© 1999 American Heart Association, Inc.
Integrative Physiology |
Matrix Metalloproteinase Inhibition During the Development of Congestive Heart Failure
Effects on Left Ventricular Dimensions and Function
From the Division of Cardiothoracic Surgery (F.G.S., M.L.C., S.R.K., R.P., W.V.H., M.J.C., S.B.K., M.R.Z.), Medical University of South Carolina, Charleston, and Cardiovascular Pharmacology (H.H., L.L.J., J.T.P.), Parke-Davis, Ann Arbor, Mich.
Correspondence to Francis G. Spinale, MD, PhD, Cardiothoracic Surgery, Room 625, Strom Thurmond Research Building, 770 MUSC Complex, Medical University of South Carolina, 114 Doughty St, Charleston, SC 29425.
Abstract—The development of congestive heart failure (CHF) is associated with left ventricle (LV) dilation and myocardial remodeling. The matrix metalloproteinases (MMPs) play a significant role in extracellular remodeling, and recent studies have demonstrated increased MMP expression and activity with CHF. Whether increased MMP activity directly contributes to the LV remodeling with CHF remains unknown. Accordingly, this study examined the effects of chronic MMP inhibition (MMPi) on LV size and function during the progression of CHF. Pigs were assigned to the following groups: (1) CHF, rapid pacing for 3 weeks at 240 bpm (n=12); (2) CHF/MMPi, rapid pacing and concomitant MMPi (PD166793, 20 mg/kg per day [n=10]), and (3) control (n=11). With pacing CHF, LV fractional shortening was reduced (19±1 versus 45±1%), and end-diastolic dimension increased (5.67±0.11 versus 3.55±0.05 cm), compared with baseline values (P<0.05). In the CHF/MMPi group, LV endocardial shortening increased (25±2%) and the end-diastolic dimension was reduced (4.92±0.17 cm) compared with CHF-only values (P<0.05). LV midwall shortening was reduced to a comparable degree in the CHF-only and CHF/MMPi groups. LV peak wall stress increased 3-fold with pacing CHF compared with controls and was significantly reduced in the CHF/MMPi group. LV myocardial stiffness was unchanged with CHF but was increased in the CHF/MMPi group. LV myocyte length was increased with pacing CHF compared with controls (180±3 versus 125±4 µm, P<0.05) and was reduced in the CHF/MMPi group (169±4 µm, P<0.05). Basal-state myocyte shortening velocity was reduced with pacing CHF compared with controls (33±2 versus 66±1 µm/s, P<0.05) and was unchanged in the CHF/MMPi group (31±2 µm/s). Using an ex vivo assay system, myocardial MMP activity was increased with pacing CHF and was reduced with chronic MMPi. In summary, concomitant MMPi with developing CHF limited LV dilation and reduced wall stress. These results suggest that increased myocardial MMP activity contributes to LV myocardial remodeling in developing CHF.
Key Words: congestive heart failure • metalloproteinases • myocyte function
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J. G.F Bronzwaer, C. Zeitz, C. A Visser, and W. J Paulus Endomyocardial nitric oxide synthase and the hemodynamic phenotypes of human dilated cardiomyopathy and of athlete's heart Cardiovasc Res, August 1, 2002; 55(2): 270 - 278. [Abstract] [Full Text] [PDF]
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R. Nakamura, K. Egashira, Y. Machida, S. Hayashidani, M. Takeya, H. Utsumi, H. Tsutsui, and A. Takeshita Probucol Attenuates Left Ventricular Dysfunction and Remodeling in Tachycardia-Induced Heart Failure: Roles of Oxidative Stress and Inflammation Circulation, July 16, 2002; 106(3): 362 - 367. [Abstract] [Full Text] [PDF]
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J. D. Stroud, C. F. Baicu, M. A. Barnes, F. G. Spinale, and M. R. Zile Viscoelastic properties of pressure overload hypertrophied myocardium: effect of serine protease treatment Am J Physiol Heart Circ Physiol, June 1, 2002; 282(6): H2324 - H2335. [Abstract] [Full Text] [PDF]
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M. M. Thompson and I. B. Squire Matrix metalloproteinase-9 expression after myocardial infarction: physiological or pathological? Cardiovasc Res, June 1, 2002; 54(3): 495 - 498. [Full Text] [PDF]
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Y. Iwanaga, T. Aoyama, Y. Kihara, Y. Onozawa, T. Yoneda, and S. Sasayama Excessive activation of matrix metalloproteinases coincides with left ventricular remodeling during transition from hypertrophy to heart failure in hypertensive rats J. Am. Coll. Cardiol., April 17, 2002; 39(8): 1384 - 1391. [Abstract] [Full Text] [PDF]
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W. S. Bradham, G. Moe, K. A. Wendt, A. A. Scott, A. Konig, M. Romanova, G. Naik, and F. G. Spinale TNF-alpha and myocardial matrix metalloproteinases in heart failure: relationship to LV remodeling Am J Physiol Heart Circ Physiol, April 1, 2002; 282(4): H1288 - H1295. [Abstract] [Full Text] [PDF]
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M. R. Zile and D. L. Brutsaert New Concepts in Diastolic Dysfunction and Diastolic Heart Failure: Part II: Causal Mechanisms and Treatment Circulation, March 26, 2002; 105(12): 1503 - 1508. [Full Text] [PDF]
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F. G. Spinale Matrix Metalloproteinases: Regulation and Dysregulation in the Failing Heart Circ. Res., March 22, 2002; 90(5): 520 - 530. [Abstract] [Full Text] [PDF]
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M. R. Zile and D. L. Brutsaert New Concepts in Diastolic Dysfunction and Diastolic Heart Failure: Part I: Diagnosis, Prognosis, and Measurements of Diastolic Function Circulation, March 19, 2002; 105(11): 1387 - 1393. [Full Text] [PDF]
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P. W.M. Fedak, R. D. Weisel, T. M. Yau, D. A.G. Mickle, and R.-K. Li Cell transplantation, ventricular remodeling, and the extracellular matrix J. Thorac. Cardiovasc. Surg., March 1, 2002; 123(3): 584 - 585. [Full Text]
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Y. Y. Li, T. Kadokami, P. Wang, C. F. McTiernan, and A. M. Feldman MMP inhibition modulates TNF-alpha transgenic mouse phenotype early in the development of heart failure Am J Physiol Heart Circ Physiol, March 1, 2002; 282(3): H983 - H989. [Abstract] [Full Text] [PDF]
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W. S. Bradham, B. Bozkurt, H. Gunasinghe, D. Mann, and F. G. Spinale Tumor necrosis factor-alpha and myocardial remodeling in progression of heart failure: a current perspective Cardiovasc Res, March 1, 2002; 53(4): 822 - 830. [Abstract] [Full Text] [PDF]
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T. Walther, A. Schubert, V. Falk, C. Binner, A. Kanev, S. Bleiziffer, C. Walther, N. Doll, R. Autschbach, and F. W. Mohr Regression of Left Ventricular Hypertrophy After Surgical Therapy for Aortic Stenosis Is Associated With Changes in Extracellular Matrix Gene Expression Circulation, September 18, 2001; 104 (2009): I-54 - I-58. [Abstract] [Full Text] [PDF]
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T. Etoh, C. Joffs, A. M. Deschamps, J. Davis, K. Dowdy, J. Hendrick, S. Baicu, R. Mukherjee, M. Manhaini, and F. G. Spinale Myocardial and interstitial matrix metalloproteinase activity after acute myocardial infarction in pigs Am J Physiol Heart Circ Physiol, September 1, 2001; 281(3): H987 - H994. [Abstract] [Full Text] [PDF]
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N. Sivasubramanian, M. L. Coker, K. M. Kurrelmeyer, W. R. MacLellan, F. J. DeMayo, F. G. Spinale, and D. L. Mann Left Ventricular Remodeling in Transgenic Mice With Cardiac Restricted Overexpression of Tumor Necrosis Factor Circulation, August 14, 2001; 104(7): 826 - 831. [Abstract] [Full Text] [PDF]
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E. E.J.M. Creemers, J. P.M. Cleutjens, J. F.M. Smits, and M. J.A.P. Daemen Matrix Metalloproteinase Inhibition After Myocardial Infarction: A New Approach to Prevent Heart Failure? Circ. Res., August 3, 2001; 89(3): 201 - 210. [Abstract] [Full Text] [PDF]
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M. L. Coker, J. R. Jolly, C. Joffs, T. Etoh, J. R. Holder, B. R. Bond, and F. G. Spinale Matrix metalloproteinase expression and activity in isolated myocytes after neurohormonal stimulation Am J Physiol Heart Circ Physiol, August 1, 2001; 281(2): H543 - H551. [Abstract] [Full Text] [PDF]
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S. M. Dolgilevich, F. M. Siri, S. A. Atlas, and C. Eng Changes in collagenase and collagen gene expression after induction of aortocaval fistula in rats Am J Physiol Heart Circ Physiol, July 1, 2001; 281(1): H207 - H214. [Abstract] [Full Text] [PDF]
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J. T. Peterson, H. Hallak, L. Johnson, H. Li, P. M. O'Brien, D. R. Sliskovic, T. M. A. Bocan, M. L. Coker, T. Etoh, and F. G. Spinale Matrix Metalloproteinase Inhibition Attenuates Left Ventricular Remodeling and Dysfunction in a Rat Model of Progressive Heart Failure Circulation, May 8, 2001; 103(18): 2303 - 2309. [Abstract] [Full Text] [PDF]
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B. K. Podesser, D. A. Siwik, F. R. Eberli, F. Sam, S. Ngoy, J. Lambert, K. Ngo, C. S. Apstein, and W. S. Colucci ETA-receptor blockade prevents matrix metalloproteinase activation late postmyocardial infarction in the rat Am J Physiol Heart Circ Physiol, March 1, 2001; 280(3): H984 - H991. [Abstract] [Full Text] [PDF]
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D. A. Siwik, P. J. Pagano, and W. S. Colucci Oxidative stress regulates collagen synthesis and matrix metalloproteinase activity in cardiac fibroblasts Am J Physiol Cell Physiol, January 1, 2001; 280(1): C53 - C60. [Abstract] [Full Text] [PDF]
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 Y. Y. Li, Y. Q. Feng, T. Kadokami, C. F. McTiernan, R. Draviam, S. C. Watkins, and A. M. Feldman Myocardial extracellular matrix remodeling in transgenic mice overexpressing tumor necrosis factor alpha can be modulated by anti-tumor necrosis factor alpha therapy PNAS, November 7, 2000; 97(23): 12746 - 12751. [Abstract] [Full Text] [PDF]
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P. Libby and R. T. Lee Matrix Matters Circulation, October 17, 2000; 102(16): 1874 - 1876. [Full Text] [PDF]
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D. A. Siwik, D. L.-F. Chang, and W. S. Colucci Interleukin-1{beta} and Tumor Necrosis Factor-{alpha} Decrease Collagen Synthesis and Increase Matrix Metalloproteinase Activity in Cardiac Fibroblasts In Vitro Circ. Res., June 23, 2000; 86(12): 1259 - 1265. [Abstract] [Full Text] [PDF]
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Y. Y. Li, C. F. McTiernan, and A. M. Feldman Interplay of matrix metalloproteinases, tissue inhibitors of metalloproteinases and their regulators in cardiac matrix remodeling Cardiovasc Res, May 1, 2000; 46(2): 214 - 224. [Abstract] [Full Text] [PDF]
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F. G Spinale, M. L Coker, B. R Bond, and J. L Zellner Myocardial matrix degradation and metalloproteinase activation in the failing heart: a potential therapeutic target Cardiovasc Res, May 1, 2000; 46(2): 225 - 238. [Abstract] [Full Text] [PDF]
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H. Li, H. Simon, T. M.A. Bocan, and J.T. Peterson MMP/TIMP expression in spontaneously hypertensive heart failure rats: the effect of ACE- and MMP-inhibition Cardiovasc Res, May 1, 2000; 46(2): 298 - 306. [Abstract] [Full Text] [PDF]
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J.T. Peterson, H. Li, L. Dillon, and J. W. Bryant Evolution of matrix metalloprotease and tissue inhibitor expression during heart failure progression in the infarcted rat Cardiovasc Res, May 1, 2000; 46(2): 307 - 315. [Abstract] [Full Text] [PDF]
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M. L. Lindsey, J. Gannon, M. Aikawa, F. J. Schoen, E. Rabkin, L. Lopresti-Morrow, J. Crawford, S. Black, P. Libby, P. G. Mitchell, et al. Selective Matrix Metalloproteinase Inhibition Reduces Left Ventricular Remodeling but Does Not Inhibit Angiogenesis After Myocardial Infarction Circulation, February 12, 2002; 105(6): 753 - 758. [Abstract] [Full Text] [PDF]
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A. L. Chancey, G. L. Brower, J. T. Peterson, and J. S. Janicki Effects of Matrix Metalloproteinase Inhibition on Ventricular Remodeling Due to Volume Overload Circulation, April 23, 2002; 105(16): 1983 - 1988. [Abstract] [Full Text] [PDF]
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