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Article "Development of the European Network in Orphan Cardiovascular Diseases" „Rozszerzenie Europejskiej Sieci Współpracy ds Sierocych Chorób Kardiologicznych” Title: Fibrosis in dilated cardiomyopathy, part II RCD code: III-1B.1 (ICD-10 code I42.7) Author: Paweł Rubiś1,2, Affiliation: 1 Department of Cardiac and Vascular Diseases, John Paul II Hospital, Institute of Cardiology 2 Center for Rare Cardiovascular Diseases, John Paul II Hospital Background The control of ECM remodeling is on multiple levels. One of the most important controlling mechanisms are non-structural matricellular proteins, such as osteopontin (OPN) and tenascin-C (TNC). Osteopontin, which was originally detected in osteoblast and osteoclastas, and thanks to cytokinelike properties, has been implicated in a variety of biological processes, mainly chemotaxis, wound repair, and remodeling. OPN is secreted by numerous cells, such as fibroblasts, macrophages, and Tcells. In the normal, unstressed human myocardium, OPN is not expressed but under pathologic conditions becomes up-regulated. In the cardiovascular system, OPN was found to be a key molecule, mediating LV remodeling, vascular and valvular calcification. In an experimental model of myocarditis, OPN mRNA was detected in infiltrating macrophages. In another murine model of myocarditis, it was elegantly shown by immunohistochemistry that OPN had an affinity to necrotic and fibrotic areas, where it is probably responsible for chemotaxis of macrophages and T-cells and the transformation of fibroblasts into myofibroblasts – the source of ECM structural proteins. In OPN knockout mice less fibrosis was observed which was associated with more benign course of mycocarditis and rare progression to DCM. John Paul II Hospital in Kraków Jagiellonian University, Institute of Cardiology 80 Prądnicka Str., 31-202 Kraków; tel. +48 (12) 614 33 99; 614 34 88; fax. +48 (12) 614 34 88 e-mail: [email protected] www.crcd.eu Discussion Published data on the association of OPN and cardiac diseases are rather limited. In patients with histopathologically and immunohistologically proven myocarditis, OPN mRNA expression was found in all biopsies (as measured by quantitative RT-PCR and in situ hybridization). Osteopontin mRNA expression was considerably decreased in the follow-up biopsies if myocarditis was healing, whereas, it was persistently increased when myocarditis was transforming into chronic disease. In the same study it was observed that OPN mRNA was not detected in biopsies of patients with DCM. In contrast, in another study of DCM patients high OPN expression, that correlated with collagen type I, was observed. The role of circulating OPN is slightly better studied. Soluble OPN concentrations are increased in patients with rheumatic mitral stenosis, stable and unstable angina, and myocardial infarction. In one study, patients with acute myocardits had higher plasma levels of OPN compared with patients with DCM and hypertrophic cardiomyopathy. A rapid decline in OPN plasma levels was correlated with myocarditis healing and absence of cardiac inflammation in the follow-up biopsies as well as an improvement in clinical symptoms and LV systolic function. Although numerous uncertainties exist, it seems that OPN plays an important role in the early phases of ECM changes during acute myocardits but loses significance when active myocardial inflammation recedes. Furthermore, the role of OPN in DCM is unknown. From a practical point of view, the relatively easy access to plasma OPN may result in OPN utilization as a non-invasive marker of myocardits activity. In an experimental study of viral myocardits, treatment of infected mice with vitamin D analog led to decreased myocardial expression levels of OPN, MMP-3 and TIMP-1, which translated into reduced fibrosis. Thus, OPN may serve as a diagnostic tool as well as a potential therapeutic target to limit cardiac remodeling in myocarditis and DCM. Similarly to OPN, little or no tenascin-C is detected in healthy adult tissue. However, it is transiently re-expressed upon tissue injury and down-regulated after tissue repair is complete. Tenascin-C is only expressed in the heart in early embryo where contributes to the development of myocardium. Tenascin-C expression was documented at very early stages of an experimental myocardits. The high TN-C expression was maintained during healing and remodeling process but was not detected in subsequent scar tissue. However, data on human pathology indicate persistent TNC expression with prolonged inflammation and tissue remodeling. In humans TN-C is re-expressed not only in acute states, such as myocarditis, myocardial infarction but also in chronic diseases, including hypertension, DCM or end-stage HF. Tenascin-C is specifically localized to sites of inflammatory cell infiltration and active fibrosis but was undetected in healed tissue. In murine models of myocarditis, TN-C was found to help to recruit and differentiate fibroblast and myofibrobalsts and stimulate their ECM production. A quantitative analysis of the percentage of collagen revealed that ECM deposition was significantly reduced in mice that do not express TN-C. Likewise, in DCM, TN-C was associated with areas of prolonged inflammation and fibrosis but was not present in healed (scar) tissue. It was found that areas with a high expression of TN-C were associated with accelerated fibrosis and remodeling in comparison to the sites where TN-C expression was lower. John Paul II Hospital in Kraków Jagiellonian University, Institute of Cardiology 80 Prądnicka Str., 31-202 Kraków; tel. +48 (12) 614 33 99; 614 34 88; fax. +48 (12) 614 34 88 e-mail: [email protected] www.crcd.eu Conclusion The molecular mechanisms by which TN-C exert theses effects on heart repair are not clear. There are only few experimental studies suggesting a close relationship between TN-C and MMP. Moreover, in a single study in humans, serum TN-C and MMP-9 levels were both elevated in patients with ongoing remodeling but were reduced in patients who responded well to CRT-reversal of remodeling. On the other hand, circulating serum TN-C has been showed to correlate with poor prognosis and mortality in myocardial infarction, DCM, and HF. References: 1. Gunasinghe SK, Spinale FG. Myocardial basis for heart failure: role of the cardiac interstitium. Heart Failure: a companion to Braunwald's Heart Disease edited by Mann DL. Saunders an Imprint of Elsevier. 2. Cohn JN, Ferrari R, Sharpe N. Cardiac remodeling – concepts and clinical implications: a consensus paper from an international forum on cardiac remodeling. J Am Coll Cardiol 2000; 35: 569-82. 3. Sackner_Bernstein JD. The myocardial matrix and the development and progression of ventricular remodeling. Curr Cardiol Rep 2000; 101; 2981-88. 4. Rutschow S, Li J, Schultheiss HP, Pauschinger M. Myocardial proteases and matrix remodeling in inflammatory heart disease. Cardiovasc Res 2006; 69: 646-56. 5. Papageorgiou AP, Heymans S. Interactions between extracellular matrix and inflammation during viral myocarditis. Immunobiology 2012; 217: 503-10. 6. Linjen PJ, Maharani T, Finahari N, Prihadi JS. Serum collagen markers and heart failure. Cardiovasc Hem Dis Drug Tar 2012; 12: 51-5. 7. Klappacher G, Franzen P, Haab D, et al. Measuring extracellular matrix turnover in the serum of patients with idiopathic or ischemic dilated cardiomyopathy and impact on diagnosis and prognosis. Am J Cardiol 1995; 75: 913-8. 8. Wu KC, Weiss RG, Thiemann DR, et al. Late gadolinium enhancement by cardiovascular magnetic resonance heralds an adverse prognosis in nonischemic cardiomyopathy. J Am Coll Cardiol 2008; 51: 2414-21. 9. 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. 10. Pauschinger M, Hoppe K, Schwimmbeck PL. Relevance of myocardial inflammation for the activation of matrix metalloproteinase expression in patients with inflammatory cardiomyopathy. Circulation 2003; 108: IV-24. ………………………….. Author’s signature* [* Signing the article will mean an agreement for its publication] John Paul II Hospital in Kraków Jagiellonian University, Institute of Cardiology 80 Prądnicka Str., 31-202 Kraków; tel. +48 (12) 614 33 99; 614 34 88; fax. +48 (12) 614 34 88 e-mail: [email protected] www.crcd.eu