Unveiling the mystery of the female heart's rhythm: a look into gender inequalities in electrophysiology.

This review explores gender disparities in cardiac electrophysiology, highlighting differences in the electrical activity of the heart between men and women. It emphasizes the importance of understanding these variances for correct diagnosis and effective treatment of cardiac arrhythmias. Women show distinct cardiac characteristics influenced by sex hormones, affecting their susceptibility to various arrhythmias. The manuscript covers the classification, mechanisms, and management of arrhythmias in women, considering factors such as pregnancy and menopause. By addressing these gender-specific nuances, it aims to improve healthcare practices and outcomes for female patients with cardiac rhythm disorders.

Esta revisión explora las disparidades de género en la electrofisiología cardiaca, destacando las diferencias en la actividad eléctrica del corazón entre hombres y mujeres. Se enfatiza la importancia de comprender estas variaciones para un diagnóstico correcto y un tratamiento efectivo de las arritmias cardiacas. Las mujeres muestran características cardiacas distintas influenciadas por las hormonas sexuales, lo que afecta su susceptibilidad a diversas arritmias. La revisión abarca la clasificación, los mecanismos y el manejo de las arritmias en las mujeres, considerando factores como el embarazo y la menopausia. Al abordar estos matices específicos de género, el objetivo es mejorar las prácticas de atención médica y los resultados para las pacientes de sexo femenino con trastornos del ritmo cardiaco.

Parallelization of Three Dimensional Cardiac Simulation on GPU.

BACKGROUND: The simulation of electrophysiological cardiac models plays an important role in facilitating the investigation of cardiac behavior under various conditions. However, these simulations often require a lot of computational resources. METHODS: To address this challenge, this study introduced a method for speeding up three-dimensional cardiac simulations using GPU parallelization. A series of optimizations was introduced, encompassing various aspects such as data storage, algorithmic enhancements, and data transfer. RESULTS: The experimental results reveal that the optimized GPU parallel simulations achieve an approximate 50-fold acceleration compared with their CPU serial program. CONCLUSION: This investigation substantiates the considerable potential of GPUs in advancing the field of cardiac electrophysiology simulations.

The Properties of the Transient Outward, Inward Rectifier and Acetylcholine-Sensitive Potassium Currents in Atrial Myocytes from Dogs in Sinus Rhythm and Experimentally Induced Atrial Fibrillation Dog Models.

AIMS: Atrial fibrillation (AF) is the most common chronic/recurrent arrhythmia, which significantly impairs quality of life and increases cardiovascular morbidity and mortality. Therefore, the aim of the present study was to investigate the properties of three repolarizing potassium currents which were shown to contribute to AF-induced electrical remodeling, i.e., the transient outward (Ito), inward rectifier (IK1) and acetylcholine-sensitive (IK,ACh) potassium currents in isolated atrial myocytes obtained from dogs either with sinus rhythm (SR) or following chronic atrial tachypacing (400/min)-induced AF. METHODS: Atrial remodeling and AF were induced by chronic (4-6 weeks of) right atrial tachypacing (400/min) in dogs. Transmembrane ionic currents were measured by applying the whole-cell patch-clamp technique at 37 °C. RESULTS: The Ito current was slightly downregulated in AF cells when compared with that recorded in SR cells. This downregulation was also associated with slowed inactivation kinetics. The IK1 current was found to be larger in AF cells; however, this upregulation was not statistically significant in the voltage range corresponding with atrial action potential (-80 mV to 0 mV). IK,ACh was activated by the cholinergic agonist carbachol (CCh; 2 µM). In SR, CCh activated a large current either in inward or outward directions. The selective IK,ACh inhibitor tertiapin (10 nM) blocked the outward CCh-induced current by 61%. In atrial cardiomyocytes isolated from dogs with AF, the presence of a constitutively active IK,ACh was observed, blocked by 59% with 10 nM tertiapin. However, in "AF atrial myocytes", CCh activated an additional, significant ligand-dependent and tertiapin-sensitive IK,ACh current. CONCLUSIONS: In our dog AF model, Ito unlike in humans was downregulated only in a slight manner. Due to its slow inactivation kinetics, it seems that Ito may play a more significant role in atrial repolarization than in ventricular working muscle myocytes. The presence of the constitutively active IK,ACh in atrial myocytes from AF dogs shows that electrical remodeling truly developed in this model. The IK,ACh current (both ligand-dependent and constitutively active) seems to play a significant role in canine atrial electrical remodeling and may be a promising atrial selective drug target for suppressing AF.

A computational study on the influence of antegrade accessory pathway location on the 12-lead electrocardiogram in Wolff-Parkinson-White syndrome.

Wolff-Parkinson-White syndrome is a cardiovascular disease characterized by abnormal atrio-ventricular conduction facilitated by accessory pathways (APs). Invasive catheter ablation of the AP represents the primary treatment modality. Accurate localization of APs is crucial for successful ablation outcomes, but current diagnostic algorithms based on the 12 lead electrocardiogram (ECG) often struggle with precise determination of AP locations. In order to gain insight into the mechanisms underlying localization failures observed in current diagnostic algorithms, we employ a virtual cardiac model to elucidate the relationship between AP location and ECG morphology. We first introduce a cardiac model of electrophysiology that was specifically tailored to represent antegrade APs in the form of a short atrio-ventricular bypass tract. Locations of antegrade APs were then automatically swept across both ventricles in the virtual model to generate a synthetic ECG database consisting of 9271 signals. Regional grouping of antegrade APs revealed overarching morphological patterns originating from diverse cardiac regions. We then applied variance-based sensitivity analysis relying on polynomial chaos expansion on the ECG database to mathematically quantify how variation in AP location and timing relates to morphological variation in the 12 lead ECG. We utilized our mechanistic virtual model to showcase limitations of AP localization using standard ECG-based algorithms and provide mechanistic explanations through exemplary simulations. Our findings highlight the potential of virtual models of cardiac electrophysiology not only to deepen our understanding of the underlying mechanisms of Wolff-Parkinson-White syndrome but also to potentially enhance the diagnostic accuracy of ECG-based algorithms and facilitate personalized treatment planning.

Stretch of the papillary insertion triggers reentrant arrhythmia: an in silico patient study.

Background: The electrophysiological mechanism connecting mitral valve prolapse (MVP), premature ventricular complexes and life-threatening ventricular arrhythmia is unknown. A common hypothesis is that stretch activated channels (SACs) play a significant role. SACs can trigger depolarizations or shorten repolarization times in response to myocardial stretch. Through these mechanisms, pathological traction of the papillary muscle (PM), as has been observed in patients with MVP, may induce irregular electrical activity and result in reentrant arrhythmia. Methods: Based on a patient with MVP and mitral annulus disjunction, we modeled the effect of excessive PM traction in a detailed medical image-derived ventricular model by activating SACs in the PM insertion region. By systematically varying the onset of SAC activation following sinus pacing, we identified vulnerability windows for reentry with 1 ms resolution. We explored how reentry was affected by the SAC reversal potential ( E SAC ) and the size of the region with simulated stretch (SAC region). Finally, the effect of global or focal fibrosis, modeled as reduction in tissue conductivity or mesh splitting (fibrotic microstructure), was investigated. Results: In models with healthy tissue or fibrosis modeled solely as CV slowing, we observed two vulnerable periods of reentry: For E SAC of -10 and -30 mV, SAC activated during the T-wave could cause depolarization of the SAC region which lead to reentry. For E SAC of -40 and -70 mV, SAC activated during the QRS complex could result in early repolarization of the SAC region and subsequent reentry. In models with fibrotic microstructure in the SAC region, we observed micro-reentries and a larger variability in which times of SAC activation triggered reentry. In these models, 86% of reentries were triggered during the QRS complex or T-wave. We only observed reentry for sufficiently large SAC regions ( > = 8 mm radius in models with healthy tissue). Conclusion: Stretch of the PM insertion region following sinus activation may initiate ventricular reentry in patients with MVP, with or without fibrosis. Depending on the SAC reversal potential and timing of stretch, reentry may be triggered by ectopy due to SAC-induced depolarizations or by early repolarization within the SAC region.

Computational Medicine: What Electrophysiologists Should Know to Stay Ahead of the Curve.

PURPOSE OF REVIEW: Technology drives the field of cardiac electrophysiology. Recent computational advances will bring exciting changes. To stay ahead of the curve, we recommend electrophysiologists develop a robust appreciation for novel computational techniques, including deterministic, statistical, and hybrid models. RECENT FINDINGS: In clinical applications, deterministic models use biophysically detailed simulations to offer patient-specific insights. Statistical techniques like machine learning and artificial intelligence recognize patterns in data. Emerging clinical tools are exploring avenues to combine all the above methodologies. We review three ways that computational medicine will aid electrophysiologists by: (1) improving personalized risk assessments, (2) weighing treatment options, and (3) guiding ablation procedures. Leveraging clinical data that are often readily available, computational models will offer valuable insights to improve arrhythmia patient care. As emerging tools promote personalized medicine, physicians must continue to critically evaluate technology-driven tools they consider using to ensure their appropriate implementation.

Computational modelling of mouse atrio ventricular node action potential and automaticity.

The atrioventricular node (AVN) is a crucial component of the cardiac conduction system. Despite its pivotal role in regulating the transmission of electrical signals between atria and ventricles, a comprehensive understanding of the cellular electrophysiological mechanisms governing AVN function has remained elusive. This paper presents a detailed computational model of mouse AVN cell action potential (AP). Our model builds upon previous work and introduces several key refinements, including accurate representation of membrane currents and exchangers, calcium handling, cellular compartmentalization, dynamic update of intracellular ion concentrations, and calcium buffering. We recalibrated and validated the model against existing and unpublished experimental data. In control conditions, our model reproduces the AVN AP experimental features, (e.g. rate = 175 bpm, experimental range [121, 191] bpm). Notably, our study sheds light on the contribution of L-type calcium currents, through both Cav1.2 and Cav1.3 channels, in AVN cells. The model replicates several experimental observations, including the cessation of firing upon block of Cav1.3 or INa,r current. If block induces a reduction in beating rate of 11%. In summary, this work presents a comprehensive computational model of mouse AVN cell AP, offering a valuable tool for investigating pacemaking mechanisms and simulating the impact of ionic current blockades. By integrating calcium handling and refining formulation of ionic currents, our model advances understanding of this critical component of the cardiac conduction system, providing a platform for future developments in cardiac electrophysiology. KEY POINTS: This paper introduces a comprehensive computational model of mouse atrioventricular node (AVN) cell action potentials (APs). Our model is based on the electrophysiological data from isolated mouse AVN cells and exhibits an action potential and calcium transient that closely match the experimental records. By simulating the effects of blocking specific ionic currents, the model effectively predicts the roles of L-type Cav1.2 and Cav1.3 channels, T-type calcium channels, sodium currents (TTX-sensitive and TTX-resistant), and the funny current (If) in AVN pacemaking. The study also emphasizes the significance of other ionic currents, including IKr, Ito, IKur, in regulating AP characteristics and cycle length in AVN cells. The model faithfully reproduces the rate dependence of action potentials under pacing, opening the possibility of use in impulse propagation models. The population-of-models approach showed the robustness of this new AP model in simulating a wide spectrum of cellular pacemaking in AVN.

Impact of resident training on cardiac electrophysiological procedures.

BACKGROUND: Modern management of cardiac arrhythmias often requires interventions in which young physicians must acquire a high level of expertise. However, concerns have been raised about the increase in side effects during procedures performed with resident involvement. AIM: This study aims to identify the effects of resident training on cardiac electrophysiological procedures within a university centre. METHODS: In a single-centre study, cardiac arrhythmia procedures were reviewed retrospectively, and resident involvement was scrutinized. Univariate and multivariable models were built for the following outcomes: fluoroscopy time; operative time; length of hospitalization after procedure; and adverse events. RESULTS: We reviewed 991 procedures, 574 without and 417 with resident involvement (650 cardiac pacemakers or defibrillators, 120 generator replacements, 188 electrophysiological studies and 153 radiofrequency ablations). Resident involvement was associated with an increase in fluoroscopy time: +1.7±0.4minutes (P<0.01) for pacemaker implantation; and +2.5±0.9minutes (P=0.01) for electrophysiological studies. Operative time was longer for electrophysiological studies (+10.8±4.9minutes; P=0.03) and pacing implantation (+8.4±2.2minutes; P<0.01). There was no significant association between resident training and adverse events (7.67 vs. 9.83%; P=0.28). CONCLUSIONS: Cardiac electrophysiological procedures performed with resident involvement have a good safety profile. However, resident training modestly, but significantly, prolongs fluoroscopy time and operative time.

Electrophysiological and sick sinus syndrome effects of Remdesivir challenge in guinea-pig hearts.

Remdesivir (RDV) is the first drug approved by the FDA for clinical treatment of hospitalized patients infected with COVID-19 because it has been shown to have good antiviral activity against a variety of viruses, including Arenaviridae and Coronaviridae viral families. However, it has been reported that its clinical treatment leads to the symptoms of sick sinus syndrome such as sinus bradycardia, conduction block, and sinus arrest, but the electrophysiological mechanism of its specific cardiac adverse events is still unclear. We report complementary, experimental, studies of its electrophysiological effects. In wireless cardiac telemetry experiments in vivo and electrocardiographic studies in ex vivo cardiac preparations, RDV significantly caused sinus bradycardia, sinus atrial block, and prolongation of the QT interval in guinea pigs. Dose-dependent effects of RDV on the electrical activities of sinoatrial node (SA node) preparations of guinea pigs were characterised by multielectrode, optical RH237 voltage mapping. These revealed reversibly reduced sinoatrial conduction time (SACT), increased AP durations (APDs), and decreased the pacemaking rate of the SA node. Patch-clamp experiments showed that RDV significantly inhibited the If current of HCN4 channels, resulting in a significant decrease in the spontaneous firing rate of SA node cells, which may underlie the development of sick sinus node syndrome. In addition, RDV significantly inhibits IKr currents in hERG channels, leading to prolongation of the QT interval and playing a role in bradycardia. Therefore, these findings provide insights into the understanding the bradycardia effect of RDV, which may be used as basic theoretical guidance for the intervention of its adverse events, and prompt safety investigations of RDV's cardiac safety in the future.

Drug-induced long QT syndrome: Concept and non-clinical models for predicting the onset of drug-induced torsade de pointes in patients in compliance with ICH E14/S7B guidance.

ICH established S7B and E14 guidelines in 2005 to prevent drug-induced torsade de pointes (TdP), effectively preventing the development of high-risk drugs. However, those guidelines unfortunately hampered the development of some potentially valuable drug candidates despite not being proven to be proarrhythmic. In response, Comprehensive In Vitro Proarrhythmia Assay (CiPA) and Exposure-Response Modeling were proposed in 2013 to reinforce proarrhythmic risk assessment. In 2022, ICH released E14/S7B Q&As (Stage 1), emphasizing a "double negative" nonclinical scenario for low-risk compounds. For "non-double negative" compounds, new Q&As are expected to be enacted as Stage 2 shortly, in which more detailed recommendations for proarrhythmia models and proarrhythmic surrogate markers will be provided. This review details the onset mechanisms of drug-induced TdP, including IKr inhibition, pharmacokinetic factors, autonomic regulation and reduced repolarization reserve. It also explores the utility of proarrhythmic surrogate markers (J-Tpeak, Tpeak-Tend and terminal repolarization period) besides QT interval. Finally, it presents various in silico, in vitro, ex vivo and in vivo models for proarrhythmic risk prediction, such as CiPA in silico model, iPS cell-derived cardiomyocyte sheet, Langendorff perfused heart preparation, chronic atrioventricular block animals (dogs, monkeys, pigs and rabbits), acute atrioventricular block rabbits, methoxamine-sensitized rabbits, and genetically engineered rabbits for specific long QT syndromes. Those models along with the surrogate markers can play important roles in quantifying TdP risk of new compounds, impacting late-phase clinical design and regulatory decision-making, and preventing adverse events on post-marketing clinical use. Significance Statement Since ICH S7B/E14 guidelines unfortunately hampered the development of some potentially valuable compounds with unproven proarrhythmic risk, Comprehensive In Vitro Proarrhythmia Assay and Exposure-Response Modeling were proposed in 2013 to reinforce proarrhythmic risk assessment of new compounds. In 2022, ICH released Q&As (Stage 1) emphasizing "double negative" nonclinical scenario for low-risk compounds, and new Q&As (Stage 2) for "non-double negative" compounds are expected. This review delves into proarrhythmic mechanisms with surrogate markers, and explores various models for proarrhythmic risk prediction.

Fibroblast growth factor homologous factors: canonical and non-canonical mechanisms of action.

Since their discovery nearly 30 years ago, fibroblast growth factor homologous factors (FHFs) are now known to control the functionality of excitable tissues through a range of mechanisms. Nervous and cardiac system dysfunctions are caused by loss- or gain-of-function mutations in FHF genes. The best understood 'canonical' targets for FHF action are voltage-gated sodium channels, and recent studies have expanded the repertoire of ways that FHFs modulate sodium channel gating. Additional 'non-canonical' functions of FHFs in excitable and non-excitable cells, including cancer cells, have been reported over the past dozen years. This review summarizes and evaluates reported canonical and non-canonical FHF functions.

Unsupervised stochastic learning and reduced order modeling for global sensitivity analysis in cardiac electrophysiology models.

BACKGROUND AND OBJECTIVE: Numerical simulations in electrocardiology are often affected by various uncertainties inherited from the lack of precise knowledge regarding input values including those related to the cardiac cell model, domain geometry, and boundary or initial conditions used in the mathematical modeling. Conventional techniques for uncertainty quantification in modeling electrical activities of the heart encounter significant challenges, primarily due to the high computational costs associated with fine temporal and spatial scales. Additionally, the need for numerous model evaluations to quantify ubiquitous uncertainties increases the computational challenges even further. METHODS: In the present study, we propose a non-intrusive surrogate model to perform uncertainty quantification and global sensitivity analysis in cardiac electrophysiology models. The proposed method combines an unsupervised machine learning technique with the polynomial chaos expansion to reconstruct a surrogate model for the propagation and quantification of uncertainties in the electrical activity of the heart. The proposed methodology not only accurately quantifies uncertainties at a very low computational cost but more importantly, it captures the targeted quantity of interest as either the whole spatial field or the whole temporal period. In order to perform sensitivity analysis, aggregated Sobol indices are estimated directly from the spectral mode of the polynomial chaos expansion. RESULTS: We conduct Uncertainty Quantification (UQ) and global Sensitivity Analysis (SA) considering both spatial and temporal variations, rather than limiting the analysis to specific Quantities of Interest (QoIs). To assess the comprehensive performance of our methodology in simulating cardiac electrical activity, we utilize the monodomain model. Additionally, sensitivity analysis is performed on the parameters of the Mitchell-Schaeffer cell model. CONCLUSIONS: Unlike conventional techniques for uncertainty quantification in modeling electrical activities, the proposed methodology performs at a low computational cost the sensitivity analysis on the cardiac electrical activity parameters. The results are fully reproducible and easily accessible, while the proposed reduced-order model represents a significant contribution to enhancing global sensitivity analysis in cardiac electrophysiology.

Re-entry in models of cardiac ventricular tissue with scar represented as a Gaussian random field.

Introduction: Fibrotic scar in the heart is known to act as a substrate for arrhythmias. Regions of fibrotic scar are associated with slowed or blocked conduction of the action potential, but the detailed mechanisms of arrhythmia formation are not well characterised and this can limit the effective diagnosis and treatment of scar in patients. The aim of this computational study was to evaluate different representations of fibrotic scar in models of 2D 10 × 10 cm ventricular tissue, where the region of scar was defined by sampling a Gaussian random field with an adjustable length scale of between 1.25 and 10.0 mm. Methods: Cellular electrophysiology was represented by the Ten Tusscher 2006 model for human ventricular cells. Fibrotic scar was represented as a spatially varying diffusion, with different models of the boundary between normal and fibrotic tissue. Dispersion of activation time and action potential duration (APD) dispersion was assessed in each sample by pacing at an S1 cycle length of 400 ms followed by a premature S2 beat with a coupling interval of 323 ms. Vulnerability to reentry was assessed with an aggressive pacing protocol. In all models, simulated fibrosis acted to delay activation, to increase the dispersion of APD, and to generate re-entry. Results: A higher incidence of re-entry was observed in models with simulated fibrotic scar at shorter length scale, but the type of model used to represent fibrotic scar had a much bigger influence on the incidence of reentry. Discussion: This study shows that in computational models of fibrotic scar the effects that lead to either block or propagation of the action potential are strongly influenced by the way that fibrotic scar is represented in the model, and so the results of computational studies involving fibrotic scar should be interpreted carefully.

Right Coronary Artery to Left Ventricular Fistula Complicated by Symptomatic Arrhythmia.

Coronary cameral fistulas (CCFs) are rare and are characterized by an abnormal connection between a coronary artery and any of the four chambers of the heart. Most cases of CCFs are asymptomatic. The most common presentation in symptomatic patients includes chest pain or heart failure; however, arrhythmias are rarely associated. We report the case of a 32-year-old male previously unknown to have any medical illnesses. He presented to the clinic with complaints of frequent palpitations, necessitating recurrent admissions. His electrocardiograms revealed regular wide complex tachycardia with a right bundle branch block pattern, suggestive of fascicular ventricular tachycardia. During hospitalization, an elective coronary angiography showed a large CCF originating from the right posterior descending coronary artery and draining into the left ventricle. Moreover, cardiac magnetic resonance imaging did not show any scar or evidence of cardiomyopathies. The patient underwent a successful catheter-based right coronary artery to left ventricular fistula occlusion with coils. In addition, the patient underwent a complex electrophysiological study with three-dimensional mapping and ablation. The presented case underscores the rarity and complexity of such clinical presentations. It also highlights the importance of a multidisciplinary approach in addressing this unique cardiac anomaly.

A Case of Transient Complete Heart Block During Left Heart Catheterization.

Iatrogenic complete heart blocks are rare but a reported complication of left heart catheterizations in patients with pre-existing right bundle branch blocks. We present the case of an 84-year-old male with a preexisting right bundle branch block who underwent a left heart catheterization for valve replacement evaluation. While attempting to engage the right coronary artery, the catheter instead crossed the aortic valve, causing the patient to become bradycardic to the 20s and hypotensive. The patient had a temporary transvenous pacer inserted and tolerated the rest of the procedure well. The cause of the complete heart block was thought to be due to the transient blockage of the left bundle branch due to ventricular septal irritation when the catheter crossed the aortic valve. When performing left heart angiograms in a patient with a right bundle branch block, operators should be prepared for a possible iatrogenic complete heart block.

Antiarrhythmic Mechanisms of Epidural Blockade After Myocardial Infarction.

BACKGROUND: Thoracic epidural anesthesia (TEA) has been shown to reduce the burden of ventricular tachycardia in small case series of patients with refractory ventricular tachyarrhythmias and cardiomyopathy. However, its electrophysiological and autonomic effects in diseased hearts remain unclear, and its use after myocardial infarction is limited by concerns for potential right ventricular dysfunction. METHODS: Myocardial infarction was created in Yorkshire pigs (N=22) by left anterior descending coronary artery occlusion. Approximately, six weeks after myocardial infarction, an epidural catheter was placed at the C7-T1 vertebral level for injection of 2% lidocaine. Right and left ventricular hemodynamics were recorded using Millar pressure-conductance catheters, and ventricular activation recovery intervals (ARIs), a surrogate of action potential durations, by a 56-electrode sock and 64-electrode basket catheter. Hemodynamics and ARIs, baroreflex sensitivity and intrinsic cardiac neural activity, and ventricular effective refractory periods and slope of restitution (Smax) were assessed before and after TEA. Ventricular tachyarrhythmia inducibility was assessed by programmed electrical stimulation. RESULTS: TEA reduced inducibility of ventricular tachyarrhythmias by 70%. TEA did not affect right ventricular-systolic pressure or contractility, although left ventricular-systolic pressure and contractility decreased modestly. Global and regional ventricular ARIs increased, including in scar and border zone regions post-TEA. TEA reduced ARI dispersion specifically in border zone regions. Ventricular effective refractory periods prolonged significantly at critical sites of arrhythmogenesis, and Smax was reduced. Interestingly, TEA significantly improved cardiac vagal function, as measured by both baroreflex sensitivity and intrinsic cardiac neural activity. CONCLUSIONS: TEA does not compromise right ventricular function in infarcted hearts. Its antiarrhythmic mechanisms are mediated by increases in ventricular effective refractory period and ARIs, decreases in Smax, and reductions in border zone electrophysiological heterogeneities. TEA improves parasympathetic function, which may independently underlie some of its observed antiarrhythmic mechanisms. This study provides novel insights into the antiarrhythmic mechanisms of TEA while highlighting its applicability to the clinical setting.