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

Tomasz J Guzik, Saidi A Mohiddin, Anthony Dimarco, Vimal Patel, Kostas Savvatis, Federica M Marelli-Berg, Meena S Madhur, Maciej Tomaszewski, Pasquale Maffia, Fulvio D'Acquisto, Stuart A Nicklin, Ali J Marian, Ryszard Nosalski, Eleanor C Murray, Bartlomiej Guzik, Colin Berry, Rhian M Touyz, Reinhold Kreutz, Dao Wen Wang, David Bhella, Orlando Sagliocco, Filippo Crea, Emma C Thomson, Iain B McInnes, Tomasz J Guzik, Saidi A Mohiddin, Anthony Dimarco, Vimal Patel, Kostas Savvatis, Federica M Marelli-Berg, Meena S Madhur, Maciej Tomaszewski, Pasquale Maffia, Fulvio D'Acquisto, Stuart A Nicklin, Ali J Marian, Ryszard Nosalski, Eleanor C Murray, Bartlomiej Guzik, Colin Berry, Rhian M Touyz, Reinhold Kreutz, Dao Wen Wang, David Bhella, Orlando Sagliocco, Filippo Crea, Emma C Thomson, Iain B McInnes

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.

Keywords: ACE2; Acute coronary syndrome; COVID-19; Cardiac; Endothelium; Microvascular; Myocardial infarction; Myocarditis; Vascular; Virus.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.

Figures

Figure 1
Figure 1
Characteristic structure of betacoronavirus. Negative stain electron microscopy showing a betacoronavirus particles with club-shaped surface projections surrounding the periphery of the particle, a characteristic feature of coronaviruses. The photograph depicts a murine coronavirus. Kindly provided by Professor David Bhella, Scottish Centre for Macromolecular Imaging; MRC Centre for Virus Research; University of Glasgow.
Figure 2
Figure 2
Basic pathobiology of SARS-CoV-2 infection and possible treatment strategies. Upon the viral spike protein priming by the transmembrane protease serine 2 (TMPRSS2), SARS-CoV-2 uses the host angiotensin-converting enzyme 2 (ACE2) to enter and infect the cell. Inhibiting TMPRSS2 activity (by camostat mesylate) could be used to prevent proteolytic cleavage of the SARS-CoV-2 spike protein and protect the cell against virus–cell fusion (1). Another approach could be neutralizing the virus from entering cells and keeping it in solution by activation of a disintegrin and metalloprotease 17 (ADMA17) which leads to shedding of the membrane-bound ACE2 and release of the soluble extracellular domain of ACE2 (2); with treatment with anti-ACE2 antibodies leading to blockage of the interaction between virus and receptors (3) or administration of soluble recombinant human ACE2 protein acting as a competitive interceptor for SARS-CoV-2 (4). Alternatively, purified polyclonal antibodies targeting/neutralizing the viral spike protein may offer some protection against SARS-CoV-2 (5). Interestingly, angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs), frequently used to treat hypertension, could alter ACE2 expression and intensify the SARS-CoV-2 infection.
Figure 3
Figure 3
Key symptoms, and biochemical and radiological features of the clinical course of COVID-19.
Figure 4
Figure 4
Multifocal pneumonia in a patient with COVID-19. (A) A cross-sectional CT image of the lungs showing two distinct pulmonary infiltrates in the left upper lobe (arrows). (B) A large posteriorly located right lower lobe infiltrate on CT scan of the chest (arrows). Data were collected as part of a retrospective study, consent was waived, and collection of these data was approved by local ethics committee of Wuhan, China. Kindly provided by Professor Dao Wen Wang.
Figure 5
Figure 5
Cardiovascular involvement in COVID-19—key manifestations and hypothetical mechanisms. SARS-CoV-2 anchors on transmembrane ACE2 to enter the host cells including type 2 pneumocytes, macrophages, endothelial cells, pericytes, and cardiac myocytes, leading to inflammation and multiorgan failure. In particular, the infection of endothelial cells or pericytes could lead to severe microvascular and macrovascular dysfunction. Furthermore, in conjunction with the immune over-reactivity, it can potentially destabilize atherosclerotic plaques and explain the development of the acute coronary syndromes. Infection of the respiratory tract, particularly of type 2 pneumocytes, by SARS-CoV-2 is manifested by the progression of systemic inflammation and immune cell overactivation, leading to a ‘cytokine storm’, which results in an elevated level of cytokines such as IL-6, IL-7, IL-22, and CXCL10. Subsequently, it is possible that activated T cells and macrophages may infiltrate infected myocardium, resulting in the development of fulminant myocarditis and severe cardiac damage. This process could be further intensified by the cytokine storm. Similarly, the viral invasion could cause cardiac myocyte damage directly leading to myocardial dysfunction and contribute to the development of arrhythmia.
Figure 6
Figure 6
Representative transthoracic echocardiography frames (selected from cine loop images) from a patient with COVID-19. (A) Apical four-chamber view showing globally reduced left ventricular contraction, especially in the apical segment. The right ventricle is dilated and an echo-free space, indicating pericardial effusion, is present. (B) Parasternal short axis view showing markedly reduced left ventricular contraction, enlarged right ventricle, and a mural thrombosis in the right ventricle outflow tract. (C) Two-dimensional speckle tracking echocardiography based on speckle tracking imaging technology (2D STE). Left panel showing a normal 2D STE, right showing a 2D STE from a patient with COVID-19 and myocarditis, depicting reduced regional peak systolic strain rates. Data were collected as part of a retrospective study, Wuhan, China; consent was waived and collection of these data was approved by the local ethics committee. Kindly provided by Professor Dao Wen Wang.

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