The Effect of Gender on Hypertrophic Cardiac Disease.

University Of Colorado At Boulder, Boulder CO

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Abstract

DESCRIPTION (the applicant?s description verbatim): Human hypertrophic cardiac disease, regardless of etiology, has been observed to have a gender specific phenotypic variation in the development of hypertrophy and progression to heart failure. Both genders appear to develop left ventricular (LV) hypertrophy initially, however, once clinical end-stage disease develops women tend to have preserved LV function and men tend to develop chamber dilation and wall thinning. In spite of these differences however mortality is equally significant in both groups. Our lab created a hypertrophic cardiomyopathy (HCM) mouse expressing a mutant myosin heavy chain transgene in a cardiac specific manner. The transgene expression causes gender specific phenotypic variation similar to that noted above in humans. Both genders initially develop similar degrees of LV hypertrophy. The male mice subsequently develop LV chamber dilation and wall thinning in contrast to the female mice, which develop progression of the LV wall thickness. I propose to evaluate the gender differences at the functional, cellular, and molecular level in this mouse model of hypertrophic cardiac disease. Prepubertal gonadectomy and hormone replacement (17b-estradiol, testosterone) will be used to test the hypothesis that sex hormones contribute to gender differences in the LV structural and functional changes associated with HCM. Cardiac morphology (heart weight, LV and right ventricular weight) will be evaluated. The functional progression of disease will be evaluated using transthoracic echocardiography and isovolumic working heart preparation to assess hemodynamics. Two dimensional protein gel electrophoresis will be performed to assess variations in protein expression, and slot blots and Affymetrix Biochip technology used to assess variations in mRNA expression. The temporal relationship of these pathophysiologic changes will be evaluated at 4, 8, and 12 months.