Convalescent COVID-19 patients are susceptible to endothelial dysfunction due to persistent immune activation

Abstract

The rapid rise of coronavirus disease 2019 patients who suffer from vascular events after their initial recovery is expected to lead to a worldwide shift in disease burden. We aim to investigate the impact of COVID-19 on the pathophysiological state of blood vessels in convalescent patients. Here, convalescent COVID-19 patients with or without preexisting conditions (i.e. hypertension, diabetes, hyperlipidemia) were compared to non-COVID-19 patients with matched cardiovascular risk factors or healthy participants. Convalescent patients had elevated circulating endothelial cells (CECs), and those with underlying cardiovascular risk had more pronounced endothelial activation hallmarks (ICAM1, P-selectin or CX3CL1) expressed by CECs. Multiplex microbead-based immunoassays revealed some levels of cytokine production sustained from acute infection to recovery phase. Several proinflammatory and activated T lymphocyte-associated cytokines correlated positively with CEC measures, implicating cytokine-driven endothelial dysfunction. Finally, the activation markers detected on CECs mapped to the counter receptors (i.e. ITGAL, SELPLG, and CX3CR1) found primarily on CD8+ T cells and natural killer cells, suggesting that activated endothelial cells could be targeted by cytotoxic effector cells. Clinical trials in preventive therapy for post-COVID-19 vascular complications may be needed.Graphical abstract

Upregulation of pulmonary tissue factor, loss of thrombomodulin and immunothrombosis in SARS-CoV-2 infection

“…Our results also underscore the potential role of endothelial cells in coagulation activation based on a positive correlation of D-dimer with angiopoietin-2 and multiple others endothelial cell markers (angiopoietin-1, P-selectin, thrombomodulin, TFPI, vWF:Ag, vWF:RCo, t-PA, P-selectin). In addition, the significance of microvascular damage is highlighted by other markers of endothelial cell activation and angiogenesis, the presence of circulating endothelial cells, and an association of endothelium activation with disease severity including respiratory and multiorgan failure [10À15,11À13, 61,63]. Moreover, it is congruent with a pathologic process affecting endothelial cells given the vast surface it occupies estimated in more than 1000 m 2 , or 10 12 endothelial cells (there are » 10 10 blood monocytes) weighting in excess of 100 gs in the adult human [64].…”

Effect of SARS-CoV-2 proteins on vascular permeability

“…Due to the impact of SARS-CoV-2, many studies have looked at the physiological responses the virus 1–4,19 . In this work, we sought to identify how specific SARS-CoV-2 proteins affect the vasculature by assessing the effect of individual SARS-CoV-2 proteins on endothelial cells (HUVEC).…”

“…Therefore, we decided to focus on individual proteins, and allow further studies to pursue any combinations of interest. Regarding the latter limitation, we did not include the coronavirus structure (including the ACE2 receptors) in this study, because many studies have already demonstrated the cellular response to this structure 19,49,50 , and how tissues that do not have significant ACE2 expression (such as neurons, immune components such as B and T lymphocytes, and macrophages) are affected by the virus remains an open question.…”

Endothelial Dysfunction and SARS-CoV-2 Infection: Association and Therapeutic Strategies

“…In addition, evidence suggests that the symptoms and signs of patients severely infected with COVID-19 are similar to the clinical phenotypes of endothelial dysfunction and have the same pathophysiological mechanism [ 6 , 14 ]. In particular, recent work by Chioh et al found that COVID-19 patients, especially those with preexisting cardiovascular risk, may show signs of persistent endothelial dysfunction even after recovery from the infection [ 15 ].…”