COVID-19 and the cardiovascular system: implications for risk assessment, diagnosis, and treatment options

Abstract

The novel coronavirus disease (COVID-19) outbreak, caused by SARS-CoV-2, represents the greatest medical challenge in decades. We provide a comprehensive review of the clinical course of COVID-19, its comorbidities, and mechanistic considerations for future therapies. While COVID-19 primarily affects the lungs, causing interstitial pneumonitis and severe acute respiratory distress syndrome (ARDS), it also affects multiple organs, particularly the cardiovascular system. Risk of severe infection and mortality increase with advancing age and male sex. Mortality is increased by comorbidities: cardiovascular disease, hypertension, diabetes, chronic pulmonary disease, and cancer. The most common complications include arrhythmia (atrial fibrillation, ventricular tachyarrhythmia, and ventricular fibrillation), cardiac injury [elevated highly sensitive troponin I (hs-cTnI) and creatine kinase (CK) levels], fulminant myocarditis, heart failure, pulmonary embolism, and disseminated intravascular coagulation (DIC). Mechanistically, SARS-CoV-2, following proteolytic cleavage of its S protein by a serine protease, binds to the transmembrane angiotensin-converting enzyme 2 (ACE2) —a homologue of ACE—to enter type 2 pneumocytes, macrophages, perivascular pericytes, and cardiomyocytes. This may lead to myocardial dysfunction and damage, endothelial dysfunction, microvascular dysfunction, plaque instability, and myocardial infarction (MI). While ACE2 is essential for viral invasion, there is no evidence that ACE inhibitors or angiotensin receptor blockers (ARBs) worsen prognosis. Hence, patients should not discontinue their use. Moreover, renin–angiotensin–aldosterone system (RAAS) inhibitors might be beneficial in COVID-19. Initial immune and inflammatory responses induce a severe cytokine storm [interleukin (IL)-6, IL-7, IL-22, IL-17, etc.] during the rapid progression phase of COVID-19. Early evaluation and continued monitoring of cardiac damage (cTnI and NT-proBNP) and coagulation (D-dimer) after hospitalization may identify patients with cardiac injury and predict COVID-19 complications. Preventive measures (social distancing and social isolation) also increase cardiovascular risk. Cardiovascular considerations of therapies currently used, including remdesivir, chloroquine, hydroxychloroquine, tocilizumab, ribavirin, interferons, and lopinavir/ritonavir, as well as experimental therapies, such as human recombinant ACE2 (rhACE2), are discussed.

COVID‐19 and heart failure: from infection to inflammation and angiotensin II stimulation. Searching for evidence from a new disease

“…6,39 Thus, although a few cases of direct virus related myocarditis may exist, other mechamisms are responsible of myocardial injury in most of the patients, rather than viral infection alone. 5,6,[39][40][41] As for SARS-CoV, a viraemic response may occur with SARS-CoV-2 shedding and migration from lungs to other organs, possible via the vascular route. This is also consistent with the large expression of ACE2, the tissue receptor of SARS-CoV-2 (see below), in the vascular system 42 as well as with the finding of acute endotheliitis in patients with COVID-19.…”

“…This is also consistent with the large expression of ACE2, the tissue receptor of SARS-CoV-2 (see below), in the vascular system 42 as well as with the finding of acute endotheliitis in patients with COVID-19. 41,43,44 This article is protected by copyright. All rights reserved.…”

“…This condition is similar to that described in oncology with immune targeted chimeric antigen receptor T cells therapies and in haemophagocytic lymphohistiocytosis syndromes. 7,41,53,56 Inflammation may take place in the endothelium. Biopsies and post-mortem hysthological findings showed lymphocytic endotheliitis with apoptotic bodies and viral inclusion structures in multiple organs including lungs, heart, kidneys, gut.…”

“…25,26 Lastly, antinflammatory therapies are currently studied for COVID-19. 41,56,58 However, also drugs active on endothelial function, such as statins and ACEi or ARBs may be beneficial. 43 The role of ACE 2 SARS-CoV attaches human cells after binding with its spikes to the angiotensin converting enzyme 2 (ACE2), a peptide highly expressed on the surface of lung alveolar epithelial cells, arterial and venous endothelial cells, arterial smooth muscle cells and enterocytes of the small intestine.…”

Androgen Regulates SARS-CoV-2 Receptor Levels and Is Associated with Severe COVID-19 Symptoms in Men

“…Our analysis of previously published single cell RNA sequencing datasets [13][14][15] showed abundant expression of SARS-CoV-2 receptor, ACE2, and co-receptors, TMPRSS2 and FURIN in adult cardiac, esophageal, lung and colon tissues (Supplementary Figure 1A). Given the highly significant association of poor outcomes in COVID-19 patients with cardiovascular complications 2,3 and the significant role of ACE2 in cardiac physiology 16 , we chose to focus on the regulation of ACE2 levels in cardiac cells. Due to limitations associated with isolation and maintenance of human cells from primary tissue, we used our previously established hESC differentiation method as an alternative strategy to generate cardiac cells (Supplementary Figure 1B) 12 Previously published transcriptomics data on hESC-derived cells generated using this method 12 confirmed the expression of SARS-CoV-2 receptor and co-receptors mRNAs in cardiomyocytes and non-cardiomyocyte (Supplementary Figure 1C).…”