Publication Detail

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Selective matrix metalloproteinase inhibition attenuates progression of left ventricular dysfunction and remodeling in dogs with chronic heart failure.

Hideaki Morita; Sanjaya Khanal; Sharad Rastogi; George Suzuki; Makoto Imai; Anastassia Todor; Victor G Sharov; Sidney Goldstein; Timothy P O'Neill; Hani N Sabbah (Profiled Author: Hani N Sabbah)

Department of Medicine, Division of Cardiovascular Medicine, Henry Ford Hospital, 2799 W. Grand Blvd., Detroit, MI 48202, USA.
American journal of physiology. Heart and circulatory physiology 2006;290(6):H2522-7.

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.

1 Originating Grant

• 1.

  Sabbah, Hani N

  PROGRESSION OF HEART FAILURE

  1 April 1994 - 31 December 2003

  NATIONAL HEART, LUNG, AND BLOOD INSTITUTE

  Total Funding: $ 2,329,997

Scientific Context

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