Coronary microvascular dysfunction pathophysiology in COVID-19

Abstract

Recently, accumulating evidence has highlighted the role of endothelial dysfunction in COVID-19 progression. Coronary microvascular dysfunction (CMD) plays a pivotal role in cardiovascular disease (CVD) and CVD-related risk factors (eg, age, gender, hypertension, diabetes mellitus, and obesity). Equally, these are also risk factors for COVID-19. The purpose of this review was to explore CMD pathophysiology in COVID-19, based on recent evidence. COVID-19 mechanisms were reviewed in terms of imbalanced renin-angiotensin-aldosterone-systems (RAAS), systemic inflammation and immune responses, endothelial dysfunction, and coagulatory disorders. Based on these mechanisms, we addressed CMD pathophysiology within the context of COVID-19, from five perspectives. The first was the disarrangement of local RAAS and Kallikrein-kinin-systems attributable to SARS-Cov-2 entry, and the concomitant decrease in coronary microvascular endothelial angiotensin I converting enzyme 2 (ACE2) levels. The second was related to coronary microvascular obstruction, induced by COVID-19-associated systemic hyper-inflammation and pro-thrombotic state. The third was focused on how pneumonia/acute respiratory distress syndrome (ARDS)-related systemic hypoxia elicited oxidative stress in coronary microvessels and cardiac sympathetic nerve activation. Fourthly, we discussed how autonomic nerve dysfunction mediated by COVID-19-associated mental, physical, or physiological factors could elicit changes in coronary blood flow, resulting in CMD in COVID-19 patients. Finally, we analyzed reciprocity between the coronary microvascular endothelium and perivascular cellular structures due to viremia, SARS-CoV-2 dissemination, and systemic inflammation. These mechanisms may function either consecutively or intermittently, finally culminating in CMD-mediated cardiovascular symptoms in COVID-19 patients. However, the underlying molecular pathogenesis remains to be clarified.

Keywords: COVID-19; SARS-CoV-2; coronary microvascular dysfunction.

FIGURE 1

CMD mechanisms in COVID‐19. 1. Coronary microvascular endothelial ACE2 levels decrease, causing microvessels constriction, eNOS/NOX‐2 imbalance, and vascular permeability, therefore, leading to CMD; 2. Coronary microvessels obstruction caused by atherosclerotic fragments and microthrombi can also induce CMD; 3. Pneumonia/ARDS‐related systemic hypoxia elicits oxidative stress in coronary microvessels, activating cardiac sympathetic nerves, and contributing to CMD; 4. Autonomic nerve dysfunction, mediated by COVID‐19‐associated mental, physical or physiological factors, elicits changes in coronary blood flow, resulting in CMD in COVID‐19 patients; 5. SARS‐CoV‐2 disseminates into perivascular cells of coronary microvessels, causing perivascular structural cell edema, causing, or intensifying CMD. CMV, coronary micro‐vascular; RAAS, renin‐angiotensin‐aldosteron‐system; KKS, Kallikrein‐kinin‐system; eNOS, endothelial nitric oxide synthase; NOX‐2, reduced nicotinamide adenine dinucleotide phosphate oxidase 2; ARDS, acute respiratory syndrome; CMD, coronary microvascular dysfunction