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Matrix metalloproteinase therapy in heart failure

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Opinion statement

Milestones in the progression to heart failure following myocardial infarction (MI) are changes in left ventricular (LV) geometry and function, termed post-MI remodeling. Critical to this adverse remodeling process are changes in the expression, synthesis, and degradation of myocardial extracellular matrix (ECM) proteins. The myocardial ECM is not a passive entity but a complex and dynamic microenvironment that represents an important structural and signaling system within the myocardium. In particular, basic and clinical studies have provided conclusive evidence that abnormal and persistent activation of the ECM degradation pathway, notably through the matrix metalloproteinases (MMPs), contribute to adverse post-MI remodeling. This review examines recent clinical studies that provide further support to the hypothesis that a specific portfolio of MMPs are diagnostic and likely contributory to LV remodeling and the progression to heart failure after MI. Future translational and clinical research focused on the molecular and cellular mechanisms regulating ECM structure and function likely will contribute to an improved understanding of post-MI LV remodeling and yield novel therapeutic targets.

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References and Recommended reading

  1. Spinale FG: Matrix remodeling and the matrix metalloproteinases: influence on cardiac form and function. Physiol Rev 2007, 87:1285–1342.

    Article  PubMed  CAS  Google Scholar 

  2. Chapman RE, Spinale FG. Extracellular protease activation and unraveling of the myocardial interstitium: critical steps toward clinical applications. Am J Physiol 2004, 286:H1–H10.

    CAS  Google Scholar 

  3. Spinale FG, Coker ML, Heung LJ, et al.: A matrix metalloproteinase induction/activation system exists in the human left ventricular myocardium and is upregulated in heart failure. Circulation 2000, 102:1944–1949.

    PubMed  CAS  Google Scholar 

  4. Gunja-Smith Z, Morales AR, Romanelli R, Woessner JF: Remodeling of human myocardial collagen in idiopathic dilated cardiomyopathy: role of metalloproteinases and pyridinoline cross links. Am J Pathol 1996, 148:1639–1648.

    PubMed  CAS  Google Scholar 

  5. Spinale FG, Krombach RS, Coker ML, et al.: Matrix metalloproteinase inhibition during developing congestive heart failure in pigs: effects on left ventricular geometry and function. Circ Res 1999, 85;364–376.

    PubMed  CAS  Google Scholar 

  6. Creemers E, Davis JN, Parkhurst AM, et al.: Deficiency of the tissue inhibitor of matrix metalloproteinase-1 gene exacerbates LV remodeling following myocardial infarction in mice. Am J Physiol 2003, 284:H364–H371.

    CAS  Google Scholar 

  7. Heymans S, Luttun A, Nuyens D, et al.: Inhibition of plasminogen activators or matrix metalloproteinases prevents cardiac rupture but impairs therapeutic angiogenesis and causes cardiac failure. Nat Med 1999, 5:1135–1142.

    Article  PubMed  CAS  Google Scholar 

  8. Ducharme A, Frantz S, Aikawa M, et al.: Targeted deletion of matrix metalloproteinase-9 attenuates left ventricular enlargement and collagen accumulation after experimental myocardial infarction. J Clin Invest 2000, 106:55–62.

    Article  PubMed  CAS  Google Scholar 

  9. Li YY, Feng Y, McTiernan CF, et al.: Downregulation of matrix metalloproteinases and reduction in collagen damage in the failing human heart after support with left ventricular assist devices. Circulation 2001, 104:1147–1152.

    Article  PubMed  CAS  Google Scholar 

  10. Su H, Spinale FG, Dobrucki LW, et al.: Noninvasive targeted imaging of matrix metalloproteinase activation in a murine model of postinfarction remodeling. Circulation 2005, 112:3157–3167.

    Article  PubMed  CAS  Google Scholar 

  11. Doughty RN, Whalley GA, Gamble G, et al.: Left ventricular remodeling with carvedilol in patients with congestive heart failure due to ischemic heart disease. J Am Coll Cardiol 1997, 29:1060–1066.

    Article  PubMed  CAS  Google Scholar 

  12. St. John Sutton M, Pfeffer MA, Plappert T, et al., for the SAVE Investigators: Quantitative two-dimensional echocardiographic measurements are major predictors of adverse cardiovascular events after myocardial infarction. The protective effects of captopril. Circulation 1994, 89:68–75.

    PubMed  CAS  Google Scholar 

  13. Li YY, Feldman AM, Sun Y, McTiernan CF: Differential expression of tissue inhibitors of metalloproteinases in the failing human heart. Circulation 1998, 98:1728–1734.

    PubMed  CAS  Google Scholar 

  14. Greene J, Wang M, Liu YE, et al.: Molecular cloning and characterization of human tissue inhibitor of metalloproteinase 4. J Biol Chem 1996, 271:30375–30380.

    Article  PubMed  CAS  Google Scholar 

  15. Liu YE, Wang M, Greene J, et al.: Preparation and characterization of recombinant tissue inhibitor of metalloproteinase 4 (TIMP-4). J Biol Chem 1997, 272:20479–20483.

    Article  PubMed  CAS  Google Scholar 

  16. Matsumura S, Iwanaga S, Mochizuki S, et al.: Targeted deletion or pharmacological inhibition of MMP-2 prevents cardiac rupture after myocardial infarction in mice. J Clin Invest 2005, 115:599–609.

    PubMed  CAS  Google Scholar 

  17. Mukherjee R, Brinsa TA, Dowdy KB, et al.: Myocardial infarct expansion and matrix metalloproteinase inhibition. Circulation 2003, 107:618–625.

    Article  PubMed  CAS  Google Scholar 

  18. Yarbrough WM, Mukherjee R, Escobar GP, et al.: Selective targeting and timing of matrix metalloproteinase inhibition in post-myocardial infarction remodeling. Circulation 2003, 108:1753–1759.

    Article  PubMed  CAS  Google Scholar 

  19. Tian H, Cimini M, Fedak PW, et al.: TIMP deficiency accelerates cardiac remodeling after myocardial infarction. J Mol Cell Cardiol 2007, 43:733–743.

    Article  PubMed  CAS  Google Scholar 

  20. Kai H, Ikeda H, Yusakawa H, et al.: Peripheral blood levels of matrix metalloproteinases-2 and -9 are elevated in patients with acute coronary syndromes. J Am Coll Cardiol 1998, 32:368–372.

    Article  PubMed  CAS  Google Scholar 

  21. Hojo Y, Ikeda U, Ueno S, et al.: Expression of matrix metalloproteinases in patients with acute myocardial infarction. Jpn Circ J 2001, 65:71–75.

    Article  PubMed  CAS  Google Scholar 

  22. Webb CS, Bonnema DD, Ahmed SH, et al.: Specific temporal profile of matrix metalloproteinase release occurs in patients after myocardial infarction: relation to left ventricular remodeling. Circulation 2006, 114:1020–1027.

    Article  PubMed  CAS  Google Scholar 

  23. Orn S, Manhenke C, Squire IB, et al.: Plasma MMP-2, MMP-9 and N-BNP in long-term survivors following complicated myocardial infarction: relation to cardiac magnetic resonance imaging measures of left ventricular structure and function. J Card Fail 2007, 13:843–849.

    Article  PubMed  CAS  Google Scholar 

  24. Fukuda D, Shimada K, Tanaka A, et al.: Comparison of levels of serum matrix metalloproteinase-9 in patients with acute myocardial infarction versus unstable angina pectoris versus stable angina pectoris. Am J Cardiol 2006, 97:175–180.

    Article  PubMed  CAS  Google Scholar 

  25. Squire IB, Evans J, Ng LL, et al.: 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.

    Article  PubMed  CAS  Google Scholar 

  26. Hlatky MA, Ashley E, Quertermous T, et al.: Atherosclerotic Disease, Vascular Function and Genetic Epidemiology (ADVANCE) Study: Matrix metalloproteinase circulating levels, genetic polymorphisms, and susceptibility to acute myocardial infarction among patients with coronary artery disease. Am Heart J. 2007, 154:1043–1051.

    Article  PubMed  CAS  Google Scholar 

  27. Manginas A, Bei E, Chaidaroglou A, et al.: Peripheral levels of matrix metalloproteinase-9, interleukin-6, and C-reactive protein are elevated in patients with acute coronary syndromes: correlations with serum troponin I. Clin Cardiol 2005, 28:182–186.

    Article  PubMed  Google Scholar 

  28. Kelly D, Khan S, Cockerill G, et al.: Circulating stromelysin-1(MMP-3): a novel predictor of LV dysfunction, remodelling and all-cause mortality after acute myocardial infarction. Eur J Heart Fail 2008, 10:133–139.

    Article  PubMed  CAS  Google Scholar 

  29. Sabatine MS, Ploughman L, Simonsen KL, et al.: Association between ADAMTS1 matrix metalloproteinase gene variation, coronary heart disease, and benefit of statin therapy. Arterioscler Thromb Vasc Biol 2008, 28:562–567.

    Article  PubMed  CAS  Google Scholar 

  30. Gurbel PA, Kreutz RP, Bliden KP, et al.: Biomarker analysis by fluorokine multianalyte profiling distinguishes patients requiring intervention from patients with long-term quiescent coronary artery disease: a potential approach to identify atherosclerotic disease progression. Am Heart J 2008, 155:56–61.

    Article  PubMed  CAS  Google Scholar 

  31. Orn S, Manhenke C, Squire IB, et al.: Plasma MMP-2, MMP-9 and N-BNP in long-term survivors following complicated myocardial infarction: relation to cardiac magnetic resonance imaging measures of left ventricular structure and function. J Card Fail 2007, 13:843–849.

    Article  PubMed  CAS  Google Scholar 

  32. Elmas E, Lang S, Dempfle CE, et al.: High plasma levels of tissue inhibitor of metalloproteinase-1 (TIMP-1) and interleukin-8(IL-8) characterize patients prone to ventricular fibrillation complicating myocardial infarction. Clin Chem Lab Med 2007, 45:1360–1365.

    Article  PubMed  CAS  Google Scholar 

  33. Schmidt R, Bültmann A, Fischel S, et al.: Extracellular matrix metalloproteinase inducer (CD147) is a novel receptor on platelets, activates platelets, and augments nuclear factor kappaB-dependent inflammation in monocytes. Circ Res 2008, 102:302–309.

    Article  PubMed  CAS  Google Scholar 

  34. Schmidt R, Bültmann A, Ungerer M, et al.: Extracellular matrix metalloproteinase inducer regulates matrix metalloproteinase activity in cardiovascular cells: implications in acute myocardial infarction. Circulation 2006, 113:834–841.

    Article  PubMed  CAS  Google Scholar 

  35. Jung K: A strong note of caution in using matrix metalloproteinase-1 and its inhibitor, TIMP-1 in serum as biomarkers in systolic heart failure. J Intern Med 2008, 264:291–293.

    Article  PubMed  CAS  Google Scholar 

  36. Hudson MP, Armstrong PW, Ruzyllo W, et al.: Effects of selective matrix metalloproteinase inhibitor (PG-116800) to prevent ventricular remodeling after myocardial infarction: results of the PREMIER (Prevention of Myocardial Infarction Early Remodeling) trial. J Am Coll Cardiol 2006, 48:15–20.

    Article  PubMed  CAS  Google Scholar 

  37. Deschamps AM, Yarbrough WM, Squires CE, et al.: Trafficking of the membrane type-1 matrix metalloproteinase (MT1-MMP) in ischemia and reperfusion: relation to interstitial MT1-MMP activity. Circulation 2005, 111:1166–1174.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Cardiothoracic Surgery, Medical University of South Carolina, Room 625, Strom Thurmond Research Building, 770 MUSC Complex, 114 Doughty Street, Charleston, SC, 29425, USA

    Francis G. Spinale

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  1. Francis G. Spinale
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  2. Nikole M. Wilbur
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Correspondence to Francis G. Spinale.

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Spinale, F.G., Wilbur, N.M. Matrix metalloproteinase therapy in heart failure. Curr Treat Options Cardio Med 11, 339–346 (2009). https://doi.org/10.1007/s11936-009-0034-4

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