title: Selective matrix metalloproteinase inhibition attenuates progression of left ventricular dysfunction and remodeling in dogs with chronic heart failure.
abstract: Matrix metalloproteinases (MMPs) contribute to the progression of left ventricular (LV) dysfunction and remodeling associated with heart failure (HF). The present study examined the long-term effects of a selective MMP inhibitor PG-530742 (PG) on the progression of LV dysfunction and remodeling in dogs with HF. Chronic HF [LV ejection fraction (LVEF), </=36%] was produced by multiple sequential intracoronary microembolizations in 24 dogs. Two weeks after the last embolization, dogs were randomized to 3 mo of therapy with either high-dose (HD) PG (3.5 mg/kg, n = 8), low-dose (LD) PG (0.2 mg/kg, n = 8), or to a matched placebo (PL, n = 8). PG has been shown to produce complete inhibition of MMP-2, -3, -9, and -13, while sparing MMPs-1 and -7. Hemodynamic and echocardiographic measurements were made before and 3 mo after initiating therapy. In PL and LD dogs, LVEF decreased significantly, and LV end-systolic volume (ESV) and LV end-diastolic volume (EDV) increased significantly during the 3-mo follow-up period. Whereas in HD dogs ejection fraction increased from 36 +/- 1 to 40 +/- 1% (P = 0.003), EDV and ESV decreased (59 +/- 4 vs. 57 +/- 4 ml, P = 0.02; and 38 +/- 2 vs. 34 +/- 2 ml, P = 0.00001, respectively). When compared with controls, HD-treated dogs showed 30% reduction in replacement fibrosis, 29% reduction in interstitial fibrosis, and 28% reduction in myocyte cross-sectional area. mRNA expression of selective MMPs was also reduced in LV tissue in HD- but not LD-treated dogs. In conclusion, in dogs with moderate HF, long-term monotherapy with HD selective MMP inhibitor PG prevents LV remodeling and the progression of global LV dysfunction.
authors.affiliation: Department of Medicine, Division of Cardiovascular Medicine, Henry Ford Hospital, 2799 W. Grand Blvd., Detroit, MI 48202, USA.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Morita
authors.forename: Sanjaya
authors.initials: S
authors.lastname: Khanal
authors.forename: Sharad
authors.initials: S
authors.lastname: Rastogi
authors.forename: George
authors.initials: G
authors.lastname: Suzuki
authors.forename: Makoto
authors.initials: M
authors.lastname: Imai
authors.forename: Anastassia
authors.initials: A
authors.lastname: Todor
authors.forename: Victor G
authors.initials: VG
authors.lastname: Sharov
authors.forename: Sidney
authors.initials: S
authors.lastname: Goldstein
authors.forename: Timothy P
authors.initials: TP
authors.lastname: O'Neill
authors.forename: Hani N
authors.initials: HN
authors.lastname: Sabbah
mesh_terms: D000818:Animals; D002908:Chronic Disease; D017023:Coronary Angiography; D018450:Disease Progression; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D004617:Embolism / Q000503:physiopathology; D015870:Gene Expression; D006333:Heart Failure / Q000150:complications*; D006439:Hemodynamics / Q000502:physiology; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D018487:Ventricular Dysfunction, Left / Q000503:physiopathology / Q000517:prevention & control*; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D012333:RNA, Messenger