bluuebunny/crossref_metadata_2025_split huggingface dataset:
Assessing aortic morphology post aortic valve replacement using unsupervised hierarchical clustering and statistical shape modelling
Authors: Aljassam Y , Sophocleous F , Bruse J , Schot V , Caputo M , Biglino G 
Published: October 2024

Abstract

Introduction
There are different surgical procedures used to treat aortic valve disease such as aortic valve replacement (AVR), the Ozaki procedure, the Ross procedure, and the valve-sparing procedure. There may be postoperative side effects associated with aortic morphology. Computational analyses that assess morphology are thus necessary in such scenario. Statistical shape modelling is used to assess three-dimensional morphology, discover unique shape features, create mean shapes, and create shape modes that display morphological variability. Hierarchical cluster analysis is a machine learning method used to classify a population into subgroups. Both of these statistical methods were applied to aortic valve replacement patients to evaluate morphological variability after aortic valve replacement (AVR) surgery.

Purpose
The purpose of this study is to assess the aortic morphology of AVR patients, identify morphological differences between different surgical procedures, identify subgroups postoperatively using statistical shape modelling and hierarchical cluster analysis, and assessing possible correlations between the resultant clusters and function i.e. ejection fraction.

Methods
Computed tomography and cardiac magnetic resonance images were used to reconstruct aortas into 3D models using segmentation and 3D reconstruction software. For each patient, two models were created (i.e. ascending aorta only and aorta including the arch and the descending aorta). N=35 patients were included in the study. Statistical shape analysis was run to create templates and shape modes. Statistical environment and language software was used to run hierarchical cluster analysis.

Results
Overall, the hierarchical cluster analysis did not classify the aortas based on type of surgery, but most patients in the Ross group demonstrated morphological differences from the other surgical groups and many of the aortas belonging to the Ross group were clustered together in both clustering analyses. No significant differences between clusters were seen (p=0.47 for ascending, p=0.19 for whole aorta). No correlation was found between clusters and ejection fraction (p=0.75, r2&lt;0.01), possibly indicating that post-AVR aortic morphology in this sample does not reflect overt functional changes.

Conclusion
Both statistical shape modelling and hierarchical cluster analyses were successful in assessing morphological variability and identifying subgroups in this population. This framework could therefore be extended to larger samples to inform on surgical decision-making allowing surgeons to choose the appropriate surgery for the patient or design prosthetic valves that are more customised to the patient’s anatomy.Cluster-Ejection Fraction Correlation
BA6b9, a novel sk4 K + channel blocker, attenuates atrial fibrillation substrate in rats with reduced ejection fraction
Authors: Burg S , Levi O , Elyagon S , Shapiro S , Murninkas M , Etzion S , Grawohl G , Makarovsky D , Lichtenstein A , Gordon Y , Attali B , Etzion Y 
Published: October 2024

Abstract

Background
Atrial fibrillation (AF), the most common cardiac arrhythmia, is strongly associated with several comorbidities including heart failure (HF). AF in general, and specifically in the context of HF, is progressive in nature and associated with poor clinical outcomes. Current therapies for AF are limited in number and efficacy and do not target the underlying causes of atrial remodeling such as inflammation or fibrosis.
We previously identified the calcium-activated SK4 K+ channels, which are preferentially expressed in the atria relative to the ventricles in both rat and human hearts, as novel druggable targets for efforts to treat AF.

Methods and Findings
We examined the ability of BA6b9, a novel allosteric inhibitor of SK4 channels that targets the specific calmodulin-PIP2 binding domain, to alter AF susceptibility and atrial remodeling in a systolic HF rat post-myocardial infarction (post-MI) model. Daily BA6b9 injection (20 mg/kg/day) for 3 weeks starting 1-week post-MI prolonged the atrial effective refractory period, reduced AF induction and duration, and dramatically prevented atrial structural remodeling. In the post-MI left atrium (LA), pronounced upregulation of the SK4 K+ channel was observed, with corresponding increases in collagen deposition, α-SMA levels, and NLRP3 inflammasome expression.
Strikingly, BA6b9 treatment reversed these changes while also significantly reducing the lateralization of the atrial connexin Cx43 in the LA of post-MI rats.

Interpretation
Our findings indicate that the blockade of SK4 K+ channels using BA6b9 not only favors rhythm control but also remarkably reduces atrial structural remodeling, a property that is highly desirable for novel AF therapies, particularly in patients with comorbid HF.
Equity and representation in cardiology research: a comprehensive analysis of authorship from low and low-middle income countries in leading cardiology journals
Authors: Martinez De Majo A , Lombardo Pascarelli G , De Oliveira-Gomes D C , Guilliod C , Abadi V , Gulati M 
Published: October 2024

Abstract

Background
Cardiovascular disease is the leading global cause of mortality, with low-income and low-middle-income countries (LICs/LMICs) bearing a disproportionate burden. Despite this, research output is skewed towards affluent regions. This study aims to assess the authorship trends from LICs/LMICs in cardiology research in 5 of the leading cardiology journals.

Methods
PubMed authorship affiliation was obtained from 2000-2022 in (1) Journal of the American College of Cardiology (JACC), (2) Circulation, (3) Journal of the American Medical Association (JAMA) Cardiology, (4) Nature Reviews Cardiology, (NRC) and (5) European Heart Journal (EHJ). Countries were classified according to the World Bank.

Results
62873 original research, clinical cases, editorials, and reviews were published in all five journals (2000-2022). The percentage of articles with at least one author affiliated with an institution from a LIC or LMIC was 1.03% (N=652): 0.96% (N=190) in JACC, 0.82% (N=198) in Circulation, 2.42% (N=51) in JAMA Cardiology, 0.84% (N=22) in NRC, and 1.33% (N=191) in EHJ. There has been an increase in the representation of authorship from LICs and LMICs in the last decade. However, the distribution of authorship between LMICs and LICs is uneven, represented mainly -by Mozambique, Uganda, Sudan, and Ethiopia for LICs, and India, Iran, Egypt, Pakistan and Lebanon for LMICs.
Discussion: Our findings reveal an underrepresentation of authors from institutions from LICs and LMICs in these 5 leading cardiology journals. Efforts to enhance funding, access, and inclusion of authors from LICs and LMICs are imperative to advance global cardiovascular outcomes and promote equity in medical research.
Education level and the incidence of heart failure, acute myocardial infarction, and stroke in patients with atrial fibrillation
Authors: Sztaniszlav A , Bjorkenheim A , Magnusson A , Edvardsson N , Poci D 
Published: October 2024

Abstract

Background
Education level is an important socioeconomic factor affecting the incidence, symptoms, and treatment of atrial fibrillation (AF). Despite this, data on the association between education level and the incidence of major AF consequences – heart failure (HF), acute myocardial infarction (AMI), and stroke – are limited.

Aim
To investigate the association between education level and the risk of HF, AMI, and stroke in patients hospitalized with AF.

Methods
This retrospective cohort study is based on data generated by crosslinking of several Swedish national registries. All patients hospitalized between 1998 and 2003 with a diagnosis of AF were included. The relative risk for incident HF, AMI, and stroke were assessed according to education level categories during a 5–year follow–up. Education levels were categorised as primary, secondary, and academic. Kaplan-Meier curves and Cox regression models adjusted for age, sex, time of AF diagnosis, and the variables of Charlson´s Comorbidity Index were used to estimate the relative risk of the examined outcomes. Hazard ratios (HR) with 95% confidence intervals (CI) were used as estimate of associations and statistical significance level was 5%.

Results
The study included 263,172 patients (56.2% male; mean age 72.5±10.4 years). There was a statistically significant dose-dependent association between education level and the risk of AMI and HF in both sexes. Compared to primary education, the HR for AMI was 0.89 (95% CI: 0.85-0.93) for secondary education and 0.71 (95% CI: 0.65-0.78) for academic education in women; and 0.91 (95% CI: 0.87-0.94) for secondary education and 0.75 (95% CI: 0.71-0.80) for academic education in men. The relative risk for HF was similar, with HRs of 0.96 (95% CI: 0.93-1.00) for secondary and 0.82 (95% CI: 0.77-0.87) for academic education in women, and HRs of 0.93 (95% CI: 0.90-0.96) for secondary and 0.76 (95% CI: 0.72-0.80) for academic education in men.
Patients with academic education had a significantly lower risk for stroke compared to those with primary education (HR 0.77 (95% CI: 0.71-0.84) in women; HR 0.84 (95% CI: 0.79-0.90) in men), while patients with secondary education did not have a significantly different relative risk for stroke compared to those with primary education.

Conclusion
Secondary and academic education levels were associated with a significantly lower risk of HF and AMI in both women and men with AF compared to primary education. Furthermore, academic education was associated with a lower risk of stroke. In conclusion, , higher education levels were associated with a lower 5-year risk of HF, AMI, and stroke compared to primary education
Non-cell-autonomous effects of arginase-II in macrophages on cardiomyocytes in aging
Authors: Potenza D M , Cheng X , Ajalbert G , Brenna A , Giraud M N , Frobert A , Cook S , Mertz K D , Yang Z , Ming X F 
Published: October 2024

Abstract

Background
Aging-associated cardiac structural and functional alterations enhance cardiac susceptibility to ischemic injury. The full elucidation of the underlying molecular mechanisms remains far from complete. The mitochondrial enzyme arginase-II (Arg-II) is implicated in cardiac injury and aging. However, contradictory results have been reported and no systemic analysis of its cellular localization has been performed. The involvement of Arg-II in cardiac aging, as well as the manner in which it participates, remains uncertain.
Aim and methods: This project focuses on investigation of Arg-II cellular localization and its functional role in cardiac aging. Experiments are conducted in young (3-4 months) and old (20-22 months) wt and arg-ii-/- mice and in human heart tissues. Cardiac function is assessed by Langendorff apparatus ex vivo. Cellular localization of Arg-II in cardiac tissues is investigated by confocal microscopy. Intercellular interactions are studied using ventricular cardiomyocytes, cardiac fibroblasts, endothelial cells, and macrophages isolated from wt and arg-ii-/- mice or humans.

Results
Cardiac Arg-II expression is enhanced with aging. Surprisingly, Arg-II is not found in cardiomyocytes from aged mice and human patients, but upregulated in non-myocytes, including macrophages, fibroblasts, endothelial cells. Arg-ii-/- mice are protected from age-associated cardiac inflammation, cardiomyocyte apoptosis, fibrosis, endothelial-mesenchymal transition (EndMT), and susceptibility to ischemic injury. Further experiments show that Arg-II mediates IL-1b release from macrophages of old mice, contributing to the above-described cardiac aging phenotype. In addition, Arg-II enhances mitochondrial reactive oxygen species (mtROS) and activates cardiac fibroblasts that is inhibited by inhibition of mtROS.

Conclusion
Our study demonstrates a non-cell-autonomous effect of Arg-II on cardiomyocytes, fibroblasts, and endothelial cells mediated by IL-1b from aging macrophages, which may explain the enhanced vulnerability of aging heart to ischemic injury.Role of Arg-II in cardiac aging
Mexiletine shortened QTc interval in an age-dependent manner but suppressed ventricular arrhythmias at all age in children with long QT syndrome type 8
Authors: Ozawa J , Ohno S , Suzuki H , Kato K , Fukuyama M , Horie M , Saitoh A 
Published: October 2024

Abstract

Background
long QT syndrome (LQTS) type 8 (LQT8) is caused by mutations in CACNA1C, a gene encoding the α-subunit of voltage-gated Ca2+ channels. Mexiletine is sodium channel blocker which is often utilized for patients with LQTS type 3. Recently, the potential QT shortening effect of mexiletine in patients with LQTS type 2, however the efficacy for LQT8 patients have not been elucidated sufficiently.

Purpose
The study aimed to examine the efficacy of mexiletine for LQT8 children.

Methods and Results
The study consisted of 5 LQT8 children diagnosed at age &lt;18 years from 4 families (female n=2). Three cases diagnosed on the first day of life, others during school-aged period. The mean age at diagnosis was 3.8 ± 4.9 years. The CACNA1C mutations identified in the patients were R518C (Case No.1), R858H (No.2), M1476R (No3 and 4), and G402S (No.5). We analyzed response in 12-lead electrocardiogram (ECG) parameters to mexiletine (3mg/kg, Max 125mg) intravenous infusion over 10 minutes. 12-lead ECGs were recorded at rest and 10 minutes after infusion. Two of them were received in the school-age period (No.1 and 2), two were in the neonatal period (No.4 and 5), and another was twice in both periods (No.3). QTc was drastically shortened in school-aged children (No.1: 521/456ms, No.2: 691/556, No.3: 568/532ms), while 3 neonatal cases showed no QTc shortening (No.3: 481/479ms, No.4: 600/601ms, No.5: Pre 689ms/Post 714ms) (Figure). T wave alternans (TWA) that had occurred incessantly in the neonatal case No.4 dramatically suppressed a few seconds after mexiletine infusion. In addition, torsades de pointes (TdP) had been recorded in 2 cases (No.2 and 5). Then, case No.2 and 5 started combination therapy of oral mexiletine and β-blocker, and No.4 mexiletine therapy. They had no cardiac event during medication for several years, although case No.2 suffered recurrent cardiac events because of non-compliance to mexiletine.

Conclusion
Mexiletine shortened QTc interval in school-aged children with LQT8, but not in neonates. Regardless of QTc shortening, mexiletine successfully reduced TWA and TdP at all age of LQT8 children.Mexiletine infusion test
Role of common variants and new genes associated with arrhythmogenic cardiomyopathy
Authors: Barc J , Ruffier L , Simonet F , Baron E , Forest V , Roux-Buisson N , Crotti L , Chevalier P , Sommariva E , Villard E , Moore-Morris T , Schott J J , Gandjbakhch E , Probst V 
Published: October 2024

Abstract

Introduction
Arrhythmogenic Cardiomyopathy (ACM) is an inherited cardiac disease, predominantly affecting males, characterized by fibro-fatty myocardial replacement mainly in the right ventricle. It leads to 5% sudden cardiac death in affected young adults (&lt;25 yo) without an implantable cardioverter defibrillator. Early diagnosis is crucial for appropriate clinical management to reduce mortality and prevent disease progression. Rare variants in desmosomal genes (PKP2,DSC2,DSG2,DSP and JUP) are found in 50% of cases. However, challenges persist since we observe a low penetrance in relatives (28-58%) and a high variability in expressivity and severity annihilating any preventive strategy.

Objective
We aim to decipher the genetic architecture of ACM by investigating the role of common variants in disease susceptibility/severity and to idendify new genes associated to ACM.

Method
A Genome Wide Association Study (GWAS) was performed on 1079 ACM index patients and 7305 controls, followed by conditional analysis. New candidate genes were knocked out (KO) in Zebrafish and/or hiPSC using CRISPR/Cas9. Impedance and external field potential measurements were performed on hiPSC derived cardiomyocytes (CM-hiPSC).

Results
The GWAS identified 5 significant loci (Figure 1, P&lt;5.10-8), including 2 desmosomal genes (PKP2 a n d DSG2) and 3 new candidates (KLF12, CTNNA3, and ARL17B/WNT3). Conditional analysis revealed 3 additional loci with suggestive p-values (P&lt;1.10-6), highlighting 3 new susceptible loci. Among them, we uncovered key non-coding regulatory regions near desmosomal genes (DSC2 and DSG2). Initial findings in PKP2-KO zebrafish present hearts with structural defects, while CM-hiPS KLF12-KO(-/-) exhibited altered interbeat interval and relaxation time compared to isogenic controls.

Conclusion
Our findings reveal ACM's complex genetic architecture, implicating common variants in disease susceptibility. A polygenic risk score will be implemented to improve patient risk stratification. Three novel loci/genes for ACM as well as specific regulatory regions of desmosomal genes have been highlighted. Their functional studies in isogenic hiPSC and Zebrafish models will offer new insights in ACM underlying molecular mechanism and potential therapeutic targets.
Serum exosomal long non-coding RNA H19 as a theragnostic target for atrial fibrillation
Authors: Kang J Y , Mun D , Park M , Yoo G , Joung B 
Published: October 2024

Abstract

Background/Introduction
Exosomes are membrane vesicles of 30- to 150-nm secreted by most cell types that can mediate intercellular communication by transmitting various forms of RNAs. Long non-coding RNAs (lncRNAs, ≥ 200 nucleotides length) have been reported to play important roles in the pathophysiological processes that promote the development and progression of many diseases. Interestingly, recent studies have shown that exosomal lncRNAs exhibit different expression profiles in various diseases and are being extensively studied in the medical field as an ideal target for the diagnosis and treatment. However, there is still little known about their role in atrial fibrillation (AF).

Purpose
The aim of this study was to identify a novel theragnostic target exosomal lncRNA for AF.

Methods
First, serum exosomes from controls and patients with persistent AF were isolated and characterized by transmission electron microscopy, nanoparticle tracking analysis, and western blot. Next, serum exosomal lncRNA expression profiles were explored using RNA-sequencing analysis. In addition, the expression levels of candidate exosomal lncRNAs were confirmed using qRT-PCR (n = 50 per group). Finally, AF-related pathophysiological mechanisms of exosomal lncRNA were investigated in angiotensin II (Ang II)-treated human induced pluripotent stem cell-derived atrial cardiomyocytes (iPSC-atrial CMs).

Results
After RNA-sequencing analysis, we identified 27 differentially expressed lncRNAs (i.e., 4 upregulated and 23 downregulated lncRNAs with a |fold change| ≥ 2 and p &lt; 0.05) in serum exosomes from patients with persistent AF compared with the controls. In fact, qRT-PCR reveled that exosomal lncRNA H19 was consistently downregulated in the serum of patients with persistent AF compared with the controls (p &lt; 0.01). In addition, exosomal lncRNA H19 exhibited significant diagnostic validity for AF. Notably, we confirmed that exosomal lncRNA H19 was involved in AF-related pathophysiological mechanisms. In Ang II-treated iPSC-atrial CMs, inhibition of lncRNA H19 significantly aggravated Ang II-induced increases in levels of hypertrophic markers (ANP, BNP and β-MHC), cell surface area and inflammation (p &lt; 0.05). Mechanistically, we found that loss of lncRNA H19 weakens the inhibition of its direct target microRNAs, miR-141-3p and miR-200a-3p, leading to downregulation of their target PTEN, thereby promoting the atrial remodeling and the consequent AF.

Conclusion
In conclusion, serum-derived exosomal lncRNA H19 could serve as a potential target for the diagnosis and treatment of AF.
Lipidomics-based deep learning algorithms can enhance prediction of obstructive coronary artery disease
Authors: Karagiannidis E , Papazoglou A , Mouskeftara T , Deda O , Liapikos T , Panteris E , Kartas A , Sianos G , Gika E 
Published: October 2024

Abstract

Background
Lipidomics emerge as a promising research field with the potential to help in personalized risk stratification and also improve our understanding on the functional role of individual lipid species in the metabolic perturbations occurring in coronary artery disease (CAD). The existing technological challenges to detect diverse yet structurally similar lipids and their isomers, as well as the need for novel statistical and computational tools to handle the high-dimensional lipidome may be responsible for the reduced clinical translation of the very first lipidomics research outcomes.

Methods
To that end, this post-hoc analysis of the prospective CorLipid trial aimed to investigate the predictive capability of a lipidomics panel for obstructive CAD risk through an extreme gradient boosting (XGBoost) machine learning (ML) approach. The lipid profiles of 146 individuals with suspected CAD were investigated through liquid chromatography-mass spectrometry. Fasting blood samples were drawn prior to invasive coronary angiography execution. Obstructive CAD was defined as SYNTAX Score (SS) &gt;0 compared to non-obstructive CAD (SS=0).

Results
Study participants (75.3% male, mean age: 61 ±10.5 years old) were divided into two categories based on the existence of obstructive CAD (54.8% with SS&gt;0 and 45.2% with SS=0). In total, 517 lipid species were identified, from which 290 lipid species were finally quantified in participants’ serum [glycerophospholipids (52.1%), glycerolipids (28.6%) and sphingolipids (19.3%)]. The levels of glycerophospholipid, sphingolipid and glycerolipid classes were significantly different in patients with obstructive CAD. Finally, a ML XGBoost algorithm identified a panel of 17 serum biomarkers (5 sphingolipids, 7 glycerophospholipids, triacylglycerols, galectin-3, glucose, LDL and LDH) as totally sensitive (100% sensitivity, 62.1% specificity and 100% negative predictive value) for the prediction of obstructive CAD.

Conclusions
These findings provide molecular insights into the role of dysregulated lipid metabolism in the development and progression of CAD while validating the existing body of evidence from similar research studies. Further (ML-based) investigation of lipid metabolism could hold promises for novel therapeutic strategies and improvement of the existing risk stratification schemes.Lipidomics panel importance