bluuebunny/crossref_metadata_2025_split huggingface dataset:
A novel technology for heart failure that utilizes the respiratory effort to shift fluids from the lung and alleviate cardiac workloads; feasibility study in sheep
Authors: Landesberg A , Livneh A , Shofti R , Amir O 
Published: November 2023

Abstract

Introduction
Hemodynamic congestion is governed by inflow from RV and drainage through LV. However, ventricle functions are affected by the intrathoracic/pleural pressure: Negative pleural pressure (PPL) increases RV outflow while decreasing LV outflow, and vice versa at high PPL. Cardiac decompensation is associated with an increase in the respiratory effort (the peak-to-peak changes in PPL). We suggest to utilize this respiratory effort to shift fluid out of the lung and alleviate hemodynamic congestion. It is done by pacing the heart when PPL is high and the LV stroke volume is larger than the RV stroke volume.

Purpose
To test the feasibility of the novel technology in sheep. To verify that it is possible to modify the distribution of the heart beat within the respiratory cycle (slightly modify the rhythm according to the PPL) with insignificant effect on mean heart rate.

Methods
The utility was validated in sheep (N=9), under spontaneous breathing before and after induction of acute infarction by balloon inflation in the mid-LAD artery. The device senses the intracardiac electrical activity and respiratory effort and paces the right atrium when the PPL is high. The R-R interval of the paced beats was shorter than the sinus R-R interval by less than 10%. The effects of PPL and device pacing on LV and RV stroke-volumes were derived from simultaneous measurements of RV and LV pressure-volume loops, utilizing two impedance catheters (CD-Leycom) within both ventricles.

Results
The respiratory effort had significant effects on RV and LV outputs before and after infarction. The stroke volumes of the two ventricles were in antiphase! At low PPL the RV output increased while the LV decreased by about 10%, and the opposite occurred at high PPL. The pacing increased cardiac beating probability at high PPL. Sequential pacing for one minute increased the systolic pressure by 5 mmHg while decreasing the pulmonary artery pressure. Based on the pressure-volume loops, each paced breath cycle increased the LV outflow by 1.14 ml and decreased RV outflow by 0.36ml, yielding a shift of 1.5 ml from the lung. Interestingly, it was associated with a decrease in the sinus rate, which further decreased cardiac beating at low PPL and may represent a decrease in sympathetic tone.

Conclusions
Pacing only 1% of the ∼20,000 daily breath-cycles can shift 300 ml from the lung per day! The technology is agnostic of the heart-failure etiology. Preclinical studies in a model of chronic heart failure are required to further validate the novel approach.
Impaired cardiac BCAA catabolism associated with impaired myocardial efficiency during exercise in a porcine model with multiple risk factors
Authors: Zandbergen L , Van Dijk C G M , Sen P , Sorop O , Van Drie R W A , Shashikadze B , Frohlich T , Verhaar M C , Cheng C , Duncker D J , Merkus D 
Published: November 2023

Abstract

Background
Diabetes mellitus (DM), chronic kidney disease (CKD) and consumption of a high-fat diet (HFD), are well known risk factors for diastolic heart failure. We recently developed a multiple comorbidity swine model (MCS), with DM (streptozotocin), HFD and CKD (kidney embolization), and showed that 6 months of sustained hyperglycemia, hypercholesterolemia and kidney dysfunction resulted in inflammation and oxidative stress associated with coronary microvascular dysfunction and left ventricular diastolic dysfunction. Additionally, MCS animals showed impaired myocardial efficiency during exercise as demonstrated by increased myocardial oxygen consumption (Fig. A), suggesting an impairment in myocardial mitochondrial function.

Purpose
Here we used a combined omics (single nuclei RNA sequencing and proteomics) approach to study the molecular pathways involved in mitochondrial dysfunction.

Methods
15 MCS and 10 healthy control female swine were included in the study. Proteome analysis and single nuclei RNA sequencing, was performed on frozen left ventricle myocardial samples.

Results
Proteome analysis of MCS hearts showed reduced expression of branched-chain amino acid (BCAA) catabolism proteins (Fig. B), most notably BCAT2, MCCC1 and MCCC2. Single nuclei RNA sequencing of a subgroup of the same animals demonstrated a downregulation of these genes specifically in cardiomyocyte subpopulations. Besides being a source of ATP, via oxidative phosphorylation in mitochondria, BCAAs, encompassing essential amino acids (leucine, valine and isoleucine), act as signaling molecules. Thus, increased BCAA levels reduce insulin sensitivity, modulate mitochondrial substrate utilization and impair mitochondrial function, resulting in increased mitochondrial production of reactive oxygen species (ROS). These findings are consistent with our data in the MCS swine indicating that impaired BCAA metabolism was found in the myocardium of animals with comorbidities and were associated with increased ROS levels (8-isoprostane 12.9±0.8 pg/mg protein in MCS vs 10.3±0.5 in healthy animals, P=0.02 by T-test) and impaired myocardial efficiency during exercise (Fig. A).

Conclusion
Taken together, these findings suggest an essential role of altered BCAA cardiomyocyte metabolism resulting in mitochondrial dysfunction, increased oxidative stress and subsequent alterations in the myocardial function.Fig.
Assessment of global and segmental strain in heterozygous APE1/Ref-1 transgenic mice using cardiac magnetic resonance imaging
Authors: An S Y , Kim S M , Lee E O , Jeon B H 
Published: November 2023

Abstract

Background
Apurinic/apyrimidinic-endonuclease1(APE1/Ref-1) is a redox factor necessary for DNA binding and transcription regulator in ROS generation. The association between APE1/Ref-1 and heart failure(HF) has been observed in previous studies. Heterozygous APE1/Ref-1 transgenic mice displayed endothelial cell dysfunction with systemic hypertension. Global strain(GS) measures the myocardium's deformation along its axis and is known to be a sensitive marker of subclinical HF in hypertensive patients with preserved ejection fraction.

Purpose
This study aims to investigate the functional dynamics and GS of the heart in heterozygous APE1/Ref-1 mice to help identify the association between APE1/Ref-1 and early signs of HF and translate to clinical applications.

Methods
A study was conducted to assess the functional parameters of both the left ventricle(LV) and right ventricle (RV) and perform LV global and segmental strain analysis using cardiac magnetic resonance imaging(CMR) in heterozygous APE1/Ref-1 transgenic mice(n=4) and wild type mice (n=4) of age 10-12 weeks. A 7T CMR scanner and FSE T1 sequence were used to acquire short-axis views of mouse cardiac images. LV and RV functional parameters including ejection fraction(EF), stroke volume(SV), cardiac output, peak filling rate, peak emptying rate and strain indices including global circumferential strain, global radial strain, segmental circumferential strain, and segmental radial strain were calculated with a software dedicated to analyzing CMR images. Global LV and RV function was quantified both manually and using an AI-based algorithm of LV and RV segmentation. The strain analysis was performed using the strain medical image tracking toolbox module. Additionally, reproducibility testing was done to validate the accuracy of AI-driven calculations.

Results
We found that heterozygous APE1/Ref-1 mice displayed a decrease in SV(8.00±0.01ul vs 9.75±0.96ul, p=0.01) and LVEF(58.75±2.63% vs 66.50±2.89%, p=0.007) compared to controls while the functional parameters of RV were similar. Interestingly, the circumferential strain rate of LV was significantly reduced in APE1/Ref-1 mice compared to controls(p&lt;0.001), particularly in the systolic phase. In addition, the study showed that manually-calculated and AI-derived indices were within an acceptable margin of error, rendering the AI system reproducible and reliable in calculating volumetric parameters and strain of the mice's hearts.

Conclusions
This study demonstrated that LV global circumferential strain rate, along with SV and LVEF decreased in heterozygous APE1/Ref-1 transgenic mice. These parameters could serve as markers for assessing early functional changes of mice hearts in a non-invasive manner. Volumetric and strain indices measured by AI-based analysis of mouse CMR images are reproducible parameters for cardiovascular research in small animals.LV strain analysis of mice CMRTable of volumetric parameters
Cardiovascular risk progression into atrial fibrillation tracked with wearables: a report from mAFA II extension cohort
Authors: Guo Y , Lip G Y H 
Published: November 2023

Abstract

Background
Cardiovascular risk, e.g. obstructive sleep apnea (OSA), hypertension, frequent ectopic, are susceptible to atrial fibrillation (AF). Smartwearable-based detection for OSA, ectopics, AF and blood pressure have been tested in mobile health technology supported screening and integrated care for atrial fibrillation (mAFA II programme).

Objective
The present study aimed to investigate the AF occurrence after the cardiovascular risk identified with wearables.

Method
The risk factors which were monitored by wearables are as follows: i) OSA: more than 80% monitoring measures with 15 &lt; apnea-hypopnea index (AHI) &lt; 30 during sleep (intermediate risk）or with AHI ≥ 30 (high risk); ii) ectopics: the proportion of the premature beats among total monitored heart beats: 0.5%-10% among over heart beats (intermediate risk) or &gt;10% premature beat (high risk); iii) High-risk blood pressure (BP): average 24-hour BP &gt;130/80 mm Hg, reverse-dippers of BP, and pulse pressure over 60mmHg. Subjects aged over 18 years old, who used smart watch/wristband (Huawei Technologies Co., Ltd., Shenzhen, China) across China were enrolled into present study analysis between October 26, 2018 to Dec 14, 2022. The first detection AF episode were analyzed since the subjects were identified with high risk for AF, that was, intermediate- or high risk-OSA, high risk-blood pressure, intermediate- or high risk-ectopic by the wearables.

Results
There were 4.37 million subjects (78.6% male, mean age, SD, 37 ± 13 years) involving in the screening programme of mAFA II extension cohort. Among these, 611495 intermediate-risk ectopic, 5037 high-risk ectopic, 43777 intermediate-risk OSA, 22886 high-risk OSA, and 25892 high-risk blood pressure were identified (Figure 1). The rates of progressed into AF from identified cardiovascular risk were as follows: 0.97% (5936/611495) of 611495 intermediate-risk ectopic, 4.80% (242/5037) of high-risk ectopic, 1.09% (478/43777) of intermediate-risk OSA, 1.51% (345/22886) of high-risk OSA, and 1.74% (450/25892) of high-risk blood pressure, respectively.
Subjects identified with high-risk blood pressure were much likely to be early monitored with AF episode than other risk, with time to first AF (median, interquartile) of 10 (3-56) days (p&lt;0.05). However, the above cardiovascular risk was possibly progressed into AF episode during five months.

Conclusion
Smartwearables facilitated the detection of risk factors, OSA, hypertension, frequent ectopic, which might progressed into AF during five months, calling for the effective proactive management on cardiovascular risk to reduce AF burden.Subjects involving in risk screening pro
Cardiac sympathetic hyperinnervation after myocardial infarction: a systematic review and qualitative analysis
Authors: Chen H S , Van Roon L , Schoones J , Zeppenfeld K , Deruiter M C , Jongbloed M R M 
Published: November 2023

Abstract

Background
Cardiac sympathetic hyperinnervation after myocardial infarction (MI) is associated with arrhythmogenesis and sudden cardiac death. The characteristics of cardiac sympathetic hyperinnervation remain largely underexposed.

Objective
To provide a systematic review on cardiac sympathetic hyperinnervation after MI taking into account: 1. Definition, experimental model and quantification method of hyperinnervation, and 2. Location, amount and timing of hyperinnervation, in order to obtain an overview of current knowledge and to expose gaps in literature.

Methods
References on cardiac sympathetic hyperinnervation were screened for inclusion. The included studies received a full-text review, and subsequently a quality appraisal was performed. Relevant data on cardiac sympathetic hyperinnervation were collected and qualitatively analysed.

Results
Our literature search identified 60 eligible studies performed between 2000 and 2022. Cardiac hyperinnervation is generally defined as an increased sympathetic nerve density or increased number of sympathetic nerves compared to another control group (100%). Studies were performed in a multitude of experimental models, but most commonly in male rats with permanent LAD ligation (male: 63%, rat: 68%, permanent ligation: 93%, LAD: 97%). Hyperinnervation seems to occur mainly in the borderzone. Quantification after MI relied on calculating the nerve density in regions of interest in µm2/mm2 (41%) or in percentage of nerve fibers (46%) and the reported amount showed a great variation ranging from 439 to 126718 µm2/mm2. Remarkably, cardiac sympathetic hyperinnervation seems to be present at all timepoints starting from 3 days onwards to &gt;3 months without an evident peak, although studies on structural evaluation over time and in the chronic phase were scarce.

Conclusion
Cardiac sympathetic hyperinnervation occurs already at 3 days after MI mainly in the borderzone and remains present at all timepoints. It is most commonly studied in male rats with permanent LAD ligation. The amount of hyperinnervation differs greatly between studies, possibly due to the differential quantification methods. Further studies are required that evaluate cardiac sympathetic hyperinnervation over time and in the chronic phase, in transmural sections, in the female sex, and in MI with reperfusion.
Factors for incorrect automated atrial fibrillation identification in large-scale screening
Authors: Zink M D , Lueken M , Leonhardt S , Freedman B , Keszei A P , Mischke K , Marx N 
Published: November 2023

Abstract

Introduction
Correct heart rhythm diagnosis in single-lead electrocardiogram (ECG) screening for atrial fibrillation (AF) is paramount for large-scale implementation.

Aim
Examine the accuracy of automated AF detection and identify patient factors and ECG signal quality leading to incorrect measurements based on human overread and a machine learning approach.

Methods
Screening for AF using a single-lead ECG device (MyDiagnostick, Biomedical Systems, Netherlands) was performed on 7295 customers in community pharmacies in Germany. ECG rhythm strips were blinded for automatic heart rhythm analysis and were analyzed by human overread for heart rhythm and signal quality from excellent to uninterpretable (Figure 1A). A machine learning-based estimation was used to score signal quality (MLSQE). Inclusion criteria were 30 seconds of consecutive ECG recording and complete data of pharmacy visit. In total, 6732 participants were eligible for analysis.

Results
An incorrect automated heart rhythm diagnosis was found for 206 subjects (false positive: 112; false negative: 94). By human overread 80% (N=5377) of the recorded ECGs were rated with excellent and good signal quality in which heart rhythm diagnosis based on visible atrial electrical activity (Figure 1A). The proportion of incorrect automated rhythm diagnosis was higher in ECGs with poorer signal quality. A regression analysis revealed patient characteristics prone to incorrect heart rhythm diagnosis included male sex (OR 1.61 95% confidence interval (CI) 1.22-2.13, P&lt;0.001), age (per year OR 1.06 95%CI 1.04-1.09, P&lt;0.001), body height (per cm OR 1.02 95%CI 1.00-1.03, P=0.03), and body weight (per kg OR 0.99 95%CI 0.98-0.99, P=0.005). A multivariate model for prediction of correct heart rhythm diagnosis showed a modest area under the curve (AUC) of 0.65 (sensitivity 61%, specificity 58%; Figure 1B). The prediction improved by adding information on signal quality rated by human overread (AUC 0.77, sensitivity 77%, specificity 62%) and even more by the machine-learning based MLSQE score (AUC 0.87, sensitivity 71%, specificity 90%).

Conclusion
The patient characteristics prone to incorrect automated heart rhythm diagnosis of male sex, older age, greater height, and lower body weight probably reflect the target population of many AF screening cohorts. Automated MLSQE scoring for ECG signal quality could improve accuracy in clinical use and potentially reduces the need for cumbersome and time-consuming human overread.Figure 1A - Signal quality by human rating and proportion of incorrect automated heart rhythm diagnosis. B - Prediction of correct heart rhythm diagnosis. Blue line - Multivariate model with forward selection considering age, height, weight, body mass index, congestive heart failure, hypertension, diabetes mellitus, vascular disease, stroke/TIA and sex. Purple line - Model with human signal quality (SQ) score. Green line – Model with MLSQE score.
Atrial fibrosis and local right atrial inflammation are characteristic of strenuous, but not moderate exercise, and underlie increased AF inducibility in heavily trained rats
Authors: Alcarraz A , Meza-Ramos A , Rubies C , Sanz-De La Garza M , Mont L , Batlle M , Guasch E 
Published: November 2023

Abstract

Introduction
The U-shaped relationship between exercise load and atrial fibrillation (AF) risk, where moderate exercise is protective but strenuous training increases the risk of AF, is currently well accepted (1, 2). Clinical and experimental data suggest that atrial fibrosis and parasympathetic tone (PT) enhancement may underlie the excess risk of AF in endurance athletes (3). Delving into the atrial differences between moderate exercise and strenuous training may be important to understand the pathophysiology of exercise-induced AF.

Purpose
To compare the atrial structural, electrophysiological and molecular remodelling occurring after long-term moderate and strenuous exercise.

Methods
Male Wistar rats were randomly assigned to sedentary (SED), moderate (MOD, 35 cm/s, 45 minutes) or high intensity exercise (INT, 60 cm/s, 60 minutes) for 16 weeks. An electrocardiogram (ECG) and electrophysiological study (EPS) were performed before sacrifice. Left (LA) and right (RA) atrial samples were collected for fibrosis assessment and a mRNA array.

Results
After the exercise protocol, weight of SED rats was higher (486±77 g) compared with both the MOD (377±28 g) and INT groups (385±43 g). In the ECG (Figure 1), INT rats presented a prolonged P-wave compared with SED and MOD. Both trained groups presented with significant bradycardia compared with SED, along with enhanced PT (heart rate variability: low to high frequency ratio). The remaining ECG parameters were similar between groups. Consistent with an enhanced PT, the Wenckebach cycle length was similarly prolonged in both trained groups in the EPS. Conversely, the sinus node recovery time was prolonged in INT rats compared with SED and MOD. AF inducibility increased from SED to MOD to INT. Myocardial fibrosis was measured in atrial samples stained with Sirius red. In both the RA and LA, fibrosis was significantly higher in the INT group (6,3±0.8 %) compared with the SED (4,4±0.2 %) and MOD (4,3±0.5 %) groups. An mRNA array showed large differences between atria. 384 and 419 genes were deregulated between INT and MOD (nominal p&lt;0.05) in the RA and LA, respectively. Only 19 genes were consistent between both atria. In pathway analyses, the inflammatory response pathway was enriched (upregulation) in the RA, but not in the LA, of INT rats compared with MOD (Figure 2).

Conclusions
In healthy rats, strenuous training promoted a differential, pathological remodelling involving atrial fibrosis and sinus node dysfunction, compared with moderate exercise. Local inflammation may play a role in strenuous exercise-induced fibrosis in the RA. PT enhancement was similar in both groups.Figure 1.Figure 2.
Estrogen-induced phenotype in hiPSC-derived cardiomyocytes of a woman affected by both Long QT Syndrome Type 2 and Polycystic Ovary Syndrome
Authors: Bastaroli F , Maniezzi C , Dusi V , Mura M , Lodola F , Zaza A , Gnecchi M 
Published: November 2023

Abstract

Introduction
Long QT Syndrome (LQTS) is an arrhythmogenic disorder caused either by genetic alteration or by exogenous factors. Polycystic Ovary Syndrome (PCOS) is a disease associated with high levels of testosterone and low levels of estrogen (E2). It has been suggested that hormones can influence the occurrence of malignant cardiac events in LQTS type 2 (LQT2) women, carriers of mutations on the potassium channel (hERG). However, the precise mechanisms governing this process still need to be clarified.

Purpose
We studied a patient affected by both LQT2 and PCOS who started experiencing cardiac symptoms after initiation of hormonal replacement therapy. We observed a correlation with the occurrence of arrhythmic events and the irregular assumption of the hormonal replacement therapy, thus we aim to dissect the underlying mechanism in patient-in-a-dish cardiac cellular model.

Methods
Induced Pluripotent Stem Cells (hiPSC) were generated from a woman affected by both LQT2 and PCOS and from a healthy donor, and then differentiated into cardiomyocytes (hiPSC-CMs). hiPSC-CMs were stimulated with E2 10nM for five time points (1, 5, 10, 15 and 30 minutes). The expression of potassium channel hERG, and of the G-coupled estrogen receptor (GPER) regulating the fast non-genomic pathway, were quantified after E2 stimulation at different time points by In Cell Western (ICW). The Unstimulated sample were used to normalize GPER and hERG expression to 100%. Electrophysiological experiments were performed using the whole-cell patch-clamp technique in current-clamp mode to record spontaneous action potentials (APs). AP duration at 30%, 50% and 90% repolarization (APD30, APD50 and APD90) was quantified. During spontaneous activity, AP duration values were rate-corrected with Bazett’s formula, thus obtaining cAPD.

Results
LQT2 hiPSC-CMs express higher levels of GPER (p&lt;0.05) and hERG (p&lt;0.01) than healthy hiPSC-CMs. A significant decrease in GPER expression was detected during 10nM E2 stimulation in healthy cardiomyocytes at the five time points (p&lt;0.0001), while any difference was detected in hERG expression levels. E2 stimulation at different time points did not affect neither GPER nor hERG expression in LQT2 hiPSC-CMs. In LQT2 hiPSC-CMs, APDC values were significantly increased (p&lt;0.0001) compared to healthy cells; pre-incubation with E2 for 10 minutes significantly shortened cAPD50 and increased spontaneous firing rate. In healthy hiPSC-CMs, E2 had no effect.

Conclusions
The hiPSC-CM model reproduces the LQT2 clinical phenotype. cAPD50 shortening by E2 was unexpected based on the proarrhythmic effect in the patient. The mechanism of LQT2-specific effects of E2 are under investigation.