This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Heart failure represents a major public health problem because of its high prevalence, hospital admission rate, unfavorable outcome, and economic burden. In the failing heart, the activation of the adrenergic system has been shown by numerous studies to be deleterious to the heart in the long term. Several large randomized trials have confirmed the beneficial role of beta-blockade in improving ejection fraction and mortality in patients with congestive heart failure. However, in spite of the clear benefits of b-blockade, clinical response to beta-blocker therapy displays a high degree of inter-individual and inter-ethnic variation; only a subset of treated patients experiences measurable benefit. Underlying genetic variation in adrenergic mechanisms is one potential explanation for this variability in response. The b 1 adrenergic receptor gene is the major subtype of adrenergic receptor in the human heart and plays a critical role for maintenance of homeostasis. Certain b-1 adrenergic receptor polymorphisms have been shown to act as disease modifiers in congestive heart failure. Thus, we may hypothesize that the different inter-individual response to beta-blockers might to be due to genetic polymorphisms of the b 1-adrenergic receptor gene. To test our hypothesis we will evaluate the influence of the different b1-adrenergic receptor polymorphisms on the response of b-blockade therapy in the CHF population with underlying dilated and ischemic cardiomyopathy. If our hypothesis proves to be true, the next step will be to develop pharmacological therapies individually tailored to each subject's genetic background with the goal of maximizing therapeutic benefit to individuals, rather than across populations as is currently practiced
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