Currently, IGCM and CS are diagnosed based on differential patterns of
inflammatory cell infiltration and non-caseating granulomas in
histological sections of endomyocardial biopsies (EMBs), after heart
explantation or postmortem. They report on a method for improved
differential diagnosis by myocardial gene expression profiling in EMBs.
They examined gene expression profiles in EMBs from 10 patients with
histopathologically proven IGCM, 10 with CS, 18 with active myocarditis
(MCA), and 80 inflammation-free control subjects by quantitative
RT-QPCR. They identified distinct differential profiles that allowed a
clear discrimination of tissues harbouring giant cells (IGCS, CS) from
those with MCA or inflammation-free controls. The expression levels of
genes coding for cytokines or chemokines (CCL20, IFNB1, IL6, IL17D; P
< 0.05), cellular receptors (ADIPOR2, CCR5, CCR6, TLR4, TLR8; P <
0.05), and proteins involved in the mitochondrial energy metabolism
(CPT1, CYB, DHODH; P < 0.05) were deregulated in 2- to 300-fold,
respectively. Bioinformatic analyses and correlation of the gene
expression data with immunohistochemical findings provided novel
information regarding the differential cellular and molecular
pathomechanisms in IGCM, CS, and MCA.
The authors concluded that
myocardial gene expression profiling is a reliable method to predict the
presence of multinuclear giant cells in the myocardium, even without a
direct histological proof, in single small EMB sections, and thus to
reduce the risk of sampling errors. This profiling also facilitates the
discrimination between IGCM and CS, as two different clinical entities
that require immediate and tailored differential therapy.
IGCM and CS are two disorders that only recently have been considered as distinct histopathological entities. Both are potentially lethal myocarditis forms that are infectious-negative and immune-mediated. For both of them the dismal prognosis can be improved by early diagnosis and tailored immunosuppressive therapy. Although both entities are perceived as rare conditions, two recent studies have suggested the possibility that they may be much more common than previously suspected, for instance in the group of young patients with apparently idiopathic atrio-ventricular blocks or in patients with atrial fibrillation. As for other diseases, the most severe cases are first clinically recognized, but then the medical community realise that such cases represent only the tip of the iceberg and that less severe forms are much more prevalent and underdiagnosed. In the case of IGCM there is no distinctive clinical presentation, but, as for other forms of myocarditis, IGCM can present as acute or chronic heart failure, arrhythmia, myocardial necrosis with normal coronary arteries, or a life-threatening condition (cardiac arrest or cardiogenic shock). Some clinical hints are the severity of cardiac symptoms, the lack of response to standard cardiological care and the association in the patient or in family members with other extra-cardiac autoimmune conditions, such as autoimmune thyroid disease, ulcerative colitis, etc. However, as shown in the paper by Lassner et al, IGCM cases are older than previous case series in keeping with the observation that the younger IGCM patients are likely to die before the clinical diagnostics including EMB is completed.
The diagnosis of CS may be easy if cardiac signs or symptoms develop in a patient with a known diagnosis of extra-cardiac disease, but is particularly challenging in isolated CS.
The diagnosis of IGCM and CS is based upon EMB with a distinctive histopathology and the lack of infectious agents by PCR-based methods, as outlined by the recent consensus ESC document on myocarditis. EMB may fail to detect the histopathological hallmarks of the diseases, that is to say the presence of multinuclear giant cells in IGCM and the non-caseating granuloma in CS. Therefore, any diagnostic adjunctive EMB tool is welcome. In the last 2 decades EMB has gained greater diagnostic potential, since conventional histology with the time-honoured Dallas criteria has been supplemented by immunohistochemistry and molecular diagnosis of infectious agents.
Myocardial gene expression profiling is emerging as yet another powerful
tool to: 1) reach an etiological diagnosis and subsequent
etiology-direct therapy, 2) reach differential diagnosis of IGCM, CS and
lymphocytic myocarditis, 3) get an insight on different intracellular
and systemic immunological pathways involved in the pathogenesis of
distinct myocarditis forms in patients in vivo. This is of clinical
relevance, since it can direct towards the future identification of
selective immunosuppressive or immunomodulatory agents, including novel
biological agents, targeting the predominant immune pathway or cell type
involved in each myocarditis form.
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Notes to editor
D. Lassner 1†*, U. Kuhl 1,2†, C. S. Siegismund1, M. Rohde1, S.
Elezkurtaj3, F. Escher 1,2, C. Tschope2, U. M. Gross1,W. Poller2, and
1Institute of Cardiac Diagnostics and Therapy,
Moltkestrasse 31, D-12203 Berlin, Germany; 2Department of Cardiology
andPneumonology, Charite´ – University Medicine Berlin, Campus Benjamin
Franklin, Berlin, Germany; and 3Institute of Pathology, Charite´ –
University Medicine Berlin, Berlin, Germany
Eur Heart J. 2014 Mar 24. [Epub ahead of print]
Alida LP Caforio, MD, PhD, FESC,
Cardiology, Dept of Cardiological Thoracic and Vascular Sciences, University of Padova, Italy.
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.