Clin Res Cardiol 101, Suppl 1, April 2012

V126 - A Cardiac Expression Profile Defined by a Long Noncoding RNA and a Panel of microRNAs Predicts Virus Elimination and Clinical Course in Coxsackievirus B3-Induced Human Cardiomyopathy
U. Kühl1, D. Lassner2, L. Gilke1, J. Tank1, X. Wang3, M. Gast1, C. Skurk4, D. Westermann1, H.-P. Schultheiss1, W. Poller1
1Med. Klinik II, Klinik für Kardiologie und Pulmologie, Charité - Universitätsmedizin Berlin, Campus Benj. Franklin, Berlin; 2Institut Kardiale Diagnostik und Therapie GmbH, Berlin; 3Med. Klinik II, Abt. für Kardiologie und Pulmologie, Charité - Universitätsmedizin Berlin, Campus Benj. Franklin, Berlin; 4Medizinische Klinik II, Kardiologie und Pulmologie, Charité Berlin, Berlin;
Background: Understanding of the roles of RNAs within the cell has expanded dramatically during the past decade. Novel therapeutic strategies are based on noncoding regulatory RNAs inducing RNA interference (RNAi) to silence single genes, and modulation of cellular microRNAs (miRs) to alter complex gene expression patterns in diseased organs. We showed therapeutic potential of cardiac-targeted RNAi, and others investigated therapies based on miR modulation. These RNA types are only part of a larger spectrum of noncoding RNAs arising from the human genome. Numerous long noncoding RNAs (lncRNAs) up to several kb in size have been identified in genome-wide surveys. We show here, for the first time, clinical predictive potential of a regulatory RNA profile including one lncRNA and 18 miRs in a cardiac disease.
Methods and Results: This lncRNA was identified by genome-wide expression profiling of endomyocardial biopsies (EMBs) from patients with Coxsackievirus B3 (CoxB3)-induced heart disease. Whereas part of these patients was able to eliminate the cardiac virus spontaneously with resulting recovery of their cardiac function, another part continued to harbour this virus unable to eliminate it, although clinical phenotype and the echocardiographic and hemodynamics parameters were indistinguishable between these groups. If patients failed to recover, virus elimination was subsequently induced by interferon-beta therapy as reported. Comparison of the initial cardiac transcription profiles of patients which recovered spontaneously, with those unable to eliminate the virus, identified a lncRNA highly conserved during evolution and processed to a peculiar tRNA-like structure, and 18 miRs expressed in distinct immune cell subpopulations, as the most strongly deregulated. A simple RNA profile was derived to predict clinical and virological course in CoxB3 cardiomyopathy patients. 
Conclusions: For the first time, clinical predictive potential of a cardiac expressed lncRNA in a cardiovascular disease has been demonstrated. Expression profiling of this lncRNA and immunregulatory miRs in an EMB taken during initial diagnostic workup of the patient, predicted later spontaneous virus elimination vs persistence. Mechanistically, the data suggest that determination of the cardiac immune response is more clearly visible at the high regulatory level of pattern-forming regulatory RNAs than at the level of single target genes.
Clin Res Cardiol 101, Suppl 1, April 2012
Zitierung mit Vortrags- oder Posternummer s.o.
DOI 10.1007/s00392-012-1100-6