key: cord-1036346-d4v39ktg
authors: Yin, Jie; Wang, Shaoshen; Liu, Yang; Chen, Junhong; Li, Dongye; Xu, Tongda
title: Coronary microvascular dysfunction pathophysiology in COVID‐19
date: 2021-06-02
journal: Microcirculation
DOI: 10.1111/micc.12718
sha: 91d5b1e5a4eb0532ad0fd67b3eee68e4b4d75d69
doc_id: 1036346
cord_uid: d4v39ktg

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.

At the end of 2019, coronavirus disease 2019 (COVID-19) was defined as a global emergency by the World Health Organization. 1 The disease went worldwide within months and was transmitted and exacerbated by international travel and human-to-human contact. 2 COVID-19 has demonstrated a wide spectrum of clinical manifestations in asymptomatic to critically ill patients, ranging from severe pneumonia, respiratory failure, cardiovascular events, diffuse intravascular coagulation, multi-organ failure, sepsis, septic shock, and death. 3, 4 Moreover, elderly males (>65 years) with underlying CVD, for example, hypertension, myocardial ischemia, heart failure, and arrhythmias, have been confirmed as independent risk factors for disease severity and in-hospital mortality. 5, 6 Prior epidemiological statistics from China reported that gross case fatality percentages for different comorbidities were as follows: 10 .5% for established CVD, 7.3% for diabetes mellitus (DM), 6 .0% for hypertension (HTN), 6.3% for respiratory disease, and 5.6% for cancer. 7 Furthermore, a recent meta-analysis recruited 49 ,076 confirmed COVID-19 cases, indicating that patients with pre-existing CVD risk factors (eg, DM and HTN) and those with established CVD were more vulnerable to SARS-CoV-2, with a higher risk of developing severe disease. 8 Additionally, autopsy findings from Germany showed that the majority (85%) of the deceased patients had established CVD, followed by lung disease (55%), kidney disease (34%), central nervous system (CNS) disease (35%), and DM (21%). 9 Coronary microvascular dysfunction (CMD) is closely related to these co-morbidities.

COVID-19 is caused by a novel β-coronavirus SARS-CoV-2, which is a single-stranded RNA virus of 60-140nm in diameter. The virus shares approximately 79% sequence identity to SARS-CoV, which was responsible for another epidemic in 2003. [10] [11] [12] The ACE2 receptor is well documented to facilitate SARS-CoV-2 entry into the human body. Emerging clinical evidence has shown that COVID-19 is implicated in renin-angiotensin-aldosterone-system (RAAS) dysregulation, hyper-inflammation, and coagulatory dysfunction. [13] [14] [15] However, further evidence has also underscored the importance of microvascular endothelial dysfunction in pathophysiology.

of microvascular dysfunction. SARS-CoV-2 has been proposed to infect blood vessels after lung incursion, thereby inducing vascular endothelial injury, activating hemostasis and coagulation, ultimately leading to thrombotic disorders in COVID-19 patients. 16, 17 The surface area of the microvascular endothelium in the human circulation is greater than that of the macrovascular endothelium, and the microvascular endothelium is the primary barrier for blood-tissue exchange. 18, 19 In addition, any microstructural (eg, microvascular remodeling, capillary density changes) or functional alterations of microvessels (eg, in endothelium, vascular smooth muscle cells) can affect organ perfusion and metabolism, resulting in direct organ injury. 20 Like other microcirculatory-dependent organs, heart hemodynamics and metabolic homeostasis are regulated by coronary microcirculation. 21 Moreover, CMD primarily presents as chest pain syndrome, accounting for myocardial ischemia in some cases, irrespective of the presence/absence of obstructive epicardial coronary vessels. 22 During SARS-CoV-2 infection, manifestations of cardiovascular dysfunction include acute coronary syndrome, myocarditis, pericarditis, heart failure, and arrhythmias, 23 with their incidences remaining obscure. Thus, the accumulating evidence suggests a dysfunctional role for the coronary microvasculature during SARS-CoV-2 infections. [24] [25] [26] [27] In this review, we would discuss COVID-19 mechanisms in terms of imbalanced renin-angiotensinaldosterone systems (RAAS), systemic inflammation and immune responses, endothelial dysfunction, and coagulatory disorders. Based on these mechanisms, we will address the CMD pathogenesis within the context of COVID-19, from five perspectives, according to existing evidence.

RAAS is an important hormonal system that modulates blood pressure and maintains fluid homeostasis. However, localized RAAS over-activation in organs and tissues augments cell growth, facilitating the proliferation and inflammation of organs and tissues. 27, 28 A major component of RAAS is the glycoprotein metalloprotease, angiotensin I converting enzyme 2 (ACE2), which catalyses multiple substrates, including kinins, apelin, neurotension, dynorphin, ghrelin, angiotensins, and des-Arginin9-bradykinin. 29, 30 ACE2 mRNA is deemed to be expressed in all organs, whereas the ACE2 protein is abundantly expressed in the epithelium of the lungs and small intestine, endothelial cells of arteries and veins, arterial smooth muscle cells, cardiomyocytes, and adipocytes. 31, 32 ACE2 downregulation stimulates a variety of ACE2-associated pathways in the lungs, including the Kallikrein-kinin system, which controls vascular permeability and vasodilatation, and assists RAAS with blood pressure regulation. Kallikrein-kinin system is also involved in endothelial dysfunction, via the production of reactive oxygen species (ROS). 33 However, pulmonary RAAS is most frequently disturbed by ACE2 dysfunction. As ACE2 levels decrease, hyperactivity of angiotensin II (Ang II)/angiotensin II type 1 receptor (AT1R) axis occurs, whereas hypoactivity of ACE2/angiotensin 1-7 (Ang(1-7))/Mas receptor axis also causes detrimental effects (eg, vasoconstriction, hypertrophy, fibrosis, proliferation, and increased ROS). [34] [35] [36] Increasing Ang II levels also elevates aldosterone levels. 37 This hormone is important for fluid maintenance as it promotes water and sodium retention and potassium excretion, leading to systemic electrolyte disturbance and arrhythmias. Hyper-aldosteronemia causes hypokalemia in COVID-19 patients. 38 However, Ang II elevation also triggers immune responses, promoting coagulatory and thrombosis states, and induces endothelial cells expressing tissue factors and plasminogen activator inhibitor-1 (PAI-1) via AT1R, resulting in imbalanced PAI-1/tissue-plasminogen activator, facilitating the hyper-coagulatory state. 17 

It is well acknowledged that inflammation is closely related to immune responses. Non-specific immune cells such as phagocytes, dendritic cells, and natural killer cells express pattern recognition receptors which identify pathogen-associated or danger-associated molecular patterns. The protective effects of type I interferon and granulocyte-macrophage colony-stimulating factor by T lymphocytes and monocytes, respectively, was concluded as central to viral-induced cytokine syndrome. 42 

Autopsy and/or biopsy findings have implicated endothelial dysfunction as a key component in COVID-19 pathogenesis. 15, 43, 44 It is speculated that when SARS-CoV-2 invades the host, immune responses are triggered, causing pro-inflammatory cytokine release, leading to a pro-inflammation state. This causes acute injury to both epithelial and microvascular endothelial cells. 45 Upon endothelial cell edema and apoptosis, and concomitant permeability in alveolar microvessels, SARS-CoV-2 enters the blood stream, causing vascular RAAS derangement, invoking viremia or sepsis, finally culminating in multi-organ damage. SARS-CoV-2 entry into the blood stream is key to its dissemination throughout the host, with the heart believed to be the first destination of pulmonary circulation outflow. 46 Sepsis is defined as severe endothelial dysfunction syndrome and is generated in response to endo-and exo-vascular infections. The infections may cause reversible or irreversible injury to the microcirculation, finally leading to septic shock, multiple organ failure, and even death. 47 About 20-35% of COVID-19 patients were with septic shock. 48 Microvasculature dysfunction is an important characteristic in septic shock. Cardiogenic shock, from imbalanced oxygen supply and demands of the heart, is also reported in COVID-19 patients. 49 Overexpressed monocytes/macrophages and polymorphonuclear neutrophils can derive tissue factors, neutrophils, and extracellular traps, respectively, triggering the endo-and exo-genetic coagulation pathway and causing imbalance between inflammation and coagulation. The complement system is an essential component of the innate immune system and is activated mainly via three pathways (ie, canonical, alternative, and lectin pathways). The activation of the complement system induces a cascade of events, such as the generation of a variety of bioactive molecules, including C3a, C5a, and membrane attack complex, resulting in coagulatory dysfunction and thrombotic vasculopathy. 17 Buja and colleagues described that pulmonary microthrombi were frequently observed in deceased COVID-19 patients at autopsy, with pulmonary thromboembolism as a common fatal complication. 50 Estrogen also activates endothelial nitric oxide synthase (eNOS) via the PI3K/Akt signaling pathway, thereby producing nitric oxide and dilating coronary arteries. 81, 82 Moreover, estrogen replacement therapy has been reported to increase coronary blood flow, and reverse detrimental changes in coronary resistance vessels. 83 In addition, estrogen could serve as an up-regulator of angiotensinogen, while downregulating renin, angiotensin-converting enzyme, and angiotensin II type 1 receptor. 84 These molecules are important for RAAS regulation, while RAAS per se plays a critical part in HTN, CAD, and HF progression. SARS-CoV-2 invades the cell via ACE2 receptor. However, the ACE2 gene is an X-located gene, and ACE2 protein mainly modulates cardiac homeostasis (including cytobiology of cardiomyocytes, cardiac fibroblasts, and coronary endothelial cells) via RAAS. 85, 86 With age advance, both men and women suffer from decreased immunity, which facilitates SARS-CoV-2 infection. Similarly, changes in coronary microvessels mediated by senescence and declining gonadal hormone levels, generate a declining health status, which may predispose to a worsened COVID-19 prognosis in those with CVD or CVD risk factors.

Cardiovascular metabolic risk factors (ie, HTN, DM, obesity, and hypercholesterolemia) and CVD are all related to CMD. 79 Responses of microvascular to cardiovascular risk factors include endothelial barrier dysfunction, oxidative stress, vasomotor function impairment, microvessel density alteration, leukocyte-endothelial adhesion, and platelet recruitment or thrombosis, as well as microvascular remodeling. [87] [88] [89] [90] Chronic heart diseases can promote CMD progression. Conversely, CMD may also facilitate hypertrophy, fibrosis of cardiomyocytes as well as microvascular rarefaction in chronic heart diseases. 91 Given the prominence of HTN, DM, obesity, and CVD in COVID-19 comorbidities, chronic CMD may play important roles during COVID-19 progression. 92, 93 Coronary microvessels may be directly injured by SARS-CoV-2 second wave infection (eg, viremia, hyper-inflammation, ARDSinduced hypoxia, RAAS imbalance, and automatic or sympathetic nerve activation), or indirectly by damage to perivascular cells (eg, cardiomyocytes edema and/or pericyte injury). However, the resultant or consequent CMD would be a co-consequence of direct and indirect factors secondary to SARS-CoV-2 infection.

Coronary microvascular dysfunction may contribute to viremia, as part of systemic endothelial dysfunction. SARS-CoV-2 RNA has been confirmed to be present in coronary microvessels in a small number of studies and has also been detected in blood as well. 94 Observation of overtly elevated biomarkers such as VWF, D-dimer, and fibrinogen degradation products suggested endothelial activation and hypercoagulation state. In general, the evidence above strongly supports the likelihood of endothelial damage, as ACE2 receptors are also expressed in endothelial cells. 58, [94] [95] [96] Hence, we might postulate that subsequent to primary attacks of the pulmonary epithelial cells and damages to the perialveolar structure including the epithelial-endothelial barrier, SARS-CoV-2 enters the blood circulation, including the heart and coronary microvessels. The resulting viremia induces coronary microvascular endothelial injury, including endothelial cell activation, endothelial structural, and functional changes, thereby resulting in hypercoagulation, microthrombosis, and myocardial injury. Therefore, this evidence suggests that viremia/sepsis may contribute to the COVID-19 mechanisms in CMD.

It has been shown that decreased local ACE2 levels in coronary microvessels led to increased AngII/Ang(1-7) ratios, resulting in a RAAS imbalance in coronary small-vessels. As AngII/Ang(1-7) ratios increase, the Ang II-AT1R pathway in the coronary small vasculature becomes overactive. It is accepted that AT1R activation induces vascular constriction, aldosterone production and release (followed by electrolyte disturbance, especially hyperkalemia, which is a mechanism in ventricular arrhythmia), vasopressin increase and cardiac hypertrophy, and autonomic nerve dysfunction. 97 Similarly, imbalanced Ang II/Ang(1-7) decreases eNOS levels, which function as vasodilators and tissue factor downregulators, thereby increasing NOX-2 activity and promoting ROS production. 98 Additionally, the bradykinin system is responsible for vascular permeability and vasodilatation, and once activated, it would exacerbate endothelial dysfunction, thereby increasing ROS production.

In short, CMD is generated by the disarrangement of local RAAS and Kallikrein-kinin-system, resulting in coronary microvascular constriction, eNOS/NOX-2 imbalance, increased ROS, and vascular permeability.

Upon internalization and duplication of SARS-CoV-2 in epithelial cells, multiple cytokines and chemokines, for example, IL-6, INFγ, and monocyte chemotactic protein 1, are released into the blood stream. As ACE2 levels decrease, vascular permeability increases, and vasodilation capacity decreases, due to the imbalanced bradykinin system. Systemic inflammation increases coronary blood flow, resulting in the activation and rupture of pre-existing atherosclerotic plaques, causing type 1 myocardial infarction. 99 In general, CMD can be caused by atherosclerotic fragments and microthrombi generated by systemic hyper-inflammation and prothrombotic state in coronary artery.

CMD could also result from oxidative stress in coronary microvessels and activation of cardiac sympathetic nerves by pneumonia/ ARDS-related systemic hypoxia. Pneumonia/ARDS-associated systemic hypoxia triggers oxidative stress in endothelial cells or myocardiocytes, stimulating several pathways for myocardium-vascular supply and demand mismatch, leading to type 2 myocardial infarction. 65 ST-elevated myocardial infarction, without obstructive coronary artery disease, has been observed in 39.3% of COVID-19 patients who required urgent angiography. 104 Oxidative stress also augments sympathetic tone, mediating catecholamine elevation in the blood. 105 Sympathetic activation is negatively correlated with coronary blood flow velocity (index of coronary microvascular function) in patients with hyperglycemia and atherosclerotic risk factors, indicating a causative role of sympathetic activation in CMD progression. 106 The inference is that coronary microvascular oxidative stress induced by SARS-CoV-2 infection increases the sympathetic tone, thereby mediating catecholamine release and leading to CMD and consequently, myocardial toxicity results, finally leading to myocardial injury and ischemia in COVID-19 patients.

Sympathetic control of coronary vasomotor tone and coronary blood flow is functionally significant in patients with endothelial dysfunction. Increased tone in sympathetic adrenergic nerves leads to the vasoconstriction of coronary vasculature and oxygen demand of cardiomyocytes. 107 However, cardiac sympathetic nerves are not only activated by oxidative stress, but also by other factors. DM is a risk factor for COVID-19, and chronic hyperglycemia affects cardiac micro-environment, resulting in CMD. 108 Cardiac autonomic dysfunction is related to cardiomyopathy and DM-induced myocardial ischemia. 106, 109 In addition, several reports on Takotsube cardiomyopathy in SARS-CoV-2 positive patients have highlighted the role of autonomic dysfunction, triggered by mental (ie, fear, anxiety, grief), physical, or physiological stress in COVID-19-associated CMD. [24] [25] [26] 110 In summary, CMD in COVID-19 may result from autonomic nerve dysfunction mediated by COVID-19-related emotional, physical or physiological factors.

Compromised perivascular cells (ie, myocytes, pericytes, and adipocytes) also elicit coronary microvascular endothelial dysfunction. A recent study showed that engineered human capillary organoids consisting of endothelial cells and platelet-derived growth factor receptor β-positive pericytes can be infected with SARS-CoV-2, whereas the administration of recombinant human ACE2 has been shown to be effective against the infection. 12 Pericytes or perivascular cells envelop the endothelial layers of microvessels in the body, including the heart, and maintain the tone and integrity of microvasculature, as well as promoting angiogenesis. With an endothelial cell/pericyte ratio of 2:1-3:1, and a density of approximately 3.6 × 10 7 pericytes/ cm 3 , pericytes are the second most common myocardial cell type in the heart, followed by cardiomyocytes. 111 In pericyte-deficient murine models, the production and release of VWF from microvascular endothelial cells are augmented, facil- 68, 69 In addition, although rarely presented, viral particles were detected in the cardiomyocytes adjacent F I G U R E 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 to myofibrils in a case from Italy. 112 Several other studies also reported SARS-CoV-2 RNA in the heart without describing the specific location. 94, [113] [114] [115] The SARS-CoV-2 virus is transported from the blood stream, through the endothelial barrier to perivascular tissues such as pericytes, myocytes, and epicardial adipocytes (which share the same microcirculation with myocardiocytes 116 

A priori, these CMD mechanisms in COVID-19 can be summarized as 

We present a state-of-the-art review of CMD pathophysiology in COVID-19 from five aspects. As SARS-CoV-2-like virus particles were detected in a coronary endothelial cells, and massive coronary small vascular microthrombi were found in deceased COVID-19 patients, we thought our review was meaningful for further studies on SARS-CoV-2 induced heart injury. However, there is a need for more and larger well-designed trials for future research.

We thank International Science Editing (http://www.inter natio nalsc ience editi ng.com) for editing this manuscript.

The authors declare that they have no conflict of interest. 

The data used to support the findings of this study are available.

https://orcid.org/0000-0003-4875-0209

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