An α _2C -Adrenergic Receptor Polymorphism Alters the Norepinephrine-Lowering Effects and Therapeutic Response of the β-Blocker Bucindolol in Chronic Heart Failure

Abstract

Background-Adrenergic activation is an important determinant of outcomes in chronic heart failure. Adrenergic activity is regulated in part by prejunctional ␣ 2C -adrenergic receptors (ARs), which exhibit genetic variation in humans. Bucindolol is a novel ␤-AR blocking agent that also lowers systemic norepinephrine and thus is also a sympatholytic agent. This study investigated whether ␣ 2C -AR polymorphisms affect sympatholytic effects of bucindolol in patients with heart failure. Methods and Results-In the ␤-Blocker Evaluation of Survival Trial, adrenergic activation was estimated by systemic venous norepinephrine measured at baseline, 3 months, and 12 months posttreatment in patients treated with placebo or bucindolol.In the ␤-Blocker Evaluation of Survival Trial AR polymorphism substudy, DNA was collected from 1040 of the 2708 randomized patients, and ␣ 2C -AR gene polymorphisms (␣ 2C Del322-325 or the wild-type counterpart) were measured by polymerase chain reaction and gel electrophoresis. Patients who were ␣ 2C Del carriers (heterozygotes or homozygotes) exhibited a much greater sympatholytic response to bucindolol (decrease in norepinephrine at 3 months of 153Ϯ57 pg/mL, Pϭ0.012 compared with placebo versus decrease of 50Ϯ13 pg/mL in ␣ 2C wild type, Pϭ0.0005 versus placebo; Pϭ0.010 by interaction test). ␣ 2C Del carriers had no evidence of a favorable survival benefit from bucindolol (mortality compared with placebo hazard ratio, 1.09; 95% CI, 0.57 to 2.08; Pϭ0.80), whereas bucindolol-treated subjects who were wild type for the ␣ 2C -AR had a 30% reduction in mortality (hazard ratio, 0.70; 95% CI, 0.51 to 0.96; Pϭ0.025). Conclusions-In the ␤-Blocker Evaluation of Survival Trial AR polymorphism substudy, the norepinephrine lowering and clinical therapeutic responses to bucindolol were strongly influenced by ␣ 2C receptor genotype. (Circ Heart Fail. 2010;3:21-28.)Key Words: genetics Ⅲ heart failure Ⅲ norepinephrine Ⅲ receptors, adrenergic, alpha Ⅲ ␤-blockers A drenergic activity is a major determinant of outcome in chronic heart failure (CHF). 1,2 Multiple lines of evidence indicate that sustained high levels of ␤-adrenergic activity produce adverse effects on myocardial structure and function. 3,4 These observations form the basis of the rationale for ␤-blocker therapy of heart failure. 4 On the other hand, a certain amount of adrenergic activity is required to support the failing heart, and too rapid or extreme removal of adrenergic drive can result in adverse outcomes. [5][6][7] Clinical Perspective on p 28The regulation of cardiac adrenergic activity is complex, involving mechanisms modulating central sympathetic outflow, norepinephrine (NE) neuronal synthesis, prejunctional NE release, and neuronal reuptake of NE. 3 Adrenergic activity is likely also influenced by genetic variation, particularly in adrenergic receptors (ARs) that regulate NE release. One such receptor is the ␣ 2C -AR, which is present on prejunctional adrenergic nerve terminals where it provides tonic inhibition of NE release. 8 Combin...

Treatment of Chronic Heart Failure With β-Adrenergic Receptor Antagonists

“…The sympatholytic effects of bucindolol and to a much lesser degree carvedilol add to these compounds' antiadrenergic profiles, and in the case of bucindolol must be considered in the therapeutic targeting of the drug. 116,117 Because NE is ␤ 1 -AR selective, reducing adrenergic drive has the effect of preferentially inhibiting ␤ 1 -AR signaling, in effect producing cross-talk from ␤ 2 -AR blockade to ␤ 1 -AR inhibition. Thus, in the treatment of chronic heart failure, the biggest contribution of ␤ 2 -AR blockade may be inhibition of ␤ 1 -AR signaling.…”

“…The BEST trial contained the first DNA bank established in a large multicenter heart failure trial. 116,163 Using this starting material Steve Liggett, whose laboratory had by this time characterized the majority of the common genetic variation in human adrenergic receptors, and colleagues conducted an investigation of six candidate adrenergic receptor polymorphisms on ␤-blocker (bucindolol) clinical responses. As expected, the allele frequency of the ␤ 2 164Ile variant 161 was too small (0.01) in the sample size of 1040 to generate enough clinical events for analysis, but the ␤ 1 389 Arg/Gly allele frequencies of 0.69/0.31 provided ample numbers of clinical events to test the prespecified hypothesis that the 389Arg variant would be associated with a greater therapeutic effect than the counterpart Gly polymorphism.…”

“…This likely means that the basis for bucindolol's differentiation is its unique pharmacological properties of ␤ 1 389 Arg inverse agonism 157 and NE lowering. 111,116 Because of the higher affinity of the ␤ 1 389 Arg receptor for NE 158 117 The hypothesis that bucindolol but not other ␤-blockers has this preferential and enhanced effect in patients with the ␤ 1 389 Arg/Arg genotype is about to be tested in a comparative effectiveness trials of bucindolol versus metoprolol CR/XL, in both heart failure and prevention of atrial fibrillation. Until these Phase 3 pharmacogenetic comparative effectiveness trials are completed, the idea that a ␤-blocker with selective effects on the ␤ 1 389Arg versus Gly AR could have differentially favorable efficacy in patients who are homozygous for the ␤ 1 389Arg allele should be considered a strongly supported hypothesis.…”

High Dose <i>β</i>-Blocker Therapy Triggers Additional Reverse Remodeling in Patients With Idiopathic Non-Ischemic Cardiomyopathy

“…However, probably because of the Westernization of Japanese dietary habits, the improvement in the average build is quite remarkable in Japan, so we may not need to set the upper limit of the dose at such a low level. In addition, genetic differences in the responses to BBs have also been suggested as the reason for the small dose among Japanese, 11) however, there is a report that 25 mg of carvedilol was well tolerated among Chinese who might be considered to be genetically similar to Japanese. 12) There is anecdotal experience in which carvedilol was used at a dose above 20 mg daily in Japan, 13) but the report was limited to 5 patients receiving ventricular assist devices.…”

The Future of Pharmacogenetics in the Treatment of Heart Failure

“…There is a growing body of evidence that variation in proteins within the sympathetic axis and RAAS influence drug response thus increasingly pharmacogenetics of HF research is being sought as a way to optimise HF treatment and advance new drug development in this area (24)(25)(26)(27)(28)(29)(30)(31). Although drug response variation in HF is likely multi-factorial, pharmacogenetic variation may partially account for therapeutic failure contributing to the remaining high mortality in HF.…”