scholarly journals Single-Cell RNA Sequencing and Quantitative Proteomics Analysis Elucidate Marker Genes and Molecular Mechanisms in Hypoplastic Left Heart Patients With Heart Failure

2021 ◽  
Vol 9 ◽  
Author(s):  
Li Ma ◽  
Na Zhou ◽  
Rongjun Zou ◽  
Wanting Shi ◽  
Yuanyuan Luo ◽  
...  
Keyword(s):  
Heart Failure ◽  
Quantitative Proteomics ◽  
Molecular Mechanisms ◽  
Marker Genes ◽  
Left Heart ◽  
Hypoplastic Left Heart ◽  
Hub Genes ◽  
Proteomics Analysis ◽  
Patients With Heart Failure ◽  
Single Cell Rna Sequencing

ObjectiveTo probe markers and molecular mechanisms of the hypoplastic left heart (HLH) by single-cell RNA sequencing (scRNA-seq) and quantitative proteomics analysis.MethodsFollowing data preprocessing, scRNA-seq data of pluripotent stem cell (iPSC)-derived cardiomyocytes from one HLH patient and one control were analyzed by the Seurat package in R. Cell clusters were characterized, which was followed by a pseudotime analysis. Markers in the pseudotime analysis were utilized for functional enrichment analysis. Quantitative proteomics analysis was based on peripheral blood samples from HLH patients without heart failure (HLH-NHF), HLH patients with heart failure (HLH-HF), and healthy controls. Hub genes were identified by the intersection of pseudotime markers and differentially expressed proteins (DE-proteins), which were validated in the GSE77798 dataset, RT-qPCR, and western blot.ResultsCardiomyocytes derived from iPSCs were clustered into mesenchymal stem cells, myocardium, and fibroblast cells. Pseudotime analysis revealed their differentiation trajectory. Markers in the three pseudotime clusters were significantly associated with distinct biological processes and pathways. Finally, three hub genes (MMP2, B2M, and COL5A1) were identified, which were highly expressed in the left (LV) and right (RV) ventricles of HLH patients compared with controls. Furthermore, higher expression levels were detected in HLH patients with or without HF than in controls.ConclusionOur findings elucidate marker genes and molecular mechanisms of HLH, deepening the understanding of the pathogenesis of HLH.

scholarly journals ASPN is a Potential Promising Biomarker for Common Heart Failure

2020 ◽  
Author(s):  
Kai Zhang ◽  
Min Wu ◽  
Xianyu Qin ◽  
Xianwu Zhou ◽  
Jianrong Zhou ◽  
...  
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Molecular Mechanisms ◽  
Adult Mortality ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Hub Genes ◽  
Ventricular Ejection Fraction ◽  
Mortality And Morbidity ◽  
Go Annotation

Abstract Background: Heart failure (HF), the leading cause of adult mortality and morbidity worldwide, is the end-stage of various diseases, especially ischemic cardiomyopathy (ICM) and dilated cardiomyopathy (DCM). This study aimed to investigate the common molecular mechanism of ICM and DCM.Methods: Four gene expression datasets, GSE1869, GSE5406, GSE57338, and GSE79962, were obtained from the Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) of ICM or DCM samples compared with those of nonfailing samples were identified. Gene ontology (GO) annotation, Kyoto encyclopedia of gene and genome (KEGG) pathway analysis, and the protein-protein network (PPI) of the coregulated DEGs in at least three datasets were performed using the online tools of DAVID, the KOBAS database, and the STRING database, respectively. Hub genes of HF were analyzed for their correlation with left ventricular ejection fraction (LVEF) in dataset GSE19303. The expression levels of notable DEGs were further validated in our tissue microarray (TMA).Results: Fifty-nine coregulated ICM and sixty-eight coregulated DCM relevant DEGs were identified (in at least three datasets). Moreover, 38 common DEGs between ICM and DCM relevant DEGs were obtained that were mainly involved in inflammatory/stress processes, proliferation, and some lipid metabolism pathways. Among the ten hub genes with top degrees, four genes showed a correlation with LVEF, and ASPN had the most significant correlation. Finally, the expression of ASPN protein was validated in our TMA and was significantly increased in ICM and DCM left ventricular samples.Conclusion: The present study revealed some common molecular mechanisms of HF with different causes. Furthermore, ASPN may be a potential promising biomarker for HF.

scholarly journals iPSC modeling shows uncompensated mitochondrial mediated oxidative stress underlies early heart failure in hypoplastic left heart syndrome

2021 ◽  
Author(s):  
Xinxiu Xu ◽  
Kang Jin ◽  
Abha S Bais ◽  
Wenjuan Zhu ◽  
Hisato Yagi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Er Stress ◽  
Hypoplastic Left Heart Syndrome ◽  
Mitochondrial Permeability Transition ◽  
Antioxidant Response ◽  
Left Heart ◽  
Hypoplastic Left Heart ◽  
Mptp Opening ◽  
Left Heart Syndrome

Hypoplastic left heart syndrome (HLHS) is a severe congenital heart defect with 30% mortality from heart failure (HF) in the first year of life, but why only some patients suffer early-HF and its cause remain unknown. Modeling using induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) showed early-HF patient iPSC-CM have increased apoptosis, redox stress, and failed antioxidant response. This was associated with mitochondrial permeability transition pore (mPTP) opening, mitochondrial hyperfusion and respiration defects. Whereas iPSC-CM from patients without early-HF had hyper-elevated antioxidant response with increased mitochondrial fission and mitophagy. Single cell transcriptomics showed dichotomization by HF outcome, with mitochondrial dysfunction and endoplasmic reticulum (ER) stress associated with early-HF. Importantly, oxidative stress and apoptosis associated with early HF were rescued by sildenafil inhibition of mPTP opening or TUDCA suppression of ER stress. Together these findings demonstrate a new paradigm for modeling clinical outcome in iPSC-CM, demonstrating uncompensated mitochondrial oxidative stress underlies early HF in HLHS.

Single-cell RNA-sequencing reveals profound changes in circulating immune cells in patients with heart failure

2020 ◽  
Author(s):  
Wesley T Abplanalp ◽  
David John ◽  
Sebastian Cremer ◽  
Birgit Assmus ◽  
Lena Dorsheimer ◽  
...  
Keyword(s):  
Heart Failure ◽  
Flow Cytometry ◽  
Single Cell ◽  
Rna Sequencing ◽  
Immune Cells ◽  
Healthy Subjects ◽  
Patients With Heart Failure ◽  
Single Cell Rna Sequencing ◽  
The Impact ◽  
Classical Monocytes

Abstract Aims Identification of signatures of immune cells at single-cell level may provide novel insights into changes of immune-related disorders. Therefore, we used single-cell RNA-sequencing to determine the impact of heart failure on circulating immune cells. Methods and results We demonstrate a significant change in monocyte to T-cell ratio in patients with heart failure, compared to healthy subjects, which were validated by flow cytometry analysis. Subclustering of monocytes and stratification of the clusters according to relative CD14 and FCGR3A (CD16) expression allowed annotation of classical, intermediate, and non-classical monocytes. Heart failure had a specific impact on the gene expression patterns in these subpopulations. Metabolically active genes such as FABP5 were highly enriched in classical monocytes of heart failure patients, whereas β-catenin expression was significantly higher in intermediate monocytes. The selective regulation of signatures in the monocyte subpopulations was validated by classical and multifactor dimensionality reduction flow cytometry analyses. Conclusion Together this study shows that circulating cells derived from patients with heart failure have altered phenotypes. These data provide a rich source for identification of signatures of immune cells in heart failure compared to healthy subjects. The observed increase in FABP5 and signatures of Wnt signalling may contribute to enhanced monocyte activation.

Abstract 14882: Outcomes of Heart Failure in Hypoplastic Left Heart Syndrome and the Impact of Recovery

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Aine Lynch ◽  
Aamir Jeewa ◽  
Sunghoon Minn ◽  
Katelyn Arathoon ◽  
Jenna Ashkanase ◽  
...  
Keyword(s):  
Heart Failure ◽  
Hypoplastic Left Heart Syndrome ◽  
Age At Onset ◽  
Angiotensin Converting Enzyme Inhibition ◽  
Left Heart ◽  
Hypoplastic Left Heart ◽  
Similar Frequency ◽  
Free Survival ◽  
Left Heart Syndrome ◽  
The Impact

Introduction: Survival for children with hypoplastic left heart syndrome (HLHS) and right ventricular (RV) dysfunction (dysfxn) remain poor. We describe outcomes of HLHS patients with RV dysfxn and the long-term impact of interval normalization. Methods: The SickKids Heart Failure (HF) Database is a retrospective cohort of HF patients from 2001 to 2017. We included patients with HLHS and at least mild RV dysfxn on echocardiogram lasting >30 days, or death or transplant within 30 days of onset of dysfxn. We defined normalization as normal RV function (fxn) lasting > 30 days after dysfxn onset. The primary endpoint was death or transplant. Descriptive statistics and time to event analysis were used. Results: We identified 99 patients with a median (IQR) age at onset of dysfxn of 2.6 (1 - 5.3) months. Of these, 51 (52%) had normalization of RV fxn for a median (IQR) duration of 3.5 (0.8 - 9.1) years and 28 (55%) had multiple periods of normal fxn. Of those who normalized, 4 (8%) normalized within a few months post Glenn procedure and 6 (13%) had normal fxn at last follow up. Patients with and without normalization had similar frequency of severe dysfxn (41 vs 52%, p=0.6). Normalization of RV fxn correlated with improved transplant free survival (78 % vs. 14 %, p<0.001, Figure 1C) independent of surgical stage (p=0.03, figure 1D). Table 1 shows risk factors independently associated with transplant-free survival, including angiotensin converting enzyme inhibition. Conclusions: HLHS patients with RV dysfxn have poor transplant-free survival, especially those at interstage, but outcomes improve in those with persistent normalization of fxn. Factors predicting normalization need further study

scholarly journals Exploration and validation of hub genes and pathways in the progression of hypoplastic left heart syndrome via weighted gene co-expression network analysis

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Xuelan Liu ◽  
Honglei Shang ◽  
Bin Li ◽  
Liyun Zhao ◽  
Ying Hua ◽  
...  
Keyword(s):  
Network Analysis ◽  
Signaling Pathway ◽  
Hypoplastic Left Heart Syndrome ◽  
Left Heart ◽  
Hypoplastic Left Heart ◽  
Hub Genes ◽  
Molecular Abnormalities ◽  
Black Module ◽  
Left Heart Syndrome ◽  
Key Pathways

Abstract Background Despite significant progress in surgical treatment of hypoplastic left heart syndrome (HLHS), its mortality and morbidity are still high. Little is known about the molecular abnormalities of the syndrome. In this study, we aimed to probe into hub genes and key pathways in the progression of the syndrome. Methods Differentially expressed genes (DEGs) were identified in left ventricle (LV) or right ventricle (RV) tissues between HLHS and controls using the GSE77798 dataset. Then, weighted gene co-expression network analysis (WGCNA) was performed and key modules were constructed for HLHS. Based on the genes in the key modules, protein–protein interaction networks were conducted, and hub genes and key pathways were screened. Finally, the GSE23959 dataset was used to validate hub genes between HLHS and controls. Results We identified 88 and 41 DEGs in LV and RV tissues between HLHS and controls, respectively. DEGs in LV tissues of HLHS were distinctly involved in heart development, apoptotic signaling pathway and ECM receptor interaction. DEGs in RV tissues of HLHS were mainly enriched in BMP signaling pathway, regulation of cell development and regulation of blood pressure. A total of 16 co-expression network were constructed. Among them, black module (r = 0.79 and p value = 2e−04) and pink module (r = 0.84 and p value = 4e−05) had the most significant correlation with HLHS, indicating that the two modules could be the most relevant for HLHS progression. We identified five hub genes in the black module (including Fbn1, Itga8, Itga11, Itgb5 and Thbs2), and five hub genes (including Cblb, Ccl2, Edn1, Itgb3 and Map2k1) in the pink module for HLHS. Their abnormal expression was verified in the GSE23959 dataset. Conclusions Our findings revealed hub genes and key pathways for HLHS through WGCNA, which could play key roles in the molecular mechanism of HLHS.

scholarly journals Quantitative proteomics analysis of Mycoplasma pneumoniae identifies potential macrolide resistance determinants

2020 ◽  
Author(s):  
shaoli li ◽  
guanhua xue ◽  
hanqing zhao ◽  
yanling feng ◽  
chao yan ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Mycoplasma Pneumoniae ◽  
Quantitative Proteomics ◽  
Molecular Mechanisms ◽  
Resistance Mechanisms ◽  
Community Acquired Pneumonia ◽  
Proteomics Analysis ◽  
Tandem Mass Tag ◽  
Peptide Biosynthesis ◽  
Resistant Strains

Abstract Mycoplasma pneumoniae is one of the leading causes of community-acquired pneumonia in children and adolescents. Because of the wide application of macrolides in clinical treatment, macrolide-resistant M. pneumoniae strains have become increasingly common worldwide. However, the molecular mechanisms underlying drug resistance in M. pneumoniae are poorly understood. In the present work, we analyzed the whole proteomes of macrolide-sensitive and macrolide-resistant strains of M. pneumoniae using a tandem mass tag-labeling quantitative proteomic technique, Data are available via ProteomeXchange with identifier PXD022220. In total, 165 differentially expressed proteins were identified, of which 80 were upregulated and 85 were downregulated in the drug-resistant strain compared with the sensitive strain. Functional analysis revealed that these proteins were predominantly involved in protein and peptide biosynthesis processes, the ribosome, and transmembrane transporter activity, which implicates them in the mechanism(s) of resistance of M. pneumoniae to macrolides. Our results provide new insights into drug resistance in M. pneumoniae and identify potential targets for further studies on resistance mechanisms in this bacterium.

scholarly journals Reverse remodelling of the heart after atrial fibrillation ablation in patients with heart failure with reduced ejection fraction

Kardiologiia ◽  
2019 ◽  
Vol 59 (8S) ◽  
pp. 37-43
Author(s):  
N. Z. Gasimova ◽  
E. N. Mikhaylov ◽  
V. S. Orshanskaya ◽  
A. V. Kamenev ◽  
R. B. Tatarsky ◽  
...  
Keyword(s):  
Heart Failure ◽  
Atrial Fibrillation ◽  
Left Ventricle ◽  
Ejection Fraction ◽  
Reverse Remodeling ◽  
Left Heart ◽  
Reduced Ejection Fraction ◽  
Patients With Heart Failure

Aim. To evaluate the effect of atrial fibrillation (AF) catheter ablation (CA) on long-term freedom from AF and left heart reverse remodeling in patients with heart failure with reduced ejection fraction (HFrEF).Methods. There were 47 patients (mean age 53.3 ± 10 years, 39 males) enrolled into single-center observational study, with left ventricular ejection fraction (LVEF) <40 %. Patients underwent CA for AF refractory to antiarrhythmic drugs. Baseline clinical data and diagnostic tests results were obtained during personal visits and / or via secure telemedical services. Personal contact with evaluation of recurrence of AF and echocardiographic values was performed with 30 (64 %) patients.Results. Paroxysmal AF was present in 12 (40 %) patients, persistent – in 18 (60 %). During mean follow-up of 3 years (0.5–6 years) redo ablation was performed in 9 patients (30 %) with average number of 1.3 procedures per patient. At 6 months 24 (80 %) patients were free from AF, at last follow-up – 16 (53 %). The mean time to first recurrence following CA was 15.6±13.3 months. Follow-up echocardiography revealed significant LVEF improvement (р<0,0001), reduction of left atrium size (р<0,0001), left ventricle end-diastolic volume (р<0,002) and left ventricle endsystolic volume (p<0,0001) and mitral regurgitation (р=0,001).Conclusion. AF CA in patients with HFrEF is associated with improvement in systolic function and left heart reverse remodeling. Durable long-term antiarrhythmic effect often requires repeated procedures.

scholarly journals Mechanisms of exercise intolerance in patients with heart failure and preserved ejection fraction. Part I: The role of impairments in the left heart chambers

Kardiologiia ◽  
2019 ◽  
Vol 59 (6S) ◽  
pp. 4-16
Author(s):  
A. G. Ovchinnikov ◽  
A. V. Potekhina ◽  
N. M. Ibragimova ◽  
E. A. Barabanova ◽  
E. N. Yushchyuk ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Left Ventricular Diastolic Dysfunction ◽  
Left Ventricular ◽  
Exercise Intolerance ◽  
Left Ventricular Ejection ◽  
Left Heart ◽  
Ventricular Ejection Fraction ◽  
Patients With Heart Failure ◽  
Ventricular Diastolic Dysfunction

During exercise an increase in oxygen delivery to working muscles is achieved through well‑coordinated interaction of many organs and systems: the heart, lungs, blood vessels, skeletal muscles, and the autonomic nervous system. In heart failure with preserved left ventricular ejection fraction, all mechanisms involved in the normal exercise tolerance are impaired. In the first part of this review, the impairments of the left heart chambers are considered ‑ left ventricular diastolic dysfunction, the weakening of the contractile and chronotropic reserves, left atrium dysfunction; the possible ways of their medical correction are also presented.

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