Angiotensin-Converting Enzyme and Matrix Metalloproteinase Inhibition with Developing Heart Failure : Comparative Effects on Left Ventricular Function and Geometry 1

The progression of congestive heart failure (CHF) is left ventricular (LV) myocardial remodeling. The matrix metalloproteinases (MMPs) contribute to tissue remodeling and therefore MMP inhibition may serve as a useful therapeutic target in CHF. Angiotensin converting enzyme (ACE) inhibition favorably affects LV myocardial remodeling in CHF. This study examined the effects of specific MMP inhibition, ACE inhibition, and combined treatment on LV systolic and diastolic function in a model of CHF. Pigs were randomly assigned to five groups: 1) rapid atrial pacing (240 beats/min) for 3 weeks (n 5 8); 2) ACE inhibition (fosinopril, 2.5 mg/kg b.i.d. orally) and rapid pacing (n 5 8); 3) MMP inhibition (PD166793 2 mg/kg/day p.o.) and rapid pacing (n 5 8); 4) combined ACE and MMP inhibition (2.5 mg/kg b.i.d. and 2 mg/kg/day, respectively) and rapid pacing (n 5 8); and 5) controls (n 5 9). LV peak wall stress increased by 2-fold with rapid pacing and was reduced in all treatment groups. LV fractional shortening fell by nearly 2-fold with rapid pacing and increased in all treatment groups. The circumferential fiber shortening-systolic stress relation was reduced with rapid pacing and increased in the ACE inhibition and combination groups. LV myocardial stiffness constant was unchanged in the rapid pacing group, increased nearly 2-fold in the MMP inhibition group, and was normalized in the ACE inhibition and combination treatment groups. Increased MMP activation contributes to the LV dilation and increased wall stress with pacing CHF and a contributory downstream mechanism of ACE inhibition is an effect on MMP activity. A milestone in the development and progression of congestive heart failure (CHF) is alterations in left ventricular (LV) geometry, commonly referred to as myocardial remodeling. LV myocardial remodeling and subsequent chamber dilation have been associated with increased morbidity and mortality in patients with CHF. Angiotensin-converting enzyme (ACE) inhibition with developing CHF improves survival in patients with CHF, and a postulated mechanism for this beneficial effect is an attenuation of the LV remodeling process (Konstam et al., 1993; Greenberg et al., 1995) Thus, LV remodeling is probably an important structural contributory event in the progression to end-stage CHF. However, the cellular and molecular bases for the changes in LV geometry that occur during the progression of CHF remain poorly understood. An important constituent of the LV myocardium is the fibrillar collagen matrix, which has been proposed to contribute to the maintenance of LV geometry and the structural alignment of adjoining myocytes (Borg et al., 1990; Weber et al., 1992). Alterations in collagen structure and composition have been reported to occur within the LV myocardium in several cardiac disease states, which in turn may influence LV geometry (Weber et al., 1988b; Spinale et al., 1991a, 1995; Komamura et al., 1993; Gunja-Smith et al., 1996). An important consequence with respect to LV remodeling in CHF is alterations in LV wall stress patterns. Fundamental determinants of LV peak and systolic wall stress are chamber dimension and myocardial wall thickness. The progressive LV dilation and wall remodeling that occurs with CHF will result in increased LV wall stress, which in turn Received for publication April 22, 1999. 1 Supported by National Institutes of Health Grant HL-59165, HL-57952 (F.G.S.), and PO1 HL48788 (M.R.Z.) and an unrestricted Basic Research Grant from Parke-Davis (F.G.S.). 2 Present address: Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston, SC 29425. F.G.S. is an Established Investigator of the American Heart Association. 3 Present address: Division of Cardiology, Medical University of South Carolina, Charleston, SC 29425. 4 Present address: Pharmaceutical Research Division, Parke-Davis, Ann Arbor, MI 48105. ABBREVIATIONS: CHF, congestive heart failure; LV, left venticular; ACE, angiotensin-converting enzyme; MMP, matrix metalloproteinase; Ang-I, angiotensin I; PRSWR, preload recruitable stroke work relation; Vcfc, velocity of circumferential fiber shortening; Kc, chamber stiffness constant; Km, myocardial stiffness constant; TIMP, tissue inhibitor of matrix metalloproteinase; AP-1, activator protein 1. 0022-3565/99/2912-0799$03.00/0 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 291, No. 2 Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics Printed in U.S.A. JPET 291:799–811, 1999 799 at A PE T Jornals on A ril 5, 2017 jpet.asjournals.org D ow nladed from will be translated into a higher LV afterload to the compromised LV myocardium. Thus, the LV remodeling with CHF can directly contribute to the progression and/or exacerbation of the LV pump dysfunction that occurs in this disease state. These observations would support the concept that modulation of the LV myocardial remodeling process would be an important therapeutic strategy in the setting of developing CHF. An endogenous family of enzymes responsible for extracellular collagen degradation and remodeling is the matrix metalloproteinases (MMPs) (Hansen-Berkedal et al., 1993; Rees et al., 1993; Dollery et al., 1995). This laboratory and others have recently identified increased expression and activity of MMPs within the LV myocardium in both patients and animals with CHF (Gunja-Smith et al., 1996; Spinale et al., 1998; Thomas, 1998). The recent development of bioavailable MMP inhibitors makes it possible to modulate MMP activity in vivo and to assess the effects of MMP inhibition on the tissue remodeling process (Hodgson, 1995; Taraboletti et al., 1995; Watson et al., 1996). Accordingly, the first goal of this study was to identify the effects of MMP inhibition on indices of LV geometry and function with developing CHF. In light of the fact that ACE inhibition influences LV geometry and function with CHF, the second goal of this study was to quantitatively determine the potential synergistic/additive effects of combined ACE and MMP inhibition on LV geometry and function with CHF. Chronic rapid pacing in animals causes a spectrum of changes in LV functional and neurohormonal profiles that resemble the clinical phenotype of dilated cardiomyopathy (Spinale, 1991a; Spinale et al., 1991b, 1995, 1997, 1998; Tomita et al., 1991; Komamura et al., 1993). This model of pacing induced CHF causes progressive LV dilation and myocardial remodeling, which is accompanied by both systolic and diastolic dysfunction (Tomita et al., 1991; Komamura, 1993). More recently, it has been demonstrated that MMP activity was increased early in the progression of pacing CHF and was temporally related to the onset of the LV dilation and pump dysfunction (Spinale et al., 1998). Accordingly, this model of CHF was used in the present study to examine the effects of MMP inhibition, ACE inhibition, or combination treatment on indices of LV systolic and diastolic performance. Materials and Methods Rationale. The first objective of this study was to select an appropriate dosing strategy for MMP inhibition. A large number of MMP species exists that possess differential substrate specificities (Hansen-Birkedal et al., 1993; Rees et al., 1993; Werb and Alexander, 1993; Dollery et al., 1995; Nagase, 1997). To examine the generalized effects of MMP inhibition on LV remodeling, the present study used an MMP inhibitor that would provide global plasma MMP inhibitory activity. The second objective was to establish the dosing strategy for ACE inhibition and combined MMP inhibition. For these studies, the criterion for adequate ACE inhibition was to effectively inhibit the pressor response to an angiotensin I (Ang-I) infusion without producing hemodynamic instability (Spinale et al., 1995, 1997). After identification of the dosing regimen, treatment with MMP inhibition, ACE inhibition, or combined inhibition was initiated in chronically instrumented pigs undergoing rapid pacing. LV size and function were measured with each week, and after 21 days of concomitant treatment and rapid pacing, terminal studies were performed in which LV systolic and diastolic function were examined. For comparison purposes, age-matched pigs that underwent chronic pacing without treatment as well as sham controls were used. Dose Selection Studies. Ten Yorkshire pigs (20 kg, male; Orangeburg, Hambone Farms, SC) were chronically instrumented to measure aortic blood pressure in the conscious state as described previously (Spinale et al., 1997, 1998). Briefly, under isoflurane anesthesia (3% in 1.5 l/min oxygen) and through a left thoracotomy, a catheter connected to a vascular access port (model GPV, 9F; Access Technologies, Skokie, IL) was placed in the thoracic aorta and sutured in place. The access port was buried in a s.c. pocket over the thoracolumbar fascia. After a recovery period of 7 to 10 days, the animal was returned to the laboratory for an initial Ang-I pressor response study. For these studies, the animals were sedated with diazepam (20 mg p.o. valium; Hoffmann-La Roche Inc., Nutley, NJ) and placed in a custom-designed sling that allowed the animal to rest comfortably. The vascular access port was entered with a 20-gauge Huber needle (Access Technologies) and resting aortic pressure and heart rate were recorded. Pressures from the fluid-filled aortic catheter were obtained with an externally calibrated transducer (Statham P23ID; Gould Inc., Oxnard, CA). The ECG and pressure waveforms were recorded and digitized to computer for subsequent analysis at a sampling frequency of 100 Hz (NI-DAQ; National Instruments, Austin, TX). Following these baseline measurements, Ang-I (10 mg; Sigma Chemical Company, St. Louis, MO) was administered through the access port and measurements recorded 10 min after