**6. References**

Abdo, A.S., Kemp, R., Barham, J. & Geraci, S.A. (2010) Dilated cardiomyopathy and role of antithrombotic therapy. *American Journal of Medical Science* 339: 557-560.

Afanasyeva, M., Wang, Y., Kaya, Z., Park, S., Zilliox, M.J., Schofield, B.H., Hill, S.L. & Rose, N.R. (2001) Experimental autoimmune myocarditis in A/J mice is an interleukin-4 dependent disease with a Th2 phenotype. *American Journal of Pathology* 159: 193-203.

Biomarkers of Heart Failure in Myocarditis and Dilated Cardiomyopathy 341

Cain, B.S., Meldrum, D.R., Dinarello, C.A., Meng, X., Joo, K.S., Banjeree, A. & Harken, A.H.

Calabrese, F., Carturan, E., Chimenti, C., Pieroni, M., Agostini, C., Angelini, A., Crosato, M.,

Carter, A.M. (2005) Inflammation, thrombosis and acute coronary syndromes. *Diabetes* 

Chen, W.-C., Tran, K.D. & Maisel, A.S. (2010) Biomarkers in heart failure. *Heart* 96: 314-320. Cheung, C., Marchant, D., Walker, E.K., Luo, Z., Zhang, J., Yanagawa, B., Rahmani, M., Cox,

Cihakova, D., Barin, J. G., Afanasyeva, M., Kimura, M., Fairweather, D., Berg, M., Talor,

Cooper, L.T. Jr., Onuma, O.K., Sagar, S., Oberg, A.L., Mahoney, D.W., Asmann, Y.W. & Liu,

Crocker, S.J., Frausto, R.F., Whitmire, J.K., Benning, N., Milner, R. & Whitton, J.L. (2007)

Daniels, M.D., Hyland, K.V., Wang, K. & Engman, D.M. (2008) Recombinant cardiac myosin

De Gennaro, L., Brunetti, N.D., Cuculo, A., Pellegrino, P.L. & Di Biase, M. (2008) Systemic inflammation in nonischemic dilated cardiomyopathy. *Heart Vessels* 23: 445-450. Devaraj, S., Singh, U. & Jialal, I. (2009) The evolving role of C-reactive protein in

Elster, S.K., Braunwald, E. & Wood, H.F. (1956) A study of C-reactive protein in the serum of patients with congestive heart failure. *American Heart Journal* 51: 533-541. Eriksson, S., Hellman, J. & Pettersson, K. (2005) Autoantibodies against cardiac troponins.

Fairweather, D. & Cihakova, D. (2009) Alternatively activated macrophages in infection and

Fairweather, D. & Rose, N.R. (2005) Inflammatory heart disease: a role for cytokines. *Lupus*

Fairweather, D. & Rose, N.R. (2007) Coxsackievirus-induced myocarditis in mice: a model of autoimmune disease for studying immunotoxicity. *Methods* 41: 118-122. Fairweather, D., Yusung, S., Frisancho(-Kiss), S., Barrett, M., Gatewood, S., Steele, R. & Rose,

coxsackievirus replication. *Journal of Immunology* 170: 4731-4737.

N.R. (2003) IL-12R1 and TLR4 increase IL-1 and IL-18-associated myocarditis and

Cooper, L.T. Jr. (2000) Giant cell myocarditis: diagnosis and treatment. *Herz* 3: 291-298. Cooper, L.T. Jr. (2009) Myocarditis. *New England Journal of Medicine* 360: 1526-1538.

human myocardial function. *Critical Care Medicine* 27: 1309-1318.

clinicopathologic correlations. *Molecular Pathology* 17: 1108-1118.

*Vascular Disease* Research 2: 113-121.

cardiomyopathy. *Heart Failure Clinics* 6: 75-85.

Th17 immunity. *Autoimmunity* 41: 490-499.

atherothrombosis. *Clinical Chemistry* 55: 229-238.

autoimmunity. *Journal of Autoimmunity* 33: 222-230.

*New England Journal of Medicine* 352: 98-100.

1574-1582.

1773.

14: 646-651.

(1999) Tumor necrosis factor-alpha and interleukin-1beta synergistically depress

Valente, M., Boffa, G.M., Furstaci, A. & Thiene, G. (2004) Overexpression of tumor necrosis factor (TNF)alpha and TNFalpha receptor I in human viral myocarditis:

J., Overall, C., Senior, R.M., Luo, H. & McManus, B.M. (2008) Ablation of matrix metalloproteinase-9 increases severity of viral myocarditis in mice. *Circulation* 117:

M.V., Baldeviano, G.C., Frisancho-Kiss, S., Gabrielson, K., Bedja, D. & Rose, N.R. (2008) Interleukin-13 protects against experimental autoimmune myocarditis by regulating macrophage differentiation. *American Journal of Pathology* 172: 1195-1208.

P. (2010) Genomic and proteomic analysis of myocarditis and dilated

Amelioration of coxsackievirus B3-mediated myocarditis by inhibition of tissue inhibitors of matrix metalloproteinase-1. *American Journal of Pathology* 171: 1762-

fragment induces experimental autoimmune myocarditis via activation of Th1 and


Afanasyeva, M., Georgakopoulos, D., Fairweather, D., Caturegli, P., Kass, D.A. & Rose, N.R.

Agewall, S., Giannitsis, E., Jernbert, T. & Katus, H. (2011) Troponin elevation in coronary vs.

Al-Biltagi, M., Issa, M., Hagar, H.A., Abdel-Hafez, M. & Aziz, N.A. (2010) Circulationg

Ali, S., Huber, M., Kollewe, C., Bischoff, S.C., Falk, W. & Martin, M.U. (2007) IL-1 receptor

Anand, I.S., Latini, R., Florea, V.G., Kuskowski, M.A., Rector, T., Masson, S., Signorini, S.,

Anker, S.D. & von Haehling, S. (2004) Inflammatory mediators in chronic heart failure: an

Antoniak, S., Boltzen, U., Riad, A., Kallwellis-Opara, A., Rohde, M., Dorner, A., Tschope, C.,

Blankenberg, S. (2003) Plasma concentrations and genetic variation of matrix

Blauwet, L.A. & Cooper, L.T. (2010) Myocarditis. *Progress in Cardiovascular Diseases* 52: 274-

Blyszczuk, P., Kania, G., Dieterle, T., Marty, R.R., Valaperti, A., Berthonneche, C.,

Bradham, W.S., Moe, G., Wendt, K.A., Scott, A.A., Konig, A., Romanova, M., Naik, G. &

Brandt, R.R., Filzmaier, K. & Hanrath, P. (2001) Circulation cardiac troponin I in acute

Braunwald, E. (2008) Biomarkers in heart failure. *New England Journal of Medicine* 358: 2148-

Bui, A.L., Horwich, T.B. & Fonarow G.C. (2011) Epidemiology and risk profile of heart

thrombogenicity. *Journal of Molecular and Cellular Cardiology* 45: 118-126. Baldeviano, G.C., Barin, J.G., Talor, M.V., Srinivasan, S., Bedja, D., Zheng, D., Gabrielson, K.,

disease in interferon- knockout mice. *Circulation* 110: 2910-2917.

non-coronary disease. *European Heart Journal* 32: 404-411.

fulminant viral myocarditis. *Acta Paediatrica* 99: 1510-1516.

*Clinical Applied Thrombosis/ Hemostasisis* 16: 628-636.

cardiomyopathy. *Circulation Research* 105: 912-920.

pericarditis. *American Journal of Cardiology* 87: 1326-1328.

*Circulation Physiology* 282: H1288-H1295.

failure. *Nature Reviews Cardiology* 8: 30-41.

*Circulation* 112: 1428-1434.

overview. *Heart* 90: 464-470.

*Research* 106: 1646-1655.

*Circulation* 107: 1579-1585.

288.

2159.

(2004) A novel model of constrictive pericarditis associated with autoimmune heart

cardiac troponin levels and cardiac dysfunction in children with acute and

accessory protein is essential for IL-33-induced activation of T lymphocytes and mast cells. *Proceedings from the National Academy of Sciences USA* 104: 18660-18665. Ames, P.R.J., Margaglione, M., Mackie, S. & Alves, J.D. (2010) Eosinophilia and

thrombophilia in Churg Strauss syndrome: a clinical and pathogenetic overview.

Mocarelli, P., Hester, A., Glazer, R., Cohn, J.N. & Val-HeFT Investigators. (2005) Creactive protein in heart failure: prognostic value and the effect of valsartan.

Noutsias, M., Pauschinger, M., Schultheiss, H.-P. & Rauch, U. (2008) Viral myocarditis and coagulopathy: increased tissue factor expression and plasma

Iwakura, Y., Rose, N.R. & Cihakova, D. (2010) Interleukin-17A is dispensable for myocarditis but essential for the progression to dilated cardiomyopathy. *Circulation* 

metalloproteinase 9 and prognosis of patients with cardiovascular disease.

Pedrazzini, T., Berger, C.T., Dirnhofer, S., Matter, C.M., Penninger, J.M., Luscher, T.F. & Eriksson, U. (2009) Myeloid differentiation factor-88/interleukin-1 signaling controls cardiac fibrosis and heart failure progression in inflammatory dilated

Spinale, F.G. (2002) TNF-alpha and myocardial matrix metalloproteinases in heart failure: relationship to LV remodeling. *American Journal of Physiology and Heart* 


Biomarkers of Heart Failure in Myocarditis and Dilated Cardiomyopathy 343

Hebert, K., Macedo, F.Y., Trahan, P., Tamariz, L., Dias, A., Palacio, A. & Arcement, L.M.

Hirayama, A., Kusuoka, H., Yamamoto, H., Sakata, Y., Asakura, M., Higuchi, Y., Mizuno,

Hochholzer, W., Morrow, D.A. & Giugliano, R.P. (2010) Novel biomarkers in cardiovascular

Huber, S.A. (2010) Tumor necrosis factor-alpha promotes myocarditis in female mice

Huber, S.A. & Pfaeffle, B. (1994) Differential Th1 and Th2 cell responses in male and female

Imazio, M., Cecchi, E., Demichelis, B., Chinaglia, A., Lerna, S., Demarie, D., Ghisio, A.,

Ishikawa, C., Tsutamoto, T., Fujii, M., Sakai, H., Tanaka, T. & Horie, M. (2006) Prediction of

Jefferis, B.J., Papacosta, O., Owen, C.G., Wannamethee, S.G., Humphries, S.E., Woodward,

Kallwellis-Opara, A., Dorner, A., Poller, W.-C., Noutsias, M., Kuhl, U., Schultheiss, H.-P. &

Kaneko, K., Kanda, T., Yamauchi, Y., Hasegawa, A., Iwasaki, T., Arai, M., Suzuki, T.,

Kaneko, K., Kanda, T., Hasegawa, A., Suzuki, T., Kobayashi, I. & Nagai, R. (2000) C-reactive

Kania, G., Blyszczuk, P. & Eriksson, U. (2009) Mechanisms of cardiac fibrosis in inflammatory heart disease. *Trends in Cardiovascular Medicine* 19: 247-252. Karamitsos, T.D. & Neubauer, S. (2011) Cardiovascular magnetic resonance in heart failure.

Kaya, Z., Goser, S., Buss, B.J., Leuschner, F., Ottl, R., Li, J., Volkers, M., Zittrich, S., Pfitzer,

patients with dilated cardiomyopathy. *Circulation Journal* 70: 857-863. Jameson, J.N., Kasper, D., Harrison, T.R., Braunwald, E., Fauci, A.S., Hauser, S.L. & Longo,

heart failure guidelines to change? *Congestive Heart Failure* 17: 85-89. Hedayat, M., Mahmoudi, M.J., Rose, N.R. & Rezaei, N. (2010) Proinflammatory cytokines in heart failure: double-edged swords. *Heart Failure Reviews* 15: 543-562. Heymans, S. (2006) Inflammation and cardiac remodeling during viral myocarditis. *Ernst* 

*Schering Research Foundation Workshop* 55: 197-218.

disease: update 2010. *American Heart Journal* 160: 583-594.

idiopathic acute pericarditis. *Heart* 94: 498-501.

review. *Atherosclerosis* April 8 [Epub ahead of print].

cardiomyopathy. *Clinical Research Cardioliology* 96: 469-480.

*Current Cardiology Report* doi: 10.1007/s11886-011-0177-2.

*Heart* 91: 1573-1577.

5126-5132.

cells. *Viral Immunology* 23: 79-86.

Publishing Division, New York.

*Cardiology* 91: 215-219.

41-47.

(2011) Routine serial echocardiography in systolic heart failure: is it time for the

H., Kashiwase, K., Ueda, Y., Okuyama, Y., Hori, M. & Kodama, K. (2005) Serial changes in plasma brain natriuretic peptide concentration at the infarct and noninfarct sites in patients with left ventricular remodeling after myocardial infarction.

infected with coxsackievirus B3 through upregulation of CD1d on hematopoeitic

BALB/c mice infected with coxsackievirus group B type 3. *Journal of Virology* 68:

Pomari, F., Belli, R. & Trinchero, R. (2008) Myopericarditis versus viral or

mortality by high-sensitivity C-reactive protein and brain natriuretic peptide in

D.L. (2005) Harrison's Principles of Internal Medicine. McGraw-Hill Medical

M., Lennon, L.T., Thomson, A., Welsh, P., Rumley, A., Lowe, G.D. & Whincup, P.H. (2011) Interleukin 18 and coronary heart disease: prospective study and systematic

Pauschinger, M. (2007) Autoimmunological features in inflammatory

Kobayashi, I. & Nagai, R. (1999) C-reactive protein in dilated cardiomyopathy.

protein as a prognostic marker in lymphocytic myocarditis. *Japan Heart Journal* 41:

G., Rose, N.R. & Katus, H.A. (2008) Identification of cardiac troponin I sequence


Fairweather, D., Frisancho-Kiss, S., Yusung, S.A., Barrett, M.A., Gatewood, S.J.L., Davis, S.E.,

IL-1, and IL-4 in the heart. *American Journal of Pathology* 165: 1883-1894. Fairweather, D., Frisancho-Kiss, S., Gatewood, S., Njoku, D., Steele, R., Barrett, M. & Rose,

Fairweather, D., Frisancho-Kiss, S., Yusung, S.A., Barrett, M.A., Davis, S.E., Steele, R.A.,

Fairweather, D., Frisancho-Kiss, S., Njoku, D.B., Nyland, J.F., Kaya, Z., Yusung, S.A., Davis,

Fairweather, D., Frisancho-Kiss, S. & Rose, N.R. (2008) Sex differences in autoimmune disease from a pathologic perspective. *American Journal of Pathology* 173: 600-609. Frisancho-Kiss, S., Nyland, J.F., Davis, S.E., Frisancho, J.A., Barrett, M.A., Rose, N.R. &

Frisancho-Kiss, S., Davis, S.E., Nyland, J.F., Frisancho, J.A., Cihakova, D., Rose, N.R. &

Frisancho-Kiss, S., Coronado, M.J., Frisancho, J.A., Lau, V.M., Rose, N.R., Klein, S.L. &

Gaddam, K.K., Ventura H.O. & Lavie C.J. (2011) Metabolic syndrome and heart failure- the risk, paradox and treatment. *Current Hypertension Research* 13: 142-148. Goser, S., Andrassy, M., Buss, S.J., Leuschner, F., Volz, C.H., Ottl, R., Zittrich, S., Blaudeck,

Grabowski, M., Karpinski, G.J., Filipiak, K., Rdzanek, A., Pietrasik, A., Wretwoski, D.,

Grzybowski, J., Bilinska, Z.T., Ruzyllo, W., Kupsc, W., Michalak, E., Szczesniewska, D.,

nonischemic dilated cardiomopathy. *Journal of Cardiac Failure* 2: 77-85. Gupta, S., Markham, D.W., Drazner, M.H. & Mammen, P.P.A. (2008) Fulminant myocarditis.

perimyocarditis- a preliminary report. *Kardiology Pol*. 61: 451-458.

populations in the heart. *Journal of Immunology* 174: 261-269.

*Journal of Immunology* 176: 3516-3524.

STAT4. *Brain Research* 1126: 139-147.

the myocardium. *Circulation* 114: 1693-1702.

*Nature Clinical Practice* 5: 693-706.

178: 6710-6714.

*Immunity* 23: 649-657.

131-145.

Njoku, D.B. & Rose, N.R. (2004a) IFN- protects against chronic viral myocarditis by reducing mast cell degranulation, fibrosis, and the profibrotic cytokines TGF-1,

N.R. (2004b) Mast cells and innate cytokines are associated with susceptibility to autoimmune heart disease following coxsackievirus B3 infection. *Autoimmunity* 37:

Gatewood, S.J.L. & Rose, N.R. (2005) IL-12 protects against coxsackievirus B3 induced myocarditis by increasing IFN- and macrophage and neutrophil

S.E., Frisancho, J.A., Barrett, M.A. & Rose, N.R. (2006) Complement receptor 1 and 2 deficiency increases coxsackievirus B3-induced myocarditis and heart failure by increasing macrophages, IL-1 and immune complex deposition in the heart.

Fairweather, D. (2006) Sex differences in coxsackievirus B3-induced myocarditis: IL-12R1 signaling and IFN- increase inflammation in males independent from

Fairweather, D. (2007) Cutting Edge: Cross-regulation by TLR4 and T cell Ig mucin-3 determines sex differences in inflammatory heart disease. *Journal of Immunology* 

Fairweather, D. (2009) Gonadectomy of male BALB/c mice increases Tim-3+ alternatively activated M2 macrophages, Tim-3+ T cells, Th2 cells and Treg in the heart during acute coxsackievirus-induced myocarditis. *Brain Behavior and* 

N., Hardt, S.E., Pfitzer, G., Rose, N.R., Katus, H.A. & Kaya, Z. (2006) Cardiac troponin I but not cardiac troponin T induces severe autoimmune inflammation in

Rudowski, R. & Opolski, G. (2004) Diagnostic value of BNP in suspected

Poplawska, W. & Rydlewska-Sadowska, W. (1996) Determinants of prognosis of


Biomarkers of Heart Failure in Myocarditis and Dilated Cardiomyopathy 345

Maisch, B. (1994) Pericardial diseases, with a focus on etiology, pathogenesis,

Mann, D.L. (2005) Targeted anticytokine therapy and the failing heart. *American Journal of* 

Marchant, D. & McManus, B.M. (2009) Matrix metalloproteinases in the pathogenesis of

Masson, S., Latini, R., Anand, I.S., Vago, T., Angelici, L., Barlera, S., Missov, E.D., Clerico, A.,

Miettinen, K.H., Eriksson, S., Magga, J., Tuomainen, P., Kuusisto, J., Vanninen, E.J.,

Miller, A.M. & Liew, F.Y. (2011) The IL-33/ST2 pathway- a new therapeutic target for cardiovascular disease. *Pharmacology and Therapeutics* Feb 26 [Epub ahead of print]. Miller, W.L., Hartman, K.A., Burritt, M.F., Burnett, J.C. & Jaffe, A.S. (2007) Troponin, B-type

Morgera, T., Di Lenarda, A., Dreas, L., Pinamonti, B., Humar, F., Bussani, R., Silvestri, F.,

Morrow, D.A. & de Lemos, J.A. (2007) Benchmarks for the assessment of novel

Nishikubo, K., Imanaka-Yoshida, K., Tamaki, S., Hiroe, M., Yoshida, T., Adachi, Y. &

Nishimura, H., Okazaki, T., Tanaka, Y., Nakatani, K., Hara, M., Matsumori, A., Sasayama, S.,

Olimulder, M.A., van Es, J. & Galjee, M.A. (2009) The importance of cardiac MRI as a

Omland, T., Sabatine, M.S., Jablonski, K.A., Rice, M.M., Hsia, J., Wergeland, R., Landaas, S.,

cardiomyopathy in PD-1 receptor deficient mice. *Science* 291: 319-322. Ogawa, T., Veinot, J.P., Kuroski de Bold, M.L., Georgalis, T. & de Bold, A.J. (2008)

ischemic and dilated cardiomyopathies. *Clinical Cardiology* 30: 245-250. Miller, A.M., Xu, D., Asquith, D.L., Denby, L., Li, Y., Sattar, N., Baker, A.H., McInnes, I.B. &

viral heart disease. *Trends in Cardiovascular Medicine* 19: 21-26.

dilated cardiomyopathy. *Journal of Cardiac Failure* 14: 481-488.

(Val-HeFT) data. *Clinical Chemistry* 52: 1528-1538.

cardiovascular biomarkers. *Circulation* 115: 949-952.

myocarditis. *Journal of Autoimmunity* 29: 146-153.

*Circulation Physiology* 294: H2596-H2603.

*in Cardiology* 9: 379-388.

*Cardiology* 95(Suppl): 9C-16C.

*Experimental Medicine* 205: 339-346.

*Journal* 124: 455-467.

*Journal* 17: 481-486.

pathophysiology, new diagnostic imaging methods, and treatment. *Current Opinion* 

Tognoni, G., Cohn, J.N. & Val-HeFT Investigators. (2006) Direct comparison of Btype natriuretic peptide (BNP) and amino-terminal proBNP in a large population of patients with chronic and symptomatic heart failure: the Valsartan Heart Fialure

Turpeinen, A., Punnonen, K.R., Pettersson, K. & Peuhkurinen, K.J. (2008) Clinical significance of troponin I efflux and troponin autoantibodies in patients with

natriuretic peptides and outcomes in severe heart failure: differences between

Liew, F.Y. (2008) IL-33 reduces the development of atherosclerosis. *Journal of* 

Chersevani, D. & Camerini, F. (1992) Electrocardiography of myocardtiis revisited: clinical and prognostic significance of electrocardiographic changes. *American Heart* 

Yasutomi, Y. (2007) Th1-type immune responses by Toll-like receptor 4 signaling are required for the development of myocarditis in mice with BCG-induced

Mizoguchi, A., Hiai, H., Minato, N. & Honjo, T. (2001) Autoimmune dilated

Angiotensin II receptor antagonism reverts the selective cardiac BNP upregulation and secretion observed in myocarditis. *American Journal of Physiology and Heart* 

diagnostic took in viral myocarditis-induced cardiomyopathy. *Netherlands Heart* 

Rouleau, J.L., Domanski, M.J., Hall, C., Pfeffer, M.A., Braunwald, E. & PEACE Investigators. (2007) Prognostic value of B-type natriuretic peptides in patients with

motifs leading to heart failure by induction of myocardial inflammation and fibrosis. *Circulation* 118: 2063-2072.


Kaya, Z., Katus, H.A. & Rose, N.R. (2010) Cardiac troponins and autoimmunity: their role in

Kindermann, I., Kindermann, M., Kandolf, R., Klingel, K., Bultmann, B., Muller, T.,

Kleinfeldt, T., Nienaber, C.A., Kische, S., Akin, I., Turan, R.G., Korber, T., Schneider, H. &

Kojima, J., Miyazaki, S., Fujiwara, H., Kumada, T. & Kawai, C. (1988) Recurrent left

Krumholz, H.M., Want, Y., Parent, E.M., Mockalis, J., Petrillo, M. & Radford, M.J. (1997)

Kuh, J.H. & Seo, Y. (2005) Transatrial resection of a left ventricular thrombus after acute

Kuhl, U., Pauschinger, M., Schwimmbeck, P.L., Seeberg, B., Lober, C., Noutsias, M., Poller,

Kumar, V., Abbas, A.K. & Fausto, N. (2005) *Robbins and Cotran Pathologic Basis of Disease*, 7th

Latini, R., Masson, S., Anand, I.S., Missov, E., Carlson, M., Vago, T., Angelici, L., Barlera, S.,

Leuschner, F., Li, J., Goser, S., Reinhardt, L., Ottl, R., Bride, P., Zehelein, J., Pfitzer, G.,

Liew, F.Y., Pitman, N.I. & McInnes, I.B. (2010) Disease-associated funcitons of IL-33: the new

Liu, P., Sun, M. & Sader, S. (2006) Matrix metalloproteinases in cardiovascular diseae.

Looi, J.L., Edwards, C., Armstrong, G.P., Scott, A., Patel, H., Hart, H. & Christiansen, J.P.

resonance imaging. *Clinical Medicine Insights in Cardiology* 4: 129-134. Mackman, N. (2009) The many faces of tissue factor. *Journal of Thombosis and* Haemostasis 7:

with stable chronic heart failure. *Circulation* 116: 1242-1249.

kid in the IL-1 family. *Nature Reviews Immunology* 10: 103-110.

*Canadian Journal of Cardiology* 22(Suppl. B): 25B-30B.

fibrosis. *Circulation* 118: 2063-2072.

myocarditis. *Circulation* 118: 639-648.

*Internal Medicine* 157: 2242-2247.

myocarditis. *Heart Vessels* 20: 230-232.

edn. Elsevier Saunders, Philadelphia.

*Medicine* 323: 236-241.

136-139.

122.

2798.

insights. *Clinical Research Cardioliology* 99: 419-427.

motifs leading to heart failure by induction of myocardial inflammation and

the pathogenesis of myocarditis and of heart failure. *Clinical Immunology* 134: 80-88.

Lindinger, A. & Bohm, M. (2008) Predictors of outcome in patients with suspected

Ince, H. (2010) Cardiac manifestation of the hypereosinophilic syndrome: new

ventricular mural thrombi in a patient with acute myocarditis. *Heart Vessels* 4: 120-

Quality of care for elderly patients hospitalized with heart failure. *Archives of* 

W. & Schultheiss, H.P. (2003) Interferon-beta treatment eliminates cardiotropic viruses and improves left ventricular function in patients with myocardial persistence of viral genomes and left ventricular dysfunction. *Circulation* 107: 2793-

Parrinello, G., Maggioni, A.P., Tognoni, G., Cohn, J.N. & Val-HeFT Investigators. (2007) Prognostic value of very low plasma concentrations of troponin T in patients

Remppis, A., Giannitsis, E., Katus, H.A. & Kaya, Z. (2008) Absence of autoantibodies against cardiac troponin I predicts improvement of left ventricular function after acute myocardial infarction. *European Heart Journal* 29: 1949-1955. Levine, B., Kalman, J., Mayer, L., Fillit, H.M. & Packer, M. (1990) Elevated circulating levels

of tumor necrosis factor in severe chronic heart failure. *New England Journal of* 

(2010) Characteristics and prognostic importance of myocardial fibrosis in patients with dilated cardiomyopathy assessed by contrast-enhanced cardiac magnetic


Biomarkers of Heart Failure in Myocarditis and Dilated Cardiomyopathy 347

Sanada, S., Hakuno, D., Higgins, L.J., Schreiter, E.R., McKenzie, A.N.J. & Lee R.T. (2007) IL-

Satoh, M., Nakamura, M., Akatsu, T., Iwasaka, J., Shimoda, Y., Segawa, I. & Hiramori, K.

Satoh, M., Nakamura, M., Akatsu, T., Shimoda, Y., Segawa, I. & Hiramori, K. (2005) C-

Senes, M., Erbay, A.R., Yilmaz, F.M., Topkaya, B.C., Zengi, O., Dogan, M. & Yucel, D. (2008)

dilated cardiomyopathy. *Clinical Chemistry Laboratory Medicine* 46: 382-386. Seta, Y., Shan, K., Bozkurt, B., Oral, H. & Mann, D.L. (1996) Basic mechanisms in heart

Shamri, R., Xenakis. J.J. & Spencer, L.A. (2011) Eosinophils in innate immunity: an evolving

Shmilovich, H., Danon, A., Binah, O., Roth, A., Chen, G., Wexler, D., Keren, G. & George, J.

Smith, S.C., Ladenson, J.H., Mason, J.W., & Jaffe, A.S. (1997) Elevations of cardiac troponin I

Soongswang, J., Durongpisitkul, K., Ratanarapee, S., Leowattana, W., Nana, A.,

Talvani, A., Rocha, M.O., Barcelos, L.S., Gomes, Y.M., Ribeiro, A.L. & Teixeira, M.M. (2004)

Tanaka, K., Ito, M., Kodama, M., Tomita, M., Kimura, S., Hoyano, M., Mitsuma, W., Hirono,

Tang, Q., Huang, J., Qian, H., Xiong, R., Shen, D., Wu, H., Bian, Z. & Wei, X. (2007)

cardiomyopathy. *Clinical Infectious Disease* 38: 943-950.

*Pharmacology and Therapy* 16: 79-86.

*Molecular Biology Letters* 12: 176-191.

ischemic cardiomyopathy. *International Journal of Cardiology* 117: 198-203. Silver, M.A., Maisel, A., Yancy, C.W., McCullough, P.A., Burnett, J.C. Jr., Francis, G.S.,

in human dilated cardiomyopathy. *European Journal Heart* 7: 748-754. Schultz, J.C., Hilliard, A.A., Cooper, L.T. & Rihal, C.S. (2009) Diagnosis and treatment of

failure: the cytokine hypothesis. *Journal of Cardiac Failure* 2: 243-249.

signaling system. *The Journal of Clinical Investigation* 117: 1538-1549.

human myocarditis. *Clinical Science (London)* 104: 577-584.

viral myocarditis. *Mayo Clinical Proceedings* 84: 1001-1009.

story. *Cell Tissue Research* 343: 57-83.

*Failure* 10(Suppl. 3): 1-30.

163-168.

23: 531-535.

33 and ST2 comprise a critical biomechanically induced and cardioprotective

(2003) Expression of Toll-like receptor 4 is associated with enteroviral replication in

reactive protein co-expresses with tumor necrosis factor-alpha in the myocardium

Coenzyme Q10 and high-sensitivity C-reactive protein in ischemic and idiopathic

(2007) Autoantibodies to cardiac troponin I in patients with idiopathic dilated and

Mehra, M.R., Peacock, W.F. 4th, Fonarow, G., Gibler, W.B., Morrow, D.A., Hollander, J. & BNP Consensus Panel. (2004) NBP Consensus Panel 2004: A clinical approach for the diagnostic, prognostic, screening, treatment monitoring, and therapeutic roles of natriuretic peptides in cardiovascular diseases. *Congestive Heart* 

associated with myocarditis. Experimental and clinical correlates. *Circulation* 95:

Laohaprasitiporn, D., Akaniroj, S., Limpimwong, N. & Kangkagate, C. (2002) Cardiac troponin T: its role in the diagnosis of clinically suspected acute myocarditis and chronic dilated cardiomyopathy in children. *Pediatric Cardiology*

Elevated concentrations of CCL2 and tumor necrosis factor-alpha in chagasic

S., Hanawa, H. & Aizawa, Y. (2011) Sulfated polysaccharide fucoidan ameliorates experimental autoimmune myocarditis in rats. *Journal of Cardiovascular* 

Microarray analysis reveals the role of matrix metalloproteinases in mouse experimental autoimmune myocarditis induced by cardiac myosin peptides. *Cell* 

stable coronary artery disease: the PEACE Trial. *Journal of American College of Cardiology* 50: 205-214.


Onyimba, J.A., Coronado, M.J., Garton, A.E., Kim, J.B., Bucek, A., Bedja, D., Gabrielson, K.L.,

Osman, R., L'Allier, P.L., Elgharib, N. & Tardif, J.-C. (2006) Critical appraisal of C-reactive

Palazzuoli, A., Antonelli, G., Quantrini, I. & Nuti, R. (2011) Natriuretic peptides in heart failure: where we are, where we are going. *Internal Emergency Medicine* 6: 63-68. Peacock, W.F. 4th, DeMarco, T., Fonarow, G.C., Diercks, D., Wynne, J., Apple, F.S., Wu, A.H.

Peerschke, E.I., Yin, W. & Ghebrehiwet, B. (2010) Complement activation on platelets:

Pepys, M.B. & Hirschfield, G.M. (2003) C-reactive protein: a critical update. *The Journal of* 

Perez-De-Lis, M., Akasbi, M., Siso, A., Diez-Cascon, P., Brito-Zeron, P., Diaz-Lagares, C.,

Piro, M., Bona, R.D., Abbate, A., Biasucci, L.M. & Crea, F. (2010) Sex-related differences in myocardial remodeling. *Journal of the American College of Cardiology* 55: 1057-1065. Rao, M., Jaber, B.L. & Balakrishnan, V.S. (2006) Inflammatory biomarkers and

Rezaizadeh, H., Sanchez-Ross, M., Kaluski, E., Klapholz, M., Haider, B. & Gerula, C. (2010)

Rhodes, B., Furnrohr, B.G. & Vyse, T.J. (2011) C-reactive protein in rheumatology: biology and genetics. *Nature Reviews Rheumatology* April 5 [Epub ahead of print]. Robinson, T., Smith, A. & Channer, K.S. (2011) Reversible heart failure: the role of

Roger, V.L., Go, A.S., Lloyd-Jones, D.M., Adams, R.J., Berry, J.D., Brown, T.M., Carnethon,

Ronaldson, K.J., Taylor, A.J., Fitzgerald, P.B., Topliss, D.J., Elsik, M. & McNeil, J.J. (2010)

analysis of 38 cases and 47 controls. *Journal of Clinical Psychiatry* 71: 976-981.

Diagnostic characteristics of clozapine-induced myocarditis identified by an

inflammatory activation. *Postgraduate Medical Journal* 87: 110-115.

*Cardiology* 50: 205-214.

*Management* 2: 221-237.

47: 2170-2175.

19: 941-948.

123: e18-e209.

36.

in male mice. *Biology of Sex Differences* 2: 2.

*Clinical Investigation* 111: 1805-1812.

failure. *New England Journal of Medicine* 15: 2117-2126.

stable coronary artery disease: the PEACE Trial. *Journal of American College of* 

Guilarte, T.R. & Fairweather, D. (2011) The innate immune response to coxsackievirus B3 predicts progression to cardiovascular disease and heart failure

protein throughout the spectrum of cardiovascular disease. *Vascular Health and Risk* 

& ADHERE Investigators. (2008) Cardiac troponin and outcome in acute heart

implications for vascular inflammation and thrombosis. *Molecular Immunolunology*

Ortiz, J., Perez-Alvarez, R., Ramos-Casals, M. & Coca, A. (2010) Cardiovascular risk factors in primary Sjogren's syndrome: a case-control study in 624 patients. *Lupus*

cardiovascular risk: association or cause and effect? *Seminars in Dialysis* 19: 129-135.

Acute eosinophilic myocarditis: diagnosis and treatment. *Acute Cardiac Care* 12: 31-

M.R., Dai, S., de Simone, G., Ford, E.S., Fox, C.S., Fullerton, H.J., Gillespie, C., Greenlund, K.J., Hailpern, S.M., Heit, J.A., Ho, P.M., Howard, V.J., Kissela, B.M., Kittner, S.J., Lackland, D.T., Lichtman, J.H., Lisabeth, L.D., Makuc, D.M., Marcus, G.M., Marelli, A., Matchar, D.B., McDermott, M.M., Meigs, J.B., Moy, C.S., Mozaffarian, D., Mussolino, M.E., Nichol, G., Paynter, N.P., Rosamond, W.D., Sorlie, P.D., Stafford, R.S., Turan, T.N., Turner, M.B., Wong, N.D., Wylie-Rosett, J., American Heart Association Statistics Committee and Stroke Statistics Subcommittee. (2011) Heart disease and stroke statistics- 2011 update. *Circulation*


**1. Introduction** 

for this pathology.

Equally contributed to the work.

 \*

**17** 

**A Proteomic Approach** 

Piero Pucci and Angela Amoresano

*Federico II University of Naples, Naples, \*Italy* 

*Facoltà di Scienze Biotecnologiche,* 

**to Investigate Myocarditis** 

Andrea Carpentieri\*, Chiara Giangrande\*,

*Department of Organic Chemistry and Biochemistry,* 

Myocarditis is an inflammatory disease of the cardiac muscle which might be related to viral (mainly parvovirus B19 and many others), protozoan (*Borrellia burgdoferi, Trypanosoma cruzi, Toxoplasma gondi*), bacterial (*Brucella, Corynebacterium diphtheriae, Gonococcus, Haemophilus influenzae, Actinomyces, Tropheryma whipplei, Vibrio cholerae, Borrelia burgdorferi, Leptospira, Rickettsia*), fungal (*Aspergillus*) and other non viral pathogens (Rezkalla SH et al., 2010, Blauwet LA et al., 2010, Cihakova D et al., 2010) infections; It has been reported, however, that this kind of inflammation might be caused by an hypersensitivity response to drugs (Kühl U et al., 2009). The final effect in each case is represented by myocardial infiltration of

Myocarditis presents with many symptoms, from chest pain that spontaneously resolves without treatment to cardiogenic shock and sudden death (Kühl U et al., 2010, Taylor CL et al 2010). The major long-term consequence is dilated cardiomyopathy with chronic heart

Nowadays, diagnostic tools available for this disease are mainly related to general investigations (such as electrocardiography) and analysis of the most abundant serum proteins, whose alteration is related to cardiac pathology, even if it's not specifically connected to myocarditis itself. Here we propose preliminary speculations on the serum proteins profiling (both in the expression level and in the characterization of post translational modifications) and on free peptides identification in myocardytis affected patients (compared to healthy individual), that could be helpful in finding specific markers

As many other inflammatory events this disease involves in fact different kinds of biological macromolecules, here we focus in particular on proteins. More than 50% of total protein content in a cell is post translationally modified. The pattern of Post Translational Modifications (PTMs) on proteins constitute a molecular code that dictates protein conformation, cellular location, macromolecular interactions and activities, depending on cell type, tissue and environmental conditions (Diernfellner AC et al., 2011, Savidge TC,

immunocompetent cells following any kind of cardiac injury.

failure(Lv H et al. 2011, Stensaeth KH et al 2011).

