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Novel Myocardial Markers GADD45G and NDUFS5 Identified by RNA

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Novel Myocardial Markers GADD45G and NDUFS5 Identified by RNA Iwahana et al. BMC Cardiovascular Disorders (2020) 20:116 https://doi.org/10.1186/s12872-020-01396-2 RESEARCH ARTICLE Open Access Novel myocardial markers GADD45G and NDUFS5 identified by RNA-sequencing predicts left ventricular reverse remodeling in advanced non-ischemic heart failure: a retrospective cohort study Togo Iwahana1, Sho Okada1* , Masato Kanda1, Motohiko Oshima2, Atsushi Iwama2, Goro Matsumiya3 and Yoshio Kobayashi1 Abstract Background: Left ventricular reverse remodeling (LVRR) has been detected in non-ischemic dilated cardiomyopathy (NIDCM) patients following optimal treatment. However, its prediction with only conventional modalities is often difficult. This study sought to examine whether RNA sequencing (RNA-seq) of myocardium tissue samples could predict LVRR in NIDCM. Methods: A total of 17 advanced NIDCM patients with left ventricular ejection fraction (LVEF) below 30% who underwent cardiac biopsy from Left ventricle (LV) were prospectively recruited. They received optimal treatment and followed with echocardiogram every 6 months. Based on LVRR status after 12 months of treatment, patients were divided into the reverse remodeling (RR) or non-RR group. Tissue samples were analyzed by RNA-seq, and a functional analysis of differentially expressed genes was carried out. Results: There were eight and nine patients in the RR and non-RR groups, respectively. No difference was found in age, sex, disease duration, LV end-diastolic diameter, and LVEF between the two groups. There were 155 genes that were differentially expressed between the two groups. Nicotinamide adenine dinucleotide ubiquinone oxidoreductase subunit (NDUF)S5 and Growth arrest and DNA-damage-inducible protein (GADD)45G, along with several genes related to the mitochondrial respiratory chain and ribosome, were significantly downregulated in the RR as compared to the non-RR group. Conclusion: GADD45G and NDUFS5 are potential biomarkers for LVRR in patients with advanced NIDCM. Keywords: NIDCM, LVRR, RNA-seq, NDUFS5, GADD45G * Correspondence: [email protected] 1Department of Cardiovascular Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Iwahana et al. BMC Cardiovascular Disorders (2020) 20:116 Page 2 of 12 Background of the LV at Chiba University Hospital from September Heart failure has a complex etiology and is associated 2014 to May 2016 were included in the study. Exclusion with various conditions, and is a major cause of adult criteria were as follows: (i) heart failure with ischemic mortality. In particular, non-ischemic dilated cardiomy- etiology (defined as past history of myocardial infarction opathy (NIDCM)—which is characterized by left ven- or significant stenosis in the main branches of coronary tricular (LV) dilation and a severely reduced LV ejection arteries); (ii) inflammatory or infiltrative heart disease fraction (LVEF) without coronary artery disease—is including myocarditis, sarcoidosis, or amyloidosis; (iii) often refractory to established drugs such as β-blockers, other secondary or metabolic cardiomyopathies such as angiotensin-converting enzyme inhibitors, and angioten- neuromuscular disease and alcoholic cardiomyopathy; sin II receptor blockers and to cardiac resynchronization (iv) dependence on hemodialysis; and (v) age younger therapy (CRT). Therefore, NIDCM often requires heart than 20 years or older than 65 years. transplantation or ventricular assist device (VAD) im- plantation. However, the former is available only to a Patient follow-up limited number of patients, whereas the latter is associ- Prior to myocardial biopsy, all patients underwent blood ated with complications like stroke, bleeding, and infec- sample collection, echocardiogram, and right heart tion that can be fatal during the long waiting period for catheterization. After myocardial biopsy, patients contin- transplantation [1]. ued to receive optimal treatment including guideline- On the other hand, many NIDCM patients show re- directed medical therapy with β-blockers and renin- covery of cardiac function after optimal pharmacological angiotensin blockers and CRT. Patients were followed or device therapy [2, 3]. This phenomenon, known as for 6 to 12 months, with echocardiogram performed at LV reverse remodeling (LVRR), is associated with im- each follow up; they were then divided into the reverse proved clinical outcomes. Accordingly, several indices remodeling (RR) and non-RR groups according to posi- have been identified as predictors of LVRR and heart tive or negative LVRR status, respectively. LVRR was failure, including blood biomarkers like suppression of defined as (i) LVEF improvement of > 10% in absolute tumorigenesis-2 and galectin-3 [4–8], late gadolinium value, and (ii) LVEF > 30%. enhancement by cardiac magnetic resonance imaging [9], cardiac fibrosis and cardiomyocyte hypertrophy by RNA extraction and cDNA library preparation histopathological examination [10, 11], and washout rate LV myocardium samples were collected at the time of in meta-iodobenzylguanidine myocardial scintigraphy cardiac catheter examination or open heart surgery, in- [12]. However, conventional modalities cannot accur- cluding for VAD implantation and valve replacement. ately predict the occurrence of LVRR. Samples were immediately treated with RNAlater RNA Analyzing myocardial gene expression can be more stabilization reagent (Qiagen, Valencia, CA, USA) and useful for this purpose. Several studies have demon- stored at − 20 °C. Total RNA was extracted using mir- strated a clear correlation between myocardial expres- Vana miRNA Isolation kit (Life Technologies, Carlsbad, sion of certain mRNAs or micro (mi)RNAs and LVRR in CA, USA) according to the manufacturer’s instructions, NIDCM patients by quantitative reverse transcription and cDNA libraries were generated using a NEBNext PCR [13, 14]. Moreover, RNA sequencing (RNA-seq) Ultra RNA Library Prep kit (New England BioLabs, and next generation sequencing (NGS)—which enables Beverly, MA, USA). Sequencing was performed using a higher throughput and greater accuracy in the evaluation HiSeq1500 system (Illumina, San Diego, CA, USA) with of gene expression than microarray analysis [15]—is in- a single-read sequencing length of 60 bp. creasingly used in clinical settings [16]. Previous NGS studies have revealed differences in gene expression pro- RNA-seq data analysis files between ischemic and non-ischemic cardiomyop- TopHat v.1.3.2 with default parameters was used to map athy [17, 18] or pre- and post VAD support [19–21]. sequences against the UCSC/hg19 reference genome. However, there have been no studies using comprehen- Gene expression level was quantified using Cufflinks sive transcriptome analysis to examine specific genes re- v.2.0.2 [22, 23] as fragments per kilobase of exon per lated to LVRR. The present study therefore aimed to million fragments (FPKM) mapped reads. In the present identify factors that can predict LVRR occurrence by study, miRNAs and genes expressed at low levels (FPKM RNA-seq. < 1 in all samples) were eliminated. To identify novel biomarkers that predict the occurrence of LVRR, we car- Methods ried out sensitivity, specificity, and receiver operating Patient selection characteristic (ROC) curve analyses for each differentially Patients with advanced NIDCM whose LVEF was < 30% expressed gene (DEG). Functional annotation was per- by echocardiogram and who underwent cardiac biopsy formed using the Database for Annotation, Visualization, Iwahana et al. BMC Cardiovascular Disorders (2020) 20:116 Page 3 of 12 and Integrated Discovery [24–26]. Gene expression pro- artery disease or other secondary or specific cardiomy- files of two groups were compared by principal compo- opathies were analyzed. LV myocardial samples were ob- nent analysis (PCA). RNA-sequencing data was deposited tained by transcatheter biopsy for four patients, by in the DNA Data Bank of Japan (accession number needle biopsy during aortic valve replacement surgery PRJDB5368). for three patients, or during VAD implantation for 10 patients. Quantitative real-time PCR Patients were divided into RR (n = 8) and non-RR (n = When the same cDNAs as for RNA-seq were available, 9) groups based on the findings of a follow-up echocar- quantitative real-time PCR (qPCR) was performed on a diogram. There were no differences between the two Light Cycler
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