bluuebunny/crossref_metadata_2025_split huggingface dataset:
Monocytic mitochondrial dysfunction and impaired monocytic bioenergetic profile in patients with heart failure symptoms in post-COVID syndrome
Authors: Semo D , Shomanova Z , Sindermann J , Mohr M , Evers G , Reinecke H , Godfrey R , Pistulli R 
Published: October 2024

Abstract

Introduction/Purpose
Approximately 35% of COVD-19 patients have persistent symptoms similar to congestive heart failure. The so called post-Covid syndrome, which includes symptoms such as dyspnea and angina pectoris, is presumably associated to cellular metabolism and oxidative stress, yet whether mitochondrial function is impaired in post-COVID patients is still unclear. We thus investigated the mitochondrial function in monocytes of symptomatic post-COVID patients compared to matched controls.

Methods
Patients with persisting cardiac symptoms in their daily activities and diagnosed with post-COVID syndrome (n=14) were recruited and matched with unaffected controls (n=10) for age, sex and cardiovascular risk factors. Structural heart disease was excluded through cardiac work-up (echocardiography, functional stress testing and when necessary coronary angiography). Primary monocytes were isolated using negative selection method. The bioenergetic status of the monocytes was assessed using the Agilent Seahorse XF Cell Mito Stress Test without and after modulation of reactive oxygen species (ROS) by buthionine sulfoximine (BSO).

Results
CD14++ monocytes isolated from post-COVID patients showed non-significantly increased basal proton leak (p=0.57), reduced maximal respiration, and reserved respiratory capacity (p=0.19) compared to controls. Induction of additional oxidative stress by ROS modulation revealed a significantly impaired bioenergetic profile of monocytes in terms of reduction of basal respiration (3-fold, p=0.0005), maximal respiration (4-fold, p=0.004) and spare respiratory capacity (5-fold, p=0.008).

Conclusions
We demonstrated an impaired bioenergetic profile of CD14++ monocytic mitochondria in patients suffering from heart failure symptoms following COVID-19 infection. Whether the findings provide a novel biomarker for measuring systemic oxidative stress conditions or whether there is a direct link between symptoms of post-COVID disease and monocytic function needs to be addressed in further studies.
Semaglutide improves contractile function in isolated human atrium
Authors: Hegner P , Seitz S , Schopka S , Schmid C , Maier L S , Wagner S 
Published: October 2024

Abstract

Background
Recently, the results of the STEP-HFpEF trial were announced, in which high-dose treatment with the antidiabetic glucagon-like-peptide 1 agonist semaglutide resulted in a significant improvement of HFpEF-associated symptoms and reduction of NT-proBNP levels. Interestingly, treatment effects were independent of initial body weight and left-ventricular ejection fraction, sparking interest regarding the precise mechanism of action.

Purpose
We tested the effects of acute semaglutide treatment in isolated human right-atrial trabeculae.

Methods
Trabeculae were prepared from right atrial appendage biopsies from 32 patients undergoing elective coronary artery bypass grafting and/or valve surgery. Regular contractions were elicited by electrical field stimulation (1Hz, 5V/50ms, 37°C). Paired experiments were performed simultaneously per patient with a control group and one exposed to semaglutide (100 or 300nM). Developed tension was analysed at steady state after 30 min. Arrhythmias were defined as deviations from baseline not arising from electrical stimulation. L-type calcium channel blockade was achieved with nifedipine (2µM) in some experiments. Rapid cooling contraction was elicited to assess sarcoplasmic reticulum Ca2+ content (RCC1) by rapidly superfusing the trabeculae with chilled solution (2°C). After a short rewarming period of 10s to 37°C, RCC was repeated to assess the Na+/Ca2+ exchanger function (RCC2). Statistical analysis was conducted using paired t-test or Wilcoxon test as appropriate (for 2 groups) and one-way ANOVA with test for trend (for &gt;2 groups).

Results
Exposure to semaglutide increased developed tension by over 3-fold in human atrial trabeculae in a dose-dependent manner: from 3.14±1.14 for control to 5.43±2.35mN/mm2 for 100nM semaglutide (p=0.03 vs. control) to 12.5±3.53 for 300nM semaglutide (p=0.004 vs. control, mean±SEM, fig. A-D, p=0.005 for linear trend). L-type calcium channel blockade with nifedipine blunted developed tension overall but did not abolish the effect of semaglutide (fig. E, p=0.02). In contrast, the developed tensions upon RCC1 and RCC2 were increased by semaglutide (300nM) compared to control, while the ratio of RCC2:RCC1 was elevated by semaglutide, indicating both increased SR Ca2+ reuptake and less external Ca2+ removal in the presence of semaglutide (fig. H-J). Relaxation time to 50% of baseline was unaltered (not shown), while relaxation time to 90% of baseline was mildly prolonged by semaglutide at 300 nM (fig. F). No increase in the rate of arrhythmias was observed by semaglutide treatment (fig. G).

Conclusion
Acute exposure of human atrial trabeculae to semaglutide results in a strong positive inotropic effect in a dose-dependent manner without increasing the propensity for arrhythmias. This effect is most likely due to increased SR Ca2+ reuptake. Treatment of heart failure patients with high-dose semaglutide can improve atrial function, which may ameliorate symptoms.
Ablation of tachyarrhythmias with zero fluoroscopy technique in patients under 18 years of age. 4-year follow-up
Authors: Chavez Gutierrez C A , Valdez Perales M F , Garcia Leon R , Mariona Montero V A 
Published: October 2024

Abstract

Introduction
Arrhythmias occur in 5% of preschool patients, with an increased incidence in adolescence. Treatment of rapid arrhythmias or tachyarrhythmias may include ablation of the cardiac structures. Catheter ablation is the possibility of producing an injury to the endocardium by administering energy through the catheter in a limited and controlled way to those parts of the cardiac tissue where tachycardias are initiated and/or maintained, it is performed through a catheter connected to an energy source, which is introduced through arterial or venous lines. to the chambers of the heart. In recent years, different technological innovations have emerged aimed at better understanding and identifying the substrate of arrhythmia, thus facilitating catheter navigation and reducing the need for fluoroscopy.
Different studies have shown that ablation without fluoroscopy is feasible, especially in the context of supraventricular tachycardia.

Objective
To describe the clinical characteristics of pediatric patients undergoing ablation with zero fluoroscopy in a pediatric hospital of the National Medical Center of the West (CMNO).

Material and Methods
descriptive and retrospective study, the clinical characteristics of 42 patients who were taken to arrhythmia ablation by zero fluoroscopy technique at the CMNO IMSS pediatric hospital for 4 years in the period from June 2019 to May 2023 were analyzed.

Results
A total of 42 patients, of which 55% were male, with a median age of 13 years with a range of 4 to 17 years, the median weight was 49 kg with a standard deviation of +- 19.5 kg. Of the arrhythmias treated, supraventricular tachycardia accounted for 97.6% of cases and ventricular arrhythmias for 2.4%. Of the supraventricular tachycardias, atrioventricular reentrant tachycardia accounted for 68.35%. 25 cases with a diagnosis of Wolff Parkinson White with 28% of the right lateral location, followed by the right postoseptal 24%. Structural heart disease was present in 31% of the cases, the most frequent being Ebstein's anomaly (41.7%). Immediate success rate was 97.3%, with recurrence in the first three months of follow-up of 5.4%. A Kaplan-Meier curve was performed, showing a success rate of 77.3% at 12 months of follow-up. No statistical significance was found in patients with congenital heart disease and recurrence, p=0.698 and with Fisher's exact test, p=0.530.

Conclusion
Ablation of cardiac arrhythmias in children under 18 years of age without the use of fluoroscopy is an effective procedure, obtaining an immediate success rate of 97.3% of patients, 77.3% of patients are free of recurrence one year after treatment. There was no statistical significance for patients with congenital heart disease who might have recurrence.
The CNP analogue vosoritide reduces arrhythmia in diabetic cardiomyopathy via cGMP-dependent PDE2 stimulation on cellular and organ level
Authors: Firneburg R , Tergau K , Cachorro E , El-Armouche A , Kaemmerer S 
Published: October 2024

Abstract

Background
Detrimental arrhythmia occurs frequently in patients with diabetic cardiomyopathy (DiabCM), but safe and effective therapies are limited. Diabetes-associated neuropathological alterations increase the sympathetic tone, leading to hyperactivation of β-adrenoceptor-mediated cAMP signalling in cardiomyocytes (CM). Increased activity of deleterious cAMP-dependent kinases causes pro-arrhythmic dysregulation of intracellular Ca2+ homeostasis. Phosphodiesterases (PDE) can reduce cAMP levels. Exceptionally, the cAMP-hydrolysing activity of PDE2 can be cGMP-dependently increased by C-type natriuretic peptide (CNP). Thus, the CNP analogue vosoritide (approved for the treatment of achondroplasia) might mediate this cGMP/cAMP crosstalk, reducing arrhythmia.

Purpose
Here, we aim to study whether the cGMP-dependent activation of PDE2 by vosoritide (VO) is sufficient to reduce arrhythmia and arrhythmogenic triggers in DiabCM.

Methods
Diabetes was induced by 5 consecutive injections of streptozotocin (50 mg/kg) in control (WT) mice and mice with a CM-specific PDE2 knockout (KO). All experiments were performed 5 weeks later. Cardiac function was characterised by echocardiography. Primary ventricular CM were isolated to assess protein expression and phosphorylation levels by Western blot (WB) and cAMP levels by ELISA. Patch-clamp and Ca2+ imaging experiments were used to investigate pro-arrhythmic triggers. Arrhythmic events were quantified in ex vivo perfused hearts after ischaemia-reperfusion (I/R) injury.

Results
Compared to healthy controls, diabetic animals showed impaired systolic function with a ~9 % reduction in ejection fraction. The significant increase in E/E’ ratio by ~34 % indicated a diastolic dysfunction. Interestingly, the cardiac function was further worsened in diabetic PDE2 KO. WB analysis revealed upregulation of the CNP receptor NPR-B and PDE2 in diabetic CM and altered regulation of proteins involved in cAMP-dependent Ca2+ cycling such as protein kinase A, Ca2+/calmodulin-dependent kinase II and phospholamban. Interestingly, VO significantly reduced isoprenaline (Iso)-induced cAMP levels in diabetic CM. The effect of VO was prevented by specific PDE2 inhibition with BAY 60-7550 (BAY). Furthermore, VO was able to reduce the Iso-induced increase in L-type Ca2+ current, whereas BAY or genetic PDE2 deletion counteracted this effect. Accordingly, VO significantly decreased the Iso-triggered Ca2+ spark frequency by ~40 %. Concomitant PDE2 inhibition or PDE2 KO prevented this anti-arrhythmic effect. Finally, ECG analysis revealed that VO clearly reduced arrhythmia development after I/R in ex vivo perfused diabetic hearts via PDE2 activation.

Conclusion
Our data indicate that vosoritide-induced PDE2 stimulation may attenuate abnormal cardiac Ca2+ cycling and thereby reduce arrhythmia in diabetic hearts. Thus, vosoritide may be repurposed as a novel anti-arrhythmic drug in DiabCM.
Mature cardiac tissues modeling Duchenne muscular dystrophy related cardiomyopathy
Authors: Inazuka F , Funakoshi S , Fujiwara Y , Sasaki M , Ida K , Kondo S , Imahashi K , Sakurai H , Yoshida Y 
Published: October 2024

Abstract

Background
The major cause of mortality in patients with Duchenne muscular dystrophy (DMD) is cardiomyopathy. This disease is caused by dystrophin gene mutations that result in the loss of dystrophin protein. Gene replacement therapies have been approved for skeletal muscle symptoms of DMD. However, these therapeutic modalities are not indicated for cardiomyopathy due to their low efficiency of delivery to the heart. Despite the significant unmet needs, a limitation in this area of research is the divergence of cardiomyopathy symptoms in model animals from those in patients. Alternatively, cardiomyocytes differentiated from patient-derived iPS cells have recently been analyzed. However, existing results are based on a single time point analysis and do not model disease progression or non-cardiomyocyte involvement.

Purpose
Our research aims to establish an in vitro model that can reproduce the pathological progression of DMD cardiomyopathy.

Methods
We have generated cardiac organoids and engineered heart tissues (EHTs) from patient-derived iPS cells, consisting of cardiomyocytes and epicardial-derived non-cardiomyocytes. An iPS cell line in which the dystrophin mutation was repaired by genome editing was used as a control. The cardiac organoids or EHTs were subjected to transient activation of fatty acid metabolism to promote the maturation of iPS-derived cardiomyocytes. Pathological conditions were then induced in these 3D-models by applying loads that mimicked the DMD-disease environment.

Results
The mature cardiac organoids displayed adult-like gene expression profiles in the components of dystrophin-associated-protein-complex and calcium handling. After continuous mechanical loading, cell death appeared in DMD-EHTs, although there was only a slight decrease in contractility and fibrosis. Elevated mitochondrial ROS production and DNA damage were observed as a part of the cell death mechanism. Furthermore, pathological stimuli in addition to mechanical loading reproduced progressive contractile dysfunction and further increase in fibrosis in DMD-EHTs.

Conclusions
From these observations, we concluded that our DMD-EHT model recapitulate the pathological development of DMD-cardiomyopathy. These results suggest that the key factors involved in the progression of DMD cardiomyopathy are (i) the fragility of cardiomyocytes to stress in early stages and (ii) the involvement of non-cardiomyocytes such as fibrosis. Our model provides insight into the molecular mechanisms underlying disease progression and novel therapeutic targets.
Peripheral immune landscape of pediatric fulminant myocarditis revealed by single-cell sequencing
Authors: Han B , Zhang L , You Y N , Zhou S , Jiang Y J 
Published: October 2024

Abstract
Fulminant myocarditis (FM) is one of the most feared diseases in children because of its fulminant nature and high mortality rate. However, the precise pathological immune subsets and molecular changes in FM are unknown. Here, we present the first comprehensive cellular and transcriptomic profiling of the peripheral blood mononuclear cells of children in FM acute and recovery phases using Single-cell RNA sequencing. 21 cell clusters are identified among 79542 cells. The proportion of T cells and NK cells increase, while myeloid cells and B cells reduce in acute phase, which were consistent with our ﬂow cytometry data of 35 FM patients. Several unique cell types in peripheral blood are identified, including regulatory B cells, MAIT cells, adaptive NK cells and CD8+Tpex cells. The transcriptomic analysis exhibited elevated expression levels of chemokine receptor CXCR4 and S100A family genes almost in all cell types in FM acute phase, as well as MHC-II molecules in antigen-presenting cells. TCR and BCR exhibit remarkable amplification and obvious skewed usages of V genes in FM. Ligand receptor analysis show myeloid cells maintained active communication with other immune cells. Considering that CXCR4 may play an important role in myocarditis, we designed experiments to explore its function in mouse model. Vital myocarditis (VMC) mouse model was constructed using Coxsackie virus type3（CVB3）.We found that myocardial inflammation and myocardial injury of VMC mice were alleviated when treated with CXCR4 blocker. CXCR4 may be a potential therapeutic target for myocarditis. Our study will provide useful insights into key immune cell subsets and transcriptomic profiles implicated in pediatric fulminant myocarditis acute phase and recovery phase, thus providing several potential diagnostic and therapeutic targets for this disease.
NCOR1 orchestrates macrophage inflammation in heart failure with preserved ejection fraction: a translational study
Authors: Gorica E , Mohammed S A , Mengozzi A , Ambrosini S , Ruschitzka F , Hamdani H , Costantino S , Paneni F 
Published: October 2024

Abstract

Background/Introduction
Inflammatory response is a key player in heart failure with preserved ejection fraction (HFpEF) but the underlying mechanisms are poorly understood. Recent studies have shown a critical involvement of cardiac macrophage activation in myocardial remodeling thus contributing to HFpEF.

Purpose
To investigate the role of cardiac macrophage inflammation in experimental and human HFpEF.

Methods
We employed a translational approach combining human and murine LV myocardial tissue, FACS analysis of cardiac immune cells, in vitro experiments in RAW 264.7 cells exposed to metabolic stress by palmitic acid (PA), bone marrow-derived macrophages from healthy and HFpEF mice, cardiomyocytes (H9c2), endothelial cells (HAECs) as well as ex vivo functional analyses in LV tissues. Human LV myocardial samples were used to evaluate the pro-inflammatory activity of macrophages in the HFpEF myocardium. Induction of HFpEF in mice was done through a validated mouse model combining metabolic (high-fat diet) and hemodynamic stress (L-NAME). Cardiac function was investigated by high resolution ultrasound imaging (Vevo3100) and the LV myocardial samples were used to study the macrophage polarization and their inflammatory activity. Based on interrogation of available RNA-seq datasets – showing the transcriptional repressor NCOR1 as a relevant signature in macrophages during cardiac inflammation, we generated myeloid cell-specific NCOR1 knockout (Ncor1-KO) transgenic mice to investigate the in vivo effects of NCOR1 deletion on the HFpEF phenotype.

Results
The expression of macrophage markers in human LV specimens showed an increase in pro-inflammatory macrophages (M1) and a decrease in regulatory macrophages (M2) as compared to age-matched control mice. HFpEF mice showed increased expression of vascular adhesion molecules (ICAM1, ICAM2, E-selectin) and a significant recruitment of M1 macrophages as proved by qPCR, WB, and flow cytometry analysis. Of interest, diastolic dysfunction - assessed by E/A ratio and isovolumic relaxation time (IVRT) – and lung congestion were significantly reduced in mice with macrophage NCOR1 deletion as compared to WT littermates, while exercise tolerance was significantly improved. These findings were associated with a reduction of myocardial inflammation (TNF-a, IL6, IL-1b) in Ncor1-KO mice. In vitro assays showed that stimulation of macrophages with PA induced M1 type switch and increased NCOR1, TNF-a, IL-6, and IL-1b levels, whereas NCOR1 depletion prevented detrimental changes of macrophage secretome (Fig.2).

Conclusion
NCOR1 is a crucial regulator of immune response and macrophage inflammation in the heart. Our findings highlight its potential as a target for therapies aimed at preventing myocardial damage in HFpEF.
MIR181A1HG is a novel long noncoding RNA regulating vascular inflammation and atherosclerosis
Authors: Ni H E 
Published: October 2024

Abstract

Background
Endothelial cell (EC) dysfunction and vascular inflammation are critical in the initiation and progression of atherosclerosis. Long noncoding RNAs (lncRNAs) plays a critical role in vascular pathology, but relatively little is known about their involvement in controlling vascular inflammation. MIR181A1HG is a lncRNA locating juxta-position with miR-181a1 and miR-181b1, both involved in vascular inflammation. However, the role of MIR181A1HG in vascular inflammation is still unknow.

Purpose
The study aims to investigate the role of MIR181A1HG in regulating vascular inflammation and atherosclerosis.

Methods
We examined expression of MIR181A1HG in both human and mouse atherosclerotic lesions. Loss-of-function and gain-of-function studies, multiple RNA–protein interaction assays luciferase reporter and chromatin immunoprecipitation assays were used to investigate the role and molecular mechanisms of MIR181A1HG in the vascular inflammation and atherosclerosis. The single-cell RNA-sequencing were used to analyze atherosclerotic phenotypes of MIR181A1HG-/-ApoE-/- mice.

Results
MIR181A1HG was abundant in ECs and significantly increased in both humans and mouse atherosclerotic lesions. Deficiency of MIR181A1HG effectively suppressed NLRP3 inflammasome, ECs activation, and atherosclerotic lesion formation. In contrast, EC-specific MIR181A1HG overexpression promoted NLRP3 inflammasome, ECs activation, and atherosclerotic lesion formation, which were reversed by pharmacological inhibition of NLRP3 (MCC950). MIR181A1HG functioned by regulating NLRP3 inflammation, ECs activation though decoying Foxp1 away from the promoters of targets genes, which is independently of miR181a1/b1 cluster. EC-specific Foxp1 silencing reversed in vivo anti-atherosclerotic effect mediated by MIR181A1HG-deletion.
Metabolomic reprogramming of subcutaneous adipose tissue aggravates atherosclerosis via impaired adipocyte-macrophage crosstalk
Authors: Lou B , Yuan Z Y , She J Q 
Published: October 2024

Abstract
Object: The bidirectional relationship between cardiometabolic syndrome and dysfunctional adipose tissue has received increasing attention. However, the metabolic alteration of subcutaneous adipose tissue during atherosclerosis has been overlooked.

Methods
In this study, we aimed to investigate the relationship between subcutaneous adipose tissue and atherosclerosis based on a combination strategy of single-cell sequencing and metabolomics in atherosclerotic mice and humans.

Result
Through our analysis of the clinical cohort with atherosclerosis, we discovered a correlation between the volume of subcutaneous adipose tissue and the characteristics of coronary plaques. Furthermore, by employing the snRNA-seq approach, we identified the metabolic landscape and cellular crosstalk within the subcutaneous adipose tissue of atherosclerotic mice. Lastly, through our analysis of the metabolic features in human adipose tissue, we successfully validated the Insulin-like Growth Factor 1 pathway as a crucial modulator in the adipocyte-macrophage crosstalk during the development of atherosclerosis.

Conclusion
The present study has provided further evidence that dysregulated metabolism of subcutaneous adipose tissue is involved in the development and progression of atherosclerosis, not only in humans but also in animal models.