Abstract P130: Higher Circulating Angiotensin Converting Enzyme 2 (ACE2) and ACE2 to ACE Ratio Are Associated With Lower COVID-19 Mortality: A Mechanistic Substudy of the ACTIV-4 Host Tissue Trials

Background: SARS-Cov-2 targets the peptidase ACE2, a key component of the renin-angiotensin system (RAS), which directly 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. Objective: Evaluate the association of circulating RAS enzymes with mortality in critically ill patients with COVID-19. Methods: We quantified serum ACE and ACE2 concentrations by ELISA among 111 patients hospitalized for confirmed SARS-Cov-2 infection with new onset hypoxemia who were randomized to the placebo arm of the ACTIV-4 Host Tissue trials investigating RAS pathway interventions. Serum was collected at baseline/randomization (Day 0) and 1, 3, and 5 days after randomization. We used multivariable Cox regression to estimate the association of baseline and longitudinal ACE and ACE2 with 90-day mortality. Hazard ratios (HR) for RAS enzyme concentrations were adjusted for age, sex, race/ethnicity, baseline level of O 2 support, obesity, hypertension, RAS inhibitor use prior to admission, and vasopressor use within 7 days of admission. Results: Participants were aged 18-90 (mean [SD] = 55 [14]) years, 62% male, 42% non-White, with 58% and 48% prevalence of obesity and hypertension, respectively. There were 22 (20%) deaths over 90 days of follow-up (median [25%, 75%] time to event = 16 [9, 29] days). Relative to participants with values below the sample median, those with higher Day 0 ACE2 (>4.9 pM; adjusted HR [95% CI] = 0.07 [0.02, 0.33]) and ACE2/ACE ratio (>6.0*10 -3 ; adjusted HR = 0.08 [0.01, 0.39]) had significantly lower mortality. Similarly, when analyzed as continuous, log 2 -normalized, time-varying predictors from Day 0 to Day 5, two-fold increments in ACE2 (adjusted HR = 0.81 [0.69, 0.96]) and ACE2/ACE ratio (adjusted HR = 0.78 [0.64, 0.96]) over this period were associated with lower mortality. Results did not differ by hypertension status (interaction p=0.385 and 0.278 for Day 0 ACE2 and ACE2/ACE ratio, respectively, and p=0.714 and 0.457 for time-varying ACE2 and ACE2/ACE ratio, respectively). In contrast, neither ACE levels at Day 0 (>1.3 nM; adjusted HR = 1.23 [0.41, 3.67]) nor time-varying ACE (adjusted HR = 1.21 [0.75, 1.95]) were associated with mortality. Conclusions: Higher baseline and longitudinal serum ACE2 levels, but not ACE, were associated with markedly reduced mortality among hospitalized patients with COVID-19, consistent with a protective role for ACE2. Whether serum ACE2 levels arise from tissue ACE2 shedding, thus binding less virus to tissue, should be explored further. A better understanding of the RAS timecourse in severe COVID-19 illness could identify patients at greater risk for adverse outcomes and inform targeted treatment strategies.