title: Mitral regurgitation augments post-myocardial infarction remodeling failure of hypertrophic compensation.
abstract: OBJECTIVE
  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 approximately 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 Ca(2+)-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.
authors.affiliation: Cardiac Ultrasound Laboratory, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
authors.forename: Ronen
authors.initials: R
authors.lastname: Beeri
authors.forename: Chaim
authors.initials: C
authors.lastname: Yosefy
authors.forename: J Luis
authors.initials: JL
authors.lastname: Guerrero
authors.forename: Francesca
authors.initials: F
authors.lastname: Nesta
authors.forename: Suzan
authors.initials: S
authors.lastname: Abedat
authors.forename: Miguel
authors.initials: M
authors.lastname: Chaput
authors.forename: Federica
authors.initials: F
authors.lastname: del Monte
authors.forename: Mark D
authors.initials: MD
authors.lastname: Handschumacher
authors.forename: Robert
authors.initials: R
authors.lastname: Stroud
authors.forename: Suzanne
authors.initials: S
authors.lastname: Sullivan
authors.forename: Thea
authors.initials: T
authors.lastname: Pugatsch
authors.forename: Dan
authors.initials: D
authors.lastname: Gilon
authors.forename: Gus J
authors.initials: GJ
authors.lastname: Vlahakes
authors.forename: Francis G
authors.initials: FG
authors.lastname: Spinale
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Hajjar
authors.forename: Robert A
authors.initials: RA
authors.lastname: Levine
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D004195:Disease Models, Animal; D019560:Echocardiography, Three-Dimensional; D006984:Hypertrophy / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008944:Mitral Valve Insufficiency / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D032342:Muscle Cells / Q000473:pathology; D009203:Myocardial Infarction / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D012756:Sheep; D013318:Stroke Volume; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D020782:Matrix Metalloproteinases; D002118:Calcium