The rationale for this proposal is that the size, transmurality and location of a myocardial infarction, the material properties of the healing infarct and the continued stimulation of the renin-angiotensin-aldosterone system determine how the left ventricle remodels and whether or not ischemic mitral regurgitation, left ventricular aneurysm or global left ventricular dilatation with progressive loss of ventricular function occurs. This proposal is based on the therapeutically attractive hypothesis that medical/surgical interventions can favorably alter ventricular remodeling after an ischemic event such that left ventricular failure/dilatation, mitral regurgitation, and left ventricular aneurysm are minimized. The PI has extensive experience in assessing ventricular geometry, myocardial material properties and ventricular mechanics in large animals (sheep) following acute myocardial infarction, anteroapical aneurysm and acute/ chronic ischemic mitral regurgitation. He has refined techniques of biaxial stress-extension testing of tissue samples, finite element analysis of left ventricular infarction, sonomicrometry array localization of left ventricular and mitral annular geometry, and quantitative echocardiography as related to the standard hemodynamic measurements of preload recruitable stroke work and end-systolic elastance. The PI will build upon his sophisticated multi-model analysis of left ventricular and mitral valvular mechanical status a series of interventions directed toward stiffening the zone of acute infarction (pedicled muscle flap, epicardial marlex mesh, direct glutaraldehyde injection) in an attempt to therapeutically influence the transmural mechanical properties of a zone of acute infarction. He will also extend his previous observations relative to acute and chronic ischemic mitral regurgitation. As this relates to mitral valvular annular reconstruction these surgical interventions are likely to influence left ventricular mechanics following acute infarction. The PI will then extend this potential surgical therapy by manipulating the renin-angiotensin system to pharmaceoutically stiffen ischemic myocardium in order to influence progressive left ventricular dilatation and functional deterioration in a microsphere induced model of ischemic cardiomyopathy.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL036308-12
Application #
2467653
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1990-07-01
Project End
2000-12-31
Budget Start
1998-01-01
Budget End
1998-12-31
Support Year
12
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Surgery
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Gorman 3rd, Joseph H; Gorman, Robert C; Jackson, Benjamin M et al. (2003) Annuloplasty ring selection for chronic ischemic mitral regurgitation: lessons from the ovine model. Ann Thorac Surg 76:1556-63
Jackson, Benjamin M; Gorman 3rd, Joseph H; Salgo, Ivan S et al. (2003) Border zone geometry increases wall stress after myocardial infarction: contrast echocardiographic assessment. Am J Physiol Heart Circ Physiol 284:H475-9
Wilson, Eric M; Moainie, Sina L; Baskin, Julia M et al. (2003) Region- and type-specific induction of matrix metalloproteinases in post-myocardial infarction remodeling. Circulation 107:2857-63
Jackson, Benjamin M; Gorman, Joseph H; Moainie, Sina L et al. (2002) Extension of borderzone myocardium in postinfarction dilated cardiomyopathy. J Am Coll Cardiol 40:1160-7; discussion 1168-71
Salgo, Ivan S; Gorman 3rd, Joseph H; Gorman, Robert C et al. (2002) Effect of annular shape on leaflet curvature in reducing mitral leaflet stress. Circulation 106:711-7
Moainie, Sina L; Gorman 3rd, Joseph H; Guy, T Sloane et al. (2002) An ovine model of postinfarction dilated cardiomyopathy. Ann Thorac Surg 74:753-60
Moainie, Sina L; Guy, T Sloane; Gorman 3rd, Joseph H et al. (2002) Infarct restraint attenuates remodeling and reduces chronic ischemic mitral regurgitation after postero-lateral infarction. Ann Thorac Surg 74:444-9; discussion 449
Bowen, F W; Hattori, T; Narula, N et al. (2001) Reappearance of myocytes in ovine infarcts produced by six hours of complete ischemia followed by reperfusion. Ann Thorac Surg 71:1845-55
Bowen, F W; Jones, S C; Narula, N et al. (2001) Restraining acute infarct expansion decreases collagenase activity in borderzone myocardium. Ann Thorac Surg 72:1950-6
Kelley, S T; Malekan, R; Gorman 3rd, J H et al. (1999) Restraining infarct expansion preserves left ventricular geometry and function after acute anteroapical infarction. Circulation 99:135-42

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