Cardiovascular disease is the leading cause of mortality worldwide. In the U.S., one million people die annually of cardiovascular disease, five million people live with congestive heart failure, and another five million have significant asymptomatic left ventricular dysfunction soon to progress to heart failure, numbers that are predicted to rise dramatically with the progressively aging population. Current therapies for heart failure consist of pharmacologic optimization of preload and afterload together with very limited reconstructive or replacement options. The overall objective of the proposed research project is to augment native cardiomyocyte function through two interrelated molecular strategies of inducing angiogenesis and localized myocardial growth. In a rodent model of ischemic cardiomyopathy, recombinant adenoviruses will be used to provide high-level, localized gene expression of the angiogenic agent hepatocyte growth factor and the trophic agent growth hormone. Effects on myocardial function will then be assessed in vivo with an intracavitary pressure volume conductance microcatheter and an ascending aortic cardiac output monitor. Effects on ventricular remodeling will also be evaluated. Specific mechanisms of action pertaining to reversal of myocardial ischemia, anti-apoptosis, and hypercontractility will be studied in-depth. The ultimate goal will be to develop an integrated heart failure therapy which promotes native cardiomyocyte growth coupled with enhanced myocardial blood flow. The candidate seeks to utilize the time and opportunities provided by this proposed research career award to engage in a concentrated period of scholarly activity dedicated to studying basic molecular and cellular mechanisms in heart failure, to design innovative treatment strategies pertinent to clinical care, to obtain additional structured didactic education and training, to acquire new scientific knowledge and research techniques, and to develop critical skills towards becoming a competitive, independent investigator. The candidate's institution, sponsor, and chairman provide a uniquely supportive, high-caliber, educationally stimulating environment highly conducive to the achievement of these goals.
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