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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...

As marbling increasedfrom "practically devoid" to ' 'moderately abundant", loin steaks were more palatable (P < 0.05) about 213 of the time, round steaks were more palatable (P< 0.05) about 1/8 of the time, and loin steaks were more likely to be assigned high (2 6.00) panel ratings and to have low (53.63 kg) shear values. However, increases in marbling from 'Slight '' to "moderately abundant" (A maturity) and from "small" to "moderately abundant" (A+ B maturity) had little or no effect on percentage incidence of loin or round steaks with panel ratings 5 2.99 or 24.00, or with shear values 2 6.35 kg or 54.99 kg. Differences in marbling explained about 33 % (loin) and 7% (top round) of the variation in overall palatability ratings in A , B , C, and A + B maturity carcasses.

BackgroundPharmacogenetics involves complex interactions of gene products affecting pharmacodynamics and pharmacokinetics, but there is little information on the interaction of multiple genetic modifiers of drug response. Bucindolol is a β-blocker/sympatholytic agent whose efficacy is modulated by polymorphisms in the primary target (β1 adrenergic receptor [AR] Arg389 Gly on cardiac myocytes) and a secondary target modifier (α2C AR Ins [wild-type (Wt)] 322–325 deletion [Del] on cardiac adrenergic neurons). The major allele homozygotes and minor allele carriers of each polymorphism are respectively associated with efficacy enhancement and loss, creating the possibility for genotype combination interactions that can be measured by clinical trial methodology.MethodologyIn a 1,040 patient substudy of a bucindolol vs. placebo heart failure clinical trial, we tested the hypothesis that combinations of β1389 and α2C322–325 polymorphisms are additive for both efficacy enhancement and loss. Additionally, norepinephrine (NE) affinity for β1389 AR variants was measured in human explanted left ventricles.Principal FindingsThe combination of β1389 Arg+α2C322–325 Wt major allele homozygotes (47% of the trial population) was non-additive for efficacy enhancement across six clinical endpoints, with an average efficacy increase of 1.70-fold vs. 2.32-fold in β1389 Arg homozygotes+α2C322–325 Del minor allele carriers. In contrast, the minor allele carrier combination (13% subset) exhibited additive efficacy loss. These disparate effects are likely due to the higher proportion (42% vs. 8.7%, P = 0.009) of high-affinity NE binding sites in β1389 Arg vs. Gly ARs, which converts α2CDel minor allele-associated NE lowering from a therapeutic liability to a benefit.ConclusionsOn combination, the two sets of AR polymorphisms 1) influenced bucindolol efficacy seemingly unpredictably but consistent with their pharmacologic interactions, and 2) identified subpopulations with enhanced (β1389 Arg homozygotes), intermediate (β1389 Gly carriers+α2C322–325 Wt homozygotes), and no (β1389 Gly carriers+α2C322–325 Del carriers) efficacy.