There are numerous differences in arrhythmia propensity and cardiac electrophysiology between women and men. One proposed reason is differences in the autonomic nervous system (ANS) activity. We therefore compared the sympathetic and parasympathetic influence (sympatho-vagal balance) on the sinoatrial node (SAN) at rest in healthy young women (n=15) and men (n=15) with a mean age of 24 years. Pharmacological blockade of the ANS activity on the SAN was induced by sequential bolus injections of atropine (0.04 mg per kg b.w) and propranolol (0.2mg per kg b.w.) during continuous electrocardiographic recordings. The heart rate (HR) at baseline, after atropine, and the intrinsic HR (IHR) after adding propranolol were used to calculate the accelerator "m" which is ≥1.00 and decelerator "n" which is ≤1.00 according to the Rosenblueth & Simeone concept and equation: HR=m*n*IHR. On the group level IHR was median (IQR) 93.3 (88.4-98.8) beats per min, m was 1.16 (1.13-1.22), n was 0.58 (0.55-0.64), and the sympatho-vagal balance m*n was 0.70 (0.65-0.76), confirming dominant parasympathetic influence at rest. There were no significant differences between women and men in any of these measures, and thus no fundamental difference in the ANS influence on the main impulse generator of the heart at rest. This result contrasts to the significant differences in electrophysiological measures at rest and their responses to stress tests, as well as to the differences in arrhythmia propensity between women and men on both the atrial and ventricular level of the heart.

Cardiac glycosides (CG) like ouabain exert positive inotropic effects by inhibiting the Na+-K+-ATPase. CGs wide spread use is limited by CGs narrow therapeutic window. Mis- or overdosing with CGs may cause cardiac arrhythmias, resulting from electrolyte disturbances. To study the ethically challenging topic of CG overdosing, we here optimized the in ovo platform to test, if treatment with the selective ouabain antagonist rostafuroxin prevents CG-mediated electrophysiological derangements and arrhythmia by restoring electrolyte homeostasis. We employed incubated chicken eggs (iCEs), a 3R-compliant model, for which we established Electrocardiograms (ECGs). ECGs were recorded under i) baseline conditions, ii) after treatment with ouabain and iii) after co-treatment with rostafuroxin. Underlying mechanisms of ouabain and rostafuroxin effects were studied using blood gas analysis and fluorescence microscopy. Isolated murine and human cardiomyocytes served as an independent model to confirm in ovo results. Ouabain treatment resulted in increased heart rate variability (HRV), transient sinus arrest, and atrio-ventricular dyssynchrony, accompanied by plasma hyperkalemia and cardiomyocyte Na+ overload. Co-treatment of ouabain and rostafuroxin led to reduced HRV and ameliorated the frequency and duration of transient sinus arrest, while plasma K+ levels remained unchanged. In isolated cardiomyocytes, ouabain treatment induced intracellular Na+ overload which was abolished by additional rostafuroxin treatment. Our work demonstrates the in ovo platform and corresponding readouts as a suitable tool to study cardiac electrophysiology in a 3R compliant manner. We found, that rostafuroxin treatment ameliorated ouabain-induced electrophysiological disturbances, suggesting rostafuroxin as a potential therapeutic intervention for ouabain mis- or overdosing.

Ion channels of the human heart: A comprehensive four-chamber analysis.

Electronic cigarettes (e-cigs) have rapidly gained popularity in the past 20 years. However, the health impacts of their use remain unclear. E-cigs generate aerosols by heating e-liquids containing solvent vehicles, nicotine, additives, and flavorant chemicals. This process not only aerosolizes the liquid ingredients but also generates a complex mixture of by-products, many of which are harmful. Recent studies have demonstrated that inhaling e-cig aerosols can disrupt cardiac electrophysiology and rhythm as well as autonomic regulation of the heart. Furthermore, recent and historical observations indicate that many individual e-cig constituents, such as nicotine, aldehydes, flavorants, polycyclic aromatic hydrocarbons, metals, and carbon monoxide, can impair cardiac electrophysiology and rhythmicity. Although it remains largely unclear which constituents pose the greatest harm, a growing body of in vivo animal experiments, in vitro studies, and clinical studies collectively indicate that e-cigs adversely alter electrophysiology and thus may increase risk for severe and fatal arrhythmias. Nonetheless, more studies are needed to determine how these effects translate to e-cig users and relate to specific constituent compounds. Here, we summarize the existing science detailing how e-cig aerosols and their individual constituents disturb cardiac electrophysiology and promote arrhythmia. Although direct evidence that e-cigs cause arrhythmias in humans remains elusive, research continues to advance the biological plausibility of a causal relationship between e-cig use and life-threatening disruptions in cardiac electrophysiology.

Selectivity Filter Mutation in NaV1.5 Promotes Ventricular Tachycardia.

TorchCor: High-performance cardiac electrophysiology simulations with the finite element method on GPUs

Mathematical modeling in systems toxicology enables a comprehensive understanding of the effects of pharmaceutical substances on cardiac health. However, the complexity of these models limits their widespread application in early drug discovery. In this article, we introduce a novel approach to solving parameterized models of cardiac action potentials (CAPs) by combining meta-learning techniques with systems biology-informed neural networks (SBINNs). The proposed method, hyperSBINN, effectively addresses the challenge of predicting the effects of various compounds at different concentrations on CAPs, outperforming traditional differential equation solvers in speed. Our model efficiently handles scenarios with limited data and complex parameterized differential equations. The hyperSBINN model demonstrates robust performance in predicting APD90 values, indicating its potential as a reliable tool for modeling cardiac electrophysiology and aiding in preclinical drug development. This framework represents an advancement in computational modeling, offering a scalable and efficient solution for simulating and understanding complex biological systems.

Cardiac electrophysiology and ECG basics

Background: Bites from spiders of the genus Loxosceles, popularly known as the brown recluse spider, can cause a syndrome called loxoscelism, which is classified into cutaneous and viscerocutaneous forms. The cutaneous form, which is more common, causes the development of a necrotizing lesion with gravitational spread at the bite site. The viscerocutaneous form, which is rarer, includes systemic symptoms such as intravascular hemolysis, thrombocytopenia, and acute kidney injury, which can lead to death. However, clinical reports suggest a potential cardiotoxic role of Loxosceles venom, although this has been little studied. It should be noted that phospholipase-D is the main toxin present in the venom and has been implicated as the factor responsible for the development of cardiac dysfunction. Given this context, the present study sought to deepen the understanding of the effects of L. intermedia spider venom on the hearts of guinea pigs, using a detailed approach involving cardiac biomarkers, electrocardiograms, and histopathological analysis through optical and electron microscopy. Materials, Methods & Results: Eighteen male guinea pigs (Cavia porcellus) weighing 600 g were used. Of these, 16 animals received intradermal injections of Loxosceles intermedia venom at doses ranging from 11.6 to 350 μg diluted in 0.5 mL of 0.9% saline, and 2 animals received only 0.5 mL of 0.9% saline, serving as controls. Cardiac function was assessed by serial electrocardiograms and by measuring serum cardiac biomarkers, such as creatine kinase (CK) and its MB fraction (CK-MB), lactate dehydrogenase (LDH), troponin I (TnI), N-terminal fragment of B-type natriuretic peptide (NT-ProBNP) and D-dimer at 24 and 72 h post-injection. After 72 h, the animals were euthanized for histopathological and ultrastructural analysis of cardiac tissue using optical and transmission electron microscopy. Survival time varied inversely with the venom dose. Electrocardiograms recorded before envenomation showed no abnormalities. However, after Loxosceles envenomation, ECG changes were observed, including cardiac arrhythmias such as junctional beats and supraventricular extrasystoles, paired ventricular extrasystoles associated with isolated junctional beats, isolated junctional beats and atrioventricular block, junctional arrhythmia, and isolated atrial extrasystole. Elevated CK, CK-MB, LDH, and TnI levels were observed. Histopathological changes included diffuse cardiac congestion and focal hemorrhage, while ultrastructural analysis revealed autophagic vacuoles and mitochondrial damage in cardiac fibers. Discussion: This research was the 1st to conduct a clinical study on systemic loxoscelism and its cardiovascular impacts. The data obtained demonstrate that loxoscelism envenomation can cause significant cardiac and biochemical alterations, with rapidly manifesting effects, such as atrial and ventricular premature beats. Atrial premature beats result from early atrial ectopic beats, and ventricular premature beats present as beats originating early in the ventricle, with a post-extrasystolic pause. In envenomations, ventricular premature beats are associated with damage to cardiac muscle fibers due to myotoxic activity and impaired perfusion of cardiac tissue. Junctional beats, which are early ectopic beats originating in the atrioventricular junction, were also observed. Therefore, these results indicate that loxoscelism venom can directly interfere with cardiac electrophysiology, causing conduction disturbances and arrhythmias. Furthermore, the venom was capable of generating histological lesions consistent with myocardial damage that may also indirectly contribute to impaired cardiac function through mechanisms such as hypoxia and hemorrhages. Keywords: Loxosceles intermedia, loxoscelism, cardiotoxicity, cardiac biomarkers, electrocardiogram.

Increasing Awareness and Reducing Occupational Hazards in the Cardiac Catheterization and Electrophysiology Laboratories

BackgroundThe cardiac isoform of phosphofructokinase-2/fructose 2,6-bisphosphatase (PFKFB2) is the heart’s strongest glycolytic regulator but is degraded in the absence of insulin signaling. This makes PFKFB2 loss critical to understand in metabolic heart disease, of which impaired insulin signaling is a hallmark. Prolongation of the QT interval, risk of arrhythmia, and sudden cardiac death are also augmented in metabolic heart disease, raising a question as to whether potential crosstalk between glycolytic dysregulation and electrophysiological dysfunction exists.MethodsWe therefore assessed the impact of PFKFB2 loss on cardiac electrophysiology using a cardiomyocyte-specific PFKFB2 knockout mouse model (cKO) and litter-matched controls (CON). To do so, we employed electrocardiography in the fed state and following 12 hours of fasting, examining physiology both at baseline and in the presence of an acute stimulant stress. To further investigate the arrhythmia mechanism, we used patch-clamp electrophysiology and IonOptix Ca2+transient measurements in ventricular cardiomyocytes isolated from CON and cKO hearts.ResultsThe hearts of cKO mice exhibited prolonged repolarization, marked by QT and action potential duration prolongations. This occurred with impaired Ca2+reuptake and increased spontaneous Ca2+release events in ventricular cardiomyocytes. Ultimately, these changes culminated in ventricular tachyarrhythmia in cKO mice, which was enhanced in the fed relative to the fasted state.ConclusionThese data suggest that in the presence of sufficient glucose availability, cardiac glycolytic dysregulation at the phosphofructokinase nexus is sufficient to promote cardiac electrophysiological instability.Clinical PerspectiveWhat is Known:Metabolic heart diseases, such as heart failure with preserved ejection fraction and diabetic cardiomyopathy, are associated with heightened risks of arrhythmogenesis and sudden cardiac death.What the Study Adds:Here, we show for the first time that PFKFB2 is decreased in human hearts with heart failure with preserved ejection fraction.Furthermore, we show that loss of cardiac PFKFB2 is sufficient to promote impaired ventricular repolarization at baseline and ventricular tachyarrhythmia upon stress test.This identifies PFKFB2 stabilization and activation as key potential targets in conferring electrophysiological stability in metabolic heart disease.

Background: Heart rhythm disturbances remain a serious problem in modern cardiology. Traditional pacemakers have certain limitations including invasiveness, risk of infection, mechanical complications, and a limited service life. Advances in bioengineering and optogenetics technologies offers new prospects for the production of minimally invasive, biocompatible, and controllable cardiac pacing systems. The combination of cell therapy and optogenetics enables to create a photo-controlled biological pacemaker, free from the key drawbacks of traditional devices. Objective: The aim of this study was to produce photosensitive cellular patches and to further investigate their functionality as an optogenetic tissue-engineered pacemaker in an ex vivo rat heart model. Methods: We engineered a cell-based construct using either human cardiomyocytes derived from induced pluripotent stem cells or neonatal rat cardiomyocytes expressing channelrhodopsin-2. These cells were seeded onto fibrous scaffolds made of poly-L-lactic acid and collagen, coated with fibronectin. The testing model was an isolated, temporarily maintained ex vivo rat heart. Optical mapping of calcium activity was used to record cardiac electrophysiology. Results: Functional coupling between the implanted patch and the host myocardium was observed 35 minutes after implantation. Photostimulation reliably increased the heart rate, which was confirmed by stochastic dominance analysis. The experiments in vitro on cell cultures demonstrated the operational capacity of channelrhodopsin-2 upon illumination with 470 nm light. Conclusion: This study successfully demonstrates a complete technology cycle, from the genetic modification of cells to the control of contractions in a whole organ. It represents a significant step towards developing targeted and safe methods for future temporary cardiac pacing. Our results confirm the fundamental feasibility of a hybrid optogenetic approach and lay the groundwork for further research into creating safe, controllable, and biocompatible next-generation pacemaker systems.

ABSTRACTEpigenetic modulators such as histone deacetylases (HDACs) and histone acetyltransferases (HATs) are known master regulators of gene expression that substantially impact cardiac electrophysiology. Novel pharmacological agents, HDAC inhibitors, are rapidly emerging as treatments for cancer and immune diseases, and their effects on cardiac ion channels (ICs) are of great interest. We used small interfering RNAs to individually suppress each of the known HDACs, including sirtuins (SIRTs), in human induced pluripotent stem-cell-derived cardiomyocytes (hiPSC-CMs), iCell2. Follow-up deep-sequencing allowed comparison to identically processed and normalized RNA sequencing data from adult human left ventricle (LV) from the GTEx database. The transcriptomics analysis revealed high similarity of gene expression patterns for cardiac ICs (with some differences in calcium influx and calcium buffering related genes), as well as strong co-regulation by cardiac transcription factors (TFs) andHDACs/SIRTsin both hiPSC-CMs and the adult LV. Partial least square regression models helped visualize links between HDACs/HATs, TFs, and cardiac ICs and helped identify potential key regulators of cardiac IC transcription. Powerful TFs, includingMEF2A, GATA4, 6exerted positive effect on IC genes whileRUNX1andSHMT2were distinct negative regulators in both sample types;TRIM28was found to serve opposite roles in the two sample types. In functional measurements,HDACsuppression primarily increased excitability, whileSIRTsuppression decreased excitability, in line with transcriptomic links. Our analysis offers insights about the role of epigenetic modifiers in regulating cardiac electrophysiology and informs the utility of hiPSC-CM as a scalable experimental model for cardiotoxicity testing of HDAC inhibitors.

BackgroundDrug-induced QT interval prolongation remains a leading indicator of proarrhythmic risk and a major challenge in cardiac safety pharmacology. While regulatory guidelines (ICH S7B/E14) call for improved non-clinical methods [2], mechanistic in silico models offer a powerful yet underused tool for early safety evaluation.PurposeThis work aims to present an AI-enhanced framework that integrates high-fidelity electrophysiology simulations with machine-learning–based emulators to assess drug-induced QT prolongation in a sex-specific manner.MethodsSex-specific virtual populations were generated using 3D finite-element cardiac electrophysiology models [1], simulating drug effects via a multi-channel pore-block model across key ion currents. From these simulations, pseudo-ECGs were extracted to quantify QT changes. To enable rapid risk evaluation, we developed Gaussian Process Regression emulators trained on over 900 3D simulations [3]. These emulators allow real-time predictions of QT prolongation with uncertainty quantification, achieving mean absolute errors below 4 ms.ResultsAs a proof of concept, we applied this framework to loperamide, a drug associated with abuse-related cardiotoxicity. The emulators were used to explore a wide concentration range beyond therapeutic exposure, identifying thresholds of arrhythmic risk across male and female profiles. Figure 1 illustrates the relationship between total concentration and QT prolongation (ΔQT), highlighting sex-specific risk thresholds and arrhythmic outcomes.ConclusionsThis case study demonstrates how AI-driven emulators can extend the reach of mechanistic models to high-throughput safety assessment, even in scenarios that would be unethical or infeasible to test clinically. This framework supports more efficient and comprehensive drug safety evaluations.Predicted ΔQT under loperamide effect

BackgroundObstructive hypertrophic cardiomyopathy (oHCM) is characterised by pronounced myocardial hypercontractility, hypertrophy and myofibrillar disarray. Approximately a third of patients demonstrate dynamic left ventricular outflow tract (LVOT) obstruction due to systolic anterior motion of the mitral valve with septal contact and associated mitral regurgitation. Recent clinical advances include cardiac myosin inhibitors, which reduce myocardial contractility and alleviate the LVOT pressure gradient. Despite these advances, personalised predictive models remain lacking for treatment planning in oHCM.PurposeThis study evaluates a computational Virtual Human Trial framework for predicting haemodynamic responses in oHCM, specifically examining whether a patient-specific 3D-0D electromechanical model of the heart and circulation can reproduce the clinically observed reduction in the LV-aortic pressure gradient (Δp) following pharmacologically induced contractility reduction.MethodsA patient-derived cardiac anatomy was reconstructed from high-resolution CMR to model a representative oHCM case with ventricular hypertrophy, myocardial fiber disarray, LVOT narrowing, and mitral regurgitation. The fully coupled electromechanical model (3D finite-element cardiac simulation coupled to a 0D closed-loop lumped-parameter systemic and pulmonary circulatory model) simulated cardiac electrophysiology, tissue mechanics, and circulation. Simulations were performed for three conditions: a healthy control, the untreated oHCM case, and a treated oHCM state with a 50% reduction in myocardial contractility, simulating the effect of myosin inhibitor therapy.ResultsThe oHCM simulation exhibited elevated peak left ventricular systolic pressure (approximately 150 mmHg), regurgitant flow through the mitral valve, reduced stroke volume and ejection fraction, and a significant LV-aortic pressure gradient (Δp ≈ 67 mmHg) during systole, reflecting LVOT obstruction. In the treated state, the model captured a marked reduction in Δp. These findings qualitatively align with reported clinical effects of myosin inhibitor therapy, which similarly decreases the LV-aortic pressure gradient by reducing contractile force.ConclusionsThis patient-specific computational framework successfully replicated key haemodynamic features of oHCM and predicted the reduction in LV-aortic pressure gradient following contractility reduction. The approach is being extended to a cohort of six patients with pre- and post-treatment imaging to validate model predictions against clinical data. Future simulations will explore individual responses under varying degrees of contractility reduction, with a view to supporting personalised therapy planning in oHCM.Pipeline to build the cardiac modelSimulation results

Existing bioelectronics often exhibit megapascal-scale moduli, despite the mechanosensitive nature of cardiomyocytes. Bridging the mechanical mismatch between tissue and bioelectronics is indispensable for building physiologically relevant in vitro cardiac models and advancing therapies. Here, we present Pliable Ultrathin Layered Sensing Electronics (PULSE), a platform with tissue-matched modulus (~10 kilopascals) and stretchable gold microcircuitry for long-term, high-fidelity monitoring of cardiac electrophysiology in vitro. Composed of a soft gel matrix and an ultrathin nanofilm embedded with gold circuits, our device achieves unprecedented tissue integration and preserves natural cardiomyocyte mechanics, resulting in a 140% increase in mechanical contraction and a 100% increase in electrical signals compared to conventional electronics. Cardiac tissue that grows our device exhibited enhanced drug sensitivity and response in cardiac dysfunction, revolutionizing disease modeling. By facilitating seamless interaction at the tissue-electronic interface, our platform offers a transformative perspective for advancing cardiac modeling and next-generation bioelectronic applications.

When patients with an implantable cardioverter-defibrillator (ICD) near the end-of-life (EOL), shock therapy from the device can cause unnecessary suffering. Professional guidelines recommend timely discussions on the shock deactivation option with ICD recipients. At the project site, many older patients with serious illnesses have shock therapy active in their ICDs. This project aimed to improve ICD recipients' knowledge, attitudes, and decision making regarding EOL device management options by providing guideline-recommended patient education. Single-site, quality improvement project employing pre/post survey design among ICD recipients in the outpatient setting. The Experiences, Attitudes, and Knowledge of End-of-Life Issues in ICD Questionnaire was used for the survey. The key intervention was a structured patient education session (SPES) in the device clinic led by a cardiac electrophysiology nurse practitioner. Of the 90 participants, 94.4% were ≥60 years old and 95.6% were males. After the SPES, the responses to all ICD knowledge items showed significant positive differences based on the McNemar test significance (p ≤ .001). Responses to five attitude items on EOL ICD discussions/actions also showed significant positive changes after the education with McNemar Test significance <.05. A SPES in the device clinic improved patients' ICD knowledge and attitude toward shock deactivation at EOL. Further work is required to assess the long-term impacts.

A novel numerical method for solving time-fractional models in cardiac electrophysiology

Respecting patient wishes regarding resuscitation is fundamental to providing patient-centered care. Despite best practice guidelines for code status management for patients undergoing invasive procedures with existing Do Not Resuscitate (DNR) orders, compliance is low. Our interdisciplinary team created a workflow for code status management of inpatients with active DNR orders undergoing cardiac catheterization (CC) or electrophysiology (EP) procedures. Representatives from nursing, cardiology, surgery, palliative care, internal medicine, and information technology (IT) were involved. We used the workflow for 32 inpatients to temporarily rescind DNR orders for cardiology procedures. Average patient age was 76.6years. Code status discussion was documented preprocedurally for 78% of patients; however, the documenting clinician varied. Over one third (37.5%) of cases were done with the primary goal of extending the patient's life. Four patients died during the same hospitalization as the procedure. The workflow was well received by stakeholders who appreciated the efficiency and clarity of the process. Interdisciplinary collaboration with key stakeholders and IT support were integral to the success of this intervention.

Analysis of the diagnostic value of pre-event intracardiac electrogram (pre-EGM) storage function in cardiac electronic implantable devices for arrhythmia diagnosis.