bluuebunny/crossref_metadata_2025 huggingface dataset:
A meta-analysis of the safety and efficacy of pulsed-field versus conventional thermal ablation for atrial fibrillation
Authors: Amin A M , Abuelazm M , Nazir A , Ibrahim A A , Elbenawi H , Aboutaleb A , Ellabban M , Arnaout M , Abouzid M , Abdelazeem B
Published: October 2024

Background

Since pulsed-field ablation (PFA) specifically targets myocardial tissue, it has become a cutting-edge substitute for radiofrequency (RF) and cryoablation.

Purpose

We aim to compare the safety and efficacy of PFA vs thermal ablation for AF ablation.

Methods

We conducted a systematic review and meta-analysis synthesizing randomized controlled trials (RCTs) and observational comparative studies, which were retrieved by systematically searching: PubMed, EMBASE, Web of Science, SCOPUS, and Cochrane through September 2023. RevMan version 5.4 software was used to pool dichotomous data using risk ratio (RR) and continuous data using mean difference (MD) with a 95% confidence interval (CI).

Results

Seventeen studies with a total of 2,255 patients were included. PFA was significantly associated with a decreased AF recurrence (RR: 0.65, 95% CI [0.51, 0.84], P= 0.0010) but not any arrhythmia recurrence (RR: 0.87, 95% CI [0.69, 1.09], P= 0.22). Also, PFA was significantly associated with decreased total procedure time (MD: -15.15, 95% CI [-20.23, -10.07], P< 0.00001) and heart rate (MD: -7.56, 95% CI [-12.78, -2.34], P= 0.005); however, there was no significant difference between PFA and thermal ablation in fluoroscopy time (MD: 2.83, 95% CI [-0.38, 6.04], P= 0.08). PFA decreased phrenic nerve palsy (RR: 0.38, 95% CI [0.15, 0.98], P= 0.05) and esophageal lesions (RR: 0.09, 95% CI [0.01, 0.69], P= 0.02); however, PFA was significantly associated with increased pericardial tamponade (RR: 6.14 with 95% CI [1.43, 26.33], P= 0.01).

Conclusion

PFA was significantly associated with decreased AF recurrence, heart rate, total procedure time, phrenic nerve palsy, esophageal lesion, and increased incidence of pericardial tamponade compared with thermal ablation. However, current evidence is mainly weighted by observational studies, requiring further large-scale randomized trials.Figure
The protective role of Baz2b ablation in aging-related heart failure
Authors: Zang T , Xu F , Cai S , Shen L
Published: October 2024

Background

The elderly population is increasing year by year. Aging has become an important risk factor for cardiac dysfunction and heart failure. Previous studies have found that bromodomain adjacent to zinc finger 2B (Baz2b) is closely associated with neurodegeneration, but its role in aging-related heart failure remains unclear.

Purpose

We aim to explore the mechanism of Baz2b in aging-induced heart failure and doxorubicin-induced heart failure. We also investigate whether Baz2b and its downstream mechanism can serve as targets for clinical intervention.

Methods

We injected doxorubicin intraperitoneally in Baz2b knockout and cardiac-specific Baz2b knockdown mice to produce in vivo models. The effects of Baz2b and its downstream regulators were further explored via RNA-sequence, chromatin immunoprecipitation-sequence (ChIP-seq) and assay for transposase-accessible chromatin-sequence (ATAC-seq). Besides, we elucidated the function of Baz2b in alpha-myosin heavy chain-induced myocarditis.

Results

we found that Baz2b expression was upregulated in both aged and doxorubicin-induced mice heart. Baz2b knockout resulted in cardiac function recovery accompanied by a decline in apoptosis in aged mice and doxorubicin-induced mice. In contrast to control mice, cardiac-specific Baz2b knockdown alleviated doxorubicin-induced cardiac dysfunction and apoptosis. Mechanistically, Baz2b was closely associated with inflammatory responses in heart. It regulates Stat1, an important inflammatory downstream regulator via H3k4me3. Furthermore, the overexpression of Stat1 was able to abolish the protective role of Baz2b in doxorubicin-induced cardiotoxicity. Besides, cardiac-specific Baz2b knockdown could alleviated myocarditis, in line with the fact that Baz2b was linked to inflammation.

Conclusion

Taken together, this study provides new insights that Baz2b plays an important role in aging-related heart dysfunction. Since epigenetic readers were previously unrecognized, these findings may shed on novel clinical therapeutic choice for patients with chemotherapy-induced cardiotoxicity.The schematic diagram of Baz2b in heart
Transoesophageal echocardiography-guided cardioversion and thromboembolism
Authors: Lunden M , Engvall J , Jansson K , Lindstrom L , Digerfeldt C , Almroth H , Hubbert L
Published: October 2024

Background

To perform electrical cardioversion of atrial fibrillation or atrial flutter with a duration of more than 48 hours, it is recommended to initiate anticoagulation therapy for at least three weeks beforehand. In cases where cardioversion is necessary earlier, it is suggested to precede the procedure with a transoesophageal echocardiography to rule out the presence of a thrombus in the left atrium (referred to as TOE-guided cardioversion). This strategy is outlined in current ESC guidelines for atrial fibrillation. However due to limited evidence, no specific level of recommendation for its use is provided.

Purpose

This study aimed to characterize patients treated by TOE-guided cardioversion in two hospitals and to conduct a safety analysis of the procedure. The 30-day incidence of thromboembolic events was chosen as the main safety objective, the 30-day mortality as the secondary.

Method

This was a retrospective, two center, cohort register study where information was obtained from patients medical records. All patients who underwent TOE-guided cardioversion between 2012-2020 in the first institute, and between 2015-2020 in the second were included. From the medical records all the patient characteristics and the clinical outcomes were identified.

Result

A total of 259 patients, with TOE-guided cardioversions, arrhythmia duration over 48 hours and without adequate anticoagulation therapy were included. Patient characteristics are shown in table 1. It was equal incidence of a 30-day thromboembolic event (n=6) and the 30-day mortality (n=6), 2,3% respectively. Three of the six patients died of non-cardiovascular cause. One of the 30-day thromboembolic event resulted in mortality at day 31. Table 2 summarize the data related to the thromboembolic events. There was no statistically significant predictor of any of the two endpoints when comparing the patients with event and patients without.

Conclusion

This study shows that the risk of thromboembolic events after TOE-guided cardioversion is not negligible, 2,3% within a 30-day follow up. The 30-day mortality was 2,3%, half of which were non-cardiovascular. To analyse potential clinical predictors for any events, larger studies specifically powered for such a question is needed.
ND15, subunit of the electron transport chain protein-complex I, age-dependently worsens cardiac performance in Drosophila melanogaster
Authors: Gaub F
Published: October 2024

Introduction

In the natural aging process of the heart, aside others, mitochondrial dysfunction is an essential driver for the development of reduced cardiac performance. Previous analysis of protein expression levels in cardiomyocytes of aged mice and have found aberrancies in subunits of the mitochondrial Complexes I – IV of the electron transport chain. Especially, the complex I subunit ND15 was highly downregulated. To elucidate the functional effects of this gene on the cardiac performance, we generated cardiomyocyte specific ND15 knock-downs in Drosophila melanogaster.

Methods

We generated Drosophila with heart-specific (+/+; Hand4.2-GAL4/UAS-ND15; tdtK/+) (ND15-KD)knockdown of ND15 using the UAS/GAL4 system. The flies' cardiomyocytes endogenously express tdTomato, facilitating fluorescence-based live imaging of the heart by high-resolution video fluorescence microscopy. The recorded data was processed using a R-Script, resulting in

Results

We compared wild type (WT) flies to ND15-KD flies at age 3 weeks(young) and 7 weeks(old).

Knockdown of ND15 resulted in impaired cardiac function. Most parameters deteriorated in aged flies in comparison to young flies. The heart frequency was significantly reduced (WT:6 beats/s – KD:4 beats/s – p<0.0001) in the 7 weeks old group, end-diastolic diameter of the heart tube increased significantly in 3 weeks old ND15KD flies compared to controls(WT:65µm – KD:74µm p<0,0001), resulting in a dilated heart tube Interestingly enough, this dilation in ND15-KD disappeared in 7 weeks old flies.

The fractional shortening was significantly decreased in young(WT:33,5% - KD:30% p<0,01) and deteriorated in old flies (WT:35% - KD:22% p<0,0001), indicating a reduced contraction capability. For both 3 weeks and 7 weeks old groups, the heart-rate adjusted interbeat interval variance (WT:22% -KD: 40% p<0,0001) as well as the time of no cardiac action (WT: 22% - KD: 35% p<0,0001) increased and showed significant irregularities. The duration of systole and diastole combined also exhibited arrhythmic patterns (WT:15% - KD:20.5% p<0,0001). A general arrhythmia index (AI) increased significantly (WT: 0.25 – KD:0.5 p<0,0001) These arrhythmia parameters emphasize the arrhythmogenic potential of the ND15-knockdown.

The relative relaxation capabilities drastically worsened with age, displaying a diastolic dysfunction in the 7 weeks old group.

At half-time relaxation, the WT was at 60% relaxation, ND15KD at 46%).

Conclusion

This study demonstrates that heart-specific deletion of ND15 results in a marked impairment of systolic and diastolic cardiac function in Drosophila accompanied by pro-arrhythmogenic actions. We could identify ND15 as a new mitochondrial molecular target for the maintenance of regular cardiac function and rhythmicity, especially with increasing age. Further mechanistic studies and translation to mammalian organisms are ongoing.
ATM: a protein involved in glucose and lipid metabolism in the heart
Authors: Carotenuto M , Paolillo R , Caterino M , D'apice S , Pezone A , Boccella N , Polese P , Ioele D , Pirozzi M , Coppola L , Lombardi A , Esposito G , Ruoppolo M , Avvedimento V E , Perrino C
Published: October 2024

Backround

Post-mitotic cells, such as neurons and cardiomyocytes, cannot repair DNA lesions with DNA replication and rely for their survival on efficient sensors and effectors that orchestrate the DNA damage response (DDR). The Ataxia Telangiectasia Mutated (ATM) protein kinase is the most important sensor of oxidative stress and the DNA damage response (DDR) and is implicated in cellular metabolism. It is believed that while transient DNA damage and DDR can temporarily improve cardiovascular function, persistent activation of DDR (and ATM) might promote the onset and development of heart failure (HF).

Purpose

We hypothesised that ATM might control and regulate energy metabolism in the heart under stress to promote DNA repair.

Methods

We analyzed the effects of ATM inactivation on cardiomyocyte hypertrophy, cardiac function, DDR and metabolism in hearts from wild-type (Atm+/+) or Atm-mutated (Atm-/-) mice under sham conditions or after pressure overload by transverse aortic constriction (TAC).

Results

ATM inactivation in Atm-/- mice induced cardiomyocyte hypertrophy, fetal gene expression re-activation and a specific metabolomic signature in the heart, characterized by significant accumulation of pyruvate, branched chain amino-acids, short-medium acyl-carnitines and metabolites of tricarboxylic acid cycle. The levels of the glycolytic enzymes, hexokinase-2 (HK2) and phosphofructokinase (PFK), were elevated. pyruvate was trapped in the cytosol because mitochondrial carriers were suppressed and the enzymes that process pyruvate were dysregulated. Because of pyruvate metabolic block, fatty acids oxidation was inefficient and resulted in the accumulation of acyl-carnitines and insulin resistance. These metabolic changes were amplified by TAC, which rapidly induced heart failure in Atm-/- mice.

ATM inactivation also increased basal and TAC-induced genomic stress in cardiomyocytes, as shown by the levels of p-γ-H2AX, 8-oxodG glycosylase (OGG1/2) and apurinic site nuclease (APE1). These results prove that ATM rewires the metabolism of cardiac cells by inducing glycolysis and fatty acids oxidation. ATM stimulates glycolysis to repair DNA lesions and protect the heart against stress-induced dysfunction. The metabolic block due to ATM inactivation accelerates heart failure.

Conclusions

Our data suggest that ATM favors the metabolic flexibility of the heart by stimulating glucose entry and balancing glucose catabolism with fatty acid oxidation, thus preventing mechanical stress-induced cardiac systolic dysfunction.
Sex differences in the expression of metabolic and pro-inflammatory markers in the initial post-COVID-19 phase
Authors: Estepa M , Haritonow N , Marx L , Nnaji M , Ladilov Y , Barcena M
Published: October 2024

Cardiovascular complications are a common manifestation of post-acute COVID-19 infection. Post-COVID-19 syndrome is often associated with the female sex and exacerbated inflammation; however, the underlying molecular mechanisms of this sex difference remain poorly understood. In the present study, we aimed to investigate several metabolic, mitochondrial, autophagy, oxidative stress, and inflammatory markers in peripheral blood mononuclear cells (PBMCs) and plasma isolated from older (>75) male and female patients at the initial phase (1-2 weeks) after COVID-19 pneumonia. Age-matched non-infected women and men were used as a control group.

We found a significantly higher plasma TNF-α in post-COVID-19 women, but not in men, compared to the control group. Similarly, a significant elevation of IL-1β and IL-18 mRNA in PBMCs from post-COVID-19 women, but not men, was observed. These effects were associated with marked activation of AMPK (defined as pAMPK/AMPK ratio), suggesting potential metabolic stress in female post-COVID-19 PBMCs. Further analysis revealed increased expression of mitochondrial genes, which may be due to AMPK activation as a compensatory reaction to metabolic stress. Analysis of autophagy or oxidative stress (serum 8-OHdG) markers did not reveal any differences between the groups investigated.

We conclude that women in the initial phase of post-COVID-19 have elevated expression of inflammatory markers in plasma and in immune cells, which is associated with metabolic stress. This may contribute to the cardiovascular complications in female post-COVID-19 patients.
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

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

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 >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

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

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

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

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

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

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

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.
Smooth muscle cell-specific deletion of S100A4 modifies smooth muscle cell fate and inflammation in murine atherosclerotic lesions
Authors: Azar P , Cardoso Dos Santos L M , Correia De Sousa M , Foti M , Bochaton-Piallat M L
Published: October 2024

Background

S100A4, a calcium-binding protein, is crucial in smooth muscle cell (SMC) phenotypic switch, yet its role in atherosclerotic plaque development and SMC plasticity remains unclear. Our previous experiments using an S100A4 neutralizing antibody approach in ApoE-/- atherosclerotic-prone mice showed reduced atherosclerotic burden but did not establish a direct link between the various S100A4-expressing cells and atherosclerosis.

Methods/Results

Herein, we show that aortic Oil RedO staining in ApoE-/-; S100A4-/- mice subjected to a 12-week high-cholesterol-diet (HCD) revealed reduced lesion areas compared to ApoE-/- mice (Figure 1, from 21.29% of the total aorta in ApoE-/-; S100A4+/+ mice to 13.27% in ApoE-/-; S100A4-/- mice), highlighting a pivotal role for S100A4 in atherosclerotic plaque development.

We then used a lineage tracing ApoE-/- mouse model, in which we induced an SMC-specific deletion of S100A4 (SMC-S100A4Δ/Δ). After 12 weeks of HCD, SMC-S100A4Δ/Δ and control mice (SMC-S100A4wt/wt) were sacrificed, and aortas were processed for en face Oil Red O staining, immunohistochemistry, and single-cell RNA sequencing (scRNA-seq). SMC-specific deletion of S100A4 reduced the necrotic core area (from 29.75% of total plaque area in SMC-S100A4wt/wt to 18.23% in SMC-S100A4Δ/Δ mice) without affecting total atherosclerotic plaque size suggesting a more potent impact on plaque composition. ScRNA-seq analysis from SMC-S100A4Δ/Δ and SMC-S100A4wt/wt mice showed that the inflammatory macrophage-like SMC phenotype was highly suppressed in the plaque and associated with increased SMC repair phenotypes as well as a global reduction of myeloid inflammatory cells. SMCs also retained specific contractile SMC markers, namely Acta2 and Myh11 (fold change of 2.285 and 2.492, respectively) hinting towards a more stable fibrous cap. Immunofluorescence staining on aortic roots plaque (Figure 2) confirmed those results with an increase of SMCs (from 11.02% to 16.18%) as well as a-smooth muscle actin (a-SMA, Acta2)-positive SMCs (from 3.25% to 5.1%) in SMC-S100A4 Δ/Δ mice.

Furthermore, the Gene Set Enrichment Analysis (GSEA) of scRNAseq data revealed that, in SMC-S100A4Δ/Δ mice, genes related to mitochondrial metabolism and oxidative respiration were highly downregulated in all SMC clusters. We investigated SMC mitochondrial fitness in vitro and showed that S100A4-/- SMCs have an increased basal oxygen consumption rate and an increased proton leak (fold change of 1.37 and 1.96 respectively) suggestive of differences in cellular metabolic adaptability.

Conclusion

Our research emphasizes the significant role of S100A4 in plaque development, demonstrating how SMC-derived S100A4 knockdown affects plaque evolution, reducing inflammation, and promoting stability likely through influencing SMC phenotypic switch through metabolic pathways.
Real world data on SVT ablation in Denmark Higher risk of need for reablation in todays patient population a Nationwide registry based Danish study
Authors: Middelfart C , Toennesen J , Lock Hansen M
Published: October 2024

Introduction

Supraventricular tachycardias (SVTs) are a common reason for healthcare contacts and can have significant impact on patient’s quality of life. Today, ablation therapy is considered the treatment of choice for many cardiac tachyarrhythmias, and it is increasingly utilized to treat SVT-patients with chronic symptoms. Ablation therapy for SVTs is considered a safe procedure with high periprocedural success rates. However, recent studies on today’s patient population have shown a tendency towards higher age and more comorbidity, which might affect these success rates. Therefore, there is a need to explore more real-world data on long-term outcomes of catheter ablations in today’s population.

Purpose

To examine the long-term success rates of ablation therapy by investigating risk of reablation in patients treated for either an accessory pathway (AP), atrioventricular nodal re-entry tachycardia (AVNRT) or ectopic atrial tachycardia (EAT).

Methods

Using Danish nationwide registries, patients of 18 years or older who underwent RFA for AP, AVNRT or EAT between January 1st 2010 and January 1st 2019 were included. Comorbidities and use of antiarrhythmic drugs were analyzed. The cumulative incidences of reablation for either AP, AVNRT or EAT were estimated at 5-year follow-up.

Results

Figure 1 shows the baseline characteristics of the study population. A total of 5.905 patients were included in the study, with a median age of 52 [38, 65], and 47% were male. Among them, the AP group comprised 1.575 patients, with a mean age of 42 [29, 55], and 61% were male. The AVNRT group consisted of 3.598 patients, with a mean age of 56 [43, 67], and 42% were male. In the EAT group, there were 732 patients, with a mean age of 57 [42, 67], and 44% were male. The comorbidity burden was generelly higher in EAT patients, who also had the highest use of antiarrhythmic drugs.

Figure 2 shows the 5-year cumulative incidence of reablation for AP, AVNRT or EAT-patients. Risk of reablation after 5 years was 12%, 5% and 12% for AP-, AVNRT- and EAT patients respectively. After 1 year the risk was 9%, 3% and 9% for AP-, AVNRT- and EAT patients respectively.

Conclusion

Despite the generally safe nature of ablation therapy with high periprocedural success rates, our findings highlight a notable risk of reablation, particularly for AP and EAT patients, after 5 years of follow-up.Baseline Characteristics5year cumulative incidence of reablation
A prospective study of a novel pocket compression device to reduce pocket hematoma after cardiac implantable electronic device implantation in a high bleeding risk population
Authors: Tijskens M , De Schouwer K , Thoen H , Strazdas A , Wolf M , De Greef Y , Schwagten B
Published: October 2024

Background

Pocket hematoma (PH) is one of the most common complications after cardiovascular implantable electronic device (CIED) implantation resulting in an up to 9 times higher risk for CIED infections.(1) Different preventive strategies have been proposed with mixed results. Current standard of care consists of preventive elastic adhesive tape leaving 2 major disadvantages: unpredictable pressure on the pocket and inability to visually assess the pocket with the bandage applied.

Aim

To evaluate the safety and effectiveness of a novel pocket compression device in patients undergoing CIED implantation in a high bleeding population.

Material and methods

This randomized controlled trial included 32 patients in the study group (pocket compression device) and 33 in the control group (elastic adhesive tape). The studied pocket compression device contains an inflatable compartment to modify the degree of pocket compression which is transparent facilitating pocket evaluation. The primary outcome was the incidence of various grades of PH. The secondary outcomes comprised the incidence of pressure lesion, pain score (0-10) and endocarditis during follow-up.

Results

There were no clinical or procedural differences between groups (age 78.01±9.71, heart failure 53.8%, kidney failure 20.0% and on antithrombotic drugs 49.2%). There were significantly less pocket hematomas in the study group (1/32 (3.1%) vs 20/33 (60.6%), P<0.001). Most pocket hematomas were grade I for which watchful waiting was applied (1/32 (3.1%) vs 17/33 (51.6%), P<0.001). Grade II and grade III PH only occurred in the control group (respectively 1/33 and 2/33) resulting in hospitalization prolongation and longer interruption of antithrombotic drugs >24hours. Two control patients eventually received the study device to control PH. None underwent reoperation. Pressure lesions did not occur. Patients in the study group had lower pain scores at application (0.75±1.12 vs 1.80±1.38, P=0.009), after 2 hours (0.81±1.36 vs 1.94±1.50, P=0.002) and the next day (0.38±0.91 vs 1.06±1.634, P=0.042). None of the patients experienced endocarditis during mean follow-up of 1 year.

Conclusion

The use of a pocket compression device in patients undergoing CIED implantation in a high bleeding population leads to less PH and postoperative pain in comparison to conventional elastic adhesive tape.bandage study
Novel parameters for micra transcatheter pacing system implantation on the right ventricular mid-septum
Authors: Pak M , Kakita K , Yamasaki T , Hattori T
Published: October 2024

Background

No procedural parameters for Micra transcatheter pacing system (Micra TPS) implantation on the right ventricular mid-septum have been established though it is encouraged for safety.

Purpose

We aimed to investigate procedural predictors for Micra TPS implantation on the ventricular mid-septum.

Methods

This is a single-center, retrospective and observational study. Eighty-two patients who underwent Micra TPS implantation were enrolled. The implantation sites of the ventricular septum were classified into basal, mid and apical-septum in the right anterior oblique 35° image. Predictors for mid-septal implantation were evaluated using univariable and multivariable logistic regression analysis which involved explanatory variables considered clinically important. The explanatory variables included the angle between the axis of a device cup of a delivery catheter and the tangent of the ventricular septum in the left anterior oblique 45° image (defined as angle θ). The diagnostic cut-off value of the significant predictor for mid-septal Micra implantation was assessed using receiver operating characteristic (ROC) curve analysis.

Results

Micra TPS was implanted on the ventricular mid-septum in 61 patients (74.4%), the apical-septum in 21 patients (25.6%), and the basal-septum in no patients. In univariable logistic regression analysis, each angle θ and α-loop shape appearance of a delivery catheter was significantly associated with mid-septal implantation (Odds ratio [OR], 1.1; 95% confidential interval [CI], 1.02-1.10; P=0.002, and OR, 4.6; 95% CI, 1.63-13.6; P=0.005, respectively). After multivariable adjustment, both angle θ and α-loop shape appearance were independently associated with mid-septal implantation (adjusted OR, 1.1; 95% CI, 1.01-1.09; P=0.010, and adjusted OR, 3.3; 95% CI, 1.01-11.4; P=0.048, respectively). Because no Micra TPS was implanted on the basal-septum, an ROC curve for binary outcome of mid-septal and apical-septal implantation was drawn. The ROC curve showed a cut-off value of angle θ for Micra TPS implantation on the ventricular mid-septum was 22° with high sensitivity and specificity at 80.0% and 70.0% (area under the curve= 0.781).

Conclusion

The angle θ ≧ 22°and the α-loop shape appearance of a delivery catheter may be useful predictors for Micra TPS implantation on the ventricular mid-septum.