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.
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.
|Morgan, Ashley E; Zhang, Yue; Tartibi, Mehrzad et al. (2018) Ischemic Mitral Regurgitation: Abnormal Strain Overestimates Nonviable Myocardium. Ann Thorac Surg 105:1754-1761|
|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|
|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|
|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; Haraldsson, Henrik; Hope, Michael D et al. (2016) Suture Forces for Closure of Transapical Transcatheter Aortic Valve Replacement: A Mathematical Model. J Heart Valve Dis 25:424-429|
|Ge, Liang (2016) A Characteristic-Based Constitutive Law for Dispersed Fibers. J Biomech Eng 138:|
|Morgan, Ashley E; Pantoja, Joe Luis; Weinsaft, Jonathan et al. (2016) Finite Element Modeling of Mitral Valve Repair. J Biomech Eng 138:021009|
|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|
|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|
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