? Five million Americans suffer from congestive heart failure (CHF). Despite 30 years of advances in revascularization techniques coronary disease still accounts for 70% of all cases of CHF. Once the diagnosis is made the 5-year mortality is 50%, regardless of treatment. We hypothesize that following acute myocardial infarction, infarct expansion occurs, which stretches adjacent perfused myocardium. This stretching induces reactive oxygen species (ROS) mediated myocyte apoptosis, which results in progressive non-ischemic myopathic process that recruits additional contiguous, fully perfused, remodeled myocardium to cause dilated cardiomyopathy, CHF and death. This project uses sonomicrometry array localization (SAL) to study a sheep model of post infarction left ventricular (LV) remodeling. SAL quantifies changes in regional myocardial strains and contractility during serial 12 week studies. Previously, we showed that myocardial wall strain and dysfunction increases progressively in this ovine model of remodeled myocardium. We now expect to show that this progressive myocardial dysfunction is the result strain induced ROS mediated myocyte apoptosis and that the process is relentlessly self-perpetuating. To quantify ROS activity, we will measure regional myocardial concentrations of ROS-catalyzed arachidonic acid products along with oxidative carbonylation and nitration of myocardial proteins. Regional myocyte apoptosis will be quantified using both nuclear and cytoplasmic measures.
In specific aim 2 we restrain infarct expansion, which prevents progressive LV dilation in this model. We expect that infarct restraint will arrest ROS production and myocyte apoptosis and prevent further extension of remodeled myocardium. These studies address the pathogenesis of post infarction LV remodeling and if our hypothesis is correct, provide the foundation for new therapy designed to prevent the self-perpetuating, myopathic process that causes post infarction CHF and death. ? ?
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| Ifkovits, Jamie L; Tous, Elena; Minakawa, Masahito et al. (2010) Injectable hydrogel properties influence infarct expansion and extent of postinfarction left ventricular remodeling in an ovine model. Proc Natl Acad Sci U S A 107:11507-12 |
| Herdrich, Benjamin J; Gorman, Robert C (2010) Progenitor Cells for the Treatment of Acute Myocardial Infarction. Adv Skin Wound Care 1:519-525 |
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| Matsuzaki, Kanji; Morita, Masato; Hamamoto, Hirotsugu et al. (2010) Elimination of ischemic mitral regurgitation does not alter long-term left ventricular remodeling in the ovine model. Ann Thorac Surg 90:788-94 |
| Matsubara, Muneaki; Ranji, Mahsa; Leshnower, Bradley G et al. (2010) In vivo fluorometric assessment of cyclosporine on mitochondrial function during myocardial ischemia and reperfusion. Ann Thorac Surg 89:1532-7 |
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