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doi:10.1016/j.jacc.2011.09.077 2012;59;1045-1057 J. Am. Coll. Cardiol.

Nico H.J. Pijls, and Jan-Willem E.M. Sels Functional Measurement of Coronary Stenosis

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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 physio-

logic 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 out-

come in most elective clinical and angiographic conditions. Recently, FFR has been upgraded to a class IA clas-

sification 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;59:1045–57) © 2012 by the American College of Cardiology Foundation

Coronary angiography still plays a pivotal role in invasiveimaging of the coronary arteries. Despite rapid develop-ments in noninvasive imaging, the temporal and spatialresolution of coronary angiography is unsurpassed andwill remain the road map for cardiologic interventional-ists and cardiac surgeons for performing revasculariza-tion. Nevertheless, it has been recognized for many yearsthat coronary angiography is of limited value in definingthe functional significance of a coronary artery stenosis.In this respect, functionally significant means hemody-namically significant or associated with inducible isch-emia in case of stress.

It is important to emphasize that in coronary arterydisease, the most important factor related to outcome isthe presence and extent of inducible ischemia (1,2). Afunctionally significant stenosis generally causes anginalsymptoms and is associated with impaired outcome.Therefore, functionally significant stenoses should berevascularized, if technically possible (3–5). On the otherhand, if a stenosis has no functional significance, it willnot cause angina by definition, and the outcome ofmedical treatment is excellent with an infarction and amortality rate of �1% per year (5,6). Therefore, fordecision making in the interventional catheterizationlaboratory with respect to revascularization, it is ofparamount importance to determine whether a stenosis isinducing reversible ischemia—in other words, to assesswhether a stenosis is functionally significant.

Although in many patients with single-vessel disease, non-invasive testing is a suitable methodology to determine thepotentially ischemic nature of a stenosis, in multivessel disease,it is often very difficult to judge which of several lesions arefunctionally significant (associated with reversible ischemia)and should be stented, and, vice versa, which stenoses couldbetter be left alone and treated medically (6,7).

Both exercise testing, technetium-99m sestamibi single-photon emission computed tomography, and other classicnoninvasive tests often indicate ischemia in patients withmultivessel disease but fail to distinguish the specific isch-emic territories and responsible stenoses. In addition, find-ings on technetium-99m sestamibi single-photon emissioncomputed tomography may even be normal in multivesseldisease because of balanced ischemia.

Fractional flow reserve (FFR) is an accurate and lesion-specific index to indicate whether a particular stenosis orcoronary segment can be held responsible for ischemia (8,9).It has been shown that deferring stenting in a FFR-negativestenosis (i.e., in the nonischemic zone) is safe and associatedwith excellent long-term outcome. It has also been shownthat revascularization of a FFR-positive stenosis (i.e., in theischemic zone) is associated with significant decrease inischemia and an improved outcome (3,6,8).

For those reasons, it is helpful in decision making in theinterventional laboratory to measure FFR for guidance ofcoronary interventions, especially if it is unclear whether astenosis causes ischemia. In this state-of-the-art paper, FFRand its practical application in the catheterization laboratory forfunctional measurement of coronary artery stenosis arediscussed.

Definition of FFR

FFR is defined as the ratio of maximum blood flow in astenotic artery to maximum blood flow if the same artery

From the Department of Cardiology, Catharina Hospital Eindhoven, and Depart-

ment 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.

Journal of the American College of Cardiology Vol. 59, No. 12, 2012© 2012 by the American College of Cardiology Foundation ISSN 0735-1097/$36.00Published by Elsevier Inc. doi:10.1016/j.jacc.2011.09.077


http://content.onlinejacc.org

were normal. Stated in anotherway, maximum flow in the pres-ence of the stenosis is expressedas a fraction of maximum flow inthe hypothetical case that theepicardial artery was completelynormal. It may be clear that FFRis a ratio of 2 flows: the maxi-mum myocardial flow in the ste-notic territory divided by themaximum myocardial flow in thesame territory in the normal case.This ratio of the 2 flows is ex-pressed as the ratio of 2 pres-sures, which can be easily mea-sured by a pressure wire and theguiding catheter, respectively.Therefore, FFR equals Pd/Pa,

where Pd is the distal coronary pressure across the stenosisand Pa is the aortic pressure, both measured at maximumcoronary hyperemia. The concept of FFR is explained inFigure 1.

FFR has a direct clinical equivalent: FFR of 0.60means that the maximum blood flow (and oxygen supply)to the myocardial distribution of the respective arteryonly reaches 60% of what it would be if that artery werecompletely normal. An increase to 0.90 after stentingindicates that maximum blood supply has now increasedby 50%.

Therefore, FFR is linearly related to maximum bloodflow and its normal value is 1.0, irrespective of the patient,artery, blood pressure, and so forth. For further details aboutthe mathematical aspects and derivation of FFR and thepossibility of distinguishing coronary and collateral blood

flow contributions to myocardial blood flow, we refer to theliterature (8–10).

Practical Aspects of FFR Measurements

Catheters. Generally, guiding catheters are used whenmeasuring FFR. The use of diagnostic catheters is techni-cally feasible. However, due to higher levels of frictionhampering wire manipulation, the smaller internal caliberinterfering with pressure measurements, and the inability toperform an ad hoc percutaneous coronary intervention(PCI) by using diagnostic catheters, the use of guidingcatheters is recommended.Wires. Measuring intracoronary pressure requires the useof a specific solid-state sensor mounted on a floppy-tippedguidewire. Two such systems exist: the PressureWire (St.Jude Medical Inc., Minneapolis, Minnesota and Uppsala,Sweden) and the PrimeWire (Volcano Inc., Rancho Cor-dova, California). In both wires, the sensor is located at thejunction between the 3-cm-long radiopaque tip and theremainder of the wire. The last generations of these 0.014-inch wires have excellent handling characteristics, althoughslightly 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 guidingcatheter should be equalized.

The pressure wire has to be connected to an interface(Analyzer Express, St. Jude Medical Inc., Uppsala, Swedenor Combomap, Volcano Inc.), which offers the possibility ofrecording the registrations and showing FFR immediately.

Recent developments in hardware and software havefurther facilitated the use of pressure wires and integrationin the regular catheterization laboratory setup (wireless

Abbreviations

and Acronyms

FFR � fractional flow

reserve

LAD � left anterior

descending coronary artery

LCx � left circumflex

coronary artery

MI � myocardial infarction

Pa � mean aortic pressure

as measured by the guiding

catheter

PCI � percutaneous

coronary intervention

Pd � distal coronary

pressure, measured by the

pressure wire

card

ial B

loo

d F

low

f N

orm

al )

50

70

80

90

100

60

Pa100

Pv 0

QNmaxmax

QSmaxmax

Hyperemic Coronary Perfusion Pressure

( % of normal )

Hyp

ere

mic

Myo

c

( %

of

40

0

10

20

30

40 50 70 80 90 1000 10 20 30 60

Pa100

Pd70

Pv 0

PaPd

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 respon-

sible 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 rela-

tionship 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/QN

max). It also illustrates how important it is to induce maximal

hyperemia. Pv � central venous pressure.

1046 Pijls and Sels JACC Vol. 59, No. 12, 2012

Functional Measurement of Coronary Stenosis March 20, 2012:1045–57



Aeris wire, St. Jude Medical Inc. and Integrated 5S CathLab System, Volcano Inc.).Anticoagulation. As soon as any device is advanced intothe coronary tree, the use of the same anticoagulationregimens as routinely used during a PCI is recommended:heparin adjusted to weight, validated by a monitored acti-vated coagulation time of at least 250 s, or a fixed number ofunits per time and/or body weight, in accordance with thelocal routine.Hyperemic stimuli. FFR, by definition, represents an in-dex of maximum blood flow. Therefore, it is essential toinduce maximal vasodilation of the 2 compartments of thecoronary circulation (epicardial or “conductance” arteriesand the microvasculature or “resistance” arteries). Thepharmacologic options for inducing hyperemia are summa-rized in Table 1 (10,11).

A 200-�g bolus of isosorbide dinitrate (or any other formof intracoronary nitrate) allows the abolition of any form ofepicardial vasoconstriction and should be administered asusual before any manipulation in the coronary artery.

Microvascular vasodilation is equally paramount for thecalculation of FFR. Gauging pressure differences at restdoes not offer a definitive measure: It cannot be emphasizedstrongly enough that there is no such thing as a baselineFFR. As a matter of fact, if the Pd/Pa ratio at baseline is inthe ischemic zone, it may only further decrease at hyperemiaand the decision to revascularize can already be made. Evenwhen the resting pressure gradient is large, inducing hyper-emia is recommended because it allows the evaluation of theresidual resistance reserve and ability to quantify the im-provement after treatment. An example of a typical coronarypressure tracing during the administration of intravenousadenosine is shown in Figure 2.

Special Features of FFR

FFR has a number of unique characteristics that make thisindex particularly suitable for functional assessment ofcoronary stenoses and clinical decision making in thecatheterization laboratory.

FFR HAS A THEORETICAL NORMAL VALUE OF 1 FOR EVERY

PATIENT, ARTERY, AND MYOCARDIAL BED. An unequivo-cally normal value is easy to refer to but is generally rare inclinical medicine. So, this is a unique advantage of FFR.Because in a normal epicardial coronary artery there isvirtually no decrease in pressure, not even during maximal

Hyperemic Stimuli forState-of-the-Art FFR MeasurementTable 1

Hyperemic Stimuli for

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, 40–80 �g

in the LCA

Papaverine ic 10–12 mg in the RCA, 15–20 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 � intrave-

nously; LCA � left coronary artery; RCA � right coronary artery.

resting state maximum hyperemia

(i.v. adenosine)

Figure 2 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.

1047JACC Vol. 59, No. 12, 2012 Pijls and Sels

March 20, 2012:1045–57 Functional Measurement of Coronary Stenosis



hyperemia (12), it is obvious that Pd/Pa will equal or be veryclose to unity. This means that normal epicardial arteries donot contribute to the total resistance to coronary blood flow.The lowest value found in individuals with strictly normalcoronary arteries (n � 65) was 0.94 (12,13). Yet it isimportant to realize that in normal-looking coronary arter-ies in patients with proven atherosclerosis elsewhere, theepicardial coronary arteries may contribute to total resis-tance to coronary blood flow even though there is nodiscrete stenosis visible on the angiogram. In �50% of thesearteries, FFR is lower than the lowest value found in normalindividuals. In approximately 10% of atherosclerotic arter-ies, FFR will even be lower than the ischemic threshold(12). Practically speaking, this finding implies that myocar-dial ischemia might be present in atherosclerotic patients inthe absence of discrete stenoses.

FFR HAS A WELL-DEFINED CUTOFF VALUE WITH A NARROW

GRAY ZONE BETWEEN 0.75 AND 0.80. Cutoff or thresholdvalues are values that distinguish ischemic from nonischemiclevels for a given measurement. To enable adequate clinicaldecision making in individual patients, it is essential that anylevel of uncertainty be reduced to a minimum. Stenoses withFFR �0.75 are almost invariably able to induce myocardialischemia, whereas stenoses with FFR �0.80 are almost neverassociated with exercise-induced ischemia. This means that thegray zone for FFR (between 0.75 and 0.80) spans �10% of theentire range of FFR values.

FFR in fact is the only index of ischemia that has beenvalidated compared with a true gold standard in a so-calledprospective multitesting Bayesian approach (14). Duringthe past years, many studies have been performed examiningthe gray zone, and in all these studies, invariably a bestcutoff value between 0.75 and 0.80 was found in manysubsets of patients including left main coronary arterydisease, diabetes, multivessel disease, and previous infarc-tion.

Therefore, the practical lesson is that in a stenosis withFFR �0.75, stenting is always justified (if technicallyfeasible), whereas in a stenosis with FFR �0.80, stentingcan be safely deferred and optimal medical treatment issufficient. Between 0.76 and 0.80, sound clinical judgment(taking into account the character of symptoms, results ofnoninvasive tests if available, and whether a gradient is focalor diffuse) should balance the final decision.

FFR IS NOT INFLUENCED BY SYSTEMIC HEMODYNAMICS. Inthe catheterization laboratory, systemic pressure, heart rate,and left ventricular contractility are prone to change. Incontrast to many other indices measured in the catheteriza-tion laboratory, changes in systemic hemodynamics do notinfluence 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 distalcoronary pressures are measured simultaneously, but also tothe capability of the microvasculature to repeatedly vasodi-late to exactly the same extent. These characteristics con-

tribute to the accuracy of the method and to the trust in itsvalue for clinical decision making.

FFR TAKES INTO ACCOUNT THE CONTRIBUTION OF

COLLATERALS. Whether myocardial flow is provided ante-gradely by the epicardial artery or retrogradely throughcollaterals does not really matter for the myocardium. Distalcoronary pressure during maximal hyperemia reflects bothantegrade and retrograde flows according to their respectivecontribution (6,13). This holds true for the stenoses sup-plied by collaterals but also for stenosed arteries providingcollaterals to another more critically diseased vessel.

FFR SPECIFICALLY RELATES THE SEVERITY OF THE STENOSIS

TO THE MASS OF TISSUE TO BE PERFUSED: NORMALIZATION

FOR PERFUSION AREA. The larger the myocardial masssubtended by a vessel is, the larger the hyperemic flow, andin turn, the larger the gradient and the lower the FFR for agiven stenosis. This explains why a stenosis with a minimalcross-sectional area of 4 mm2 has totally different hemody-namic significance in the proximal left anterior descendingartery (LAD) versus the second marginal branch, as recentlydemonstrated by Iqbal et al. (17). It also means that thehemodynamic significance of a particular stenosis maychange if the perfusion territory changes (as is the case aftermyocardial infarction [MI]).These changes are accountedfor by FFR.

FFR HAS UNEQUALED SPATIAL RESOLUTION. The exact po-sition of the sensor in the coronary tree can be monitoredunder fluoroscopy and documented angiographically. Pull-ing back the sensor under maximal hyperemia provides theoperator an instantaneous assessment of the abnormalresistance of the arterial segment located between the guidecatheter and the sensor. Although other functional testsreach a per-patient accuracy (exercise electrocardiography)or, at best, a per-vessel accuracy (myocardial perfusionimaging or stress echocardiography/magnetic resonance im-aging), FFR reaches a per-segment accuracy with a spatialresolution of a few millimeters.

FFR in Different Patient Subsets

FFR in angiographically intermediate stenoses. One ofthe standard indications for FFR is the precise assessment ofthe functional consequences of a given coronary stenosis withunclear hemodynamic significance (14). In a study of 45patients with angiographically dubious stenoses, it was shownthat FFR has a much greater accuracy in distinguishinghemodynamically significant stenoses than exercise electrocar-diography, myocardial perfusion scintigraphy, and stress echo-cardiography performed separately. This was shown using aso-called sequential Bayesian approach, proving that FFR canindeed be considered as a true gold standard (14).

Furthermore, results of different noninvasive tests areoften contradictory, which renders appropriate clinical de-cision making difficult. In addition, the clinical outcome ofpatients in whom PCI is deferred because FFR indicated no





hemodynamically significant stenosis is very favorable. Insuch population, the risk of cardiac death or MI is approx-imately 1% per year, and this risk is not decreased by PCI(6). These results strongly support the use of FFR measure-ments as a guide for decision making about the need forrevascularization in intermediate lesions. Figure 3 illustrateshow 2 angiographically similar stenoses may have a com-pletely different hemodynamic severity. One of them shouldbe revascularized, and the other should not. Based solely onthe angiogram, the decision should be identical in bothcases, which would lead to an inappropriate interventionaldecision in 1 of these patients.FFR in left main coronary artery stenosis. The presenceof a significant stenosis in the left main stem is of criticalprognostic importance (18). Conversely, revascularization ofa nonsignificant stenosis in the left main may lead to earlyocclusion of the conduits, especially when internal mam-mary arteries are used (19). Furthermore, the left main isamong the most difficult segments to assess by angiography(20). Noninvasive testing is often noncontributive in pa-tients with a left main stenosis. Perfusion defects are often

seen in only 1 vascular territory, especially when the rightcoronary artery is significantly diseased (21). In addition,tracer uptake may be reduced in all vascular territories(balanced ischemia), giving rise to studies with false-negative results (22). Several studies have shown that FFRcould be used safely in left main stenosis and that thedecision not to operate on left main stenosis with FFR�0.80 is safe (23,24). In addition, angiographic assessmentsof left main lesions with FFR �0.80 were no different fromthose with FFR �0.80, further reinforcing the importanceof physiologic parameters in case of doubt. Therefore,patients with an intermediate left main stenosis deservephysiologic assessment before blindly making a decisionabout the need for revascularization. Two examples shownin Figure 4 illustrate how FFR measurements in the leftmain did drastically influence the type of treatment in thesepatients.

Left main disease is rarely isolated. When tight stenosesare present in the LAD or in the LCx the presence of theselesions will tend to increase the FFR measured across theleft main. The influence of a LAD/left circumflex coronary

Figure 3Example 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.





artery (LCx) lesion on the FFR value of the left main willdepend on the severity of this distal stenosis but, even more,on the vascular territory supplied by this distal stenosis. Forexample, if the distal stenosis is in the proximal LAD, itspresence will markedly affect the stenosis in the left main. Ifthe distal stenosis is located in a small second marginalbranch, its influence on the left main stenosis will beminimal. Nevertheless, even in the presence of other steno-ses in addition to left main coronary artery stenosis, thedistal FFR value indicates to what degree maximum perfu-sion of the different left coronary artery territories is de-creased. In a recent prospective study by Hamilos et al. (24),an excellent outcome of FFR-guided revascularization wasfound in 213 consecutive patients with equivocal left maincoronary artery disease, whether or not in conjunction withLAD or LCx stenosis.FFR in multivessel disease. Patients with multivesseldisease actually represent a very heterogeneous population.

Their anatomic features (number of lesions, location, andrespective degree of complexity) may vary tremendously andhave major implications for the revascularization strategy.Moreover, there is often a large discrepancy between theanatomic description and the actual physiologic severity ofeach stenosis. For example, a patient may have 3-vesseldisease based on the angiogram, but actually have only 2hemodynamically significant stenoses. Conversely, a patientcan angiographically be considered as having 1-vessel dis-ease of the right coronary artery but actually have a hemo-dynamically significant stenosis of the left main. Figure 5shows a typical example of a patient in whom the rightcoronary artery and the LCx are critically narrowed and inwhom the mid LAD shows a mild stenosis. Myocardialperfusion imaging showed a reversible perfusion defect inthe inferolateral segments and a normal flow distribution inthe segments supplied by the LAD. In contrast, FFR showsthat all 3 vessels are significantly narrowed but to a different

Figure 4Example 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.





extent. By nuclear scintigraphy, the significant defect inthe anterior wall is masked by the more severe defects inthe other areas. This has a major implication with regardto revascularization. FFR-guided revascularization strat-egies in patients with multivessel disease were veryencouraging (25–27). Tailoring the revascularization ac-cording to the functional significance of the stenosesrather than to their mere angiographic appearance de-creased costs and avoided the need for surgical revascu-larization (25). Recently, incontrovertible proof of thebenefit of FFR-guided multivessel PCI compared withstandard angiography was provided in the large random-ized, multicenter FAME (Fractional Flow Reserve VersusAngiography for Multivessel Evaluation) study (5,28). In that

study, it was demonstrated that all types of adverse eventswere decreased by 30% in the first year after PCI inmultivessel disease, when guided by FFR. This was achievedat a lower cost and without prolonging the interventionalprocedure, whereas angina in FFR-guided patients wasrelieved at least as effectively (5,29), as is outlined in furtherdetail in the following. After 2 years, the advantage of FFRguidance of PCI in multivessel disease even increased withrespect to lower mortality and MI rates, whereas somecatching up occurred with respect to repeat revasculariza-tion. Importantly, in this study, the progression of deferredlesions was excellent. Only 1 late MI occurred on apreviously deferred lesion (0.2%) and 16 late PCIs wereperformed (3.2%) (5).

A B

RCA LCx LAD

C D E

Figure 5 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 nonsignifi-

cant 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.





FFR after MI. After a MI, previously viable tissue ispartially replaced by scar tissue. Therefore, the total mass ofviable myocardium supplied by a given stenosis in aninfarct-related artery will tend to decrease (30). By defini-tion, hyperemic flow and thus hyperemic gradient will bothdecrease as well. Assuming that the morphology of thestenosis remains identical, FFR must therefore increase.This does not mean that FFR underestimates lesion severityafter MI. It simply illustrates the relationship that existsamong flow, pressure gradient, and myocardial mass andconversely illustrates that the mere morphology of a stenoticsegment does not necessarily reflect its functional impor-tance. This principle is illustrated in Figure 6. Recent dataconfirm that the hyperemic myocardial resistance in viablemyocardium within the infarcted area remains normal (31).This further supports the application of the established FFRcutoff value in the setting of partially infarcted territories. Inthe acute phase of MI, FFR is neither reliable nor useful toassess the culprit lesions, and the electrocardiographytrumps any other investigation. From 5 days after theinfarction, FFR can be used as usual to indicate residualischemia of the infarct-related or remote arteries.

Earlier data had suggested that microvascular functionwould be abnormal in regions remote from a recent MI(32,33). However, more recent work taking into account distalcoronary pressure indicates that hyperemic resistance is normalin those remote segments (34). These data support the use ofFFR to evaluate stenoses remote from a recent MI.FFR in diffuse disease. Histopathology studies and, morerecently, intravascular ultrasound and optical coherencetomography have shown that atherosclerosis is diffuse innature. The presence of diffuse disease is often associatedwith a progressive decrease in coronary pressure and flow,and this can often not be clearly assessed from the angio-gram (12,35). In contrast, this decrease in pressure corre-lates with the total atherosclerotic burden (35). In approx-

imately 10% of patients, this abnormal epicardial resistancemay be responsible for reversible myocardial ischemia. Inthese patients, chest pain is often considered noncoronarybecause no single focal stenosis is found, and the myocardialperfusion imaging is wrongly considered false positive(36,37). Such diffuse disease and its hemodynamic impactshould always be kept in mind when performing functionalmeasurements. In a large multicenter registry of 750 pa-tients, FFR was obtained after technically successful stent-ing. A post-PCI FFR value of �0.9 was still present inalmost one third of patients (despite the absence of agradient across the stent), reflecting diffuse disease, and wasassociated with a poor clinical outcome (38). The only wayto demonstrate the hemodynamic impact of diffuse diseaseis to perform a careful pull-back maneuver of the pressuresensor under steady-state maximal hyperemia (Fig. 7).FFR in sequential stenoses. When several stenoses arepresent in the same artery, the concept and the clinical value ofFFR are still valid to assess the effect of all stenoses together.However, it is important to realize in such cases that each ofseveral stenoses will influence hyperemic blood flow andtherefore FFR across the other one. The influence of the distallesion on the proximal is more important than the reverse.Theoretically, the FFR can be calculated for each stenosisindividually (39). However, this is neither practical nor easy toperform and therefore of little use in the catheterizationlaboratory. Practically, as for diffuse disease, a pull-back ma-neuver under maximal hyperemia is the best way to appreciatethe exact location and physiologic significance of sequentialstenoses and to guide the interventional procedure step-by-step(Fig. 7). After the most severe stenosis (i.e., the stenosis withthe largest gradient) has been stented, the pull-back recordingcan be repeated, and it can be decided whether and where asecond stent should be placed.FFR in bifurcation lesions. Overlapping of vessel seg-ments and radiographic artifacts render bifurcation stenosesparticularly difficult to evaluate on angiography, whereasPCI of bifurcations is often more challenging than forregular stenoses. The principle of FFR-guided PCI appliesin bifurcation lesions even though clinical outcome data arecurrently limited. Two recent studies by Koo et al. (40,41)used FFR in the setting of bifurcation stenting. The resultsof these studies can be summarized as follows: 1) afterstenting the main branch, the ostium of the side branchoften looks pinched. Yet such stenoses are grossly overesti-mated by angiography: few of these ostial lesions with astenosis diameter �75% were found to have FFR �0.75;and 2) when kissing balloon dilation was performed only inostial stenoses with FFR �0.75, the FFR at 6 months was�0.75 in 95% of cases. These studies favor an approach inbifurcation lesions of stenting the main branch and kissingballoon dilation thereafter only if FFR of the side branch is�0.75. If FFR of the side branch is �0.75, the outcome isexcellent without further intervention.

Normal MyocardiumNormal MyocardiumFFR=0.50FFR=0.50

DS=75%DS=75%

MyocardialMyocardial

Pa=100 Pd=50

Normal MyocardiumNormal Myocardium

ScarFFR=0.84FFR=0.84

DS=75%DS=75%

Myocardial Myocardial

InfarctionInfarction

Pa=100 Pd=84

Figure 6Schematic 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.





Optimizing Treatment in Multivessel Coronary Disease

and Consequences of the FAME Study

In the past years, 3 large studies were conducted to examinethe best possible treatment of patients with multivesselcoronary artery disease. In these studies, the respective valueof optimal medical treatment only, PCI in addition tomedical treatment, and coronary bypass surgery were inves-tigated (5,28,42,43).

These studies were the COURAGE (Clinical OutcomesUtilizing Revascularization and Aggressive Drug Evalua-tion) study, SYNTAX (TAXUS Drug-Eluting Stent Ver-sus Coronary Artery Bypass Surgery for the Treatment ofNarrowed Arteries) study, and FAME study (5,28,42,43).In the COURAGE study, optimal medical treatment onlyand PCI in addition to medical treatment were investigatedin patients with multivessel disease and moderately severecoronary disease. In most patients, bare metal stents wereused. In the SYNTAX–3-Vessel Disease (3VD) study, onlypatients with 3-vessel disease were included, and onlydrug-eluting stents were used. The degree of disease wasmore severe than that in the COURAGE trial, and in thesepatients, standard angiography-guided PCI with drug-eluting stents only was compared with bypass surgery. In theFAME study, also in patients with mainly 3-vessel diseasebut excluding left main stenosis, standard angiography-guided PCI with drug-eluting stents was compared with

FFR-guided multivessel PCI with drug-eluting stents. TheSYNTAX-3VD and FAME studies had broader inclusioncriteria, including unstable patients and non–ST-segmentelevation MI, and decreased left ventricular function, and

1.

2.

Figure 10

Distal LAD Proximal LAD

1.

2.

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

%

MACE in COURAGE, SYNTAX–3VD, and FAME STUDY

19.1 18.4>20

>20

0

10

COURAGE SYNTAX FAME

11.2 13.2

Figure 8 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.





the FAME study also included patients who had undergonea previous PCI.

The most important results of these 3 studies are pre-sented in Figure 8. Although the baseline characteristics ofthe studies were slightly different (with the angiographicallymost complex disease in the SYNTAX study and leastcomplex disease in the COURAGE study), it can be seenthat outcome was comparable in all studies for standardangiography-guided PCI, whereas FFR-guided PCI im-proved outcome significantly. Not only the total number ofmajor adverse cardiac events was significantly reduced byroutine measurement of FFR as well as mortality andoccurrence of MI. From Figure 8, it can be hypothesizedthat multivessel PCI guided by FFR is superior to optimalmedical treatment and yields results comparable to those ofcoronary artery bypass graft surgery in many patients.

Therefore, it may be hypothesized that the indications forperforming PCI will be further extended when guided byFFR measurements and that more patients, previouslytreated by medical treatment alone or by coronary arterybypass graft surgery, can be better candidates for sophisti-cated PCI-guided by FFR measurements. Adding functionaldata to the SYNTAX score to stratify patients with multivessel

disease to either coronary artery bypass graft surgery or PCI, asrecently suggested, is also an interesting development (44).Further prospective, randomized trials are mandatory (andongoing) to investigate these hypotheses.

Finally, one can wonder why outcome after FFR-guidedPCI is so good compared with standard angiography-guided PCI, despite the use of fewer stents.

This can be understood from considering the combinedmortality and MI rate associated with ischemic and non-ischemic stenoses in general and with stents (Fig. 9). Frommany studies it is known that such an event rate is �1% peryear for a functionally nonsignificant stenosis if treatedappropriately by medication (5,6,42,44), between 5% and10% per year for a functionally significant stenosis if onlytreated by medication (4,45), and approximately 3% per yearfor a stented lesion whether it was functionally significant ornot (4,5,45).

This means that stenting a functionally significant steno-sis improves outcome, but stenting a functionally nonsig-nificant stenosis worsens outcome.

Both FFR-guided PCI and angiography-guided PCIeliminate all ischemic lesions very effectively and thereforehave a similar positive effect on relief of angina pectoris.

= no limitation of oxygensupply

= limitation of oxygensupply

coronary

artery

coronary

artery

aorta

Ischemic lesion intrinsic risk 5 % per year

Non-ischemic lesion intrinsic risk 1 % per year

Stented stenosis intrinsic risk 3 % per year

“Stent ‘m all” intrinsic risk 12% 12%

“Stent only the ischemic ones” intrinsic risk 12 8 %

Both strategies eliminate ischemia similar functional class

Stenting Strategies

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 non-

ischemic 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.





If, however, indiscriminate stenting is performed based onthe angiogram, the positive influence on reducing the mortalityand MI rate by stenting of ischemic stenoses is eradicated byinadvertent stenting of the nonischemic stenoses. Such unin-tended damage is prevented by FFR guidance.

Based on the results of studies such as DEFER andFAME, use of FFR in multivessel PCI has been upgradedrecently in the European Society of Cardiology guidelines toa class IA classification (46).

FFR Post-Intervention

The use of FFR to evaluate the results of PCI is less wellinvestigated. An inverse relationship has been shown be-tween post-PCI FFR and the restenosis rate (38). Aftersuccessful stenting, no noticeable hyperemic gradient shouldbe present across a well-deployed stent (47). The opposite isnot always true, and in case of doubt, intravascular ultra-sound or optical coherence tomography is a better way tostudy stent deployment.

Finally, the hyperemic pressure pull-back recording is aninformative tool for analyzing the extent and significance ofresidual disease proximal or distal to the stent.

Limitations and Pitfalls of FFR

There are several pitfalls related to FFR measurement and afew clinical situations in which it is not reliable and shouldnot be applied. The most important of these is acuteST-segment elevation MI. During primary PCI for acuteMI, the combination of the symptoms, electrocardiogram,and angiogram makes it mostly possible to determine theculprit lesion in the majority of cases. In addition, thrombusembolization, myocardial stunning, acute ischemic micro-

vascular dysfunction, and other factors make reaching com-plete microvascular vasodilation unlikely.

Therefore, FFR measurement makes no sense in thesetting of acute ST-segment elevation MI. When a severaldays have passed (usually 5 days are considered sufficient),FFR can be applied as in routine practice. The question ofwhether FFR can be applied during primary PCI to assessthe hemodynamic severity of remote lesions has recentlybeen answered (34).

From the technical point of view, there are several pitfallsto watch when performing FFR measurement. The 2 mostimportant pitfalls are submaximal hyperemia (underestimat-ing the stenosis severity) and issues related to the guidingcatheter. A large guiding catheter may interfere with max-imum blood flow and a guiding catheter with side holes mayinfluence proximal coronary pressure and interfere withintracoronary administration of adenosine. Such situationscan be easily recognized and avoided once the operator hassome experience with FFR. For a more in-depth discussionof pitfalls, we refer the reader to several excellent overviewsin the literature (36,48).

Finally, there are a number of physiologic reasons whyFFR can be high despite an apparently tight stenosis. Thisis further clarified in Table 2.

Conclusions

FFR is an indispensable tool in the state-of-the-art cathe-terization laboratory to support decision making in revas-cularization in almost all elective clinical and angiographicconditions. 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 func-tional complete revascularization (i.e., stenting of ischemicstenoses and medical treatment of nonischemic ones). Bysystematic use of FFR in equivocal stenosis and multivesseldisease, PCI can be made an even more effective and bettertreatment than it is currently.

Reprint requests and correspondence: Dr. Nico H. J. Pijls,Catharina Hospital, PO Box 1350, 5602 ZA Eindhoven, theNetherlands. E-mail: [email protected].

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Reasons for Nonischemic FFRDespite Apparently Tight StenosisTable 2

Reasons for Nonischemic FFR

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

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Interpretation explanations

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● Equalization with introducing needle and measurement without it

Actual false-negative FFR

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● Severe left ventricular hypertrophy

● Exercise-induced spasm

FFR � fractional flow reserve.




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





doi:10.1016/j.jacc.2011.09.077 2012;59;1045-1057 J. Am. Coll. Cardiol.

Nico H.J. Pijls, and Jan-Willem E.M. Sels Functional Measurement of Coronary Stenosis

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Functional Measurement of Coronary StenosisDefinition of FFRPractical Aspects of FFR MeasurementsCathetersWiresAnticoagulationHyperemic stimuli

Special Features of FFRFFR has a theoretical normal value of 1 for every patient, artery, and myocardial bedffr has a well-defined cutoff value with a narrow gray zone between 0.75 and 0.80ffr is not influenced by systemic hemodynamicsffr takes into account the contribution of collateralsffr specifically relates the severity of the stenosis to the mass of tissue to be perfused: norm ...ffr has unequaled spatial resolution

FFR in Different Patient SubsetsFFR in angiographically intermediate stenosesFFR in left main coronary artery stenosisFFR in multivessel diseaseFFR after MIFFR in diffuse diseaseFFR in sequential stenosesFFR in bifurcation lesions

Optimizing Treatment in Multivessel Coronary Disease and Consequences of the FAME StudyFFR Post-InterventionLimitations and Pitfalls of FFRConclusionsReferences

functional measurement of coronary stenosis€¦ · that revascularization of a ffr-positive...

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