Effects of Age and Immune Dysfunction on the Cardiac Extracellular Matrix and Diastolic Function

by Alwardt, Cory M.

Cardiomyopathy is defined as CVD affecting the gross structure of the myocardium and represents a significant portion of CVD. Cardiomyopathies are often initiated by diastolic dysfunction which can be fatal, even in the absence of systolic dysfunction. Currently, treatment of diastolic dysfunction remains empirical with an emphasis on prevention. This dissertation is focused on the mechanism of cardiomyopathy and diastolic dysfunction during aging and immune dysfunction. The governing hypothesis of this dissertation is that altered cytokine release such as that seen during aging and immune dysfunction is capable of causing diastolic dysfunction in the form of fibrosis and left ventricular stiffness. We hypothesized that reversal of immune dysfunction is a potential therapeutic mechanism to reverse diastolic dysfunction. Our first study examined the role of aging and immunosenescence on the cardiac extracellular matrix and left ventricular stiffness. We demonstrated age-related immune dysfunction, myocardial fibrosis, and diastolic dysfunction. We also found that exogenous dehydroepiandrosterone (DHEA), an adrenal steroid hormone popular due to its anti-aging effects, at least partially reversed each of these pathologies in aged mice. In this model, fibrosis and its reversal were strongly associated with alterated regulation of matrix metalloproteinases and collagen cross-linking. We proposed two mechanisms for the protective effects of DHEA: (1) a direct effect on cardiac fibroblasts, or (2) downstream effects of immune modulation. In the subsequent study on the effects of DHEA, we found that DHEA is capable of 11 directly altering cardiac fibroblast function, suggesting a mechanism for the effects of DHEA on cardiac function in vivo. Interestingly, we also demonstrated age-related functional changes in cardiac fibrolasts. Due to pleiotropic effects of DHEA, we then decided to specifically target the immune system using novel T- cell receptor peptides during murine AIDS (mAIDS). Mice with mAIDS suffer from cardiomyopathy in the absence of myocarditis and opportunistic pathogens. Further, these mice have dramatic immune dysfunction that can be reversed with these T-cell receptor peptides. We demonstrated that reversal of immune dysfunction in mAIDS mice was associated with reversal of myocardial fibrosis and ventricular stiffness. In conclusion, we have demonstrated age- and immune-related diastolic dysfunction that can be reversed by modulation of the T-cells of the immune system. We feel that immune modulation should be further investigated as a therapeutic target to treat diastolic dysfunction during immune dysfunction. We also found that MMPs and collagen cross-linking are highly involved in extracellular matrix regulation in the models used in this dissertation. Key words: diastolic function, cardiomyopathy, aging, immune dysfunction, extracellular matrix, fibrosis