scholarly journals Altered microRNA and target gene expression related to Tetralogy of Fallot

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Marcel Grunert ◽  
Sandra Appelt ◽  
Ilona Dunkel ◽  
Felix Berger ◽  
Silke R. Sperling
Keyword(s):  
Tetralogy Of Fallot ◽  
Target Genes ◽  
Cardiac Development ◽  
Heart Diseases ◽  
Target Prediction ◽  
Left Ventricular ◽  
Heart Malformation ◽  
Transcriptional Gene Regulation ◽  
Stringent Target ◽  
And Function

AbstractMicroRNAs (miRNAs) play an important role in guiding development and maintaining function of the human heart. Dysregulation of miRNAs has been linked to various congenital heart diseases including Tetralogy of Fallot (TOF), which represents the most common cyanotic heart malformation in humans. Several studies have identified dysregulated miRNAs in right ventricular (RV) tissues of TOF patients. In this study, we profiled genome-wide the whole transcriptome and analyzed the relationship of miRNAs and mRNAs of RV tissues of a homogeneous group of 22 non-syndromic TOF patients. Observed profiles were compared to profiles obtained from right and left ventricular tissue of normal hearts. To reduce the commonly observed large list of predicted target genes of dysregulated miRNAs, we applied a stringent target prediction pipeline integrating probabilities for miRNA-mRNA interaction. The final list of disease-related miRNA-mRNA pairs comprises novel as well as known miRNAs including miR-1 and miR-133, which are essential to cardiac development and function by regulating KCNJ2, FBN2, SLC38A3 and TNNI1. Overall, our study provides additional insights into post-transcriptional gene regulation of malformed hearts of TOF patients.

Abstract 17266: Right Atrial Volumes Changes in Tetralogy of Fallot

Circulation ◽  
2018 ◽  
Vol 138 (Suppl_1) ◽  
Author(s):  
Ashish Patel ◽  
Divya Shakti ◽  
Chad Blackshear
Keyword(s):  
Diastolic Dysfunction ◽  
Diastolic Function ◽  
Tetralogy Of Fallot ◽  
Surgical Repair ◽  
Left Ventricular ◽  
Right Atrial ◽  
Before And After ◽  
Ventricular Diastolic Dysfunction ◽  
And Function ◽  
Averaged Model

Introduction & Hypothesis: There is limited information on right atrial (RA) function in the congenital heart defects. RA volume and function may give insight into the right ventricle (RV) diastolic function. We sought to assess RA function in tetralogy of Fallot (TOF) patients prior to and after complete surgical repair. Methods: Infants with TOF prior to complete repair were included for retrospective chart review and offline analysis of 2-dimensional echocardiograms (echo) before and after surgical repair. RA phasic volumes and stroke volumes were calculated. All volumes were indexed to body surface area. Results: There were 40 infants with TOF (45% females), of which 70% had pulmonary stenosis, 30% pulmonary atresia. Roughly 85% and 60% had 3, or more, echo available pre- and postoperatively. Table 1 (attached) shows the patient characteristics and phasic RA volumes. The indexed RA phasic volumes were in normal range in initial echo prior to surgery. We used normal index RA phasic volumes published by European Society of Echocardiography. There was the increasing trend of indexed RA phasic volume on follow up echo immediately before TOF repair. These phasic volumes continued to remain elevated after complete surgical repair (Table 1). Trends in RA stroke volumes for all available echos before and after surgery were modeled using a population-averaged model with an exchangeable within-panel correlation structure (Figure 2), showing no statistically significant difference after surgery. But there was statistical significance noted in RA ejection fraction. Please see attached image for statistical analysis and results of the study. Conclusions: The indexed RA phasic volumes in children with TOF are normal initially and increases before TOF repair and it continued to increase after TOF repair. The increase RA phasic volumes suggest RV diastolic dysfunction similar to the findings of LA phasic volumes and left ventricular diastolic dysfunction. Our findings indicate slow worsening RV diastolic function in patients with TOF after surgical repair. RA volume and function can be the novel marker to diagnose and monitor right ventricular diastolic dysfunction.

Abstract 96: Inactivation of Neddylation Causes Left Ventricular Noncompaction Cardiomyopathy Through Suppressing YAP Signaling

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Jianqiu Zou ◽  
Wenxia Ma ◽  
Jie Li ◽  
Rodney Littlejohn ◽  
Il-man Kim ◽  
...  
Keyword(s):  
Cardiac Development ◽  
Heart Diseases ◽  
Left Ventricular ◽  
Late Gestation ◽  
Mouse Heart ◽  
Cardiomyocyte Proliferation ◽  
Transcription Cofactor ◽  
Wild Type Counterpart

Rationale: Cardiac development is orchestrated by a number of growth factors, transcription factors and epigenetic regulators, perturbation of which can lead to congenital heart diseases and cardiomyopathies. However, the role of novel ubiquitin-like protein modifiers, such as NEDD8 (neural precursor cells expressed developmentally downregulated 8), in cardiac development is unknown. Objectives: The objective of this study was to determine the significance of NEDD8 modification (neddylation) during perinatal cardiac development. Methods and Results: Neddylated proteins and NEDD8 enzymes were highly abundant in fetal and neonatal hearts but downregulated in adult hearts. We employed an αMHC Cre transgene to delete NAE1, a subunit of the NEDD8 E1 enzyme, in the perinatal mouse heart. Cardiac-specific deletion of NAE1 (NAE1 CKO ) significantly decreased neddylated proteins in the heart. The NAE1 CKO mice displayed cardiac hypoplasia, ventricular non-compaction and heart failure during late gestation, which became more pronounced by postnatal day 1 and led to perinatal lethality. Mechanistically, genetic deletion or pharmacological inhibition of NAE1 resulted in accumulation of Hippo kinases Mst1 and LATS1/2, which in turn phosphorylated and inactivated YAP, a transcription cofactor necessary for cardiomyocyte proliferation, leading to dysregulation of a number of cell cycle-regulatory genes and blockade of cardiomyocyte proliferation in vivo and in vitro . Reactivation of YAP signaling by overexpression of a constitutively-active YAP mutant (YAP 5SA ), but not its wild-type counterpart, overcame the blockade of cardiomyocyte proliferation induced by inhibition of NAE1. Conclusions: Our findings establish the importance of neddylation in the heart, more specifically, in ventricular chamber maturation, and identify neddylation as a novel regulator of Hippo-YAP signaling to promote cardiomyocyte proliferation.

scholarly journals Circulating miRNA Expression Profiling and Target Prediction in Patients Receiving Dexmedetomidine

2018 ◽  
Vol 50 (2) ◽  
pp. 552-568 ◽  
Author(s):  
Xuehui Yang ◽  
Hongmei Chen ◽  
Yan Chen ◽  
Yochai Birnbaum ◽  
Rongbi Liang ◽  
...  
Keyword(s):  
Target Genes ◽  
Heart Diseases ◽  
Target Prediction ◽  
Enrichment Analysis ◽  
Cerebrovascular Diseases ◽  
Differentially Expressed ◽  
Pathway Enrichment Analysis ◽  
Protective Effects ◽  
Circulating Mirnas ◽  
Differentially Expressed Mirnas

Background/Aims: Circulating miRNAs could serve as biomarkers for diagnosis or prognosis of heart diseases and cerebrovascular diseases. Dexmedetomidine has protective effects in various organs. The effects of dexmedetomidine on circulating miRNAs remain unknown. Here, we investigated differentially expressed miRNA and to predict the target genes of the miRNA in patients receiving dexmedetomidine. Methods: The expression levels of circulating miRNAs of 3 patients were determined through high through-put miRNA sequencing technology. Target genes of the identified differentially expressed miRNAs were predicted using TargetScan 7.1 and miRDB v.5. Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to conduct functional annotation and pathway enrichment analysis of target genes respectively. Results: Twelve differentially expressed miRNAs were identified. Five miRNAs were upregulated (hsa-miR-4508, hsa-miR-novel-chr8_87373, hsa-miR-30a-3p, hsa-miR-novel-chr16_26099, hsa-miR-4306) and seven miRNAs (hsa-miR-744-5p, hsa-miR-320a, hsa-miR-novel-chr9_90035, hsa-miR-101-3p, hsa-miR-150-5p, hsa-miR-342-3p, and hsa-miR-140-3p) were downregulated after administration of dexmedetomidine in the subjects. The target genes and pathways related to the differentially expressed miRNAs were predicted and analyzed. Conclusion: The differentially expressed miRNAs may be involved in the mechanisms of action of dexmedetomidine. Specific miRNAs, such as hsa-miR-101-3p, hsa-miR-150-5p and hsa-miR-140-3p, are new potential targets for further functional studies of dexmedetomidine.

scholarly journals Plasma microrna expression profile for reduced ejection fraction in dilated cardiomyopathy

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Maria Calderon-Dominguez ◽  
Thalía Belmonte ◽  
Maribel Quezada-Feijoo ◽  
Mónica Ramos ◽  
Juan Calderon-Dominguez ◽  
...  
Keyword(s):  
Ejection Fraction ◽  
Dilated Cardiomyopathy ◽  
Target Genes ◽  
Heart Diseases ◽  
Characteristic Curve ◽  
Smoking Habit ◽  
Left Ventricular ◽  
Lower Systolic Blood Pressure ◽  
Circulating Micrornas ◽  
Clinical Variables

AbstractThe left ventricular (LV) ejection fraction (EF) is key to prognosis in dilated cardiomyopathy (DCM). Circulating microRNAs have emerged as reliable biomarkers for heart diseases, included DCM. Clinicians need improved tools for greater clarification of DCM EF categorization, to identify high-risk patients. Thus, we investigated whether microRNA profiles can categorize DCM patients based on their EF. 179-differentially expressed circulating microRNAs were screened in two groups: (1) non-idiopathic DCM; (2) idiopathic DCM. Then, 26 microRNAs were identified and validated in the plasma of ischemic-DCM (n = 60), idiopathic-DCM (n = 55) and healthy individuals (n = 44). We identified fourteen microRNAs associated with echocardiographic variables that differentiated idiopathic DCM according to the EF degree. A predictive model of a three-microRNA (miR-130b-3p, miR-150-5p and miR-210-3p) combined with clinical variables (left bundle branch block, left ventricle end-systolic dimension, lower systolic blood pressure and smoking habit) was obtained for idiopathic DCM with a severely reduced-EF. The receiver operating characteristic curve analysis supported the discriminative potential of the diagnosis. Bioinformatics analysis revealed that miR-150-5p and miR-210-3p target genes might interact with each other with a high connectivity degree. In conclusion, our results revealed a three-microRNA signature combined with clinical variables that highly discriminate idiopathic DCM categorization. This is a potential novel prognostic biomarker with high clinical value.

scholarly journals POSTNATAL IMPLICATIONS FOR PRENATAL DIAGNOSED TETRALOGY OF FALLOT

2016 ◽  
Vol 65 (3) ◽  
pp. 264-267
Author(s):  
Georgiana Nicolae ◽  
◽  
Cristina Filip ◽  
Adriana Diaconu ◽  
Alin Nicolescu ◽  
...  
Keyword(s):  
Tetralogy Of Fallot ◽  
Congenital Heart ◽  
Heart Diseases ◽  
Developed Countries ◽  
Postnatal Period ◽  
Diagnostic Methods ◽  
Term Survival ◽  
Heart Malformation ◽  
Cardiovascular Surgical Procedures

Over the last few years, prenatal diagnosis of congenital heart diseases experienced an important development. Overall survival of patients with congenital heart disease was improved in the last decade due to the advanced diagnostic methods and progression of cardiovascular surgical procedures in this field. Due to the significant increase of the long-term survival rate, currently, in most developed countries, there are departments dedicated to monitoring the adults with congenital heart malformation due to the particularities and special needs of this type of patients, compared with the regular cardiac pathology of adults. This article proposes a review of existing data at this moment related to the prenatal and postnatal diagnosis and their impact on the evolution regarding the most common cyanotic congenital malformation – Tetralogy of Fallot. In the following pages, we is emphasize the importance of knowing the precise fetal pathology for early determination of medical behavior in the postnatal period for the best care of these children.

scholarly journals Reliability of respiratory-triggered two-dimensional cine k-adaptive-t-autocalibrating reconstruction for Cartesian sampling for the assessment of biventricular volume and function in patients with repaired tetralogy of Fallot

2021 ◽  
Vol 94 (1120) ◽  
pp. 20201249
Author(s):  
Makoto Orii ◽  
Tsuyoshi Sugawara ◽  
Hidenobu Takagi ◽  
Satoshi Nakano ◽  
Hironobu Ueda ◽  
...  
Keyword(s):  
Image Quality ◽  
Tetralogy Of Fallot ◽  
Left Ventricular ◽  
Breath Hold ◽  
Two Dimensional ◽  
Reliable Technique ◽  
Repaired Tetralogy Of Fallot ◽  
Scan Time ◽  
Significant Difference ◽  
And Function

Objective: To compare left ventricular (LV) and right ventricular (RV) volume, function, and image quality of a respiratory-triggered two-dimensional (2D)-cine k-adaptive-t-autocalibrating reconstruction for Cartesian sampling (2D kat-ARC) with those of the standard reference, namely, breath-hold 2D balanced steady-state free precession (2D SSFP), in patients with repaired tetralogy of Fallot (TOF). Methods: 30 patients (14 males, mean age 32.2 ± 13.9 years) underwent cardiac magnetic resonance, and 2D kat-ARC and 2D SSFP images were acquired on short-axis view. Biventricular end-diastolic volume (EDV) and end-systolic volume (ESV), stroke volume (SV), ejection fraction (EF), and LV mass (LVM) were analysed. Results: The 2D kat-ARC had significantly shorter scan time (35.2 ± 9.1 s vs 80.4 ± 16.7 s; p < 0.0001). Despite an analysis of image quality showed significant impairment using 2D kat-ARC compared to 2D SSFP cine (p < 0.0001), the two sequences demonstrated no significant difference in terms of biventricular EDV, LVESV, LVSV, LVEF, and LVM. However, the RVESV was overestimated for 2D kat-ARC compared with that for 2D SSFP (73.8 ± 43.2 ml vs 70.3 ± 44.5 ml, p = 0.0002) and the RVSV and RVEF were underestimated (RVSV = 46.2±20.5 ml vs 49.4 ± 20.4 ml, p = 0.0024; RVEF = 40.2±12.7% vs. 43.5±14.0%, p = 0.0002). Conclusion: Respiratory-triggered 2D kat-ARC cine is a reliable technique that could be used in the evaluation of LV volumes and function. Advances in knowledge: 2D cine kat-ARC is a reliable technique for the assessment LV volume and function in patients with repaired TOF.

scholarly journals MicroRNAs and long non-coding RNAs in the pathophysiological processes of diabetic cardiomyopathy: emerging biomarkers and potential therapeutics

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Daniel Jakubik ◽  
Alex Fitas ◽  
Ceren Eyileten ◽  
Joanna Jarosz-Popek ◽  
Anna Nowak ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Diabetic Cardiomyopathy ◽  
Target Genes ◽  
Heart Diseases ◽  
Systolic Dysfunction ◽  
Left Ventricular ◽  
Non Coding Rnas ◽  
Potential Therapeutics

AbstractThe epidemic of diabetes mellitus (DM) necessitates the development of novel therapeutic and preventative strategies to attenuate complications of this debilitating disease. Diabetic cardiomyopathy (DCM) is a frequent disorder affecting individuals diagnosed with DM characterized by left ventricular hypertrophy, diastolic and systolic dysfunction and myocardial fibrosis in the absence of other heart diseases. Progression of DCM is associated with impaired cardiac insulin metabolic signaling, increased oxidative stress, impaired mitochondrial and cardiomyocyte calcium metabolism, and inflammation. Various non-coding RNAs, such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), as well as their target genes are implicated in the complex pathophysiology of DCM. It has been demonstrated that miRNAs and lncRNAs play an important role in maintaining homeostasis through regulation of multiple genes, thus they attract substantial scientific interest as biomarkers for diagnosis, prognosis and as a potential therapeutic strategy in DM complications. This article will review the different miRNAs and lncRNA studied in the context of DM, including type 1 and type 2 diabetes and the contribution of pathophysiological mechanisms including inflammatory response, oxidative stress, apoptosis, hypertrophy and fibrosis to the development of DCM .

Abstract 11940: Mineralocorticoid Receptor Dysregulation by MicroRNA-135a in Bradycardic Arrhythmogenic Remodeling

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Eric Duong ◽  
Jiening Xiao ◽  
Khai Le Quang ◽  
Patrice Naud ◽  
Yan- F Shi ◽  
...  
Keyword(s):  
Cardiac Remodeling ◽  
Mineralocorticoid Receptor ◽  
Target Genes ◽  
Ventricular Remodeling ◽  
Ventricular Tachyarrhythmia ◽  
Target Prediction ◽  
Torsades De Pointes ◽  
Left Ventricular ◽  
Luciferase Assay ◽  
Microrna Target

Introduction: Complete atrioventricular block (CAVB) causes arrhythmogenic remodeling and increases the risk of Torsades de Pointes (TdP) arrhythmias. MicroRNAs (miRs) are key regulators of gene expression that contribute to cardiac remodeling. Here, we assess microRNA changes after CAVB and their potential significance in arrhythmogenic cardiac remodeling. Methods: CAVB was induced in mice via His bundle ablation. Expression of miRs was evaluated by pan-microRNA microarray with qPCR confirmation on samples from controls and at 24 hrs and 4 wks post-CAVB. Arrhythmias were detected by continuous monitoring. MicroRNA target prediction algorithms were used to identify potential target genes. Biological confirmation of targets was by luciferase assay and overexpression (OE) studies in HEK and H9c2 cells respectively. Results: TdP occurred within 24 hrs in 6/17 CAVB mice, vs no controls. Ventricular tachyarrhythmia episodes were frequent at 4 wks CAVB (212±83 per 24 hrs) and were not seen in controls. CAVB was followed by increased left ventricular (LV) dimension (by 31%, ***p<.001), LV mass (by 33%, *p<.05) and LV fractional shortening (by 33%*) at 4 wks. Of >400 miRs assayed, only miR-135a was altered at 24 hrs (downregulated by 96%***, Fig. A), with 70% decrease at 4 wks. TargetScan predicted miR-135a regulation of the mineralocorticoid receptor (MCR), encoded by the NR3C2 gene. miR-135a OE suppressed NR3C2 3’UTR reporter activity 3.2-fold* (n=5, Fig. B). miR-135a OE did not affect NR3C2 mRNA (Fig. C) but significantly reduced NR3C2 protein expression (n=4, Fig. D). Coexpression with anti-miR-135a eliminated the NR3C2 downregulating effect of miR-135a OE. Conclusions: The mineralocorticoid receptor, encoded by the NR3C2 gene, is translationally regulated by miR-135a, a microRNA that is downregulated in the heart following CAVB in mice. These results implicate miR-135a/mineralocorticoid modulation in arrhythmogenic ventricular remodeling caused by CAVB.

Use of echocardiography for the phenotypic assessment of genetically altered mice

2003 ◽  
Vol 13 (3) ◽  
pp. 227-239 ◽  
Author(s):  
Keith A. Collins ◽  
Claudia E. Korcarz ◽  
Roberto M. Lang
Keyword(s):  
Molecular Mechanisms ◽  
Cardiac Development ◽  
Contrast Echocardiography ◽  
Left Ventricular ◽  
Mouse Heart ◽  
Endocardial Border ◽  
Heart Beating ◽  
Cardiac Evaluation ◽  
Endocardial Border Delineation ◽  
And Function

Transgenic mice displaying abnormalities in cardiac development and function represent a powerful new tool for understanding molecular mechanisms underlying normal cardiovascular function and the pathophysiological bases of human cardiovascular disease. Complete cardiac evaluation of phenotypic changes in mice requires the ability to noninvasively assess cardiovascular structure and function in a serial manner. However, the small mouse heart beating at rates in excess of 500 beats/min presents unique methodological challenges. Two-dimensional and Doppler echocardiography have been recently used as effective, noninvasive tools for murine imaging, because quality images of cardiac structures and valvular flows can be obtained with newer high-frequency transthoracic transducers. We will discuss the use of echocardiography for the assessment of 1) left ventricular (LV) chamber dimensions and wall thicknesses, 2) LV mass, 3) improved endocardial border delineation using contrast echocardiography, 4) LV contractility using ejection phase indices and load-independent indices, 5) vascular properties, and 6) LV diastolic performance. Evaluation of cardiovascular performance in closed chest mice is feasible in a variety of murine models using Doppler echocardiographic imaging.

scholarly journals MicroRNA Clusters in the Adult Mouse Heart: Age-Associated Changes

2015 ◽  
Vol 2015 ◽  
pp. 1-12 ◽  
Author(s):  
Xiaomin Zhang ◽  
Gohar Azhar ◽  
Emmanuel D. Williams ◽  
Steven C. Rogers ◽  
Jeanne Y. Wei
Keyword(s):  
Signaling Pathway ◽  
Target Genes ◽  
Cardiac Development ◽  
Mouse Heart ◽  
Substantial Impact ◽  
Genomic Location ◽  
Microrna Cluster ◽  
Protein Components ◽  
And Function ◽  
Cytoskeleton Dynamics

The microRNAs and microRNA clusters have been implicated in normal cardiac development and also disease, including cardiac hypertrophy, cardiomyopathy, heart failure, and arrhythmias. Since a microRNA cluster has from two to dozens of microRNAs, the expression of a microRNA cluster could have a substantial impact on its target genes. In the present study, the configuration and distribution of microRNA clusters in the mouse genome were examined at various inter-microRNA distances. Three important microRNA clusters that are significantly impacted during adult cardiac aging, the miR-17-92, miR-106a-363, and miR-106b-25, were also examined in terms of their genomic location, RNA transcript character, sequence homology, and their relationship with the corresponding microRNA families. Multiple microRNAs derived from the three clusters potentially target various protein components of the cdc42-SRF signaling pathway, which regulates cytoskeleton dynamics associated with cardiac structure and function. The data indicate that aging impacted the expression of both guide and passenger strands of the microRNA clusters; nutrient stress also affected the expression of the three microRNA clusters. The miR-17-92, miR-106a-363, and miR-106b-25 clusters are likely to impact the Cdc42-SRF signaling pathway and thereby affect cardiac morphology and function during pathological conditions and the aging process.

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