title: Long-term pharmacological activation of PPARgamma does not prevent left ventricular remodeling in dogs with advanced heart failure.
abstract: BACKGROUND
  Peroxisome proliferator-activated receptor gamma (PPARgamma) activators affect the myocardium through inhibition of inflammatory cytokines and metabolic modulation but their effect in the progression of heart failure is unclear. In the present study, we examined the effects of the PPARgamma activator, GW347845 (GW), on the progression of heart failure.
  
  
  RESULTS
  Heart failure was produced in 21 dogs by intracoronary microembolizations to LV ejection fraction (EF) less than 30% and randomized to 3 months of therapy with high-dose GW (10 mg/Kg daily, n = 7), low-dose GW (3 mg/Kg daily, n = 7), or no therapy (control, n = 7). In control dogs, EF significantly decreased (28 +/- 1 vs. 22 +/- 1%, p < 0.001) and end-diastolic volume (EDV) and end-systolic volume (ESV) increased during the 3 months of the follow-up period (64 +/- 4 vs. 76 +/- 5; p = 0.003, 46 +/- 3 vs. 59 +/- 4 ml, p = 0.002, respectively). In dogs treated with low-dose GW, EDV increased significantly (69 +/- 4 vs.81 +/- 5 ml, p = 0.01), whereas ESV remained statistically unchanged (50 +/- 3 vs. 54 +/- 3 ml, p = 0.10) resulting in modestly increased ejection fraction (27 +/- 1 vs. 32 +/- 3%, p = 0.05). In dogs treated with high-dose GW, both EDV and ESV increased (72 +/- 4 vs. 79 +/- 5 ml, p = 0.04; 53 +/- 3 vs. 62 +/- 5 ml, p = 0.04) and EF decreased (26 +/- 1 vs. 23 +/- 1%, p = 0.04) as with control dogs. There was significantly increased myocardial hypertrophy as evidenced by increased LV weight to body weight ratio and myocyte cross-section area in the GW treated animals compared to controls. Compared to control, treatment with GW had no effect on mRNA expression of PPARgamma, inflammatory cytokines, stretch response proteins, or transcription factors that may induce hypertrophy.
  
  
  CONCLUSIONS
  Long-term PPARgamma activation with GW did not prevent progressive LV remodeling in dogs with advanced heart failure.
authors.affiliation: Division of Cardiovascular Medicine, Henry Ford Heart & Vascular Institute, Detroit, MI, USA.
authors.forename: George
authors.initials: G
authors.lastname: Suzuki
authors.forename: Sanjaya
authors.initials: S
authors.lastname: Khanal
authors.forename: Sharad
authors.initials: S
authors.lastname: Rastogi
authors.forename: Hideaki
authors.initials: H
authors.lastname: Morita
authors.forename: Takayuki
authors.initials: T
authors.lastname: Mishima
authors.forename: Petros V
authors.initials: PV
authors.lastname: Anagnostopoulos
authors.forename: Omar
authors.initials: O
authors.lastname: Nass
authors.forename: Victor G
authors.initials: VG
authors.lastname: Sharov
authors.forename: Elaine J
authors.initials: EJ
authors.lastname: Tanhehco
authors.forename: Sidney
authors.initials: S
authors.lastname: Goldstein
authors.forename: Hani N
authors.initials: HN
authors.lastname: Sabbah
mesh_terms: D000284:Administration, Oral; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics; D001835:Body Weight / Q000187:drug effects; D016207:Cytokines / Q000235:genetics; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects; D006333:Heart Failure / Q000188:drug therapy / Q000503:physiopathology*; D006339:Heart Rate / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D047495:PPAR gamma / Q000819:agonists* / Q000235:genetics; D051059:PTEN Phosphohydrolase / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D011494:Protein Kinases / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013318:Stroke Volume / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases; D016277:Ventricular Function, Left / Q000187:drug effects*; D020257:Ventricular Remodeling / Q000187:drug effects* / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics
chemical_list: D009320:Atrial Natriuretic Factor; D016207:Cytokines; D047495:PPAR gamma; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D016283:Proto-Oncogene Proteins p21(ras); D012333:RNA, Messenger; D058570:TOR Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases