scholarly journals Identification of Upstream Transcriptional Regulators of Ischemic Cardiomyopathy Using Cardiac RNA-Seq Meta-Analysis

2020 ◽  
Vol 21 (10) ◽  
pp. 3472
Author(s):  
Ahmad Alimadadi ◽  
Sachin Aryal ◽  
Ishan Manandhar ◽  
Bina Joe ◽  
Xi Cheng

Ischemic cardiomyopathy (ICM), characterized by pre-existing myocardial infarction or severe coronary artery disease, is the major cause of heart failure (HF). Identification of novel transcriptional regulators in ischemic HF can provide important biomarkers for developing new diagnostic and therapeutic strategies. In this study, we used four RNA-seq datasets from four different studies, including 41 ICM and 42 non-failing control (NF) samples of human left ventricle tissues, to perform the first RNA-seq meta-analysis in the field of clinical ICM, in order to identify important transcriptional regulators and their targeted genes involved in ICM. Our meta-analysis identified 911 differentially expressed genes (DEGs) with 582 downregulated and 329 upregulated. Interestingly, 54 new DEGs were detected only by meta-analysis but not in individual datasets. Upstream regulator analysis through Ingenuity Pathway Analysis (IPA) identified three key transcriptional regulators. TBX5 was identified as the only inhibited regulator (z-score = −2.89). F2R and SFRP4 were identified as the activated regulators (z-scores = 2.56 and 2.00, respectively). Multiple downstream genes regulated by TBX5, F2R, and SFRP4 were involved in ICM-related diseases such as HF and arrhythmia. Overall, our study is the first to perform an RNA-seq meta-analysis for clinical ICM and provides robust candidate genes, including three key transcriptional regulators, for future diagnostic and therapeutic applications in ischemic heart failure.

Genes ◽  
2020 ◽  
Vol 11 (1) ◽  
pp. 60 ◽  
Author(s):  
Ahmad Alimadadi ◽  
Patricia B. Munroe ◽  
Bina Joe ◽  
Xi Cheng

Dilated cardiomyopathy (DCM) is one of the most common causes of heart failure. Several studies have used RNA-sequencing (RNA-seq) to profile differentially expressed genes (DEGs) associated with DCM. In this study, we aimed to profile gene expression signatures and identify novel genes associated with DCM through a quantitative meta-analysis of three publicly available RNA-seq studies using human left ventricle tissues from 41 DCM cases and 21 control samples. Our meta-analysis identified 789 DEGs including 581 downregulated and 208 upregulated genes. Several DCM-related genes previously reported, including MYH6, CKM, NKX2–5 and ATP2A2, were among the top 50 DEGs. Our meta-analysis also identified 39 new DEGs that were not detected using those individual RNA-seq datasets. Some of those genes, including PTH1R, ADAM15 and S100A4, confirmed previous reports of associations with cardiovascular functions. Using DEGs from this meta-analysis, the Ingenuity Pathway Analysis (IPA) identified five activated toxicity pathways, including failure of heart as the most significant pathway. Among the upstream regulators, SMARCA4 was downregulated and prioritized by IPA as the top affected upstream regulator for several DCM-related genes. To our knowledge, this study is the first to perform a transcriptomic meta-analysis for clinical DCM using RNA-seq datasets. Overall, our meta-analysis successfully identified a core set of genes associated with DCM.


EP Europace ◽  
2021 ◽  
Vol 23 (Supplement_3) ◽  
Author(s):  
T Atabekov ◽  
R Batalov ◽  
S Sazonova ◽  
S Gusakova ◽  
S Krivolapov ◽  
...  

Abstract Funding Acknowledgements Type of funding sources: None. Introduction. The cardioverter-defibrillator (ICD) implantation is the most effective method for the sudden cardiac death (SCD) prevention. However, about 25% patients did not receive an ICD therapy during the first 5-years follow-up. At the same time ICD does not register ventricular tachyarrhythmias (VTA) events in patients with ICD implanted for the primary prevention of SCD. So, it’s necessary to find out new prognostic markers of the VTA incidence, which will help to optimize the selection of patients who really need an ICD implantation. Currently, ST-2 and galectin-3 are actively studied in patients with coronary artery disease (CAD) and chronic heart failure due to their high potential prognostic value. Moreover, their role in the development of life-threatening arrhythmias is still poorly understood. In this regard, the study of the level of biomarkers of inflammation and myocardial fibrosis is relevant. Aim. To evaluate the prognostic value of the ST-2 and galectin-3 in VTA predicting in patients with coronary artery disease and left ventricular ejection fraction less than 35 %. Material and methods. The study included 40 patients (males – 36, median age – 64,5 [57,5; 68,5] years) with CAD, II and III functional class of chronic heart failure, left ventricle ejection fraction less than 35 % and ICD implantation indications (primary prevention of the SCD). ST-2 and galectin-3 blood concentration were determined before ICD implantation. All patients were followed-up during 18 months. There were assessed arrhythmological events recorded in ICD memory and ICD-lead parameters. Results. The 1st group consisted of 10 (25,0 %) patients with VTA events terminated with ICD antitachycardia pacing or shock, the 2nd group – 30 (75,0 %) patients without VTA events. The univariate ROC-analysis showed that the high values of the ST-2 (p = 0,003) and galectin-3 (p = 0,045) were associated with frequent VTA events. Kaplan-Meier analysis showed that the ST-2 > 22,48 ng/ml (p = 0,02) and galectin-3 > 10,95 ng/ml (p = 0,009) significantly increase the risk of the VTA events. The multivariate ROC-analysis showed that only ST-2 increase (OR = 1,1053; CI 95 %: 1,0134-1,2056; р = 0,023) leaded to frequent VTA events. Conclusion. An increase of ST-2 more than 22,48 ng/ml and galectin-3 more than 10,95 ng/ml has predictive value in VTA assessing risk in patients with ischemic cardiomyopathy. In multivariate analysis, an independent predictor of VTA is the ST-2 increase more than 22,48 ng/ml.


2019 ◽  
Vol 22 (1) ◽  
pp. 45-56 ◽  
Author(s):  
Su-Chen Fang ◽  
Yu-Lin Wu ◽  
Pei-Shan Tsai

Lower heart rate variability (HRV) is associated with a higher risk of cardiovascular events and mortality, although the extent of the association is uncertain. We performed a meta-analysis of cohort studies to elucidate the association between HRV and the risk of all-cause death or cardiovascular events in patients with cardiovascular disease (CVD) during a follow-up of at least 1 year. We searched four databases (PubMed, MEDLINE, Embase, and Cochrane Central Register of Controlled Trials) and extracted the adjusted hazard ratio (HR) from eligible studies. We included 28 cohort studies involving 3,094 participants in the meta-analysis. Results revealed that lower HRV was associated with a higher risk of all-cause death and cardiovascular events; the pooled HRs were 2.12 (95% confidence interval [CI] = [1.64, 2.75]) and 1.46 (95% CI [1.19, 1.77]), respectively. In subgroup analyses, the pooled HR of all-cause death was significant for patients with acute myocardial infarction (AMI) but not for those with heart failure. The pooled HR for cardiovascular events was significant for the subgroup of patients with AMI and acute coronary syndrome but not for those with coronary artery disease and heart failure. Additionally, both time and frequency domains of HRV were significantly associated with risk of all-cause death and cardiovascular events in patients with CVD.


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