Review Article
Genetic Tailoring of Pharmacotherapy in Heart Failure: Optimize the Old, While We Wait for Something New

https://doi.org/10.1016/j.cardfail.2012.01.002Get rights and content

Abstract

Background

The combination of angiotensin-converting enzyme (ACE) inhibitors and beta-adrenergic receptor blockers remains the essential component of heart failure (HF) pharmacotherapy. However, individual patient responses to these pharmacotherapies vary widely. The variability in response cannot be explained entirely by clinical characteristics, and genetic variation may play a role. The purpose of this review is to examine our current state of understanding of beta-blocker and ACE inhibitor pharmacogenetics in HF.

Methods and Results

Beta-blocker and ACE inhibitor pharmacogenetic studies performed in patients with HF were identified from the Pubmed database from 1966 to July 2011. Thirty beta-blocker and 10 ACE inhibitor pharmacogenetic studies in patients with HF were identified. The ACE deletion variant was associated with greater survival benefit from ACE inhibitors and beta-blockers compared with the ACE insertion. Ser49 in the beta-1 adrenergic receptor, the insertion in the alpha-2C adrenergic receptor, and Gln41 in G-protein–coupled receptor kinase 5 are associated with greater survival benefit from beta-blockers, compared with Gly49, the deletion, and Leu41, respectively. However, many of these associations have not been validated.

Conclusions

The HF pharmacogenetic literature is still in its very early stages, but there are promising candidate genetic variants that may identify which HF patients are most likely to benefit from beta-blockers and ACE inhibitors and patients that may require additional therapies.

Section snippets

Methods

Beta-blocker and ACE inhibitor pharmacogenetic studies were identified in the Pubmed database from 1966 to July 2011 by combining the following search terms: heart failure, variant, polymorphism, pharmacogenetics, pharmacogenomics, beta-blocker, ACE inhibitor, and each individual drug name. Studies were also identified from the reference lists of articles. Studies were limited to those performed in patients with HF and those published in English.

Beta-Blockers

Thirty beta-blocker pharmacogenetic studies in patients with HF have been published from 2000 to 2011, and the genetic variants studied for an association with (FDA-approved) beta-blocker response in HF patients are summarized in Table 1. These studies are heterogeneous in many aspects: design, sample size, end point, HF patient population, specific beta-blockers, and genetic variants tested. The study designs include retrospective and prospective nonrandomized cohorts, pharmacogenetic

Discussion

The first report of a pharmacogenetic interaction in HF patients was published 13 years ago.59 Since then, the work of Liggett et al concerning the investigational drug bucindolol provides the best evidence yet to support that genetic variation can be associated with differential response to HF pharmacotherapy, which can in turn affect the risk of adverse outcomes. Unfortunately, the literature as a whole does not provide sufficient evidence to guide application of available HF drug therapy

Disclosures

None.

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    Funding: J.A.T. is supported by a predoctoral fellowship from the American Foundation for Pharmaceutical Education.

    See page 346 for disclosure information.

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