Viral Endothelial Dysfunction: A Unifying Mechanism for COVID-19

Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly transmissible virus with significant global impact, morbidity, and mortality. The SARS-CoV-2 virus may result in widespread organ manifestations including acute respiratory distress syndrome, acute renal failure, thromboembolism, and myocarditis. Virus-induced endothelial injury may cause endothelial activation, increased permeability, inflammation, and immune response and cytokine storm. Endothelial dysfunction is a systemic disorder that is a precursor of atherosclerotic vascular disease that is associated with cardiovascular risk factors and is highly prevalent in patients with atherosclerotic cardiovascular and peripheral disease. Several studies have associated various viral infections including SARS-CoV-2 infection with inflammation, endothelial dysfunction, and subsequent innate immune response and cytokine storm. Noninvasive monitoring of endothelial function and identification of high-risk patients who may require specific therapies may have the potential to improve morbidity and mortality associated with subsequent inflammation, cytokine storm, and multiorgan involvement.

Figure 1

We postulate viral-induced endothelial dysfunction as the underlying pathophysiologic mechanism leading to the multisystem involvement seen with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The initial viral infection results in endothelial injury and abnormal function of the endothelium that activates inflammatory pathways with cytokine production and cytokine storm, immune cell infiltration, increased vascular permeability, abnormal vasomotor function, and microvascular ischemia, which in turn lead to multiorgan clinical manifestations including development of acute respiratory distress syndrome (ARDS), thrombosis, renal dysfunction, and myocarditis.

Figure 2

This central illustration schematically illustrates our proposed mechanism of viral endothelial injury. The virus may infect the endothelial cell and monocytes, leading to cytopathic effects, increasing levels of cytotoxins including interleukin 6 (il-6) and tumor necrosis factor α (tnf alpha), and cytokine dysregulation, and cause platelet activation and alterations in platelet binding, vascular permeability, endothelial platelet interactions that may in turn cause widespread endothelial dysfunction, cytokine storm, heightened immune response, and multiorgan system involvement and potentially failure. NET, neutrophil extracellular trap; PMN, polymorphonuclear; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; TF, tissue factor; VE, vascular endothelial; VWF, von Willebrand factor.