C Noel Bairey Merz, Carl J Pepine, Hiroki Shimokawa, Colin Berry, Treatment of coronary microvascular dysfunction, Cardiovascular Research, Volume 116, Issue 4, 15 March 2020, Pages 856–870, https://doi.org/10.1093/cvr/cvaa006
Contemporary data indicate that patients with signs and symptoms of ischaemia and non-obstructive coronary artery disease (INOCA) often have coronary microvascular dysfunction (CMD) with elevated risk for adverse outcomes. 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 strategies have not been completed. We review evidence regarding CMD pharmacotherapy. Potent statins in combination 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 microvascular 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.
This article is part of the Spotlight Issue on Coronary Microvascular Dysfunction.
Older reports suggested the prognosis of angina with evidence of ischaemia and non-obstructive coronary artery disease (INOCA) was benign. Now, considerable contemporary data support the conclusion that these patients often have coronary microvascular dysfunction (CMD) and are at higher risk for adverse outcomes vs. reference subjects. Nevertheless, INOCA patients currently remain under-treated, because management guidelines do not address this population due to the absence of evidence-based data.
Mechanistically, coronary endothelial (constriction with acetylcholine) and/or microvascular [limited coronary flow reserve (CFR) with adenosine] dysfunction (Figure 1) are well-documented and associated with adverse prognosis. Furthermore, diffuse non-obstructive atherosclerosis with ‘compensatory’ coronary remodelling is well documented in women. Persistent angina, ischaemia on stress testing, multiple risk factors, and more extensive non-obstructive plaque (multi-vessel) predict higher risk for adverse events.
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.
Relatively small sample-sized, short-term pilot studies of INOCA subjects, mostly women, using intense medical therapies targeting endothelial, microvascular, and/or atherosclerosis mechanisms suggest symptom, ischaemia, and coronary vascular functional improvement, however, randomized, controlled major outcome trials testing treatment strategies have not been completed. We review the evidence regarding the treatment of CMD.
Statins, angiotensin-converting enzyme inhibitor (ACE-I) or receptor blockers (ARB), and low-dose aspirin are secondary prevention anti-atherothrombosis treatments that beneficially impact many mechanisms summarized above that likely contribute to symptoms and outcomes in INOCA patients; they counteract oxidative stress, are anti-inflammatory, improve both endothelial and microvascular function, and rebalance sympathetic dysregulation (Table 1). These treatments improve angina, stress testing, myocardial perfusion, coronary endothelial function, and microvascular function in small-size trials. Statins reduce plaque lipid-rich core, inflammation, macrophage, and foam cell formation, promote fibrous cap thickening, and decrease platelet reactivity. Drug combinations (e.g. statins plus ACE-I) appear to amplify some benefits.
Table 1 Pharmacotherapy of coronary microvascular dysfunction mechanistic trials
|Conventional treatments||Intermediate outcome impact|
|ACE-I, angiotensin renin blockers||+|
|Enhanced external counter-pulsation||+|
|Imipramine, amitriptyline, nortriptyline||+|
|Spinal cord stimulation||+|
|RAAS active agents|
|PDE type 3 inhibition—cilostazol||+|
|PDE type 5 inhibition—sildenafil||+|
|Calcium channel antagonism—benidpine||+|
|Selective If-channel blockade—ivabradine||+/−|
|Endothelin receptor antagonists—darusentan and atrasentan||+|
|Adenosine active agents—dipyridamole, caffeine, aminophylline, paraxanthine, pentoxifylline, theobromine, and theophylline||+/−|
|Myocardial metabolic active agents|
|Carnitine analogues—acetyl-L-carnitine, propionyl-L-carnitine, and L-carnitine||−|
|IL-1b inhibition-canakinumab, rilonacept||−|
|Glycaemic active agents—SGLT 1 and 2 inhibitors, GLP-1 agonists||−|
|Androgen analogues—testosterone (T), low-dose T (transdermal patch), and T undecanoate injection||+|
|Oestrogen analogues—norethindrone/ethinyl oestradiol, CEOs and medroxyprogesterone acetate, and CEO||+/−|
|Nervous system active agents—neuropeptide Y and selective serotonin reuptake inhibitors (escitalopram)||+/−|
|Gene and cell-based therapies—autologous CD34 cells||−|
+, benefit; +/−, no benefit; −, mixed benefit and no benefit; ACE-I, angiotensin-converting enzyme inhibitor; CEO, conjugated equine oestrogen; GLP-1, glucagon-like peptide 1; PDE, phosphodiesterase inhibition.
Thromboxane A2 (TXA2) inhibitors (low-dose aspirin and P2Y12 platelet inhibitors) are also likely useful in preventing adverse outcomes of INOCA patients. They minimize platelet-rich microemboli and related downstream events. Activation of thromboxane A2 synthase (TXAS)/TXA2/thromboxane prostanoid (TP) receptors leads to arterial constriction, platelet aggregation, and vascular injury. Microvascular dysfunction was characterized in ischaemia/reperfusion injury using genetically modified knock-out (TXAS−/−, TP−/−, and TXAS−/−TP−/−) mice. Activation of TXAS/TXA2/TP receptors led to microvascular constriction, platelet aggregation, and vascular injury; aspirin reduced endothelial platelet adhesion. Thus, inhibiting TXAS/TXA2/TP signalling confers microvascular protection against oxidative injury in the microcirculation.
Calcium antagonists fail to ameliorate CFR limitations in CMD patients but can prevent epicardial coronary vasospasm. Few controlled long-acting nitrate studies have been reported and beta-blockers are effective only for some. Notably, a highly selective beta-1 blocker with vasodilatory effects via nitric oxide (NO) production, nebivolol, has effects on angina and exercise capacity and is being studied in women with CMD. Intracoronary nebivolol increases CFR either due to reduction in resting flow (controls) or increase in maximal coronary flow [coronary artery disease (CAD) patients] as collateral flow index decreased parallel to reduction in myocardial oxygen consumption. Importantly, nebivolol improved left ventricular (LV) filling pressure and CFR in uncomplicated arterial hypertension suggesting myocardial stimulation of NO release and improvement in coronary microvascular function.
Ranolazine is an antianginal that inhibits the late sodium channel and reduces intracellular calcium in cardiomyocytes, leading to improved ventricular relaxation which should facilitate microvascular function. Results on CMD are conflicting. One pilot study showed improved symptoms in women with INOCA, and patients with low CFR improved CFR with treatment. A similar sized study showed some symptom improvement but no effect on CFR. A large randomized-crossover trial of ranolazine vs. placebo found no difference in symptoms or cardiac magnetic resonance imaging (cMRI)-myocardial perfusion reserve. But stratification by baseline invasive CFR suggested that those with reduced CFR improved with ranolazine.
Other treatments include exercise training, which beneficially modulates adrenergic and NO pathways, but training trials are problematic for patient compliance and expense. Enhanced external counter-pulsation therapy can improve angina. Tricyclics (e.g. imipramine, amitriptyline, and nortriptyline) block multiple receptors, including muscarinic acetylcholine receptors, H1 and H2-histamine receptors, sodium and calcium channel receptors, and inhibit serotonin and norepinephrine reuptake. In a randomized, placebo-controlled trial of patients with INOCA, imipramine improved angina, possibly through visceral analgesic effects but not quality of life (QoL). Specific mechanism(s) for improvement require(s) additional investigation. L-arginine improved angina and vascular function, but increased myocardial infarction in obstructive CAD patients. Hormone therapy improved chest pain symptoms, menopausal symptoms, and quality of life, but did not improve ischaemia or endothelial dysfunction. Spinal cord stimulation normalizes abnormal pain perception, improves angina, and increases exercise tolerance.
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Authors: Bairey Merz, C Noel; Pepine, Carl J
Publication: Cardiovascular Research
Publisher: Oxford University Press
Date published: February 22nd, 2020
Copyright © 2020, Oxford University Press
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