Generic placeholder image

Current Cardiology Reviews


ISSN (Print): 1573-403X
ISSN (Online): 1875-6557

Fractional Flow Reserve: Physiological Basis, Advantages and Limitations, and Potential Gender Differences

Author(s): George J. Crystal and Lloyd W. Klein

Volume 11, Issue 3, 2015

Page: [209 - 219] Pages: 11

DOI: 10.2174/1573403X10666141020113318

Price: $65


Fractional flow reserve (FFR) is a physiological index of the severity of a stenosis in an epicardial coronary artery, based on the pressure differential across the stenosis. Clinicians are increasingly relying on this method because it is independent of baseline flow, relatively simple, and cost effective. The accurate measurement of FFR is predicated on maximal hyperemia being achieved by pharmacological dilation of the downstream resistance vessels (arterioles). When the stenosis causes FFR to be impaired by > 20%, it is considered to be significant and to justify revascularization. A diminished hyperemic response due to microvascular dysfunction can lead to a false normal FFR value, and a misguided clinical decision. The blunted vasodilation could be the result of defects in the signaling pathways modulated (activated or inhibited) by the drug. This might involve a downregulation or reduced number of vascular receptors, endothelial impairment, or an increased activity of an opposing vasoconstricting mechanism, such as the coronary sympathetic nerves or endothelin. There are data to suggest that microvascular dysfunction is more prevalent in post-menopausal women, perhaps due to reduced estrogen levels. The current review discusses the historical background and physiological basis for FFR, its advantages and limitations, and the phenomenon of microvascular dysfunction and its impact on FFR measurements. The question of whether it is warranted to apply gender-specific guidelines in interpreting FFR measurements is addressed.

Keywords: Angiography, coronary flow reserve, coronary stenosis, coronary vasodilators, fractional flow reserve, gender variation, microvascular dysfunction.

Graphical Abstract
Gould KL, Lipscomb K, Hamilton GW. Physiologic basis for assessing critical coronary stenosis. Instantaneous flow response and regional distribution during coronary hyperemia as measures of coronary flow reserve. Am J Cardiol 1974; 33: 87-94.
Vogel RA, Bates ER, O’Neill WW, et al. Coronary flow reserve measured during cardiac catheterization. Arch Intern Med 1984; 144: 1773-6.
Pijls NH, van Son JA, Kirkeeide RL, et al. 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: 1354-67.
De Bruyne B, Pijls NH, Paulus WJ, et al. Transstenotic coronary pressure gradient measurement in humans: in vitro and in vivo evaluation of a new pressure monitoring angioplasty guide wire. J Am Coll Cardiol 1993; 22: 119-26.
Reis SE, Holubkov R, Lee JS, et al. Coronary flow velocity response to adenosine characterizes coronary microvascular function in women with chest pain and no obstructive coronary disease. Results from the pilot phase of the Women’s Ischemia Syndrome Evaluation (WISE) study. J Am Coll Cardiol 1999; 33: 1469-75.
Merz CN, Kelsey SF, Pepine CJ, et al. The Women’s Ischemia Syndrome Evaluation (WISE) study: protocol design, methodology and feasibility report. J Am Coll Cardiol 1999; 33: 1453-61.
Chilian WM. Coronary microcirculation in health and disease. Summary of an NHLBI workshop. Circulation 1997; 95: 522-8.
Camici PG, Crea F. Coronary microvascular dysfunction. N Engl J Med 2007; 356: 830-40.
Feigl EO. Coronary physiology. Physiol Rev 1983; 63: 1-205.
Kern MJ. Coronary physiology revisited: Practical insights from the cardiac catheterization laboratory. Circulation 2000; 101: 1344-51.
Spaan JA, Piek JJ, Hoffman JI, et al. Physiological basis of clinically used coronary hemodynamic indices. Circulation 2006; 113: 446-55.
Deussen A, Ohanyan V, Jannasch A, et al. Mechanisms of metabolic coronary flow regulation. J Mol Cell Cardiol 2012; 52: 794-801.
Webb RC. Smooth muscle contraction and relaxation. Adv Physiol Educ 2003; 27: 201-6.
Moncada S, Palmer RM, Higgs EA. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev 1991; 43: 109-42.
Heerdt PM, Crystal GJ. Cardiovascular physiology: Cellular and molecular regulation. In: Hemmings HC, Egan TD, Eds. Pharmacology and physiology for anesthesia: Foundations and clinical applications. Philadelphia: Elsevier 2013; pp. 351-65.
Crystal GJ, Zhou X, Alam S, et al. Lack of role for nitric oxide in cholinergic modulation of myocardial contractility in vivo. Am J Physiol 2001; 281: H198-206.
Baumgart D, Haude M, Gorge G, et al. Augmented alpha-adrenergic constriction of atherosclerotic human coronary arteries. Circulation 1999; 99: 2090-7.
Gregorini L, Marco J, Kozakova M, et al. Alpha-adrenergic blockade improves recovery of myocardial perfusion and function after coronary stenting in patients with acute myocardial infarction. Circulation 1999; 99: 482-90.
Gregorini L, Marco J, Farah B, et al. Effects of selective alpha1- and alpha2-adrenergic blockade on coronary flow reserve after coronary stenting. Circulation 2002; 106: 2901-7.
White CW, Wright CB, Doty DB, et al. Does visual interpretation of the coronary arteriogram predict the physiologic importance of a coronary stenosis? N Engl J Med 1984; 310: 819-24.
Zir LM, Miller SW, Dinsmore RE, et al. Interobserver variability in coronary angiography. Circulation 1976; 53: 627-32.
DeRouen TA, Murray JA, Owen W. Variability in the analysis of coronary arteriograms. Circulation 1977; 55: 324-8.
Gould KL, Johnson NP, Bateman TM, et al. Anatomic versus physiologic assessment of coronary artery disease. Role of coronary flow reserve, fractional flow reserve, and positron emission tomography imaging in revascularization decision-making. J Am Coll Cardiol 2013; 62: 1639-53.
Lotfi A, Jeremias A, Fearon WF, et al. Expert consensus statement on the use of fractional flow reserve, intravascular ultrasound, and optical coherence tomography: A consensus statement of the society of cardiovascular angiography and interventions. Catheter Cardiovasc Interv 2014; 83: 509-18.
Olsson RA, Gregg DE. Myocardial reactive hyperemia in the unanesthetized dog. Am J Physiol 1965; 208: 224-30.
Bradley AJ, Alpert JS. Coronary flow reserve. Am Heart J 1991; 122: 1116-28.
Silver PJ, Walus K, DiSalvo J. Adenosine-mediated relaxation and activation of cyclic AMP-dependent protein kinase in coronary arterial smooth muscle. J Pharmacol Exp Ther 1984; 228: 342-7.
Hein TW, Kuo L. cAMP-independent dilation of coronary arterioles to adenosine: role of nitric oxide, G proteins, and K(ATP) channels. Circ Res 1999; 85: 634-42.
Hein TW, Belardinelli L, Kuo L. Adenosine A(2A) receptors mediate coronary microvascular dilation to adenosine: role of nitric oxide and ATP-sensitive potassium channels. J Pharmacol Exp Ther 1999; 291: 655-64.
Nelson MT, Patlak JB, Worley JF, et al. Calcium channels, potassium channels, and voltage dependence of arterial smooth muscle tone. Am J Physiol 1990; 259: C3-C18.
Parent R, Pare R, Lavallee M. Contribution of nitric oxide to dilation of resistance coronary vessels in conscious dogs. Am J Physiol 1992; 262: H10-6.
Davis CA 3rd, Sherman AJ, Yaroshenko Y, et al. Coronary vascular responsiveness to adenosine is impaired additively by blockade of nitric oxide synthesis and a sulfonylurea. J Am Coll Cardiol 1998; 31: 816-22.
Buus NH, Bottcher M, Hermansen F, et al. Influence of nitric oxide synthase and adrenergic inhibition on adenosine-induced myocardial hyperemia. Circulation 2001; 104: 2305-10.
Canty JM Jr, Schwartz JS. Nitric oxide mediates flow-dependent epicardial coronary vasodilation to changes in pulse frequency but not mean flow in conscious dogs. Circulation 1994; 89: 375-84.
Quyyumi AA, Dakak N, Andrews NP, et al. Contribution of nitric oxide to metabolic coronary vasodilation in the human heart. Circulation 1995; 92: 320-6.
Gurevicius J, Salem MR, Metwally AA, et al. Contribution of nitric oxide to coronary vasodilation during hypercapnic acidosis. Am J Physiol 1995; 268: H39-47.
Sato A, Terata K, Miura H, et al. Mechanism of vasodilation to adenosine in coronary arterioles from patients with heart disease. Am J Physiol 2005; 288: H1633-40.
Christensen CW, Rosen LB, Gal RA, et al. Coronary vasodilator reserve. Comparison of the effects of papaverine and adenosine on coronary flow, ventricular function, and myocardial metabolism. Circulation 1991; 83: 294-303.
De Bruyne B, Pijls NH, Barbato E, et al. Intracoronary and intravenous adenosine 5′-triphosphate, adenosine, papaverine, and contrast medium to assess fractional flow reserve in humans. Circulation 2003; 107: 1877-83.
Koglin J, von Scheidt W. Isolated defect of adenosine-mediated coronary vasodilation: functional evidence for a new microangiopathic entity. J Am Coll Cardiol 1997; 30: 103-7.
Endoh M, Schumann HJ. Effects of papaverine on isolated rabbit papillary muscle. Eur J Pharmacol 1975; 30: 213-20.
Crystal GJ, Gurevicius J. Nitric oxide does not modulate myocardial contractility acutely in in situ canine hearts. Am J Physiol 1996; 270: H1568-76.
McGinn AL, White CW, Wilson RF. Interstudy variability of coronary flow reserve. Influence of heart rate, arterial pressure, and ventricular preload. Circulation 1990; 81: 1319-30.
Hoffman JI. A critical view of coronary reserve. Circulation 1987; 75: I6-1.
Rossen JD, Winniford MD. Effect of increases in heart rate and arterial pressure on coronary flow reserve in humans. J Am Coll Cardiol 1993; 21: 343-8.
Gould KL, Kirkeeide RL, Buchi M. Coronary flow reserve as a physiologic measure of stenosis severity. J Am Coll Cardiol 1990; 15: 459-74.
Heusch G. Adenosine and maximum coronary vasodilation in humans: myth and misconceptions in the assessment of coronary reserve. Basic Res Cardiol 2010; 105: 1-5.
van de Hoef TP, Meuwissen M, Escaned J, et al. Fractional flow reserve as a surrogate for inducible myocardial ischaemia. Nat Rev Cardiol 2013; 10: 439-52.
Pijls NH, De Bruyne B, Peels K, et al. Measurement of fractional flow reserve to assess the functional severity of coronary-artery stenoses. N Engl J Med 1996; 334: 1703-8.
De Bruyne B, Bartunek J, Sys SU, et al. Simultaneous coronary pressure and flow velocity measurements in humans. Feasibility, reproducibility, and hemodynamic dependence of coronary flow velocity reserve, hyperemic flow versus pressure slope index, and fractional flow reserve. Circulation 1996; 94: 1842-9.
De Bruyne B, Bartunek J, Sys SU, et al. Relation between myocardial fractional flow reserve calculated from coronary pressure measurements and exercise-induced myocardial ischemia. Circulation 1995; 92: 39-46.
Melikian N, De Bondt P, Tonino P, et al. Fractional flow reserve and myocardial perfusion imaging in patients with angiographic multivessel coronary artery disease. JACC Cardiovasc Interv 2010; 3: 307-14.
Petraco R, Sen S, Nijjer S, et al. Fractional flow reserve-guided revascularization: practical implications of a diagnostic gray zone and measurement variability on clinical decisions. JACC Cardiovasc Interv 2013; 6: 222-5.
van de Hoef TP, Nolte F, Rolandi MC, et al. Coronary pressure-flow relations as basis for the understanding of coronary physiology. J Mol Cell Cardiol 2012; 52: 786-93.
Shiono Y, Kubo T, Tanaka A, et al. Impact of myocardial supply area on the transstenotic hemodynamics as determined by fractional flow reserve. Catheter Cardiovasc Interv 2014; 84: 406-13.
Meuwissen M, Chamuleau SA, Siebes M, 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: 184-7.
Chamuleau SA, Siebes M, Meuwissen M, et al. Association between coronary lesion severity and distal microvascular resistance in patients with coronary artery disease. Am J Physiol 2003; 285: H2194-200.
Cannon RO 3rd, Camici PG, Epstein SE. Pathophysiological dilemma of syndrome X. Circulation 1992; 85: 883-92.
Greenberg MA, Grose RM, Neuburger N, et al. Impaired coronary vasodilator responsiveness as a cause of lactate production during pacing-induced ischemia in patients with angina pectoris and normal coronary arteries. J Am Coll Cardiol 1987; 9: 743-51.
Crake T, Canepa-Anson R, Shapiro L, et al. Continuous recording of coronary sinus oxygen saturation during atrial pacing in patients with coronary artery disease or with syndrome X. Br Heart J 1988; 59: 31-8.
Cannon RO 3rd, Epstein SE. “Microvascular angina” as a cause of chest pain with angiographically normal coronary arteries. Am J Cardiol 1988; 61: 1338-43.
Buffon A, Rigattieri S, Santini SA, et al. Myocardial ischemia-reperfusion damage after pacing-induced tachycardia in patients with cardiac syndrome X. Am J Physiol 2000; 279: H2627-33.
Buchthal SD, den Hollander JA, Merz CN, et al. Abnormal myocardial phosphorus-31 nuclear magnetic resonance spectroscopy in women with chest pain but normal coronary angiograms. N Engl J Med 2000; 342: 829-35.
Motz W, Vogt M, Rabenau O, et al. Evidence of endothelial dysfunction in coronary resistance vessels in patients with angina pectoris and normal coronary angiograms. Am J Cardiol 1991; 68: 996-1003.
Chauhan A, Mullins PA, Taylor G, et al. Both endothelium-dependent and endothelium-independent function is impaired in patients with angina pectoris and normal coronary angiograms. Eur Heart J 1997; 18: 60-8.
Egashira K, Inou T, Hirooka Y, et al. Evidence of impaired endothelium-dependent coronary vasodilatation in patients with angina pectoris and normal coronary angiograms. N Engl J Med 1993; 328: 1659-64.
Quyyumi AA, Cannon RO 3rd, Panza JA, et al. Endothelial dysfunction in patients with chest pain and normal coronary arteries. Circulation 1992; 86: 1864-71.
Opherk D, Zebe H, Weihe E, et al. Reduced coronary dilatory capacity and ultrastructural changes of the myocardium in patients with angina pectoris but normal coronary arteriograms. Circulation 1981; 63: 817-25.
Bottcher M, Botker HE, Sonne H, et al. Endothelium-dependent and -independent perfusion reserve and the effect of L-arginine on myocardial perfusion in patients with syndrome X. Circulation 1999; 99: 1795-801.
Adamopoulos S, Rosano GM, Ponikowski P, et al. Impaired baroreflex sensitivity and sympathovagal balance in syndrome X. Am J Cardiol 1998; 82: 862-8.
Gulli G, Cemin R, Pancera P, et al. Evidence of parasympathetic impairment in some patients with cardiac syndrome X. Cardiovasc Res 2001; 52: 208-16.
Lanza GA, Giordano A, Pristipino C, et al. Abnormal cardiac adrenergic nerve function in patients with syndrome X detected by [123I] metaiodobenzylguanidine myocardial scintigraphy. Circulation 1997; 96: 821-6.
Chauhan A, Mullins PA, Taylor G, et al. Effect of hyperventilation and mental stress on coronary blood flow in syndrome X. Br Heart J 1993; 69: 516-24.
Vlahakes GJ, Baer RW, Uhlig PN, et al. Adrenergic influence in the coronary circulation of conscious dogs during maximal vasodilation with adenosine. Circ Res 1982; 51: 371-84.
Johannsen UJ, Mark AL, Marcus ML. Responsiveness to cardiac sympathetic nerve stimulation during maximal coronary dilation produced by adenosine. Circ Res 1982; 50: 510-7.
Lorenzoni R, Rosen SD, Camici PG. Effect of alpha 1-adrenoceptor blockade on resting and hyperemic myocardial blood flow in normal humans. Am J Physiol 1996; 271: H1302-6.
Barbato E, Bartunek J, Aarnoudse W, et al. Alpha-adrenergic receptor blockade and hyperaemic response in patients with intermediate coronary stenoses. Eur Heart J 2004; 25: 2034-9.
Aarnoudse W, Geven M, Barbato E, et al. Effect of phentolamine on the hyperemic response to adenosine in patients with microvascular disease. Am J Cardiol 2005; 96: 1627-30.
Lanza GA, Luscher TF, Pasceri V, et al. Effects of atrial pacing on arterial and coronary sinus endothelin-1 levels in syndrome X. Am J Cardiol 1999; 84: 1187-91.
Epstein SE, Cannon RO 3rd. Site of increased resistance to coronary flow in patients with angina pectoris and normal epicardial coronary arteries. J Am Coll Cardiol 1986; 8: 459-61.
Rosano GM, Peters NS, Lefroy D, et al. 17-beta-Estradiol therapy lessens angina in postmenopausal women with syndrome X. J Am Coll Cardiol 1996; 28: 1500-5.
Thompson J, Khalil RA. Gender differences in the regulation of vascular tone. Clin Exp Pharmacol Physiol 2003; 30: 1-15.
Darkow DJ, Lu L, White RE. Estrogen relaxation of coronary artery smooth muscle is mediated by nitric oxide and cGMP. Am J Physiol 1997; 272: H2765-73.
Knot HJ, Lounsbury KM, Brayden JE, et al. Gender differences in coronary artery diameter reflect changes in both endothelial Ca2+ and ecNOS activity. Am J Physiol 1999; 276: H961-9.
Wellman GC, Bonev AD, Nelson MT, et al. Gender differences in coronary artery diameter involve estrogen, nitric oxide, and Ca(2+)-dependent K+ channels. Circ Res 1996; 79: 1024-30.
Rahimian R, Wang X, van Breemen C. Gender difference in the basal intracellular Ca2+ concentration in rat valvular endothelial cells. Biochem Biophys Res Commun 1998; 248: 916-9.
Barbacanne MA, Rami J, Michel JB, et al. Estradiol increases rat aorta endothelium-derived relaxing factor (EDRF) activity without changes in endothelial NO synthase gene expression: possible role of decreased endothelium-derived superoxide anion production. Cardiovasc Res 1999; 41: 672-81.
Johnson BD, Zheng W, Korach KS, et al. Increased expression of the cardiac L-type calcium channel in estrogen receptor-deficient mice. J Gen Physiol 1997; 110: 135-40.
Mehta PK, Milic M, Bharadwaj M, et al. Cardiac autonomic function in response to emotional mental stress in women with microvascular coronary dysfunction. American Psychosomatic Society - 72nd Annual Scientific Meeting; San Francisco, CA; 2014.
Bybee KA, Prasad A, Barsness GW, et al. Clinical characteristics and thrombolysis in myocardial infarction frame counts in women with transient left ventricular apical ballooning syndrome. Am J Cardiol 2004; 94: 343-6.
Cecchi E, Parodi G, Giglioli C, et al. Stress-induced hyperviscosity in the pathophysiology of takotsubo cardiomyopathy. Am J Cardiol 2013; 111: 1523-9.
Sadamatsu K, Tashiro H, Maehira N, et al. Coronary microvascular abnormality in the reversible systolic dysfunction observed after noncardiac disease. Jap Circ J 2000; 64: 789-92.
Ueyama T, Kasamatsu K, Hano T, et al. Emotional stress induces transient left ventricular hypocontraction in the rat via activation of cardiac adrenoceptors: a possible animal model of ‘tako-tsubo’ cardiomyopathy. Circ J 2002; 66: 712-3.
Lyon AR, Rees PS, Prasad S, et al. Stress (Takotsubo) cardiomyopathy--a novel pathophysiological hypothesis to explain catecholamine-induced acute myocardial stunning. Nat Clin Pract Cardiovasc Med 2008; 5: 22-9.
Bielecka-Dabrowa A, Mikhailidis DP, Hannam S, et al. Takotsubo cardiomyopathy--the current state of knowledge. Int J Cardiol 2010; 142: 120-5.
Ueyama T, Hano T, Kasamatsu K, et al. Estrogen attenuates the emotional stress-induced cardiac responses in the animal model of Tako-tsubo (Ampulla) cardiomyopathy. J Cardiovasc Pharmacol 2003; 42: S117-9.
Ueyama T, Ishikura F, Matsuda A, et al. Chronic estrogen supplementation following ovariectomy improves the emotional stress-induced cardiovascular responses by indirect action on the nervous system and by direct action on the heart. Circ J 2007; 71: 565-73.
Kim HS, Tonino PA, De Bruyne B, et al. The impact of sex differences on fractional flow reserve-guided percutaneous coronary intervention: a FAME (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation) substudy. JACC Cardiovasc Interv 2012; 5: 1037-42.
Kang SJ, Ahn JM, Han S, et al. Sex differences in the visual-functional mismatch between coronary angiography or intravascular ultrasound versus fractional flow reserve. JACC Cardiovasc Interv 2013; 6: 562-8.
Li J, Rihal CS, Matsuo Y, et al. Sex-related differences in fractional flow reserve-guided treatment. Circ Cardiovasc Interv 2013; 6: 662-70.
Fineschi M, Guerrieri G, Orphal D, et al. The impact of gender on fractional flow reserve measurements. EuroIntervention 2013; 9: 360-6.
Bairey Merz CN, Shaw LJ, Reis SE, et al. Insights from the NHLBI-Sponsored Women’s Ischemia Syndrome Evaluation (WISE) Study: Part II: Gender differences in presentation, diagnosis, and outcome with regard to gender-based pathophysiology of atherosclerosis and macrovascular and microvascular coronary disease. J Am Coll Cardiol 2006; 47: S21-9.
Lin FY, Devereux RB, Roman MJ, et al. Cardiac chamber volumes, function, and mass as determined by 64-multidetector row computed tomography: mean values among healthy adults free of hypertension and obesity. JACC Cardiovasc Imaging 2008; 1: 782-6.
Iqbal MB, Shah N, Khan M, et al. Reduction in myocardial perfusion territory and its effect on the physiological severity of a coronary stenosis. Circ Cardiovasc Interv 2010; 3: 89-90.

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy