THE ROLE OF IMMUNITY SUPPRESSION IN TREATMENT OF MYOCARDITIS

Regardless the common consensus on the benefits of immunity suppression in eosinophilic, granulomatous, giant cell and lymphocyte myocarditis, associated with systemic connective tissue diseases, and in rejection of transplanted heart, role of immune suppression therapy (IST) in treatment of lymphocyte inflammatory cardiomyopathy remains controversial. Previous retrospective studies revealed clinical improvement in 90% of patients with virus-negative inflammatory cardiomyopathy and absence of response or worsening of heart function in 85% of virus-positive inflammatory cardiomyopathy after immunity suppression. Other studies identified the enhanced expression of HLA in cardiomyocytes as an additional indicator of sensitivity of inflammatory cardiomyopathy to IST. Recently, the singlecenter randomized study was performed with double blind application of prednisone and azatioprin as addition to maintenance therapy in 85 patients with virus-negative inflammatory cardiomyopathy. The results of the study showed significant improvement of the left ventricle ejection fraction and decrease of the left ventricle dimensions in 88% patients among 43 of treated comparing to 42 patients on placebo demonstrated worsening of cardiac functioning in 83% cases (the TIMIC study).

This data confirms the efficacy of immunity suppression in virus-negative inflammatory cardiomyopathy. Insufficiency of response in 12% cases undermines existence of non-revealed viruses and mechanisms of damage and inflammation, non-sensitive to immunity suppression. Restoring of cardiac function in patients actively responded to immunity suppression, was determined by inhibition of cardiomyocytes death and increase of cells proliferation with ad novo synthesized contractile material.

1. Dec GW Jr, Palacios IF, Fallon JT, Aretz HT, Mills J, Lee DC, Johnson RA. Active myocarditis in the spectrum of acute dilated cardiomyopathies: clinical features, histologic correlates, and clinical outcome. N Engl J Med 1985;312:885–890.

2. Miyagawa M, Yokoyama R, Nishiyama Y, Ogimoto A, Higaki J, Mochizuki T. Positron emission tomography-computed tomography for imaging of inflammatory cardiovascular diseases. Circ J 2014; 78: 1302 –1310.

3. Kawai S, Shimada T. Inflammation in takotsubo cardiomyopathy? Inquiry from "Guidelines for Diagnosis and Treatment of Myocarditis (JCS 2009)". J Cardiol. 2014; 63: 247–249. doi: 10.1016/j.jjcc.2013.11.002.

4. Moiseeva OM. The outstanding issues of myocarditis treatment. Serdtse (Heart). 2013; 12(1): 57-64. Russian: (Моисеева О. М. Спорные вопросы лечения миокардитов. Сердце. 2013; 12(1): 57-64.).

5. Amoah BP, Yang H, Zhang P, Su Z, Xu H. Immunopathogenesis of myocarditis: the interplay between cardiac fibroblast cells, dendritic cells, macrophages and CD4+ T cells. Scand J Immunol. 2015; 82(1):1-9. doi: 10.1111/sji.12298.

6. Jensen LD, Marchant DJ. Emerging pharmacologic targets and treatments for myocarditis. Pharmacol Ther. 2016; 161:40-51. doi: 10.1016/j.pharmthera.2016.03.006

7. Nakamura H, Kunitsugu I, Fukuda K, Matsuzaki M, Sano M. Diverse stage-dependent effects of glucocorticoids in a murine model of viral myocarditis. J Cardiol. 2013; 61: 237–242.

8. Matitiau A, Perez-Atayde A, Sanders SP, Sluysmans T, Parness IA, Spevak PJ, Colan SD. Infantile dilated cardiomyopathy. Relation of outcome to left ventricular mechanics, hemodynamics, and histology at the time of presentation. Circulation 1994;90:1310–1318.

9. Lee KJ, McCrindle BW, Bohn DJ, Wilson GJ, Taylor GP, Freedom RM, Smallhorn JF, Benson LN. Clinical outcomes of acute myocarditis in childhood. Heart 1999;82:226–233.

10. Parrillo JE, Cunnion RE, Epstein SE, Parker MM, Suffredini AF, Brenner M, Schaer GL, Palmeri ST, Cannon RO III, Alling D. A prospective, randomized, controlled trial of prednisone for dilated cardiomyopathy. N Engl J Med 1989;321:1061–1068.

11. Mason JW, O’Connell JB, Herskowitz A, Rose NR, McManus BM, Billingham ME, Moon TE. A clinical trial of immunosuppressive therapy for myocarditis: the Myocarditis Treatment Trial Investigators. N Engl J Med 1995;333:269–275.

12. Chimenti C, Calabrese F, Thiene G, Pieroni M, Maseri A, Frustaci A. Inflammatory left ventricular microaneurysms as a cause of apparently idiopathic ventricular tachyarrhythmias. Circulation 2001;104:168–173.

13. Feldman AM, McNamara D. Myocarditis. N Engl J Med 2000;343:1388–1398.

14. Chen HS, Wang W, Wu SN, Liu JP. Corticosteroids for viral myocarditis. Cochrane Database Syst Rev. 2013; (10): CD004471. doi: 10.1002/14651858.CD004471.pub3.

15. Frustaci A, Gentiloni N, Chimenti C, Natale L, Gasbarrini G, Maseri A. Necrotizing myocardial vasculitis in Churg-Strauss syndrome: clinicohistologic evaluation of steroids and immunosuppressive therapy. Chest. 1998;114:1484-9.

16. Fozing T, Zouri N, Tost A, Breit R, Seeck G, Koch C, Oezbek C. Management of a patient with eosinophilic myocarditis and normal peripheral eosinophil count. Circ Heart Fail. 2014;7:692-694. DOI: 10.1161/CIRCHEARTFAILURE.114.001130.

17. Badorff C, Schwimmbeck PL, Kühl U, Gerhold M, Stein H, Schultheiss HP. [Cardiac sarcoidosis: diagnostic validation by endomyocardial biopsy and therapy with corticosteroids]. Z Kardiol. 1997;86:9-14.

18. Cooper LT Jr, Berry GJ, Shabetai R. Idiopathic giant-cell myocarditis – natural history and treatment. Multicenter Giant Cell Myocarditis Study Group Investigators. N Engl J Med. 1997;336:1860-6.

19. Kandolin R, Lehtonen J, Salmenkivi K, Räisänen-Sokolowski A, Lommi J, Kupari M. Diagnosis, treatment, and outcome of giant-cell myocarditis in the era of combined immunosuppression. Circ Heart Fail. 2013;6:15-22. DOI: 10.1161/CIRCHEARTFAILURE.112.969261

20. Steinhaus D, Gelfand E, VanderLaan PA, Kociol RD. Recovery of giant-cell myocarditis using combined cytolytic immunosuppression and mechanical circulatory support. J Heart Lung Transpl. 2014;33(7): 769–771. doi.org/10.1016/j.healun.2014.02.018

21. Chaudhry MA, Correa A, Lee C, Yoon A, Grazette L, Saremi F, Fong MW. Modern day management of giant cell myocarditis. Int J Cardiol. 2015; 178: 82–84. doi.org/10.1016/j.ijcard.2014.10.131.

22. Frustaci A, Gentiloni N, Caldarulo M. Acute myocarditis and left ventricular aneurysm as presentations of systemic lupus erythematosus. Chest. 1996;109:282-4.

23. Fairley SL, Herron B, Wilson CM, Roberts MJD. Acute fulminant necrotising lymphocytic myocarditis in a patient with mixed connective tissue disease: a rapid clinical response to immunosuppression. Ulster Med J. 2014; 83(2): 119–120.

24. Wojnicz R, Nowalany-Kozielska E, Wojciechowska C, Glanowska G, Wilczewski P, Niklewski T, Zembala M, Polonski L, Rozek MM, Wodniecki J. Randomized, placebo-controlled study for immunosuppressive treatment of inflammatory dilated cardiomyopathy: two-year follow-up results. Circulation 2001;104:39–45.

25. Frustaci A, Chimenti C, Calabrese F, Pieroni M, Thiene G, Maseri A. Immunosuppressive therapy for active lymphocytic myocarditis: virological and immunologic profile of responders versus nonresponders. Circulation 2003;107:857–863.

26. Mahfoud F, Gartner B, Kindermann M, Ukena C, Gadomski K, Klinkel K. Virus serology in patients with suspected myocarditis: utility or futility ? Eur Heart J 2011; 32: 897-903.

27. Frustaci A, Russo MA, Chimenti C. Randomized study on the efficacy of immunosuppressive therapy in patients with virus-negative inflammatory cardiomyopathy: the TIMIC study. Eur Heart J. 2009;30:1995-2002.

28. Lu C, Qin F, Yan Y, Liu T, Li J, Chen H. Immunosuppressive treatment for myocarditis: A meta-analysis of randomized controlled trials. J Cardiovasc Med (Hagerstown) 2014 July 4, doi:10.2459/ JCM.0000000000000134.

29. Caforio AL, Pankuweit S, Arbustini E, Basso C, Gimeno-Blanes J, Felix SB, et al; European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: A position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J. 2013; 34: 2636 – 2648, 2648a – 2648d.

30. JCS Joint Working Group. Guidelines for diagnosis and treatment of myocarditis (JCS 2009): Digest version. Circ J 2011; 75: 734 – 743.

31. Tereshchenko S.N, Arutyunov G.P., Gilyarevskii S.R., Zhirov I.V., Zykov K.A., Masenko V.P., Narusov O.Yu., Nasonova S.N., Naumov V.G., Osmolovskaya Yu.F., Samko A.N., Stukalova O.V., Sychev A.V., Shariya M.A. The Clinical Guidelines on Myocarditis Diagnostics and Treatment. Evraziiskii kardiologicheskii zhurnal (Eurasian J Cardiology). 2015; 3: 5-17. Russian: (Терещенко С.Н, Арутюнов Г.П., Гиляревский С.Р., Жиров И.В., Зыков К.А., Масенко В.П., Нарусов О.Ю., Насонова С.Н., Наумов В.Г., Осмоловская Ю.Ф., Самко А.Н., Стукалова О.В., Сычёв А.В., Шария М.А. Диагностика и лечение миокардитов: клинические рекомендации. Евразийский кардиологический журнал. 2015; 3: 5-17.).

32. Frustaci A, Chimenti C, Pieroni M, Salvatori L, Morgante E, Sale P, Ferretti E, Petrangeli E, Gulino A, Russo MA. Cell death, proliferation and repair in human myocarditis responding to immunosuppressive therapy. Mod Pathol. 2006; 19: 755-65.