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State-of-the-Art Paper
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.
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
Abbreviations
and Acronyms
Pa
Pv
100
Pa
100
Pd
70
Pv
0
max
QN
100
Hyperemic Myoc
cardial Blood Flow
( % off Normal )
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90
80
max
QS
70
60
50
40
30
20
Pd
10
Pa
10
20
30
40
50
60
70
80
90
100
Figure 1
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.
State-of-the-Art
Hyperemic
Stimuli
FFRforMeasurement
Hyperemic
Stimuli for
Table 1
State-of-the-Art FFR Measurement
Epicardial vasodilation
Isosorbide dinitrate
Microvascular vasodilation
Adenosine or ATP ic
Papaverine ic
Adenosine or ATP iv
ATP adenosine triphosphate; FFR fractional flow reserve; ic intracoronary; iv intravenously; LCA left coronary artery; RCA right coronary artery.
resting state
Figure 2
maximum hyperemia
(i.v. 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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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 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.
Figure 3
1049
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.
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Figure 4
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.
Downloaded From: http://content.onlinejacc.org/ on 06/14/2015
D
RCA
Figure 5
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E
LCx
LAD
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.
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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
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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.
%
20
>20
>20
19.1
18.4
10
11.2
13.2
0
COURAGE
Figure 8
SYNTAX
FAME
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= no limitation of oxygen
supply
= limitation of oxygen
supply
aorta
coronary
coronary
artery
artery
Ischemic lesion
Non-ischemic lesion
Stented stenosis
Stenting Strategies
Stent m all
Stent only the ischemic ones
Both strategies eliminate ischemia
Figure 9
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.
Despite Apparently
Reasons
for Reasons
Nonischemic
Tight
Stenosis
FFR
for Nonischemic
FFR
Table 2
Despite Apparently Tight Stenosis
Physiologic explanations
Small perfusion territory, old myocardial infarction, little viable tissue, small vessel
Abundant collaterals
Interpretation explanations
Technical explanations
Exercise-induced spasm
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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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47. Vant Veer M, Pijls NHJ, Aarnoudse W, Koolen JJ, Van de Vosse FN.
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48. Pijls NHJ. Optimum guidance of complex PCI by coronary pressure
measurement. Heart 2004;90:108593.
Key Words: fractional flow reserve y myocardial ischemia y
percutaneous coronary intervention y revascularization.