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ma=86400 Myocarditis and inflammatory cardiomyopathy: current evidence and future directions | Nature Reviews Cardiology
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Myocarditis and inflammatory cardiomyopathy: current evidence and future directions

Nature Reviews Cardiology volume 18, pages 169–193 (2021)Cite this article

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Abstract

Inflammatory cardiomyopathy, characterized by inflammatory cell infiltration into the myocardium and a high risk of deteriorating cardiac function, has a heterogeneous aetiology. Inflammatory cardiomyopathy is predominantly mediated by viral infection, but can also be induced by bacterial, protozoal or fungal infections as well as a wide variety of toxic substances and drugs and systemic immune-mediated diseases. Despite extensive research, inflammatory cardiomyopathy complicated by left ventricular dysfunction, heart failure or arrhythmia is associated with a poor prognosis. At present, the reason why some patients recover without residual myocardial injury whereas others develop dilated cardiomyopathy is unclear. The relative roles of the pathogen, host genomics and environmental factors in disease progression and healing are still under discussion, including which viruses are active inducers and which are only bystanders. As a consequence, treatment strategies are not well established. In this Review, we summarize and evaluate the available evidence on the pathogenesis, diagnosis and treatment of myocarditis and inflammatory cardiomyopathy, with a special focus on virus-induced and virus-associated myocarditis. Furthermore, we identify knowledge gaps, appraise the available experimental models and propose future directions for the field. The current knowledge and open questions regarding the cardiovascular effects associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are also discussed. This Review is the result of scientific cooperation of members of the Heart Failure Association of the ESC, the Heart Failure Society of America and the Japanese Heart Failure Society.

Key points

  • The role of specific viruses, immune cells and autoimmunity in the pathogenesis of myocarditis and inflammatory cardiomyopathy is still incompletely understood, and advanced animal and cell models are required for future research.

  • Advanced animal models that take into account immune experience and exposure to environmental factors and in vitro models with immune cell interactions are needed to facilitate better clinical translation of the findings.

  • Improved standardization of available invasive and noninvasive diagnostic tools and a consensus on their specific use are needed to allow specific diagnosis and stratification of patient cohorts for the implementation of aetiology-based therapies.

  • To develop aetiology-based therapies, the efficacy of many existing, repurposed or emerging therapies needs to be evaluated in large, controlled, randomized trials.

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Fig. 1: Prominent viruses associated with inflammatory cardiomyopathy over time.
Fig. 2: Cardiosplenic axis in coxsackievirus B3-induced myocarditis.
Fig. 3: Diagnosis of lymphocytic myocarditis.
Fig. 4: Visualization of viral nucleic acids in acute myocarditis.
Fig. 5: Electroanatomical voltage mapping to guide endomyocardial biopsy.
Fig. 6: Improving the subclassification of patients with inflammatory cardiomyopathy.
Fig. 7: Gaps in evidence for endomyocardial biopsy-guided therapy in myocarditis and inflammatory cardiomyopathy.

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Acknowledgements

C.T. acknowledges the support of the Federal Ministry of Education and Research (BMBF), Germany, for the CaPACITY (Cortisone in Parvovirus Inflammatory Cardiomyopathy) programme. A.L.P.C. acknowledges the support of Budget Integrato per la Ricerca dei Dipartimenti (BIRD, year 2019), Padova University, Padova, Italy (project title: Myocarditis: Genetic Background, Predictors of Dismal Prognosis and of Response to Immunosuppressive Therapy). S.H. acknowledges the support of the ERA-Net-CVD project MacroERA (01KL1706) and IMI2-CARDIATEAM (no. 821508); the support of the Netherlands Cardiovascular Research Initiative, an initiative with support of the Dutch Heart Foundation, CVON2016-Early HFPEF, 2015-10, CVON She-PREDICTS, grant 2017-21, CVON Arena-PRIME, 2017-18; and the support of the Flemish FWO G091018N and FWO G0B5930N. C.T. and S.V.L. acknowledge the support of the German Centre for Cardiovascular Research (DZHK) for the ‘Voltage-mapping-guided and MRI-guided endomyocardial biopsy in myocarditis and DCMi’ study.

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Authors and Affiliations

  1. Berlin Institute of Health Center for Regenerative Therapies (BCRT), Charité – University Medicine Berlin, Campus Virchow Clinic, Berlin, Germany

    Carsten Tschöpe & Sophie Van Linthout

  2. German Centre for Cardiovascular Research (DZHK), partner site Berlin, Berlin, Germany

    Carsten Tschöpe, Norbert Hübner, Sebastian Kelle & Sophie Van Linthout

  3. Department of Cardiology, Charité – University Medicine Berlin, Campus Virchow Klinikum, Berlin, Germany

    Carsten Tschöpe, Sebastian Kelle, Abdul S. Parwani & Frank Spillmann

  4. De Gasperis Cardio Center and Transplant Center, Niguarda Hospital, Milan, Italy

    Enrico Ammirati

  5. Winters Center for Heart Failure Research, Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX, USA

    Biykem Bozkurt

  6. Michael E. DeBakey VA Medical Center, Houston, Texas, USA

    Biykem Bozkurt

  7. Division of Cardiology, Department of Cardiological, Thoracic and Vascular Sciences and Public Health, Centro Gallucci, University of Padova-Policlinico, Padova, Italy

    Alida L. P. Caforio

  8. Department of Cardiovascular Medicine, Mayo Clinic, Jacksonville, FL, USA

    Leslie T. Cooper

  9. Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany

    Stephan B. Felix

  10. German Centre for Cardiovascular Research (DZHK), partner site Greifswald, Greifswald, Germany

    Stephan B. Felix

  11. University of Miami, Miller School of Medicine, Miami, FL, USA

    Joshua M. Hare

  12. Department of Cardiology, Charité – University Medicine Berlin, Campus Benjamin Franklin, Berlin, Germany

    Bettina Heidecker

  13. Department of Cardiology, CARIM, Maastricht University, Maastricht, Netherlands

    Stephane Heymans

  14. Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium

    Stephane Heymans

  15. Cardiovascular and Metabolic Sciences, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany

    Norbert Hübner & Henrike Maatz

  16. Berlin Institute of Health (BIH), Charité – University Medicine Berlin, Berlin, Germany

    Norbert Hübner

  17. Department of Internal Medicine/Cardiology, German Heart Center Berlin, Berlin, Germany

    Sebastian Kelle

  18. Cardiopathology, Institute for Pathology and Neuropathology, University Hospital Tübingen, Tübingen, Germany

    Karin Klingel

  19. Kaufman Center for Heart Failure, Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH, USA

    Randall C. Starling

  20. Department of Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan

    Hiroyuki Tsutsui

  21. Faculty of Medicine, University of Belgrade, Belgrade, Serbia

    Petar Seferovic

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Contributions

C.T., N.H., H.M., K.K. and S.V.L. researched data for the article; C.T., E.A., K.K. and S.V.L. contributed to discussion of the content; C.T., E.A., B.B., A.L.P.C., L.T.C, S.B.F., J.M.H., B.H., S.H., S.K., K.K., H.M., A.S.P., F.S., R.C.S., H.T., P.S. and S.V.L. wrote the article and C.T., A.L.P.C., L.T.C., S.B.F., J.M.H., B.H., S.H., N.H., K.K. and S.V.L. reviewed and/or edited the article before submission.

Corresponding author

Correspondence to Carsten Tschöpe.

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Competing interests

C.T. is a consultant for Cardiotropic Labs, Miami, FL, USA. S.B.F. reports grants from Fresenius Medical Care and ENDI Foundation. J.M.H. holds equity in Heart Genomics. J.M.H. and B.H. are both inventors on a patent involving the use of RNA as a biomarker for myocarditis. The other authors declare no competing interests.

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Nature Reviews Cardiology thanks D. Cihakova, D. Fairweather, A. Frustaci, G. Thiene and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

CD8+ T cells

A subpopulation of MHC class I-restricted T cells and mediators of adaptive immunity. They include cytotoxic T cells, which are important for killing cancerous or virus-infected cells, and CD8+ suppressor T cells, which block certain types of immune response.

T helper 1 cells

(TH1 cells). A subset of T helper cells that primarily secrete IFNγ, which is associated with protection against intracellular microbes (predominantly viruses) and the onset of antitumorigenic or pro-tumorigenic effects.

T helper 2 cells

(TH2 cells). A subset of T helper cells that fight parasitic infections by secreting specific interleukins, including IL-4, IL-5 and IL-13.

Regulatory T cells

(Treg cells). A subpopulation of CD4+ T cells, constituting 5–10% of the peripheral T cells, that have a pivotal role in the induction and maintenance of immune homeostasis and tolerance. Treg cells have multiple effector functions and execute their regulatory potency by directly suppressing T cells, B cells and antigen-presenting cells, and also by interacting with non-immune tissue cells.

Antigen-presenting cells

(APCs). A heterogeneous group of immune cells that mediate the cellular immune response by processing and presenting antigens recognizable by T cells. Classic APCs include macrophages, dendritic cells, B cells and Langerhans cells.

Neutrophil extracellular traps

Complexes of chromosomal DNA, histones and granule proteins that are released by neutrophils and can entangle bacteria, thereby limiting infection.

Experimental autoimmune myocarditis

(EAM). EAM can be induced in susceptible mouse strains by immunization with self-peptides derived from the myosin H chain together with a strong adjuvant, or by injection of activated, myosin H chain-loaded dendritic cells.

TH17 cells

A subset of T helper cells that fight microbial pathogens by secreting cytokines such as IL-17A, IL-17F and IL-22.

Dallas criteria

The Dallas criteria were proposed in 1986 and provide a histopathological categorization for the diagnosis of myocarditis. According to the Dallas criteria, myocarditis requires an inflammatory infiltrate and associated myocyte necrosis or damage not characteristic of an ischaemic event, whereas in borderline myocarditis, a less intense inflammatory infiltrate and no light-microscopic evidence of myocytolysis (myocyte destruction) is evident.

Immunoadsorption

Selective apheresis method for the removal of specific antibodies and immune complexes through high-affinity adsorbers, achieved by passing a patient’s plasma over columns that remove immunoglobulins. The adsorbed plasma is then reinfused into the patient.

Intravenous immunoglobulin

(IVIG). Therapy based on the intravenous administration of a blood product prepared from the serum of 1,000–15,000 donors per batch. IVIG therapy is the treatment of choice for patients with antibody deficiencies and is commonly used after immunoadsorption.

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Tschöpe, C., Ammirati, E., Bozkurt, B. et al. Myocarditis and inflammatory cardiomyopathy: current evidence and future directions. Nat Rev Cardiol 18, 169–193 (2021). https://doi.org/10.1038/s41569-020-00435-x

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