Transcriptional and Free Radical Responses to LVAD Therapy
| Autor: | Alexandra M. Moulton, Hesham Basma, Daniel G. Anderson, John Y. Um, Matthew C. Zimmerman, Asmini Kc, Krupa K. Savalia, Marshall Hyden, Jocelyn Jones, Kajari Dhar, Fang Qiu, Brian D. Lowes |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Pyruvate LVAD Population Dilated cardiomyopathy PDK4 lcsh:Medicine Heart failure Free radicals 030204 cardiovascular system & hematology Biological pathway Andrology 03 medical and health sciences 0302 clinical medicine Gene expression Medicine education Gene education.field_of_study business.industry lcsh:R General Medicine medicine.disease equipment and supplies Transplantation 030104 developmental biology DNA methylation business |
| Zdroj: | Translational Medicine Communications, Vol 5, Iss 1, Pp 1-10 (2020) |
| Popis: | BackgroundMyocardial recovery with Left ventricular assistant device (LVAD) therapy is dichotomous with some patients obtaining remission from end-stage heart failure whereas most require transplantation or remain on pump support long term. Our goal was to determine transcriptional and free radical responses to LVAD treatment.MethodsTissues were collected from patients before and after LVAD placement in non-ischemic dilated cardiomyopathy patients (n = 14) along with controls (n = 3). RNA sequencing (RNASeq) analysis quantified transcriptional profiles by using a custom targeted panel of heart failure related genes on the PGM sequencer. The differential expression analysis between groups was conducted using edgeR (Empirical analysis of digital gene expression data in R) package in Bioconductor. Ingenuity Pathway Analysis (IPA) was carried out on differentially expressed genes to understand the biological pathways involved. Electron Paramagnetic Resonance (EPR) Spectroscopy was utilized to measure levels of free radicals in whole blood collected pre- and post-LVAD implantation (n = 16).ResultsThirty-five genes were differentially expressed in pre-LVAD failing hearts compared to controls. In response to LVAD therapy, only Pyruvate dehydrogenase kinase 4 (PDK4) and period circadian protein homolog 1(PER1) were altered with 34 heart failure related genes still differentially expressed post-LVAD compared to controls. IPA showed that DNA methylation-related genes were upregulated in both pre- and post-LVAD and was persistent with a Z-score of 2.00 and 2.36 for DNA Methyltransferase 3A (DNMT3A) and DNA methyltransferase 3B (DNMT3B), respectively. Inhibition of micro RNA21 (mir21) was also significant on pathway analysis in the post-LVAD population with a Z-score of − 2.00. Levels of free radicals in blood of pre- and post-LVAD patients did not change significantly.ConclusionLVAD therapy does not reverse many of the transcriptional changes associated with heart failure. Persistent changes in gene expression may be related to ongoing oxidative stress, continued DNA methylation, or changes in metabolism. PDK4 is a key regulator of glucose metabolism and its increased expression by LVAD therapy inhibited pyruvate metabolism. |
| Databáze: | OpenAIRE |
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