Journal of the American College of Cardiology

2012 by the American College of Cardiology Foundation

Published by Elsevier Inc.

Vol. 59, No. 12, 2012

ISSN 0735-1097/$36.00
doi:10.1016/j.jacc.2011.09.077

MINI-FOCUS ISSUE: OPTICAL COHERENCE TOMOGRAPHY

State-of-the-Art Paper

Functional Measurement of Coronary Stenosis

Nico H. J. Pijls, MD, PHD, Jan-Willem E. M. Sels, MD
Eindhoven, the Netherlands
Fractional flow reserve (FFR) is considered nowadays as the gold standard for invasive assessment of physiologic stenosis significance and an indispensable tool for decision making in coronary revascularization. Use of
FFR in the catheterization laboratory accurately identifies which lesions should be stented and improves the outcome in most elective clinical and angiographic conditions. Recently, FFR has been upgraded to a class IA classification in multivessel percutaneous coronary intervention in the guidelines on coronary revascularization of
the European Society of Cardiology. In this state-of-the-art paper, the basic concept of FFR and its application,
characteristics, and use in several subsets of patients are discussed from a practical point of view. (J Am Coll
Cardiol 2012;59:104557) 2012 by the American College of Cardiology Foundation

Coronary angiography still plays a pivotal role in invasive

imaging of the coronary arteries. Despite rapid developments in noninvasive imaging, the temporal and spatial
resolution of coronary angiography is unsurpassed and
will remain the road map for cardiologic interventionalists and cardiac surgeons for performing revascularization. Nevertheless, it has been recognized for many years
that coronary angiography is of limited value in defining
the functional significance of a coronary artery stenosis.
In this respect, functionally significant means hemodynamically significant or associated with inducible ischemia in case of stress.
It is important to emphasize that in coronary artery
disease, the most important factor related to outcome is
the presence and extent of inducible ischemia (1,2). A
functionally significant stenosis generally causes anginal
symptoms and is associated with impaired outcome.
Therefore, functionally significant stenoses should be
revascularized, if technically possible (35). On the other
hand, if a stenosis has no functional significance, it will
not cause angina by definition, and the outcome of
medical treatment is excellent with an infarction and a
mortality rate of 1% per year (5,6). Therefore, for
decision making in the interventional catheterization
laboratory with respect to revascularization, it is of
paramount importance to determine whether a stenosis is
inducing reversible ischemiain other words, to assess
whether a stenosis is functionally significant.

From the Department of Cardiology, Catharina Hospital Eindhoven, and Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven,
the Netherlands. Dr. Pijls has received institutional research grants from St. Jude
Medical, Abbott, and Maquet; and is a consultant for St. Jude Medical. Dr. Sels has
reported that he has no relationships relevant to the contents of this paper to disclose.
Manuscript received June 22, 2011; revised manuscript received August 5, 2011,
accepted September 5, 2011.

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Although in many patients with single-vessel disease, noninvasive testing is a suitable methodology to determine the
potentially ischemic nature of a stenosis, in multivessel disease,
it is often very difficult to judge which of several lesions are
functionally significant (associated with reversible ischemia)
and should be stented, and, vice versa, which stenoses could
better be left alone and treated medically (6,7).
Both exercise testing, technetium-99m sestamibi singlephoton emission computed tomography, and other classic
noninvasive tests often indicate ischemia in patients with
multivessel disease but fail to distinguish the specific ischemic territories and responsible stenoses. In addition, findings on technetium-99m sestamibi single-photon emission
computed tomography may even be normal in multivessel
disease because of balanced ischemia.
Fractional flow reserve (FFR) is an accurate and lesionspecific index to indicate whether a particular stenosis or
coronary segment can be held responsible for ischemia (8,9).
It has been shown that deferring stenting in a FFR-negative
stenosis (i.e., in the nonischemic zone) is safe and associated
with excellent long-term outcome. It has also been shown
that revascularization of a FFR-positive stenosis (i.e., in the
ischemic zone) is associated with significant decrease in
ischemia and an improved outcome (3,6,8).
For those reasons, it is helpful in decision making in the
interventional laboratory to measure FFR for guidance of
coronary interventions, especially if it is unclear whether a
stenosis causes ischemia. In this state-of-the-art paper, FFR
and its practical application in the catheterization laboratory for
functional measurement of coronary artery stenosis are
discussed.
Definition of FFR
FFR is defined as the ratio of maximum blood flow in a
stenotic artery to maximum blood flow if the same artery

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were normal. Stated in another

way, maximum flow in the presence of the stenosis is expressed
FFR fractional flow
as a fraction of maximum flow in
reserve
the hypothetical case that the
LAD left anterior
epicardial artery was completely
descending coronary artery
normal. It may be clear that FFR
LCx left circumflex
is a ratio of 2 flows: the maxicoronary artery
mum myocardial flow in the steMI myocardial infarction
notic territory divided by the
Pa mean aortic pressure
maximum myocardial flow in the
as measured by the guiding
catheter
same territory in the normal case.
This ratio of the 2 flows is exPCI percutaneous
coronary intervention
pressed as the ratio of 2 presPd distal coronary
sures, which can be easily meapressure, measured by the
sured by a pressure wire and the
pressure wire
guiding catheter, respectively.
Therefore, FFR equals Pd/Pa,
where Pd is the distal coronary pressure across the stenosis
and Pa is the aortic pressure, both measured at maximum
coronary hyperemia. The concept of FFR is explained in
Figure 1.
FFR has a direct clinical equivalent: FFR of 0.60
means that the maximum blood flow (and oxygen supply)
to the myocardial distribution of the respective artery
only reaches 60% of what it would be if that artery were
completely normal. An increase to 0.90 after stenting
indicates that maximum blood supply has now increased
by 50%.
Therefore, FFR is linearly related to maximum blood
flow and its normal value is 1.0, irrespective of the patient,
artery, blood pressure, and so forth. For further details about
the mathematical aspects and derivation of FFR and the
possibility of distinguishing coronary and collateral blood

flow contributions to myocardial blood flow, we refer to the

literature (8 10).

Abbreviations
and Acronyms

Practical Aspects of FFR Measurements

Catheters. Generally, guiding catheters are used when
measuring FFR. The use of diagnostic catheters is technically feasible. However, due to higher levels of friction
hampering wire manipulation, the smaller internal caliber
interfering with pressure measurements, and the inability to
perform an ad hoc percutaneous coronary intervention
(PCI) by using diagnostic catheters, the use of guiding
catheters is recommended.
Wires. Measuring intracoronary pressure requires the use
of a specific solid-state sensor mounted on a floppy-tipped
guidewire. Two such systems exist: the PressureWire (St.
Jude Medical Inc., Minneapolis, Minnesota and Uppsala,
Sweden) and the PrimeWire (Volcano Inc., Rancho Cordova, California). In both wires, the sensor is located at the
junction between the 3-cm-long radiopaque tip and the
remainder of the wire. The last generations of these 0.014inch wires have excellent handling characteristics, although
slightly inferior to most standard angioplasty guidewires.
Before introducing the sensor into the vessel to be studied,
the pressures recorded by the sensor and by the guiding
catheter should be equalized.
The pressure wire has to be connected to an interface
(Analyzer Express, St. Jude Medical Inc., Uppsala, Sweden
or Combomap, Volcano Inc.), which offers the possibility of
recording the registrations and showing FFR immediately.
Recent developments in hardware and software have
further facilitated the use of pressure wires and integration
in the regular catheterization laboratory setup (wireless

Pa

Pv

100

Pa
100

Pd
70

Pv
0

max

QN

100

Hyperemic Myoc
cardial Blood Flow
( % off Normal )

1046

90
80

max

QS

70
60
50
40
30
20

Pd

10

Pa

10

20

30

40

50

60

70

80

90

100

Hyperemic Coronary Perfusion Pressure

( % of normal )

Figure 1

Concept of Fractional Flow Reserve Measurements

When no epicardial stenosis is present (blue lines), the driving pressure Pa determines a normal (100%) maximal myocardial blood flow. In the case of stenosis responsible for a hyperemic pressure gradient of 30 mm Hg (red lines), the driving pressure will no longer be 100 mm Hg but instead will be 70 mm Hg (Pd). Because the relationship between driving pressure and myocardial blood flow is linear during maximal hyperemia, myocardial blood flow will only reach 70% of its normal value. This
numerical example shows how a ratio of 2 pressures (Pd/Pa) corresponds to a ratio of 2 flows (QSmax/QNmax). It also illustrates how important it is to induce maximal
hyperemia. Pv central venous pressure.

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A 200-g bolus of isosorbide dinitrate (or any other form

of intracoronary nitrate) allows the abolition of any form of
epicardial vasoconstriction and should be administered as
usual before any manipulation in the coronary artery.
Microvascular vasodilation is equally paramount for the
calculation of FFR. Gauging pressure differences at rest
does not offer a definitive measure: It cannot be emphasized
strongly enough that there is no such thing as a baseline
FFR. As a matter of fact, if the Pd/Pa ratio at baseline is in
the ischemic zone, it may only further decrease at hyperemia
and the decision to revascularize can already be made. Even
when the resting pressure gradient is large, inducing hyperemia is recommended because it allows the evaluation of the
residual resistance reserve and ability to quantify the improvement after treatment. An example of a typical coronary
pressure tracing during the administration of intravenous
adenosine is shown in Figure 2.

State-of-the-Art
Hyperemic
Stimuli
FFRforMeasurement
Hyperemic
Stimuli for
Table 1
State-of-the-Art FFR Measurement
Epicardial vasodilation
Isosorbide dinitrate

At least 200-g ic bolus, at least 30 s before

the first measurements

Microvascular vasodilation
Adenosine or ATP ic

At least 40-g ic bolus in the RCA, 4080 g

in the LCA

Papaverine ic

1012 mg in the RCA, 1520 mg in the LCA

Adenosine or ATP iv

140 g/kg/min (preferably through a central

venous, e.g., femoral line)

ATP adenosine triphosphate; FFR fractional flow reserve; ic intracoronary; iv intravenously; LCA left coronary artery; RCA right coronary artery.

Aeris wire, St. Jude Medical Inc. and Integrated 5S Cath

Lab System, Volcano Inc.).
Anticoagulation. As soon as any device is advanced into
the coronary tree, the use of the same anticoagulation
regimens as routinely used during a PCI is recommended:
heparin adjusted to weight, validated by a monitored activated coagulation time of at least 250 s, or a fixed number of
units per time and/or body weight, in accordance with the
local routine.
Hyperemic stimuli. FFR, by definition, represents an index of maximum blood flow. Therefore, it is essential to
induce maximal vasodilation of the 2 compartments of the
coronary circulation (epicardial or conductance arteries
and the microvasculature or resistance arteries). The
pharmacologic options for inducing hyperemia are summarized in Table 1 (10,11).

resting state

Figure 2

Special Features of FFR

FFR has a number of unique characteristics that make this
index particularly suitable for functional assessment of
coronary stenoses and clinical decision making in the
catheterization laboratory.
FFR HAS A THEORETICAL NORMAL VALUE OF 1 FOR EVERY
PATIENT, ARTERY, AND MYOCARDIAL BED. An unequivocally normal value is easy to refer to but is generally rare in
clinical medicine. So, this is a unique advantage of FFR.
Because in a normal epicardial coronary artery there is
virtually no decrease in pressure, not even during maximal

maximum hyperemia
(i.v. adenosine)

Maximum Hyperemia Induced by Intravenous Adenosine

Typical example of simultaneous aortic pressure (Pa) and distal coronary pressure (Pd) recordings at rest and during maximal steady-state hyperemia as induced
by an intravenous (i.v.) infusion of adenosine. Fractional flow reserve (FFR) is simply calculated as the ratio of Pd and Pa during steady-state maximum hyperemia.

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hyperemia (12), it is obvious that Pd/Pa will equal or be very

close to unity. This means that normal epicardial arteries do
not contribute to the total resistance to coronary blood flow.
The lowest value found in individuals with strictly normal
coronary arteries (n 65) was 0.94 (12,13). Yet it is
important to realize that in normal-looking coronary arteries in patients with proven atherosclerosis elsewhere, the
epicardial coronary arteries may contribute to total resistance to coronary blood flow even though there is no
discrete stenosis visible on the angiogram. In 50% of these
arteries, FFR is lower than the lowest value found in normal
individuals. In approximately 10% of atherosclerotic arteries, FFR will even be lower than the ischemic threshold
(12). Practically speaking, this finding implies that myocardial ischemia might be present in atherosclerotic patients in
the absence of discrete stenoses.
FFR HAS A WELL-DEFINED CUTOFF VALUE WITH A NARROW
GRAY ZONE BETWEEN 0.75 AND 0.80. Cutoff or threshold
values are values that distinguish ischemic from nonischemic
levels for a given measurement. To enable adequate clinical
decision making in individual patients, it is essential that any
level of uncertainty be reduced to a minimum. Stenoses with
FFR 0.75 are almost invariably able to induce myocardial
ischemia, whereas stenoses with FFR 0.80 are almost never
associated with exercise-induced ischemia. This means that the
gray zone for FFR (between 0.75 and 0.80) spans 10% of the
entire range of FFR values.
FFR in fact is the only index of ischemia that has been
validated compared with a true gold standard in a so-called
prospective multitesting Bayesian approach (14). During
the past years, many studies have been performed examining
the gray zone, and in all these studies, invariably a best
cutoff value between 0.75 and 0.80 was found in many
subsets of patients including left main coronary artery
disease, diabetes, multivessel disease, and previous infarction.
Therefore, the practical lesson is that in a stenosis with
FFR 0.75, stenting is always justified (if technically
feasible), whereas in a stenosis with FFR 0.80, stenting
can be safely deferred and optimal medical treatment is
sufficient. Between 0.76 and 0.80, sound clinical judgment
(taking into account the character of symptoms, results of
noninvasive tests if available, and whether a gradient is focal
or diffuse) should balance the final decision.
FFR IS NOT INFLUENCED BY SYSTEMIC HEMODYNAMICS. In
the catheterization laboratory, systemic pressure, heart rate,
and left ventricular contractility are prone to change. In
contrast to many other indices measured in the catheterization laboratory, changes in systemic hemodynamics do not
influence the value of FFR in a given coronary stenosis (15).
In addition, FFR measurements are extremely reproducible
(16). This is due not only to the fact that aortic and distal
coronary pressures are measured simultaneously, but also to
the capability of the microvasculature to repeatedly vasodilate to exactly the same extent. These characteristics con-

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tribute to the accuracy of the method and to the trust in its

value for clinical decision making.
FFR TAKES INTO ACCOUNT THE CONTRIBUTION OF

Whether myocardial flow is provided antegradely by the epicardial artery or retrogradely through
collaterals does not really matter for the myocardium. Distal
coronary pressure during maximal hyperemia reflects both
antegrade and retrograde flows according to their respective
contribution (6,13). This holds true for the stenoses supplied by collaterals but also for stenosed arteries providing
collaterals to another more critically diseased vessel.
COLLATERALS.

FFR SPECIFICALLY RELATES THE SEVERITY OF THE STENOSIS

TO THE MASS OF TISSUE TO BE PERFUSED: NORMALIZATION

The larger the myocardial mass

subtended by a vessel is, the larger the hyperemic flow, and
in turn, the larger the gradient and the lower the FFR for a
given stenosis. This explains why a stenosis with a minimal
cross-sectional area of 4 mm2 has totally different hemodynamic significance in the proximal left anterior descending
artery (LAD) versus the second marginal branch, as recently
demonstrated by Iqbal et al. (17). It also means that the
hemodynamic significance of a particular stenosis may
change if the perfusion territory changes (as is the case after
myocardial infarction [MI]).These changes are accounted
for by FFR.

FOR PERFUSION AREA.

FFR HAS UNEQUALED SPATIAL RESOLUTION. The exact position of the sensor in the coronary tree can be monitored
under fluoroscopy and documented angiographically. Pulling back the sensor under maximal hyperemia provides the
operator an instantaneous assessment of the abnormal
resistance of the arterial segment located between the guide
catheter and the sensor. Although other functional tests
reach a per-patient accuracy (exercise electrocardiography)
or, at best, a per-vessel accuracy (myocardial perfusion
imaging or stress echocardiography/magnetic resonance imaging), FFR reaches a per-segment accuracy with a spatial
resolution of a few millimeters.

FFR in Different Patient Subsets

FFR in angiographically intermediate stenoses. One of
the standard indications for FFR is the precise assessment of
the functional consequences of a given coronary stenosis with
unclear hemodynamic significance (14). In a study of 45
patients with angiographically dubious stenoses, it was shown
that FFR has a much greater accuracy in distinguishing
hemodynamically significant stenoses than exercise electrocardiography, myocardial perfusion scintigraphy, and stress echocardiography performed separately. This was shown using a
so-called sequential Bayesian approach, proving that FFR can
indeed be considered as a true gold standard (14).
Furthermore, results of different noninvasive tests are
often contradictory, which renders appropriate clinical decision making difficult. In addition, the clinical outcome of
patients in whom PCI is deferred because FFR indicated no

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Figure 3

Pijls and Sels

Functional Measurement of Coronary Stenosis

1049

Example of 2 Patients in Whom an Angiographically Similar Stenosis Is Found

in the Proximal Left Anterior Descending Coronary Artery

In the example on the left, the lesion has no hemodynamic significance and does not need any form of mechanical revascularization.
In the example on the right, the stenosis is hemodynamically very significant and warrants percutaneous intervention. FFR fractional flow reserve.

hemodynamically significant stenosis is very favorable. In

such population, the risk of cardiac death or MI is approximately 1% per year, and this risk is not decreased by PCI
(6). These results strongly support the use of FFR measurements as a guide for decision making about the need for
revascularization in intermediate lesions. Figure 3 illustrates
how 2 angiographically similar stenoses may have a completely different hemodynamic severity. One of them should
be revascularized, and the other should not. Based solely on
the angiogram, the decision should be identical in both
cases, which would lead to an inappropriate interventional
decision in 1 of these patients.
FFR in left main coronary artery stenosis. The presence
of a significant stenosis in the left main stem is of critical
prognostic importance (18). Conversely, revascularization of
a nonsignificant stenosis in the left main may lead to early
occlusion of the conduits, especially when internal mammary arteries are used (19). Furthermore, the left main is
among the most difficult segments to assess by angiography
(20). Noninvasive testing is often noncontributive in patients with a left main stenosis. Perfusion defects are often
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seen in only 1 vascular territory, especially when the right

coronary artery is significantly diseased (21). In addition,
tracer uptake may be reduced in all vascular territories
(balanced ischemia), giving rise to studies with falsenegative results (22). Several studies have shown that FFR
could be used safely in left main stenosis and that the
decision not to operate on left main stenosis with FFR
0.80 is safe (23,24). In addition, angiographic assessments
of left main lesions with FFR 0.80 were no different from
those with FFR 0.80, further reinforcing the importance
of physiologic parameters in case of doubt. Therefore,
patients with an intermediate left main stenosis deserve
physiologic assessment before blindly making a decision
about the need for revascularization. Two examples shown
in Figure 4 illustrate how FFR measurements in the left
main did drastically influence the type of treatment in these
patients.
Left main disease is rarely isolated. When tight stenoses
are present in the LAD or in the LCx the presence of these
lesions will tend to increase the FFR measured across the
left main. The influence of a LAD/left circumflex coronary

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Figure 4

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Example of 2 Patients in Whom FFR Measurements in an

Intermediate Ostial Left Main Stenosis Changed the Therapeutic Strategy

The first (upper panel) represents a 67-year-old man with massive mitral regurgitation who was assessed for minimally invasive (port access) mitral valvuloplasty. The
coronary angiogram showed an intermediate ostial left main stenosis. The fractional flow reserve (FFR) of the left main stenosis was 0.69. Accordingly, this patient
underwent conventional coronary artery bypass graft surgery and mitral valvuloplasty via a median sternotomy. The second (lower panel) represents an 89-year-old man
with critical aortic stenosis referred for aortic valve replacement and bypass surgery because of the presence of an ostial left main stenosis. FFR of the left main stem
was 0.83. Accordingly, only a percutaneous aortic valve implantation was performed. Abbreviations as in Figure 1.

artery (LCx) lesion on the FFR value of the left main will
depend on the severity of this distal stenosis but, even more,
on the vascular territory supplied by this distal stenosis. For
example, if the distal stenosis is in the proximal LAD, its
presence will markedly affect the stenosis in the left main. If
the distal stenosis is located in a small second marginal
branch, its influence on the left main stenosis will be
minimal. Nevertheless, even in the presence of other stenoses in addition to left main coronary artery stenosis, the
distal FFR value indicates to what degree maximum perfusion of the different left coronary artery territories is decreased. In a recent prospective study by Hamilos et al. (24),
an excellent outcome of FFR-guided revascularization was
found in 213 consecutive patients with equivocal left main
coronary artery disease, whether or not in conjunction with
LAD or LCx stenosis.
FFR in multivessel disease. Patients with multivessel
disease actually represent a very heterogeneous population.
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Their anatomic features (number of lesions, location, and

respective degree of complexity) may vary tremendously and
have major implications for the revascularization strategy.
Moreover, there is often a large discrepancy between the
anatomic description and the actual physiologic severity of
each stenosis. For example, a patient may have 3-vessel
disease based on the angiogram, but actually have only 2
hemodynamically significant stenoses. Conversely, a patient
can angiographically be considered as having 1-vessel disease of the right coronary artery but actually have a hemodynamically significant stenosis of the left main. Figure 5
shows a typical example of a patient in whom the right
coronary artery and the LCx are critically narrowed and in
whom the mid LAD shows a mild stenosis. Myocardial
perfusion imaging showed a reversible perfusion defect in
the inferolateral segments and a normal flow distribution in
the segments supplied by the LAD. In contrast, FFR shows
that all 3 vessels are significantly narrowed but to a different

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D
RCA

Figure 5

1051

E
LCx

LAD

A 69-Year-Old Man With Severe Angina

Myocardial perfusion imaging showed a reversible defect in the inferolateral segments. From the angiogram, it is obvious that the right coronary artery (RCA) and the left
circumflex artery (LCx) are significantly narrowed (no pressure measurements are needed). However, the mid left descending artery (LAD) stenosis, considered nonsignificant on the angiogram, appears to be hemodynamically significant. This LAD stenosis was undetected by myocardial perfusion imaging because the uptake of tracer is
markedly worse in the LCx territory than in the LAD territory. Abbreviations as in Figure 2.

extent. By nuclear scintigraphy, the significant defect in

the anterior wall is masked by the more severe defects in
the other areas. This has a major implication with regard
to revascularization. FFR-guided revascularization strategies in patients with multivessel disease were very
encouraging (2527). Tailoring the revascularization according to the functional significance of the stenoses
rather than to their mere angiographic appearance decreased costs and avoided the need for surgical revascularization (25). Recently, incontrovertible proof of the
benefit of FFR-guided multivessel PCI compared with
standard angiography was provided in the large randomized, multicenter FAME (Fractional Flow Reserve Versus
Angiography for Multivessel Evaluation) study (5,28). In that
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study, it was demonstrated that all types of adverse events

were decreased by 30% in the first year after PCI in
multivessel disease, when guided by FFR. This was achieved
at a lower cost and without prolonging the interventional
procedure, whereas angina in FFR-guided patients was
relieved at least as effectively (5,29), as is outlined in further
detail in the following. After 2 years, the advantage of FFR
guidance of PCI in multivessel disease even increased with
respect to lower mortality and MI rates, whereas some
catching up occurred with respect to repeat revascularization. Importantly, in this study, the progression of deferred
lesions was excellent. Only 1 late MI occurred on a
previously deferred lesion (0.2%) and 16 late PCIs were
performed (3.2%) (5).

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FFR after MI. After a MI, previously viable tissue is

partially replaced by scar tissue. Therefore, the total mass of
viable myocardium supplied by a given stenosis in an
infarct-related artery will tend to decrease (30). By definition, hyperemic flow and thus hyperemic gradient will both
decrease as well. Assuming that the morphology of the
stenosis remains identical, FFR must therefore increase.
This does not mean that FFR underestimates lesion severity
after MI. It simply illustrates the relationship that exists
among flow, pressure gradient, and myocardial mass and
conversely illustrates that the mere morphology of a stenotic
segment does not necessarily reflect its functional importance. This principle is illustrated in Figure 6. Recent data
confirm that the hyperemic myocardial resistance in viable
myocardium within the infarcted area remains normal (31).
This further supports the application of the established FFR
cutoff value in the setting of partially infarcted territories. In
the acute phase of MI, FFR is neither reliable nor useful to
assess the culprit lesions, and the electrocardiography
trumps any other investigation. From 5 days after the
infarction, FFR can be used as usual to indicate residual
ischemia of the infarct-related or remote arteries.
Earlier data had suggested that microvascular function
would be abnormal in regions remote from a recent MI
(32,33). However, more recent work taking into account distal
coronary pressure indicates that hyperemic resistance is normal
in those remote segments (34). These data support the use of
FFR to evaluate stenoses remote from a recent MI.
FFR in diffuse disease. Histopathology studies and, more
recently, intravascular ultrasound and optical coherence
tomography have shown that atherosclerosis is diffuse in
nature. The presence of diffuse disease is often associated
with a progressive decrease in coronary pressure and flow,
and this can often not be clearly assessed from the angiogram (12,35). In contrast, this decrease in pressure correlates with the total atherosclerotic burden (35). In approx-

Pd=50

Pa=100
DS=75%

FFR=0.50

Normal Myocardium

Myocardial
Infarction
Pa=100

Pd=84
DS=75%

FFR=0.84

Scar
Normal Myocardium

Figure 6

Schematic Representation of the

Relationship Between FFR and Myocardial
Mass Before and After Myocardial Infarction

See text for details. DS diameter stenosis; other abbreviations as in

Figure 2.

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imately 10% of patients, this abnormal epicardial resistance

may be responsible for reversible myocardial ischemia. In
these patients, chest pain is often considered noncoronary
because no single focal stenosis is found, and the myocardial
perfusion imaging is wrongly considered false positive
(36,37). Such diffuse disease and its hemodynamic impact
should always be kept in mind when performing functional
measurements. In a large multicenter registry of 750 patients, FFR was obtained after technically successful stenting. A post-PCI FFR value of 0.9 was still present in
almost one third of patients (despite the absence of a
gradient across the stent), reflecting diffuse disease, and was
associated with a poor clinical outcome (38). The only way
to demonstrate the hemodynamic impact of diffuse disease
is to perform a careful pull-back maneuver of the pressure
sensor under steady-state maximal hyperemia (Fig. 7).
FFR in sequential stenoses. When several stenoses are
present in the same artery, the concept and the clinical value of
FFR are still valid to assess the effect of all stenoses together.
However, it is important to realize in such cases that each of
several stenoses will influence hyperemic blood flow and
therefore FFR across the other one. The influence of the distal
lesion on the proximal is more important than the reverse.
Theoretically, the FFR can be calculated for each stenosis
individually (39). However, this is neither practical nor easy to
perform and therefore of little use in the catheterization
laboratory. Practically, as for diffuse disease, a pull-back maneuver under maximal hyperemia is the best way to appreciate
the exact location and physiologic significance of sequential
stenoses and to guide the interventional procedure step-by-step
(Fig. 7). After the most severe stenosis (i.e., the stenosis with
the largest gradient) has been stented, the pull-back recording
can be repeated, and it can be decided whether and where a
second stent should be placed.
FFR in bifurcation lesions. Overlapping of vessel segments and radiographic artifacts render bifurcation stenoses
particularly difficult to evaluate on angiography, whereas
PCI of bifurcations is often more challenging than for
regular stenoses. The principle of FFR-guided PCI applies
in bifurcation lesions even though clinical outcome data are
currently limited. Two recent studies by Koo et al. (40,41)
used FFR in the setting of bifurcation stenting. The results
of these studies can be summarized as follows: 1) after
stenting the main branch, the ostium of the side branch
often looks pinched. Yet such stenoses are grossly overestimated by angiography: few of these ostial lesions with a
stenosis diameter 75% were found to have FFR 0.75;
and 2) when kissing balloon dilation was performed only in
ostial stenoses with FFR 0.75, the FFR at 6 months was
0.75 in 95% of cases. These studies favor an approach in
bifurcation lesions of stenting the main branch and kissing
balloon dilation thereafter only if FFR of the side branch is
0.75. If FFR of the side branch is 0.75, the outcome is
excellent without further intervention.

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2.

1.

2.
1.

Distal LAD

Proximal LAD
Figure 10

Figure 7

Hyperemic Pressure Pull-back Recording in a Diffusely Diseased LAD Artery With Superimposed Focal Lesions

The pressure recording shows that all the disease in the LAD combined is responsible for inducible ischemia (FFR 0.74) and indicates the exact origin of the gradient
(arrows). The numbers 1 and 2 in the angiogram correspond to the respective numbers in the pressure tracings Abbreviations as in Figures 2 and 5.

Optimizing Treatment in Multivessel Coronary Disease

and Consequences of the FAME Study
In the past years, 3 large studies were conducted to examine
the best possible treatment of patients with multivessel
coronary artery disease. In these studies, the respective value
of optimal medical treatment only, PCI in addition to
medical treatment, and coronary bypass surgery were investigated (5,28,42,43).
These studies were the COURAGE (Clinical Outcomes
Utilizing Revascularization and Aggressive Drug Evaluation) study, SYNTAX (TAXUS Drug-Eluting Stent Versus Coronary Artery Bypass Surgery for the Treatment of
Narrowed Arteries) study, and FAME study (5,28,42,43).
In the COURAGE study, optimal medical treatment only
and PCI in addition to medical treatment were investigated
in patients with multivessel disease and moderately severe
coronary disease. In most patients, bare metal stents were
used. In the SYNTAX3-Vessel Disease (3VD) study, only
patients with 3-vessel disease were included, and only
drug-eluting stents were used. The degree of disease was
more severe than that in the COURAGE trial, and in these
patients, standard angiography-guided PCI with drugeluting stents only was compared with bypass surgery. In the
FAME study, also in patients with mainly 3-vessel disease
but excluding left main stenosis, standard angiographyguided PCI with drug-eluting stents was compared with
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FFR-guided multivessel PCI with drug-eluting stents. The

SYNTAX-3VD and FAME studies had broader inclusion
criteria, including unstable patients and nonST-segment
elevation MI, and decreased left ventricular function, and

MACE in COURAGE, SYNTAX3VD, and FAME STUDY

%
20
>20
>20

19.1

18.4

10
11.2

13.2

0
COURAGE

Figure 8

SYNTAX

FAME

Major Adverse Event Rate

Death of all causes, myocardial infarction, and (repeat) revascularization in the

COURAGE study, SYNTAX-3VD study, and FAME study. Note: the exact major
adverse cardiac event (MACE) rate in the COURAGE study at 1 year has not
been published to our knowledge, but from published data, a MACE rate 20%
can be deduced. angio angioplasty; CABG coronary artery bypass graft;
FFR fractional flow reserve; PCI percutaneous coronary intervention.

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March 20, 2012:104557

the FAME study also included patients who had undergone

a previous PCI.
The most important results of these 3 studies are presented in Figure 8. Although the baseline characteristics of
the studies were slightly different (with the angiographically
most complex disease in the SYNTAX study and least
complex disease in the COURAGE study), it can be seen
that outcome was comparable in all studies for standard
angiography-guided PCI, whereas FFR-guided PCI improved outcome significantly. Not only the total number of
major adverse cardiac events was significantly reduced by
routine measurement of FFR as well as mortality and
occurrence of MI. From Figure 8, it can be hypothesized
that multivessel PCI guided by FFR is superior to optimal
medical treatment and yields results comparable to those of
coronary artery bypass graft surgery in many patients.
Therefore, it may be hypothesized that the indications for
performing PCI will be further extended when guided by
FFR measurements and that more patients, previously
treated by medical treatment alone or by coronary artery
bypass graft surgery, can be better candidates for sophisticated PCI-guided by FFR measurements. Adding functional
data to the SYNTAX score to stratify patients with multivessel

disease to either coronary artery bypass graft surgery or PCI, as

recently suggested, is also an interesting development (44).
Further prospective, randomized trials are mandatory (and
ongoing) to investigate these hypotheses.
Finally, one can wonder why outcome after FFR-guided
PCI is so good compared with standard angiographyguided PCI, despite the use of fewer stents.
This can be understood from considering the combined
mortality and MI rate associated with ischemic and nonischemic stenoses in general and with stents (Fig. 9). From
many studies it is known that such an event rate is 1% per
year for a functionally nonsignificant stenosis if treated
appropriately by medication (5,6,42,44), between 5% and
10% per year for a functionally significant stenosis if only
treated by medication (4,45), and approximately 3% per year
for a stented lesion whether it was functionally significant or
not (4,5,45).
This means that stenting a functionally significant stenosis improves outcome, but stenting a functionally nonsignificant stenosis worsens outcome.
Both FFR-guided PCI and angiography-guided PCI
eliminate all ischemic lesions very effectively and therefore
have a similar positive effect on relief of angina pectoris.

= no limitation of oxygen
supply
= limitation of oxygen
supply

aorta

coronary

coronary

artery

artery

Ischemic lesion
Non-ischemic lesion
Stented stenosis

intrinsic risk 5 % per year

intrinsic risk 1 % per year
intrinsic risk 3 % per year

Stenting Strategies
Stent m all
Stent only the ischemic ones
Both strategies eliminate ischemia
Figure 9

intrinsic risk 12%

12%
intrinsic risk 12
8%
similar functional class

Schematic Explanation of Why FFR-Guided PCI Decreases the Rate of Death and Myocardial Infarction

The hypothetical patient in this figure has 4 angiographically significant stenoses, 2 of them are also functionally significant (i.e., causing reversible ischemia; yellow
circles). The intrinsic risk of such ischemic stenosis of death or myocardial infarction (MI) is at least 5% per stenosis per year (see text). The intrinsic risk of the nonischemic lesions (green circles), in contrast, is 1% per year. By stenting a stenosis (whether functionally significant or not), the risk of death or MI is approximately
3% per year. Stenting all 4 lesions based on angiography eliminates ischemia very effectively and relieves angina pectoris. The risk of death or MI, however, is
decreased for 2 of the lesions but increased for the other 2. The benefit in terms of survival by stenting the ischemic lesions is eliminated by collateral damage by
unnecessary stenting of the other 2 lesions. By FFR-guided percutaneous coronary intervention, ischemia and angina pectoris are eliminated as effectively, but also the
net risk of death or MI is decreased by 30% to 35%. Abbreviations as in Figure 8.

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March 20, 2012:104557

Despite Apparently
Reasons
for Reasons
Nonischemic
Tight
Stenosis
FFR
for Nonischemic
FFR
Table 2
Despite Apparently Tight Stenosis
Physiologic explanations

Stenosis hemodynamically nonsignificant despite angiographic appearance

Small perfusion territory, old myocardial infarction, little viable tissue, small vessel

Abundant collaterals

Severe microvascular disease (rarely affecting FFR)

Interpretation explanations

Other culprit lesion

Diffuse disease rather than focal stenosis (make pull-back recording)

Chest pain of noncardiac origin

Technical explanations

Insufficient hyperemia (check system and solution or use other stimulus)

Guiding catheterrelated pitfall (deep engagement, small ostium, side holes)

Electrical drift (pull sensor back to ostium to check and equalize)

Equalization with introducing needle and measurement without it

Actual false-negative FFR

Acute phase of ST-segment elevation myocardial infarction

Severe left ventricular hypertrophy

Exercise-induced spasm

FFR fractional flow reserve.

If, however, indiscriminate stenting is performed based on

the angiogram, the positive influence on reducing the mortality
and MI rate by stenting of ischemic stenoses is eradicated by
inadvertent stenting of the nonischemic stenoses. Such unintended damage is prevented by FFR guidance.
Based on the results of studies such as DEFER and
FAME, use of FFR in multivessel PCI has been upgraded
recently in the European Society of Cardiology guidelines to
a class IA classification (46).
FFR Post-Intervention
The use of FFR to evaluate the results of PCI is less well
investigated. An inverse relationship has been shown between post-PCI FFR and the restenosis rate (38). After
successful stenting, no noticeable hyperemic gradient should
be present across a well-deployed stent (47). The opposite is
not always true, and in case of doubt, intravascular ultrasound or optical coherence tomography is a better way to
study stent deployment.
Finally, the hyperemic pressure pull-back recording is an
informative tool for analyzing the extent and significance of
residual disease proximal or distal to the stent.
Limitations and Pitfalls of FFR
There are several pitfalls related to FFR measurement and a
few clinical situations in which it is not reliable and should
not be applied. The most important of these is acute
ST-segment elevation MI. During primary PCI for acute
MI, the combination of the symptoms, electrocardiogram,
and angiogram makes it mostly possible to determine the
culprit lesion in the majority of cases. In addition, thrombus
embolization, myocardial stunning, acute ischemic microDownloaded From: http://content.onlinejacc.org/ on 06/14/2015

1055

vascular dysfunction, and other factors make reaching complete microvascular vasodilation unlikely.
Therefore, FFR measurement makes no sense in the
setting of acute ST-segment elevation MI. When a several
days have passed (usually 5 days are considered sufficient),
FFR can be applied as in routine practice. The question of
whether FFR can be applied during primary PCI to assess
the hemodynamic severity of remote lesions has recently
been answered (34).
From the technical point of view, there are several pitfalls
to watch when performing FFR measurement. The 2 most
important pitfalls are submaximal hyperemia (underestimating the stenosis severity) and issues related to the guiding
catheter. A large guiding catheter may interfere with maximum blood flow and a guiding catheter with side holes may
influence proximal coronary pressure and interfere with
intracoronary administration of adenosine. Such situations
can be easily recognized and avoided once the operator has
some experience with FFR. For a more in-depth discussion
of pitfalls, we refer the reader to several excellent overviews
in the literature (36,48).
Finally, there are a number of physiologic reasons why
FFR can be high despite an apparently tight stenosis. This
is further clarified in Table 2.
Conclusions
FFR is an indispensable tool in the state-of-the-art catheterization laboratory to support decision making in revascularization in almost all elective clinical and angiographic
conditions. With modern equipment, as is available today,
measurement can be easily, rapidly, and safely performed,
and the methodology is cost-effective, if not cost-saving.
FFR strongly supports the developing paradigm of functional complete revascularization (i.e., stenting of ischemic
stenoses and medical treatment of nonischemic ones). By
systematic use of FFR in equivocal stenosis and multivessel
disease, PCI can be made an even more effective and better
treatment than it is currently.
Reprint requests and correspondence: Dr. Nico H. J. Pijls,
Catharina Hospital, PO Box 1350, 5602 ZA Eindhoven, the
Netherlands. E-mail: nico.pijls@inter.nl.net.

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Key Words: fractional flow reserve y myocardial ischemia y
percutaneous coronary intervention y revascularization.