Lack of Association Between Adrenergic Receptor Genotypes and Survival in Heart Failure Patients Treated With Carvedilol or Metoprolol

Lack of Association Between Adrenergic Receptor Genotypes and Survival in Heart Failure Patients Treated With Carvedilol or Metoprolol

Amy J. Sehnert, Susan E. Daniels, Michael Elashoff, James A. Wingrove, Christopher R. Burrow, Benjamin Horne, Joseph B. Muhlestein, Mark Donahue, Stephen B. Liggett, Jeffrey L. Anderson, William E. Kraus

Discordant results exist for genetic associations between adrenergic receptor alleles and end points of β-blocker response. We studied the role of adrenergic receptor genetics on transplant-free survival in 637 patients with heart failure from 2 U.S. cardiovascular genetic registries. The patients were discharged on contemporary pharmacotherapy including β-blockers (metoprolol or carvedilol). Although multivariable analysis showed a significant effect of 4 clinical factors on survival, no significant effect of genotypes or haplotypes in ADRB1, ADRB2, and ADRA2C was observed. These results do not currently support clinical use of adrenergic receptor genotypes to individualize metoprolol or carvedilol therapy to improve survival in heart failure patients.

Objectives

This study investigated the role of adrenergic receptor genetics on transplant-free survival in heart failure (HF).

Background

Discordant results exist for genetic associations between adrenergic receptor alleles and end points of β-blocker response in HF patients.

Methods

We identified 637 patients enrolled in 2 U.S. cardiovascular genetic registries with HF and left ventricular systolic dysfunction who were discharged on β-blocker, angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB), and diuretic medications. End points were determined through the national Social Security Death Master File and transplant records. We genotyped 5 polymorphisms in 3 genes: ADRB1 (S49G, R389G), ADRB2 (G16R, Q27E), and ADRA2C (Del322-325) using 5′ nuclease assays and performed a multivariable clinical-genetic analysis.

Results

A total of 190 events (29.8%) occurred over a median follow-up of 1,070 days. Multivariable analysis showed a significant effect of 4 clinical factors on survival: age (p = 0.006), gender (p = 0.005), ejection fraction (p = 0.0002), and hemoglobin (p = 0.00010). There was no significant effect of the polymorphisms or haplotypes analyzed on survival.

Conclusions

Genotypes and haplotypes of ADRB1, ADRB2, and ADRA2C did not significantly affect survival in metoprolol-treated or carvedilol-treated HF patients in this study. These results complement the findings of 2 similarly designed previous studies, but do not replicate an association of ADRB2 haplotypes and survival. All 3 studies differ from a survival benefit reported for bucindolol-treated homozygous ADRB1 R389 individuals. This may be attributable to a drug-specific interaction between genotype and outcome with bucindolol that does not seem to occur with metoprolol or carvedilol.

Key Words: heart failure, genetics, adrenergic receptors, β-blockers, haplotypes

Abbreviations and Acronyms: ACEI, angiotensin-converting enzyme inhibitor, AR, adrenergic receptor, ARB, angiotensin II receptor blocker, CI, confidence interval, EF, ejection fraction, HF, heart failure, HR, hazard ratio, ICD, implantable cardioverter-defibrillator, LV, left ventricle/ventricular, LVEF, left ventricular ejection fraction, NYHA, New York Heart Association, SNP, single-nucleotide polymorphism