Clin Res Cardiol (2021). 10.1007/s00392-021-01933-9 |
||
Immune checkpoint inhibitor-associated myocarditis is associated with inflammasome activation in the human heart | ||
D. Finke1, M. Heckmann1, J. Salatzki1, L. Heinzerling2, B. Meder1, M. Völkers1, O. J. Müller3, N. Frey1, H. A. Katus1, F. Leuschner1, Z. Kaya1, L. H. Lehmann1 | ||
1Klinik für Innere Med. III, Kardiologie, Angiologie u. Pneumologie, Universitätsklinikum Heidelberg, Heidelberg; 2Klinik für Dermatologie, Univesitätsklinikum Erlangen, Erlangen; 3Klinik für Innere Medizin III, Schwerpunkt Kardiologie und Angiologie, Universitätsklinikum Schleswig-Holstein, Kiel; | ||
Immune checkpoint inhibitors (ICIs) are a hallmark of novel cancer therapies. Nevertheless, their broad use leads to an increase of immune related adverse events (irAEs). The ICI-associated myocarditis (ICIM) is a rare irAE, but it is associated with a high mortality of up to 50%. Diagnostic as well as therapeutic options of this severe phenomenon are limited. We aimed to characterize the transcriptional changes of ICIM-myocardial biopsies in order to explore unique, ICIM-defining genes/pathways. Patients with ICIM (n=19) showed a variety of clinical presentations, e.g. asymptomatic elevation of cardiac biomarkers (hs-cTnT, NT-proBNP, CK), a drop in left ventricular ejection fraction or signs and symptoms of heart failure or acute coronary syndrome. Via RNA sequencing of myocardial biopsies, we compared transcriptional changes of ICIM (n=9) with samples from dilatative cardiomyopathy (DCM, n=11), virus-induced myocarditis (VIM, n=5) and with samples of patients receiving ICIs without further evidence of myocarditis (n = 4). We found 3784 upregulated genes in ICIM (FDR <0.05). In the overrepresented pathway ‘response to interferon-gamma’ we found guanylate binding protein 5 and 6 (compared to VIM: GBP5 (log2 fc 3.21), GBP6 (log2 fc 5.37) to be significantly increased in ICIM on RNA- and protein-level and confirmed these with further histological assessment. IFN gamma-dependent genes and activation of the cardiac inflammasome are unique parts of this gene program and may be additional targets for specific treatments. Pre-existing changes in the activity of endogenous checkpoint pathways or inflammasome pathway might help to identify patients at risk. |
||
https://dgk.org/kongress_programme/ht2021/P970.htm |