Mathematical Modeling of Matrix Metalloproteinase-9 Driven Left Ventricular Remod

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DESCRIPTION (provided by applicant): This is an application in response to PA-06-180: NIH Small Research Grant Program (Parent R03) which supports secondary analysis of existing data and small, self-contained research projects. Targeted Problem: More than 100,000 myocardial infarction (MI) patients undergo adverse remodeling of left ventricle (LV) and progress to congestive heart failure each year. Currently, the 5 year mortality rate for CHF is 50%. A lack of early diagnostic indicators and effective therapeutic strategies accounts for the high mortality rate. Adverse LV remodeling is a fundamental process in the progression to CHF and is therefore a target for new strategies and early diagnostic indicators. LV remodeling is associated with extracellular matrix (ECM) changes and matrix metalloproteinase-9 (MMP-9) plays a significant role in cardiac ECM changes by degrading collagen I and III, the predominant components in ECM. While MMP-9 is closely associated with LV remodeling outcomes, the underlying mechanism and the quantitative relationship between MMP-9 levels and LV remodeling have not been fully delineated. The objective of this study is to establish the mathematical model to predict MMP-9 driven left ventricular remodeling post-MI. Our central hypothesis is that elevated MMP-9 levels at early stage post-MI modulate ECM synthesis and determine LV remodeling outcomes. The two specific aims are to establish a mathematical model that quantitatively links MMP-9 level, ECM composition, and LV remodeling, and to validate the predictions of the mathematical model by comparing the in silico results with real in vivo measurements of LV remodeling in response to reduced MMP-9 levels. Methods: Our mathematical model will be a set of differential equations based on fundamental physical chemistry laws. Model parameters will be determined based on the existing in vivo evaluation of elevated MMP-9 levels, ECM deposition, and structural adaptation post-MI. This model will be validated by evaluating in vivo LV remodeling progress of MI mice treated with MMP-9 blocking antibodies at day 1 and day 3. The potential outcomes of this study include: a mathematical tool capable of predicting LV remodeling outcomes; 2) a defined temporal relationship of LV remodeling affected by ECM production and modulated MMP-9 levels; 3) effect of intervention time on LV remodeling post-MI. Benefits: This project will provide a tool for reliable predictions of LV remodeling outcomes with modulated MMP-9 levels and facilitate the development of early interventions post-MI to prevent adverse LV remodeling. PUBLIC HEALTH RELEVANCE: Left ventricular remodeling outcomes determine the long term morbidity and mortality post myocardial infarction (MI). Extracellular matrix changes are significant parts of left ventricular remodeling and matrix metalloproteinase-9 plays an important role in extracellular matrix changes by degrading the predominant ECM components: Collagen I and III. Understanding the mechanisms of how matrix metalloproteinase-9 affects left ventricular remodeling will lay foundations to predict remodeling outcomes and provide potential clinical interventions to prevent adverse remodeling post MI at early stages.