• Cardiac Failure
• Cardiomyopathies
• Gene Therapy
• Gene Expression
• Molecular Biology
• Transgenic Mice

Our cardiovascular research group is focused on the molecular mechanisms of cardiac hypertrophy and failure. We are using a variety of approaches including isolated cardiac myocytes, transgenic models of hypertrophic cardiomyopathy and explanted human hearts and b myosin heavy chain gene expression in heart failure. The normal human heart expresses two distinct isoforms of myosin heavy chain (MyHC), a and b , and their relative expression levels have a profound effect on cardiac contractility and heart function. In human heart failure, b -MyHC mRNA drops from 30% of total MyHC mRNA to 2%, while protein levels decrease from 7-10% to undetectable levels. We are probing the role of transcriptional and post-transcriptional regulation in these isoform changes. We have identified what apears to be a novel transcription factor that is elevated in heart failure which appears to repress expression of a MyHC.

• The role of the adrenergic system in the development of cardiomyopathy

The medical treatment of chronic heart failure has undergone a dramatic transition in the past decade. Short-term approaches for altering hemodynamics have given way to long-term, reparative strategies, including b -adrenergic receptor blockade. Cardiac myocytes from failing hearts show changes in b -adrenergic receptor signaling and excitation-contraction coupling that can impair cardiac contractility, but the role of these abnormalities in the progression of heart failure is controversial. We therefore tested the impact of different manipulations which increase contractility on the progression of cardiac dysfunction in a mouse model of hypertrophic cardiomyopathy. Three manipulations of cardiac contractility had distinct effects on disease progression, suggesting that selective modulation of particular aspects of b -adrenergic receptor signaling or excitation-contraction coupling can provide therapeutic benefit.

• Sex hormones influence the phenotype of hypertrophic cardiomyopathy in a transgenic mouse model

Human hypertrophic cardiac disease has been observed to have a sex specific phenotypic variation in the development of hypertrophy and progression to heart failure. Both sexes develop left ventricular (LV) hypertrophy initially, however, later, women tend to have preserved LV function and men tend to develop chamber dilation and wall thinning. Our lab created a hypertrophic cardiomyopathy (HCM) mouse expressing a mutant myosin heavy chain transgene in a cardiac specific manner. Transgene expression causes sex specific phenotypic variation similar to that noted above in humans. Both sexes 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 continue the progression of LV wall thickness. We are testing the hypothesis that sex hormones contribute to gender differences in the LV structural and functional changes associated with HCM.

• TnT hypertrophic cardiomyopathy transgenic mice

We have made several mouse models of hypertrophic cardiomyopathy (HCM) due to cardiac expression of mutant TroponinT transgenes. All lines of mice exhibit significant decreases in ventricular mass, leading to the hypothesis that hypertrophic pathways may be blocked in these mice. To determine whether these hearts can respond to a physiologic hypertrophic stimulus, we exercised mice. All the mutant TnT mice achieved running distances and times similar to non-transgenic mice again with a gender difference in that female mice exercised more. The transgenic mice also developed a physiologic hypertrophy with a significant increase in heart weight of about 15%. Furthermore the pathologic marker b myosin heavy chain that is increased in transgenic mice was reduced to wild-type levels with 3 weeks of endurance exercise suggesting a beneficial effect on this mouse model.

• Tardiff JC, Factor SM, Tompkins BD, Hewett TE, Palmer BM Moore RL, Robbins J, and Leinwand LA (1998) A truncated cardiac troponin T molecule in transgenic mice suggests a cellular phenotype for familial hypertrophic cardiomyopathy. J. Clin. Invest. 101:2800-2811.

• Tardiff J, Hewett T, Palmer B, Olsson M, Factor S, Moore R, Robbins J, and Leinwand LA (1999) Cardiac troponin T mutations result in allele-specific phenotypes in a mouse model for hypertrophic cardiomyopathy. J. Clin. Invest. 104:469-481.

• Miyata SM, Minobe W, Bristow MR, and Leinwand LA (2000) Myosin heavy chain isoform expression in the failing and non-failing human heart. Circ. Res. 86:386-390.

• Freeman K, Colon-Rivera C, Olsson MC, Moore RL, Weinberger HD, Grupp IL, Vikstrom KL, Iaccarino G, Koch WJ, and Leinwand LA (2001) Progression from hypertrophic to dilated cardiomyopathy in transgenic mice that express a mutant myosin. Am. J. Physiol. (280:H151-159).

• Freeman K, Lerman I, Kranias EG, Bohlmeyer T, Bristow MR, Lefkowitz RJ, Iaccarino G, Koch WJ, and Leinwand LA. (2001) Manipulations of cardiac adrenergic signaling and calcium cycling have markedly different effects on the progression of cardiomyopathy. J Clin. Invest. 107:967-974.

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