In response to altered hemodynamic loading, the heart will induce hypertrophic remodeling of the myocardium and extracellular matrix (ECM).{09}The primary constituent of the ECM is the ubiquitous protein collagen. However, collagen crosslinks also reinforce the ECM and appear to help regulate vascular and myocardial tissue properties. Diastolic tissue properties play an important role in heart failure, especially in diastolic dysfunction that is characterized by abnormal filling, improper relaxation, or decreased myocardial compliance.; We tested the hypothesis that enhanced collagen crosslinking contributes to increased myocardial stiffness in volume overload hypertrophy. We examined this hypothesis by disrupting crosslinks with the administration of three different drugs in experimental rats. Chronic volume overload developed in rats after the surgical creation of an abdominal arteriovenous fistula. We measured diastolic cardiac mechanics via passive inflation experiments, in vivo hemodynamics, and myocardial collagen content.; Chapter 1 of the dissertation provides the introduction, background information, and the main objectives of the research. In Chapter 2, we examined the influence of enzymatic collagen crosslinks on cardiac mechanics by inhibiting new hydroxylysyl pyridinoline (HP) crosslinks with the drug β-aminopropionitrile. Next, we studied the structural role of advanced glycation endproduct (AGE) crosslinks on myocardial properties. Chapter 3 describes how we administered the drug aminoguanidine, which inhibits AGE formation, to rats during the chronic development of volume overload. In Chapter 4, we further investigated the structural role of AGE crosslinking by administering a drug called ALT-1016 that cleaves pre-existing AGE collagen crosslinks after rats developed hypertrophy. Chapter 5 provides a summary of the research and conclusions of the dissertation.; In summary, these studies examined different structures of collagen crosslinking and their role in determining myocardial properties in volume overload hypertrophy. We found that volume overload increased myocardial stiffness without modifying collagen concentration, and was characterized by regional collagen crosslink remodeling. The results of the intervention studies suggest that the upregulation of AGE collagen crosslinking, but not enzymatic HP crosslinking, contributed to increased myocardial stiffness. These studies provide important information regarding hypertrophy material properties due to the importance of myocardial compliance associated with heart failure and diastolic dysfunction.
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