Endothelialitis plays a central role in the pathophysiology of severe COVID-19 and its cardiovascular complications

Abstract

This clinical review paper discusses the pathophysiology of the pulmonary and cardiovascular manifestations of a SARS-CoV-2 infection and the ensuing implications on acute cardiovascular care in patients presenting with a severe COVID-19 syndrome admitted to an intensive acute cardiac care unit. The high prevalence of old age, obesity, diabetes, hypertension, heart failure, and ischaemic heart disease in patients who develop a severe to critical COVID-19 syndrome suggests shared pathophysiological mechanisms. Pre-existing endothelial dysfunction and an impaired innate immune response promote the development by the viral infection of an acute endothelialitis in the pulmonary microcirculation complicated by abnormal vasoconstrictor responses, luminal plugging by inflammatory cells, and intravascular thrombosis. This endothelialitis extends into the systemic circulation what may lead to acute myocardial injury, myocarditis, and thromboembolic complications both in the arterial and venous circulation.

Keywords: COVID-19; SARS-CoV-2; adult respiratory distress syndrome; cytokine storm; diabetes; endothelialitis; endothelium; microcirculation; obesity; thrombosis; ventilation.

Figure 1.

Mortality and case fatality rates due to COVID-19. Left: relative contribution of different age groups to the mortality related to COVID-19 in China, Italy, Spain, the Netherlands (NL) and the UK. Right: case fatality rate for different age groups in China, Italy, Spain, the Netherlands and England and Wales.

Figure 2.

COVID-19 and the lung: functional ventilatory phenotypes and clinical course. HFNC (high flow nasal canula); NIV (non-invasive ventilation); IMV (invasive mechanical ventilation); ECMO (extracorporeal membrane oxygenation), PEEP (positive end-expiratory pressure). Figure in part redrawn and adapted from [37].

Figure 3.

Role of ACE2 in the renin-angiotensin system (RAS). ACE2 balances the two axes of the RAS. Normal activity of ACE2 promotes the protective ACE2/Ang 1-7/Mas receptor axis and loss of ACE2 results in overactivity in the ACE/Ang II/AT1 receptor axis causing a shift towards diseased states.

Figure 4.

COVID-19 uses angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) as cell entry receptors. Viral spike glycoprotein activated by TMPRSS2 interacts with cell surface ACE2 and both are internalised through endocytosis, resulting in decreased surface ACE2 expression. Endocytosis upregulates ADAM17 activity, which cleaves ACE2 from the cell membrane, perpetuating the loss of ACE2 from tissue RAS. Loss of ACE2 leads to the accumulation of Ang II, which through AT1 receptors also upregulates ADAM17, resulting in further cleavage of cell surface ACE2. The activation of ADAM17 by Ang II also generates TNFα and soluble IL-6R, which can lead to activation of the transcription factor STAT3. SARS-CoV-2 itself leads to the activation of NF-kB via pattern recognition receptors (PPRs). The combined activation of NF-kB and STAT3 leads to the activation of the IL-6 amplifier, causing a massive production of cytokines and the development of ARDS.

Figure 5.

Pathophysiological conundrum. Top: In older patients with obesity, diabetes, pre-existing cardiovascular diseases and associated endothelial dysfunction, SARS-CoV-2 infection critically unbalances the fragile equilibrium between the protective ACE2-Ang [1-7]-MAS -axis and the inflammation- and disease-promoting ACE -Ang II-AT1 axis of the RAS. Viral infection worsens the age-related dysregulation of the innate immune system slowing down the early immune response allowing increased and prolonged viral replication in the lung. The acute lung injury caused by the viral infection involves also the endothelium of the peri-alveolar capillaries. The ensuing endothelialitis promotes alveolar edoema formation due to increased vascular leakage through increased gap formation between the inflamed endothelial cells. Clogging and occlusion by inflammatory cells and intravascular thrombus formation within the lung capillaries worsens the ventilation-perfusion mismatch causing the impaired oxygen uptake by the lung. The acute lung injury triggers a later on-setting but overwhelming acute myeloid immune response and associated cytokine storm leading to further lung injury with the development of ARDS. Bottom: Viral infection extends into the peri-alveolar capillaries turning the pre-existent endothelial dysfunction into a severe endothelialitis with vascular leakage and impaired fluid and ion clearance causing pulmonary edoema, intense inflammation and intravascular and intra-alveolar thrombosis. ATI: alveolar epithelial cell type I; ATII: alveolar epithelial cell type II. Figure redrawn and adapted from [126,155].