MYOCARDIAL FA METABOLISM GENE-GENE INTERACTIONS IN HYPERTENSIVE HEART DISEASE

Washington University, Saint Louis MO

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Abstract

DESCRIPTION (provided by applicant): Hypertensive heart disease (HHD) results from long-standing hypertension (HTN) and manifests early as left ventricular hypertrophy (LVH) and/or left ventricular diastolic dysfunction (LVDD). Although initially an adaptive response, over-time LVH and LVDD become maladaptive leading to ventricular enlargement, systolic dysfunction (LVSD), and/or dilated cardiomyopathy/heart failure. Our group and others have shown that alterations in myocardial fatty acid (FA) metabolism are important determinants of the presence and development of LVH, LVDD, and LVSD in animal models and in humans. Long-chain fatty acids (LCFA) are an essential source of energy for the heart. Although some LCFAs diffuse passively across the sarcolemma, a protein-facilitated transporter, the fatty acid translocase (FAT or CD36) confers tissue-specific expression entrained to substrate availability. The CD36-PPAR1/3-PGC11 FA metabolism regulatory pathway plays an important role in the etiology of cardiovascular diseases, especially LVH and cardiomyopathy. Thus, the hypothesis of the proposal is that genetic variations of FA metabolism pathway genes modulate the phenotypic expression of HHD in humans. This hypothesis will be tested as follows: Specific Aim 1) Identify CD36 tagSNPs associated with the presence and severity of individual HHD traits (i.e. LV mass, LV size, and indices of LV systolic and diastolic function) in a Caucasian and an African-American cohort using conventional regression analyses controlling for potential confounders;and Specific Aim 2) Investigate modifying factors of latent HHD-related phenotypes by exploring gene-gene and gene-environment interactions using innovative data-reduction methods including factor analysis and Bayesian network-based decomposable graphical models. Gene-gene interactions will be tested between CD36 and 3 regulatory pathway genes involved in FA metabolism (i.e., PPAR1, PPAR3, and PGC11). The results of this research will generate robust data in support of a subsequent submission by this new investigator of an R01 proposal to perform deep resequencing of high-risk haplotypes, to refine the analytic techniques, and to further validate the findings of the R21 pilot study. This research is designed to provide an understanding of the association between gene regulation of the cardiac hypertrophic response and the associated phenotypic changes in myocardial metabolism. Allowing better elucidation of the mechanisms that lead to the transition from HTN to HHD phenotypes and their associated morbidity may allow identification of individuals at high risk of cardiovascular morbidity and mortality and may facilitate future efforts at identifying novel therapeutic strategies in the prevention and/or treatment of HHD. PUBLIC HEALTH RELEVANCE Hypertensive heart disease, which results from long-standing hypertension and manifests early as left ventricular hypertrophy and/or left ventricular diastolic dysfunction (LVDD), is responsible for significant cardiovascular morbidity and mortality including progression to heart failure. The purpose of this research is to explore the potential role of variants in myocardial metabolism genes to modulate hypertensive heart disease traits in a biracial population by use of sophisticated techniques capable of analyzing complex genetic and phenotype data.