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The Circulating Renin-Angiotensin System and Mortality among Patients Hospitalized for COVID-19: A Mechanistic Substudy of the ACTIV-4 Host Tissue Trials.

The Circulating Renin-Angiotensin System and Mortality among Patients Hospitalized for COVID-19: A Mechanistic Substudy of the ACTIV-4 Host Tissue Trials. American journal of physiology. Lung cellular and molecular physiology Schaich, C. L., Chappell, M. C., Shotwell, M. S., Joly, M. M., Gibbs, K. W., Barksdale, A., Douglas, I. S., Chen, P., Levitt, J. E., Puskarich, M. A., Rice, T. W., Harkins, M. S., Hudock, K. M., Lanspa, M. J., Ginde, A. A., Self, W. H., Collins, S. P., Files, D. C. 2025

Abstract

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 (mean [SD]: 55 [14]) years 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 (=6.0×10-3; 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, two-fold 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.

View details for DOI 10.1152/ajplung.00372.2024

View details for PubMedID 39884670