Giant Cell Myocarditis: Still a Conundrum. The Need for a Worldwide Registry

This article refers to ‘Long-term outcome and its predictors in giant cell myocarditis’ by K. EkstrÖm et al., published in this issue on pages 1452–1458. Giant cell myocarditis (GCM) is a rare disease characterized by myocardial necrosis and the formation of unspecific giant cells. The underlying pathophysiological mechanisms are not yet defined, but appear to involve autoimmune disorders, genetics, and possibly environmental factors such as viruses. The disease often results in progressive pump failure requiring urgent cardiac transplantation or the need for mechanical circulatory support. The diagnosis was historically made only at autopsy, but with the advent of cardiac bioptoms in the 1980s the diagnosis became more commonly made with endomyocardial biopsy (EMB). Today the clinical scenario indicative of GCM is one of the few class I indications for EMB investigations, since EMB is pertinent for establishing the diagnosis, and for the choice of specific treatment.1 The prognosis of GCM depends largely on aggressive immunosuppression and early cardiac transplantation. The low median transplant-free survival of GCM patients can be improved significantly by immunosuppression from 3.0 to 12.3 months.2 The knowledge of the disease is still limited and new insights are needed. The single-centre experience presented by Ekström et al.3 adds substantially to our knowledge referring to this rare disease, spanning a relatively long time between 1991 and 2015. During these 24 years, the annual incidence increased from 0.03 to 0.67, which may be attributed to the expanding knowledge of this rare disease. These data confirm the decreasing rate of mortality also reported in other recent publications, after the landmark trial on the decisive role of immunosuppression for GCM.2 Ekström et al. identified the presence of either necrosis or fibrosis in EMB, NT-proBNP, and troponin T levels as factors being associated with the outcome of GCM, and a further significance was calculated for LVEF. Of note, in these patients with a mean age of 51 ± 12 years, no fatal outcome was due to non-cardiovascular causes, which highlights the decisive role of GCM for prognosis when it is diagnosed. Finally, comparative data infer a borderline superior outcome of triple immunosuppression with prednisone, cyclosporine, and azathioprine over any other immunosuppressive regimen.3 These are important issues aiding the prognostic assessment and the therapeutic regimen of this rare disease, contributing to deciphering this conundrum. This important scientific work spanning a wide time frame should stimulate centres to publish their available data on GCM. Thereby several questions need to be further addressed. Giant cell myocarditis deserves special attention in light of its high cardiovascular mortality and rate of cardiac transplantation or mechanical circulatory support, and its substantially better prognosis under immunosuppression, since many important facets of this rare disease are still incompletely understood. Autoimmunity is involved in the pathogenesis of GCM, as may be deduced from animal experiments.4 Although the majority of GCM cases occur in apparently otherwise healthy subjects, the concurrent diseases which may be observed in these patients, i.e. inflammatory bowel disease, fibromyalgia, and optic neuritis, may indicate a general susceptibility to autoimmunity in these patients.2 Thus, it has to be further investigated whether GCM represents a heterogeneous syndrome triggered by different risk factors, which allow the development of more specific treatment options at least for subgroups of patients. The issue of autoimmunity may be of paramount importance, since cessation of exposure to the inducing agent might also limit the natural course of human GCM, as well as its recurrence. The precise conditions leading to the emergence of multinucleated giant cells in the myocardium, as well as the pathways contributing to resolution of GCM, and eventually also its recurrence, are obscure and need clarification. In the publication by Ekström et al., the histological diagnosis of GCM was confirmed by consensus of two expert pathologists.3 However, we need also to know more about the interobserver variability of EMB evaluation in the context of GCM, especially for differentiating sarcoidosis. Interobserver variability hampers the diagnostic value of EMB in myocarditis considerably.5 Sampling error, an additional issue contributing substantially to false-negative results in the histological diagnosis of myocarditis,6 has not been studied systematically in GCM. Furthermore, potentially specific diagnostic issues in cardiac magnetic resonance (CMR) imaging have not been established for GCM, so far. CMR has an acknowledged role in myocarditis as a non-invasive diagnostic tool with synergistic importance as compared with EMB.7, 8 Insights from one GCM case refractory to immunosuppression infer a distinct CMR pattern with transmural late gadolinium enhancement (LGE) and multiple myocardial areas with LGE and T2-weighted CMR imaging, being grossly co-localized with the infiltration pattern as detected by histological post-mortem analysis.9 The paucity of published CMR results in GCM reflects the rarity of GCM. The very low prevalence of GCM also led to the cessation of the Giant Cell Myocarditis Treatment Trial due to low accrual.10 To date, two immunosuppressive regimens have been established for GCM,10, 11 Of note, GCM may also show complete histological resolution in the natural course of the disease, without any immunosuppression, as shown in a female patient after 12 months under assist device support.12 GCM could also be detected in patients with near normal EF. We are lacking data on the disease-modifying effects of heart failure medication in GCM, especially also regarding the duration of this treatment after apparent resolution under immunosuppression and normalization of LVEF and heart failure symptoms. We have only limited data on the course of clinical values such as echocardiographic parameters (i.e. LVEF), as well as functional heart failure parameters and scores in GCM under immunosuppression.10 The possible predictive role of established myocardial biomarkers such as natriuretic peptides and troponin has been elaborated by Ekström et al.3 This argues for prospective data for prognostic evaluation of GCM, and especially for monitoring the effects of immunosuppression in GCM hearts, and eventually also the possible recurrence of GCM after cessation of immunosuppression. Further biomarkers reflecting more precisely fibrosis and inflammation (i.e. ST2 and galectin-3)13 might be excellent candidates for non-invasive prognostic and follow-up investigations of GCM patients under immunosuppression. CMR follow-up analyses in GCM patients under immunosuppression might also provide important information, albeit that a significant proportion of GCM patients will be not accessible due to the presence of an impantable cardioverter defibrillator (ICD). The clinical value of follow-up EMB diagnostics to monitor the histological effects of immunosuppression14 before cessation of this treatment needs to be defined in GCM. Digital image analysis for the morphometric quantification of interstitial fibrosis15, 16 might aid in overcoming the overt shortcomings deriving from subjective semi-quantitative evaluation of prognostically relevant processes. Gene expression analyses of EMB17, 18 are potential new diagnostic fields. Such diagnostic avenues yielding precise values as opposed to the subjective histological evaluation are candidates for a more precise prognostic assessment of GCM patients. After the landmark publication by Cooper et al.,2 GCM is diagnosed more often, and treated more efficiently, as this single-centre experience, by Ekström et al., spanning 24 years, clearly shows.3 To gather the information available from the contributing centres worldwide, which would provide more reliable data on the overall prevalence of GCM, the diagnostic findings of CMR, the applied immunosuppressive treatment and its duration, heart failure medication, rate of implanted ICD (for both primary and secondary prevention of sudden cardiac death), rate of appropriate ICD shocks, information about biomarkers, clinical follow-up analyses, transplant-free survival, recurrence rates after heart transplantation, rate of mechanical support, we propose an up to date international registry for this rare disease characterized by high mortality and heart transplantation rates. The pronounced low prevalence of GCM hampers substantial scientific progress by single-centre approaches. The decisive role of such platforms for a better understanding of rare diseases has been typified, for example, by Takotsubo syndrome.19 Conflict of interest: M.N. and C.T. have received grants from the Sonderforschungsbereich Transregio 19 ‘Inflammatory cardiomyopathy’ through the German Research Foundation (DFG). M.N. has received a grant from the UKGM (University Hospital Giessen and Marburg) related to inflammatory cardiomyopathy. M.N. has a past consultancy to the IKDT (Institute of Cardiac Diagnostics and Therapy). M.N. is local principal investigator of the IA-2006-001 trial (immunoadsorption in DCM) at the University Hospital Jena.