title: Late repair of ischemic mitral regurgitation does not prevent left ventricular remodeling: importance of timing for beneficial repair.
abstract: BACKGROUND
  Ischemic mitral regurgitation (MR) is a frequent complication of myocardial infarction associated with left ventricular (LV) dilatation and dysfunction, which doubles mortality. At the molecular level, moderate ischemic MR is characterized by a biphasic response, with initial compensatory rise in prohypertrophic and antiapoptotic signals, followed by their exhaustion. We have shown that early MR repair 30 days after myocardial infarction is associated with LV reverse remodeling. It is not known whether MR repair performed after the exhaustion of compensatory mechanisms is also beneficial. We hypothesized that late repair will not result in LV reverse remodeling.
  
  
  RESULTS
  Twelve sheep underwent distal left anterior descending coronary artery ligation to create apical myocardial infarction and implantation of an LV-to-left atrium shunt to create standardized moderate volume overload. At 90 days, animals were randomized to shunt closure (late repair) versus sham (no repair). LV remodeling was assessed by 3-dimensional echocardiography, dP/dt, preload-recruitable stroke work, and myocardial biopsies. At 90 days, animals had moderate volume overload, LV dilatation, and reduced ejection fraction (all P<0.01 versus baseline, P=NS between groups). Shunt closure at 90 days corrected the volume overload (regurgitant fraction 6 ± 5% versus 27 ± 16% for late repair versus sham, P<0.01) but was not associated with changes in LV volumes (end-diastolic volume 106 ± 15 versus 110 ± 22 mL; end-systolic volume 35 ± 6 versus 36 ± 6 mL) or increases in preload-recruitable stroke work (41 ± 7 versus 39 ± 13 mL mm Hg) or dP/dt (803 ± 210 versus 732 ± 194 mm Hg/s) at 135 days (all P=NS). Activated Akt, central in the hypertrophic process, and signal transducer and activator of transcription 3 (STAT3), a critical node in the hypertrophic stimulus by cytokines, were equally depressed in both groups.
  
  
  CONCLUSIONS
  Late correction of moderate volume overload after myocardial infarction did not improve LV volume or contractility. Upregulation of prohypertrophic intracellular pathways was not observed. This contrasts with previously reported study in which early repair (30 days) reversed LV remodeling. This suggests a window of opportunity to repair ischemic MR after which no beneficial effect on LV is observed, despite successful repair.
authors.affiliation: Cardiac Ultrasound Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA (J.B., R.A.L., J.L.G., C.Y., S.S., M.D.H., C.S., N.O.P., G.J.V., R.B.); Cardiovascular Research Center, Heart Institute, Hadassah-Hebrew University Medical Center, Ein-Karem, Jerusalem, Israel (S.A., D.G., R.B.); and Cardiovascular Research Center, Cardiovascular Institute, Mt Sinai School of Medicine, New York, NY (R.J.H.).
authors.forename: Jonathan
authors.initials: J
authors.lastname: Beaudoin
authors.forename: Robert A
authors.initials: RA
authors.lastname: Levine
authors.forename: J Luis
authors.initials: JL
authors.lastname: Guerrero
authors.forename: Chaim
authors.initials: C
authors.lastname: Yosefy
authors.forename: Suzanne
authors.initials: S
authors.lastname: Sullivan
authors.forename: Susan
authors.initials: S
authors.lastname: Abedat
authors.forename: Mark D
authors.initials: MD
authors.lastname: Handschumacher
authors.forename: Catherine
authors.initials: C
authors.lastname: Szymanski
authors.forename: Dan
authors.initials: D
authors.lastname: Gilon
authors.forename: Nicholas O
authors.initials: NO
authors.lastname: Palmeri
authors.forename: Gus J
authors.initials: GJ
authors.lastname: Vlahakes
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Hajjar
authors.forename: Ronen
authors.initials: R
authors.lastname: Beeri
mesh_terms: D000818:Animals; D008944:Mitral Valve Insufficiency / Q000503:physiopathology / Q000601:surgery*; D017202:Myocardial Ischemia / Q000503:physiopathology / Q000601:surgery*; D012756:Sheep; D016037:Single-Blind Method; D013997:Time Factors; D020257:Ventricular Remodeling / Q000502:physiology*
keywords: heart disease, ischemic; mitral valve regurgitation; remodeling
references.citation: Circulation. 1985 May;71(5):994-1009
references.pmid: 3986986
references.citation: Circ Cardiovasc Imaging. 2010 Nov;3(6):679-86
references.pmid: 20826595
references.citation: Circulation. 2006 Jul 4;114(1 Suppl):I529-34
references.pmid: 16820632
references.citation: Am J Physiol. 1989 Apr;256(4 Pt 2):H974-81
references.pmid: 2523200
references.citation: Ann Thorac Surg. 2010 Sep;90(3):788-94
references.pmid: 20732497
references.citation: Circulation. 2007 Sep 11;116(11 Suppl):I259-63
references.pmid: 17846314
references.citation: Am Heart J. 1992 Jul;124(1):24-31
references.pmid: 1535474
references.citation: Circulation. 2007 Sep 11;116(11 Suppl):I288-93
references.pmid: 17846319
references.citation: Circulation. 1997 Sep 16;96(6):1999-2008
references.pmid: 9323092
references.citation: J Am Coll Cardiol. 2005 Feb 1;45(3):381-7
references.pmid: 15680716
references.citation: J Thorac Cardiovasc Surg. 1993 Dec;106(6):1147-57
references.pmid: 8246553
references.citation: N Engl J Med. 1996 Nov 7;335(19):1417-23
references.pmid: 8875918
references.citation: J Am Coll Cardiol. 2004 Feb 4;43(3):377-83
references.pmid: 15013117
references.citation: J Thorac Cardiovasc Surg. 2004 Dec;128(6):916-24
references.pmid: 15573077
references.citation: Circulation. 2001 Jul 17;104(3):330-5
references.pmid: 11457753
references.citation: J Thorac Cardiovasc Surg. 1997 Feb;113(2):292-300; discussion 300-1
references.pmid: 9040623
references.citation: Circulation. 2004 Sep 14;110(11 Suppl 1):II85-90
references.pmid: 15364844
references.citation: J Heart Valve Dis. 2001 Nov;10(6):754-62
references.pmid: 11767182
references.citation: Circulation. 2001 Apr 3;103(13):1759-64
references.pmid: 11282907
references.citation: Circulation. 1990 Apr;81(4):1161-72
references.pmid: 2138525
references.citation: J Thorac Cardiovasc Surg. 1993 Mar;105(3):439-42; discussion 442-3
references.pmid: 8445923
references.citation: Am Heart J. 1994 May;127(5):1231-41
references.pmid: 8172051
references.citation: Circulation. 2007 Feb 13;115(6):782-91
references.pmid: 17283262
references.citation: J Am Coll Cardiol. 2008 Jan 29;51(4):476-86
references.pmid: 18222360
references.citation: Circulation. 2012 May 29;125(21):2639-48
references.pmid: 22553307