Angiotensin II Receptor Blocker Treatment Research Articles

P4556Thrombin generation and platelet function in patients on RAAS inhibitors

Abstract Background ACE inhibitors (ACEI) and angiotensin II receptor blockers (ARB) are beneficial for patients with cardiovascular disease. However, little is known about whether one of these drugs is superior. First analyses show that the inhibition of the renin-angiotensin-aldosterone system (RAAS) affects platelet reactivity. Therefore we evaluated the effects of ACEI and ARB on platelet reactivity and thrombin generation. Methods In a time series analysis, samples of 24 patients before, 4h and 24h after initial intake of ACEI were analysed. Also we included 10 patients with permanent ACEI treatment and 4h, 24h and 3 months after switching to ARB. Platelet reactivity was measured via light transmission aggregometry (LTA). Thrombin generation was measured as endogenous thrombin potential (ETP) by calibrated automated thrombogram. Protease-activated receptor (PAR) expression was analysed by flow cytometry. Thrombin-antithrombin (TAT) complexes were measured with an enzyme-linked immunosorbent assay. Results TRAP-6 induced platelet reactivity increased during ACEI treatment (prior vs. 4h post ACEI: 41.9±16.2% vs. 55.2±16.7%; p=0.003, prior vs. 24h post ACEI: 52.3±12.7%; p=0.003). Switching from chronic ACEI to ARB treatment decreased platelet reactivity (permanent ACEI vs. 3 months after switching: 50.3±20.9% vs. 34.7±20.9%; p=0.033). ACEI reduced ETP from prior to 3 months post ACEI (1527±437 nM*min vs. 1088±631 nM*min; p=0.025). ARB did not affect ETP (1526±587 nM*min vs. 1369±516 nM*min; p=0.3). PAR1 levels rose from 37.38±10.97% before to 49.53±6.04% after ACEI treatment (p=0.036). ARB did not have an effect on PAR1 (33.16±11.73 vs. 32.86±8.99; p=0.89). ACEI slightly decreased plasma thrombin concentration. ARB treatment showed a minor but again not significant decrease in TAT complexes as well. (TAT complexes prior vs. 3 months post ACEI: 8.4±11.9 μg/l vs. 6.3±6.8 μg/l; p=0.99, permanent ACEI vs. 3 months after switching to ARB: 4.3±1.9 μg/l vs. 3.0±1.0 μg/l; p=0.3). Conclusion ACEI increased platelet reactivity. This can be reversed by switching to ARB. The mechanism behind RAAS influencing platelet function needs to be further investigated in larger trials. Acknowledgement/Funding Medical Faculty of the Heinrich-Heine-University Düsseldorf

P2641Renal and cardiovascular benefits of treatment with angiotensin receptor blockers in patients with hypertension and chronic kidney disease: A systematic review and meta-analysis

Abstract Background Blood pressure (BP) control is critical in delaying the progression of chronic kidney disease (CKD), which otherwise results in an increased risk of cardiovascular morbidity and mortality. Angiotensin II receptor blockers (ARBs) or angiotensin-converting enzyme inhibitors, are recommended by several guidelines as first-line treatment for patients with hypertension and CKD. Purpose We reviewed and analysed the effect of ARB treatment on BP and renal outcomes (estimated glomerular filtration rate (eGFR), serum creatinine (SCr), creatinine clearance (CrCl) or proteinuria) in patients with hypertension and CKD with or without diabetes, including large clinical trials such as RENAAL and IDNT. Methods MEDLINE, EMBASE, and BIOSIS databases were searched for literature from the earliest available date to July 2017. Randomised (parallel-group) controlled trials of ≥8 weeks assessed the impact of ARBs on systolic/diastolic BP (SBP/DBP), eGFR, SCr, CrCl or proteinuria were included in the analysis. Meta-analysis (post- versus pre-treatment) and meta-regression were conducted in R-statistical software (v3.4.1) using meta- and metafor-packages. Mean difference (MD, generic inverse variance) with 95% confidence intervals (CIs) was used to pool data for an outcome in a single forest plot. The risk of bias (quality) of included studies was assessed by the six items of the Cochrane instrument. Results Of the 165 articles assessed for eligibility, 24 studies were included in the analysis (19 evaluated ARBs as monotherapy, 4 evaluated ARBs in combination with other antihypertensives and 1 evaluated ARBs both as mono- and combination therapy). Treatment with ARBs as monotherapy for ≥8 weeks to <1 year significantly reduced mean office SBP (MD, −12.60 mmHg; 95% CI, −18.53 to −6.67)/DBP (−6.52 mmHg; −11.27 to −1.77) (p<0.01). BP reduction was also significant (p<0.01) with ARB monotherapy for ≥1 year SBP (−14.84 mmHg; −17.82 to −11.85)/DBP (−10.27 mmHg; −12.26 to −8.27). ARBs also significantly reduced SBP/DBP when combined with other antihypertensive treatments for ≥8 weeks to <1 year as well as for ≥1 year (Figure). Moreover, ARBs induced significant reductions (p<0.01) in proteinuria (≥8 weeks to <1 year [MD, −0.6 g/L; 95% CI, −0.93 to −0.26; ≥1 year [−0.9 g/L; −1.22 to −0.59]), but no significant changes in eGFR, CrCl or SCr levels. The beneficial effect of ARBs was maintained overtime with no significant additional impact on SBP change (estimate: 0.025; 95% CI, –0.14 to 0.19) or eGFR (estimate: 0.068; 95% CI, −0.14 to 0.28; p=0.53). The overall risk of bias was judged to be low. Effect of ARBs on blood pressure changes Conclusion Treatment with ARBs effectively and sustainably lowered BP and proteinuria with no significant change in eGFR in patients with hypertension and CKD with or without diabetes.

Sex differences in the response to angiotensin II receptor blockade in a rat model of eccentric cardiac hypertrophy.

Background. Men and women differ in their susceptibility to cardiovascular disease, though the underlying mechanism has remained elusive. Heart disease symptoms, evolution and response to treatment are often sex-specific. This has been studied in animal models of hypertension or myocardial infarction in the past but has received less attention in the context of heart valve regurgitation. The aim of the study was to evaluate the development of cardiac hypertrophy (CH) in response to left ventricle (LV) volume overload (VO) caused by chronic aortic valve regurgitation (AR) in male and female rats treated or not with angiotensin II receptor blocker (ARB), valsartan. We studied eight groups of Wistar rats: male or female, AR or sham-operated (sham) and treated or not with valsartan (30 mg/kg/day) for 9 weeks starting one week before AR surgical induction.Results. As expected, VO from AR resulted for both male and female rats in significant LV dilation (39% vs. 40% end-diastolic LV diameter increase, respectively; p < 0.0001) and CH (53% vs. 64% heart weight increase, respectively; p < 0.0001) compared to sham. Sex differences were observed in LV wall thickening in response to VO. In untreated AR males, relative LV wall thickness (a ratio of wall thickness to end-diastolic diameter) was reduced compared to sham, whereas this ratio in females remained unchanged. ARB treatment did not prevent LV dilation in both male and female animals but reversed LV wall thickening in females. Systolic and diastolic functions in AR animals were altered similarly for both sexes. ARB treatment did not improve systolic function but helped normalizing diastolic parameters such as left atrial mass and E wave slope in female AR rats. Increased LV gene expression of Anp and Bnp was normalized by ARB treatment in AR females but not in males. Other hypertrophy gene markers (Fos, Trpc6, Klf15, Myh6 and Myh7) were not modulated by ARB treatment. The same was true for genes related to LV extracellular matrix remodeling (Col1a1, Col3a1, Fn1, Mmp2, Timp1 and Lox). In summary, ARB treatment of rats with severe AR blocked the female-specific hypertrophic response characterized by LV chamber wall thickening. LV dilation, on the other hand, was not significantly decreased by ARB treatment. This also indicates that activation of the angiotensin II receptor is probably more involved in the early steps of LV remodeling caused by AR in females than in males.

Pathological presentation of cardiac mitochondria in a rat model for chronic kidney disease.

BackgroundMitochondria hold crucial importance in organs with high energy demand especially the heart. We investigated whether chronic kidney disease (CKD), which eventually culminates in cardiorenal syndrome, could affect cardiac mitochondria and assessed the potential involvement of angiotensin II (AngII) in the process.MethodsMale Lewis rats underwent 5/6 nephrectomy allowing CKD development for eight months or for eleven weeks. Short-term CKD rats were administered with AngII receptor blocker (ARB). Cardiac function was assessed by echocardiography and cardiac sections were evaluated for interstitial fibrosis and cardiomyocytes’ hypertrophy. Electron microscopy was used to explore the spatial organization of the cardiomyocytes. Expression levels of mitochondrial content and activity markers were tested in order to delineate the underlying mechanisms for mitochondrial pathology in the CKD setting with or without ARB administration.ResultsCKD per-se resulted in induced cardiac interstitial fibrosis and cardiomyocytes’ hypertrophy combined with a marked disruption of the mitochondrial structure. Moreover, CKD led to enhanced cytochrome C leakage to the cytosol and to enhanced PARP-1 cleavage which are associated with cellular apoptosis. ARB treatment did not improve kidney function but markedly reduced left ventricular mass, cardiomyocytes’ hypertrophy and interstitial fibrosis. Interestingly, ARB administration improved the spatial organization of cardiac mitochondria and reduced their increased volume compared to untreated CKD animals. Nevertheless, ARB did not improve mitochondrial content, mitochondrial biogenesis or the respiratory enzyme activity. ARB mildly upregulated protein levels of mitochondrial fusion-related proteins.ConclusionsCKD results in cardiac pathological changes combined with mitochondrial damage and elevated apoptotic markers. We anticipate that the increased mitochondrial volume mainly represents mitochondrial swelling that occurs during the pathological process of cardiac hypertrophy. Chronic administration of ARB may improve the pathological appearance of the heart. Further recognition of the molecular pathways leading to mitochondrial insult and appropriate intervention is of crucial importance.

WITHDRAWAL OF ANGIOTENSIN ANTAGONISTS IN ELDERLY CHRONIC KIDNEY DISEASE PATIENTS

Objective: Hypertension guidelines worldwide recommend first-line treatment with Angiotensin Convertor Enzyme Inhibitors (ACEI) or Angiotensin II Receptor Blockers (ARBs) in almost all groups of patients. Nevertheless, some population as elderly or CKD patients at high risk to develop renal complications may benefit from avoidance of these commonly used drugs. Design and method: We reviewed our registry of out-hospital patients who had to suspend ACEI or ARBs treatment selecting those without kidney loss, known renal artery stenosis, active neoplasms or drug withdrawal in a condition of Acute Kidney Injury and we performed 12 months follow up. Finally, 36 resulting patients completed the one year period and data of basal, three months and 12-month visits have been compared. A case-control study examining the glomerular filtration rate (GFR), first-day urine albuminuria, blood pressure control and plasmatic potassium has been performed. Results: Baseline characteristics: 17 males and 19 females both with an average age of 78.3 (SD 7.7) years, Charlson's comorbidity index of 6.8 (SD 2), 14 treated previously with ACEI and 22 with ARBs. Comparison of average blood pressure, GFR, proteinuria and potassium levels showed: 1. There were no significant variations in blood pressure at 3 and 12 months. 2. GFR increased at 3 and 12 months from 31.9 (SD 9.4) to 39.6 (SD 14.9) and 43.1 (SD 17.3) ml/min/1.73m2 [p < 0.001] 3. Plasma potassium level decreased at 3 and 12 months from 5.1 (SD 0.6) to 4.7 (SD 0.5) and 4.6 (SD 0.5) mg/dl respectively [p < 0.001] 4. First-day urine albuminuria increased significantly at the 12-month visit in the overall group(from 127.4 (SD 301.8) to 233 (SD 557) mg/g, p < 0.05). Nevertheless, no significant change was observed in the group of 27 patients without significant previous proteinuria (from 13.9 (SD 16.8) to 21.5 (SD 24.8), p = 0.1 NS). Conclusions: Elderly patients with prolonged hypertension are at risk to develop slowly progressive kidney failure associated with the use of ACEI and ARBs, especially if renal atrophy is present. These patients without previous proteinuria would benefit from the first-line use of antihypertensive drugs without suppressive effect over the renin-angiotensin system.

Does the Use of Angiotensin-Converting Enzyme Inhibitors or Angiotensin II Receptor Blockers Improve Survival in Bladder Cancer?

Introduction: The use of angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARB) has been associated with improved bladder cancer outcomes. The objective of this study was to perform a systematic review of the literature and investigate the effects of these medications on survival from our own retrospective database. Methods: A systematic literature search of PubMed and the Cochrane database was conducted and 34 relevant articles identified. No randomised control trials were identified. After exclusion, five observational studies were included in our analysis. Since there was a paucity of data, we then performed a retrospective cohort study using clinical data from our electronic medical record. All patients who underwent radical cystectomy, with or without adjuvant chemotherapy, at a single tertiary care centre in Ontario, Canada between 2001 and 2016 were identified. Results: Our literature review found that ACEI or ARB use in upper urinary tract and lower urinary tract non-muscle invasive bladder cancer was associated with increased 5-year recurrence-free, cancer-specific, and overall survival. Our own analysis identified 464 patients who underwent radical cystectomy for muscle-invasive bladder cancer during the study period. Ninety-nine individuals received ACEI or ARB treatment during this time. Cox-proportion hazards modelling suggested that the use of ACEI or ARB was not significantly associated with a survival benefit. Conclusions: We are unable to support or oppose the use of ACEI or ARB as adjuvant treatment in bladder cancer due to the heterogeneity and quality of published data. Our own study data do not support the use of these medications as adjuvant therapy for muscle-invasive bladder cancer. A randomised control trial in this area of research is required.

Angiotensin II receptor blockers for the treatment of portal hypertension in patients with liver cirrhosis: a systematic review and meta-analysis of randomized controlled trials.

Randomized controlled trials (RCTs) showed inconsistent results regarding the efficacy of angiotensin II receptor blockers (ARBs) on portal pressure as indicated by hepatic venous pressure gradient (HVPG). A meta-analysis of RCTs was performed to evaluate the influence of ARBs treatment on HVPG. PubMed, Embase, and Cochrane's Library were searched for relevant RCTs. A fixed or a randomized effect model was used to pool the results according the heterogeneity. Subgroup analyses were performed to explore the source of heterogeneity. Eleven RCTs with 394 patients were included. ARBs treatment did not significantly change HVPG as compared with controls (weighted mean difference [WMD] = -0.63, 95% confidence interval [CI] -1.73 to 0.47mmHg, p= 0.26; I2= 60%). These results were consistent in studies comparing ARBs with propranolol (WMD = -0.40, 95% CI -2.22 to 1.41mmHg, p= 0.67; I2= 68%), and those comparing ARBs with non-active controls including placebo or no treatment (WMD = -1.05, 95% CI -2.33 to 0.24mmHg, p= 0.13; I2= 44%). These results were also not affected by the individual ARBs used. Moreover, treatment of ARBs significantly reduced mean arterial blood pressure (WMD = -6.12, 95% CI -9.69 to -2.55mmHg, p= 0.008; I2= 53%), and the risk of symptomatic hypotension was increased (RR = 4.13, 95% CI 0.94 to 18.18, p= 0.06; I2= 0%). ARBs did not reduce portal pressure in patients with cirrhosis; moreover, the risk of symptomatic hypotension may increase.

Effects of cilostazol and renin-angiotensin system (RAS) blockers on the renal disease progression of Korean patients: a retrospective cohort study.

Background Decline in estimated glomerular filtration rate (eGFR) is an important surrogate marker for the assessment of renal function. Addition of a second agent to angiotensin-converting-enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) treatment may improve current therapeutic strategies aimed at suppressing renal disease progression. Objective To determine the effect of cilostazol in combination with ACEI or ARB treatment on the decline in eGFR. Setting Atertiary hospital in Korea. MethodIn an observational cohort study, we analyzed 5505 patients who were prescribed ACEI or ARB and cilostazol or other antiplatelet agents. Main outcome measure The primary outcome assessed was worsening of renal function defined as a 30% decline in eGFR per year. The secondary outcomes included commencement of dialysis, renal transplantation, death, myocardial infarction, and ischemic stroke. Results Following propensity score matching, eGFR decreased over time in the majority of patients, but the decline was less in patients in the cilostazol treated (CT) group of stage 1-2 category compared to the cilostazol untreated (CU) group (OR 0.80; 95% CI 0.66-0.98). In the subgroup analysis, the strongest effect in slowing eGFR decline was observed in CT patients at a high risk of diabetes (OR 0.782; 95% CI 0.615-0.993) and the elderly (OR 0.693; 95% CI 0.504-0.953) in the stage 1-2 category. No significant increase in cardiovascular risk was observed between the CT and CU groups. Conclusion Treatment with cilostazol plus ACEI or ARB was observed to prevent worsening of renal progression in patients in the stages 1-2.

Effect of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers on cardiovascular events in patients with heart failure: a meta-analysis of randomized controlled trials

BackgroundHeart failure (HF) remains a significant cause of morbidity and mortality. Multiple trials over the past several years have examined the effects of both angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) in the treatment of left ventricular dysfunction, both acutely after myocardial infarction and in chronic heart failure. Yet, there is still confusion regarding the relative efficacy of rennin-angiotensin-aldosterone system (RAAS) inhibition. Our study was conducted to assess efficacy of ACEIs and ARBs in reducing all-cause and cardiovascular mortality in heart failure patients.MethodsWe included randomized clinical trials compared ACEIs and ARBs treatment (any dose or type) with placebo treatment, no treatment, or other anti-HF drugs treatment, reporting cardiovascular or total mortality with an observation period of at least 12 months. Data sources included Pubmed, EMBASE, the Cochrane Central Register of Controlled Trials. Dichotomous outcome data from individual trials were analyzed using the risk ratio measure and its 95%CI with random-effects/ fixed-effects models. We performed meta-regression analyses to identify sources of heterogeneity. All-cause mortality and CV mortality were thought to be the main outcomes.ResultsA total of 47,662 subjects were included with a mean/median follow-up ranged from 12 weeks to 4.5 years. Of all 38 studies, 32 compared ACEIs with control therapy (included 13 arms that compared ACEIs with placebo, 10 arms in which the comparator was active treatment and 9 arms that compared ACEIs with ARBs), and six studies compared ARBs with placebo. ACEIs treatment in patients with HF reduced all-cause mortality to 11% (risk ratio (RR): 0.89, 95% confidence interval (CI): 0.83–0.96, p = 0.001) and the corresponding value for cardiovascular mortality was 14% (RR: 0.86, 95% CI: 0.78–0.94, p = 0.001). However, ARBs had no beneficial effect on reducing all-cause and cardiovascular mortality. In head-to-head analysis, ACEIs was not superior to ARBs for all-cause mortality and cardiovascular deaths.ConclusionsIn HF patients, ACEIs, but not ARBs reduced all-cause mortality and cardiovascular deaths. Thus, ACEIs should be considered as first-line therapy to limit excess mortality and morbidity in this population.

Angiotensin Receptor Blockers Do Not Reduce Risk of Myocardial Infarction, Cardiovascular Death, or Total Mortality: Further Evidence for the ARB-MI Paradox.

Opposing Viewpoint, see p 2085 Individual trials of angiotensin II receptor blockers (ARBs) and systematic meta-analyses have repeatedly demonstrated the ARB class to significantly reduce systemic blood pressure, stroke, and the subsequent development of heart failure and diabetes mellitus.1 However, no individual trial or meta-analysis has observed an impact of ARB treatment on the incidence of myocardial infarction (MI), cardiovascular mortality, or all-cause mortality (Table). All-cause mortality is the most comprehensive summary indicator of cardiovascular benefit of treatment2 and, consequently, it is surprising that ARBs have no impact given the other clinical benefits we have just acknowledged. View this table: Table. Risk of Myocardial Infarction, Cardiovascular Mortality, and All-Cause Mortality in Parallel Meta-Analyses of Placebo-Controlled Trials of Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers A systematic review/meta-analysis conducted by Bangalore et al3 demonstrated that in 20 trials of ARB versus placebo (n=66 282) and 21 trials of ARB versus active comparator (n=39 738), ARB in no individual trial improved all-cause mortality. Furthermore, when the trials were analyzed in combination, the impact of ARB on mortality was precisely zero compared with placebo (odds ratio, 1.01; 95% confidence limit, 0.96–1.06) and virtually zero compared with an active comparator (odds ratio, 0.99; 95% confidence limit, 0.95–1.03). Placebo-controlled trials are the most rigorous method of assessing treatment efficacy (as well as harm), and, consequently, it is concerning that other meta-analyses of ARBs versus …

Preserved cognition and reduced age-related cognitive decline during treatment with angiotensin II receptor blockers: A 20-year follow-up study

IntroductionModulators of the brain renin-angiotensin system (RAS) have been shown to improve cognitive functioning in several animal models of neuropsychiatric disorders. Moreover, the brain RAS has been considered a new target for the treatment of Alzheimer's disease (AD). However, there are no population-based follow-up studies supporting this hypothesis.ObjectivesCross-sectional and prospective relationships between cognitive decline and ARB treatment were examined in the population-based Kuopio Ischemic Heart Disease Risk Factor Study.AimsTo evaluate procognitive/antidementia capacity of orally delivered angiotensin II receptor blockers (ARB).MethodsThe study was conducted on a sample of 1774 subjects (920 females, 854 males; age range at baseline: 42–61 years) from Eastern Finland. An established cutoff score of at least 2-point decrease in the Mini Mental State Examination over a 9-year follow-up was used to detect age-related cognitive decline in the cross-sectional setting. In the prospective setting, a hospital discharge diagnosis of dementia/AD was used as outcome variable. Cross-sectional relationships were determined with logistic regression and prospective analyses were conducted with the Cox proportional hazards model (both adjusted for relevant background variables).ResultsCross-sectional analysis displayed a decrease of the odds of cognitive decline (n = 87; 4.9% of participants) in those with ARB treatment; OR = 0.445, 95% CI: 0.22–0.90, P = 0.024. Furthermore, in the prospective setting, the risk of dementia/AD diagnosis (n = 149; 8.4% of participants) was significantly reduced in ARB treated participants; HR = 0.621, 95% CI: 0.40–0.98, P = 0.038.ConclusionsARB treatment is associated with a decreased risk for age-related cognitive decline and dementia/AD manifestation.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Long-term effects of angiotensin II blockade with irbesartan on inflammatory markers in hemodialysis patients: A randomized double blind placebo controlled trial (SAFIR study).

Low-grade chronic inflammation is common in hemodialysis (HD) patients. Previous studies suggest an anti-inflammatory effect of angiotensin II receptor blocker (ARB) treatment. The aim of this study was to compare the effect of ARB vs. placebo on plasma concentrations of inflammatory markers in HD patients. Adult HD patients were randomized for double-blind treatment with the ARB irbesartan 150-300 mg/day or placebo. At baseline, 1 week, 3, 6, 9, and 12 months plasma high sensitivity C-reactive protein (hsCRP), interleukin (IL)-1β, IL-6, IL-8, IL-18, and transforming growth factor-β (TGF-β) were measured using Luminex and enzyme-linked immunosorbent assay (ELISA) technology. Eighty-two patients were randomized (placebo/ARB: 41/41). The groups did not differ in initial levels of any of the inflammatory markers (placebo/ARB median(range)): hsCRP 3.3(0.2-23.4)/2.7(0.2-29.6) μg/mL; IL-1β 1.1(0.0-45.9)/1.1(0.0-7.2) pg/mL; IL-6 10(1-90)/12(1-84) pg/mL; IL-8 31(9-134)/34(5-192) pg/mL; IL-18 364(188-1343)/377(213-832) pg/mL; TGF-β 3.2(0.8-13.9)/3.6(1.3-3.8) ng/mL. Overall, there was no significant difference in hsCRP, IL-6, IL-8, and TGF-β between placebo and ARB-treated patients during the study period, and hsCRP, IL-6, IL-8, and TGF-β were relatively stable during the study period (P ≥ 0.18 in all tests for parallel curves, equal levels, and constant levels). The IL-1β level was slightly different in the two groups over time, but not significantly (P = 0.09 in test for parallel curves) and it was also relatively stable during the study period (P ≥ 0.49 in tests for equal levels and constant level). IL-18 was the only inflammatory marker which was not constant during the study period (P = 0.001 in test for constant level), but there was no significant difference between placebo and ARB-treated (P ≥ 0.51 in tests for parallel curves and equal levels). Inflammatory biomarkers were neither acutely, nor in the long-term significantly affected by the ARB irbesartan. Our findings suggest that ARB treatment in HD patients does not offer protective anti-inflammatory effects.

REN C-5312T, but not C-5434T, correlates to increase serum angiotensin I level in angiotensin II receptor blockers-treated hypertensive patients

&lt;p class="Abstract"&gt;Renin distal enhancer plays a crucial role in regulating renin gene (REN) expression. REN C-5312T enhancer&lt;span lang="IN"&gt; polymorphism increased enhancer activity. REN C-5434T was also identified which supposed to part of enhancer region. Therefore, this study aimed to investigate contribution of both C-5312T and C-5434T to serum angiotensin I in response to angiotensin II receptor blockers (ARB). C-5312T was identified in 46 hypertensive patients by using multiplex polymerase chain reaction (PCR), while C-5434T by using PCR-restiction fragment length of polymorphism (RFLP). Angiotensin I was measured using enzyme linked immunosorbent assay (ELISA). A significant difference of baseline angiotensin I was observed between -5312CC and -5312CT/TT (p=0.038) as well as the angiotensin I after 5 months of ARB treatment (p=0.008) in -5434CT/TT population, but not REN C-5434T. In conclusion, C-5312T resulted in increased mRNA renin level as consequence of higher enhancer activity not only at the baseline but also after 5 months ARB treatment.&lt;/span&gt;&lt;/p&gt;

A trial of telmisartan prevention of cardiovascular diseases (ATTEMPT-CVD): Biomarker study.

A trial of telmisartan prevention of cardiovascular disease (ATTEMPT-CVD) was performed to compare the effects of angiotensin II receptor blocker (ARB) therapy and those of non-ARB standard therapy on biomarker level changes and the incidence of cardiovascular events in hypertensive patients. In this multicenter, open-label, randomized, parallel-group, comparative study, the effects of ARB therapy and those of non-ARB standard therapy on urinary albumin creatinine ratio (UACR) and plasma brain natriuretic peptide (BNP) level changes were investigated for three years from the start of antihypertensive treatment as the primary endpoints. The incidences of cardiovascular composite events were compared between the two groups, and the relationship between the incidence of the events and biomarker changes were investigated as secondary endpoints. The study started with 615 patients in the ARB group and 613 patients in the non-ARB group. The ARB group had a significant effect on UACR and plasma BNP level changes compared with the non-ARB group. Fewer cardiovascular events occurred in the ARB group, but the difference was not statistically significant. UACR and plasma BNP levels at baseline were associated with cardiovascular events. This study provided the first evidence that ARB treatment caused a smaller increase in plasma BNP and a greater decrease in UACR than non-ARB treatment, independently of blood pressure control, and gives a novel insight into the significance of BNP and UACR as predictors of cardiovascular and renal risk on antihypertensive treatment.

The Decrement of Hemoglobin Concentration with Angiotensin II Receptor Blocker Treatment Is Correlated with the Reduction of Albuminuria in Non-Diabetic Hypertensive Patients: Post-Hoc Analysis of ESPECIAL Trial.

Blockade of the renin-angiotensin-aldosterone system exhibits a renoprotective effect; however, blockade of this system may also decrease hemoglobin (Hb) and erythropoietin (EPO) levels. We evaluated the correlation between reduced albuminuria and decreased hemoglobin concentrations after treatment with an angiotensin II receptor blocker (ARB). Two hundred forty-five non-diabetic hypertensive participants with established albuminuria and relatively preserved renal function were treated with an ARB (40 mg/day olmesartan) for eight weeks. Subsequent changes in various clinical parameters, including Hb, EPO, and albuminuria, were analyzed following treatment. After the 8-week treatment with an ARB, Hb and EPO levels significantly decreased. Patients with a greater decrease in Hb exhibited a greater reduction in 24-hour urinary albumin excretion compared with patients with less of a decrease or no decrease in Hb, whereas no associations with a decline in renal function and EPO levels were noted. Multivariate logistic regression analysis demonstrated a correlation between the reduction of urine albumin excretion and the decrease in Hb levels (after natural logarithm transformation, adjusted odds ratio 1.76, 95% confidence interval 1.21-2.56, P = 0.003). Linear regression analysis also supported this positive correlation (Pearson correlation analysis; R = 0.24, P < 0.001). Decreased Hb concentrations following ARB treatment were positively correlated with reduced albuminuria in non-diabetic hypertensive patients, regardless of decreased blood pressure and EPO levels or renal function decline.

Short and Long-Term Effects of the Angiotensin II Receptor Blocker Irbesartan on Intradialytic Central Hemodynamics: A Randomized Double-Blind Placebo-Controlled One-Year Intervention Trial (the SAFIR Study).

Background and AimLittle is known about the tolerability of antihypertensive drugs during hemodialysis treatment. The present study evaluated the use of the angiotensin II receptor blocker (ARB) irbesartan.DesignRandomized, double-blind, placebo-controlled, one-year intervention trial.Setting and ParticipantsEighty-two hemodialysis patients with urine output >300 mL/day and dialysis vintage <1 year.InterventionIrbesartan/placebo 300 mg/day for 12 months administered as add-on to antihypertensive treatment using a predialytic systolic blood pressure target of 140 mmHg in all patients.Outcomes and MeasurementsCardiac output, stroke volume, central blood volume, total peripheral resistance, mean arterial blood pressure, and frequency of intradialytic hypotension.ResultsAt baseline, the groups were similar regarding age, comorbidity, blood pressure, antihypertensive medication, ultrafiltration volume, and dialysis parameters. Over the one-year period, predialytic systolic blood pressure decreased significantly, but similarly in both groups. Mean start and mean end cardiac output, stroke volume, total peripheral resistance, heart rate, and mean arterial pressure were stable and similar in the two groups, whereas central blood volume increased slightly but similarly over time. The mean hemodynamic response observed during a dialysis session was a drop in cardiac output, in stroke volume, in mean arterial pressure, and in central blood volume, whereas heart rate increased. Total peripheral resistance did not change significantly. Overall, this pattern remained stable over time in both groups and was uninfluenced by ARB treatment. The total number of intradialytic hypotensive episodes was (placebo/ARB) 50/63 (P = 0.4). Ultrafiltration volume, left ventricular mass index, plasma albumin, and change in intradialytic total peripheral resistance were significantly associated with intradialytic hypotension in a multivariate logistic regression analysis based on baseline parameters.ConclusionUse of the ARB irbesartan as an add-on to other antihypertensive therapy did not significantly affect intradialytic hemodynamics, neither in short nor long-term, and no significant increase in hypotensive episodes was seen.Trial registrationClinicaltrials.gov NCT00791830

Urinary angiotensinogen level and its risk factors in patients with " subclinical" diabetic nephropathy

Objective To evaluate the level and related factors of urinary angiotensinogen in patients with subclinical diabetic nephropathy. Methods (1)A total of 80 type 2 diabetic patients without angiotensin-converting enzyme inhibitor (ACEI) or angiotensin Ⅱ receptor blocker(ARB) treatment and hypertension were divided into 3 groups according to 24-hour urinary albuminuria and estimated glomerular filtration rate(eGFR): normoalbuminuria with normal glomerular filtration rate group[urinary microalbuminuria(UMA) <30 mg/24 h, 90≤eGFR <120 ml·min-1·(1.73 m2)-1, NC group, n=28], normoalbuminuria with glomerular hyperfiltration group[UMA<30 mg/24 h, eGFR≥120 ml·min-1·(1.73 m2)-1, SDN group, n=36], microalbuminuria group[30 h≤UMA<300 mg/24 h, 90≤eGFR<120 ml·min-1·(1.73 m2)-1, EDN group, n=16]. The levels of urinary angiotensinogen among various groups were compared.(2)The levels of urine retinol binding protein(RBP), N-acetyl-β-D-glucosaminadase, α-galactosidase, and β2-microglobubin were used to evaluate the renal tubular function. Then all the patients were divided into 4 groups according to the degree of renal tubular injury; the urinary angiotensinogen was compared and the independent related factors were analyzed. (3)20 type 2 diabetic patients with microalbuminuria and ACEI or ARB treatment were also enrolled in this study. The level of urinary angiotensinogen was compared between patients with and without ACEI or ARB treatment. Results Compared with NC group, the level of urinary angiotensinogen in the SDN group was lowered[(1.47±0.11 vs 1.59±0.11)ng/ml, P<0.05], but was raised in the EDN group[(1.62±0.15)ng/ml, P<0.05]. With the aggravation of renal tubular injury, the level of urinary angiotensinogen was increased. Multiple regression analysis showed that urinary angiotensinogen was positively correlated with RBP(P<0.05)and negatively correlated with eGFR(P<0.05). Compared with the patients without ACEI or ARB treatment, the level of urinary angiotensinogen was decreased in patients with ACEI or ARB treatment [(1.43±0.16 vs 1.62±0.15)ng/ml, P<0.05]. Conclusion The level of urinary angiotensinogen in patients with subclinical diabetic nephropathy is lowered, but is then raised in patients with microalbuminuria, which may participate in the progression of renal glomerular and tubular injury in diabetic nephropathy. The renin-angiotensin system inhibitors may delay the progression of diabetic nephropathy via decreasing urinary angiotensinogen level. (Chin J Endocrinol Metab, 2015, 31: 395-399) Key words: Subclinical; Diabetic nephropathy; Urinary angiotensinogen; Renal tubular injury

Differences in 24-h blood pressure profile of Japanese hypertensive patients under ARB treatment

Blood pressure (BP) control throughout the entire day is recommended for cardiovascular protection. Angiotensin-II receptor blockers (ARBs) are widely used in hypertensive patients because of beneficial class effects. It is uncertain, however, whether are there any differences in 24-h BP profiles among ARBs. We examined ambulatory blood pressure monitoring (ABPM) among 211 Japanese hypertensive patients (age, 69.4 ± 9.6 years; female, 59.2%) under treatment with five different ARBs. Patients were divided into five groups according to ARBs prescribed. Patient backgrounds were almost identical in all the groups and there were no differences in office, 24-h and daytime BP; however, nighttime BP with olmesartan was significantly lower than with other ARBs. Office BPs with candesartan and telmisartan, but not other ARBs, correlated well with 24-h BP (p < 0.01). Also, there were higher correlations between daytime and nighttime BP with candesartan and telmisartan. In all patients, pulse pressure with office BP was significantly correlated with ambulatory arterial stiffness index (p = 0.001) and fluctuation of systolic BP on ABPM (p = 0.002). In conclusion, different ARB treatments produced meaningful differences in 24-h profiles.

ESC guidelines adherence is associated with improved survival in patients from the Norwegian Heart Failure Registry.

To assess the adherence to heart failure (HF) guidelines for angiotensin-converting enzyme-I (ACE-I), angiotensin II receptor blockers (ARB), and β-blockers and the possible association of ACE-I or ARB, β-blockers, and statins with survival in the large contemporary Norwegian Heart Failure Registry. The study included 5761 outpatients who were diagnosed with HF of any aetiology (mean left ventricular ejection fraction 32% ± 11%) from January 2000 to January 2010 and followed up until death or February 2010. Adherence to treatment according to the guidelines was high. Cox regression analysis to identify risk factors for all-cause mortality, after adjustment for many factors, showed that ACE-I ≥ 50% of target dose, use of beta-blockers, and statins were significantly related to improved survival (P = 0.003, P < 0.001, and P < 0.001, respectively). Propensity scoring showed the same benefit for these variables. Both multivariable and propensity scoring analyses showed survival benefits with β-blockers, statins, and adequate doses of ACE-I in this contemporary HF cohort. This study stresses the importance of guidelines adherence, even in the context of high levels of adherence to guidelines. Moreover, respecting the recommended target doses of ACE-I appears to have a crucial role in survival improvement and, in the multivariate Cox regression analysis, ARB treatment was not significantly associated with a lower all-cause mortality.

Transplantation of periaortic adipose tissue from angiotensin receptor blocker-treated mice markedly ameliorates atherosclerosis development in apoE-/- mice.

Perivascular adipose tissue is implicated in vasoreactivity; however, its effect on atherosclerosis remains undefined. We examined the effect of a high-cholesterol diet (HCD) on phenotypic alterations of the thoracic periaortic adipose tissue (tPAT) in apoE-deficient (apoE(-/-)) mice. Gene expression of the components of the renin angiotensin system and that of macrophage markers were significantly higher in apoE(-/-) mice fed an HCD than in those fed a chow diet (CD). These changes were absent both in angiotensin II (AngII) receptor blocker (ARB)-treated apoE(-/-) mice and in Ang II type 1 (AT1) receptor-deficient apoE(-/-) (Agtr1(-/-)/apoE(-/-)) mice. To evaluate their effect on atherosclerosis, we transplanted tPAT into apoE(-/-) mice alongside the distal abdominal aorta. Transplanted tPAT was harvested from apoE(-/-) and Agtr1(-/-)/apoE(-/-) mice fed a CD (tPAT-CD/apoE(-/-), tPAT-CD/Agtr1(-/-)/apoE(-/-)), HCD (tPAT-HCD/apoE(-/-), tPAT-HCD/Agtr1(-/-)/apoE(-/-)), or HCD in combination with ARB treatment (tPAT-HCD/ARB/apoE(-/-)). Four weeks after transplantation, a significantly increased oil red O-positive area was observed in the aorta of tPAT-HCD/apoE(-/-) mice than in tPAT-CD/apoE(-/-) mice. Such a change was absent in tPAT-HCD/ARB/apoE(-/-) and tPAT-HCD/Agtr1(-/-)/apoE(-/-) mice. Our findings demonstrated that AT1 receptor plays a crucial role in HCD-induced phenotypic alterations of tPAT, modulation of which could exert beneficial effects on atherosclerosis.