Schaich Christopher L, Chappell Mark C, Shotwell Matthew S, Joly Meghan M, Gibbs Kevin W, Barksdale Aaron, Douglas Ivor S, Chen Peter, Levitt Joseph E, Puskarich Michael A, Rice Todd W, Harkins Michelle S, Hudock Kristin M, Lanspa Michael J, Ginde Adit A, Self Wesley H, Collins Sean P, Files D Clark
Department of Surgery, Hypertension and Vascular Research Center, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States.
Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, United States.
Am J Physiol Lung Cell Mol Physiol. 2025 Mar 1;328(3):L405-L412. doi: 10.1152/ajplung.00372.2024. Epub 2025 Jan 30.
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 × 10; adjusted HR: 0.08 [0.02, 0.39]) were associated with significantly lower mortality. Similarly, when analyzed as continuous, log-normalized, time-varying predictors from to , 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. We measured circulating components of the renin-angiotensin system (RAS) longitudinally over 5 days among patients hospitalized with COVID-19 and new-onset hypoxemia. We found that higher serum angiotensin-converting enzyme (ACE)-2 protein and ACE2/ACE ratio, both at baseline and when analyzed as time-varying, repeated measures, were associated with lower 90-day mortality. Results suggest a role for circulating ACE2 as a biomarker of adverse outcomes and could inform treatment strategies targeting the RAS in severe COVID-19 illness.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）靶向血管紧张素转换酶2（ACE2），这是肾素-血管紧张素系统（RAS）的一种关键肽酶，该系统调节血管收缩剂/炎性肽血管紧张素II（Ang II）和血管舒张剂/抗炎肽血管紧张素-(1-7)之间的平衡。很少有研究纵向量化SARS-CoV-2感染中RAS的循环成分及其与2019冠状病毒病（COVID-19）结局的关联。因此，我们评估了COVID-19患者中循环RAS酶和肽与死亡率的关联。在美国19家医院收集了111例在德尔塔和奥密克戎毒株流行期间感染COVID-19并新发低氧血症患者的血样。在随机分组后的0（基线）、1、3和5天，通过放射免疫测定或酶联免疫吸附测定对循环RAS成分进行定量。我们使用多变量Cox回归来估计基线和纵向RAS浓度与90天死亡率的关联。参与者年龄在18至90岁之间（均值[标准差]：55[14]岁），62%为男性。在90天的随访中有22例（20%）死亡。ACE2水平高于样本中位数（≥4.9 pM；调整后风险比[95%置信区间]：0.10[0.02，0.43]）以及ACE2/ACE比值（≥6.0×10；调整后风险比：0.08[0.02，0.39]）与显著较低的死亡率相关。同样，当作为连续的、对数正态化的、从基线到第5天的随时间变化预测因子进行分析时，在此期间ACE2和ACE2/ACE比值增加两倍与较低的死亡率相关（调整后风险比分别为：0.79[0.65，0.97]和0.78[0.63，0.97]）。循环Ang II、血管紧张素-(1-7)和ACE水平与死亡率无关。这些结果表明，住院的COVID-19患者中较高的循环ACE2蛋白与死亡率降低相关。我们对住院的COVID-19并新发低氧血症患者在5天内纵向测量了肾素-血管紧张素系统（RAS）的循环成分。我们发现，无论是在基线时还是作为随时间变化的重复测量进行分析时，较高的血清血管紧张素转换酶（ACE）-2蛋白和ACE2/ACE比值都与较低的90天死亡率相关。结果表明循环ACE2作为不良结局生物标志物的作用，并可为重症COVID-19疾病中靶向RAS的治疗策略提供信息。
