Pathologic left ventricular hypertrophy (LVH) is a major determinant of morbidity and mortality for patients with cardiovascular disease. The molecular mechanisms responsible for the development of LVH have not been well characterized. Alterations in myocardial energy metabolism are implicated in the pathogenesis of contractile dysfunction and heart failure in both animals and humans. Peroxisome proliferator-activated receptor-alpha (PPAR-(alpha), a transcriptional regulator of myocardial fatty acid (FA) transport and beta-oxidation enzymes, is down-regulated in pathologic LVH in association with decreased myocardial FA metabolism and increased glucose utilization. Variants of the human PPAR-alpha gene likely modulate phenotypic expression of LVH and ventricular function in humans. We hypothesize that individuals with single nucleotide variations of the PPAR-alpha-gene that render this transcriptional regulator less active will display greater degrees of LVH and alterations in myocardial fatty acid metabolism. The hypothesis will be tested by the following specific aims: 1) Characterization of eight single nucleotide variations in the human PPAR-alpha gene that correlate with the presence and severity of LVH, and 2) Characterization of the phenotypic expression of G/C intron 7 polymorphism in the human PPAR-alpha gene in terms of myocardial fatty acid metabolism. As previously show in animal models of pressure-overload hypertrophy and in heart failure, we have recently demonstrated similar abnormalities in myocardial metabolism, contractile function and efficiency in patients with LVH. We have built upon our strengths in cardiac imaging and have assembled a multidisciplinary team with expertise in molecular mechanisms regulating the cardiac hypertrophic program, molecular genetics and genetic epidemiology.
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