PDF
Abstract
In recent years, there has been important progress in the evolving field of coronary vasomotor disorders regarding diagnostic assessments and therapeutic strategies. It is now commonly accepted that patients with angina and unobstructed coronary arteries (ANOCA) frequently suffer from coronary vasomotor disorders. The latter can be reliably diagnosed using invasive diagnostic procedures. They comprise the detection of epicardial and/or microvascular spasm, impaired coronary vasodilatation, and enhanced microvascular resistance. As these mechanisms may overlap in one given patient, various endotypes of disease can be distinguished. Although evidence from randomized clinical trials in this setting is still sparse, it has been suggested that - in addition to strict risk factor control-targeted pharmacological therapies/treatments based on the identified mechanism of disease can improve symptoms and prognosis. In patients with coronary spasm as the predominant mechanism, first-line treatment consists of high-dose calcium channel blockers and nitrates. In patients with impaired vasodilatation or enhanced microvascular resistance, beta-blockers, angiotensin-converting enzyme inhibitors, and statins represent first-line treatment. In the group of patients with symptoms refractory to first-line medication, second-line drugs such as nicorandil, molsidomine, ranolazine, ivabradine, and others for microvascular dysfunction are available. Moreover, ongoing studies in this area are evaluating the usefulness of newer pharmacological agents such as endothelin-receptor antagonists or soluble guanylate cyclase stimulators. This article summarizes the currently available evidence for pharmacological treatment strategies in patients with ANOCA due to coronary microvascular dysfunction.
Keywords
Angina with unobstructed coronary arteries
/
coronary microvascular dysfunction
/
coronary spasm
/
vasodilatation
Cite this article
Download citation ▾
Johanna McChord, Astrid Hubert, Raffi Bekeredjian, Peter Ong.
Contemporary pharmacological treatment strategies for patients with angina and unobstructed coronary arteries (ANOCA) due to coronary microvascular dysfunction.
Vessel Plus, 2021, 5(1): 49 DOI:10.20517/2574-1209.2021.63
| [1] |
Camici PG.Coronary microvascular dysfunction.N Engl J Med2007;356:830-40
|
| [2] |
Crea F,Bairey Merz CN.Coronary microvascular dysfunction: an update.Eur Heart J2014;35:1101-11 PMCID:PMC4006091
|
| [3] |
Murthy VL,Taqueti VR.Effects of sex on coronary microvascular dysfunction and cardiac outcomes.Circulation2014;129:2518-27 PMCID:PMC4076200
|
| [4] |
Gulati M,McClure C.Adverse cardiovascular outcomes in women with nonobstructive coronary artery disease: a report from the Women's Ischemia Syndrome Evaluation Study and the St James Women Take Heart Project.Arch Intern Med2009;169:843-50 PMCID:PMC2782882
|
| [5] |
Huang FY,Lv WY.The prognosis of patients with nonobstructive coronary artery disease versus normal arteries determined by invasive coronary angiography or computed tomography coronary angiography: a systematic review.Medicine (Baltimore)2016;95:e3117 PMCID:PMC4839942
|
| [6] |
Johnson BD,Buchthal SD.National Institutes of Health-National Heart, Lung, and Blood InstitutePrognosis in women with myocardial ischemia in the absence of obstructive coronary disease: results from the National Institutes of Health-National Heart, Lung, and Blood Institute-Sponsored Women's Ischemia Syndrome Evaluation (WISE).Circulation2004;109:2993-9
|
| [7] |
Lin FY,Dunning AM.Mortality risk in symptomatic patients with nonobstructive coronary artery disease: a prospective 2-center study of 2,583 patients undergoing 64-detector row coronary computed tomographic angiography.J Am Coll Cardiol2011;58:510-9
|
| [8] |
Pepine CJ,Sharaf BL.Coronary microvascular reactivity to adenosine predicts adverse outcome in women evaluated for suspected ischemia results from the National Heart, Lung and Blood Institute WISE (Women's Ischemia Syndrome Evaluation) study.J Am Coll Cardiol2010;55:2825-32 PMCID:PMC2898523
|
| [9] |
Mohandas R,Huo T.Renal function and coronary microvascular dysfunction in women with symptoms/signs of ischemia.PLoS One2015;10:e0125374 PMCID:PMC4423851
|
| [10] |
Kunadian V,Camici PG.An EAPCI expert consensus document on ischaemia with non-obstructive coronary arteries in Collaboration with European Society of Cardiology Working Group on Coronary Pathophysiology & Microcirculation Endorsed by Coronary Vasomotor Disorders International Study Group.Eur Heart J2020;41:3504-20 PMCID:PMC7577516
|
| [11] |
Camici PG,Rimoldi OE.The coronary circulation and blood flow in left ventricular hypertrophy.J Mol Cell Cardiol2012;52:857-64
|
| [12] |
Ong P,Borgulya G,Kaski JC.High prevalence of a pathological response to acetylcholine testing in patients with stable angina pectoris and unobstructed coronary arteries. The ACOVA Study (Abnormal COronary VAsomotion in patients with stable angina and unobstructed coronary arteries).J Am Coll Cardiol2012;59:655-62
|
| [13] |
Reis SE,Conrad Smith AJ.WISE InvestigatorsCoronary microvascular dysfunction is highly prevalent in women with chest pain in the absence of coronary artery disease: results from the NHLBI WISE study.Am Heart J2001;141:735-41
|
| [14] |
Wessel TR,McGorray SP.NHLBI Women's Ischemia Syndrome Evaluation (WISE)Coronary microvascular reactivity is only partially predicted by atherosclerosis risk factors or coronary artery disease in women evaluated for suspected ischemia: results from the NHLBI Women's Ischemia Syndrome Evaluation (WISE).Clin Cardiol2007;30:69-74 PMCID:PMC6653045
|
| [15] |
Patel MR,Dai D.Low diagnostic yield of elective coronary angiography.N Engl J Med2010;362:886-95 PMCID:PMC3920593
|
| [16] |
Sara JD,Matsuzawa Y,Lerman LO.Prevalence of coronary microvascular dysfunction among patients with chest pain and nonobstructive coronary artery disease.JACC Cardiovasc Interv2015;8:1445-53
|
| [17] |
Lee BK,Fearon WF.Invasive evaluation of patients with angina in the absence of obstructive coronary artery disease.Circulation2015;131:1054-60 PMCID:PMC5295466
|
| [18] |
Ford TJ,Good R.Stratified medical therapy using invasive coronary function testing in angina: The CorMicA Trial.J Am Coll Cardiol2018;72:2841-55
|
| [19] |
Ong P,Seitz A,Beltrame JF.Diagnosis of coronary microvascular dysfunction in the clinic.Cardiovasc Res2020;116:841-55
|
| [20] |
Ong P,Beltrame JF.Coronary Vasomotion Disorders International Study Group (COVADIS)International standardization of diagnostic criteria for microvascular angina.Int J Cardiol2018;250:16-20
|
| [21] |
Hoffman JI.Maximal coronary flow and the concept of coronary vascular reserve.Circulation1984;70:153-9
|
| [22] |
Gould K,Hamilton GW.Physiologic basis for assessing critical coronary stenosis.Am J Cardiol1974;33:87-94
|
| [23] |
Goodwill AG,Kiel AM. Regulation of coronary blood flow. In: Terjung R, editor. Comprehensive physiology. Wiley; 2011. p. 321-82.
|
| [24] |
Bruyne B, Bartunek J, Sys SU, Pijls NH, Heyndrickx GR, Wijns W. 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.Circulation1996;94:1842-9
|
| [25] |
Adjedj J,Johnson NP.Intracoronary adenosine: dose-response relationship with hyperemia.JACC Cardiovasc Interv2015;8:1422-30
|
| [26] |
Granger DN,Yildirim A.Microvascular responses to cardiovascular risk factors.Microcirculation2010;17:192-205 PMCID:PMC3071571
|
| [27] |
Chahine RA,Giles TD.Randomized placebo-controlled trial of amlodipine in vasospastic angina.J Am Coll Cardiol1993;21:1365-70
|
| [28] |
Rosenthal SJ,Lamb IH,Schroeder JS.Efficacy of diltiazem for control of symptoms of coronary arterial spasm.Am J Cardiol1980;46:1027-32
|
| [29] |
Lanza GA,Pasceri V.Atenolol versus amlodipine versus isosorbide-5-mononitrate on anginal symptoms in syndrome X.Am J Cardiol1999;84:854-6
|
| [30] |
Masumoto A,Takeshita A.Three-year follow-up of the Japanese patients with microvascular angina attributable to coronary microvascular spasm.Int J Cardiol2001;81:151-6
|
| [31] |
Sorop O,Pistea A,VanBavel E.Calcium channel blockade prevents pressure-dependent inward remodeling in isolated subendocardial resistance vessels.Am J Physiol Heart Circ Physiol2006;291:H1236-45
|
| [32] |
Yao K,Miki H.Pharmacological, pharmacokinetic, and clinical properties of benidipine hydrochloride, a novel, long-acting calcium channel blocker.J Pharmacol Sci2006;100:243-61
|
| [33] |
Abe M,Maruyama N.Benidipine reduces albuminuria and plasma aldosterone in mild-to-moderate stage chronic kidney disease with albuminuria.Hypertens Res2011;34:268-73
|
| [34] |
Tani S,Nagao K.Effects of the T/L-type calcium channel blocker benidipine on albuminuria and plasma aldosterone concentration. A pilot study involving switching from L-type calcium channel blockers to benidipine.Int Heart J2014;55:519-25
|
| [35] |
Unger T,Sica DA.Therapeutic perspectives in hypertension: novel means for renin-angiotensin-aldosterone system modulation and emerging device-based approaches.Eur Heart J2011;32:2739-47 PMCID:PMC3214724
|
| [36] |
Kosaka H,Yoda N.The L-, N-, and T-type triple calcium channel blocker benidipine acts as an antagonist of mineralocorticoid receptor, a member of nuclear receptor family.Eur J Pharmacol2010;635:49-55
|
| [37] |
Fuji Y,Katsumata H,Saruta T.Hormonal and renal responses to oral once-daily calcium entry blocker in normotensive and hypertensive persons.J Cardiovasc Pharmacol1988;11:438-43
|
| [38] |
Nishigaki K,Yamanouchi Y.Prognostic effects of calcium channel blockers in patients with vasospastic angina--a meta-analysis.Circ J2010;74:1943-50
|
| [39] |
Kim SE,Han SH.Comparison of calcium-channel blockers for long-term clinical outcomes in patients with vasospastic angina.Korean J Intern Med2021;36:124-34 PMCID:PMC7820640
|
| [40] |
Miwa Y,Shimizu M.Differential effects of calcium-channel blockers on vascular endothelial function in patients with coronary spastic angina.Circ J2009;73:713-7
|
| [41] |
Day L.Clinical features and follow-up of patients with angina and normal coronary arteries.Lancet1976;308:334-7
|
| [42] |
Isner JM,Del Negro AA.Right ventricular infarction with hemodynamic decompensation due to transient loss of active atrial augmentation: successful treatment with atrial pacing.Am Heart J1981;102:792-4
|
| [43] |
Matsumoto T,Omura T.Heterogeneity in the vasorelaxing effect of nicorandil on dog epicardial coronary arteries: comparison with other NO donors.J Cardiovasc Pharmacol1997;29:772-9
|
| [44] |
Kim CH,Cho SW.Impact of different nitrate therapies on long-term clinical outcomes of patients with vasospastic angina: a propensity score-matched analysis.Int J Cardiol2018;252:1-5
|
| [45] |
Kukovetz WR,Braida C.Dual mechanism of the relaxing effect of nicorandil by stimulation of cyclic GMP formation and by hyperpolarization.J Cardiovasc Pharmacol1991;17:627-33
|
| [46] |
Kukovetz WR,Pöch G.Molecular mechanism of action of nicorandil.J Cardiovasc Pharmacol1992;20:S1-7
|
| [47] |
Tarkin JM.Vasodilator therapy: nitrates and nicorandil.Cardiovasc Drugs Ther2016;30:367-78 PMCID:PMC5658472
|
| [48] |
Brodmann M,Lueger A,Pilger E.The effect of the K+ agonist nicorandil on peripheral vascular resistance.Int J Cardiol2006;111:49-52
|
| [49] |
Kool MJ,Struyker Boudier HA.Acute and subacute effects of nicorandil and isosorbide dinitrate on vessel wall properties of large arteries and hemodynamics in healthy volunteers.Cardiovasc Drugs Ther1995;9:331-7
|
| [50] |
Ishibashi Y,Tokumaru A.Effects of long-term nicorandil administration on endothelial function, inflammation, and oxidative stress in patients without coronary artery disease.J Cardiovasc Pharmacol2008;51:311-6
|
| [51] |
Lindemann H,Hill S.Biopsy-confirmed endothelial cell activation in patients with coronary microvascular dysfunction.Coron Artery Dis2018;29:216-22
|
| [52] |
Frishman WH.β-Adrenergic blockade in cardiovascular disease.J Cardiovasc Pharmacol Ther2013;18:310-9
|
| [53] |
Duncker DJ,Merkus D.Regulation of coronary blood flow in health and ischemic heart disease.Prog Cardiovasc Dis2015;57:409-22 PMCID:PMC5856234
|
| [54] |
Kalinowski L,Szczepanska-Konkel M.Third-generation beta-blockers stimulate nitric oxide release from endothelial cells through ATP efflux: a novel mechanism for antihypertensive action.Circulation2003;107:2747-52
|
| [55] |
Mason RP,Corbalan JJ,Matysiak K.The favorable kinetics and balance of nebivolol-stimulated nitric oxide and peroxynitrite release in human endothelial cells.BMC Pharmacol Toxicol2013;14:48 PMCID:PMC3856588
|
| [56] |
Shahin Y,Samuel N.Angiotensin converting enzyme inhibitors effect on endothelial dysfunction: a meta-analysis of randomised controlled trials.Atherosclerosis2011;216:7-16
|
| [57] |
Büchner N,Krämer BK.Telmisartan, ramipril, or both in patients at high risk of vascular events.N Engl J Med2008;359:426
|
| [58] |
Dagenais GR,Bourassa MG.HOPE InvestigatorsEffects of ramipril on coronary events in high-risk persons: results of the Heart Outcomes Prevention Evaluation Study.Circulation2001;104:522-6
|
| [59] |
Pauly DF,Anderson RD.In women with symptoms of cardiac ischemia, nonobstructive coronary arteries, and microvascular dysfunction, angiotensin-converting enzyme inhibition is associated with improved microvascular function: A double-blind randomized study from the National Heart, Lung and Blood Institute Women's Ischemia Syndrome Evaluation (WISE).Am Heart J2011;162:678-84 PMCID:PMC3191889
|
| [60] |
Suhrs HE,Prescott E.Treatment strategies in coronary microvascular dysfunction: a systematic review of interventional studies.Microcirculation2019;26:e12430
|
| [61] |
Lefer A.Vascular effects of HMG CoA-reductase inhibitors (statins) unrelated to cholesterol lowering: new concepts for cardiovascular disease.Cardiovasc Res2001;49:281-7
|
| [62] |
Rosenson RS.Statin therapy: new therapy for cardiac microvascular dysfunction.Eur Heart J2003;24:1993-4
|
| [63] |
Zhang X,Zhao J.Effects of combination of statin and calcium channel blocker in patients with cardiac syndrome X.Coron Artery Dis2014;25:40-4
|
| [64] |
Yokoyama I,Moritan T,Nagai R.Impaired myocardial vasodilatation during hyperaemic stress is improved by simvastatin but not by pravastatin in patients with hypercholesterolaemia.Eur Heart J2004;25:671-9
|
| [65] |
Jia Q,Yuan G.The effect of nicorandil in patients with cardiac syndrome X: a meta-analysis of randomized controlled trials.Medicine (Baltimore)2020;99:e22167 PMCID:PMC7489721
|
| [66] |
Bassenge E.Effect of molsidomine on cardiac preload, coronary artery diameter, and coronary resistance.Am Heart J1985;109:627-30
|
| [67] |
Tagliamonte E,Cirillo T.Effects of ranolazine on noninvasive coronary flow reserve in patients with myocardial ischemia but without obstructive coronary artery disease.Echocardiography2015;32:516-21
|
| [68] |
D'Elia E,Ferrero P.Ranolazine in heart failure with preserved left ventricular ejection fraction and microvascular dysfunction: case report and literature review.J Clin Pharmacol2013;53:665-9
|
| [69] |
Cattaneo M,Gallino A.Ranolazine: Drug overview and possible role in primary microvascular angina management.Int J Cardiol2015;181:376-81
|
| [70] |
Sharp RP,Sirajuddin R.Use of ranolazine for the treatment of coronary microvascular dysfunction.Am J Cardiovasc Drugs2021;
|
| [71] |
DiFrancesco D.Characterization of single pacemaker channels in cardiac sino-atrial node cells.Nature1986;324:470-3
|
| [72] |
DiFrancesco D.The contribution of the 'pacemaker' current (if) to generation of spontaneous activity in rabbit sino-atrial node myocytes.J Physiol1991;434:23-40 PMCID:PMC1181405
|
| [73] |
Borer JS,Jaillon P.Ivabradine Investigators GroupAntianginal and antiischemic effects of ivabradine, an I(f) inhibitor, in stable angina: a randomized, double-blind, multicentered, placebo-controlled trial.Circulation2003;107:817-23
|
| [74] |
Villano A,Nerla R.Effects of ivabradine and ranolazine in patients with microvascular angina pectoris.Am J Cardiol2013;112:8-13
|
| [75] |
Skalidis EI,Chlouverakis G,Vardas PE.Ivabradine improves coronary flow reserve in patients with stable coronary artery disease.Atherosclerosis2011;215:160-5
|
| [76] |
Camici PG,Levy BI.Ivabradine in chronic stable angina: effects by and beyond heart rate reduction.Int J Cardiol2016;215:1-6
|
| [77] |
Maseri A,Kaski JC.Mechanisms of angina pectoris in syndrome X.J Am Coll Cardiol1991;17:499-506
|
| [78] |
Lanza GA.Primary coronary microvascular dysfunction: clinical presentation, pathophysiology, and management.Circulation2010;121:2317-25
|
| [79] |
Emdin M,Lattanzi F.Improved exercise capacity with acute aminophylline administration in patients with syndrome X.J Am Coll Cardiol1989;14:1450-3
|
| [80] |
Ferrari R,Crea F.Expert consensus document: a 'diamond' approach to personalized treatment of angina.Nat Rev Cardiol2018;15:120-32
|
| [81] |
Yasaei R,Saadabadi A.StatPearls: Chronic Pain Syndrome. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021.
|
| [82] |
Sanderson JE,Waterhouse D,Neubauer K.Epidural spinal electrical stimulation for severe angina: a study of its effects on symptoms, exercise tolerance and degree of ischaemia.Eur Heart J1992;13:628-33
|
| [83] |
Lanza GA,Sgueglia GA.Effect of spinal cord stimulation on spontaneous and stress-induced angina and 'ischemia-like' ST-segment depression in patients with cardiac syndrome X.Eur Heart J2005;26:983-9
|
| [84] |
Mannheimer C,Augustinsson LE.Electrical stimulation versus coronary artery bypass surgery in severe angina pectoris: the ESBY study.Circulation1998;97:1157-63
|
| [85] |
Sgueglia GA,Spinelli A.Long-term follow-up of patients with cardiac syndrome X treated by spinal cord stimulation.Heart2007;93:591-7 PMCID:PMC1955539
|
| [86] |
Arora RR,Jain D.Effects of enhanced external counterpulsation on Health-Related Quality of Life continue 12 months after treatment: a substudy of the Multicenter Study of Enhanced External Counterpulsation.J Investig Med2002;50:25-32
|
| [87] |
Arora RR,Jain D.The multicenter study of enhanced external counterpulsation (MUST-EECP): effect of EECP on exercise-induced myocardial ischemia and anginal episodes.J Am Coll Cardiol1999;33:1833-40
|
| [88] |
Maccarthy PA,Prendergast BD,Groves PH.The physiological role of endogenous endothelin in the regulation of human coronary vasomotor tone.J Am Coll Cardiol2001;37:137-43
|
| [89] |
Mather KJ,Veeneman E.Role of endogenous ET-1 in the regulation of myocardial blood flow in lean and obese humans.Obesity (Silver Spring)2010;18:63-70
|
| [90] |
Kaski JC,Salomone O.Concentration of circulating plasma endothelin in patients with angina and normal coronary angiograms.Br Heart J1995;74:620-4 PMCID:PMC484117
|
| [91] |
Cox ID,Bagger JP,Kristensen BØ.Elevated endothelin concentrations are associated with reduced coronary vasomotor responses in patients with chest pain and normal coronary arteriograms.J Am Coll Cardiol1999;34:455-60
|
| [92] |
Johnson NP.Physiology of endothelin in producing myocardial perfusion heterogeneity: a mechanistic study using darusentan and positron emission tomography.J Nucl Cardiol2013;20:835-44 PMCID:PMC3779022
|
| [93] |
Reriani M,Prasad A.Long-term administration of endothelin receptor antagonist improves coronary endothelial function in patients with early atherosclerosis.Circulation2010;122:958-66 PMCID:PMC2946239
|
| [94] |
Ford TJ,Good R.Systemic microvascular dysfunction in microvascular and vasospastic angina.Eur Heart J2018;39:4086-97 PMCID:PMC6284165
|
| [95] |
Greene SJ,Borlaug BA.The cGMP signaling pathway as a therapeutic target in heart failure with preserved ejection fraction.J Am Heart Assoc2013;2:e000536 PMCID:PMC3886746
|
| [96] |
Follmann M,Redlich G.Discovery of the soluble guanylate cyclase stimulator vericiguat (BAY 1021189) for the treatment of chronic heart failure.J Med Chem2017;60:5146-61
|
| [97] |
Martínez Pereyra V,Hubert A.Repurposing riociguat for treatment of refractory angina resulting from coronary spasm.JACC: Case Reports2021;3:392-6
|
| [98] |
AlBadri A,Johnson BD.Impact of abnormal coronary reactivity on long-term clinical outcomes in women.J Am Coll Cardiol2019;73:684-93 PMCID:PMC6383781
|