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Meta-analysis on the immunohistological detection of inflammatory cardiomyopathy in endomyocardial biopsies

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Abstract

Meta-analysis on immunohistological (IHC) concepts for the detection of inflammatory cardiomyopathy (InfCM) in endomyocardial biopsies (EMB). We included 61 publications, with 10,491 patients (mean age 47.1 years; men 66%) who underwent EMB and IHC evaluation. The 460 control patients were devoid of IHC proof of InfCM. The mean IHC detection rate of InfCM was 50.8% (95% CI 47.7–53.8%; range 18.4–91.7%). A publication bias was excluded (Funnel Plot p = 0.4264). This IHC detection rate was significantly (p < 0.0001) higher compared to the histological detection of myocarditis according to the Dallas criteria (mean 8.04%; 95% CI 5.08–12.5%; subset of 3274 patients in 30 publications). However, 13 different diagnostic IHC criteria were described in the publications, with various thresholds of diverse phenotypes of quantified infiltrates, and endothelial expression of diverse cell adhesion molecules (CAM), quantified either visually or by digital image analysis (DIA). The comparison of IHC with cardiac magnetic resonance (CMR) data available in a subset of 13 publications with 1185 patients revealed a sensitivity for CMR of 69% (95% CI 58–79%), a specificity of 73% (95% CI 59–84%), and a ROC-AUC of 0.77 (95% CI 0.73–0.81). This meta-analysis encompassing 10,491 patients confirms a mean detection rate of InfCM in 50.8% of EMB, being significantly more sensitive compared to the histological Dallas criteria. IHC cannot be fully substituted by CMR. However, standardization of the diverse IHC markers and protocols seems pertinent, especially considering the published adverse prognostic impact of IHC-confirmed InfCM and its published suitability for the selection of candidates responding favorably to immunosuppression.

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Abbreviations

CAM:

Cell adhesion molecule(s)

CD:

Cluster of differentiation

CI:

Confidence interval

CMR:

Cardiac magnetic resonance

DCM:

Dilated cardiomyopathy

DIA:

Digital image analysis

EMB:

Endomyocardial biopsy or biopsies

GME:

Global myocardial edema/myocardial edema ratio

GRE:

Global relative enhancement

IHC:

Immunohistology, immunohistological

InfCM:

Inflammatory cardiomyopathy

LGE:

Late gadolinium enhancement

LVEF:

Left ventricular ejection fraction

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Funding

This study was partly supported by the Deutsche Forschungsgemeinschaft through the Sonderforschungsbereich Transregio 19 “Inflammatory Cardiomyopathy” (SFB TR19) to MN (TP B2), MP (TP A3) and to CT (TP B5) and by the University Hospital Giessen and Marburg Foundation Grant “T cell functionality” (UKGM 10/2009 to MN).

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Author notes

  1. Julius L. Katzmann and Peter Schlattmann both first and second authors contributed equally to this scientific work.

Authors and Affiliations

  1. Department of Internal Medicine I, Division of Cardiology, Pneumology, Angiology and Intensive Medical Care, University Hospital Jena, Friedrich-Schiller-University Jena, Jena, Germany

    Julius L. Katzmann, P. Christian Schulze & Michel Noutsias

  2. Department of Cardiology, University Hospital of Leipzig, Leipzig, Germany

    Julius L. Katzmann

  3. Institute of Medical Statistics, Informatics and Data Science (IMSID), University Hospital Jena, Friedrich-Schiller University Jena, Jena, Germany

    Peter Schlattmann

  4. Mid-German Heart Center, Department of Internal Medicine III, Division of Cardiology, Angiology and Intensive Medical Care, University Hospital Halle, Martin-Luther-University Halle-Wittenberg, Ernst-Grube-Strasse 40, 06120, Halle (Saale), Germany

    Angelos G. Rigopoulos, Daniel Sedding & Michel Noutsias

  5. Department of Psychiatry, Theodor-Wenzel-Werk, Berlin, Germany

    Ewa Noutsias

  6. Department of Cardiology, Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin (CBF), Berlin, Germany

    Boris Bigalke

  7. Department of Cardiology, Nuremberg General Hospital, Internal Medicine 8, Paracelsus Medical University, Nuremberg, Germany

    Matthias Pauschinger

  8. Department of Cardiology, Charité - Universitätsmedizin Berlin, Campus Virchow Klinikum (CVK), Berlin, Germany

    Carsten Tschope

  9. Deutsches Zentrum für Herz Kreislaufforschung (DZHK) – Standort Berlin, Charité - Universitätsmedizin Berlin, Campus Virchow Klinikum (CVK), Berlin, Germany

    Carsten Tschope

  10. BCRT - Berlin Institute of Health Center for Regenerative Therapies, Campus Virchow Klinikum (CVK), Berlin, Germany

    Carsten Tschope

Authors
  1. Julius L. Katzmann
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  2. Peter Schlattmann
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  3. Angelos G. Rigopoulos
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  4. Ewa Noutsias
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  5. Boris Bigalke
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  6. Matthias Pauschinger
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  7. Carsten Tschope
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  8. Daniel Sedding
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  9. P. Christian Schulze
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  10. Michel Noutsias
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Contributions

JK, EN, and MN were involved in the selection of publications and data collection for the meta-analysis. MN designed the study. BB and CT reviewed the selected studies. JK, PS, EN, and MN participated in data analysis. JK, EN, and MN wrote the manuscript, and all authors reviewed and approved of the final manuscript.

Corresponding author

Correspondence to Michel Noutsias.

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Conflict of interest

MN has been consultant to the IKDT (Institute for Cardiac Diagnosis and Therapy GmbH, Berlin) 2004–2008 and has received honoraria for presentations and/or participated in advisory boards from Abbot, Abiomed, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Fresenius, Miltenyi Biotech, Novartis, Pfizer, and Zoll. AR has received honoraria for presentations from Astra-Zeneca. The other authors declare no potential conflict of interest.

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Katzmann, J.L., Schlattmann, P., Rigopoulos, A.G. et al. Meta-analysis on the immunohistological detection of inflammatory cardiomyopathy in endomyocardial biopsies. Heart Fail Rev 25, 277–294 (2020). https://doi.org/10.1007/s10741-019-09835-9

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