Dose Response of β-Blockers in Adrenergic Receptor Polymorphism Genotypes.

Area of Science:

• Pharmacogenomics
• Cardiovascular Medicine
• Clinical Trials

Background:

• Heart failure with reduced ejection fraction (HFrEF) treatment may be influenced by genetic variations.
• Previous trials suggested interactions between beta-blockers (BBs) and the ADRB1 Arg389Gly polymorphism, with unclear dose-dependent effects.

Purpose of the Study:

• To investigate the interaction between BB dose, ADRB1 Arg389Gly polymorphism, and clinical outcomes in HFrEF.
• To determine if pharmacogenetic findings can optimize HFrEF precision therapy.

Main Methods:

• Retrospective analysis of DNA substudies from the BEST and HF-ACTION trials.
• Genotyping for ADRB1 Arg389Gly and ADRA2C Ins322-325Del polymorphisms.
• Standardized BB dose categorization (no/low vs. high) using carvedilol equivalents.

Main Results:

• High-dose BBs reduced all-cause mortality in ADRB1 Arg389Arg genotype patients in both trials.
• High-dose bucindolol showed a 46% greater benefit in Arg389Arg vs. Gly carrier genotypes.
• Low-dose BBs in HF-ACTION showed increased mortality in Arg389Arg vs. Gly carriers, with no difference at high doses.

Conclusions:

• Enhanced efficacy of bucindolol in HFrEF for ADRB1 Arg389Arg genotype is observed at high doses.
• Low-dose BBs may have reduced efficacy in Arg389Arg genotype patients compared to Gly carriers.
• High, guideline-recommended doses of BBs are crucial for optimizing HFrEF treatment across genotypes.