Beta 1 and alpha 2c adrenergic receptor polymorphisms and response to beta blockers in heart failure patients

Heart Failure (HF) represents a major public health problem because of its high prevalence, unfavorable outcome, and economic burden. In HF, activation of the adrenergic system has been shown by numerous studies to be deleterious to the heart in the long term. Several large randomized trials have confirmed the beneficial role of beta-blockade in improving left ventricular ejection fraction (LVEF) and mortality in HF patients. However, in spite of the clear benefits of beta-blockade, clinical response to beta-blocker therapy displays a high degree on interindividual and inter-ethnic variation. Underlying genetic variation in adrenergic mechanisms is one potential explanation for this variability in response. The beta1 and alpha2c adrenergic receptors (ARs) play a critical role for maintenance of homeostasis in the human heart. Certain beta1 (specifically at amino acid position 49 and 389) and alpha2c(deletion 322-325) AR polymorphisms have been shown to act as disease modifiers in HF. Thus, we hypothesized that the different interindividual response to beta-blockers might be due to genetic polymorphisms of the beta1 and alpha2c AR genes.; 600 patients with LVEF≤40% from any etiology were selected from the HF Clinic at the University of Colorado Hospital and correlation between the different beta1 and alpha2c-AR polymorphisms and LVEF response to beta-blockade therapy was evaluated.; We demonstrated in this retrospective study: (1) A significant association between beta1 AR genotype and the magnitude of improvement in LVEF in patients with HF when treated with beta-blockers. In other words, beta 1 AR polymorphisms are predictive of improvement in LVEF in patients who otherwise present with similar clinical features, including LVEF and similar beta-blocker usage. Specifically subjects that were Arginine389 homozygous and/or Glycine49 had a greater LVEF improvement compared with Glycine389 carriers and/or Serine49 carriers. (2) A strong correlation between the different beta1-AR haplotypes (based on codon 49 and 389 polymorphisms) and the difference in the LVEF improvement when treated with beta-blockers. (3) The combination of the beta1 Arginine389 homozygous and alpha 2cDeletion322-325 demonstrated a significant change in LVEF on beta-blockers compared to beta1 Glycine389 carrier and alpha2cwild-type.; In conclusion, in HF these different beta1 and alpha 2c AR polymorphisms are important predictor of LVEF improvement with beta-blockers.