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.

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.

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.

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.

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.

Chronic Mexiletine Administration Increases Sodium Current in Non-Diseased Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes.

A sodium current (INa) reduction occurs in the setting of many acquired and inherited conditions and is associated with cardiac conduction slowing and increased arrhythmia risks. The sodium channel blocker mexiletine has been shown to restore the trafficking of mutant sodium channels to the membrane. However, these studies were mostly performed in heterologous expression systems using high mexiletine concentrations. Moreover, the chronic effects on INa in a non-diseased cardiomyocyte environment remain unknown. In this paper, we investigated the chronic and acute effects of a therapeutic dose of mexiletine on INa and the action potential (AP) characteristics in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) of a healthy individual. Control hiPSC-CMs were incubated for 48 h with 10 µM mexiletine or vehicle. Following the wash-out of mexiletine, patch clamp analysis and immunocytochemistry experiments were performed. The incubation of hiPSC-CMs for 48 h with mexiletine (followed by wash-out) induced a significant increase in peak INa of ~75%, without any significant change in the voltage dependence of (in)activation. This was accompanied by a significant increase in AP upstroke velocity, without changes in other AP parameters. The immunocytochemistry experiments showed a significant increase in membrane Nav1.5 fluorescence following a 48 h incubation with mexiletine. The acute re-exposure of hiPSC-CMs to 10 µM mexiletine resulted in a small but significant increase in AP duration, without changes in AP upstroke velocity, peak INa density, or the INa voltage dependence of (in)activation. Importantly, the increase in the peak INa density and resulting AP upstroke velocity induced by chronic mexiletine incubation was not counteracted by the acute re-administration of the drug. In conclusion, the chronic administration of a clinically relevant concentration of mexiletine increases INa density in non-diseased hiPSC-CMs, likely by enhancing the membrane trafficking of sodium channels. Our findings identify mexiletine as a potential therapeutic strategy to enhance and/or restore INa and cardiac conduction.

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.

Electroanatomical adaptations in the guinea pig heart from neonatal to adulthood.

AIMS: Electroanatomical adaptations during the neonatal to adult phase have not been comprehensively studied in preclinical animal models. To explore the impact of age as a biological variable on cardiac electrophysiology, we employed neonatal and adult guinea pigs, which are a recognized animal model for developmental research. METHODS AND RESULTS: Electrocardiogram recordings were collected in vivo from anaesthetized animals. A Langendorff-perfusion system was employed for the optical assessment of action potentials and calcium transients. Optical data sets were analysed using Kairosight 3.0 software. The allometric relationship between heart weight and body weight diminishes with age, it is strongest at the neonatal stage (R2 = 0.84) and abolished in older adults (R2 = 1E-06). Neonatal hearts exhibit circular activation, while adults show prototypical elliptical shapes. Neonatal conduction velocity (40.6 ± 4.0 cm/s) is slower than adults (younger: 61.6 ± 9.3 cm/s; older: 53.6 ± 9.2 cm/s). Neonatal hearts have a longer action potential duration (APD) and exhibit regional heterogeneity (left apex; APD30: 68.6 ± 5.6 ms, left basal; APD30: 62.8 ± 3.6), which was absent in adults. With dynamic pacing, neonatal hearts exhibit a flatter APD restitution slope (APD70: 0.29 ± 0.04) compared with older adults (0.49 ± 0.04). Similar restitution characteristics are observed with extrasystolic pacing, with a flatter slope in neonates (APD70: 0.54 ± 0.1) compared with adults (younger: 0.85 ± 0.4; older: 0.95 ± 0.7). Neonatal hearts display unidirectional excitation-contraction coupling, while adults exhibit bidirectionality. CONCLUSION: Postnatal development is characterized by transient changes in electroanatomical properties. Age-specific patterns can influence cardiac physiology, pathology, and therapies for cardiovascular diseases. Understanding heart development is crucial to evaluating therapeutic eligibility, safety, and efficacy.

The Dynamic Clamp Technique: A Robust Toolkit for Investigating Potassium Channel Function.

The dynamic clamp technique has emerged as a powerful tool in the field of cardiac electrophysiology, enabling researchers to investigate the intricate dynamics of ion currents in cardiac cells. Potassium channels play a critical role in the functioning of cardiac cells and the overall electrical stability of the heart. This chapter provides a comprehensive overview of the methods and applications of dynamic clamp in the study of key potassium currents in cardiac cells. A step-by-step guide is presented, detailing the experimental setup and protocols required for implementing the dynamic clamp technique in cardiac cell studies. Special attention is given to the design and construction of a dynamic clamp setup with Real Time eXperimental Interface, configurations, and the incorporation of mathematical models to mimic ion channel behavior. The chapter's core focuses on applying dynamic clamp to elucidate the properties of various potassium channels in cardiac cells. It discusses how dynamic clamp can be used to investigate channel kinetics, voltage-dependent properties, and the impact of different potassium channel subtypes on cardiac electrophysiology. The chapter will also include examples of specific dynamic clamp experiments that studied potassium currents or their applications in cardiac cells.

Micronano Synergetic Three-Dimensional Bioelectronics: A Revolutionary Breakthrough Platform for Cardiac Electrophysiology.

Cardiovascular diseases (CVDs) are the leading cause of mortality and therefore pose a significant threat to human health. Cardiac electrophysiology plays a crucial role in the investigation and treatment of CVDs, including arrhythmia. The long-term and accurate detection of electrophysiological activity in cardiomyocytes is essential for advancing cardiology and pharmacology. Regarding the electrophysiological study of cardiac cells, many micronano bioelectric devices and systems have been developed. Such bioelectronic devices possess unique geometric structures of electrodes that enhance quality of electrophysiological signal recording. Though planar multielectrode/multitransistors are widely used for simultaneous multichannel measurement of cell electrophysiological signals, their use for extracellular electrophysiological recording exhibits low signal strength and quality. However, the integration of three-dimensional (3D) multielectrode/multitransistor arrays that use advanced penetration strategies can achieve high-quality intracellular signal recording. This review provides an overview of the manufacturing, geometric structure, and penetration paradigms of 3D micronano devices, as well as their applications for precise drug screening and biomimetic disease modeling. Furthermore, this review also summarizes the current challenges and outlines future directions for the preparation and application of micronano bioelectronic devices, with an aim to promote the development of intracellular electrophysiological platforms and thereby meet the demands of emerging clinical applications.

Consistency of ablations with trainee and increasing independence during fellowship training-Analysis of ablation data by CARTONET.

INTRODUCTION: Training in clinical cardiac electrophysiology (CCEP) involves the development of catheter handling skills to safely deliver effective treatment. Objective data from analysis of ablation data for evaluating trainee of CCEP procedures has not previously been possible. Using the artificial intelligence cloud-based system (CARTONET), we assessed the impact of trainee progress through ablation procedural quality. METHODS: Lesion- and procedure-level data from all de novo atrial fibrillation (AF) and cavotricuspid isthmus (CTI) ablations involving first-year (Y1) or second-year (Y2) fellows across a full year of fellowship was curated within Cartonet. Lesions were automatically assigned to anatomic locations. RESULTS: Lesion characteristics, including contact force, catheter stability, impedance drop, ablation index value, and interlesion time/distance were similar over each training year. Anatomic location and supervising operator significantly affected catheter stability. The proportion of lesion sets delivered independently and of lesions delivered by the trainee increased steadily from the first quartile of Y1 to the last quartile of Y2. Trainee perception of difficult regions did not correspond to objective measures. CONCLUSION: Objective ablation data from Cartonet showed that the progression of trainees through CCEP training does not impact lesion-level measures of treatment efficacy (i.e., catheter stability, impedance drop). Data demonstrates increasing independence over a training fellowship. Analyses like these could be useful to inform individualized training programs and to track trainee's progress. It may also be a useful quality assurance tool for ensuring ongoing consistency of treatment delivered within training institutions.

Myocardial ischemia simulation based on a multi-scale heart electrophysiology model.

BACKGROUND: Myocardial ischemia, caused by insufficient myocardial blood supply, is a leading cause of human death worldwide. Therefore, it is crucial to prioritize the prevention and treatment of this condition. Mathematical modeling is a powerful technique for studying heart diseases. OBJECTIVE: The aim of this study was to discuss the quantitative relationship between extracellular potassium concentration and the degree of myocardial ischemia directly related to it. METHODS: A human cardiac electrophysiological multiscale model was developed to calculate action potentials of all cells simultaneously, enhancing efficiency over traditional reaction-diffusion models. RESULTS: Contrary to the commonly held view that myocardial ischemia is caused by an increase in extracellular potassium concentration, our simulation results indicate that level 1 ischemia is associated with a decrease in extracellular potassium concentration. CONCLUSION: This unusual finding provides a new perspective on the mechanisms underlying myocardial ischemia and has the potential to lead to the development of new diagnostic and treatment strategies.

Feeding behavior modifies the circadian variation in RR and QT intervals by distinct mechanisms in mice.

Rhythmic feeding behavior is critical for regulating phase and amplitude in the ≈24-h variation of heart rate (RR intervals), ventricular repolarization (QT intervals), and core body temperature in mice. We hypothesized changes in cardiac electrophysiology associated with feeding behavior were secondary to changes in core body temperature. Telemetry was used to record electrocardiograms and core body temperature in mice during ad libitum-fed conditions and after inverting normal feeding behavior by restricting food access to the light cycle. Light cycle-restricted feeding modified the phase and amplitude of 24-h rhythms in RR and QT intervals, and core body temperature to realign with the new feeding time. Changes in core body temperature alone could not account for changes in phase and amplitude in the ≈24-h variation of the RR intervals. Heart rate variability analysis and inhibiting ß-adrenergic and muscarinic receptors suggested that changes in the phase and amplitude of 24-h rhythms in RR intervals were secondary to changes in autonomic signaling. In contrast, changes in QT intervals closely mirrored changes in core body temperature. Studies at thermoneutrality confirmed that the daily variation in QT interval, but not RR interval, primarily reflected daily changes in core body temperature (even in ad libitum-fed conditions). Correcting the QT interval for differences in core body temperature helped unmask QT interval prolongation after starting light cycle-restricted feeding and in a mouse model of long QT syndrome. We conclude feeding behavior alters autonomic signaling and core body temperature to regulate phase and amplitude in RR and QT intervals, respectively.NEW & NOTEWORTHY We used time-restricted feeding and thermoneutrality to demonstrate that different mechanisms regulate the 24-h rhythms in heart rate and ventricular repolarization. The daily rhythm in heart rate reflects changes in autonomic input, whereas daily rhythms in ventricular repolarization reflect changes in core body temperature. This novel finding has major implications for understanding 24-h rhythms in mouse cardiac electrophysiology, arrhythmia susceptibility in transgenic mouse models, and interpretability of cardiac electrophysiological data acquired in thermoneutrality.

A Review of Personalised Cardiac Computational Modelling Using Electroanatomical Mapping Data.

Computational models of cardiac electrophysiology have gradually matured during the past few decades and are now being personalised to provide patient-specific therapy guidance for improving suboptimal treatment outcomes. The predictive features of these personalised electrophysiology models hold the promise of providing optimal treatment planning, which is currently limited in the clinic owing to reliance on a population-based or average patient approach. The generation of a personalised electrophysiology model entails a sequence of steps for which a range of activation mapping, calibration methods and therapy simulation pipelines have been suggested. However, the optimal methods that can potentially constitute a clinically relevant in silico treatment are still being investigated and face limitations, such as uncertainty of electroanatomical data recordings, generation and calibration of models within clinical timelines and requirements to validate or benchmark the recovered tissue parameters. This paper is aimed at reporting techniques on the personalisation of cardiac computational models, with a focus on calibrating cardiac tissue conductivity based on electroanatomical mapping data.

Trends in safety of catheter-based electrophysiology procedures in the last 2 decades: A meta-analysis.

BACKGROUND: Rapid technologic development and expansion of procedural expertise have led to widespread proliferation of catheter-based electrophysiology procedures. It is unclear whether these advances come at cost to patient safety. OBJECTIVE: This meta-analysis aimed to assess complication rates after modern electrophysiology procedures during the lifetime of the procedures. METHODS: A comprehensive search was performed to identify relevant data published before May 30, 2023. Studies were included if they met the following inclusion criteria: prospective trials or registries, including comprehensive complications data; and patients undergoing atrial fibrillation ablation, ventricular tachyarrhythmia ablation, leadless cardiac pacemaker implantation, and percutaneous left atrial appendage occlusion. Pooled incidences of procedure-related complications were individually assessed by random effects models to account for heterogeneity. Temporal trends in complications were investigated by clustering trials by publication year (2000-2018 vs 2019-2023). RESULTS: A total of 174 studies (43,914 patients) met criteria for analysis: 126 studies of atrial fibrillation ablation (n = 24,057), 25 studies of ventricular tachyarrhythmia ablation (n = 1781), 21 studies of leadless cardiac pacemaker (n = 8896), and 18 studies of left atrial appendage occlusion (n = 9180). The pooled incidences of serious procedure-related complications (3.49% [2000-2018] vs 3.05% [2019-2023]; P < .001), procedure-related stroke (0.46% vs 0.28%; P = .002), pericardial effusion requiring intervention (1.02% vs 0.83%; P = .037), and procedure-related death (0.15% vs 0.06%; P = .003) significantly decreased over time. However, there was no significant difference in the incidence of vascular complications over time (1.86% vs 1.88%; P = .888). CONCLUSION: Despite an increase in cardiac electrophysiology procedures, procedural safety has improved over time.

Bradycardia, Renal Failure, Atrioventricular Nodal Block, Shock, and Hyperkalemia (BRASH) Syndrome-Induced Atrial Fibrillation: A Case Report.

BRASH syndrome is a syndrome that comprises bradycardia, renal failure, atrioventricular nodal block, shock, and hyperkalemia. This syndrome is usually associated with a junctional rhythm. Early recognition of this clinical entity is crucial for appropriate management. In this case report, we describe a 70-year-old female who presented with BRASH syndrome-induced atrial fibrillation with a slow ventricular response.

ForCEPSS-A framework for cardiac electrophysiology simulations standardization.

BACKGROUND AND OBJECTIVE: Simulation of cardiac electrophysiology (CEP) is an important research tool that is increasingly being adopted in industrial and clinical applications. Typical workflows for CEP simulation consist of a sequence of processing stages starting with building an anatomical model and then calibrating its electrophysiological properties to match observable data. While the calibration stages are common and generalizable, most CEP studies re-implement these steps in complex and highly variable workflows. This lack of standardization renders the execution of computational CEP studies in an efficient, robust, and reproducible manner a significant challenge. Here, we propose ForCEPSS as an efficient and robust, yet flexible, software framework for standardizing CEP simulation studies. METHODS AND RESULTS: Key processing stages of CEP simulation studies are identified and implemented in a standardized workflow that builds on openCARP1 Plank et al. (2021) and the Python-based carputils2 framework. Stages include (i) the definition and initialization of action potential phenotypes, (ii) the tissue scale calibration of conduction properties, (iii) the functional initialization to approximate a limit cycle corresponding to the dynamic reference state according to an experimental protocol, and, (iv) the execution of the CEP study where the electrophysiological response to a perturbation of the limit cycle is probed. As an exemplar application, we employ ForCEPSS to prepare a CEP study according to the Virtual Arrhythmia Risk Prediction protocol used for investigating the arrhythmogenic risk of developing infarct-related ventricular tachycardia (VT) in ischemic cardiomyopathy patients. We demonstrate that ForCEPSS enables a fully automated execution of all stages of this complex protocol. CONCLUSION: ForCEPSS offers a novel comprehensive, standardized, and automated CEP simulation workflow. The high degree of automation accelerates the execution of CEP simulation studies, reduces errors, improves robustness, and makes CEP studies reproducible. Verification of simulation studies within the CEP modeling community is thus possible. As such, ForCEPSS makes an important contribution towards increasing transparency, standardization, and reproducibility of in silico CEP experiments.