Is There an Association Between COVID-19 Mortality and the Renin-Angiotensin System? A Call for Epidemiologic Investigations

Abstract

Mortality from coronavirus disease 2019 (COVID-19) is strongly associated with cardiovascular disease, diabetes, and hypertension. These disorders share underlying pathophysiology related to the renin-angiotensin system (RAS) that may be clinically insightful. In particular, activity of the angiotensin-converting enzyme 2 (ACE2) is dysregulated in cardiovascular disease, and this enzyme is used by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to initiate the infection. Cardiovascular disease and pharmacologic RAS inhibition both increase ACE2 levels, which may increase the virulence of SARS-CoV-2 within the lung and heart. Conversely, mechanistic evidence from related coronaviruses suggests that SARS-CoV-2 infection may downregulate ACE2, leading to toxic overaccumulation of angiotensin II that induces acute respiratory distress syndrome and fulminant myocarditis. RAS inhibition could mitigate this effect. With conflicting mechanistic evidence, we propose key clinical research priorities necessary to clarify the role of RAS inhibition in COVID-19 mortality that could be rapidly addressed by the international research community.

Keywords: COVID-19; SARS-CoV-2; angiotensin-converting enzyme 2; cardiovascular disease; renin-angiotensin system.

Figure 1.

SARS-CoV-2 and ACE2. ACE2 inhibits Ang II activity in the renin-angiotensin system through degradation of Ang I and Ang II into Ang 1–9 and Ang 1–7. Ang II and the AT₁R have proinflammatory effects that may lead to acute lung injury or myocarditis, whereas the AT₂ and Mas receptors have anti-inflammatory effects. SARS-CoV-2 uses ACE2 as its functional receptor and induces acute lung injury and myocarditis through unknown mechanisms. ACEi and ARBs inhibit the Ang II/AT₁R axis, which may be anti-inflammatory; they also increase ACE2 expression, which may increase SARS-CoV-2 virulence. Abbreviations: ACEi, angiotensin-converting enzyme inhibitors; ACE2, angiotensin-converting enzyme 2; Ang, angiotensin; ARB, angiotensin receptor blocker; AT, angiotensin; AT₁R, AT₁ receptor; AT₂R, AT₂ receptor; Mas, mitochondrial assembly; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.