Left ventricular (LV) enlargement (remodeling) after myocardial infarction (MI) is a consequence of infarct expansion, extension of the infarct borderzone (BZ), and hypertrophy of the remote myocardium in addition to the effects of neuro-humoral compensatory pathways. Post-infarct LV remodeling is a strong predictor of mortality and a high incidence of heart failure (HF). Acellular hydrogels that limit LV remodeling when injected into an MI or BZ are receiving increasing attention. We term this therapy matrix-assisted infarct stabilization (MAIS) and suggest that MAIS works by decreasing myofiber stress in the infarct, BZ and remote myocardium thereby decreasing infarct expansion, improving BZ contractility and decreasing hypertrophy of the remote myocardium. Optimal design parameters of MAIS need to be determined and although initial work using finite element (FE) simulations and animal experiments to determine the effect of injection volume and hydrogel stiffness have been performed, a systematic investigation of MAIS design parameters is clearly needed. Therefore, Aim 1 seeks to determine optimal MAIS design parameters using FE element models validated with diastolic and systolic regional LV strain and LV volumes measured with cardiac magnetic resonance imaging (MRI) before and after MAIS in sheep. Sheep for validation studies will have MAIS performed with a tunable non-degradable hydrogel (semi- interpenetrating polymer networks;sIPN) injected 1) directly into the MI and BZ and 2) by intracoronary injection.
In Aim 2 the effect of MAIS on regional LV stress, infarct expansion and contractility will be calculated in sheep with MI + BZ sIPN injection, intra-coronary sIPN injection and in the optimal MAIS design determined in Aim 1. The proposed work will continue our focus on BZ contractile dysfunction that was begun during the previous funding period where recent studies in sheep after antero-apical MI revealed a critical role for intracellular (IC) matrix metalloproteinase-2 (MMP-2) as a mediator of contractile protein and mitochondrial dysfunction. Further, recent studies have characterized two IC MMP-2 isoforms. First, full length IC MMP-2 cleaves contractile proteins troponin I and myosin light chain 1 (MCL-1) in the setting of oxidative stress (reactive oxygen species: ROS). Second, an N-terminal truncated constituitively active isoform (NTT-MMP-2) is induced by ROS and predominately located in the mitochondria where it is associated with abnormalities in mitochondrial ultrastructure and respiration. Further, transgenic mice with NTT-MMP-2 develop progressive LV hypertrophy and eventual HF. Based on preliminary studies, we believe that MAIS will prevent BZ injury by interrupting a process mediated by mechanical stress, ROS, and activation of the IC MMP-2 that causes damage to BZ contractile proteins, mitochondrial dysfunction and impaired ATP production.
Aim 3 therefore seeks to determine the effect of optimized MAIS on ROS, IC MMP-2 expression, mitochondrial function and ATP production.

Public Health Relevance

Myocardial infarction (MI) happens when blood flow to part of heart is blocked. As a consequence, the heart gradually enlarges, heart function decreases and there is eventual onset of heart failure. Injection of hydrogel polymers into the damaged area of the heart has been shown to slow and in some cases stop heart enlargement. This study uses state-of-the-art computational modeling tools and advanced biochemical analysis to find the optimal hydrogel injection strategies to prevent heart enlargement. The study will lead to improved therapies for patients with MI.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL063348-15
Application #
8773179
Study Section
Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
Program Officer
Miller, Marissa A
Project Start
2000-04-17
Project End
2018-04-30
Budget Start
2014-07-15
Budget End
2015-04-30
Support Year
15
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Northern California Institute Research & Education
Department
Type
DUNS #
City
San Francisco
State
CA
Country
United States
Zip Code
94121
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Ge, Liang (2016) A Characteristic-Based Constitutive Law for Dispersed Fibers. J Biomech Eng 138:
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