Effect of amlodipine on the circulating renin-angiotensin-aldosterone system in healthy cats.

BACKGROUND: Systemic hypertension (SH) is a common cardiovascular disease in older cats that is treated primarily with the calcium channel blocker amlodipine besylate (AML). The systemic effect of AML on the classical and alterative arms of the renin-angiotensin-aldosterone system (RAAS) in cats is incompletely characterized. HYPOTHESIS/OBJECTIVES: To determine the effect of AML compared to placebo on circulating RAAS biomarkers in healthy cats using RAAS fingerprinting. ANIMALS: Twenty healthy client-owned cats. METHODS: Cats were administered amlodipine besylate (0.625 mg in toto) or placebo by mouth once daily for 14 days in a crossover design with a 4-week washout period. Plasma AML concentrations and RAAS biomarker concentrations were measured at multiple timepoints after the final dose in each treatment period. Time-weighted averages for RAAS biomarkers over 24 hours after dosing were compared between treatment groups using Wilcoxon rank-sum testing. RESULTS: Compared to placebo, AML treatment was associated with increases in markers of plasma renin concentration (median 44% increase; interquartile range [IQR] 19%-86%; P = .009), angiotensin I (59% increase; IQR 27-101%; P = .006), angiotensin II (56% increase; IQR 5-70%; P = .023), angiotensin IV (42% increase; -19% to 89%; P = .013); and angiotensin 1-7 (38% increase; IQR 9-118%; P = .015). CONCLUSIONS AND CLINICAL IMPORTANCE: In healthy cats, administration of AML resulted in nonspecific activation of both classical and alternative RAAS pathways.

Renin-Angiotensin System Modulation With Synthetic Angiotensin (1-7) and Angiotensin II Type 1 Receptor-Biased Ligand in Adults With COVID-19: Two Randomized Clinical Trials.

Importance: Preclinical models suggest dysregulation of the renin-angiotensin system (RAS) caused by SARS-CoV-2 infection may increase the relative activity of angiotensin II compared with angiotensin (1-7) and may be an important contributor to COVID-19 pathophysiology. Objective: To evaluate the efficacy and safety of RAS modulation using 2 investigational RAS agents, TXA-127 (synthetic angiotensin [1-7]) and TRV-027 (an angiotensin II type 1 receptor-biased ligand), that are hypothesized to potentiate the action of angiotensin (1-7) and mitigate the action of the angiotensin II. Design, Setting, and Participants: Two randomized clinical trials including adults hospitalized with acute COVID-19 and new-onset hypoxemia were conducted at 35 sites in the US between July 22, 2021, and April 20, 2022; last follow-up visit: July 26, 2022. Interventions: A 0.5-mg/kg intravenous infusion of TXA-127 once daily for 5 days or placebo. A 12-mg/h continuous intravenous infusion of TRV-027 for 5 days or placebo. Main Outcomes and Measures: The primary outcome was oxygen-free days, an ordinal outcome that classifies a patient's status at day 28 based on mortality and duration of supplemental oxygen use; an adjusted odds ratio (OR) greater than 1.0 indicated superiority of the RAS agent vs placebo. A key secondary outcome was 28-day all-cause mortality. Safety outcomes included allergic reaction, new kidney replacement therapy, and hypotension. Results: Both trials met prespecified early stopping criteria for a low probability of efficacy. Of 343 patients in the TXA-127 trial (226 [65.9%] aged 31-64 years, 200 [58.3%] men, 225 [65.6%] White, and 274 [79.9%] not Hispanic), 170 received TXA-127 and 173 received placebo. Of 290 patients in the TRV-027 trial (199 [68.6%] aged 31-64 years, 168 [57.9%] men, 195 [67.2%] White, and 225 [77.6%] not Hispanic), 145 received TRV-027 and 145 received placebo. Compared with placebo, both TXA-127 (unadjusted mean difference, -2.3 [95% CrI, -4.8 to 0.2]; adjusted OR, 0.88 [95% CrI, 0.59 to 1.30]) and TRV-027 (unadjusted mean difference, -2.4 [95% CrI, -5.1 to 0.3]; adjusted OR, 0.74 [95% CrI, 0.48 to 1.13]) resulted in no difference in oxygen-free days. In the TXA-127 trial, 28-day all-cause mortality occurred in 22 of 163 patients (13.5%) in the TXA-127 group vs 22 of 166 patients (13.3%) in the placebo group (adjusted OR, 0.83 [95% CrI, 0.41 to 1.66]). In the TRV-027 trial, 28-day all-cause mortality occurred in 29 of 141 patients (20.6%) in the TRV-027 group vs 18 of 140 patients (12.9%) in the placebo group (adjusted OR, 1.52 [95% CrI, 0.75 to 3.08]). The frequency of the safety outcomes was similar with either TXA-127 or TRV-027 vs placebo. Conclusions and Relevance: In adults with severe COVID-19, RAS modulation (TXA-127 or TRV-027) did not improve oxygen-free days vs placebo. These results do not support the hypotheses that pharmacological interventions that selectively block the angiotensin II type 1 receptor or increase angiotensin (1-7) improve outcomes for patients with severe COVID-19. Trial Registration: ClinicalTrials.gov Identifier: NCT04924660.

Effect of Angiotensin-Converting Enzyme Inhibitor and Angiotensin Receptor Blocker Initiation on Organ Support-Free Days in Patients Hospitalized With COVID-19: A Randomized Clinical Trial.

IMPORTANCE: Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective: To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS: In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non-critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS: Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES: The primary outcome was organ support-free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS: On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support-free days among critically ill patients was 10 (-1 to 16) in the ACE inhibitor group (n = 231), 8 (-1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support-free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE: In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02735707.

Renin-Angiotensin-Aldosterone System Inhibitors and Development of Gynecologic Cancers: A 23 Million Individual Population-Based Study.

The chronic receipt of renin-angiotensin-aldosterone system (RAAS) inhibitors including angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) have been assumed to be associated with a significant decrease in overall gynecologic cancer risks. This study aimed to investigate the associations of long-term RAAS inhibitors use with gynecologic cancer risks. A large population-based case-control study was conducted from claim databases of Taiwan's Health and Welfare Data Science Center (2000-2016) and linked with Taiwan Cancer Registry (1979-2016). Each eligible case was matched with four controls using propensity matching score method for age, sex, month, and year of diagnosis. We applied conditional logistic regression with 95% confidence intervals to identify the associations of RAAS inhibitors use with gynecologic cancer risks. The statistical significance threshold was p < 0.05. A total of 97,736 gynecologic cancer cases were identified and matched with 390,944 controls. The adjusted odds ratio for RAAS inhibitors use and overall gynecologic cancer was 0.87 (95% CI: 0.85-0.89). Cervical cancer risk was found to be significantly decreased in the groups aged 20-39 years (aOR: 0.70, 95% CI: 0.58-0.85), 40-64 years (aOR: 0.77, 95% CI: 0.74-0.81), ≥65 years (aOR: 0.87, 95% CI: 0.83-0.91), and overall (aOR: 0.81, 95% CI: 0.79-0.84). Ovarian cancer risk was significantly lower in the groups aged 40-64 years (aOR: 0.76, 95% CI: 0.69-0.82), ≥65 years (aOR: 0.83, 95% CI: 0.75-092), and overall (aOR: 0.79, 95% CI: 0.74-0.84). However, a significantly increased endometrial cancer risk was observed in users aged 20-39 years (aOR: 2.54, 95% CI: 1.79-3.61), 40-64 years (aOR: 1.08, 95% CI: 1.02-1.14), and overall (aOR: 1.06, 95% CI: 1.01-1.11). There were significantly reduced risks of gynecologic cancers with ACEIs users in the groups aged 40-64 years (aOR: 0.88, 95% CI: 0.84-0.91), ≥65 years (aOR: 0.87, 95% CI: 0.83-0.90), and overall (aOR: 0.88, 95% CI: 0.85-0.80), and ARBs users aged 40-64 years (aOR: 0.91, 95% CI: 0.86-0.95). Our case-control study demonstrated that RAAS inhibitors use was associated with a significant decrease in overall gynecologic cancer risks. RAAS inhibitors exposure had lower associations with cervical and ovarian cancer risks, and increased endometrial cancer risk. ACEIs/ARBs use was found to have a preventive effect against gynecologic cancers. Future clinical research is needed to establish causality.

Renin-Angiotensin System Inhibition in Advanced Chronic Kidney Disease.

BACKGROUND: Renin-angiotensin system (RAS) inhibitors - including angiotensin-converting-enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) - slow the progression of mild or moderate chronic kidney disease. However, the results of some studies have suggested that the discontinuation of RAS inhibitors in patients with advanced chronic kidney disease may increase the estimated glomerular filtration rate (eGFR) or slow its decline. METHODS: In this multicenter, open-label trial, we randomly assigned patients with advanced and progressive chronic kidney disease (eGFR, <30 ml per minute per 1.73 m2 of body-surface area) either to discontinue or to continue therapy with RAS inhibitors. The primary outcome was the eGFR at 3 years; eGFR values that were obtained after the initiation of renal-replacement therapy were excluded. Secondary outcomes included the development of end-stage kidney disease (ESKD); a composite of a decrease of more than 50% in the eGFR or the initiation of renal-replacement therapy, including ESKD; hospitalization; blood pressure; exercise capacity; and quality of life. Prespecified subgroups were defined according to age, eGFR, type of diabetes, mean arterial pressure, and proteinuria. RESULTS: At 3 years, among the 411 patients who were enrolled, the least-squares mean (±SE) eGFR was 12.6±0.7 ml per minute per 1.73 m2 in the discontinuation group and 13.3±0.6 ml per minute per 1.73 m2 in the continuation group (difference, -0.7; 95% confidence interval [CI], -2.5 to 1.0; P = 0.42), with a negative value favoring the outcome in the continuation group. No heterogeneity in outcome according to the prespecified subgroups was observed. ESKD or the initiation of renal-replacement therapy occurred in 128 patients (62%) in the discontinuation group and in 115 patients (56%) in the continuation group (hazard ratio, 1.28; 95% CI, 0.99 to 1.65). Adverse events were similar in the discontinuation group and continuation group with respect to cardiovascular events (108 vs. 88) and deaths (20 vs. 22). CONCLUSIONS: Among patients with advanced and progressive chronic kidney disease, the discontinuation of RAS inhibitors was not associated with a significant between-group difference in the long-term rate of decrease in the eGFR. (Funded by the National Institute for Health Research and the Medical Research Council; STOP ACEi EudraCT number, 2013-003798-82; ISRCTN number, 62869767.).

Is the prognosis of non-hypertensive, COVID-19 patients treated with renin-angiotensin-aldosterone system inhibitors more uncertain?

Previous studies suggested that ongoing treatment with renin-angiotensin-aldosterone system (RAAS) inhibitor drugs may alter the course of SARS-CoV-2 infection and promote the development of more severe forms of the disease. The authors conducted a comparative, observational study to retrospectively analyze data collected from 394 patients admitted to ICU due to SARS-CoV-2 pneumonia. The primary aim of the study was to establish an association between the use of RAAS inhibitor drugs and mortality in the ICU. The secondary aims of the study were to establish an association between the use of RAAS inhibitor drugs and clinical severity at ICU admission, the need for tracheal intubation, total days of mechanical ventilation, and the ICU length of stay. The authors found no statistically significant difference in ICU mortality between patients on RAAS inhibitor drugs at admission and those who were not (31.3% versus 26.2% mortality, p-value 0.3). However, the group of patients taking RAAS inhibitor drugs appeared to be more critical at ICU admission, and this difference became statistically significant in the subgroup of non-hypertensive patients. ICU mortality in the subgroup of non-hypertensive patients treated with RAAS inhibitor drugs also tended to be higher. Overexpression of the angiotensin-converting enzyme 2 (ACE2) in human cells, induced by RAAS inhibitor drugs, promotes viral entry-replication of SARS-CoV-2 and alters the basal balance of the RAAS, which may explain the findings observed in the present study. These phenomena may be amplified in non-hypertensive patients treated with RAAS inhibitor therapy.

Impact of Salt Intake and Renin-Angiotensin-Aldosterone System Blockade on Lung Severe Acute Respiratory Syndrome Coronavirus 2 Host Factors.

INTRODUCTION: The angiotensin-converting enzyme 2 (ACE2) as well as the transmembrane protease serine type 2 (TMPRSS2) have been found to play roles in cell entry for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus causing coronavirus disease 2019 (COVID-19). SARS-CoV-2 infection risk and severity of COVID-19 might be indicated by the expression of ACE2 and TMPRSS2 in the lung. METHODS: A high-salt diet rat model and renin-angiotensin-aldosterone system (RAAS) blockade were used to test whether these factors affect ACE2 and TMPRSS2 expression in the lung. A normal (0.3% NaCl), a medium (2% NaCl), or a high (8% NaCl) salt diet was fed to rats for 12 weeks, along with enalapril or telmisartan, before examining the lung for histopathological alteration. Using immunofluorescence and qRT-PCR, the localization as well as mRNA expression of ACE2 and TMPRSS2 were investigated. RESULTS: The findings provide evidence that both TMPRSS2 and ACE2 are highly expressed in bronchial epithelial cells as well as ACE2 was also expressed in alveolar type 2 cells. High-salt diet exposure in rats leads to elevated ACE2 expression on protein level. Treatment with RAAS blockers had no effect on lung tissue expression of ACE2 and TMPRSS2. CONCLUSIONS: These findings offer biological support regarding the safety of these drugs that are often prescribed to COVID-19 patients with cardiovascular comorbidity. High salt intake, on the other hand, might adversely affect COVID-19 outcome. Our preclinical data should stimulate clinical studies addressing this point of concern.