Heart failure
Relation of β2-Adrenoceptor Haplotype to Risk of Death and Heart Transplantation in Patients With Heart Failure

https://doi.org/10.1016/j.amjcard.2006.08.020Get rights and content

Heart failure (HF) is characterized by neurohormonal activation of the sympathetic nervous and renin-angiotensin systems. Genetic polymorphisms in these systems could alter the prognosis in HF. We hypothesized the genetic polymorphisms in the sympathetic nervous and renin-angiotensin systems are associated with adverse outcomes, defined as death or heart transplantation in patients with HF. A total of 227 patients with HF were enrolled from a tertiary care clinic and followed for outcomes for ≤4 years. Eight polymorphisms in 6 genes were genotyped: β1-adrenergic receptor (ADRB1, S49G, R389G), β2-adrenergic receptor (ADRB2, G16R, Q27E), α2c-adrenergic receptor (ADRA2C, insertion/deletion 322-325), angiotensinogen (AGT, M235T), angiotensin receptor type 1 (AGTR1, 1166A>C), and angiotensin-converting enzyme (ACE, insertion/deletion in intron 16). Most patients were treated according to consensus guidelines. Male gender (hazard ratio 2.24, 95% confidence interval 1.27 to 3.94), higher New York Heart Association functional class (hazard ratio 2.54, 95% confidence interval 1.84 to 3.52), and 2 copies of ADRB2 Arg16Gln27 haplotype (hazard ratio 1.91, 95% confidence interval 1.09 to 3.36) increased the risk of adverse outcomes. In contrast, a higher serum sodium level (hazard ratio 0.91, 95% confidence interval 0.86 to 0.97) and higher creatinine clearance (hazard ratio 0.99, 95% confidence interval 0.98 to 0.99) decreased the risk of adverse outcomes. None of the other genotypes/haplotypes were associated with adverse outcomes. In conclusion, ADRB2 Arg16Gln27 haplotype may significantly increase the risk of adverse outcomes in patients with HF receiving contemporary HF pharmacotherapy.

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Patients

Patients ≥18 years with a diagnosis of HF were recruited from Shands Hospital at the University of Florida from May 2000 to August 2002. No screening procedure was required to participate in the study. The patients were followed until February 15, 2005. The exclusion criteria included previous heart transplantation and any condition other than HF that could limit survival, such as cancer or terminal illness with a life expectancy of <6 months. The institutional review board approved the study,

Baseline characteristics

All patients who agreed to participate (n = 247) did participate in this study. Of the 247 patients, 227 had complete genetic and clinical data (Table 2). Other than a significantly lower New York Heart Association functional class (p = 0.02), those with incomplete data were not different from those included in the analysis when compared using the data available. Baseline drug therapy showed high use rates of the drugs that reduce the adverse outcomes in patients with HF. Specifically, 95% of

Discussion

The data from our study suggest that the ADRB2 RQ haplotype may increase the risk of death or heart transplantation in patients with HF. Specifically, possession of 2 copies of the ADRB2 RQ haplotype was associated with an approximately 90% increase in the risk of death or heart transplantation. This effect was seen after adjustment for nongenetic risk factors, including male gender, etiology, New York Heart Association functional class, left ventricular ejection fraction, serum sodium levels,

Acknowledgment

We thank Tara Andrisin and Lindy Taylor for their recruitment assistance and Robert Rantinella, Melanie Potvin, and Amanda Hudson for their genotyping assistance.

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    This study was supported by Grant HL68834 from the National Institutes of Health, Bethesda, Maryland, and by Postdoctoral Fellowship Grant 0525474B from the American Heart Association, St. Petersburg, Florida.

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