Angiotensin II Receptor Blocker Treatment Research Articles

14-LB: Abdominal Obesity Indices Predict Incident Renal Events in a 10-Year Cohort with Type 2 Diabetes Mellitus

Background: Obesity, especially abdominal obesity, has been associated with diabetes. However, few studies focused on the association between obesity indices and diabetic nephropathy, let alone the longitudinal studies. Waist circumference (WC), visceral adiposity index (VAI), Chinese visceral adiposity index (CVAI) and lipid accumulation product (LAP) are described as abdominal obesity indices. The present study aimed to explore the associations between these indices and incident renal events in a 10-year cohort with type 2 diabetes mellitus (T2DM). Methods: A total of 2709 participants with T2DM from the Beijing Community Diabetes Study were included. Prespecified renal outcomes included incident or worsening nephropathy (progression to macroalbuminuria, doubling of the serum creatinine, initiation of renal-replacement therapy, or renal death) and incident albuminuria. Multivariable Cox regression were applied to analyze the associations between these indices and renal events. Results: Multivariable analyses indicated that each 1-SD increase in WC, VAI, CVAI and LAP was associated with a higher risk of renal events, with adjusted hazard ratios (HRs) being 1.236 [95% CI (confidence interval): 1.079-1.417], 1.135 (1.026-1.257), 1.295 (1.132-1.483), and 1.144 (1.036-1.263), respectively. Moreover, participants in the highest quartile of abdominal obesity indices were at higher risk of renal events compared to those in the lowest quartile (all P for trend<0.05). However, only CVAI was always significantly positively associated with incident renal events in all subgroups, including gender (male vs. female), age (< 60 years vs. ≥60 years) and ACEI (angiotensin-converting enzyme inhibitor) or ARB (angiotensin II receptor blocker) treatment (no vs. yes). Conclusion: Abdominal obesity indices could predict renal events in a 10-year cohort with T2DM, and CVAI may be more universal to predict renal events than WC, VAI and LAP in certain population. Disclosure C. Ma: None. M. Yuan: None. Funding Capital's Funds for Health Improvement and Research (2022-1-1101, 2016-1-2057)

#4321 ACTION3 PHASE 3 STUDY: EVALUATING A NOVEL THERAPEUTIC STRATEGY OF A CCR2 INHIBITOR (DMX-200) WITH ANGIOTENSIN RECEPTOR BLOCKADE IN FSGS

Abstract Background and Aims Focal segmental glomerulosclerosis (FSGS) is a disease of podocytes. Complications include nephrotic syndrome and progressive kidney failure. FSGS is a condition with high unmet need and there is no approved treatment. The angiotensin II receptor type 1 (AT1R) and chemokine receptor 2 (CCR2) are G protein coupled receptors that form functional heteromers. Simultaneous antagonism of these receptors suggested synergistic renoprotective effects in preclinical and early phase clinical studies of proteinuric kidney disease. DMX-200 (repagermanium) is a C-C chemokine receptor type 2 (CCR2) inhibitor that, when administered concurrently with an angiotensin II receptor blocker (ARB), is designed to inhibit recruitment of monocytes implicated in the inflammatory chemokine environment of chronic disease. In a Phase 2a open-label study of 27 patients with proteinuric chronic kidney disease, 25% of patients achieved > 50% reduction in uPCR with combined use of DMX-200 and irbesartan. A Phase 2a placebo-controlled cross-over study in 8 patients with primary FSGS receiving stable dose of irbesartan demonstrated evidence of promising efficacy with clinically relevant reduction in uPCR of 17% with DMX-200 compared with placebo. These encouraging data suggest that treatment with DMX-200 may result in clinically meaningful reduction in proteinuria when added to ARB in patients with glomerular diseases such as FSGS. Proteinuria reduction is a positive prognostic sign for preserving kidney function. The observations from earlier trials have led to the initiation of an international randomised double-blind, placebo-controlled Phase 3 clinical trial (ACTION3) to further evaluate the efficacy of DMX-200 in patients with FSGS receiving an ARB. Method Eligible patients are adults (18-80 years) with biopsy-proven primary FSGS, genetic FSGS or FSGS of undetermined cause (FSGS-UC), and uPCR of >1.5g/g based on 24hr urine collection and eGFR of ≥25 ml/min/1.73 m2. Blood pressure ≤160/100 mmHg and BMI ≤40kg/m2. Patients with secondary FSGS or those treated with strong immunomodulatory agents (other than corticosteroids) are excluded. All patients are required to receive concomitant ARB treatment at a dose of at least 50% of the maximum approved dose according to the relevant product label. Patients receiving ACE-inhibitors are required to switch to an ARB. Other background therapies such as SGLT-2 inhibitors and mineralocorticoid receptor antagonists are permitted if receiving a stable dose in the 3 months prior to screening. Patients are randomized in a 1:1 ratio to DMX-200 (120 mg twice daily) or placebo. The primary objective is to evaluate the efficacy of DMX-200 on reduction in PCR after 35 weeks of treatment and eGFR slope after 104 weeks of treatment. Secondary objectives are safety and tolerability of DMX-200 and to evaluate the effect of DMX-200 on response criteria and composite endpoint of worsening kidney function. Exploratory objectives include assessment of changes in inflammatory biomarkers such as MCP-1 and the pharmacokinetic profile of DMX-200. Two interim analyses (IA) are planned, first planned IA for futility will be performed by an Independent Data Monitoring Committee after the first ​72 randomized patients (36 patients per group) complete 35 weeks ​of treatment. A second IA will be performed once approximately​ 144 enrolled patients complete 35 weeks ​of treatment.​ The final analysis will be performed once approximately 286 patients complete 104 weeks of treatment. The study is currently open in 11 countries at approximately 75 investigational sites and will be expanded to include more countries and sites subject to a successful first interim analysis. Results ACTION3 is a trial in progress and is expected to be completed in 2026. Conclusion ACTION3 is a Phase 3 randomized, placebo-controlled efficacy and safety trial which evaluates the novel approach of combining an investigational CCR2 inhibitor, DMX-200, with angiotensin receptor blockade in patients with FSGS.

A collaborative study of the impact of N-nitrosamines presence and ARB recall on ARB utilization – results from IQVIA™ Disease Analyzer Germany

PurposeRegulators are increasingly concerned with the impact of recalls on drug adherence. In 2018, N-nitrosamines impurities were detected in valsartan containing medical products. Concerned products were immediately recalled in July 2018 by regulatory agencies internationally. In Germany, recalls were issued for valsartan, losartan and irbesartan from July 2018 to March 2019. This study examined angiotensin II receptor blocker (ARB) utilization trends and switching patterns in Germany before and after July 2018.MethodsPatients prescribed ARBs from January 2014 to June 2020 in general practices in Germany were included in a collaborative framework common protocol drug utilization study led by the US Food and Drug Administration. Trends in monthly and quarterly proportions of total ARB prescribing were analysed for individual ARBs using descriptive statistics and interrupted time series analysis. The rate of switching to an alternative ARB was analysed before and after the recalls.ResultsThe proportion of valsartan prescriptions immediately decreased from 35.9 to 17.8% following the first recalls in July 2018, mirrored by an increased proportion for candesartan. Increased switching from valsartan to candesartan was observed. No increased switching was observed after losartan recalls, whereas for irbesartan, increased switching was observed 6–12 months after the last recall. Increased switching from ARBs to angiotensin-converting enzyme (ACE) inhibitors or ARB treatment discontinuations were not observed.ConclusionThis study showed that patients were able to continue ARB treatment despite the July 2018–March 2019 recalls, although many patients needed to switch to an alternative ARB. The duration of the impact of ARB recalls appeared to be limited.

689 IMPACT OF RENIN-ANGIOTENSIN SYSTEM INHIBITORS ON CLINICAL OUTCOME IN HYPERTENSIVE PATIENTS WITH SEVERE AORTIC STENOSIS UNDERGOING TRANSCATHETER AORTIC VALVE IMPLANTATION: INSIGHT FROM THE EFFECTAVI REGISTRY

Abstract Aims Left ventricular pressure overload is connected with cardiac renin–angiotensin system activation, which may lead to myocardial fibrosis and poorer clinical outcomes. Hypertensive patients with symptomatic, severe aortic stenosis (AS) undergoing transcatheter aortic valve implantation (TAVI) in the EffecTAVI registry were evaluated for the association between baseline treatment with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) and clinical outcomes. Methods and results The research comprised 373 patients with moderate, high, or prohibitive risk who had TAVI in the EffecTAVI registry (NCT05235555). Using Kaplan–Meier event rates and study-stratified multivariable Cox proportional hazards regression models, we evaluated clinical outcomes at 2 years according to ACEi/ARB therapy status at baseline. Among the 327 patients with hypertension included in the present study, 222 (67.9%) were treated with ACEI/ARB at baseline, whereas 105 (32.1%) were not. Treatment with ACEI/ARB was related with decreased all-cause mortality (HR=0.46, 95% CI 0.25-0.90, p=0.011), although this association was not statistically significant after multivariable adjustment for important covariates. Analyzing pre-procedural ACEi and ARBs separately, ARBs administration was related with a 58% decrease in all-cause mortality (HR=0.42, 95% CI 0.18-0.98, p=0.04), which was confirmed in multivariate analysis. Conclusion In a small cohort of hypertensive patients with severe symptomatic AS from the EffecTAVI registry, ARBs treatment at baseline was independently associated with a lower risk of 2-year all-cause mortality.

THE RENIN-ANGIOTENSIN SYSTEM INHIBITORS IN HAEMODIALYSIS: CARDIOPROTECTIVE? TO WHAT EXTENT?

Objective: The renin-angiotensin-aldosterone (RAAS) system is one of the most important systems in the pathogenesis of coronary heart disease. Its blockage constitutes a central pillar of cardiovascular therapeutics. Patients in end-stage renal disease or on dialysis are almost invariably excluded from trials evaluating antihypertensive treatments. Angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) are more cardioprotective than other antihypertensive agents in patients with chronic renal disease but whether this applies also to patients on dialysis is unknown. This study followed a cohort of haemodialysis patients over a median of three years, we analysed all-cause mortality and cardio-vascular admissions for patients under RAAS inhibitors. Design and method: Twenty-seven HD patients were cross-sectionally analysed in the following groups: G1: patients with hypertension under ACE or ARB treatment (n = 10), G2: patients with hypertension under another class (n = 7), G3: non-hypertensive patients (n = 10). Associations with all-cause and cardiovascular mortality were assessed over a median of 3 years of follow-up. Results: Overall we had three homogeneous groups, there was no significant difference between median ages (46,3 vs52,7 vs49,9), initial nephropathy or dialysis vintage (5,9 years vs 5,1 vs 11,4). In G1: 4 patients experienced cardiovascular events (40%), but none of them died of cardiovascular causes/complications. In G2: 4 patients had cardiovascular events (57%) amongst whom two died of its complications. In G3: two patients had cardiovascular events (20%) amongst whom one died. There was statistically no significant difference between our groups in terms of cardiovascular morbidity or mortality and in all-causes mortality. Nevertheless, patients under SRA inhibitors presented the lowest number of cardiovascular mortalities. Conclusions: In the study, we observed that patients with SRA inhibitors experienced less cardio-vascular related death, although it is not enough to conclude its cardioprotective status. Larger studies need to be carried to unveil its utility among haemodialysis patients.

Angiotensin-Converting Enzyme (ACE) Inhibitors May Moderate COVID-19 Hyperinflammatory Response: An Observational Study with Deep Immunophenotyping.

Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin-II receptor blockers (ARB), the most commonly prescribed antihypertensive medications, counter renin-angiotensin-aldosterone system (RAAS) activation via induction of angiotensin-converting enzyme 2 (ACE2) expression. Considering that ACE2 is the functional receptor for SARS-CoV-2 entry into host cells, the association of ACEi and ARB with COVID-19 outcomes needs thorough evaluation. We conducted retrospective analyses using both unmatched and propensity score (PS)-matched cohorts on electronic health records (EHRs) to assess the impact of RAAS inhibitors on the risk of receiving invasive mechanical ventilation (IMV) and 30-day mortality among hospitalized COVID-19 patients. Additionally, we investigated the immune cell gene expression profiles of hospitalized COVID-19 patients with prior use of antihypertensive treatments from an observational prospective cohort. The retrospective analysis revealed that there was no increased risk associated with either ACEi or ARB use. In fact, the use of ACEi showed decreased risk for mortality. Survival analyses using PS-matched cohorts suggested no significant relationship between RAAS inhibitors with a hospital stay and in-hospital mortality compared to non-RAAS medications and patients not on antihypertensive medications. From the analysis of gene expression profiles, we observed a noticeable up-regulation in the expression of 1L1R2 (an anti-inflammatory receptor) and RETN (an immunosuppressive marker) genes in monocytes among prior users of ACE inhibitors. Overall, the findings do not support the discontinuation of ACEi or ARB treatment and suggest that ACEi may moderate the COVID-19 hyperinflammatory response.

Angiotensin II receptor blockers in modulation of transforming growth factor-beta effects on mitral valve myxomatous degeneration

Abstract Growing evidence supports role transforming growth factor-β (TGF-β) as a mediator of the myxomatous changes in the mitral valve prolapse. Recently, angiotensin II receptor blockers (ARB) emerged as a potentially effective inhibitor of TGF-β signaling. Treatment of valvular interstitial cells (VICs) with ARB resulted in effective inhibition of TGF-β-induced ECM expression. Our aim was to evaluate the effect of preoperative ARB therapy in modulation of transforming growth factor-β effects on mitral valve myxomatous degeneration. Methods A total of 233 asymptomatic patients (mean age: 53.8±12.9) undergoing mitral valve surgery for severe mitral regurgitation due to mitral valve prolapse were enrolled in our retrospective, non-randomized, single-center study. Resected abnormal segments of the mitral leaflets (segment of the posterior leaflet or the entire valve) were obtained during mitral valve repair/replacement surgery and examined by experienced pathologists. Immunohistochemical characterization of mitral valve sections was performed with the primary antibodies. Quantification was performed by counting TGF-β1 and TGF-β2 positive cells within 10 random high-power fields divided by the total number of cells in specimens. Quantification of immunohistochemical staining for collagen III was performed by measurement of staining area divided by the total area of the specimens. Results Two hundred thirty-three consecutive patients (66% males, mean age 53.8±12.9 years, range 19–80) with severe MR were enrolled in the study. According to the case reports, 43 patients (18.5%) received losartan or telmisartan before surgery and were included in study group. 190 patients (81.5%) did not receive any ARB and were enrolled in the control group. Histological examination showed disorganized collagen and elastin fibers, expansion of the spongiosa layer in both groups. However, MV specimens' immunohistochemistry revealed a lower expression of type III collagen in ARB group as compared to controls (31.3% ± 10.8% vs. 43.8% ± 15.3%; p<0.001). MV leaflets in control group showed the increased VICs density (95.3±39.9 vs. 70.0±21.7/high-power field, p=0.0001). TGF-β1 and TGF-β2 positive cells were significantly rare in the ARB than in control MV specimens (18% vs. 33%, p=0.012 and 16% vs. 38%, p<0.ehab724.15541, respectively). Expression of type III collagen and TGF-β2 positive cells count showed a weak, but significant correlation (r=0.28; p=0.ehab724.155414). The multivariate Cox analysis showed a decrease in the relative risk of valvular thickening (myxomatous degeneration) with ARB therapy (0.85; 95% CI: 0.61 – 1.17; p=0.01). Conclusions We indicate a beneficial effect of ARB treatment through the inhibition of TGF-β pathway on valvular myxomatous degeneration in patients with MVP. Modulation of the progression of MVP with such therapeutic agents may have great clinical significance. Funding Acknowledgement Type of funding sources: None.

Effect of medical treatment on heart failure incidence in patients with a systemic right ventricle

To date, clinical trials have been underpowered to demonstrate a benefit from ACE inhibitors (ACEis) or angiotensin II receptor blockers (ARBs) in preventing systemic right ventricle (sRV) failure and disease progression in patients with transposition of the great arteries (TGA). This observational study aimed to estimate the effect of ACEi and ARB on heart failure (HF) incidence and mortality in a large population of patients with an sRV. Data on all patients with an sRV under active follow-up at two tertiary centres between January 2007 and September 2018 were studied. The effect of ACEi and ARB on the incidence of HF and mortality was estimated using a propensity score weighting approach to control confounding. Among the 359 patients with an sRV (32.2 (IQR 26.4–38.3) years, 59.3% male, 66% complete TGA with atrial switch repair and 34% congenitally corrected TGA), 79 (22%) had a moderate to severe sRV dysfunction and 138 (38%) were treated with ACEi or ARB. Fourteen (3.6%) patients died, 8 (2.1%) underwent heart transplantation and 46 (11.8%) had a new HF event over a median follow-up of 7.1 (IQR 4.0–9.4) years. On multivariate Cox analysis with adjustment using propensity score weighting approaches, ACEi or ARBs treatment was not significantly associated with a lower HF incidence or mortality in patients with an sRV. Despite significant neurohormonal activation described in patients with an sRV, there is still no evidence of a beneficial effect of ACEi or ARB on morbidity and mortality in this population.

Effect of ACEI and ARB treatment on nitric oxide-dependent endothelial function.

Background: Angiotensin-converting-enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB) are widely used as a first-line therapy for the treatment of cardiovascular disease. Here, ACEI modulate the bradykinin receptor (BDKRB1 and BDKRB2) system and NO-dependent endothelial function, thus determining cardiovascular health and regenerative arteriogenesis. The current study aims at evaluating nitric oxide-dependent endothelial function, and gene expression of bradykinin receptors in peripheral blood mononuclear cells (PBMC) from patients with ACEI or ARB treatment. Patients and methods: The WalkByLab has been established to screen cardiovascular patients for peripheral artery disease and coronary artery disease. In total 177 patients from WalkByLab with heterogenous disease and risk status were randomly selected, divided according to their medication history into the following groups: 1. ACEI group, 2. ARB group or 3. non-ACE/ARB group. Total plasma nitrite/nitrate (NO) levels were measured, endothelial function was evaluated by assessing flow meditated dilation (FMD). PBMC were isolated from peripheral whole blood, and gene expression (qRT-PCR) of bradykinin receptors and angiotensin converting enzyme were assessed. Results: Plasma total NO concentration in the ACEI group (24.66±16.28, µmol/l) was increased as compared to the ARB group (18.57±11.58, µmol/l, P=0.0046) and non-ACE/ARB group (16.83±8.64, µmol/l, P=0.0127) in patients between 40 to 90 years of age. However, FMD values (%) in the ACEI group (7.07±2.40, %) were similar as compared to the ARB (6.35±2.13, %) and non-ACE/ARB group (6.51±2.15, %), but significantly negatively correlated with age. Interestingly, BDKRB1 mRNA level was significantly higher and BDKRB2 mRNA level lower in the ACEI group (BDKRB1 3.88-fold±1.05, BDKRB2 0.22-fold±0.04) as compared to the non-ACE/ARB group (BDKRB1 1.00-fold±0.39, P<0.0001, BDKRB2 1.00-fold±0.45, P=0.0136). Conclusions: ACEI treatment enhances total nitrite/nitrate concentration, furthermore, upregulates BDKRB1 in PBMC, but downregulates BDKRB2 mRNA expression. FMD is a strong determinant of vascular aging and is sensitive to underlying heterogenous cardiovascular diseases.

Effects of angiotensin II receptor blockers on serum potassium level and hyperkalemia risk: retrospective single-centre analysis

ObjectiveTo examine the effect of angiotensin II receptor blocker (ARB) treatment on serum potassium level and hyperkalaemia risk in a clinical setting with inpatients and outpatients using calcium channel blockers...

Declines in heart rate variability associated with short-term PM2.5 exposure were modified by blood pressure control and treatment: A multi-city panel study in China

Exposure to fine particulate matter (PM2.5) was associated with altered heart rate variability (HRV). However, whether blood pressure (BP) control and angiotensin II receptor blocker (ARB) treatment modifies the associations was seldom addressed. Therefore, we conducted a 3-phase panel study among 282 hypertensive subjects aged 35–74 years in four cities of China to address this issue. Real-time personal PM2.5 sampling and 24-h ambulatory electrocardiogram monitoring were performed repeatedly in 3 different seasons. Linear mixed-effects models were fitted overall and by control status of BP and ARB treatment to assess the associations between short-term PM2.5 exposure and HRV. The average hourly PM2.5 concentrations (Mean ± SD) ranged from 19.3 ± 18.2 μg/m3 to 99.4 ± 76.9 μg/m3 across study phases and cities. Generally, PM2.5 exposure was associated with decreased hourly and 24-h HRV. However, these adverse impacts were attenuated among patients with controlled BP (<140/90 mmHg). For each 10 μg/m3 increment in moving average of previous 2 days' (MA2d) PM2.5 exposure, 24-h SDNN (standard deviation of NN intervals) and rMSSD (root mean square of successive RR interval differences) decreased by 0.89% (95% CI: 0.19%–1.59%) and 2.98% (95% CI: 1.04%–4.89%) among patients with uncontrolled BP (≥140/90 mmHg), whereas no obvious declines were observed among those with controlled BP (Pdifference = 0.007 and 0.022, respectively). Furthermore, ARB treatment alleviated or eliminated PM2.5-associated declines in hourly and 24-h HRV among those with uncontrolled BP. For instance, 24-h SDNN decreased by 1.31% (95% CI: 0.54%–2.07%) with a 10 μg/m3 increment in lag 2 days’ PM2.5 exposure in ARB nonusers, whereas no obvious changes were observed in ARB users (Pdifference = 0.021). In conclusion, although PM2.5 exposure would decrease HRV, better BP control and ARB treatment could attenuate these adverse impacts, which provides supporting evidence for alleviating autonomic dysfunction of hypertension patients living in areas with high-level PM2.5.

Effect of medical treatment on heart failure incidence in patients with a systemic right ventricle

BackgroundTo date, clinical trials have been underpowered to demonstrate a benefit from ACE inhibitors (ACEis) or angiotensin II receptor blockers (ARBs) in preventing systemic right ventricle (sRV) failure and disease...

Effects of angiotensin II receptor blocker usage on viral load, antibody dynamics, and transcriptional characteristics among COVID-19 patients with hypertension.

Epidemiological evidence suggests that patients with hypertension infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are at increased risk of acute lung injury. However, it is still not clear whether this increased risk is related to the usage of renin-angiotensin system (RAS) blockers. We collected medical records of coronavirus disease 2019 (COVID-19) patients from the First Affiliated Hospital, Zhejiang University School of Medicine (Hangzhou, China), and evaluated the potential impact of an angiotensin II receptor blocker (ARB) on the clinical outcomes of COVID-19 patients with hypertension. A total of 30 hypertensive COVID-19 patients were enrolled, of which 17 were classified as non-ARB group and the remaining 13 as ARB group based on the antihypertensive therapies they received. Compared with the non-ARB group, patients in the ARB group had a lower proportion of severe cases and intensive care unit (ICU) admission as well as shortened length of hospital stay, and manifested favorable results in most of the laboratory testing. Viral loads in the ARB group were lower than those in the non-ARB group throughout the disease course. No significant difference in the time of seroconversion or antibody levels was observed between the two groups. The median levels of soluble angiotensin-converting enzyme 2 (sACE2) in serum and urine samples were similar in both groups, and there were no significant correlations between serum sACE2 and biomarkers of disease severity. Transcriptional analysis showed 125 differentially expressed genes which mainly were enriched in oxygen transport, bicarbonate transport, and blood coagulation. Our results suggest that ARB usage is not associated with aggravation of COVID-19. These findings support the maintenance of ARB treatment in hypertensive patients diagnosed with COVID-19.

Sphingosine-1-phosphate: A mediator of the ARB-MI paradox?

BackgroundAngiotensin converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB) are important in the prevention of cardiovascular disease. The “ARB-MI paradox” implies that no risk reduction of myocardial infarction (MI) was found in ARB-treated patients despite target blood pressure control. Sphingosine-1-phosphate (S1P) is a cardioprotective sphingolipid which is released by platelets during activation. In this study we aimed to investigate differences of S1P homeostasis mediated by bradykinin and sphingosine kinases during ACEI/ARB treatment. MethodsIn this hypothesis generating pilot study, we investigated S1P plasma concentrations in 34 patients before and 3 months after ARB/ACEI medication. S1P levels were measured via liquid chromatography–tandem mass spectrometry. Bradykinin levels were measured by an enzyme-linked immunosorbent assay. ResultsPatient characteristics were not different between the ACEI and ARB group. Baseline S1P plasma concentrations were similar before ARB and ACEI treatment (7.4 SD 1.9 pmol vs. 7.8 SD 2.7 pmol, p = 0.54). After 3 months, S1P plasma levels were significantly higher in ACEI (9.3 SD 2.2 pmol) as compared to ARB treated patients (7.4 SD 2.4 pmol, p = 0.001). Pearson correlation showed no significant association between bradykinin and S1P levels before (r = −0.219; 95% CI [−0.54–0.15]; p = 0.245) or after three months of treatment with ACEI or ARB (r = −0.015; 95% CI [−0.48–0.45]; p = 0.95). ConclusionsS1P plasma concentrations are higher in ACE treated patients as compared to ARB treatment. This leads to the hypothesis, that differences in S1P metabolism might partially explain the ARB-MI paradox. This needs to be tested in clinical trials.

Effects of Angiotensin II Receptor Blockers on Ventricular Hypertrophy in Hypertrophic Cardiomyopathy: A Meta-Analysis of Randomized Controlled Trials.

Animal studies have suggested that angiotensin II receptor blockers (ARBs) can attenuate or reverse the progression of hypertrophic cardiomyopathy, while clinical studies yielded conflicting results. We sought to conduct a meta-analysis to investigate the effect of ARBs in patients with hypertrophic cardiomyopathy. PubMed and EMBASE databases were searched through June 2020. Only randomized controlled trials (RCTs) were included, and each study's quality was assessed using the Jadad scale. The primary outcome was left ventricular mass reduction, and the secondary outcome was the change in left ventricular ejection fraction (LVEF). Data were pooled using the random effects model. A total of 1294 articles were screened. Five RCTs were included in the final analysis, enrolling 209 patients with hypertrophic cardiomyopathy (101 patients were in the ARB arm). ARB treatment was not associated with either significant left ventricular mass reduction (standardized mean difference: - 0.25; 95% CI: - 0.73, 0.22; p = 0.29) or change in LVEF (weighted mean difference: 0.73%; 95% CI: - 1.10%, 2.56%; p = 0.43). Subgroup analysis showed that losartan, one of the most investigated and commonly used ARBs, was also not associated with significant decreases of left ventricular mass (standardized mean difference: - 0.13; 95% CI: - 0.61, 0.36; p = 0.61). This meta-analysis showed that ARB treatment is not associated with reduced left ventricular mass nor remarkable LVEF change among patients with hypertrophic cardiomyopathy. Further studies with a larger number of patients will be required to confirm these findings.

Angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers and prognosis of hypertensive patients hospitalised with COVID-19.

BackgroundAmong hypertensive patients, the association between treatment with angiotensin‐converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARB) and the clinical severity of COVID‐19, remains uncertain.AimsTo determine whether hypertensive patients hospitalised with COVID‐19 are at risk of worse outcomes if on treatment with ACEI or ARB compared to other anti‐hypertensive medications.MethodsThis is a retrospective study conducted at a single academic medical centre (Fondazione Policlinico A. Gemelli IRCCS, Rome, Italy) from 1 to 31 March 2020. We compared patients on treatment with an ACEI/ARB (ACEI/ARB group) to patients receiving other anti‐hypertensive medications (No‐ACEI/ARB group). The end‐points of the study were the all‐cause in‐hospital death and the combination of in‐hospital death or need for intensive care unit (ICU) admission.ResultsThe sample included 166 COVID‐19 patients; median age was 74 years and 109 (66%) were men. Overall, 111 (67%) patients were taking an ACEI or ARB. Twenty‐nine (17%) patients died during the hospital stay, and 51 (31%) met the combined end‐point. After adjustment for comorbidities, age and degree of severity at the presentation, ACEI or ARB treatment was an independent predictor neither of in‐hospital death nor of the combination of in‐hospital death/need for ICU. No differences were documented between treatment with ACEI compared to ARB.ConclusionsAmong hypertensive patients hospitalised for COVID‐19, treatment with ACEI or ARB is not associated with an increased risk of in‐hospital death.

Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers During the COVID-19 Pandemic: A Modeling Analysis.

Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARB) are frequently prescribed for a range of diseases including hypertension, proteinuric chronic kidney disease, and heart failure. There is evidence indicating that these drugs upregulate ACE2, a key component of the renin-angiotensin system (RAS) and is found on the cells of a number of tissues, including the epithelial cells in the lungs. While ACE2 has a beneficial role in many diseases such as hypertension, diabetes, and cardiovascular disease, it also serves as a receptor for both SARS-CoV and SARS-CoV-2 via binding with the spike protein of the virus, thereby allowing it entry into host cells. Thus, it has been suggested that these therapies can theoretically increase the risk of SARS- CoV-2 infection and cause more severe COVID-19. Given the success of ACEi and ARBs in cardiovascular diseases, we seek to gain insights into the implications of these medications in the pathogenesis of COVID-19. To that end, we have developed a mathematical model that represents the RAS, binding of ACE2 with SARS-CoV-2 and the subsequent cell entry, and the host's acute inflammatory response. The model can simulate different levels of SARS-CoV-2 exposure, and represent the effect of commonly prescribed anti-hypertensive medications, ACEi and ARB, and predict tissue damage. Model simulations indicate that whether the extent of tissue damage may be exacerbated by ACEi or ARB treatment depends on a number of factors, including the level of existing inflammation, dosage, and the effect of the drugs on ACE2 protein abundance. The findings of this study can serve as the first step in the development of appropriate and more comprehensive guidelines for the prescription of ACEi and ARB in the current and future coronavirus pandemics.

Association between serum 25-hydroxyvitamin D and the effects of Angiotensin II receptor blocker on renal function among African Americans: A post hoc analysis of a randomized placebo-controlled trial.

We tested the hypothesis that vitamin D status may modify the effect of Angiotensin II receptor blocker (ARB) on renal function among African Americans. Sixty-four participants were included in this ancillary study from a randomized, double-blind, placebo-controlled, crossover trial among normotensive African Americans to test the effect of ARB on stress response of blood pressure and renal sodium handling. The participants were randomly assigned to receive either ARB or placebo for one week, washed out for one week and then cross-overed to receive the other intervention for one week. On the final day of each intervention, the participant underwent a mental stress test. Baseline serum 25-hydroxyvitamin D [25(OH)D] level was measured in this ancillary study. Sixty-four participants were included, aged 26.5±10.2years and 47% were female. Among the participants with the serum 25(OH)D concentrations in the low tertile, ARB treatment was associated with 2.58mg/dL higher blood urea nitrogen (BUN) (P<.001) and was not associated with serum creatinine (SCr) or estimated glomerular filtration rate (eGFR) (Ps>.05). Among the participants in the high 25(OH)D tertile, ARB was associated with 1.59mg/dL lower BUN (P<.001), 0.08mg/dL lower SCr (P=.001), and 8.59mL/min/1.73 m2 higher eGFR (P=.001). The interactions between vitamin D and ARB on renal function were more significant during stress and recovery than at rest. The effects of ARB treatment on renal function are modified by the vitamin D status among African Americans. ARB may improve renal function only among the ones with optimal vitamin D status.

Short-Term Systolic Blood Pressure Variability and Kidney Disease Progression in Patients With Chronic Kidney Disease: Results From C-STRIDE.

BackgroundIt is unclear whether short‐term blood pressure variability is associated with renal outcomes in patients with chronic kidney disease.Methods and ResultsThis study analyzed data from participants in the C‐STRIDE (Chinese Cohort Study of Chronic Kidney Disease) who had chronic kidney disease stages 1 to 4. Short‐term blood pressure variability was measured by calculating the weighted SD (w‐SD) of systolic blood pressure (SBP). Renal outcomes were defined as dialysis initiation and/or transplantation. Risk factors associated with w‐SD of SBP were evaluated by linear regression. Associations of short‐term SBP variability with renal outcomes were evaluated by Cox regression. In total, 1421 patients with chronic kidney disease were included in this study (mean age, 49.4±13.6 years; 56.2% men; estimated glomerular filtration rate, 50.5±29.3 mL/min per 1.73 m2; proteinuria, 0.9 [0.3–2.0] g/d). Mean w‐SD of SBP was 12.6±4.4 mm Hg. w‐SD of SBP was independently associated with older age, 24‐hour SBP, blood pressure circadian pattern, and angiotensin II receptor blocker treatment. During a median follow‐up of 4.9 years, 237 patients developed renal outcomes (37.01 per 1000 patient‐years). The incidence rate increased across the quartiles of w‐SD (log‐rank P=0.005). w‐SD of SBP was associated with an increased risk of renal outcomes, both as a continuous variable (hazard ratio [HR], 1.47; 95% CI, 1.09–1.99) and as a categorical variable (quartile 4 versus quartile 1: HR, 1.60; 95% CI, 1.08–2.36), independent of 24‐hour SBP, daytime SBP, and nighttime SBP.ConclusionsShort‐term SBP was independently associated with the risk of dialysis initiation and/or transplantation in patients with chronic kidney disease.

Association Between Renin-Angiotensin System Blockade Discontinuation and All-Cause Mortality Among Persons With Low Estimated Glomerular Filtration Rate

It is uncertain whether and when angiotensin-converting enzyme inhibitor (ACE-I) and angiotensin II receptor blocker (ARB) treatment should be discontinued in individuals with low estimated glomerular filtration rate (eGFR). To investigate the association of ACE-I or ARB therapy discontinuation after eGFR decreases to below 30 mL/min/1.73 m2 with the risk of mortality, major adverse cardiovascular events (MACE), and end-stage kidney disease (ESKD). This retrospective, propensity score-matched cohort study included 3909 patients from an integrated health care system that served rural areas of central and northeastern Pennsylvania. Patients who initiated ACE-I or ARB therapy from January 1, 2004, to December 31, 2018, and had an eGFR decrease to below 30 mL/min/1.73 m2 during therapy were enrolled, with follow-up until January 25, 2019. Individuals were classified based on whether they discontinued ACE-I or ARB therapy within 6 months after an eGFR decrease to below 30 mL/min/1.73 m2. The association between ACE-I or ARB therapy discontinuation and mortality during the subsequent 5 years was assessed using multivariable Cox proportional hazards regression models, adjusting for patient characteristics at the time of the eGFR decrease in a propensity score-matched sample. Secondary outcomes included MACE and ESKD. Of the 3909 individuals receiving ACE-I or ARB treatment who experienced an eGFR decrease to below 30 mL/min/1.73 m2 (2406 [61.6%] female; mean [SD] age, 73.7 [12.6] years), 1235 discontinued ACE-I or ARB therapy within 6 months after the eGFR decrease and 2674 did not discontinue therapy. A total of 434 patients (35.1%) who discontinued ACE-I or ARB therapy and 786 (29.4%) who did not discontinue therapy died during a median follow-up of 2.9 years (interquartile range, 1.3-5.0 years). In the propensity score-matched sample of 2410 individuals, ACE-I or ARB therapy discontinuation was associated with a higher risk of mortality (hazard ratio [HR], 1.39; 95% CI, 1.20-1.60]) and MACE (HR, 1.37; 95% CI, 1.20-1.56), but no statistically significant difference in the risk of ESKD was found (HR, 1.19; 95% CI, 0.86-1.65). The findings suggest that continuing ACE-I or ARB therapy in patients with declining kidney function may be associated with cardiovascular benefit without excessive harm of ESKD.