COVID-19 and cardiovascular disease: from basic mechanisms to clinical perspectives

Abstract

Coronavirus disease 2019 (COVID-19), caused by a strain of coronavirus known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a global pandemic that has affected the lives of billions of individuals. Extensive studies have revealed that SARS-CoV-2 shares many biological features with SARS-CoV, the zoonotic virus that caused the 2002 outbreak of severe acute respiratory syndrome, including the system of cell entry, which is triggered by binding of the viral spike protein to angiotensin-converting enzyme 2. Clinical studies have also reported an association between COVID-19 and cardiovascular disease. Pre-existing cardiovascular disease seems to be linked with worse outcomes and increased risk of death in patients with COVID-19, whereas COVID-19 itself can also induce myocardial injury, arrhythmia, acute coronary syndrome and venous thromboembolism. Potential drug-disease interactions affecting patients with COVID-19 and comorbid cardiovascular diseases are also becoming a serious concern. In this Review, we summarize the current understanding of COVID-19 from basic mechanisms to clinical perspectives, focusing on the interaction between COVID-19 and the cardiovascular system. By combining our knowledge of the biological features of the virus with clinical findings, we can improve our understanding of the potential mechanisms underlying COVID-19, paving the way towards the development of preventative and therapeutic solutions.

Figures

Fig. 1. Structure, genome and life cycle of SARS-CoV-2.

a | Coronaviruses form an enveloped spherical particle that consists of four structural proteins (spike (S), envelope (E), membrane (M) and nucleocapsid (N)) and a positive-sense, single-stranded RNA (ssRNA) genome that is 30 kb in length. b | The 5′-terminal two-thirds of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome encodes polyproteins pp1a and pp1ab, which are cleaved into 16 different non-structural proteins. Structural proteins are encoded in the 3′-terminal one-third of the genome. The S protein consists of two subunits; the S1 subunit contains a receptor-binding domain (RBD) that binds to angiotensin-converting enzyme 2 (ACE2) on the surface of host cells, whereas the S2 subunit mediates fusion between the membranes of the virus and the host cell. Compared with the S protein of SARS-CoV, the S protein of SARS-CoV-2 has two notable features. First, within the RBD of the S1 subunit, five of the six residues that are crucial for binding to human ACE2 are mutated. Second, an insertion of four amino acid residues at the boundary between the S1 and S2 subunits is present in SARS-CoV-2 but not in SARS-CoV, which introduces a novel furin cleavage site. c | SARS-CoV-2 infection is triggered by the binding of the S protein to ACE2 on the surface of host cells, and the viral complex is incorporated into the cytoplasm either by direct fusion with the cell membrane or via endocytosis with later release into the cytoplasm from the endocytic vesicle. The S protein is cleaved at the S1/S2 boundary and the S2 subunit facilitates membrane fusion. The viral genome RNA is released into the cytoplasm, and the first open reading frame (ORF) is translated into polyproteins pp1a and pp1ab, which are then cleaved by viral proteases into small, non-structural proteins such as RNA-dependent RNA polymerase (RdRP). The viral genomic RNA is replicated by RdRP. Viral nucleocapsids are assembled from genomic RNA and N proteins in the cytoplasm, whereas budding of new particles occurs at the membrane of the endoplasmic reticulum (ER)–Golgi intermediate compartment. Finally, the genomic RNA and structural proteins are assembled into new viral particles, leading to their release via exocytosis. 3CL, 3-chymotrypsin-like protease.

Fig. 2. Bidirectional interaction between cardiovascular diseases and COVID-19.

Cardiovascular comorbidities such as hypertension and coronary artery disease are associated with high mortality in patients with coronavirus disease 2019 (COVID-19). Drugs used to reduce cardiovascular risk such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) have numerous effects that might influence susceptibility to or the severity of COVID-19. Furthermore, although the main presentation of COVID-19 is viral pneumonia, COVID-19 can also induce cardiovascular manifestations including myocardial injury, myocarditis, arrhythmias, acute coronary syndrome and thromboembolism. Among these cardiovascular manifestations, myocardial injury has been independently associated with high mortality among patients with COVID-19 (ref.). Finally, medications that have been proposed as treatments for COVID-19 such as hydroxychloroquine and azithromycin have pro-arrhythmic effects. AF, atrial fibrillation; VF, ventricular fibrillation; VT, ventricular tachycardia.

Fig. 3. ACE2 as a part of the RAAS.

Angiotensin II, the main effector molecule in the renin–angiotensin–aldosterone system (RAAS), is upregulated in many pathological conditions, for which inhibition of angiotensin II by RAAS inhibitors is a common therapeutic strategy.Angiotensin-converting enzyme (ACE) produces angiotensin II from angiotensin I, whereas ACE2 inactivates angiotensin II by converting it to angiotensin (1–7). Therefore, ACE2 has a protective effect against cardiovascular disease and lung injury. In the setting of coronavirus disease 2019, downregulation of ACE2 by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection might be involved in mediating cardiovascular damage. ARB, angiotensin II receptor blocker.