Aleong Ryan G, Sauer William H, Davis Gordon, Murphy Guinevere A, Port J David, Anand Inder S, Fiuzat Mona, O'Connor Christopher M, Abraham William T, Liggett Stephen B, Bristow Michael R
Section of Cardiac Electrophysiology, University of Colorado Denver, Denver, Colorado.
Section of Cardiac Electrophysiology, University of Colorado Denver, Denver, Colorado.
JACC Heart Fail. 2013 Aug;1(4):338-344. doi: 10.1016/j.jchf.2013.04.002.
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).
β-blockers have modest efficacy for AF prevention in HFREF patients. Bucindolol's effects on HF and ventricular arrhythmic endpoints are genetically modulated by β₁- and α(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.
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 β₁-AR position 389 Arg/Gly and the α(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.
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 β₁389 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 β₁389 Gly carriers (HR: 1.01 [95% CI: 0.56 to 1.84], interaction test = 0.008). When β₁389 Gly carriers were subdivided by α(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 β₁389 Arg homozygotes.
Bucindolol prevented new-onset AF; β₁ and α(2c) polymorphisms predicted therapeutic response; and the 47% of patients who were β₁389 Arg homozygotes had an enhanced effect size of 74%. (Beta-Blocker Evaluation in Survival Trial [BEST]; NCT00000560)
本研究评估了β受体阻滞剂/交感神经阻滞剂布新洛尔对入选β受体阻滞剂生存试验（BEST）的左心室射血分数降低的晚期慢性心力衰竭（HFREF）患者房颤（AF）发生发展的影响。
β受体阻滞剂对HFREF患者预防房颤的疗效一般。布新洛尔对心力衰竭和室性心律失常终点的影响受到β₁和α(2c)肾上腺素能受体（AR）多态性的基因调控，这些多态性可用于将HFREF人群细分为布新洛尔有效性水平增强、不变或丧失的人群。
BEST研究纳入了2708例纽约心脏协会（NYHA）心功能III至IV级的HFREF患者。一项子研究对1040例患者的DNA进行了β₁-AR第389位精氨酸/甘氨酸和α(2c)322 - 325野生型（Wt）/缺失（Del）多态性基因分型，并根据不良事件病例报告表或基线、3个月和12个月时的心电图评估新发房颤情况。
在整个队列中，与安慰剂相比，布新洛尔使新发房颤发生率降低了41%（风险比[HR]：0.59[95%置信区间（CI）：0.44至0.79]，p = 0.0004）。在DNA子研究中的493例β₁389精氨酸纯合子（Arg/Arg）中，布新洛尔使新发房颤降低了74%（HR：0.26[95%CI：0.12至0.57]），而对β₁389甘氨酸携带者无影响（HR：1.01[95%CI：0.56至1.84]，交互检验 = 0.008）。当根据α(2c)Wt纯合子（n = 413，HR：（此处原文有误，应为0.94）0.94[95%CI：0.48至1.82]，p = 0.84）或Del变异携带者（n = 134，HR：1.33[95%CI：0.32至5.64]，p = 0.70）对β₁389甘氨酸携带者进行细分时，与β₁389精氨酸纯合子一起分析时存在阳性交互检验（p = 0.016）。
布新洛尔可预防新发房颤；β₁和α(2c)多态性可预测治疗反应；47%的β₁389精氨酸纯合子患者效果增强，降低幅度达74%。（β受体阻滞剂生存试验[BEST]；NCT00000560）
