Temporal changes in myocardial collagen, matrix metalloproteinases, and their tissue inhibitors in the left ventricular myocardium in experimental chronic mitral regurgitation in rodents

Abstract

Mitral regurgitation (MR) imposes left ventricular volume overload, triggering rapid ventricular dilatation, increased myocardial compliance, and, ultimately, cardiac dysfunction. Breakdown of the extracellular matrix has been hypothesized to drive these rapid changes, partially from an imbalance in the matrix metalloproteinases (MMPs) and their tissue inhibitors [tissue inhibitors of metalloproteinase (TIMPs)]. In the present study, we developed a rat model of severe MR that mimics the human condition and investigated the temporal changes in extracellular matrix-related genes, collagen biosynthesis proteins, and proteolytic enzymes over a 20-wk period. 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 wk, with some animals terminated at 2, 10, and 20 wk for analysis of left ventricular tissue. A sham group that underwent the same surgery without mitral leaflet perforation and MR were used as controls. At 2 wk post-MR, increased collagen gene expression was measured, but protein levels of collagen did not corroborate this finding. In parallel, MMP-1-to-TIMP-4, MMP-2-to-TIMP-1, and MMP-2-to-TIMP-3 ratios were significantly elevated, indicating a proteolytic milieu in the myocardium, possibly causing collagen degradation. By 20 wk, many of the initial differences seen in the proteolytic ratios were not observed, with an increase in collagen compared with the 2-wk time point. Altogether, this data indicates that an imbalance in the MMP-to-TIMP ratio may occur early and potentially contribute to the early dilatation and compliance observed structurally.

NEW & NOTEWORTHY In this rodent model of severe mitral regurgitation that mimics the human condition, eccentric left ventricular dilatation occurred rapidly and persisted over the 20-wk period with parallel changes in myocardial collagen and matrix metalloproteinases that may drive the extracellular matrix breakdown.