COVID-19 and Cardiovascular Disease: From Bench to Bedside

Abstract

A pandemic of historic impact, coronavirus disease 2019 (COVID-19) has potential consequences on the cardiovascular health of millions of people who survive infection worldwide. Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), the etiologic agent of COVID-19, can infect the heart, vascular tissues, and circulating cells through ACE2 (angiotensin-converting enzyme 2), the host cell receptor for the viral spike protein. Acute cardiac injury is a common extrapulmonary manifestation of COVID-19 with potential chronic consequences. This update provides a review of the clinical manifestations of cardiovascular involvement, potential direct SARS-CoV-2 and indirect immune response mechanisms impacting the cardiovascular system, and implications for the management of patients after recovery from acute COVID-19 infection.

Keywords: COVID-19; angiotensin-converting enzyme 2; inflammation; magnetic resonance imaging; thrombosis.

Figure 1.

Structural components of the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) spike protein, interactions with ACE2 (angiotensin-converting enzyme 2) and host cell entry. A, Spike protein structural and functional elements. B, Interaction of the spike protein and processing resulting in viral entry to host cells. C and D, Structural and membrane topology of ACE2 and binding to SARS-CoV-2 S-protein receptor binding domain (RBD). C, ACE2 as a transmembrane protein with an N-terminal extracellular protease ectodomain and a short cytoplasmic C-terminus. Protease enzymatic activity is in the ectodomain (protease domain [PD]), containing a carboxypeptidase catalytic site. The receptor binding site for SARS-CoV-2 is more toward the N-Terminus, involving the N-terminal helix (NTH). D, X-ray crystallography of SARS-Cov-2 RBD bound to ACE2. ACE2 is in green, RBD in cyan and the CoV-2 receptor binding moiety (RBM) in red. Reproduced from Lan et al with permission. Copyright©2020, Springer Nature. ACE2 indicates angiotensin-converting enzyme 2; FP, fusion peptide; HR, heptad repeat domain; NRP1 BD, neuropilin-1 binding domain; NTD, N-terminal domain; SS, signal sequence; TM, transmembrane domain; and TMPRSS2, transmembrane protease serine 2.

Figure 2.

Gene expression by tissue of genes encoding viral entry proteins that interact with severe acute respiratory syndrome-coronavirus 2 from GTEx. The lung and intestines express high levels of ACE2 (angiotensin-converting enzyme 2) and transmembrane protease serine 2 (TMPRSS2), whereas the heart left ventricle expresses ACE2 at high levels, but TMPRSS2 at low levels. However, CTSB and CTSL (encoding cathepsins B and L, respectively), FURIN, NRP1, and ITGA5 and ITGB1 (integrins) show expression in all tissues displayed. Obtained from the Genotype-Tissue Expression (GTEx) Portal, accessed on January 14, 2021.

Figure 3.

ACE2 (angiotensin-converting enzyme 2) expression in human myocardium. A, Relative expression of ACE2, TMPRSS2, and CTSL in left ventricle by snRNASeq. B, snRNASeq showing expression of ACE2 in cell subtypes, demonstrating increases in ACE2 expression in cardiomyocytes but reduced expression in fibroblasts, pericytes, and vascular smooth muscle cells (VSMCs) in dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) ventricles. C, Effects of ACE inhibitors on ACE2 expression across cell types in HCM, showing no significant change. D and E, ACE2 expression in adult human heart from public scRNASeq databases. D, Age and (E) normal vs heart failure and male vs female stratification. A, B, and C reproduced from Tucker et al with permission. Copyright©2020, Wolters Kluwer Health, Inc. D and E reproduced from Liu et al with permission. Copyright©2020, Oxford University Press.

Figure 4.

Renin-angiotensin system and ACE2 (angiotensin-converting enzyme 2).

Figure 5.

Approximate time course of immune response and cardiovascular effects. ACE2 indicates angiotensin-converting enzyme 2.

Figure 6.

Network-based drug repurposing paradigm for severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). A, Network-based drug discovery strategy for SARS-CoV-2 in which the viral proteome is depicted overlapping with the human protein interactome, which, in turn, is shown overlapping with the drug-target protein interactome. B, Network-based proximity strategy for drug repurposing in which the proximity of a drug target for another disease to the disease module of interest serves as the basis for pursuing repositioning of that drug. C, The covidome, or the subnetwork or disease module in the protein interactome, is used as the basis for identifying drug targets for drug repurposing, which is evaluated through 3 complementary methods—network proximity, network diffusion, and AI prioritization, leading to a ranking algorithm that yields repurposable drugs for experimental analysis.