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

Cardiomyopathies are often initiated by diastolic dysfunction, and treatment of diastolic dysfunction remains empirical with an emphasis on prevention. This dissertation focuses on the mechanism of cardiomyopathy and diastolic dysfunction during aging and immune dysfunction. The governing hypothesis is that altered cytokine release such as that seen during aging and immune dysfunction can lead to diastolic dysfunction and myocardial fibrosis. Our first study examined the role of aging and immunosenescence on the cardiac extracellular matrix (ECM) 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, partially reversed these pathologies in aged mice. In this model, fibrosis and its reversal were associated with altered regulation of matrix metalloproteinases (MMP) and collagen cross-linking. We propose 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, we found that DHEA is capable of directly altering cardiac fibroblasts, suggesting a mechanism for the effects of DHEA on cardiac function. Due to pleiotropic effects of DHEA, we decided to specifically target the immune system using T-cell receptor peptides during murine AIDS(mAIDS). Mice with mAIDS suffer from cardiomyopathy in the absence of myocarditis and opportunistic pathogens. We demonstrated that reversal of immune dysfunction in mAIDS 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. 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.