Recent large clinical trials have demonstrated the beneficial effects of angiotensin converting enzyme (ACE) inhibitor therapy in both symptomatic and asymptomatic heart failure patients that cannot be explained by a lowering of the blood pressure. The applicant proposes to test the hypotheses that local expression of renin- angiotensin system (RAS) components and Chymase are turned on by diastolic stretch and severity of heart failure in a dog model of volume overload hypertrophy.
Specific Aim 1 relates cardiac angiotensin II (ANGII), ACE and Chymase activity, and steady state mRNA of Chymase and RAS components to matched regional stress estimates of the left ventricle derived from a validated finite element model that is applied to magnetic resonance images and high-fidelity pressures. Because Chymase and ACE activity are increased in this model, studies using selective inhibitors will be performed to establish an etiologic relationship between increased ANGII and left ventricular remodeling.
Specific Aims 2 and 3 examine the effect of ACE inhibitor therapy and angiotensin 1 receptor (AT1) antagonists on mechanical, biochemical, and molecular indices as well as geometric changes in isolated myocytes and interstitial collagen. These results will be related to heart tissue levels and the source(s) of the ACE, Chymase, and angiotensinogen steady state mRNA levels (i.e., myocyte vs endothelial cell vs fibroblast) using the technique of in situ hybridization.
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