The circulating renin-angiotensin system and mortality among patients hospitalized for COVID-19: a mechanistic substudy of the ACTIV-4 Host Tissue trials

SARS-CoV-2 targets angiotensin-converting enzyme-2 (ACE2), a key peptidase of the renin-angiotensin system (RAS), which regulates the balance of the vasoconstrictor/inflammatory peptide Ang II and the vasodilator/anti-inflammatory peptide Ang-(1–7). Few studies have quantified the circulating elements of the RAS longitudinally in SARS-CoV-2 infection and their association with COVID-19 outcomes. Thus, we evaluated the association of circulating RAS enzymes and peptides with mortality among patients with COVID-19. Blood samples were collected from 111 patients with COVID-19 and new-onset hypoxemia during the delta and omicron waves at 19 hospitals in the United States. Circulating RAS components were quantified via radioimmunoassay or ELISA at 0 (baseline), 1, 3, and 5 days after randomization. We used multivariable Cox regression to estimate the association of baseline and longitudinal RAS concentrations with 90-day mortality. Participants were aged 18–90 (means [SD]: 55 [14]) yr and 62% were male. There were 22 (20%) deaths over 90 days of follow-up. ACE2 levels above the sample median (4.9 pM; adjusted HR [95% CI]: 0.10 [0.02, 0.43]) and ACE2/ACE ratio (6.0 10³; adjusted HR: 0.08 [0.02, 0.39]) were associated with significantly lower mortality. Similarly, when analyzed as continuous, log₂-normalized, time-varying predictors from day 0 to day 5, twofold increments of ACE2 and ACE2/ACE ratio over this period were associated with lower mortality (adjusted HR: 0.79 [0.65, 0.97] and 0.78 [0.63, 0.97], respectively). Circulating Ang II, Ang-(1–7), and ACE levels were not associated with mortality. These results suggest higher circulating ACE2 protein in hospitalized patients with COVID-19 is associated with reduced mortality.