bluuebunny/crossref_metadata_2025_split huggingface dataset:
Electrical auricular tragus stimulation induces release of circulating cardioprotective factors in healthy human volunteers
Authors: Lieder H R , Paket U , Skyschally A , Kleinbongard P , Heusch G 
Published: November 2023

Abstract

Background
Vagal activation during remote ischemic conditioning (RIC) with subsequent release of cardioprotective factors from the spleen into the circulation reduces infarct size. These humoral cardioprotective factors can be transferred with plasma-dialysate from human donors undergoing RIC to isolated recipient hearts where they reduce infarct size. Electrical auricular tragus stimulation (ATS) has been demonstrated to reduce the release of cardiac injury biomarkers and ventricular arrhythmias and to improve contractile function in patients with acute myocardial infarction.

Purpose
To determine whether ATS, as RIC, induces release of cardioprotective factors into the circulation.

Methods
Healthy volunteers (3 females, 7 males, 26±5 years) were randomized to receive ATS or RIC, respectively, with an interval of at least two weeks between protocols. ATS was induced by bipolar electrical rectangular pulses of 200 µs width and a frequency of 30 Hz. The amplitude (5.5 ± 0.81 mA) was set for each volunteer to not be perceived as uncomfortable. A microprocessor-controlled circuit periodically interrupted the stimulation signal after 5 s of stimulation for 5 s. ATS was continued over 30 min. RIC served as a reference to induce the release of cardioprotective factors by 3 x 5 min blood pressure cuff inflation at 200 mmHg on the left upper arm/ 5 min deflation. Venous blood samples were taken before and 60 min after ATS or RIC, respectively, and used to prepare plasma-dialysates (1:10 dialysis against buffer for 24 h, cut-off 12-14 kDa). Male Lewis rats were sacrificed and their hearts isolated and perfused at constant pressure with buffer. Plasma-dialysates from samples taken before and 60 min after ATS or RIC, respectively, were infused for 8 min into rat hearts followed by 2 min washout before global 30 min ischemia/ 120 min reperfusion. Infarct size was demarcated by triphenyl tetrazolium chloride staining and calculated as percent of ventricular mass.

Results
With infusion of plasma-dialysate before ATS, infarct size was 30.9 ± 4.5% of ventricular mass and not different from that with infusion of plasma-dialysate before RIC (35.8 ± 5.8 %). Infusion of plasma-dialysate after ATS reduced infarct size to 18.3 ± 3.9 %. This cardioprotective effect was similar to that seen with infusion of plasma-dialysate after RIC (20.1 ± 3.5 %).

Conclusion
ATS induces the release of cardioprotective factors into the circulation of healthy volunteers. Plasma-dialysates after ATS or RIC, respectively, reduce myocardial infarct size by the same magnitude in ex vivo isolated perfused rat hearts with global ischemia/ reperfusion.
Enhancing autophagic flux via FYCO1 confers protection against adverse cardiac remodeling in response to myocardial ischemia
Authors: Senger F , Remes A , Tannert C , Schmiedel N , Mueller O , Kuhn C , Frey N 
Published: November 2023

Abstract

Background
Dysregulation of autophagy is known to have detrimental effects on cardiac function. Yet, the autophagy-lysosome pathway in the context of ischemia is still widely unexplored. Fyco1 is highly expressed in the heart and facilitates transport of autophagosomes in cardiomyocytes, thereby enhancing global autophagic flux.

Purpose
The purpose of our study was to study the potentially beneficial effects of activation of autophagy via FYCO1 on cardiac remodeling post myocardial infarction.

Methods
FYCO1-Tg mice were crossbred with RFP-EGFP-LC3-Tg reporter mice (FYCO1-TGxRGFP) to enable analysis of autophagic flux in vivo using confocal microscopy. Myocardial ischemia was induced by permanent ligation of left anterior descending artery (LAD). Mice were analyzed 3 and 30 days post LAD ligation. Cardiac function (ejection fraction, EF) was measured by echocardiography. Fibrosis and Infarct size (%) were assessed in Masson’s Trichrome staining. Autophagy activity was analysed by Western blot for p62 and LC3 II. Furthermore, Evans blue/TTC staining was performed to assess the area at risk and to define perfused, ischemic and necrotic area post LAD ligation.

Results
Under conditions of FYCO1 overexpression isolated cardiomyocytes were capable to remain a status of activated autophagy in hypoxia; presented with significantly increased protein levels of p62 (ctrl: 1±0,02; OE: 3,1±0,4) and LC3 II (ctrl: 1±0,05; OE: 5,5±0,4). In FYCO1-TGxRGFP mice we observed an overall increased autophagic flux demonstrated by significantly increased p62 expression (WT LAD: 2,9±0,4; TG LAD:4,0±0,5) and LC3 II protein levels (WT LAD: 1,6±0,2; TG LAD:14,0±1,4) post LAD ligation. While WT mice revealed accumulation of autolysosomes 30 days post LAD ligation as assessed by confocal microscopy (WT autophagosomes: 1±0,4; WT autolysosomes: 38,6±3,8), in FYCO1-TGxRGFP mice the ratio between autophagosomes and autolysosomes remained even (TG autophagosomes:43,3±5,1; TG autolysosomes: 73,5±12,4), suggesting preservation of adequate autophagic flux. In Evans blue/TTC staining, FYCO1-TGxRGFP mice demonstrated comparable ischemic but a markedly decreased necrotic area (ischemic: 1,9±1,8%; necrotic: 37,1±11,5%) of the LV as compared to WT (ischemic: 2,1±1,9%; necrotic: 53,4±31,4%). Fibrosis (WT: 19,6±1,8%; TG: 10,6±1,6%) and infarct size (WT: 34,5 ±3,9%; TG: 5,5±2%) was found significantly decreased in FYCO1-TGxRGFP-mice. Importantly, global heart function of FYCO1-TGxRGFP-mice was significantly improved post LAD compared to WT (EF WT: 36,7±6,3%; TG: 46,3±18,3%).

Conclusion
Our study demonstrates that activation of autophagy via FYCO1 protects against accumulation of autolysosomes and therefore protects against adverse cardiac remodeling and improves cardiac function post myocardial ischemia. These findings may offer translational potential in enhancing autophagic flux in the context of myocardial ischemia.
Treatment with empagliflozin improves cardiac function in infarcted animals associated with increased baroreflex sensitivity
Authors: Da Silva B , Nascimento-Carvalho B , De Souza L I , Da Silva M B , Marques J R , Dourado P M M , Consolim-Colombo F , Irigoyen M C C 
Published: November 2023

Abstract

Background
Several clinical and experimental studies have shown an improvement in cardiac function in infarcted patients and animals (diabetic or not) when treated with empagliflozin, as well as an improvement in outcomes in patients with heart failure with reduced ejection fraction or with preserved ejection fraction.
Hypothesis: Treatment with empagliflozin for 14 days (10 mg/kg) improves cardiac function in infarcted rats, secondary to increased baroreflex sensitivity.

Methods
Wistar rats were divided into 2 groups: AMI - acute myocardial infarction (n=8) and AMI+EMPA - acute myocardial infarction + Empagliflozin (n=8). The animals in both groups were anesthetized and submitted to thoracotomy and ligature of the left coronary artery. The animals in the AMI+EMPA group received daily, through oral gavage, 10 mg/kg of empagliflozin, for 14 days. After this period, an echocardiographic examination was performed, followed by cannulation of the femoral vein and artery, to assess hemodynamic parameters and baroreflex activity. The results were evaluated for normality. Data were compared by Student's t tests. And the relationship between the parameters was tested by Pearson's correlation. Results are presented as mean and standard deviation.

Results
In the echocardiographic evaluation, an improvement in diastolic function indexes was observed in the AMI+EMPA group in relation to the AMI group: E'/A' ratio (1.584 ± 0.437 vs 0.589 ± 0.129), E/E' ratio (14.11 ± 3.946 vs 29.92 ± 6.878) and systolic function: SF (29.30% ± 7.974 vs 19.20% ± 2.445), EF (53.86% ± 11.78 vs 37.91% ± 4.212), FAC (39.31% ± 7.135 vs 23.51 ± 3.940).
There was a reduction in mean blood pressure in the AMI+EMPA group (102.4 mmHg ± 6,408) compared to the AMI group (110.7 mmHg ± 8,514) and in diastolic blood pressure (84.4 mmHg ± 3.889 vs 92.8 mmHg ± 7.664).
In the assessment of baroreflex sensitivity, an improvement in tachy and bradycardic indexes was observed in the treated animals: tachycardic index (5.021 bpm/mmHg ± 0.346 vs 3.214 bpm/mmHg ± 0.418) and bradycardic index (1.569 bpm/mmHg ± 0.148 vs 0.73 bpm/ mmHg ± 0.046). In addition, the systolic function expressed by the FAC was positively associated with the reflex tachycardic index (p: 0.008; r: 0.616) and to the E'/A' ratio (p: 0.025; r: 0.576) and negatively with PAD (p: 0.040; r: -0.503).

Conclusion
Treatment with Empagliflozin in infarcted rats was able to improve left ventricular systolic and diastolic function associated with improved performance of arterial baroreceptors.
Glu298Asp variant of endothelial nitric oxide synthase gene and acute or early presentation of coronary artery disease: An updated systematic review and meta-analysis
Authors: Rai H , Fitzgerald S , Coughlan J J , Spence M , Colleran R , Joner M , Byrne R A 
Published: November 2023

Abstract

Background
Several published reports have attested the association of Glu298Asp polymorphism (rs1799983) residing in the endothelial nitric oxide synthase (NOS3) gene with lower levels of circulating nitric oxide as well as coronary artery disease (CAD). However, its association status with acute or early presentation of CAD such as acute/sub-acute myocardial infarction, acute coronary syndrome, premature CAD and unstable angina is still unclear.

Purpose
Against this background, we conducted an updated systematic review and a study level meta-analysis to assess the association of NOS3 Glu298Asp polymorphism with acute or early CAD.

Methods
A comprehensive online search to identify relevant studies and sub-studies was performed on several databases including PubMed, EMBASE, MEDLINE, Scopus, Cochrane library and Web of Science and later stratified into two ancestral subgroups: ‘European ancestry’ and ‘All other ancestries combined’. Study level odds ratios (ORs) and their 95% confidence intervals (CI) were pooled using random effects employing a Z test.

Results
Out of a total of 193 distinct records identified through online search, 36 articles with 38 different studies, with a total sample of 27,244 (11,444 cases / 15,800 controls) were included for quantitative synthesis. (Figure 1.) Pooled results suggested significant associations of NOS3 Glu298Asp polymorphism with acute or early CAD through dominant as well as allelic genetic models (p≤0.004), driven by the ‘All other ancestries combined’ subgroup. Our ‘All other ancestries combined’ subgroup demonstrated an additional risk of 36% and 37% for acute or early CAD, through dominant and allelic genetic models respectively (OR= 1.36, 95%CI= 1.12, 1.65, p= 0.002 and OR= 1.37, 95%CI= 1.14, 1.64, p= 0.0007 respectively). On the other hand, the European ancestry subgroup failed to show any meaningful associations. Sensitivity analysis (Figure 2.) and a substudy for myocardial infarction endpoint further attested our observed associations.

Conclusions
Our present meta-analysis indicates the association of NOS3 Glu298Asp polymorphism with acute or early presentation of CAD, predominantly driven by ‘All other ancestries combined’ subgroup. In contrast, ‘European ancestry’ subgroup does not demonstrate any significant association. Further large-scale investigations are required to confirm our derived results.Figure 1.Figure 2.
Upregulation of mitochondrial fusion as potential cardioprotective strategies against trastuzumab-induced cardiotoxicity in rats
Authors: Maneechote C , Khuanjing T , Ongnok B , Arinno A , Prathumsap N , Chunchai T , Arunsak B , Kerdphoo S , Chattipakorn S C , Chattipakorn N 
Published: November 2023

Abstract

Background
Trastuzumab (TRZ) is a commonly used chemotherapeutic drug for treating advanced malignancies that express human epidermal growth factor receptor type 2. However, TRZ has been linked with cardiotoxicity, which is an unfavourable clinical side effect of cancer treatment. Alterations in mitochondrial dynamic mechanisms, particularly reduced fusion, have been shown to be a key mechanistic insight into the progression of chemotherapy-induced cardiotoxicity. Despite the cardioprotective benefits of a mitochondrial fusion promoter (M1) that have been established in various cardiovascular settings, its ability to counteract the cardiotoxicity caused by TRZ remains unknown.

Purpose
To examine the effect of M1 treatment on mitochondrial fusion, myocardial oxidative stress, apoptosis, and cardiac injury biomarker in TRZ-induced cardiotoxicity rats.

Methods
Male Wistar rats (n=18) were divided into the TRZ group (4 mg/kg/day for 7 days, I.P., n=12) and the control group (CON, n=6). In the TRZ group, at the time of first TRZ injection all rats also received the intervention with either the vehicle injection (VEH, n=6) or M1 (M1, 2 mg/kg/day, n=6) via I.P. injection for 7 days. The left ventricular ejection fraction (LVEF) was measured using echocardiography, and troponin-I levels were determined using blood serum. Then, the cardiac tissue was processed to assess the levels of malondialdehyde (MDA) for oxidative stress, mitochondrial fusion, and apoptotic proteins.

Results
TRZ induced cardiotoxicity via downregulation of mitochondrial fusion along with upregulation of myocardial oxidative stress and apoptosis, as indicated by decreasing Mfn1 protein expression and increasing the levels of MDA and Bax to Bcl-2 ratio, respectively (Fig. 1A, B, C, and E). TRZ also showed markedly higher levels of serum Troponin-I (Fig. 1D) and impaired LV function (77% LVEF for TRZ vs. 89% LVEF for CON). M1 co-treatment promoted Mfn1-mediated mitochondrial fusion, resulting in a reduction in MDA-associated oxidative stress, apoptosis, Troponin-I, and cardiac dysfunction (16% improvement over the TRZ group) (Fig. 1A-E).

Conclusion
M1 effectively protected the heart against TRZ-induced cardiotoxicity by promoting mitochondrial fusion and preventing oxidative stress and apoptosis-mediated myocardial injury. These findings suggest that the pharmacological promotion of mitochondrial fusion could be a novel anti-cardiotoxicity strategy in TRZ-induced cardiotoxicity.
Overexpression of cardiac calsequestrin as a novel gene-therapy approach to treat CPVT1: in silico and in vivo proves of principle
Authors: Santiago Castillo D , Bongianino R , Trancuccio A , Kukavica D , Tarifa C , Denegri M , Mazzanti A , Priori S G 
Published: November 2023

Abstract

Background
More than 200 gain-of-function mutations in the cardiac ryanodine receptor (RyR2) cause catecholaminergic polymorphic ventricular tachycardia type 1 (CPVT1). From a molecular point of view, 3 types of mutations exist [1]: Class 1 mutants enhance RyR2 opening in response to sarcoplasmic reticulum (SR) free Ca2+; Class 2 and Class 3 mutants enhance RyR2 opening in response to both cytosolic and SR free Ca2+.

Purpose
The study's objective was to evaluate in silico and in vivo, in CPVT1 knock-in mice carriers of the Class 1 mutation RyR2(R4496C/+), whether overexpression of cardiac calsequestrin (CASQ2) rescues the arrhythmic phenotype in CPVT1 mice.
Rationale: Several studies performed in the 2000’s have collectively demonstrated that an increase in CASQ2 promotes the closure of RyR2 channels [2]: inspired by this evidence, here we test the hypothesis that CASQ2 gene therapy might be a novel treatment for CPVT1.

Methods
(1) In silico study: Properties of Class 1 and Class 2 RyR2s mutants (Figure, panels A-C) were introduced into an in silico model of the murine ventricular myocyte [3]. Virtual myocytes were paced either at baseline or during simulated delivery of 100 nM Isoproterenol at 1 Hz for 180 seconds. To simulate CASQ2 overexpression, protein levels were progressively increased, and the changes in the arrhythmic burden were documented.
(2) In vivo study (performed in compliance with ethical regulations): an adeno-associated viral vector containing the cDNA sequence of CASQ2 was injected into RyR2(R4496C/+) mice (tail iv, 3×10^13 vg/kg) at 4 weeks of age. Eight weeks post-infection, animals were treated with an ip bolus of caffeine (120mg/kg) and epinephrine (2 mg/kg) to elicit arrhythmias (Epi/Caff Test).

Results
(1) In silico: dose-response curves were simulated to correlate CASQ2 levels with arrhythmia inducibility during virtual Isoproterenol delivery. For the simulated prototypical Class 1 mutation, 1.4-fold CASQ2 expression suppressed arrhythmias. For the prototypical Class 2 mutation, 1.8-fold CASQ2 expression was needed (Figure, panel D).
(2) In vivo: At 12 weeks of age, both RyR2(R4496C/+) treated and non-treated littermates received the ip Epi / Caff bolus. Arrhythmias were observed in 17/32 (53%) untreated mice and in 0/12 treated animals (p=0.0012).

Conclusion(s)
We provide proof-of-principle demonstrating that in mice, the overexpression of CASQ2 may be a powerful and safe therapeutic strategy for CPVT1.
Smart-device ECGs and inconclusive results: impact of ECG anomalies
Authors: Weidlich S , Mannhart D , Serban T , Krisai P , Knecht S , Du Fay De Lavallaz J , Schaer B , Osswald S , Kuehne M , Sticherling C , Badertscher P 
Published: November 2023

Abstract

Background
Evermore smart-devices are capable of recording single-lead (SL) electrocardiograms (ECGs). Each recording comes with an automated rhythm interpretation usually consisting of sinus rhythm (SR), atrial fibrillation (AF) or inconclusive. The impact of common ECG anomalies possibly leading to an inconclusive interpretation by the devices algorithm is largely unknown.

Purpose
to assess the impact of baseline ECG anomalies on automated smart-device rhythm classification.

Methods
In this prospective study, consecutive hospitalized patients undergoing electrophysiological procedures in a tertiary referral center were included. Each participant obtained a 12-lead ECG followed by SL-ECGs with 5 different smart-devices (AliveCor KardiaMobile, Apple Watch 6, Fitbit Sense, Samsung Galaxy Watch3 and Withings ScanWatch). The smart-device generated rhythm determination was compared to manual interpretation. ECG anomalies were assessed by 2 independent cardiologists and included atrial Flutter (AFlut), pacing and conduction delay consisting of AV-block or left/right bundle branch block, artifacts and ectopy. Inconclusive tracings were labelled false-positive if the goldstandard was SR in the 12-lead ECG and false-negative if the goldstandard was AF in the 12-lead ECG. Relative Risk (RR) for anomalies to result as inconclusive diagnosis by the smart-device was calculated.

Results
245 participants were included (34% female, mean age 64±13 years) resulting in a total of 1’165 recorded SL-ECGs. Among these, 247 SL-ECGs (21%) were labeled as inconclusive by at least one smart-device (Figure 1). Overall, 834 ECG anomalies were present. 169 inconclusive SL-ECGs were labelled false-positive with 192 anomalies present. Among these, 34 (18%) had ventricular pacing, RR 2.9 (CI 2.2-3.8), 52 (27%) showed conduction delay, RR 1.5 (CI 1.1-2), 44 (23 %) had ectopy, RR 2.3 (CI 1.7-3), and 62 (32%) some sort of artifacts, RR 1.9 (CI 1.5-2.5). Among 78 inconclusive SL-ECGs with false-negative results, 84 anomalies were present. 18 (21%) were in AFlut, RR 1.5 (CI 0.94-2.3), 12 (14%) had ventricular pacing RR, 4.2 (CI 3.1-5.6), 14 (17%) showed conduction delay, RR 1.3 (CI 0.8-2.1), 9 (11%) had ectopy, RR 0.99 (CI 0.54-1.8), and 31 (37%) some sort of artifacts, RR 1.7 (CI 1.2-2.5). There were no differences between assessed smart-devices.

Conclusion
Underlying ECG anomalies are common in inconclusive SL-ECGs and impact automated rhythm classification.Figure 1
Betaine therapy of cardiac hypertrophy through inhibition of Hydroxy-carboxylic Acid Receptor 1 signaling
Authors: Fan M , Yao L 
Published: November 2023

Abstract

Background
Hydroxy-carboxylic Acid Receptor 1 (HCAR1), formerly known as G protein-coupled Receptor 81 (GPR81), is a cell membrane receptor for lactate, and essential for activation of a variety of intracellular signaling pathways. We found a correlation between the activation of lactate-HCAR1 signaling and occurrence of cardiac hypertrophy. However, the regulatory mechanism remains unclear.

Purpose
Our purpose is to investigate the regulatory mechanism between the activation of lactate-HCAR1 signaling and occurrence of cardiac hypertrophy.

Methods
Neonatal rat cardiomyocytes (NRCMs) were used for preparing cardiac hypertrophy model in vitro by phenylephrine (PE) stimulation, and C57 BL/6 mice were used for preparing pressure overloaded-induced cardiac hypertrophy model in vivo by TAC (transverse aortic constriction) surgery. Adenovirus containing shRNA-HCAR1 (ADV-shHCAR1) were constructed to knockdown HCAR1 in NRCMs. Binding interaction between HCAR1 and Betaine was predicted by AUTODOCK 4 and further validated with RNA-seq analysis.

Results
Lactate concentration and HCAR1 expression were both increased in the NRCMs upon PE treatment. Activation of HCAR1 by its agonist 3-Chloro-5-hydroxybenzoic acid (3Cl-HBA) specially induced hypertrophy in NRCMs. Furthermore, the hypertrophy phenotypes in NRCMs showed alleviation by transfection of ADV-shHCAR1. An AI-based molecule-docking screening analysis identified Betaine as a potential molecule to bind HCAR1. Treatment with Betaine significantly attenuated PE- or 3Cl-HBA- induced hypertrophy in NRCMs in vitro. In addition, Betaine administration of TAC mice (i.g. 50 mg/kg/day) for 4 weeks in vivo led to increase of ejection fraction (EF) and decreases of left ventricular (LV) posterior wall thickness, heart weight/tibia length ((HW/TL), cross-sectional area and cardiac fibrosis area as well. RNA-seq analysis and functional assays demonstrated that Betaine could bind to HCAR1, activated Hippo signaling pathway, and thereby blocked the HCAR1-mediated hypertrophy in cardiomyocytes.

Conclusions
In summary, the current study not only identified HCAR1 as a therapeutic target of cardiac hypertrophy, but also demonstrated Betaine as a therapeutic candidate molecule holding potential to benefit cardiac hypertrophy patients.