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Progress toward genetic tailoring of heart failure therapy.

ABSTRACT: Heart failure (HF) is a modern epidemic and a heterogeneous disorder with many therapeutic options. While the average response to each individual treatment is favorable, significant interindividual variation exists in the response to HF therapeutics. As a result, the optimal regimen for an individual patient or subgroup of patients is elusive, with current treatment being mainly empirical. Pharmacogenetic customization of HF therapy may provide an important opportunity to improve the treatment of HF. Common genetic variations exist in genes related to most classes of HF drugs, many of which have known functional consequences for or established relationships with drug response. This review summarizes the current understanding of the pharmacogenetics of HF therapeutics, including angiotensin-converting enzyme inhibitors and beta-blockers, and focuses on recent advances and medium-term expectations for the field.

SUBMITTER: Lillvis JH

PROVIDER: S-EPMC3048822 | biostudies-literature | 2010 Jun

REPOSITORIES: biostudies-literature

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Progress toward genetic tailoring of heart failure therapy.

Lillvis John H JH Lanfear David E DE

Current opinion in molecular therapeutics 20100601 3

Heart failure (HF) is a modern epidemic and a heterogeneous disorder with many therapeutic options. While the average response to each individual treatment is favorable, significant interindividual variation exists in the response to HF therapeutics. As a result, the optimal regimen for an individual patient or subgroup of patients is elusive, with current treatment being mainly empirical. Pharmacogenetic customization of HF therapy may provide an important opportunity to improve the treatment o ...[more]

PMID: 20521218

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Project description:Pathogenic causes underlying nonischemic cardiomyopathies are increasingly being resolved, yet repair therapies for these commonly heritable forms of heart failure are lacking. A case in point is human dilated cardiomyopathy 10 (CMD10; Online Mendelian Inheritance in Man #608569), a progressive organ dysfunction syndrome refractory to conventional therapies and linked to mutations in cardiac ATP-sensitive K(+) (K(ATP)) channel subunits. Embryonic stem cell therapy demonstrates benefit in ischemic heart disease, but the reparative capacity of this allogeneic regenerative cell source has not been tested in inherited cardiomyopathy. Here, in a Kir6.2-knockout model lacking functional K(ATP) channels, we recapitulated under the imposed stress of pressure overload the gene-environment substrate of CMD10. Salient features of the human malignant heart failure phenotype were reproduced, including compromised contractility, ventricular dilatation, and poor survival. Embryonic stem cells were delivered through the epicardial route into the left ventricular wall of cardiomyopathic stressed Kir6.2-null mutants. At 1 month of therapy, transplantation of 200,000 cells per heart achieved teratoma-free reversal of systolic dysfunction and electrical synchronization and halted maladaptive remodeling, thereby preventing end-stage organ failure. Tracked using the lacZ reporter transgene, stem cells engrafted into host heart. Beyond formation of cardiac tissue positive for Kir6.2, transplantation induced cell cycle activation and halved fibrotic zones, normalizing sarcomeric and gap junction organization within remuscularized hearts. Improved systemic function induced by stem cell therapy translated into increased stamina, absence of anasarca, and benefit to overall survivorship. Embryonic stem cells thus achieve functional repair in nonischemic genetic cardiomyopathy, expanding indications to the therapy of heritable heart failure. Disclosure of potential conflicts of interest is found at the end of this article.

Dataset Information

Progress toward genetic tailoring of heart failure therapy.

Publications

Progress toward genetic tailoring of heart failure therapy.

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