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.

Renin-Angiotensin System Inhibition in Cardiovascular Patients at the Time of COVID19: Much Ado for Nothing? A Statement of Activity from the Directors of the Board and the Scientific Directors of the Italian Society of Hypertension

“…The favorable effects of ACE inhibitors and ARBs on the control of the progression of CVDs in general and in particular of hypertensive patients have been confirmed for many years and for this reason RAS inhibitors represent central agents for the management of cardiovascular conditions that cannot be easily substituted [10]. C. In hypertensive patients with COVID-19 or at risk of COVID-19 infection, ACE inhibitors and ARBs treatment should be maintained according to the recommendations contained in the 2018 ESC/ESH guidelines [10]. D. Similarly, in all patients currently on therapy with ACE inhibitors, ARBs and in the case of patients with heart failure, also the ARNIs, these drugs must not be suspended.…”

“…Indeed, the observed prevalence of male and elderly patients, observed especially in the Italian COVID-19 population, is a confounding factor that needs to be corrected for before any conclusive association is drawn. This concern has been expressed by many [8][9][10].…”

Lipid-lowering therapy and renin-angiotensin-aldosterone system inhibitors in the era of the COVID-19 pandemic

“…The overexpression of ACE2 was reported to enhance viral entry and replication intracellularly [4]. COVID-19, also called SARS-CoV-2, may also use ACE2 as a receptor to initiate infection, leading to severe complications from the heart (acute coronary syndrome (ACS) and fulminant myocarditis), lungs (pneumonia and acute respiratory distress syndrome (ARDS)) and GI tract (diarrhoea syndrome) [5].…”

“…However, before implementing such strategies, we should consider several issues. Firstly, as the COVID-19 infection progresses, ACE2 is downregulated, thus potentially generating an inflammatory response leading to impaired cardiac contractility and acute lung injury [5,7,12]. Therefore, reduced ACE2 expression is linked to worse outcomes.…”

Clinical features and management of severe COVID-19: A retrospective study in Wuxi, Jiangsu Province, China

“…When infected with SARS-CoV-2, the virus predominantly targeted ACE2 in human alveolar type 2cells, resulting in pulmonary symptoms [27]. It has been reported that ACE2 was associated with comorbidities, symptoms and complications in COVID-19 patients, such as hypertension, diabetes, cardiovascular disease and gastrointestinal abnormalities [28]. However, the mechanism still remains unclear.…”