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Mitral Regurgitation Augments Post-Myocardial Infarction Remodeling

Failure of Hypertrophic Compensation

Ronen Beeri, MD^_*, Chaim Yosefy, MD^_*, J. Luis Guerrero, BS^_*, Francesca Nesta, MD^_*, Suzan Abedat, MSc, Miguel Chaput, MD^_*, Federica del Monte, MD, PhD, Mark D. Handschumacher, BS^_*, Robert Stroud, MS^||, Suzanne Sullivan, BS^_*, Thea Pugatsch, PhD, Dan Gilon, MD, FACC, Gus J. Vlahakes, MD, FACC, Francis G. Spinale, MD, FACC^||, Roger J. Hajjar, MD, FACC and Robert A. Levine, MD, FACC^_*,_*

^_* Cardiac Ultrasound Laboratory, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
Cardiac Surgery Department, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
Heart Institute and Cardiovascular Research Laboratory, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
^|| Cardiothoracic Surgery Department, Medical University of South Carolina, Charleston, South Carolina.

Manuscript received May 3, 2007; revised manuscript received July 9, 2007, accepted July 16, 2007.

^_* Reprint requests and correspondence: Dr. Robert A. Levine, Cardiac Ultrasound Laboratory YAW5, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114. (Email: rlevine{at}partners.org).

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.

Abbreviations and Acronyms   EF = ejection fraction   LA = left atrium/atrial   LV = left ventricle/ventricular   MI = myocardial infarction   MMP = matrix metalloproteinase   MR = mitral regurgitation   MT-MMP = membrane-type matrix metalloproteinase   SERCA2a = sarcoplasmic reticulum Ca2+-ATPase   TIMP = tissue inhibitor of matrix metalloproteinase   2D = 2-dimensional   3D = 3-dimensional

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