Opinion statement
Fractional flow reserve (FFR)-guided coronary revascularization is associated with an unequivocal clinical benefit compared with angiographic guidance. However, the well-documented clinical merit of FFR-guided revascularization has resulted in several misunderstandings as to its diagnostic characteristics. Moreover, it has led to the use of FFR as a gold-standard reference test for the identification of stenosis-related inducible myocardial ischemia. Frequently overlooked is the fact that FFR was originally validated against noninvasive stress-testing to document its ability to identify ischemia-generating stenoses, as well as its optimal cut-off value to do so, which illustrates the paradox of using FFR as a gold-standard reference for this purpose. The diagnostic characteristics of FFR are more complex than is widely understood, and its conceptual validity is based on multiple assumptions that are not considered in clinical practice. In contrast, the validity of FFR as a clinical tool is based on empirical evidence derived from multiple large-scale randomized controlled trials. It is, therefore, of great importance to understand the fundamental physiological basis of FFR, and to be aware of the underlying assumptions and their implications, for appropriate application and interpretation of FFR on an individual basis. This review aims to elucidate the assumptions that underlie the concept of FFR, to provide insight into their consequences for daily practice, and to highlight the practical methodology that is critical for its interpretation in clinical practice.
Similar content being viewed by others
References and Recommended Reading
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
Sones Jr FM, Shirey EK. Cine coronary arteriography. Mod Concepts Cardiovasc Dis. 1962;31:735–8.
Hale G, Jefferson K. Technique and interpretation of selective coronary arteriography in man. Br Heart J. 1963;25:644–54.
Zir LM, Miller SW, Dinsmore RE, Gilbert JP, Harthorne JW. Interobserver variability in coronary angiography. Circulation. 1976;53(4):627–32.
Galbraith JE, Murphy ML, de Soyza N. Coronary angiogram interpretation. Interobserver variability. JAMA. 1978;240(19):2053–6.
Arnett EN, Isner JM, Redwood DR, Kent KM, Baker WP, Ackerstein H, et al. Coronary artery narrowing in coronary heart disease: Comparison of cineangiographic and necropsy findings. Ann Intern Med. 1979;91(3):350–6.
Topol EJ, Nissen SE. Our preoccupation with coronary luminology. The dissociation between clinical and angiographic findings in ischemic heart disease. Circulation. 1995;92(8):2333–42.
Blankenhorn DH, Curry PJ. The accuracy of arteriography and ultrasound imaging for atherosclerosis measurement. A review. Arch Pathol Lab Med. 1982;106(10):483–9.
Fischer JJ, Samady H, McPherson JA, Sarembock IJ, Powers ER, Gimple LW, et al. Comparison between visual assessment and quantitative angiography versus fractional flow reserve for native coronary narrowings of moderate severity. Am J Cardiol. 2002;90(3):210–5.
Goldstein RA, Kirkeeide RL, Demer LL, Merhige M, Nishikawa A, Smalling RW, et al. Relation between geometric dimensions of coronary artery stenoses and myocardial perfusion reserve in man. J Clin Invest. 1987;79(5):1473–8.
Zijlstra F, Fioretti P, Reiber JH, Serruys PW. Which cineangiographically assessed anatomic variable correlates best with functional measurements of stenosis severity? A comparison of quantitative analysis of the coronary cineangiogram with measured coronary flow reserve and exercise/redistribution thallium-201 scintigraphy. J Am Coll Cardiol. 1988;12(3):686–91.
Di Carli M, Czernin J, Hoh CK, Gerbaudo VH, Brunken RC, Huang SC, et al. Relation among stenosis severity, myocardial blood flow, and flow reserve in patients with coronary artery disease. Circulation. 1995;91(7):1944–51.
Pijls NH, van Son JA, Kirkeeide RL, De Bruyne B, Gould KL. Experimental basis of determining maximum coronary, myocardial, and collateral blood flow by pressure measurements for assessing functional stenosis severity before and after percutaneous transluminal coronary angioplasty. Circulation. 1993;87(4):1354–67.
Wijns W, Kolh P, Danchin N, Di Mario C, Falk V, Folliguet T, et al. Guidelines on myocardial revascularization: The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J. 2010;31(20):2501–55.
Walcher T, Manzke R, Hombach V, Rottbauer W, Wohrle J, Bernhardt P. Myocardial perfusion reserve assessed by T2-prepared steady-state free-precession Blood Oxygen Level-Dependent (BOLD) magnetic resonance imaging in comparison to fractional flow reserve. Circ Cardiovasc Imaging. 2012.
Lockie T, Ishida M, Perera D, Chiribiri A, De Silva K, Kozerke S, et al. High-resolution magnetic resonance myocardial perfusion imaging at 3.0-Tesla to detect hemodynamically significant coronary stenoses as determined by fractional flow reserve. J Am Coll Cardiol. 2011;57(1):70–5.
Sen S, Escaned J, Malik IS, Mikhail GW, Foale RA, Mila R, et al. Development and validation of a new adenosine-independent index of stenosis severity from coronary wave-intensity analysis: Results of the ADVISE (ADenosine Vasodilator Independent Stenosis Evaluation) study. J Am Coll Cardiol. 2012;59(15):1392–402.
Tonino PA, De Bruyne B, Pijls NH, Siebert U, Ikeno F, van’ t Veer M, et al. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N Engl J Med. 2009;360(3):213–24.
De Bruyne B, Pijls NH, Kalesan B, Barbato E, Tonino PA, Piroth Z, et al. Fractional flow reserve-guided PCI versus medical therapy in stable coronary disease. N Engl J Med. 2012;367(11):991–1001.
van de Hoef TP, Meuwissen M, Escaned J, Davies JE, Siebes M, Spaan JA, et al. Fractional flow reserve as a surrogate for inducible myocardial ischaemia. Nat Rev Cardiol. 2013;10(8):439–52. Contemporary review of the physiological basis of fractional flow reserve as a surrogate test for non-invasive stress testing.
Koolen JJ, Pijls NH. Coronary pressure never lies. Catheter Cardiovasc Interv. 2008;72(2):248–56.
Young DF, Cholvin NR, Kirkeeide RL, Roth AC. Hemodynamics of arterial stenoses at elevated flow rates. Circ Res. 1977;41(1):99–107.
Spaan JA, Piek JJ, Hoffman JI, Siebes M. Physiological basis of clinically used coronary hemodynamic indices. Circulation. 2006;113(3):446–55. In-depth analysis of the physiological basis of clinically used coronary hemodynamic indices.
Perera D, Biggart S, Postema P, Patel S, Lambiase P, Marber M, et al. Right atrial pressure: Can it be ignored when calculating fractional flow reserve and collateral flow index? J Am Coll Cardiol. 2004;44(10):2089–91.
Christou MA, Siontis GC, Katritsis DG, Ioannidis JP. Meta-analysis of fractional flow reserve versus quantitative coronary angiography and noninvasive imaging for evaluation of myocardial ischemia. Am J Cardiol. 2007;99(4):450–6.
Meuwissen M, Siebes M, Chamuleau SAJ, Verhoeff B, Henriques JPS, Spaan JAE, et al. Role of fractional and coronary flow reserve in clinical decision making in intermediate coronary lesions. Interv Cardiol. 2009;1(2):237–55.
de Bruyne B, Bartunek J, Sys SU, Heyndrickx GR. Relation between myocardial fractional flow reserve calculated from coronary pressure measurements and exercise-induced myocardial ischemia. Circulation. 1995;92(1):39–46.
Pijls NH, De Bruyne B, Peels K, Van Der Voort PH, Bonnier HJ, Bartunek JKJJ, et al. Measurement of fractional flow reserve to assess the functional severity of coronary-artery stenoses. N Engl J Med. 1996;334(26):1703–8. First clinical study showing clinical benefit of fractional flow reserve-guided revascularization over angiography-guided revascularization.
Bech GJ, De Bruyne B, Pijls NH, de Muinck ED, Hoorntje JC, Escaned J, et al. Fractional flow reserve to determine the appropriateness of angioplasty in moderate coronary stenosis: A randomized trial. Circulation. 2001;103(24):2928–34.
De Bruyne B, Pijls NH, Kalesan B, Barbato E, Tonino PA, Piroth Z, et al. Fractional flow reserve-guided PCI versus medical therapy in stable coronary disease. N Engl J Med. 2012. Pivotal study aiming to document the benefit of revascularization over optimal medical therapy in fractional flow reserve-positive stenoses.
Boden WE. Which is more enduring–FAME or COURAGE? N Engl J Med. 2012;367(11):1059–61.
Boden WE, O’Rourke RA, Teo KK, Hartigan PM, Maron DJ, Kostuk WJ, et al. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med. 2007;356(15):1503–16.
Plein S, Motwani M. Fractional flow reserve as the reference standard for myocardial perfusion studies: Fool’s gold? Eur Heart J Cardiovasc Imaging. 2013.
Heusch G. Adenosine and maximum coronary vasodilation in humans: Myth and misconceptions in the assessment of coronary reserve. Basic Res Cardiol. 2010;105(1):1–5.
van de Hoef TP, Nolte F, Rolandi MC, Piek JJ, van den Wijngaard JP, Spaan JA, et al. Coronary pressure-flow relations as basis for the understanding of coronary physiology. J Mol Cell Cardiol. 2012;52(4):786–93.
Verhoeff BJ, Siebes M, Meuwissen M, Atasever B, Voskuil M, de Winter RJ, et al. Influence of percutaneous coronary intervention on coronary microvascular resistance index. Circulation. 2005;111(1):76–82.
Meuwissen M, Chamuleau SA, Siebes M, Schotborgh CE, Koch KT, de Winter RJ, et al. Role of variability in microvascular resistance on fractional flow reserve and coronary blood flow velocity reserve in intermediate coronary lesions. Circulation. 2001;103(2):184–7.
Chareonthaitawee P, Kaufmann PA, Rimoldi O, Camici PG. Heterogeneity of resting and hyperemic myocardial blood flow in healthy humans. Cardiovasc Res. 2001;50(1):151–61.
Baumgart D, Haude M, Gorge G, Liu F, Ge J, Grosse-Eggebrecht C, et al. Augmented alpha-adrenergic constriction of atherosclerotic human coronary arteries. Circulation. 1999;99(16):2090–7.
Gregorini L, Marco J, Farah B, Bernies M, Palombo C, Kozakova M, et al. Effects of selective alpha1- and alpha2-adrenergic blockade on coronary flow reserve after coronary stenting. Circulation. 2002;106(23):2901–7.
Gregorini L, Marco J, Kozakova M, Palombo C, Anguissola GB, Marco I, et al. Alpha-adrenergic blockade improves recovery of myocardial perfusion and function after coronary stenting in patients with acute myocardial infarction. Circulation. 1999;99(4):482–90.
Rimoldi O, Spyrou N, Foale R, Hackett DR, Gregorini L, Camici PG. Limitation of coronary reserve after successful angioplasty is prevented by oral pretreatment with an alpha1-adrenergic antagonist. J Cardiovasc Pharmacol. 2000;36(3):310–5.
Kolyva C, Verhoeff BJ, Spaan JA, Piek JJ, Siebes M. Increased diastolic time fraction as beneficial adjunct of alpha1-adrenergic receptor blockade after percutaneous coronary intervention. Am J Physiol Heart Circ Physiol. 2008;295(5):H2054–60.
Mangiacapra F, Peace AJ, Di Serafino L, Pyxaras SA, Bartunek J, Wyffels E, et al. Intracoronary enalaprilat to reduce MICROvascular damage during percutaneous coronary intervention (ProMicro) study. J Am Coll Cardiol. 2013;61(6):615–21.
Barbato E, Bartunek J, Aarnoudse W, Vanderheyden M, Staelens F, Wijns W, et al. Alpha-adrenergic receptor blockade and hyperaemic response in patients with intermediate coronary stenoses. Eur Heart J. 2004;25(22):2034–9.
Aarnoudse W, Geven M, Barbato E, Botman KJ, De Bruyne B, Pijls NH. Effect of phentolamine on the hyperemic response to adenosine in patients with microvascular disease. Am J Cardiol. 2005;96(12):1627–30.
De Luca G, Venegoni L, Iorio S, Giuliani L, Marino P. Effects of increasing doses of intracoronary adenosine on the assessment of fractional flow reserve. J Am Coll Cardiol Intv. 2011;4(10):1079–84.
Rioufol G, Caignault JR, Finet G, Staat P, Bonnefoy E, de Gevigney G, et al. 150 microgram intracoronary adenosine bolus for accurate fractional flow reserve assessment of angiographically intermediate coronary stenosis. EuroIntervention. 2005;1(2):204–7.
Cubero JM, Diaz de la Llera LS, Cerrato García P, Villa Gil-Ortega M, Benezet Mazuecos J, Sanchez-Gonzalez A. TCT-702: A comparative study between intravenous and intracoronary administration of high doses adenosine for fractional flow reserve measurements, in the “FAME” era. J Am Coll Cardiol. 2011;58(20_Suppl_S):B187-b-.
Lopez-Palop R, Carrillo P, Frutos A, Cordero A, Agudo P, Mashlab S, et al. Comparison of effectiveness of high-dose intracoronary adenosine versus intravenous administration on the assessment of fractional flow reserve in patients with coronary heart disease. Am J Cardiol. 2013;111(9):1277–83.
van de Hoef TP, Nolte F, Damman P, Delewi R, Bax M, Chamuleau SA, et al. Diagnostic accuracy of combined intracoronary pressure and flow velocity information during baseline conditions: Adenosine-free assessment of functional coronary lesion severity. Circ Cardiovasc Interv. 2012;5(4):508–14.
Li J, Elrashidi MY, Flammer AJ, Lennon RJ, Bell MR, Holmes DR, et al. Long-term outcomes of fractional flow reserve-guided vs. angiography-guided percutaneous coronary intervention in contemporary practice. Eur Heart J. 2013;34(18):1375–83.
Vranckx P, Cutlip DE, McFadden EP, Kern MJ, Mehran R, Muller O. Coronary pressure-derived fractional flow reserve measurements: recommendations for standardization, recording, and reporting as a core laboratory technique. Proposals for integration in clinical trials. Circ Cardiovasc Interv. 2012;5(2):312–7.
Pijls NH, Sels JW. Functional measurement of coronary stenosis. J Am Coll Cardiol. 2012;59(12):1045–57.
Biaggioni I, Olafsson B, Robertson RM, Hollister AS, Robertson D. Cardiovascular and respiratory effects of adenosine in conscious man. Evidence for chemoreceptor activation. Circ Res. 1987;61(6):779–86.
Feigl EO. Coronary physiology. Physiol Rev. 1983;63(1):1–205.
Biaggioni I, Killian TJ, Mosqueda-Garcia R, Robertson RM, Robertson D. Adenosine increases sympathetic nerve traffic in humans. Circulation. 1991;83(5):1668–75.
Siebes M, Chamuleau SA, Meuwissen M, Piek JJ, Spaan JA. Influence of hemodynamic conditions on fractional flow reserve: Parametric analysis of underlying model. Am J Physiol Heart Circ Physiol. 2002;283(4):H1462–70.
Wijns W, Pyxaras SA. Chasing numbersthe reinvention of clinical science. J Am Coll Cardiol Intv. 2013;6(3):226–7.
Petraco R, Sen S, Nijjer S, Echavarria-Pinto M, Escaned J, Francis DP, et al. Fractional flow reserve–Guided revascularization practical implications of a diagnostic gray zone and measurement variability on clinical decisions. J Am Coll Cardiol Intv. 2013;6(3):222–5.
Kern MJ, Lerman A, Bech JW, De Bruyne B, Eeckhout E, Fearon WF, et al. Physiological assessment of coronary artery disease in the cardiac catheterization laboratory: A scientific statement from the American Heart Association Committee on Diagnostic and Interventional Cardiac Catheterization. Council on Clinical Cardiology. Circulation. 2006;114(12):1321–41.
Berry C, Vant Veer M, Witt N, Kala P, Bocek O, Pyxaras SA, et al. VERIFY (VERification of Instantaneous Wave-Free Ratio and Fractional Flow Reserve for the Assessment of Coronary Artery Stenosis Severity in EverydaY Practice): A multicenter study in consecutive patients. J Am Coll Cardiol. 2013;61(13):1421–7.
Kleiman NS. Bringing it all together: Integration of physiology with anatomy during cardiac catheterization. J Am Coll Cardiol. 2011;58(12):1219–21.
Dattilo PB, Prasad A, Honeycutt E, Wang TY, Messenger JC. Contemporary patterns of fractional flow reserve and intravascular ultrasound use among patients undergoing percutaneous coronary intervention in the United States: Insights from the National Cardiovascular Data Registry. J Am Coll Cardiol. 2012;60(22):2337–9.
Meuwissen M, Siebes M, Chamuleau SA, van Eck-Smit BL, Koch KT, de Winter RJ, et al. Hyperemic stenosis resistance index for evaluation of functional coronary lesion severity. Circulation. 2002;106(4):441–6.
Meuwissen M, Siebes M, Spaan JA, Piek JJ. Rationale of combined intracoronary pressure and flow velocity measurements. Z Kardiol. 2002;91 Suppl 3:108–12.
Kern MJ. Basal stenosis resistance: Another adenosine-free contender for the lesion assessment crown? Circ Cardiovasc Interv. 2012;5(4):456–8.
Petraco R, Escaned J, Sen S, Nijjer S, Asrress KN, Echavarria-Pinto M, et al. Classification performance of instantaneous wave-free ratio (iFR) and fractional flow reserve in a clinical population of intermediate coronary stenoses: Results of the ADVISE registry. EuroIntervention. 2012;9(1):91–101.
Compliance with Ethics Guidelines
Conflict of Interest
Dr. Tim P van de Hoef, Dr. Martijn A van Lavieren, Dr. José PS Henriques, and Dr. Bimmer EPM Claessen each declare no potential conflicts of interest relevant to this article.
Dr. Jan J Piek is a board member for Abbott Vascular and consultant for Miracor Medical Systems.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Author information
Authors and Affiliations
Corresponding author
Additional information
This article is part of the Topical Collection on Coronary Artery Disease
Rights and permissions
About this article
Cite this article
van de Hoef, T.P., van Lavieren, M.A., Henriques, J.P.S. et al. Fractional Flow Reserve-Guided Percutaneous Coronary Intervention: Does Coronary Pressure Never Lie? . Curr Treat Options Cardio Med 16, 294 (2014). https://doi.org/10.1007/s11936-014-0294-5
Published:
DOI: https://doi.org/10.1007/s11936-014-0294-5