bluuebunny/crossref_metadata_2025 huggingface dataset:
Mortality rate of percutaneous coronary interventions in st-segment elevation myocardial infarction patients under the public health insurance schemes of thailand
Authors: Chumsantivut S , Srimahachota S , Lertmaharit S , Rattananupong T
Published: October 2024

Background

ST-elevation myocardial infarction (STEMI) presents a critical public health challenge internationally, including in Thailand. Currently, standard therapeutic interventions, particularly primary percutaneous coronary interventions (pPCI), are administered to Thai citizens. However, selected healthcare systems restrict access to specific pharmaceuticals and medical devices, causing inequalities in the quality of medical care amongst different healthcare systems. Such inequalities have the potential to significantly impact the quality of life of patients, particularly in the long term.

Purpose

The primary objective is to compare mortality rates within one year of STEMI patients after treatment with pPCI among the public health insurance schemes of Thailand. The secondary objective is to study prognostic determinants for one-year mortality rates among patients diagnosed with STEMI who have undergone pPCI.

Methodology

This study is a single-centre retrospective analysis of patients with STEMI treated with pPCI. It involves patients utilising various state health insurance schemes in Thailand from 1 January 2010 to 31 December 2020. Data collection occurred through the hospital's computerised management system and the registration administration office of the Department of Provincial Administration. The data analysis employed the Kaplan-Meier survival analysis, log-rank test, and Cox proportional hazards regression modelling method.

Results

The study involved 1,077 patients, categorised into three groups based on their state health insurance: Universal Health Coverage (UC) (546 patients, 50.7%), Social Security System (SS) (199 patients, 18.5%), and Civil Service Reimbursement (CS) (332 patients, 62.6%). The one-year mortality rates in these groups were 10.57%, 4.21%, and 6.47%, respectively (p=0.010). In the unadjusted model, the SS group showed a lower risk of one-year mortality rate (HR 0.38, 95% CI 0.18-0.80, p=0.011), and the CS group also demonstrated a lower risk (HR 0.59, 95% CI 0.35-0.99, p=0.047) compared to the UC group. In the adjusted model, only the CS group significantly reduced the risk of one-year mortality. Other factors that affected one-year mortality were age ≥65 years, a Killip score of 3-4, pre-discharge prescription of angiotensin-converting enzyme inhibitors, occlusion in the left anterior descending artery, and pericardial effusion.

Conclusion

Healthcare schemes play a significant role in influencing one-year mortality rates among STEMI patients treated with pPCI. The use of civil service reimbursement is a protective factor for the one-year mortality rate in STEMI patients. This information would be crucial for developing strategies and programs to aid healthcare policymakers at both regional and international levels in reducing morbidity and mortality.
Real world economic evaluation of CT-FFR in patients with suspected coronary artery disease
Authors: Becker L M , Peper J , Dijksman L , Leiner T , Swaans M J
Published: October 2024

Background

Incorporation of CT-derived fractional flow reserve (CT-FFR) enhances the precision of Coronary CT Angiography (CCTA) to detect hemodynamically significant coronary artery disease (CAD). However, the financial consequences remain unclear.

Purpose

Our objective is to assess the economic implications of CT-FFR in the Dutch Healthcare system.

Methods

This retrospective, single-center cost effectiveness analysis includes patient data of a previously published study assessing the impact of routine CT-FFR availability on clinical management. We collected medical resource use for both diagnostic and therapeutic cardiovascular care with a follow-up duration of 1 year. Costs of CT-FFR analysis were set at €1000, its current price for Dutch hospitals. Median total costs at were compared using the Wilcoxon rank sum test, including a sensitivity analysis in which cost estimations (without registered maximum tariffs) were increased or decreased with 10%.

Results

A total of 360 patients, classified as having low to intermediate risk of CAD, were enrolled in the study – 224 in the CCTA group and 136 in the CT-FFR group. In addition to undergoing more (invasive) diagnostic testing and revascularization procedures over the studied period, patients in the CCTA-group had more outpatient clinic consultations (p<0.001), presented more frequently to the emergency department (p=0.035) and spend more nights in the hospital (p=0.11).

Median costs were €3.347 (IQR €1.066 – €4.862) in the CCTA-group and €1.436 (IQR €1.362 - €3.943) in the CT-FFR group (p=0.091). Increasing cost estimation with 10% revealed a median of €3.431 in the CCTA-group versus €1.479 in the CT-FFR group (p=0.078), decreasing with 10% showed median costs of €3.263 in the CCTA-group and €1.392 in the CT-FFR group (p=0.118). In our sample, CT-FFR guided care would have been significantly cheaper than CCTA-guided care at or below a market price of €770.

Conclusion

Despite the significant reduction in additional diagnostic testing and hospital visits in the CT-FFR group, CT-FFR guided care was not cheaper than CCTA-guided care at its current market price of €1.000. Economic cost-effectiveness would have occurred from a price of €770 per analysis. The large difference between medians suggests that the lack of significance might partially be attributed to insufficient power in this relatively small sample size. Additionally, this study did not account for costs associated with loss of productivity and quality of life.

However, less additional diagnostic testing, less revascularization procedures and less hospital consultations and admissions leads to reduction in hospital resource consumption and patient burden, which is an important advantage of CT-FFR as the number of referred patients increases yearly.
Analyzing the economic ramifications of the broad implementation of generic prasugrel
Authors: Gerardo F , Santos M , Faria D , Nedio M , Monteiro C , Baptista S , Mateus C , Passos M , Miranda I , Lopes J , Fialho I , Farto E. Abreu P , Morais C
Published: October 2024

Introduction

The 2023 European Acute Coronary Syndrome (ACS) guidelines state that prasugrel (PRG) should be considered in preference to ticagrelor (TCG) in patients (pts) who proceed to percutaneous coronary angioplasty (PCI). In Portugal, PRG is less available due to earlier evidence considering pretreatment and contraindications for each drug. PRG (10mg) is currently a generic drug, while TCG is not. We aimed to evaluate the proportion of pts that could be switched from TCG to PRG, and the economic impact of a widespread national adoption.

Methods

To determine eligibility for generic PRG 10mg, we examined a single center prospective database of consecutive ACS pts undergoing PCI in a full year. Eligibility for TCG and PRG was based on drug specific contraindications, previous stroke for PRG and chronic liver disease (CLD) for TCG, and indication for PRG dose reduction (≤60 kg and ≥75 years). To estimate hospital costs we used the price per pill indicated by the pharmacy (0.98€ TCG, 0.67€ PRG). To obtain post-discharge and NHS savings we used the INFARMED public information. We estimated 3500 PCIs per year on a national level, based on published data.

Results

A total of 780 pts were included, median age 68±10.4years, 523 (67.1%) were male, 51.9% (n=406) had non-ST elevation ACS. Mean admission time was 8.36 days. Considering PRG and TCG contraindications, 157 pts (20.3%) had a previous history of stroke and 20pts (2.6%) had CLD. 150 pts (19.2%) had PRG dose reduction criteria. Eligible for PRG 10mg and TCG 90mg were 434 pts (57.8% of total PCI pts). Cost per admission would be 33 697.35€ for TCG and 17 617.28€ for PRG. At a national level, hospital costs can be reduced by 16080.07€. Considering the 1-year outpatient setting and a widespread generic PRG 10mg adoption, NHS savings are estimated in 898 323.59€, and patient savings in 401248.25€ (198.38€ per patient).

Conclusions

ACS pts in real-world scenarios exhibit both eligibility for PRG and TCG. Considering the lower cost, the NHS can potentially save 914 403,66€ (figure 1) annually through the widespread adoption of generic PRG 10mg.
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

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<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

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

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

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

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

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 <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

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 (<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<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<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

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 < 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 < 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 < 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

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) >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>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
Semaglutide modulates adipogenic differentiation and extracellular acidification in epicardial (EAT) and subcutaneous (SAT) adipose tissue stromal cells from patients with cardiovascular disease
Authors: Basdas R , Sanchez-Lopez D , Nunez Caamano J R , Al-Rubaye S , Fu X , Martinez-Cereijo J M , Fernandez A L , Reija L , Gonzalez-Juanatey J R , Eiras S
Published: October 2024

Backround

Cardiovascular disease (CVD) is the main cause of death in the world. One of the known risk factors is the epicardial fat (EAT) accumulation, which is around the myocardium and coronaries playing a paracrine role over them. Although mature and functional adipocytes are involved in energy balance and glucose metabolism, the hypertrophic state increases the production of fatty acid binding protein 4 (FABP4), which is a pro-inflammatory adipokine, with consequences on extracellular acidification. Recent data shows that glucagon-like peptide receptor agonists 1 (GLP1ra) drug improves the insulin response and reduces EAT thickness. Although GLP1ra has a direct effect on hypothalamus for reducing food intake, this drug might play a direct role on adipogenesis process in this fat stromal cells.

Purpose

Our study aims to demonstrate the effect of semaglutide on adipogenesis and metabolism in epicardial and subcutaneous stromal cells from patients with cardiovascular disease.

Methods

The study was approved by the Galician Research Ethics Committee, and subcutaneous adipose tissue (SAT) and EAT samples from 17 patients were obtained undergoing open-heart surgery with informed consent. Stromal cells from biopsies were isolated and cultured. Adipogenesis was induced for 15 days with or without 1 nM semaglutide, given by Novo-Nordisk (Bagsværd, Denmark), using an adipogenesis cocktail. Cells were lysed and RNA was isolated for RT-qPCR. Target genes were amplified for Glucagon like peptide 1- receptor (GLP1R), differentiation, adipogenesis, glucose metabolism and cellular markers. Extracellular acidification rate was measured with glycolytic rate assay on Seahorse. Lipids accumulation was tested by AdipoRed staining.

Results

Stromal cells from both tissues express GLP1R but higher differentiation factor (PGC1α) was detected in SAT compared to EAT (p=0.02), as well as adipogenesis induction. After semaglutide treatment, we observed a downregulation of FABP4 and GLUT1 in EAT (p=0.01 and p=0.02, respectively). Despite FABP4 was not modulated on SAT, there was a reduction of PGC1α levels. (p=0.02). Since glitazones upregulate PGC1α, which is used for adipogenesis induction, these results might suggest the counteract mechanism of semaglutide. The metabolism assay showed that semaglutide reduces extracellular acidification rate in EAT cells (p=0.04) and oxidative glycolysis with semaglutide treatment (p=0.003) but not in SAT cells.

Conclusions

Semaglutide reduces adipogenesis, through modulation of PGC1α transcription factor in EAT from patients with cardiovascular disease and extracellular acidification and oxidative glycolysis. These results might help to understand one of the mechanisms associated with EAT reduction in patients with semaglutide treatment.
Skeletal myocyte-specific knockout of Ptpn1 and Ptpn2 enhances inflammatory response in muscle and increases mortality in polymicrobial sepsis
Authors: Brinschwitz B , Wulfert C , Stein V , Kappert K , Fielitz J
Published: October 2024

Background

Critically ill patients often suffer from heart and skeletal muscle atrophy and failure (intensive care unit acquired weakness; ICUAW). Inflammation and sepsis are major risk factors for ICUAW. Critically ill patients with sepsis frequently develop insulin resistance that decreases protein synthesis and increases protein degradation in muscle eventually leading to ICUAW. The link between inflammation and insulin resistance is not well understood, but protein tyrosine phosphatases (PTP), that inhibit insulin signaling via insulin receptor (INSR) dephosphorylation as well as inflammation-associated pathways, are implicated.

Hypothesis: We hypothesized that PTP1B and TC-PTP mediate inflammation-induced insulin resistance and muscle atrophy in heart and skeletal muscle.

Methods and Results

qRT-PCR analyses showed that the proinflammatory cytokines tumor necrosis factor (TNF), interleukin (IL)-1β, and IL-6 caused a ~2-fold increase in Ptpn1/PTP1B and Ptpn2/TC-PTP mRNA expression in C2C12 myocytes as well as in neonatal rat ventricular cardiomyocytes. Inhibition of the IL-6/GP130 pathway by siRNA and inhibitors in myocytes in vitro and skeletal muscle specific gp130 knockout mice in vivo attenuated IL-6-induced Ptpn1/PTP1B and Ptpn2/TC-PTP mRNA expression. CLP-induced polymicrobial sepsis was associated with a significant increase in gene expression and protein content of pro-inflammatory cytokines (Tnf, Il1b, Ifng) and leukocyte markers (CD68, CD11c, F4/80) in muscle of skeletal myocyte specific double knockout (Ptpn1+Ptpn2loxP/loxP, MCK cre, dKO) compared to wildtype (Ptpn1+Ptpn2loxP/loxP) mice in sepsis. This also resulted in a lower survival rate of dKO mice in sepsis (42% WT vs. 23% dKO). Immunohistological analyses revealed centralized nuclei, macrophage/monocyte infiltration and enhanced regeneration (Myh3, Pax7, Ki67) in tibialis anterior muscle of septic dKO mice. A strong activation of the NLRP3-inflammasome, as indicated by cleavage of caspase 1, GSDMD, GSDME and caspase 8, indicative for a pronounced inflammation and activated cell death pathways was observed in muscle of septic dKO mice.

Conclusion

The proinflammatory cytokine IL-6 increases the expression of Ptpn1 and Ptpn2 and enhances overall PTP activity. Selective inhibition of the IL-6R/GP130 signaling pathway by JAK2- and STAT3-inhibition as well as Gp130 deletion in myocytes in vivo attenuates those effects. Muscle-specific deletion of Ptpn1 and Ptpn2 in skeletal muscle leads to increased mortality, enhanced pro-inflammatory response and induced inflammatory, programmed cell death pathways in sepsis. Our data show that Ptpn1 and Ptpn2 play a key anti-inflammatory role in skeletal muscle.
Human macrophages are immunnoprofiled by pericardial fluid small extracellular vesicles modulating lipid metabolism mechanisms
Authors: Ben-Aicha S , Anwar A , Martino F , Kyriazis P , Sattler S , Punjabi P , Emanueli C
Published: October 2024

Background

Coronary artery disease (CAD) is the main cause of myocardial infarction and consequent ischemic heart disease (IHD). Macrophages are central to CAD. Small extracellular vesicles (sEVs) can shuttle microRNAs and other molecular cargos from cell to cell, mediating response in target cells. Recent evidence supports the sEVs role in modulating macrophage phenotype. The pericardial fluid (PF) contains sEVs and immune cells including cavity-like macrophages.

Purpose

This study investigates whether PF-sEVs regulate macrophages, contributing to a specific immunophenotype in CAD patients.

Methods

PF was collected from CAD patients undergoing coronary bypass surgery (CABG) and non-atherosclerotic patients operated for mitral valve repair (control group). sEVs were isolated and characterised for size (Nanosight tracking analysi), tetrasapanin content (Nanoview chips) and microRNA content (RNA seq analysis). Monocytes from healthy donors were isolated from buffy coats and differentiated into macrophages following established protocols. Macrophages were incubated with either CAD-sEVs or non-CAD sEVs for 24h at 37oC. The cells were collected and processed for mRNA analyses (qRT-PCR) and flow cytometry. Further bioinformatics were employed to understand functional pathways targeted by PF-sEVs-miRNA.

Results

In line with the human-PF macrophages profile, exposure to CAD-sEVs reduces the anti-inflammatory profile of human macrophages. CAD-sEVs treated macrophages showed a CCR2-, CD36+low, CD206+low profile. While non-CAD-sEVs did not statistically differ from PBS nor untouched groups, CAD-sEVs increased the mRNA level of IL1a, IL1b, TNFa and decreased MRC1. Bioinformatic analysis showed that 861 miRNAs were decreased in the PF-sEVs from CAD patients compared to non-CAD. miRNA targets prediction and pathway analyses reported that clusters of PF-miRNAs could regulate CD36, decreased in PF-macrophages.

Conclusions

We demonstrate, that sEVs isolated from PF-CAD reduce the anti-inflammatory profile of human macrophages, and target crucial lipid metabolism pathways. These clinically relevant results could drive to decipher improved therapeutics to modulate the epicardial/myocardial immune response in CAD patients.
Synthetic torpor confers cardioprotection against myocardial ischaemia/reperfusion injury in the rat
Authors: Ali Khan M , Taddei L , Elley M , Wilcox R , Pickering A , Ambler M
Published: October 2024

Introduction

Torpor is a hypothermic, bradycardic, hypometabolic state enabling animals, such as mice, to survive in unfavourable environmental conditions such as cold exposure or reduced food availability. It is thought to be a cardioprotective state. There is interest in developing models that mimic aspects of torpor in clinical settings such as ischaemia-reperfusion injury. The preoptic area of the hypothalamus (POA) has emerged as a key centre for triggering torpor in the mouse.

Purpose

Induce a synthetic torpor-like state in a species that does not naturally enter torpor (the rat) by chemoactivation of neurons in the POA that correspond to those that induce torpor in the mouse. Test the cardioprotective effects of synthetic torpor in the Langendorff ischaemia-reperfusion preparation.

Methods

Designer receptors exclusively activated by designer drugs (DREADDs) were used to exogenously activate excitatory neurons in the POA of the rat hypothalamus. Viral vectors (pAAV-CaMKIIa-hM3D(Gq)-mCherry) were stereotaxically injected bilaterally into the POA under ketamine and medetomidine anaesthesia, resulting in expression of DREADDs in excitatory neurons. Control animals received a vector delivering the gene for a fluorescent protein only. DREADD receptors in transfected neurons were activated by subsequent injection of Clozapine-N-Oxide (CNO, 2mg/kg IP), which results in neuronal activation and induces synthetic torpor. Heart rate and core temperature were monitored using implanted telemeters. 2 weeks after vector injection, animals were anaesthetised using 5% isoflurane and culled by cervical dislocation. Hearts were excised and ex-vivo whole heart perfusion at 37°C was performed using the Langendorff apparatus. Hearts were subjected to 30 minutes of global warm ischaemia followed by 60 minutes of reperfusion. Hearts were stained using tetrazolium triphenyl chloride, and infarct size as a proportion of the total heart area calculated.

Results

Chemoactivation of rat POA neurons induced synthetic torpor characterised by bradycardia (pre: 341.0 ± 17.73bpm, post: 233.4 ± 20.47bpm, paired t (4) = 5.4791, p = .0054) and hypothermia (36.2 ±0.40°C vs 31.6 ± 0.55°C (paired t (4) = 7.9023, p = .0014). CNO had no effect on heart rate or core temperature in control animals. The mean infarct size was significantly lower in synthetic torpor (21.54 ±2.84%) compared to control hearts (29.62 ±2.59%) (unpaired t (23) = 2.1054, p = .0464).

Conclusions

Synthetic torpor, induced centrally in a species for which torpor is not a natural behaviour, confers striking cardioprotection in an ex-vivo ischaemia-reperfusion model. This novel approach to cardioprotection against myocardial ischaemia/reperfusion injury should be further investigated as a potential therapeutic target for use in clinical practice.
The impedance drop early after energy delivery predicts steam pops during radiofrequency ablation
Authors: Takahashi S , Mine T , Miki T , Nakai M , Yoshikawa F , Takai K , Takada M , Fujita K , Nishibori M , Maruyama T , Ishihara M
Published: October 2024

Background

Steam pops during radiofrequency ablation (RFA) can cause serious complications. However, predictive factors for steam pops remain unclear.

Purpose

To investigate predictors for steam pops.

Methods

An in vitro experiment was performed using fresh bovine left ventricular myocardium. A myocardium cut into 4-5 cm slabs was fixed at the bottom of a constant temperature bath with temperature adjusted to 36.5 degrees Celsius, and a non-pulsatile flow rate of 5 L/min was generated. Using the catheter with a laser-cut 8Fr4.0mm flexible tip, RFA was applied at 30W, 60 seconds, perpendicular catheter placement to the tissue at various contact forces (5, 10, 20, 30, 40, 50g). A total of 138 lesions were created by applying RFA 23 times at each setting. Lesion depth and width were measured after RFA.

Results

Steam pops were observed in 49 of 138 lesions (36%). The higher impedance decrease in the first 5 seconds (-21.0±11.0Ω vs. -7.6±8.5Ω, P<0.0001), the larger impedance drop from initial to minimum impedance (if steam pop occurred, minimum impedance before steam pop was applied) (-28.9±13.0Ω vs. -13.1±12.9Ω, P<0.0001), higher initial impedance (132±48Ω vs. 87±38Ω, P<0.0001), power regulation by temperature control (44.9% vs 4.5%, P<0.0001), higher contact force (31.2±14.9g vs. 22.9±15.9g, P=0.0030), larger LSI (6.8±2.1 vs. 7.5±1.8, P=0.0037) were associated with steam pops. In multivariate analysis, the high impedance drops in the first 5 seconds (OR 2.0 for each 5Ω increase, 95%CI 1.0-1.3; P=0.033) and the power regulation by temperature control (OR 7.3, 95%CI 2.2-29.9; P=0.001) were independently related. In ROC curve analysis of the impedance drops in the first 5 seconds, an optimal cut-off value of steam pops was 8.0Ω (AUC 0.85, sensitivity 88%, specificity 73%) (figure 1). Steam pops were predicted with a sensitivity of 45% and specificity of 97% using both the impedance drop ≥ 8.0Ω in the first 5 seconds and power regulation by temperature control. Lesion depth and width were associated with total impedance reduction in lesions with an impedance drop < 8.0Ω during the first 5 seconds (R²=0.14, P=0.0012 with depth, R²=0.21, P<0.0001 with width), while were not associated with in lesions with an impedance drop ≥ 8.0Ω (figure 2).

Conclusion

The impedance drop early after RF energy delivery may predict steam pops during RFA.
Protective role of Metrnl on macrophage recruitment during the acute inflammatory phase in a mouse model of myocardial infarction
Authors: Ferrer-Curriu G , Soler-Botija C , Monguio-Tortajada M , Poblador F , Navarro Gascon A , Blasco Roset A , Villarroya F , Galvez-Monton C , Roura S , Bayes-Genis A , Planavila A
Published: October 2024

Introduction

Meteorin-like protein (Metrnl) is a cytokine involved in the attenuation of inflammation. Previously, a cardioprotective role of Metrnl against cardiac hypertrophy and ischemia/reperfusion has been described. After myocardial infarction (MI), macrophages recruited from the spleen, and their capacity to shift from inflammatory (M1) to reparative (M2) phases determines the fate of cardiac repair.

Purpose

The aim of this study was to analyse the function of Metrnl in a mouse model of permanent MI during the acute inflammatory phase.

Methods

Wild-type (WT), Metrnl Knock-out (Metrnl-/-) and Metrnl-reconstituted Metrnl-/- mice (AAV9-Metrnl, with myocardial-specific tropism) were subjected to MI by coronary artery ligation. After 4 days, cardiac function was assessed using echocardiography at baseline and 4 days post-MI. Monocyte populations were analysed in spleen and blood by flow cytometry, and macrophages infiltrating the infarcted myocardium by gene expression analyses.

Results

Echocardiographic analysis demonstrated that Metrnl deficiency led to cardiac dysfunction (FAC p=0.02) accompanied by myocardial dilation 4 days post-MI (EDV p=0.02; ESV p=0.01). On the contrary, the overexpression of Metrnl in the myocardium of AVV9-Metrnl mice restored cardiac function compared to Metrnl-/- group (FAC p=0.01, EDV p=0.04, ESV p=0.09). Furthermore, we observed a reduction in splenic monocytes (CD11b+F4/80+) in Metrnl-/- mice compared to the WT group at 4 days post-MI (p=0.06). In particular, a significant decrease in pro-inflammatory Ly6CHigh and CD86+ monocytes was noted in the spleens of Metrnl-/- mice compared to the WT group (p=0.03; p=0.04 respectively), suggesting their mobilization out of the spleen, but not in the AVV9-Metrnl group. Although the total number of Ly6CHigh and Ly6CLow monocytes in the bloodstream was similar in all groups, there was a trend to different expression in the CCR2 and CCR5 chemokine receptors (p=0.07; p=0.06 respectively). At the same time, M1 macrophage recruitment chemokines (CCL2) and inflammatory markers (TNFα) were significantly induced in the ischemic area of the infarcted myocardium compared to the remote zone in the WT and Metrnl-/- groups (CCL2 p=0.03; p=0.01 respectively; TNFα p=0.008;p=0.04 respectively). In contrast, TNFα and CCL2 genes were not induced in the ischemic area of AVV9-Metrnl mice. Regarding M2 macrophages, the Arg1 marker was significantly reduced in the ischemic zone of Metrnl-/- mice compared to the WT group (p= 0.01), while in the AVV9-Metrnl group was recovered (p= 0.04).

Conclusions

Our results demonstrate that the absence of Metrnl promotes the recruitment of inflammatory macrophages to the ischemic myocardium and is associated to cardiac dysfunction.