Uwe Kuehl1, Dirk Lassner1, Martina Gast1, Andrea Stroux1, Maria Rohde1, Christine Siegismund1, Xiaomin Wang1, Felicitas Escher1, Michael Gross1, Carsten Skurk1, Carsten Tschoepe1, Madlen Loebel1, Carmen Scheibenbogen1, Heinz-Peter Schultheiss1, Wolfgang Poller2. 1. From the Department of Cardiology and Pneumology (U.K., M.G., X.W., F.E., M.G., C. Skurk, C.T., H.-P.S., W.P.), Institute for Biometry and Clinical Epidemiology, Campus Benjamin Franklin (A.S.), Institute for Medical Immunology, Campus Virchow Klinikum (M.L., C. Scheibenbogen), Berlin Center for Regenerative Therapies (BCRT) (C.T., M.L., C. Scheibenbogen, W.P.), Charité-Universitätsmedizin Berlin, Berlin, Germany; and Institute for Cardiac Diagnostics and Therapy (IKDT), Berlin, Germany (D.L., M.R., C. Siegismund). 2. From the Department of Cardiology and Pneumology (U.K., M.G., X.W., F.E., M.G., C. Skurk, C.T., H.-P.S., W.P.), Institute for Biometry and Clinical Epidemiology, Campus Benjamin Franklin (A.S.), Institute for Medical Immunology, Campus Virchow Klinikum (M.L., C. Scheibenbogen), Berlin Center for Regenerative Therapies (BCRT) (C.T., M.L., C. Scheibenbogen, W.P.), Charité-Universitätsmedizin Berlin, Berlin, Germany; and Institute for Cardiac Diagnostics and Therapy (IKDT), Berlin, Germany (D.L., M.R., C. Siegismund). wolfgang.poller@charite.de.
Abstract
BACKGROUND: Investigation of disease pathogenesis confined to protein-coding regions of the genome may be incomplete because many noncoding variants are associated with disease. We aimed to identify novel predictive markers for the course of enterovirus (CVB3) cardiomyopathy by screening for noncoding elements influencing the grossly different antiviral capacity of individual patients. METHODS AND RESULTS: Transcriptome mapping of CVB3 cardiomyopathy patients revealed distinctive cardiac microRNA (miR) patterns associated with spontaneous virus clearance and recovery (CVB3-ELIM) versus virus persistence and progressive clinical deterioration (CVB3-PERS). Profiling of protein-coding genes and 754 miRs in endomyocardial biopsies of test cohorts was performed at their initial presentation, and those spontaneously eliminating the virus were compared with those with virus persistence on follow-up. miR profiling revealed highly significant differences in cardiac levels of 16 miRs, but not of protein-coding genes. Evaluation of this primary distinctive miR pattern in validation cohorts, and multivariate receiver operating characteristic curve analysis, confirmed this pattern as highly predictive for disease course (area under the curve, 0.897±0.071; 95% confidence interval, 0.758-1.000). Eight miRs were strongly induced in CVB3-PERS (miRs 135b, 155, 190, 422a, 489, 590, 601, 1290), but undetectable in CVB3-ELIM or controls. They are predicted to target multiple immune response genes, and 2 of these were confirmed by antisense-mediated ablation of miRs 135b, 190, and 422a in the monocytic THP-1 cell line. CONCLUSIONS: An immediate clinical application of the data is cardiac miR profiling to assess the risk of virus persistence and progressive clinical deterioration in CVB3 cardiomyopathy. Patients at risk are eligible for immediate antiviral therapy to minimize irreversible cardiac damage.
BACKGROUND: Investigation of disease pathogenesis confined to protein-coding regions of the genome may be incomplete because many noncoding variants are associated with disease. We aimed to identify novel predictive markers for the course of enterovirus (CVB3) cardiomyopathy by screening for noncoding elements influencing the grossly different antiviral capacity of individual patients. METHODS AND RESULTS: Transcriptome mapping of CVB3cardiomyopathypatients revealed distinctive cardiac microRNA (miR) patterns associated with spontaneous virus clearance and recovery (CVB3-ELIM) versus virus persistence and progressive clinical deterioration (CVB3-PERS). Profiling of protein-coding genes and 754 miRs in endomyocardial biopsies of test cohorts was performed at their initial presentation, and those spontaneously eliminating the virus were compared with those with virus persistence on follow-up. miR profiling revealed highly significant differences in cardiac levels of 16 miRs, but not of protein-coding genes. Evaluation of this primary distinctive miR pattern in validation cohorts, and multivariate receiver operating characteristic curve analysis, confirmed this pattern as highly predictive for disease course (area under the curve, 0.897±0.071; 95% confidence interval, 0.758-1.000). Eight miRs were strongly induced in CVB3-PERS (miRs 135b, 155, 190, 422a, 489, 590, 601, 1290), but undetectable in CVB3-ELIM or controls. They are predicted to target multiple immune response genes, and 2 of these were confirmed by antisense-mediated ablation of miRs 135b, 190, and 422a in the monocytic THP-1 cell line. CONCLUSIONS: An immediate clinical application of the data is cardiac miR profiling to assess the risk of virus persistence and progressive clinical deterioration in CVB3cardiomyopathy. Patients at risk are eligible for immediate antiviral therapy to minimize irreversible cardiac damage.
Authors: Fabiola B Sozzi; Elisa Gherbesi; Andrea Faggiano; Eleonora Gnan; Alessio Maruccio; Marco Schiavone; Laura Iacuzio; Stefano Carugo Journal: Front Cardiovasc Med Date: 2022-06-20
Authors: Wolfgang Poller; Stefanie Dimmeler; Stephane Heymans; Tanja Zeller; Jan Haas; Mahir Karakas; David-Manuel Leistner; Philipp Jakob; Shinichi Nakagawa; Stefan Blankenberg; Stefan Engelhardt; Thomas Thum; Christian Weber; Benjamin Meder; Roger Hajjar; Ulf Landmesser Journal: Eur Heart J Date: 2018-08-01 Impact factor: 29.983