Objective: Previous studies have demonstrated that an imbalance of matrix metalloproteinases (MMPs)/tissue inhibitors of metalloproteinase-1 (TIMP-1) and a loss of fibronectin are associated with postmyocardial infarction remodeling in rats. The present study was designed to examine this issue in patients with congestive heart failure (CHF). Methods: We measured plasma levels and the cardiac protein expression of MMPs/TIMP-1 and fibronectin in 39 patients with CHF and 38 controls. Results: Plasma levels of MMP-2, MMP-3, and MMP-9 tended to be higher in patients with CHF (NYHA II: 276 ± 18, 613 ± 118, and 245 ± 43 µg/l, respectively; NYHA III: 302 ± 20, 850 ± 132, and 310 ± 39 µg/l, respectively; NYHA IV: 367 ± 15, 998 ± 99, and 392 ± 27 µg/l, respectively) than in controls (213 ± 23, 485 ± 102, and 158 ± 31 µg/l, respectively), while the plasma TIMP-1 level tended to be lower in patients with CHF (NYHA II: 126 ± 12 µg/l, NYHA III: 83 ± 11 µg/l, and NYHA IV: 61 ± 12 µg/l) than in controls (208 ± 15 µg/l). Interestingly, the changes in protein expression of MMPs/TIMP-1 were consistent with their plasma concentration. Furthermore, the fibronectin level in the patients with CHF was significantly lower than in the controls. Conclusions: These data suggest that human CHF is associated with an imbalance of MMPs/TIMP-1 and a concurrent loss of fibronectin.

1.
Rodriguez-Artalejo F, Guallar-Castillon P, Banegas Banegas JR, del Rey Calero J: Trends in hospitalization and mortality for heart failure in Spain, 1980–1993. Eur Heart J 1997;18:1771–1779.
2.
Takano H, Hasegawa H, Nagai T, Komuro I: Implication of cardiac remodeling in heart failure: mechanisms and therapeutic strategies. Intern Med 2003;42:465–469.
3.
Florea VG, Mareyev VY, Samko AN, Orlova IA, Coats AJ, Belenkov YN: Left ventricular remodelling: common process in patients with different primary myocardial disorders. Int J Cardiol 1999;68:281–287.
4.
Hilfiker-Kleiner D, Landmesser U, Drexler H: Molecular mechanisms in heart failure: focus on cardiac hypertrophy, inflammation, angiogenesis, and apoptosis. J Am Coll Cardiol 2006;48:56–66.
5.
Sutton MG, Sharpe N: Left ventricular remodeling after myocardial infarction: pathophysiology and therapy. Circulation 2000;101:2981–2988.
6.
Borer JS, Herrold EM, Carter JN, Catanzaro DF, Supino PG: Cellular and molecular basis of remodeling in valvular heart diseases. Heart Fail Clin 2006;2:415–424.
7.
Brower GL, Gardner JD, Forman MF, Murray DB, Voloshenyuk T, Levick SP, Janicki JS: The relationship between myocardial extracellular matrix remodeling and ventricular function. Eur J Cardiothorac Surg 2006;30:604–610.
8.
Zamilpa R, Lindsey ML: Extracellular matrix turnover and signaling during cardiac remodeling following MI: causes and consequences. J Mol Cell Cardiol 2010;48:558–563.
9.
Visse R, Nagase H: Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ Res 2003;92:827–839.
10.
Yarbrough WM, Mukherjee R, Brinsa TA, Dowdy KB, Scott AA, Escobar GP, Joffs C, Lucas DG, Crawford FA Jr, Spinale FG: Matrix metalloproteinase inhibition modifies left ventricular remodeling after myocardial infarction in pigs. J Thorac Cardiovasc Surg 2003;125:602–610.
11.
Chen CL, Huang SK, Lin JL, Lai LP, Lai SC, Liu CW, Chen WC, Wen CH, Lin CS: Upregulation of matrix metalloproteinase-9 and tissue inhibitors of metalloproteinases in rapid atrial pacing-induced atrial fibrillation. J Mol Cell Cardiol 2008;45:742–753.
12.
Thomas CV, Coker ML, Zellner JL, Handy JR, Crumbley AJ 3rd, Spinale FG: Increased matrix metalloproteinase activity and selective upregulation in LV myocardium from patients with end-stage dilated cardiomyopathy. Circulation 1998;97:1708–1715.
13.
Gunja-Smith Z, Morales AR, Romanelli R, Woessner JF Jr: Remodeling of human myocardial collagen in idiopathic dilated cardiomyopathy: role of metalloproteinases and pyridinoline cross-links. Am J Pathol 1996;148:1639–1648.
14.
Spinale FG, Coker ML, Thomas CV, Walker JD, Mukherjee R, Hebbar L: Time-dependent changes in matrix metalloproteinase activity and expression during the progression of congestive heart failure: relation to ventricular and myocyte function. Circ Res 1998;82:482–495.
15.
McElmurray JH 3rd, Mukherjee R, New RB, Sampson AC, King MK, Hendrick JW, Goldberg A, Peterson TJ, Hallak H, Zile MR, Spinale FG: Angiotensin-converting enzyme and matrix metalloproteinase inhibition with developing heart failure: comparative effects on left ventricular function and geometry. J Pharmacol Exp Ther 1999;291:799–811.
16.
Chancey AL, Brower GL, Peterson JT, Janicki JS: Effects of matrix metalloproteinase inhibition on ventricular remodeling due to volume overload. Circulation 2002;105:1983–1988.
17.
Yang D, Ma S, Li D, Tang B, Yang Y: Angiotensin II receptor blockade improves matrix metalloproteinases/tissue inhibitor of matrix metalloproteinase-1 balance and restores fibronectin expression in rat infarcted myocardium. Biochem Biophys Res Commun 2009;388:606–611.
18.
Peterson JT, Hallak H, Johnson L, Li H, O’Brien PM, Sliskovic DR, Bocan TM, Coker ML, Etoh T, Spinale FG: Matrix metalloproteinase inhibition attenuates left ventricular remodeling and dysfunction in a rat model of progressive heart failure. Circulation 2001;103:2303–2309.
19.
Lindsey ML, Gannon J, Aikawa M, Schoen FJ, Rabkin E, Lopresti-Morrow L, Crawford J, Black S, Libby P, Mitchell PG, Lee RT: Selective matrix metalloproteinase inhibition reduces left ventricular remodeling but does not inhibit angiogenesis after myocardial infarction. Circulation 2002;105:753–758.
20.
van den Borne SW, Cleutjens JP, Hanemaaijer R, Creemers EE, Smits JF, Daemen MJ, Blankesteijn WM: Increased matrix metalloproteinase-8 and -9 activity in patients with infarct rupture after myocardial infarction. Cardiovasc Pathol 2009;18:37–43.
21.
Squire IB, Evans J, Ng LL, Loftus IM, Thompson MM: Plasma MMP-9 and MMP-2 following acute myocardial infarction in man: correlation with echocardiographic and neurohumoral parameters of left ventricular dysfunction. J Card Fail 2004;10:328–333.
22.
Spinale FG, Coker ML, Heung LJ, Bond BR, Gunasinghe HR, Etoh T, Goldberg AT, Zellner JL, Crumbley AJ: A matrix metalloproteinase induction/activation system exists in the human left ventricular myocardium and is upregulated in heart failure. Circulation 2000;102:1944–1949.
23.
Sawicki G, Menon V, Jugdutt BI: Improved balance between TIMP-3 and MMP-9 after regional myocardial ischemia-reperfusion during AT1 receptor blockade. J Card Fail 2004;10:442–449.
24.
Nagase H, Visse R, Murphy G: Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc Res 2006;69:562–573.
25.
Cleutjens JP: The role of matrix metalloproteinases in heart disease. Cardiovasc Res 1996;32:816–821.
26.
Peterson JT, Li H, Dillon L, Bryant JW: Evolution of matrix metalloprotease and tissue inhibitor expression during heart failure progression in the infarcted rat. Cardiovasc Res 2000;46:307–315.
27.
Romanic AM, Burns-Kurtis CL, Gout B, Berrebi-Bertrand I, Ohlstein EH: Matrix metalloproteinase expression in cardiac myocytes following myocardial infarction in the rabbit. Life Sci 2001;68:799–814.
28.
Lindsey ML: MMP induction and inhibition in myocardial infarction. Heart Fail Rev 2004;9:7–19.
29.
Brower GL, Levick SP, Janicki JS: Inhibition of matrix metalloproteinase activity by ACE inhibitors prevents left ventricular remodeling in a rat model of heart failure. Am J Physiol Heart Circ Physiol 2007;292:H3057–H3064.
30.
Jaworski DM, Fager N: Regulation of tissue inhibitor of metalloproteinase-3 (Timp-3) mRNA expression during rat CNS development. J Neurosci Res 2000;61:396–408.
31.
Creemers EE, Davis JN, Parkhurst AM, Leenders P, Dowdy KB, Hapke E, Hauet AM, Escobar PG, Cleutjens JP, Smits JF, Daemen MJ, Zile MR, Spinale FG: Deficiency of TIMP-1 exacerbates LV remodeling after myocardial infarction in mice. Am J Physiol Heart Circ Physiol 2003;284:H364–H371.
32.
Jourquin J, Tremblay E, Bernard A, Charton G, Chaillan FA, Marchetti E, Roman FS, Soloway PD, Dive V, Yiotakis A, Khrestchatisky M, Rivera S: Tissue inhibitor of metalloproteinases-1 (TIMP-1) modulates neuronal death, axonal plasticity, and learning and memory. Eur J Neurosci 2005;22:2569–2578.
33.
Abou-Raya S, Naim A, Marzouk S: Cardiac matrix remodelling in congestive heart failure: the role of matrix metalloproteinases. Clin Invest Med 2004;27:93–100.
34.
Heeneman S, Cleutjens JP, Faber BC, Creemers EE, van Suylen RJ, Lutgens E, Cleutjens KB, Daemen MJ: The dynamic extracellular matrix: intervention strategies during heart failure and atherosclerosis. J Pathol 2003;200:516–525.
35.
Mann DL, Taegtmeyer H: Dynamic regulation of the extracellular matrix after mechanical unloading of the failing human heart: recovering the missing link in left ventricular remodeling. Circulation 2001;104:1089–1091.
36.
Berk BC, Fujiwara K, Lehoux S: ECM remodeling in hypertensive heart disease. J Clin Invest 2007;117:568–575.
37.
Spinale FG: Myocardial matrix remodeling and the matrix metalloproteinases: influence on cardiac form and function. Physiol Rev 2007;87:1285–1342.
38.
Carlyle WC, Jacobson AW, Judd DL, Tian B, Chu C, Hauer KM, Hartman MM, McDonald KM: Delayed reperfusion alters matrix metalloproteinase activity and fibronectin mRNA expression in the infarct zone of the ligated rat heart. J Mol Cell Cardiol 1997;29:2451–2463.
39.
Mamuya WS, Brecher P: Fibronectin expression in the normal and hypertrophic rat heart. J Clin Invest 1992;89:392–401.
40.
Gunduz K, Demireli P, Inanir I, Nese N: Expression of matrix metalloproteinases (MMP-2, MMP-3, and MMP-9) and fibronectin in lichen planus. J Cutan Pathol 2006;33:545–550.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.