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 #
5R01HL063348-13
Application #
8270479
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
2012-06-01
Budget End
2013-05-31
Support Year
13
Fiscal Year
2012
Total Cost
$383,625
Indirect Cost
$136,125
Name
Northern California Institute Research & Education
Department
Type
DUNS #
613338789
City
San Francisco
State
CA
Country
United States
Zip Code
94121
Lee, Lik Chuan; Ge, Liang; Zhang, Zhihong et al. (2014) Patient-specific finite element modeling of the Cardiokinetix Parachute(®) device: effects on left ventricular wall stress and function. Med Biol Eng Comput 52:557-66
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
Lee, Lik Chuan; Genet, Martin; Dang, Alan B et al. (2014) Applications of computational modeling in cardiac surgery. J Card Surg 29:293-302
Pantoja, Joe Luis; Ge, Liang; Zhang, Zhihong et al. (2014) Posterior papillary muscle anchoring affects remote myofiber stress and pump function: finite element analysis. Ann Thorac Surg 98:1355-62
Wall, Samuel T; Guccione, Julius M; Ratcliffe, Mark B et al. (2012) Electromechanical feedback with reduced cellular connectivity alters electrical activity in an infarct injured left ventricle: a finite element model study. Am J Physiol Heart Circ Physiol 302:H206-14
Wenk, Jonathan F; Sun, Kay; Zhang, Zhihong et al. (2011) Regional left ventricular myocardial contractility and stress in a finite element model of posterobasal myocardial infarction. J Biomech Eng 133:044501
Wenk, Jonathan F; Eslami, Parastou; Zhang, Zhihong et al. (2011) A novel method for quantifying the in-vivo mechanical effect of material injected into a myocardial infarction. Ann Thorac Surg 92:935-41
Zhang, Zhihong; Tendulkar, Amod; Sun, Kay et al. (2011) Comparison of the Young-Laplace law and finite element based calculation of ventricular wall stress: implications for postinfarct and surgical ventricular remodeling. Ann Thorac Surg 91:150-6
Jhun, Choon-Sik; Wenk, Jonathan F; Zhang, Zhihong et al. (2010) Effect of adjustable passive constraint on the failing left ventricle: a finite-element model study. Ann Thorac Surg 89:132-7
Sun, Kay; Zhang, Zhihong; Suzuki, Takamaro et al. (2010) Dor procedure for dyskinetic anteroapical myocardial infarction fails to improve contractility in the border zone. J Thorac Cardiovasc Surg 140:233-9, 239.e1-4

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