Angiotensin II Receptor Blockers Research Articles

The Prevalence and Characteristic of Patients Achieve Target Doses of Medications Used to Treat Heart Failure with Reduced Ejection Fraction at Heart Failure Clinic

OBJECTIVES: To determine the prevalence and characteristics of patients who achieved target doses of angiotensin converting enzyme inhibitors (ACEIs)/ angiotensin II receptor blockers (ARBs), beta-blocker, and mineralocorticoid receptor antagonists (MRAs). MATERIALS AND METHODS: A retrospective chart review study of heart failure with reduced ejection fraction (HFrEF) patients who received ACEIs/ARBs, beta-blockers, or MRAs and follow-up more than four times at the heart failure outpatient clinic, Chonburi hospital from February 1st, 2017 to February 29th, 2020. Patient data were retrieved from electronic medical records. Two authors collected data into record form (CRF) independently. Achieving target doses was defined by recommended doses according to the ACC/AHA/HFSA Guideline, 2017. The comparison of continuous data was conducted with the Mann-Whitney U test. Pearson Chi-Square and Fisher’s exact test were used for the comparison of categorical data. RESULTS: Patients who achieved target doses of ACEIs/ARBs, beta-blockers and MRAs was 73.3%, 55.3%, and 7.1% respectively. Patients’ characteristics of achieved target doses of ACEIs/ARBs were higher baseline left ventricular ejection fractions (p = 0.026). Younger age (p = 0.016), body mass index (BMI) ≥ 23 kg/m2 (p = 0.037; OR 5.3) and serum creatinine ≤ 2 mg/dL (p = 0.004) were the characteristics of patients who achieved target doses of beta-blockers. CONCLUSION: Most patients in heart failure clinic achieved target doses of ACEIs/ARBs followed by beta-blockers but only a few patients for MRAs. Patient and medical characteristics were different in target doses achievable.

Evaluating Medication Day-Supply for Improving Adherence and Clinical Biomarkers of Hemoglobin A1c, Blood Pressure, and Low-Density Lipoprotein

Objectives: To compare a 90-day-supply and a less than 90-day-supply of medication on adherence to refilling prescriptions and clinical biomarkers for hemoglobin A1c (HbA1c), blood pressure (BP), and low-density lipoprotein (LDL). Methods: A retrospective chart review was completed for a cohort of patients prescribed an oral hypoglycemic agent (OHA), angiotensin-converting enzyme inhibitor (ACEI), or angiotensin II receptor blocker (ARB), and/or a statin. Data were categorized into 90-day-supply and less than 90-day-supply and on the minimum value for control determined by the CMS Star Ratings system. Adherence was defined by the Health Plan Quality Improvement Department as ≥ 85% of days covered. Clinical biomarker cutoffs were HbA1c (<9% or ≥ 9%), BP (Systolic BP ≤ 140 mm Hg and >140 mm Hg or Diastolic BP ≥ 90 mm Hg regardless of SBP), and LDL (<100 mg/dl or ≥100 mg/dl). Results: The analysis included 251 patients: 159 females (mean 64.9 ± 11.7 years) and 92 males (mean 61.5 ± 11.3 years). Patients with medications from multiple classes were included in more than one analysis. Adherence was statistically in favor of the 90-day-supply compared to less than 90-day-supply for all three classes of drugs. The clinical biomarkers were statistically not different for each drug group. Conclusion: A 90-day-supply was statistically greater than a less than 90-day-supply for CMS Star Ratings metrics, but was not statistically significant for clinical biomarkers for HbA1c, SBP, and LDL.

Effectiveness of Sacubitril/Valsartan in Heart Failure with Reduced Ejection Fraction Using Real-World Data: An Updated Systematic Review and Meta-Analysis

We conducted a systematic review and meta-analysis to assess all-cause mortality and heart failure (HF) hospitalization with sacubitril/valsartan (S/V) compared to standard HF therapy in patients with HF with reduced ejection fraction (HFrEF) using real-world data. We performed a systematic review and meta-analysis following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We searched PubMed and Google Scholar for the observational studies published in English exploring the clinical outcomes of S/V use in HFrEF till March 14, 2022. Two independent reviewers assessed the quality and risk of bias of the included studies. A random-effect model was used to combine data. The outcomes assessed were all-cause mortality and HF hospitalization associated with S/V use in comparison to standard HF therapy. A total of 9 observational studies comparing S/V to Angiotensin-converting enzyme inhibitors (ACE-I)/Angiotensin II receptor blockers (ARB) in HFrEF were included in the systematic review, with more than 32000 patients included in the final analysis. Overall, S/V use was associated with a significant reduction in all-cause mortality (Risk Ratio [RR] = 0.70, 95% CI 0.53-0.93, I2 = 83%) and HF hospitalization (RR = 0.62; 95% CI, 0.48-0.80, I2= 94%). Similar to the landmark controlled evidence, real-world data of S/V use in HFrEF demonstrated a significant reduction in all-cause mortality and HF hospitalization.

Starting Neurohormonal Antagonists in Patients With Acute Heart Failure With Mid-Range and Preserved Ejection Fraction.

The clinical benefits of neurohormonal antagonists for patients with heart failure (HF) with mid-range and preserved ejection fraction (HFmrEF and HFpEF) are uncertain. This study analyzed 858 consecutive patients with HFmrEF (EF: 40-49%) or HFpEF (EF ≥50%), who were hospitalized for acute HF, and who were discharged alive, and were not taking angiotensin-converting enzyme inhibitors (ACE)-I/ angiotensin II receptor blockers (ARB) or β-blockers at admission. The study population was classified into 4 groups according to the status of prescription of ACE-I/ARB and β-blocker at discharge: no neurohormonal antagonist (n=342, 39.9%), ACE-I/ARB only (n=128, 14.9%), β-blocker only (n=189, 22.0%), and both ACE-I/ARB and β-blocker (n=199, 23.2%) groups. The primary outcome measure was a composite of all-cause death or HF hospitalization. The cumulative 1-year incidence of the primary outcome measure was 41.2% in the no neurohormonal antagonist group, 34.0% in the ACE-I/ARB only group, 28.6% in the β-blocker only group, and 16.4% in the both ACE-I/ARB and β-blocker group (P<0.001). Compared with the no neurohormonal antagonist group, both the ACE-I/ARB and β-blocker groups were associated with a significantly lower risk for a composite of all-cause death or HF hospitalization (HR: 0.46, 95% CI: 0.28-0.76, P=0.002). In hospitalized patients with HFmrEF and HFpEF, starting both ACE-I/ARB and a β-blocker was associated with a reduced risk of the composite of all-cause death or HF hospitalization compared with patients not starting on an ACE-I/ARB or β-blocker.

Adherence with cardiovascular medications and the outcomes in patients with coronary arterial disease: "Real-world" evidence.

Cardiovascular medications are vital for the secondary prevention of coronary arterial disease (CAD). However, the effect of cardiovascular medication may depend on the optimal adherence of the patients. This meta-analysis aims to determine the magnitude of adherence to vascular medications that influences the absolute and relative risks (RRs) of mortality in patients with CAD in real-world settings. The Cochrane Library, PubMed, and EMBASE databases were searched through March 1, 2022. Prospective studies reporting association as RR and 95%confidence interval between cardiovascular medication adherence and any cardiovascular events and/or all-cause mortality in patients with CAD were included. A one-stage robust error meta-regression method was used to summarize the dose-specific relationships. A total of 18 studies were included. There is a significant inverse linear association between cardiovascular medication adherence and cardiovascular events (pnonlinearity = .68) or mortality (pnonlinearity = .82). The exposure-effect analysis showed that an improvement of 20% cardiovascular medication adherence was associated with 8% or 12% lower risk of any cardiovascular events or mortality, respectively. In subgroup analysis, the benefit was observed in adherence of stain (RR: 0.90, for cardiovascular events, RR: 0.85,for mortality), angiotensin-converting enzyme inhibitors (ACEI)/angiotensin II receptor blockers (ARB)(RR: 0.90, for mortality), and antiplatelet agent (RR: 0.89 for mortality) but not in beta-blocker (RR: 0.90,p = .14, for cardiovascular events, RR: 0.97,p = .32 for mortality). Estimated absolute differences per 1 million individuals per year for mortality associated with 20% improvement were 175 cases for statin, 129 cases for antiplatelet,and 117 cases for ACEI/ARB. Evidence from the real word showed poor adherence to vascular medications contributes to a considerable proportion of all cardiovascular disease eventsand mortality in patients with CAD.

Readability of information imprinted in patient information leaflets (PILs) in Saudi Arabia: The case of antihypertensive medications

BackgroundThe Saudi Food and Drug Authority (SFDA) requires marketing authorization holders to submit a PIL in both Arabic and English language. However, the readability of imprinted and disseminated Patient information leaflets (PILs) was not assessed extensively in Saudi Arabia. This study aims to assess the readability of PIL of antihypertensive drugs in both Arabic and English languages. MethodThis study was a descriptive quantitative analysis conducted in Saudi Arabia in August 2021. PILs of all oral antihypertensive medications in Saudi Arabia were included in the study. The Arabic and English PILs were extracted from the Saudi Drugs Information System (SDI) and pharmaceutical companies' registration documents. The study used Flesch-Kincaid grade level to assess the readability of English and sentence length to assess the Arabic texts. Descriptive analyses were used to assess the readability scores and the mean differences. ResultsIt was found that almost 88% of English PILs were above recommended readability level compared to 79% of Arabic PILs. About 89% of English PILs of generic and 86% of brand-name medications were above the readability cutoff point compared with 83% of Arabic PILs of generic and 68% of brand-name medications. The means of grade level for readability of PILs for the widely used antihypertensive medications including angiotensin II receptor blockers (ARBs), antiadrenergic, diuretics, Beta-blockers (BBs), calcium channel blockers (CCBs), and combination antihypertensive medications, and CCBs were higher than the recommended readability level (p < 0.05). The highest mean grade level for readability among English PILs was for combinations of antihypertensive agents (9.35 ± 1.38, p 0.01) and among Arabic PILs was for ARBs (6.15 ± 1.62, p < 0.01). ConclusionsThe majority of PILs of antihypertensive medications were above the recommended readability level that can be understood by the majority of the public, especially among generic medications and the most widely used antihypertensive medications. The study findings highlight the need of implementing guidelines to improve the readability of information imprinted in PILs and adopt new regulations requiring readability assessment for manufactures before submitting the PILs to the SFDA.

Control of aging by the renin–angiotensin system: a review of C. elegans, Drosophila, and mammals

The free-living, non-parasitic nematode Caenorhabditis elegans is a premier model organism for the study of aging and longevity due to its short lifespan, powerful genetic tools, and conservation of fundamental mechanisms with mammals. Approximately 70 percent of human genes have homologs in C. elegans, including many that encode proteins in pathways that influence aging. Numerous genetic pathways have been identified in C. elegans that affect lifespan, including the dietary restriction pathway, the insulin/insulin-like growth factor (IGF) signaling pathway, and the disruption of components of the mitochondrial electron transport chain. C. elegans is also a powerful system for performing drug screens, and many lifespan-extending compounds have been reported; notably, several FDA-approved medications extend the lifespan in C. elegans, raising the possibility that they can also extend the lifespan in humans. The renin–angiotensin system (RAS) in mammals is an endocrine system that regulates blood pressure and a paracrine system that acts in a wide range of tissues to control physiological processes; it is a popular target for drugs that reduce blood pressure, including angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs). Emerging evidence indicates that this system influences aging. In C. elegans, decreasing the activity of the ACE homolog acn-1 or treatment with the ACE-inhibitor Captopril significantly extends the lifespan. In Drosophila, treatment with ACE inhibitors extends the lifespan. In rodents, manipulating the RAS with genetic or pharmacological interventions can extend the lifespan. In humans, polymorphisms in the ACE gene are associated with extreme longevity. These results suggest the RAS plays a conserved role in controlling longevity. Here, we review studies of the RAS and aging, emphasizing the potential of C. elegans as a model for understanding the mechanism of lifespan control.

The renoprotective effect of esaxerenone independent of blood pressure lowering: a post hoc mediation analysis of the ESAX-DN trial

Angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) are recommended as first-line drugs for hypertension with diabetic nephropathy owing to their renoprotective effect; however, their effect beyond lowering blood pressure (BP) has not been confirmed. Recent studies have shown that aldosterone plays a key role in causing renal injury; therefore, it is likely that mineralocorticoid receptor (MR) blockers inhibit aldosterone-induced renal damage in different ways from ACE inhibitors and ARBs. Therefore, we investigated the mechanism of the effect of an MR blocker on reducing the urinary albumin-to-creatinine ratio (UACR) using data from a randomized, double-blind, placebo-controlled phase 3 study (ESAX-DN) of a new nonsteroidal MR blocker, esaxerenone. This post hoc analysis used a novel statistical method to quantitatively estimate the effect of esaxerenone on UACR reduction mediated, or not mediated, by changes in systolic BP (SBP) and/or estimated glomerular filtration rate (eGFR). The proportion of the mediated effect by SBP changes to the total effect on UACR reduction was 9.8–10.7%; the UACR was reduced to 0.903–0.911 times the baseline at the end of treatment through the SBP-related pathway and to 0.422–0.426 times the baseline through the non-SBP-related pathway. Even considering both SBP and eGFR simultaneously, the proportion of the mediated effect was 21.9–28.1%. These results confirm that esaxerenone has a direct UACR-lowering effect independent of BP lowering and that its magnitude is much larger than that of the BP-dependent effect. Thus, esaxerenone could be a UACR-reducing treatment option for patients with diabetic nephropathy.

Cancer risk associated with the use of valsartan in Korea: A nationwide cohort study

BackgroundDespite valsartan’s widespread use, few studies have explored its potential carcinogenicity. We evaluated the association between valsartan and cancer. MethodsWe conducted a retrospective cohort study using data from 2002 to 2015 gathered from the National Health Insurance database. Patients with hypertension aged ≥ 30 who used valsartan or other angiotensin II receptor blockers (ARBs) were included. Eligible patients were those with no prior history of the use of any ARBs, diagnosis of cancer, or organ transplantation in the 4 years predating their first use of the drugs of interest. The primary and secondary outcomes included the occurrence of all cancers and site-specific solid cancers, respectively. After applying propensity score (PS) matching, Cox regression was used to calculate the hazard ratios (HRs) and 95 % confidence intervals (CIs). ResultsA total of 1,550,734 individuals were identified as new users of valsartan or other ARBs. Of the 153,047 valsartan users, 16,047 were diagnosed with cancer. No increased risk of overall cancer was observed in valsartan users as compared to other ARB users (aHR = 1.00; 95 % CI, 0.98–1.02). Valsartan was, however, associated with a slightly elevated risk of liver (aHR = 1.09; 95 % CI, 1.01–1.16) and kidney cancer (aHR = 1.11; 95 % CI, 1.02–1.22). ConclusionCompared with other ARBs, valsartan did not increase the risk of overall cancer. A slightly increased risk for some solid cancers was associated with valsartan use, though the absolute rate difference was small.

The ACE Inhibitor Lisinopril Stimulates Melanoma Cell Invasiveness by Inducing MMP2 Secretion.

Hypertension is treated primarily with angiotensin II (ATII) receptor blockers (ARBs) and angiotensin converting enzyme (ACE) inhibitors (ACEIs). Both ATII and ACEIs can trigger signal transduction via ACE, and a possible correlation between ARB/ACEI therapy and an increased risk of cancer is highly controversial. The question of whether or not ACE as a potential signal transducer affects human melanoma (MV3) cell behavior prompted the present study. Expression of ACE, ATII receptor types 1, 2 (AT1R, AT2R), COX2 and MMP2 in MV3 cells was examined by qPCR. AT1R, AT2R and ACE were inhibited with losartan, EMA401 and lisinopril, respectively. Adhesion, migration and invasiveness of MV3 cells seeded on a hepatocyte (Huh7) monolayer or a reconstituted collagen type I matrix were analyzed using video microscopy and Boyden chambers. Integrity of the Huh7 cell layer was confirmed by measuring transepithelial electrical resistance (TEER). ERK1/2 phosphorylation and MMP2 secretion were evaluated by Western blotting. MMP2 activity was inhibited with ARP-100. Losartan, EMA401 and lisinopril stimulated MV3 melanoma cell migration and invasion in a coculture model with Huh7 cells while leaving proliferation and adhesion largely unaffected. The drugs did not interfere with TEER of the hepatocyte monolayer nor with MV3 cell proliferation, but tended to increase the phosphorylation of ERK1/2 and the expression of both COX2 and MMP2. Lisinopril caused a significant increase in MV3 cells' MMP2 secretion and an accelerated MV3 cell-mediated TEER breakdown. The MMP2 inhibitor ARP-100 could antagonize the lisinopril-stimulated invasion of the hepatocyte layer. Lisinopril stimulates MV3 cell invasion by increasing the expression and secretion of MMP2.

Pharmacotherapies and Aortic Heme Oxygenase-1 Expression in Patients with Abdominal Aortic Aneurysm.

Background: Treatment of cardiovascular risk factors slows the progression of small abdominal aortic aneurysms (AAA). Heme oxygenase-1 (HO-1) is a stress- and hemin-induced enzyme providing cytoprotection against oxidative stress when overexpressed. However, nothing is known about the effects of cardiometabolic standard therapies on HO-1 expression in aortic walls in patients with end-stage AAA. Methods: The effects of statins, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), calcium channel blockers (CCBs), beta-blockers, diuretics, acetylsalicylic acid (ASA), and therapeutic anticoagulation on HO-1 mRNA and protein expressions were analyzed in AAA patients using multivariate logistic regression analysis and comparison of monotherapy. Results: Analysis of monotherapy revealed that HO-1 mRNA and protein expressions were higher in patients on diuretics and lower in patients on statin therapy. Tests on combinations of antihypertensive medications demonstrated that ACE inhibitors and diuretics, ARBs and diuretics, and beta-blockers and diuretics were associated with increase in HO-1 mRNA expression. ASA and therapeutic anticoagulation were not linked to HO-1 expression. Conclusion: Diuretics showed the strongest association with HO-1 expression, persisting even in combination with other antihypertensive medications. Hence, changes in aortic HO-1 expression in response to different medical therapies and their effects on vessel wall degeneration should be analyzed in future studies.

Adverse Events After Initiating Angiotensin-Converting Enzyme Inhibitor/Angiotensin II Receptor Blocker Therapy in Individuals with Heart Failure and Multimorbidity

BackgroundCurrent clinical practice guidelines recommend routine kidney function and serum potassium testing within 30 days of initiating angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) therapy. However, evidence is lacking on whether routine follow-up testing reduces therapy-related adverse events in adults with heart failure and if multimorbidity influences the association between laboratory testing and these adverse events. MethodsWe conducted a retrospective cohort study among adults with heart failure from 4 US integrated health care delivery systems. Multimorbidity was defined using counts of chronic conditions. Patients with outpatient serum creatinine and potassium tests in the 30 days after starting ACEI or ARB therapy were matched 1:1 to patients without follow-up tests. We evaluated the association of follow-up testing with 30-day all-cause mortality and hospitalization with acute kidney injury or hyperkalemia using Cox regression. ResultsWe identified 3629 matched adults with heart failure initiating ACEI or ARB therapy between January 1, 2005, and December 31, 2012. Follow-up testing was not significantly associated with 30-day all-cause mortality (adjusted hazard ratio [aHR] 0.45, 95% confidence interval [CI] 0.14; 1.39) and hospitalization with hyperkalemia (aHR 0.73, 95% CI, 0.33; 1.61). However, follow-up testing was significantly associated with hospitalization with acute kidney injury (aHR, 1.40, 95% CI, 1.01; 1.94). Interaction between multimorbidity burden and follow-up testing was not statistically significant in any of the outcome models examined. ConclusionsRoutine laboratory monitoring after ACEI or ARB therapy initiation was not associated with risk of 30-day all-cause mortality or hospitalization with hyperkalemia across the spectrum of multimorbidity burden in a cohort of patients with heart failure.

The Association of Renin-Angiotensin System Blockades and Mortality in Patients with Acute Exacerbation of Chronic Obstructive Pulmonary Disease and Acute Respiratory Failure: A Retrospective Cohort Study.

BackgroundAcute respiratory failure (ARF) is a common cause of admission to the intensive care unit (ICU) for patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). There is still a lack of effective interventions and treatments. ACE inhibitors (ACEI)/ angiotensin II receptor blockers (ARB) were effective in COPD patients. We aimed to study the effect of ACEI/ARB use on AECOPD combined with ARF and evaluate the effect of in-hospital continuation of medication.MethodsWe included patients with AECOPD and ARF from the Medical Information Bank for Intensive Care (MIMIC-III) database. MIMIC III is a large cohort database from Boston, USA. Patients were divided into two groups according to the use of ACEI/ARB before admission. Propensity score matching (PSM) was used to reduce potential bias between the two groups. Cox regression and Kaplan-Meier curves compared 30-day mortality in ACEI/ARB users and non-users. We also defined and analyzed the use of in-hospital ACEI/ARB. Multiple models were used to ensure the robustness of the findings. Subgroup analysis was used to analyze the variability between groups.ResultsA total of 544 patients were included in the original study. After PSM, 256 patients were included in the matched cohort. Multivariate Cox regression showed 30-day mortality was significantly lower in ACEI/ARB users compared with controls (HR = 0.50, 95% CI: 0.29–0.86, p= 0.013). In PSM and inverse probability-weighted models, the results are stable Continued in-hospital use of ACEI/ARB remains effective (HR 0.40, 95% CI 0.22–0.74, p = 0.003). Kaplan-Meier showed a significant difference in survival between the two groups.ConclusionThis study found that pre-hospital ACEI/ARB use was associated with reduced mortality in patients with AECOPD and ARF.

The Impact of Angiotensin Receptor-Neprilysin Inhibitors on Arrhythmias in Patients with Heart Failure: A Systematic Review and Meta-analysis.

Angiotensin receptor–neprilysin inhibitor (ARNI) use has become increasingly popular. Current guidelines recommend using ARNI therapy for heart failure with reduced (HFrEF) and preserved ejection fraction (HFpEF). As therapies become more widely available, heart failure-associated burdens such as ventricular arrhythmias and sudden cardiac death (SCD) will become increasingly prevalent. We conducted a systematic review and meta-analysis to assess the impact of ARNI therapy on HFrEF and HFpEF pertaining to arrhythmogenesis and SCD. We performed a search of MEDLINE (PubMed), the Cochrane Library, and ClinicalTrials.gov for relevant studies. The odds ratios (ORs) of SCD, ventricular tachycardia (VT), ventricular fibrillation (VF), atrial fibrillation/flutter (AF), supraventricular tachycardia (SVT), and implantable cardioverter-defibrillator (ICD) shocks were calculated. A total of 10 studies, including 6 randomized controlled trials and 4 observational studies, were included in the analysis. A total of 18,548 patients from all studies were included, with 9,328 patients in the ARNI arm and 9,220 patients in the angiotensin-converting enzyme inhibitor (ACEI)/angiotensin II receptor blocker (ARB) arm, with a median follow-up time of 15 months. There was a significant reduction in the composite outcomes of SCD and ventricular arrhythmias in patients treated with ARNIs compared to those treated with ACEIs/ARBs (OR, 0.71; 95% confidence interval, 0.54–0.93; P = .01; I2 = 17%; P = .29). ARNI therapy was also associated with a significant reduction in ICD shocks. There was no significant reduction in the VT, VF, AF, or SVT incidence rate in the ARNI group compared to the ACEI/ARB group. In conclusion, the use of ARNIs confers a reduction in composite outcomes of SCD and ventricular arrhythmias among patients with heart failure. These outcomes were mainly driven by SCD reduction in patients treated with ARNIs.

Abstract A3: Possible Differential Effects Of Angiotensin Receptor-neprilysin Inhibitor And Angiotensin Receptor Blocker Against Hypertension And Cardiorenal Injury In A Mouse Model Of Cardiorenal Syndrome

Objective: Angiotensin receptor-neprilysin inhibitors (ARNI) are potential therapeutic candidates for the treatment of cardiorenal syndrome (CRS). Although evidence is accumulating on the therapeutic effects of ARNI for heart failure and hypertension, the effects of ARNI on kidney disease or CRS are controversial. Here, we assessed the hypothesis that ARNI has poor renal protective effect beyond its antihypertensive effect, in contrast to its promised cardioprotective effect, by using the ANS [Ang II (A) + nephrectomy (N) + saline (S)] mice, which is the CRS model. Method: C57BL/6 mice were divided into 5 groups (N = 5-6): Control (sham operation) group, ANS (ANS + vehicle treatment) group, Val M [ANS + moderate dose of valsartan treatment (30 mg/kg/day)] group, ARNI [ANS + sacubitril/valsartan treatment (60 mg/kg/day)] group, and Val H [ANS + high dose of valsartan treatment (60 mg/kg/day)] group. Sacrifice was performed after 4 weeks, and various analyses were conducted. Results: ARNI, Val M, and Val H groups attenuated the elevation of blood pressure (BP) in ANS mice (BP [mean ± standard error (SEM)] [mmHg]: ANS, 164 ± 3; ARNI, 133 ± 4; Val M, 143 ±1; Val H, 129 ± 2). Regardless of the strength of the antihypertensive effect, the ARNI group was most effective in preventing the decrease in cardiac contraction and cardiac fibrosis in ANS mice. However, the ARNI group was insufficient to suppress urinary albumin excretion (UAE) (UAE [mean ± SEM] [μg]; ANS, 5351 ± 2391; ARNI, 1169 ± 700) and renal fibrosis in ANS mice. Both valsartan groups suppressed UAE in ANS mice (UAE [mean ± SEM] [μg]; Val M, 243 ± 141; Val H, 305 ± 179), as well as renal fibrosis and glomerular swelling. In addition, the results of kidney RNA sequencing analysis showed that the receptor for advanced glycation end-products (RAGE) signaling pathway was activated in the kidney of ARNI group compared with the Val M and Val H groups. Conclusions: The ARNI group showed better cardioprotective effects than valsartan treatment groups, but not sufficient kidney protection. These results suggested that the relationship between the antihypertensive effects and the organ protective effects of cardiorenal injury in CRS pathology may be different between angiotensin II receptor blocker (ARB) and ARNI.

311.3: A 5-Year Prospective, Randomized, Open-Label Study of Standard Versus Low-Dose Prolonged-Release Tacrolimus With Or Without ACEi/ARB in Kidney Transplantation

Introduction: Optimizing tacrolimus (TAC) exposure and/or using angiotensin-converting enzyme inhibitors (ACEi) or angiotensin II receptor blockers (ARB) may modulate inflammation (i) as well as interstitial fibrosis and tubular atrophy (IFTA) after kidney transplant (KTx). Two-year data from a study in KTx patients receiving prolonged-release TAC coupled with either ACEi/ARB or other antihypertensives (OAHT) showed that low-dose TAC coupled with ACEi/ARB was associated with less IFTA severity and progression, less IFTA + i, and delayed onset of clinical rejection compared with low-dose TAC without ACEi/ARB (Cockfield et al. Am J Transplant 2019;19:1730–44). We now report 5-year results from this study. Methods: This was a Canadian multicenter, prospective, open-label, controlled study in adult de novo KTx recipients randomized in a 2x2 design to standard dose (0.15–0.20 mg/kg) or low dose (LOW; 0.05–0.15 mg/kg) prolonged-release TAC combined with either ACEi/ARB or OAHT. All patients received basiliximab induction, mycophenolate mofetil and prednisone. Protocol biopsies were taken at implantation, 6 and 24 months. Five-year data include patient and graft survival, renal function, proteinuria, blood pressure and the incidence of Class II de novo donor-specific antibody (dnDSA). Results: Overall, 281 patients were randomized. Between 3 and 5 years, mean TAC trough levels were ~6 ng/mL. Patient survival at 5 years was 95.7% and comparable between groups (94.2–97.2% across groups). Overall graft survival was 94.3% (89.7% in the LOW+OAHT group vs 94.4–97.1% in the other groups). Graft function, blood pressure, and proteinuria were similar in all groups. At 5 years, class II dnDSA incidence was 13.2% in the LOW+OAHT group vs 5.6–7.2% in other groups. There were no unexpected safety findings observed at 5 years. Conclusion: KTx patients receiving low-dose prolonged-release TAC combined with ACEi/ARB have comparable outcomes to those receiving standard doses of prolonged-release TAC with or without ACEi/ARB, while treatment with low-dose prolonged release TAC without ACEi/ARB may be associated with worse outcomes. This study was sponsored by Astellas Pharma Inc. Editorial support was provided by Cello Health MedErgy, funded by Astellas Pharma Inc.

Correlation of Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers with serum GDF-15 in a group of hypertensive Iraqi patients

The Growth Differentiation Factor -15 (GDF-15) is a member of the transforming growth factor β superfamily. İt represents an example of the stress response cytokines. It's mostly found in cardiac myocytes, adipocytes, macrophages, endothelial cells, and vascular endothelial cells, whether they're generated normally or not. GDF-15 levels have increased and are associated with cardiovascular risk. Aim of the study: To investigate the correlation between angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) with the level of plasma GDF-15 in a group of hypertensive patients. Materials and methods: A case-control study involved 90 individuals, 60 hypertensive patients (36 on ACE inhibitors and 24 on ARBs) and 30 healthy individuals. Serum GDF-15 was measured and compared statistically between the two groups. Results: serum GDF-15 was significantly higher in both groups of hypertensive patients compared to the control group. İn addition, there was no significant difference in mean serum GDF-15 concentration between patients treated with ACE inhibitors with those treated with angiotensin II receptor blockers. Conclusion: GDF-15 increases in hypertensive patients and might be a reasonable marker of cardiovascular disease. Both ACE inhibitors and ARBs are not powerful enough to decrease GDF-15 concentration to that of the control group.

Charlson comorbidity index, neutrophil-to-lymphocyte ratio and undertreatment with renin-angiotensin-aldosterone system inhibitors predict in-hospital mortality of hospitalized COVID-19 patients during the omicron dominant period.

PurposeTo investigate the clinical predictors of in-hospital mortality in hospitalized patients with Coronavirus disease 2019 (COVID-19) infection during the Omicron period.MethodsAll consecutive hospitalized laboratory‐confirmed COVID-19 patients between January and May 2022 were retrospectively analyzed. All patients underwent accurate physical, laboratory, radiographic and echocardiographic examination. Primary endpoint was in-hospital mortality.Results74 consecutive COVID-19 patients (80.0 ± 12.6 yrs, 45.9% males) were included. Patients who died during hospitalization (27%) and those who were discharged alive (73%) were separately analyzed. Compared to patients discharged alive, those who died were significantly older, with higher comorbidity burden and greater prevalence of laboratory, radiographic and echographic signs of pulmonary and systemic congestion. Charlson comorbidity index (CCI) (OR 1.76, 95%CI 1.07-2.92), neutrophil-to-lymphocyte ratio (NLR) (OR 1.24, 95%CI 1.10-1.39) and absence of angiotensin-converting enzyme inhibitors (ACEI)/angiotensin II receptor blockers (ARBs) therapy (OR 0.01, 95%CI 0.00-0.22) independently predicted the primary endpoint. CCI ≥7 and NLR ≥9 were the best cut-off values for predicting mortality. The mortality risk for patients with CCI ≥7, NLR ≥9 and not in ACEI/ARBs therapy was high (86%); for patients with CCI <7, NLR ≥9, with (16.6%) or without (25%) ACEI/ARBs therapy was intermediate; for patients with CCI <7, NLR <9 and in ACEI/ARBs therapy was of 0%.ConclusionsHigh comorbidity burden, high levels of NLR and the undertreatment with ACEI/ARBs were the main prognostic indicators of in-hospital mortality. The risk stratification of COVID-19 patients at hospital admission would help the clinicians to take care of the high-risk patients and reduce the mortality.

Sustainable spectrophotometric determination of antihypertensive medicines reducing COVID-19 risk via paired wavelength data processing technique - Assessment of purity, greenness and whiteness

Recent studies have reported that using certain antihypertensive therapies such as angiotensin II receptor blockers (ARBs) is associated with mitigation of fatal outcomes and enhancing clinical features of patients having hypertension during coronavirus pandemic. Thus, in the current work an innovative, effective, white and sustainable spectrophotometric technique called paired wavelength data processing technique (PWDPT) was developed for evaluation of recommended antihypertensive combination therapies incorporating candesartan cilexetil (CAN) and hydrochlorothiazide (HCT). This technique included three methods, namely, absorbance resolution (AR), amplitude resolution (PR) and ratio extraction (RE). Linearity ranges were (5.0 μg/mL - 50.0 μg/mL) and (2.0 μg/mL - 24.0 μg/mL) for CAN and HCT, respectively. Validation and confirmation of all suggested methods were conducted in accordance with ICH guidelines, producing satisfactory results within the accepted limits. Statistical comparison was achieved between the attained results from suggested methods and those attained from official methods, in which insignificant difference was existed. The suggested methods were successfully employed for identification of the studied drugs as well as determination of their spectral recognition and evaluation of the purity in their combined formulations. The proposed methods followed the principles of green analytical chemistry, where their greenness was evaluated and compared with the official potentiometric and HPLC methods via using four tools, namely, National Environmental Methods Index (NEMI), the Analytical Eco-Scale, the Green Analytical Procedure Index (GAPI) and Analytical greenness metric (AGREE) which affirmed the eco-friendly nature of the proposed methods. Moreover, studying the whiteness features was performed using the recently introduced RGB12 model. The acceptable results along with the sustainability, simplicity, affordability and low-cost of the proposed methods encourages their utilization in the quality control laboratories.

Activation of TRPC6 by AngⅡ Induces Podocyte Injury and Participates in Proteinuria of Nephrotic Syndrome.

Background: Nephrotic syndrome (NS) is a common glomerular disease, and podocyte injury is the character of primary NS, usually caused by minimal change disease and membranous nephropathy. Podocytopathy is primarily associated with glomerular proteinuria. Losartan, an angiotensin receptor blocker (ARB), is commonly used in the treatment of NS, and the AngiotensinⅡ (AngⅡ)–transient receptor potential ion channel 6 (TRPC6) axis has been reported to act on podocytes to regulate proteinuria in NS. Therefore, the purpose of this study was to explore the relationship in between AngⅡ–TRPC6, podocyte injury, and proteinuria based on the adriamycin (ADR) NS rat model. Method: All male rats were divided into three groups: control group, model group, and ARB group. The rats in the model group were induced by ADR, and the rats in the ARB group received losartan after induction of renal injury for 4 weeks. The changes in parameters related to renal dysfunction, and glomerular and podocyte structural damage, such as AngⅡ, AngⅡ type I receptor (AT1R), TRPC6, CaN, Caspase-3, Nephrin, and Podocin, were analyzed. Furthermore, the kidneys were isolated for study via transmission electron microscopy (TEM), immunohistochemistry, and western blot (WB) after the rats were sacrificed. In vitro, immortalized mouse MPC5 podocytes were used to investigate the regulatory effect of flufenamic acid (Flu) and SAR7334 (SAR) on the AngⅡ-TRPC6 signaling axis. Flow cytometry and WB were conducted to determine the relationship between podocyte injury and AngⅡ-TRPC6. Results: In vivo results showed that NS rats developed massive albuminuria and abnormal renal function, accompanied by abnormally increased levels of AngⅡ, TRPC6, AT1R, and CaN and a decreased expression of actin molecules in podocytes, extensive fusion of foot processes (FP), loss of glomerular structural integrity, collapse of podocyte structure, and skeletal reorganization. In vitro experiments indicated that both AngⅡ and Flu (the specific agonist of TRPC6) stimulated the expressions of TRPC6, AT1R, and Caspase-3 in podocytes. The AngⅡ receptor–blocker losartan and TRPC6-specific inhibitor SAR blocked the overexpression of the aforementioned proteins. In addition, SAR also attenuated the degradation of podocyte structural proteins and inhibited the fluorescence intensity of intracellular calcium (Ca2+) and cell apoptosis. Conclusion: The involvement of AngⅡ in the occurrence of NS proteinuria may be related to podocyte injury induced by activated TRPC6.