Beta-Adrenergic Receptor Blockade By Propranolol Enhances Retention In A Multitrial Passive-Avoidance Procedure

The effect of beta -adrenergic receptor blockade on retention in a mildly aversive passive-avoidance procedure was investigated. Rats were given passive-avoidance training-1 trial per day for 4 days-and were administered saline, the centrally and peripherally acting beta -adrenergic blocker propranolol (4 or 10 mg/kg ip), or the peripherally acting P-adrenergic blocker sotalol (4 or 10 mg/kg ip) immediately or 2 hr after the Ist trial. Enhanced retention occurred only with the higher dose (10 mg/kg) of propranolol and only when it was administered immediately after training. The enhanced retention produced by propranolol is discussed in terms of opposing, regionally specific actions of beta -adrenergic receptor-mediated neural circuits on modulation of memory

Beta-blocker initiation and adherence after hospitalization for acute myocardial infarction.

Aims: We sought to: (1) estimate the proportion of patients who initiated beta-blocker therapy after acute myocardial infarction (AMI) in Regione Emilia-Romagna (RER); (2) examine predictors of post-AMI beta-blocker initiation; and (3) assess adherence to such therapy. Methods and Results: Using healthcare claims data covering all of RER, we identified a cohort of 24,367 patients with a hospitalization for AMI between 2004 and 2007, who were discharged from the hospital alive and without contraindications to beta-blocker therapy. We estimated the proportion of eligible patients with at least one prescription for a beta-blocker following discharge and performed a multivariable logistic regression analysis to identify independent predictors of post-AMI beta-blocker initiation. We computed the proportion of days covered (PCD) as a measure of medication adherence at 6 and 12 months post-discharge. Following discharge, 16,383 (67%) cohort members initiated beta-blocker therapy. Independent predictors of beta-blocker initiation included age and receipt of invasive procedures during hospitalization, such as coronary artery bypass graft surgery (odds ratio [OR], 2.37; 95% confidence interval [CI], 2.00-2.81), percutaneous transluminal coronary angioplasty (OR, 1.42; 95% CI, 1.31-1.54), and cardiac catheterization (OR, 1.21; 95% CI, 1.11-1.32). Among initiators, adherence to beta-blocker treatment at 6 and 12 months was low and decreased in each study year. Conclusion: Overall, use of and adherence to post-AMI beta-blocker therapy was suboptimal in RER between 2004 and 2007. Older patients and those with indicators of frailty were less likely to initiate therapy. The proportion of patients adherent at 6 and 12 months decreased over time

Post-operative atrial fibrillation is influenced by beta-blocker therapy but not by pre-operative atrial cellular electrophysiology

We investigated whether post-cardiac surgery (CS) new-onset atrial fibrillation (AF) is predicted by pre-CS atrial cellular electrophysiology, and whether the antiarrhythmic effect of beta-blocker therapy may involve pre-CS pharmacological remodeling. Atrial myocytes were obtained from consenting patients in sinus rhythm, just prior to CS. Action potentials and ion currents were recorded using whole-cell patch-clamp technique. Post-CS AF occurred in 53 of 212 patients (25%). Those with post-CS AF were older than those without (67 ± 2 vs 62 ± 1 years, P = 0.005). In cells from patients with post-CS AF, the action potential duration at 50% and 90% repolarization, maximum upstroke velocity, and effective refractory period (ERP) were 13 ± 4 ms, 217 ± 16 ms, 185 ± 10 V/s, and 216 ± 14 ms, respectively (n = 30 cells, 11 patients). Peak L-type Ca2+ current, transient outward and inward rectifier K+ currents, and the sustained outward current were −5.0 ± 0.5, 12.9 ± 2.4, −4.1 ± 0.4, and 9.7 ± 1.0 pA/pF, respectively (13-62 cells, 7-19 patients). None of these values were significantly different in cells from patients without post-CS AF (P > 0.05 for each, 60-279 cells, 29-86 patients), confirmed by multiple and logistic regression. In patients treated >7 days with a beta-blocker pre-CS, the incidence of post-CS AF was lower than in non-beta-blocked patients (13% vs 27%, P = 0.038). Pre-CS beta-blockade was associated with a prolonged pre-CS atrial cellular ERP (P = 0.001), by a similar degree (∼20%) in those with and without post-CS AF. Conclusion: Pre-CS human atrial cellular electrophysiology does not predict post-CS AF. Chronic beta-blocker therapy is associated with a reduced incidence of post-CS AF, unrelated to a pre-CS ERP-prolonging effect of this treatment

Beta-blocker under-use in COPD patients

Background: Cardiovascular (CVS) comorbidities are common in COPD and contribute significantly to morbidity and mortality, especially following acute exacerbations of COPD (AECOPD). Beta-blockers (BBs) are safe and effective in COPD patients, with demonstrated survival benefit following myocardial infarction. We sought to determine if BBs are under-prescribed in patients hospitalized with AECOPD. We also sought to determine inpatient rates of CVS and cerebrovascular complications, and their impact on patient outcomes. Methods: Retrospective hospital data was collected over a 12-month period. The medical records of all patients 40 years of age coded with a diagnosis of AECOPD were analyzed. Prevalent use and incident initiation of BBs were assessed. Comorbidities including indications and contraindications for BB use were analyzed. Results: Of the 366 eligible patients, 156 patients (42.6%) had at least one indication for BB use – of these patients, only 53 (34.0%) were on BB therapy and 61 (39.1%) were not on BB therapy but had no listed contraindication. Prevalent use of BBs at the time of admission in all 366 patients was 19.7%, compared with 45.6%, 39.6% and 45.9% use of anti-platelets, statins and angiotensin-converting enzyme inhibitor/angiotensin II receptor blockers, respectively. CVS and cerebrovascular complications were common in this population (57 patients, 16%) and were associated with longer length of stay (p,0.01) and greater inpatient mortality (p=0.02). Conclusions: BBs are under-prescribed in COPD patients despite clear indication(s) for their use. Further work is required to explore barriers to BB prescribing in COPD patients

A nurse-led up-titration clinic improves chronic heart failure optimization of beta-adrenergic receptor blocking therapy : a randomized controlled trial

BACKGROUND: Beta-adrenergic blockade has been shown to improve left ventricular function, reduce hospital admissions and improve survival in chronic heart failure with reduced ejection fraction (HFrEF), with mortality reduction starting early after beta-adrenergic receptor blocker initiation and being dose-related. The aim of this pilot study was to determine the effectiveness of a nurse-led titration clinic in improving the time required for patients to reach optimal doses of the beta-adrenergic receptor blocking agents. METHOD: We conducted a prospective pilot randomized controlled trial. Twenty eight patients with CHF were randomized to optimisation of beta-adrenergic receptor blocker therapy over six months by either a nurse-led titration (NLT) clinic, led by a nurse specialist with the support of a cardiologist in a CHF clinic, or by their primary care physician (usual care (UC)). The primary endpoint was time to maximal beta-adrenergic receptor blocker dose. The secondary end-point was the proportion of patients reaching the target dose of beta-adrenergic receptor blocker by six months. RESULTS: The patients were predominantly men (72%), age 67 ± 16 years; New York Heart Association (NYHA) functional class I (32%), II (44%) and III (20%); baseline left ventricular ejection fraction 33 ± 10%, and a low mean Charlson co-morbidity score of 2.5 ± 1.4. The time to maximum dose was shorter in the NLT group compared to the UC group (90 ± 14 vs 166 ± 8 days, p < 0.0005). At six months, in the NLT group there were nine patients (82%) on high dose and one patient (9%) on low dose beta-adrenergic receptor blocker compared to the UC group with five (42%) patients reaching maximum dose and five (42%) patients on low dose (p = 0.04). The patients allocated to the NLT group also had significantly less worsening of depression between baseline and six months (p = 0.006). CONCLUSION: A NLT clinic improves optimisation of beta-adrenergic receptor blocker therapy through increasing the proportion of patients reaching maximal dose and facilitating rapid up-titration of beta-adrenergic receptor blocker agents in patients with chronic HFrEF. TRIAL REGISTRATION: Australian Clinical Trials Registry (ACTRN012606000383561)

Influence of heart rate, blood pressure, and beta-blocker dose on outcome and the differences in outcome between carvedilol and metoprolol tartrate in patients with chronic heart failure: results from the COMET trial.

AIMS: We studied the influence of heart rate (HR), systolic blood pressure (SBP), and beta-blocker dose on outcome in the 2599 out of 3029 patients in Carvedilol Or Metoprolol European Trial (COMET) who were alive and on study drug at 4 months after randomization (time of first visit on maintenance therapy). METHODS AND RESULTS: By multivariable analysis, baseline HR, baseline SBP, and their change after 4 months were not independently related to subsequent outcome. In a multivariable analysis including clinical variables, HR above and SBP below the median value achieved at 4 months predicted subsequent increased mortality [relative risk (RR) for HR>68 b.p.m. 1.333; 95% confidence intervals (CI) 1.152-1.542; P120 mmHg 0.78; 95% CI 0.671-0.907; P<0.0013]. Achieving target beta-blocker dose was associated with a better outcome (RR 0.779; 95% CI 0.662-0.916; P<0.0025). The superiority of carvedilol as compared to metoprolol tartrate was maintained in a multivariable model (RR 0.767; 95% CI 0.663-0.887; P=0.0004) and there was no interaction with HR, SBP, or beta-blocker dose. CONCLUSION: Beta-blocker dose, HR, and SBP achieved during beta-blocker therapy have independent prognostic value in heart failure. None of these factors influenced the beneficial effects of carvedilol when compared with metoprolol tartrate at the pre-defined target doses used in COMET

Angiotensin II blockade and aortic-root dilation in Marfan's syndrome

Background: Progressive enlargement of the aortic root, leading to dissection, is the main cause of premature death in patients with Marfan's syndrome. Recent data from mouse models of Marfan's syndrome suggest that aortic-root enlargement is caused by excessive signaling by transforming growth factor (beta) (TGF-(beta)) that can be mitigated by treatment with TGF-(beta) antagonists, including angiotensin II-receptor blockers (ARBs). We evaluated the clinical response to ARBs in pediatric patients with Marfan's syndrome who had severe aortic-root enlargement. Methods: We identified 18 pediatric patients with Marfan's syndrome who had been followed during 12 to 47 months of therapy with ARBs after other medical therapy had failed to prevent progressive aortic-root enlargement. The ARB was losartan in 17 patients and irbesartan in 1 patient. We evaluated the efficacy of ARB therapy by comparing the rates of change in aortic-root diameter before and after the initiation of treatment with ARBs. Results: The mean (+/-SD) rate of change in aortic-root diameter decreased significantly from 3.54+/-2.87 mm per year during previous medical therapy to 0.46+/-0.62 mm per year during ARB therapy (P<0.001). The deviation of aortic-root enlargement from normal, as expressed by the rate of change in z scores, was reduced by a mean difference of 1.47 z scores per year (95% confidence interval, 0.70 to 2.24; P<0.001) after the initiation of ARB therapy. The sinotubular junction, which is prone to dilation in Marfan's syndrome as well, also showed a reduced rate of change in diameter during ARB therapy (P<0.05), whereas the distal ascending aorta, which does not normally become dilated in Marfan's syndrome, was not affected by ARB therapy. Conclusions: In a small cohort study, the use of ARB therapy in patients with Marfan's syndrome significantly slowed the rate of progressive aortic-root dilation. These findings require confirmation in a randomized trial

Should beta-blocker therapy be reduced or withdrawn after an episode of decompensated heart failure? Results from COMET.

BACKGROUND: It is unclear whether beta-blocker therapy should be reduced or withdrawn in patients who develop acute decompensated heart failure (HF). We studied the relationship between changes in beta-blocker dose and outcome in patients surviving a HF hospitalisation in COMET. METHODS: Patients hospitalised for HF were subdivided on the basis of the beta-blocker dose administered at the visit following hospitalisation, compared to that administered before. RESULTS: In COMET, 752/3029 patients (25%, 361 carvedilol and 391 metoprolol) had a non-fatal HF hospitalisation while on study treatment. Of these, 61 patients (8%) had beta-blocker treatment withdrawn, 162 (22%) had a dose reduction and 529 (70%) were maintained on the same dose. One-and two-year cumulative mortality rates were 28.7% and 44.6% for patients withdrawn from study medication, 37.4% and 51.4% for those with a reduced dosage (n.s.) and 19.1% and 32.5% for those maintained on the same dose (HR,1.59; 95%CI, 1.28-1.98; p<0.001, compared to the others). The result remained significant in a multivariable model: (HR, 1.30; 95%CI, 1.02-1.66; p=0.0318). No interaction with the beneficial effects of carvedilol, compared to metoprolol, on outcome was observed (p=0.8436). CONCLUSIONS: HF hospitalisations are associated with a high subsequent mortality. The risk of death is higher in patients who discontinue beta-blocker therapy or have their dose reduced. The increase in mortality is only partially explained by the worse prognostic profile of these patients

Atenolol versus losartan in children and young adults with Marfan's syndrome

BACKGROUND : Aortic-root dissection is the leading cause of death in Marfan's syndrome. Studies suggest that with regard to slowing aortic-root enlargement, losartan may be more effective than beta-blockers, the current standard therapy in most centers. METHODS : We conducted a randomized trial comparing losartan with atenolol in children and young adults with Marfan's syndrome. The primary outcome was the rate of aortic-root enlargement, expressed as the change in the maximum aortic-root-diameter z score indexed to body-surface area (hereafter, aortic-root z score) over a 3-year period. Secondary outcomes included the rate of change in the absolute diameter of the aortic root; the rate of change in aortic regurgitation; the time to aortic dissection, aortic-root surgery, or death; somatic growth; and the incidence of adverse events. RESULTS : From January 2007 through February 2011, a total of 21 clinical centers enrolled 608 participants, 6 months to 25 years of age (mean [+/- SD] age, 11.5 +/- 6.5 years in the atenolol group and 11.0 +/- 6.2 years in the losartan group), who had an aorticroot z score greater than 3.0. The baseline-adjusted rate of change (+/- SE) in the aortic-root z score did not differ significantly between the atenolol group and the losartan group (-0.139 +/- 0.013 and -0.107 +/- 0.013 standard-deviation units per year, respectively; P = 0.08). Both slopes were significantly less than zero, indicating a decrease in the degree of aortic-root dilatation relative to body-surface area with either treatment. The 3-year rates of aortic-root surgery, aortic dissection, death, and a composite of these events did not differ significantly between the two treatment groups. CONCLUSIONS : Among children and young adults with Marfan's syndrome who were randomly assigned to losartan or atenolol, we found no significant difference in the rate of aorticroot dilatation between the two treatment groups over a 3-year period

Chronic beta-adrenoceptor blockade and human atrial cell electrophysiology: evidence of pharmacological remodelling

&lt;b&gt;Objective:&lt;/b&gt; Chronic beta-adrenoceptor antagonist (&#946;-blocker) treatment reduces the incidence of reversion to AF in patients, possibly via an adaptive myocardial response. However, the underlying electrophysiological mechanisms are presently unclear. We aimed to investigate electrophysiological changes in human atrial cells associated with chronic treatment with &#946;-blockers and other cardiovascular-acting drugs. &lt;b&gt;Methods:&lt;/b&gt; Myocytes were isolated enzymatically from the right atrial appendage of 40 consenting patients who were in sinus rhythm. The cellular action potential duration (APD), effective refractory period (ERP), L-type Ca&lt;sup&gt;2+&lt;/sup&gt; current (&lt;i&gt;I&lt;/i&gt;&lt;sub&gt;CaL&lt;/sub&gt;), transient (&lt;i&gt;I&lt;/i&gt;&lt;sub&gt;TO&lt;/sub&gt;) and sustained (&lt;i&gt;I&lt;/i&gt;&lt;sub&gt;KSUS&lt;/sub&gt;) outward K&lt;sup&gt;+&lt;/sup&gt; currents, and input resistance (&lt;i&gt;R&lt;/i&gt;&lt;sub&gt;i&lt;/sub&gt;) were recorded using the whole cell patch clamp. Drug treatments and clinical characteristics were compared with electrophysiological measurements using simple and multiple regression analyses. P&#60;0.05 was taken as statistically significant. &lt;b&gt;Results:&lt;/b&gt; In atrial cells from patients treated chronically with &#946;-blockers, the APD&lt;sub&gt;90&lt;/sub&gt; and ERP (75 beats/min stimulation) were significantly longer, at 213&#177;11 and 233&#177;11 ms, respectively (&lt;i&gt;n&lt;/i&gt; = 15 patients), than in cells from non-&#946;-blocked patients, at 176&#177;12 and 184&#177;12 ms (n = 11). These cells also displayed a significantly reduced action potential phase 1 velocity (22&#177;3 vs. 34&#177;3 V/s). Chronic &#946;-blockade was also associated with a significant reduction in the heart rate (58&#177;3 vs. 69&#177;5 beats/min) and in the density of ITO (8.7&#177;1.3 vs. 13.7&#177;2.1 pA/pF), an increase in the Ri (214&#177;24 vs. 132&#177;14 M&#937;), but no significant change in &lt;i&gt;I&lt;/i&gt;&lt;sub&gt;CaL&lt;/sub&gt; or &lt;i&gt;I&lt;/i&gt;&lt;sub&gt;KSUS&lt;/sub&gt;. The &lt;i&gt;I&lt;/i&gt;&lt;sub&gt;TO&lt;/sub&gt; blocker 4-aminopyridine largely mimicked the changes in phase 1 and ERP associated with chronic &#946;-blockade, in cells from non-&#946;-blocked patients. Chronic treatment of patients with calcium channel blockers or angiotensin converting enzyme inhibitors (&lt;i&gt;n&lt;/i&gt; = 11–13 patients) was not associated with any significant changes in atrial cell electrophysiology. &lt;b&gt;Conclusion:&lt;/b&gt; The observed atrial cellular electrophysiological changes associated with chronic &#946;-blockade are consistent with a long-term adaptive response, a type of ‘pharmacological remodelling’, and provide mechanistic evidence supportive of the anti-arrhythmic actions of &#946;-blockade