Angiotensin Receptor Blocker Treatment Research Articles

Angiotensin-converting-enzyme inhibitors and angiotensin receptor blockers for preventing the progression of diabetic kidney disease.

Angiotensin-converting-enzyme inhibitors and angiotensin receptor blockers for preventing the progression of diabetic kidney disease.

Abstract 13617: Spironolactone Use is Associated With Better Survival in Heart Failure Patients With Preserved Ejection Fraction With Concomitant Angiotensin Receptor Blocker Treatment

Introduction: The guidelines recommend using renin-angiotensin-aldosterone system inhibitors, including spironolactone and angiotensin II receptor blocker (ARB), and spironolactone rather than angiotensin-converting enzyme inhibitors (ACEI) for treating heart failure with preserved ejection fraction (HFpEF). However, it is unclear whether there is an additive effect of spironolactone when combined with ACEI/ARB on HFpEF. Hypothesis: Spironolactone combined with ACEI or ARB may provide additional benefits in patients with HFpEF. Methods: We conducted a post hoc analysis of the TOPCAT (Heart Failure Trial with Aldosterone Antagonist for Preservation of Heart Function) trial using Cox proportional hazards models to evaluate the effect of spironolactone on the clinical prognosis of HFpEF patients, with or without ACEI or ARB. Our primary outcomes were defined as death from cardiovascular causes, aborted cardiac arrest, and hospitalization for heart failure. Results: A total of 1767 HFpEF patients from the Americas were included (49.9% women, median age 71.5 years). During a median follow-up of 2.98 years, 522 (29.5%) primary outcomes occurred. Compared with placebo, spironolactone use was associated with a lower incidence of primary outcomes (hazard ratio [HR]: 0.69, P=0.02), cardiovascular mortality (HR: 0.45, P=0.004) and all-cause mortality (HR: 0.58, P=0.01) after adjustments in HFpEF patients who were concomitantly taking ARB at baseline but not in those without ARB use. Significant interactions were found between spironolactone use and baseline ARB use for cardiovascular and all-cause death (P=0.01). In contrast, spironolactone use was associated with lower cardiovascular death (HR: 0.59, P=0.01) in patients without ACEI baseline use but not in those with ACEI use. There was no significant interaction observed between spironolactone use and baseline ACEI for adverse outcomes. Conclusions: Among HFpEF patients enrolled in TOPCAT-Americas, the survival benefit of spironolactone was enhanced by ARB use but not ACEI use. Further prospective studies are necessary to validate these findings.

Urinary peptide analysis to predict the response to blood pressure medication.

The risk of diabetic kidney disease (DKD) progression is significant despite treatment with renin-angiotensin system (RAS) blocking agents. Current clinical tools cannot predict whether or not patients will respond to treatment with RAS inhibitors (RASi). We aimed to investigate whether proteome analysis could identify urinary peptides as biomarkers that could predict the response to angiotensin-converting enzyme inhibitor and angiotensin-receptor blockers treatment to avoid DKD progression. Furthermore, we investigated the comparability of the estimated glomerular filtration rate (eGFR), calculated using four different GFR equations, for DKD progression. We evaluated urine samples from a discovery cohort of 199 diabetic patients treated with RASi. DKD progression was defined based on eGFR percentage slope results between visits (∼1 year) and for the entire period (∼3 years) based on the eGFR values of each GFR equation. Urine samples were analysed using capillary electrophoresis-coupled mass spectrometry. Statistical analysis was performed between the uncontrolled (patients who did not respond to RASi treatment) and controlled kidney function groups (patients who responded to the RASi treatment). Peptides were combined in a support vector machine-based model. The area under the receiver operating characteristic curve was used to evaluate the risk prediction models in two independent validation cohorts treated with RASi. The classification of patients into uncontrolled and controlled kidney function varies depending on the GFR equation used, despite the same sample set. We identified 227 peptides showing nominal significant difference and consistent fold changes between uncontrolled and controlled patients in at least three methods of eGFR calculation. These included fragments of collagens, alpha-1-antitrypsin, antithrombin-III, CD99 antigen and uromodulin. A model based on 189 of 227 peptides (DKDp189) showed a significant prediction of non-response to the treatment/DKD progression in two independent cohorts. The DKDp189 model demonstrates potential as a predictive tool for guiding treatment with RASi in diabetic patients.

Comparison of angiotensin converting enzyme ınhibitor and/or angiotensin receptor blocker treatments of patients in 3 different patient groups with proteinuria

Amaç: Proteinürisi olan üç farklı hasta grubunda anjiyotensin dönüştürücü enzim (ACE) inhibitörleri ve anjiyotensin reseptör blokörlerinin etkinlik ve güvenliliğini değerlendirmek 
 Gereç ve Yöntemler: 24 saatlik idrarda 1 gramdan fazla proteinürisi olan diyabetik nefropati, glomerülonefrit ve böbrek transplantasyonu tanısı olan 168 hasta çalışmaya alındı. Hastalar 1. grup ACE inhibitörü kullananlar, 2. grup anjiyotensin reseptör blokörü (ARB) kullananlar ve 3. grup hem ACE inhibitörü hem de ARB kullananlar olarak üç gruba ayrıldı. Hastaların eşlik eden hastalıkları, kullandığı ilaçlar ve kan üre nitrojeni, kreatinin, potasyum, 24 saatlik idrar protein atılımı, kreatinin klirensini içeren laboratuvar değerleri 0-1-3-6-9-12-18-24.aylarda kaydedildi. Hastaların çalışma başlangıcı ve takibi sonunda ekokardiyografik değişiklikleri kaydedildi.
 Bulgular: Her üç grupta da 0. aydaki proteinüri değerleri ile diğer tüm aylardaki proteinüri değerleri arasında istatistiksel olarak anlamlı bir düşüş gözlendi. Hem ACE inhibitörü hem de ARB'leri kullanan grup 3 hastalarda 9. aydan itibaren kreatinin seviyeleri anlamlı derecede yükseldi. Grup 1'deki ACE inhibitörü kullanan hastalarda takibin 9. ayından sonra kreatinin klirensi değerlerinde anlamlı bir azalma saptanırken, grup 3'teki ACE inhibitörü ve ARB kullanan hastaların 12. aydan sonra kreatinin klirensleri değerlerinde istatiksel olarak anlamlı bir düşüş saptandı. Grup 2'de ARB kullanan hastalarda kreatinin klirensinde anlamlı bir azalma görülmedi.
 Sonuç:24 saatlik idrarda 1 g'dan yüksek proteinürisi olan hastalar ACEi veya ARB tedavileri almalı ve ACE inhibitörü ve anjiotensin reseptör blokörlerinin kombine tedavisi ise sadece yakından izlenebilecek seçilmiş hastalarda kullanılmalıdır.

Angiotensin Receptor Blockers Restore Skeletal Muscle in Patients with Chronic Obstructive Pulmonary Disease

Age-related muscle decline, called sarcopenia, and hypertension are commonly observed in patients with chronic obstructive pulmonary disease (COPD). Angiotensin receptor blockers (ARBs) are common antihypertensive medications with muscle protective effects. However, the anti-sarcopenic potential and associated mechanisms of ARBs in hypertensive patients with COPD are unknown. We aimed to investigate the potential contribution of neuromuscular junction (NMJ) stability as a driving mechanism of ARBs-induced muscle protection. We categorized 236 patients with COPD into normotensive (n = 79) and hypertensive, based on treatment with ARB (n=82), and other antihypertensive drugs (n = 75). Hypertensive patients with COPD were evaluated at two time points one year apart. Handgrip strength (HGS), body composition, short physical performance battery (SPPB), and plasma c-terminal agrin fragment-22 (CAF22) as a marker of NMJ degradation were measured. Patients with COPD exhibited reduced HGS and SPPB scores, and higher levels of CAF22 than controls, regardless of hypertension status. ARBs treatment improved HGS and gait speed and reduced plasma CAF22 levels in hypertensive patients with COPD (all p <0.05). ARBs also prevented the decline in SPPB components, including maintaining balance, gait speed, and the ability to rise from a chair in hypertensive patients with COPD (all p <0.05). We also found dynamic associations of plasma CAF22 with HGS, gait speed, and SPPB scores in hypertensive patients with COPD. Altogether, ARB treatment preserves skeletal muscle health and functional capacity in hypertensive patients with COPD by reducing plasma CAF22 and possibly repairing NMJs.

Decoding Angiotensin Receptors: TOMAHAQ-Based Detection and Quantification of Angiotensin Type-1 and Type-2 Receptors.

Background The renin-angiotensin system plays a crucial role in human physiology, and its main hormone, angiotensin, activates 2 G-protein-coupled receptors, the angiotensin type-1 and type-2 receptors, in almost every organ. However, controversy exists about the location, distribution, and expression levels of these receptors. Concerns have been raised over the low sensitivity, low specificity, and large variability between lots of commercially available antibodies for angiotensin type-1 and type-2 receptors, which makes it difficult to reconciliate results of different studies. Here, we describe the first non-antibody-based sensitive and specific targeted quantitative mass spectrometry assay for angiotensin receptors. Methods and Results Using a technique that allows targeted analysis of multiple peptides across multiple samples in a single mass spectrometry analysis, known as TOMAHAQ (triggered by offset, multiplexed, accurate mass, high resolution, and absolute quantification), we have identified and validated specific human tryptic peptides that permit identification and quantification of angiotensin type-1 and type-2 receptors in biological samples. Several peptide sequences are conserved in rodents, making these mass spectrometry assays amenable to both preclinical and clinical studies. We have used this method to quantify angiotensin type-1 and type-2 receptors in postmortem frontal cortex samples of older adults (n=28) with Alzheimer dementia. We correlated levels of angiotensin receptors to biomarkers classically linked to renin-angiotensin system activation, including oxidative stress, inflammation, amyloid-β load, and paired helical filament-tau tangle burden. Conclusions These robust high-throughput assays will not only catalyze novel mechanistic studies in the angiotensin research field but may also help to identify patients with an unbalanced angiotensin receptor distribution who would benefit from angiotensin receptor blocker treatment.

Spontaneous Epiretinal Membrane Resolution and Angiotensin Receptor Blockers: Case Observation, Literature Review and Perspectives.

Epiretinal membrane (ERM) is a relatively common condition affecting the macula. When symptoms become apparent and compromise a patient's quality of vision, the only therapeutic approach available today is surgery with a vitrectomy and peeling of the ERM. Angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACE-Is) reduce the effect of angiotensin II, limit the amount of fibrosis, and demonstrate consequences on fibrinogenesis in the human body. Case Description and Materials and Methods: A rare case of spontaneous ERM resolution with concomitant administration of ARB is reported. The patient was set on ARB treatment for migraines and arterial hypertension, and a posterior vitreous detachment was already present at the first diagnosis of ERM. The scientific literature addressing the systemic relationship between ARB, ACE-Is, and fibrosis in the past 25 years was searched in the PubMed, Medline, and EMBASE databases. In total, 38 and 16 original articles have been selected for ARBs and ACE-Is, respectively, in regard to fibrosis modulation. ARBs and ACE-Is might have antifibrotic activity on ERM formation and resolution. Further clinical studies are necessary to explore this phenomenon.

Renin-Angiotensin-Aldosterone System Inhibitions and Cardiovascular Outcomes in Acute Myocardial Infarction With Renal Impairment

ObjectiveTo compare the clinical outcomes of patients with acute myocardial infarction with renal impairment (AMI-RI) treated with either angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) in real-world clinical settings. Patients and MethodsA total of 4790 consecutive patients with AMI-RI between November 1, 2011, and December 31, 2015, were subdivided into ACEI (n=2845) and ARB (n=1945) treatment groups. The primary end points were major adverse cardiac and cerebrovascular events, including all-cause mortality, nonfatal myocardial infarction, any revascularization, cerebrovascular accident, rehospitalization, and stent thrombosis. Propensity score matching (PSM) was used to adjust for group differences. ResultsThe ARB group had a significantly higher incidence of major adverse cardiac and cerebrovascular events (at 3-year follow-up) than the ACEI group according to the unadjusted analysis (3-year hazard ratio [HR], 1.60; 95% CI, 1.43 to 1.78) and the PSM-adjusted analysis (3-year HR, 1.34; 95% CI, 1.15 to 1.56). However, any revascularization (3-year HR, 1.21; 95% CI, 0.95 to 1.54) and rehospitalization (3-year HR, 1.21; 95% CI, 0.88 to 1.67) were not significantly different between groups in the PSM-adjusted analysis. Compared with the ARB group, the ACEI group had lower rates of all-cause mortality at estimated glomerular filtration rates of at least 15 or less than 90 mL/min/1.73 m2 in the unadjusted data and at least 60 or less than 90 mL/min/1.73 m2 in the PSM-adjusted analysis. ConclusionTreatment with ACEIs seemed to be more beneficial than treatment with ARBs for patients with AMI-RI; further prospective studies are required to confirm these results.

Effect of Discontinuation of Renin Angiotensin-System Inhibitors in Patients With Advanced Chronic Kidney Disease: A Meta-Analysis.

Renin-angiotensin system inhibitors (RAS) inhibitors include angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme (ACE) inhibitors decrease proteinuria, progression of chronic kidney disease (CKD), and protect against heart failure hospitalizations and cardiovascular events. There is uncertainty about the appropriate time for discontinuing ARB and ACE inhibitor treatment in patients with low estimated glomerular filtration rate (eGFR). In the present meta-analysis, we examined the effect of RAS inhibitor discontinuation on clinical outcomes in patients with advanced CKD compared to the continuation of RAS inhibitors. Two authors conducted electronic database searches in PubMed, the Cochrane Library, and Excerpta Medica Database (EMBASE) for relevant studies published from the inception of the databases to March 15th, 2023, using the following combination of keywords or key terms: "Renin-angiotensin-system," "angiotensin-converting-enzyme inhibitors", "Angiotensin receptor blockers," and "advanced chronic kidney disease."Primary outcomes assessed in this meta-analysis included cardiovascular events. Secondary outcomes assessed included all-cause mortality and end-stage kidney disease (ESKD). A total of four studies were included in this meta-analysis.The pooled analysis showed thatcardiovascular eventswere significantly higher in patients in the discontinuation group compared to the continuation group (HR: 1.38, 95% CI: 1.21-1.58), ESKD was also significantly higher in the discontinuation group (HR: 1.29, 95% CI: 1.18-1.41). No significant differences were reported between the two groups in all-cause mortality.In conclusion, our meta-analysis provides evidence that continuation of RAS inhibitors could be beneficial in patients with advanced CKD, as it is associated with less risk of cardiovascular events and ESKD.

Long-term mortality and cardiovascular events of seven angiotensin receptor blockers in hypertensive patients: Analysis of a national real-world database: A retrospective cohort study.

Although many angiotensin receptor blockers (ARBs) are widely used, comparative data regarding their impact on clinical outcomes are limited. We aimed to compare the clinical effectiveness of seven ARBs on long-term cardiovascular outcomes in Korean patients with hypertension. Using the Korean National Health Insurance Service database, the data of 780,785 patients with hypertension without cardiovascular disease (CVD) who initiated ARB treatment (candesartan, fimasartan, irbesartan, losartan, olmesartan, telmisartan, or valsartan) in 2014 and underwent this treatment for more than 6 months, were analyzed. Cox-regression analysis was performed using Losartan as a comparator, as it was the most widely used drug, by adjusting age, sex, diabetes, dyslipidemia, smoking, alcohol drinking, exercise, body mass index, systolic blood pressure, albuminuria, estimated glomerular filtration rate, and concomitant medications. The occurrence of mortality and the rate of major adverse cardiovascular events (MACEs) of the six ARBs was compared with that of losartan. The median follow-up duration was 5.94 (interquartile range, 5.87-5.97) years. In the crude analysis of all-cause mortality and MACEs, fimasartan exhibited the lowest event rates. In the Cox-regression analysis with adjustment, there was no significant difference in all-cause mortality among ARBs. The risk of MACEs with ARBs was similar to that with losartan, although the risks with irbesartan (hazard ratio [HR], 1.079; 95% confidence interval [CI], 1.033-1.127; p = 0.007) and candesartan (HR: 1.066; 95% CI,1.028-1.106; p = 0.015) were slightly higher. In a Korean population of patients with hypertension without CVD, six different ARBs showed similar efficacy to losartan in terms of long-term mortality and MACEs. Further well-designed prospective studies are required to confirm our findings.

PS-BPB08-4: IMPAIRED TCA CYCLE METABOLISM IN DIABETIC NEPHROPATHY IS LINKED TO ALBUMINURIA AND KIDNEY INJURY

Objective: Recent work has highlighted potential contributions of impaired renal energy metabolism, including mitochondrial dysfunction and altered fatty acid metabolism, in chronic kidney diseases including diabetic nephropathy (DN). However, causal connections between specific metabolic abnormalities and pathophysiology of DN have been difficult to establish. Here, we approach this question using a mouse model recapitulating characteristic features of human DN and a targeted metabolomics platform designed to assess key metabolic pathways involving amino acids, fatty acids, glycolysis and the TCA cycle. Design and method: We generated a mouse model of DN with underlying activation of the renin-angiotensin system (RAS) by a renin transgene (R) driven by the albumin promoter on the Akita background of type I diabetes (A). We have shown that on a susceptible 129/Sv background, Akita-ReninTg (AR) mice exhibit cardinal characteristics of human DN including high-grade albuminuria and glomerulosclerosis, whereas AR mice on a C57BL/6 background do not develop DN. To assess the impact of genetic background on energy metabolism in DN, kidneys from 24-week-old male AR mice on both backgrounds were evaluated by the targeted metabolome analysis. To further distinguish the impact of RAS activation on relevant pathways associated with kidney disease development, 12-week-old male 129/Sv AR mice were treated with the angiotensin receptor blocker (ARB) losartan 10 mg/kg/day for 12 weeks. 24-hour urine samples were collected in metabolic cages and urine albumin levels were measured by EIA. Kidneys from age-matched parental 129/Sv and C57BL/6 wild-type mice were analyzed as controls. Results: A distinct metabolic profile was observed in kidneys of DN-susceptible 129/Sv AR mice including reduced levels of C2 acetyl-carnitine that reflect a deficiency in acetyl-CoA, perturbations of TCA cycle intermediates and increased lactate levels. In addition, levels of phosphorylated-AMPK were reduced. These metabolic changes were absent in DN-resistant C57BL/6 AR mice. Treatment of 129/Sv AR mice with the ARB dramatically reduced albuminuria (906 ± 169 vs 193 ± 42 μg/day, p &lt; 0.01) and attenuated kidney pathology while restoring levels of C2 acetyl-carnitine, TCA intermediates, lactate and phosphorylated-AMPK toward normal. ARB treatment also increased kidney ATP content. In 129/Sv mice, there were statistically significant correlations between albuminuria and kidney levels of lactate, acetyl-carnitine, citrate and succinate. Conclusions: Thus, there is a distinct profile of impaired energy metabolism associated with DN susceptibility that is attenuated by RAS blockade. Impaired TCA cycle function and coincident increases in lactate are linked to albuminuria in mice with DN, and may contribute to kidney injury.

PS-C02-2: THE USE OF HYDROCHLOROTHIAZIDE FOR THE TREATMENT OF HYPERTENSION INCREASES THE CARDIOVASCULAR RISK ACCORDING TO THE CENTRAL HAEMODYNAMIC PARAMETERS

Objective: The chronic use of the diuretic hydrochlorothiazide (Hct) can activate the neurohormonal system, increasing metabolic risk factors it is potentially arrhythmogenic; and can stimulate the escape of aldosterone, even during Angiotensin Receptor Blockers (ARB) treatment. Aldosterone is a hormone with dangerous effects on the cardiovascular system, from arterial/myocardium stiffness to sodium and water retention; also, is involved in the production of reactive oxygen species and endothelial dysfunction. Psoriasis is a systemic disease that exemplifies the intersection of inflammation, immune dysregulation; and accelerating cardiovascular disease. This study aimed to know if the hydrochlorothiazide added to ARB therapy for the treatment of hypertension can produce a deleterious effect on the cardiovascular system similar to psoriasis, and compare the different responses of ARB therapy alone, according to the measuring of the Central Hemodynamic Parameters (CHP). Design &amp; Methods: For this cross-sectional retrospective study data were collected from 994 patients divided into three groups, both sexes. One group of patients with psoriasis female-male (F-M) (65–57) average age (SD) 55.7 (14.7) - 52.1 (12.5). A second group, in the regime of ARB therapy, F-M (237–217) average age (SD), 62.6 (12.8) - 58.5 (13.6). In the third group, during ARB+Hct therapy, F-M (253–165) average age (SD) was 65.2 (11.2) - 61.9 (12.6). For this study were entered anthropomorphic measures, Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP), Heart Rate, CHP, and the Difference between observed values and normal levels of Augmentation Index (Diff-AIx), the surrogate value of arterial stiffness, assessing with a validated device employing the high-fidelity technique of applanation tonometry according to standard methods (SphygmoCor-PVX). All patients had a therapy time length of more than 6 months. The presence in brief phases of atrial fibrillation was in 24hs-Holter monitoring in the 3 groups were registered. Results: Data of SBP, DBP, Central Aortic Pressure, End-Systolic Pressure, Mean Arterial Pressure and Diff-AIx were highest among the groups with ARB+Hct and psoriasis, and ARB therapy with a statistically significant difference, while between the group psoriasis and ARB+Hct was not found a statistically significant. The highest percentage of patients with phases of atrial fibrillation during 24hs-Holter monitoring were found in the group ARB+Hct (13.6%) than ARB therapy (7.5%) with a statistically significant (p &lt; 0.001). Conclusions: The chronic use of Hydrochlorothiazide for hypertension treatment produces deleterious action on hemodynamics and cardiovascular parameters and can increase the development of atrial fibrillation.

Angiotensin receptor blockade with olmesartan alleviates brain pathology in obese OLETF rats.

Metabolic syndrome (MetS) is a rapidly increasing health concern during midlife and is an emerging risk factor for the development of neurodegenerative diseases, such as Alzheimer's disease (AD). While angiotensin receptor blockers (ARB) are widely used for MetS-associated hypertension and kidney disease, its therapeutic potential in the brain during MetS are not well-described. Here, we tested whether treatment with ARB could alleviate the brain pathology and inflammation associated with MetS using the Otsuka Long-Evans Tokushima Fatty (OLETF) rat. Here, we report that chronic ARB treatment with olmesartan (10mg/kg/day by oral gavage for 6 weeks) partially but significantly ameliorated accumulation of oxidized and ubiquitinated proteins, astrogliosis and transformation to neurotoxic astrocytes in the brain of old OLETF rats, which otherwise exhibit the progression of these pathological hallmarks associated with MetS. Additionally, olmesartan treatment restored claudin-5 and ZO-1, markers of the structural integrity of the blood-brain barrier as well as synaptic protein PSD-95, which were otherwise decreased in old OLETF rats, particularly in the hippocampus, a critical region in cognition, memory and AD. These data demonstrate that the progression of MetS in OLETF rats is associated with deterioration of various aspects of neuronal integrity that may manifest neurodegenerative conditions and that overactivation of angiotensin receptor directly or indirectly contributes to these detriments. Thus, olmesartan treatment may slow or delay the onset of degenerative process in the brain and subsequent neurological disorders associated with MetS.

Role of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in cryoballoon ablation outcomes for paroxysmal atrial fibrillation.

Cryoballoon ablation (CBA) is recommended for patients with paroxysmal atrial fibrillation (AF) refractory to antiarrhythmic drugs. However, only 80% of patients benefit from initial CBA. There is growing evidence that pretreatment with angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) decreases the recurrence of AF postablation, particularly in nonparoxysmal AF undergoing radiofrequency ablation. The role of ACEIs and ARBs in patients with paroxysmal AF in CBA remains unknown. We decided to investigate the role of ACEIs and ARBs in preventing the recurrence of atrial arrhythmia (AA) following CBA for paroxysmal AF. To investigate the role of ACEIs and ARBs in preventing recurrence of AA following CBA for paroxysmal AF. We followed 103 patients (age 60.6 ± 9.1 years, 29% women) with paroxysmal AF undergoing CBA 1-year post procedure. Recurrence was assessed by documented AA on electrocardiogram or any form of long-term cardiac rhythm monitoring. A multivariable Cox proportional hazard model was used to assess if ACEI or ARB treatment predicted the risk of AA recurrence. After a 1-year follow-up, 19 (18.4%) participants developed recurrence of AA. Use of ACEI or ARB therapy was noted in the study population. Patients on ACEI/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 (P = 0.72). Similarly, on Kaplan-Meier analysis pretreatment with ACEI/ARB did not predict the time to first recurrence of AA (P = 0.2173). In our study population, preablation treatment with an ACEI or ARB had no influence on the recurrence of AA following CBA for paroxysmal AF.

Angiotensin-receptor blocker losartan alleviates atrial fibrillation in rats by downregulating frizzled 8 and inhibiting the activation of WNT-5A pathway.

Atrial fibrillation (AF) is a common arrhythmia. Angiotensin-receptor blocker (ARB) is related to AF treatment. This study explored the mechanism of ARB in AF. AF rat models were established by Ach-CaCl2 mixed solution injection. Rats were treated with ARB by gavage and injected with pcDNA3.1-based frizzled homolog 8(FZD8) overexpression plasmids (oe-FZD8) through the tail vein. The 12-lead electrocardiogram was recorded by biological signal acquisition and processing system and AF duration was recorded, and atrial effective refractory period (AERP) was monitored by electrophysiology. Atrial fibrosis degree, FZD8 messenger RNA and protein levels, collagen I, collagen III, transforming growth factor β1 (TGF-β1), fibronectin, α smooth muscle actin (α-SMA), WBT-5B, and p-JNK1/2 levels, interleukin 1 β (IL-1β) and interleukin 6 (IL-6) levels were detected by Masson staining, reverse transcription quantitative polymerase chain reaction, western blot assay, immunohistochemistry, and enzyme-linked immunosorbent assay. ACh-CaCl2-induced AF rats showed a large area of fused necrosis, abnormal collagen fibre proliferation, high atrial fibrosis degree, and increased atrial fibrosis area in atrial interstitium, elevated collagen I, collagen III, TGF-β1, fibronectin, α-SMA, IL-1β, and IL-6 levels, whereas these trends were averted by ARB treatment. FZD8 was highly expressed in AF rat myocardium. ARB repressed FZD8 expression, prolonged AERP and reduced AF incidence. FZD8 overexpression annulled the effects of ARB on improving AF rat myocardial fibrosis. ARB inactivated the WNT-5A pathway by suppressing FZD8. ARB inactivated the WNT-5A pathway by silencing FZD8, therefore, alleviating AF rat atrial fibrosis.

Comparison Between Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers in Patients with Unstable Angina with Preserved Left Ventricular Systolic Function.

The present study evaluated the clinical results of angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) treatment in patients with unstable angina (UA) with preserved left ventricular systolic function who underwent percutaneous coronary intervention (PCI) due to uncertainty regarding the long-term prognosis using ACEI or ARB. A total of 1627 UA patients with preserved left ventricular systolic function after PCI were enrolled. After propensity score matching, there were no differences in major adverse cardiovascular and cerebrovascular events (MACCEs) (hazard ratio (HR) = .860, 95% confidence interval (CI): .465-1.590, P = .630), all-cause death (HR = .334, 95% CI: .090-1.238, P = .101), nonfatal myocardial infarction (HR = 4.929, 95% CI: .576-42.195, P = .145), stroke (HR = 1.049, 95% CI: .208-5.290, P = .954) and target vessel revascularization (TVR) (HR = 1.276, 95% CI: .537-3.031, P = .581) between the ACEI and ARB groups. In conclusion, prognoses were comparable between ACEI or ARB treatment in UA patients who had preserved left ventricular systolic function after PCI.

Overexpression of TRPM7 suppresses AngII-induced phenotypic changes in hypertensive human vascular smooth muscle cells

Purpose: To study the role of TRPM7 in suppressing AngII-induced phenotype changes in human vascular smooth muscle cells (HAVSMCs).Methods: Relative levels of TRPM7, α-SMA and OPN in AngII-induced HAVSMCs were determined, and the regulatory effects of TRPM7 on levels of α-SMA and OPN, wound healing effect, 5-ethynyl-2’- deoxyuridine (EdU)-positive ratio, and viability in AngII-induced HAVSMCs were assessed. A total of 159 patients with essential hypertension attending The Second Xiangya Hospital, Central South University, Changsha, China, and 70 healthy controls were enrolled; after treatment with angiotensin receptor blocker (ARB), changes in SBP, DBP and plasma level of TRPM7 in hypertension patients were examined. Potential correlation between TRPM7 level with SBP and DBP was assessed.Results: TRPM7 and α-SMA were downregulated, while OPN was upregulated in AngII-induced HAVSMCs, but this trend was partially reversed by losartan treatment (p &lt; 0.05). Overexpression of TRPM7 reversed the expression changes of α-SMA and OPN in AngII-induced HAVSMCs. In addition, the overexpression of TRPM7 significantly inhibited the enhanced migratory and proliferative capacities in AngII-induced HAVSMCs (p &lt; 0.05). After ARB treatment, SBP, DBP and plasma TRPM7 were significantly reduced in hypertension patients, while TRPM7 level positively correlated with SBP and DBP in hypertensive patients.Conclusion: Overexpression of TRPM7 blocked AngII-induced phenotype changes in HAVSMCs under the pathological circumstance of hypertension.

Improved lipogenesis gene expression in liver is associated with elevated plasma angiotensin 1-7 after AT1 receptor blockade in insulin-resistant OLETF rats

Increased angiotensin II (Ang II) signaling contributes to insulin resistance and liver steatosis. In addition to ameliorating hypertension, angiotensin receptor blockers (ARBs) improve lipid metabolism and hepatic steatosis, which are impaired with metabolic syndrome (MetS). Chronic blockade of the Ang II receptor type 1 (AT1) increases plasma angiotensin 1-7 (Ang 1–7), which mediates mechanisms counterregulatory to AT1 signaling. Elevated plasma Ang 1–7 is associated with decreased plasma triacylglycerol (TAG), cholesterol, glucose, and insulin; however, the benefits of RAS modulation to prevent non-alcoholic fatty liver disease (NAFLD) are not fully investigated. To better address the relationships among chronic ARB treatment, plasma Ang 1–7, and hepatic steatosis, three groups of 10-week-old-rats were studied: (1) untreated lean Long Evans Tokushima Otsuka (LETO), (2) untreated Otsuka Long Evans Tokushima Fatty (OLETF), and (3) OLETF + ARB (ARB; 10 mg olmesartan/kg/d × 6 weeks). Following overnight fasting, rats underwent an acute glucose load to better understand the dynamic metabolic responses during hepatic steatosis and early MetS. Tissues were collected at baseline (pre-load; T0) and 1 and 2 h post-glucose load. AT1 blockade increased plasma Ang 1–7 and decreased liver lipids, which was associated with decreased fatty acid transporter 5 (FATP5) and fatty acid synthase (FASN) expression. AT1 blockade decreased liver glucose and increased glucokinase (GCK) expression. These results demonstrate that during MetS, overactivation of AT1 promotes hepatic lipid deposition that is stimulated by an acute glucose load and lipogenesis genes, suggesting that the chronic hyperglycemia associated with MetS contributes to fatty liver pathologies via an AT1-mediated mechanism.

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.