1,095 research outputs found
The β-blocker Nebivolol Is a GRK/β-arrestin Biased Agonist
No full textNebivolol, a third generation β-adrenoceptor (β-AR) antagonist (β-blocker), causes vasodilation by inducing nitric oxide (NO) production. The mechanism via which nebivolol induces NO production remains unknown, resulting in the genesis of much of the controversy regarding the pharmacological action of nebivolol. Carvedilol is another β-blocker that induces NO production. A prominent pharmacological mechanism of carvedilol is biased agonism that is independent of Gαs and involves G protein-coupled receptor kinase (GRK)/β-arrestin signaling with downstream activation of the epidermal growth factor receptor (EGFR) and extracellular signal-regulated kinase (ERK). Due to the pharmacological similarities between nebivolol and carvedilol, we hypothesized that nebivolol is also a GRK/β-arrestin biased agonist. We tested this hypothesis utilizing mouse embryonic fibroblasts (MEFs) that solely express β2-ARs, and HL-1 cardiac myocytes that express β1- and β2-ARs and no detectable β3-ARs. We confirmed previous reports that nebivolol does not significantly alter cAMP levels and thus is not a classical agonist. Moreover, in both cell types, nebivolol induced rapid internalization of β-ARs indicating that nebivolol is also not a classical β-blocker. Furthermore, nebivolol treatment resulted in a time-dependent phosphorylation of ERK that was indistinguishable from carvedilol and similar in duration, but not amplitude, to isoproterenol. Nebivolol-mediated phosphorylation of ERK was sensitive to propranolol (non-selective β-AR-blocker), AG1478 (EGFR inhibitor), indicating that the signaling emanates from β-ARs and involves the EGFR. Furthermore, in MEFs, nebivolol-mediated phosphorylation of ERK was sensitive to pharmacological inhibition of GRK2 as well as siRNA knockdown of β-arrestin 1/2. Additionally, nebivolol induced redistribution of β-arrestin 2 from a diffuse staining pattern into more intense punctate spots. We conclude that nebivolol is a β2-AR, and likely β1-AR, GRK/β-arrestin biased agonist, which suggests that some of the unique clinically beneficial effects of nebivolol may be due to biased agonism at β1- and/or β2-ARs. © 2013 Erickson et al
sj-pdf-1-ppo-10.1177_07439156241246274 - Supplemental material for Transitioning to New Paradigms for Societally Impactful Research: Recommendations from the TCR Impact Task Force and an Agenda
No full textSupplemental material, sj-pdf-1-ppo-10.1177_07439156241246274 for Transitioning to New Paradigms for Societally Impactful Research: Recommendations from the TCR Impact Task Force and an Agenda by Julie L. Ozanne, Brennan Davis, Christopher P. Blocker, Benét DeBerry-Spence and Rebecca Ballenger Gann in Journal of Public Policy & Marketing</p
Beta Blocker/Calcium Channel Blocker Overdose
No full textBeta blocker and calcium channel blocker overdose is a rare perioperative complication that manifests with symptoms of altered mental status, hypotension, bradycardia, and cardiovascular collapse. Although the clinical presentation is often similar, the underlying pathophysiology can differ between either cardiogenic or vasodilatory shock. Standard therapies such as calcium administration or beta-adrenergic agonists may be effective but often require much higher doses than normal. The evidence for targeted therapies, such as high-dose insulin infusion and glucagon, is mixed, but these should be considered. Refractory toxicity may require advanced lifesaving measures such as intra-arterial balloon counterpulsation or extracorporeal membrane oxygenation. If prompt cardiovascular support can be achieved, patient outcomes are generally very positive.</p
Beta-Blocker Use and Outcomes Among Hospitalized Heart Failure Patients
No full textOBJECTIVES The purpose of this study was to determine the effect of beta-blocker therapy on outcomes of hospitalized heart failure (HF) patients enrolled in the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization (ESCAPE). BACKGROUND The effect of beta-blocker therapy on outcomes among hospitalized HF patients is not well documented. METHODS We studied the association between beta-blocker therapy and outcomes among 432 hospitalized HF patients in the ESCAPE trial. RESULTS A total of 268 patients (62%) were on beta-blockers before admission. These patients had a shorter length of stay (7.9 ± 6.3 days vs. 9.4 ± 6.7 days; p < 0.01) and a lower six-month mortality rate (16% vs. 24%; p = 0.03) compared with those who were not on beta-blockers. Of the patients who were on admission beta-blockers and were discharged alive (n = 263), beta-blockers were discontinued in 54 and significantly modified (>50% dose reduction or changed to alternative beta-blocker) in 28 patients during hospitalization. Factors associated with discontinuation of beta-blockers during hospitalization included respiratory rate >24 breaths/min (30.8% vs. 16.9%; p = 0.03), heart rate >100 beats/min (19.2% vs. 7.3%; p = 0.01), lower ejection fraction (17.9 ± 5.4% vs. 20.2 ± 7.1%; p = 0.04), diabetes (21.2% vs. 37.1%; p = 0.03), and systolic blood pressure <100 mm Hg during hospitalization (70.3% vs. 54.1%; p = 0.03). After adjusting for factors associated with beta-blocker use and those with outcomes, consistent beta-blocker use during hospitalization was associated with a significant reduction in the rate of rehospitalization or death within six months after discharge (odds ratio 0.27, 95% confidence interval 0.10 to 0.71; p < 0.01). CONCLUSIONS Beta-blocker therapy before and during hospitalization for HF is associated with improved outcomes
Pretreatment with beta-blockers and the frequency of hypokalemia in patients with acute chest pain
No full textPlasma potassium concentration was measured at admission in 1234 patients who presented with acute chest pain. One hundred and ninety five patients were on P blockers before admission. The potassium concentrations of patients admitted early (within four hours of onsetof symptoms) were compared with those admitted later (4-18 hours after onset of symptoms). There was a transient fall in plasma potassium concentrations in patients not pre-treated with , B blockers. This was not seen in patients who had been on P blockers before admission. Nonselective, B blockers were more effective than cardioselective agents in maintaining concentrationsof plasma potassium. These findings suggest a mechanism for the beneficial effects of ,B blockers on morbidity and mortality in acute myocardial infarction
Influence of β(1) Adrenergic Receptor Genotype on Longitudinal Measures of Left Ventricular Ejection Fraction and Responsiveness to ß-Blocker Therapy in Patients With Duchenne Muscular Dystrophy
No full textThe purpose of this study was to determine whether the longitudinal progression of decline in left ventricular ejection fraction (LVEF) in Duchenne muscular dystrophy (DMD) patients is moderated by ADRB1 genotype and whether the efficacy of ß-blocker therapy is influenced by genotype status. About 147 DMD patients (6-34 years.) were analyzed with a focus on β(1) adrenergic receptor (ADRB1) genotype variants. Patients were grouped by ADRB1 genotype resulting in Gly389 patients and Arg389 patients. A generalized additive mixed effects model was used to examine differences in the nonlinear trend of LVEF across patient ages between genotype groups and for ß-blocker use. Both genotype groups displayed a progressive decline in LVEF starting around the mean age of ambulation loss (~12 years). However, there was no difference between genotype groups in the progression of decline in LVEF. There was a significant effect of ß-blocker use on longitudinal LVEF, wherein patients on ß-blockers had systematically lower LVEF when compared to patients not on ß-blockers. However, the effect of ß-blocker therapy on LVEF was not affected by ADRB1 genotype. The current study did not demonstrate an influence of patient ADRB1 genotype on longitudinal LVEF in our cohort. Despite previous literature suggesting a positive influence of ß-blocker use on cardiac function in DMD patients and of an ADRB1 genotypic difference in responsiveness to ß-blocker use, we did not observe this in our cohort. Interestingly, our cohort did not demonstrate a positive influence of ß-blocker use on LVEF measures
Effects of Angiotensin-Converting Enzyme Inhibitors and Beta Blockers on Clinical Outcomes in Patients With and Without Coronary Artery Obstructions at Angiography (from a Register-Based Cohort Study on Acute Coronary Syndromes)
No full textWe sought to determine the effectiveness of angiotensin-converting enzyme (ACE) inhibition and β-blocker treatment as a function of the degree of coronary artery disease (CAD) obstruction at angiography. The Evaluation of Methods and Management of Acute Coronary Events registry enrolled patients who had been hospitalized for an acute coronary syndrome. There were 1,602 patients who had cardiac catheterization that were used for this analysis. The main outcome measures were evidence-based therapies prescribed at discharge and 6-month incidence of all-cause mortality. The cohort consisted of 1,252 patients with obstructive CAD (>50% luminal diameter obstructed) and 350 patients with nonobstructive CAD. Multivariate logistic regression analysis adjusted for further medications and other clinical factors was performed. Patients with nonobstructive CAD had significantly (p <0.001) higher rates of β-blocker (77.8% vs 63.3%) and lower rates of ACE-inhibitor (57.7% vs 66.4%) prescriptions. In patients with nonobstructive CAD, ACE-inhibitor therapy was clearly associated with a lower 6-month mortality (odds ratio [OR] 0.31, 95% confidence interval [CI] 0.03 to 0.78, p = 0.004). No significant association between β-blocker use and death was found. In patients with obstructive CAD, both β blockers (OR 0.47, 95% CI 0.32 to 0.67, p <0.001) and ACE inhibitors (OR 0.47, 95% CI 0.26 to 0.87, p = 0.01) were significantly associated with a reduced risk of 6-month mortality. In conclusion, ACE-inhibitor therapy seems to be an effective first-line treatment for preventing the occurrence of mortality in patients with nonobstructive CAD
Insufficient reduction in heart rate during hospitalization despite beta-blocker treatment in acute decompensated heart failure: insights from the ASCEND-HF trial
No full textAims:
Heart failure (HF) can be associated with a higher resting heart rate (HR), and an elevated HR is associated with adverse long-term events. However, the mechanistic and causal role of HR in HF is unclear. This study aimed to investigate changes in HR during hospitalization, and the association between discharge HR and clinical outcomes as well as an interaction with beta-blocker therapy in patients with acute decompensated HF (ADHF).
Methods and results:
We studied 2906 patients with an LVEF ≤35%, without AF, who were enrolled in the ASCEND-HF trial. A total of 2492 (85.8%) patients had a HR ≥70 b.p.m. at baseline and 1580 (54.4%) patients were on beta-blocker treatment. Although HR was gradually reduced from baseline to discharge (85.5 ± 15.9 b.p.m. at baseline, 81.7 ± 14.1 b.p.m. at 24 h from treatment initiation, and 79.1 ± 12.2 b.p.m. at discharge), 80.2% of the patients still had a HR ≥70 b.p.m. at discharge. Patients with a HR ≥70 b.p.m. at discharge had significantly lower survival rates than those with a HR <70 b.p.m. (adjusted hazard ratio 1.02, 95% confidence interval 1.01–1.04, P = 0.002). Moreover, HR at discharge had a curvilinear association with mortality, and had no significant interaction effect with beta-blocker therapy at discharge (P = 0.82).
Conclusions:
Despite current beta-blocker therapy, many patients with hospitalized ADHF with reduced LVEF have relatively high discharge HR, and discharge HR is associated with higher mortality. Further studies are warranted to determine the optimal strategy for HR control to improve outcomes
The effects of a globin blocker on theresolution of 3’mRNA sequencing data inporcine blood
No full textBackground:Gene expression profiling in blood is a potential source of biomarkers to evaluate or predict phenotypic differences between pigs but is expensive and inefficient because of the high abundance of globin mRNA in porcine blood. These limitations can be overcome by the use of QuantSeq 3’mRNA sequencing(QuantSeq) combined with a method to deplete or block the processing of globin mRNA prior to or during library construction. Here, we validated the effectiveness of QuantSeq using a novel specific globin blocker (GB) that is included in the library preparation step of QuantSeq.Results:In data set 1, four concentrations of the GB were applied to RNA samples from two pigs. The GB significantly reduced the proportion of globin reads compared to non-GB (NGB) samples (P= 0.005) and increased the number of detectable non-globin genes. The highest evaluated concentration (C1) of the GB resulted in the largest reduction of globin reads compared to the NGB (from 56.4 to 10.1%). The second highest concentration C2,which showed very similar globin depletion rates (12%) as C1 but a better correlation of the expression of non-globin genes between NGB and GB (r= 0.98), allowed the expression of an additional 1295 non-globin genes to be detected, although 40 genes that were detected in the NGB sample (at a low level) were not present in the GBlibrary. Concentration C2 was applied in the rest of the study. In data set 2, the distribution of the percentage of globin reads for NGB (n= 184) and GB (n= 189) samples clearly showed the effects of the GB on reducing globin reads, in particular for HBB, similar to results from data set 1. Data set 3 (n= 84) revealed that the proportion of globin reads that remained in GB samples was significantly and positively correlated with the reticulocyte count int he original blood sample (P< 0.001). Conclusions: The effect of the GB on reducing the proportion of globin reads in porcine blood QuantSeq was demonstrated in three data sets. In addition to increasing the efficiency of sequencing non-globin mRNA, the GBfor QuantSeq has an advantage that it does not require an additional step prior to or during library creation.Therefore, the GB is a useful tool in the quantification of whole gene expression profiles in porcine blood
Reduced occurrence of appropriate therapy for ventricular arrhythmias after beta-blocker uptitration following implant of a primary prevention CRT-defibrillator
No full textBackground: Absence of beta-blocker use independently predicts appropriate therapy. Following cardiac resynchronisation therapy (CRT) implant, reverse remodelling and protection against bradycardia allows for beta-blocker dose uptitration. The differential dosing effects on the occurrence of a first episode of appropriate therapy in primary prevention CRT-defibrillator (CRT-D) patients remains unstudied. Methods and Results: Changes in beta-blocker dose following CRT-D in consecutive primary prevention patients implanted between 2008 and 2015 were retrospectively studied. Beta-blocker dose was expressed as percent of target dose. Uptitration of beta-blocker dose following implant was calculated as the change in percent of target dose between implant and 6-months follow-up. Results from a prospectively maintained database of all device analysis were used to determine the occurrence of appropriate therapy. A total of 162 patients (68 +/- 8 years) were studied. One hundred and ten (68%) patients underwent uptitration (mean 47 +/- 19% in target dose) and 52 (32%) remained on a stable beta-blocker dose. During 37 +/- 22 months follow-up, the cumulative percent of appropriate therapy was 31% in patient receiving no-uptitration versus 10% in the uptitrated patients (p < 0.001). After correction for known predictors of appropriate therapy, uptitration was independently associated with an OR = 0.263 (CI = 0.103-0.675; p = 0.001) for the occurrence of appropriate therapy. Every 1%-increase in target dose for beta-blocker associated with a significant lower risk for appropriate therapy, OR = 0.982 (CI = 0.965-0.999; p = 0.042). Conclusion: Following implantation of a primary prevention CRT-D, uptitration of beta-blockers associated with a reduced occurrence of a first episode of appropriate therapy for ventricular arrhythmias. An inverse dose-response effect was seen between beta-blocker dose and appropriate therapy.Martens, P (reprint author), Ziekenhuis Oost Limburg, Dept Cardiol, Schiepse Bos 6, B-3600 Genk, Belgium.
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