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EXPEDITED PUBLICATION

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

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

^_* CardioDx, Inc., Palo Alto, California
Departments of Cardiology and Cardiovascular Research, Intermountain Medical Center, University of Utah, Salt Lake City, Utah
Department of Medicine and Cardiology, Duke University Medical Center, Durham, North Carolina
Departments of Medicine and Physiology, University of Maryland School of Medicine, Baltimore, Maryland

Manuscript received February 7, 2008; revised manuscript received April 29, 2008, accepted May 5, 2008.

^_* Reprint requests and correspondence: Dr. Amy J. Sehnert, CardioDx, Inc., 2500 Faber Place, Palo Alto, California 94303 (Email: asehnert{at}cardiodx.com).

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 beta-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 beta-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 • beta-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

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