Angiotensin Receptor Blocker Candesartan Research Articles

Angiotensin Receptor Blocker-Related Sprue-like Enteropathy: Review of Food and Drug Administration Adverse Event Reporting System.

Sprue-like enteropathy (SE) related to olmesartan use was first reported in 2012. In 2017, the manufacturer of Benicar paid $300 million for 2300 claims for olmesartan-related SE. A study in 2019 suggested that SE was related to olmesartan and with the possibility of angiotensin receptor blocker (ARB) class effect. To further characterize this condition, our group examined reports of ARB-related SE to Food and Drug Administration Adverse Event Reporting System (FAERS). All reports of ARB-related SE from January 2017 to December 2021 were downloaded from the FAERS database. Gastrointestinal adverse events including SE were reviewed. Reporter categories included physicians, pharmacists, other health care professionals, consumers, and attorneys. A total of 106 590 reports of ARB-related adverse effects were analyzed. Sprue-like enteropathy was identified in 4337 cases (4.1% of total reports). Of these, 4240 cases (98.0%) of ARB-related SE were reported in patients using products with olmesartan, and 97 cases of SE were reported for all other ARBs (eprosartan, losartan, telmisartan, irbesartan, valsartan, and candesartan). Reports of olmesartan-related SE increased rapidly in 2017, continued at a high rate in 2018 and 2019, and essentially stopped in 2020 and 2021. Reports to FAERS for ARB-related SE are mostly related to olmesartan. There was a steep decline in reports of olmesartan-related SE following the lawsuit with potential of lawyer interference. There are reports of SE related to ARBs other than olmesartan, with increased physician awareness and the potential to discover a class effect with future studies.

Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy (PRADA): Extended Follow-Up of a 2×2 Factorial, Randomized, Placebo-Controlled, Double-Blind Clinical Trial of Candesartan and Metoprolol.

Adjuvant breast cancer therapy containing anthracyclines with or without anti-human epidermal growth factor receptor-2 antibodies and radiotherapy is associated with cancer treatment-related cardiac dysfunction. In the PRADA trial (Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy), concomitant treatment with the angiotensin receptor blocker candesartan attenuated the reduction in left ventricular ejection fraction (LVEF) in women receiving treatment for breast cancer, whereas the β-blocker metoprolol attenuated the increase in cardiac troponins. This study aimed to assess the long-term effects of candesartan and metoprolol or their combination to prevent a reduction in cardiac function and myocardial injury. In this 2×2 factorial, randomized, placebo-controlled, double-blind, single-center trial, patients with early breast cancer were assigned to concomitant treatment with candesartan cilexetil, metoprolol succinate, or matching placebos. Target doses were 32 and 100 mg, respectively. Study drugs were discontinued after adjuvant therapy. All 120 validly randomized patients were included in the intention-to-treat analysis. The primary outcome measure was change in LVEF assessed by cardiovascular magnetic resonance imaging from baseline to extended follow-up. Secondary outcome measures included changes in left ventricular volumes, echocardiographic peak global longitudinal strain, and circulating cardiac troponin concentrations. A small decline in LVEF but no significant between-group differences were observed from baseline to extended follow-up, at a median of 23 months (interquartile range, 21 to 28 months) after randomization (candesartan, 1.7% [95% CI, 0.5 to 2.8]; no candesartan, 1.8% [95% CI, 0.6 to 3.0]; metoprolol, 1.6% [95% CI, 0.4 to 2.7]; no metoprolol, 1.9% [95% CI, 0.7 to 3.0]). Candesartan treatment during adjuvant therapy was associated with a significant reduction in left ventricular end-diastolic volume compared with the noncandesartan group (P=0.021) and attenuated decline in global longitudinal strain (P=0.046) at 2 years. No between-group differences in change in cardiac troponin I and T concentrations were observed. Anthracycline-containing adjuvant therapy for early breast cancer was associated with a decline in LVEF during extended follow-up. Candesartan during adjuvant therapy did not prevent reduction in LVEF at 2 years, but was associated with modest reduction in left ventricular end-diastolic volume and preserved global longitudinal strain. These results suggest that a broadly administered cardioprotective approach may not be required in most patients with early breast cancer without preexisting cardiovascular disease. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01434134.

Inhibition of angiotensin II type 1 receptor by candesartan reduces tumor growth and ameliorates fibrosis in colorectal cancer.

Colorectal cancer (CRC) is an important cause of cancer-related mortality. Aberrant activation of the renin-angiotensin system (RAS) is reported to be associated with poor clinical outcomes in patients with CRC. This study was designed to explore the anti-tumor effects of the angiotensin receptor blocker Candesartan either alone or in combination with 5-FU in in vitro and in vivo models of CRC. The cytotoxic effects of Candesartan were assessed using the MTT assay in two colorectal cancer cell lines (CT-26 and SW-480). To investigate the potential regulatory role of Candesartan on tumor growth, apoptosis, and migration, the expression levels of Cyclin D1, Survivin, MMP3, MMP9, and E-cadherin mRNAs were evaluated. The oxidant/antioxidant balance was also examined by determining the levels of MDA, thiols, SOD, and CAT. We used a xenograft model of colon cancer to investigate the effects of Candesartan alone, or in combination with 5-FU, on tumor growth following histological staining (Hematoxylin & Eosin and Masson trichrome staining) and biochemical studies as well as gene expression analyses by RT-PCR and western blotting. Candesartan suppressed tumor cell proliferation and migration by modulating Cyclin D1, MMP3/9, and E-cadherin. Treatment with Candesartan either alone, or in combination with 5-FU decreased tumor size in the mouse model, and also increased the level of oxidative markers MDA and reduced CAT, SOD, and thiols. Histological evaluation showed that Candesartan increased tumor necrosis, reduced tumor density and attenuated collagen deposition reducing tumor fibrosis in tumor xenograft. Candesartan, an inhibitor of the RAS, when used in combination with 5-FU reduced tumor growth by inhibiting fibrosis and inducing ROS production, supporting further clinical studies on this therapeutic approach for treatment of CRC.

No effect of the angiotensin receptor blocker candesartan on cerebrovascular autoregulation in rats during very high and low sodium intake.

Autoregulation of cerebral blood flow (CBF) denotes that CBF is constant despite fluctuation of blood pressure within wide limits. Inhibition of the renin–angiotensin system (RAS) is known to decrease the lower and upper limits of CBF autoregulation. We have previously shown that this includes inhibition by the angiotensin receptor blocker (ARB) candesartan. In the present study we investigated the influence of the ARB candesartan on the lower limit of CBF autoregulation in two groups of Sprague-Dawley rats, on high (4.0% Na+) and low (0.004% Na+) sodium diet, respectively. Control animals were given the same diet, but no ARB. CBF was studied with the laser Doppler method. Blood pressure was lowered by controlled bleeding. Results revealed that both high and low sodium diet with low and high renin levels respectively block the influence of candesartan on CBF autoregulation. This was expected in rats on a high salt diet with a low renin level, but unexpected in rats with a low salt intake with a high renin level.

Abstract TP88: Delayed Therapeutic Window for Prevention of Progressive Cognitive Impairment After Experimental Stroke

Background: With the aging population, the prevalence and incidence of cerebrovascular disease will continue to rise, as will the number of individuals with post-stroke cognitive impairment (PSCI). Unfortunately, no specific FDA approved treatments for PSCI exist. Although clinical trial evidence supports that renin angiotensin system (RAS) modulation by angiotensin receptor blockers (ARBs) prevent cognitive decline in older adults. The aim of our study was to determine the impact of the ARB candesartan or the AT2R agonist, C21, after stroke, on long-term cognitive function in spontaneously hypertensive rats (SHRs). Methods: Thirty three SHRs were subjected to a 60 minute transient middle cerebral artery occlusion (MCAO) and randomly assigned to either Saline/ C21 (0.3 mg/kg, IP) only or Saline/ C21 (7 days) followed by candesartan (0.3 mg/kg) IP for the remainder of the study. Outcome measures included sensorimotor and cognitive function, performed using a sequence of blinded tests, and assessed at baseline and up to 28 days post-stroke. Animals were sacrificed at 30 days and their brains collected for amyloid-β protein determination and histopathologic analyses. Results: Chronic administration of C21, or candesartan prevented PSCI, even when treatment was initiated at 7 days after the ischemic insult. The groups treated with C21 and candesartan demonstrated superior performance on the novel NOR test, compared to saline treated animals. C21 (first 7 days) only or C2 and candesartan treatments had markedly lower hippocampal concentrations of Aβ1-42 at 30 days post-stroke than those treated with saline. Sensorimotor deficits (Bederson and beam walk scores) were pronounced at 24 h post-stroke and all treatment groups showed similar recovery at 28 days post stroke. C21 had no effect on BP compared to saline-treated controls. Conclusion: Collectively, our findings demonstrate that RAS modulators effectively prevent PSCI, even when treatment is delayed.

Add-On Effect of Angiotensin Receptor Blockade (Candesartan) on Clinical Remission in Active IgA Nephropathy Patients Treated with Steroid Pulse Therapy and Tonsillectomy: a Randomized, Parallel-Group Comparison Trial

Background/Aims: Angiotensin receptor blockers (ARBs) may be beneficial for clinical remission during conventional therapy with tonsillectomy and steroid pulse (TSP) for active IgA nephropathy. Methods: Seventy-seven patients with active IgA nephropathy were randomly assigned to the control arm with conventional regimen (TSP followed by oral prednisolone) (n = 37) or the ARB arm with conventional regimen plus ARB candesartan for the first 6 months (n = 40). Patients not achieving proteinuria remission at 12 months in either arm were administered candesartan, which was titrated until the 24-month follow-up. The primary endpoints were remission of proteinuria (< 0.3 g/gCr) and hematuria at 12 months. Results: Baseline proteinuria (g/g Cr) were comparable between the control and ARB arm (1.02 vs. 0.97, P = 0.97). Similarly, cumulative remission rates at 6, 12, and 24 months were comparable between the control and ARB arms (37.8% vs. 35% [P = 0.80], 48.7% vs. 38.5% [P = 0.37], 71.4% vs. 51.3% [P = 0.08]). Proteinuria, which was slightly worse in the control arm than in the ARB arm at 6 months, was comparable afterwards (0.20 vs. 0.23 g/g Cr at 12 months; 0.12 vs. 0.13 g/g Cr at 24 months). Significant reductions observed in urinary angiotensinogen were almost comparable between the two treatment arms at both 6 and 12 months. Conclusion: Early candesartan treatment combined with TSP may not benefit clinical remission regardless of the blood pressure. ARB titration later during the treatment might provide benefit for patients with active IgA nephropathy.

Novel Therapeutic Role for Dipeptidyl Peptidase III in the Treatment of Hypertension.

Dipeptidyl peptidase III (DPP III) cleaves dipeptide residues from the N terminus of polypeptides ranging from 3 to 10 amino acids in length and is implicated in pathophysiological processes through the breakdown of certain oligopeptides or their fragments. In this study, we newly identified the biochemical properties of DPP III for angiotensin II (Ang II), which consists of 8 amino acids. DPP III quickly and effectively digested Ang II with Km = 3.7×10(-6) mol/L. In the in vivo experiments, DPP III remarkably reduced blood pressure in Ang II-infused hypertensive mice without alteration of heart rate. DPP III did not affect hemodynamics in noradrenalin-induced hypertensive mice or normotensive mice, suggesting specificity for Ang II. When DPP III was intravenously injected every other day for 4 weeks after Ang II osmotic minipump implantation in mice, Ang II-induced cardiac fibrosis and hypertrophy were significantly attenuated. This DPP III effect was at least similar to that caused by an angiotensin receptor blocker candesartan. Furthermore, administration of DPP III dramatically reduced the increase in urine albumin excretion and kidney injury and inflammation markers caused by Ang II infusion. Both DPP III and candesartan administration showed slight additive inhibition in the albumin excretion. These results reveal a novel potential use of DPP III in the treatment of hypertension and its protective effects on hypertension-sensitive organs, such as the heart and kidneys.

Prevention of cardiac dysfunction during adjuvant breast cancer therapy (PRADA): a 2 × 2 factorial, randomized, placebo-controlled, double-blind clinical trial of candesartan and metoprolol.

AimsContemporary adjuvant treatment for early breast cancer is associated with improved survival but at the cost of increased risk of cardiotoxicity and cardiac dysfunction. We tested the hypothesis that concomitant therapy with the angiotensin receptor blocker candesartan or the β-blocker metoprolol will alleviate the decline in left ventricular ejection fraction (LVEF) associated with adjuvant, anthracycline-containing regimens with or without trastuzumab and radiation.Methods and resultsIn a 2 × 2 factorial, randomized, placebo-controlled, double-blind trial, we assigned 130 adult women with early breast cancer and no serious co-morbidity to the angiotensin receptor blocker candesartan cilexetil, the β-blocker metoprolol succinate, or matching placebos in parallel with adjuvant anticancer therapy. The primary outcome measure was change in LVEF by cardiac magnetic resonance imaging. A priori, a change of 5 percentage points was considered clinically important. There was no interaction between candesartan and metoprolol treatments (P = 0.530). The overall decline in LVEF was 2.6 (95% CI 1.5, 3.8) percentage points in the placebo group and 0.8 (95% CI −0.4, 1.9) in the candesartan group in the intention-to-treat analysis (P-value for between-group difference: 0.026). No effect of metoprolol on the overall decline in LVEF was observed.ConclusionIn patients treated for early breast cancer with adjuvant anthracycline-containing regimens with or without trastuzumab and radiation, concomitant treatment with candesartan provides protection against early decline in global left ventricular function.

Evaluation of the effect of angiotensin converting enzyme inhibitors and angiotensin receptors blockers on aspirin antiplatelet effect.

Cardiovascular disease (CVD) is one of the major burdens on societies and healthcare systems. Antiplatelet aspirin is used to prevent the occurrence or reoccurrence of cardiovascular events. However, studies have shown that a good portion of patients still suffer from cardiovascular events in spite of using aspirin (also called aspirin nonresponders). On the other hand, angiotensin-converting enzyme inhibitors (ACEIs) as well as angiotensin-receptor blockers (ARBs) are widely used in patients with different spectrums of cardiovascular diseases. In this study, the possible interactive effect of ACEIs and ARBs on aspirin response was evaluated in vitro. A multiplate analyzer was used to assay the possible interactions between ACEIs and ARBs drugs on antiplatelet effect of aspirin using blood obtained from 6 healthy volunteers. Means of area under the aggregation curves (AUCs) of the blood samples treated with 10 μg/mL aspirin were calculated before and after exposure to captopril, lisinopril, candesartan, or losartan. Results showed potential antithrombotic effect of ACEIs and ARBs only at high concentrations (3.3 μg/mL).The antiplatelet effect of aspirin 10 μg/mL was significantly enhanced by the addition of captopril or lisinopril at high dose (3.3 μg/mL), candesartan at all tested doses (0.03 μg/mL, 0.33 μg/mL, 3.3 μg/mL), and losartan at doses of 0.33 μg/mL and 3.3 μg/m. Treatment with ACEIs (captopril and lisinopril) and ARBs (candesartan and losartan) improved the antiplatelet response to aspirin. Further studies are needed to confirm this action and potentially apply it to clinical practice.

Revealed Opportunism: How Physicians Game Prior Authorization Protocols Until They Are Rescinded

Prior authorization (PA) is a management technique that has been implemented to manage the utilization of expensive drugs and to improve the precision of drug prescribing. PA requirements may incentivize physicians to document adverse effects, sometimes falsely, to meet the eligibility requirements. To identify documentation patterns that may facilitate the quantitative analysis of physician gaming and underreporting behaviors associated with the prescribing of angiotensin-converting enzyme (ACE) inhibitors in a primary care setting, and to evaluate the effect of a PA requirement on the documentation of adverse events as a way to receive approval for more expensive drugs. We conducted a retrospective analysis of physician electronic reporting of adverse effects associated with ACE inhibitors before and after the revocation of a PA requirement for angiotensin receptor blockers (ARBs) between 2004 and 2013 in an Israeli HMO. The data were stratified into 2 groups-patients who were newly prescribed an ACE inhibitor or those who had been receiving an ACE inhibitor for at least 1 year. The annual rate of adverse events related to ACE inhibitors (ie, the number of reported cases of adverse events per 1000 patients receiving an ACE inhibitor) was calculated from data captured on the date the events were first reported for the 5 years before and 5 years after the revocation of the PA constraint. A total of 151,845 patients treated with ACE inhibitors were identified during the 10-year study period. The reported adverse events among patients newly treated with an ACE inhibitor peaked in 2007 to 10 cases per 1000 patients, and gradually decreased to 4.6 cases in 2012, which was the year after the PA requirements for the ARBs valsartan and candesartan were rescinded by the HMO. Among previously treated patients, adverse events rates decreased from a high of 5.4 per 1000 patients in 2008 to 1.9 in 1000 patients in 2012, the year after the PA restraints for the last 2 ARBs with a requirement were revoked. The PA requirement influenced physician propensity for reporting drug side effects, possibly encouraging reporting inaccuracies. The decline in the incidence of reported side effects, in both subpopulations in the study, with the revocation of the PA requirement confirms our hypothesis that physicians were incentivized to document the side effects related to ACE inhibitors to meet the eligibility requirements for the approval of an ARB by the HMO.

The angiotensin receptor blocker candesartan attenuates the subjective effects of methamphetamine in humans

The angiotensin receptor blocker candesartan attenuates the subjective effects of methamphetamine in humans

Treatment of hypertension in patients with coronary artery disease: a scientific statement from the American Heart Association, American College of Cardiology, and American Society of Hypertension.

1. Relationship Between Hypertension and CAD e437 2. Prevention of Cardiovascular Events in Patients With Hypertension and CAD e443 3. BP Goals e445 4. Management of Hypertension in Patients With CAD and Stable Angina e449 5. Management of Hypertension in Patients With ACS e451

Effects of blood pressure lowering in patients with acute ischemic stroke and carotid artery stenosis.

The Scandinavian Candesartan Acute Stroke Trial (SCAST) showed no beneficial clinical effects of blood pressure lowering with the angiotensin receptor blocker candesartan in the acute phase of stroke. In the present analysis we wanted to see if the effects of blood pressure lowering are harmful in the subgroup of patients with carotid artery stenosis. SCAST was a randomized- and placebo-controlled, double-masked trial of 2029 patients with acute stroke and high systolic blood pressure (≥ 140 mmHg). Of 1733 patients with ischemic stroke 993 underwent carotid artery imaging, and the degree of stenosis was categorized as no/insignificant (0-49%, n = 806), moderate (50-69%, n = 97) or severe (≥ 70%, n = 90). The trial's two co-primary effect variables were the composite end-point of vascular death, stroke or myocardial infarction, and functional outcome at six-months, according to the modified Rankin Scale. Among patients with moderate or severe carotid artery stenosis the vascular end-point occurred in 9 of 87 patients (10.3%) treated with candesartan and in 17 of 100 controls (17.0%), and there was no evidence of a different risk in patients with severe stenosis (adjusted hazard ratio 0.74, 95% confidence interval 0.28-1.96, P = 0.54). For functional outcome there was also no clear difference, although in patients with severe stenosis the risk of a poor outcome was somewhat higher than in any of the other groups (adjusted odds ratio 2.24, 95% confidence interval 0.71-7.09, P = 0.16). Progressive stroke also occurred more often in patients with carotid artery stenosis treated with candesartan (10 of 87 patients (11.5%) vs. 4 of 100 patients (4.0%)), with a trend towards an increased risk with increasing severity of stenosis (P-value for linear trend = 0.04). There is no clear evidence that the effect of candesartan is qualitatively different in patients with carotid artery stenosis, but there are signals that patients with severe stenosis are at particularly high risk of stroke progression and poor functional outcome.

Female spontaneously hypertensive rats are more dependent on ANG (1-7) to mediate effects of low-dose AT1 receptor blockade than males

ANG (1-7) contributes to the blood pressure (BP)-lowering effect of angiotensin receptor blockers (ARBs) in male experimental animals. Females have greater ANG (1-7) concentrations than males; however, the contribution of ANG (1-7) to ARB-mediated decreases in BP in females is unknown. The current study tested the hypothesis that female spontaneously hypertensive rats (SHR) have a larger ANG (1-7) contribution to the BP-lowering effects of the ARB candesartan than male SHR. Twelve-week-old male and female SHR were randomized to receive candesartan (0.5 mg·kg(-1)·day(-1); 7 days), candesartan plus ANG II (200 ng·kg(-1)·min(-1); 7 days), the ANG (1-7) antagonist A-779 (48 μg·kg(-1)·h(-1)) plus candesartan and ANG II. Candesartan decreased basal BP in males and females (baseline vs. candesartan: 142 ± 2 vs. 122 ± 3 and 129 ± 1 vs. 115 ± 1 mmHg, respectively; P < 0.05); however, the decrease was greater in males. ANG II increased BP in males in the presence of candesartan (149 ± 2 mmHg; P < 0.05); candesartan blocked ANG II-induced increases in BP in females (116 ± 1 mmHg). Pretreatment with A-779 abolished candesartan-mediated decreases in BP in females, but not males. A-779 also exacerbated ANG II-induced proteinuria (26 ± 6 vs. 77 ± 11 μg·kg(-1)·day(-1), respectively; P < 0.05) and nephrinuria (20 ± 5 vs. 202 ± 58 μg·kg(-1)·day(-1), respectively; P < 0.05) in candesartan-treated female SHR, with no effect in males. In conclusion, females are more sensitive to the BP-lowering effect of ARBs during ANG II infusion, whereas males are more sensitive under basal conditions. In addition, ANG (1-7) has a greater contribution to ARB-mediated decreases in BP, protein, and nephrin excretion in females relative to males.

In prehypertension leukocytosis is associated with body mass index but not with blood pressure or incident hypertension

Previous studies reported increased white blood cell counts (WBCCs), an inflammatory marker, in hypertension, prehypertension and metabolic syndrome. Evidence suggests that inflammation precedes blood pressure (BP) elevation and may contribute to incident hypertension. Angiotensin receptor blockers (ARBs) may reduce inflammation. We analyzed WBCC trends in TRial Of Preventing HYpertension (TROPHY) to determine if this inflammatory marker predicted incident hypertension in prehypertensive individuals and whether randomized assignment to the ARB candesartan (391 individuals) for 2 years, lowered WBCC compared with placebo-treated controls (381 individuals). A new analysis of TROPHY trial data. In the total population, baseline BMI correlated with WBCC (r = 0.185, P < 0.0001), neutrophils (r = 0.135, P < 0.001) and lymphocytes (r = 0.204, P < 0.0001). Baseline triglycerides also correlated significantly with inflammatory markers. Despite a wide range of home BP (HBP) values, HBP did not correlate with baseline WBCC counts. After 2 years, candesartan decreased placebo corrected HBP by -5.5/-2.5 mmHg, (P < 0.0001), but WBCC, neutrophil and lymphocyte counts were not different in placebo and in candesartan groups. Baseline WBCC, neutrophils and lymphocyte counts did not predict incident hypertension in the placebo group. In TROPHY, candesartan lowered BP but did not alter WBCC. Baseline WBCC did not predict incident hypertension. Our findings do not support the hypothesis that inflammation contributes to incident hypertension or that ARB treatment suppresses inflammation. The significant independent association of WBCC with baseline BMI and triglycerides is consistent with the evidence that obesity and insulin resistance are associated with inflammation. The findings highlight the importance of effective lifestyle modification in prehypertension to reduce inflammatory cardio-metabolic risk and suppress transition to hypertension.

Bradykinin Antagonist Counteracts the Acute Effect of Both Angiotensin-Converting Enzyme Inhibition and of Angiotensin Receptor Blockade on the Lower Limit of Autoregulation of Cerebral Blood Flow

The lower limit of autoregulation of cerebral blood flow (CBF) can be modulated with both angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB). The influence of bradykinin antagonism on ARB-induced changes was the subject of this study. CBF was measured in Sprague-Dawley rats with laser Doppler technique. The blood pressure was lowered by controlled bleeding. Six groups of rats were studied: a control group and five groups given drugs intravenously: an ACE inhibitor (enalaprilat), an ARB (candesartan), a bradykinin-2 receptor antagonist (Hoe 140), a combination of enalaprilat and Hoe 140, and a combination of candesartan and Hoe 140. In the control group, the lower limit of CBF autoregulation was 54±9 mm Hg (mean±s.d.), with enalaprilat it was 46±6, with candesartan 39±8, with Hoe 140 53±6, with enalaprilat/Hoe 140 52±6, and with candesartan/Hoe 140 50±7. Both enalaprilat and candesartan lowered the lower limit of autoregulation of CBF significantly. The bradykinin antagonist abolished not only the effect of the ACE inhibitor but surprisingly also the effect of the ARB on the lower limit of CBF autoregulation, the latter suggesting an effect on intravascular bradykinin.

STAR CAST: Preliminary Results of Trial to Regress Hypertension

Results from animal models have shown that hypertension can be regressed to normal blood pressure (BP) levels [Smallegange C et al. Hypertension 2004] and that this reduction can be maintained after pulse treatment with an angiotensin receptor blocker [Ishiguro K et al. Hypertension 2009]. The Short Treatment with Angiotensin Receptor Blocker Candesartan Surveyed by Telemedicine study [STAR CAST; Sasamura H. Hypertens Res 2008; UMIN-CTR UMIN000000941] tested the feasibility of regressing hypertension in humans.

Angiotensin II blockade, YKL-40 and maintenance of sinus rhythm after electrical cardioversion for atrial fibrillation

High levels of the novel inflammatory marker YKL-40 have been demonstrated in inflammatory environments and in remodeling of the extracellular matrix. Both are key components in atrial wall remodeling in atrial fibrillation (AF). We studied the relation between rhythm outcome after electrical cardioversion (ECV) for persistent AF and serum levels of YKL-40. A secondary point of interest was a potential effect of the angiotensin receptor blocker candesartan on YKL-40 levels. In the Candesartan in the Prevention of Relapsing Atrial Fibrillation (CAPRAF) study, 171 patients with persistent AF were randomized to receive candesartan 8mg once daily or placebo for 3–6 weeks before ECV and candesartan 16mg once daily or placebo for 6 months after ECV. Serum levels of YKL-40 were measured in fasting blood samples collected at baseline and at end of the study. Mean age was 64±11 years, and 39 (22.8%) were women. Sinus rhythm was maintained for 6 months after ECV in 41 (23.9%). Baseline levels of YKL-40 were significantly correlated to age (Spearmans rho; rs=0.442; p<0.001), CHA2DS2-VASc11A scoring system used to stratify AF patients according to risk of stroke; assigning 1 point for each of the following: Congestive heart failure, Hypertension, Age 65–74 years, Diabetes, Vascular disease or Sex category (=female sex), and 2 points each for Age ≥75 years or Stroke (previous stroke or transitory ischemic attack). score (rs=0.256; p<0.001) and left atrial diameter (rs=0.185; p=0.017). By use of Kaplan–Meier quartile analysis of baseline YKL-40 levels, no relation between YKL-40 levels and risk of AF recurrence was found. End of study YKL-40 levels were unchanged from baseline, both in patients with AF recurrence and those maintaining sinus rhythm for 6 months. Treatment with candesartan had no influence on serum YKL-40 levels.

PCV24 - Comparative effectiveness of angiotensin receptor blockers in chronic heart failure: A network meta-analysis

Chronic Heart failure (CHF) is associated with significant morbidity and mortality. Angiotensin receptor blockers (ARBs) are one of most commonly prescribed drug class for patients with CHF among patients who are intolerant to angiotensin converting enzyme inhibitors (ACEI). A recently published Cochrane review concluded that ARBs as a class confer no additional benefit on mortality or total hospitalization as compared to placebo or ACEI. The aim is to compare efficacy of ARBs (losartan, valsartan, candesartan, and telmisartan) on hospitalization and mortality relative to each other and to placebo among patients with CHF. Studies on ARBs were identified from a recently published Cochrane systematic review. A network meta-analysis (NMA) was conducted for three outcomes; all-cause hospitalizations, hospitalization due to heart failure, and all-cause mortality using WinBUGs. Binomial likelihood models were run for each outcome and analyses were conducted on an odds ratio scale. Fixed or random effects models were run to estimate relative treatment effects Sixteen studies were identified from the review. Five studies reported data on all-cause hospitalization and six on hospitalizations due to heart failure, for two drugs (candesartan and losartan).Data on mortality was reported in 16 studies for losartan, valsartan, candesartan, and telmisartan. ARBs did not have significantly different effects from placebo or each other on all the three outcomes studied. NMA can also be used to rank treatments. Within this we found that compared to all other ARBs, telmisartan and losartan had the highest probabilities of being the best treatments to reduce mortality and hospitalizations, respectively. Results of the NMA indicated that there was no significant difference between any of the individual ARBs, ACEI or placebo on mortality and hospitalization. A further analysis that uses meta-regression to adjust for co-morbid conditions such as diabetes, hypertension and ischemic heart disease is warranted.

Ang (1–7) Has a Greater Contribution to the Blood Pressure Lowering Effects of AT1 Receptor Blockade in Female Spontaneously Hypertensive Rats (SHR) Compared to Males

Ang (1–7) contributes to the blood pressure (BP) lowering effects of renin angiotensin system inhibitors in male SHR. We have previously published that female SHR have greater Ang (1–7) levels than males, however, the functional implications of this with regards to BP control remains largely unknown. Therefore, the goal of this study was to test the hypothesis that female SHR have a larger Ang (1–7) contribution to the BP lowering effects of the angiotensin receptor blocker (ARB) candesartan than male SHR. BP was measured via telemetry in 12 week old male and female SHR (n=4–8). Animals were pre‐treated with either the Ang (1–7) antagonist A‐779 (4 days; 48 μg/kg/hr via osmotic minipump) or vehicle. Candesartan was then co‐administered (0.5 mg/kg/day via drinking water) for a week. A‐779 alone did not alter basal BP in either sex. In male SHR, candesartan‐mediated decreases in BP were comparable in vehicle (15% decrease: 143±2 to 122±3 mmHg; p&lt;0.05) and A‐779 treated (12% decrease: 147±3 to 129±4 mmHg; p&lt;0.05). In contrast, A‐779 attenuated candesartan‐mediated decreases in BP (5% decrease: 127±1 to 121±2 mmHg; NS) in female SHR compared to vehicle treatment (10% decrease: 128±1 to 115±1 mmHg; p&lt;0.05). In conclusion, female SHR have a greater Ang (1–7) contribution to ARB‐mediated decreases in BP than males. This study was funded by National Institutes of Health grant 1R01 HL093271–01A1 to J.C.S.