Bucindolol

Bucindolol hydrochloride in atrial fibrillation and concomitant heart failure.[Pubmed:25959096]

Expert Rev Cardiovasc Ther. 2015 Jun;13(6):627-36.

Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia and it increases the risk of thromboembolic stroke and death. AF is common in patients with heart failure and reduced ejection fraction (HFrEF), affecting between 30 and 40% of patients with HFrEF. AF increases the risk of death and hospitalization in patients with HFrEF. Only two antiarrhythmic drugs (amiodarone and dofetilide) are guideline-recommended in patients with AF and heart failure (HF). Meta-analyses of studies of major trials in HF suggest that patients with AF/HFrEF do not benefit from conventional beta-blockers. Bucindolol has shown promise in the treatment of patients with AF/HFrEF. We will explore how the shared pathophysiology of AF/HF is targeted by the unique pharmacology of Bucindolol and review the existing data for Bucindolol in AF/HF. We will explore findings that support a pharmacogenetically modulated effect of Bucindolol in patients with polymorphisms in beta1-adrenergic receptor and provide an overview of ongoing studies.

Pharmacokinetic drug evaluation of bucindolol for the treatment of atrial fibrillation in heart failure patients.[Pubmed:28162002]

Expert Opin Drug Metab Toxicol. 2017 Apr;13(4):473-481.

INTRODUCTION: Atrial fibrillation (AF) and heart failure (HF) often coexist. When AF and HF are both present, they are associated with negative outcomes, increased hospitalizations and mortality. As beta-blockade is effective inF and may be useful in presence of AF, Bucindolol, a non-selective beta-blocker with alpha-1 vasodilatory effect, may be used. Area covered: This review evaluates the efficacy and safety of Bucindolol in HF patients with AF. The largest amount of data comes from BEST trial which evaluated the efficacy of Bucindolol in HF patients. Since Bucindolol's effects are genetically modulated by beta1 and alpha2c-adrenergic receptor polymorphisms BEST genetic substudy arose. Expert opinion: In the BEST Trial, Bucindolol demonstrated efficacy in HF patients showing a 74% reduction in new-onset atrial fibrillation events particularly in beta1 389 Arg/Arg homozygous. GENETIC-AF study was designed to determine whether Bucindolol therapy is superior to metoprolol in preventing recurrent AF in a genetically targeted population of HF patients. Furthermore, this drug is safe, but presents the same side effects as all beta-blockers and has showed no clear benefits in African-Americans and in class IV NYHA patients. Further studies are needed to confirm and validate the role of Bucindolol and its economic implications.

Bucindolol improves right ventricle function in rats with pulmonary arterial hypertension through the reversal of autonomic imbalance.[Pubmed:28011346]

Eur J Pharmacol. 2017 Mar 5;798:57-65.

Pulmonary arterial hypertension (PAH) is characterised by an elevation in afterload imposed on the right ventricle (RV), leading to hypertrophy and failure. The autonomic nervous system (ANS) plays a key role in the progression to heart failure, and the use of beta-blockers attenuates this process. The aim of this study was to verify the role of Bucindolol, abeta1-, beta2- and alpha1-blocker, on the ANS, and its association with RV function in rats with PAH. Male Wistar rats were divided into four groups: control, monocrotaline, control+Bucindolol, and monocrotaline+Bucindolol. PAH was induced by a single intraperitoneal injection of monocrotaline (60mg/kg). After two weeks, animals were treated for seven days with Bucindolol (2mg/kg/day i.p.) or vehicle. At the end of the treatment, animals underwent echocardiographic assessment, catheterisation of the femoral artery and RV, and tissue collection for morphometric and histological evaluation. In the monocrotaline+Bucindolol group, there was a decrease in mean pulmonary artery pressure (33%) and pulmonary congestion (21%), when compared to the monocrotaline. Bucindolol treatment also reduced RV pleomorphism, necrosis, fibrosis and infiltration of inflammatory cells. An improvement in RV systolic function was also observed in the monocrotaline+Bucindolol group compared to the monocrotaline. In addition, Bucindolol promoted a decrease in the cardiac sympathovagal balance (93%) by reducing sympathetic drive (70%) and increasing parasympathetic drive (142%). Bucindolol also reduced blood pressure variability (75%). Our results show that the beneficial effects from Bucindolol treatment appeared to be a consequence of the reversal of monocrotaline-induced autonomic imbalance.

Prevention of atrial fibrillation by bucindolol is dependent on the beta(1)389 Arg/Gly adrenergic receptor polymorphism.[Pubmed:24159564]

JACC Heart Fail. 2013 Aug;1(4):338-344.

OBJECTIVES: This study assessed the impact of Bucindolol, a beta-blocker/sympatholytic agent, on the development of atrial fibrillation (AF) in advanced chronic heart failure with reduced left ventricular ejection fraction (HFREF) patients enrolled in the BEST (Beta-Blocker Evaluation of Survival Trial). BACKGROUND: beta-blockers have modest efficacy for AF prevention in HFREF patients. Bucindolol's effects on HF and ventricular arrhythmic endpoints are genetically modulated by beta(1)- and alpha(2c)-adrenergic receptor (AR) polymorphisms that can be used to subdivide HFREF populations into those with Bucindolol effectiveness levels that are enhanced, unchanged, or lost. METHODS: BEST enrolled 2,708 New York Heart Association (NYHA) class III to IV HFREF patients. A substudy in which 1,040 patients' DNA was genotyped for the beta(1)-AR position 389 Arg/Gly and the alpha(2c)322-325 wild type (Wt)/deletion (Del) polymorphisms, and new-onset AF was assessed from adverse event case report forms or electrocardiograms at baseline and at 3 and 12 months. RESULTS: In the entire cohort, Bucindolol reduced the rate of new-onset AF compared to placebo by 41% (hazard ratio [HR]: 0.59 [95% confidence interval (CI): 0.44 to 0.79], p = 0.0004). In the 493 beta(1)389 arginine homozygotes (Arg/Arg) in the DNA substudy, Bucindolol reduced new-onset AF by 74% (HR: 0.26 [95% CI: 0.12 to 0.57]), with no effect in beta(1)389 Gly carriers (HR: 1.01 [95% CI: 0.56 to 1.84], interaction test = 0.008). When beta(1)389 Gly carriers were subdivided by alpha(2c) Wt homozygotes (n = 413, HR: 0.94 [95% CI: 0.48 to 1.82], p = 0.84) or Del variant carriers (n = 134, HR: 1.33 [95% CI: 0.32 to 5.64], p = 0.70), there was a positive interaction test (p = 0.016) when analyzed with beta(1)389 Arg homozygotes. CONCLUSIONS: Bucindolol prevented new-onset AF; beta(1) and alpha(2c) polymorphisms predicted therapeutic response; and the 47% of patients who were beta(1)389 Arg homozygotes had an enhanced effect size of 74%. (Beta-Blocker Evaluation in Survival Trial [BEST]; NCT00000560)