Surgery to Prevent Postinfarction Ventricular Remodeling

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DESCRIPTION (Verbatim from Applicant's Abstract): The most common causes of chronic congestive heart failure relate to remodeling that occurs after myocardial infarctions. This remodeling process can lead to ischemic mitral regurgitation (MR), ischemic cardiomyopathy, and/or left ventricular (LV) aneurysm formation. The focus of this proposal, by a new young investigator, is to test the hypothesis that increased regional wall stress and changes in the material properties of the infarcted border zone drive the remodeling process. The first Specific Aim is to determine the changes in mitral valve geometry and border zone expansion that occurs after ventricular remodeling in three different infarct sheep models. The second Specific Aim is designed to evaluate different interventions that may prevent the heart failure that occurs as a result of ventricular remodeling. The third Specific Aim is to evaluate the physical mechanism(s) that drive the changes in ventricular and mitral valve stress distribution that occur as a result of the remodeling process. With respect to Specific Aim 1, the PI proposes to utilize high-resolution sonomicrometry array localization technique (SAL) to measure changes in mitral annular and subvalvular geometry that results from the remodeling process. The PI will measure changes in the size and location of the infarct, border zone, and remote myocardium over time in three different chronic sheep infarct models. Serial microsphere injections will be used to precisely measure regional contractility and blood flow. Quantitative color flow Doppler echocardiography will be used to assess the degree of mitral valve regurgitation and left ventricular dilation. Histologic sections for light microscopy will be obtained from the infarct, border zone and remote myocardium at predetermined intervals to assess the relative concentrations of Type III and Type I collagen. The three sheep models to be studied includes: 1) ligation of the first and second obtuse marginal vessels to produce an infarct consisting of 24 percent of the left ventricular mass and moderate left ventricular dilation without evidence of heart failure or ischemic mitral regurgitation, 2) ligation of the first and second diagonal branches of the left anterior descending coronary artery which produces an acute infarction of approximately 24 percent of the left ventricular mass which results in progressive dilation of the left ventricle and heart failure, and 3) ligation of the second and third obtuse marginal arteries of the circumflex coronary artery to produce an acute infarction consisting of 21 percent of the left ventricular mass which results in heart failure and progressively severe ischemic mitral regurgitation over an 8-12 week period. In Specific Aim 2, three interventions will be studied to evaluate their efficacy in preventing heart failure due to post infarction left ventricular remodeling. These include: 1) reperfusion at 1 and 6 hours after the onset of ischemia in the area at risk, 2) reperfusion 6 hours after ischemia and performance of a ring annuloplasty, and 3) mechanical restraint of the infarct using a Marlex mesh and gelatin-resorcinol-formalin glue. Specific Aim 3 will be addressed by analyzing the data obtained from the studies in Specific Aims 1 and 2 to generate a three dimensional mitral construct using precise left ventricular geometric data. A finite element method described in the preliminary work section will be employed to calculate changes in regional left ventricular circumferential wall stress distribution. It is anticipated that the results of these studies will lead to a better understanding of how remodeling results in heart failure and the development of a new surgical procedure to prevent it.