TY - JOUR
T1 - Mitral Regurgitation Augments Post-Myocardial Infarction Remodeling. Failure of Hypertrophic Compensation
AU - Beeri, Ronen
AU - Yosefy, Chaim
AU - Guerrero, J. Luis
AU - Nesta, Francesca
AU - Abedat, Suzan
AU - Chaput, Miguel
AU - del Monte, Federica
AU - Handschumacher, Mark D.
AU - Stroud, Robert
AU - Sullivan, Suzanne
AU - Pugatsch, Thea
AU - Gilon, Dan
AU - Vlahakes, Gus J.
AU - Spinale, Francis G.
AU - Hajjar, Roger J.
AU - Levine, Robert A.
PY - 2008/1/29
Y1 - 2008/1/29
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=38349121080&partnerID=8YFLogxK
U2 - 10.1016/j.jacc.2007.07.093
DO - 10.1016/j.jacc.2007.07.093
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C2 - 18222360
AN - SCOPUS:38349121080
SN - 0735-1097
VL - 51
SP - 476
EP - 486
JO - Journal of the American College of Cardiology
JF - Journal of the American College of Cardiology
IS - 4
ER -