Adrenergic receptor (AR) function is critical for homeostasis in heart failure. Presynaptic alpha-2-AR control norepinephrine release from sympathetic nerves, while beta-1-and beta-2-AR expressed on cardiomyocytes increase inotropy and chronotropy. However, the expression and function of ARs, clinical progression, and response to beta-blockers is highly variable in heart failure, and the basis of this interindividual variability remains unknown. A role for common genetic variants in susceptibility, progression and therapeutic response is suggested by familial clustering of phenotypes, reduced penetrance in familial cardiomyopathies, and the existence of functionally significant polymorphisms of the three alpha2AR and two betaAR subtypes. The overall goal of this project is to define the relationships between AR polymorphisms and heart failure phenotypes, and to determine the mechanism by which they affect heart failure in the intact human, which will lead to personalized prognosis and treatment, based on receptor genotype.
In Aim 1 we will complete polymorphism discovery in these intronless genes, assemble haplotypes and carry out in vitro studies to assess the consequences of genetic variation on receptor expression, function or regulation.
In Aim 2, we will carry out an association and sibling study of 2-gene haplotypes of the alpha2c and beta1AR to ascertain heart failure risk. In an initial study of individual alpha2c and beta1AR polymorphisms, we found a 10-fold risk for heart failure in African-Americans. The use of extended haplotypes will potentially provide greater discrimination and precisely define the gene-gene and gene-environment interactions.
In Aim 3 the functional status of cardiac beta1AR in patients with early and late failure in the absence of beta-blocker treatment, stratified by homozygous beta1AR haplotypes, will be ascertained. From transgenic mice, we have found that polymorphic beta1AR undergo phenotypic switching during the course of failure, which implies that there are """"""""windows"""""""" of opportunity for therapeutic intervention. Studies will involve invasive hemodynamic testing of cardiac function in response to the beta1AR agonist dobutamine, the nonreceptor inotrope milrinone, and exercise. In retrospective studies we have shown that a beta1AR polymorphism may be associated with treatment response to beta-blocker. To further examine this, in Aim 4 we will carry out a prospective, double-blind, long-term, study of patients with homozygous beta1AR haplotypes to ascertain the effect of beta1AR genetic variability on carvedilol response. If the relationship holds, this would be the first pharmacogenetic test to predict who will be most likely to respond, and not respond, to this class of therapeutics.
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