Skip to main content

Advertisement

SpringerLink
Log in

Long-term outcome of patients with virus-negative chronic myocarditis or inflammatory cardiomyopathy after immunosuppressive therapy

  • Original Paper
  • Published:
Clinical Research in Cardiology Aims and scope Submit manuscript

Abstract

Aim

To analyze the long-term outcome after immunosuppressive treatment of patients with virus-negative chronic myocarditis or inflammatory cardiomyopathy (CMi).

Methods and results

We investigated 114 patients with endomyocardial biopsy (EMB)-proven virus-negative chronic myocarditis or CMi, who were treated with prednisone and azathioprine for 6 months. Myocardial inflammation was assessed by quantitative immunohistology. We examined hemodynamic measurements after 6 months and long-term follow-up periods of up to 10 years {median 10.5 months [95 % confidence interval (CI) 11.69–59.16]}. At follow-up, the patients showed a significant improvement of left ventricular ejection fraction (LVEF) compared to baseline after 6-month period (LVEF rising from 44.6 ± 17.3 to 51.8 ± 15.5 %, p = 0.006) and in the long-term follow-up (LVEF 52.1 ± 15.6 %, p = 0.006). Simultaneously, EMB-analysis revealed significant reduction of quantified inflammatory infiltrates (CD3+ cells 16.03 ± 29.09–8.2 ± 9.0/mm2, p = 0.002; CD2+ cells 12.62 ± 20.01 to 6.61 ± 8.47/mm2, p = 0.001; perforin+ cells 3.94 ± 4.65–1.03 ± 1.47/mm2, p = 0.0001), and cell-adhesion molecule HLA-1 [9.91 ± 5.55–6.65 ± 2.81/area fraction (AF), p = 0.0001]. In a subgroup analysis, patients with initial LVEF ≤45 % (n = 53) significantly increased with LVEF at follow-up (29.3 ± 8.8–41.7 ± 13.2–42.1 ± 13.1 %, p < 0.0001, Group I), defined as CMi. Patients with initial LVEF >45–60 % (n = 25) significantly improved further or recovered completely, regarding LVEF (53.0 ± 3.6–59.0 ± 9.4–59.8 ± 10.0 %, p = 0.03, Group II). Patients with initial LVEF >60 % (n = 36) remained stable and did not deteriorate over long-term follow-up (68.8 ± 6.7–67.5 ± 10.9–68.8 ± 10.7 %, p = 0.5, Group III). Groups II and III were defined as chronic myocarditis.

Conclusions

In patients with virus-negative chronic myocarditis or CMi, we could show the effectiveness and beneficial effects of immunosuppressive treatment. Based on the normalization of the inflammatory process LVEF improvement is lasting for a long-term period of time.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Abbreviations

AF:

Area fraction

CAMs:

Cell-adhesion molecules

CMi:

Inflammatory cardiomyopathy

DIA:

Digital image analysis

EMB:

Endomyocardial biopsy

HLA-1:

Human leukocyte antigen-1

IH:

Immunohistology

LVEDD:

Left ventricular end-diastolic diameter

LVESD:

Left ventricular end-systolic diastolic diameter

LVEF:

Ejection fraction

Npcr:

Nested polymerase chain reaction

RT-PCR:

Reverse transcription PCR

References

  1. Cooper LT Jr (2009) Myocarditis. N Engl J Med 360:1526–1538

    Article  CAS  PubMed  Google Scholar 

  2. Feldman AM, McNamara D (2000) Myocarditis. N Engl J Med 343:1388–1398

    Article  CAS  PubMed  Google Scholar 

  3. Caforio AL, Pankuweit S, Arbustini E, Basso C, Gimeno-Blanes J, Felix SB, Fu M, Heliö T, Heymans S, Jahns R, Klingel K, Linhart A, Maisch B, McKenna W, Mogensen J, Pinto YM, Ristic A, Schultheiss HP, Seggewiss H, Tavazzi L, Thiene G, Yilmaz A, Charron P, Elliott PM, European Society of Cardiology Working Group on Myocardial and Pericardial Diseases (2013) 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 34(33):2636–2648

    Article  PubMed  Google Scholar 

  4. Richardson P, McKenna W, Bristow M (1996) Report of the 1995 World Health Organization/International Society and Federation of Cardiology Task Force on the Definition and Classification of cardiomyopathies. Circulation 93(5):841–842

    Article  CAS  PubMed  Google Scholar 

  5. Elliott P, Andersson B, Arbustini E, Bilinska Z, Cecchi F, Charron P, Dubourg O, Kühl U, Maisch B, McKenna WJ, Monserrat L, Pankuweit S, Rapezzi C, Seferovic P, Tavazzi L, Keren A (2008) Classification of the cardiomyopathies: a position statement from the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J 29(2):270–276

    Article  PubMed  Google Scholar 

  6. Liu PP, Mason JW (2001) Advances in the understanding of myocarditis. Circulation 104:1076–1082

    Article  CAS  PubMed  Google Scholar 

  7. Kindermann I, Kindermann M, Kandolf R, Klingel K, Bultmann B, Muller T, Lindinger A, Bohm M (2008) Predictors of outcome in patients with suspected myocarditis. Circulation 118:639–648

    Article  PubMed  Google Scholar 

  8. Pankuweit S, Portig I, Maisch B (2002) Pathophysiology of cardiac inflammation: molecular mechanisms. Herz 27:669–676

    Article  PubMed  Google Scholar 

  9. Schultheiss HP, Kühl U, Cooper LT (2011) The management of myocarditis. Eur Heart J 32:2616–2625

    Article  PubMed  Google Scholar 

  10. Bowles NE, Javier FGF, Makar KA (2002) Analysis of the coxsackievirus B-adenovirus receptor gene in patients with myocarditis or dilated cardiomyopathy. Mol Genet Metab 77(3):257–259

    Article  CAS  PubMed  Google Scholar 

  11. Pauschinger M, Noutsias M, Lassner D, Schultheiss HP, Kuehl U (2006) Inflammation, ECG changes and pericardial effusion: whom to biopsy in suspected myocarditis? Clin Res Cardiol 95(11):569–583

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Schultheiss HP, Piper C, Sowade O, Waagstein F, Kapp JF, Wegscheider K, Groetzbach G, Pauschinger M, Escher F, Arbustini E, Siedentop H, Kuehl U (2016) Betaferon in chronic viral cardiomyopathy (BICC) trial: effects of interferon-β treatment in patients with chronic viral cardiomyopathy. Clin Res Cardiol. doi:10.1007/s00392-016-0986-9

  13. Weitsman T, Weisz G, Keren A, Hasin T (2016) Prompt benefit of early immunosuppressive therapy in acute lymphocytic myocarditis with persistent heart failure. Clin Res Cardiol. doi:10.1007/s00392-016-0985-x

  14. Frustaci A, Chimenti C, Pieroni M (2006) Cell death, proliferation and repair in human myocarditis responding to immunosuppressive therapy. Mod Pathol 19:755–765

    CAS  PubMed  Google Scholar 

  15. Parrillo JE, Cunnion RE, Epstein SE (1989) A prospective, randomized, controlled trial of prednisone for dilated cardiomyopathy. N Engl J Med 321:1061–1068

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  17. Frustaci A, Chimenti C (2014) Immunosuppressive therapy in myocarditis. Circ J 79(1):4–7

    Article  PubMed  Google Scholar 

  18. Cooper LT, Baughman KL, Feldman AM, Frustaci A, Jessup M, Kuhl U, Levine GN, Narula J, Starling RC, Towbin J, Virmani R, American Heart Association, American College of Cardiology, European Society of Cardiology, Heart Failure Society of America, Heart Failure Association of the European Society of Cardiology (2007) The role of endomyocardial biopsy in the management of cardiovascular disease: a scientific statement from the American Heart Association, the American College of Cardiology, and the European Society of Cardiology. Endorsed by the Heart Failure Society of America and the Heart Failure Association of the European Society of Cardiology. J Am Coll Cardiol 50(19):1914–1931

    Article  PubMed  Google Scholar 

  19. Escher F, Lassner D, Kühl U, Gross U, Westermann D, Poller W, Skurk C, Weitmann K, Hoffmann W, Tschöpe C, Schultheiss HP (2014) Analysis of endomyocardial biopsies in suspected myocarditis-diagnostic value of left versus right ventricular biopsy. Int J Cardiol 177(1):76–78

    Article  CAS  PubMed  Google Scholar 

  20. Kühl U, Pauschinger M, Noutsias M, Seeberg B, Bock T, Lassner D, Poller W, Kandolf R, Schultheiss HP (2005) High prevalence of viral genomes and multiple viral infections in the myocardium of adults with “idiopathic” left ventricular dysfunction. Circulation 111(7):887–893

    Article  PubMed  Google Scholar 

  21. Bock CT, Klingel K, Kandolf R (2010) Human parvovirus B19-associated myocarditis. N Engl J Med 362:1248–1249

    Article  CAS  PubMed  Google Scholar 

  22. Aretz HT (1987) Myocarditis: the Dallas criteria. Hum Pathol 18(6):619–624

    Article  CAS  PubMed  Google Scholar 

  23. Zuern CS, Walker B, Sauter M, Schaub M, Chatterjee M, Mueller K, Rath D, Vogel S, Tegtmeyer R, Seizer P, Geisler T, Kandolf R, Lang F, Klingel K, Gawaz M, Borst O (2015) Endomyocardial expression of SDF-1 predicts mortality in patients with suspected myocarditis. Clin Res Cardiol 104(12):1033–1043

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  26. Wojnicz R, Nowalany-Kozielska E, Wojciechowska C (2001) Randomized, placebo-controlled study for immunosuppressive treatment of inflammatory dilated cardiomyopathy: two-year follow-up results. Circulation 104:39–45

    Article  CAS  PubMed  Google Scholar 

  27. Cihakova D, Rose NR (2008) Pathogenesis of myocarditis and dilated cardiomyopathy. Adv Immunol 99:95–114

    Article  CAS  PubMed  Google Scholar 

  28. Bulut D, Scheeler M, Niedballa LM, Miebach T, Mügge A (2011) Effects of immunoadsorption on endothelial function, circulating endothelial progenitor cells and circulating microparticles in patients with inflammatory dilated cardiomyopathy. Clin Res Cardiol 100(7):603–610

    Article  CAS  PubMed  Google Scholar 

  29. Kallwellis-Opara A, Dörner A, Poller WC, Noutsias M, Kühl U, Schultheiss HP, Pauschinger M (2007) Autoimmunological features in inflammatory cardiomyopathy. Clin Res Cardiol 96(7):469–480

    Article  CAS  PubMed  Google Scholar 

  30. Devaux B, Scholz D, Hirche A, Klovekorn WP, Schaper J (1997) Upregulation of cell adhesion molecules and the presence of low grade inflammation in human chronic heart failure. Eur Heart J 18(3):470–479

    Article  CAS  PubMed  Google Scholar 

  31. Noutsias M, Pauschinger M, Schultheiss HP, Kühl U (2003) Cytotoxic perforin-positive and TIA-1+ infiltrates are associated with cell adhesion molecule expression in dilated cardiomyopathy. Eur J Heart Fail 5:469–479

    Article  CAS  PubMed  Google Scholar 

  32. Badorff C, Noutsias M, Kühl U, Schultheiss HP (1997) Cell-mediated cytotoxicity in hearts with dilated cardiomyopathy: correlation with interstitial fibrosis and foci of activated T lymphocytes. J Am Coll Cardiol 29:429–434

    Article  CAS  PubMed  Google Scholar 

  33. Young LH, Joag SV, Zheng LM, Lee CP, Lee YS, Young JD (1990) Perforin-mediated myocardial damage in acute myocarditis. Lancet 336:1019–1021

    Article  CAS  PubMed  Google Scholar 

  34. Camina-Tato M, Morcillo-Suarez C, Bustamante MF et al (2010) Gender-associated differences of perforin polymorphisms in the susceptibility to multiple sclerosis. J Immunol 185:5392–5404

    Article  CAS  PubMed  Google Scholar 

  35. Thomas HE, Trapani JA, Kay TW (2010) The role of perforin and granzymes in diabetes. Cell Death Differ 17:577–585

    Article  CAS  PubMed  Google Scholar 

  36. Pandya JM, Venalis P, Al-Khalili L, Hossain MS, Stache V, Lundberg IE, Malmström V, Fasth AE (2016) CD4+ and CD8+ CD28null T cells are cytotoxic to autologous muscle cells in polymyositis patients. Arthritis Rheumatol. doi:10.1002/art.39650

  37. Escher F, Kühl U, Lassner D, Stroux A, Westermann D, Skurk C, Tschöpe C, Poller W, Schultheiss HP (2014) Presence of perforin in endomyocardial biopsies of patients with inflammatory cardiomyopathy predicts poor outcome. Eur J Heart Fail 16(10):1066–1072

    Article  CAS  PubMed  Google Scholar 

  38. Yang JJ, Ye Y, Carroll A, Yang W, Lee HW (2001) Structural biology of the cell adhesion protein CD2: alternatively folded states and structure-function relation. Curr Protein Pept Sci 2(1):1–17

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by the Deutsche Forschungsgesellschaft (DFG; SFB/TR-19). We thank Ms. E. Hertel, M. Willner (Charité-Universitätsmedizin Berlin), K. Winter, S. Ochmann, and C. Seifert (IKDT Berlin) for excellent assistance.

Author information

Authors and Affiliations

  1. Institute for Cardiac Diagnostics and Therapy (IKDT), Berlin, Germany

    Felicitas Escher, Uwe Kühl, Dirk Lassner & Heinz-Peter Schultheiss

  2. Department of Cardiology, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany

    Felicitas Escher, Uwe Kühl, Burkert Pieske & Carsten Tschöpe

  3. Department of Cardiology, CBF, Charité-Universitätsmedizin Berlin, Berlin, Germany

    Wolfgang Poller & Heinz-Peter Schultheiss

  4. University Heart Center Hamburg, Hamburg, Germany

    Dirk Westermann

  5. Department of Cardiology, Deutsches Herzzentrum Berlin (DHZB), Berlin, Germany

    Burkert Pieske

  6. Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Berlin, Germany

    Carsten Tschöpe

  7. Deutsches Zentrum für Herz-Kreislaufforschung (DZHK), Berlin, Germany

    Felicitas Escher, Wolfgang Poller, Burkert Pieske & Carsten Tschöpe

Authors
  1. Felicitas Escher
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Uwe Kühl
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dirk Lassner
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wolfgang Poller
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Dirk Westermann
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Burkert Pieske
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Carsten Tschöpe
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Heinz-Peter Schultheiss
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Felicitas Escher.

Ethics declarations

Conflict of interest

None declared.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Escher, F., Kühl, U., Lassner, D. et al. Long-term outcome of patients with virus-negative chronic myocarditis or inflammatory cardiomyopathy after immunosuppressive therapy. Clin Res Cardiol 105, 1011–1020 (2016). https://doi.org/10.1007/s00392-016-1011-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00392-016-1011-z

Keywords

Search

Navigation