Coronary Microvascular Dysfunction Across the Spectrum of Cardiovascular Diseases: JACC State-of-the-Art Review

Abstract

Coronary microvascular dysfunction (CMD) encompasses several pathogenetic mechanisms involving coronary microcirculation and plays a major role in determining myocardial ischemia in patients with angina without obstructive coronary artery disease, as well as in several other conditions, including obstructive coronary artery disease, nonischemic cardiomyopathies, takotsubo syndrome, and heart failure, especially the phenotype associated with preserved ejection fraction. Unfortunately, despite the identified pathophysiological and prognostic role of CMD in several conditions, to date, there is no specific treatment for CMD. Due to the emerging role of CMD as common denominator in different clinical phenotypes, additional research in this area is warranted to provide personalized treatments in this "garden variety" of patients. The purpose of this review is to describe the pathophysiological mechanisms of CMD and its mechanistic and prognostic role across different cardiovascular diseases. We will also discuss diagnostic modalities and the potential therapeutic strategies resulting from recent clinical studies.

Keywords: HFpEF; INOCA; MINOCA; angina; coronary flow reserve; coronary microvascular dysfunction; coronary spasm; heart failure; ischemia; ischemic heart disease; microcirculation; microvascular angina; provocative testing.

Conflict of interest statement

Funding Support and Author Disclosures Dr Montone is supported by a Grant for Young Investigators “Ricerca Finalizzata GR-2019-12370197” from the Italian Ministry of Health. Dr Carbone is supported by a Career Development Award 19CDA34660318 from the American Heart Association and by the Clinical and Translational Science Awards Program UL1TR002649 from National Institutes of Health to Virginia Commonwealth University. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1:. Coronary artery circulation and diagnostic tools for CMD assessment.

The coronary arterial system is composed of large conductive vessels and the microcirculation (prearterioles and arterioles). Different invasive and non-invasive modalities can be used to characterize CMD. Notably, using non-invasive techniques, the diagnosis of CMD should be made only after the exclusion of obstructive CAD. Abbreviations:CFR:coronary flow reserve;; CFRV: coronary flow reserve velocity; CMR = cardiac magnetic resonance; CT: computed tomography; IMR: microcirculatory resistance index;HMR: hyperaemic microvascular resistance; MPR: myocardial perfusion reserve; MPRI: myocardial perfusion reserve index; PET: positron emission tomography;

Figure 2:. Role of CMD in determining ischemia.

Ischemia may be cause by subtended by epicardial and/or microvascular structural and functional mechanisms. Epicardial causes determining ischemia include acute plaque disruption with lumen occlusion and epicardial coronary spasm, myocardial bridge, or progressive obstruction with vessel narrowing. CMD can result from an abnormal vasodilatory ability of the microvasculature, compressive external forces affecting the intramural microvessels or microvascular spasm. Abbreviations:CAD:coronary artery disease;VSMC:vascular smooth muscle cells.

Figure 3:. Assessment of CMD in a patient with microvascular angina.

Patient with effort angina and positive non-invasive stress testing. Coronary angiography documented an angiographically normal right coronary artery (right) and intermediate coronary stenosis on mid-left anterior descending artery (left) without haemodynamic significance (FFR 0.95) (Panel A). Microvascular function measured using a pressure wire coupled with thermodilution advanced into the distal part of the left anterior descending artery, at rest and during adenosine-induced maximal hyperaemia, demonstrated an impaired coronary microvascular function (CFR 1.5 and IMR 40) (Panel B). Intracoronary provocative test with acetylcholine on left anterior descending artery was negative for epicardial and/or microvascular spasm, suggesting a mechanism of CMD due to impaired vasodilation. Abbreviations:CFR:coronary flow reserve;FFR:fractional flow reserve;IMR:index of microcirculatory resistance.

Figure 4:. Evidence of CMD in a patient with Anderson-Fabry Disease Cardiomyopathy.

13N-labelled ammonia cardiac PET images show no significant perfusion defects at rest with a severe global subendocardial ischemia after pharmacological stress (Panel A). Cardiac CT-scan was previously performed to rule out obstructive CAD as the cause of angina. PET show abnormal left ventricular wall motions as well as a significant reduction in left ventricle ejection fraction from rest to peak stress (Panel B). Reproduced from Circulation, Cardiovascular Imaging (78).

Central Illustration:. Role of CMD across different cardiovascular diseases.

CMD plays a major role in determining myocardial ischemia in many cardiovascular conditions, including angina with and without obstructive CAD, myocardial infarction, non-ischemic cardiomyopathies, Takotsubo syndrome and heart failure (especially HFpEF). Many molecular, functional and structural mechanisms may be involved and are related to the underlying disease. Abbreviations:ACS:acute coronary syndrome;CABG:coronary artery bypass graft;CAD:coronary artery disease;HFpEF:HF with preserved ejection fraction;INOCA:ischemia with non-obstructive coronary arteries;MINOCA;myocardial infarction with non-obstructive coronary arteries;PCI:percutaneous coronary intervention.