Document Detail


Adrenergic Receptor Polymorphisms and Prevention of Ventricular Arrhythmias with Bucindolol in Patients with Chronic Heart Failure.
MedLine Citation:
PMID:  23275278     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
BACKGROUND: -In patients with chronic heart failure and reduced left ventricular ejection fraction (HFREF) β-blockers prevent cardiac arrhythmias, including ventricular tachycardia/fibrillation (VT/VF). We hypothesized that prevention of ventricular arrhythmias by the β-blocker/sympatholytic agent bucindolol is influenced by genetic variation in adrenergic receptors (ARs). METHODS AND RESULTS: -From a substudy of the β-Blocker Evaluation of Survival Trial (BEST, n = 1040), we identified those with the high functioning 389Arg vs. the lower function 389Gly β(1) adrenergic receptor (AR) variant, and the loss of function (α2C)322-325 AR deletion vs. the 322-325 wild type (Wt)/deletion (Del) variant. VT/VF was recorded on case report forms as an adverse event. There were 493 Arg 389 β(1) receptor homozygotes (β(1)389 Arg/Arg) vs. 547 Gly389 carriers and 207 (α2C)322-325 Del carriers vs. 833 homozygous Wts ((α2C)322-325 Wt/Wt). In all genotypes bucindolol was associated with a lower incidence of VT/VF (subhazard ratio (SHR) 0.42 (0.27, 0.64), P=0.00006). Bucindolol reduced VT/VF in β(1)389 Arg homozygotes (SHR 0.26 (0.14, 0.50), P=0.00005) but not in β(1)389 Gly carriers (SHR 0.60 (0.34, 1.07), P=0.09). For genotype combinations, the (α2C)322-325 polymorphism altered the VT/VF bucindolol response in β(1)389 Gly carriers, with (α2C) Del genotypes associated with complete efficacy loss. A test of interaction was statistically significant (P=0.028) for treatment group and a β(1)389/(α2C)322-325 three genotype construct, effectively identifying patients who exhibited enhanced response, no substantial response modification and loss of response. CONCLUSIONS: -Bucindolol prevents VT/VF in HFREF subjects, and this effect is modulated by β(1)389 Arg/Gly and (α2C)322-325 Wt/Del AR polymorphisms.
Authors:
Ryan G Aleong; William H Sauer; Alastair D Robertson; Stephen B Liggett; Michael R Bristow
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-12-30
Journal Detail:
Title:  Circulation. Arrhythmia and electrophysiology     Volume:  -     ISSN:  1941-3084     ISO Abbreviation:  Circ Arrhythm Electrophysiol     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-12-31     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101474365     Medline TA:  Circ Arrhythm Electrophysiol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
1 University of Colorado, Aurora, CO;
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