Advancing Precision Medicine in Myocarditis: Current Status and Future Perspectives in Endomyocardial Biopsy-Based Diagnostics and Therapeutic Approaches

Figures

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  Figure 1. Various forms of acute myocarditis and inflammatory cardiomyopathy demonstrated by histological and immunohistochemical staining using endomyocardial biopsies. (A) Inflammatory cardiomyopathies are characterized by diffuse, low-grade infiltration of CD3+ T cells and MAC-1+ macrophages, as well as HLA-DR activation. (B) Lymphocytic myocarditis is also characterized by diffuse infiltration of mainly lymphocytic cells and HLA-DR activation, in combination with myocytolysis. (C) In eosinophilic myocarditis, the main inflammatory cells are eosinophilic granulocytes and macrophages. (D) Giant cell myocarditis is characterized by patchy infiltration of mononuclear and lymphocytic cells, HLA-DR activation, myocytolysis, and eosinophils in the presence of giant cells (arrows). (E) Cardiac sarcoidosis is also characterized by evidence of granulomas (*) and patchy immune cell infiltrates plus HLA-DR activation, but without myocytolysis. Magnification: 200× or 400×, scale bar: 50 µm.

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  Figure 2. Differentiated evaluation of immunohistochemical markers in EMBs refines the diagnosis of intramyocardial inflammation. In a patient cohort of 450 patients with unexplained heart failure, 30.8% were characterized as inflammation negative (white) by immunohistochemistry, 43% of the patients showed elevated CD3 levels (grey), while the remaining 26% showed CD3 levels below the cut-off value (colored). Consideration of additional markers such as CD45R0, MAC-1, and LFA-1 provides evidence of inflammation in these patients despite normal CD3 levels (own data). These data indicate that an expansion of immunohistochemical parameters is urgently needed.

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  Figure 3. Incidence of viral infections in endomyocardial biopsies of n = 872 virus-positive patients. A consecutive cohort of EMBs from 1132 patients with unclear heart failure was tested for presence of cardiotropic viruses via PCR. A total of 872 samples were virus positive (77%), of which B19V viral DNA alone (B19V DNA, 64.8%) or in combination with viral transcripts (B19V RNA, 21.3%) were the main contributors. SARS-CoV-2 constituted 1.9% of virus-positive cases. EV, HHV-6, EBV, and CMV, as well as co-infections therewith constitutes the remaining bulk of cases (14.1%). Detection of iciHHV-6 in heart failure patients was rare (0.2%).

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  Figure 4. Schematic representation of the decision-making process on the basis of a comprehensive, differentiated, EMB-based diagnosis. Red: no evidence of inflammation and virus genomes; blue: detection of inflammatory infiltrates without detection of viral genomes; green: simultaneous detection of inflammation and viral genomes.