Angiotensin Receptor Blocker Treatment Research Articles

Retrospective analysis of the effect of angiotensin receptor blockers and angiotensin converting enzyme inhibitors on the efficacy of anti-PD-1/PD-L1 immunotherapy in patients with advanced cancer.

2605 Background: Components of the renin angiotensin system (RAS) are expressed in tumors with activation leading to tumor and stromal cell release of immunomodulatory cytokines promoting an immunosuppressive microenvironment and increased infiltration of tumor associated macrophages. Angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) are anti-hypertensives that inhibit the RAS. It is unknown if ACEi and ARB treatment modulates the efficacy of anti-PD-1/PD-L1 immunotherapy. Methods: A retrospective chart review was conducted to identify patients with unresectable malignancies initiating treatment with a PD-1 or PD-L1 inhibitor based regimen between 1/1/13 and 6/1/19 at Valley Hospital in New Jersey. IRB approval was obtained. Efficacy of treatment was measured by medical oncologist documentation of clinical benefit (CB = stable disease / treatment response) versus disease progression. Chi-square tests were performed to assess relationship between ACEi or ARB exposure and immunotherapy benefit. To assess for a broader anti-hypertensive effect, the relationship in patients on a beta-blocker but not ACEi/ARB was assessed. Results: 197 patients were identified of which 190 had documentation of clinical outcome. The mean age was 72.8 years with 54% female and 46% male. 56 patients were exposed to ACEi (N = 28) or ARB (N = 28) and 141 patients to neither. 37 patients were exposed to beta blocker but not ACEi or ARB. 60 patients had nonsquamous NSCLC (16 on ACEi or ARB), 26 squamous NSCLC (7 on ACEi or ARB) and 24 melanoma (10 on ACEi or ARB). 71% of ACEi/ARB exposed patients had CB by clinician assessment as opposed to 47% in those not on ACEi or ARB (p = 0.003). In ACEi exposed patients, 71% had CB versus 51% in unexposed patients (p = 0.048). In ARB exposed patients, 70% had CB versus 51% in unexposed patients (p = 0.069). By contrast, 51% of beta-blocker treated patients had CB versus 55% in untreated patients (p = 0.72). 36% of ACEi/ARB exposed patients remained on treatment at 12 months versus 22% of ACEi/ARB unexposed patients. Subset analyses were performed on the 3 largest patient populations: squamous NSCLC, nonsquamous NSCLC and melanoma. ACEi/ARB exposed melanoma patients had CB rate of 70% versus 43% in those unexposed. ACEi/ARB exposed squamous NSCLC patients had CB rate of 86% versus 47% in unexposed patients. By contrast, ACEi/ARB exposed nonsquamous NSCLC patients had a 56% CB rate versus 48% in unexposed patients. Conclusions: Based on retrospective analysis, advanced cancer patients treated with anti-PD-1/PD-L1 regimens had a statistically significant increase in clinical benefit if administered in the context of renin angiotensin system blockade. Prospective disease specific trials can further validate these findings and define the degree of clinical benefit.

Podocyte-Related Mechanisms Underlying Survival Benefit of Long-Term Angiotensin Receptor Blocker.

We previously found that short-term treatment (week 8 to 12 after injury) with high-dose angiotensin receptor blocker (ARB) induced the regression of existing glomerulosclerosis in 5/6 nephrectomy rats. We therefore assessed the effects of long-term intervention with ARB vs. nonspecific antihypertensives in this study. Adult rats underwent 5/6 nephrectomy and renal biopsy 8 weeks later. The rats were then divided into three groups with equivalent renal function and glomerular sclerosis and treated with high-dose losartan (ARB), nonspecific antihypertensive triple-therapy (TRX), or left untreated (Control) until week 30. We found that blood pressure, serum creatinine levels, and glomerulosclerosis were lower at sacrifice in ARB and TRX vs. Control. Only ARB reduced proteinuria and maintained the density of WT-1-positive podocytes. Glomerular tufts showed more double-positive cells for CD44, a marker of activated parietal epithelial cells, and synaptopodin after ARB vs. TRX or Control. ARB treatment reduced aldosterone levels. ARB-treated rats had significantly improved survival when compared with TRX or Control. We conclude that both long-term ARB and triple-therapy ameliorate progression, but do not sustain the regression of glomerulosclerosis. ARB resulted in the superior preservation of podocyte integrity and decreased proteinuria and aldosterone, linked to increased survival in the uremic environment.

FC082: Effects of Dapagliflozin in Patients with Chronic Kidney Disease According to Background Angiotensin-Converting Enzyme Inhibitor and Angiotensin Receptor Blocker Dose

Abstract BACKGROUND AND AIMS Treatment guidelines for patients with chronic kidney disease (CKD) recommend renin–angiotensin system inhibition (RASi) with angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs) to reduce the risk of kidney failure. However, patients with more advanced CKD do not always tolerate RASi. The sodium-glucose cotransporter 2 inhibitor dapagliflozin reduced the risk of kidney failure in patients with CKD in the DAPA-CKD trial. We performed a post hoc analysis of this trial to assess the efficacy of dapagliflozin by baseline dose level of ACEi or ARB. METHOD Participants with CKD [estimated glomerular filtration rate (eGFR) 25–75 mL/min/1.73 m2; urinary albumin-to-creatinine ratio (UACR) 200–5000 mg/g), with or without type 2 diabetes, were randomized 1:1 to dapagliflozin 10 mg or placebo, once daily. Participants were to be treated with the recommended target dose, or a stable tolerated dose of ACEi or ARB, unless medically contraindicated, for ≥4 weeks prior to inclusion. The primary outcome was a composite of sustained ≥50% eGFR decline, end-stage kidney disease or death from a kidney or cardiovascular cause. A prespecified kidney-specific secondary outcome was the same as the primary endpoint, but without cardiovascular death. A composite cardiovascular outcome (heart failure hospitalization or cardiovascular death), and all-cause mortality were other secondary endpoints. Time-to-event analyses were performed to assess the effects of dapagliflozin versus placebo according to baseline prescription and dose of ACEi or ARB treatment. RESULTS Of 4296 (99.9%) participants with available data on ACEi/ARB doses, 1231 (28.7%) were using the target dose, 1867 (43.5%) a dose ≥50% to <100% of target, 1068 (24.9%) a dose 0 to <50% of target and 130 (3.0%) were not using an ACEi/ARB. In the placebo group, the event rate for the primary outcome was highest among participants not using ACEi/ARBs compared to the other subgroups (figure 1). The benefit of dapagliflozin on the primary composite outcome was consistent regardless of use or non-use of the target dose of ACEi/ARBs. This consistency was maintained for the secondary outcomes (Figure 1). Dapagliflozin compared to placebo reduced the rate of eGFR decline over the study by –0.93 [95% confidence interval (95% CI) 0.61–1.25] mL/min/1.73 m2. This effect was present regardless of the use or non-use of target doses of ACEi/ARBs (P for interaction 0.877). CONCLUSION Dapagliflozin was similarly efficacious in reducing major adverse kidney and cardiovascular outcomes in participants with CKD regardless of the use or dose of ACEi/ARB.

The Effect of Angiotensin II Receptor Blockers in Patients with Hypertrophic Cardiomyopathy: An Updated Systematic Review and Meta-analysis of Randomized Controlled Trials.

Angiotensin receptor blocker (ARB) therapy has been evaluated to slow down the disease progression in patients with hypertrophic cardiomyopathy (HCM), but there is scarce evidence available to date. Therefore, our meta-analysis aimed to explore the efficacy of ARB therapy as a potential disease-modifying treatment in patients with HCM. A literature search was performed using PubMed, Scopus, Web of Science, Embase, Cochrane library, and Clinicaltrials.gov databases from inception to December 13th, 2021. We included only randomized controlled trials (RCTs). The quality of included studies was assessed by the Cochrane Collaboration's tool. Primary outcomes included the reduction in left ventricular mass and improvement in other echocardiographic features of myocardial dysfunction. The secondary outcome was a net reduction in systolic blood pressure. Meta-analysis was performed using pooled standardized mean difference (SMD) and corresponding 95% confidence interval (CI). A total of 1286 articles were screened. Seven RCTs met the inclusion criteria representing a total of 397 patients with HCM (195 patients were in the ARB group). ARB treatment was associated with significant reduction in left ventricular mass (SMD: -0.77; 95% CI: -1.40, -0.03; p = 0.04). ARB therapy was also associated with a significant reduction in systolic blood pressure (SMD: -0.33; 95% CI: -0.61, -0.05: p = 0.02). ARB therapy is associated with a marked reduction in left ventricular mass and systolic blood pressure in patients with hypertrophic cardiomyopathy. We recommend further studies with a larger patient population size to confirm the findings of our meta-analysis. OSF Registries, DOI: 10.17605/OSF.IO/DAS7C.

Angiotensin-converting enzyme inhibitors prevent liver-related events in nonalcoholic fatty liver disease.

Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) can inhibit liver fibrogenesis in animal models. We aimed to evaluate the impact of ACEI/ARB use on the risk of liver cancer and cirrhosis complications in patients with NAFLD. We conducted a retrospective, territory-wide cohort study of adult patients with NAFLD diagnosed between January 2000 and December 2014 to allow for at least 5 years of follow-up. ACEI or ARB users were defined as patients who had received ACEI or ARB treatment for at least 6 months. The primary endpoint was liver-related events (LREs), defined as a composite endpoint of liver cancer and cirrhosis complications. We analyzed data from 12,327 NAFLD patients (mean age, 54.2±14.7 years; 6163 men [50.0%]); 6805 received ACEIs, and 2877 received ARBs. After propensity score weighting, ACEI treatment was associated with a lower risk of LREs (weighted subdistribution hazard ratio [SHR], 0.48; 95% CI, 0.35-0.66; p<0.001), liver cancer (weighted SHR, 0.46; 95% CI, 0.28-0.75; p=0.002), and cirrhosis complications (weighted SHR, 0.42; 95% CI, 0.27-0.66; p<0.001), but ARB was not. In subgroup analysis, ACEI treatment was associated with greater reduction in LREs in patients with chronic kidney diseases (CKDs) than those without (CKD-weighted SHR, 0.74; 95% CI, 0.52-0.96; p=0.036; non-CKD-weighted SHR, 0.15; 95% CI, 0.07-0.33; p<0.001). ACEI, rather than ARB, treatment is associated with a lower risk of LREs in NAFLD patients, especially among those with CKD.

ACE inhibitor or ARB treatment among patients with diabetes and chronic kidney disease.

Many patients with type 2 diabetes (T2D) and chronic kidney disease (CKD) experience a delay in treatment or fail to initiate treatment with guideline-recommended angiotensin-converting enzyme inhibitors (ACEis) or angiotensin receptor blockers (ARBs) after CKD diagnosis. This study aimed to describe treatment patterns and treatment initiation after initial CKD diagnosis among patients with T2D. Retrospective analysis using data from the Optum Clinformatics Data Mart administrative claims database (January 2014-September 2018). Adult patients with T2D entered the cohort if they met the criteria for CKD, defined as 2 laboratory test results 90 to 365 days apart (January 2014-September 2017) indicating CKD. Included were patients with no prior use of ACEis or ARBs or evidence of kidney disease in the 365 days prior to cohort entry (baseline). Patients were followed for a maximum of 365 days and were censored on death, disenrollment, or end of data. Patient demographics, comorbidities, and medication use were assessed at baseline, and treatments were assessed over a 1-year followup period. Multivariate logistic regression was used to identify factors associated with ACEi or ARB initiation. Among 15,400 eligible patients without prior ACEi or ARB treatment, only 17% initiated such therapy within a year after meeting CKD criteria. Patients who were White, resided in the northeastern United States, had more comorbidities, had less advanced albuminuria, or used sodium-glucose cotransporter 2 inhibitors were less likely to initiatetreatment. A large proportion of patients with T2D meeting criteria for CKD do not initiate the recommended therapy within 1 year of CKD diagnosis, highlighting a need for new therapies that can slow the progression of CKD.

Association of the patterns of use of medications with mortality of COVID-19 infection: a hospital-based observational study

ObjectivesSARS-CoV-2 enters cells using the ACE2 receptor. Medications that affect ACE2 expression or function such as angiotensin receptor blockers (ARBs) and ACE inhibitors (ACE-I) and metformin have the potential to...

Neutrophil percentage‐to‐albumin ratio and monocyte‐to‐lymphocyte ratio as predictors of free‐wall rupture in patients with acute myocardial infarction

BackgroundsFree‐wall rupture (FWR) has a high mortality rate. We aimed to find sensitive predictive indicators to identify high‐risk FWR patients by exploring the predictive values of neutrophil percentage‐to‐albumin ratio (NPAR) and monocyte‐to‐lymphocyte ratio (MLR) on patients with acute myocardial infarction (AMI).Methods76 FWR patients with AMI were collected, and then 228 non‐CR patients with AMI were randomly selected (1:3 ratio) in this retrospective study. The independent influencing factors of FWR were evaluated by univariate and multivariate logistic regression analysis. The receiver‐operating characteristic (ROC) curve analysis was applied to evaluate the predictive value of NPAR and MLR for FWR.ResultsAccording to the results of multivariate logistic regression analysis, emergency percutaneous coronary intervention (PCI) (OR = 0.27, 95% CI: 0.094–0.751, p = 0.012), angiotensin‐converting enzyme inhibitor (ACEI)/angiotensin receptor blocker (ARB) treatment (OR = 0.17, 95% CI: 0.044–0.659, p = 0.010), NPAR (OR = 2.69, 95% CI: 1.031–7.044, p = 0.043), and MLR (OR = 5.99, 95% CI: 2.09–17.168, p = 0.001) were the influencing factors of the FWR patients with AMI, independently. Additionally, the NPAR and MLR were the predictors of FWR patients, with AUC of 0.811 and 0.778, respectively (both p < 0.001).ConclusionsIn summary, the emergency PCI and ACEI/ARB treatment were independent protective factors for FWR patients with AMI, while the increase of MLR and NPAR were independent risk factors. What's more, NPAR and MLR are good indicators for predicting FWR.

Abstract 14496: The Role of ACE Inhibitors and Angiotensin Receptor Blockers in Cryoballoon Ablation Outcomes for Paroxysmal Atrial Fibrillation

Background: Cryoballoon ablation (CBA) is recommended for patients with paroxysmal atrial fibrillation (AF) refractory to anti-arrhythmic drugs. However, only 70% of patients benefit from an initial CBA. There is a growing evidence that pretreatment with angiotensin converting enzyme inhibitors (ACE-I) and angiotensin receptor blocker (ARB) decreases recurrence of AF post ablation, particularly in non-paroxysmal AF undergoing radiofrequency ablation. The role of ACE-I and ARB in patients with paroxysmal AF in CBA remains unknown. We decided to investigate the role of ACE-I and ARB in preventing recurrence of atrial arrhythmias (AA) following CBA for paroxysmal AF. Methods: We followed 103 patients (Age 60.6 ± 9.1, 29% women) with paroxysmal AF undergoing CBA for one year post procedure. Recurrence was assessed by documented AA on EKG or any form of long-term cardiac rhythm monitoring. A multivariable cox proportional hazard model was used to assess if ACE-I or ARB treatment predicted risk of AA recurrence. Results: After a one year follow up, 19 (18.4%) participants developed recurrence of AA. Use of ACE-I or ARB therapy was noted in the study population. Patients on ACE-I/ARB had a greater prevalence of hypertension and coronary artery disease. On a multivariate model adjusted for baseline demographics and risk factors for AF, ACEI or ARB therapy did not prevent recurrence of AA following CBA (Table, p=0.72). Similarly, on Kaplan-Meier analysis pretreatment with ACE-I/ARB did not predict time to first recurrence of AA (Figure, p=0.2173). Conclusion: In our study population pre-ablation treatment with an ACE-I or an ARB had no influence on the recurrence of AA following CBA for paroxysmal AF.

Kidney single-cell transcriptome profile reveals distinct response of proximal tubule cells to SGLT2i and ARB treatment in diabetic mice

Angiotensin receptor blockers (ARBs) and sodium-glucose cotransporter 2 inhibitors (SGLT2i) have been used as the standard therapy for patients with diabetic kidney disease (DKD). However, how these two drugs possess additive renoprotective effects remains unclear. Here, we conducted single-cell RNA sequencing to profile the kidney cell transcriptome of db/db mice treated with vehicle, ARBs, SGLT2i, or ARBs plus SGLT2i, using db/m mice as control. We identified 10 distinct clusters of kidney cells with predominant proximal tubular (PT) cells. We found that ARBs had more anti-inflammatory and anti-fibrotic effects, while SGLT2i affected more mitochondrial function in PT. We also identified a new PT subcluster, was increased in DKD, but reversed by the treatments. This new subcluster was also confirmed by immunostaining of mouse and human kidneys with DKD. Together, our study reveals kidney cell-specific gene signatures in response to ARBs and SGLT2i and identifies a new PT subcluster, which provides new insight into the pathogenesis of DKD.

Effect of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on the short-term prognosis of COVID-19 infection

Abstract Background Questions emerged about safety renin-angiotensin system (RAS) inhibitors (angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs)) in patients diagnosed with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Our objective was to evaluate the safety of this treatment in a Spanish cohort during 2020 pandemic. Methods Observational study including all consecutive patients (≥40 years old) diagnosed with SARS-CoV-2 through PCR in the microbiology laboratory of our hospital, since March 2nd to 20th 2020. Clinical characteristics and drugs were recorded. Primary end-point (PE) was the combined of all-cause death or need for orotracheal intubation until 30 days of infection symptoms onset. To assess the effect of RAS inhibitors, we performed a double statistical approach, with multivariate logistic regression and propensity-score matching. Results We included 704 patients (table). Median age was 61 years old (IQR 52.9–72.9); 52.7% were female. 34.7% and 12.6% had hypertension (HTA) and diabetes (DM) respectively. 92 patients (13.1%) and 87 patients (12.4%) were taking ACEI and ARB respectively. Baseline characteristics of both subgroups are shown in the table. Patients on RAS inhibitors treatment had a worse clinical profile: were older, more males and with higher prevalence of HTA, DM, dyslipemia, ischemic heart disease and heart failure. There were no differences in terms of respiratory nor neoplasic disease. After 30 days, 112 patients (15.9%) had died, 148 (21.4%) had died or had required invasive mechanical ventilation (PE); 390 patients (55.4%) had needed hospital admission. PE was reached in 33.3% patients under ACEI treatment (vs. 19.6% in control group, p=0.005) and in 41.9% patients under ARB treatment (vs. 18.5% in control group, p&amp;lt;0.001). In the analysis to estimate the effect of ACEI no differences between groups were found (OR 1.01 [0.55–1.85], p=0.973). Likewise, in terms of ARB treatment, there were no differences among both groups (OR 1.66 [0.91–3.03], p=0.097). Using a propensity-score approach 79 patients under ACEI treatment and 72 patients under ARB treatment were matched 1:1 with control patients (characteristics of matched population are described in the table) Logistic binary regression showed no significant differences on incidence of the PE in patients under ACEI treatment (OR 0.84, 95% CI [0.43–1.63], p=0.613) nor ARB treatment (OR 1.82, 95% CI [0.92–3.60], p=0.085). Nevertheless, there was a trend towards worse prognosis in ARB patients. Kaplan-Meier curves of survival free of death or need for mechanical ventilation in matched population (ACEI and ARB treatment) are shown in the figure. Conclusions We have not found any correlation between the severity of the disease and the treatment with ACEI nor ARB. We do not recommend the withdrawal of these drugs during the current epidemic situation. Further studies are needed to assess this finding. Funding Acknowledgement Type of funding sources: None. Description of studied populationKaplan-Meier curve in matched population

Clinical and genetic characterization of a cohort of proteinuric patients with biallelic CUBN variants.

Proteinuria is a well-known risk factor for progressive kidney impairment. Recently, C-terminal cubilin (CUBN) variants have been associated with isolated proteinuria without progression of kidney disease. Genetic testing of 347 families with proteinuria of suspected monogenic cause was performed by next-generation sequencing of a custom-designed kidney disease gene panel. Families with CUBN biallelic proteinuria-causing variants were studied at the clinical, genetic, laboratory and pathologic levels. Twelve families (15 patients) bearing homozygous or compound heterozygous proteinuria-causing variants in the C-terminal CUBN gene were identified, representing 3.5% of the total cohort. We identified 14 different sequence variants, five of which were novel. The median age at diagnosis of proteinuria was 4 years (range 9 months to 44 years), and in most cases proteinuria was detected incidentally. Thirteen patients had moderate to severe proteinuria at diagnosis without nephrotic syndrome. These patients showed lack of response to angiotensin-converting enzyme inhibitor (ACEi) and angiotensin receptor blocker (ARB) treatment, normal kidney biopsy and preservation of normal kidney function over time. The two remaining patients presented a more severe phenotype, likely caused by associated comorbidities. Identification of C-terminal pathogenic CUBN variants is diagnostic of an entity characterized by glomerular proteinuria, normal kidney histology and lack of response to ACEi/ARB treatment. This study adds evidence and increases awareness about albuminuria caused by C-terminal variants in the CUBN gene, which is a benign condition usually diagnosed in childhood with preserved renal function until adulthood.

Effect of Neprilysin Inhibition for Ischemic Mitral Regurgitation after Myocardial Injury.

Angiotensin receptor neprilysin inhibitor (ARNI) treatment reduces functional mitral regurgitation (MR) to a greater extent than angiotensin receptor blocker (ARB) treatment alone, but the mechanism is unclear. We evaluated the mechanisms of how ARNI has an effect on functional MR. After inducing functional MR by left circumflex coronary artery occlusion, male Sprague Dawley rats (n = 31) were randomly assigned to receive the ARNI LCZ696, the ARB valsartan, or corn oil only (MR control). Excised mitral leaflets and left ventricle (LV) were analyzed, and valvular endothelial cells were evaluated focusing on molecular changes. LCZ696 significantly attenuated LV dilatation after 6 weeks when compared with the control group (LV end-diastolic volume, 461.3 ± 13.8 µL versus 525.1 ± 23.6 µL; p < 0.05), while valsartan did not (471.2 ± 8.9 µL; p > 0.05 to control). Histopathological analysis of mitral leaflets showed that LCZ696 strongly reduced fibrotic thickness compared to the control group (28.2 ± 2.7 µm vs. 48.8 ± 7.5 µm; p < 0.05). Transforming growth factor-β and downstream phosphorylated extracellular-signal regulated kinase were also significantly lower in the LCZ696 group. Consequently, excessive endothelial-to-mesenchymal transition (EndoMT) was mitigated in the LCZ696 group compared to the control group and leaflet area was higher (11%) in the LCZ696 group than in the valsartan group. Finally, the MR extent was significantly lower in the LCZ696 group and functional improvement was observed. In conclusion, neprilysin inhibitor has positive effects on LV reverse remodeling and also attenuates fibrosis in MV leaflets and restores adaptive growth by directly modulating EndoMT.

An ACE inhibitor reduces bactericidal activity of human neutrophils in vitro and impairs mouse neutrophil activity in vivo.

Angiotensin-converting enzyme inhibitors (ACEIs) are used by millions of patients to treat hypertension, diabetic kidney disease, and heart failure. However, these patients are often at increased risk of infection. To evaluate the impact of ACEIs on immune responses to infection, we compared the effect of an ACEI versus an angiotensin receptor blocker (ARB) on neutrophil antibacterial activity. ACEI exposure reduced the ability of murine neutrophils to kill methicillin-resistant Staphylococcus aureus (MRSA), Pseudomonas aeruginosa, and Klebsiella pneumoniae in vitro. In vivo, ACEI-treated mice infected with MRSA had increased bacteremia and tissue bacteria counts compared to mice treated with an ARB or with no drug. Similarly, ACEIs, but not ARBs, increased the incidence of MRSA-induced infective endocarditis in mice with aortic valve injury. Neutrophils from ACE knockout (KO) mice or mice treated with an ACEI produced less leukotriene B4 (LTB4) upon stimulation with MRSA or lipopolysaccharide, whereas neutrophils overexpressing ACE produced more LTB4 compared to wild-type neutrophils. As a result of reduced LTB4 production, ACE KO neutrophils showed decreased survival signaling and increased apoptosis. In contrast, neutrophils overexpressing ACE had an enhanced survival phenotype. Last, in a cohort of human volunteers receiving the ACEI ramipril for 1 week, ACEI administration reduced neutrophil superoxide and reactive oxygen species production and neutrophils isolated from volunteers during ramipril treatment had reduced bactericidal activity. Together, these data demonstrate that ACEI treatment, but not ARB treatment, can reduce the bacterial killing ability of neutrophils.

Association of ACEi/ARB Use and Clinical Outcomes of COVID-19 Patients With Hypertension.

Objectives: Evidence has shown that angiotensin-converting enzyme 2 (ACE2), which can be upregulated after angiotensin-converting enzyme inhibitor (ACEi) and angiotensin receptor blocker (ARB) treatment, may play a dual role in the pathogenesis and progression of coronavirus disease 2019 (COVID-19). We aimed to assess the association between the use of ACEi/ARB and the outcome of COVID-19 patients with preexisting hypertension in non-endemic areas.Methods: From January 17, 2020, to February 19, 2020, 286 patients with hypertension were enrolled in this retrospective study out of 1,437 COVID-19 patients from 47 centers in Zhejiang and Jiangsu Province. The composite endpoints consisted of mechanical ventilation, intensive care unit (ICU) admission, or death. Cox proportional hazards analysis was performed to assess the association between ACEi/ARB and clinical outcomes of COVID-19 patients with hypertension.Results: In the main analysis, 103 patients receiving ACEi/ARB were compared with 173 patients receiving other regimens. Overall, 44 patients (15.94%) had an endpoint event. The risk probability of crude endpoints in the ACEi/ARB group (12.62%) was lower than that in the non-ACEi/ARB group (17.92%). After adjusting for confounding factors by inverse probability weighting, the results showed that the use of ACEi/ARB reduced the occurrence of end events by 47% [hazard ratio (HR) = 0.53; 95% CI, 0.34–0.83]. Similar results were obtained in multiple sensitivity analyses.Conclusions: In this retrospective study, among COVID-19 patients with hypertension, the use of ACEi/ARB is not associated with an increased risk of disease severity compared with patients without ACEi/ARB. The trends of beneficial effects of ACEi/ARB need to be further evaluated in randomized clinical trials.

MO1008IMPACT OF RAMIPRIL ON ENDOTHELIAL DYSFUNCTION IN CHILDREN ON REGULAR HEMODIALYSIS

Abstract Background and Aims Endothelial dysfunction is an important risk factor for cardiovascular disease and therefore for increased mortality in end-stage renal disease patients. Asymmetric dimethyl arginine (ADMA), a potent inhibitor of nitric oxide synthase, strongly contributes to endothelial dysfunction. In dialysis patients, ADMA levels are markedly elevated. Previous studies have shown that angiotensin-converting enzyme inhibitors (ACEIs) can significantly reduce ADMA levels in a variety of patients. In contrast, a previous study suggested that short-term treatment with ACEIs may even increase ADMA levels in adult patients on maintenance hemodialysis. However, no study has evaluated the effect of ACEIs in pediatric patients undergoing hemodialysis. Method We conducted a prospective, randomized, double-blinded and placebo-controlled trial (NCT04582097) at two nephrology centers in Cairo, Egypt. Patients below the age of 16 years and on regular hemodialysis for 6 months or longer were eligible for inclusion. Exclusion criteria at screening included uncontrolled hypertension, serum potassium level &amp;gt; 5.5 mmol/L, acute infection or treatment with immunosuppressive agents within the previous month, known intolerance of ACEI treatment and inability to discontinue previous ACEI or angiotensin receptor blocker treatment. A total of 135 eligible patients (mean age, 12.6 years; range 7-15 years; 53.3% males) were randomly (1:1) assigned to once oral daily treatment with identical capsules containing either 2.5 mg ramipril (n=68) or placebo (n=67) for four months. Systolic and diastolic blood pressure (BP) and serum ADMA concentrations were measured as primary efficacy and serum potassium levels as primary safety parameter. Results At baseline, systolic and diastolic BP and ADMA levels were similar between both treatment groups (Table). After four months, both systolic and diastolic BP were significantly lower in the ramipril compared to the placebo group. Treatment with ramipril resulted in a profound reduction in ADMA levels (-77% compared to baseline) while ADMA levels were unchanged in the placebo group after four months (p &amp;lt;0.001). Serum levels of potassium increase in both groups with no reported symptoms of severe hyperkalemia No serious adverse events were reported in neither group. Conclusion Ramipril treatment in pediatric patients on maintenance hemodialysis causes a marked reduction in ADMA levels. This may contribute to improved endothelial vascular function besides its efficacious BP lowering effect.

Beta-blockers and inhibitors of the renin-angiotensin aldosterone system for chronic heart failure with preserved ejection fraction.

Beta-blockers and inhibitors of the renin-angiotensin aldosterone system for chronic heart failure with preserved ejection fraction.

Thirst distress in outpatients with heart failure in a Mediterranean zone of Spain.

AimsThis study aimed to evaluate psychometric properties of the Spanish version of the Thirst Distress Scale for patients with Heart Failure (TDS‐HF) and to describe thirst distress‐associated factors in outpatients at a heart failure (HF) clinic in Spain. Thirst is common in patients with HF, but thirst distress has rarely been addressed and may significantly decrease quality of life.Methods and resultsA cross‐sectional study was performed assessing perceived thirst distress by patients with HF during the preceding 3 days, with the TDS‐HF (scores 8 to 40). Univariable and multivariable linear regression analyses were performed to identify variables independently associated with thirst distress. Three‐hundred two HF outpatients were included (age 67 ± 12 years, 74% male, HF duration 82 ± 75 months, left ventricular ejection fraction 42 ± 14%). Most patients were on treatment with fluid restriction (99%), sodium restriction (99%), and diuretics (70%). The psychometric evaluation of the Spanish version of the TDS‐HF showed satisfactory item‐total and inter‐item correlations (range from 0.77 to 0.85 and 0.60 to 0.84, respectively), and internal consistency was 0.95 (Cronbach's alpha). The majority perceived mild to moderate thirst distress, and 18% perceived it as high or severe. The mean score obtained was 16.2 ± 9.3 (median 13, Q1–Q3 8–20). Higher serum urea {beta coefficient 1.6 [95% confidence interval (CI) 0.267 to 2.92], P = 0.019} and lower potassium [beta coefficient −3.63 (85% CI −6.32 to −0.93), P = 0.009] remained significantly associated with thirst distress in the multivariable analysis, together with the dose of diuretics [beta coefficient 2.98 (95% CI 1.37 to 4.59), P < 0.001]. Treatment with angiotensin receptor blocker showed an independent protective effect [beta coefficient −3.62 (95% CI −6.89 to −0.345), P = 0.03].ConclusionsThe psychometric evaluation of the Spanish version of the TDS‐HF showed good psychometric properties. One in five patients experienced severe distress by thirst, but the majority had mild to moderate thirst distress. The dose of diuretics and angiotensin receptor blocker treatment influence thirst distress and could be clinically important targets to relieve thirst distress in patients with HF.

Update Alert 8: Risks and Impact of Angiotensin-Converting Enzyme Inhibitors or Angiotensin-Receptor Blockers on SARS-CoV-2 Infection in Adults

LettersJune 2021Update Alert 8: Risks and Impact of Angiotensin-Converting Enzyme Inhibitors or Angiotensin-Receptor Blockers on SARS-CoV-2 Infection in AdultsFREEKatherine Mackey, MD, MPP, Devan Kansagara, MD, MCR, and Kathryn Vela, MLIS, AHIPKatherine Mackey, MD, MPPVA Portland Health Care System, Portland, OregonSearch for more papers by this author, Devan Kansagara, MD, MCRVA Portland Health Care System, Portland, OregonSearch for more papers by this author, and Kathryn Vela, MLIS, AHIPVA Portland Health Care System, Portland, OregonSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/L21-0223 SectionsSupplemental MaterialAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail In update alert 7, we summarized the state of the evidence for the key questions of this systematic review: whether angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin-receptor blockers (ARBs) increase the risk for SARS-CoV-2 infection or worse outcomes and whether these medications are effective in the treatment of COVID-19 (1). Given our high confidence in evidence indicating that use of ACEIs or ARBs does not increase the risk for SARS-CoV-2 infection, we retired this key question from our living review. In this update alert, we provide a summary of results from 2 clinical trials addressing the question of whether continuing ACEIs or ARBs in the treatment of COVID-19 is associated with worse outcomes. We also provide an update on completed and in-progress clinical trials on the effectiveness of ACEIs or ARBs in the treatment of COVID-19 and results of our literature surveillance from 23 November 2020 to 4 April 2021 using the same search strategy as described in the original review (2).Key Question 2: Is Use of ACEIs and ARBs Associated With More Severe COVID-19 Illness?Because of high confidence based on 78 studies (77 observational studies and 1 randomized controlled trial) in the finding that ACEI or ARB use is not associated with COVID-19 severity, we ended our routine literature surveillance for this key question but planned to report on the findings of 3 in-progress clinic trials. Results are now available for 2 trials that compared COVID-19 severity and mortality in adults who continued or discontinued ACEI or ARB treatment once COVID-19 was diagnosed; the third trial was suspended because of challenges with funding and a low incidence of COVID-19 at the study site (3–5).In the REPLACE COVID (Randomized Elimination or ProLongation of ACEIs and ARBs in COronaVIrus Disease 2019) trial, a randomized, open-label multicenter trial of 152 adults, continuation of ACEIs or ARBs did not result in more severe disease as measured by a composite outcome incorporating time to death, duration of mechanical ventilation, time on renal replacement or vasopressor therapy, and multiorgan dysfunction (6). Similarly, the BRACE-CORONA (Blockers of Angiotensin Receptor and Angiotensin-Converting Enzyme inhibitors suspension in hospitalized patients with coronavirus infection) trial done in Brazil of 659 adults with mild to moderate COVID-19 found no significant difference in days alive and out of the hospital in the ACEI or ARB continuation group compared with the discontinuation group (7). These findings support our conclusion that use of ACEIs or ARBs before COVID-19 illness is not associated with increased severity. Because we consider these findings to be stable (meaning that future studies are likely to have the same results), we will retire this key question from our living review.Key Question 3: What Are the Benefits and Harms of Initiating ACEI or ARB Treatment for Patients With COVID-19?We identified published results of 1 study in our search—a single-group, open-label trial on the safety of losartan initiation among 34 adults at the University of Kansas Hospital—finding that use of losartan in the intervention group was associated with a lower incidence of adverse events (defined as any untoward medical occurrence in a person during the study) compared with external, nonrandomized controls (8). This study was not designed to evaluate the effectiveness of losartan in COVID-19 treatment. We previously identified 5 planned or in-progress clinical trials evaluating ACEI or ARB initiation in COVID-19 treatment (Supplement Table) (9–13). Three of these trials remain in progress (9–11). Two are complete, but results are not published yet (11,12). We will monitor these trials for updates monthly and provide a brief status update in the fall of 2021. When results are available, we will provide an updated evidence synthesis.

Роль ренин-ангиотензиновой системы в патогенезе болезни Паркинсона

Введение. В настоящее время в научной литературе имеется большой объем данных, посвященных болезни Паркинсона. В то же время недостаточно освещена роль ренин-ангиотензиновой системы (РАС) в патогенезе заболевания. Цель - оценка современных патогенетически обоснованных подходов к терапии болезни Паркинсона. Методика. В базах данных Medline (PubMed) и eLibrary осуществлен подбор и анализ современных источников литературы, посвященных изучению роли ренин-ангиотензиновой системы в патогенезе болезни Паркинсона. Результаты. Болезнь Паркинсона является хроническим нейродегенеративным заболеванием, которое проявляется моторными и немоторными нарушениями. Анализ литературы показал, что помимо системной ренин-ангиотензиновой системы во многих тканях и органах имеется локальная РАС. Авторами было показано, что дофамин и ангиотензин II взаимодействуют в черной субстанции (SN) и стриатуме в реципрокном отношении. В модельных экспериментах на животных доказано, что снижение уровней дофамина сопровождается гиперактивацией ренин-ангиотензиновой системы. При этом так же отмечается выброс активных форм кислорода, индуцируемый микроглиальной тканью, и развитие нейровоспаления, что сопровождается нейродегенерацией. Применение блокаторов ангиотензиновых рецепторов в моделях на животных и в клинических испытаниях позволило значительно снизить прогрессирование нейродегенерации черной субстанции. Заключение. Авторами изложены результаты, свидетельствующие о том, что развитие болезни Паркинсона сопровождается гиперактивацией мозговой РАС. Подразумевается, что на новое звено патогенеза можно терапевтически воздействовать. Необходимы дополнительные исследования для понимания механизмов данных процессов. Background. A large amount of literature on Parkinson’s disease is currently available. However, the role of the renin-angiotensin system in the pathogenesis of this disease is not sufficiently covered. Aim. To highlight new therapeutic possibilities based on pathophysiological mechanisms of Parkinson’s disease. Methods. The literature retrieved from the PubMed, Medline, and eLibrary databases focusing on the role of the renin-angiotensin system in the pathogenesis of Parkinson’s disease was analyzed. Results. Parkinson’s disease (PD) is a chronic neurodegenerative disease associated with persistent neurological disorders. Studies have demonstrated that a local renin-angiotensin system (RAS) exists in many tissues and organs along with the systemic RAS. The authors showed that dopamine and angiotensin II interact reciprocally in the substantia nigra (SN) and striatum. In animal models, a decrease in the dopamine level was accompanied by RAS overactivation. Furthermore, microglial tissue induced production of reactive oxygen species, which was associated with neuroinflammation. The angiotensin receptor blocker treatment used in animal models and clinical trials significantly reduced the progression of SN neurodegeneration. Conclusions. The authors reviewed the data of literature demonstrating that the progression of Parkinson’s disease is associated with overactivation of the cerebral RAS. Apparently, it is possible to influence therapeutically this new pathogenetic component of Parkinson’s disease. Further study is required for understanding the mechanisms of this process.