Cardiovascular disease and COVID-19: a consensus paper from the ESC Working Group on Coronary Pathophysiology & Microcirculation, ESC Working Group on Thrombosis and the Association for Acute CardioVascular Care (ACVC), in collaboration with the European Heart Rhythm Association (EHRA)

Abstract

The cardiovascular system is significantly affected in coronavirus disease-19 (COVID-19). Microvascular injury, endothelial dysfunction, and thrombosis resulting from viral infection or indirectly related to the intense systemic inflammatory and immune responses are characteristic features of severe COVID-19. Pre-existing cardiovascular disease and viral load are linked to myocardial injury and worse outcomes. The vascular response to cytokine production and the interaction between severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and angiotensin-converting enzyme 2 receptor may lead to a significant reduction in cardiac contractility and subsequent myocardial dysfunction. In addition, a considerable proportion of patients who have been infected with SARS-CoV-2 do not fully recover and continue to experience a large number of symptoms and post-acute complications in the absence of a detectable viral infection. This conditions often referred to as 'post-acute COVID-19' may have multiple causes. Viral reservoirs or lingering fragments of viral RNA or proteins contribute to the condition. Systemic inflammatory response to COVID-19 has the potential to increase myocardial fibrosis which in turn may impair cardiac remodelling. Here, we summarize the current knowledge of cardiovascular injury and post-acute sequelae of COVID-19. As the pandemic continues and new variants emerge, we can advance our knowledge of the underlying mechanisms only by integrating our understanding of the pathophysiology with the corresponding clinical findings. Identification of new biomarkers of cardiovascular complications, and development of effective treatments for COVID-19 infection are of crucial importance.

Keywords: COVID-19; Cardiovascular disease; Infection; Myocardial injury; SARS-CoV-2; cytokines; endothelial dysfunction; inflammation; microcirculation; post-acute COVID-19; thrombosis.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.

Figures

Graphical Abstract

Figure 1

Interplay between angiotensin II, ACE2 (angiotensin-converting enzyme 2), and SARS-CoV-2 binding in the pathogenesis of COVID-19, the inflammatory response and cardiovascular protection lost. Left panel: In physiological conditions, ACE2 balances renin–angiotensin system expression. Increased ACE2 increase the protective axis of ACE2/Angiotensin (Ang)1-7/Mas receptor axis counter-regulates the actions of the ACE/Ang II/angiotensin receptors 1 (AT1) axis. Right panel: SARS-CoV-2 spike (S) protein has a strong binding affinity to ACE2 which facilitate viral entry into target cells by transmembrane protease serine 2 (TMPRSS2) priming. Following binding of ACE2 with S protein, down-regulation of ACE2 is observed. Accumulation of Ang II increases the activity of AT1 receptors leading to internalization, down-regulation, and degradation of ACE2. In addition, endocytosed SARS-CoV-2 up-regulates the proteolytic cleavage of ACE2 mediated a disintegrin and metalloproteinase 17 (ADAM17), which activity is further increased by activation of AT1 receptors due to the accumulation of Ang II. Viral RNA activates toll-like receptor (TLR) 3, TLR 7, TLR 8. These receptors activate interferon regulatory factors (IRFs) and nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB) to induce inflammatory cytokines including interferons (INF). Dendritic cells are able to produce IFN and augment the IFN signal, which also represents a risk for immunopathology. Systemic cytokines release in combination with cardiovascular risk factor and comorbidities can lead to a cytokine storm, whereas increased activity of Ang II/AT1 receptor axis, due to ACE2 loss of function, exerts vasoconstrictor, profibrotic, prothrombotic and proinflammatory effects. Figure created with BioRender.com. H2O, water; IL, interleukin; Na+, sodium; ROS, reactive oxygen species; SARS-CoV-2, Severe Acute Respiratory Syndrome-Coronavirus 2; TNF-α, tumour necrosis factor alpha.

Figure 2

Tissue expression of ACE2 and potential mechanisms involved in systemic inflammatory response and cardiovascular complications of COVID-19. ACE2 is widely expressed in endothelial cells, arterial smooth muscle cells, renal alveolar epithelial cells adipocytes, and cardiovascular system. Severe Acute Respiratory Syndrome-Coronavirus 2 (SARS-CoV-2) infection cause immune activation, tissue accumulation of T cells, and macrophages leading to myocardial injury. Cytokines release cause systemic inflammatory response which may cause further impairment in micro and macro-circulation and plaque rapture. Blood desaturation may further impair microcirculation and myocardial performance. SIRS, systemic inflammatory response system.

Figure 3

Mechanisms of endothelial activation/dysfunction and immunothrombosis in COVID-19. SARS-CoV-2 activates the endothelium, either directly by interacting with angiotensin-converting enzyme (ACE) 2 receptor or indirectly by triggering hyperinflammation. Inflammatory cytokines induce the activation of tissue factor (TF) and exocytosis of Weibel Palade bodies (WPB) from endothelial cells, enhancing expression of P-selectin and E-selectin which in turn recruits’ neutrophils and monocytes/macrophages. Monocytes/macrophages activate and deliver through their microvesicles, TF to the sites of SARS-CoV-2 exposure, initiating the TF pathway activation (or extrinsic pathway). Neutrophils release neutrophil extracellular traps (NETs), which capture SARS-CoV-2, promote thrombus formation activation of factor XII (contact or intrinsic pathway of coagulation cascade), and promote platelet recruitment by binding von Willebrand factor (vWF). The NETs propagate coagulation by inactivating endogens anticoagulants such as tissue factor pathway inhibitor (TFPI) and antithrombin III (ATII). Concomitantly, thrombomodulin is shed from endothelial cells, which further promotes a procoagulant and pro-inflammatory milieu. Spike (S) protein binding to ACE2 endothelial receptor reduce angiotensin (Ang) II conversion to Ang 1-7. Accumulation of Ang II leads to plasminogen-activator inhibitor-type 1 (PAI-1) production inhibiting fibrinolysis and thrombus dissolution. Figure created with BioRender.com. IL, interleukin; TNF-α, tumour necrosis factor alpha; TLR, toll-like receptors.

Figure 4

Post-acute sequelae of SARS-CoV-2 infection. As for the current literature, post-acute sequelae of SARS-CoV-2 infection may be defined as persistent signs and symptoms or long-term complications beyond 4 weeks from symptoms onset. The most frequent symptoms and complications are summarized in the figure. Figure created with BioRender.com.