Haplotype Targeting in Heart Failure Using a Biased Ligand β-blocker

ADRB1 and ADRB2, encoding β1- and β 2-adrenergic receptors (ARs), each contain 2-SNP 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 substudies we investigated effects of internalizing vs. internalization-resistant βDRB1/ADRB2 haplotypes on clinical responses to the biased ligand β-blocker bucindolol vs. placebo or the nonbiased β1-antagonist metoprolol. ERK1/2 activation was also measured, in haplotyped isolated human heart preparations. In subjects with ≥3 internalizing ADRB1+ADRB2 haplotypes (18% subcohort) placebo treatment was associated with fewer clinical events compared to internalization-resistant counterparts (Odds Ratio (OR) 0.39, 95% CI (0.27,0.55)). Bucindolol vs. placebo lowered event rates in subjects with ≥3 (70% subcohort) internalization-resistant haplotypes vs. their counterparts, 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 < all-haplotypes parent population and additive to 1.92 ±0.58 fold when ADRB1 contained Arg389). The same bucindolol vs. placebo pattern was observed for NT-proBNP reduction vs. metoprolol. Bucindolol but not metoprolol activated ERK1/2 signaling in isolated ventricular preparations with ≥3 internalization-resistant haplotypes. Haplotype targeting, long a goal in pharmacogenetics, is feasible in HF.