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

Abstract

Selective matrix metalloproteinase inhibition attenuates progression of left ventricular dysfunction and remodeling in dogs with chronic heart failure. Am J Physiol Heart Circ Physiol 290: H2522-H2527, 2006. First published January 20, 2006 doi:10.1152/ajpheart.00932.2005 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), Յ36%] 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 ϭ 8), low-dose (LD) PG (0.2 mg/kg, n ϭ 8), or to a matched placebo (PL, n ϭ 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 Ϯ 1 to 40 Ϯ 1% (P ϭ 0.003), EDV and ESV decreased (59 Ϯ 4 vs. 57 Ϯ 4 ml, P ϭ 0.02; and 38 Ϯ 2 vs. 34 Ϯ 2 ml, P ϭ 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.hemodynamics; PG-530742; left ventricular ejection fraction THE BALANCE BETWEEN extracellular matrix synthesis and degradation has been considered to play a key role in maintaining left ventricular (LV) geometry and function. The extracellular matrix provides structural support for myocyte alignment and blood vessels (26,27). It also coordinates the conversion of myocyte contraction into myocardial force. Furthermore, it can affect myocardial stiffness and diastolic function (26,27).Matrix metalloproteinases (MMPs) are enzymes responsible for proteolytic degradation of specific extracellular matrix components. MMPs are synthesized as inactive zymogens and secreted into the extracellular space. MMPs have been shown to be involved in a variety of pathological and healing processes, such as tumor growth and metastasis, rheumatoid arthritis, and periodontal disease. In the cardiovascular field, it is now becoming clear that extracellular matrix degradation is involved in the pathogenesis of atherosclerosis, restenosis, dilated cardiomyopathy, and myocardial infarction.Expression and activity of MMPs are elevated in both patients and experimental animal mo...

Myocardial Matrix Remodeling and the Matrix Metalloproteinases: Influence on Cardiac Form and Function

“…In this model, multiple discrete areas of myocardial injury occur that are accompanied by degradation of the normal matrix and focal fibrosis. Moreover, both pharmacological and mechanical strategies that reduced the degree of LV dilation in this canine model of DCM were associated with a favorable directional change in myocardial MMP levels (282,347). In the rapid-pacing pig model, a direct temporal relationship was observed between relative increases in certain myocardial MMP levels and LV remodeling (408,526).…”

“…Two animal models that reasonably recapitulate ischemic DCM and idiopathic DCM are the microembolization model and the rapid pacing model, respectively (202,282,347,408). While there are inherent limitations in both of these model systems of DCM (526), these largeanimal models allow for deriving relationships between the LV remodeling process and changes in relative myocardial MMPs.…”

“…While there are inherent limitations in both of these model systems of DCM (526), these largeanimal models allow for deriving relationships between the LV remodeling process and changes in relative myocardial MMPs. In the canine model of repetitive coronary microembolization, LV dilation and dysfunction occurs that is accompanied by increased levels of MMP-2, -3, and -13 (282,347). In this model, multiple discrete areas of myocardial injury occur that are accompanied by degradation of the normal matrix and focal fibrosis.…”

Telmisartan, a unique ARB, improves left ventricular remodeling of infarcted heart by activating PPAR gamma

“…[30][31][32] Recent studies using MMP knockout mice or administration of MMP inhibitors have provided insights into the involvement of particular MMP species in unfavorable LV remodeling after MI. [33][34][35][36] In this study, the area of myocardial fibrosis, TGF-b1 protein level, CTGF and OPN mRNA levels, and the activity of MMP-2 and MMP-9 were all increased in the noninfarcted myocardium 7 days after induction of MI compared with sham-operated rats.…”

Oxidized Low-Density Lipoprotein Cholesterol Is Associated With Decreases in Cardiac Function Independent of Vascular Alterations

“…45,46 In these models, increased sphericity can be prevented by selective matrix metalloproteinase inhibition. 47 Further studies with novel functional parameters (strain and strain-rate analysis) are eagerly awaited.…”