Treatment of Coronary Microvascular Dysfunction
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Cardiovascular Research (2020) 116, 856–870 SPOTLIGHT REVIEW doi:10.1093/cvr/cvaa006 Treatment of coronary microvascular dysfunction Downloaded from https://academic.oup.com/cardiovascres/article-abstract/116/4/856/5748315 by Cedars Sinai Medical Center Library user on 10 March 2020 C. Noel Bairey Merz1*, Carl J. Pepine 2, Hiroki Shimokawa3, and Colin Berry 4 1Barbra Streisand Women’s Heart Center, Smidt Heart Institute, Cedars-Sinai, 127 S. San Vicente Blvd, Suite A3600, Los Angeles, CA 90048, USA;2Division of Cardiovascular Medicine, University of Florida, 1329 SW 16th Street, PO Box 100288, Gainesville, FL 32610-0288, USA;3Division of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan; and 4Institute of Cardiovascular & Medical Sciences, University of Glasgow, Glasgow G12 8QQ, UK Received 14 August 2019; revised 18 November 2019; editorial decision 28 December 2019; online publish-ahead-of-print 22 February 2020 Abstract Contemporary data indicate that patients with signs and symptoms of ischaemia and non-obstructive coronary ar- tery disease (INOCA) often have coronary microvascular dysfunction (CMD) with elevated risk for adverse out- comes. Coronary endothelial (constriction with acetylcholine) and/or microvascular (limited coronary flow reserve with adenosine) dysfunction are well-documented, and extensive non-obstructive atherosclerosis is often present. Despite these data, patients with INOCA currently remain under-treated, in part, because existing management guidelines do not address this large, mostly female population due to the absence of evidence-based data. Relatively small sample-sized, short-term pilot studies of symptomatic mostly women, with INOCA, using intense medical therapies targeting endothelial, microvascular, and/or atherosclerosis mechanisms suggest symptom, ischaemia, and coronary vascular functional improvement, however, randomized, controlled outcome trials testing treatment strat- egies have not been completed. We review evidence regarding CMD pharmacotherapy. Potent statins in combina- tion with angiotensin-converting enzyme inhibitor (ACE-I) or receptor blockers if intolerant, at maximally tolerated doses appear to improve angina, stress testing, myocardial perfusion, coronary endothelial function, and microvas- cular function. The Coronary Microvascular Angina trial supports invasive diagnostic testing with stratified therapy as an approach to improve symptoms and quality of life. The WARRIOR trial is testing intense medical therapy of high-intensity statin, maximally tolerated ACE-I plus aspirin on longer-term outcomes to provide evidence for guidelines. Novel treatments and those under development appear promising as the basis for future trial planning. * Corresponding author. Tel: þ1 310 423 9680; fax: þ1 310 423 9681, E-mail: [email protected] Published on behalf of the European Society of Cardiology. All rights reserved. VC The Author(s) 2020. For permissions, please email: [email protected]. Treatment of CMD 857 Graphical Abstract Downloaded from https://academic.oup.com/cardiovascres/article-abstract/116/4/856/5748315 by Cedars Sinai Medical Center Library user on 10 March 2020 .................................................................................................................................................................................................... Keywords INOCA • CMD • Women • Angina • Ischaemia This article is part of the Spotlight Issue on Coronary Microvascular Dysfunction. 1. Introduction . because management guidelines do not address this population due to . 10 . the absence of evidence-based data. Older reports suggested the prognosis of angina with evidence of ischae- . Mechanistically, coronary endothelial (constriction with acetylcholine) . mia and non-obstructive coronary artery disease (INOCA) was be- . and/or microvascular [limited coronary flow reserve (CFR) with adeno- 1–3 . nign. Now, considerable contemporary data support the conclusion . sine] dysfunction (Figure 1) are well-documented and associated with ad- that these patients often have coronary microvascular dysfunction . verse prognosis.11 Furthermore, diffuse non-obstructive atherosclerosis . (CMD) and are at higher risk for adverse outcomes vs. reference sub- . with ‘compensatory’ coronary remodelling is well documented in jects.4–9 Nevertheless, INOCA patients currently remain under-treated, . women.12,13 Persistent angina, ischaemia on stress testing, multiple risk 858 C.N.B. Merz et al. Downloaded from https://academic.oup.com/cardiovascres/article-abstract/116/4/856/5748315 by Cedars Sinai Medical Center Library user on 10 March 2020 Figure 1 CMD reactivity testing and prognosis. Women with no obstructive coronary artery disease and the potential role of coronary reactive testing to identify those at higher risk for adverse events. Permission granted to reproduce figure from AlBadri et al.11 . factors, and more extensive non-obstructive plaque (multi-vessel) pre- . reduce plaque lipid-rich core, inflammation, macrophage, and foam cell 14–17 . dict higher risk for adverse events. formation, promote fibrous cap thickening, and decrease platelet reactiv- . 23 Relatively small sample-sized, short-term pilot studies of INOCA sub- . ity. Drug combinations (e.g. statins plus ACE-I) appear to amplify some . 20 jects, mostly women, using intense medical therapies targeting endothe- . benefits. lial, microvascular, and/or atherosclerosis mechanisms suggest symptom, . Thromboxane A2 (TXA2) inhibitors (low-dose aspirin and P2Y12 18 . ischaemia, and coronary vascular functional improvement, however, . platelet inhibitors) are also likely useful in preventing adverse outcomes randomized, controlled major outcome trials testing treatment strate- . of INOCA patients.12 They minimize platelet-rich microemboli and re- . gies have not been completed. We review the evidence regarding the . lated downstream events. Activation of thromboxane A2 synthase treatment of CMD. (TXAS)/TXA2/thromboxane prostanoid (TP) receptors leads to arterial . constriction, platelet aggregation, and vascular injury. Microvascular dys- . function was characterized in ischaemia/reperfusion injury using geneti- . 24 2. Review of pharmacotherapy . cally modified knock-out (TXAS-/-, TP-/-, and TXAS-/-TP-/-) mice. Activation of TXAS/TXA2/TP receptors led to microvascular constric- . 2.1 Conventional therapy—anti- . tion, platelet aggregation, and vascular injury; aspirin reduced endothelial atherosclerosis treatment . platelet adhesion. Thus, inhibiting TXAS/TXA2/TP signalling confers mi- . Statins, angiotensin-converting enzyme inhibitor (ACE-I) or receptor . crovascular protection against oxidative injury in the microcirculation. blockers (ARB), and low-dose aspirin are secondary prevention anti- . atherothrombosis treatments that beneficially impact many mechanisms . 2.2 Conventional therapy—anti-anginal . summarized above that likely contribute to symptoms and outcomes in . treatment INOCA patients; they counteract oxidative stress, are anti- . Calcium antagonists fail to ameliorate CFR limitations in CMD patients25 19,20 . inflammatory, improve both endothelial and microvascular function, . but can prevent epicardial coronary vasospasm. Few controlled long- 19–22 . and rebalance sympathetic dysregulation (Table 1). These treat- . acting nitrate studies have been reported and beta-blockers are effective . 26 ments improve angina, stress testing, myocardial perfusion, coronary en- . only for some. Notably, a highly selective beta-1 blocker with vasodila- dothelial function, and microvascular function in small-size trials. Statins . tory effects via nitric oxide (NO) production, nebivolol, has effects on Treatment of CMD 859 Table 1 Pharmacotherapy of coronary microvascular dysfunction mechanistic trials Conventional treatments Intermediate outcome impact ............................................................................................................................................................................................................................... Anti-atherosclerosis treatment Downloaded from https://academic.oup.com/cardiovascres/article-abstract/116/4/856/5748315 by Cedars Sinai Medical Center Library user on 10 March 2020 Statins þ ACE-I, angiotensin renin blockers þ Low-dose aspirin þ Anti-angina treatments Calcium antagonists þ Alpha beta-blockers þ Beta-blockers þ Nitrates þ Ranolazine þ/- Exercise þ Enhanced external counter-pulsation þ Imipramine, amitriptyline, nortriptyline þ L-arginine þ Spinal cord stimulation þ Novel treatments RAAS active agents ACE-I quinapril þ Mineralocorticoid inhibition-eplerenone - PDE PDE type 3 inhibition—cilostazol þ PDE type 5 inhibition—sildenafil þ Calcium channel antagonism—benidpine þ Selective If-channel blockade—ivabradine þ/- Rho-kinase inhibition—fasudil þ Endothelin receptor antagonists—darusentan and atrasentan þ Adenosine active agents—dipyridamole, caffeine, aminophylline, paraxanthine, pentoxifylline, theobromine, and theophylline þ/- Myocardial metabolic active agents Dichloroacetate - Carnitine analogues—acetyl-L-carnitine, propionyl-L-carnitine, and L-carnitine - Perhexiline - Trimetazidine þ Metformin þ Amiodarone/dronedarone þ Anti-inflammation