Volume I No.

II december 2015

BENGAL
HEART JOURNAL A PUBLICATION OF THE CSI - WEST BENGAL BRANCH

Secretariat :
INDIAN HEART HOUSE
P-60, C.I.T. Road, Scheme VII-M
Editor : Dr. P. K. Deb Kankurgachi, Kolkata-700054
Published by : Dr. D. Roy Ph : (033) 2355-1500/6308 = Tele Fax : (033) 2355-6308
E-Mail : csi_westbengal@eth.net = Website : www.csiwb.org.in
 BENGAL HEART JOURNAL
Volume I No. II december 2015

Contents

1. Editorial Dr. P. K. Deb 2

2. Bentall operation in a 27 year old doctor with Atanu Saha 3
Type A Stanford Aortic Dissection
A case report
3. An interesting case of transient left ventricular Debanu GhoshRoy 6
dysfunction following urinary fact infection in a
post- menopausal woman

4. HIV, Cardiovascular Diseases, and Chronic Arghya Panigrahi, 9

Arsenic Exposure co-exist in a Positive Synergy Amit K Chattopadhyay,
Goutam Paul, Soumya Panigrahi

5. Struma Cordis - A Case Report Bhabani Prasad Chattopadhyay, 20

Sanhita Chatterjee,
Sudakshina Chanda, Kunal Sarkar,
Sanjeev Garg

6. Memorable Change in Shape of interventional B. P. Chattopadhyay, Sunip Bannerjee, 24

Cardiology by Shape Memory Alloys (SMA) S. Das, A. S. Tripathi

7. Febrile Neonate - An Atypical Presentation Indira Banerjee, 28

Amitabha Chattopadhyay, Mahua Roy,
Prabhat Kumar,Biswajit Bandopadhyay,
Kuntal Bhattacharyya

1
 EDITORIAL
Dr. P. K. Deb

A STRIVE FOR 'MADE IN INDIA':A STEP FORWARD

Any present day search of scientic journals would yield loads of epidemiological and
clinical trials done on Indian soil. But when it comes to innovation, the result is
surprisingly meager. Unfortunately most of our research is predominantly a
reproduction of existing data with an Indian touch on some occasion. Innovative
techniques or innovative ideas originating on Indian soil and from Indian minds is
strikingly rare.
However, absence of such scientic articles does not warrant a dearth of basic medical
research done in India by Indians. In fact, a good number of such works have been
already done or are underway at various Indian institutes as a multidisciplinary effort
involving cardiologists, engineers and scholars of basic sciences. In this journal we
endeavour to publish such works and take a step forward from reproduction to
procration.
In this present issue, two important review articles on innovative ideas and techniques
by A. Panigrahi et al (1) and B. P. Chattopadhyay et al (2) were published.
The article by A. Panigrahi et al, explored the suitability of application of a mathametical
model in predicting a positive synergistic action of arsenic exposure with HIV infection in
precipitating cardiovascular disease.
On the other hand, the article by B. P. Chattopadhyay et al, reviewed the development of
various cardiolocal devices made up of a special alloy, including their own ongoing
research in collaboration with IIT, Kharagpur, towards development of a dedicated
bifurcation wire.
The journal, however, is still in its neonatal stage and the present issue failed to publish
any original article which it can nd worthy of. But it boasts of four excellent case reports
which surely will make interesting reading.
Wishing you all a happy reading experience in the new year !
References:
1. A. Panigrahi , A. K. Chattopadhyay, G. Paul, S. Panigrahi, HIV, Cardiovascular
diseases and chronic arsenic exposure co-exit in a positive synergy. Bengal Heart
J.2015; 1(2) : pg. 9-19.
2. B. P. Chattopadhyay, S. Banerjee, S. Das, A. S. Tripathi. Memorable change in
shape of interventional cardiology by shape memory alloy. Bengal Heart J.2015;
1(2):Pg. 24-27.

3
 Bentall operation in a 27 year old doctor with
Type A Stanford Aortic Dissection A case report
Atanu Saha
Senior Consultant Cardiac Surgeon, NH-RTIICS

Abstract :
Type A Stanford aortic dissection has a worse prognosis and requires emergency surgical repair. The present
case report describes a rare case of Type A Stanford dissection along with anomalous origin of the right coronary
artery from left sinus. The clinical presentation, investigation ndings and operative procedure were discussed.

Key-words :
Type A Stanford aortic dissection, anomalous origin of the right coronary artery, Bentalli opration.
Introduction :
Acute aortic dissection is an event of sudden onset in which blood leaves the normal aortic lumen through a
usually discrete point of exit (intimal tear) and rapidly dissects the inner from outer layers of the media to produce a
1
false lumen. There are two classication systems for Acute aortic dissection: DeBakey classication and Stanford
2
classication . The 2 classication systems are depicted in the gure below :
Without surgical treatment Type A Stanford has a worser prognosis than Type B Stanford. During the acute episode
patient can succumb to the false lumen rupture leading to hemothorax or hemopericardium and exsanguination. If
the patient survives the initial period, death may strike later consequent to organ dysfunction secondary to arterial
occlusions or delayed rupture.
Morris and colleagues in Houston reported the rst successful repair of acute ascending aortic dissection with
3
aortic regurgitation in 1963 . Ever since that period technological advancements in CPB and synthetic
replacements has grown to a great extent contributing to improved outcomes following surgical treatment of acute
aortic dissection. The main principle involved in surgery is to replace the aortic segment containing the intimal tear
with a synthetic conduit without removing the entire false lumen.

5
In this case report, we are reporting the real time management strategies undertaken in treating a 27 year old
doctor with Type A Stanford Acute aortic dissection.
Case Report :
A 27 year old doctor presented with sudden onset retrosternal pain radiating to the neck. Echocardiography done
outside was suggestive of dissecting aortic aneurysm. CT angiography thorax was ordered immediately.
CT Angio Thorax Findings :
Fusiform dilatation with intimal dissection was seen extending from the aortic root to the aortic arch involving the
proximal parts of the arch branches(Stanford Type A Dissection). Anomalous origin of the right coronary artery
from the left coronary sinus near the origin of left main coronary artery was also noted.
Plan of management :
Bentall operation was planned for the patient. Patient was immediately shifted to the operating Room after high risk
of the procedure was informed to the patient party and consent obtained.
Operation :
Bentall Operation with 21mm Aortic Valved Conduit + along with RSVG to RCA grafting was done.
Procedure :
Medican sternotomy was done, thymus was dissected, pericardial cradle was made. Right groin was prepared,
femoral artery was exposed and cannulated using a 8 mm Haemashield side graft. Similarly axillary and left
common carotid cannulation was done after systemic heparinization. CPB started after bicaval cannulation. LV
0
vent placed through right superion Pulmonary vein. Patient was cooled to 26 C. Aorta was cross clamped just
below the innominate artery. Aorta was opened obliquely .Antegrade direct ostial cardioplegia was given. Left
coronary button was harvested, after keeping about 1 cm of aortic margin around the ostia. Right coronary artery
had an abnormal origin from left coronary sinus and had an intramural course.
Aortic valve was excised. 21 mm St. Jude aortic valve conduit was sutured with interrupted 2/0 Ethibond
plegdetted sutures.Periacardial strip was used as a sandwich between the sutures. A 1 mm hole was made in the
corresponding site over the graft for LCA anastomosis. Anastomosis was done with 6-0 prolene. Right coronary
artery was bypassed using RSVG graft. The origin of the artery was closed using 5-0 prolene sutures. Patient was
0
cooled to 18 C and cross clamp was removed. Distal arch was inspected. No internal tear was found. Distal part of
the conduit was xed to the proximal arch using 4-0 prolene sutures. Proximal end of RSVG was attached to the
conduit using 7-0 prolene sutures. Patient was re warmed. CPB was gradually weaned off. Patient came off bypass
in normal sinus rhythm with mild doses of inotropes. Protamine was started. Hemostasis was achieved. One left
pleural and two mediastinal drains were left. One RV and one RA pacing were put. Chest was closed in layers.
Discussion :
It has been proven beyond doubt that emergency surgical repair is the treatment of choice in Type A Stanford aortic
dissection. According to data collected by International Registry on Aortic Dissection(IRAD), during the period
between 1996 and 2003, there is an in-hospital mortality of 54% in people who were managed medically owing to
4
other contraindications for surgery .
In addition to the dissection of the ascending aorta, the patient also had anomalous origin of right coronary artery
from the left coronary sinus.
Another interesting observation made is that the patient had some of the marfan traits. However the patient was not
evaluated for Marfan's syndrome or any other connective tissue disorders during the hospital stay. Plan is drawn to
evaluate him for Marfan's syndrome during the follow-up visits and also prophylactic echocardiographic
evaluation of his rst degree relatives to rule out ascending aorta aneurysm in them.

6
Conclusion :
In this case report we try to explore the management strategies of Acute Aortic Dissection. In our institution we
have performed signicant number of Bentall operation with good results. We also stress the importance of
evaluating the patient for connective tissue disorders.

References :
1. Daily PO, Trueblood HW, Stinson EB, Wuerein RD, Shumway NE. Management of acute aortic dissections. Ann Thorac Surg .
1970;10:237.
2. DeBakey ME, McCollum CH, Crawford ES, Morris GC, Jr., Howell J, Noon GP, et al. Dissection and dissecting aneurysms of the aorta:
twenty- year follow- up of ve hundred twenty- seven patients treated surgically. Surgery . 1982;92:1118.
3. Morris GC, Jr., Henly WS, DeBakey ME. Correction of acute dissecting aneurysm of aorta with valvular insufciency. JAMA .
1963;184:63
4. Thomas T. Tsai, Arturo Evangelista, Christoph A. Nienber: Long Term Survival in Patients with Type A Acute Aortic Dissection: Insights
from the International Registry of Acute Aortic Dissection(IRAD): Circulation 2006;114[suppl I]:I-350-I-356

7
 An interesting case of transient left ventricular
dysfunction following urinary fact infection in a post-
menopausal woman
Debanu GhoshRoy
Assoc. Prof. of Cardiology , KPC Medical Collage, Kolkata

Abstract :
Takotsubo cardiomyopathy is characterized by transient systolic dysfunction of left ventricle in presence of normal
coronary arteries, and occurs especially in post-menopausal women. In the present case report, one such patient
is described who developed the syndrome following urinary tract infection.
Key-words :
Takotsubo cardiomyopathy, urinary treat infection.
Introduction :
Here we report a case of Takotsubo cardiomyopathy following urinary treat infection.
Case Report :
A 67 years old female was admitted for evaluation of chronic constipation for 2months. She was receiving
amlodipine 5mg for hypertension. Investigations done 15 days before admission showed normal serum
electrolytes, serum creatinine and liver function test. She started taking lactulose and sodium picosulphate 2
weeks back.
On admission blood pressure was 130/80 mm of Hg. Examination was normal except for slight abdominal
distension. Investigations on day 1 showed haemoglobin was 10.4 g /dl (hypochromic microcytic). Total and
differential counts were normal. ESR was 47mm. Blood sugar, prothrombin time and thyroid function test were
normal. Abdominal X ray was normal. ECG showed minor ST T changes (Fig 1). CT scan of abdomen was
normal but the colon was loaded with stool. She was posted for colonoscopy next day. She was given lesuride and
Librium.
On day 2 she was given polyethylene glycol for bowel preparation. As she was taking the medicine she had
vomiting followed by syncope. She was shifted to the intensive care unit and IV uids were given rapidly. BP
increased to 90/60 mm and she felt better. She developed high grade fever. All drugs were stopped and antibiotics
were given.Normal saline was continued . Urgent ECG showed minor non -specic ST-T changes. Chest Xray was
normal (Fig 2). Blood reports were as follows : Sodium 135mEq/L, Potassium 2.4mEq/L, g/dl, Magnesium
1.8mg/dl, Troponin T 17.99ng/l (normal upto 14ng/l), Creatine Kinase was 64 U/L and MB faction was 13U/L.
Echocardiogram showed mild global hypokinesia of left ventricle with ejection fraction of 50%.
She became afebrile and asymptomatic. Potassium supplements and spironolactone were given. Patient was
closely monitored. CRP was 124.9mg/l. Procalcitonin was 3.39ng/ml. Urine showed plenty of pus cells and grew
Klebsiella. Haemoglobin HPCL showed she was heterozygous for HbE. Tests for Dengue and Malaria were
negative.
She remained asymptomatic but serial ECG showed worsening of ST T changes (Fig 3). She developed left
ventricular failure on day 5 and received intravenous diuretics. Repeat chest X ray(Fig 4) showed cardiomegaly.
Repeat echocardiogram showed akinesia of anterolateral wall and apex of left ventricle. Ejection fraction now was
37%. Creatine Kinase now increased to 813U/L and MB fraction was 32U/L. Troponin T was now 175.4ng/L. She
was given dual antiplatelet , statin and ramipril.
After control of failure, coronary angiogram was done which showed normal coronary arteries. Final diagnosis
was Takotsubo cardiomyopathy. Beta blockers were given . Patient went home with advice to do echocardiogram
and follow up after 1 month.

8
Discussion :
Takotsubo cardiomyopathy was reported in Japan in the early 90s. It is characterized by transient systolic
dysfunction in the absence of obstructive coronary artery disease. It is also known as stress induced
cardiomyopathy, apical ballooning syndrome, ampulla cardiomyopathy and broken heart syndrome.
Symptoms typically occur in post-menopausal women after an emotionally or physically stressful event. Stress
induced cardiomyopathy may follow other stressful events such as hypoglycaemia, hyperthyroidism, cocaine,
opiate or alcohol withdrawal, pneumothorax, non-cardiac surgery, severe pain, neurological injuries, cardiac
stress testing, all of which increase catecholamine levels. In one fth of cases there is no identied trigger.
More than 90% of Takotsubo cardiomyopathy patients are females. The usual age of presentation is the 7th decade
of life. Chest pain is the commonest symptom present in two third of patients. One fth of patients have dyspnea.
Rare presentations include cardiogenic shock and ventricular brillation. ECG changes are present in almost all
patients. ST segment elevations were observed in four fth of patients, whereas T wave abnormalities and q waves
were observed in two third and one third of patients respectively(1). Rarely there could be left bundle branch block.
Mild elevations in cardiac enzymes were seen in more than 85% patients. Echocardiography showed LV systolic
dysfunction with ejection fraction of 20% to 50%. There is hypokinesia or akinesia of the middle and apical
segments of the left ventricle, which results in ballooning of the apical wall and sparing of the basal systolic
function. Occasionally there is transient dysfunction localized to basal portion of the left ventricle (reverse
Takotsubo) or mid portion of the left ventricle only (Figure5). They do not demonstrate delayed hyperenhancement
by magnetic resonance imaging (MRI) with gadolinium. Coronary angiography shows absence of obstructive
coronary artery disease.
Criteria for diagnosis of stress cardiomyopathy was proposed by Mayo clinic in 2004 and later modied in 2008. It
includes (a) transient hypokinesis, akinesis, or dyskinesis in the LV mid-segments with or without apical
involvement; RWMA extending beyond a single epicardial vascular distribution ; the presence (often, but not
always) of a stress trigger ; (b) the absence of obstructive coronary disease or angiographic evidence of acute
plaque rupture; (c) new electrocardiographic abnormalities (ST-segment elevation and/or T-wave inversion ) or
modest elevation of cardiac troponin levels in the serum; (d) the absence of pheochromocytoma or myocarditis.
All four criteria must be met for diagnosis(2).
The pathophysiology of this disorder is not entirely clear. Many believe it is high levels of stress induced
catecholamine and stress related neuropeptides that leads to myocardial stunning. Serum catecholamine levels
are higher in stress induced cardiomyopathy than in acute myocardial infarction. High levels of catecholamine may
cause impaired myocardial perfusion, left ventricular outow tract obstruction, myocyte injury or a combination of
these features. Exact mechanism may differ in different patients. Some studies have shown multi vessel coronary
artery spasm, whereas others have not. There may be a genetic bias of this disease. As this disease accurs in
postmenopausal women , it could be due to hormonal disturbances, perhaps deciency in oestrogens. Smaller
size of left ventricle in women may have a propensity to develop left ventricular outow tract obstruction with an
interventricular pressure gradient causing oxygen mismatch at the apex of the ventricle, leading to ballooning.
Microvascular dysfunction may also contribute to LV dysfunction.
It is essential to exclude acute coronary syndrome (ACS), especially myocardial infarction due to occlusion of the
left anterior descending artery (See Table 1). Once ACS is excluded, treatment is largely supportive with diuretics
and vasodilators. Vasopressors and inotropes should be avoided if possible.
The prognosis is generally good with reversal of LV systolic dysfunction within few weeks. Prognosis does not
depend on age at onset, sex, presenting symptoms, type of stress, degree of LV systolic dysfunction or ECG
changes. The in-hospital mortality is 2%. The recurrence rate is less than 10%. The 4 year survival rate is same as
age and gender matched general population.
References :
1. Gianni M, Dentali F, Grandi AM, et al: Apical ballooning syndrome or takatsubo cardiomyopathy: a systematic review. Eur Heart J
27:1523, 2006.
2. A.Prasad, A. Lerman, and C. S. Rihal, Apical ballooning syndrome (Tako-Tsubo or stress cardiomyopathy): a mimic of acute myocardial
infarction, The American Heart Journal, vol.155, no.3, pp. 408-417, 2008.

9
Fig 1 : Ecg on day 1 Fig 2 : Chest Xray on Day 2

Fig 3 : Ecg on day 4 Fig 4 : Chest Xray on Day 5

Fig 5 : Different ventricographic morphogies in takotsubo cardiomyopathy

Table 1

10
 HIV, Cardiovascular Diseases, and
Chronic Arsenic Exposure co-exist in a Positive Synergy
Arghya Panigrahi1, Amit K Chattopadhyay2, Goutam Paul3, Soumya Panigrahi4*
1. Department of Physiology, Jhargram Raj College, Govt. of West Bengal. Jhargram, West Midnapore, WB, India. (apandada1@gmail.com);
2. Non-linearity and Complexity Research Group - Aston University, Aston Triangle, Birmingham, B4 7ET, UK. (a.k.chattopadhyay@aston.ac.uk);
3. Department of Physiology, University of Kalyani, West Bengal, India. (gpaul@klyuniv.ac.in)
4. Department of Medicine, Division of Infectious Diseases, Case Western Reserve University/University Hospitals of Cleveland, Cleveland, OH,
44106 (sxp579@case.edu). *corresponding author)

Abstract
Recent epidemiological evidences indicate that arsenic exposure increases risk of atherosclerosis, cardio vascular
diseases (CVD) such as hypertension, atherosclerosis, coronary artery disease (CAD) and microangiopathies in
addition to the serious global health concern related to its carcinogenic effects. In experiments on animals, acute
and chronic exposure to arsenic directly correlates with cardiac tachyarrhythmia, and atherogenesis in a
concentration and duration dependent manner. Moreover, the other effects of long-term arsenic exposure include
induction of non-insulin dependent diabetes by mechanisms yet to be understood. On the other hand, there are
controversial issues, gaps in knowledge, and future research priorities in accelerated incidences of CVD and
mortalities in patients with HIV who are under long-term anti-retroviral therapy (ART). Although, both HIV infection
itself and various components of ART initiate signicant pathological alterations in the myocardium and the
vasculature, simultaneous environmental exposure to arsenic which is more convincingly being recognized as a
facilitator of HIV viral cycling in the infected immune cells, may contribute an additional layer of adversity in these
patients. A high degree of suspicion and early screening may allow appropriate interventional guidelines to
improve the quality of lives of those affected. In this mini-review which have been fortied with our own preliminary
data, we will discuss some of the key current understating of chronic arsenic exposure, and its possible impact on
the accelerated HIV/ART induced CVD. The review will conclude with notes on recent developments in
mathematical modeling in this eld that probabilistically forecast incidence prevalence as functions of aging and
life style parameters, most of which vary with time themselves; this interdisciplinary approach provides a
complementary kernel to conventional biology.
ABBREVIATIONS : As2O3, arsenic trioxide; AsV, arsenate; AsIII, arsenite; CAD, coronary artery disease; CVD,
cardiovascular disease; EC, endothelial cell; NO, nitric oxide; NOS, nitric oxide synthase; eNOS, endothelial nitric
oxide synthase; ROS, reactive oxygen species; HUVEC, Human Umbilical Vein Endothelial Cell.
Key-words : HIV, arsenic exposure, cardiovascular diseases, positive synergy.
Introduction
The World of Arsenic
The knowledge of medicinal and homicidal use of arsenic can be traced back to the early days of human
1. In the 1800s, Fowler's solution, a 1%
civilization. The poisonous and carcinogenic proper ties of arsenic
potassium arsenite solution, was used compounds, or Arsenicals, have been known for more than 2000 years
as a general tonic for treating [2,3]. In the west, much of the current awareness can be traced back to the
leukemia, psoriasis, and asthma.
Fowler's solution was not withdrawn 1 9 4 4 c o m e d y m o v i e A r s e n i c a n d O l d L a c e
from the US market until the 1950s. (http://www.imdb.com/title/tt0036613/). Emperors, kings, arctic explorers,
2. T h e a r s e n i c - c o n t a i n i n g d r u g heirs and commoners have been treated with arsenicals for both legitimate
melarsoprol is still the drug of choice
for treating African trypanosomiasis. and homicidal purposes. A popular myth suggests that in 55 AD, the infamous

11
Roman emperor Nero poisoned his stepbrother Britannicus with Air : Arsenic in air range from 0.02 to 4ng/m3) in
arsenic before his 14th birthday. Conversely, Hippocrates used remote and rural areas, to (3 to ~ 200ng/m3) in urban
areas, higher concentrations (more than 1000 ng/ m3)
arsenicals to treat ulcers. can be found near industrial area, in some countries.
An ACUTE FATAL DOSE of Arsenic is in the
range of 2-20 mg/kg body weight/day. Thus, In the course of time, Water : Open ocean seawater are typically low
a relatively healthy person with a body (12g/l) whereas surface waters may be 1000 times
weight of 75 kg may die if he ingests about Arsenicals made their place higher (up to 5000 g/l)in arsenic content. Arsenic
145 mg to 1.45gm of Arsenic Trioxide (most in medicine for treating levels in groundwater are typically as low as in open
commonly available arsenic compound).
Considering the high density of the oxide,
sleeping sickness, syphilis, ocean water (about 12 g/l), except in areas with
volcanic rock and sulphide mineral deposits where
less than 1/8 of a tea spoon can be fatal. tuberculosis and cer tain arsenic levels can range up to 3000 g/l.
Smaller amounts may be fatal for exposed skin diseases. In the early In sediment : Arsenic concentrations range from 5 to
unhealthy people, elderly or children. The
symptoms of poisoning by SMALL amounts 1800s, Arsenic exposure 3000 mg/kg. The higher levels are found in areas
contaminated by mining and smelting. In soil,
of Arsenic are indistinguishable from was linked to cancer leading concentrations range from 1 to 40 mg/kg, usually
symptoms of other illness.
to a progressive diminution averaging around 5 mg/kg.
i n i t s m e d i c i n a l u s e . Marine biome : Marine organisms normally contain
arsenic residues ranging from < 1 to more than
Arsenical have widespread use in embalming during and after the 100mg/kg, predominantly as organic arsenic species
American Civil War, and today, Arsenic leaching from old s u c h a s a r s e n o s u g a r s ( m a c r o a l g a e ) a n d
cemeteries is a known groundwater pollutant in the Unites States. arsenobetaine (invertebrates and sh).
Terrestrial plants : Plants may accumulate arsenic by
Arsenic has been used widely in the United States as a wood root uptake from the soil or by adsorption of airborne
preservative until the year 2004 [4]. Eventually, as wood comes arsenic deposited on the leaves. Arsenic levels are
into contact with higher in biota collected near anthropogenic sources
Sources of Occupational Exposure to Arsenic or in areas with geothermal activity.
soil and water, it
1. Semi-conductors industry, notably of fast chips
based on gallium arsenide often involving the toxic releases Arsenic to
gas ARSINE, AsH3. the environment. This is a major source of Arsenic in the
2. Glass manufacturing. environment, in particular in children playgrounds. In addition,
3. Mining operations and purification of metal ores Arsenic plays an important role in the semiconductor industry in
and metals. Specically, sulde base ore
processing (iron pyrite, lead sulde) the form of gallium arsenide, a compound used in a wide range of
4. Manufacturing of certain drugs, Cattle and electronic devices [5].
poultry food additives (some anti-cancer drugs,
e.g. Roxarsone). Most Arsenic in the terrestrial environment is found in rocks and
5. Manufacturing and use of pesticides and soils. Arsenic in surface and ground water is mostly a mixture of
insecticides which contain Arsenic. arsenite and arsenate. Arsenic is widely distributed in food;
6. Wood Treatment
particularly high levels are found in seafood [6]. The major man-
7. Rat and animal poisons.
made sources of
8. Old paints
N.B. Although in most countries the use of Arsenic and its compounds for
Arsenic include coal Sources of Exposure to Arsenic in Daily Life.
Applications 5, 6, 7 and 8 has been banned or discontinued, there are still
many products that contain Arsenic which were manufactured before the
c o m b u s t i o n , 1. Most drinking water contains small amounts of
ban took effect. This includes treated wood in children playgrounds and old
containers of rat poison.
nonferrous metal Arsenic. Natural water leaches small amounts of
Arsenic from rocks and sand. Some industrial
smelting, and the
operations sometimes contaminate water with
burning of agricultural wastes. Arsenic compounds have been Arsenic.
widely used as herbicides, fungicides, wood preservatives, 2. Arsenic was found in items such as wine, juice,
desiccants, cattle and sheep dips, and as coloring agents. Arsenic syrup, glues and pigments.
3. Arsenic is found in many foods both as organic
continues to be widely used in agriculture, in glass and ceramics, as compounds such as methyl arsines, and as
a metal alloy, and in semiconductors and other electronic devices. inorganic arsenates and arsinates. The organic
In the past, Arsenic containing rodenticides and ant poisons were compounds are less toxic than the inorganic
compounds.
responsible for many exposures. Suicidal and homicidal poisonings
4. Inorganic arsenic compounds were found in apple
continue to be reported. Bacteria within soils and sediments can juice, orange and grapefruit juice, in vinegars and
transform arsenate to arsenite, which can be converted into salad dressings, in milk and dairy products, beef,
pork, poultry and in cereal.
methylarsenic acid. Also within the soils and sediments, bacteria
5. Arsenic is found in most unshelled rice but also in
can transform methylarsenic acid into dimethylarsinic acid. All shelled rice and in its products.

12
these arsenic compounds are then sublimated through rain and Roxarsone is an organoarsenic compound that is widely
thereby percolate into drinking water. Molds can convert used in the poultry, pork, and cattle industry as a food
methylarsenic acid into trimethylarsine, which can then also be additive to increase weight gain and improve feed
efciency. The drug was also approved in the United
available within water. In addition, molds and bacteria can States for use in pigs.Roxarsone is marketed** as 3-Nitro
convert dimethylarsinic acid into both trimethylarsine and by Zoetis, a former subsidiary of Pzer. In 2006,
approximately one million kilograms of Roxarsone were
dimethylarsine in water. Once in water, trimethylarsine and produced in the U.S.
dimethylarsine can volatilize into the atmosphere. Therefore, **Use of Roxarsone was discontinued in the US since 2011
different forms of Arsenic can be found in the soil, sediments,
water, atmosphere and the food chain. (Reviewed in:[7]).
A few important facts pertinent to Arsenic
Poisoning: Non-occupational human exposure to arsenic in the environment is
1. Every person is exposed daily to Arsenic because primarily through the ingestion of food and water[8,9]. Arsenic has
most drinking waters and foods contain trace
amounts of arsenic. been detected in groundwater in several countries of the world, with
2. The body can tolerate small doses of Arsenic concentration levels exceeding the WHO drinking water guideline
without noticeable immediate physiological value of 10 g/L (WHO) as well as the national regulatory
effects.
standards (e.g. 50 g/L in India and Bangladesh) [10, 11]. Arsenic
3. Arsenic atoms may be present in compounds in the
trivalent or the pentavalent form. in groundwater is often associated with geologic sources. Today,
4. Arsenic may be connected to carbon atoms, in arsenic contamination of drinking water is a major worldwide
which case the compound is called ORGANIC or public health problem. A very large number of people in India and in
may be connected to other types of atoms, when it
will be called INORGANIC. Inorganic arsenic different parts of the world (countries like Bangladesh, Chile,
compounds are in general much more toxic than Taiwan, Mexico, Thailand, Germany and parts of China) are being
organic compounds.
highly affected due to the intake of arsenic contaminated ground
5. Many Arsenic compounds will impart a garlic-like
smell to a food or to the breath of the person who water [8, 10-12]. A signicant fraction of the population living in the
consumes them. districts of West Bengal, India, (e.g. Malda, Murshidabad, Nadia,
6. Since the chemical properties of Arsenic are very Bardhaman, Hooghly, 24-Parganas, and Kolkata) are also under
similar to the properties of phosphorous, and
because phosphorous compounds are critical in heavy environmental exposure to arsenic and suffer from the
numerous biochemical functions in the body, effects of chronic
Arsenic is toxic in all biochemical reactions that
involve phosphorous.
arsenic toxicities Overview of the human exposure to arsenic
- Non-occupational human exposure to arsenic in
initiating an the environment is primarily through the ingestion
alarmingly high of food and water.
incidence of skin, bladder and lung cancer and also Blackfoot - The daily intake of total arsenic from food and
beverages is generally between 20 and 300
disease (arsenic induced oxidative stress leading to microvascular g/day.
damage and gangrene of foot) [13-16]. - Foodstuffs such as meat, poultry, dairy products
and cereals have higher levels of inorganic
The daily intake of total arsenic from food and beverages is arsenic.
generally between 20 and 300 g/day. Foodstuffs such as meat, - Pulmonary exposure may contribute up to
poultry, dairy products and cereals have higher levels of inorganic approximately 10 g/day in a smoker and about 1
g/day in a non-smoker, and more in polluted
Arsenic [17]. Pulmonary exposure may contribute up to areas.
approximately 10 g/day in a smoker and about 1 g/day in a non- - The concentration of metabolites of inorganic
smoker, and more in polluted areas. The concentration of arsenic in urine ranges from 5 to 20 g of
metabolites of inorganic arsenic in urine ranges from 5 to 20 g of arsenic/liter, but may even exceed 1000 g/liter.
- In workplaces with up-to-date occupational
Arsenic/liter, but may even exceed 1000 g/liter. In workplaces hygiene practices, exposure generally does not
with up-to-date occupational hygiene practice, exposure generally exceed 10 g/m3 (8-h time-weighted average).
3
does not exceed 10 g/m (8-h time-weighted average).
Concentrations as low as 0.5 ppm Arsenic may trigger the initial symptoms of exposure [18].
The symptoms of small-to-moderate exposure to arsenic may appear immediately or only after several hours and
include headaches, vertigo and nausea. Subsequently, problems related to oxygen transfer in the body due to
interferences with the hemoglobin, along with possible impairment of renal functions occur.

13
Exposure to small doses of Arsenic compounds over a long period of time can result in lung, skin or liver cancer, or
cancer of the lymphatic system [19], and damage to organs, such as the esophagus, as also confusion and
disorientation. Arsenic mainly enters via drinking water or food that has been taken but it can also penetrate into the
body through the skin or the lungs [20]. Most Arsenic compounds are soluble in water to some extent and thus are
easily transported in the blood stream and assimilated by the body. The water solubility also helps to remove some
of the Arsenic via the urine and the excrement. The urine and other excrements may change to darker red-brown or
even greenish color [21]. Notably, a signicant portion of the ingested Arsenic is absorbed by various bodily
tissues and is retained over an extended period of time. Some of the Arsenic that enters the body is excreted out of
the body rather rapidly but a fraction of it accumulates in various organs including the blood vessels in addition to
the hair and the nails. The fraction of Arsenic that is retained in the body depends on the specic Arsenic compound
that has entered, the portal that it entered through, i.e. ingestion or inhalation, and other components present in the
food that were consumed together. While such arsenic based toxic wastes are liberated very slowly, nevertheless
they cause physiological damage in various organ systems [22].
Recent clinical research has shown that arsenic trioxide, administered intravenously, could induce cancer
remission in some people with refractory acute promyelocytic leukemia [23, 24]. There are highly suggestive but
inconclusive epidemiological evidences that support the increased incidence of arteriosclerotic lesions, ischemic
heart disease and thereby increased mortality risk among arsenic-exposed persons [25, 26]. Arsenic can trigger
multiple abnormal electrocardiographic patterns not limited to ventricular tachyarrhythmia [27, 28]. While the
carcinogenic and cancer therapeutic potentials of arsenic have widely been studied, there is a relatively smaller
attention to arsenic induced CVDs [29].

Arsenic and Cardiovascular diseases

Being long considered a potent human
health hazard due to its neoplastic
outcomes, Arsenic also shows
increasing epidemiological evidence of
links between Arsenic exposure and
risks of CAD and CVDs. As mentioned
earlier, Arsenic is a major risk factor for
the endemic peripheral artery disease
characterized by severe arteriosclerosis
Figure 1 : Arsenic induce tachycardia in isolated amphibian heart.
and subsequent gangrene of affected Brief exposure of inorganic Arsenic (Na-Arsenate) induce tachycardia that could be
extremities, so-called Blackfoot counteracted by beta blockers in isolated amphibian heart.
disease (BFD) [30, 31]. In addition,
systemic vascular disease have been epidemiologically linked to chronic Arsenic exposure. High mortality from
ischemic heart disease was rst reported in copper smelter workers who were exposed to arsenic [32]. In the
United States epidemiological studies correlated between standard mortality ratios for cardiovascular diseases
and arsenic levels in food and drinking water [33, 34]. In our experimental system, acute exposure of inorganic
arsenic induced tachycardia in isolated amphibian hearts ,similar to adrenalin ,and could be blocked by a beta
blocker - atenolol (Figure 1). Ischemic heart disease and cerebral infarction are considered late clinical
manifestations of generalized atherosclerotic process and ultrasound studies in the supercial carotid artery
indicated a dose response relationship between carotid atherosclerosis and chronic exposure to arsenic [33, 35,
36]been observed after careful adjustment of the statistical data for major CVD risk factors, signifying arsenic
exposure as a potential independent risk factor for atherosclerosis, CAD, and increased incidences of
cardiovascular morbidity and mortality.

14
Chronic low dose exposure to Arsenic induce endothelial dysfunction
The endothelium, being most sensitive to systemic or micro-environmental stress, is one of the prime target of
chronic arsenic toxicity. Naturally occurring and highly toxic inorganic form of arsenic rapidly induces reactive
oxygen species (ROS) formation and thereby induce proliferation response in vascular smooth muscle cells. The
net effect of such activity is attenuation of endothelium-dependent conduit artery dilation via downregulation of
endothelial NO synthase- events that are temporally matched to the accumulation of oxidants across the vessel
wall. Reduced expression of endothelial nitric oxide synthase (eNOS) leading to diminished bioavailability of
vasodilating nitric oxide (NO) is a hallmark of endothelial dysfunction.
A number of earlier publications indicate that Arsenic imposes serious threats to cardiovascular health and co-
morbidity. Reports of chronic arsenic exposure induced CVD related mortality, endothelial dysfunction,
dysregulated lipid metabolism are available, and some other detailed mechanistic studies are also starting to
emerge [1,37-41]. Moreover, in a recent study, it was shown that even habitual sh intake, although generally
reect healthier dietary habits with favorable effects on the endothelial function, can actually increase the chronic
exposure levels of Arsenic and subsequently lead to deleterious alteration in the arterial ow mediated dilation
(FMD) a clinical indicator of endothelial dysfunction [42]. Chronic low exposure to arsenic induce Cyclin D1
dependent NFkB/BCL3 mediated pathways leading to cellular proliferation [43]. In addition, other associated
deleterious effects of chronic Arsenic exposure includes generation and persistence of proactive platelet, induction
of dyslipidemia and increase in endothelial adhesion of activated monocytes initiating a pro-atherogenic condition
[38, 44].
Our recent studies indicate that a range of ultra-low concentrations of Arsenic (10nM 10M) exposure
signicantly down-regulate the mRNA levels of eNOS in addition to signicantly diminished expression of Krppel-
like Factor 2 (KLF2) and Krppel-like Factor 4 (KLF4) in HUVEC (not shown), and in primary human aortic
endothelial cells respectively. Krppel-like factors 2 and 4 are pivotal laminar ow inducible transcription factors
that modulate several genes critical for maintaining an antithrombotic endothelial surface [45, 46]. KLF2 is also a
key determinant of the anti-inammatory and anti-atherogenic vascular environment [47-49], and a potent inducer
of endothelial nitric oxide synthase (eNOS) [50]. KLF2 blocks expression of the procoagulant Tissue Factor [51]
and also inhibits thrombin-induced activation of endothelial cells by decreasing expression of the thrombin-
activated protease activated receptor type 1 (PAR-1), Conversely, TNF-, IL-1, and oxidative stress, repress KLF2
expression in the endothelial cells (EC)[52]. KLF4 is also an independent regulator of EC function, and is protective
against atherosclerosis [53].According to reports, Krppel-like factors (KLFs) are important mediators of
monocyte differentiation and activation as well. KLF2 is a negative regulator of proinammatory genes both in the
ECs and monocytes and expression of KLF2 in monocytes is reduced following exposure to TNF- or LPS and in
monocytes from patients with coronary artery disease [54]. Krppel-like factor 4 is also involved in myeloid cell
differentiation [55] and is a critical regulator of macrophage polarization. In vitro exposure of mouse macrophages
to LPS, proinammatory cytokines, or oxLDL, results in decreased KLF4 levels [53, 56]. Mouse macrophages
decient in KLF4 have enhanced foam cell formation in response to oxLDL [53]. Our preliminary observations
shows brief exposure of inorganic Arsenic in nanomolar concentration induce signicant down-regulation of
several other endothelial regulator genes resulting in increased expression of VCAM-1, and E-selectin
(unpublished observations, not shown) in HUVEC.
To determine whether the reduced eNOS expression in Arsenic exposed endothelial cells and other peripheral blood
mononuclear cells (not shown), could be linked to a reduced expression of endothelial KLF4 (and KLF2: not
shown), we examined nuclear KLF4 levels by immunouorescence microscopy, normalizing the digitized nuclear
KLF4 uorescence to nuclear DNA (as measured by DAPI uorescence). We observed signicantly reduced KLF4
expression in Arsenic exposed primary human aortic endothelial cells when compared to the KLF4 expression in
untreated control cells (Figure 2a. ***p < 0.001).

15

Figure 2 : Arsenic exposure reduce Krppel-like Factor 4 expression in
human aortic endothelial cells in a time and dose dependent manner.
Human primary aortic endothelial cells were grown in sterile chamber
slides, and exposed to 10M of Arsenic at the indicated time points. The
cells were subsequently immunostained and digital images were recorded
by epi-uorescence microscopy (EVOSFL, Life Technologies) using a
100X objective (20X images for large scale data acquisition and analyses)
for the detection and analysis of nuclear KLF4 (Panel a) and Histone H3
(Panel b.) as internal control. Quantitative uorescence intensity ratio
(KLF4:DAPI) data of 100 cells at each time point from 3 independent
experiments are presented to the right of each panel. The data were
compared using a two tailed Mann Whitney test. ***p<0.001.
Interestingly, when the nuclear levels of histone H3,
as an internal control, was measured using identical
parameters no such dose or time dependent effect of
Arsenic exposure on the endothelial cells was
observed (Figure 2b.). We confer that the vascular
micro-environment during Arsenic exposure is
pathologically modied characterized by a
diminished expression of the anti-inammatory and
anti-atherogenic transcriptional regulator KLF2 and
KLF4 in addition to signicant reduction in eNOS
production and increased expression of endothelial
adhesion molecules, like VCAM-1 and E-selectin.
Here, we provide a comprehensive set of data
showing the effects of low dose Arsenic exposure
(10M) at different time point on cultured primary
human aor tic endothelium from descending
thoracic aorta (Figure 2).
Arsenic-induced molecular and cellular events
related to atherogenesis : In vitro studies on
cultured human endothelial cell indicate that arsenic

can initiate oxidative damage, activation of

transcription factors, and gene expression relevant
to endothelial dysfunction and CVD (Figure 3).
Chronic exposure to Arsenic is also a potential risk
factor for type 2 diabetes.
Exposure to inorganic Arsenic induces pre-diabetic
effects by altering or deregulating lipid metabolism,
gluconeogenesis and insulin secretion in healthy
individuals. It worsens glucose metabolism in
established diabetics. Alteration of insulin resistance
might be not the sole reason of diabetic effects
caused by inorganic Arsenic [57].
Figure 3:Schematic view of plausible arsenic induced oxidative
damage and endothelial dysfunction. Arsenic interacts with G Protein
Coupled Receptors (GPCR) to initiate signal amplication schemes
Arsenic exposure, cardiovascular diseases and regulating NOX-dependent redox signaling. Downstream signaling for
global HIV incidences : Cardiovascular dysfunction was (partially adapted from: States JC, et al., Toxicol Sci.
2009.[1]).
abnormalities are common in HIV-infected
individuals but often go unrecognized or untreated,
which results in increased cardiovascular-related morbidity and mortality and reduced quality of life. Clinicians
may mistakenly attribute signs of cardiovascular abnormalities to pulmonary or infectious causes, an error that
can delay appropriate treatment.Despite a dramatic improvement in survival in the antiretroviral therapy (ART) era,
there remains an increased risk of thromboembolic and cardiovascular co-morbidities in those treated [58-60].
The core mechanism(s) that contribute to this increased risk of CVD in HIV disease have not been fully elucidated,
but may be partially related to chronic immune activation [61, 62]. Systemic indices of inammation and

16
coagulation have been linked to cardiovascular risk in HIV infection [63] and PET CT scans have demonstrated
metabolic evidence of aortic inammation in treated HIV infection [64].
Endothelium is a highly reactive sur face,
responding to a myriad of micro-environmental
stress-inducing factors resulting from infection
tissue injury, and inammation [65]. ECs serve as
selective micro environmental barriers for the
exchange of uid and macromolecules from the
vascular compartment to the tissue.In addition, the
bidirectional relationship that follows between the
coagulation pathways and vascular inammation
modulating endothelial homeostasis is widely
recognized [66, 67].
We showed in one of our recent reports that eNOS
and KLF2 are signicantly downregulated inducing
endothelial dysfunction alongwith a dramatic
increase in the subendothelial migration of CD8 T
cells and inammatory monocytes in the aortic
endothelium of Rhesus macaque who are acutely
infected with simian immunodeciency virus (SIV)-
the HIV homologue infecting non-human primates
[68]How such downregulation affects the formation
and sustenance of the immunological synapse bond
is of extreme importance in dening the immune
lifeline of an affected individual. An immediate future
extension of our present line of research in this eld
is to analyze such effects based on mathematical
and probabilistic models that will also highlight the
quantitative importance of all affecting factors.
Association of chronic low dose exposure to
inorganic Arsenic and Arsenicals, endothelial
dysfunction, CVD, and endemic HIV infections
opens up future avenues of research into a relatively
Figure 4 : Global Arsenic exposure (A), Cardiovascular/other diseases poorly understood topic with major implications for
(B), HIV/AIDS Prevalence in 2013 (C), and the projected overlaps (lower human health. While the data acquisition on the
panel).
world prevalence of HIV and cardiovascular
diseases is thorough, the data on chronic exposure
to Arsenic is still incomplete for most part of the world. But, we know a large sum of the world population, mostly
unknowingly, is exposed to Arsenic irrespective of the socioeconomic status or geographical location of their
country. This is a fact which generally indicate that the HIV infected population who are on continued anti-retroviral
therapy (ART) with controlled viremia, are also exposed to low, moderate or high levels of environmental Arsenic
that might be an additional trigger in initiating their accelerated endothelial dysfunction and atherosclerotic lesions.
Determination of the true risk of CVD in HIV and measuring the synergistic effects of Arsenic exposure that further
complicates the pathogenesis of CVD will become increasingly important in the long-term management of HIV-
infected patients receiving antiretroviral therapy.

17
Arsenic Modelling and Transport
As described above, Arsenic is now widely accepted to have not only a dual role as a causative and a curative agent
primarily for non-infectious disease proliferation [69] but also as a secondary instigator of population infection
[70]. While conventional biology is typically a rst resort, probabilistic prediction of affectation and disease
proliferation often stretch beyond the realms of experimental data, especially in predicting what levels of uctuation
of the affecting parameters could instigate a certain threshold of arsenic inicted persecution. As an example,
consider this - if the water arsenic toxicity factor increases by 5% over the next 3 years while the glutathione
depletion factor decreases by 7% leading to an overall increase in protein inactivation by 8% (considering only a
few token factors) during the same time span, what will be the increase in arsenic aficted atherosclerosis and CVD
during this time? To address such questions in a non-invasive method, computer based data analysis and
statistical modeling is the new genre of science in this interdisciplinary arena.
Techniques from statistical mechanics, thermodynamics and nonlinear mechanics, together with native computer
simulation, has started unearthing lots of features that have so far remained outside the conventional research
purview. In a recent ensemble modeling approach, a mathematical model has been studied that predicts
intracellular arsenic ow rates under varying mutant conditions, focusing on the toxicity mechanism of arsenic.
This data based analysis clearly highlight an array of important conclusions like a) protein based arsenic proles
have short-term implications while glutathione based arsenic compounds have long term ramications; b) arsenic
dynamics is mostly a transient mechanism that probabilistically escapes the vacuole via natural export
mechanism. While this work was studied on a yeast substrate, more indicative suggestions towards the protein-
versus-glutathione debate have been advised. While this line of modeling directly assesses the microbiological
origin of its affectation, secondary infections in the form of (Buruli) ulcerous swellings, believed to be arsenic
inicted, have recently been studied using data from chosen African countries [70]. The results from this study
indicate without conrming as much the importance of environmental implication of arsenic disease propagation.
Similar results were obtained a while ago by a South African modeling group who studied the optimal control of
arsenic transmission dynamics targeting mycobacterium ulceran infection [71]. While the data analysis results
[70] indicated the roots of the proliferation mode, this more recent kinetic equation based nonlinear modeling [71]
traced the mitigation mechanism as an optimal combination of environmental and health education together with
water purication protocols.
Modeling attempts at arsenic retention processes in wetland areas is another line of complementary research that
focuses on the role of trace elements in arsenic effect proliferation. Analyzing a model representing arsenic
propagation dynamics in constructed wetlands targeting a quantitative prediction of the mutual relationship
between iron and arsenic retention efciency increase, the model results indicate a maximum arsenic retention
efciency of 85-95% [72]. What all such effects ultimately culminate at is in the population response to exposure of
chemical carcinogens at low to high exposure levels often leading to a mutation of a single-cell DNA, hastening a
terminal illness. A consummate detailing of such carcinogenesis modeling can be availed from a self-sufcient
overview by Vineis, et al. [73]. Of the ve models discussed here, only Model 4 indirectly alludes to arsenic
affectation of carcinoma, another indication of insufcient research in this eld.
The above highlighted areas are only the tips of the proverbial iceberg. More concerted efforts combining
complementary inter- and cross- disciplinary efforts are needed to tackle this problem, an approach that has taken
pace off late.

Concluding Remarks
Studies summarized in this mini-review suggest that chronic Arsenic exposure induces pathophysiological events
relevant to the atherogenic potential including impaired vascular nitric oxide homeostasis, low Krppel-like factor

18
2, 4 expression, and enhanced expression of endothelial adhesion molecule like VCAM-1. These detrimental
changes in the endothelial microenvironment, collectively expressed as endothelial dysfunction are the key
molecular events in the cardiovascular system which are surprisingly common to Arsenic exposure and in the HIV
infected patients on long-term ART. Based on the accumulating epidemiological evidences and experimental data,
we conclude, arsenic exposure could be considered as an important modifying factor in the understating and
intervention strategies of atherosclerosis and related cardiovascular diseases in virologically controlled HIV
patients on ART, at least under certain circumstances (including genetic background, diet, co-exposure and
geographical location). Also, we would argue that the considerable overlap with the worldwide exposure of
Arsenic, incidences of HIV infection positively reinforce the initiation, persistence, and progress of HIV infection
itself and the pathogenesis of related cardiovascular complications. While mathematical modeling of arsenic
poisoning, infection and its impact on carcinogenesis is a vital and newly adopted line of research, the sheer
paucity of material in gelling together known biological observations against data and mathematical models clearly
indicates the need for more detailed and target driven studies. Over the next couple of years, such cross-platform
research is expected to hold center stage in throwing light in this eld.

____________________________________________________________________________________
Conflict of Interest Statement :
All other authors declare that they have no competing interests.
Authors' contribution :
AP and SP designed, performed, analyzed experiments, and SP, AKC, and AP wrote the manuscript with collaborations from GP, and AKC. All
authors contributed to general design and discussion of the project and reviewed and approved the manuscript.
Acknowledgements :
SP acknowledge the Fasenmyer Foundation; the CWRU Center for AIDS Research; the Cleveland Immunology Consortium (CLIC) for supporting
this study without having any role in study design, data collection or analysis, the preparation of the manuscript or the decision to publish it.

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60. Stein, J.H. and P.Y. Hsue, Inflammation, immune activation, and CVD risk in individuals with HIV infection. JAMA, 2012. 308(4): p. 405-6.
61. Funderburg, N.T. and M.M. Lederman, Coagulation and morbidity in treated HIV infection.Thromb Res, 2014. 133 Suppl 1: p. S21-4.
62. Appay, V. and D. Sauce, Immune activation and inflammation in HIV-1 infection: causes and consequences. J Pathol, 2008. 214(2): p. 231-41.
63. Funderburg, N.T., et al., Increased tissue factor expression on circulating monocytes in chronic HIV infection: relationship to in vivo
coagulation and immune activation. Blood, 2010. 115(2): p. 161-7.
64. Subramanian, S., et al., Arterial inflammation in patients with HIV. JAMA, 2012. 308(4): p. 379-86.
65. Franses, J.W. and E.R. Edelman, The evolution of endothelial regulatory paradigms in cancer biology and vascular repair. Cancer Res, 2011.
71(24): p. 7339-44.
66. Schulz, C., B. Engelmann, and S. Massberg, Crossroads of coagulation and innate immunity: the case of deep vein thrombosis. J
ThrombHaemost, 2013. 11 Suppl 1: p. 233-41.
67. Levi, M., T. van der Poll, and H.R. Buller, Bidirectional relation between inflammation and coagulation. Circulation, 2004. 109(22): p. 2698-704.
68. Panigrahi, S., et al., SIV/SHIV Infection Triggers Vascular Inflammation, Diminished Expression of Krppel-like factor 2 (KLF2) and Endothelial
Dysfunction. J Infectious Disease, 2015((In Press)).
69. Talemi, S. R., et al., Mathematical modelling of arsenic transport, distribution and detoxification processes in yeast. Molecular Microbiology
92(6), 1343-1356 (2014).
70. Bonyah, E., et al. Theoretical Model for the Transmission Dynamics of the Buruli Cancer with Saturated Treatment. Computational and
Mathematical Methods in Medicine, 2014: 576039 (2014).
71. Kimaro, M. A., et al. Modelling the Optimal Control of Transmission Dynamics of Mycobacterium ulceran Infection. Open Journal of
Epidemiology 5, 229-243 (2015).
72. Llorens, E., et al. Modelling of arsenic retention in constructed wetlands.Bioresource Technology 147, 221-227 (2013).
73. Vineis, P., Schatzkin, A. and Potter, J. D. Models of carcinogenesis: an overview. Carcinogenesis 31(10), 1703-1709 (2010).

21
 Struma Cordis - A Case Report
Bhabani Prasad Chattopadhyay 1, Sanhita Chatterjee 2,
3 4 5
Sudakshina Chanda , Kunal Sarkar , Sanjeev Garg
1. Associate Professor, Medical College and Hospital, Kolkata, 2. Consultant Pathologist, Medica Superspeciality Hospital, Kolkata, 3. Consultant
Pathologist, Medica Superspeciality Hospital, Kolkata, 4. Vice Chairman, Cardiac Surgeon, Medica Superspeciality Hospital, Kolkata, 5. Consultant
Cardiologist, Medica Superspeciality Hospital, Kolkata

Abstract : A case of Pyrexia of unknown origin on admission was provisionally thought to be suffering from
infective endocarditis. A space occupying lesion in the LVOT causing signicant gradient across it was observed
that led ultimately to surgical exploration. The excised specimen on gross examination revealed multiple grayish
white tissue bits measuring 2 cm x1.5cm. Microscopic examination revealed nodular areas composed of thyroid
follicles of varying sizes lled with colloid . There was moderate lymphocytic inltration into the stroma. The bro-
muscular wall of left ventricle surrounding the stromal tissue was unremarkable. Mass in the LVOT is rare and
presence of thyroid tissue in it in is further rarer. The authors on net searching could not nd any such case
reporting from Indian subcontinent. In this background we are presenting this case report of clinical signicance.

Key Words : Struma cordis, LVOT(Left Ventricular Outow Tract).

Introduction : Ectopic thyroid in the heart is rare. The infrequent case reports in this context available
predominantly narrates location of ectopic thyroid in the right ventricle and inter ventricular septum. Presence of
ectopic thyroid tissue in the left ventricle is more rare and till date there are few such reports. Till 2011 out of 33
case reports of intracardiac ectopic thyroid only three were located in the LVOT and rest of the 30 cases were
1
localized either in the RV or in the IVS .The authors on net searching could not nd any such case reporting from
Indian subcontinent. In this background we are presenting this case report.

Clinical Summary : A 61 year old gentleman presented with pyrexia of unknown origin along with complaint of
discomfort and pain in chest on exertion of 4 weeks duration .It was insideous in onset but progressive in nature.
He was treated outside with antibiotics without proper investigations before reaching our Institute. Due to non-
responsiveness to antibiotics outside he was re-evaluated and thoroughly investigated. In our Institute he was
provisionally diagnosed to be suffering from Infective Endocarditis. Cardiac Echo-doppler study revealed round
Space Occupying Lesion in the LVOT and aortic cusp and that caused haemodynamically signicant obstruction in
the LVOT. Vegetation/Tumour were considered in the differential diagnosis. Surgical exploration and excision of the
mass in the LVOT was done and sent for histopathological examination.

Corresponding address : Dr. B. P. Chattopadhyay. Department of Cardiology, Medical College and Hospital, 88,
College Street, Kolkata-73. E-mail add: bhabani07@yahoo.co.in

22
Investigation Summary :
_3
Haemoglobin-11.3g/dl Total Leucocyte Count 14,500mm N86%, L10%, M2%, E2% ESR78 mm/1st hour C-
Reactive Protein was elevated (18). Widal test (tube agglutination) was negative for enteric fever. Repeated Blood
Cultures were negative. ECG12 leads revealed Left Ventricular Hypertrophy and strain pattern. Digital X-Ray Chest
PA View was within normal limits.
Echodoppler study (Fig1) revealed mass in the non-coronary cusp causing obstruction at the level of Left
Ventricular Outow Tract and the aortic valve. Flow velocity was observed to be 4.19 m/sec and the peak systolic
gradient across the LVOT was 70.4 mm of Hg (Fig2).Vegetation of infective endocarditis and intra cardiac tumour
were kept under consideration of the differential diagnosis.

Fig 1 : 2D Echo-Image of LVOT Mass Fig 2 : Gradient across the LVOT

128 slice MDCT Coronary Angiography (Fig 3) revealed normal epicardial coronaries but the Cardiac CT revealed
SOL in the LVOT (23 X 22 mm). Probablity of vegetation/tumor was kept under consideration. In view of the
negative blood culture and signicant haemodynamic obstruction to LV outow surgical excision was done and
specimen was sent for histopathological examination.

Fig 3 : Cardiac CT ..Round Filling defect in the LVOT Fig 4 : Thyroid Tissue within the ventricular wall

23
Histo-Pathological Examination of the excised specimen : Gross examination revealed : Multiple grayish white bits
of tissue measuring 2 cm x1.5cm. Microscopic examination revealed nodular areas composed of thyroid follicles
of varying sizes lled with colloid. There was moderate lymphocytic inltration into the stroma. The bro-muscular
wall surrounding the stromal tissue was unremarkable .
After availability of histopathological diagnosis Serum T3,T4,TSH level assay was done and was within normal
limits.

Fig 5 : ventricular wall and adjoining thyroid tissue

Discussion :
Development of the Thyroid Gland:Embryologically the development of the thyroid gland and the tongue are closely
related .Before the ventral ends of the rst and second branchial arches join with counterparts of opposite side,
three endodermal elevations appear -a pair of lingual swellings and unpaired median swelling called Tuberculum
Impar between the rst and second arches.The endodermal cells dorsal to the tuberculum impar proliferate to form
a surface elevation called median thyroid rudiment. Thereafter the cells evaginate caudally through the substance
of the tongue to form the thyroglossal duct which goes further down in the median plane lying successively
anterior to the laryngeal bones, hyoid bone and tracheal cartilage where it divides to become bilobed. The middle
isthmus and two rudimentary lateral lobes develop. The fourth pharyngeal pouch complex fuse with the two
rudimentary lateral lobes which arrests further caudal migration and the thyroglossal duct starts
regressing.Before complete regression the duct divides and subdivides into a series of double cellular plates on
either side of the median plane.When colloid materials accumulate between the two layer of cells the latter are
converted to primary thyroid follicles .Subsequent budding result in formation of the secondary follicles. The
parafollicular cells or C cells and parathyroid glands develop from the Ultimobranchial body of the caudal
pharyngeal complex(mostly from 4th branchial arch).
Developmental Anomalies:There may be developmental anomalies of the thyroid gland which include
thyroglossal cyst/stula, lingual thyroid, accessory thyroid, agenesis of thyroid and Ectopic thyroid. Ectopic
thyroid is the presence of thyroid tissue away from its normal anatomical position anywhere in the body.When it is
located in the heart it is called Struma Cordis.
Review of Literature on struma cordis :
1
Struma cordis i.e. ectopic thyroid tissue in the heart is extremely rare and was rst reported in 1941 . The review
article1 on ectopic thyroid by J. Besik et al is an exhaustive one. In the year 1986 one case of heterotopic thyroid
2
gland causing haemodynamically signicant LVOT obstruction was reported .In the same year another case

24
 3
report of ectopic thyroid in the right ventricle was reported. In the year 2000 another case report entitled Ectopic
Thyroid tissue in the left ventricular outow tract. was published4.
Conclusion : Mass in the LVOT is rare and most often is due to vegetation in relation to infective endocarditis.
Tumour in the LVOT is rare and presence of thyroid tissue in it is very very infrequent. However echocardiologists
and clinicians should keep this possibility in mind to avoid missing the diagnosis.

References :
1. Josef Besik, Ondrej Szarszoi et al : Intracardiac Ectopic Thyroid (Struma Cordis) : Journal of Cardiac Surgery 2014, Vol29 Page 155-158
2. Kantelip B, Lusson J R, De Riberolles et al : Intracardiac Ectopic Thyroid. Hum Pathol.1986:17:1293-1296.
3. Pollice L, Caruso G : Struma Cordis-Ectopic Thyroid in the right ventricle Archive Pathol Lab Med May 1986, Vol 110(5) Page 452-53
4. Baykut D, Fiegen U, Krian A : Ectopic Thyroid tissue in the left ventricular outow tract. Ann Thorac Surg 2000 Feb Vol 69 Issue 2 Pages 620-
621

25
Memorable Change in Shape of interventional Cardiology
by Shape Memory Alloys (SMA)
B. P. Chattopadhyay1, Sunip Bannerjee2, S. Das3, A. S. Tripathi4
1. Assocociate Professor, Medical College and Hospital, Kolkata (Corresponding author). 2. Head of the Dept. of Cardiology, Medica Superspecialty
Hospital, Mukundapur, Kolkata. 3. Associate Professor, School of Medical Science and Technology, IIT, Kharagpur. 4. Ph.D. Student, School of
Medical Science and Technology, IIT, Kharagpur

Abstract : Shape memory alloys are special type of alloys that can regain their original shape when heated.
Development of renual cardiological devices like IVC lter, DSD closure device, Nitinal heart valve with this alloy
has brought a radical change in the eld of cardiology. Presently a project is underway to develop a dedicated
bifurcation wire with this alloy.
Key-words : Shape memory alloys, dedicated bifurcation wire.
Introduction : Interventional Cardiology, Paediatric Interventional Cardiology, Interventional Radiology,
Interventional Neuro-Radiology are relatively newer branches of medical science and have some common
denominators. All these subspecialities concentrate in identication of vascular narrowing (stenosis) and
restoration of normal calibre by balloon dilatation and /or deployment of Stents/Stent grafts (for aneurysms).
Techniques of identication of structural holes in vessels or organs and techniques of minimally invasive repair of
the holes by occluders (e.g. ASD / VSD/ PDA closing devices), covered stents (for perforations)etc. are replacing
extensive surgeries. Closure of undesired vessel and aneurysm by coils etc are also very common. All these
techniques and technologies have brought memorable changes in shape of interventional cardiology. Considering
the economic potential of the devices, implants, hardwares and accessories, the big Multi National Corporate
Houses have invested a lot for research in the eld of Interventional Cardiology and allied branches. This has led to
ever expanding innovations in Interventional Cardiology and allied subjects in last few decades. It has changed the
dimensions and equations of Cardiovascular Medicine and Surgery as well. The paradigm shift to minimally
invasive approach in treating structural defects whenever possible is a consequence of it. Amongst many
innovations, application of Shape Memory Alloy (SMA) in Interventional Techniques has made these disciplines
ourish to a signicant extent. Till date nearly 3000 patents of SMA based research works are pending all over the
world.

Background Concepts : Minoo Masani stated that Change is the only unchanging thing in the world. On application
of force on some object or body there is change in length, volume or shape .On removal of force it may regain
original length, volume and shape. The property by virtue of which a body regains its original length ,volume and
shape after removal of the deforming force is called elasticity. Within elastic limit ,the extension of an elastic body is
directly proportional to the force responsible for the extension. Bodies possessing the property of elasticity are
called elastic bodies. Plasticity is the property of remaining deformed even after removal of the deformimng force.
Rigid bodies retain their shape under inuence of limited deforming force beyond which it is broken.
Pseudoelasticity or superelasticity is a property by virtue of which a deformed body can restore or regain its
original shape following exposure to stimulus like heat or cold. Shape Memory Alloy possess the property of
pseudoelasticity.
Superelasticity, or pseudoelasticity, is a unique property of shape memory alloys (SMAs), wherein up to 13%
deformation strain can be sustained and the material can recover its original shape after removing the stress. The

26
shape memory effect occurs in SMA and is dened as when a material can remember its original shape upon
heating or cooling.

What is Shape Memory Alloy? An Alloy is a mixture or combination of two or more metallic elements. Mixture of
Nickel and Titanium gives rise to an alloy named Nitinol. This is a shape memory alloy(SMA). There are many other
SMAs . SMA constitute a group of alloys which has the ability to recover a previously dened shape or length when
subjected to an appropriate thermo-mechanical load i.e. they can recover apparent permanent strainsi.e. original
shape when they are heated above a certain temperature(transformation temperature). The SMAs have two stable
phases - the high-temperature phase, called austenite and the low-temperature phase, called martensite. This
phenomenon of recovery of original shape results from a change of one crystalline phase to another in response
to heat. This is known as thermo elastic transformation from martensitic (cooled) to austentite (heated) phase.
When change in reverse direction is also possible that is called two way memory. At temperatures below the
transformation temperature shape memory alloys are martensitic, In this condition. their microstructure is
characterized by self-accommodating twins, The martenensite is soft and can be deformed quite easily by de-
twinning. Heating above the transformation temperature recovers the original shape. Due to this property and
added biocompatibility there are many biomedical applications of SMA in dentistry(orthodontics),orthopaedics,
neurosurgery and intervention in vascular elds including cardiology.
1-3
Shape Memory Alloy has many properties . On subjecting to force or load the length of metals can be increased or
decreased and the shape can be deformed. The external force applied on the metal is equivalent to the Stress on the
metal. The difference between the original length and nal length (L1-L2) divided by the original length is called
strain (L1-L2)/L1. Restoration of the original length or shape usually does not occur spontaneously without
application of force or energy from outside. The alteration in length and shape is usually unidirectional and
apparently permanent. Deformation done at low temperature(e.g.10 degree Celsius) can be corrected and original
length or shape may be restored at higher temperature(e.g.37 degree Celsius.

Application of SMA in interventional cardiology : The rst cardiovascular device developed with shape memory
was the inferior vena cava (IVC) lter(Fig1). The purpose of this device is to lter clots that travel upstream to the
lungs. The lter traps these clots. The insertion of the lter inside the inferior vena cava is done by exploiting the
shape memory effect. In its original shape in the martensitic state the lter is deformed (in compressed form and
packaged within the container catheter). When the catheter releases out the lter within IVC, it faces warm blood.
As a result, the lter returns to its former shape (austentite phase). This is a landmark change in treatment modality
of recurrent pulmonary thrombo-embolism in patients of deep vein thrombosis.
Like the IVC lter peripheral and coronary stents made up of SMA (Fig4) have been successfully used. Stents
which are commonly used for coronary arteries are Balloon Expandable whereas stents used for peripheral
arteries and aneurysms (stent graft) are usually self expandable. Balloon Expandable stents are manufactured in
the crimped state and expanded to the vessel diameter by inating the stent with a balloon (thus plastically
deforming the stent). Self-expandable stents are manufactured targeting the vessel diameter and are crimped and
constrained to the smaller diameter until the release at the target area, where the constraint is removed and the
stent is deployed. Balloon Expandable stents resist the balloon expansion process, whereas self expandable stents
assist vessel expansion. Balloon Expandable stents are usually made up of stainless steel, platinum, chromium
etc. and self expandable stents are usually made up of nitinol. Self expanding stent is intended to be used for the
treatment of stenotic or occlusive lesions in iliac or femoro-popliteal arteries to establish patency and to maintain
patency. Covered stents provide a circumferentially occlusive boundary between the stent and the vessel and they
are used for stenting vessels that are at risk for rupturing (or have already ruptured/are aneurismal. Trials are

27
undergoing for treating Bifurcation, trifurcation, tapered lesions with specially designed stents made up of SMA.
The stent is pre-compressed in its martensitic state and as the stent is exposed to the warm blood, it tends to
4,5
recover its original shape, expanding itself. APPOSITION I to APPOSITION V trials are denitive trials on coronary

Fig 1 : IVC FILTER Fig 2 : ASD CLOSURE DEVICE

Fig 3 : NITINOL HEART VALVE

stents made up of SMA. These studies sought to

investigate whether self-expanding stents are more
effective than balloon-expandable stents for reducing
stent malapposition at 3 days after implantation in
patients with ST-segment elevation myocardial
infarction undergoing primary percutaneous coronary
intervention. This randomized study in acute MI using
OCT as primary endpoint showed for the rst time a
lower rate of strut malapposition with a self-expanding
stent versus a balloon-expandable stent at 3 days after
primary PCI. Further studies are needed to assess the
clinical signicance of improved early stent apposition.
Once the full potential of SMA stents are successfully
applicable in coronary tree the shape of PCI will undergo
memorable change.
The atrial septal defect closure device (Fig1) is
deployed to close the atrial septal defect. The atrial
septal occlusion device despite some limitations is an
effective alternative to surgical closure of the ASD. The
device is composed of mesh of shape memory wires Fig 4 : NITINOL STENT

28
and polyurethane. Nitinol has also been used for devices designed to close defects or holes in other sites as well
e.g interventricular septum(ventricular septal defect-VSD) and the patent ductus arteriosus (PDA) by application
of the shape memory property. Similarly heart valves made up of SMA(Fig3) are now in clinical use.Transcatheter
valves which incorporate thin lm of nitinol would certainly have a lower prole (less than even 5 Fr), would have
shape memory leaets and would likely have very favorable fatigue properties. Clinical study on Ventricular Assist
Device (VAD) made up of SMA is going on.
Future Directions and works going on in West Bengal : Despite availability of new hardwares the difculty of
accessing the branch vessels having critical angulation with the main vessel pose challenge to the interventional
cardiologists. Time is consumed in reaching the target vessel. But in a critically ill patient in the Cath Lab saving of
time is important to save the life. Operator is in need of enjoying the ease and comfort of maneuvering the tip of the
PTCA guide wire from outside. Maneuverability and steerability of the guide wire from exterior is essential to
overcome the problem. The active PTCA Guidewire equipped with Shape Memory Alloy (SMA) based-actuator
having interesting properties for applications in adaptive structures may provide enhanced maneuverability
compared to conventional PTCA Guidewires. At present use of SMA actuation elements is demonstrated to deliver
large actuation strains and/or stresses while the designs remain relatively simple. However, none of the devices
entirely satisfy the constraints imposed in catheterization process. Tips of the conventional PTCA guide wires are
manually bent by the interventional cardiologists for accessing branches at angulation with the main vessel or to
cross a tortuous segment of a vessel. In complicated cases, reaching the target lesion and crossing the intended
site with presently available wires demands operator's subjective experience and expertise to a large extent. This
can be made more objective if movement of the tip of the PTCA guide wire can be controlled by some actuator
mounted at the distal portion of it. The active PTCA Guidewire equipped with Shape Memory Alloy (SMA) based-
actuator may provide enhanced maneuverability compared to conventional PTCA Guidewires. Miniature active
device at the tip of PTCA guide wire is under study for operator's desire-based manoeuvring of the tip of the PTCA
guide wire to access desired main or side branch vessel. Authors of this article are carrying out research works to
this effect in the School of Medical Science and Technology, IIT, Kharagpur in collaboration with Medica
Superspecialty Hospital, Kolkata.

Conclusion : Already shape memory alloys have found its position in the eld of interventional cardiology Different
stents and devices made up of smart materials like nitininol and others have further potential of generating PTCA
guide wires and other hardwares that may help re-shape the interventional cardiology to a newer dimension.

References :
1. Dr. Siu Wing OR, Overview of Smart Materials Technology, Department of Applied Physics, Hong Kong Polytechnic University.
2. Nitinol a shape memory Alloy, Goldman Sach University, Word Press.
3. Darel E. Hodgson, Ming H. Wu and Robert J. Biermann, Shape Memory Alloy, Johnson Matthey Publication.
4. Amoroso G., van Geuns R.J., Spaulding C., Assessment of the safety and performance of the STENTYS self-expanding coronary stent in
acute myocardial infarction: results from the APPOSITION I study. EuroIntervention. 2011;7:428-436.
5. Van Geuns R.-J., Tamburino C., Fajadet J., Self-expanding versus balloon-expandable stents in acute myocardial infarction: results from
the APPOSITION II study: Self-expanding stents in ST-segment elevatation myocardial infarctiion. J Am Coll Cardiol Intv. 2012;5:1209-1219.

29
 Febrile Neonate - An Atypical Presentation
1, 2 3 4
Indira Banerjee Amitabha Chattopadhyay , Mahua Roy , Prabhat Kumar ,
5 6
Biswajit Bandopadhyay , Kuntal Bhattacharyya

1. Felloe Pediatric Cardiology, RTIICS, Kolkata, 2. Consultant Pediatric Cardiology, RTIICS, Kolkata, 3. Associate Consultant Pediatric Cardiology,
RTIICS, Kolkata, 4. Felloe Pediatric Cardiology, RTIICS, Kolkata, 5. Consultant Pediatric Cardiology, RTIICS, Kolkata, 6. Consultant Cardiology,
RTIICS, Kolkata,

Abstract : A case is reported of febrile neonate younger than one month of age without any infective foci.
Echocardiography detected a coronary artery aneurysm with two clots. Diagnosis of Incomplete Kawasaki
disease was suspected. Administration of intravenous globulin resulted in rapid improvement. Rapid but
cautious coronary thrombolysis protocol was formulatedand executed to prevent any myocardial infarction.
Kawasaki disease is rare in neonates, but it may follow a rapid and severe course.

Keywords : Febrile neonate, Kawasaki disease, coronary thrombolysis.

Introduction : Kawasaki disease is an acute febrile disease of unknown etiology. It is characterized by systemic
vascular inammation involving the small and medium sized arteries, with a predilection for the coronary arteries.
The disease was rst described by Tomisaku Kawasaki in Japan in 1967 [1,2] and is named after him. The disease
accounts for the most important cause of acquired cardiac disease in the developed countries, with an annual
estimated incidence of 112 cases/100000 children in Japan and 2.9 - 6.9 cases/100000 children in Europe[3].
Though the clinical criteria for diagnosis of Kawasaki disease the age limit is less than 5 years, but about 80% of the
children with Kawasaki disease are within this range with the peak of incidence between 6 and 11 months. The
disease is rare in neonates and infants (only 1.6% of patients are under 90 days of age) [3]. Kawasaki disease (KD)
is unusual in newborn infants. Of the 105755 patients with KD registered in Japan over the past 25 years, only six
were neonates, with the youngest one being only 20 days at presentation [4]. Neonatal KD reports have been rare
from other parts of the world as well. The disease is extremely rare in adolescents and adults. The diagnosis is
entirely clinical and relies on fever associated with transient signs and symptoms appearing sequentially. As all are
usually not simultaneously present at the time of physical examination, precise case history and thorough clinical
examination is extremely important. Unusual and incomplete presentation makes the diagnosis more difcult,
which may lead to delay in recognition and treatment with severe sequelae, particularly in infants - who are
reported to have a higher incidence of coronary artery aneurysms [5-11]. Coronary arterty thrombosis per se in
neonatal Kawasaki disease is not well reported in the existing literature. Prompt and appropriate treatment with
intravenous immunoglobulin (IVIG) along with acetyl salicylic acid reduces the risk of cardiac complications [12-
16]. Among the untreated patients 25% of patients develop cardiac complications, declining to 5% in the patients
who receive the IVIG [16].
We report a male neonate with persistent fever presenting with aneurysms of both coronary arteries with two
thombii noted on echocardiography.Rapid but cautious coronary thrombolysis protocol was formulated to prevent
any myocardial compromise.

30
Case history :
Baby VA is the rst born, male baby of a 30 years old primigravida from a non-consanguinous marriage, with an
uneventful antenatal period. He was born by an uneventful normal delivery at term with a birth weight of 2580 g and
was exclusively breast fed. His perinatal period was normal. He presented at 28 days of age withfever for 48 hours,
irritability and poor feeding at a private hospital in Kolkata.
0
At presentation he looked sick, with the highest recorded temperature 103 F, pulse 166/minute, respiration
52/minute, capillary rell less than three seconds, colour pink, vigorous cry with all four limbs were moving
spontaneously in full range. On examination, bilateral air entry in chest was normal without any added sounds.
Cardiovascular examination was within normal limit without any murmur or features of congestive cardiac failure.
Abdomen was soft on palpation, with and there was no organomegaly. Neurological examination showed the
anterior fontanelle was soft and muscle tone was normal. He was a bit irritable which was thought due to the high
grade fever(103 F). On the third day of admission, baby had transient appearance of erythematous non tender
rash, concentrated over both lower extremities, which lasted for around 15 hours and faded by its own without
seeking much attention. The remaining examination was unremarkable.
Relevant investigations were sent to nd out the cause for this fever. Laboratory investigations included:
9
Haemoglobin : 132g/L (normocytic normochromic),White Blood Cells 13.1x10 /L (Neutrophils 31%,
Lymphocytes 62%, Monocytes 4%), Platelets 812 x 109 / L (thought to be of reactive thrombocytosis), Sodium
137 mmol/l, Potassium 4.7 mmol/l, Calcium 2.6 mmol/l, Creatinine 52 mol/L, Glucose 4.8 mmol/L, total bilirubin
101 mol/L, albumin 32 g/L, C - reactive Protein 13.1mg/dL (0-20 mg/dl ), blood culture were negative,
6 6
cerebrospinal uid examination was within normal limits (contained 3 x 10 /L white blood cells, 1 x 10 /L red blood
cells, protein 0.43 g/ L, and glucose 2.1 mmol/L). There were no signs of metabolic acidosis. Catheter urine was
analysed as follows: pH 5.0, 12-15 pus cells / HPF with no red blood cells, protein, or bacteria were detected. As
further investigation for the cause of pyuria, urine was sent for culture sensitivity which revealed growth of E. coli
5
with insignicant colony count (<10 / cmm ). Chest x-ray, USG whole abdomen and KUB were within normal
limits.
The baby still continued to have high grade fever with partial response to oral antipyretics. As there was no
apparent cause for fever the baby was provisionally treated as a case of Baby was put on IV antibiotics as per
culture sensitivity report and further investigations in the line of neonatal UTI were planned in this male baby. But
despite appropriate IV antibiotic in proper dosage, the fever was unabated and he deteriorated further. Cardiological
opinion was sought after to rule out infective endocarditis as a remote cause of this prolonged non-responsive
fever. Cardiological examination was unremarkable, except a grade 2/6 ow murmur at the left lower sternal
border. ECG was within normal limit for this baby with no ischaemic changes. Echo revealed a structurally normal
heart with no vegetations. However the coronaries were bright along the whole coronary system and had
remarkable perivascular cufng. The left main coronary artery (LMCA) was dilated ( 8 mm ) and housing a clot
(3mm x 2mm). There was a fusiform aneurysm (5 x 15 mm) with tapered end, involving proximal left anterior
descending artery (LAD) which had a clot (4mm x 2 mm) adhered to it's lateral wall (Fig 1 and Fig 2). The origin of
the left circumex was mildly dilated (3mm). The right coronary ar tery (RCA) was uniformly
dilated(5mm).Ventricular function was good. There were no valvular regurgitation or pericardial effusion.
The baby was transferred to our institution for further management. Repeat complete blood count and CRP
revealed thrombocytosis (119 x 109/ L) and high CRP (40mg/dl). In view of high grade non-responsive fever,
irritability, transient rash, thrombocytosis, sterile pyuria and coronary changes the baby was diagnosed as a
suspected case of incomplete Kawasaki disease. The baby received 2gm/Kg intravenous immunoglobulin (IVIG)
. Fever subsided completely after IVIG without any recurrence . Though the baby became afebrile the aneurismal
coronaries with thrombus in situ remaind a point of concern. There was a continuous threat ofa myocardial
infarction with adverse outcome due to the further progression or sudden dislodgement of the clot into distal

31
coronaries. On subsequent echocardiograms, the size of the clot was found to be increasing at an alarming rate.
Catheter intervention was not considered as a good option in this small baby due to access and hardware issue and
also because of the high chance of accidental dislodgement of the clot distally with catastrophic consequences.
Hence clot lysis was attempted with Streptokinase (Loading dose of 2000units/Kg over 30 mins followed by
continuous infusion of 1000 units/Kg/hour ) . As there was no change in the size of the clot even after 48hrs, and
the platelet counts were increasing, Tissue plasminogen activator (Alteplase - rTPA) was substituted for
streptokinase. Echocardiographically, the rate of growth of the size of the clot seemed to be decreased compared
to the past few days. In view of the persistently high platelet counts, Tiroban( a platelet aggregation inhibitor) was
started along with IV heparin to prevent further enlargement of the clot and it's propagation. Gradually a regimen of
Warfarin, Aspirin and Clopidogrel were established after all other medications were tapered off. His PT/APTT and
CBC were regularly monitored along with regular echocardiogram.
The baby was discharged in a hemodynamically stable condition with full oral feeding and on oral medications
(Warfarin, Aspirin and Clopidogrel) and has been advised close follow up. At six months follow up echocardiogram
revealed persistent aneurysmal dilatation of the LMCA/LAD(6mm in post treatment period) and aneurysmal RCA
(3mm in post treatment period) with gradual disappearance of the clots(Fig 3). The baby is on regular follow up to
let us understand the progression and course of coronary aneurysms and thrombosis in neonatal
Kawasakidisease in a better way.

Fig 1 : Aneurysmal dilation of LMCA and LAD( proximal part) with Fig 2 : Clot in LAD narrowing its lumen
Clot in LMCA (3mm X 2mm) and LAD ( 4mm X 2mm - measured )

Fig 3 : post treatment period No more clots, but still persisting aneurysmal dilation in LAD (6mm) and RCA (3mm)
Discussion :
This case is unique and important and we want to stress on the following points:
- we had a febrile neonate with no foci apparently (though rare, we have to keep in mind the possibility of neonatal
and atypical KD )
- Kawasaki disease is a clinical diagnosis it should be suspected mainly on the basis of signs, symptoms.
Laboratory features and echocardiographic changes often do not appear until the second / third week.

32
- Incomplete Kawasaki (fever plus fewer than four criteria) Is difcult to diagnose, and one has to rely heavily on
clinical suspicion.
- In our case, the features more suggestive of diagnosis were - irritability, thrombocytosis, sterile pyuria,
increased CRP.
- In this baby, gross coronary changeswere noted with thrombosis.
- The risk of myocardial infarction and sudden deterioration, including the risk of death always loomed large.
- Thrombolysis in neonates and young infants is difcult and risky as coagulation and brinolysisboth cascades
are immature in them so ne balanace of drug dosing is a utmost requirement for safety. As there are no
statdardised protocols for coronary thrombolysis in this age group, we formulated the protocol and used the
medications on clinical guidelines according to the response of the patient.
- The baby responded well to treatment and is on further follow up.
References :
1. Kawasaki T: Acute febrile mucocutaneous syndrome with lymphoid involvement with specic desquamation of the ngers and toes in
children. Arerugi 1967, 16:178-222.
2. Kawasaki T, Kosak F, Okawa S, Shigematsu I, Yanagawa H: A new infantile acute febrile mucocutaneous lymph node syndrome prevailing in
Japan. Pediatrics 1974, 54:271-276.
3. Bhatt M, Anil SR, Sivakumar K, Kumar K: Neonatal Kawasaki disease. Indian J Pediatr 2004, 71:353-354.
4. Tsuchida S, Yamanaka T, Tsuchida R, et al. Epidemiology of infant Kawasaki disease with a report of the youngest neonatal case ever
reported in Japan. Acta Paediatr 1996;85:9957.
5. Burns JC, Wiggins JW Jr, Toews WH, Newburger JW, Leung DY, Wilson H, Glod MP: Clinical spectrum of Kawasaki disease in infants
younger than 6 months of age. J Pediatr 1986, 109:759-763.
6. Rosenfeld EA, Corydon KE, Shulman ST: Kawasaki disease in infants less than one year of age.
J Pediatr 1995, 126:524-529. PubMed Abstract | Publisher Full Text
7. Anderson MS, Todd JK, Glode MP: Delayed diagnosis of Kawasaki syndrome: an analysis of the problem. Pediatrics 2005., 115(4).
8. Belay ED, Maddox RA, Holman RC, Curns AT, Ballah K, Schonberger LB: Kawasaki syndrome and risk factors for coronary artery
abnormalities: United States, 1994-2003. Pediatr Infect Dis J 2006, 25(3):245-249.
9. Genizi J, Miron D, Spiegel R, Fink D, Horowitz Y: Kawasaki disease in very young infants: high prevalence of atypical presentation and
coronary arteritis. Clin Pediatr (Phila) 2003, 42(3):263-267.
10. Rosenfeld EA, Corydon KE, Shulman ST: Kawasaki disease in infants less than one year of age. J Pediatr 1995, 126:524-529.
11. Witt MT, Minich LL, Bohnsack JF, Young PC: Kawasaki disease: more patients are being diagnosed who do not meet American Heart
Association criteria. Pediatrics 1999, 104(1):e10.
12. Newburger JW, Takahashi M, Burns JC, Beiser AS, Chung KJ, Duffy CE, Glode MP, Mason WH, Reddy V, Sanders SP, Shulman ST, Wiggins
WJ, Hicks RV, Fulton DR, Lewis AB, Leung DYM, Colton T, Rosen FS, Melish ME: The treatment of Kawasaki syndrome with intravenous G
globulin. N Engl J Med 1986, 315:341-7.
13. Kato H, Sugimura T, Akagi T, Sato N, Hashino K, Maeno Y, Kazue T, Eto G, Yamakawa R:Long-term consequences of Kawasaki disease. A 10-
to 21-year follow-up study of 594 patients. Circulation 1996, 94:1379-1385.
14. Fong NC, Hui YW, Li CK, Chiu MC: Evaluation of the efcacy of treatment of Kawasaki disease before day 5 of illness. Pediatr Cardiol 2004,
25:31-34.
15. Takahashi M, Mason W, Lewis AB: Regression of coronary aneurysms in patients with Kawasaki syndrome. Circulation 1987, 75:387-394.
16. Newburger JW, Takahashi M, Gerber MA, Gewitz MH, Tani LY, Burns JC, Shulman ST, Bolger AF, Ferrieri P, Baltimore RS, Wilson WR, Baddour
LM, Levison ME, Pallasch TJ, Falace DA, Taubert KA: Diagnosis, treatment, and longterm management of Kawasaki disease: a statement for
health professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in
the Young, American Heart Association. Pediatrics 2004, 114:1708-1733.

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 Instructions to authors
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35
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