Surgical ventricular restoration (SVR) or ventriculoplasty of the dilated left ventricle (LV) after antero-apical myocardial infarction (MI) has been proposed as surgical treatment for congestive heart failure (CHF). Patch aneurymorraphy (Dor procedure), infarct exclusion (no patch), Surgical Anterior Ventricular Restoration (SAVER;performed on akinetic infarcts), passive constraint device procedures such as the Acorn CorCapTM Cardiac Support Device (CSD), and cell transplantation are currently being performed. The long-term goal of this research is to use experimental and theoretical models to arrive at an optimal design for SVR of the dilated LV after antero-apical Mi. First, using the finite element (FE) models developed during the previous funding period, designs of Dor, infarct exclusion, SAVER, modified Acorn CSD, and cell transplantation operations will be optimized. FE models will simulate the effect of the location and amount of injected cells in cell transplantation, residual contracting myocytes (dyskinetic vs akinetic infarct), the amount of excluded or resected myocardium, patch stiffness and location (endocardium vs. epicardium) in the Dor/ SAVER operations and the compliance of the Acorn jacket. Next, the ability to enhance BZ systolic function late (3 months) after antero-apical MI will be tested in sheep. Local AAV mediated gene transfer will be used to up-regulate SERCA2a and systemic Doxycyclin will be used to inhibit MMP in the infarct BZ. BZ contractile function will be measured in isolated myocytes and BZ contractile function determined using cardiac MRI with tags based inverse FE calculations. Next, using conductance and micromanometer-tipped catheters, we will test the ability of the Dor procedure or Dor procedure + enhanced BZ systolic function (best therapy identified in Aim 2) in sheep after antero-apical MI to both stabilize LV volume and improve pump function. Finally, the long term (6 month) effect of the Dor procedure + enhanced BZ systolic function (best therapy identified in Aim 3) on LV volume and global LV pump function after transmural antero-apical MI will be measured in sheep. These findings should have a major impact on current surgical practice.

Public Health Relevance

Enlargement of the heart after a myocardial infarction is associated with an increased incidence of congestive heart failure and mortality. However, it remains unclear whether or how the heart should be fixed. In this grant application, we propose to use sophisticated mathematical simulations to determine the optimal design of heart failure operations. In addition, we will use animal experiments to determine whether those heart failure operations produce a stable reduction is heart size. Finally, we will test whether gene and medical therapy, used to supplement the effect of the heart failure operation, allows the heart to squeeze harder and pump better after surgery.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL063348-12
Application #
8101331
Study Section
Special Emphasis Panel (ZRG1-SBIB-E (03))
Program Officer
Miller, Marissa A
Project Start
2000-04-17
Project End
2014-05-31
Budget Start
2011-06-01
Budget End
2012-05-31
Support Year
12
Fiscal Year
2011
Total Cost
$387,500
Indirect Cost
Name
Northern California Institute Research & Education
Department
Type
DUNS #
613338789
City
San Francisco
State
CA
Country
United States
Zip Code
94121
Pantoja, Joe Luis; Morgan, Ashley E; Grossi, Eugene A et al. (2017) Undersized Mitral Annuloplasty Increases Strain in the Proximal Lateral Left Ventricular Wall. Ann Thorac Surg 103:820-827
Morgan, Ashley E; Wozniak, Curtis J; Gulati, Sarthak et al. (2017) Association of Uneven MitraClip Application and Leaflet Stress in a Finite Element Model. JAMA Surg 152:111-114
Ge, Liang; Wu, Yife; Soleimani, Mehrdad et al. (2016) Moderate Ischemic Mitral Regurgitation After Posterolateral Myocardial Infarction in Sheep Alters Left Ventricular Shear but Not Normal Strain in the Infarct and Infarct Borderzone. Ann Thorac Surg 101:1691-9
Ge, Liang (2016) A Characteristic-Based Constitutive Law for Dispersed Fibers. J Biomech Eng 138:
Morgan, Ashley E; Pantoja, Joe L; Grossi, Eugene A et al. (2016) Neochord placement versus triangular resection in mitral valve repair: A finite element model. J Surg Res 206:98-105
Morgan, Ashley E; Pantoja, Joe Luis; Weinsaft, Jonathan et al. (2016) Finite Element Modeling of Mitral Valve Repair. J Biomech Eng 138:021009
Ratcliffe, Mark; Cambronero, Neil; Takaba, Kiyoaki et al. (2015) Studies on postinfarct left ventricular remodeling: state of the art. Ann Thorac Surg 99:755-6
Yaffee, David W; Grossi, Eugene A; Ratcliffe, Mark B (2015) Progressive design concepts in off-pump left ventricular remodeling mitral valve repair devices. Ann Cardiothorac Surg 4:352-4
Pantoja, Joe Luis; Zhang, Zhihong; Tartibi, Mehrzad et al. (2015) Residual Stress Impairs Pump Function After Surgical Ventricular Remodeling: A Finite Element Analysis. Ann Thorac Surg 100:2198-205
Shimkunas, Rafael; Makwana, Om; Spaulding, Kimberly et al. (2014) Myofilament dysfunction contributes to impaired myocardial contraction in the infarct border zone. Am J Physiol Heart Circ Physiol 307:H1150-8

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