Carroll Ian A, Slavov Dobromir, Jonas Eric R, Minobe Wayne A, Walker Lori A, Ambardekar Amrut V, McKinsey Timothy A, Knaupp Ammon D, Kim Donghwa, Liggett Stephen B, Bristow Michael R
Department of Medicine (Cardiology) University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
Section of Pharmacogenomics, University of Colorado Cardiovascular Institute, Boulder (80309) and Aurora (80045) CO, USA.
medRxiv. 2025 Sep 11:2025.08.22.25333921. doi: 10.1101/2025.08.22.25333921.
and , encoding cardiac myocyte β- and β-adrenergic receptors (ARs) that mediate pathologic myocardial remodeling in response to chronically increased signaling, contain N-terminus haplotype variants capable of influencing agonist- or biased ligand-induced receptor internalization that uncouples canonical signaling and initiates EGFR/ERK1/2 cardioprotection.
In two heart failure (HF) clinical trial genetic substudies we investigated effects of internalizing vs. internalization-resistant / haplotypes on clinical or biomarker responses to the biased ligand β-blocker bucindolol vs. placebo or vs. the nonbiased β-antagonist metoprolol, and in haplotyped isolated human heart preparations we measured ERK1/2 activation in response to these same interventions.
In subjects with ≥3 internalizing + haplotypes (6.7% subcohort) placebo treatment was associated with fewer clinical events compared to subjects with internalization-resistant haplotypes (Odds Ratio (OR) 0.28, 95% CI (0.10, 0.82)). In contrast, placebo treatment in subjects with ≥3 internalization-resistant haplotypes (70% subcohort) was associated with more clinical events in comparison to subjects with internalizing haplotype counterparts (OR 1.64 (1.46, 1.84)). Bucindolol treatment was equal to placebo in the ≥3 internalizing subcohort, but was superior to placebo in the internalization-resistant subcohort (bucindolol vs. placebo OR 0.49 (0.41, 0.58)). In subjects with all 4 haplotypes internalization-resistant (25% subcohort), bucindolol vs. placebo reduced time to first event rates by 62.3±17.5% (P <0.01, 1.68±0.34 fold > the all-haplotypes parent population and additive to 1.92±0.58 fold when the haplotype contained Arg389 rather than Gly389). The same bucindolol vs. placebo pattern was observed for NT-proBNP or norepinephrine reduction vs. metoprolol. In these comparisons and haplotypes behaved similarly, and although the haplotypes differed in frequency between Black and non-Black subjects, within haplotypes there were no by-race differences in therapeutic effects. Bucindolol but not metoprolol activated ERK1/2 signaling in isolated ventricular preparations with ≥3 internalization-resistant haplotypes.
和 ,编码心肌细胞β - 和β - 肾上腺素能受体(ARs),其介导病理性心肌重塑以应对长期增加的信号传导,包含能够影响激动剂或偏向性配体诱导的受体内化的N端单倍型变体,这种内化会解偶联经典信号传导并启动EGFR/ERK1/2心脏保护作用。
在两项心力衰竭(HF)临床试验基因亚研究中,我们研究了内化型与抗内化型 / 单倍型对偏向性配体β受体阻滞剂布新洛尔与安慰剂或与非偏向性β拮抗剂美托洛尔相比的临床或生物标志物反应的影响,并且在单倍型分型的离体人心脏制剂中,我们测量了对这些相同干预措施的ERK1/2激活情况。
在具有≥3种内化型 + 单倍型的受试者(6.7%亚组)中,与具有抗内化型单倍型的受试者相比,安慰剂治疗与较少的临床事件相关(比值比(OR)0.28,95%置信区间(0.10,0.82))。相反,在具有≥3种抗内化型单倍型的受试者(70%亚组)中,与具有内化型单倍型对应物的受试者相比,安慰剂治疗与更多的临床事件相关(OR 1.64(1.46,1.84))。在≥3种内化型亚组中,布新洛尔治疗与安慰剂相当,但在抗内化型亚组中优于安慰剂(布新洛尔与安慰剂相比OR 0.49(0.41,0.58))。在所有4种单倍型均为抗内化型的受试者(25%亚组)中,布新洛尔与安慰剂相比使首次事件发生率的时间缩短了62.3±17.5%(P <0.01,比所有单倍型亲本群体高1.68±0.34倍,当 单倍型包含Arg389而非Gly389时增加至1.92±0.58倍)。在NT - proBNP或去甲肾上腺素降低方面,布新洛尔与安慰剂相比与美托洛尔相比呈现相同模式。在这些比较中, 和 单倍型表现相似,并且尽管单倍型在黑人和非黑人受试者中的频率不同,但在各单倍型内治疗效果不存在种族差异。布新洛尔而非美托洛尔在具有≥3种抗内化型单倍型的离体心室制剂中激活ERK1/2信号传导。
1)β - 和β - AR单倍型均调节HF中的治疗反应;内化型单倍型在安慰剂治疗的受试者中对临床事件具有保护作用,而在抗内化型单倍型中,偏向性配体β受体阻滞剂布新洛尔而非非偏向性配体美托洛尔具有有益作用。2)偏向性配体的心脏保护作用可能与内化依赖性或非依赖性ERK1/2激活有关。