Dysfunction of the endothelium in COVID-19
Endothelial dysfunction in COVID-19: a position paper of the ESC Working Group for Atherosclerosis and Vascular Biology, and the ESC Council of Basic Cardiovascular Science
The position paper of the ESC Working Group for Atherosclerosis and Vascular Biology, and the ESC Council of Basic Cardiovascular Science draws attention towards the role of endothelium in the pathophysiology of COVID-19. The article discusses effects of a systemic inflammatory cytokine storm in COVID-19 on endothelial phenotype and function. Possible direct effects of SARS-CoV-2 infection of endothelial cells (ECs) on endothelial dysfunction are addressed as well. Moreover, the authors discuss outstanding questions that need to be addressed to improve our understanding of the role of the vascular endothelium in COVID-19.
Endothelial dysfunction in COVID-19 and its role in inflammation and thrombosis
The hyperinflammatory and procoagulatory state which has been observed in COVID-19 patients suggests that the endothelium plays an important role in this disease. SARS-CoV-2 infection can lead to dysfunctional or injured endothelium. Endothelial dysfunction can have an impact on multiple levels, including reduced integrity, increased permeability, activation of an immune response and thrombosis [1-4].
The endothelium plays a crucial role in an amplification loop of the inflammatory response in COVID-19 [5,6]. The endothelium is exposed to proinflammatory cytokines due to a systemic inflammatory cytokine storm. This induces -via a cascade of processes- leucocyte recruitment and inflammation . This process can also cause death of ECs, which in turn may lead to increased vascular permeability and end-organ damage. This raises the question whether anti-inflammatory therapies that are currently used in the treatment of chronic inflammatory and autoimmune diseases may be beneficial in the treatment of COVID-19. On the other hand, it can be argued that anti-inflammatory agents can be counterproductive in the immune response against the virus. The RECOVERY trial showed positive effects of the use of low dose dexamethasone in hospitalized COVID-19 patients .
The thrombotic and coagulant properties of endothelium change when it becomes dysfunctional . A prothrombotic and proinflammatory state can cause the recruitment and activation of platelets to intact endothelial monolayers . This can subsequently induce secondary recruitment of circulating leucocytes [10-12]. The authors argue that it is reasonable to assume that aggregates of ECs, platelets and leucocytes on the walls of smaller vessels can lead to loss of microvascular perfusion in organs.
SARS-CoV-2 infection in endothelial cells
Besides indirect effects of COVID-19 on endothelial function through a systemic inflammatory state, evidence from several studies point to SARS-CoV-2 infection of ECs as a possible direct trigger of endothelial adverse effects in COVID-19 [13-18]. SARS-CoV-2 infection of ECs has been associated with EC apoptosis, which may point to a direct mechanism of how COVID-19 can cause endothelial dysfunction . In addition, an inflammatory multisystem syndrome has been associated with COVID-19 in children [20,21]. This syndrome shows similarities to Kawasaki disease, a systemic vasculitis which particularly targets coronary arteries and the myocardium. However, important differences to Kawasaki disease were reported .
The authors also refer to a study that suggests that pericytes may act as a direct target for SARS-CoV-2 infection . Pericytes are essential for the maintenance of the integrity of endothelium. Apoptosis of pericytes could therefore play an important role in microvascular dysfunction and coagulopathy.
Therapeutic targets and position statements
The authors emphasize the need for prospective clinical studies with clearly defined CV endpoints in COVID-19 patients. Such studies should also investigate interventions with current CV drugs which could potentially reduce endothelial dysfunction in COVID-19. Potential candidates include modulators of RAAS (ACEi, ARBs, ACE2), anti-inflammatory drugs (cytokine inhibitors, dexamethasone, statins), inhibitors of reactive oxygen species (ROS) and apoptosis (statins), platelet inhibitors and anticoagulants.
Finally, the authors provide five position statements on role of endothelium in the pathophysiology of COVID-19. The detailed statements can be found in the original position paper. In short, these statements are: i) endothelial biomarkers and EC function should be monitored in studies to assess vascular consequences of COVID-19; ii) the significance of SARS-CoV-2-mediated endocytosis and down-regulation of ACE1 on CV health needs to be clarified; iii) studies of EC activation, leucocyte recruitment, platelet activation, turnover and signaling in COVID-19 are needed to reveal the principle effects of SARS-CoV-2 on endothelial function. Since ageing is an established determinant of COVID-19 outcome, features of aging on SARS-CoV-2 infection of ECs should be investigated; iv) effects of common CV drugs on endothelial responses in COVID-19 should be studied; v) long-term CV effects of COVID-19 after recovery should be determined during patient follow-up. Endothelial function testing can be valuable for early detection of vascular consequences of COVID-19.