Abstract 2704: Early Repair of Moderate Ischemic MR Reverses LV Remodeling: A Functional and Molecular Study
Mitral regurgitation (MR) doubles mortality following myocardial infarction (MI). We have shown that moderate MR causes excess remodeling in an apical MI model. We hypothesized that repairing moderate MR one month after MI reverses this remodeling. We used a model of apical MI (no intrinsic MR) with independent LV-to-LA MR-type flow to address this question.
Methods: In 18 sheep, an apical MI was created, and an LV-LA shunt implanted in 12, producing regurgitant fractions of 30%. Six sheep had the shunt closed at 1 month (repair group). Sheep were compared at baseline, 1 and 3 months.
Results: Sheep in the MI+MR (unrepaired) and repair groups remodeled during the first month (EDV rose by 81.5%, ESV by 120%, P<0.01), but after shunt closure reverse remodeling occurred, with a significant reduction of EDV and ESV, compared with continued rises without repair (EDV and ESV respectively increased by 37.9% and 62.9% in the unrepaired group and decreased by 29% and 38.7% in the repaired group, P<0.001). The decrease in dP/dt relative to baseline at 3 months was smaller in the repair and MI-only groups (21.4 ± 5.8%, 22.4 ± 12.4%) than in the unrepaired group (51.2 ± 9.3%). Pro-hypertrophic gp130 showed an increase followed by exhaustion below baseline in the MI+MR group, but remained elevated at 3 months in the repair animals, as with MI only; a similar pattern was observed for anti-apoptotic pAkt. In the repair group, matrix metalloproteinase (MMP)-2 significantly decreased to ≤ 50% of levels in the MI+MR group in remote and border zones at 3 months. The MMP inhibitor TIMP-4 increased dramatically in the remote and border zones of repair sheep.
Conclusion: Early repair of moderate MR in the setting of an apical MI substantially reverses the remodeling process that otherwise progresses, with reduction in LV volumes, relatively maintained contractility, persistent activation of intracellular signaling cascades promoting hypertrophy and opposing apoptosis, and reduction of matrix proteolytic activity. These findings are of interest for the current controversy regarding potential benefits of repair of MR following MI.