Association of beta-adrenergic receptor polymorphisms and mortality in carvedilol-treated chronic heart-failure patients.

Laboratory of Clinical Pharmacology Q7642, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.
British Journal of Clinical Pharmacology (Impact Factor: 3.69). 04/2011; 71(4):556-65. DOI: 10.1111/j.1365-2125.2010.03868.x
Source: PubMed

ABSTRACT Pharmacogenetics can be used as a tool for stratified pharmacological therapy in cardiovascular medicine. We investigated whether a predefined combination of the Arg389Gly polymorphism in the adrenergic β(1) -receptor gene (ADRB1) and the Gln27Glu polymorphism in the adrenergic β(2) -receptor gene (ADRB2) could predict survival in carvedilol- and metoprolol-treated chronic heart failure (HF) patients.
Five hundred and eighty-six HF patients (carvedilol n= 82, metoprolol n= 195) were genotyped for ADRB1 Arg389Gly (rs1801253) and ADRB2 Gln27Glu (rs1042714). The end-point was all-cause mortality, and median follow-up time was 6.7 years. Patients were classified into two functional genotype groups: group 1 combination of Arg389-homozygous and Gln27-carrier (46%) and group 2 any other genotype combination (54%). Results were fitted in two multivariate Cox models.
There was a significant interaction between functional genotype group and carvedilol treatment (adjusted(1) P= 0.033, adjusted(2) P= 0.040). Patients treated with carvedilol had shorter survival in functional genotype group 1 (P= 0.004; adjusted(1) hazard ratio (HR) 2.67, 95% CI 1.27, 5.59, P= 0.010; adjusted(2) HR 2.05, 95% CI 1.06, 3.95, P= 0.033). There was no interaction between genotype group and metoprolol treatment (P= 0.61), and there was no difference in overall survival between genotype groups (P= 0.69).
A combination of ADRB1 Arg389-homozygous and ADRB2 Gln27-carrier in HF patients treated with carvedilol was associated with a two-fold increase in mortality relative to all other genotype combinations. There was no difference in survival in metoprolol-treated HF patients between genotype groups. Patients in genotype group 1 may benefit more from metoprolol than carvedilol treatment.

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    ABSTRACT: Background: β1-adrenergic receptor blockers are an important drugs recommended as first-line treatment of Heart Failure (HF) as they improve survival in left ventricular systolic dysfunction due to chronic β1-Adrenergic Receptor (β1-AR) activation. However, responses to these drugs are variable among patients due to genetic polymorphism in β1-AR gene. We conducted a systematic review to summarize all published case-control and prospective studies on pharmacogenetics of β1-adrenergic receptor blockers (β1-ARBs) used for the management of HF. Methods and findings: We performed a systematic search of the literature using Medline (source PubMed, January 1, 1980 to November 30, 2011) with restrictions for English language and polymerase chain reaction assay method of genotyping the receptor polymorphism. Both experimental and observational studies investigating the pharmacogenetics effect of β1-adrenergic receptor blockers in heart failure were included. The main outcome measure was improvement of HF symptoms which is reflected in a decrease in mortality, hospitalisation and the rate of major clinical events. Of the 30 included studies, 17 articles reporting on effect of genetic polymorphisms of β1-AR on heart failure, 11 articles reporting on pharmacogenetics of β1-ARBs in HF, and 2 articles reporting on both β1-AR gene polymorphisms and pharmacogenetics of β1-ARBs, were included into the results. Conclusions: The findings of the current study have shown that β1-AR polymorphisms have an effect on survival and improvement in left ventricular ejection fraction in HF patients who were Arg389 homozygotes carriers treated with metoprolol and bucindolol. Therefore, the Arg389 of β1-AR variation alters the β1-ARBs therapeutic response, and might be used to individualize treatment of HF.
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    ABSTRACT: Heart failure is becoming increasingly prevalent in the United States and is a significant cause of morbidity and mortality. Several therapies are currently available to treat this chronic illness; however, clinical response to these treatment options exhibit significant interpatient variation. It is now clearly understood that genetics is a key contributor to diversity in therapeutic response, and evidence that genetic polymorphisms alter the pharmacokinetics, pharmacodynamics, and clinical response of heart failure drugs continues to accumulate. This suggests that pharmacogenomics has the potential to help clinicians improve the management of heart failure by choosing the safest and most effective medications and doses. Unfortunately, despite much supportive data, pharmacogenetic optimization of heart failure treatment regimens is not yet a reality. In order to attenuate the rising burden of heart failure, particularly in the context of the recent paucity of new effective interventions, there is an urgent need to extend pharmacogenetic knowledge and leverage these associations in order to enhance the effectiveness of existing heart failure therapies. This review focuses on the current state of pharmacogenomics in heart failure and provides a glimpse of the aforementioned future needs.

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