a T-graft constructed
from the attached left LITA and the free right ITA with an average of 4.34 distal
anastomoses.158 The mortality at 30 days was 2.3%; two of 92 women and 9 of
394 men died. The perioperative infarction rate was 1.2%. Postoperative
angiography in 34 patients showed 98.3% of left ITA and 86.5% of right ITA
anastomoses to be patent. In 1994, Calafiore and colleagues reported the results of
complex arterial CABG performed on 130 patients between October 1991 and
May 1993.159 One hundred and thirty six complex arterial conduits (branched,
lengthened or both) were constructed using 360 arterial conduits, 163 as free
grafts (three left ITAs, 16 right ITAs, 86 inferior epigastric arteries, 57 RAs, and
one right gastroepiploic artery). One hundred and fifty four free grafts were
anastomosed to one or both ITAs and one to an RA. There was no operative
mortality and no inotropic or mechanical supports were used. The overall
mortality rate was 1.5%. Early angiographic controls (between the 7th and 15th
postoperative days) demonstrated 100% patency; late angiographic controls (at a
mean interval of 9.5 months after operation) documented a mean patency rate
ranging from 94.1% of the RAs to 100% of the left ITAs and right gastroepiploic
arteries. At a mean follow-up of 7.2 months (range: 1 to 15 months) all patients
are alive without recurrence of symptoms. In 1995, Calafiore and colleagues
reported patency rates of 93.1% for the RA and 95.7% for the inferior epigastric
artery at a mean follow-up of 18.5 ± 10.4 months (range: 1 to 39 months) using a
composite graft in 240 patients comprising 163 RAs and 124 inferior epigastric
arteries with one (224 instances) or both (two instances) ITAs as inflow
157
Sauvage, Wu, Kowalsky, et al. Ann Thorac Surg 1986; 42:449-65., Tector. Ann Thorac
Surg 1986; 42:S22-7.
158
Tector, Kress, Schmahl and Amundsen. J Cardiovasc Surg (Torino) 1994; 35:19-23.
159
Calafiore, Di Giammarco, Luciani, et al. Ann Thorac Surg 1994; 58:185-90.
43
Background 57
conduits.160 In 2000, Calafiore and colleagues compared the results of patients

having in situ ITA (n = 1378, group A) or Y grafts (n = 440, group B).161 The
number of anastomoses per patient and the number of bilateral ITA anastomoses
per patient were higher in group B (3.1 ± 0.9 and 2.7 ± 0.9) than in group A (2.9 ±
0.8 and 2.2 ± 0.6) (both P <0.001). The number of right ITA anastomoses per
patient rose from 1.0 ± 0. 3 in group A to 1.4 ± 0.6 in group B (P <0.001), and the
number of sequential anastomoses per right ITA graft increased from 4.1% to
34.3% (P <0.001). Eight-year survivals were 95.8% ± 2.7% in group A versus
94.8% ± 4.0% in group B (P = not significant). Event-free survivals were 95.2% ±
2.9% in group A versus 93.6% ± 4.4% in group B (P = not significant). Early
angiograms were obtained in 295 patients (945 anastomoses, 863 distal and 82
proximal Y grafts) comprising 213 patients in group A and 82 patients in group B.
The patency rate was 98.8% in group A and 96.0% in group B (P = not
significant), whereas the grade A patency rate was 97.2% in group A and 96.4%
in group B (P = not significant). Late angiograms were obtained in 88 patients (25
in group A and 63 in group B) at a mean of 17.5 ± 18.4 months: the patency rate
was 100% in group A and 99.2 in group B (P = not significant), and the grade A
patency rate (excellent graft with unimpaired runoff)162 was 98.6% in group A and
98.8% in group B (P = not significant). No Y anastomosis was occluded or
stenosed.
In 2001, Iaco and colleagues reported the RA graft patency in 164 RAs.163
In group A (128), the RAs were connected end to side (115) or end to end (13) to
160
Calafiore, Di Giammarco, Teodori, et al. Ann Thorac Surg 1995; 60:517-23; discussion
523-4.
161
Calafiore, Contini, Vitolla, et al. J Thorac Cardiovasc Surg 2000; 120:990-6.
162
Fitzgibbon, Kafka, Leach, et al. J Am Coll Cardiol 1996; 28:616-26.
163
Iaco, Teodori, Di Giammarco, et al. Ann Thorac Surg 2001; 72:464-8; discussion 468-
9.
44
Background 57
the left ITA. In group B, 36 proximal anastomosis of the RAs were anastomosed
on the ascending aorta. Eight-year survival was 83.2% ± 3.2% (group A 82.1% ±
3.8% and group B 86.7% ± 6.2%, P = not significant). Event free survival was
80.1% ± 3.5% (group A 79.9% ± 4.4% and group B 80.2% ± 7.3%, P = not
significant). Sixty-one patients (37.2%) had early angiography within 90 days of
the operation. The patency rates of RA distal anastomoses were 98.9% (88 of 89),
In group A, the patency rates of RA distal anastomoses was 98.7% (77 of 78), in
group B 100% (11 of 11; P = not significant). After a mean of 48 ± 27 months (6
to 96), 72 patients (51.1% of the survivors) had a repeat angiogram. The patency
rate of RA distal anastomoses was 95.6% (87 of 91). In group A, the patency rate
of RA distal anastomoses was 93.8% (61 of 65) and in group B 100% (26 of 26; P
= not significant). All the intermediate RA-left ITA anastomoses were patent at
the early and late control angiogram. The patency rates for RA and ITAs were
similar both early (88 of 89 versus 82 of 82; P = not significant) and after 48 ± 27
months (87 of 91 versus 93 of 93; P = not significant).
Concerning the flow in the graft after multiple distal anastomoses from a
single graft, with either sequential anastomoses or a Y-graft. In 1984, Minale and
colleagues performed an aorto-coronary by-pass graft to the left anterior
descending artery and to a major diagonal branch in 35 patients.164 Flows through
the by-passes were measured electromagnetically during the operation. Flow to
left anterior descending artery was significantly higher through an isolated by-
pass than through a sequential by-pass. Flow to diagonal branch showed no
significant difference in the two groups. However this was a study in the
saphenous vein graft. In 1986, Lee and colleagues demonstrated the ability of the
ITA in increasing the flow in the canine ITA.165 The left ITA was anastomosed to
the circumflex coronary artery. In situ, blood flow in the ITA was 27 ml/min.
Blood flow was 63 ml/min in the circumflex coronary artery and 42 ml/min in the
164
Minale, Bourg, Bardos and Messmer. J Cardiovasc Surg 1984; 25:12-5.
165
Lee, Orszulak, Schaff and Kaye. J Thorac Cardiovas Surg 1986; 91:405-10.
45
Background 57
left anterior descending coronary artery. After anastomosis of the ITA to the
circumflex coronary artery, the left main coronary artery was ligated; flow
through the bypass graft increased to 92 ml/min, and systemic hemodynamics
remained stable. Isoproterenol stimulation further increased flow through the ITA
to 160 ml/min.
In 1999, Wendler performed a flow study comparing two types of grafts

(right ITA or RA) in the composite T graft in 251 patients. Flow was measured in
the proximal left ITA with a Doppler guide wire at one week and six months after
the operation. At angiography (n = 142, 56.6%) the patency rate was 96.3% (right
ITA group) versus 98.2% (RA group). There was no significant difference
between baseline flow, maximum flow, and coronary flow reserve between the
two groups. Coronary flow reserve increased in both groups within the first six
postoperative months (right ITA group, 1.85 ± 0.31 vs. 2.77 ± 0.77, P =0.0002;
RA group, 1.82 ± 0.4 vs. 2.53 ± 0.73, P =0.009).
In 2000, Speziale and colleagues studied the flow in the composite Y

arterial grafts in 76 patients.166 All patients received sequential grafting by using
both ITAs, inferior epigastric and RGEA joined as a composite Y graft. All
patients except one showed good flow (ml/min and waveform) in either branch of
composite graft. Temporary occlusion of either branch did not significantly affect
flow in the other side of the arterial Y. Mid-term follow-up (three and 15 months)
and angiographic studies showed a high graft patency rate. Flow reserve of the left
ITA did not affect blood flow and resistance on either branch of the Y graft when
temporary occlusion on the other side of the arterial Y was performed. However
the blood flow in the bypasses was affected by the degree of stenosis in native
166
Speziale, Ruvolo, Coppola and Marino. Eur J Cardiothorac Surg 2000; 17:505-8.
46
Background 57
coronary artery.167 There was a higher flow in the graft when the native coronary
had more severe stenosis or occluded.
In 2000, Wendler and colleagues, using combined skeletonized ITA and T

graft, performed complete arterial grafting in 490 patients with two arterial
conduits, either both ITAs (23%) or the left ITA and RA (77%).168 Triple-vessel
disease was present in 88% of the patients. T graft was performed in 85% of the
patients. The rate of perioperative myocardial infarction was 1.2%. Hospital
mortality was 2.2%. Postoperative coronary angiography in 172 patients (35%)
documented excellent patency rates at one week after surgery (left ITA 98.3%,
right ITA 96.5%, and RA 96.6%). In 2001, Wendler and colleagues demonstrated
a good outcome of coronary artery bypass grafting in diabetic patients using
skeletonized ITA, RA and T graft techniques.169 Bilateral ITA graft was used in
20% of patients. Sternal complication and in hospital mortality was not different
when compared with non diabetic patients who had complete arterial grafting with
the same technique.
Also in 2001, Tector and colleagues reported a series of purely ITA

reconstruction in 897 patients with a total of 3,784 ITA grafts (4.2 grafts per
patient).170 Early mortality for the group was 2.3%. Freedom from death was 86%
and freedom from reintervention was 94% at five years after the operation. In the
same year, Barner and colleagues reported 7-year experience with the ITA/RA T
graft as the only conduits.171 There were 909 patients with a mean age of 60 and
167
Markwirth, Hennen, Scheller, Schafers and Wendler. Ann Thorac Surg 2001; 71:788-
93.
168
Wendler, Hennen, Demertzis, et al. Circulation 2000; 102:III79-83.
169
Wendler, Hennen, Markwirth, et al. Thorac Cardiovasc Surg 2001; 49:5-9.
170
Tector, McDonald, Kress, Downey and Schmahl. Ann Thorac Surg 2001; 72:450-5.
171
Barner, Sundt, Bailey and Zang. Ann Surg 2001; 234:447-52; discussion 452-3.
47
Background 57
20% age 70 or older. The incidence of triple-vessel disease was 73%, female
gender 28%, diabetes mellitus 27%, peripheral vascular disease 11%,
cerebrovascular disease 10% and chronic obstructive pulmonary disease 6%;
ejection fraction was less than 35% in 11%. Follow-up information was obtained
at a mean of 35.4 months (range 1-88) and was 95% complete. Operative
mortality was 0.08%. The incidence of perioperative infarction was 3.3%, low
cardiac output 2.7%, stroke 2.2%, reoperation for bleeding 3.8%, and deep sternal
infection 0.8%. The actuarial survival rate was 90% at 5 years, freedom from
infarction was 94%, freedom from catheterization was 83%, and freedom from
reintervention (angioplasty or reoperation) 93%.
All of these procedures are technical demand and run a risk of major
multiple grafts failure because in some procedures the inflow comes from one
source. One anastomosis problem can cause large myocardial ischemia. There is
no long term data on atherosclerosis on T or Y graft, in addition naturally the
atherosclerosis often is prone to occur at the origin of the side branch. One
unfavorable target artery, e.g. poor run off, might cause complete graft failure.
The combined use of several techniques might achieve an excellent long-term
outcome with a minimal risk such as combination of bilateral ITA in which one
side skeletonized and one side pedicle, with some other arterial conduits such as
RA or gastroepiploic artery. Y or T graft reserve in case there is insufficient
number of conduit or length of the graft.
Vasoreactivity of vascular grafts
One of the key successes of arterial grafting has been the elimination of
vasospasm of the graft during intraoperative and postoperative periods. He GW
and colleagues have extensive studies on this subject. The following points
summarise the key issues.
48
Background 57
1. Different vessels react differently to vasoconstrictors and vasodilators.172

Glyceryl trinitrate (GTN) caused relaxation of the ITA, saphenous vein and
coronary artery but was less sensitive, less potent and had a reduced range of
relaxation in the ITA. Shapira and colleagues demonstrated the superiority of
GTN in dilating RA, ITA and saphenous vein compared with the diltiazem.173
Zabeeda and colleagues proves the efficacy of intravenous GTN as a systemic
vasodilator for in vivo vasodilatation of both the ITA and RA.174 Hillier found that
in the human ITA, the use of intraluminal papaverine increased the lumen size by
20% (P < 0.05), and the contractions elicited by noradrenaline were significantly
less in the papaverine group than in the control group (P < 0.05).175 Endothelium-
dependent relaxation to acetylcholine or bradykinin was not affected by
papaverine treatment. Endothelium-independent relaxation was the same in both
groups, with almost 100% relaxation achieved by sodium nitroprusside. He and
colleagues found that papaverine was less sensitive in the ITA as compared with
the coronary artery and saphenous vein. Nifedipine, verapamil, and diltiazem were
potent relaxing agents in all three vessels when pre-contracted by potassium
chloride (K+), but less potent in vessels contracted by the thromboxane mimetic
U46619 or phenylephrine, especially in the saphenous vein. Pretreatment of
vessels with GTN failed to alter subsequent contraction to U46619 or K+ while
nifedipine pretreatment abolished subsequent contraction to K+ and reduced
sensitivity of the ITA to U46619.176 Therefore perioperative ITA spasm could be
treated with the rapid-onset, nonspecific, vasodilator glyceryl trinitrate, but for
prophylaxis of ITA spasm, calcium antagonists or specific receptor antagonists
172
He, Angus and Rosenfeldt. Journal of Cardiovascular Pharmacology 1988; 12:12-22.
173
Shapira, Xu, Vita, et al. J Thorac Cardiovasc Surg 1999; 117:906-11.
174
Zabeeda, Medalion, Jackobshvilli, et al. Ann Thorac Surg 2001; 71:138-41.
175
Hillier, Watt, Spyt and Thurston. Ann Thorac Surg 1992; 53:1033-7.
176
He, Rosenfeldt, Buxton and Angus. Circulation 1989; 80:I141-50.
49
Background 57
should be tested in the clinical setting. Beta-adrenoceptors contribute little to the

reactivity of the human ITA graft to sympathomimetic drugs.177 The
postjunctional alpha-adrenoceptors are predominantly of the alpha 1-subtype in
the human ITA and therefore the alpha-adrenoceptor agonist-induced contraction
and the sympathetic nerve stimulation-induced contraction is mediated mainly by
activation of the alpha 1-adrenoceptors.178 This is also true for the RA. The human
RA is an alpha-adrenoceptor-dominant artery with little beta-adrenoceptor
function.179 The use of beta-blockers is not likely to evoke the spasm of the RA.
Furthermore, the RA has a dominant alpha1-adrenoceptor function. Circulating
catecholamines will mainly contract the RA by activation of the alpha1-
adrenoceptors and to a lesser extent also by alpha2-adrenoceptors. Dipp and
colleagues demonstrated the efficacy of phenoxybenzamine (alpha-antagonist) in
the prevention of RA spasm for at least 6 hours.180 Phenoxybenzamine’s effect is
longer lasting than papaverine and is also less harmful to the endothelium
compared with papaverine. The distal section of the human ITA is the most
reactive part of the graft to some vasoconstrictors (norepinephrine and endothelin-
1) compared with the middle and the proximal sections.181 In contrast the
proximal part of the RA showed a significantly greater response to K+ than that of
distal RA and both contracted more than the left ITA and the right ITA.182 There
was no difference in the response to noradrenaline and adrenaline between
proximal and distal RA, both of which contracted more than the left and right
177
He, Buxton, Rosenfeldt, Wilson and Angus. J Thorac Cardiovas Surg 1989; 97:259-66.
178
He, Shaw, Hughes, et al. Journal of Cardiovascular Pharmacology 1993; 21:256-63.
179
He and Yang. J Thorac Cardiovas Surg 1998; 115:1136-41.
180
Dipp, Nye and Taggart. Eur J Cardiothorac Surg 2001; 19:482-6.
181
He, Acuff, Yang, Ryan and Mack. J Thorac Cardiovas Surg 1994; 108:741-6.
182
Chester, Marchbank, Borland, Yacoub and Taggart. Ann Thorac Surg 1998; 66:1972-6;
discussion 1976-7.
50
Background 57
ITA. Comparing the ITA with the inferior epigastric artery, both respond the same
to vasoconstrictors e.g. potassium, norepinephrine, U46619 and endothelin-1. The
responses to vasorelaxants e.g. glyceryl trinitrate or acetylcholine are also the
same. However, a non-receptor agonist for endothelium-derived relaxing factor
e.g. A23187 induced significantly less relaxation in the inferior epigastric artery
than in the ITA. Mugge and colleagues demonstrated that the endothelium-
independent relaxation in response to nitroglycerin was identical in both inferior
epigastric artery and ITA.183 In contrast, the endothelium-dependent relaxation in
response to acetylcholine, substance P, and bradykinin was significantly greater in
the inferior epigastric artery than in the ITA. Comparing the ITA with the RA, the
human RA has a higher receptor-mediated contractility (to endothelin-I and
angiotensin-II) but similar response to either endothelium-dependent (substance P
and A23187) or endothelium-independent (nitroglycerin) relaxation compared to
the ITA.184 However, Cable and colleagues demonstrated diminished endothelial
regulation of vascular smooth muscle in the RA compared with the ITA.185
Comparing the ITA and the RGEA, Yang and colleagues found that
norepinephrine and K+ evoked threefold greater contraction in the RGEA than in
the ITA (P < 0.01 to 0.05), whereas the sensitivity to the catecholamine was
comparable.186 Acetylcholine induced endothelium-dependent relaxations in the
RGEA and ITA, but the sensitivity and maximal relaxation were slightly less in
the RGEA than in the ITA (P < 0.05). Histamine induced endothelium-dependent
relaxation showed a similar sensitivity, whereas the maximal relaxation was
slightly enhanced in the RGEA. Comparing the ITA, RA and the RGEA,
Chardigny and colleagues found that the RA had stronger contractions to K+ than
183
Mugge, Barton, Cremer, Frombach and Lichtlen. Ann Thorac Surg 1993; 56:1085-9.
184
He and Yang. Ann Thorac Surg 1997; 63:1346-52.
185
Cable, Caccitolo, Pfeifer, et al. Ann Thorac Surg 1999; 67:1083-90.
186
Yang, Siebenmann, Studer, Egloff and Luscher. J Thorac Cardiovasc Surg 1992;
104:459-64.
51
Background 57
the other vessels.187 The radial and the gastroepiploic arteries with endothelium
presented a higher contraction force than the ITA in response to norepinephrine
and serotonin. The three vessels had equal sensitivities to norepinephrine and
serotonin. The RGEA had a lower response to thromboxane A2 mimetic than the
two other vessels.
2. A combined solution of glyceryl trinitrate-verapamil provides a rapid onset

and long action for use in preparing the saphenous vein, RA and ITA.188 Both
nitroglycerin and sodium nitroprusside are potent vasodilators in the RA.189
Nitroglycerin may have more potent effects in certain situations (constriction
related to thromboxane A2). However, tolerance to nitroglycerin may develop. A
cross tolerance to sodium nitroprusside may exist but the effect is weak so that
sodium nitroprusside may be preferable to nitroglycerin as a vasodilator in the RA
postoperatively. Other vasodilators may be the drugs of choice under such
circumstances. Although all calcium channel antagonists have antispastic effects
in the RA, they have different sensitivities.190 Dihydropyridine derivatives may be
the most potent calcium channel antagonists. Phosphodiesterase III inhibitors are
potent vasodilators of human ITA and may have a slight selectivity with greater
potency to receptor stimulants than to the depolarizing agent K+.191
Phosphodiesterase III inhibitor-induced relaxation is also not affected by
denudation of endothelium. Phosphodiesterase III inhibitor is also a potent
187
Chardigny, Jebara, Acar, et al. Circulation 1993; 88:II115-27.
188
He. J Thorac Cardiovas Surg 1998; 115:1321-7, He, Buxton, Rosenfeldt, Angus and
Tatoulis. J Thorac Cardiovas Surg 1994; 107:1440-4, He, Buxton, Rosenfeldt, Angus and
Tatoulis. J Thorac Cardiovasc Surg 1994; 107:1440-4., He, Rosenfeldt and Angus. Ann Thorac
Surg 1993; 55:1210-7, He and Yang. Ann Thorac Surg 1996; 61:610-4.
189
He and Yang. British Journal of Clinical Pharmacology 1999; 48:99-104.
190
191
He and Yang. Journal of Cardiovascular Pharmacology 1996; 28:208-14.
52
Background 57
vasodilator for the RA, with possibly higher potency when mediated by alpha-
adrenoceptor- and depolarizing agent K+, but less potency in thromboxane A(2)-
mediated, contraction.192 Neither dobutamine nor dopexamine caused
vasoconstriction from baseline tension, whereas vessels exposed to dopamine
showed constriction at high concentrations.193 The vessel responses to the
dopaminergic agents did not differ according to the functional status of the
endothelium as initially assessed by acetylcholine-induced vessel relaxation.
3. "Vasoactivator" substances have been named because the previous known

of vasoconstrictors also demonstrated a vasodilatation effect through the
mechanism of endothelium-derived relaxing factor (EDRF) release.194 This
“vasoactivator” may be classified as (1) Type I: vasoconstriction-predominant
type such as acetylcholine and U46619 in porcine which mainly cause contraction
in endothelium-intact arteries; (2) Type II: balanced type such as norepinephrine
and 5-hydroxytryptamine in porcine coronary artery which cause little contraction
in endothelium-intact arteries but a great contraction when the endothelium is
denuded.195
4. In 1995, He and colleagues proposed the classification of arterial conduits

into three types based on pharmacological reactivity of the grafts and anatomical
locations: type I: (somatic arteries) e.g. ITA and inferior epigastric artery, type II:
(splanchnic arteries) e.g. gastroepiploic artery, and type III: (limb arteries) e.g.
192
193
Myers, Li, Yaghi and McCormack. Circulation 1993; 88:II110-4.
194
He and Yang. Angiology 1994; 45:265-71.
195
He, Yang and Starr. Ann Thorac Surg 1995; 59:676-83.
53
Background 57
RA.196 Types II and III are prone to spasm because of higher contractility whereas
type I arteries are usually less spastic.
The development of coronary artery surgery up until 1990 is summarized in

figure 1.
196
54
Background 57
55
Background 57
The Role of the Radial Artery as a Bypass Graft

Early Patency
In 1992, Acar and colleagues published the results of a study of 104 patients
who received 122 RA grafts.197 They found that the patency rate of the radial
arteries was 93.5% at 9 months, better than the reported patency of free internal
thoracic arteries (69.3%). This improvement was thought to be due to better
harvesting techniques, the use of calcium channel blocking agents, and the
administration of aspirin. Following Acar’s findings, several cardiac centers in
Europe and North America confirmed these results, finding excellent patency
rates at early to mid-term follow-up.198 Brodman and colleagues in 1996 reported
a patency rate of 95.7% at 12 weeks while Calafiore and associates in 1995
demonstrated a patency rate of 94% at a mean of 14 months. More recently, Acar
and colleagues confirmed the long-term patency of RA grafts, reporting a patency
rate of 83% at 5 years compared with 91% for the LITA grafts.199 The authors
suggested that the difference in patency may have been due to the fact that the two
conduits were grafted to different target arteries. The RA was anastomosed to
small vessels, while the LITA, for the most part, was grafted to the LAD.
Conclusion
As indicated in the introduction to this chapter, the history of the surgical

treatment of coronary artery disease has been far from linear but the summary of
197
Acar, Jebara, Portoghese, et al. Ann Thorac Surg 1992; 54:652-9; discussion 659-60.
198
Brodman, Frame, Camacho, et al. J Am Coll Cardiol 1996; 28:959-63, Chen, Nakao,
Brodman, et al. J Thorac Cardiovas Surg 1996; 111:1208-12, da Costa, da Costa, Poffo, et al.
Ann Thorac Surg 1996; 62:475-9; discussion 479-80, Dietl and Benoit. Ann Thorac Surg 1995;
60:102-9; discussion 109-10, Manasse, Sperti, Suma, et al. Ann Thorac Surg 1996; 62:1076-82;
discussion 1082-3., Weinschelbaum, Gabe, Macchia, Smimmo and Suarez. J Thorac Cardiovas
Surg 1997; 114:911-6.
199
Acar, Ramsheyi, Pagny, et al. J Thorac Cardiovasc Surg 1998; 116:981-9.
56
Background 57
events presented in figure 1 show a clear progression from indirect to direct

methods of surgical treatment. One of the most useful developments in recent
years is the direct coronary revascularization using arterial conduits for CABG.
The need for a viable alternative to the ITA has seen a growing interest in the RA,
a vessel that offers excellent potential as a bypass graft. Despite recent reports that
the RA has high short and mid-term patency rates, more investigations are needed
before it can be viewed as a vessel for CABG. The central aim of this thesis is to
closely examine the potential role of the radial as a coronary artery graft. The
main issues addressed in the thesis relate to the suitability, safety and
effectiveness of the RA as a conduit for CABG. Accordingly, the three
interconnected hypotheses presented below attempt to address these specific
issues.
57
Background 57
(b) Hypotheses and Specific Aims

This thesis posits three main hypotheses.
First Hypothesis: The radial artery (RA) is a suitable conduit for coronary artery
bypass grafting in most patients.
The specific aims are:
1. To examine the anatomy and anatomical variations of the arteries of the upper
extremity.
2. To document the prevalence of RA disease (intimal hyperplasia,
atherosclerosis and medial calcification) in a group of patients selected for
coronary artery bypass grafting (CABG).
3. To compare the pre-existing disease processes in the RA with those of the
internal thoracic artery in patients undergoing CABG.
Second Hypothesis: The harvesting of the RA is safe.

1. To outline the collateral circulation of the hand, or more specifically, to define
the anatomical connections (including the variations) between the RA and
other arteries in the hand.
2. To validate the modified Allen test using digital systolic blood pressure via
photophlethysmography and Doppler ultrasound as points of comparison.
Third Hypothesis: The RA is an effective alternative to other conduits

commonly used for coronary artery bypass grafting
1. To compare the survival rate in patients who receive the RA, right internal
thoracic artery or the saphenous vein graft as a second graft for CABG.
2. To compare RA graft patency with that of the internal thoracic artery and the
great saphenous vein.
58
Background 57
59
Chapter 2
Surgical Anatomy and Variations of the Arterial System of
the Upper Extremity
Introduction
(a) Surgical Anatomy of the Arterial System of the Upper Extremity
Development of the Arterial System of the Upper Extremity
Normal Arterial Systems of the Upper Extremity
The Arm
The Brachial artery
The Forearm
The Radial artery
The Ulnar artery
Anatomical Consideration for Radial Artery Harvesting

Surgical Incision
Surgical Exposure
(b) Variations of the Arterial Systems of the Upper Extremity
Introduction
Materials and Methods
Results
Variations of the forearm arteries

Variations of the arterial connections in the hand
Radial artery
Deep palmar arch of the radial artery
Ulnar artery
Superficial palmar arch of the ulnar artery
Median artery
Combined contributions of ulnar and radial arteries
Discussion
Variations of the arteries in the forearm

Surgical Anatomy and Variations 95
Introduction
Intermittent reports have indicated that radial artery (RA) harvesting has
some potentially serious complications including radial nerve injury200 and
impaired hand circulation.201 Several other RA interventions such as vascular
access for hemodialysis and percutaneous RA catheterization also cause hand
ischemia.202 In 1998 Morsy and colleagues reported an incidence of hand
ischemia of 4.3% (13 of 299 arteriovenous grafts) and 1.8% (2 of 110 direct
forearm arteriovenous fistulas).203 There were sporadic reports of hand ischemia
after RA cannulation, but in 1983, Slogoff and colleagues reported the frequency
of complications after RA cannulation in 1,699 cardiovascular surgical patients
and in 83 patients in whom cannulation was performed in another artery after
failure at the radial site.204 RA flow was determined by a Doppler technique 1 day
200
Arons, Collins and Arons. Annals of Plastic Surgery 1999; 43:299-301, Denton, Trento,
Cohen, et al. J Thorac Cardiovasc Surg 2001; 121:951-6., Royse, Royse, Shah, et al. Eur J
201
Baker, Chunprapaph and Nyhus. Surgery 1976; 80:449-57, Nunoo-Mensah. Ann
Thorac Surg 1998; 66:929-31, Serricchio, Gaudino, Tondi, et al. Am J Cardiol 1999; 84:1353-6,
A8., Sessa, Pecher, Maurizi-Balzan, et al. Ann Vasc Surg 2000; 14:583-93., Sfeir, Khoury,
Khoury, Rustum and Ghabash. Cardiovascular Surgery 1996; 4:456-8, Tatoulis, Buxton, Fuller
and Royse. Ann Thorac Surg 1999; 68:2093-9, Valji, Hye, Roberts, et al. Radiology 1995;
196:697-701.
202
Baker, Chunprapaph and Nyhus. Surgery 1976; 80:449-57., Chemla, Raynaud,
Carreres, et al. Ann Vasc Surg 1999; 13:618-21., Goff, Sato, Bloch, et al. Ann Vasc Surg 2000;
14:138-44., Lazarides, Staramos, Panagopoulos, et al. J Am Coll Surg 1998; 187:422-6.,
Porcellini, Selvetella, De Rosa, et al. G Chir 1997; 18:27-30., Trerotola, Johnson, Shah,
Namyslowski and Filo. J Vasc Interv Radiol 1997; 8:557-62., Valji, Hye, Roberts, et al.
Radiology 1995; 196:697-701.
203
Morsy, Kulbaski, Chen, Isiklar and Lumsden. J Surg Res 1998; 74:8-10.
204
Slogoff, Keats and Arlund. Anesthesiology 1983; 59:42-7.
61
and 7 days after decannulation. Although partial or complete RA occlusion after

decannulation occurred in more than 25% of the patients, no ischemic damage to
the hand or disability occurred in any patient. Generally, the causes of hand
ischemia include previous trauma, vascular pathologies or anatomically
insufficient arterial collateral blood supplies. The last factor may be due to
dominance of the RA or absence of the ulnar artery. In addition to possessing
competency in basic surgical techniques, the surgeon must have a detailed
knowledge of the anatomy and variations of the blood supply of the upper limb in
order to avoid these complications.
The aims of this chapter are to investigate: 1) the suitability of the RA as a

bypass graft in terms of the ease with which the vessel can be accessed and
harvested by assessing the surgical anatomy of the forearm arteries; and 2) the
collateral circulation in the forearm and hand to ascertain whether it is safe to
routinely remove the RA. Accordingly, the first part of this chapter reviews the
current literature pertaining to the normal vascular anatomy of the upper
extremity. Given the lack of information in standard anatomy textbooks regarding
crucial variations in the circulation of the upper limb, the second part of the
chapter discusses the results of a study undertaken by me and others of the upper
extremities of 50 cadaveric upper extremities.
a) Surgical Anatomy of the Arterial System of the Upper Extremity
Development of the Arteries of the Upper Extremity
In order to contextualize the variations of the arterial blood supply of the

upper extremity, this section first briefly reviews the embryologic development of
the circulation of the upper limb.205 The embryologic development of the arterial
supply of the arm commences as vascular plexuses in the limb bud which then
205
Larsen. Essentials of human embryology 1998., Lippert. Arterial variations in man:
classification and frequency c1985., Moore. The developing human : clinically oriented
embryology c1998., Singer. Anat Rec 1933; 55:403-409.
62
coalesce into a central artery. The main artery in the arm is axial in position and
represents a continuation of the 6th cervical segmental artery. Proximally it
becomes the main subclavian-axillary-brachial trunk. Initially it extends as a
single main stem; below the elbow it persists in reduced form as the interosseous
artery; and at the carpus, it terminates by dividing into digital branches. In the
forearm it lies between two bones resting on the interosseous membrane, in the
position occupied by the adult anterior interosseous artery.
At the next stage, a parallel branch - the median artery - runs with the
median nerve in the forearm. The median artery gradually becomes larger and
temporarily takes over the supply to the fingers, while the anterior interosseous
artery undergoes a corresponding retroregression.
Both the radial and ulnar arteries form comparatively late in development.
In human embryos of about 18mm crown-heel length, the ulnar artery develops as
a branch from the original brachial trunk artery, extends down the ulnar side of
the forearm and anastomoses with the median artery to form a superficial palmar
arch from which digital branches arise. After the development of the ulnar artery,
the median artery begins to regress. In adults, the RA is the residual part of the
embryologic superficial brachial artery. In embryos of 21-mm length, the
superficial brachial artery emerges from the axillary region and develops parallel
to the original brachial artery where it lies superficial to the median nerve.206 After
it traverses the arm, it travels down the radial side of the forearm and near the
wrist, passes to the posterior surface and divides over the carpus into branches for
the dorsum of the thumb and index finger. At the next stage, the antibrachial
(forearm) part of the superficial brachial artery forms the RA while the upper part
of the superficial brachial artery degenerates until it is normally represented in the
adult by a small branch of the brachial which passes to the biceps muscle. The
deep (profunda) branch of the brachial artery and the smaller branches to the
206
Senior. Anat Rec 1926; 32:220-221.
63
shoulder and elbow develop at a relatively late stage as new offshoots of the
primary axial vessel (Figure 2.1).
Figure 2.1 Diagrams illustrating the development of the arteries of the upper
extremity. The original system (a, b). Regressed arteries (in c-f) are shown as faded.
64
Normal Arterial Systems of Upper Extremity
In this section I review the normal anatomy of the arteries in the upper
extremities, discussing in particular: 1) the relationship between the arteries and
adjacent structures; and 2) the collateral circulation of the arterial system in the
arm, forearm and hand.207
The Arm
Arteries of the upper extremity arise from the subclavian system. The
subclavian artery becomes the axillary artery when it passes the lateral border of
the first rib at the midpoint of the clavicle. The axillary artery enters the apex of
the axilla by passing the first digitation of serratus anterior and runs from deep to
superficial. It is divided into three parts by the pectoralis minor- the part above,
the part behind and the part below - and changes its name to the brachial artery at
the lower border of the teres major muscle.
The Brachial artery
Beginning at the lower border of the tendon of the teres major, the brachial
artery runs down the arm, lying immediately under the deep fascia through which
it can be palpated throughout its length. It terminates by dividing into the radial
and ulnar arteries at a point about a finger’s breadth below the bend of the elbow,
that is, opposite the inner border of the neck of the radius. An important surface
landmark for the brachial artery runs along a line from the medial bicipital groove
behind the coraco-brachialis muscle to the middle of the cubital fossa at a point
level with the neck of the radius. Therefore, the surgeon can approach the brachial
artery by making an incision at the medial border of the biceps, in the groove
between the biceps and triceps muscles. The brachial artery lies within the
neurovascular bundle under the deep fascia. The median nerve is closely related to
the brachial artery. It lies lateral to the brachial artery in the upper part of the arm
207
Grant. Grant's atlas of anatomy c1991., Lippert. Arterial variations in man:
classification and frequency c1985., Moore. Clinically oriented anatomy c1999.
65
and then obliquely crosses the artery and lies medial to it in the lower part of the
arm. In the upper part, the ulnar nerve lies posterior to the brachial artery,
however, in the lower part of the arm, it pierces the medial intermuscular septum
and lies in the groove behind the medial epicondyle of the humerus where it is
readily palpable.
Branches in the arm
The brachial artery gives off five branches in the arm: 1) the profunda
brachii, 2) the superior ulnar collateral artery, 3) the inferior ulnar collateral
artery, 4) the nutrient artery to the humerus, and 5) the muscular arteries. The
first branch forms anastomoses with the branches from the axillary artery and
recurrent branch of the RA. The second and third branches form anastomoses with
the anterior and posterior ulnar recurrent branches of the ulnar artery.
The major branch of the brachial artery is the profunda brachii artery. It
arises from the medial and posterior aspect of the brachial artery just below the
lower border of the teres major muscle. Running alongside the radial nerve, the
profunda brachii artery travels backwards between the long and medial heads of
the triceps and then runs along the groove with the radial nerve where it is
covered by the lateral head of the triceps. It ends by forming anterior and posterior
anastomotic branches with the recurrent branches of the RA. The profunda brachii
artery supplies the triceps muscle and also forms anastomoses with the posterior
circumflex artery.
The superior ulnar collateral artery is a small branch of the brachial artery
arising just below the middle of the arm and running with the ulnar nerve. The
inferior ulnar collateral artery arises about 5 cm above the elbow, passing
medially between the median nerve and the brachialis muscle before running
distally. Both superior and inferior ulnar collateral arteries form anastomoses with
the ulnar collateral branch of the ulnar artery.
The nutrient artery of the humerus usually arises approximately in the

middle of the arm before entering the nutrient canal and running distally.
66
Finally, the muscular branches of the brachial artery supply the

coracobrachialis, biceps and brachialis muscles.
The Forearm
The Radial Artery
The RA arises from the bifurcation of the brachial artery in the cubital fossa
and terminates by forming a deep palmar arch in the hand. The surface marking of
the RA is along a line, slightly convex laterally, from a point medial to the biceps
tendon in the cubital fossa to the medial side of the styloid process of the radius
where pulsation can be detected between the flexor carpi radialis medially and the
salient anterior border of the radius. It then runs along the floor of the anatomical
snuffbox across the scaphoid bone and the trapezium, where its pulsation is
obvious. Finally, it travels towards the dorsal aspect of the hand running deep into
the palmar side of the hand.
The RA is accompanied by paired venae comitantes. In the upper part of the

forearm it is overlapped anteriorly by the brachioradialis muscle. The distal one
third is covered only by skin and by superficial and deep layers of fasciae. As it
runs its course, the RA passes over the tendon of biceps, the supinator muscle, the
insertion of pronator teres, the radial origin of flexor digitorum superficialis, the
flexor pollicis longus muscle, the pronator quadratus muscles, and the lower end
of the radius. In the middle third of its course it runs medial to the superficial
branch of the radial nerve.
At its distal end it disappears beneath the tendons of the abductor pollicis
longus and extensor pollicis brevis muscles to cross the anatomical snuffbox. As it
passes between the heads of the first dorsal interosseous muscle it is crossed by
the beginning of the cephalic vein and the digital branches of the radial nerve. In
84% of cases the normal arterial anatomy of the forearm presents as follows
(Figure 2.2).
67
Figure 2.2 Diagram showing the right forearm and hand: normal arterial anatomy of the
forearm (from: Gabella G. Subclavian System of Arteries. In: Williams Pl, Bannister LH, Berry
th
MM, Collins P, Dyson M, Dussek JE, Ferguson MWJ, eds. Gray’s Anatomy 28 Edition. New
York, Edinburg, London, Tokyo, Madrid and Melbourne: Churchill Livingstone; 1995:1542.; by
permission of Churchill Livingstone)
Branches at the elbow

Immediately below the elbow, the RA gives off the radial recurrent artery, a
branch that is duplicated in some cases. It then passes between the superficial and
deep branches of the radial nerve and ascends behind the brachioradialis muscle in
front of the supinator and brachialis muscles; it supplies all of these muscles as
well as the elbow joint. Finally, its branches run upwards, both anterior and
posterior to the elbow joint, to anastomose with the descending articular branches
of the profunda brachii and with the ulnar collateral arteries.
Branches in the forearm

The RA gives off several muscular branches supplying the muscles on the
radial side of the forearm.
Branches in the hand

The RA gives off two carpal branches (palmar carpal and dorsal carpal
branches), two palmar branches (superficial palmar branch, deep palmar branch)
and three single branches (the first dorsal metacarpal artery, the arteria princeps
pollicis and the arteria radialis indicis).
At the wrist the RA gives off a small palmar (anterior) and a small dorsal
(posterior) carpal branch. The palmar carpal branch arises near the lower border
of pronator quadratus, and, running medially across the palmar surface of the
carpus, anastomoses behind the flexor tendons with the palmar carpal branch of
the ulnar artery, thereby forming the palmar carpal arch. The dorsal carpal branch
arises deep to the extensor tendons of the thumb. Running medially across the
dorsal carpal surface under these tendons, it anastomoses with the dorsal carpal
branch of the ulnar artery and with the anterior and posterior interosseous arteries
to form a dorsal carpal arch. The palmar and dorsal carpal arches both lie close to
the bone and supply the lower epiphyseal parts of the radius and ulna. The palmar
carpal arch also sends branches distally into the hand to anastomose with the deep
palmar arch, while the dorsal carpal arch, lying transversely across the distal row
of carpal bones, sends three small dorsal metacarpal arteries distally into the
second, third and fourth metacarpal spaces. These bifurcate into dorsal digital
branches for the adjacent sides of the index, middle, ring and little fingers. Near
69
their origin, the dorsal metacarpal arteries anastomose with the deep palmar arch
by the proximal perforating arteries, and, near their points of bifurcation, with the
palmar digital branches of the superficial palmar arch by the distal perforating
arteries.
The superficial palmar branch originates from the RA at the wrist before it
travels to the dorsal side of the hand. It passes through, and occasionally over, the
muscles of thenar eminence, which it supplies, sometimes anastomosing with the
ulnar artery to form the superficial palmar arch.
The last three branches of the RA are varied and often have been neglected
or not clearly described in textbooks. One branch at the dorsal side is called the
first dorsal metacarpal artery. It arises just before the RA passes between the two
heads of the first dorsal interosseous, and divides almost immediately into two
branches that supply the adjacent sides of the thumb and index finger. The dorsal
metacarpal artery provides the main blood supply to the thumb in about 15% of
hands. The other two branches of the RA are on the palmar side. The first branch
represents the principal artery of the thumb (in 80% of hands) and is named the
princeps pollicis artery. It generally provides the largest blood supply to the deep
palmar arteries which originate from the deep palmar arch, closely corresponding
to the palmar metacarpal arteries of the other digits. It runs along the first
metacarpal bone either anterior to the adductor pollicis or between the first dorsal
interosseous and adductor pollicis muscles. At the level of the
metacarpophalangeal joint and deep to the flexor pollicis tendon, the artery
usually terminates as two palmar digital arteries supplying the thumb and
sometimes the index finger. The last branch of the RA is the radialis indicis
artery. It originates from the proximal part of the princeps pollicis artery in about
50% of cases, travels distally between the first dorsal interosseous muscle and the
transverse head of the adductor pollicis muscle, and then runs along the lateral
side of the index finger. It anastomoses with the digital artery supplying the
medial side of the finger. At the distal border of the transverse head of the
adductor pollicis, the radialis indicis artery anastomoses with the princeps pollicis
artery and gives a communicating branch to the superficial palmar arch.
70
The ulnar artery
The ulnar artery is generally the larger of the two terminal branches of the
brachial artery, extending along the inner side of the forearm into the palm of the
hand where it forms the superficial palmar arch. The surface marking of the ulnar
artery is along a line, slightly convex medially, from a point medial to the biceps
tendon in the cubital fossa to the radial side of the pisiform bone. The lower two-
thirds of its course is straight and is indicated by a line drawn from the front of the
medial epicondyle to the radial surface of the pisiform bone with the forearm in
full supination. At this point it runs alongside and lateral to the ulnar nerve.
Immediately beyond the pisiform bone it gives off carpal branches and continues
across the palm as the superficial palmar arch. Given its course, the best surgical
approach to the artery is to make an incision lateral to the flexor carpi ulnaris
tendon at the lower forearm and to then follow the artery upwards by displacing
the flexor carpi ulnaris muscle.
In the upper part of the forearm, the ulnar artery passes obliquely to the
medial side and deep to most of the flexor muscles, including the pronator teres,
flexor carpi radialis, palmaris longus and flexor digitorum superficialis muscles.
In its middle third, it is overlapped anteriorly by the flexor carpi ulnaris and lies
upon the brachialis and flexor digitorum profundus muscles. The distal half of the
ulnar artery lies upon the flexor digitorum profundus and runs between the flexor
carpi ulnaris and flexor digitorum superficialis muscles. In this area, it is covered
only by skin, and by superficial and deep layers of fascia.
At the wrist, it enters the palm in front of the flexor retinaculum in company
with the ulnar nerve and is covered by skin, fasciae and the palmaris brevis
muscle.
Branches at the elbow

Immediately below the elbow joint, the ulnar artery gives off the anterior
and posterior ulnar recurrent arteries, branches that are the equivalent of the
recurrent branch of the RA. The anterior branch is the smaller of the two and
travels upwards between the brachialis and pronator teres muscles, supplying
71
these muscles and anastomosing with the superior and inferior ulnar collateral
branches from the brachial artery. The posterior ulnar recurrent artery arises lower
than the anterior branch, although sometimes the two arteries arise by a short
common trunk. The posterior branch passes backwards and medially between the
flexor digitorum profundus and flexor digitorum superficialis muscles and then
ascends behind the medial epicondyle of the humerus. In the region between this
point and the olecranon, it lies deep to the flexor carpi ulnaris, ascending between
the two heads of this muscle and running alongside the ulnar nerve, supplies the
neighboring muscles, bone and elbow joint, and anastomoses with the two ulnar
collateral arteries from the brachial artery as well as the interosseous recurrent
arteries.
Branches in the forearm

The ulnar artery gives off several muscular branches supplying the muscles
on the medial side of the forearm and hand as well as the common flexor synovial
sheath and the ulnar nerve. One important branch in the forearm is the common
interosseous artery, which is about a centimetre long and arises from the ulnar
artery about 2.5 centimetres from its commencement before passing backwards to
the upper border of the interosseous membrane. Here it divides into two branches,
the anterior and posterior interosseous arteries.
The anterior interosseous artery runs distally and lies anterior to the
interosseous membrane. It is accompanied by the interosseous branch of the
median nerve and overlapped by the adjacent margins of the flexor digitorum
profundus and flexor pollicis longus. It continues its course directly downwards as
far as the upper border of the pronator quadratus muscle before piercing the
interosseous membrane and anastomosing with the posterior interosseous artery. It
then descends to the back of the wrist in the compartment of the extensor
retinaculum to join with the dorsal carpal arch. At this point it gives off four
branches:
1. The median artery, which accompanies and supplies the median nerve,
arises at the beginning of the anterior interosseous artery. However, it
also often arises from the common interosseous artery. This artery is
72
sometimes greatly enlarged and runs with the median nerve into the
palm of the hand where it may join the superficial palmar arch or end as
one or two of the palmar digital arteries.
2. Muscular branches to the flexor profundus, flexor longus pollicis,

pronator quadratus muscles and to other muscles that perforate the
interosseous membrane to supply the extensors of the thumb.
3. The medullary arteries (nutrient arteries) of the radius and ulna which
enter the foramina and distribute interiorly.
4. An anterior communicating branch arises from the anterior interosseous

artery before it pierces the interosseous membrane, descending beneath
the pronator quadratus muscle to anastomose with the anterior carpal
arteries.
The posterior interosseous artery, usually much smaller than the anterior,
passes backwards over the upper border of the interosseous membrane to enter the
posterior compartment of the forearm. It appears on the back of the forearm
between the supinator and abductor pollicis longus muscles, where it gives off the
interosseous recurrent artery. The interosseous recurrent artery ascends to the
interval between the lateral epicondyle and olecranon on or through the fibres of
the supinator but deep to anconeus muscle and anastomoses with the middle
collateral branch of the profunda brachii and with the posterior ulnar recurrent and
radial recurrent arteries. The main posterior interosseous artery descends between
the superficial and deep layers of extensor muscles. It ends as a very small artery,
anastomosing with the anterior interosseous artery and with the dorsal carpal arch.
Branches in the hand

The ulnar artery divides into two carpal branches (palmar carpal and dorsal
carpal branches), two palmar branches (superficial palmar branch, deep palmar
branch) and forms anastomoses with equivalent branches of the RA.
At the wrist, there is a small palmar (anterior) and a small dorsal (posterior)
73
carpal branch. The palmar carpal branch is a very small artery. It runs laterally
across the palmar surface of the carpus while passing behind the flexor digitorum
profundus, anastomosing with the palmar carpal branch of the RA to form the
palmar carpal arch. The dorsal carpal branch, varies in size, arises immediately
above the pisiform bone and winds back under the tendon of the flexor carpi
ulnaris to reach the dorsal surface of the carpus. It then passes laterally under the
extensor tendons and anastomoses with the dorsal carpal branch of the RA,
forming the dorsal carpal arch which provides three dorsal metacarpal arteries.
Near its origin, it gives off a small branch which runs along the ulnar side of the
fifth metacarpal bone and supplies the ulnar side of the dorsal surface of the little
finger.
Anatomical Considerations for Radial Artery Harvesting

Surgical incision
Having outlined the normal arterial anatomy of the upper limb, in this
section I briefly discuss the surgical procedure used to harvest the RA, focusing in
particular on the possible anatomical risks associated with this procedure. When
harvesting the RA, the skin incision is made on the ventral surface of the forearm
above the RA along an imaginary line from the centre of the bent elbow to the
fore part of the styloid process of the radius (Fig 2.3). The first obstacles
encountered are the anterior branches of the medial and lateral antebrachial
cutaneous nerves of the forearm. The medial antebrachial cutaneous nerve, a
branch of the medial cord (C8, T1) of the brachial plexus, supplies skin on the
medial side of the forearm. The lateral antebrachial cutaneous nerve represents
the cutaneous branch of the musculocutaneous nerve, which is a branch of the
lateral cord (C5-C7). This cutaneous branch supplies the skin over the lateral half
of the anterior surface of the forearm and distributes branches which turn around
the radial border of the forearm to communicate with the posterior cutaneous
nerve of the forearm and the terminal branch of the radial nerve. If one uses the
skin incision described above, these nerves should be left intact. The median vein
(intermediate antebrachial vein) of the forearm is usually situated at, or near the
site of the incision, and can be ligated. However, venous anastomoses near the
74
elbow should be preserved to prevent forearm and hand edema. Care should also
be taken at the distal third of the forearm because the RA is very superficial where
it lies medial to the flexor carpi radialis tendon; it is only covered by skin and
subcutaneous tissue.
Surgical exposure
The second area of potential risk is in the middle third of the RA where the
superficial branch of the radial nerve runs along the lateral side of the artery (Fig.
2.4). The superficial radial is a pure sensory branch of the radial nerve. It
originates from the main radial nerve, soon after the nerve enters the forearm, and
descends from the front of the lateral epicondyle along the lateral side of the
forearm upon the supinator while running lateral to the RA and behind the
brachioradialis. In the middle third of its course it runs close to the lateral side of
the RA where it can be injured during RA harvesting. It leaves the artery about
7cm above the wrist passing deep to the tendon of the brachioradialis and winding
round the lateral side of the radius before crossing the roof of the anatomical
snuffbox. It then descends, pierces the deep fascia, and divides into five, or
sometimes four, dorsal digital nerves. It supplies a number of joints in the hand, as
well as the skin on the lateral two-thirds of the dorsum of hand, the dorsum of the
thumb and the proximal parts of the lateral one and a half digits. However even if
the superficial branch of the radial nerve is severely damaged during arterial
harvesting, the region of sensory loss is confined to a coin-shaped area distal to
the base of the first and second metacarpals. The considerable overlap of neural
supply from cutaneous branches of the median and ulnar nerves explains why the
area of anesthesia is less than expected.
The third structure at risk during this operation is the deep branch of the
radial nerve which is the larger of the two terminal branches of the radial nerve
and is a pure motor nerve. It gives off branches supplying the extensor carpi
radialis brevis and supinator muscles before piercing the supinator, winding
around the lateral aspect of the neck of the radius and entering the posterior
compartment of the forearm. At this stage the deep branch of the radial nerve
continues distally and changes its name to the posterior interosseous nerve. Soon
75
after emerging from the supinator the posterior interosseous nerve gives off: (1)
three short branches supplying the extensor digitorum, the extensor digiti minimi
and the extensor carpi ulnaris muscles; and (2) two long branches – a medial
branch which supplies the extensor pollicis longus and extensor indicis muscles,
and a lateral branch which supplies the abductor pollicis longus muscle and ends
in the extensor pollicis brevis muscle. The posterior interosseous nerve terminates
at the dorsum of the carpus, supplying the ligament and joints of the carpus. The
deep branch of the radial nerve can be injured by deep extensive retraction at the
elbow especially proximally. Severance of the deep branch of the radial nerve
results in an inability to extend the thumb and the metacarpophalangeal joints of
the other digits. Injury to the radial nerve at a higher level can cause wrist drop.
Thus, the four structures potentially at risk during RA harvesting are the
medial and lateral antibrachial cutaneous nerves, the superficial branch of the
radial nerve and the deep branch of the radial nerve. The latter structure, in
particular, is cause for concern given its role in the motor function of the hand and
wrist.
76
Figure 2.3 Radial artery harvesting. The incision was made on the ventral surface of the
forearm avoiding injury to the medial and lateral cutaneous nerves of forearm. Brachioradialis
muscle which covered the proximal two thirds of the radial artery was elevated by sharp
dissection.
Figure 2.4 Full exposure of the radial artery. The superficial branch of the radial nerve
(pure sensory nerve) lies along the lateral side of the artery.
b) Variations of the Arterial Systems of the Upper Extremities
INTRODUCTION
The major problems leading to hand ischemia following RA harvesting are:

(1) dominant RA; (2) absent ulnar artery; and (3) inadequate collateral circulation.
There are several studies describing the variations of the complex anatomy of the
hand and forearm. However, standard anatomy textbooks lack information about
crucial variations (such as the combination of an incomplete superficial palmar
arch and incomplete deep palmar arch together in the same hand). Such
information is very important when considering RA harvesting. For example,
when the superficial palmar arch is incomplete, the RA can sometimes still be
harvested safely if a complete deep palmar arch is present.
Thus, Part B of this chapter analyses arterial variations in the upper limb. In
the first section I discuss a study ¾ performed by myself and colleagues at the
Department of Anatomy and Cell Biology at the University of Melbourne ¾
examining anatomical variations in the arterial supply of the forearm and hand.
This study focused in particular on the arterial connections between the superficial
and deep palmar arches in the hand, the latter representing an important feature of
collateral circulation of the hand. In the second section I review the literature on
the arterial anatomy of the upper limb, comparing conventional anatomical
accounts and the findings of our study.
MATERIALS AND METHODS
The study was carried out on 50 randomly selected cadaver upper

extremities in the dissecting room at the Department of Anatomy and Cell
Biology at the University of Melbourne. All of the cadavers had been embalmed
soon after death. The dissection commenced with the subclavian artery and
progressed to the metacarpal branches of the superficial and deep palmar arch in
the hand. In the hand, the dissection focused on the arteries providing the major
blood supply and the communications between the radial and ulnar arteries.
Sketches and photographs were used to document the dissected specimens.
78
RESULTS
Variations in the arterial supply were organized into two categories, namely
the forearm variations and the hand variations.
Variations of forearm arteries
The incidence of forearm artery variations was 30% (15/50). There was a
high division of the brachial artery in seven extremities (14%). Three limbs
possessed superficial ulnar arteries (6%). One limb possessed a superficial RA
(2%).
One superficial dorsal branch of the RA was found. In this variation the RA
divided into two branches about 7 cm proximal to the wrist (Fig 2.5). One ran in
the normal position of the RA lateral to the tendon of the flexor carpi radialis. The
other branch, the superficial dorsal branch of the RA, ran towards the dorsal
aspect of the forearm and terminated by following the normal dorsal course of the
RA but superficial to the extensor tendons. This artery then gave off branches to
supply the thumb and form the deep palmar arch with the ulnar artery. In this
case, the RA gave off a small superficial palmar branch that did not communicate
with the ulnar artery. The superficial palmar branch of the ulnar artery supplied
the thumb and anastomoses with the RA on the dorsum of the hand.
Three median arteries were found (6%). One originated from the ulnar
artery (UA) while the other branched off the interosseous artery, ran alongside the
median nerve and terminated in the middle of the palm.
79
Figure 2.5 Superficial dorsal branch of the radial artery. SPA, superficial palmar arch;
DPA, deep palmar arch.

Radial Artery
The terminal branches of the RA at the wrist were: (1) the superficial palmar
branch of the RA; and (2) the dorsal RA. The superficial palmar branch of the RA
connected with the superficial palmar branch of the UA to form the superficial
palmar arch in 10% (5/50) of hands (Fig 2.6, a). In the remaining 90% of cases the
superficial palmar branch of the RA was absent or small (Fig 2.6, b-e) and only
supplied a minor part of the thenar muscles. The main RA passed to the dorsal
side of the hand under the abductor pollicis longus and extensor pollicis brevis
tendons. It then pierced the first interosseous space and formed the deep palmar
arch with the deep palmar branch of the UA in 94% (47/50) of hands (Fig 2.6, a,
b, c and e). In three hands there were anatomical variations of the origin of the
deep palmar arch. In these cases the RA formed the deep arch by passing through
the second interosseous space (Fig 2.7, a and b).
80
Figure 2.6 Variations of the hand collateral circulation, palmar aspect of left hand.
The black line represents the superficial palmar arch; the grey line the deep palmar arch;
and the dotted line the dorsal artery.
a. Complete (classic) superficial palmar arch: the superficial palmar arch from the ulnar
artery supplies the index finger and thumb and anastomoses with the superficial palmar
branch of the radial artery in 10% of hands
b. Complete superficial palmar arch: the superficial palmar arch from the ulnar artery
supplies the thumb. Complete deep palmar arch: the distal end of the deep palmar arch
anastomoses with the deep palmar branch of the ulnar artery.
c. Incomplete superficial palmar arch: the superficial palmar arch does not provide a
metacarpal branch to supply the thumb.
d. Incomplete deep palmar arch: no continuity is found between the deep palmar branch
of the ulnar artery and the radial artery.
e. Median artery.
81
a.
b.
Figure 2.7 The origin of the deep palmar arch in which the radial artery passes to the
palmar side via the second interosseous space.
(a) Dorsolateral aspect of the left wrist showing the origin of the deep palmar arch.
(b) Palmar aspect of the left wrist and hand.
SPA= superficial palmar arch; DPA= deep palmar arch
82
Deep palmar arch
The deep palmar arch lies on the proximal ends of the metacarpal bone and
the interossei. In our samples, two types of deep palmar arches were found: 1) a
complete deep palmar arch, and 2) an incomplete deep palmar arch.
Complete deep palmar arch. In this variation the terminal portion of the
deep palmar branch of the RA had a connection with the deep palmar branch of
the UA. This type of arch was found in 90% (45/50) of hands (Fig 2.6, a, b, c and
e).
Incomplete deep palmar arch. In this variation the deep palmar branch of
the RA did not have any connection with the UA at the deep palmar level. This
was found in 10% (5/50) of hands (Fig 2.6, d).
Ulnar artery
The UA terminated by dividing into superficial palmar and deep palmar

branches in all of the hands. The UA made no visible contribution to the dorsal
side of the hand at the level of the wrist.
Superficial palmar arch
The superficial palmar arch lies just beneath the aponeurosis palmaris and
rests upon the tendons of the flexor digitorum sublimis, its convex side facing
distally. It is formed primarily from the terminal portion of the ulnar artery. The
arch gives off four common palmar digital arteries which arise from its convex
aspect and proceed distally on the second, third and fourth lumbrical muscles and
the medial side of the little finger. Each of the palmar digital arteries is joined by
the corresponding palmar metacarpal artery from the deep palmar arch. The latter,
which is formed chiefly by the RA, then divides into a pair of proper palmar
digital arteries which run along the contiguous sides of the index, middle, ring and
little fingers. The palmar digital arteries supply nutrient branches to the phalanges
and to the metacarpophalangeal and interphalangeal joints.
83
Two types of superficial palmar arch were found:
Complete superficial palmar arch. The superficial palmar arch was defined
as complete when it supplied all the fingers and the ulnar side of the thumb. This
variation was found in 66% (33/50) of hands (Fig 2.6, a, b, d and e), (Fig 2.8).
Incomplete superficial palmar arch. This arch was defined as incomplete

when it only supplied the little, ring and middle fingers. This variation occurred in
34 % (17/50) of hands (Fig 2.6 c and Fig 2.9).
a. b.
Figure 2.8 Complete superficial palmar arch.

a. The superficial palmar arch.
All fingers including the index finger and ulnar
side of the thumb are supplied by the superficial
palmar branch of the ulnar artery.
b. Superficial palmar branch of the ulnar artery
supplies the thumb without anastomosed with
the radial artery
c. Superficial palmar branch of the ulnar artery
supplies the thumb and anastomoses with the
digital branch of the radial artery from the
dorsal aspect.
(T= thumb, SPA=superficial palmar arch,
DPA = deep palmar arch)
C.
84
Figure 2.9 Incomplete superficial palmar arch.
Only the little, ring and middle fingers,

sometime ulnar side of the index fingers are
supplied by the superficial palmar branch of
the ulnar artery.
Superficial palmar branch of ulnar artery
The distal end of the superficial palmar arch of the UA communicated with
the RA in only 34% (17/50) of hands. There were four types of this
communication between the superficial palmar branch of the UA and the RA at
the level of the arches (Fig 2.10):
a. via the superficial palmar branch of the RA (the ‘classic’ superficial palmar
arch) in 10% (Fig 2.10 a),
b. via the digital branch of the dorsal RA in 18% (Fig 2.10 b),
c. via the deep palmar arch of the RA in 4% (Fig 2.10 c),
d. via the median artery and digital branch of the dorsal RA in 2% (Fig 2.10 d).
Figure 2.10 Four types of communication

between the superficial palmar arch of the
ulnar artery and the radial artery in the hand.
a. via superficial palmar branch of RA (10%)
b. via digital branch of the dorsal RA (18%)
c. via deep palmar arch (4%)
d. via median artery and digital branch of the
dorsal RA (2%)
SPA= superficial palmar arch;

DPA= deep palmar arch
85
Median artery
A median artery was found in three cadavers (6%). One terminated at the
wrist and one anastomosed with the superficial palmar arch (Fig 2.6 e and Fig
2.11). The third median artery terminated by dividing into branches to the index
finger and thumb at the palmar side without anastomosing with the RA or UA.
a.
Figure 2.11 Median artery

a. The median artery at wrist
runs along with the median
nerve and terminates at the
wrist.
b. The median artery passes
the wrist and anastomoses
with the ulna and radial
arteries forming a superficial
palmar arch.
b.
86
Combined contributions of the ulnar and radial arteries
Even though the superficial palmar branch of the UA did not supply the
thumb in about 34% of hands, a deep palmar branch of the UA anastomosed with
the deep palmar branch of the RA in all cases. Similarly even though an
incomplete deep palmar arch was found in 10% of hands, all of these cases had a
complete superficial palmar arch.
DISCUSSION
Variations of the arteries in the forearm
Variations and anomalies of the arterial supply to the upper extremities in

humans are common and, as previously mentioned, have significant surgical
implications. A number of studies have attempted to document both the incidence
and types of arterial variations. In one of the larger studies, McCormack and
colleagues (1953)208 reported a series of 750 consecutive upper extremities from
386 adult cadavers (in 22 cadavers only one limb was available for study). The
incidence of major variations in the brachial or antebrachial arterial patterns was
18.5 % (139/750). However, considering cadavers with both extremities, the
probability of finding a major variation was 30.8% (112/364). Arterial variations
occurred bilaterally in 6.2% (23/364) and unilaterally in 24.5%. The prevalence of
right-sided variations was slightly higher than on the left. In other studies the
reported incidence of arterial variations ranges from 9% to 20%. In our series,
variations of the forearm artery were found in 30% of the limbs, possibly because
of the very detailed analysis of the forearm and presence of bilateral variations in
cadavers. Variations of the RA were the most common.
Variations of the RA can be classified into three types: (1) an RA with a

high origin; (2) the presence of a superficial RA; and (3) the absence of the RA. In
McCormack and colleagues’ study, an RA with a high origin ¾ here defined as
an RA originating proximal to the intercondylar line ¾ was found in 14.3%
208
McCormack, Cauldwell and Anson. Surg Gynaecol Obstet 1953; 96:43-54.
87
(107/750) of all specimens, that is, 77% (107/139) of all arterial variations. In
most cases, this artery represented the continuation of a persistent superficial
brachial artery with the true brachial artery branching into the other forearm
arteries in the cubital fossa. In McCormack’s series 15% (16/107) of the arteries
with high origins commenced at the axillary artery while the rest (85%) arose
from some part of the brachial artery. In our series, we found a high origin of the
RA in 14% of all specimens, that is, this ‘anomaly’ accounted for 54.5% of all
arterial variations. A superficial RA was found in only one of the limbs in our
series. The third variation of the RA, namely its absence from the forearm,209 is
rare and was not found in any of the limbs in our series. When this anomaly does
occur, the anterior interosseous artery provides the main blood supply to the hand.
The median artery is very small and the ulnar is replaced by a superficial ulnar
artery. The superficial brachial and superficial radial arteries, as well as the deep
palmar arch, are absent. Clinical examination may reveal absence of a radial pulse
at the normal site although a pulse may be present at the anatomical snuffbox. The
absence of the RA is sometimes accompanied by another limb defect such as the
absence of the radius.
Others variations also found in anatomical studies include high origin of the
ulnar artery, superficial brachial artery and the presence of an accessory brachial
artery. The overall incidence of these variations was 12.2%, 5.75% and 0.7%
respectively.210 A literature review also revealed that the superficial ulnar artery is
found in 2-3% of cases.211 In our study, it was found in 6% of the limbs examined.
209
Lippert. Arterial variations in man: classification and frequency c1985., Odero,
Chierichetti, Canidio and Savasta. Cardiovascular Surgery 1993; 1:270-2.
210
McCormack, Cauldwell and Anson. Surg Gynaecol Obstet 1953; 96:43-54.
211
Adachi. Anatomie der Japner 1928, McCormack, Cauldwell and Anson. Surg Gynaecol
Obstet 1953; 96:43-54.
88
The persistent median artery is an embryonic remnant of the axial artery of

the upper limb. In general it derives from the ulnar artery (usually via the anterior
interosseous artery) and occurs in 8% of cases.212 It is extremely rare for the
median artery to originate from the RA.213 The median artery accompanies the
median nerve which is located between the radial and the ulnar arteries. It may
terminate at the wrist or contribute to the superficial palmar arch. The contribution
of the median artery to the superficial palmar arch has been stated as ranging from
1.1% to 16.1%.214 The prevalence of a median artery was 6% in our series.
The blood supply of the hand is mainly provided by the radial and ulnar
arteries. Additional blood supply may come from the median artery ¾ which was
present in 3 of the 50 hands (6%) dissected in our study ¾ and/or the interosseous
arterial system. Normally however, the radial and ulnar arteries form four circuits
in the hand. These circuits are made up of the anterior and posterior carpal arch at
the level of the carpal bone and the superficial and deep palmar arch at the level of
the mid-palmar area, that is, three circuits in the palmar side and one circuit on the
dorsal side. The superficial and deep palmar arches are the most important of the
circuits because they provide the blood supply to all of the fingers. Figure 2.12
shows the possible anastomoses in the hand which may provide a collateral
circulation as typically demonstrated in anatomy textbooks. However, I found a
number of variations which were not included.
212
Lippert. Arterial variations in man: classification and frequency c1985.
213
Henneberg and George. J Anat 1992; 180:185-8.
214
Coleman and Anson. Surg Gynecol Obstet 1961; 113:409-424, Gray. Stanford M Bull
1945; 3:120-127, Tandler. Anat Hefte 1897; 7:263-282.
89
Figure 2.12 Typical anatomy of hand collateral circulation as conventionally

represented in textbooks. (Gabella G. Subclavian System of Arteries. In: Williams Pl,
Bannister LH, Berry MM, Collins P, Dyson M, Dussek JE, Ferguson MWJ, eds. Gray’s
th
Anatomy 28 Edition. New York, Edinburg, London, Tokyo, Madrid and Melbourne:
Churchill Livingstone; 1995:1544.; by permission of Churchill Livingstone)
I found that the collateral blood supply of the hand is complex and often
marked by variations. A number of variations of the superficial palmar arch of the
UA were detected, the most common type found in this study being the complete
superficial palmar arch (66%) and the complete deep palmar arch (90%). As
noted, even though the superficial palmar branch of the UA did not supply the
thumb in about 34% of hands, a complete deep palmar arch was present in all of
these hands, thereby enabling the RA to be safely harvested.
90
Our study confirmed the findings from a larger series reported by Coleman
and Anson in 1961.215 Of 650 hands examined, they observed a complete
superficial palmar arch in 78.5% of hands. In this series, a complete superficial
palmar arch was recorded when the superficial palmar branches of the RA and
UA anastomosed, or when the UA reached the thumb and index finger. The
classic type of superficial palmar arch (as typically demonstrated in anatomy
textbooks)216 in which the superficial branch of the RA joins the superficial
palmar arch of the UA, was found in 34.5% of hands. In our series, this classic
type of arch occurred more rarely, being found in only 10% of hands.
In contrast, in 1988, Ikeda and associates217 reported a high prevalence of

complete superficial palmar arches using the same definition (96.4% of 220
cadaver hands). They also found a higher proportion of classic superficial palmar
arches (55.9%). However, in this classic type, the contribution of the RA was
small in 34.6% of hands and equal in size in only 21.3% of hands.
Two large studies (Coleman and Anson 1961, 650 specimens and Ikeda et
al. 1988, 220 specimens) classified the superficial palmar arch as following:
Group I. Complete superficial palmar arch. As defined in our study,

when complete, the superficial palmar arch supplies palmar digital arteries to all
the fingers including the index finger and thumb. The arches found in these
studies can be subdivided into five types:
Type 1. Ulno-superficial radial arch. The superficial arch is formed by the

superficial branch of the radial and the ulnar artery. This type was found in 34.5%
(Coleman and Anson) and 55.9% (Ikeda et al.) of all specimens.
215
Coleman and Anson. Surg Gynecol Obstet 1961; 113:409-424.
216
Gray. Gray's anatomy 1995., Moore. Clinically oriented anatomy c1999.
217
Ikeda, Ugawa, Kazihara and Hamada. J Hand Surg (Am) 1988; 13:501-9.
91
Type 2. Ulnar arch. This arch is formed solely by the ulnar artery. It was
present in 37% (Coleman and Anson) and 25.5% (Ikeda et al) of cases.
Type 3. Ulno-median arch. The arch consists of the ulnar artery and
remaining median artery. It was seen in 3.8% (Coleman and Anson) and 0.9%
(Ikeda et al) of all specimens.
Type 4. Ulno-deep radial arch. In this type, the arch is formed by the ulnar
artery and a branch from the radial end of the deep palmar arch. It was observed
in 2.0% (Coleman and Anson) and 14.1% (Ikeda et al) of all cases.
Type 5. Ulno-medio-radial arch. The arch is composed of all three vessels.

This type was found in only 1.2% (Coleman and Anson) of all specimens.
These studies demonstrate that RA harvesting should have little effect on

patients who have a complete superficial palmar arch, that is, in 80-95% of cases.
However, in our series, we found complete superficial palmar arches in only
67.5% of the upper limbs examined. One observation is that in the Coleman and
Anson series, the superficial palmar branch of the RA anastomosed with the
superficial palmar arch in 34.5% of all specimens. However in our series we
found this in only 10% of all specimens. The second observation is that in the
Coleman and Anson series, they did not find any superficial palmar arch
anastomoses with the RA on the dorsal side, which we found in 18% of hands.
Group II. Incomplete superficial palmar arch. When the contributing

arteries to the superficial arch do not anastomose or when the ulnar artery fails to
reach the thumb and index finger, the arch is incomplete. This variation was found
in 21.5% (Coleman and Anson) and 3.6% (Ikeda et al) of cases, with the Coleman
and Anson series subdividing into four types of incomplete arch. The following
classification is from the Coleman and Anson series.
Type 1. Both the RA and the ulnar artery form the superficial palmar arch
but fail to anastomose. Only 3.2% belonged in this division.
92
Type 2. In 13.4% of specimens, the superficial arch is formed by the ulnar

artery alone and does not provide any blood supply to the thumb and index finger.
Type 3. The median and ulnar arteries contribute to the arch but do not
anastomose. Only 3.8% showed this pattern.
Type 4. In 1.1% of cases, the radial, ulnar and median arteries all give origin
to the superficial arch but do not anastomose.
The findings of these two large studies suggest that the presence of an
incomplete arch may complicate RA harvesting. In particular, they indicated that
on average in 13% of patients who have RA harvesting the blood supply of the
index finger and thumb will be affected by the presence of an incomplete
superficial palmar arch.
In our study we found the deep palmar arch to be variable in size. The size
of the superficial palmar arch was inversely proportional to that of the deep
palmar arch. Coleman and Anson found a complete deep palmar arch in which the
deep branch of the RA anastomosed with the deep branch of the UA in 97% of
hands. Ikeda and associates found a complete deep palmar arch in 76.9% of
hands. In our series we found this type of arch in 90% of hands. In contrast, in
1994, Mezzogiorno and colleagues218 found that the deep palmar arch was formed
by the RA and UA in only 66.7% of 60 hands. In 21.7% of hands, the deep palmar
arch was formed by the RA and an anastomotic branch formed a digital artery.
The deep palmar arch was formed solely by the RA or the UA in 8.3% and 3.3%
of cases, respectively.
In the case of the incomplete deep palmar arch (found in 10% of the hands
in our study) all had complete superficial palmar arches. This implies that the
thumb received its blood supply from the UA at the ulnar side and that the RA
could be removed without endangering the circulation of the hand.
93
In 1978, Parks and colleagues219 published a study of the variations of the

arterial supply of the thumb in 50 cadaver hands. They found that in 80% of
hands, the arterial supply of the thumb usually came from the first palmar
metacarpal artery (the first branch of the deep palmar arch of the RA). In 5% of
hands, a branch of the second palmar metacarpal artery formed the main artery of
the thumb. The first dorsal metacarpal artery, which is a branch of the RA at the
dorsal side, was the main artery to the thumb in 15% of hands. This latter result
was consistent with our finding that 18% of hands had a digital branch of the
dorsal RA, which supplied the thumb and anastomosed with the superficial palmar
arch.
In 1999, Olave and Prates220 reported the findings of an anatomical study of

both hands in 30 cadavers. In 13.3% of the hands the deep palmar arch was
formed by the RA passing through the second interosseous space, a variation we
found in 6% of cases in our series. However, the significance of this variation in
RA harvesting is minimal because the RA and UA both contribute blood supply to
the arch.
My study is unique in that the anastomoses between the RA and UA have

been documented and correlated in individual hands. The major finding from the
series of 50 hands examined was that there were no cases of an incomplete
superficial and deep palmar arch being present in the same hand. From an
anatomical perspective, this study confirms that it is safe to remove the RA from
its origin proximally to the level of the wrist distally. It should be noted, however,
that in patients with coronary artery disease, vascular disease affecting the upper
218
Mezzogiorno, Passiatore and Mezzogiorno. Acta Anat 1994; 149:221-4.
219
Parks, Arbelaez and Horner. J Hand Surg (Am) 1978; 3:383-5.
220
Olave and Prates. Surg Radiol Anat 1999; 21:267-71.
94
extremities may be present. In 1999, Rauch and colleagues221 reviewed 66 upper

extremities from 60 patients who underwent angiography prior to skin/muscle
transplantation (63.6% of hands), creation of a hemodialysis fistula (6.1%), or
evaluation of vascular diseases (30.3%). Classic superficial palmar arches and
deep palmar arches were detected in 31.8% and 84.8% of the patients,
respectively. These findings suggest that patients with coronary artery disease
should be screened before RA harvesting in order to confirm the presence of a
viable collateral circulation.
Thus, despite the findings of previous studies, our study demonstrated that,
from an anatomical point of view, removing one artery from the arm down to the
wrist level is safe in the majority of cases. There is, however, one situation in
which RA harvesting may cause problems. In 10% of cases in our series ¾ the
RA gives off a superficial palmar branch and runs down to join with the
superficial palmar arch from the ulnar artery. In this situation, the RA sometimes
bifurcates early at a point 3-4 cm proximal to the radial styloid (superficial dorsal
branch of the RA). It also may originate in the mid or proximal parts of the
forearm. The superficial dorsal branch of the RA is present in about 3% of cases.
This connection should not be divided because it might provide an important
anastomosis between the radial and ulnar arteries. It seems that when one
connection between these two arteries is well developed, the other connection will
be less developed or absent.
While my results suggest the overall safety of RA harvesting it must be

noted that my study suffers from two limitations. Firstly, I studied the
anastomoses between the radial and ulnar arteries only at the level of the palmar
arches. Therefore, while I may have designated an arch as incomplete, it may have
possessed anastomotic connections at the level of the digital circulation. Secondly,
even though there is always an anatomic connection between the two arterial
221
Rauch, Fischer, Achenbach, Klose and Wagner. Rofo Fortschr Geb Rontgenstr Neuen
1999; 171:207-10.
95
systems, such as that between the deep palmar arch of the RA and the superficial
palmar arch of the UA, it is possible that these anastomoses may be insufficient.
Thus, despite the presence of an anatomic collateral circulation, the blood supply
may still be compromised when a RA is removed. The other possible limitation
however is that the small anastomoses between the two systems may enlarge after
the RA is harvested, thereby compensating for any initial reduction in the blood
supply to the hand.
CONCLUSION
This chapter sought to demonstrate: 1) the feasibility, from a surgical

perspective, of extracting the RA for use as a coronary bypass graft; and 2) the
relative safety of RA harvesting in the face of considerable variations in the
arterial anatomy of the upper limb. In particular, the discussion showed that it is
important for surgeons to have a knowledge of the arterial supply and its
variations over and above that of standard anatomical textbooks. Such knowledge
is not only important for safety reasons but can also produce other benefits. For
instance if recognized, a common variation such as a RA with a high origin can be
useful in terms of being able to harvest a RA which is long enough to reconstruct
two or three target coronary arteries.
One of the possible problems associated with RA harvesting is impaired

hand circulation. However, the anatomical study conducted with my associates
showed that the anastomoses between the superficial and deep palmar arch are
complex and varied. Generally we found some degree of collateral circulation
between the radial and ulnar arteries in all of the hands in the study suggesting, at
least at a gross anatomic level, that in the majority of cases it is safe to harvest one
artery from the forearm. There are two concerns: (1) some previous data showed
that in some forearms and hands the ulnar artery is non-dominant and therefore
unable to provide an adequate alternative blood supply; (2) even though some
form of collateral circulation is usually present, in the case of an incomplete
superficial or deep palmar arch, these anastomoses may be minimal. Furthermore,
the degree and quality of hand collateral blood supply is not just determined by
anatomical factors, but also can be affected by the presence of trauma or disease
96
in the ulnar artery or the arteries in the hands and adaptation to blood flow and
pressure.
In Chapters 6 and 7 I examine the efficacy of various screening devices for

assessing the collateral circulation of the hand preoperatively.
One of the major concerns discussed in this chapter, and which runs through
the thesis as a whole, is the question of the suitability of the RA as a bypass
conduit. In this chapter I have demonstrated its suitability from the point of view
of surgical anatomy. In the next three chapters, I discuss this issue in relation to
the histology and histopathology of the RA.
97
Chapter 3
Vascular Histology and Histopathology
Introduction
The Structure of Blood Vessels
Tunica intima
Tunica media
Tunica adventitia
Arteries
Elastic artery
Muscular artery
Mixed artery
Histopathology of the Radial Artery
Adaptive Intimal Thickening

Atherosclerosis
Medial Calcification
Summary
Vascular Histology and Pathology of the RA 97
Introduction
As noted in my first chapter, one of the reasons that the use of radial artery
(RA) for coronary artery bypass grafting (CABG) was abandoned in 1976 was the
fact that evidence of concentric intimal hyperplasia was found in the RA at
reoperation.222 Following the revival of interest in the RA for coronary artery
bypass grafting in the early 1990s, there were further reports of pathology in the
grafted RA. However, one of the problems with these studies was that the
definitions of normal versus diseased vessels used were unclear. In this chapter
then, I discuss the histology of arteries, the differences between normal and
diseased vessels and the classification of the various types of arterial disease.
The Structure of Blood Vessels
The early development of blood vessels begins in the mesenchymal or

mesoderm germ layer. The first stage of development occurs when a group of
mesenchymal cells become arranged so as to enclose a space. These cells become
endothelial cells, their edges merging with those of adjacent cells until the
endothelium forms a continuous membrane. In the formation of an artery
mesenchymal cells on the periphery of the developing endothelial tube become
arranged so that they loosely encircle the tube. These mesenchymal cells
differentiate into a type of cell which will eventually have the characteristics of a
smooth muscle cell. This type of cell is generally accepted as being responsible
for the production of elastin and probably other intercellular substances in the
media and intima of a developing artery. The outer cells which form the adventitia
resemble ordinary connective tissue cells rather than smooth muscle cells. Mature
vessels, apart from precapillaries, follow a common plan of organization. Each
specific type of vessel merely shows adaptations for particular purposes.
Accordingly, every typical blood vessel wall consists of three layers: (1) the
tunica intima (the innermost layer), (2) the tunica media (the middle layer) and (3)
222
Curtis, Stoney, Alford, Burrus and Thomas. Ann Thorac Surg 1975; 20:628-35.
Vascular Histology and Pathology of RA 107
the tunica adventitia. In this section, I focus specifically on the structural

organization of arteries (Figure 3.1).
Figure 3.1 Structural organization of the artery: Intima, Media and Adventitia
Tunica intima
The intima is defined as the region of the arterial wall from the endothelial
surface of the lumen up to but not including the internal elastic lamina. An
endothelial layer, resting upon a thin basement membrane, bounds the lumen. The
subendothelial layer, underlying the endothelium, is composed of delicate fibro-
elastic tissue which is mostly longitudinal.
Tunica media
The internal elastic lamina which consists of a longitudinally dispersed layer

of elastic fibres is generally accepted as a part of the media. It is typically a
fenestrated membrane that allows substances to diffuse to and nourish cells deep
in the vessel wall. The primary constituent of the tunica media is smooth muscle,
which is arranged circularly. Elastic fibres are also commonly present, but occur
in variable quantities. They are arranged in one or more fenestrated layers
separated by alternating layers of smooth muscle cells. The outer limit of the
media consists of a poorly defined condensation of the elastic tissue termed the
external elastic lamina. In general the media is poorly vascularized. Thus the inner
smooth muscle layers depend largely on direct diffusion from the vessel lumen for
their nutritional needs. The middle portion receives its blood supply through small
vessels (vasa vasorum) in the media and the outer layer is nourished by diffusion
100
of nutrients from adventitial vessels.223 The contribution of each source depends

on the thickness of the vessel. For example, blood vessels thinner than 0.5 mm
have few, if any, small vessels in the media224 and must be nourished entirely by
diffusion from the lumen or adventitial vessels. Vessels thicker than 0.5 mm, such
as the thoracic aorta of large animals, usually have small vessels in the outer
layers of the media.225
Tunica adventitia
External to the media, the adventitial layer is composed of moderately

compact fibro-elastic tissue whose fibres take a predominantly longitudinal (or
loose spiral) course. It merges with the surrounding connective tissue. Arteries
more than 1 mm in diameter have nutrient arteries, termed vasa vasorum (vessels
of vessel). They supply and are mostly limited to the adventitia. Lymphatics are
also present in the walls of larger arteries. Unmyelinated nerve fibres, known as
vasomotor fibres, form networks beneath the adventitia and terminate on the
smooth muscle of the media. Myelinated sensory fibres arborize in the adventitia.
Arteries
Arteries can be classified into three types based on the major component in
the medial layer.
Elastic artery
The media constitutes the bulk of the wall and consists chiefly of
concentrically arranged fenestrated laminae of elastin similar to the internal elastic
lamina which separates the intima and media (Figure 3.2). Large arteries are
223
Heistad, Armstrong and Amundsen. Am J Physiol 1986; 250:H434-42, Heistad,
Marcus, Larsen and Armstrong. Am J Physiol 1981; 240:H781-7, Werber and Heistad. Am J
Physiol 1985; 248:H901-6.
224
Geiringer. J Pathol Bacteriol 1951; 63:201-211.
225
Wolinsky and Glagov. Circ Res 1967; 20:409-421.
101
predominantly elastic arteries, such as the aorta, however smaller arteries such as
the internal thoracic artery, popliteal artery, intercostal artery and the tibial artery
may contain many elastic lamellae thereby resembling larger arteries.
Figure 3.2 Elastic artery

(Internal thoracic artery)
There are multiple dark
staining elastic lamella.
Muscular artery
Here the media is a fairly thick layer. It consists only one elastic lamina and
mainly of circular smooth muscle fibres held together to form a cohesive whole by
reticular, collagenic and delicate elastic fibres (Figure 3.3). The proportion of
intercellular substance in relation to smooth muscle varies with the size of the
vessel; hence the media of a small vessel is mostly smooth muscle, whereas that
of a large muscular artery may contain much elastin. Examples of muscular
arteries are the RA, celiac artery, and external iliac artery.
102
Figure 3.3 Muscular artery

(Radial artery)
There is a single internal
elastic lamina.
Mixed artery
This type is the intermediate form of the elastic and muscular artery such as
the axillary artery, external carotid artery and common iliac artery.
Histopathology of the Radial Artery
The definitions of intimal hyperplasia and atherosclerosis used in this thesis

are based on a report from the Committee on Vascular Lesions of the Council on
Atherosclerosis, American Heart Association.226 The aim of this section is to
summarize all of the definitions and define the clinical importance of these
pathologies.
Adaptive intimal thickening
The arteries of all human beings normally have regions in which the intima
is thicker than elsewhere. The thick regions are present from infancy are self-
limited in growth and do not obstruct blood flow at any age. They are defined here
to allow separation from atherosclerotic and other vascular disease. The thick
226
Stary, Blankenhorn, Chandler, et al. Arterioscler & Thromb 1992; 12:120-34, Stary,
Chandler, Dinsmore, et al. Arterioscler Thromb Vasc Biol 1995; 15:1512-31, Stary, Chandler,
Glagov, et al. Circulation 1994; 89:2462-78.
103
regions represent physiological adaptations of the artery to local changes in blood

flow or wall tension. Adaptive intimal thickening can be classified into two
patterns: (1) eccentric and (2) diffuse.227 However the two patterns may be
contiguous and therefore cannot be clearly delineated from each other.
Eccentric thickening is a focal increase in the thickness of the intima

associated with branches and orifices. At an arterial bifurcation the thickening
involves about half the circumference of the parent and daughter vessels and
extends for a short distance along the length of a bifurcation.228
Diffuse thickening is a spread-out and often circumferential pattern of

adaptive intimal thickening not clearly related to specific geometric configurations
of arteries.
a. b. c.
Figure 3.4 Intimal hyperplasia, a. Eccentric intimal hyperplasia, b. Eccentric intimal

hyperplasia at the branch of the artery (arrow), c. Diffuse intimal hyperplasia
Various terms have been used to describe intimal thickening of the eccentric
type including: intimal cushion, spindle cell cushion, intimal pad, musculoelastic
227
Stary. Virchows Archiv - A, Pathological Anatomy & Histopathology 1992; 421:277-
90.
228
Wright. Nature 1968; 220:78-9.
104
plaque, localized fibrous plaque, mucoid fibromuscular plaque, normal intimal

cell mass and focal intimal hyperplasia, while the diffuse pattern is sometimes
called diffuse intimal fibrosis. Many authors have not distinguished between the
eccentric and diffuse patterns but have included them within general terms such as
musculoelastic intimal thickening, fibromuscular intimal thickening and intimal
fibromuscular hypertrophy. In this thesis I have employed the terms intimal
hyperplasia or intimal thickening.
Even though adaptive intimal thickening is considered a normal response to

physiological stimuli, in laboratory animals, areas of adaptive intimal thickening
have been found to differ functionally from adjacent regions without thickening.
The turnover of endothelial cells, smooth muscle cells, and the concentrations of
lipoproteins and other plasma components are greater in adaptively thickened
regions of intima than in adjacent regions without thickening.
The relationship between adaptive intimal thickening and atherosclerosis is

that when there are excessive levels of plasma lipoprotein lipid tends to
accumulate mainly in the sections of intima with adaptive intimal thickening.
The colocalization of intimal thickening by lipids has led to the view that
intimal thickening is part of the atherosclerotic process. However, if intimal
thickening is accepted as a self-limited physiological response to hemodynamic
forces in specific artery locations, then the development of a lesion refers only to
changes that are superimposed. The hemodynamic forces cause thickening
whether or not high concentrations of atherogenic lipoproteins are present.
However when atherogenic plasma lipoproteins exceed critical levels, the same
forces enhance lipoprotein accumulation in the same locations, leading to
atheroma.
Atherosclerosis
Atherosclerosis is a disease of the medium and large-sized muscular arteries

(e.g., the coronary, carotid arteries, and the arteries of the lower extremities), and
the elastic arteries, such as the aorta and iliac vessels. The basic lesion – the
atheroma or fibrofatty plaque – consists of a raised focal plaque within the intima,
105
having a core of lipid (mainly cholesterol, usually complexed with proteins and
cholesterol esters) and a covering fibrous cap. The Committee on Vascular
Lesions of the Council on Arteriosclerosis, American Heart Association (1995)
classifies atheroscleosis into 8 types based on the histological and histochemical
composition as well as the structure and ultrastructure of both the cell and matrix
components of the lesions (Table 3.1).229 The composition of the 8
morphologically characteristic types of atherosclerotic lesions are described in the
sequence in which they may evolve in the course of a human life. In the first three
decades, the composition of the lesions is predominantly lipidic and relatively
predictable. In the fourth decade and subsequently, the composition of advanced
lesions becomes unpredictable because some continue to increase by mechanisms
additional to lipid deposition.
Type I and II lesions, sometimes combined under the term early lesions, are
generally the only ones which occur in infants and children, although they also
occur in adults. Both type I and type II lesions represent small lipid deposits in the
arterial intima. Type I lesions consist of the first microscopically and chemically
detectable lipid deposits in the intima and cell reactions associated with such
deposits. Type II lesions include those lesions generally referred to as fatty
streaks, which on gross inspection may be visible as yellow-colored streaks,
patches, or spots on the intimal surface of arteries. Such lesions do not obstruct or
modify blood flow. Type III lesions may evolve soon after puberty and, in their
composition, are intermediate between fatty streaks (type II) and atheroma
(typeIV). In this classification, the term advanced lesion is used as an umbrella
term for lesions beyond type III. Advanced lesions of type IV are frequent from
the third decade while lesions more advanced (type V-VIII) typically occur from
the fourth decade of life. Destruction and deformity of a part of the intima are
used to classify a lesion as advanced. In type IV, destruction of the intima is
caused almost solely by mean of a mass of extracellular lipid localized deep in the
intima (the lipid core); when an additional fibrous component forms it becomes
229
Stary, Chandler, Dinsmore, et al. Arterioscler Thromb Vasc Biol 1995; 15:1512-31.
106
type V (Fig 3.5). Type VI is type V with a complication, for example hemorrhage,
thrombosis, or erosion. In type VII, the lesion is largely calcific and in type VIII it
is predominantly fibrotic.
a. b.
Figure 3.5 Atherosclerosis in the radial artery a. Type V fibroatheroma demonstrated

fibrous cap and calcification (Haematoxylin-eosin´20 original magnification), b. High
magnification of atherosclerosis shows cholesterol cleft (Haematoxylin-eosin´40 original
magnification).
107
Table 3.1 Terms and cross-sectional diagrams of arteries used to designate different
types of human atherosclerotic lesions in pathology
Modified from Stary HC, Chandler AB, Dinsmore RE, Fuster V, Glagov S, Insull W,
Rosenfeld ME, Schwartz CJ, Wagner WD, Wissler RW. A definition of advanced types of
atherosclerosis lesions and a histological classification of atherosclerosis. A report from
the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart
Association. Circulation 1995; 92: 1355-74.
Nomenclature and main Sequences in Earliest Clinical

histology progression onset correlation
Type I (Initial) lesion
isolated macrophage foam cells
from
first
Type II (fatty streak) lesion decade
mainly intracellular lipid clinically

accumulation silent
Type III (intermediate) lesion
Type II changes & small

extracellular lipid pool
from
third
decade
Type IV (atheroma) lesion
Type II changes & core of

extracellular lipid
Type V (fibroatheroma) lesion

clinically
lipid core & fibrotic layer, or silent or
multiple lipid cores & fibrotic overt
layers, or mainly calcific, or from
mainly fibrotic fourth
decade
108
Type VI (complicated) lesion
Surface defect, hematoma-

hemorrhage, thrombus
“Medial calcification” is synonymous with “Mockenberg’s arteriosclerosis”

or “medial calcific sclerosis”. It is characterized by ring like calcifications within
the media of medium-sized to small arteries of the muscular type (Figure 3.6).230
Although medial calcification may occur together with atherosclerosis in the same
individual, or in the same vessel, the two disorders are totally distinct
anatomically, clinically, and presumably etiologically. The vessels most severely
affected are the femoral, tibial, radial, and ulnar arteries, and the arterial supply of
the genital tract in both sexes. The pathogenesis is still obscure, but according to
prevailing concepts, medial calcification is related to prolonged vasotonic
influences. In animals, analogous medial calcifications can be produced by the
prolonged intravascular infusion of vasoconstrictors such as epinephrine and
nicotine.
Figure 3.6 Medial calcification:

shows calcification within the media
Haematoxylin-eosin´20
(original magnification)
230
Fuessl, Schalzky, Schewe, Frey and Goebel. Klin Wochenschr 1985; 63:211-6,
Lachman, Spray, Kerwin, Shugoll and Roberts. Am J Med 1977; 63:615-22.
109
SUMMARY
In this chapter, I defined the terms used in histopathology of arteries:

“normal”, “intimal hyperplasia”, “atherosclerosis”, and “medial calcification”. In
the next chapter, I investigate the histopathology of the RA in a coronary artery
disease population in order to determine whether the RA is suitable for use as a
conduit for coronary artery bypass grafting.
110
Chapter 4
Comparative Histopathology of the Radial Artery
versus the Internal Thoracic Artery and
Clinical Predictors for Development of Intimal Hyperplasia
and Atherosclerosis
(a) Comparative Histopathology of the Radial Artery versus the

Introduction
Materials and Methods
Patients
Histopathology
Morphometric Analysis
Statistical Analysis
Results
Histopathology
Risk factors
Intimal hyperplasia and atherosclerosis
Medial calcification
Discussion
Histopathology
Prediction of Intimal Hyperplasia and Atherosclerosis
Conclusion
(b) Selection Criteria for the Radial Artery for Coronary Artery
Bypass Grafting
SUMMARY
Comparative Histopathology and Risk Factors 112
In this chapter, I present two related studies ¾ conducted by myself and a

number of colleagues ¾ which sought to investigate the histopathology of the
radial artery (RA). The chapter is divided into two sections, the first is a
comparative study of the radial and internal thoracic arteries while the second
focuses on an investigation of clinical risk factors for RA disease and selection
criteria for the RA for coronary artery bypass grafting.
(a) Comparative Histopathology of the Radial Artery versus the

Introduction
The internal thoracic artery (ITA) is generally accepted as the conduit of

choice for coronary artery bypass grafting due to its biological properties, and
excellent long-term graft patency. In 1990, Jacques van Son compared
morphology of various arterial conduits, ITA, right gastroepiploic artery, inferior
epigastric artery and RA in 17 patients (aged 15 to 85 years, mean 64 years) who
died of nonvascular disease.231 Atherosclerosis was absent or mild in all four
conduits. Intima-media thickness in the ITA and right gastroepiploic artery did not
differ from that in the left anterior descending artery. However, the intima-media
thickness in the RA and inferior epigastric artery was much greater than in the left
anterior descending artery. In 1993, Son performed serial sections of the ITA from
11 individuals who had died of noncardiac disease.232 Most of the ITAs
demonstrated an alternating histological pattern in the media, that of the proximal
and distal segments being elastomuscular and that of the mid segment being
elastic. The vessel with purely muscular media had a higher degree of intimal
hyperplasia than those with an elastic or elastomuscular media.
231
van Son, Smedts, Vincent, van Lier and Kubat. J Thorac Cardiovas Surg 1990; 99:703-
7.
232
van Son, Smedts, de Wilde, et al. Ann Thorac Surg 1993; 55:106-13.
112
The prevalence of atherosclerosis and the risk factors for the development of
intimal disease in the RA in patients who have coronary artery disease have not
been widely investigated. The aim of this study was to compare the prevalence of
disease and degree of intimal disease by morphometric analyses in the RA and
ITA in a group of patients in whom both arteries were harvested for coronary
artery bypass grafting (CABG). Prospective population studies investigating the
risk of coronary, cerebrovascular and peripheral vascular events suggest that
atherosclerotic manifestations in different arterial beds have different risk factor
profiles.233 Therefore the association between potential clinical risk factors for
intimal hyperplasia and atherosclerosis of the RA was examined.
MATERIALS AND METHODS

Patients
Paired segments of RAs and ITAs were obtained from 150 patients who
underwent CABG between May 1995 and October 1997. Their ages ranged from
42 to 83 years (average 66 yrs). There were 132 males (88%) and 18 females
(12%). All patients underwent myocardial revascularization using ITAs and RAs.
Initially, the specimens were obtained after intraluminal hydrostatic dilatation
with papaverine in an attempt to maintain physiologic distension prior to formalin
fixation. This was abandoned because double clamping of short arterial segments,
required in this technique, produced unacceptable distortion. Even single
clamping, required for surgical excision, distorted some specimens making them
unsuitable for morphometry. Also, it has been shown that there is no significant
difference in the combined width of the intima and media in arteries fixed in a
flaccid state or at a pressure of 100 mmHg. The vessels used in this study were
discarded distal segments of RA and ITA grafts which were approximately five
mm to one cm long. A total of 300 RAs and ITAs were evaluated. The potential
risk factors for atherosclerosis considered were: age, gender, diabetes mellitus,
233
Salonen, Puska and Kottke. Eur Heart J 1981; 2:365-73, Salonen, Puska, Tuomilehto
and Homan. Stroke 1982; 13:327-33, Salonen and Salonen. J Intern Med 1994; 236:561-6.
113
history of cigarette smoking, hypertension, peripheral vascular disease (PVD),

cerebrovascular disease (CVD) and hypercholesterolemia.
Histopathology
One hundred and fifty paired distal segments of RA and ITA were fixed in
4% formaldehyde solution. Multiple transverse slices of the vessels were
processed to paraffin wax. Sections were cut at 5mm and all were stained with
hematoxylin-eosin and Verhoeff Van Gieson’s elastin stain. The slides were
examined by a pathologist blinded to the clinical data. Vessels were recorded as
normal if there was no cellular or stromal tissue between the endothelium and the
internal elastic lamina (Fig. 4.1). Vessels with any fibrous tissue and/or any
myointimal cells between the endothelium and the internal elastic lamina were
recorded as showing intimal thickening (Fig. 4.2, 4.3). Medial calcification was
recorded if present. An atherosclerotic lesion was defined by the presence of
intimal lipid lying free as cholesterol clefts or in aggregates of foamy
macrophages (Fig. 4.4, 4.5). Any atherosclerotic lesion present was categorized
according to Stary’s classification of vascular lesions (see Table 3.1).234
234
114
Figure 4.1 Normal radial artery with characteristic

single internal elastic lamina. The intima is a very thin
layer consisting mainly of endothelium resting on the
internal elastic lamina.
Verhoeff Van Gieson’s elastin ´ 20 (original

magnification)
Figure 4.2 Radial artery with mild concentric non-

atheromatous intimal thickening. The lumen of this
large vessel is only slightly narrowed.

magnification)
Figure 4.3 Internal thoracic artery showing mild non-

atheromatous intimal thickening. The internal elastic
lamina is focally discontinuous. The multiple elastic
laminae within the media are characteristic of the
internal thoracic artery.

magnification)
115
Figure 4.4 Radial artery with severe atheromatous

narrowing and focal medial calcification (black arrow).
Free lipid with cholesterol clefts is present in the base
of the atheromatous plaque (empty arrows).
Haematoxylin-eosin´25 (original magnification)
Figure 4.5 Detail of an atheromatous plaque in the

intima of a radial artery. Foam cells (arrow) are
present with scattered narrow cholesterol clefts in a
fibrous background.
Haematoxylin-eosin´70(original magnification)
For the purposes of quantitative measurement we excluded 40 pairs of

specimens which were either distorted by the surgical or pathological preparation
(38 patients), or, accompanied by incomplete risk factor data (2 patients). One
hundred and ten pairs of arteries were suitable for morphometric analysis. The
morphometric measurement of both arteries was analyzed by a Color Image
Analysis System (Video Pro 32, Leading Edge Pty Ltd.). The internal elastic
lamina circumference (IELC), intimal area, medial area, width of the intima and
width of the media were measured. The diameter internal to the media
(lumen+intima) (DLI) and the internal elastic lamina area (luminal area+intimal
116
area) (IEL area) were calculated (DLI = IELC/p, IEL area = IELC2/4p).
Previous investigators have suggested that the intima-to-media ratio is the

most sensitive method available for grading atherosclerosis.235 In this study 3
methods were used to evaluate the degree of intimal thickening and
atherosclerosis: (1) percentage of luminal narrowing, (2) intimal thickness index
(ITI) and (3) intima-to-media ratio (IMR) (Fig. 4.6). The severity indices were
calculated from the most severely diseased section of the specimens. The
following formulae were used:
% of luminal narrowing = 100´Intimal area / Internal elastic lamina area
Intimal thickness index = Intimal area / Medial area
Intima-to-media ratio = Width of intima at maximal intimal thickness/

Width of media at maximal intima thickness
235
Kaufer, Factor, Frame and Brodman. Ann Thorac Surg 1997; 63:1118-22, Kay, Korns,
Flemma, Tector and Lepley. Ann Thorac Surg 1976; 21:504-7, Kobayashi, Kitamura, Kawachi, et
al. Surgery Today 1993; 23:697-703, Malhotra, Bedi, Bazaz, Jain and Trehan. Ann Thorac Surg
1996; 61:124-7.
117
Figure 4.6 Schematic diagram depicting the indices used to evaluate the severity of
intimal hyperplasia and atherosclerosis in the radial artery and the internal thoracic artery.
Morphometric measurements
1. Circumference of internal elastic lamina (IELC) (Internal elastic lamina separates
intima from the muscular media)
2. Medial area – area between internal and external elastic lamina (external elastic
lamina separates media from adventitia), width of media also measured.
3. Width of intima – the distance between the inner surface of the endothelium and the
internal elastic lamina.
Calculated measurements
1. Diameter internal to the media (DLI) = IELC/p
2
2. Internal elastic lamina area (area of intima plus area of lumen) = IELC /4p
Statistical methods
The difference between the histopathology and the morphometric

parameters for paired specimens of RAs and ITAs were analyzed by McNemar’s
test and paired t-test, respectively. A P value of less than 0.05 was considered
significant.
Correlations between pairs of continuous variables were evaluated using

Spearman’s correlation coefficients (rho). The comparison of the severity of
intimal hyperplasia and atherosclerosis in the RA, with or without medial
calcification, was evaluated by two sample t- tests.
118
Eight clinical risk factors for intimal hyperplasia and atherosclerosis (age,
gender, smoking, diabetes, hypertension, peripheral vascular disease,
cerebrovascular disease and hypercholesterolemia) of the RA and the ITA were
included in stepwise linear regression analyses as independent variables.
Percentage of luminal narrowing, intimal thickness index, and intima-to-media
ratio were analyzed as dependent variables. For each regression model we
calculated the percentage of variation in the dependent variable explained by the
model. This is a standard measure of the usefulness of the model. If this
percentage is high, the model can predict most of the variation in the dependent
variable; if it is low, although the model may be useful, a large part of the
variation in the dependent variable is explained by other factors. Logistic
regression analysis was used to identify risk factors for medial calcification in
RAs.
RESULTS
Histopathology (n=150 paired segments)
Intimal hyperplasia was seen in 94% of RAs and 68.7% of ITAs (P<0.001,
McNemar's test). Atherosclerosis was found in 5.3 % of RAs and 0.7% of ITAs
(P=0.04). All of the atherosclerotic lesions were type V (fibroatheroma); pure
lipid plaques were not seen. Medial calcification was found only in RAs (20/150,
13.3%).
Morphometric Analysis (n=110 paired segments)
Morphometric measurement showed that the DLI, IEL area, intimal area,
medial area, width of the intima and width of the media were significantly greater
in the RA compared with the ITA (all P<0.001) (Table 4.1). The means of the
indices of intimal hyperplasia and atherosclerosis (percentage of luminal
narrowing, ITI and IMR) in the RA were statistically higher than in the ITA
(Table 4.2).
119
Table 4.1 Comparative morphometry of the radial and the internal thoracic arteries
(n = 110 pairs)
Radial Artery Internal Thoracic Artery
Variables Range Mean SD Range Mean SD P Value
DLI (mm) 0.91-3.06 2.03 0.45 0.72-2.53 1.47 0.36 <0.001
IEL area 0.65-7.34 3.38 1.44 0.41-5.04 1.79 0.89 <0.001

(mm2)
Intimal area 0.15-3.30 0.70 0.52 0.05-1.13 0.19 0.15 <0.001

(mm2)
Medial area 0.71-5.25 2.80 0.90 0.47-3.62 1.31 0.56 <0.001

(mm2)
Width of 0.054-1.63 0.27 0.26 0.01-0.52 0.08 0.07 <0.001

intima (mm)
Width of 0.10-0.85 0.41 0.14 0.10-0.60 0.26 0.08 <0.001

media (mm)
DLI–Diameter internal to media (lumen+intima); IEL area–Internal elastic lamina area

(luminal area+intimal area); SD-Standard deviation
Table 4.2 Severity indices of intimal hyperplasia and atherosclerosis of the radial and
internal thoracic arteries
Severity Radial Artery Internal Thoracic Artery
indices Range Mean SD Range Mean SD P Value
% LN 6-66 21 11 5-34 11 6 <0.001
ITI 0.06-1.71 0.26 0.22 0.06-0.56 0.15 0.80 <0.001
IMR 0.09-10.90 0.85 1.38 0.03-2.73 0.36 0.37 =0.001
% LN–Percentage of luminal narrowing, ITI–Intimal thickness index, IMR–Intima-to-media

ratio
The correlation of the severity indices of the RA and ITA are summarized in
Table 4.3. There was a weak correlation between the percentage of luminal
narrowing of the RA and the ITA from the same patients (rho = 0.28, P<0.01).
120
Table 4.3 Correlation of the severity indices of intimal hyperplasia and

atherosclerosis of the radial and internal thoracic arteries
Radial artery Internal thoracic artery
% LN ITI %LN ITI
ITI rho=0.67 1 rho = 0.59 1
P<0.01 P<0.01
IMR rho = 0.56 rho = 0.74 rho = 0.54 rho = 0.73
P<0.001 P<0.01 P<0.01 P<0.01

ratio
Comparisons were made between RAs with (n=14) and without (n=96)
medial calcification. For each of the three indices of intimal hyperplasia and
atherosclerosis there were no significant differences between the two groups (P >
0.5 for all three indices). However, the median levels of intimal hyperplasia were
generally lower in the group with medial calcification (Table 4.4).
Table 4.4 Comparison of severity of intimal hyperplasia and atherosclerosis in the

radial arteries with and without medial calcification
Severity RA without medial RA with medial P value Using Log

indices calcification (n=96) calcification (n= 14) (dep. variables)
median median
% LN 18.7 15.1 0.6
ITI 0.21 0.21 0.6
IMR 0.50 0.44 0.8

ratio
Risk factors (n=110 pairs)
Intimal hyperplasia and atherosclerosis

Table 4.5 summarizes the clinical features which were investigated as risk
factors for intimal hyperplasia and atherosclerosis. The patient’s ages ranged from
121
42 to 81 years (average 66, SD 9 yrs).
Table 4.5 Clinical characteristics of 110 patients
Patients characteristic N (%)
Gender Male 98 (89.1%)
Female 12 (10.9%)
Smoking Never smoked 37 (33.6%)
Previous 69 (62.7%)
Current 4 (3.6%)
Diabetes None 83 (75.5%)
Diet control 8 (7.3%)
Oral hypoglycemic drugs 17 (15.5%)
Insulin injection 2 (1.8%)
Hypertension 55 (50%)
Peripheral vascular disease (PVD) 19 (17.3%)
Cerebrovascular disease 11 (10%)
Hypercholesterolemia 53 (48.2%)
The results of stepwise regression analyses on risk factors of intimal

hyperplasia and atherosclerosis in RAs are shown in Table 4.6. For these analyses
smoking was categorized as “never smoked” or “other” and diabetes was
categorized as “none” or “diabetes” (any type). The distributions of the dependent
variables were all positively skewed and better fits to the data were obtained by
transforming to the logarithmic scale (base 10). PVD and a history of smoking
were independently associated with log (percentage of luminal narrowing) and
together explained 11.4% of its variability. Age and diabetes were independently
associated with log (ITI) and explained 14.1% of ITI variability. Log (IMR) was
122
independently predicted by age , which explained 6.2% of variability.
Table 4.6 Radial artery: Results of stepwise linear regression analysis of dependent
variables: Log (percentage of luminal narrowing of RA), Log (ITI of RA) and Log (IMR of
RA)
Variables b SE t-ratio P R Square

coefficient value
Log10 (%luminal narrowing)
Constant = 0.952
PVD 0.142 0.051 2.81 0.006 0.073

Smoker 0.09 0.040 2.23 0.03 0.041
Log10 (ITI)
Constant = -1.385
Age (years) 0.0085 0.002 3.63 <0.001 0.090

Diabetes 0.127 0.050 2.52 0.01 0.051
Log10 (IMR)
Constant = -0.896
Age (years) 0.0095 0.004 2.68 0.009 0.062
PVD: 1= no, 2 = yes, smoker: 1=never, 2=ever, diabetes: 1=no, 2=yes
Table 4.7 shows the results of regression analyses on the risk factors of
intimal hyperplasia and atherosclerosis in the ITA. Age and a history of smoking
were independently associated with log (percentage of luminal narrowing) and
together explained 15.0% of its variability. Smoking and age were independently
associated with log (ITI), which explained 12.6% of ITI variability. Log (IMR)
was independently predicted by age, explaining 5.7% of the variability.
123
Table 4.7 Internal thoracic artery: Results of stepwise linear regression analysis of
dependent variables: Log (percentage of luminal narrowing of ITA), Log (ITI of ITA) and
Log (IMR ratio of ITA)
Variables b SE t-ratio P R Square

coefficient value
Log10 (%luminal narrowing)
Constant = 0.388
Age (years) 0.0067 0.02 3.74 <0.001 0.91

Smoker 0.102 0.035 2.90 0.004 0.059
Log10 (ITI)
Constant = -1.379
Smoker 0.131 0.036 3.62 <0.001 0.079

Age (years) 0.0042 0.02 2.27 0.025 0.047
Log10 (IMR)
Constant = -1.112
Age (years) 0.0092 0.004 2.54 0.012 0.57

smoker: 1=never, 2=ever
Logistic regression was used to model medial calcification in the RA using
the same eight risk factors that were employed for the evaluation of intimal
hyperplasia and atherosclerosis. The only significant predictor was age (P = 0.01);
increased age was associated with a higher probability of medial calcification. The
odds ratio corresponding to a difference in age of 10 years was 2.7 (95% CI 1.2,
5.8).
DISCUSSION
Histopathology
Three arterial abnormalities were found in this study: intimal hyperplasia,

atherosclerosis and medial calcification. Mild forms of intimal hyperplasia were
found in the majority of conduit samples removed from patients undergoing
124
CABG aged between 42 and 83 years. Intimal hyperplasia occurred more

frequently in RA grafts than in ITA.
Intimal hyperplasia occurs as a consequence of physiologic stimuli,

constituting an attempt by the tissue to maintain normal conditions of flow and/ or
wall tension. Regions of the intima with adaptive increases in thickness differ
functionally from adjacent, thinner regions. As discussed in the previous chapter,
excessive lipoprotein in the plasma tends to accumulate preferentially in the
hyperplastic intima causing atherosclerosis.236
In this series, the incidence of atherosclerosis in the RA was 5.3% compared

with 0.7% in the ITA (P = 0.04). The true incidence of atherosclerosis in the RA
was actually higher because some of the patients had severe macroscopic
atherosclerosis of their RA, precluding its use as a bypass conduit. In addition, the
prevalence of atherosclerosis in both the RA and the ITA was probably
underestimated in our study because only the distal ends of arteries were
examined and atherosclerosis is a segmental disease. In 1976, Kay et al. examined
215 ITAs from routine postmortem examinations and found more than a 25%
reduction in lumen diameter in 4.2% of ITAs.237 No patient had more than a 50%
narrowing. Other postmortem and angiographic studies have reported an
incidence of ITA atherosclerosis ranging from 2.4-5%.238 According to the
definitions and histological classification of atherosclerosis,239 we found only type
236
Stary. Virchows Archiv - A, Pathological Anatomy & Histopathology 1992; 421:277-
90.
237
Kay, Korns, Flemma, Tector and Lepley. Ann Thorac Surg 1976; 21:504-7.
238
Mestres, Rives, Igual, Vehi and Murtra. Thoracic & Cardiovascular Surgeon 1986;
34:356-8, Singh. Cardiovasc Intervent Radiol 1983; 6:72-7, Sisto and Isola. Ann Thorac Surg
1989; 47:884-6, Sons, Godehardt, Kunert, Losse and Bircks. J Thorac Cardiovas Surg 1993;
106:1192-5.
239
125
V advanced atherosclerosis in this series. The age of the patients may explain why
only advanced lesions were found.
The incidence of medial calcification (Monckeberg’s calcinosis) in the RA

was 13.3% in our study. Medial calcification of an artery, even when extensive, is
not necessarily associated with extensive intimal changes and the lumen of the
artery is not to be compromised by the medial change. On the contrary, vessels
with marked calcification often show less intimal involvement than is average for
that age.240 However in our study, the RAs with medial calcification did not have
less intimal hyperplasia or atherosclerosis. Monckeberg’s calcinosis is
independent of, and unrelated to, the presence of atherosclerosis. However both
are commonly found in patients older than 50 years and in patients with
diabetes.241 Ninety four percent of patients who have had diabetes for longer than
35 years will also have medial calcification.242 Renal failure and familial
amyloidosis with polyneuropathy have been associated with medial
calcification.243 In our study however, age was the only risk factor for medial
calcification. The effect of medial calcification on arteries used for CABG is
unknown.
Morphometric analysis
Our morphometric analyses showed the RA to have a greater internal

diameter and a thicker intima and media than the ITA. The severity indices were
strongly correlated with each other and all were significantly greater in the RA
than in the ITA.
240
Sappington and Cook. Am J Med Sci 1936; 192:822-839, Sappington and Horneff. Am
J Med Sci 1941; 201:862-871.
241
Sappington and Horneff. Am J Med Sci 1941; 201:862-871.
242
Goebel and Fuessl. Diabetologia 1983; 24:347-50.
243
Everhart, Pettitt, Knowler, Rose and Bennett. Diabetologia 1988; 31:16-23.
126
The percentage of luminal narrowing is a measure of the severity of intimal

thickening, including atherosclerosis. The area rather than the thickness of the
intima was measured to allow accurate evaluation of eccentric or irregular disease.
The percentage of luminal narrowing is the most useful parameter for comparing
intimal thickening in different vascular beds. However, although this parameter in
the RA was statistically greater than in the ITA, this may not be clinically
significant because the internal luminal diameter of the RA was significantly
greater than in the ITA.
The intimal thickness index and the intima to media ratio are alternative
methods of comparing intimal disease in different vascular beds.244 Of these two,
the ITI is more accurate because it uses areas of intima and media rather than
width. However when comparing the RA and the ITA an assumption is made that
any thickening of the media (the denominator in both ITI and IMR), for example,
in hypertension, occurs to the same degree in both vascular beds. This assumption
may not be valid. In addition, the greater thickness of the media of the RA
compared with the ITA may invalidate the use of the ITI and the IMR as a
comparative index in different vascular beds.
Kaufer and colleagues reported on the pathology of RAs and ITAs used as
coronary artery bypass grafts.245 Using the IMR for grading atherosclerotic
lesions, the mean RA grade was significantly greater than the mean ITA grade.
However in this study the classification of lesions was not clear, that is, whether
the lesions were intimal hyperplasia or true atherosclerosis and the IMR may not
have been a good indicator for comparative grading of vascular diseases. The
greater thickness of the media in the RA may lead to a misleadingly low IMR
compared with an ITA with the same severity of intimal disease. In my opinion
the IMR should be used to compare the severity of atherosclerosis in the same
244
Kaufer, Factor, Frame and Brodman. Ann Thorac Surg 1997; 63:1118-22, Malhotra,
Bedi, Bazaz, Jain and Trehan. Ann Thorac Surg 1996; 61:124-7.
245
Kaufer, Factor, Frame and Brodman. Ann Thorac Surg 1997; 63:1118-22.
127
artery amongst different patients, but should not be used to compare

atherosclerosis in two different arteries (e.g. the RA and the ITA). Therefore in
the case of comparison of different type of arteries I prefer to use the percentage
of luminal narrowing.
Prediction of intimal hyperplasia and atherosclerosis
Prospective studies have demonstrated that different arterial beds have

different risk factors for the development of atherosclerosis. Smoking,
hypercholesterolemia and hypertension are common risk factors for coronary
artery disease, CVD and PVD, but these factors appear to impact differently on
arteries in different parts of the body.246
For example, Kay et al found that intimal thickening of the ITA correlated
with age, hypertension, diabetes and PVD.247 Another autopsy series from Sisto
and Isola in 1989 showed that only hypertension correlated with intimal thickness
of the ITA in the 160 cadavers studied. Age, cigarette smoking, body mass index
and diabetes were not associated with atherosclerosis.248
Singh used angiography to study both ITAs in 150 patients with coronary
artery disease. The incidence of atherosclerosis in ITAs was 2%. Atherosclerosis
in the ITA did not appear to be influenced by age or PVD.249 Sons et al performed
246
Salonen, Puska and Kottke. Eur Heart J 1981; 2:365-73, Salonen, Puska, Tuomilehto
and Homan. Stroke 1982; 13:327-33, Salonen and Salonen. J Intern Med 1994; 236:561-6.
247
Kay, Korns, Flemma, Tector and Lepley. Ann Thorac Surg 1976; 21:504-7.
248
Sisto and Isola. Ann Thorac Surg 1989; 47:884-6.
249
Singh. Cardiovasc Intervent Radiol 1983; 6:72-7.
128
angiograms on 117 patients with cardiac disease. PVD and hyperlipidemia

significantly increased the relative risk of atherosclerosis in the ITA.250
Kaufer et al found that the degree of disease in the RA was related to

gender, age, the presence of diabetes, aorto-iliac atherosclerosis and femoro-
popliteal atherosclerosis. These factors explained 60.67% of the variance (P <
0.001) using multivariate regression. None of the risk factors above correlated
with the degree of ITA pathology.251
In my study, when using the percentage of luminal narrowing as the

dependent variable, the strongest predictors of intimal hyperplasia in the RA were
PVD and cigarette smoking. When ITI was used as the dependent variable, age
and diabetes were the most important factors. When the IMR was used, the
strongest predictor was age. In the ITA, age and smoking were risk factors of
marked luminal narrowing and elevated ITI. Age was the only significant risk
factor for a high IMR. However, unlike Kaufer, we found a large amount of
unexplained variation. The predictive variables analyzed here, therefore, cannot
indicate precisely the risk of intimal hyperplasia and atherosclerosis.
From the regression analysis, we can predict future observations from our
model. For example, from Table 4.6 we derived this following equation for
prediction of the percentage of luminal narrowing and plotted the probability
density function (distribution) (Fig. 4.7).
Log10 (%luminal narrowing of RA) = 0.952 +0.142PVD+0.09Smoker
250
Sons, Godehardt, Kunert, Losse and Bircks. J Thorac Cardiovas Surg 1993; 106:1192-
5.
251
Kaufer, Factor, Frame and Brodman. Ann Thorac Surg 1997; 63:1118-22.
129
Figure 4.7 Estimated cumulative distribution of the percentage of luminal narrowing

in patient without peripheral vascular disease and who do not smoke.
We can calculate the upper limit of the percentage of luminal narrowing of

the RA in patients with and without risk factors (Table 4.8). There is a 95%
probability that future observation will be the same as, or lower than, the upper
limit value. The best-case scenario in this instance is for patients who are non-
smokers and do not have a peripheral vascular disease. The worst-case scenario is
the opposite.
Table 4.8 The upper limit of the percentage of luminal narrowing of the radial artery
in patients with or without peripheral vascular disease and nonsmoker or smoker.
Upper limit of the percentage Peripheral vascular disease Smoker

of luminal narrowing
33.2 No No
41.0 No Yes
43.0 Yes No
53.0 Yes Yes
130
For the intimal thickness index, I derived the following equation.
Log10(intimal thickness index of the RA) = -1.385+0.0085Age +

0.127Diabetes
Using the probability density function, we calculated the upper limit of the
intimal thickness index (Table 4.9). I assume that an intimal thickness index of 0.5
is unsuitable for grafting (50% luminal narrowing predicted an intimal thickness
index of 0.5 from the regression equation), then patients without diabetes must be
younger than 70 years old to have a 95% probability of an index of 0.5 or less. In
diabetic patients, they must younger than 57 years to have an index of 0.5 or less.
Table 4.9 The upper limit of the intimal thickness index of the radial artery in patients
with or without diabetes in various age.
Upper limit of intimal Age Diabetes

thickness index of RA
0.49 69 No
0.50 70 No
0.51 71 No
0.52 71 No
0.49 55 Yes
0.50 56 Yes
0.50 57 Yes
0.52 58 Yes
For the ITA, the regression equation for the percentage of luminal
narrowing is as following.
Log10 (% luminal narrowing of ITA) = 0.388+0.007Age+0.102Smoker
I then calculated the upper limit of the percentage of luminal narrowing

(Table 4.10). In patients who are non-smoker it is safe to use the ITA
131
even if they are 79 years old because 95% of these patients will have a percentage
of luminal narrowing less than 20.6. In smokers, 95% of patients who are 78
years old will have a percentage of luminal narrowing less than 25.6.
Table 4.10 The upper limit of the percentage of luminal narrowing of the internal
thoracic artery in smoker and nonsmoker in various age.
Upper limit of percentage of Age Smoker

luminal narrowing of ITA
19.6 76 No
19.9 77 No
20.3 78 No
20.6 79 No
19.5 61 Yes
19.8 62 Yes
20.1 63 Yes
20.5 64 Yes
24.3 75 Yes
24.7 76 Yes
25.1 77 Yes
25.6 78 Yes
CONCLUSION
The findings of this study suggest that the RA have a significantly greater
prevalence of intimal hyperplasia, atherosclerosis and medial calcification than
the ITA. Morphometric analyses of percentage of luminal area narrowing, ITI and
IMR also led me to conclude that the RA has a significantly higher degree of
intimal hyperplasia and atherosclerosis than the ITA. Despite the increased
prevalence of disease in the RA compared with the internal thoracic artery, overall
the severity indices for intimal hyperplasia and atherosclerosis were fairly low in
132
both vessels.
In terms of risk factors for disease, age, smoking, diabetes and peripheral
vascular disease correlated with intimal hyperplasia and atherosclerosis in the RA
and the ITA. However there was considerable unexplained variation in these
predictive variables.
The left ITA is used almost exclusively as a pedicled graft to the left
anterior descending artery. However the choice of the second graft varies widely
amongst surgeons. In the light of the findings of this study I would advocate
caution in selecting the RA in favor of the right ITA as a bypass conduit in
patients who are elderly, diabetic, smoke or have peripheral vascular disease, and
especially if the patient has a combination of these characteristics.
133
(b) Selection Criteria for the RA for Coronary Artery Bypass Grafting
INTRODUCTION
As described above, I found that, compared with the ITA, the RA is

associated with a significantly higher prevalence of intimal hyperplasia, medial
calcification and atherosclerosis. A major concern regarding the variability of the
RA as a bypass conduit is the fact that these changes may affect the mid and long-
term patency of grafts. Accordingly, I carried out a second study: 1) to identify the
clinical risk factors for disease in the RA in a larger group of patients thereby
establishing objective guidelines for identifying patients who are not suitable for
RA grafts; and 2) to compare disease severity in the distal versus the proximal RA
in order to be able to select that portion of the artery which has the least intimal
disease.
METHODS
One hundred and eighty-four patients who underwent CABG were included
in the study. The clinical characteristics, which were selected as potential risk
factors for intimal disease, are summarized in Table 4.11. The patients’ ages
ranged from 42 to 81 years (average 66.6, SD 9.1 yrs). RA segments from 184
patients were examined by histopathology and morphometry. In this study, we
used only the percentage of luminal narrowing (%LN) and intimal thickness index
(ITI) to evaluate the degree of intimal disease. Eighty-three paired segments of
distal and proximal RA segments were compared morphometrically. For the distal
and proximal RA comparisons, only the %LN was used, the other indices being
unsuitable because the proximal RA segment had a larger medial area than the
distal segment.
134
Patient characteristic N (%)
Female 20 (10.9%)
Smokers Never 54 (29.3%)
Previous 119 (64.7%)
Current 11 (6.0%)
Hypertension 98 (53.3%)
Aortoiliac disease 7 (3.8%)
Femoropopliteal disease 27 (14.7%)
Carotid disease 19 (17.3%)
Cerebrovascular disease 27 (14.7%)
Statistical Methods
Ten potential clinical risk factors for vascular disease were included in
stepwise linear regression analyses as independent variables. The %LN and the
ITI were analyzed separately as dependent variables as each of these variables are
severity indices of intimal hyperplasia and atherosclerosis. Due to the positively
skewed distribution of both dependent variables, we transformed the data to the
logarithmic scale (base 10) and used log dependent variables to analyze the data
by stepwise linear regression analysis. Any association was examined by
Spearman’s measure of correlation, rho. The difference between the
morphometric parameters for paired specimens of distal and proximal
135
RAs was analyzed by the Wilcoxon signed rank test. A P-value of less than 0.05
was considered significant.
For each of the two severity indices we constructed a predictive model in

order to: (1) indicate which risk factors were most strongly associated with
disease; and (2) determine before surgery which RAs were unsuitable for grafting.
To develop these models we used a one-sided prediction interval. In order to be
confident that the RAs had acceptable severity indices, we set values of 50% for
%LN and 0.5 for ITI as levels of serious concern. Setting the upper limit of the
95% prediction interval equal to these values enabled us to determine clinical
profiles of concern and identify a cut-off point for age of concern.
RESULTS
Of 184 distal RA segments, intimal hyperplasia and atherosclerosis were

found in 92.9% (171) and 6% (11) of vessels, respectively (Figures 4.8A and
4.8B). There was only one entirely normal RA while one showed chronic
inflammation. The percentage of luminal narrowing correlated with the ITI
(Spearman’s rho= 0.68, P<0.01).
a. b.
Figure 4.8 Both intimal hyperplasia (a) and atherosclerosis (b) may be associated
with significant luminal narrowing. (a) Intimal hyperplasia (41.81% LN, 0.53 ITI); (b)
Atherosclerosis (47.13% LN, 0.80 ITI).
Verhoeff Van Gieson’s elastin stain a) ´ 5, b) ´ 8 (original magnification)
LN = percentage of luminal narrowing, ITI = intimal thickness index
136
Medial calcification was found in 13.3% (11/83) of the distal RA segments

and 14.5% (12/83) in the proximal RA segments.
Aortoiliac disease and diabetes were found to be significant (P<0.05)

predictors of severe intimal disease for %LN, while these two risk factors along
with age were significant predictors for ITI (Table 4.12). Aortoiliac disease and
diabetes were independently associated with log (%LN) and together explained
14.1% of its variability. Aortoiliac disease, age and diabetes were independently
associated with log (ITI), accounting for 22.5% of ITI variability. The severity
indices in patients with and without aortoiliac disease are shown in table 4.13 and
Figure 4.9 and 4.10.
Table 4.12 Results of stepwise linear regression analysis of dependent variables
Variables b SE t ratio P R Square

coefficient
Log10 (% luminal narrowing)
Constant = 1.247
Aortoiliac disease 0.257 0.074 3.47 0.001 0.09

Diabetes 0.096 0.032 3.01 0.003 0.051
Log10 (ITI)
Constant = -1.211
Aortoiliac disease 0.340 0.078 4.37 <0.001 0.106

Age (years) 0.0073 0.002 4.47 <0.001 0.073
Diabetes 0.110 0.034 3.27 0.001 0.046
Aortoiliac disease: 0 = no, 1 = yes: diabetes: 0 = no, 1 = yes
137
Table 4.13 Comparison of severity of intimal hyperplasia and atherosclerosis in the

radial arteries in the patients with and without aortoiliac disease
Severity indices Patients without aortoiliac Patients with aortoiliac

disease (n=177) median disease (n=7) median
% LN 18.6 35.2
ITI 0.21 0.53
% LN–Percentage of luminal narrowing, ITI–Intimal thickness index
Figure 4.9. Boxplot of the Aortoiliac disease groups (no, yes) and the percentage of
luminal narrowing in the distal RA segments. The boxes indicates the lower and upper
quartiles and the central line is the median. The whiskers extend to the extreme values of
the data, not including outliers (*) which are the values more than 1.5 times the
interquartile distance from the upper and lower edges of the box and which are shown
separately. The label numbers in the plot are the case number.
138
Figure 4.10. Boxplot of the Aortoiliac disease groups (no, yes) and the intimal thickness
index in the distal RA segments. The boxes show the median and interquartile distance.
The whiskers extend to the extreme values of the data, not including outliers (*) which are
the values more than 1.5 times the interquartile distance from the upper and lower edges
of the box and which are shown separately. The label numbers in the plot are the case
number.
Morphometric analysis (Table 4.14) showed that the diameters of the lumen
and the intima in the proximal versus the distal RA segments were not
significantly different. However, the proximal RA had a significantly lower %LN
compared with the distal RA (P<0.001) (Figure 4.11a, b). In this comparison, we
did not use the intimal thickness index as it can produce misleading results due to
the fact that the proximal RA has a larger medial area.
There was no significant difference in the prevalence of medial calcification

between the distal and proximal RA segments (P = 1, McNemar’s test).
139
a. b.
Figure 4.11 The distal radial artery (a) shows moderate intimal thickening while the
proximal radial artery (b) is nearly normal. (a) Distal radial artery (25.34% LN, 0.16 ITI);
(b) Proximal radial artery (5.94% LN, 0.04 ITI).
Verhoeff Van Gieson’s elastin stain a) ´ 10, b) ´ 11 (original magnification)
LN = percentage of luminal narrowing, ITI = intimal thickness index
Table 4.14 Comparative morphometry of the distal and proximal segments of the
radial artery (n = 83 pairs)
Distal Radial Artery Proximal Radial Artery
Variables Range Mean SD Range Mean SD P
DLI (mm) 0.69-2.99 1.86 0.45 0.81-3.21 1.93 0.54 0.3
Intimal area 0.12-2.13 0.59 0.33 0.09-1.62 0.46 0.31 <0.001

(mm2)
Medial area 0.57-5.07 2.67 0.86 0.24-7.43 3.32 1.31 <0.001

(mm2)
% LN 5.82-74.58 21.74 9.85 3.54-73.54 15.74 9.56 <0.001
DLI indicates diameter internal to media (lumen+intima), %LN indicates percentage of

luminal narrowing, SD indicates standard deviation.
140
DISCUSSION
The RA is associated with a high incidence of intimal hyperplasia, a

pathological process thought to be a major cause of graft atherosclerosis and graft
failure.252 Although we found severe intimal hyperplasia, that is, hyperplasia
causing luminal narrowing of more than 50%, in only 2.7% (5/184) of distal RAs
and 1.2% (1/83) of proximal RAs prior to coronary bypass grafting, a large
number of the RAs in our sample demonstrated some degree of intimal
hyperplasia. These findings raise concerns about the possible effects of intimal
disease in the RA following grafting.
In the first study the risk of intimal disease explained by the risk factors
studied was low (6.2-14.1%). In contrast, Kaufer and colleagues who used IMR as
a severity index RA disease found that gender, age, diabetes, aortoiliac disease
and femoropopliteal atherosclerosis were the risk factors and these explained
60.67% of variance. Therefore, in the second study, I included and specified some
of the risk factors which related to vascular disease such as aortoiliac, carotid and
femoropopliteal disease. I used a percentage of luminal narrowing and intimal
thickness index as severity indices. The risk factors in the second study were
slightly different from the first. Aortoiliac disease replaced smoking and
peripheral vascular disease. However they only explained 10.5-22.5% of
variability. It is clear that other possible risk factors, such as genetic factors,
remain unidentified.
The level of concern for intimal thickening was arbitrarily set at 50% for
%LN as there is no set guideline for assessing the degree of intimal disease. The
level of concern of 0.5 for ITI was derived from a regression analysis which
252
Davies, Dalen, Kim, et al. J Surg Res 1995; 59:35-42, Davies, Fulton, Huynh, et al.
Ann Vasc Surg 1999; 13:484-93, Davies and Hagen. European Journal of Vascular &
Endovascular Surgery 1995; 9:7-18, Davies, Huynh, Fulton, et al. Ann Vasc Surg 1999; 13:378-
85, Dietrich, Hu, Zou, et al. Am J Pathol 2000; 157:659-69, Zou, Dietrich, Hu, et al. Am J Pathol
1998; 153:1301-10.
141
indicated that 50% luminal narrowing predicts an ITI of 0.5. Adopting these cut-
off points, we found that the main variables associated with a risk of intimal
hyperplasia were aortoiliac disease, age and diabetes. We then constructed
profiles of those cases in which we could not be confident that the severity index
was less than the pre-specified level of concern. For patients with aortoiliac
disease for example, we found that we could not be 95% confident that the %LN
was less than 50% and that the ITI was less than 0.5 (Figure 4.11). While this did
not indicate that we could be certain that the %LN would be greater than 50%, it
suggested that we should think carefully when considering such patients for RA
grafting. For all other clinical profiles, however, we were at least 95% confident
that the %LN was less than 50%. For ITI, we found that in patients aged 78 or
over, even without aortoiliac disease or diabetes, we could not be (95%) confident
that the ITI was less than 0.5. Furthermore, according to our analysis, in diabetic
patients with no aortoiliac disease the RA should not be used in those aged over
age 63.
142
Figure 4.11 Estimated cumulative distribution of percentage of luminal narrowing in

patients with aortoiliac disease, with and without diabetes. In either group, we cannot be
95% confident that the percentage of luminal narrowing will be less than 50%. For those
patients without diabetes it is estimated that 84% will have a percentage of luminal
narrowing of less than 50%, while for those with diabetes the estimated percentage is
70%.
In terms of selecting an appropriate segment of RA for grafting, our study

found that the distal RA had a significantly higher degree of intimal disease than
the proximal RA. Therefore, when the RA harvested is longer than required we
recommend that the distal end be discarded. Although the proximal RA has a
significantly wider medial area compared with the distal RA, this difference can
be overcome by using topical and systemic vasodilatation. Excessive trimming of
the RA can be eliminated by carefully measuring the length of the graft and
preparing it before performing the distal anastomosis. Another way of avoiding
this problem is to reverse the RA. The latter method allows the surgeon to
perform the distal anastomosis without cutting the RA graft. When the RA is too
short, an alternative option is to perform a Y or T graft with another graft such as
an ITA.
CONCLUSION
The findings of the second study indicate the need for applying considerable
caution in using the RA in patients with aortoiliac disease, in diabetic patients
who are 63 or older, and in those aged ³ 78 without diabetes. In terms of further
minimizing the risk of intimal disease, I recommend using the proximal rather
than the distal part of the RA.
SUMMARY
In this chapter I have sought to examine the variability of the RA as a

bypass graft from a histopathologic perspective. In the first study discussed, the
RA was found to have a significantly higher prevalence of intimal hyperplasia,
atherosclerosis and medial calcification than in the internal thoracic artery. The
RA also has a higher degree of intimal hyperplasia and atherosclerosis than in the
143
internal thoracic artery. I sought to identify the risk factors associated with the
development of intimal hyperplasia and atherosclerosis in both arteries. The high
prevalence and degree of intimal hyperplasia in the RA ¾ a process associated
with atherosclerosis ¾ gave cause for concern regarding the possible effects on
graft patency. Accordingly, in the second study, I sought to identify in a larger
group of patients the clinical risk factors which were associated with intimal
hyperplasia and atherosclerosis in the RA. The significant risk factors were
aortoiliac disease, diabetes and aging, especially in a patients with a combination
of risk factors. I defined the characteristics of patients for whom I am not
confident that the RA is suitable for use as a conduit based on the degree of
preexisting intimal hyperplasia and the clinical risk factor data. These
characteristics are: patients with aortoiliac disease, diabetic patients who are 63 or
older, and those aged ³ 78 without diabetes. Comparing the distal and proximal
segments of the RA, the distal segment showed significantly higher degree of
intimal hyperplasia. I recommend using the more proximal segment of the RA.
One limitation of this histopathology study is that we only examined the RA

at the distal end. This is likely to have underestimated the incidence of focal
atherosclerosis and intimal hyperplasia. In the next chapter, I describe
examination of the RA by ultrasound, a technique which allows study of the
whole length of the vessel.
144
Chapter 5
The Use of Ultrasound for Assessing the Radial Artery
before Coronary Artery Bypass Grafting
(a) The Detection of Intimal Plaque and Arterial Calcification

Introduction
Patients and Methods
Patients
Ultrasound examination
Comparative study of the ultrasound and histopathology
Histopathology
Statistical Methods
Results
Calcification
Luminal diameter
Risk factors
Histopathology
Comparison between ultrasound calcification and histopathology
Discussion
Conclusion
(b) The Measurement of Intimal hyperplasia

Introduction
Results
Discussion
Conclusion
Summary
Ultrasound of the RA 173
In the previous chapter, I examined the histological viability of the radial

artery (RA) as a graft conduit and found that the RA has a higher rate of intimal
hyperplasia, atherosclerosis and medial calcification. It therefore would be useful
if a method could be found to screen patients for possible arterial disease prior to
RA harvesting.
Accordingly, in this chapter I examine the efficacy of ultrasound for

assessing the RA prior to coronary artery bypass grafting (CABG). The chapter is
divided into two sections. In the first section I present a study examining the
prevalence of intimal plaque and calcification in the RA by ultrasound and also
the efficacy of ultrasound for assessing luminal diameter in the RA. In the second
section I investigate whether ultrasound measurement of intima-media thickness
is useful for assessing the degree of intimal hyperplasia and atherosclerosis in the
RA.
(a) The Detection of Intimal Plaque and Arterial Calcification
Introduction
Intimal atherosclerosis makes an artery unusable for use as a bypass graft.

We do not know the effect of medial calcification on long-term graft patency.
Without the shock-absorbing capacity of a normal artery, the calcified wall may
be subjected to greater shear and intramural stresses, exposing the intima to
greater injury. Calcification may also limit an artery’s ability to protect itself
through the mechanism of compensatory dilatation.253 In peripheral vessels, the
presence of medial calcification increases the likelihood of ischemia and is
significantly associated with severe arterial occlusive disease of the lower
limbs.254 For these reasons, in our current surgical practice, we do not use RAs
253
Glagov, Weisenberg, Zarins, Stankunavicius and Kolettis. N Engl J Med 1987;
316:1371-5.
254
Christensen. Acta Medica Scandinavica 1968; 183:449-54, Fuessl, Schalzky, Schewe,
Frey and Goebel. Klin Wochenschr 1985; 63:211-6, Neubauer, Christensen, Christensen,
146
which are heavily calcified especially when associated with poor intraoperative
flow.
Another undesirable feature of any conduit is a small luminal diameter,

whether caused by intimal hyperplasia or small vessel size. This potentially
increases the risk of graft complications. In addition it is known that the pressure
drop across an area of stenosis is related to the absolute luminal diameter.255 Pre-
operative, non-invasive detection of RA calcification and small luminal diameter
may therefore be important.
Doppler ultrasound has been widely used for investigating atherosclerosis

and evaluating the progression of disease in both carotid disease and peripheral
vascular disease. It has also proved to be useful and accurate for measuring the
wall thickness of arteries. In this study, we used Doppler ultrasound to examine
the RA before CABG. It is also useful to know which patients are prone to arterial
disease and have an RA with a small luminal diameter prior to CABG. Therefore
the clinical risk factors of the patients were also examined.
The aims of this study were: (1) to use ultrasound to document the
prevalence of intimal plaque and arterial calcification and to identify arteries with
a small luminal diameter; (2) to investigate the efficacy of ultrasound in assessing
arterial calcification in the RA by comparing it to histopathology; and (3) to
identify the clinical risk factors for arterial calcification and small luminal
diameter radial arteries in a coronary artery patient population.
Gundersen and Jorgensen. Acta Medica Scandinavica - Supplementum 1984; 687:37-45,

Niskanen, Suhonen, Siitonen, Lehtinen and Uusitupa. Atherosclerosis 1990; 84:61-71.
255
Deweese, May, Lipchik and Rob. Stroke 1970; 1:149-57.
147
PATIENTS AND METHODS
Patients
Seventy-three patients scheduled for coronary artery bypass grafting were

included in the study. Their ages ranged from 40 to 85 years (average 67.1±9.8
yrs). There were 60 males (82.2%) and 13 females (17.8%). The patients
characteristics and potential risk factors for atherosclerosis considered were: age,
gender, diabetes mellitus, history of cigarette smoking, hypertension, carotid
disease, aortoiliac disease, femoropopliteal disease, cerebrovascular disease
(CVD) and hypercholesterolemia (Table 5.1).
Age (mean±SD) yrs 67.1 ± 9.8
Smokers Never smoked 16 (21.9%)
Previous 50 (68.5%)
Current 7 (9.6%)
Hypertension 43 (58.9%)
Carotid disease 19 (26.0%)
Aortoiliac disease 6 (8.2%)
Femoropopliteal disease 17 (23.3%)
Cerebrovascular disease 11 (10%)
148
Ultrasound examination (n=73)
Ultrasound examination was performed the day before surgery by one of

two sonographers using an ATL (Advanced Technology Laboratories, Bothell,
Washington), HDI (High DefinitionTM Imaging) 5000 system with a 10 MHz
compact linear array transducer. The entire length of the RA was examined for
calcification and echogenic plaques. Echogenic foci in the arterial wall with
posterior acoustic shadowing were recorded as calcification. Those without
posterior acoustic shadowing were recorded as echogenic plaques. Stenosis was
defined as a focal increase in peak systolic velocity compared with the proximal
arterial segment.
The luminal diameter is the distance between the leading edge echo from the
lumen-intima interface from the near wall and the leading edge of the second
bright echo, which is created by the lumen-intima interface from the far wall.256
Over three systolic cardiac cycles, the luminal diameter of the RA at a point 1 cm
from its origin and 2 cm from the RA styloid was measured (Figure 5.1 a, b). A
hypoplastic RA was defined as an artery with either a distal or proximal luminal
diameter of less than 1.5 mm.
A similar examination was carried out on 10 normal volunteers by the same

two sonographers on the same day and at a 7-day interval in order to confirm the
reliability of the ultrasound measurements.
256
Wikstrand and Wendelhag. J Intern Med 1994; 236:555-9.
149
a.
b.
Figure 5.1 The ultrasound measurement of radial artery luminal diameter

a. diagram depicts a cross section of the artery demonstrating the intima, media,
lumen and adventitial layers The luminal diameter is the distance between the
leading edge echo from the lumen-intima interface (brown) from the near wall
and the leading edge of the second bright echo, which is created by the lumen-
intima interface (brown) from the far wall
b. ultrasound image of the distal end of the radial artery 2 cm proximal to radial
styloid process demonstrating the luminal diameter.
Comparative study of ultrasound and histopathology (n=78 specimens)
Ten patients with severe RA calcification observed by ultrasound (US) were

regarded as having arteries unsuitable for grafting therefore the RAs were not
harvested. In one of the patients undergoing RA exploration, the RA was found to
be unsuitable for use as a conduit for grafting. Fourteen other patients were
excluded because their surgeons were non-compliant (7), the patients were either
enrolled in other studies (5), or their operations were cancelled (2). Nine patients
were excluded due to the absence of specimens. This process of elimination
resulted in RA specimens from forty of the seventy-three patients being available
for histopathologic examination. In one of these patients the distal RA was not
able to be sampled as only the proximal part was harvested. In another patient,
one proximal RA segment was not accessed leaving 78 specimens for
examination by histopathology. All discarded RAs were also examined.
Histopathology
Distal and proximal segments of RA (1 cm from origin and 2 cm from RA

styloid) were sampled at the time of RA harvesting. Specimens were fixed in 4%
formaldehyde solution. Multiple transverse slices of the vessels were processed to
paraffin wax. Sections were cut at 5mm and all were stained with hematoxylin-
eosin and Verhoeff Van Gieson’s elastin stain. The slides were examined by a
pathologist blinded to the ultrasound results.
Statistical methods
A comparison of the mean diameters of the distal and proximal RA

segments as measured by US was performed by paired sample t-test. Correlations
between pairs of continuous variables were evaluated using Pearson correlation
coefficients (r).
151
Intra-and inter-observer variability was estimated by calculating the

difference between paired measurements according to the method of Bland and
Altman.257 Correlation coefficients were also used. Since the data were not
normally distributed, Spearman rank order correlations (rho) were used.
Ten clinical risk factors (Table 5.1) for RA plaques and calcification were
included in logistic regression analyses as independent variables. A forward
stepwise procedure was used to identify a suitable model. Exact logistic
regression was used to fit the model to the data after the model was identified.258
Positive RA calcification and any RA abnormality (RA calcification or echogenic
plaques) observed by US were included as dependent variables. The presence of
plaques was not analyzed as a dependent variable since only 5 out of 73 patients
had plaques. P values and 95% confidence intervals were reported for key
results.259
To identify the risk factors for hypoplasia we used the same ten risk factors,
and the distal luminal diameter as a continuous independent variable, in the
stepwise linear regression analysis.
Comparison between ultrasound and histopathology
A comparative analysis of the difference between paired dichotomous data

was performed by McNemar’s test. Statistical significance was considered to be
P<0.05.
Using histopathologic examination as a “gold” standard, the test

characteristics of the ultrasound in detecting arterial calcification (sensitivity,
specificity, positive predictive value, negative predictive value, diagnostic
257
Bland and Altman. Lancet 1986; 1:307-10.
258
Mehta and Patel. LogXact for windows 1996.
259
Gardner and Altman. Br Med J 1986; 292:746-50.
152
accuracy) were calculated. Confidence intervals of test characteristics for the

distal and proximal RA segments’ results were obtained using the exact
method.260 When the combined data were considered, confidence intervals were
calculated using the bootstrap method261, since segments from the same patient
cannot be assumed to be independent.
RESULTS
Ultrasound examination (n=73)

Calcification
RA calcification (intimal or medial) was detected by ultrasound in 24.7%

(18/73) of radial arteries (Figure 5.2 a). Echogenic intimal plaques were found in
6.8% (5/73) (Figure 5.2 b). The overall incidence of RA abnormality (RA
calcification or echogenic intimal plaques) was 31.5%.
a. b.
260
Armitage and Berry. Statistical Methods in Medical Research 1987; Blackwell
Scientific.
261
Efron and Tibshirani. An Introduction to the bootstrap 1993:168-77.
153
Figure 5.2 Longitudinal ultrasound images of radial artery. A, calcification with

acoustic shadow. B, echogenic plaque.
Luminal diameter
The inter- and intra-observer variability of the luminal diameter of the

proximal and distal segments of the RA based on data from the 10 volunteers is
summarized in Table 5.2. For reliability, we require that the test have a mean
difference between paired measurements which is close to zero and a small
standard deviation for the differences. The “repeatability coefficient” shows the
variability of the difference between the two tests. A reliable test will have a small
repeatability coefficient. The repeatability coefficients ranged between 0.65 and
1.01 mm. This indicated that the difference in diameter measurement between two
observations is likely to be less than 1 mm.
Table 5.2 Test-retest reliability of ultrasound measurement of the luminal diameter of

the radial artery.
Intra-observer variability Inter-observer variability
(n=10 pairs) (n=10 pairs)
Mean±SD rho P Mean±SD rho P
Distal radial artery
1st Mean luminal diameter 2.26±0.34 0.55 0.012 2.27±0.32 0.66 0.001
2nd Mean luminal diameter 2.27±0.43 2.27±0.44

Mean difference* -0.01±0.39 0±0.34
Repeatability Coefficient† 0.74 0.65
Proximal radial artery
1st Mean luminal diameter 2.68±0.33 0.48 0.033 2.53±0.50 0.58 0.007
2nd Mean luminal diameter 2.59±0.54 2.74±0.36

Mean difference* 0.09±0.50 0.22±0.48
Repeatability Coefficient† 1.01 0.98
st nd
*Mean difference between paired measurements (1 and 2 measurements)
154
†
Repeatability coefficient = (2.77 ´ estimated standard deviation of repeat observations) =
approximately 95% of differences between two repeated measurements will be less than
the repeatability coefficient
In the 73 patients examined by ultrasound, the luminal diameters of the

distal and proximal RAs were 2.35±0.56 mm (range 1.0-3.70 mm) and 3.17±0.72
mm (range 1.13-4.60 mm), respectively (Figures 5.3, 5.4).
Figure 5.3 The distribution of the luminal diameter of the distal radial artery (mm).
155
Figure 5.4 The distribution of the luminal diameter of the proximal radial artery (mm).
The mean proximal luminal diameter was significantly greater than that of
the distal luminal diameter (P<0.001). The distal RA luminal diameter correlated
significantly with that of the proximal luminal diameter (r=0.51, P<0.001).
Hypoplasia (designated arbitrarily as a luminal diameter less than 1.5 mm; Figure
5.5) was found in 2.7% (2/73) of the distal segments and 2.7% (2/73) of the
proximal segments; the two distal cases were different from the two proximal
cases.
156
Figure 5.5 Ultrasound

image of radial artery
which is 1.3 mm in
luminal diameter
Risk factors
The forward stepwise logistic procedure selected a model with the clinical
risk factors of age, male gender (male worse), and carotid artery disease for RA
calcification alone. Since two of these factors were of borderline significance, the
logistic regression model involving all three factors was fitted to the data using an
exact procedure (age: P=0.03, gender: P=0.08, carotid disease: P=0.02; Table
5.3).
The stepwise logistic regression procedure identified carotid disease and

peripheral vascular disease as suitable risk factors for any ultrasound-detected RA
disease (calcification or plaque). Using these two variables, a logistic regression
was fitted to the data employing an exact procedure. The results are shown in
Table 5.4. The risk factors for a small distal luminal diameter were diabetes and
female gender (P=0.002 and 0.03, respectively).
Table 5.3 Results of exact logistic regression analysis of dependent variables for
radial artery calcification
157
P value Odds ratios 95% confidence interval
Age 0.03 2.3* 1.1 – 5.6
Gender 0.08 0.1 0.0 – 1.2
Carotid disease 0.02 5.5 1.3 – 27
* Odds ratio corresponding to an increase of 10 years.
Table 5.4 Results of exact logistic regression analysis of dependent variables for
radial artery calcification and echogenic plaques
P value Odds ratio 95% confidence interval
Peripheral vascular disease 0.05 3.6 1.0 – 13
Carotid disease 0.08 3.3 0.9 – 13
Histopathology (n=78 specimens)
In the proximal segments of the RA, intimal hyperplasia was found in

94.9% (37/39). Atherosclerosis was found in 2.6% (1/39). One of the proximal
RA segments (2.6%; 1/39) showed chronic inflammation. Only 2.8% of the
proximal RA segments (1/36) demonstrated more than 50% luminal narrowing by
morphometric analysis. Three specimens were unsuitable for morphometric
analysis. The proximal RA segments had slightly more medial calcification than
the distal segments (20.5%; 8/39); however, this finding was not statistically
significant (P=0.73, McNemar’s test).
Intimal hyperplasia or atherosclerosis was found in 97.4% (38/39) and 2.6%

(1/39) of the distal RA segments, respectively. However, only 5.7% (2/35) of the
distal RA segments demonstrated more than 50% luminal narrowing by
morphometric analysis. Four specimens were unsuitable for morphometric
analysis. Medial calcification was found in 15.4% (6/39) of the distal RA
segments.
Comparison between ultrasound and histopathology for detection of radial
158
artery calcification (n=78 specimens)
The combined results (distal and proximal RA segments) of the comparison

between ultrasound and histopathology for detection of arterial calcification are
shown in Tables 5.5 and 5.6. Ten patients who demonstrated heavy diffuse RA
calcification by ultrasound prior to surgery did not have RA harvesting therefore
only three cases with ultrasound positive focal calcification of the proximal (1) or
distal (2) RA were harvested (Fig 5.6). All three cases showed calcification
histologically. When pathological calcification was present, surgical examination
identified calcification in only 28.6% (2/7) for the distal RA and in 37.5% (3/8)
for the proximal RA. However most of the calcification that was missed by
ultrasound and by surgical examination was minimal or minor (Fig 5.7).
Table 5.5 Comparison between ultrasound and histopathology in detecting arterial

calcification in the distal and proximal RA segment (n=78)
Ultrasound Calcification Histopathology Calcification Total
Positive Negative
Positive 3 0 3
Negative 12 63 75
Total 15 63 78
159
Table 5.6 Arterial calcification: ultrasound versus histopathology
Ultrasound detection of Distal RA (%) Proximal RA (%) Combined (%)
calcification % 95% CI % 95% CI % 95% CI
Sensitivity 28.6 4-71 12.5 0.3-53 20 6-43
Specificity 100 89-100 100 89-100 100 *
Positive predictive value 100 16-100 100 3-100 100 *
Negative predictive value 86.5 71-96 81.6 66-92 84 73-92
Diagnostic accuracy 87.2 73-96 82.1 67-93 85 74-91
Confidence intervals (CI) of test characteristics for the distal and proximal RA segments
by exact method. Confidence intervals of test characteristics for the combined data by the
bootstrap method.
* No meaningful bootstrap confidence interval could be obtained because there was no
variation in the data.
a. b.
Figure 5.6 Ultrasound image of RA calcification compared with pathological examination
in the same patient. In this case the calcification was moderate. Ultrasound, surgical and
pathological examinations were positive for calcification.
Figure 5.7 Minor medial calcification
160
DISCUSSION
The prevalence of RA calcification and echogenic intimal plaques as

detected by ultrasound was 25% and 7% respectively in patients with coronary
artery disease who underwent CABG. This prevalence was higher than in chapter
4 which only distal portion of the RAs was examined by histopathology. This
might reflect underestimation of disease in our previous chapter 4, a
histopathological study, due to limited tissue sampling. There is also a tendency
for more severe vasculopathic patients in our current surgical practice (Table 5.1).
Ultrasound (US) failed to detect calcification in 80% of cases (12/15, false

negative rate). However, the specimens usually had only a very small amount of
calcium in the histopathology sections and such a limited degree of calcification is
not likely to affect graft quality. A long-term graft patency study would be
required to address this issue definitively.
The specificity of US for calcification was very high, since it produced no

false positive diagnoses. The other valuable measurements are the positive and
negative predictive values, which combine the sensitivity and specificity with
prevalence. The higher the prevalence of a disease in the population, the higher
the positive predictive value and the lower the negative predictive value of the test
in question. In the case of the US detection of RA calcification, the positive
predictive value was calculated to be 100%, indicating that there is a 100% chance
that a patient with US positive for calcification actually has RA calcification. This
result may reflect the very high prevalence (25%) of calcification in this study;
however, in contemporary clinical practice, there are an increasing number of
patients at high risk for systemic vascular disease. In this study there was a wide
range of arterial calcification from minimal to extensive calcification while the
other reported severe calcification detected during the operation.262 In my study,
262
Acar, Ramsheyi, Pagny, et al. J Thorac Cardiovasc Surg 1998; 116:981-9., Possati,
Gaudino, Alessandrini, et al. J Thorac Cardiovasc Surg 1998; 116:1015-21.
161
the negative predictive value was 84%. This means that when the US is negative,
it is likely that 84% of patients do not have RA calcification.
In terms of risk factors for arterial disease, we found that age, male gender
and the presence of carotid artery disease predicted RA calcification detected by
US, while the risk factors associated with RA disease in general (including
echogenic intimal plaques and calcification) were carotid disease and peripheral
vascular disease. Note that some of these associations are of borderline statistical
significance (see Table 5.3 and 5.4) but involve quite large odds ratios. The
estimation of these effects, however, is imprecise due to the relatively small size
of the study and the wide confidence intervals.
Another important piece of information obtained from preoperative US

screening is the internal luminal diameter of the graft. From our data, we found
that female patients and patients with diabetes were more likely to have smaller
RAs.
In relation to the reliability of ultrasound for assessing vessel luminal

diameter, our study demonstrated significant inter- and intra-observer correlations
between test and retest measurement. However significant correlations do not
mean that the test is reliable263 and in any case the observed correlations were not
large. Therefore we calculated the mean and standard deviation of the difference
between the two tests. The repeatability coefficient of up to 1.01 mm is relatively
high. This becomes especially significant when measuring vessels less than 3 mm
in diameter and may lead to clinically significant measurement error. For
example, the RA in the proximal segment is large (around 3mm), so the
consequence of the measurement being recorded at a value between 2 and 4 is not
serious. On the other hand, for smaller luminal diameters this level of reliability
may be problematic.
263
162
There were three weaknesses in this study. Firstly, using non-invasive US it

is not possible to differentiate between medial calcification and calcification in the
intima. It is important to distinguish between these two types because intimal
calcification is associated with atherosclerosis which often leads to luminal
compromise; a selection in which the artery should not be used for grafting. In
contrast, medial calcification affects the media of the artery exclusively264 and the
effect on graft patency remains unknown.
Secondly, we were only able to histologically examine the RA at the distal

and proximal end as well as those small portions of artery left over from the
operation. Accordingly, we could not confirm the presence of all echogenic
intimal plaques thereby limiting the comparative power of the study.
The third problem is that in most of the patients with severe calcification on
US we could not confirm the presence of calcification histologically because we
did not harvest the RA in these patients. As a result, the sensitivity rate calculated
for US was low. However if we assume that all 10 cases of severe calcification by
US were true positives, then the sensitivity, negative predictive value and
diagnostic accuracy of US is 65.7% (23/35), 84% (63/75) and 87.7% (86/98),
respectively. The specificity and positive predictive value remains the same at
100%.
Is it worth screening the RA in all patients before RA harvesting? In order

to determine whether or not a vessel is suitable for use as a bypass graft, the
standard practice is to examine the RA visually and by palpation during surgery.
Usually RAs with gross calcification are excluded. Such evaluation is subjective
and likely to underestimate the degree of arterial disease present. Furthermore,
compared with US, RA exploration is a highly invasive procedure and as such
carries the risk of possible complications, such as paresthesia, infection and
264
Sappington and Cook. Am J Med Sci 1936; 192:822-839, Sappington and Horneff. Am
J Med Sci 1941; 201:862-871.
163
scarring. In contrast, ultrasound is a noninvasive procedure that can be performed

preoperatively. Therefore RA screening by US improves the graft selection
process and may potentially improve graft patency by avoiding the use of diseased
arteries. An immediate advantage to patients is the avoidance of unnecessary
forearm surgery. Another benefit of ultrasound is that it can also be used to
preoperatively assess the collateral circulation of the hand. It is also useful for
identifying anatomical variations (e.g. the site of brachial bifurcation and diameter
of the RA) as well as previous traumatic injury to the RA due to, for instance,
previous catheterisation.
CONCLUSION
Although the samples were small, my results indicate that ultrasound has a
high specificity for identifying RA calcification. It is also a useful diagnostic test
for detecting radial arteries of small internal luminal diameter. The study also
demonstrated that patients with carotid artery disease and peripheral vascular
disease are at high risk of RA disease while female patients and diabetic patients
are at risk of possessing radial arteries with a small internal diameter of the RA.
Ultrasound has the advantage of being a non-invasive technique. Based on the
findings of this study ultrasound may have a role in the preoperative assessment
of RA grafts.
164
(b) The Measurement of Intimal Hyperplasia
Introduction
The intima-media thickness measured by ultrasound (IMTu) has been used

as a noninvasive marker of atherosclerosis.265 These studies have demonstrated a
link between intima-media thickness in the carotid artery, the prevalence of
cardiovascular disease and the presence of atherosclerotic disease in other arterial
beds. Also, the thickness of the intima and media of the carotid artery, as
measured by ultrasound (US), is associated with an increased risk of myocardial
infarction and stroke in older adults without a history of cardiovascular disease. It
is therefore possible that the IMTu in the radial artery (RA) might also reflect a
degree of RA intimal disease.
Accordingly, in this section I investigate the degree of correlation between

the intima-media thickness complex as measured by US and the severity of
intimal hyperplasia and atherosclerosis as determined by morphometric analysis
from histopathology in the RAs of patients with coronary artery disease. The
hypothesis is that the intima-media thickness as measured by ultrasound is useful
for assessing the degree of intimal hyperplasia and atherosclerosis in the RA.
265
Blankenhorn, Selzer, Crawford, et al. Circulation 1993; 88:20-8, Bonithon-Kopp,
Touboul, Berr, Magne and Ducimetiere. Stroke 1996; 27:654-60, Bots, Hoes, Koudstaal, Hofman
and Grobbee. Circulation 1997; 96:1432-7, Crouse, Goldbourt, Evans, et al. Stroke 1994;
25:1354-9, Crouse, Goldbourt, Evans, et al. Stroke 1996; 27:69-75, Geroulakos, O'Gorman,
Kalodiki, Sheridan and Nicolaides. Eur Heart J 1994; 15:781-5, Hodis, Mack, LaBree, et al.
Annals of Internal Medicine 1998; 128:262-9, O'Leary, Polak, Kronmal, et al. N Engl J Med
1999; 340:14-22, O'Leary, Polak, Kronmal, et al. Stroke 1996; 27:224-31, Pignoli, Tremoli, Poli,
Oreste and Paoletti. Circulation 1986; 74:1399-406, Salonen and Salonen. J Intern Med 1991;
229:225-31, Simons, Algra, Bots, et al. Atherosclerosis 1999; 146:243-8, Wendelhag, Wiklund
and Wikstrand. Arterioscler & Thromb 1992; 12:70-7, Zureik, Ducimetiere, Touboul, et al.
Arterioscler Thromb Vasc Biol 2000; 20:1622-9.
165
Forty patients scheduled for coronary artery bypass grafting between July
1998 and May 1999 in whom the RA was used as one of the graft conduits were
included in the study. The ultrasound (US) study was performed on the day prior
to surgery. All patients with RA grafts long enough to allow a specimen to be
retained were included. There was no other selection of patients in relation to
patient characteristics. Their ages ranged from 40 to 80 years (mean 65.6, SD 10.5
yrs). There were 35 males (87.5%) and 5 females (12.5%). Seventy five percent of
patients were smokers, 55% hypertensive, 35% diabetic, 25% had peripheral
vascular disease, 22.5% carotid artery disease, 10% cerebrovascular disease, and
65% had hypercholesterolemia.
Ultrasound examination was performed between 3-5 PM on the day before

surgery in a quiet room with a stable ambient temperature of 22±3 °C by one of
Washington), HDI (High DefinitionTM Imaging) 5000 system with a 10 MHz
compact linear array transducer. Measurements were made using electronic
calipers. The US measurement method used in this study is the same as that
described by Wikstrand & Wendelhag.266 Due to the relatively high echogenicity
of the adventitia compared with the intima and media in the anterior wall, the
large trailing echoes from the adventitia tend to obscure the weaker signals from
the closely spaced intima. Therefore, the IMTu measurement was only taken from
the far wall of the artery. The far wall intima-media thickness (IMTu) is defined as
the distance between the leading edge echoes from the lumen-intima interface and
the media-adventitia interface from the far wall (Figure 5.8). The IMTu of the RA
was measured 1 cm from the artery’s origin and 2 cm from the radial styloid at
end diastole over 3 cardiac cycles. The average of these IMTu measurements was
calculated. The sonographers were blinded to the cardiovascular risk factors.
266
Wikstrand and Wendelhag. J Intern Med 1994; 236:555-9.
166
The reliability of the ultrasound measurements was investigated by

performing these measurements on 10 normal volunteers. To assess the inter-
observer variability, the same two sonographers in this study examined the RA
twice on the same day. To assess the intra-observer variability, the sonographers
performed US measurements with the same machines twice one week after the
first US. The sonographers were blinded to each other’s results as well as those of
the previous examination.
Figure 5.8 Typical radio frequency (RF) signal of artery

The far wall IMTu is the distance between the leading edge echo of lumen-intima interface
(orange) and the leading edge of the second bright echo from the far wall which is
created by the media-adventitia interface (green).
Modified from Mourad J, Priollet P, Girerd X, Safar M, Lazareth I, Laurent S. The wall to
lumen ratio of the radial artery in patients with Raynaud’s phenomenon. J Vasc Res
1997;34:298-305.
Histopathology
Distal and proximal segments of RA 1 cm from the origin and 2 cm from

the RA styloid were sampled at the time of harvesting. Preparation techniques
were the same as those described in the previous chapter. The slides were
167
examined by a pathologist blinded to the ultrasound measurement.
The morphometric analysis, as outlined in the previous chapter, was

performed on the RA 1 cm from the origin and 2 cm from the radial styloid (at the
same sites as the US measurement). The internal elastic lamina circumference
(IELC), intimal area, and medial area were measured. The internal elastic lamina
area (IEL area = luminal area+intimal area) was calculated (IEL area =
IELC2/4p).
Three parameters were used to assess the degree of intimal thickening and
atherosclerosis: (1) the percentage of luminal narrowing (%LN); (2) the intimal
thickness index (ITI); and (3) the average width of the intima-media thickness
complex (IMTm) (Figure 5.9). The severity indices were calculated from the most
severely diseased section of the specimens. The following formulae were used:
Percentage of luminal narrowing = 100´Intimal area / Internal elastic lamina area
Intimal thickness index = Intimal area / Medial area
Average width of the intima-media thickness complex = Combined width of the

intima and media in eight 45-degree sectors / 8
The last parameter, the average width of the intima-media thickness

complex (IMTm) as determined by morphometry, was measured in order to
provide a direct comparison with the far wall intima-media complex thickness as
measured by US (IMTu).
168
Figure 5.9 Schematic diagram depicting the histological indices used to evaluate the
severity of radial artery intimal hyperplasia and atherosclerosis.
Morphometric measurements: Circumference of internal elastic lamina (IELC) (Internal

elastic lamina separates intima from the muscular media), Intima-media complex – the
distance between the intima (normally an extremely thin layer) and the external elastic
lamina (external elastic lamina separates media from adventitia).
Calculated measurements: Internal elastic lamina area (area of intima plus area of
2
lumen) = IELC /4p
Statistical methods
The distributions of IMTm, ITI and %LN were all positively skewed and
therefore transformed into the logarithmic scale (base 10) and correlated with the
IMTu. Correlations between pairs of continuous variables were evaluated using
Pearson correlation coefficients (r). The factors influencing medial area were
analyzed by stepwise linear regression analysis. Nine clinical risk factors for
intimal hyperplasia and atherosclerosis (age, gender, smoking, diabetes,
hypertension, carotid artery disease, peripheral vascular disease, cerebrovascular
disease and hypercholesterolemia) were included as candidate independent
variables.
169
Intra-and inter-observer variabilities were estimated by calculating the

difference between paired measurements according to the method of Bland and
Altman.267
Results
Out of 40 RAs, there were four far wall ultrasound measurements missing
for the distal RA and three missing for the proximal RA, therefore 36 distal and
37 proximal far wall thickness of RAs were analyzed. Due to distortion from
surgical clamping, five of the distal RA specimens were unsuitable for
histological morphometry and four of the proximal RA specimens were also
unsuitable, therefore 35 distal and 34 proximal RA segments were analyzed by
morphometric analyses. The IMTu and the severity indices for intimal hyperplasia
and atherosclerosis as measured by morphometry are shown in Table 5.7.
The repeatability coefficients of the far wall intima-media complex of the

proximal and distal segments of the RA are shown in Table 5.8. I regard the
average repeatability coefficient of 0.35 as high.
267
170
Table 5.7 The far wall intima-media thickness as measured by ultrasound compared
with severity indices for atherosclerosis measured by morphometry.
Distal RA segments Proximal RA segments
Range Median Range Median
Ultrasound IMTu* (mm) 0.37-1.75 0.97 0.50-1.90 1.13
IMTm† (mm) 0.34-0.88 0.48 0.31-0.76 0.48
Morphometry ITI‡ 0.07-0.98 0.18 0.05-0.80 0.10
%LN§ 9.70-77.66 19.96 7.23-74.23 17.62
*IMTu = intima-media thickness measured by ultrasound.

†
IMTm = intima-media thickness measured by morphometry.
‡
ITI = intimal thickness index measured by morphometry.
§%LN = percentage of luminal narrowing measured by morphometry.
Table 5.8 Test-retest reliability of ultrasound measurement of far wall intima-media

thickness complex
Far wall intima-media thickness
Distal RA Proximal RA
Intraobserver: Repeatability Coefficient 0.38 0.35
Interobserver: Repeatability Coefficient 0.38 0.29
Repeatability coefficient = (2.77 ´ estimated standard deviation of repeat observations) =

approximately 95% of differences between two repeated measurements will be less than
the repeatability coefficient
Table 5.9 shows the correlation between the IMTu and the severity indices
for intimal hyperplasia and atherosclerosis as measured by morphometry. The
IMTu did not correlate significantly with the Log10 IMTm, Log10 ITI, or Log10
%LN in the distal RA [r = 0.2 (95%CI: -0.15 to 0.5; P = 0.3), 0.19 (95%CI: -0.16
to 0.50; P = 0.3) and -0.01 (95%CI: -0.35 to 0.33; P = 1), respectively] or in the
proximal RA [r = 0.06 (95%CI: -0.28 to 0.39; P = 0.8), -0.17 (95%CI: -0.47 to
0.17; P = 0.3) and -0.11 (95%CI: -0.42 to 0.23; P = 0.54), respectively].
171
In relation to the morphometry, the Log10 IMTm correlated moderately with

Log10 %LN [r =0.48 (95% CI, 0.19 to 0.69), P = 0.004] in the proximal RA
segments (Table 5.10). Hence Log10 IMTm explained 23% of the variation in
Log10 %LN (r2 = 0.23). However no correlation was demonstrated at the distal
end of RA. The Log10 IMTm was moderately correlated with the Log10 ITI in both
distal and proximal RA segments. [r = 0.48 (95%CI, 0.19 to 0.69) and 0.52
(95%CI, 0.24 to 0.72), respectively]. Thus Log10 IMTm explained 23% and 27%
of the variation in Log10 ITI in the distal and proximal segments of the RAs,
respectively. The Log10 %LN correlated well with the Log10 ITI in the distal and
proximal RA segments [r = 0.81 (95%CI, 0.66-0.90) and 0.79 (95%CI, 0.63 to
0.88), respectively, P <0.001].
The number of samples is relatively small. However, the correlations would

be sensitive to outliers even if the sample was not small. More importantly, the
test we have used of whether the true correlation is zero or not, depends on
bivariate normality. Taking logarithms transformed the data to a scale on which
the assumption of bivariate normality was reasonable. On the untransformed
scale the data were too skew. The bivariate associations summarized by the
correlations shown in Tables 5.9 and 5.10 were examined graphically. On the
scales used, with logarithmic transformations as indicated, the assumption of
bivariate normality was appropriate, as assessed by visual inspection of the
relevant scatter plots. Further, in no case was there any outlier of note.
Therefore, we preferred to use the more powerful test based on Pearson’s
correlation, given that its assumptions are reasonably justified for these data.
172
Table 5.9 Correlation between far wall intima-media thickness as measured by

ultrasound and severity indices (Log10 of IMTm, ITI, and %LN) for atherosclerosis in the
paired histopathologic sections as measured by morphometry in distal and proximal
segments of the radial artery
Distal radial artery Proximal radial artery
Variables correlated n r P value n r P value
IMTu* Log10 IMTm† 31 0.20 0.27 32 0.06 0.76
IMTu Log10 ITI‡ 31 0.19 0.30 33 -0.17 0.33
IMTu Log10 %LN§ 31 -0.01 0.96 33 -0.11 0.54
*
IMTu = far wall intima-media thickness measured by ultrasound.
†
IMTm = average of intima-media thickness measured by morphometry.
‡
§%LN = Percentage of luminal narrowing measured by morphometry.
Table 5.10 Correlation between severity indices (Log10 of %LN, ITI and IMTm) in the
paired histopathologic sections as measured by morphometry in the distal and proximal
segments of the radial artery
Distal radial artery Proximal radial artery
Variables correlated n r P value n r P value
Log10IMTm* Log10(% LN)† 35 0.31 0.07 35 0.48 0.004*
Log10IMTm Log10(ITI)‡ 35 0.48 0.004* 35 0.52 0.001*
Log10% LN Log10(ITI) 35 0.81 < 0.001* 36 0.79 < 0.001*
*IMTm = average of intima-media thickness measured by morphometry.

†
% LN = Percentage of luminal narrowing measured by morphometry.
‡
Discussion
The main finding of this study is that the intima-media complex thickness as
measured by ultrasound (US) was not a good indicator of the severity of intimal
disease in the RA. Even though it is well known that histological preparation will
173
cause all soft tissue to shrink by about 10%,268 the far wall IMTu should have
some degree of correlation with the IMTm. Wong and colleagues compared the
US and histology IMT in the carotid and femoral arterial segments.269 Histological
preparation caused 2.5% shrinkage. Intraobserver reading variation was 0.7% for
the histology and 5.4% for the US. US overestimated the thickness of the intima
and the adventitia and underestimated the thickness of the media. For combined
intima-media thickness, the differences between histology and imaging were
insignificant, averaging 4% for the carotid artery and 9% for the femoral artery in
the far-wall projection. In the near-wall projection, sonographic intima-media
thickness was 20% less than that determined histologically. The authors
concluded that ultrasonography is limited mainly by axial resolution in
quantifying the dimensions of individual arterial tunica but is capable of
accurately measuring far-wall intima-media thickness. Persson and colleagues
measured the IMTu in vitro in 19 common carotid arteries and compared the
results with the IMT measured by light microscopy.270 They found that those two
measurements were closely correlated (r=0.82, P<0.001). Gamble and colleagues
compared intima-media thickness measurement using US and histology in 27
segments of human carotid arteries in vitro and in situ in cadavers.271 They found
that IMTu best represented the total wall thickness of intima plus media plus
adventitia and not intima plus media alone. This is quite similar to my study
where the IMTu was larger than that of the IMTm because of shrinkage and the
measurement by US might have included the adventitia.
268
Bahr, Bloom and Friberg. Exp Cell Res 1957; 12:342-355, Siegel, Swan, Edwalds and
Fishbein. J Am Coll Cardiol 1985; 5:342-6, Stowell. Stain Technol 1941; 16:67-83.
269
Wong, Edelstein, Wollman and Bond. Arterioscler & Thromb 1993; 13:482-6.
270
Persson, Formgren, Israelsson and Berglund. Arterioscler & Thromb 1994; 14:261-4.
271
Gamble, Beaumont, Smith, et al. Atherosclerosis 1993; 102:163-73.
174
In my study, in the RA, surprising and contrary to previous US in the

carotid or femoral artery, the IMTu did not correlate with the IMTm and therefore
the IMTu could not be used to evaluate the severity of intimal disease. The high
repeatability coefficient also cost a doubt on the reliability of the US measurement
of IMTu in the RA. One factor contributing to this finding may have been that the
RA has a smaller diameter than that of the carotid artery making it more difficult
to accurately measure the far wall intima-media thickness.
A moderate correlation between the IMTm and the ITI in both distal and
proximal RA segments was found. There was also a moderate correlation between
the %LN and the IMTm in the proximal RA segment but not in the distal
segments. These findings, contrary to previous studies by others, suggest that if
we are to attempt to estimate the severity of the intimal disease using US, we
would need to examine several sections of the artery circumferentially.
My study had several limitations. These included a sampling error and

problems with the US. Firstly, we measured the IMTu at 1 cm from the origin and
2 cm from the RA styloid of the RA. While we attempted to perform the
morphometric measurements at the same sites there is likely to have been some
degree of variation in the site of the sampling. Also we selected the most severely
diseased section in the morphometry for comparison. Another problem was that
atherosclerosis is often a focal and eccentric disease but US often only measures
one wall of the artery. It is also important that US cannot measure the width of the
intima and media separately. Thus, while some factors that increase the IMT, such
as hypertension, may have a disproportionate effect on the media, noninvasive US
techniques conflate intimal and medial change. In the data set in the previous
chapter, 184 distal segments of the RA were examined by histopathology and
morphometry. Factors associated with higher media area were age and male
gender. In contrast, age, patients with femoropopliteal disease or diabetes were at
risk of a higher intimal area. Therefore age was the only common factor, while
male sex may have an effect on the media but not on the intima. Therefore we
may have overestimated the degree of intimal disease in male patients by using
the IMT. Lastly, the US image sometimes makes it impossible to clearly identify
175
the leading edge of the media-adventitia interface, resulting in a measurement that

might not accurately reflect the intima-media thickness.
CONCLUSION
The measurement of far wall intima-media thickness by US was not useful

for assessing the severity of intimal disease in the RA since it was associated with
high measurement variability, and it was influenced by the thickness of the media
and by the eccentric nature of intimal disease.
To accurately assess intimal disease by ultrasound we would need to: (1)

overcome the technical obstacles that prevent the measurement of separate intimal
and medial components of the arterial wall; (2) have an ability to examine arteries
circumferential; and (3) measure at multiple sites along the length of the artery.
SUMMARY
In this chapter, I presented two studies carried out by myself and colleagues
in which we examined the RA by the noninvasive ultrasound technique. In the
first study we documented the prevalence of arterial calcification and hypoplasia
in the RA. I identified a group of patients whose RA might not be suitable for
coronary artery bypass grafting because of calcification or small luminal diameter.
In the second study, I found, contrary to what was expected, that current
ultrasound was not useful for assessing intimal hyperplasia in the RA. Technical
advances in ultrasound would be necessary for it to be possible to accurately
assess intimal disease in the RA.
In the next chapter, I compare the modified Allen test with Doppler
ultrasound for the preoperative assessment of collateral circulation in the hand.
176
Chapter 6
Preoperative Assessment of Hand Circulation by Doppler
Ultrasound and Modified Allen Test
Introduction
Study Patients
Modified Allen test
Doppler dynamic test
Statistical Methods
Results
Forearm
Hand
Comparison of Modified Allen Test and Doppler dynamic test
Ulnar artery
Superficial palmar branch of the radial artery
Main thumb artery
Test characteristics for the modified Allen test
Clinical outcome
Discussion
Conclusion
Summary
Modified Allen Test and Doppler Dynamic Test 189
INTRODUCTION
As described in Chapter 2, the blood supply to the hand typically is

provided by the radial and ulnar arteries which are linked by four anastomoses.
The anterior and posterior carpal arches lie adjacent to the wrist. The superficial
palmar arch is primarily formed by the ulnar artery and the deep palmar arch
mainly by the radial artery (RA). The latter two are the most important circuits.
The success of procedures such as RA harvesting for coronary artery bypass

grafting depends upon an adequate collateral hand circulation. As my anatomical
study demonstrated, there is considerable variability in the collateral blood supply
to the hand. While there is usually at least one connection between the radial and
ulnar artery in the hand, I found that this anastomosis can be small and may not
provide an adequately supply to the hand. Furthermore, patients with coronary
artery disease are at high risk of suffering from other vascular diseases such as
carotid, aortoiliac disease, and peripheral vascular disease. The variability of the
hand collateral blood supply, in combination with the pathology of the RA as
described in Chapter 4 brought me a concern that I cannot assume that every
patient will have adequate hand collateral blood supply based on anatomical
study. Thus, this chapter discusses a study, carried out by me and my colleagues,
of techniques for assessing the hand collateral circulation before RA harvesting.
With the resurgence of the use of the RA for coronary artery bypass
grafting, tests such as the Doppler ultrasound and the Allen test have been
increasingly employed as screening devices for assessing the hand collateral
circulation. The Allen test was first described by Dr. Edgar V. Allen in 1929 to
evaluate the patency of the arterial supply to the hand in a patient with
thromboangiitis obliterans.272 Originally, the test was performed on both hands
simultaneously. The examiner stood at the side or in front of the patient, placing
one thumb lightly over each RA, with the four fingers of each hand behind the
272
Allen. Am J Med Sci 1929; 178:237-244.
178
patient’s wrist, thus holding the wrist lightly between the thumb and fingers. The
patient closed his/her hands as tightly as possible for one minute in order to
squeeze the blood out of the hand while the examiner compressed each wrist
between his/her thumb and fingers, thus occluding the radial arteries. The patient
then quickly extended his/her fingers partially while compression of the radial
arteries was maintained by the examiner. The return of color to the hand and
fingers was then noted, with this recovery time theoretically reflecting the
adequacy of the blood supply to the hand from the ulnar artery and its collaterals
with the RA.
The Allen test has subsequently been adapted and renamed the modified
Allen test,273 the primary difference between the original and the modified Allen
test being that the latter is performed on one hand at a time. The fact that the
modified Allen test is noninvasive and can be easily performed at the bedside has
resulted, not surprisingly, in its widespread use over the years as a screening
device for evaluating hand circulation. As noted, despite its popularity, its efficacy
and reliability have not been proven.
Doppler ultrasound has a number of benefits as I demonstrated in Chapter 5.

In relation to using the Doppler ultrasound for evaluation of hand collateral
circulation, one of the drawbacks is that there are no established standard criteria
for differentiating between “normal” and “abnormal” results. Several published
studies have attempted to establish a standard set of criteria.274 All studies have
agreed on the need for a dynamic component comparing Doppler signals with and
273
Ejrup, Fischer and Wright. Circulation 1966; 33:778-80.
274
Doscher, Viswanathan, Stein and Margolis. Annals of Surgery 1983; 198:776-9,
Doscher, Viswanathan, Stein and Margolis. J Cardiovasc Surg 1985; 26:171-4, Fuhrman and
McSweeney. Acad Emerg Med 1995; 2:195-9, Marcillon, Maestracci, Guillot, et al. Ann Fr
Anesth Reanim 1982; 1:403-6, Mercier, Basdevant, De Tovar and Fischler. Ann Fr Anesth
Reanim 1994; 13:785-8, Mozersky, Buckley, Hagood, Capps and Dannemiller. Am J Surg 1973;
126:810-2, Ruland, Borkenhagen and Prien. Ultraschall Med 1988; 9:63-6.
179
without compression of the RA. However, the criteria for an “abnormal” result
vary from study to study depending on which vessels are scanned.
The specific aims of this chapter, then, are: (1) to evaluate Doppler
ultrasound in assessing the hand collateral circulation; (2) to establish the criteria
for defining an abnormal Doppler dynamic test; and (3) to validate the modified
Allen test in the assessment of hand circulation before the removal of the RA.
Study Patients
Seventy-one patients (59 males, 12 females; mean age 67.3±9.8 years) who
were eligible for coronary artery bypass grafting between July 1998 and May
1999 entered into this study. The non-dominant hands of patients were tested
using both the modified Allen test and Doppler ultrasound. All observers were
blinded to other results. In terms of the patients’ characteristics, 79% (56/71) were
smokers including 9.9% (7/71) active smokers; 61% (43/71) were hypertensive;
31% (22 of 71) diabetic; 30% (21 of 71) had peripheral vascular disease; 27%
(19/71) carotid artery disease; 13% (9/71) cerebrovascular disease; and 72% (51
of 71) had hypercholesterolemia.
Testing Methods
1) Modified Allen Test
The modified Allen test was performed according to the following protocol.
The examiner faces the patient whose hand is supinated. The radial and ulnar
arteries are located by their pulses. The examiner places each thumb lightly over
the radial and ulnar artery simultaneously, with the four fingers of each hand
placed behind the patient’s wrist thus holding the wrist lightly between the thumb
and fingers. The patient’s hand is closed as tightly as possible for a period of one
minute. The patient is then asked to relax the hand and extend the fingers into a
slightly flexed position while the examiner maintains pressure on the radial and
ulnar arteries. The hand at this point should appear blanched. The examiner then
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releases the pressure on the ulnar artery and continues applying pressure to the
radial artery. The return of color to the hand and fingers is noted. In our study, the
recovery time was recorded as the time taken (in seconds) for the hand to return to
its normal color following the release of the ulnar artery. One experienced
observer performed all of the tests. An abnormal modified Allen test result was
defined as a recovery time exceeding10 seconds.
(2) Doppler dynamic test
Doppler US examination was performed the day before surgery by one of

Washington), HDI 5000 system with a 10 MHz compact linear array transducer.
The temperature in the ultrasound laboratory was maintained between a range of
23 to 25 degrees Celsius. Patients sat comfortably on a chair with their forearms
and hands positioned at the level of the heart.
Ultrasound was used to identify the bifurcation of the brachial, radial and
ulnar arteries in the forearm. A high division of the brachial artery was recorded. I
then examined: (1) the ulnar artery (UA) at the wrist; (2) the superficial palmar
branch of the RA (SPA), arising from the distal RA on the palmar aspect; and (3)
the dorsal digital thumb artery (TA), located at the medial side of the base of the
thumb. The Doppler probe was placed over the expected anatomical position of
the artery and aligned with it at an angle of less than 60º. By moving the probe
from side to side across the vessel, the center of the artery could be located readily
by a characteristic noise produced at the frequency of the pulse rate. When a
steady state was achieved, the RA was firmly compressed. The peak systolic
velocity of flow in the UA, SPA and TA with and without RA compression was
recorded. To ensure a consistent sample volume, the sonographers attempted to
keep the Doppler tracing on the same screen before and after RA compression
while the peak systolic velocity was recorded.
Flow patterns in the UA were categorized into 3 groups: (1) no flow; (2)
decreased flow; and (3) increased flow. Flow patterns in the SPA and TA with RA
compression were categorized into 4 groups: (1) no flow; (2) decreased flow; (3)
181
reversed flow; and (4) increased flow.
Statistical Methods
Data analysis was carried out using SPSSPC version 10. The data were
summarized in terms of a mean and standard deviation. Analysis of variance
(ANOVA) was used to compare the mean differences of the recovery time by
modified Allen test between the four categories of flow patterns in the SPA, UA
and TA. The recovery time by modified Allen test was used as a single continuous
response variable. Tests of normality were carried out and, where necessary, Box-
Cox transformations275 were used to obtain scales for which the assumptions of
the ANOVA were justified. Tukey’s multiple comparisons procedure was used to
test for pair-wise differences between the flow patterns in the UA, SPA, and TA
groups. Statistical significance was assumed for P values less than 0.05.
Standard estimates of sensitivity, specificity, and positive and negative

predictive values were obtained by using a two-by-two contingency table.
RESULTS
Forearm
Ultrasound identified a high division of the brachial artery in 5.6% (4/71) of

the patients. All of the ulnar and radial arteries were patent at the bifurcation and
the elbow.
Hand
An abnormal modified Allen test was found in 5.6% (4/71) of the patients.
The distribution of the flow patterns of the UA, SPA and TA is summarized in
Table 6.1. In the group of three patients who had a “no flow” pattern in the UA,
one had a high division of the brachial artery, one had calcification of the UA, and
the other had an occluded UA at the wrist. The SPA could not be identified in five
patients (7%).
275
Box and Cox. J Roy Stat Soc 1964; 26:211-252.
182
Table 6.1. The distribution flow patterns in ulnar artery (UA), superficial palmar
branch of RA (SPA) and thumb artery (TA).
Changes in peak systolic UA flow pattern SPA flow pattern TA flow pattern
velocity with RA
compression n (%) n (%) n (%)
No flow 3 (4.2) 7 (10.6) 2 (2.8)
Decreased flow 13 (18.3) 26 (39.4) 61 (85.9)
Reversed flow 0 18 (27.3) 2 (2.8)
Increased flow 55 (77.5) 15 (22.7) 6 (8.5)
Total 71 (100) 66 (100) 71 (100)
Comparison of modified Allen test and Doppler dynamic test

Ulnar artery
For UA, the data did not meet the assumptions of analysis of variance. In
particular, the three groups (no flow, increased flow and decreased flow) showed
significantly different variances. Box-Cox transformations were attempted to find
a scale on which the assumptions of ANOVA were more satisfactorily met. For
UA, the transformation used was: (Recovery time by the modified Allen test)* =
1/(Recovery time by the modified Allen test0.3); on this transformed scale
Bartlett’s test for heterogeneity of variance was not significant. This gave the
following ANOVA:
Table 6.2 Results of an ANOVA: Analyzing the differences among three flow patterns
groups of the ulnar artery (UA).
DF Seq SS Adj SS MS F P value
UA 2 0.192 0.192 0.096 13.13 <0.0001
Error 68 0.496 0.496 0.007
Total 70 0.688
DF = Degree of freedom, Adj = Adjusted, SS = Sum of Squares, MS = Mean Square
Using Tukey’s method to adjust for multiple comparisons, it was found that
the no flow group had Allen tests, on average, which were significantly higher
183
than each of the other two groups (P<0.001). There was no significant difference
between the increased flow and decreased flow groups (P>0.9).
Superficial palmar branch of the radial artery
For SPA, the same transformation (as for UA) proved to be an appropriate
scale for analysis. This gave the following ANOVA (Table 6.3):
Table 6.3 Results of an ANOVA: Analyzing the differences among four flow patterns
groups of the superficial palmar branch (SPA) of the radial artery.
DF Seq SS Adj SS Adj MS F P value
SPA 3 0.172 0.172 0.057 7.0 <0.0001
Error 62 0.507 0.507 0.008
Total 65 0.678
Tukey’s multiple comparisons procedure showed that the recovery time by

modified Allen test in the “no flow” group was significantly different from each
of the “decreased” (P = 0.002), “increased” (P = 0.01) and “reversed flow” (P <
0.001) groups. However, the “decreased, increased and reversed flow” groups
were not significantly different from each other (P > 0.4 for all pair-wise
comparisons).
Main thumb artery
For TA, the same transformation (as for UA) was used. This gave the
following ANOVA (Table 6.4). The pairwise comparisons were as for UA and
SPA: using Tukey’s method to adjust for multiple comparisons, it was found that
the “no flow” group had Allen tests, on average, which were significantly higher
than each of the “decreased” (P < 0.001), “increased” (P < 0.001) and “reversed
flow” (P < 0.01) groups, and there were no significant pairwise differences
between those groups (P > 0.4 for all pair-wise comparison).
Table 6.4 Results of an ANOVA: Analyzing the differences among four flow patterns
groups of the main thumb artery (TA).
184
DF Seq SS Adj SS Adj MS F P value
TA 3 0.188 0.188 0.063 8.4 <0.0001
Error 67 0.500 0.500 0.007
Total 70 0.688
Test characteristics for the modified Allen test
The “no flow” pattern in the Doppler dynamic test was defined as abnormal
and the others as normal. Table 6.5 shows the comparison of the modified Allen
test results with the Doppler dynamic test in the UA, SPA and TA groups. Table
6.7 represents a summary of the test characteristics of the modified Allen test
compared with the Doppler dynamic test.
Table 6.5 Comparison of the modified Allen test and Doppler dynamic test in the ulnar
artery (UA), superficial palmar branch of RA (SPA), and dorsal digital thumb artery (TA)
flow pattern groups
UA flow SPA flow TA flow
Absent Present Absent Present Absent Present
Allen test > 10 Secs 2 2 2 2 2 2
(recovery 0-10 Secs 1 66 5 57 0 67

time)
Total 3 68 7 59 2 69
Present = Increased, decreased and reversed flow patterns.
185
Table 6.7 Test characteristics of the modified Allen test compared with the Doppler
dynamic test
Characteristic UA flow SPA flow TA flow
% 95%CI % 95% CI % 95%CI
Sensitivity 66.7 9.4-99.2 28.6 3.7-71.0 100 15.8-100
Specificity 97.1 89.8-99.6 96.6 88.3-99.6 97.1 89.9-99.6
PPV 50 6.8-93.2 50 6.8-93.2 50 6.7-93.2
NPV 98.5 92.0-100 91.9 82.2-97.3 100 94.6-100
Diagnostic accuracy 95.8 88.1-99.1 89.4 79.4-95.6 97.2 90.2-99.7

UA=Ulnar artery, SPA=Superficial palmar branch of the radial artery, TA=Thumb artery,
CI=Confidence interval, PPV=Positive predictive value, NPV=Negative predictive value.
Clinical outcome
Among the 71 patients, 48 (67.7%) had their RAs harvested for CABG. The
choice of conduit depended on the surgeon’s preference and on patient enrolment
in other clinical trials. None of the patients who had RA harvesting showed signs
of hand ischemia in the immediate postoperative period. All of the patients
harvested had modified Allen test recovery times of less than 10 seconds. Among
the three patients who demonstrated a “no flow” pattern in the UA when the RA
was compressed, one patient had his RA harvested. However, this case was
associated with a high origin of the RA and only the proximal two thirds of the
RA was harvested. Four of seven patients who had a “no flow” pattern in the SPA
had RA harvesting. None of these patients suffered from hand ischemia
postoperatively. Two patients who had “no flow” patterns in the thumb artery did
not have RA harvesting as they both had modified Allen test recovery times of
more than 10 seconds. In three cases who had “no” flow in the UA, only one case
also had “no” flow in the thumb artery and in two cases who had “no” flow in the
thumb artery, only one case also had “no” flow in the UA. Therefore “no” flow in
the thumb artery does not necessary predict “no” flow in the UA, vice versa.
DISCUSSION
186
While there has been debate about over the reliability of the modified Allen
test, it has been used for assessing the hand collateral circulation with some
proven efficacy.276 It also has been used as a screening test at the Austin &
Repatriation Medical Centre since 1994. Between October 1994 and April 2000, a
total of 1657 RAs were harvested from 1323 patients (mean age 64.4, SD 10.5
years). The cut-off point of the recovery time of the modified Allen test used in
the selection of these patients for RA harvesting was 10 seconds. So far there have
been no ischemic complications of the hand. However, the modified Allen test is a
subjective, operator/patient-dependent test and there have been a number of
reports of hand ischemia after RA intervention including RA harvesting.277
Therefore I attempted to find an objective practical method for assessing the hand
collateral circulation.
This study thus also sought to evaluate the utility of Doppler ultrasound for
assessing hand collateral circulation. The advantage of the Doppler ultrasound
technique over other tests is that it can demonstrate the anatomy, measure the flow
velocity and assess the physiologic adaptation of vessels by observing the
direction of the blood flow after RA compression. However, the methods of
testing and criteria for evaluation vary considerably.
In 1973, Mozersky and colleagues assessed the completeness of the

superficial palmar arch in 70 normal volunteers (140 hands) by using a Doppler
ultrasonic velocity detector.278 They defined the superficial palmar arch as the
most distal transverse vessel in the palm. By observing the changing direction and
quantity of the flow velocity when the artery was compressed, they were able to
276
Husum and Berthelsen. Br J Anaesth 1981; 53:635-7.
277
Baker, Chunprapaph and Nyhus. Surgery 1976; 80:449-57, Crossland and Neviaser.
Hand 1977; 9:287-90, Jones and O'Brien. Br J Plast Surg 1985; 38:396-7, Nunoo-Mensah. Ann
Thorac Surg 1998; 66:929-31, Valji, Hye, Roberts, et al. Radiology 1995; 196:697-701.
278
Mozersky, Buckley, Hagood, Capps and Dannemiller. Am J Surg 1973; 126:810-2.
187
identify a complete arch (65.7%) and an incomplete arch (34.3%). Of 140 hands,
ulnar dominant collateral circulation was found in 87.1%, while a radial
dominant-complete arch with good retrograde flow was found in 2.1%. Therefore,
in this series, 89.2% of hands were expected to retain adequate circulation when
the RAs were occluded.
Doscher and colleagues in 1983 and 1985, examined 100 asymptomatic

volunteers (200 hands) with Doppler ultrasound.279 The superficial palmar arch
was scanned at the same position as Mozersky’s study. In most instances, RA
occlusion produced an increase in the ulnar to radial velocity. This finding was
interpreted as a complete superficial palmar arch. When RA compression failed to
produce a change in velocity, this was interpreted as an incomplete superficial
palmar arch. The incidence of a physiologically incomplete superficial palmar
arch in this study was 11%.
In 1976, Kamienski and Barnes used a Doppler ultrasonic velocity detector

for assessing the continuity of the palmar arch.280 There were two criteria used for
defining the continuity. Firstly, the normal arterial velocity signal was described
as multiphasic with a prominent systolic component and one or more diastolic
sounds. An arterial obstruction results in distal arterial velocity signals which are
attenuated with a resultant decrease in the systolic component and loss of the
normal diastolic sounds. Secondly, the arterial velocity is increased in response to
compression of the opposite artery at the wrist in normal subjects. Using these
“abnormal” criteria of Doppler ultrasound, the modified Allen test showed
complete concordance with the findings by Doppler ultrasound. However, in our
study the ulnar velocity was found to be decreased in 13 patients (18.3%). Of
these 13 patients, 6 had RA harvesting without ischemic complications. I
279
Doscher, Viswanathan, Stein and Margolis. Annals of Surgery 1983; 198:776-9,
Doscher, Viswanathan, Stein and Margolis. J Cardiovasc Surg 1985; 26:171-4.
280
Kamienski and Barnes. Surg Gynecol Obstet 1976; 142:861-4.
188
therefore considered both decreasing and increasing flow velocity in the UA to be

normal. These findings emphasize the importance of scanning multiple sites.
Pola and colleagues in 1996 established criteria for an abnormal Doppler

dynamic test in order to determine which RAs could be harvesting.281 These
criteria included patients without an increase in blood flow velocity in the UA
associated with flow disappearance in the SPA during RA compression. In this
study, 5.9% had an abnormal Doppler dynamic test.
Finally, in 1999 Kochi and colleagues suggested the snuffbox technique.

This technique involves examining the RA in the anatomical snuffbox area using
color Doppler ultrasound.282 In this study, all 10 normal volunteers demonstrated
reversed flow in the RA with RA compression. However, our study was more
concerned with assessing thumb artery flow and with patients who might have
digital arterial diseases.
In my study, I firstly examined the bifurcation point of the brachial artery to

confirm the patency of the radial and ulnar arteries in the forearm and the UA at
the wrist. Next, I measured the flow velocity at three different sites: (1) the UA, in
order to assess the inflow of blood supply after RA harvesting; (2) the SPA, which
is the terminal branch of the RA at the palmar side; and (3) the TA, which
supplies the area of the hand at most risk of ischemia after RA harvesting. The
advantage of the Doppler ultrasound technique is that it can demonstrate the
vessels, measure the flow velocity and assess the physiologic adaptation by
observing the direction of the flow in the vessels after the RA compression. In the
hand, however, the arteries are small and varied as mentioned in Chapter 2. The
complex patterns of anastomoses between these arteries give rise to a wide range
of responses to RA compression in the different hand arteries. This makes
interpretation of results more complicated; also the small size of vessels in the
281
Pola, Serricchio, Flore, et al. J Thorac Cardiovas Surg 1996; 112:737-44.
282
Kochi, Sueda, Orihashi and Matsuura. J Thorac Cardiovas Surg 1999; 118:756-8.
189
hand can make the detection of arterial flow difficult. The area which was
particularly difficult to scan was the SPA. Accordingly, we could not demonstrate
this vessel in 7% of cases (5/71). This is consistent with the finding in anatomical
dissection studies that this vessel is sometimes very small.283
In terms of the direction of blood flow with RA compression, our study

showed increased flow in the UA in the majority of cases. This result indicated a
functional continuity between the radial and ulnar circulation in the hand. With
the RA compressed, the distal perfusion pressure of the capillary bed is reduced.
This results in an increase in the pressure gradient between the UA and the
capillary bed causing an increase in UA flow. The reasons for reduced or absent
ulnar flow with RA compression are less clear. It is possible that other arteries
such as the median and interosseous arteries take over from the RA, thereby
diverting blood away from the distal UA. In order to minimize the risk of hand
ischemia following RA harvesting, we considered “no flow” in the UA with RA
compression as an abnormal result. Before harvesting the RA in this group, an
adequate collateral blood supply should be demonstrated.
The most common flow pattern in the SPA was “decreased flow”. This can
be explained by the reduced perfusion pressure beyond the point of compression
of the RA, the SPA’s main source of inflow. “Increased flow” suggests the
presence of a large collateral supply flowing in the same direction as the RA,
whereas “reversed flow” indicates that the RA flow has been replaced by a
collateral supply flowing in the opposite direction. However, regardless of the
direction of the flow, blood flow was still maintained by collateral flow following
RA compression, indicating continuity between the arteries in the hand. Given
their potential risk of hand ischemia following RA harvesting, the group of cases
of most concern are those that demonstrated a “no flow” pattern. Accordingly, we
considered this as an abnormal test since it might indicate incomplete superficial
and deep palmar arches. Despite this risk, in this study, four patients with “no
283
Coleman and Anson. Surg Gynecol Obstet 1961; 113:409-424.
190
flow” in the SPA with RA compression had RA harvesting without hand ischemia
postoperatively. “No flow” in the SPA with RA compression could also be due to
the presence of balanced perfusion pressure at each end of the SPA, or a
watershed effect via the deep and superficial palmar arch.
The greatest area at risk of ischemia after RA harvesting is the thumb. In our
opinion, the presence of “no flow” in the TA represents an absolute
contraindication for RA harvesting. Even though some collateral blood supply
may develop postoperatively, this group of patients carries a very high risk of
hand ischemia.
Comparing the modified Allen test with the Doppler ultrasound, the former
accurately predicts the Doppler flow patterns, particularly in the TA. Even though
there were only two patients in the “no flow” group of the TA, there was a highly
significant correlation with the modified Allen test. Comparing the modified
Allen test with the flow pattern in the TA, the false positive rate was only 2.9 %.
Furthermore, no patients with a normal modified Allen test had “no flow” in the
TA with RA compression. Overall, this study supports the validity of the use of
the modified Allen test as a primary screening test for assessing the hand
collateral circulation. The Doppler ultrasound is a useful tool for assessing hands
which produce an abnormal modified Allen test but have a good collateral
circulation, therefore increasing the number of candidates for RA harvesting.
CONCLUSION
The absence of flow in the TA during RA compression is an absolute

contraindication to RA harvesting. Absent flow in the SPA and UA is not an
absolute contraindication but requires demonstration of adequate digital artery
blood flow prior to RA harvesting. Doppler ultrasound of the forearm is useful to
exclude patients whose ulnar artery is absent, hypoplastic or diseased.
An increased recovery time using the modified Allen test predicts absence
of flow in the TA in Doppler ultrasound flow patterns, demonstrating its validity
as a primary screening test. The use of the Doppler dynamic test in conjunction
191
with the Allen test permits the safe harvesting of some RAs in patients with a
false positive abnormal modified Allen test.
In the next chapter I compare the modified Allen test with the measurement
of digital systolic blood pressure via photoplethysmography to confirm the
validity of the modified Allen test and define the appropriate cut-off point for the
recovery time for the modified Allen test.
192
Chapter 7
Evaluating the Safety of Radial Artery Removal: Allen Test
versus Digital Brachial Systolic Blood Pressure Index
using Photoplethysmography
Introduction
Study Patients
Modified Allen test
Photoplethysmography
Statistical Methods
Results
Modified Allen test

Thumb-brachial index with radial artery occlusion
Comparison of modified Allen test and thumb-brachial index
Appropriate cut-off point of the recovery time of the modified Allen test
Clinical outcome
Discussion
Conclusion
Summary
Modified Allen Test and Digital Thumb Pressure Index 200
INTRODUCTION
Currently, the methods of assessing hand circulation include the modified

Allen test, Doppler ultrasound, photoplethysmography, oximetric techniques, and
angiography.284 The modified Allen test is easily performed by the bedside and
requires no special equipment. Accordingly it is by far the most commonly used
procedure for assessing the circulation of the hand. Despite its widespread use,
there have been few attempts to systematically study the efficacy of the modified
Allen test such a study was described in Chapter 6 and also there was a difference
in the cut-off point for the modified Allen test recovery time.
Photoplethysmography is a precise and proven method for recording the pulse
wave and blood pressure in the fingers.285
The first purpose of this study was to compare the accuracy of the modified
Allen test with the thumb-brachial systolic blood pressure indices using
photoplethysmography in the assessment of hand circulation before the removal
of the radial artery (RA). The second aim was to define the appropriate cut-off
point for the modified Allen test recovery time.
284
Hirai. Circulation 1978; 58:902-8, Hirai and Kawai. J Cardiovasc Surg 1980; 21:353-
60, Husum and Berthelsen. Br J Anaesth 1981; 53:635-7, Johnson, Cromartie, Arrants, Wuamett
and Holt. Ann Thorac Surg 1998; 65:1167, Pola, Serricchio, Flore, et al. J Thorac Cardiovas Surg
1996; 112:737-44, Starnes, Wolk, Lampman, et al. J Thorac Cardiovas Surg 1999; 117:261-6.
285
Bone and Pomajzl. Surgery 1981; 89:569-74, Gahtan. Surgical Clinics of North
America 1998; 78:507-18, Kempczinski. J Cardiovasc Surg 1982; 23:125-9, Raines, Darling,
Buth, Brewster and Austen. Surgery 1976; 79:21-9, Ramsey, Manke and Sumner. J Cardiovasc
Surg 1983; 24:43-8.
194
Study Patients
Eighty-four patients (70 males, 14 females; mean age 65.99±9.73 years)

who were eligible for coronary artery bypass grafting were entered into this study.
In 79 patients the left hand, and in 75 patients the right hand, were tested using
both the modified Allen test and photoplethysmography.
Testing Methods
(1) Modified Allen Test
The modified Allen test was performed similar as described in Chapter 6

and was performed by one experienced observer.
(2) Photoplethysmography
Systolic blood pressures were measured using a digital blood pressure cuff
with a photoplethysmography amplifier module (PPG 100A) using the BIOPAC
System Inc.’s TSD100 photoelectric plethysmogram transducer. Blood pressure
analyses were obtained using the AcqKnowledge@ III software and the
MP100WSW (manufactured by BIOPAC Systems, Inc. 275 South Orange Ave,
California). Brachial blood pressure measurement was performed using a blood
pressure cuff inflated over the upper arm and a transducer secured over the
brachial artery to detect the return of blood flow on deflation of the cuff. For
thumb blood pressure measurements, blood pressure cuffs of 20mm in width were
inflated over the thumb, while transducers secured to the volar surface of the
distal phalanx were used to measure blood pressure.
Vascular assessment of the hand was performed in a laboratory and a

temperature of between 23 to 25 degrees Celsius was maintained. Patients were
positioned to lie comfortably on a bed with the upper body angled at 45 to 60
degrees from the horizontal. The forearm undergoing testing was rested on a table
at or slightly above the level of the heart. Prior to the commencement of testing
the patient’s systolic blood pressure was recorded. This was repeated at
195
five-minute intervals. When the systolic blood pressure returned to within 5

mmHg of the previous recording a steady state condition was considered to have
been achieved and testing commenced. In order to minimize fluctuations in
central blood pressure, patients were encouraged to remain relaxed and not to
speak or move during data collection.
The brachial and thumb systolic blood pressures were recorded at rest.
Occlusive clamps were then applied to the RA near its origin distal to the elbow
and about 3cm proximal to the wrist. Doppler ultrasound was used to confirm the
completeness of occlusion of the distal and proximal segments of the RA, and to
verify that the clamps were not occluding other vessels. The brachial and thumb
systolic blood pressures were recorded sequentially. The thumb-brachial index
with RA occlusion (TBIO) was also calculated (TBIO = systolic blood pressure of
thumb artery with RA occlusion/ brachial systolic blood pressure). In our study
we used a thumb-brachial index rather than the index finger-brachial index
because the RA contributes more to the blood supply of the thumb than to the
index finger. Abnormal thumb-brachial indices were defined as those less than
0.75.
Statistical Methods
Data analysis was carried out using MINITAB version 12 PC and SPSSPC
version 8. The data were summarized in terms of a mean and standard deviation.
An analysis of thumb-brachial indices was performed by analysis of variance
(ANOVA). The three categorical explanatory variables (factors) were the
recovery time from the modified Allen test, the hand (right or left) tested, and
factors relating to the individual patient. Hand and individual patient variables
were factored into the analyses in order to accurately assess the impact of the
modified Allen test factor. Recovery time from the modified Allen test was
divided into three groups: (1) less than or equal to 10 seconds, (2) 11 to 20
seconds, and (3) greater than 20 seconds.
The TBIO was used as a single continuous response variable. Tests of

normality were carried out and, where necessary, transformations were used to
196
obtain scales for which the assumptions of ANOVA were justified. Tukey’s
multiple comparisons procedure was used to test for pair-wise differences among
the three modified Allen test groups. Correlation between the TBIO and the
modified Allen test was performed by Spearman’s correlation. Statistical
significance was assumed for P values less than 0.05.
RESULTS
Modified Allen Test
The distribution of the modified Allen test categories across the three groups
is shown in Table 7.1. Among the 154 hands, most (107, 69.5%) had a recovery
time by modified Allen test of less than or equal to 10 seconds. The modified
Allen test weakly correlated with age in the right hand (Spearman’s rho=0.27, P
=0.02) and the left hand (Spearman’s rho = 0.38, P = 0.001).
Table 7.1 Distribution of recovery time from the modified Allen test
Modified Allen test groups (recovery time) Number of hands (%)
1 (0-10 seconds) 107 (69.5)
2 (11-20 seconds) 14 (9.1)
3 (> 20 seconds) 33 (21.4)
Thumb-brachial index with radial artery occlusion
The thumb-brachial indices data are summarized in Table 7.2. The

distribution of response variables (TBIO) is shown in Figure 7.1. The TBIO was £
0.75 in 34 hands (22.1%).
Table 7.2 The Thumb-brachial index without and with RA occlusion (n=154)
Variables Mean (SD) Median Minimum Maximum
TBI 0.98 (0.11) 0.99 0.65 1.31
TBIO 0.87 (0.25) 0.94 0 1.31
TBI indicates thumb-brachial index; and TBIO, thumb-brachial index with RA occlusion
197
Figure 7.1 The distribution of the thumb-brachial index with RA occlusion (TBIO).
Comparison of Modified Allen Test and Thumb Brachial Index with Radial
Artery Occlusion
There was a moderate correlation between the recovery time from the
modified Allen test and the TBIO in both left and right hands (Table 7.3).
Table 7.3 Correlations (Spearman’s rho) between recovery time from the modified
Allen test in the right hand and thumb-brachial index with radial artery occlusion (TBIO)
Hand Variables N rho P value
Right Modified Allen test TBIO 75 - 0.40 <0.001
Left Modified Allen test TBIO 79 - 0.51 <0.001
TBIO indicates thumb-brachial index with radial artery occlusion.
After adjustment for patient and hand factors, there was a significant
difference among the modified Allen test groups for TBIO (F = 6.5, P = 0.003;
Table 7.4). Tukey’s multiple comparisons procedure showed that Groups 2 and 3
198
had significantly lower TBIO levels than Group 1 (P = 0.01 and P = 0.02
respectively), but Groups 2 and 3 were not significantly different (P > 0.9).
Table 7.4 Results of analysis of variance for thumb-brachial index with radial artery
occlusion (TBIO)
Source DF SS Adj MS F P
Subject 83 8.57 0.06 2.19 0.001

Hand 1 0.03 0.03 0.57 0.453
Allen 2 0.61 0.31 6.47 0.003
Error 67 3.16 0.05
Total 153*
Hand indicates right or left hand; and Allen, the three categories of recovery time from the
modified Allen test.
df, degrees of freedom; SS, sum of squares; Adj MS, adjusted mean square; F, ratio of
mean squares.
*One outlier excluded from results.
The group of hands that had a recovery time of more than 10 seconds in the
modified Allen test had a mean and median TBIO of 0.67 and 0.70 respectively
(Fig. 7.2).
Figure 7.2 Boxplot of the Allen groups (normal £10 seconds, abnormal >10 seconds)
and thumb- brachial index with radial artery occlusion (TBIO). The boxes show the
median and interquartile distance. The whiskers extend to the extreme values of the data,
not including outliers (*) which are the values more than 1.5 times the interquartile
distance from the upper and lower edges of the box and which are shown separately.
Defining an abnormal recovery time of the modified Allen test as more than
10 seconds and abnormal TBIO as less than 0.75, the false positive, false negative
rate and diagnostic accuracy of the modified Allen test were 17%, 21%, and 82%
respectively, using TBIO as a gold standard. Of the set of hand measurements for
which the TBIO was ³ 0.75, twenty-one measurements (44.7%) had an abnormal
modified Allen test (Table 7.5).
Table 7.5 Results of the modified Allen test groups compared with the thumb-
brachial index with radial artery occlusion (n=154)
Modified Allen test Thumb-brachial index with radial artery occlusion
199
Abnormal (< 0.75) Normal (³ 0.75) Total
Abnormal (> 10 seconds) 26 21† 47
Normal (£ 10 seconds) 7* 100 107
Total 33 121 154

*False negative, †False positive; based on the thumb-brachial index with radial artery
occlusion.
Appropriate cut-off point of the recovery time of the modified Allen test
When a TBIO greater than or equal to 0.75 was defined as normal, the
probability of a false positive was 21 out of 121 hands, or 17.4%. The probability
of a false negative using the modified Allen test was estimated to be 7 out of 33
hands (21.2%). The most desirable test is one that has both a low false positive
and a low false negative rate. Taking the false positive and the false negative rate
into account simultaneously and giving them equal weight, the best measure of
the accuracy of the Allen test is Youden’s misclassification index.286
Youden’s index = 100 - [false positive rate (%) + false negative rate (%)]
Using this measure, the best cut-off point for the modified Allen test time is
12 seconds, as demonstrated in the receiver operating characteristics (ROC) curve
(figure 7.3). At this point, both the sensitivity and specificity estimates are high
(79% and 84%, respectively), and Youden’s index achieves its maximum value of
63%.
Figure 7.3 The receiver operating characteristic (ROC) curve. In this plot the cut-off in
seconds varies from a low of 2 seconds at the top right hand corner to a maximum of 25
seconds at the bottom left hand corner. The intersection of the diagonal line and the
curved plotted line provides an objective cut-off point.
286
Armitage. Statistical methods in medical research 1994.
200
If we are to rely on the modified Allen test as a screening procedure

however, it is important to reduce the false negative rate and thus the number of
patients at risk of hand ischemia. Therefore we will need to reduce the threshold
recovery time used to determine abnormality. From our data we can generate the
plot between the false negative rate and modified Allen test recovery time. The
false negative rate can be estimated to be 12.1%, 15.2% and 18.2 % if we reduce
the threshold recovery time from the modified Allen test to 3, 4 and 5 - 8 seconds
respectively. The false negative rate increases to 21.2% when we use 9 - 12
seconds as a cut-off point (figure 7.4).
Figure 7.4 Plot of the false negative rate (%) versus the cut-off point of the recovery
time for the modified Allen test (seconds).
Figure 7.5 Plot of Youden’s index (%) versus the cut-off point of
the recovery time for the modified Allen test (seconds).
To reduce the false negative rate to around 15-18%, it would be necessary to

use a cut-off point of four to eight seconds. For the threshold of eight seconds, the
sensitivity was estimated to be 82%, the specificity 80% and Youden’s index was
62% (Figure 7.5).
Clinical outcome
Among the 84 patients, 36 patients had single RAs harvested and six
patients had bilateral RAs harvested. The average recovery time using the
modified Allen test in patients who had RA harvesting was 6.6±14.1 seconds
(mean ± SD) while the average TBIO was 0.96 ± 0.20 (mean ± SD). All patients
who had RA harvesting had normal Allen test (recovery time of the Allen test
equal to or less than 10 seconds). Interestingly, one patient had a TBIO of 0.3 and
recovery time by Allen test of 3 seconds and did not suffer from postoperative
201
hand ischemia. This may relate to the TBIO test error. To date, no cases of hand
ischemia have occurred in these patients.
DISCUSSION
Being the simplest screening tool, the modified Allen test’s advantages are
that it is easy to perform, repeatable, and does not require any instruments.
Obviously, the results will be unreliable, if the Allen test is performed
incorrectly.287 For example, the test may produce a falsely positive result if the
hand is hyperextended. Moreover, if the RA is compressed too firmly it may
cause partial compression to the ulnar artery by shearing stress thereby
confounding the results.
There have been few attempts to systematically study the efficacy of the
modified Allen test when performed correctly. Benit and colleagues performed
modified Allen tests on 1,000 consecutive patients undergoing cardiac
catheterisation.288 The times to recovery were less than 5 seconds in 49% of
patients, between 5 to 9 seconds in 24%, and 10 seconds or more in 27% of cases.
Defining an abnormal recovery time as greater than 10 seconds, the authors noted
the relatively high proportion of patients in their sample who were contraindicated
for the procedure of transradial coronary angioplasty.
Hosokawa and colleagues examined 2,940 arms in patients who underwent

surgery or had an examination in the anaesthesiology department. In this study, an
abnormal Allen test was defined by a recovery time of more than 5 seconds.289
The Allen test showed abnormalities in 3.6% of cases. A significant finding in this
287
Hirai and Kawai. J Cardiovasc Surg 1980; 21:353-60.
288
Benit, Vranckx, Jaspers, et al. Catheterization & Cardiovascular Diagnosis 1996;
38:352-4.
289
Hosokawa, Hata, Yano, et al. Annals of Plastic Surgery 1990; 24:149-51.
202
study was that the incidence of an abnormal Allen test increased with age. The
incidence was 2.2% in the first decade rising to 6.9% in the ninth decade and later.
In contrast, our study showed only a weak correlation between the modified Allen
test and age, which may be due to the fact that our patient population did not
include young patients (with a mean age of around 66 years).
Johnson and associates used the modified Allen test in combination with
pulse oximetry to assess the adequacy of the collateral circulation of the hand.290
They arbitrarily chose a recovery time of 12 seconds. On the basis of this
screening criterion, they harvested 452 radial arteries and experienced no
instances of vascular compromise in these patients. Five percent of patients tested
were not suitable for RA harvesting using this method. While these three reports
support the use of the Allen test as a screening device, the results of these studies
cannot be generalized as they assessed the Allen test without comparing it to an
objective technique. There have been few comparative studies investigating the
relative efficacy of the Allen test.
In 1981, Husum and Berthelsen compared the modified Allen test with
thumb systolic arterial pressure as measured by strain-gauge plethysmography in
118 patients.291 A normal Allen test recovery time was defined as less than six
seconds while an abnormal result with plethysmography was defined by a thumb
systolic pressure of less than 40 mm Hg after RA occlusion. Using these criteria,
they obtained unusually high results. For example, they found that the predictive
value of a negative Allen test was 0.99, that is, in only 0.8% of cases did the Allen
test falsely indicate the adequacy of the collateral hand circulation. At the same
time, however, they also found that the Allen test had a very high false positive
rate. It falsely indicated an inadequate collateral circulation in 50% of positive
tests.
290
Johnson, Cromartie, Arrants, Wuamett and Holt. Ann Thorac Surg 1998; 65:1167.
291
Husum and Berthelsen. Br J Anaesth 1981; 53:635-7.
203
In 1999, Starnes and colleagues published the results of a study in which

129 consecutive patients, referred for preoperative evaluation of hand circulation
before coronary artery bypass grafting, were assessed by using both the modified
Allen test and photoplethysmography.292 The modified Allen test was performed
using a Doppler probe to assess blood flow in the superficial palmar arch. A
decrease in the audible Doppler signal with RA compression was considered a
positive modified Allen test. The digital artery systolic pressure was measured in
both the thumb and index fingers. In this study, an abnormal result was defined as
a reduction in digital artery systolic pressure with RA compression of equal to or
greater than 40 mmHg. Using this criterion, they found that 50 percent of
extremities with an abnormal modified Allen test had a digital blood pressure
reduction of less than 40 mm Hg indicating a high false positive rate. In terms of
false negatives, 9 percent of cases with a negative Allen test experienced a
reduction in blood pressure of 40mm Hg or more. However, the validity of this
study’s findings is questionable given the flawed nature of the criterion used to
identify abnormal circulation. For example, in patients who have low digital
artery systolic pressure before RA compression, after RA compression the
pressure can decrease to critical levels while producing a pressure reduction of
less than 40 mmHg. In order to avoid this problem in our study we used the
digital-brachial index, that is, the digital systolic blood pressure compared with
the patient’s normal proximal systemic pressure.
There have been several reports showing a correlation between abnormal

digital-systemic blood pressure indices and the risk of clinical ischemia.293
However, these studies examined the lower, rather than upper extremities. Thus,
the cut-off of 0.75 used in our study to distinguish normal from abnormal digital
292
Starnes, Wolk, Lampman, et al. J Thorac Cardiovas Surg 1999; 117:261-6.
293
Bone and Pomajzl. Surgery 1981; 89:569-74, Gahtan. Surgical Clinics of North
America 1998; 78:507-18, Kempczinski. J Cardiovasc Surg 1982; 23:125-9, Raines, Darling,
Buth, Brewster and Austen. Surgery 1976; 79:21-9, Ramsey, Manke and Sumner. J Cardiovasc
Surg 1983; 24:43-8.
204
brachial indices, was derived from a study of peripheral vascular disease in the
lower limb and we assumed that the optimal pressure for supplying the tissue in
the upper extremity is the same as the lower extremity. According to the ankle-
brachial index, the following indices are consistent with the following clinical
diagnoses: normal (1.0 to 1.2), claudicating (0.5 to 0.9), existing tissue loss
unlikely to heal (<0.5), irreversible ischemia (0.0), and non-compressible vessels
secondary to medial calcification (>1.3).294
Dumanian and colleagues recommend not using the RA when digital

brachial indices are less than 0.75 or when there is a low pulse-volume recording
ratio (<0.4) in the index finger with RA compression at the wrist.295 This was
based on a previous study performed to evaluate lower extremity peripheral
vascular disease. Using this method, the authors determined that 98 patients out of
122 (80%) were suitable for harvesting the RA.
In our study, when a TBIO ³ 0.75 was defined as normal, the false negative
rate was 21% of cases which passed the modified Allen test while being deemed
as unsatisfactory according to the TBIO test. This means that among cases where
we might decide to use the RA based on the normal modified Allen test alone,
21% would be potentially at risk from hand ischemia. In order to reduce the false
negative rate, we recommend to reduce the threshold of the modified Allen test to
8 seconds based on TBIO. Of course, the presence of an abnormal TBIO does not
necessarily translate into clinical ischemia as both the modified Allen test and
thumb-brachial indices measure the events immediately after occlusion of the RA
and do not take into account the subsequent compensatory events that lead to the
development of the collateral circulation. On the basis of these results, we
recommend using the TBIO only when the modified Allen test is abnormal, thus
saving the time and cost of the TBIO test.
294
Gahtan. Surgical Clinics of North America 1998; 78:507-18.
205
It must be noted at this point that our study suffers from two potential
deficiencies. Firstly, the TBIO cannot necessarily be regarded as the gold standard
of circulatory screening and therefore may not represent the most accurate
baseline against which to measure the Allen test. Secondly, given that the data we
used came from patients with coronary heart disease referred to the Cardiac
Surgery Unit, questions might be raised about whether the results of this study are
applicable to patients in other clinical settings.
This study sought to comprehensively assess the validity of the Allen test
against an objective measurement of thumb systolic blood pressure. In our
experience, because it is easy to perform, the modified Allen test is excellent for
use as a screening test. In contrast, the TBIO is relatively time consuming and
hard to measure. While the Allen test correlates reasonably well with the TBIO it
has a high false positive rate. Therefore, we recommend the use of the modified
Allen test for primary screening. In the event of an abnormal result, however, we
suggest that a more sophisticated test, such as digital blood pressure
plethysmography or Doppler ultrasound, be performed.
CONCLUSIONS
In conclusion, both the modified Allen test and the thumb-brachial indices
can be used to determine the safety of RA intervention. Both methods, however,
have certain pitfalls and should be performed and interpreted carefully. Our study
found that when the modified Allen test was equal to or less than 10 seconds, it
was safe to harvest the RA. If the modified Allen test was more than 10 seconds,
there was still a possibility that the RA might be harvested. In these latter cases,
we recommend the performance of an additional more accurate test, such as
photoplethysmography, to evaluate the hand circulation.
295
Dumanian, Segalman, Buehner, et al. Plastic & Reconstructive Surgery 1998;
102:1993-8, Dumanian, Segalman, Mispireta, et al. Ann Thorac Surg 1998; 65:1284-7.
206
SUMMARY
In this chapter, I presented a study that examined and confirmed the efficacy
and validity of the modified Allen test as a screening test for assessing hand
collateral circulation by comparing it with the digital systolic blood pressure as
measured by plethysmography. Based on sensitivity, specificity and false negative
rates, this study identified the best cut off point for modified Allen test recovery
time to be 8 seconds.
Comparing the digital systolic blood pressure as measured by

plethysmography with the Doppler dynamic test (Chapter 6) for assessing the
hand collateral circulation, I would recommend the use of the Doppler dynamic
test instead of plethysmography in case of an abnormal modified Allen test for
several reasons. Firstly, it is relatively simple. Secondly, it examines the anatomy
and flow in the digital arteries simultaneously. Thirdly, as I describe in Chapter 5,
ultrasound can also identify arterial intimal plaque, calcification and hypoplasia of
RA and ulnar artery.
207
Chapter 8
Survival after Coronary Artery Bypass Grafting:
Comparison of the Internal Thoracic Artery, Radial Artery
and Saphenous Vein as the Second Graft of Choice
Introduction
Patient Population
Surgical Techniques
Left and right internal thoracic arteries harvesting
Radial artery harvesting
Great saphenous vein harvesting
Cardiopulmonary bypass and coronary anastomotic technique
Follow-up
Results
Kaplan-Meier Estimated Survival

Cox’s Proportional Hazards Model
Discussion
Summary
Survival after radial artery grafting 222
Introduction
In this chapter I tested the hypothesis that the radial artery (RA) is a viable
coronary artery bypass graft by undertaking a survival analysis. This analysis
involved an observational study of a large group of patients who had received RA
grafts for coronary artery bypass grafting (CABG). We modeled the survival data
on patients who had had CABG with two conduits. The first graft used was the
left internal thoracic artery (LITA) while the second graft used was the right
internal thoracic artery (RITA), RA or saphenous vein (SV).
The aims of this study were to: (1) determine the survival rate of patients
after CABG with RA, and (2) compare the mid-term survival data of the RA as a
second graft compared with the SV and RITA while adjusting for the different
risk factors for mortality after CABG.
Patient Population
Between 3 January 1995 and 26 June 2000, 1,231 patients who underwent
isolated primary CABG at the Austin & Repatriation Medical Centre and Epworth
Hospital using exactly two conduits were included in this study. Patients
undergoing reoperative CABG, associated cardiac valvular repair/replacement,
repair/resection of left ventricular aneurysm or other cardiac/vascular operations
were excluded. The mean age of patients was 64.3 years with a standard deviation
(SD) of 10.35 years. The data were prospectively collected, verified and entered
into a database and maintained by Dr. John Fuller, Cardiologist, at the Epworth
Hospital, Melbourne, Australia. The data definitions were compiled using the
Society of Thoracic Surgeons’ definitions. The RA began to be used as a second
graft at our Centre in 1995 and patients were recruited from this time onwards.
Nineteen surgeons participated in this study. Graft selection for the second graft
occurred at the discretion of the attending surgeons. We avoided using the RITA
in older or diabetic patients. The collateral circulation of the hand was assessed
before RA harvesting using the modified Allen test. A recovery time (the time
209
required for the color to return to the hand after release of the ulnar artery) of
more than 10 seconds was regarded as a contraindication for RA harvesting.
During surgery, grafts with obvious calcification were also excluded. Saphenous
veins with varicosities were not used for grafting.
All patients received a left internal thoracic artery (LITA) as their first graft.
The second graft used was the RA in 700 patients (56.9% of cases), the RITA in
333 patients (27.1% of cases), and the SV in 198 patients (16.1% of cases).
Fourteen potential risk factors for death are summarized in Table 8.1.
210
Table 8.1. Baseline clinical characteristics.
Characteristic Overall RITA RA SV P

(n=1,231) (n=333) (n=700) (n=198) value*
Age (mean±SD) yrs 64.3±10.35 59.2±9.75 65.7±10.09 67.9±9.06 <0.001
Sex: male 75.9% 83.8% 73.9% 69.7% <0.001

Diabetes 20.1% 6.3% 23.4% 31.3% <0.001
Hypertension 46.1% 36.6% 48.6% 53% <0.001
Peripheral vascular 6.1% 5.1% 6.6% 6.1% 0.7
disease
Carotid disease 11.5% 6.6% 12.9% 15.2% 0.003
Cigarette smoker 54.4% 54.1% 53.3% 59.1% 0.3
Aortic stenosis 2.6% 1.8% 2.9% 3% 0.6
Aortic regurgitation 3.7% 2.7% 3.9% 5.1% 0.4
Mitral regurgitation 5.9% 3.3% 7.4% 5.1% 0.03
Previous myocardial 38.5% 31.2% 38% 52.5% <0.001
infarction
Urgent and 15.8% 15% 14.4% 21.7% 0.04
emergency surgery
Ventricular function 0.1
EF ³ 50% 81.6% 85.6% 81.1% 76.8%

EF = 30-49% 16.5% 13.5% 16.9% 20.2%
EF < 30% 1.9% 0.9% 2.0% 3.0%
No. of anastomoses <0.001
2 66% 77.8% 56.7% 78.8%
3 27.4% 21.6% 32.6% 18.7%
4-5 6.7% 0.6% 10.7% 2.5%
* P value for comparison of differences between the RITA, RA and SV groups.
Surgical techniques
211
Left and right internal thoracic arteries harvesting
Following a conventional sternotomy, the LITA, and then the RITA, were
harvested with a pedicle containing the pleura, the transversus thoracis muscle and
fascia, and the internal thoracic veins (Fig. 8.1). The dissection commenced at the
lower end of the sternum, near the internal thoracic artery bifurcation, and
extended proximally to the inferior border of the subclavian vein. On the right
side, the internal thoracic vein was mobilized to its termination with the right
brachiocephalic vein. The upper branches of the ITA, including the
pericardiacophrenic artery, were ligated with small clips adjacent to the ITA. The
pedicle was sprayed with 1 mmol of a solution containing 80mg/ml papaverine
and Ringer’s lactate solution. Following the transsection of either the lower end of
the RITA pedicle or its terminal branches, and prior to implantation, the free flow
was checked to exclude any proximal obstruction. Two to three cc of an equal
mixture of the papaverine and Ringer’s lactate solution mixed with blood
(1mmol/l, pH 7.4) was injected into the distal end of the ITA or one of its terminal
branches. The distal end was then clipped using hemostatic clips (Weck hemoclip,
North Carolina, U.S.A.) and allowed to distend under arterial pressure.
Figure 8.1 The left internal thoracic artery (LITA), In situ, pedicle. The LITA can be seen
emerging from the left chest through the pericardial window, lying on the heart.
Prior to the commencement of cardiopulmonary bypass, the right pedicle
212
was passed through a window in the right pleura and pericardium, immediately
anterior to the phrenic nerve, and its length assessed in relation to the left or right
coronary artery system. If deemed inadequate, the right internal thoracic vein was
divided by double clipping, using medium Weck hemoclips. The RITA was then
similarly clipped at the level of the inferior border of the right subclavian vein.
The graft was stored in the mixture of papaverine, Ringer’s lactate and
heparinized blood.
Radial artery harvesting
The RA often was harvested concurrently with the LITA harvesting and
sometimes before the sternotomy. The arm was supinated and abducted to 70
degrees from the torso, on the arm board. The incision was made from 2 cm
below the elbow to 2 cm above the wrist, slightly medial to the line of the RA in
order to avoid injury to the medial and lateral cutaneous nerves of forearm as
described in Chapter 2. The distal third of the RA was superficial and covered
only by the subcutaneous tissue. The proximal two thirds of the RA was covered
by the brachioradialis muscle (Fig. 8.2a). The medial border of the brachioradialis
muscle was divided and retracted laterally (Fig. 8.2b). This step can start at the
distal or the proximal forearm. For the distal forearm the fascia lining above the
RA was divided, then the dissection was continued proximally. It was necessary
to divide the 3-4 branches from the RA which supply the brachioradialis
superficially (Fig. 8.2c).
After the RA was fully exposed, it was mobilized with its two venae
comitantes (Fig. 8.2d). Direct handling of the artery was avoided to prevent
arterial spasm. Muscular branches were divided with metal clips, not too close to
the artery to avoid compromising the lumen. The distal end of RA was double
clipped and divided at about 2 cm above the wrist joint. Two to three cc of the
same papaverine mixture used for the ITA was injected into the distal end of the
RA (Fig. 8.2 e and f). Dissection was undertaken towards the bifurcation of the
brachial artery proximally while the artery was dilated under arterial pressure.
However injury to the venous plexus around the bifurcation was avoided to
prevent arm edema. The recurrent radial artery, sometimes present, could be
213
divided. The proximal end of RA was double clipped and divided 1 cm below the
brachial bifurcation. The RA was then stored in the papaverine and Ringer’s
lactate solution until implantation.
a. b.
c. d.
e. f.
Figure 8.2 The radial artery (RA) harvesting technique (Left forearm)
(a). The skin incision is made along an imaginary line from the centre of the bent elbow,
three cm below the elbow, to the fore part of the styloid process of the radius, three cm
above the radial styloid.
(b),(c). The radial artery is exposed.
(d). Complete mobilization of the radial artery,
(e),(f). The radial artery is dilated with the papaverine mixture under physiologic pressure.
214
Great saphenous vein harvesting
The SV was always harvested simultaneously with the ITA. Most of the SV
used in this study was from the lower part of the leg. The patient was in the frog
leg position. The incision was made just lateral to the anterior edge of the medial
malleolus and followed the course of the vein. The tributaries of the vein were
divided with silk no. 3-0 or metal clips using atraumatic techniques, holding the
adventitia of the vein and avoiding excessive direct grasping of the vein wall. The
distal end of the vein was double clipped divided at about 2-4 cm above the
medial malleolus. The same papaverine and Ringer’s lactate solution mixed with
blood (1mmol/l, pH 7.4) used to dilate the ITA and RA, was injected into the
distal end of the SV, avoiding excessive pressure. The SV was then checked for
the residual tributaries and divided. The proximal end was double clipped and the
graft stored in the same solution as for the free RITA and RA.
Cardiopulmonary bypass and coronary anastomotic technique
Cardiopulmonary bypass was performed at 34oC and combined antegrade

and retrograde blood cardioplegia at 25oC employed, using a single cross clamp
for all distal and proximal anastomoses. All distal anastomoses were performed
using 7/0 polypropylene sutures with the pedicle attached to the adjacent
epicardium. Sequential anastomoses were performed when the grafts and target
arteries were suitable. Proximal anastomoses, if required, were performed directly
with the ascending thoracic aorta using a continuous 6/0 polypropylene suture.
Postoperatively, the mean arterial pressure was maintained at 70 to 80 mmHg or
above, with a cardiac index of over two l.min-1.m-2 and a systemic vascular
resistance of greater than 800 to 1,000 dynes.sec.cm-5. Dilatation of the arterial
grafts relied on topical papaverine and the systemic vasodilators nitroglycerine,
sodium nitroprusside, or the phosphodiesterase III inhibitor (milrinone) were
added to produce a cardiac index of three l.min-1.m-2.
Follow-up
Patients were followed up by mailing questionnaires and by contacting

general practitioners and surgeons. Deaths were confirmed by reference to the
215
Australian National Death Index, a computer-based system that updates its

records on a 3 monthly basis, and used by the Australian Institute of Health and
Welfare to track all deaths. The average follow-up time in our study was 32.9
months (SD 18.8). The primary end point of this study was all-cause mortality.
Continuous data are presented as means and standard deviations (SD).

Differences in baseline characteristics were compared between patients in the
three different second graft groups by analyses of variance and chi-square tests.
The Kaplan-Meier method296 was used for the unadjusted survival of the patients
in the graft groups separately. The logrank test was used to test the difference in
survival rates.
To control for potential imbalances in baseline risk factor variables related

to the non-randomized nature of this study, we used Cox’s proportional hazards
model297 to adjust for the type of second graft used, the individual surgeons
involved, and the 14 other potential risk factors shown in Table 8.1. The variables
included in the model were all those considered prior to surgery to be major risk
factors for survival following CABG298 as well as any other statistically
296
Kaplan and Meier. J Am Stat Assoc 1958; 53:457-481.
297
Cox. J R Stat Soc B 1972; 34:187-220.
298
Birkmeyer, Quinton, O'Connor, et al. Arch Surg 1996; 131:316-21, Brooks, Jones,
Bach, et al. Circulation 2000; 101:2682-9, Christakis, Weisel, Fremes, et al. J Thorac Cardiovas
Surg 1992; 103:1083-91; discussion 1091-2, Cosgrove, Loop, Lytle, et al. Annals of Surgery
1985; 202:480-90, DeBusk, Blomqvist, Kouchoukos, et al. N Engl J Med 1986; 314:161-6,
Fremes, Goldman, Christakis, et al. Eur J Cardiothorac Surg 1991; 5:235-42; discussion 242-3,
Higgins, Estafanous, Loop, et al. JAMA 1992; 267:2344-8, Ivanov, Weisel, David and Naylor.
Circulation 1998; 97:673-80, Jones, Hannan, Hammermeister, et al. J Am Coll Cardiol 1996;
28:1478-87, Kirklin, Naftel, Blackstone and Pohost. Circulation 1989; 79:I81-91, Morris, Smith,
Jones, et al. Circulation 1991; 84:III275-84, Myers, Blackstone, Davis, Foster and Kaiser. J Am
Coll Cardiol 1999; 33:488-98, Schaff, Gersh, Fisher, et al. J Thorac Cardiovas Surg 1984; 88:972-
216
significant differences between the second graft groups. The variables considered
to be prior major risk factors were: age, gender, diabetes, hypertension, peripheral
vascular disease, carotid disease, positive history of cigarette smoking, associated
valvular lesion, previous myocardial infarction, urgency of operation, ventricular
function, number of anastomoses, type of second graft, and surgeons. The surgeon
involved was included in the model because of different graft preferences,
surgical abilities and techniques. Ten surgeons who each performed fewer than 22
operations over the whole study were combined into one group. Two other
variables which might be considered as important risk factors in general are
congestive heart failure and renal failure. However, for patients eligible for this
study CHF and renal failure are quite rare: there were six subjects with CHF
among the 1,231 patients analysed, and none of these died. There were 10
patients with renal failure, one of whom died; this patient had a saphenous vein
graft. The Grambsch-Therneau test of goodness-of-fit for Cox’s proportional
hazards model was used to validate the model.299 A P-value of less than 0.05 was
assumed for statistical significance. All analyses were done using the SPSS
version 10.0 (SPSS Inc. Chicago, Illinois, USA) and S-Plus 4 statistical package
(MathSoft, Seattle, Washington, USA).
RESULTS
Of 1,231 patients, age, gender, diabetes, hypertension, carotid disease,

presence of mitral regurgitation, previous myocardial infarction,
urgent/emergency surgery, and a number of anastomoses showed statistically
significant differences among the three graft groups (Table 8.1). There was also a
significant difference in graft selection and distribution between surgeons (P
<0.001). Two thousand nine hundred and seventy-four coronary artery
anastomoses were performed. The LITA was used as an in situ graft in 98%
(1418/1447) of anastomoses. The RITA was used as an in situ graft in 24.4%
81, Smith, Harrell, Rankin, et al. Circulation 1991; 84:III245-53, Tu, Sykora and Naylor. J Am
Coll Cardiol 1997; 30:1317-23, Voors, van Brussel, Plokker, et al. Circulation 1996; 93:42-7.
299
Grambsch and Therneau. Biometrika 1994; 81:515-526.
217
(86/352) of anastomoses. Sequential anastomoses were performed in the LITA,

RITA, RA and SV in 216 (14.9%), 19 (5.4%), 253 (26.5%) and 24 cases (10.8%),
respectively. There was no statistically significant difference in terms of target
coronary artery (left versus right coronary artery) or degree of stenosis of grafted
coronary artery (low versus high grade stenosis) in the three graft groups (Table
8.2).
Forty-one patients died during follow-up (4/333 in the RITA group, 20/700
in the RA group and 17/198 in the SV group). The median time of death was 8.1
months and ranged between 0.01-34.8 months. Fifteen (36.6%) were operative
deaths (< 30 days after operation) and 26 (63.4%) were late deaths (³30 days after
operation).
Table 8.2. Comparison of target coronary artery and coronary artery stenosis
between the right internal thoracic artery (RITA), the radial artery (RA) and the
saphenous vein (SV) groups.
Type of second graft P value
RITA RA SV
Target Left 200 (56.8%) 570 (59.8%) 130 (58.6 %) 0.6

coronary
artery Right 152 (43.2%) 383 (40.2%) 92 (41.4%)
Coronary Low (<60%) 53 (15.1%) 121 (12.7%) 24 (10.8%) 0.3

artery
stenosis High (³60%) 299 (84.9%) 832 (87.3%) 198 (89.2%)
Total 352 953 222
Kaplan-Meier Estimate
The observed survival rate at two years for the RITA group was 99.0%
(95%CI, 97.9% - 100%). For the RA group, the survival rate at two years was
97.1% (95% CI, 95.8% - 98.4%) and for the SV group the survival at two years
was 92.1% (95% CI, 88.4% - 96.0%). There was a statistically significant
difference between these survival rates (P= 0.001, logrank test). At the three-years
218
follow-up, the number of subjects not censored had fallen to below 50% in the SV
group, and the latest death in all three graft groups was between two and three
years, therefore two years was chosen as the longest estimated survival time.
However, the crude comparison of survival between the second graft groups is
potentially biased because there were differences between the patient
characteristics of each group. Figure 8.3 shows survival curves by type of second
graft before adjustment for baseline differences. Observed and adjusted survival
estimates by type of second graft over time are summarized in Table 8.3.
Table 8.3. Comparison of survival rate between the RITA, RA and SV groups.
Time RITA (n=333) RA (n=700) SV (n=198)

elapsed
since N Obs. Adj. N Obs. Adj. N Obs. Adj.
surgery
30d 327 0.994 0.997 684 0.989 0.997 192 0.975 0.994
1 yr 281 0.994 0.997 558 0.981 0.995 176 0.943 0.985
2 yrs 231 0.990 0.996 419 0.971 0.991 160 0.921 0.978
N = number at risk, Obs. = Observed, Adj. = Adjusted
Figure 8.3 Observed Kaplan-Meier Survival estimates with right internal thoracic
artery (RITA), radial artery (RA) and saphenous vein (SV) as a second graft
219
Cox’s Proportional Hazards Model
The five explanatory variables that were statistically significant in the Cox’s
model were age, urgent/emergency surgery, ventricular function, concomitant
aortic stenosis, and type of second graft. The adjusted rate ratios and 95%
confidence intervals (CI) of the variables included in the model are shown in
Table 8.4.
In relation to the type of second graft employed, after statistically adjusting

for the other 15 risk factors, the rate ratios were as follows: RITA versus RA: 0.55
(95% CI: 0.17 – 1.77, P=0.3); SV versus RA: 2.21 (95% CI: 1.05 – 4.65,
P=0.04); SV versus RITA: 4.01 (95% CI: 1.21 - 13.3, P=0.02). The Grambsch-
Therneau test of goodness-of-fit for Cox’s proportional hazards model was not
significant (P > 0.9), indicating that the data were consistent with the assumption
of proportional hazards. Figure 8.4 shows survival curves by type of second graft
after adjustment for baseline differences. The survival rate was significantly better
in the patient group receiving the RITA and RA than the SV.
220
Figure 8.4 Kaplan-Meier survival estimates with right internal thoracic artery (RITA),
radial artery (RA) and saphenous vein (SV) as a second graft, adjusted for the 15 other
potential explanatory variables shown in Table 8.4.
221
Table 8.4. Results of Cox’s proportional hazards model: risk factors for death.
Variables Reference Index RR* (95% CI) P value Overall

P value
Age X yrs X + 10 yrs 1.58 (1.05-2.39) 0.03
Urgent/ emergency Elective Urgent/ 2.81 (1.35-5.82) 0.006

Emergency
Ventricular function EF ³ 50% EF=30-49% 1.97 (0.89-4.33) 0.09 0.012

EF < 30% 5.93 (1.77-19.99) 0.004
Aortic stenosis Presence Absence 4.79 (1.51-15.21) 0.008

Type of second RA RITA 0.55 (0.17-1.77) 0.3 0.03
graft
SV 2.21 (1.05-4.65) 0.036
Gender Male Female 0.54 (0.27-1.08) 0.8
Diabetes Yes No 0.93 (0.44-1.99) 0.9
Peripheral vascular Yes No 1.85 (0.67-5.11) 0.2
disease
Carotid artery Yes No 1.11 (0.47-2.59) 0.8
disease
Myocardial Yes No 1.32 (0.63-2.75) 0.5
infarction
Hypertension Yes No 1.17 (0.60-2.27) 0.6
Cigarette smoker Yes No 1.18 (0.59-2.36) 0.6
Aortic regurgitation Presence Absence 1.40 (0.44-4.49) 0.6
Mitral regurgitation Presence Absence 0.88 (0.31-2.50) 0.8
No. of anastomoses 2 3 1.08 (0.49-2.40) 0.9 0.7
4 and 5 1.66 (0.53-5.20) 0.4
Surgeon Comparisons between individual surgeons not shown 0.8
*RR (rate ratio) and 95%CI (confidence interval) for index category relative to reference
category.
For risk factors at more than two levels, the overall P-value assesses the presence of any
effect, while pairwise P-values are also shown.
222
DISCUSSION
This study identified the choice of second graft as a risk factor for death in
addition to age, urgency of operation, ventricular function, and presence of aortic
stenosis, after adjustment for other factors. Use of the SV significantly increased
the rate of death - 2.21 compared with the RA and 4.01 compared with the RITA.
The RITA demonstrated a non-significant reduction in mortality compared with
the RA.
The study population was restricted solely to CABG patients receiving two
conduits so that we could accurately assess the survival impact of the second
graft. For the first time, we used the newly developed Australian National Death
index from the Australian Institute of Health and Welfare, which enabled us to
confirm accurately the patients’ status. This is similar to the linkage between
valve surgery and the national death registry employed in the United Kingdom.300
We used appropriate statistical controls and adjusted for all recognized

confounding factors. The rate of urgent or emergency surgery reflected the degree
and severity of coronary artery disease such as acute coronary syndrome or left
main artery disease. The number of anastomoses also reflected the extent of
coronary artery disease and the actual number of arteries grafted. This also took
into account the number of sequential anastomoses. We also adjusted for the
surgeon performing the operation as this variable was associated with potential
bias in terms of graft selection, myocardial protection and grafting technique. The
coronary artery targeted and the degree of coronary artery stenosis, both factors
considered to affect the clinical outcome and graft patency,301 were similar in the
300
Taylor, Gray, Livingstone and Brannan. Journal of Heart Valve Disease 1992; 1:152-9.
301
Cashin, Sanmarco, Nessim and Blankenhorn. N Engl J Med 1984; 311:824-8,
Cosgrove, Loop, Saunders, Lytle and Kramer. J Thorac Cardiovas Surg 1981; 82:520-30, Dion,
Glineur, Derouck, et al. Eur J Cardiothorac Surg 2000; 17:407-14, Hashimoto, Isshiki, Ikari, et al.
J Thorac Cardiovas Surg 1996; 111:399-407, Pagni, Storey, Ballen, et al. Eur J Cardiothorac Surg
1997; 11:1086-92.
223
three graft groups. We were unable to adjust for a number of variables that may
potentially affect the outcome of CABG, such as liver disease and other systemic
diseases.
The RITA has a graft patency equivalent to that of the LITA when used as a
pedicled graft.302 Furthermore, in several studies,303 the RITA has shown a
survival benefit when used in addition to the LITA. However there are risks
involved in using the RITA in elderly or diabetic patients.304 Therefore the RA has
an important role to play in achieving complete arterial revascularization in
patients with multivessel disease.
In 1998, Borger and colleagues demonstrated a significant decrease in

sternal wound infections and blood transfusions in patients who received the RA
as a second graft compared with the RITA.305 They also found no difference in the
perioperative or intermediate term morbidity and mortality rate. In 2001, Cohen
and associates reported the findings of a case-matched study in which grafting
with the RA was compared to the SV.306 They found that the RA was associated
with a lower early mortality and morbidity rate despite a high incidence of
diabetes, hypertension and peripheral vascular disease in the RA group.
302
Dion, Etienne, Verhelst, et al. Eur J Cardiothorac Surg 1993; 7:287-93; discussion 294.
303
Blackstone and Lytle. J Thorac Cardiovas Surg 2000; 119:1221-30, Buxton, Komeda,
Fuller and Gordon. Circulation 1998; 98:II1-6, Cameron, Kemp and Green. Circulation 1986;
74:III30-6, Lytle, Blackstone, Loop, et al. J Thorac Cardiovas Surg 1999; 117:855-72, Morris,
Smith, Jones, et al. Circulation 1991; 84:III275-84, Pick, Orszulak, Anderson and Schaff. Ann
Thorac Surg 1997; 64:599-605.
304
Borger, Rao, Weisel, et al. Ann Thorac Surg 1998; 65:1050-6, Grmoljez and Barner.
Angiology 1978; 29:272-4.
305
Borger, Cohen, Buth, et al. Circulation 1998; 98:II7-13; discussion II13-4.
306
Cohen, Tamariz, Sever, et al. Ann Thorac Surg 2001; 71:180-186.
224
A drawback of this survival study is the lack of collaborative graft patency

data. A number of re-angiograms have been performed for symptoms suggesting
ischemia. However these are likely to produce a biased result. To address the
issue of graft patency, we are conducting a prospective randomized controlled
study, now in its fourth year, comparing the late graft patency in patients who
receive a RITA, RA or SV as their second graft. Four hundred patients have been
enrolled to date. The results are not available at present.
Our study suggests that using the RA in CABG is safe. The risk adjusted
mortality rate of the RA group was significantly lower compared with the SV
group but not significantly different to the RITA group. Even though the number
of deaths was small over the five-year study period, a positive survival trend
favoring the RITA and RA compared with the SV was demonstrated. A longer
follow-up is required to demonstrate a clear difference between these three
different types of second graft.
SUMMARY
This study indicates that the RA is safe for use in coronary artery bypass
grafting. Furthermore, the RA offers a significant survival benefit compared with
the SV when used as a second graft. The next chapter analyzes some of the
scheduled angiography with a view to comparing the graft patency between the
RITA, RA and SV from a randomised trial which is being conducted at the
Cardiac Surgery Department, Austin & Repatriation Medical Centre, The
University of Melbourne.
225
Chapter 9
Semi-quantitative and Quantitative Coronary Angiography
of the Radial Artery, Internal Thoracic Artery and
Saphenous Vein in an Elective Cohort
(a) Preliminary angiographic results of Australian Radial Artery Study Trial
Introduction
Study Protocol
Patients
Clinical follow-up
Study endpoint
Angiographic protocol
Semi-quantitative Analysis
Quantitative Analysis
Reproducibility of semi-quantitative and quantitative Analysis
Statistical Methods
Results
Clinical outcome
Angiographic results
Reproducibility of semi-quantitative and quantitative Analyses
Factors influencing graft stenosis
Discussion
Conclusion
(b) Angiographic and Quantitative Analysis protocol
Appendix
Australian Radial Artery Study Protocol
Semiquantitative and Quantitative Coronary Angiography of RA 280
(a) Preliminary angiographic results of Australian Radial Artery

Study Trial
Introduction
In the observational study discussed in the previous chapter we

demonstrated a survival benefit in patients receiving the radial artery (RA) or the
right internal thoracic artery (RITA) compared with the saphenous vein (SV) over
a three-year follow-up period. Although there was a survival benefit associated
with using the RA graft in addition to the left internal thoracic artery (LITA),
there was a concern that the benefit was not directly related to the RA. The most
important information regarding the efficacy of the RA is the graft patency.
In this chapter I analyze the early results of a prospective randomized

controlled trial, the Australian Radial Artery Trial. This trial is currently in
progress at the Austin & Repatriation Medical Centre (1996 - ) examining the
graft patency of the RA compared with that of the free RITA and SV.
Quantitative coronary angiography (QCA) is a well-established technique

measuring the degree of stenosis in the coronary artery. However, there is little
known about the QCA of grafts after coronary bypass grafting.307 In early
angiographic follow-up of the graft, there is usually no or mild stenosis compared
with the native coronary artery. Mild stenoses are measurable by QCA and should
not affect the reliability. In general the wider the vessel, the more pixels across the
vessel are available for analysis, the higher the reliability of QCA.
The aims of this study were: (1) to evaluate the reproducibility of semi-
quantitative (SQCA), i.e. a planimetry measurement, and quantitative coronary
angiography (QCA), a digital assessment, for analyses of diameter and area loss
307
Gurne, Buche, Chenu, et al. Circulation 1994; 90:II148-54, Seki, Kitamura, Kawachi, et
al. J Thorac Cardiovas Surg 1992; 104:1532-8, Syvanne, Nieminen and Frick. International
Journal of Cardiac Imaging 1994; 10:243-52.
227
of target arteries and grafts, respectively; (2) to evaluate the early diameter and
cross-sectional area loss of the grafts using semi-quantitative and quantitative
coronary angiography; (3) to compare the diameter and area loss of RA vs RITA
and RA vs SV; (4) to determine factors influencing diameter and area loss in the
grafts; and (5) to establish the QCA technique for graft evaluation.
Study Protocol
Patients scheduled for primary coronary artery bypass surgery using more
than one graft were included in this study. To be included, they were required to
have at least two coronary artery stenoses of ³ 70% and a coronary artery
diameter ³ 1.5 mm. They were randomised to receive a RITA, RA or SV as their
second graft in addition to the left internal thoracic artery. Additional saphenous
veins were used to complete the reconstruction when more than two grafts were
necessary. This study consisted of two clinical trials randomized to: (1) RA versus
RITA; and (2) RA versus SV based on age and presence or absence of diabetes.
Trial 1. (RA-RITA Trial)
RA versus free RITA in patients aged ≤ 70 years or diabetic patients ≤ 60 years.
Trial 2. (RA-SV Trial)
RA versus SV in patients aged >70 years or diabetic patients > 60 years.
Exclusion criteria
1. Renal disease with a creatinine > 0.30 mmol/L.

2. Chronic heart failure (NYHA Class III or IV or ejection fraction < 35% on
angiography or radionuclide ventriculography).
3. Associated major illnesses e.g., malignancy.
4. Body mass index (BMI) > 35 weight (kg)/height2 (m2).
5. Acute presentation, that is, those patients who had an acute myocardial
infarct in the week leading up to surgery or who presented with
cardiogenic shock.
6. Technical exclusions e.g. sequential grafting.
228
Specific exclusion criteria in RA-RITA Trial.
1. Inability to use the RA because of an abnormal Allen test (> 10 seconds).
2. Inability to use the free RITA due to, for example, previous chest trauma.
3. FEV1 < 50% of expected value.
Specific exclusion criteria in RA-SV Trial.
4. Inability to use the RA because of an abnormal Allen test (> 10 seconds).
5. Inability to use the SV due to, for example, varicose veins or past trauma.
Randomization was carried out by the Statistical Consulting Centre, the

University of Melbourne, using random number generation in the statistical
package “Minitab”. Opaque envelopes containing randomly allocated numbers
were provided in small batches to the Research Nurse responsible for record
keeping and obtaining informed consent. Each envelope had the individual
randomization sequence number printed on the outside of the envelope. Details
of the subject to be randomly allocated and the date were recorded on the outside
of the envelope prior to opening. The staff involved in the clinical management
of the patients and in the surgical interventions had no involvement in the
randomization procedure.
Intraoperative exclusion
RAs with extensive calcification were excluded from use. Damaged grafts
were also excluded. Patients whose chosen graft conduit proved unsuitable intra-
operatively were included in the analysis on an intention-to-treat basis.
Patients
Three hundred and ninety four patients undergoing surgery between June
1996 and December 2000 were enrolled in this study. Two hundred and fifty four
patients were included in the RA-RITA Trial. These consisted of 128 and 126
patients who were randomized to the RA and RITA groups, respectively. One
hundred and forty patients were included in the RA-SV Trial. Sixty-seven patients
were randomized to receive a RA and 73 patients a SV. The graft harvesting and
229
operative techniques were the same as described in Chapter 8.
Clinical follow-up
All patients (including control patients) were given calcium channel

blockers (amlodipine 2.5-5 mg daily) for six months after surgery on the unproven
assumption that spasm in the muscular RA conduit would be less frequent. This
was undertaken using the long acting dihydropyridimone, amlodipine 5 mg per
day (reducing to 2.5 mg per day if hypotension occurred). Clinical follow-up by
the research nurse was carried out every year by telephone or mail and by
contacting the surgeons involved.
Study endpoints
The study endpoints were: (1) clinical outcomes including recurrent angina,
recurrent myocardial infarction, re-operation, and death; and (2) graft patency. I
have focused on the evaluation of semi-quantitative (SQCA) and quantitative
analysis (QCA) for measuring the diameter and cross-sectional area loss of the
target arteries and grafts, and early angiographic results in this chapter.
Angiographic protocol
The planned coronary angiographic schedule for postoperative

catheterisation was organized as follows: 10% of patients during the first month,
10% at two years, 20% at five years, 30% at 7.5 years, and 30% at 10 years.
Forty-two patients addressed in this chapter had re-angiograms over the first four
years. All patients had further randomization to determine which one of the five
times angiography was to be scheduled.
Diagnostic coronary angiography was performed using the standard femoral

approach. Selective injections of the native coronary arteries and grafts were
obtained. The native coronary arteries and grafts were examined in left oblique
(LAO) and right oblique (RAO) projections. These were subjected to both semi-
quantitative and automated quantitative analyses. An analysis was also made of
the preoperative coronary angiograms of those vessels on which the study graft
was subsequently placed (target coronary artery).
230
QCA of the study graft and native coronary artery was performed using the
Quantitative Coronary Analysis, Cardiovascular Measurement Solutions system,
Version 4.0 (QCA-CMSÒ, Leiden, The Netherlands). Since 1997, coronary
arteriograms were acquired in digital format using the Toshiba X-Ray
catheterization system; image data was exchanged on CD using the Digital
Imaging and Communication standard (DICOM, Toshiba). Conventional 35 mm
cinefilms were analyzed by semi-quantitative coronary angiography.
Semi-quantitative analysis
At re-angiography, the severity of stenosis was assessed in two planes

(planimetry) by two different experienced observers and a cardiologist.
Measurement was taken of the most severely diseased segments of the coronary
artery and graft using a standard ruler. The severity of stenosis of the coronary
artery and study grafts was recorded as “percent diameter stenosis”, which
represented the percent reduction in diameter relative to nearby “normal” lumen.
Grafts in which the diameter was less than 1.0 mm and localized stenosis
was not evident were regarded as indicating the “string sign”. The proximal and
distal anastomoses of the graft and trunk were assessed separately.
Quantitative analysis
The following criteria were used to decide the most appropriate frame to be
analyzed: (1) the graft/coronary artery segment should be well-filled with contrast
medium; this is usually achieved by selecting an image from the diastolic phase in
the second or third cardiac cycle following the contrast administration; (2) the
stenosed segment of the graft/coronary artery should be clearly visible, preferably
without any overlap from other vessels or side branches.
For each graft and coronary segment, a corresponding calibration factor was
obtained on the basis of the size of the contrast catheter. The image selected for
calibration was not necessarily the same image in which the obstruction was
measured. Criteria for calibration and frame selection included: (1) the
nontapering segment of the catheter being visible with a sufficient length (~ 2
231
cm), and (2) the catheter not being obscured by contrast flowing back into the
aorta. As a result, the catheter image selected was usually in the early phase of the
cardiac study.
The study grafts and native coronary arteries were measured using
automated contour detection algorithms. The start and end points of the analyses
for the native coronary artery were defined according to the bifurcations of major
arterial segments as recommended by the American Heart Association.308 The
start point for the study graft was defined as the normal part of the graft near the
aorta and the end point was at the distal anastomosis. QCAs were performed on
two projections: the most severe lesion and the perpendicular view where
possible. The segment under consideration was positioned in the center of the
field where distortion is minimal.
Lesions not measurable by QCA included those with stenosis > 85% that
could not be reliably edge tracked or segments with diffuse disease or ectasia that
had no reliable reference diameter. Lesions in the graft or coronary artery that
were smaller than 1.0 mm could not be measured by QCA.309
Automated detection of the arterial contours
Following calibration of the catheter size and definition of the start and end
points of the analyzed segment, QCA-CMS software automatically created the
pathline. The line lay entirely inside the selected vessel connecting the start and
end point. The contour detection procedure was carried out automatically. The
pathline and the vessel contour were adjusted with manual correction in particular
areas by the analyst, in case of some unavoidable objects such as wires. An
accurate centerline was computed. A diameter function was determined by
308
Austen, Edwards, Frye, et al. Circulation 1975; 51:5-40.
309
Beauman, Reiber, Koning and Vogel. Catheterization & Cardiovascular Diagnosis
1996; 37:24-31., Mack, Selzer, Pogoda, et al. Arterioscler & Thromb 1992; 12:348-56.
232
measuring the width of the vessel for every position along this centerline and
subsequently the site of maximal percent diameter stenosis was defined. The
reference diameter was defined as the estimated size of the vessel prior to the
occurrence of a focal obstruction shown as a straight line in the diameter function.
This reference diameter function was assessed by a linear regression technique,
which was calculated through all points of the vessel diameter function (Figure
9.1).
Figure 9.1 The diagram shows the true and reference diameter functions where the
straight line is the interpolated reference diameter function (red line). The position of the
minimum obstruction (o) and reference diameters (r) and the proximal (p) and distal (d)
boundaries of the obstruction are indicated by the vertical lines.
Percent diameter and area stenosis were calculated from the following
formulas. Circular cross sections have been assumed when calculating areas from
diameter (Area = pdiameter2/4).
Diameter stenosis = (1- Dobtr/ Dref) ´ 100%

Area stenosis = (1- Aobtr/ Aref) ´ 100%
Dobtr = the obstruction diameter
Dref = the reference diameter at the position of the obstruction
Aobtr = the obstruction area
Aref = the reference area at the position of the obstruction
233
Figure 9.2 Quantitative coronary angiogram of graft demonstrating the automated

detection of the graft contour and area of stenosis.
Reproducibility of Semi-quantitative and Quantitative analysis
To assess the intraobserver variability of the SQCA, 22 preoperative

cinefilms containing a coronary artery stenosis of target artery were repeatedly
analysed at two months interval. Coronary obstructions were analyzed in a
standardized manner, i.e., from one major bifurcation to the next of the native
coronary artery according to the recommendations of the American Heart
Association.
For QCA, 22 different digital study graft coronary angiograms were used.
Study grafts were analyzed in a standardized manner, i.e., from the proximal to
the distal anastomoses of the graft. The same set of selected frame images were
reanalyzed three days later by the same observer without knowledge of the first
analysis session. This meant that the observer defined the beginning and end
234
points of grafts based on the proximal and distal anastomoses visible in the
images, but without knowing the precise positions of these reference points from
the corresponding analyses. To evaluate additional variations in terms of frame
selection, reanalyses were also performed two months later without any
knowledge of the first analysis except the identification of the grafted target
artery.
The digitized target artery angiography (n=7) and the cinefilm of study
grafts (n=13) were not used for the reliability study because of the small number
of samples.
Statistical methods
All data were expressed as mean ± SD. Intraobserver variability was

estimated by calculating the differences between paired measurements according
to the method of Bland and Altman310: Repeatability coefficient = (2.77 ´
estimated standard deviation of repeat observations on the same angiogram). This
means that approximately 95% of differences between two repeated
measurements would be less than the repeatability coefficient. The coefficient of
variation (CV) of the two means was computed in order to compare the difference
of the repeatability of SQCA and QCA, and between the interval differences of
QCA. The CV was calculated as: CV = 100 (estimated standard deviation of
repeat observations on the same angiogram)/ mean of the two measurements.
Correlation coefficients were also used. As some of the data did not follow a
bivariate normal distribution, the usual test of correlation based on Pearson’s
sample correlation coefficient may not have been reliable. Therefore, the
significance of correlations was tested using Spearman’s rho, a non-parametric
test which does not assume bivariate normality
310
Bland and Altman. Lancet 1986; 1:307-10, Bland. An introduction to medical statistics
1995.
235
The differences at baseline between the two groups in each trial were
examined. Statistical tests were carried out: t-tests for continuous variables and
Fisher’s exact test (2-sided) for binary variables.
Linear model, univariate analysis was used to estimate the mean differences
in degrees of diameter and area stenosis in two different grafts (RA vs RITA or
RA vs SV) adjusted for the time interval between the operation and the
angiography.
Linear models were fitted to assess the effects of the following five factors
on the postoperative diameter and area stenosis of the study grafts: age at
operation, gender, time from operation to angiography, diabetes, smoking history,
and types of study graft. This analysis was only performed for the RA-RITA trial,
because of the small sample size in the RA-SV trial.
RESULTS
Demographic data are summarized in Table 9.1. In both trials, patients

randomized to receive either RA, RITA or SV had similar clinical risk factors for
vascular disease and number of vessels grafted. One patient in the RA-RITA trial,
randomised to the RITA, did not have the RITA harvested and was therefore
excluded from the angiographic analysis.
There was no significant difference in degree of target coronary artery

stenosis (RA group: 71.21±24.11 vs RITA group: 66.36±19.64, P =0.6) in the
RA-RITA trial and also in the RA-SV trial (RA group: 70.95±19.39 vs SV group:
75.43±17.83, P =0.6). Table 9.2 shows the native target coronary artery in each
group.
236
Table 9.1 Baseline clinical characteristics of the Australian Radial Artery Study patients
who had elective angiography
Characteristic RA-RITA Trial RA-SV Trial
RA (n=12) RITA (n=13) RA (n=9) SV (n=7)
Age (mean±SD) years 60.7±6.7 60.7±6.3 74.7±5.3 74.3±5.8
Sex: male 10 12 8 7
Diabetes 2 0 1 2
Cigarette smoker 7 8 6 6
Hypertension 7 6 6 2
Peripheral vascular 0 1 1 1
disease
Cerebrovascular 1 1 2 0
disease
Hypercholesterolemia 6 7 0 0
No. of anastomoses 2.85±0.80 3.0±0.71 2.89±0.33 2.86±0.69
Interval to 237.7±210.8 516.8±432.5 318.6±358.8 470.4±328.8

angiography (days)
Table 9.2 The target coronary artery of the study graft
Target artery RA-RITA Trial RA-SV Trial
RA (n=12) RITA (n=13) RA (n=9) SV (n=7)
Diagonal 0 1 0 0
Intermediate 2 1 1 1
Marginal 5 9 5 3
Posterior 5 2 0 3
descending
from right
coronary
Clinical outcome
237
All patients in the RA-RITA trial have survived. Two patients in the RA-SV
trial died at 23 and 36 months after operation, respectively. Both of these patients
received RA and both RAs were patent (one had no stenosis and the other had a
9.31 % diameter stenosis in the RA) at the time of scheduled angiography. One
case passed away at home in his sleep. An autopsy report indicated the cause of
death as ischemic heart disease with generalised atherosclerosis, chronic
obstructive airway disease as contributing factors. The other case had underlining
chronic renal failure and died in nursing home, unknown cause of death.
Angiographic results
Of 42 angiograms, four patients had localized stenosis of the study graft at

anastomotic sites. One RA in the RA-RITA demonstrated a “string sign” in the
RA-RITA trial and was excluded from the semi-quantitative and quantitative
analyses.
Reproducibility of semi-quantitative and quantitative analyses
Semi-quantitative analysis
Table 9.3 shows the intraobserver variation of the SQCA of the target
coronary artery segments at two months interval. There was moderate correlation
between the two measurements (rho = 0.67, P = 0.001). The coefficient of
variation is relatively high. Bland-Altman plots were performed to demonstrate
the variability within observer (Figure 9.3).
238
Table 9.3 Test-retest reliability of semiquantitative (SQCA) measurement of the

target coronary artery segment at 2 months interval.
Intra-observer variability (n=22 pairs)

Mean±SD (%) rho P
1st Mean diameter stenosis 72.94±16.98 0.671 0.001

2nd Mean diameter stenosis 73.23±18.03
Mean difference* -0.29±11.94
†
Repeatability Coefficient 22.87
††
Coefficient of variation (%) 31.3
*Mean difference between paired measurements (1st and 2nd measurements)
†Repeatability coefficient = (2.77 ´ estimated standard deviation of repeat observations
on the same angiogram) = approximately 95% of differences between two repeated
measurements will be less than the repeatability coefficient
††
Coefficient of variation = 100(estimated standard deviation of repeat observations on
the same angiogram)/ mean of the two observations
Figure 9.3 Reproducibility of the diameter stenosis measured by semi-quantitative

analysis at 2 months interval: Bland–Altman Plots showing the differences in
measurement within observer against the mean value.
239
Quantitative analysis
Table 9.4 shows the reliability of the diameter and area stenosis
measurements from the QCA. There was a substantial increase in repeatability
coefficient between the repeated measurements at 3 days and the repeated
measurements at the 2 months. Figures 9.4-9.7 plot the differences between the
two measurements against the mean of two measurements.
Table 9.4 Intraobserver variability in the repeated analysis quantitative analysis (QCA) of
bypass graft stenosis
Intra-observer variability at 3 Intra-observer variability at 2

days interval (n=22 pairs) months interval (n=22 pairs)
Mean±SD rho P Mean±SD rho P

(%) (%)
1st diameter stenosis 19.07±9.85 0.919 <0.001 19.07±9.85 0.652 0.001
2nd diameter stenosis 17.30±8.19 16.44±6.46
Mean difference 1.77±2.96 2.64±8.18

Repeatability 6.65 16.49
Coefficient
Coefficient of 36.6 92.9

variation (%)
1st area stenosis 33.58±14.80 0.919 <0.001 33.58±14.80 0.652 0.001
2nd area stenosis 30.96±12.99 29.77±10.35

Mean difference 2.6±2.96 3.8±12.23
Repeatability 9.11 24.59
Coefficient
Coefficient of 28.2 77.6

variation (%)
240
Figure 9.4 Reproducibility of the diameter stenosis (at 3 days interval).

Bland–Altman Plots showing the differences in measurement within an observer against
the mean value.
Figure 9.5 Reproducibility of the area stenosis (at 3 days interval).

the mean value.
Figure 9.6 Reproducibility of the diameter stenosis (at 2 months interval).

the mean value.
Figure 9.7 Reproducibility of the area stenosis (at 2 months interval)

the mean value.
Combined results of semi-quantitative and quantitative analysis of diameter

stenosis of study graft
The average graft stenosis was 13.6±19.9% for the RITA (n=13) and
15.7±11.5% for the RA (n=12) in the RA-RITA trial at average 382.80±360.94
days of follow up (range 6-1546 days).
The average graft stenosis was 2.8±4.8 % for the RA (n=9) and 12.9±9.4%
for the SV (n=7) in the RA-SV trial at average 385±343.45 days of follow up
(range 30-1042 days).
Quantitative Analysis
Table 9.5 and Figures 9.8-11 show the diameter stenosis and area stenosis in
the study grafts in RA-RITA Trial. There was no significant difference of graft
stenosis between the RA and RITA in RA-RITA Trial. There was also no
difference in graft stenosis between RA and SV in RA-SV Trial (Table 9.6,
Figure 9.12 and 9.13). The comparisons between RA and RITA, and RA and SV,
were adjusted for differences in the time interval between operation and
angiogram using a general linear model with types of study graft (RA or RITA) as
a factor at two levels, and ‘interval from the operation to angiography’ as a
covariate. Therefore, the estimates of the treatment comparisons are not equal to
the simple differences between the two treatment means. The estimates and 95%
confidence intervals for the treatment comparisons are given as (RA – RITA) and
(RA – SV), and are adjusted for ‘interval from the operation to angiography’.
Table 9.5 Comparison of diameter stenosis and area stenosis by quantitative

analysis (QCA) between grafts in the RA-RITA Trial adjusted for the difference in interval
after CABG (at average 382.80±360.94 days of follow up).
RA-RITA Trial
RA (n=8) RITA (n=7) Mean difference (95% CI) P value
Diameter 18.40±9.55 14.62±2.62 4.31 (-4.80, 13.41) 0.3

stenosis
Area stenosis 32.62±15.20 27.04±4.52 6.48 (-8.08, 21.04) 0.4
243
Figure 9.8 Histogram of the diameter stenosis by quantitative analysis (QCA) of RITA
grafts in the RA-RITA Trial
Figure 9.9 Histogram of the area stenosis by quantitative analysis (QCA) of RITA
244
Figure 9.10 Histogram of the diameter stenosis by quantitative analysis (QCA) of RA

Figure 9.11 Histogram of the area stenosis by quantitative analysis (QCA) of RA grafts
245
in the RA-RITA Trial
Table 9.6 Comparison of diameter stenosis and area stenosis by quantitative

analysis (QCA) between grafts in the RA-SV trial adjusted for the difference in interval
after CABG (at average 385±343.45 days of follow up).
RA-SV Trial
RA (n=2) SV (n=5) Mean difference (95% CI) P value
Diameter 10.99±2.36 18.02±4.03 -8.33 (-19.01, 2.35) 0.09

stenosis
Area 20.74±4.23 32.67±6.50 -14.02 (-31.41, 3.37) 0.2

stenosis
Figure 9.12 Histogram of the diameter stenosis by quantitative analysis (QCA) of SV

grafts in the RA-SV Trial
246
Figure 9.13 Histogram of the area stenosis by quantitative analysis (QCA) of SV

grafts in the RA-SV Trial
Factors influencing graft stenosis
Linear models were fitted to assess the effects of the following five factors
on the postoperative diameter and area stenosis of the study graft: age at
operation, gender, time from operation to angiography, diabetes, smoking history,
and types of study graft. The only factor that affected the diameter and area
stenosis in the study graft in the RA-RITA trial was diabetes (P =0.044 and 0.036,
respectively).
DISCUSSION
This preliminary angiographic result of the Australian prospective
247
randomized trial demonstrated that the RA was an excellent conduit comparable

to the RITA, using both semiquantitative and quantitative analysis techniques.
Using automated edge-detection methodologies allowed precise quantitative
analysis of the diameter and area of graft stenosis. At 12 months after
implantation, the diameter and area stenoses of the RA and RITA did not
significantly differ from each other. In other words, the contour of the RA and
RITA were quite smooth. These stenotic indices tended to be lower in the RA
when compared with the SV; however the number of grafts was too small to draw
a meaningful conclusion. Although a number of SVs demonstrated some degree
of irregularity and stenosis, the diameter of SVs was much larger than the RA.
There was no clinical significance from the diameter and cross-sectional area loss
in the first 12 months. The hemodynamic significance of a stenosis depends on
both degree of stenosis, diameter of the vessel, pressure gradient across the
stenosis and distal vascular resistance.311
The only independent factor influencing the diameter and area loss of the
grafts (QCA measurement) in the RA-RITA Trial was diabetes. The combined
results of the SQCA and QCA were not used for comparison of diameter and area
stenosis between the grafts and risk factors analysis because of unequal numbers
of grafts analysed by SQCA technique in each group of the study graft.
Graft stenoses found in the angiographic analyses were: (1) in the trunk of
the graft; and (2) in the area around the proximal and distal anastomoses. In this
study four anastomotic problems (4/42, 9.5%) were found. Possible causes were
an inadequate anastomotic techniques or vascular healing process. This study was
primarily directed at the properties of the coronary artery bypass grafts rather than
the surgical techniques or complex changes of vascular healing mediated by
311
Gallagher, Folts and Rowe. American Heart Journal 1978; 95:338-47, Gallagher,
Osakada, Matsuzaki, Kemper and Ross. Am J Physiol 1982; 243:H698-707, Harrison, White,
Hiratzka, et al. Circulation 1984; 69:1111-9, Lipscomb and Gould. American Heart Journal 1975;
89:60-7, Marcus, Harrison, White and Hiratzka. Can J Cardiol 1986; Suppl:195A-199A, Marcus,
Hiratzka, Doty, et al. Ann Thorac Surg 1986; 42:S5-8.
248
growth factors and smooth muscle cell proliferation at the site of the
anastomoses.312 Therefore, in this study I focused on the luminal changes in the
trunk of the graft.
The limitations of the visual assessment included inter- and intra-observer

variability313, poor correlation with postmortem measurements of coronary
stenosis and poor correlation with physiologic measures of coronary lesions.314 In
this study we utilised SQCA using visual assessment and planimetry. This
technique has demonstrated reproducibility compared with the QCA.315 From the
reproducibility study, SQCA demonstrated a standard deviation of the difference
between two measurements of 12 %.
QCA techniques have resulted in substantial success in reducing the

variability of anatomic measurements and assessment of coronary artery stenoses.
312
Campbell, Campbell, Manderson, Horrigan and Rennick. Arch Pathol Lab Med 1988;
112:977-86, Dilley, McGeachie and Tennant. Cell & Tissue Research 1992; 269:281-7, Gutierrez-
Diaz, Cuevas-Sanchez, Carceller-Benito, et al. Surgical Neurology 1985; 24:153-9, Hajjar,
Gavish, Breslow and Nachman. Nature 1989; 339:303-5, Risau and Zerwes. Zeitschrift fur
Kardiologie 1989; 78:9-11, Wautier. Journal des Maladies Vasculaires 1989; 14:13-6,
Wieslander, Mecklenburg and Aberg. Scandinavian Journal of Plastic & Reconstructive Surgery
1984; 18:193-9.
313
Beauman and Vogel. J Am Coll Cardiol 1990; 16:108-13, Goldberg, Kleiman, Minor,
Abukhalil and Raizner. American Heart Journal 1990; 119:178-84, Marcus, Skorton, Johnson, et
al. J Am Coll Cardiol 1988; 11:882-5, Zir, Miller, Dinsmore, Gilbert and Harthorne. Circulation
1976; 53:627-32.
314
Grondin, Dyrda, Pasternac, et al. Circulation 1974; 49:703-8, Isner, Kishel, Kent, et al.
Circulation 1981; 63:1056-64, Schwartz, Kong, Hackel and Bartel. Am J Cardiol 1975; 36:174-8,
Vlodaver, Frech, Van Tassel and Edwards. Circulation 1973; 47:162-9.
315
Folland, Vogel, Hartigan, et al. Circulation 1994; 89:2005-14.
249
There were however some variations when different QCA systems were used.316
The technique may also give variable results depending on frame selection,
selection of the normal reference segment and methods of edge detection.317
Sirnes and colleagues found that precision (SD of signed errors) for percent
diameter stenosis in the same angiography ranged from 4.2% to 5.8%.318
Herrington and colleagues studied day-to-day variations in patients, equipment or
variability in selection of frames for analysis.319 Coronary angiograms were
reviewed from 20 patients who underwent diagnostic angiography followed by
percutaneous transluminal coronary angioplasty on average of 2.9 days later. The
coefficient of variation for QCA, which measures the same lesions from separate
angiograms ranged from 8.11% to 14.01%. Average diameter was the least
variable and percent diameter stenosis the most variable. Day-to-day variations in
the patient, procedure and equipment, accounted for an average of 30% of the
total variability. Of the remaining variability, only 13.26% was due to frame
selection.
Lesperance and colleagues reported the measurement reproducibility of 24

vein grafts in 24 patients who had symptom-directed control angiography.320
Focal narrowings expressed in percent stenosis varied from 5 to 80% (mean 20.8
± 15.9%). They assessed the reproducibility of measurements obtained from two
separate imagings of the graft in the same view but at least 20 minutes apart, near
316
Beauman, Reiber, Koning and Vogel. Catheterization & Cardiovascular Diagnosis
1996; 37:24-31, Keane, Haase, Slager, et al. Circulation 1995; 91:2174-83.
317
Klein, Boccuzzi, Treasure, et al. Am J Cardiol 1996; 77:815-22.
318
Sirnes, Myreng, Molstad and Golf. International Journal of Cardiac Imaging 1996;
12:197-203.
319
Herrington, Siebes, Sokol, Siu and Walford. J Am Coll Cardiol 1993; 22:1068-74.
320
Lesperance, Campeau, Reiber, et al. International Journal of Cardiac Imaging 1996;
12:299-303.
250
the beginning and at the end of the angiographic procedure (simulating baseline
and end-trial examinations). The SD for differences in measurements (variability)
was 3.72% for the percent diameter stenosis.
In 2001 White and colleagues reported variability inherent in repeated

studies of atherosclerotic saphenous vein grafts during the course of the Post
Coronary Artery Bypass Graft (CABG) clinical trial, a randomised controlled trial
designed to assess whether a strategy of lipid lowering (aggressive vs moderate)
or low-dose warfarin anticoagulation could prevent atherosclerotic changes in
saphenous vein grafts.321 In this study, they used the coefficient of variation (CV)
as in our study and a new way of evaluating measurement error, “percent increase
in standard deviation among patients”.322 The difference between these two
methods is that the CV takes into account the mean of the observation but not in
the “percent increase in standard deviation among patients”. For repeated
angiographic views within a short time period, the variability of calculation of
lesion minimal diameter increased by 1.5% in standard deviation among patients
and CV was 5.32%, whereas the increase in standard deviation among patients
after repeating the entire process of quantitative angiographic readings was 6.4%
and CV 8%. The CV for the percent stenosis in this study was high compared with
the “percent increase in standard deviation among patients”. For repeated
angiographic views within a short time period, the variability of calculation of
percent stenosis increased by 2.5% in standard deviation and CV 11.9%, whereas
the increase in standard deviation among patients for repetition of the entire
process of quantitative angiographic readings in the follow-up angiogram
increased variability 21% and CV was 95.7%. In my opinion, the CV is more
appropriate for evaluating the measurements error because it takes the mean of the
magnitude of the dimension under inspection into account. A bigger magnitude of
the dimension of observation will have a smaller CV, in other words when
321
White, Campeau, Canner, et al. Am J Cardiol 2001; 87:40-3.
322
Canner, Krol and Forman. Control Clin Trials 1983; 4:441-66.
251
measuring a big magnitude of the dimension, a small measurement error perhaps

is not important. However when measuring a small magnitude of the dimension,
the small measurement error is important. The second point is that in White’s
study the angiogram was not blinded to the previous angiogram. They evaluated
the films simultaneously, therefore the selected frame and reference points were
not taken into account when assessing variability, unlike our study.
In my study, I evaluated the variation of the QCA when used for measuring
the graft diameter and area loss. I found the variations were high compared with
other studies that evaluated discrete coronary artery stenosis. Possible
explanations are: Firstly, in the early angiographic graft study, there was no
obvious discrete lesion. The start and end points of the pathline were defined near
the proximal and distal anastomoses. As a result, I used the nine-inch image
intensifier mode in order to evaluate the whole length of the study graft. This
results in loss of sensitivity by the software when detecting the lesions due to a
significant increase in the size of the individual pixels. Initially, I attempted to
divide the graft into three segments. There was however some difficulty such as
end-on graft and finding a dividing point, unlike the coronary artery anatomy in
which the start and end points can be defined at the point of branches as described
by the American Heart Association. Difficulty in defining the start and end points
was also a cause of variation in the analysis. Secondly, although the same frame
was used for the second analysis, there was a variation between observers’
definitions of start and end points. Thirdly, the diameter and area losses were
minimal and often these were not detected by visual techniques. Therefore, the
second analysis may have utilised a different frame and a different projection
selection by the observer. Following the first analysis, a second reanalysis (two
months’ interval) was undertaken without any knowledge of the original
information. This resulted in substantially more variation when compared with the
first reanalysis (three days). Fourthly, the sample size in our study was small, 22
pairs; increasing the sample size ia likely to reduce the variations. Finally,
variations occurred in the postoperative graft study as a result of sternal wires and
overlapping shadows from the native coronary artery making it necessary to
correct manually the automatically defined vessel contours. QCA variation could
252
also be attributed to poor imaging techniques e.g. overexposure or insufficient

image contrast in grafts.
A specific limitation of this study was that the early angiograms of patients
were recorded on conventional 35 mm cinefilm, which meant quantitative
analysis could not be performed at this time. Secondly, the earlier angiograms
were not primarily set up for QCA, the catheter used was not large enough for
accurate calibration. The most common catheter size used in this study was a 5
French catheter making calibration unreliable. Therefore, some significant values
such as the stenotic flow reserve323, lesion diameter, reference diameter could not
be measured accurately and were omitted. In addition, some angiograms were
recorded on VHS videotape and the quality was unacceptable for quantitative
coronary angiography.324 I have now established a coronary angiography
protocol with colleagues from the Leiden University Medical Center, The
Netherlands as described in the next section.
CONCLUSION
Quantitative analysis of coronary artery grafts can be performed. The

reproducibility can be increased by improving coronary angiographic techniques,
defining rigid criteria of start and end points, and careful selection of the frame to
be analysed.
The early graft patency of RA, RITA and SV were excellent at an average
interval of one year from implantation. There was no difference in graft stenosis
between RA and RITA in young age patients and also no difference in graft
stenosis between RA and SV in older age group. An independent factor
323
Zijlstra, Fioretti, Reiber and Serruys. International Journal of Cardiac Imaging 1988;
3:133-9, Zijlstra, van Ommeren, Reiber and Serruys. Circulation 1987; 75:1154-61.
324
Reiber, Koning, van der Zwet and Schiemanck. Catheterization & Cardiovascular
Diagnosis 1996; 37:32-8.
253
influencing the diameter and area loss in the graft in the younger group was
diabetes regardless of the type of the graft (RA or RITA used). The
reproducibility of QCA when analysing the bypass grafts needs to be established,
a larger number of study grafts and a longer follow-up are required to make a firm
conclusion about the relative graft patency of the RA, RITA and SV.
254
(b) Angiographic and Quantitative Analysis Protocol
Following are the protocols for future angiography and QCA developed in
conjunction with Professor Johan H.C. Reiber, Laboratory for Clinical and
Experimental Image Processing (LKEB), Department of Radiology at the Leiden
University Medical Center, The Netherlands, and the Interuniversity Cardiology
Institute of the Netherlands (ICIN), Utrecht, The Netherlands.
Coronary Angiography
Diagnostic coronary angiography is performed by using the standard

femoral approach with a premedication (diazepam, 5 mg PO). All vasoactive
medications are discontinued one to two days before the study. The angiogram is
performed using catheters (Cordis Europa, Roden, The Netherlands) of six French
or larger. TIMI frame counting method is performed for the study graft and left
internal thoracic artery as a control.325 During angiography, the native coronary
arteries anastomosed to the study graft and left internal thoracic artery graft are
also injected. LAO and RAO views of the grafts and native vessel are obtained
using a 6 to 7 inch image intensifier mode to avoid overlapping of the sternal
wires. Patients receive 0.5 mg nitroglycerine sublingually to control vasomotor
tone and the same dose of nitroglycerine is repeated every 20 minutes during the
procedure. The nonionic contrast agent iohexol (Omnipague, 350 mg iodine per
ml, Nycomed, Oslo, Norway) is used. Great care will be taken to record the gantry
settings (rotations and cranio-caudal angulations, table height, and height of the
image intensifier) as well as nitroglycerine administration on specially designed
forms.
Quantitative analysis protocol
All QCA will be performed using the Quantitative Coronary Analysis,

Cardiovascular Measurement Solutions system, Version 4.0 (QCA-CMSÒ,
325
Dodge, Rizzo, Nykiel, et al. Am J Cardiol 1998; 81:1268-70, Gibson, Cannon, Daley, et
al. Circulation 1996; 93:879-88.
255
Leiden, The Netherlands).326 A physician experienced in QCA, blinded to the

clinical data, selects the frames for analysis. The following criteria are used to
decide which appropriate frame should be analyzed: (1) the graft/coronary artery
segment should be well-filled with a contrast medium; this is usually achieved by
selecting an image from the second or third cardiac cycle following the contrast
administration; (2) the stenosed segment of the graft/coronary artery should be
clearly visible, preferably without any overlap from other vessels or side
branches; (3) The vessel or graft segments are in the centre of the field; (4) the
projection is perpendicular to the long axis of the vessel and appropriate
collimation is applied.
For each study graft and coronary segment, a corresponding calibration

factor is obtained on the basis of the contrast catheter size. The image selected for
calibration may not necessarily be the same as the image in which the obstruction
is measured. Criteria for calibration frame selection included: (1) the nontapering
segment of the catheter being visible with a sufficient length (~ 2 cm), and (2) the
catheter not being obscured by contrast flowing back into the aorta. As a result,
the catheter image is usually selected in the early phase of the cardiac study.
The study grafts and native coronary arteries are measured using
automated contour detection algorithms. The study graft will be divided into three
segments, proximal third, middle third and distal third according to the length of
the graft. The start point for the study graft is defined at the normal part of the
graft in each segment. Anastomotic lesions will be analyzed separately. QCA will
be performed on two projections: the most severe lesion and the perpendicular
view if available. The segment under consideration will be positioned in the
centre of the field, where distortion is minimal. The start and end points of the
analyses for the native coronary artery will be defined according to the
326
Reiber and Serruys. Advances in quantitative coronary arteriography 1993:633, Reiber
and van der Wall. Cardiovascular imaging 1996:574.
256
bifurcations of major arterial segments as recommended by the American Heart

Association.
Lesions unsuitable for QCA will include those with stenosis > 85% that
cannot be reliably edge tracked, and segments with diffuse or ectasis disease that
do not have reliable reference diameter.
The mean, standard deviation, range of diameter and area of analyzed

segment will be recorded, as will obstruction, reference, percent stenosis of
diameter and area of the obstructed segment. The length of obstructed segments
also will be recorded. Flow-related measurements (Poisseuille resistance,
turbulent resistance) are computed from the geometry of the obstruction. This
stenotic flow reserve is derived using the model of Kirkeeide and Gould.327 This
model is based on fluid dynamic equations.
327
Gould, Kelley and Bolson. Circulation 1982; 66:930-7, Gould, Kirkeeide and Buchi. J
Am Coll Cardiol 1990; 15:459-74.
257
APPENDIX
AUSTRALIAN RADIAL ARTERY STUDY PROTOCOL
BACKGROUND
One of the major challenges facing medical practitioners today is the

prevention and treatment of ischemic heart disease. The enormity of the problem
is highlighted by the fact that half of all deaths in the developed world are caused
by coronary artery disease [Mueller 1997]. Since the 1960s, a common method of
treatment has been coronary artery bypass surgery. Not surprisingly, however, the
techniques and types of bypass surgery performed have changed over the years. In
particular, recently there has been a shift towards using arterial rather than venous
conduits and treating patients with multivessel disease.
The first coronary artery bypass graft with a successful clinical outcome was
performed in 1964 using the saphenous vein [Garrett 1973]. Despite reports of
good results using the internal mammary artery as a bypass graft [Barner 1975;
Geha 1975; Tector 1976], up until the 1980s the saphenous vein was the conduit
of choice for coronary artery bypass grafting. In 1983, however, Campeau et al
reported that the vein grafts examined had a patency rate of only 63% at 10 to 12
years [Campeau]. Meanwhile, a 1986 study reported better survival rates for
patients who had received both internal mammary artery and saphenous vein
grafts compared with those who were only given vein grafts [Loop].
The accumulated evidence from studies of long-term graft patency

confirmed the superiority of internal mammary artery over saphenous vein grafts
[Cameron 1996] and saw a resurgence of interest in arterial revascularisation. The
shift towards multi-vessel grafting and the increasing number of reoperations
[Grinda 1998] being performed led to a search for other arterial conduits that
might be suitable for grafting, such as the RGEA [Pym 1987; Lytle 1989; Suma
1993] and the inferior epigastric artery [Puig 1990; Mills 1991; Buche 1992].
While these arteries (in particular the gastroepiploic artery) have demonstrated
good early patency rates, morphologically they have some limitations.
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The radial artery, first used for coronary artery bypass grafting by
Carpentier and colleagues in 1973 [Carpentier 1973], is similar in length and size
to the internal thoracic artery, has a similar diameter to the coronary artery and is
easily harvested from one or both arms in most patients. It can be used as a single
graft, anastomosed in a ‘Y’ fashion with the internal mammary artery, or used as a
sequential graft. Furthermore, the radial artery can be used instead of the
saphenous vein as a supplementary graft in complete arterial revascularisation
thereby avoiding the hospital costs and clinical complications association with an
incision in the leg [Buxton 1996]. Despite these potential advantages, however,
the radial artery has been under-utilised as a graft conduit due to the early
publication of two reports indicating that the radial artery has a poor short to mid-
term patency rate [Curtis 1975; Fisk 1976]. In 1992, however, a study
reinvestigating the viability of the radial artery as a graft conduit found that the
patency rate of radial grafts was 93% at 9 months, better than the reported patency
of free internal thoracic arteries (69%) [Acar]. Following this report, several
cardiac centres in Europe and North America confirmed these results [Calafiore
1995, Brodman 1996]. The improvement in the results of radial artery grafting in
the 1990s is thought to be due to better harvesting techniques and the use of
calcium channel blockers to prevent vasospasm and early graft occlusion [Reyes
1995]. While the internal mammary artery remains the first choice of most
surgeons, these improved results have seen the radial artery being increasingly
used as an alternative to the saphenous vein [Buxton 1997a; He 2000]. However,
while the improvement in the early results of radial artery grafting are
encouraging further follow-up is required to establish the long-term patency and
survival rates associated with using this vessel [Fremes 1995].
PATENCY DATA
Radial artery
There is mounting evidence supporting the excellent short-term patency of

the radial artery as a coronary bypass graft [Chen 1996; Brodman 1996].
However, there is a relative lack of data concerning long term patency. Calafiore
and colleagues’ 1995 study of 148 patients who underwent bypass grafting with a
radial artery graft found that at follow-up angiography the early patency rate (30
259
days, 41 patients) was 100% while the late patency rate (mean 14 months, 30/32
patients) was 94% [Calafiore 1995]. A 1996 study found that in 61 patients who
had angiography following radial artery grafting 97% were patent in the early
post-operative period while in the 12 patients who had repeat angiograms at a
mean interval of 9 months all grafts were patent [da Costa 1996]. In a longer term
study of 68 patients with radial artery grafts, Possati and colleagues reported an
angiographic patency rate of 92% 5 years after surgery [Possati 1998]. Acar and
colleagues also conducted a five year follow up study, reporting a patency rate of
83% for patients receiving RA grafts and a rate of 91% for those receiving IMA
grafts. They note that the difference between these two rates may be due to the
different implantation sites of the two grafts with the RA mostly being grafted to
the circumflex artery while the IMA was grafted primarily to the left anterior
descending artery [Acar 1998].
Internal mammary artery versus saphenous vein
Comparative studies indicate that using either the internal mammary artery
or the saphenous vein for coronary artery bypass grafting produces excellent short
term results. For instance, both Goldman and colleagues and Sethi et al have
reported a one-year patency rate of 93% for the internal mammary artery and 90%
for the saphenous vein [Goldman 1990; Sethi 1991]. However, supporting the
findings of Campeau and colleagues, a number of groups have demonstrated a
marked gap between the long-term patency of saphenous vein compared with
internal mammary artery grafts. Barner and colleagues, following up patients from
1 to 12 years after coronary artery bypass surgery, found the patency rate of the
internal mammary artery versus the saphenous vein was 96% versus 94% at 1
year, 88% versus 74% at 5 years and 83% versus 41% at 10 years [Barner 1985].
In a 1988 study the cumulative 11-year patency rate was 88% for internal
mammary artery grafts and 61% for saphenous vein grafts [Ivert 1988] while in a
more recent study, the 10-year cumulative patency rate of internal mammary
artery versus saphenous vein grafts was 90 and 67% respectively [Kitamura
1996]. The divergence in patency rates between the two vessels is believed to be
primarily due to the saphenous vein’s propensity for developing atherosclerosis or
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‘vein graft disease’ [Suma 1999].
SURVIVAL/MORBIDITY
Radial artery
One of the benefits of using the radial artery as a bypass graft is that from a
surgical point of view it is easily accessible. However, theoretically there are a
number of risks associated with radial artery harvesting. Studies to date, however,
suggest a low risk of complications. In a study of 200 patients who underwent
bypass surgery with radial artery grafts 1% suffered donor site hematomas and 2%
had temporary dysethesias [Sudhakar 1998] while in a series of 328 patients who
had had their radial arteries harvested only 2 patients reported late hand ischemia
while there was no decrease in hand strength post-surgery although scar
hypersensivity occurred in 20% of the patients [Royse 1999]. In a University of
Melbourne study, out of 2,417 patients who had their radial arteries removed at a
hospital only two patients, both of whom suffered from scleroderma, developed
fingertip ischemia while 0.4% of patients developed a major forearm hematoma
[Tatoulis 1999]. Four other studies have reported no complications following
radial artery harvesting [Acar 1992; Dietl 1995; Fremes 1995; Bhan 1999]
indicating the safety of this procedure.
The mortality and cardiac morbidity rates associated with using the radial
artery as a bypass graft are also low. A 1995 study followed up 50 patients who
received radial artery grafts in addition to other conduits and reported no early or
late deaths and no myocardial ischemic complications associated with the use of
the radial artery [Fremes 1995]. A study of 165 patients who received radial artery
grafts reported a mortality rate of 3% (no deaths were caused by radial graft
failure) and found that after 14 months angina had recurred in 3% of patients
(angiography indicated that the radial artery grafts were still widely patent) [Dietl
1995]. In 200 patients who underwent bypass surgery with radial artery grafts, 1%
had a myocardial infarction caused by graft failure while 2 deaths were caused by
co-morbid factors [Sudhakar 1998]. Finally, in a recent study of 62 patients with
radial artery grafts there were no perioperative or late myocardial infarctions and
no deaths [Bhan 1999]. Data is lacking, however, on the effect of radial artery
261
grafting on long term survival and morbidity rates.
Internal mammary artery versus saphenous vein
In terms of short term data, a US study analysing the Department of

Veterans Affairs Cardiac Surgery Database found that over the period from
October 1990 to September 1991 the operative mortality rate for patients who
received internal mammary artery grafts versus those who had saphenous vein
grafts was 3.2% and 6.5% respectively [Grover 1994] while Sethi and colleagues
found no difference between the operative mortality rates of these two groups
[Sethi 1991].
The findings of long term studies of the mortality and morbidity rates
associated with internal mammary artery versus saphenous vein grafts not
surprisingly have tended to mirror the findings of patency studies, showing that
over time arterial grafts perform better than vein grafts. As noted previously, in
1986 Loop and colleagues reported the findings of a study in which they had
compared the survival and morbidity rates of patients who received an internal
mammary artery with or without a saphenous vein graft versus those who had
received only a saphenous vein graft. They found that over a ten-year period those
who had only had vein grafts had a 1.61 times greater risk of death, 1.41 times the
risk of late myocardial infarction and 2 times the risk of cardiac reoperation
compared with patients who had received internal mammary artery grafts [Loop
1986]. In 1988, a long-term, prospectively randomised study of patients with
saphenous vein versus left internal mammary artery grafts to the left anterior
descending coronary artery showed a mortality rate of 18% versus 8% while
myocardial infarctions occurred in 20% of the vein graft group compared with 8%
of the arterial graft patients [Zeff 1988]. Lastly, a 1996 study found that the 10-
year overall survival and cardiac event-free rates for internal mammary artery
versus saphenous vein grafts were 89% versus 80% and 84% versus 73%,
respectively [Kitamura 1996].
262
Multiple arterial grafts
While it has been proven that the use of internal mammary artery grafts
results in improved survival compared with vein grafting alone, there has been
controversy over whether the use of bilateral internal mammary artery grafting
further improves survival. In 1990, Fiore and colleagues found that 13 years after
following up 100 patients who had received bilateral internal mammary artery
grafts and a saphenous vein graft versus 100 patients who had been grafted with
one internal mammary artery graft and a saphenous vein graft the survival and
morbidity rates of the first group were significantly better than those of the second
[Fiore 1990]. However, two later studies found the survival rates for patients
with bilateral versus single internal mammary artery grafts to be comparable
[Berreklouw 1995; Dewar 1995]. Recently, however, a very large, long term
study by Lytle and colleagues found that patients who received two internal
mammary artery grafts had a decreased risk of death, reoperation and angioplasty
compared with those with only one internal mammary artery graft [Lytle 1999].
A number of groups have also begun to report the early findings of complete
arterial grafting using combinations of internal mammary, inferior epigastric,
gastroepiploic, and radial artery grafts [Dietl 1993; Grandjean 1996; Antona
1997]. In 1997, Weinschelbaum and colleagues reported excellent patency rates
and minimal morbidity and mortality when using the radial artery combined with
the left and sometimes the right internal mammary artery to achieve total arterial
revascularisation [Weinschelbaum 1997]. In 1998 a University of Toronto-based
study (described below) found not only an improved perioperative cardiac
morbidity and mortality with the use of two arterial grafts but they also noted that
patients who received a radial artery rather a right internal mammary artery as
their second graft had comparable perioperative and intermediate-term cardiac
morbidity and mortality rates and that radial artery grafting was associated with a
lower incidence of sternal wound infection and decreased transfusion
requirements [Borger 1998]. Furthermore, Bhan et al have found the mid-term
results of grafting the radial artery to be comparable with that of the pedicled
internal mammary artery. However, they caution that the two vessels cannot be
263
given comparable status until long-term results become available [Bhan 1999].
THE UNIVERSITY OF MELBOURNE EXPERIENCE
Since the 1980s, three cardiac surgical centres with links to the University
of Melbourne have been at the leading edge of research into arterial
revascularisation and the use of alternative graft conduits. In 1984, following
concerns over the long-term patency of the saphenous vein, the University of
Melbourne began to use the internal mammary artery as a first-line graft conduit
and soon progressed to bilateral internal mammary artery grafting, although the
saphenous vein continued to be used as a supplement when required. In 1995, the
University team moved towards performing complete arterial grafting by using
combinations of both radial and internal mammary arteries [Buxton 1997b].
While a single radial artery was used initially, the team soon progressed to
performing bilateral radial artery grafting, Y grafting and sequential anastomoses
[Buxton 1998] and have also had good results with using the right internal
mammary artery as a free graft [Tatoulis 1997]. In tandem with their research into
the surgical application of arterial grafts, the researchers at the University of
Melbourne also began investigating a number of related issues including: the
effect of radial artery harvesting on post-operative hand function [Hare 1997]; the
pharmacologic management of spasm in arterial grafts [Liu 1997; Rosenfeldt
1999]; and the comparative histopathology of arterial conduits [Ruengsakulrach
1999].
While the benefits of multiple arterial grafts have been somewhat

controversial, the most recent report from the University of Melbourne
demonstrates the safety and efficacy of total arterial coronary revascularisation.
Following up 3,220 patients who underwent complete arterial grafting between
1988 and 1998, the Melbourne group reported patency rates of 97% at 5 years for
the left internal mammary artery grafted to the LAD, 89% at 5 years for the right
internal mammary artery and 91% at 1 year for the radial artery, with the latest
unpublished data indicating a patency rate at 10 years of 96% for the left internal
mammary artery [Tatoulis 1999]. While these results are excellent the data
collected on radial artery grafting is limited. As previously noted, there is a lack of
264
randomised, long term studies examining the patency, mortality and survival rates
associated with radial artery grafting. The prospective University of Melbourne
study described below is a randomised, multicentre trial that was set up in 1996 in
order to assess both the late-patency and clinical effects of grafting with the radial
artery versus the free right internal mammary artery and the saphenous vein.
In this study patients are randomised into two groups, the first consisting of
a younger patient group who are grafted with a left internal mammary artery and a
radial artery or free right internal mammary artery while the second, older group
of patients receive a left internal mammary artery and a radial artery or saphenous
vein graft. The collateral circulation of the hand is assessed using either the
modified Allen test [Cable 1999] or by measuring the blood pressure in the
fingers by photoplethysmography and any patients with abnormal results are
excluded from the study. To date the study has managed to recruit 320 patients,
147 of whom have had radial artery grafts.
As previously noted, the improvement in the results of radial artery grafting

since the seventies is probably due to a combination of better harvesting
techniques and the use of calcium channel blockers. Accordingly, in this study the
radial artery is removed using a minimally traumatic technique. The radial artery
is particularly prone to vasospasm. Therefore, in order to prevent post-operative
vasoconstriction, all the patients in the study are given amlodipine (Norvasc), a
calcium channel blocker which has recently been shown to be one of the more
potent agents in preventing radial artery spasm [He 2000]. In terms of follow up,
in comparing the overall efficacy of the radial artery versus the free right internal
mammary artery and the saphenous vein, this study examines both angiographic
and clinical data rather than relying solely on the results of post-operative
angiography.
OTHER MAJOR RADIAL ARTERY TRIALS
Excluding our study, there are three long term, large scale trials that we
265
know of that are currently investigating the comparative efficacy of the radial
artery as a coronary artery graft.
At the Sunnybrook Health Science Centre at the University of Toronto,

Stephen Fremes and colleagues have been conducting a comparative radial artery
graft patency study since 1992. The study is a multicentre, randomised trial and its
aim is to determine the long-term patency of radial, saphenous vein and internal
thoracic artery grafts 5 to 10 years postoperatively. To enter the study patients
must have graftable triple vessel coronary disease, an LVEF > 35% and be
scheduled solely for primary coronary artery bypass surgery. Five hundred and
sixty patients are to be recruited into the study. Follow-up currently consists of
angiography which is performed 7 to 12 months postoperatively although the
study also plans to assess long-term patency (5 to 10 years postoperatively). Like
our study, then, the Sunnybrook trial aims to investigate the long-term,
comparative patency of radial artery, internal mammary artery and saphenous vein
grafting. In contrast, however, in this trial the patients serve as their own control
while no data has been collected on clinical (as opposed to purely angiographic)
outcomes.
THE UNIVERSITY OF MELBOURNE STUDY
AIM
The primary aim of the project is to compare the patency of the radial artery
(RA) when used as a coronary artery bypass graft with that of the free right
internal mammary artery (FRIMA) and the saphenous vein (SV). The rates of
patient survival, relief from angina, freedom from myocardial infarction and
cardiac failure, and the frequency of re-operation in the different patient groups
will be compared.
HYPOTHESES
Ø The radial artery is superior to the long saphenous vein when used as a
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coronary artery bypass graft.
Ø The radial artery is superior to the free right internal mammary artery
when used as a coronary artery bypass graft.
ENTRY CRITERIA
Ø The patient is scheduled for primary coronary artery bypass surgery

alone.
Ø The patient requires more than 1 graft, that is, there are at least 2
coronary artery stenoses of > 70%.
GENERAL EXCLUSIONS
Ø Renal disease with a creatinine >0.30 mmol/L.
Ø Chronic heart failure (NYHA Class III or IV or ejection fraction < 35%
on angiography or radionuclide ventriculography).
Ø Associated major illnesses e.g., malignancy.
Ø Body mass index (BMI) > 35 : weight (kg)/height(m2).
Ø Acute presentation, that is, those patients who have an acute myocardial
infarct within one week prior to surgery or who present with cardiogenic shock.
Ø Technical exclusions e.g., sequential grafting.
Ø Failure to obtain informed consent.
SPECIFIC EXCLUSIONS
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RANDOMISATION GROUP 1 - Radial Artery or Free Right Internal
Mammary Artery
Ø Failure to be able to use the radial artery because of an abnormal Allen

Test (> 10 seconds) or abnormal digital/brachial index (< 0.8).
Ø Failure to be able to use the free right internal mammary artery due to,
for example, previous chest trauma.
Ø FEV1 < 50% of expected value.
Ø Diabetics > 60 years.
Ø Other patients > 70 years.
RANDOMISATION GROUP 2 - Radial Artery or Saphenous Vein Graft
Ø Failure to be able to use a radial artery because of an abnormal Allen

test (> 10 seconds) or an abnormal digital/brachial index (< 0.8).
Ø Failure to be able to use the saphenous vein – e.g. due to varicies, past
trauma.
Ø Diabetics < 60 years.
Ø Other patients < 70 years.
CORONARY ARTERY EXCLUSIONS
Ø Diameter < 1.5mm
Ø Stenosis < 70%
Ø Diffuse Disease
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GRAFT EXCLUSIONS
Ø Luminal narrowing > 20%
Ø Atherosclerosis
Ø Calcification (except mild / focal)
Ø Wall thickness > 1mm
Ø Diameter < 1.5mm or > 5mm
RANDOMISATION
Randomisation will be organised and supervised by Dr Ian Gordon,

Statistical Consulting Centre, University of Melbourne.
RANDOMISATION GROUP 1: Radial Artery or Free Right Internal Mammary

Artery
Ø Patients < 70 years

Ø Diabetic patients < 60 years
Coronary Artery Graft 1 2 Subsequent
Current Operation LIMA RIMA SV
Study Operation LIMA RA/RIMA SV
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RANDOMISATION GROUP 2: Radial Artery or Saphenous Vein Graft
Ø Patients > 70 years
Ø Diabetic patients > 60 years
Coronary Artery Graft 1 2 Subsequent
Current Operation LIMA SV SV
Study Operation LIMA RA/SV SV
CONDUIT ASSESSMENT
Radial Artery
The ability to use the radial artery safely as a graft will be judged by a
normal Allen test (return of circulation to the hand in < 10 seconds with radial
artery occlusion), or by normal digital/brachial systolic blood pressure index
(<0.8).
The radial artery is satisfactory for use as a bypass graft if it measures > 2
mm. The radial artery will not be used in patients with proximal subclavian artery
disease where the systolic brachial artery pressure on the affected side is 20
mmHg lower than that on the opposite side.
Saphenous Vein
The saphenous vein may be used as a coronary artery bypass graft if it is

without varicies, gross wall thickening or atheroma, and peripheral pulses are
present. In the absence of peripheral pulses, the saphenous vein may be used as a
graft if the leg/arm Doppler pressure ratio exceeds 0.7.
270
Internal Mammary Artery
The internal mammary artery is satisfactory for use as a bypass graft if it

measures > 1.5 mm in diameter and the flow rate is > 60 ml/min.
At the time of operation, if the study vessel is found to be clinically unsuitable
by the surgeon, it will not be used.
SURGICAL TECHNIQUES
Internal Mammary Artery Dissection

The Left Internal Mammary Artery
The left internal mammary artery is mobilised as a pedicle with its adjacent
veins, fascia, pleura and connective tissue. Side branches are clipped close to the
IMA and divided with diathermy. Large branches are divided between hemo
clips. The distal extent includes the bifurcation into the musculophrenic and the
superior epigastric branches. Superiorly, the IMA is mobilised to the inferior
border of the subclavian vein so that the pedicle is free to lie medial to the lung
near the hilum.
The Right Internal Mammary Artery
The harvesting of the right internal mammary artery must be performed by

the senior surgeon. The technique proceeds as for the left internal mammary
artery. After mobilisation up to the inferior border of the right subclavian vein, the
lower end of the pedicle is displaced medially and the mediastinal pleura divided
over the lateral side of the pedicle to display the internal mammary vein (IMV),
internal mammary artery and the phrenic nerve. The IMV is divided between
large Weck clips. The upper right internal mammary artery is isolated and divided
at the lower border of the right subclavian vein resulting in a free graft.
Vasodilatation
Five ml of a solution of Papaverine 60 mg in 100 ml of Ringer’s lactate

solution and 60 ml of whole blood containing 1000 IU Heparin is injected into the
271
distal IMA and the IMA clipped. Blood flow of greater than 60 ml per minute and
a mean arterial blood pressure of 60 mmHg are required for use of the internal
mammary artery as a graft.
Radial Artery Removal
The radial artery is removed through an incision that extends from 2 cm

below the level of the elbow to 2 cm above the wrist, in the line of the radial
artery. After entering the deep fascia of the forearm, the radial artery is removed
together with the collateral veins. Meticulous dissection is performed without
touching the radial artery. The wound is irrigated with a solution of either
papaverine or milrinone. The branches of the radial artery and associated veins are
divided between Weck clips. 2 cm above the wrist, the venae comitante are
separated from the radial artery and ligated with clips. The artery is also ligated at
that level. The radial artery is dilated with intraluminal papaverine or milrinone
10-3M and the distal end of the radial artery is clipped. The dissection is continued
up to the level of the bifurcation of the brachial artery or 2 cm below the elbow, at
which site the artery is again separated from the veins and clipped proximally
with medium Weck clips. The radial artery is stored at room temperature in a
solution of 50% heparinized blood and 50% papaverine in Ringer’s lactate until
implantation.
Harvesting of the Saphenous Vein
This is performed through an incision along the medial aspect of the calf
extending to less than 2 cm above the medial malleolus. The saphenous vein is
removed and the side branches ligated carefully with silk or with metal clips. The
wound and vein are irrigated with papaverine or milrinone. The vessel is stored in
the same solution of milrinone or papaverine with 50% blood.
Coronary Artery Bypass Grafting Technique
All anastomoses must be performed by the senior surgeon. The chest is

opened through a median sternotomy. The patient is placed on cardiopulmonary
bypass by cannulating the aorta, right atrium and inferior vena cava. The patient’s
temperature is lowered to 340C. A separate cannula is placed in the
272
coronary sinus for retrograde coronary perfusion. The aorta is clamped and blood
cardioplegic solution is introduced initially into the aortic root and subsequently
via the coronary sinus to maintain cardiac arrest. Proximal and distal anastomoses
are performed under aortic cross clamp. The left IMA is anastomosed to the left
anterior descending coronary artery (LAD) if > 1.5 mm, or to the largest artery
requiring grafting. The study graft is anastomosed to an artery with a stenosis of >
80%. The proximal anastomosis is marked at the aorta with 2 medium Weck
hemoclips for identification in future angiograms. At the end of the procedure,
the patient is rewarmed to 370C.
Histopathology
A 5mm segment of the distal study artery is removed prior to implantation.

This specimen is distended with blood and placed in 4% formalin for
histopathological examination. These results will be correlated with graft
occlusion.
POST-OPERATIVE MANAGEMENT
Vasodilator Therapy
All patients in the study are commenced on milrinone intra-operatively.

Before release of the aortic cross clamp milrinone 25 mcg/kg is given over 15
minutes followed by 0.25 mcg/kg/min for up to 18 hours post-operatively, until
the administration of amlodopine (see below). In patients with an elevated
creatinine the milrinone dose may be reduced. Milrinone may be discontinued if
the mean blood pressure (BP) < 70 mmHg, cardiac index >3 L/min/m2 or
systemic vascular resistance index (SVRI) < 1200 dynes/sec/cm-5. Alternate
regimes such as glyceryl trinitrate/sodium nitroprusside infusions may be used.
Calcium Channel Blockers
All patients in the study are commenced on amlodipine. Amlodipine

(Norvasc) 2.5 mg orally is commenced the first post-operative day after the
discontinuation of milrinone. The dose is then increased to 5 mg daily on the
second post operative day if tolerated; i.e. if the systolic blood pressure > 100
273
mmHg and Norvasc can be tolerated in combination with other cardiac drugs.
Norvasc is continued for a minimum period of six months.
NB. Vasodilator therapy is commenced on all patients in the study

including those in the control groups.
PRIMARY END POINTS
1. Graft patency
Graft patency will be assessed by angiography of all grafts. As the most

important data will occur in the late part of the study, the schedule for
catheterisation is as follows:
Ø 10% of patients during the first month.
Ø 10% of patients at 2 years.
Ø 20% of patients at 5 years.
Ø 30% of patients at 7.5 years.
Ø 30% of patients 10 years.
2. Clinical
Ø Onset of ischaemic chest pain.
Ø Acute myocardial infarct.
Ø Re-operation for coronary artery bypass grafting.
Ø Death.
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SECONDARY END POINTS
1. Morbidity from saphenous vein removal compared with morbidity from

radial artery removal.
2. Quality of life will be assessed using the Hare/Davies Cardiac

Depression Score.
STATISTICAL ANALYSIS
Graft patency and survival analysis will be performed using the Kaplan
Meier technique and differences assessed using the log rank statistic. The
threshold of statistical significance is confirmed at p < 0.05.
Power Calculation
To detect a difference of 10% between the two groups, at the 5% level of

significance, power calculations suggest that 402 patients are required in each
group (where the power is 80%).
Survival Data and Post-operative Assessment
Patients will be reviewed annually by their surgeon, this will include a

clinical assessment and collection of survival data. Patients will be contacted
every six months by the study co-ordinator. Time related comparisons will be
made of survival and freedom from angina or myocardial infarction, freedom
from re-operation and actual survival between patients having a radial artery graft
and the control graft.
275
COMMITTEES
Each committee will meet every twelve months.
Steering Committee
1. Professor Brian Buxton, Director of Cardiac surgery, Austin &

Repatriation Medical Centre
2. Professor Andrew Tonkin, Director of Health, Medical and

Scientific Affairs, National Heart Foundation
3. Professor John McNeil, Epidemiologist, Monash University
4. Associate Professor Franklin Rosenfeldt, Head Cardiac Surgical

Research Unit, Baker Medical Research Institute, Alfred Hospital
Patient Safety Committee
1. Mrs. Lyn Roberton, Patient Advocate, Austin & Repatriation

Medical Centre
2. Dr Rinaldo Bellomo, Department of Intensive Care, Austin &

3. Dr Laurie Doolan, Director of Operating Suite, Austin &

4. Mr. A C Wilson, Director Cardiac Surgery, St Vincent’s Hospital
Data Management Committee
1. Dr Ian Gordon, Statistical Consulting Centre, University of

Melbourne
2. Professor Brian Buxton, Director of Cardiac surgery, Austin &
276
3. Ms Kathleen Cowie, Research Co-ordinator, Department of Cardiac

Surgery, Austin & Repatriation Medical Centre
4. Dr Jai Raman, Cardiac Surgeon, Austin & Repatriation Medical

Centre
5. Dr John Fuller, Victorian Heart Centre, Epworth Hospital
277
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285
Chapter 10
Summary
RESULTS OF HYPOTHESIS TESTING
CONCLUSIONS
Summary 285
RESULTS OF HYPOTHESIS TESTING
In this thesis, I have addressed three main concerns in relation to the role of the
radial artery (RA) as a coronary artery bypass graft, namely the question of its
suitability, its safety and its efficacy.
In Chapter 2, I argued the suitability of the RA as an alternative to other graft

conduits by demonstrating the ease with which this vessel can be accessed and
harvested. I also documented the important variations of the forearm and hand
arteries, defined the possible anatomical connections between the radial and ulnar
arteries in the hand, and demonstrated the safety of RA harvesting by showing that it
is very unusual for a hand not to possess some degree of collateral circulation. All the
hands examined in my study had at least one artery supplying the thumb either via the
ulnar dominant type or through the deep palmar arch and there was no hand with an
ulnar non-dominant superficial palmar arch and an incomplete deep palmar arch.
However, at the same time I emphasised the fact that it is common for patients
requiring coronary artery surgery to have multiple sites of vascular disease such as
carotid disease, aortoiliac disease and femoropopliteal disease. I therefore emphasized
the importance of considering vascular pathology in the arm, forearm and hand
arteries when harvesting the RA.
In order to further assess the suitability of the RA as a bypass graft, in Chapter 3

I described the histology and histopathology of the artery. In Chapter 4, I discussed a
study performed by myself and colleagues in which we sought to investigate the
histopathology of the RA by comparing radial arteries sampled from patients who
underwent coronary artery bypass grafting with the internal thoracic artery, the
standard conduit for grafting. I found that the RA had a much higher rate of intimal
hyperplasia and atherosclerosis than the internal thoracic artery, both in relation to
prevalence and severity indices such as the percentage of luminal narrowing, the
intimal thickness index and the intima-to-media ratio. On the basis of our
histopathologic study, I believe that most radial arteries are suitable as a graft.
However severe disease present in a minority of vessels might compromise long-term
287
Summary 285
graft patency. The RA therefore needs to be selected carefully before being used as a
graft. My studies indicate the necessity for applying considerable caution in using the
RA in patients with aortoiliac disease, in diabetic patients who are 63 or older, and in
those aged ³ 78 without diabetes.
These findings highlight the importance of determining a way of identifying

disease-free radial arteries prior to surgery. Accordingly, in Chapter 5 I examined the
efficacy of ultrasound for preoperatively screening the RA for calcification and
intimal hyperplasia and found that ultrasound had a diagnostic accuracy rate of 85%
for detecting calcification in the RA. It should be noted that while it is recommended
not to use the RA when it is calcified there are some concerns that ultrasound is not
able to distinguish between atherosclerosis calcification from medial calcification.
There is a lack of data on the effect of medial calcification on graft patency. To
answer this question, long-term follow up of patients whose grafted RA show medial
calcification is required. Even though ultrasound was not useful for evaluating the
degree of intimal hyperplasia in the RA, it can be employed to evaluate the luminal
diameter of the RA with reasonable reliability. Accordingly, I concluded that
ultrasound is a useful tool for screening for disease in the RA. However, further
development of ultrasound techniques and technology is needed in order for it to
accurately detect the degree of intimal hyperplasia in the RA.
A major concern about RA grafting is whether or not RA harvesting is a safe

procedure. To determine this, I evaluated three tools for preoperatively assessing the
RA and the collateral circulation of the hand. The first screening test examined was
the modified Allen test, a procedure that can be performed by the bedside without any
sophisticated equipment. In chapter 6, I confirmed the advantage of using the
modified Allen test by comparing it with Doppler ultrasound. An abnormal Doppler
dynamic test occurred when there was no flow in the thumb with RA occlusion and
this indicated that if the RA was harvested, there is a high risk of hand ischemia.
Compared with the Doppler dynamic test, the modified Allen test accurately detected
poor collateral circulation in the hand. The modified Allen test was also easier to
conduct. In Chapter 7, I discussed a study undertaken by colleagues and myself in
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Summary 285
which we used the thumb brachial index with RA occlusion measured by

photoplethysmography as a baseline against which to compare the accuracy of the
modified Allen test. The modified Allen test correlated well with the thumb brachial
index with RA occlusion. The diagnostic accuracy of the modified Allen test was
82%. One of the problems I faced was identifying an appropriate cut-off point for the
modified Allen test which would indicate that a patient was at risk of ischemic
complications following RA harvesting. To be conservative, we used a recovery time
of 8 seconds as a cut-off point with a sensitivity rate of 82% and specificity rate of
80% compared with the thumb brachial index with RA occlusion.
In Chapter 8 and 9, the efficacy of the RA for use as a bypass conduit for CABG
was tested. The survival rate of patients using the RA as a second graft in addition to
the left internal thoracic artery was comparable with the survival rate of patients using
both left and right internal thoracic arteries in an average three-year follow-up.
Survival was better than in patients where the saphenous vein was used with the left
internal thoracic artery. This study included a wide spectrum of patients, however it
was an observational study subjected to bias of graft selection by surgeons. In Chapter
9, semi-quantitative and quantitative coronary angiography in a prospective
randomized controlled trial demonstrated that at one year, in younger patients (≤70
years without diabetes and ≤60 years with diabetes), the RA grafts had a similar
diameter and area stenosis compared with the right internal thoracic artery. In older
age patients (>70 years without diabetes and >60 years with diabetes), the RA grafts
demonstrated less stenosis than saphenous vein grafts. However these preliminary
results involved a very small number of patients, which is a limitation.
289
Summary 285
CONCLUSIONS
Overall in my thesis, I concluded that the RA grafting is safe and the RA is a

potentially effective alternative conduit for coronary artery bypass grafting. The RA
showed higher prevalence and severity of intimal hyperplasia and atherosclerosis than
the internal thoracic artery but the diameter loss was still relatively low. The early
survival rate in patients having a RA graft as a second conduit were comparable with
those receiving a right internal thoracic artery. The early result also suggested that the
survival rate was better than those patients having a saphenous vein. In order to
investigate the effect of pre-existing disease processes on the RA graft patency, a
long-term follow-up study with graft angiography is required. A prospective
randomised study to assess the relative graft patency of the RAs, right internal
thoracic arteries and saphenous veins more conclusively is currently underway.
290
286
Chapter 11
Future
FUTURE DEVELOPMENTS
(a) Laboratory Experimental Trials

(b) Clinical Trials
GENE THERAPY
SYNTHETIC CONDUITS
SURGICAL TECHNIQUES
Future 303
FUTURE DEVELOPMENTS
In this section, some of the questions left unanswered in my thesis will be

briefly discussed. Possible future approaches to these issues will also be explored.
(a) Laboratory Experimental Trials
I have shown that some radial arteries demonstrate a high degree of intimal
hyperplasia. Low-density lipoprotein (LDL) preferentially accumulates at sites of
intimal thickening in human arteries.328 It has been shown that the RA produces
less endothelial relaxing factors compared with the internal thoracic artery
suggesting diminished endothelial regulation of vascular smooth muscle in the
RA.329 Thus the RA may be prone more to spasm than the internal thoracic artery.
Endothelial injury during harvesting and surgical preparation of the graft,330
together with the decreasing of nitric oxide and prostacyclin production from
endothelial dysfunction permit platelet adhesion and aggregation.331 This is
followed by stimulation of vascular smooth muscle cells to proliferate and to
migrate to the intima. The smooth muscle cells undergo a phenotypic change from
contractile to secretory cells, and extracellular matrix accumulates. Platelet
activation provokes the release of platelet-derived growth factor and basic
fibroblast growth factor. These processes might result in flow limiting intimal
hyperplasia in the graft. This intimal hyperplasia consists of secretory vascular
328
Schwenke and Carew. Circ Res 1988; 62:699-710, Spring and Hoff. Exp Mol Pathol
1989; 51:179-85.
329
Cable, Caccitolo, Pfeifer, et al. Ann Thorac Surg 1999; 67:1083-90.
330
Holt, Francis, Newby, et al. Ann Thorac Surg 1993; 55:1522-8., Soyombo, Angelini,
Bryan and Newby. Cardiovasc Res 1993; 27:1961-7.
331
Angelini, Breckenridge, Psaila, et al. Cardiovasc Res 1987; 21:28-33., Angelini, Bryan,
Williams, et al. J Thorac Cardiovasc Surg 1992; 103:1093-103., Jeremy, Izzat, Birkett, et al. Ann
Thorac Surg 1996; 61:143-8.
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Future 303
smooth muscle cells and extracellular matrix. It must be noted that most of these
studies were based on saphenous vein models.
Thus, to prevent RA graft failure, we need to understand the

pathophysiologic changes of the arterial conduit occurring after implantation into
the coronary system, develop different methods for prevention of each step
leading graft failure. The methods that might be used to study arterial graft failure
can be taken from the models of vein graft failure suggested by Baker and
colleagues.332
1. In Vitro: The human artery organ culture model
The advantage of this in vitro model is that the use of human endothelia
produces results which can be applied directly in humans. The aim would be to
compare the difference between neointimal formation in arterial versus vein
grafts, and to identify a number of genes important to neointimal development
including platelet-derived growth factor (PDGF) and its receptors,
metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMPs).
This model also offers the potential for further research into gene therapy.
2. In Vivo: The porcine model of arterial interposition grafting
This in vivo experimental model would allow examination of the free

arterial graft compared with the pedicled arterial graft in terms of both physiologic
and pathologic changes. The advantage of an in vivo model is that the graft is
exposed to an active physiological environment consisting of arterial
hemodynamics and circulating blood products (cells, hormones, coagulation
332
Baker, Mehta, George and Angelini. Cardiovascular Research 1997; 35:442-50, George,
Baker, Angelini and Newby. Gene Therapy 1998; 5:1552-60, George, Johnson, Angelini, Newby
and Baker. Human Gene Therapy 1998; 9:867-77, George, Lloyd, Angelini, Newby and Baker.
Circulation 2000; 101:296-304, Kranzhofer, Baker, George and Newby. Arterioscler Thromb
Vasc Biol 1999; 19:255-65, Newby and Baker. Curr Opin Cardiol 1999; 14:489-94.
293
Future 303
factors etc.). Even though this would be an animal study, the pig shares a similar
coagulation profile and lipoprotein metabolism to that of humans and is
susceptible to spontaneous and diet-induced atherosclerosis. Of the other animal
groups, only primates show such similarities, but their use is limited by their
higher cost and special handling requirements.
In this study, we could examine the differences between T, Y and end-to-

end (extension) grafts in order to provide scientific evidence for the expanded use
of arterial conduits including the RA. The hypotheses would be that the primary
pedicled graft has less neointimal formation than the graft extension, the graft
extension has less neointimal formation than the Y graft and the Y graft has less
neointimal formation than the T graft.
(b) Clinical trials
Another important question raised by the histopathologic analysis relates to

the effect of pre-existing intimal disease on graft patency. To date, most
investigators have assumed that intimal hyperplasia is a sign of pathology and is
the first step in atherogenesis. However intimal hyperplasia may develop as an
adaptive response to physiologic stimuli. Cable and colleagues studied the
development of intimal hyperplasia in human saphenous veins, internal thoracic
arteries and RAs in an organ culture with Rosewell Park Memorial Institute 1640
(30% serum) for 0, 4, 7, 10 and 14 days.333 The intima-to-media ratio using
quantitative histological studies was significantly increased in the saphenous vein
after 10 and 14 days of culture and not significantly increased in the internal
thoracic arteries and RAs. Questions arising thus are: (1) Does intimal hyperplasia
increase after aortocoronary bypass?; and (2) Does the pre-existing degree of
intimal hyperplasia affect the graft patency? Given that the development of graft
atherosclerosis is a long and slow process, such a study would need to be long-
term (perhaps 5-10 years). Quantitative coronary angiography is needed to
examine the correlation between the degree of pre-existing intimal hyperplasia,
333
Cable, Caccitolo, Caplice, et al. Circulation 1999; 100:II392-6.
294
Future 303
progression of intimal hyperplasia and graft patency. To examine this issue, a

study has been organized in which my colleagues and I will follow up 184
patients who have had histopathologic examination of their radial arteries, and we
will correlate the histopathologic findings with long-term clinical outcome and
graft patency. The hypothesis is that the radial arteries which had a higher degree
of intimal hyperplasia pre-implantation will be associated with a poor outcome
and lower graft patency rate. If a relationship between the degree of intimal
hyperplasia and subsequent poor graft performance is proven the next step would
be to attempt to minimize the intimal hyperplasia process early on through
blockade of growth factors e.g. using ACE inhibitor or the future development of
gene therapy.
The randomized studies comparing the RA with the saphenous vein and
the free internal thoracic artery are mentioned in Chapter 9. The end points of this
study are the clinical and angiographic findings and require a longer-term follow-
up.
GENE THERAPY
The Human Genome Project began in the United States in 1989, has been
completed. The aim of this project was to map or locate the complete nucleotide
sequence of human DNA. With the genetic map available it becomes possible to
manipulate genes thus creating a whole new research area as well as tremendous
future applications for what is known as “gene therapy”.
Molecular biology has made a number of recent advances in the field of

cardiovascular medicine. For example, in the area of congenital heart disease,
recent breakthroughs in the understanding of the regulation of genetic markers
associated with cardiac chamber formation and specification, combined with
insights into the molecular switches that regulate the expression of these markers,
are beginning to provide a foundation for the analysis of the complex process of
cardiogenesis. In this area, the study of the in vitro differentiation of totopotent
mouse embryonic stem cells into cardiac muscle cells with ventricular specific
properties, may ultimately allow investigators to examine the early process of
295
Future 303
chamber specification in genetically engineered cardiac muscle cells. As the

factors that play roles in cardiac expression become identified, gene knockouts of
these candidate loci may uncover connections with specific congenital defects in
humans - a long awaited event in the field.
To date, gene therapy has been used for the treatment of ischemic heart
disease in three areas: (1) graft modification; (2) angiogenesis; and (3)
xenotransplantation. Research has also been commenced on the prevention of
angioplasty restenosis and in gene therapy for hypercholesterolemia and
hypertension.
In terms of the prevention of coronary artery bypass graft failure, one of the
major drawbacks in the use of gene therapy has been the problem of gene
delivery. Two delivery systems have been used to insert genes into cell: (1) non
viral and (2) viral. Non-viral methods include calcium phosphate, dithyl-
aminoethyl (DEAE)-dextran and liposome mediated gene transfer. Viral methods
include retroviruses, adenoviruses, herpes viruses, lentiviruses and parvoviruses.
The major limitation of these delivery systems is that a number of these methods
have proved unable to induce high efficiency gene delivery in vivo. Baker and
associates in 1997 recommended the use of recombinant adenoviruses as the most
efficient delivery system in which high level transient gene expression can be
achieved in vitro and in vivo.334 They have the ability to infect both dividing and
non-dividing cells. The lack of viral DNA integration into the host genome results
in transient recombinant gene expression. A major problem with the use of
adenoviral gene delivery systems is the host inflammatory response to infected
cells induced in vivo. This can lead to the elimination of infected cells in vivo and
hence, a rapid decline in the level of transgenic production. Subsequently, the
adenoviral genome has been modified in an attempt to eliminate or substantially
reduce the immune response evoked. Further development and evaluation of these
systems in vivo will determine their applicability for use in clinical gene therapy.
334
Baker, Mehta, George and Angelini. Cardiovascular Research 1997; 35:442-50.
296
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Another limitation of gene therapy for the prevention of graft failure is that
the expression of factors inhibiting platelet activation or adhesion may reduce
early graft failure transiently during gene expression provided by most vectors. It
is also unknown whether early transient gene expression can provide long-term
benefits, such as the prevention of late graft failure. Unlike restenosis, where the
injury is brief and the response occurs relatively rapidly, the stimuli for smooth
muscle cell proliferation in grafts (shear stress, tangential wall stress, etc) persist
long after graft implantation and thus may require prolonged expression of a given
therapeutic gene. The antiproliferative gene transfer technology that has been used
to prevent smooth muscle cell proliferation includes (1) the cytotoxic approach
involving the transfer of the viral thymidine kinase (TK) gene and the systemic
delivery of the pro-drug ganciclovir to induce cell death, (2) the cytostatic
approach, and (3) the diffusible inhibitor approach which involves the gene
transfer of the endothelial form of nitric oxide synthase complexed to the Sendai
virus-liposome complex. The latter approach has demonstrated a reduction in
restenosis of 70% in a rat carotid injury model. Like the cytotoxic approach, this
requires lower transduction efficiency than cytostatic strategies as the nitric oxide
produced from tranduced cells produces a bystander effect on non-tranduced cells.
In addition to these approaches, several other experimental mechanisms for the
prevention of graft failure have been investigated. These included the adenoviral-
mediated gene transfer of the tissue inhibitor of metalloproteinases (TIMPs) to the
vessel wall,335 the adenoviral-mediated gene transfer of COX-1 in order to
augment prostaglandin I2 synthesis and the gene transfer of a soluble vascular cell
adhesion molecule (sVCAM) in order to block monocyte binding to the vascular
endothelium through competitive inhibition of binding to wild type, cell surface
associated VCAM.
335
George, Baker, Angelini and Newby. Gene Ther 1998; 5:1552-60.
297
Future 303
Cable and colleagues demonstrated adenoviral-mediated gene transfer of

bovine endothelial nitric oxide synthase inhibition of intimal hyperplasia in the
human saphenous vein in vitro.336
The transcription factor E2F regulates the expression of several genes

involved in the progression of G1/S transition and DNA replication in mammalian
cells. The ability to inhibit transcription by blocking E2F expression has great
potential in the treatment of proliferative disorders.337 The effect of double-
stranded phosphorothioate oligonucleotides containing E2F transcription factor
cis element, a so called 'decoy' has examined on the growth of cultured human
cells and the intimal hyperplasia in vessels. In 1999, Mann and colleagues
performed a prospective, randomised, double blind in 41 patients underwent
infrainguinal arterial bypass grafting using E2F decoy oligodeoxynucleotide,
delivered by a novel method of pressure-mediated DNA transfection into human
vein grafts that does not require viral or exogenous lipid formulations.338
Fluorescent microscopy of vein transfected with fluorescein-isothiocyanate-
labelled oligodeoxynucleotide showed successful delivery and nuclear
localization in a mean of 89.0% (SD 1.9) of cells throughtout the vessel wall. The
expression of proliferative-cell nuclear antigen and c-myc was lower in vein
segments transfected with E2F decoy oligodeoxynucleotide than in segments of
untreated veins from the same patients. At 12 months, fewer graft occlusions,
revisions, or critical stenoses were seen in the E2F-decoy group than in the
untreated group (hazard ratio 0.34 [95% CI 0.12-0.99]). Primary patency also
continued to decline in the untreated group compare with E2F-decoy group after
336
Cable, Caccitolo, Caplice, et al. Circulation 1999; 100:II392-6.
337
Akimoto, Hangai, Okazaki, et al. Exp Eye Res 1998; 67:395-401., Black and Azizkhan-
Clifford. Gene 1999; 237:281-302., Sladek. Cell Prolif 1997; 30:97-105.
338
Mann, Whittemore, Donaldson, et al. Lancet 1999; 354:1493-8.
298
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six months follow-up. This result was confirmed in animal models.339 A single
intraoperative pressure-mediated delivery of E2F decoy effectively provides vein
grafts an inhibition of neointimal hyperplasia and atherosclerotic plaque formation
and remained stable throughout the 6 months of cholesterol feeding.
Kawauchi and colleagues tested the efficacy of double-stranded DNA with

specific affinity for E2F (E2F decoy) in preventing intimal hyperplasia using ex
vivo single intraluminal delivery of E2F decoy into cardiac allografts of mice and
Japanese monkeys using the hemagglutinating virus of Japan (HVJ) artificial viral
envelope-liposome method.340 E2F decoy prevented neointimal formation and
suppressed these genes for up to 8 weeks and neither complication nor
dissemination of HVJ into other organs was observed.
SYNTHETIC CONDUITS
Three types of synthetic conduits have been developed: (1)

polytetrafluoroethylene (PTFE) graft; (2) Perma-Flow graft; and (3) autogenous
endothelial cell seeded graft.
The PTFE graft, 4 mm in diameter, has been used in a number of patients

who had no suitable alternative conduit. In early experience, patency rates were
reported to be 60% at one year but only 14% at 45 months in early experiences.341
The Perma-Flow prosthetic coronary graft designed as an arteriovenous

configuration was developed in North America. The graft was constructed
339
Ehsan, Mann, Dell'Acqua and Dzau. J Thorac Cardiovasc Surg 2001; 121:714-22.
340
Kawauchi, Suzuki, Morishita, et al. Circ Res 2000; 87:1063-8.
341
Chard, Johnson, Nunn and Cartmill. J Thorac Cardiovas Surg 1987; 94:132-4, Hehrlein,
Schlepper, Loskot, et al. J Cardiovasc Surg 1984; 25:549-53, Sapsford, Oakley and Talbot. J
Thorac Cardiovas Surg 1981; 81:860-4, Scheld, Gorlach, Moosdorf, Loskot and Hehrlein. Herz
1987; 12:237-40, Tomizawa. Artificial Organs 1995; 19:39-45.
299
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proximally at the aorta, end to side, and then sequentially anastomosed side to
side to the coronary arteries. The distal end of the graft was anastomosed to the
superior vena cava. The graft was incorporated with a Venturi flow restrictor,
which controlled the flow maintaining arterial pressure proximally and venous
pressure distally. Scheduled coronary angiograms in 28 patients one week to one
year postoperatively demonstrated that seven of 73 studied coronary anastomoses
(9.5%) and two distal extensions and restrictors (7%) were occluded.342
Advances in molecular biology have led to the development of a promising

alternative conduit in which the surface of a synthetic prosthesis is subjected to
endothelial seeding. In a report from Germany, graft patency was 90.5% at an
average of 27.7 months follow-up (range, 7.5 – 48 months) in 14 patients with 21
autogenous endothelial cell-seeded 4 mm polytetrafluoroethylene grafts.343
It is possible that continued development of prosthetic grafts would provide

an unlimited source of conduits with excellent long-term patency.
SURGICAL TECHNIQUES
Apart from vascular graft development, surgical techniques have been

modified. The minimally invasive coronary artery bypass grafting (CABG) has
become popular. Modified skin incision techniques include minimally invasive
direct coronary artery bypass (MICAB)344, lateral anterior sternotomy
342
Emery, Mills, Teijeira, et al. Ann Thorac Surg 1996; 62:691-5; discussion 695-6.
343
Laube, Duwe, Rutsch and Konertz. J Thorac Cardiovas Surg 2000; 120:134-41.
344
Diegeler, Matin, Falk, et al. Eur J Cardiothorac Surg 1999; 16:S79-82., Diegeler,
Spyrantis, Matin, et al. Eur J Cardiothorac Surg 2000; 17:501-4., Mack, Acuff and Osborne. J
Card Surg 1998; 13:290-6., Mack, Magovern, Acuff, et al. Ann Thorac Surg 1999; 68:383-9;
discussion 389-90., Subramanian, McCabe and Geller. Ann Thorac Surg 1997; 64:1648-53;
discussion 1654-5.
300
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technique345, Transabdominal CABG346, Port-access CABG347, Endoscopic

CABG348 and Robotic CABG.349 All of these techniques must combine with
surgery without cardiopulmonary bypass (Off-pump) or modified
cardiopulmonary bypass techniques. The advantage of Off-pump CABG is it
avoids neurological deficit including neurocognitive dysfunction, transient
neurological deficit and stroke.350 In addition Off-pump surgery also avoids the
345
Calafiore and Angelini. Lancet 1996; 347:263-4., Calafiore, Di Giammarco, Teodori, et
al. J Thorac Cardiovasc Surg 1998; 115:763-71., Calafiore, Giammarco, Teodori, et al. Ann
Thorac Surg 1996; 61:1658-63; discussion 1664-5., Calafiore, Teodori, Di Giammarco, et al. Eur
J Cardiothorac Surg 1997; 12:393-6; discussion 397-8., Calafiore, Vitolla, Mazzei, et al. Ann
Thorac Surg 1998; 66:998-1001., Mishra, Mehta, Mittal, et al. Eur J Cardiothorac Surg 1998;
14:S31-7.
346
Minakawa, Takahashi, Kondo, et al. Kyobu Geka 2001; 54:288-92, Sakurada, Kikuchi,
Obata, et al. Kyobu Geka 2000; 53:1073-5, Subramanian and Patel. Eur J Cardiothorac Surg
2000; 17:485-7.
347
Diegeler, Falk, Krahling, et al. Eur J Cardiothorac Surg 1998; 14:S13-9., Mohr,
Onnasch, Falk, et al. Eur J Cardiothorac Surg 1999; 15:233-8; discussion 238-9.
348
Acuff, Landreneau, Griffith and Mack. Ann Thorac Surg 1996; 61:135-7., Benetti and
Ballester. J Cardiovasc Surg (Torino) 1995; 36:159-61., Benetti, Ballester, Sani, Doonstra and
Grandjean. J Card Surg 1995; 10:620-5., Landreneau, Mack, Magovern, et al. Ann Surg 1996;
224:453-9; discussion 459-62., Mack, Acuff, Casimir-Ahn, Lonn and Jansen. Ann Thorac Surg
1997; 63:S100-3.
349
Damiano, Tabaie, Mack, et al. Ann Thorac Surg 2001; 72:1263-8; discussion 1268-9.,
Falk, Diegeler, Walther, et al. Eur J Cardiothorac Surg 2000; 17:38-45., Falk, Gummert, Walther,
et al. Eur J Cardiothorac Surg 1999; 15:260-4; discussion 264-5., Kappert, Schneider, Cichon, et
al. Circulation 2001; 104:I102-7., Kodera, Boyd, Kiaii, et al. Kyobu Geka 2001; 54:987-91;
discussion 991-4., Mohr, Falk, Diegeler, et al. J Thorac Cardiovasc Surg 2001; 121:842-53.,
Shennib, Bastawisy, Mack and Moll. Ann Thorac Surg 1998; 66:1060-3., Vassiliades, Rogers,
Nielsen and Lonquist. Ann Thorac Surg 2000; 70:1063-5.
350
Anderson, Hansson and Vaage. Ann Thorac Surg 1999; 67:1721-5., Diegeler, Hirsch,
Schneider, et al. Ann Thorac Surg 2000; 69:1162-6.
301
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cardiopulmonary bypass and cardioplegic arrested heart which stimulate systemic

inflammatory responses and endothelial dysfunction.351 The issue of the reduction
of the inflammatory response using Off-pump CABG technique is
352
controversial.
Off-pump CABG was performed originally in experimental surgery in the

1970s. In 1972, Ankeny reported CABG without cardiopulmonary bypass in 143
patients at The Society of Thoracic Surgeons.353 In 1975 Trapp and Bisarya
reported an Off-pump CABG in 63 patients.354 In 1982, Buffolo and colleagues
reported their Off-pump CABG technique.355 In 1984, Akin and colleagues
reported an abnormal septal motion in patients having CABG with
cardiopulmonary bypass compared with Off-pump CABG.356 In 1985, Buffolo
and colleagues presented the results of 160 patients who underwent Off-pump
CABG.357 The distal sutures were performed with interruption of the coronary
flow without any devices for perfusion of the coronary artery: the proximal
sutures were performed with tangential clamping of the aorta. Hospital mortality
was 3.1% and perioperative myocardial infarction 2.5%. Postoperative
angiography in 41 of the 160 patients (25.6%) showed a patency rate of 83.9% in
the 62 grafts restudied. In 1985, Benetti reported his good result of Off-pump
351
Lockowandt and Franco-Cereceda. Eur J Cardiothorac Surg 2001; 20:1147-1151.
352
Diegeler, Doll, Rauch, et al. Circulation 2000; 102:III95-100.
353
Ankeny. Ann Thorac Surg 1975; 19:108-9.
354
Trapp and Bisarya. Ann Thorac Surg 1975; 19:1-9.
355
Buffolo, Andrade, Succi, et al. Arq Bras Cardiol 1982; 38:365-73.
356
Akins, Boucher and Pohost. Am Heart J 1984; 107:304-9.
357
Buffolo, Andrade, Succi, Leao and Gallucci. Thorac Cardiovasc Surg 1985; 33:26-9.
302
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CABG in 30 selected patients between October, 1980 and April, 1983.358 Larger
series were reported with a good outcome in experts’ centre and selected
patients.359 Gundry and colleagues, based on their experience from June 1989 to
July 1990, raised the issue of the quality of the anastomoses.360 One hundred and
seven patients underwent Off-pump CABG and 112 patients revascularization
with the aid of bypass with cardioplegia. Mean ages (65 +/- 10 years) and risk
factors were identical. Patients operated on with the heart beating had 2.4 ± 0.9
grafts versus 3.2 ± 1.1 for patients having cardiopulmonary bypass. They found
that despite one less graft per patient, survival and cardiac death rates were similar
for the two groups. However, twice as many patients in the Off-pump CABG
group required recatheterization (30% versus 16%) and 20% needed a second
intervention. Only 7% of the bypass with cardioplegia group required
reintervention.
In 1996, Borst and colleagues assessed the feasibility of coronary artery

bypass grafting on the beating heart with a suction of stabilizer “Octopus” in 31
pigs.361 They studied the motion of the epicardium and anastomoses using
“Octopus”. The motion was about 1 ´ 1 mm and anastomoses can be performed
without adverse consequences.
358
Benetti. J Cardiovasc Surg (Torino) 1985; 26:217-22.
359
Benetti, Mariani and Ballester. J Cardiovasc Surg (Torino) 1996; 37:391-5., Benetti,
Naselli, Wood and Geffner. Chest 1991; 100:312-6., Buffolo, Andrade, Branco, et al. Eur J
Cardiothorac Surg 1990; 4:504-7; discussion 507-8., Buffolo, de Andrade, Branco, et al. Ann
Thorac Surg 1996; 61:63-6., Buffolo and Gerola. Int J Cardiol 1997; 62:S89-93., Buffolo, Gomes,
Andrade, et al. Arq Bras Cardiol 1994; 62:149-53.
360
Gundry, Romano, Shattuck, Razzouk and Bailey. J Thorac Cardiovasc Surg 1998;
115:1273-7; discussion 1277-8.
361
Borst, Jansen, Tulleken, et al. J Am Coll Cardiol 1996; 27:1356-64.
303
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In 1997, Jansen and colleagues reported results of Off-pump CABG using

“Octopus” stabiliser in 27 patients.362 Surgical access was achieved via a 10-cm
anterior thoracotomy (n = 26) or 10-cm subxiphoid incision (n = 1).
Immobilization with the “Octopus” was effective and facilitated precise
anastomosis suturing of 20 single and 7 sequential grafts. Immobilization did not
change cardiac index and mean arterial blood pressure. During coronary surgery,
however, inotropic drug support was used in 5 of 27 (18%) of patients. There was
no myocardial infarction. At 6 months angiography was performed in 15 of 27
patients. The patency rate of 19 of 20 anastomoses was 95%. This technique was
expanded to use for revascularization at the posterior wall of the left ventricle.363
In 1997, Suen and colleagues reported results in 32 patients of Off-pump

CABG via a small anterior thoracotomy.364 Twenty, five, and seven patients had
one, two and three vessels diseased respectively. One patient required intra-
operative conversion to conventional CABG for an intramyocardial target vessel.
Two patients had conversion after post-operative angiogram demonstrated
incorrect target identification and early graft occlusion. Four patients had limited
access graft revision (two kinks, one graft injury, and one hemorrhage). Thirty-
one of the 32 patients were followed from 0.5 to 16 months with 30 reporting no
post-operative cardiac events (one required PTCA to another vessel). In 1997,
Carrier and colleagues quantitatively evaluated coronary anastomoses with Off-
362
Jansen, Grundeman, Borst, et al. Eur J Cardiothorac Surg 1997; 12:406-12.
363
Grundeman, Borst, van Herwaarden, Mansvelt Beck and Jansen. Ann Thorac Surg
1997; 63:S88-92., Grundeman, Borst, van Herwaarden, Verlaan and Jansen. Ann Thorac Surg
1998; 65:1348-52., Grundeman, Borst, Verlaan, et al. J Thorac Cardiovasc Surg 1999; 118:316-
23., Jansen, Grundeman, Mansvelt Beck, Heijmen and Borst. Ann Thorac Surg 1997; 63:S93-6.,
Mathison, Buffolo, Jatene, et al. Ann Thorac Surg 2000; 70:1083-5., Mathison, Edgerton,
Horswell, Akin and Mack. Ann Thorac Surg 2000; 70:1355-60; discussion 1360-1.
364
Suen, Johnson, Weintraub, et al. Int J Cardiol 1997; 62:S95-100.
304
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pump CABG in 19 patients.365 Twenty ITA grafts and seven saphenous vein
grafts were studied by quantitative angiography in the immediate postoperative
period (4 ± 2 days). Diameter stenosis of the native coronary artery averaged 19 ±
26% proximal to the anastomosis, 36 ± 31% distal to the anastomosis and 27 ±
32% at the anastomotic site of ITA grafts. One native coronary artery distal to the
anastomosis was occluded and an occluded anastomosis was reopened by
percutaneous angioplasty 72 h after surgery. Saphenous vein grafted to the right
coronary artery had only minimal stenosis at anastomotic sites.
In 1998, Jaber and colleagues studied the relationship of the anastomosis

stenosis and graft flow in 14 mongrel dogs that underwent Off-pump CABG.366
Moderate to severe degrees of stenosis were created at the anastomosis by an
additional suture. ITA graft flow was measured before and after the stenosis was
created with the left anterior descending artery occluded. Postoperative
angiography was performed randomly to validate the degree of stenosis. Mean
flow and flow tracing morphology were compared under various degrees of
stenosis. There were no significant differences in mean graft flow or the
morphology of the flow tracing between patent (<15%), mild (<25%), moderate
(<50%) and moderately severe (<75%) stenosis. However, mean graft flow
decreased (P < 0.05) with severe stenosis (>75%). Jaber also conducted a survey
with the cooperation of 19 international surgeons to assess the ability of surgeons
to detect anastomotic errors by evaluating mean flow and flow waveform
morphology.367 Responders were able to clearly identify a highly stenotic graft
(>90% stenosis). However 24% would re-do a fully patent anastomosis, 58%
accepted an anastomosis with moderate stenosis, and 72% accepted anastomoses
with severe stenosis.
365
Carrier, Lesperance, Cote, et al. Can J Cardiol 1997; 13:653-6.
366
Jaber, Koenig, BhaskerRao, et al. Ann Thorac Surg 1998; 66:1087-92.
367
Jaber, Koenig, BhaskerRao, VanHimbergen and Spence. Eur J Cardiothorac Surg 1998;
14:476-9.
305
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The quality assessments of the anastomoses performed using Off-pump

technique have been developed.368
Several prospective randomised trials have been performed with

encouraging results.369 The Off-pump technique is also being used for complete
arterial coronary artery bypass grafting including bilateral ITA, RA and right
gastroepiploic artery.370 In 1999, Pym reported results of total arterial grafting in
125 patients operated on between 1997 and 1998 using suction stabilizer.371
Aortic anastomoses were avoided: both ITAs and the RGEA were used as pedicle
grafts in all but one case. All RAs and one right ITA were used as Y-grafts from
the left ITA. Various skin incisions were used. Sternotomy incision group: 187
grafts were performed in 98 patients (mean 1.9 grafts per patient). There were 99
grafts to anterior wall vessels, 47 to posterior wall vessels and 41 to lateral wall
vessels. Left anterior thoracotomy incision group: 20 patients had a single graft to
the left anterior descending artery. Left anterolateral thoracotomy incision group:
three patients had a single graft to a circumflex branch while three had composite
grafts to the left anterior descending artery and circumflex systems. Subxiphoid
incision group: one patient had a single graft to the posterior descending branch of
368
Diegeler, Matin, Falk, et al. Eur J Cardiothorac Surg 1999; 16:S67-72., Falk, Diegeler,
Walther, et al. J Thorac Cardiovasc Surg 1997; 114:507-9., Falk, Walther, Philippi, et al. J Card
Surg 1995; 10:147-60., Mohr and Falk. Ann Thorac Surg 1997; 63:1506-7., Mohr, Falk, Krieger,
et al. Eur J Cardiothorac Surg 1991; 5:534-41., Mohr, Grundfest, Litvack, et al. Z Kardiol 1989;
78:441-52., Mohr, Matloff, Grundfest, et al. Ann Thorac Surg 1989; 47:441-9.
369
van Dijk, Nierich, Eefting, et al. Control Clin Trials 2000; 21:595-609., van Dijk,
Nierich, Jansen, et al. Circulation 2001; 104:1761-6.
370
Corbineau, Verhoye, Langanay, Menestret and Leguerrier. Eur J Cardiothorac Surg
2001; 20:918-22., Cuenca, Herrera, Rodriguez-Delgadillo, et al. Rev Esp Cardiol 2000; 53:632-
41., Hirose, Amano, Takahashi and Nagano. Ann Thorac Cardiovasc Surg 2000; 6:405-7.,
Quigley, Weiss, Highbloom and Pym. Ann Thorac Surg 2001; 72:793-7., Subramanian. Ann
Thorac Surg 1997; 63:S68-71.
371
Pym. Eur J Cardiothorac Surg 1999; 16:S88-94.
306
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the right coronary artery. There were no peri-operative deaths in any group. No
patient required conversion to cardiopulmonary bypass. Three patients required
conversion from a limited-access approach to sternotomy. By avoiding aortic
manipulation and meticulous anastomosis with pedicled and composite arterial
graft, maximum benefit in terms of neurological preservation and graft patency
can be achieved.
However there are several concerns about the quality of anastomoses and
compromised numbers, locations and grafting techniques.372 For experienced
surgeons, surgery will be less compromised. Learner surgeons will avoid
complicated techniques such as anastomosis of pedicle left or right ITA to the
circumflex system, sequential anastomoses, and proximal location of target artery.
A simulated beating heart for coronary artery bypass grafting training will be
useful.
Furthermore automated anastomotic devices373 and a nonsuturing

anastomosis technique374 have been developed. Another area of development is
the minimally invasive graft harvesting techniques such as endoscopic saphenous
vein or RA harvesting.375 These endoscopic techniques might be able to reduce
the wound complication in some patients.
372
Fonger, Doty, Salazar, Walinsky and Salomon. Ann Thorac Surg 1999; 68:431-6.
373
Guyton, McClenathan and Michaelis. Ann Thorac Surg 1979; 28:342-5., Heijmen,
Hinchliffe, Borst, et al. J Thorac Cardiovasc Surg 1999; 117:117-25.
374
Gundry, Black and Izutani. J Thorac Cardiovasc Surg 2000; 120:473-7., Kirsch, Gupta
and Zhu. Cardiovasc Surg 2001; 9:523-5.
375
Fabricius, Diegeler, Doll, Weidenbach and Mohr. Ann Thorac Surg 2000; 70:473-8.
307
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“The progression of humanity appears to us to be very slow because we, the

observers, are units of the herd. Each one of us can make but few observations.
Our life is too short. Many experiments should be conducted for a century at the
least. Institutions should be established in such a way that observations and
experiments commenced by one scientist would not be interrupted by his death.
Such organizations are still unknown in the realm of science. But they already
exist in the other lines of endeavor. In monastery of solesmans three successive
generations of Benedictine monks have devoted themselves, over a period of
about fifty-five years, to the reconstruction of Gregorian music. A similar method
should be applied to the investigation of certain problems of human biology.
Institutions, in some measure immortal, like religious orders, which would allow
the uninterrupted continuation of an experiment as long as might be necessary,
should compensate for the too short duration of the existence of individual
observers.”
Alexis Carrel
Man, The Unknown
Harper & Brothers Publishers, New York and London,1935
“Study is continuing until the final answer is determined.”
Permyos Ruengsakulrach
June 30, 2001
308
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Safety and Efficacy of

Radial Artery Conduits

for Coronary Artery Bypass Surgery

A thesis submitted for the degree of

Cardiac Surgery Department

Patients and volunteers

Coronary artery bypass grafting (CABG) is the most common cardiac

Ruengsakulrach P., Buxton B., Eizenberg N., Fahrer M. Anatomical assessment

Finalist of 2000 TAG Young Achievers Award

Travel Award 2000

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Ruengsakulrach P., Sinclair R., Gordon I., Buxton B.

Ruengsakulrach P., Eizenberg N., Fahrer C., Fahrer M., Buxton B.

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Buxton B., Ruengsakulrach P., Komeda M., Hare DL.

Ruengsakulrach P., Sinclair R., Gordon I., Buxton B.

Publications and Communications.................................................................................... viii

Chapter 1 Introduction ........................................................................................................ 1

Chapter 3 Vascular Histology and Histopathology ........................................................... 98

Chapter 6 Preoperative Assessment of Hand Circulation by Doppler Ultrasound and

Chapter 9 Semi-quantitative and Quantitative Coronary Angiography of the Radial Artery,

Chapter 10 Summary...................................................................................................... 289

Chapter 11 Future ........................................................................................................... 294

Bibliography .................................................................................................................... 289

An ageing population and the use of angioplasty have resulted in an

Furthermore, in an attempt to avoid the complications associated with

(a) The History of the Development of Coronary Artery Surgery and

Extracardiac Operations for Angina

Indirect Coronary Revascularization

Direct Coronary Revascularization

The Role of the RA as a Bypass Graft

Expanded Use of Arterial Grafting

Vasoreactivity of Vascular Grafts

(b) Hypotheses and Specific Aims

(a) The History of the Development of Coronary Artery Surgery and

The history of cardiac surgery provides interesting insights into the

While the development of techniques for managing ischemic heart disease

work in an appropriate historical context. It also provides many useful examples

Extracardiac Operations for Angina

In the late 19th and early 20th centuries, a number of extracardiac

Several other techniques of cardiac denervation emerged in this period

December 14, 1932.13 He also performed subtotal thyroidectomies in several

Indirect Coronary Revascularization

In 1930, Claude Beck championed early attempts at increasing the blood

October 2, 1936. He also performed cardiopneumopexy in August 1937. He

Redirection of venous drainage of the heart

In 1934, Robertson while experimenting on dogs, ligated the great cardiac

combining coronary vein ligation with pericoronary neurectomy.26 However, great

Increasing left heart volume

In 1939, Lillehei created a surgical communication between the pulmonary

Increasing coronary collaterals

Increasing pulmonary collaterals

The concept of transmyocardial revascularization was based on knowledge

Direct Coronary Revascularization

The idea of operating directly on the coronary arteries was conceived as

The first report of direct implantation of vessels into the myocardium of a

The idea of direct coronary revascularization was also included the

portion of the coronary artery or occlusion of important side branches, and

Following this, Murray engaged in work which was to be of great

Murray had already received an intravenous injection of a small dose of

In the 1950s cardiopulmonary bypass techniques were developed that paved