Mitral regurgitation(MR) imposes left ventricular (LV)volume overload, triggering rapid ventricular dilatation, increased myocardial compliance and ultimately cardiac dysfunction. Breakdown of extracellular matrix(ECM) is hypothesized to drive these rapid changes, partially from an imbalance in the matrix metalloproteinases(MMPs) and their tissue inhibitors(TIMPs). In this study, we developed a rat model of severe MR that mimics the human condition, and investigated the temporal changes in ECM related genes, collagen biosynthesis proteins, and proteolytic enzymes, over 20 weeks. Male Sprague-Dawley rats were anesthetized to a surgical plane with mechanical ventilation, and a thoracotomy was performed to expose the apex. Using transesophageal ultrasound guidance, a needle was inserted into the beating heart to perforate the anterior mitral leaflet and create severe MR. Animals were survived for 20 weeks, with some animals terminated at 2,10 and 20 weeks for analysis of LV tissue. A sham group that underwent the same surgery without mitral leaflet perforation and MR were used as controls. At 2 weeks post-MR, increased collagen gene expression was measured, but protein levels of collagen did not corroborate this finding. In parallel, MMP1-TIMP4, MMP2-TIMP1, MMP2-TIMP3 ratios were significantly elevated indicating a proteolytic milieu in the myocardium, possibly causing collagen degradation. By 20 weeks, may of the initial differences seen in the proteolytic ratios were not observed, with an increase in collagen compared to the 2-week timepoint. Altogether this data indicates that imbalance in MMP-TIMP ratio may occur early and potentially contribute to the early dilatation and compliance observed structurally.

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