Mary E Haywood1, Andrea Cocciolo2, Kadijah F Porter3, Evgenia Dobrinskikh4, Dobromir Slavov5, Sharon L Graw6, T Brett Reece7, Amrut V Ambardekar8, Michael R Bristow9, Luisa Mestroni10, Matthew R G Taylor11. 1. Human Medical Genetics and Genomics, University of Colorado, Aurora, CO, USA. Electronic address: mary.sweet@ucdenver.edu. 2. Cardiovascular Institute and Adult Medical Genetics Program, University of Colorado, Aurora, CO, USA. 3. Cardiovascular Institute and Adult Medical Genetics Program, University of Colorado, Aurora, CO, USA. Electronic address: kfporter@umail.iu.edu. 4. Division of Renal Diseases and Hypertension, Department of Medicine University of Colorado, Aurora, CO, USA. Electronic address: evgenia.dobrinskikh@ucdenver.edu. 5. Cardiovascular Institute and Adult Medical Genetics Program, University of Colorado, Aurora, CO, USA. Electronic address: dobromir.slavov@ucdenver.edu. 6. Cardiovascular Institute and Adult Medical Genetics Program, University of Colorado, Aurora, CO, USA. Electronic address: Sharon.graw@ucdenver.edu. 7. Department of Cardiothoracic Surgery, University of Colorado Hospital, Aurora, CO, USA. Electronic address: brett.reece@ucdenver.edu. 8. Division of Cardiology, Department of Medicine, University of Colorado, Aurora, CO, USA. Electronic address: amrut.ambardekar@ucdenver.edu. 9. Division of Cardiology, Department of Medicine, University of Colorado, Aurora, CO, USA. Electronic address: Michael.bristow@ucdenver.edu. 10. Human Medical Genetics and Genomics, University of Colorado, Aurora, CO, USA; Cardiovascular Institute and Adult Medical Genetics Program, University of Colorado, Aurora, CO, USA. Electronic address: luisa.mestroni@ucdenver.edu. 11. Human Medical Genetics and Genomics, University of Colorado, Aurora, CO, USA; Cardiovascular Institute and Adult Medical Genetics Program, University of Colorado, Aurora, CO, USA. Electronic address: matthew.taylor@ucdenver.edu.
Abstract
AIMS: One-third of DCM patients experience ventricular tachycardia (VT), but a clear biological basis for this has not been established. The purpose of this study was to identify transcriptome signatures and enriched pathways in the hearts of dilated cardiomyopathy (DCM) patients with VT. METHODS AND RESULTS: We used RNA-sequencing in explanted heart tissue from 49 samples: 19 DCM patients with VT, 16 DCM patients without VT, and 14 non-failing controls. We compared each DCM cohort to the controls and identified the genes that were differentially expressed in DCM patients with VT but not without VT. Differentially expressed genes were evaluated using pathway analysis, and pathways of interest were investigated by qRT-PCR validation, Western blot, and microscopy. There were 590 genes differentially expressed in DCM patients with VT that are not differentially expressed in patients without VT. These genes were enriched for genes in the TGFß1 and TP53 signaling pathways. Increased fibrosis and activated TP53 signaling was demonstrated in heart tissue of DCM patients with VT. CONCLUSIONS: Our study supports that distinct biological mechanisms distinguish ventricular arrhythmia in DCM patients.
AIMS: One-third of DCMpatients experience ventricular tachycardia (VT), but a clear biological basis for this has not been established. The purpose of this study was to identify transcriptome signatures and enriched pathways in the hearts of dilated cardiomyopathy (DCM) patients with VT. METHODS AND RESULTS: We used RNA-sequencing in explanted heart tissue from 49 samples: 19 DCMpatients with VT, 16 DCMpatients without VT, and 14 non-failing controls. We compared each DCM cohort to the controls and identified the genes that were differentially expressed in DCMpatients with VT but not without VT. Differentially expressed genes were evaluated using pathway analysis, and pathways of interest were investigated by qRT-PCR validation, Western blot, and microscopy. There were 590 genes differentially expressed in DCMpatients with VT that are not differentially expressed in patients without VT. These genes were enriched for genes in the TGFß1 and TP53 signaling pathways. Increased fibrosis and activated TP53 signaling was demonstrated in heart tissue of DCMpatients with VT. CONCLUSIONS: Our study supports that distinct biological mechanisms distinguish ventricular arrhythmia in DCMpatients.
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Authors: Mary E Sweet; Andrea Cocciolo; Dobromir Slavov; Kenneth L Jones; Joseph R Sweet; Sharon L Graw; T Brett Reece; Amrut V Ambardekar; Michael R Bristow; Luisa Mestroni; Matthew R G Taylor Journal: BMC Genomics Date: 2018-11-12 Impact factor: 3.969
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