Selective Matrix Metalloproteinase Inhibition With Developing Heart Failure

Abstract

Abstract-The matrix metalloproteinases (MMPs) are an endogenous family of proteolytic enzymes implicated to contribute to LV remodeling. However, broad-spectrum MMP inhibition (MMPi), particularly inhibition of interstitial collagenase (MMP-1), may not be clinically applicable. This study examined the effects of selective MMPi (sparing MMP-1) in a model of developing congestive heart failure. Pigs were randomly assigned to 3 groups: (1) rapid pacing for 3 weeks (240 bpm, nϭ10); (2) selective MMPi (20 mg/kg per day-PO;PGE7113313) and rapid pacing (nϭ12); and (3) controls (nϭ10 Key Words: left ventricular systolic function Ⅲ myocardial stiffness Ⅲ myocardial structure Ⅲ matrix metalloproteinases Ⅲ heart failure A structural milestone in the progression of congestive heart failure (CHF) is alterations in left ventricular (LV) geometry, commonly referred to as myocardial remodeling. The myocardial extracellular matrix contributes to the maintenance of LV geometry, structural alignment of adjoining myocytes, as well as modulating transmembrane signaling pathways. A family of enzymes that contributes to extracellular collagen degradation and tissue remodeling is the matrix metalloproteinases (MMPs). 1-3 Increased expression and activity of MMPs within the LV myocardium occurs in both patients and animals with CHF. 4 -8 Orally active nonselective MMP inhibitors, termed as broad spectrum MMP inhibitors, have been used in several animal models of CHF and demonstrated to attenuate the LV remodeling process. 7-9 Therefore, modulating MMP activity represents a potential therapeutic target in the context of LV remodeling and CHF. However, long-term inhibition of all MMP species will likely interfere with normal tissue remodeling processes and can give rise to undesirable systemic effects. 10 -12 Thus, selective targeting of MMP species that contribute to pathological myocardial remodeling in developing CHF will likely hold greater therapeutic potential. Whereas a number of MMP species are expressed within the human myocardium, not all MMPs are upregulated in end-stage CHF. 6,13,14 Specifically, the abundance of interstitial collagenase-1, or MMP-1, is significantly reduced in patients with cardiomyopathic disease. 6 However, it remains unknown whether inhibition of MMP-1 is a fundamental requirement in order to alter the myocardial remodeling process during the initiation and development of CHF. Accordingly, the overall goal of this study was to institute selective MMP inhibition that would effectively spare MMP-1 inhibition in an animal model of developing CHF. Materials and Methods Selective MMP InhibitionPast studies have demonstrated that several classes of MMPs are increased in CHF including the interstitial collagenase MMP-13, stromelysins such as MMP-3, and the gelatinases such as MMP-2 and MMP-9. 4 -8,14 In order to identify an MMP inhibition dosage regimen that would provide acceptable plasma profiles with respect to inhibition of these species but effectively spare MMP-1 inhibition, pharmacokinetic studies were p...

Inhibition of Matrix Metalloproteinase Activity by TIMP-1 Gene Transfer Effectively Treats Ischemic Cardiomyopathy

“…13,14 However, clinical trials in patients with metastatic cancer have necessitated withdrawal of MMP inhibitor treatment secondary to the development of tendonitis and severe musculoskeletal pain. 15,16 In addition, MMP inhibition impairs wound healing after injury.…”

“…9 In animal models of diverse pathologic processes, pharmacologic inhibition of MMPs attenuated acute pancreatitis, 10 improved the strength of intestinal anastomoses, 11 decreased retinal neovascularization, 12 and inhibited ventricular remodeling. 13,14 However, systemic MMP inhibition was associated with severe musculoskeletal pain and tendonitis in clinical trials in patients with metastatic cancer, 15,16 necessitating treatment withdrawal in some cases. Systemic inhibition of MMP activity needs further investigation to demonstrate clinical viability without significant side effects.…”

Heart Failure and Sudden Death in Patients With Tachycardia-Induced Cardiomyopathy and Recurrent Tachycardia

“…The patients (42,36, and 44 years of age) had atrial fibrillation that caused cardiomyopathy (Table 3). None had new symptoms, and all had NYHA functional class I heart failure immediately before sudden, unexpected death, according to witnesses.…”

“…Cytoskeletal changes include increased ␤-actin, ␥-actin, and ␣-tubulin 34 ; alteration in matrix metalloproteinases (gelatinase, collagenase, and stromolysin) 35,36 ; and depletion of high energy stores. Atrial natriuretic peptide levels, renin-angiotensin, and endothelin activity change.…”

Xanthine Oxidase Inhibition and Heart Failure

“…13 Concomitant with these adverse effects on cardiomyocyte function, ROS stimulates a number of responses associated with the ventricular remodeling processes. These include ROS-mediated activation of matrix metalloproteinases to alter the architecture of the extracellular matrix, 14 modulation of signal transduction pathways that initiate cardiomyocyte hypertrophy, 15 and apoptosis or cell death. 16 Taken together, these observations suggest that one mechanism to halt deleterious ventricular remodeling and abnormal cardiomyocyte functional responses is to decrease oxidant stress by limiting ROS production.…”