bluuebunny/crossref_metadata_2025_split huggingface dataset:
Single cell multi-omics analysis unveils a distinct mechanism of exercise-mediated cardioprotection in ischemic cardiomyopathy
Authors: Jimba T , Ko T , Zhang B , Nomura S , Takeda N , Komuro I 
Published: October 2024

Abstract

Background
Exercise is pivotal in heart disease prevention, with proven cardioprotective effects in clinical trials. However, its precise molecular mechanisms remain elusive. Recent advancements in single-cell omics have revealed cellular heterogeneity within heart tissues, offering a deeper understanding of the pathophysiology of cardiac diseases.

Purpose
To investigate the exercise-induced physiological changes in heart tissue at the single-cell level and elucidate the molecular mechanisms underlying its cardioprotective effect on ischemic cardiomyopathy.

Methods
Murine myocardial infarction (MI) model was established by ligating the left ascending coronary artery, and a six-week voluntary wheel running exercise regimen was implemented to investigate the effect of aerobic exercise on ischemic cardiomyopathy. Integrated multi-omics analyses of single-cell DNA methylation profiling, single-nucleus assay for transposase-accessible chromatin sequencing (snATAC-seq) and single-nucleus RNA sequencing (snRNA-seq) were conducted to clarify the molecular mechanism of exercise-mediated cardioprotection at single-cell resolution. Overexpression and short hairpin RNA-mediated knockdown of gene X were conducted for murine MI model using cardiomyocyte-specific Myo-AAV2a vector. snRNA-seq of heart tissues from heart failure patients was performed to validate the clinical significance of the expression of gene X in cardiomyocytes.

Results
Exercise attenuates pathological cardiac remodeling, inducing physiological hypertrophy in non-infarcted areas while suppressing pathological remodeling of cardiomyocytes in infarct border zones. Single-cell epigenetic analysis unveiled intricate molecular mechanisms underlying exercise-induced transcriptome changes, providing insights into the gene regulatory networks modulated by exercise in the heart. In addition, integrated with snRNA-seq, we identified exercise-specific cardiomyocyte clusters, highlighting the substantial role of gene X in the molecular mechanism of exercise. Functional studies confirmed the essential role of gene X in exercise-induced cardioprotection, as its overexpression suppressed the adverse remodeling after MI and knockdown abolished the beneficial effects of exercise. Furthermore, snRNA-seq of heart failure patients revealed that higher expression of gene X was associated with ventricular reverse remodeling and favorable clinical outcomes, underscoring its significance in the pathophysiology of patients with heart failure.

Conclusion
Our study elucidates exercise-specific gene expression regulation networks in ischemic cardiomyopathy by unraveling the cellular heterogeneity and molecular changes associated with exercise. We identified gene X as a central player in exercise-mediated cardioprotection and further confirmed its significance in clinical settings, providing a potential therapeutic target for heart failure.
Proteogenomic analysis in population biobanks identifies new therapeutic targets across heart failure subtypes
Authors: Henry A , Finan C , Gratton J , Paliwal N , Chopade S , Jassal S , Hedman A K , Fauman E B , Malarstig A , Hingorani A D , Lumbers R T 
Published: October 2024

Abstract

Background
Heart failure (HF) represents a multifactorial clinical syndrome with differential response to existing therapies across its subtypes. Proteogenomic analysis of genetic variants associated with changes in circulating protein level and risk of heart failure subtypes provides an opportunity for a systematic identification of proteins with subtype-specific causal effects as novel therapeutic targets.

Purpose
To identify proteins as potential therapeutic targets for specific heart failure subtypes by leveraging proteomics and genomics data in population biobanks.

Methods
We evaluated the causal effects of 2,773 proteins on 5 HF-related outcomes, including overall HF, non-ischaemic HF (ni-HF), ni-HF with reduced / preserved ejection fraction (ni-HFrEF / ni-HFpEF), and dilated cardiomyopathy (DCM). For each protein-phenotype pair, we performed a two-sample Mendelian randomisation (MR) analysis using protein-specific genetic association estimates derived from protein quantitative trait locus (pQTL) studies in 114,145 individuals from deCODE, UK Biobank, Fenland study, and SCALLOP consortium and genome-wide association studies (GWAS) of HF outcomes in 145,795 individuals by HERMES Consortium. We further prioritised candidate protein targets based on replication of results across datasets, model parameters, assays, and colocalization of causal genetic variants. Finally, we profiled the causal effects of identified proteins on 32 related cardiac traits and risk factors to explore potential mechanisms of actions and on-target side effects.

Results
We identified 493 proteins associated with at least one HF outcome at a false discovery rate (FDR) &lt; 1% in the primary MR analysis. We further prioritised 44 proteins with concordant effect direction across datasets, model parameters, and assays or colocalization in at least one dataset. All 44 identified proteins showed cross association with at least one of 35 tested traits other than HF or cardiomyopathies at FDR &lt;1%, including coronary artery disease (18 proteins), body mass index (11 proteins), type 2 diabetes (6 proteins), systolic / diastolic blood pressure (13 proteins), and chronic kidney disease (9 proteins).

Conclusion
We characterised the causal associations of 2,773 circulating proteins across HF-related outcomes and prioritised 44 proteins by integrating proteomics and genomics data in population biobanks. These findings extend our understanding of the molecular mechanism underlying different forms of HF and may inform the development of new therapeutic strategies.Study design
The implantation of a left ventricular assist device causes changes in the aortic miRNome and proteome - an integrative analysis
Authors: Dlouha D , Pompach P , Chytilova S , Ivak P , Novakova S , Tucanova Z , Hlavacek D , Netuka I 
Published: October 2024

Abstract

Background
Left ventricular assist devices (LVAD) have been widely used and accepted to treat patients with end-stage heart failure. LVAD non-physiological blood flow velocity, wall shear stress distribution, vorticity current intensity, and vorticity flow generation affect the pathophysiology of vascular changes in aortic tissue.

Purpose
In this study, we performed multi-omics-based analysis of the aorta to identify molecular markers that could clarify vascular remodeling during LVAD support.

Methods
Aortic specimens from 48 patients (pair matched samples N=96) were excised during implantation and explantation of LVAD. Small RNA-Seq screening using Next Generation Sequencing and proteomic profile using Data-Independent Acquisition mass spectroscopy were conducted. Experimental and computational approaches, proteomics and transcriptomics data, were integrated and bioinformatics analyses were performed.

Results
The principal component analysis of miRNome and permutational multivariate analysis of variance of proteomic profile clearly segregated samples before and after LVAD support. We identified a total of 113 differently expressed (DE) miRNAs (61 up-regulated; Padj&lt;0.05 and log2 fold change&gt;|0.5|) after long-term LVAD support. Proteomic analysis identified in total 93 protein significantly changed (47 increased; Padj&lt;0.05 and log2 fold change&gt;|0.5|). Correlation analysis identified strong association between 270 proteins and 66 DE-miRNAs (Padj&lt;0.05 and correlation coefficient&gt;|0.7|). Gene Set Enrichment Analysis revealed, that predicted target genes of DE-miRNAs were mainly engaged in axon guidance, regulation of actin cytoskeleton, endocytosis, and MAP signaling pathway (Padj&lt;0.05). DE-proteins participated mainly in ECM-receptor interaction, focal adhesion, and platelet activation (Padj&lt;0.05).

Conclusion
Our study presents a network-based method of integrating microRNAs and proteome data and reveals molecular signatures that reflects aortic vascular remodeling due to LVAD treatment.PCA of miRNA DESeq2PCA of protemic profile
The effect of CD38 inhibition in age-associated vascular dysfunction
Authors: Puspitasari Y M , Yang K , Ministrini S , Bengs S , Luscher T F , Camici G G 
Published: October 2024

Abstract

Introduction
Aging is characterized by age-related vascular dysfunction, mainly caused by endothelial dysfunction and arterial stiffness. Levels of nicotinamide adenine dinucleotide (NAD) decrease with aging and accordingly, NAD is thought to be involved in the progression of age-related vascular dysfunction. Recent studies reported the involvement of CD38 in NAD regulation; indeed, its inhibition significantly prolongs the lifespan of progeroid and aged mice. However, whether CD38 is involved in the progression of age-related vascular dysfunction remains to be investigated.

Methods
CD38 expression was investigated in aortic homogenates of young (12-16 weeks) and aged (18-24 months) C57BL/6 wild-type mice, as well as in vitro in young (passage 5-7) and senescent (passage 14-15) primary human aortic endothelial cells (HAECs). Ex vivo tension myograph experiments were performed on thoracic aortas isolated from aged C57BL/6 mice (22-24 months old) pre-incubated for 1 hour with CD38-specific inhibitor, 78c, or DMSO as control. The effect of CD38 inhibition was also observed in vitro in senescent HAECs.

Results
A significant upregulation of CD38 expression was detected in the aortas of aged mice compared to the young ones as well as in senescent HAECs compared to young cells. Ex vivo tension myograph experiments showed a significant increase in endothelium-dependent relaxation responses to acetylcholine upon CD38 inhibition. The improvement of endothelial function was prevented by the addition of endothelial nitric oxide synthase (eNOS) inhibitor (L-NAME), but not by the COXs inhibitor, indomethacin, indicating that the observed effect achieved by CD38 inhibition is eNOS dependent. The involvement of the eNOS pathway was further supported by the in vitro finding in HAECs of increased eNOS activation upon CD38 inhibition.

Conclusion
The herein-reported data suggests an involvement of CD38 in the development of age-related endothelial dysfunction. Further studies are ongoing to investigate the underlying molecular mechanisms as well as the effect of long-term CD38 inhibitor supplementation on the progression of age-related vascular dysfunction.
Lipoprotein(a) induces spontaneous aortic dissection via increasing monocyte mediated vascular smooth muscle cell phenotype transformation in human Lp(a) transgenic mice
Authors: Han C Z , Wang Z M , Fu Y Y , Wang Q Z , Huang Z Y , Ge J B 
Published: October 2024

Abstract

Background
Elevated lipoprotein(a) [Lp(a)] is a prevalent, independent risk factor of atherosclerotic cardiovascular disease and aortic valve stenosis. Recent studies have reported that high levels of Lp(a) are strongly associated with aortic dissection (AD), independent of other cardiovascular risk factors. However, orthologues of Lp(a) are only found in humans, Old World monkeys, apes, and hedgehogs. The lack of a proper animal model has hindered elucidation of the true pathophysiological mechanisms of Lp(a). Here, we conducted the first humanized Lp(a) transgenic mice experiment to verify the pathological mechanism of Lp(a) in aortic dissection.

Methods
We conducted ApoE knock out and human ApoA transgenic mice via CRISPR-Cas9 and then crossed with human ApoB transgenic mice to achieve high levels of human-like Lp(a) particles in plasma. Plasma was assayed by ELISA for the concentrations of each lipoprotein. Echocardiography was performed to detect aortic morphology in vivo. Single cell transcriptome analysis was performed on the dissection lesion. Cell interaction was examined in macrophage from Lp(a) transgenic mice and vascular smooth muscle cell (VSMC) coculture system.

Result
Our results indicate that the concentration of ApoA and ApoB in plasma were increased in transgenic mice fed a chow diet. Low density lipoprotein (LDL) levels were increased and shows that LDL is the major cholesterol carrier in these mice. We were surprised to find that the dissection of the ascending aortic arch could be seen by echocardiography in transgenic mice as early as 2 months, and transgenic mice showed significant increase in aortic enlargement, dissection, and rupture in both the thoracic and abdominal aortic regions, resulting in a survival rate of only 58% after 12 months. Single cell transcriptome analysis revealed that Lp(a) transgene induced the inflammatory response, dedifferentiation and pathological VSMC phenotypical switch, and matrix metalloproteinase expression in macrophages. Monocytes isolated from transgenic mice with elevated Lp(a) remain in a long-lasting primed state, as evidenced by an increased capacity to transmigrate and produce proinflammatory cytokines on stimulation. Monocytes isolated from wild type mice cultured in media with high level Lp(a) for 24h also showed the ability to facilitated cocultured VSMC phenotype transformation, which was reversed by E06, a monoclonal antibody blocking the oxidized phospholipids in Lp(a).

Conclusion
These findings demonstrate that Lp(a) induces spontaneous aortic dissection via increasing monocyte trafficking to the arterial wall, mediating proinflammatory responses and VSMC phenotype transformation through its OxPL content. The study presents a rodent model of spontaneous aortic dissection and provide a novel mechanism by which Lp(a) mediates aortic dissection.Graphical abstract
STING-mediated DNA damage response in diabetes-induced vascular complications
Authors: Bavuu O , Pham P, T , Sata M , Fukuda D 
Published: October 2024

Abstract

Background
Hyperglycemia drives endothelial dysfunction, a key factor in the development of diabetes vascular complications. The stimulator of interferon genes (STING) signal, plays a crucial role in the immune system and is implicated in the pathogenesis of inflammatory diseases. Therefore we investigated the role of STING in endothelial dysfunction in streptozotocin (STZ)-induced diabetic mice.

Methods and Results
Diabetes was induced by single-dose administration of STZ in 8-week-old C57BL/6 and Sting-/- mice. STZ injection promoted the expression of STING and DNA damage markers in the aorta of C57BL/6 mice. Genetic deletion of STING ameliorated endothelial dysfunction as determined by vascular reactivity assay (P &lt; 0.001) and increased aortic eNOS phosphorylation (P &lt; 0.05) in STZ-injected mice. Stimulation of STING agonist (cGAMP), or mtDNA increased inflammatory molecules expression (e.g., VCAM1 and IFNB) and decreased eNOS phosphorylation in HUVECs. In ex-vivo experiments, cGAMP significantly impaired endothelial function which was ameliorated in the presence of an STING inhibitor or a neutralizing IFN-β antibody. Furthermore, the administration of STING inhibitor ameliorated endothelial dysfunction in STZ-induced diabetic mice (P &lt; 0.01).

Conclusion
The DNA damage response regulated by STING aggravated diabetes-induced endothelial dysfunction. STING signaling may be a potential therapeutic target for diabetic vascular complications.
Elevation of circulating FGF23 in chronic kidney disease promotes atrial fibrosis through the AKT pathway
Authors: Gao P , Xie B , Zhou Z , Tse G , Liu T 
Published: October 2024

Abstract

Background
The relationship between chronic kidney disease (CKD) and atrial fibrillation (AF) remains unclear. Elevated level of fibroblast growth factor 23 (FGF23) is highly associated with increased cardiovascular disease and mortality in patients suffering from CKD. In recent years, studies have shown that FGF23 promotes cardiac hypertrophy through FGFR4, suggesting that FGF23 may be an important bridge between the heart and kidney.

Purpose
In this study, we sought to use a well-established rat model of CKD to further characterize the effects of CKD on AF and to identify potential drivers of CKD-induced AF.

Methods
14 SD rats were randomly selected to undergo 5/6 nephrectomy and fed for 15 weeks to establish a CKD model, while the SHAM group (8 rats) underwent the same surgery without removing kidney tissue. Body weight, blood pressure, renal function, cardiac ultrasound, epicardial electrocardiography, and pathological indices were monitored in both groups. Gene sequencing was performed on the left atria to search for differentially expressed genes. Rat atrial fibroblasts were selected for further mechanism exploration. We chose TGF-β to stimulate fibroblasts to mimic the process of fibrosis in vivo, and then administered FGFR inhibitors to explore the downstream molecular mechanisms.

Results
Systolic blood pressure and creatinine were elevated in the CKD group. Compared with the SHAM group, the incidence of AF was significantly higher, left atrial diameter was significantly larger, and epicardial electrical markers showed that left atrial electrical conduction velocity was significantly slower and conduction heterogeneity was significantly increased in the CKD group. Pathologic staining of the left atrium showed significant fibrosis in the CKD group. Consistent with previous findings, FGF23 was significantly elevated in CKD rats. Transcriptomic sequencing revealed that FGFR4 expression was significantly upregulated in the left atrium of CKD rats, The results in rat atrial fibroblasts showed that blocking FGFR4 expression inhibited TGF-β-induced fibrosis and was mediated by the AKT pathway.

Conclusions
The mechanism of CKD-induced AF is that CKD promotes both structural and electrical remodeling of the atria. Further investigation of its possible downstream molecules revealed that elevated FGF23 in the CKD circulation promotes the development of atrial fibrosis by binding to FGFR4 through the AKT pathway.
Treated obstructive sleep apnoea and incident arrhythmias
Authors: He H , Lachlan T , Osman F 
Published: October 2024

Abstract

Background
Obstructive sleep apnoea (OSA) is prevalent in approximately 15% of western populations. Cardiovascular disease and arrhythmia are extremely common in this group with significant morbidity overlap. Whilst treatment of OSA with continuous positive airways pressure (CPAP) appears to reduce hypertension, bradycardia and recurrence of atrial fibrillation (AF), large randomised control trials and meta-analyses do not demonstrate a significant reduction of incident tachyarrhythmias such as atrial fibrillation or sudden cardiac death. Some smaller studies suggest that AF may have up to 20% incidence. Analysis of these studies suggest that there may be significant heterogeneity in both CPAP usage and OSA phenotype, confounding the results. Furthermore, standard arrhythmia detection often underestimates paroxysmal arrhythmias. This on-going trial investigates a treated OSA population using CPAP monitoring and implantable loop recorders (ILR).

Purpose
This study aims to identify the incidence of arrhythmia in a treated OSA population with comprehensive arrhythmia monitoring and CPAP usage. It also explores the mechanisms linking OSA and arrhythmia such as heart rate variability and turbulence and cardiac biomarkers in order to identify at risk sub populations.

Methods
Continuous moderate-to-severe OSA patients were recruited from a major UK sleep centre after ECG and medical history confirmed the absence of arrhythmia. Each patient was then randomised to receive either standard-care or standard-care with an ILR with 24-hour heart rate variability/turbulence measurements, echocardiography (where possible) and cardiac biomarkers at baseline and 12 months. All patients had remote CPAP usage monitoring (where possible). The trial ended at 36 months after enrolment.

Results
200 patients were recruited to the trial. Current mean average follow-up is 28 months in this on-going trial. Mean age and apnoea hypopnea index at enrolment was 53 years and 43.8 respectively. To date we have diagnosed atrial fibrillation in 15% of the ILR group compared to 2% in the standard care group. Other arrhythmias detected in the ILR group include two with supraventricular tachycardia and 2 with significant pauses but not requiring further treatment. Final analysis of arrhythmia incidence with CPAP usage and heart rate variability/turbulence, and cardiac biomarkers is ongoing with final results due by the time of final submission.

Conclusion
Arrhythmias, particularly AF, are highly incident in OSA despite CPAP treatment. This study may determine if heterogenous CPAP usage confounds the above observation and whether there may be predictors of arrhythmia that may indicate a need for arrhythmia screening in the OSA population.
Secretoneurin plasma levels are decreased after catheter ablation for atrial fibrillation, patients with AF produce lower SN levels than healthy individuals
Authors: Plasek J , Jiri Vrtal J V , David Sipula D S , Jozef Dodulik J D , Diana Drienikova D D , Martin Rachela M R , Jiri Pudich J P , Zdenek Svagera Z S , Nela Chobolova N C H , David Stejskal D S , Jan Vaclavik J V 
Published: October 2024

Abstract

Background
Secretoneurin (SN) is a novel biomarker with potential use in cardiovascular medicine. The main effect of SN is mediated through its inhibition of calmodulin-dependent kinase II (CaMKII), which influences calcium handling[1], plasma SN levels differ in ischemic vs. dilated cardiomyopathy [2]. We aim to associate the levels of SN pre- and postprocedurally and according to the type of atrial fibrillation (AF).

Methods
We prospectively enrolled patients indicated for catheter ablation (CA) for AF, sequentially sampled patients for SN before, during and after CA for AF. We also sampled healthy individuals as controls. SN was analysed from venous, left atrial and coronary sinus (CS) blood by the use of the ELISA method. Values are expressed as means±SD, variables are compared by standard statistical methods.

Results
A total of 104 patients (59.4% male) with AF aged 64±10.4, with BMI 30.1±5 and 34 healthy individuals (38% male) were included in the analysis. SN plasma levels were significantly lower 32.3±15.1 after the procedure (SN2) as compared to levels before (SN1) 38.4±17.5 pmol/L (P=0.02, Fig.1). SN was not associated with any marker of cardiac injury or overload, echocardiographic parameters, or ablation characteristics (P=NS), even though Troponin I was significantly increased after the procedure (P&lt;0.0001, Fig.2). Left atrial SN was numerically higher 40.9±19.1 than SN sampled from CS 32.9±13 (P=NS).The SN levels in our patients with AF were generally lower than in healthy individuals (50.7±15.3 pmol/L) before (P=0.0004) as well as after the procedure (P=0.0001).

Conclusion
Catheter ablation of AF leads to a decrease in SN plasma levels even though markers of cardiac injury are increased. Patients with AF irrespective of actual rhythm produce lower levels of SN than healthy individuals.