Mitral Regurgitation Augments Post-Myocardial Infarction Remodeling. Failure of Hypertrophic Compensation

Ronen Beeri, Chaim Yosefy, J. Luis Guerrero, Francesca Nesta, Suzan Abedat, Miguel Chaput, Federica del Monte, Mark D. Handschumacher, Robert Stroud, Suzanne Sullivan, Thea Pugatsch, Dan Gilon, Gus J. Vlahakes, Francis G. Spinale, Roger J. Hajjar, Robert A. Levine*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

76 Scopus citations

Abstract

Objectives: We examined whether mitral regurgitation (MR) augments post-myocardial infarction (MI) remodeling. Background: MR doubles mortality after MI, but its additive contribution to left ventricular (LV) remodeling is debated and has not been addressed in a controlled fashion. Methods: Apical MIs were created in 12 sheep, and 6 had an LV-to-left atrial shunt implanted, consistently producing regurgitant fractions of ∼30%. The groups were compared at baseline, 1, and 3 months. Results: Left ventricular end-systolic volume progressively increased by 190% with MR versus 90% without MR (p < 0.02). Pre-load-recruitable stroke work declined by 82 ± 13% versus 25 ± 16% (p < 0.01) with MR, with decreased remote-zone sarcoplasmic reticulum Ca2+-ATPase levels (0.56 ± 0.03 vs. 0.76 ± 0.02, p < 0.001), and decreased isolated myocyte contractility. In remote zones, pro-hypertrophic Akt and gp130 were upregulated in both groups at 1 month, but significantly lower and below baseline in the MR group at 3 months. Pro-apoptotic caspase 3 remained high in both groups. Matrix metalloproteinase (MMP)-13 and membrane-type MMP-1 were increased in remote zones of MR versus infarct-only animals at 1 month, then fell below baseline. The MMP tissue inhibitors rose from baseline to 3 months in all animals, rising higher in the MI + MR-group border zone. Conclusions: In this controlled model, moderate MR worsens post-MI remodeling, with reduced contractility. Pro-hypertrophic pathways are initially upregulated but subsequently fall below infarct-only levels and baseline; with sustained caspase 3 elevation, transformation to a failure phenotype occurs. Extracellular matrix turnover increases in MR animals. Therefore, MR can precipitate an earlier onset of dilated heart failure.

Original languageAmerican English
Pages (from-to)476-486
Number of pages11
JournalJournal of the American College of Cardiology
Volume51
Issue number4
DOIs
StatePublished - 29 Jan 2008
Externally publishedYes

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