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Key points A fundamental question in cardiovascular and muscle physiology is how the heart operates in synchrony with distinct muscles to regulate homeostasis, enable movement and adapt to exercise demands and fatigue. Here we investigate how autonomic regulation of cardiac function synchronizes and integrates as a network with the activity of distinct muscles during exercise. Further, we establish how the network of cardio‐muscular interactions reorganizes with fatigue. Thirty healthy young adults performed two body weight squat tests until exhaustion. Simultaneous recordings were taken of a 3‐lead electrocardiogram (EKG) along with electromyography (EMG) signals from the left and right vastus lateralis, and left and right erector spinae. We first obtained instantaneous heart rate (HR) derived from the EKG signal and decomposed the EMG recordings in 10 frequency bands (F1–F10). We next quantified pair‐wise coupling (cross‐correlation) between the time series for HR and all EMG spectral power frequency bands in each leg and back muscle. We uncovered the first profiles of cardio‐muscular network interactions, which depend on the role muscles play during exercise and muscle fibre histochemical characteristics. Additionally, we observed a significant decline in the degree of cardio‐muscular coupling with fatigue, characterized by complex transitions from synchronous to asynchronous behaviour across a range of timescales. The network approach we utilized introduces new avenues for the development of novel network‐based markers, with the potential to characterize multilevel cardio‐muscular interactions to assess global health, levels of fatigue, fitness status or the effectiveness of cardiovascular and muscle injury rehabilitation programmes. The heart operates in synchrony with muscles to regulate homeostasis, enable movement, and adapt to exercise demands and fatigue. However, the precise mechanisms regulating cardio‐muscular coupling remain unknown. This study introduces a pioneering approach to assess cardio‐muscular network interactions by examining the synchronization of cardiac function with muscle activity during exercise and fatigue. We uncover the first profiles of cardio‐muscular interactions characterized by specific hierarchical organization of link strength. We observe a significant decline in the degree of cardio‐muscular coupling with fatigue, marked by complex transitions from synchronous to asynchronous behaviour. This network approach offers new network‐based markers to characterize multilevel cardio‐muscular interactions to assess global health, levels of fatigue, fitness status or the effectiveness of cardiovascular and muscle injury rehabilitation programmes. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Electromechanical reciprocity – comprising electro‐mechanical (EMC) and mechano‐electric coupling (MEC) – provides cardiac adaptation to changing physiological demands. Understanding electromechanical reciprocity and its impact on function and heterogeneity in pathological conditions – such as (drug‐induced) acquired long QT syndrome (aLQTS) – might lead to novel insights in arrhythmogenesis. Our aim is to investigate how electrical changes impact on mechanical function (EMC) and vice versa (MEC) under physiological conditions and in aLQTS. To measure regional differences in EMC and MEC in vivo, we used tissue phase mapping cardiac MRI and a 24‐lead ECG vest in healthy (control) and IKr‐blocker E‐4031‐induced aLQTS rabbit hearts. MEC was studied in vivo by acutely increasing cardiac preload, and ex vivo by using voltage optical mapping (OM) in beating hearts at different preloads. In aLQTS, electrical repolarization (heart rate corrected RT‐interval, RTn370) was prolonged compared to control (P < 0.0001) with increased spatial and temporal RT heterogeneity (P < 0.01). Changing electrical function (in aLQTS) resulted in significantly reduced diastolic mechanical function and prolonged contraction duration (EMC), causing increased apico‐basal mechanical heterogeneity. Increased preload acutely prolonged RTn370 in both control and aLQTS hearts (MEC). This effect was more pronounced in aLQTS (P < 0.0001). Additionally, regional RT‐dispersion increased in aLQTS. Motion‐correction allowed us to determine APD‐prolongation in beating aLQTS hearts, but limited motion correction accuracy upon preload‐changes prevented a clear analysis of MEC ex vivo. Mechano‐induced RT‐prolongation and increased heterogeneity were more pronounced in aLQTS than in healthy hearts. Acute MEC effects may play an additional role in LQT‐related arrhythmogenesis, warranting further mechanistic investigations. Key points: Electromechanical reciprocity comprising excitation‐contraction coupling (EMC) and mechano‐electric feedback loops (MEC) is essential for physiological cardiac function.Alterations in electrical and/or mechanical heterogeneity are known to have potentially pro‐arrhythmic effects.In this study, we aimed to investigate how electrical changes impact on the mechanical function (EMC) and vice versa (MEC) both under physiological conditions (control) and in acquired long QT syndrome (aLQTS).We show that changing the electrical function (in aLQTS) results in significantly altered mechanical heterogeneity via EMC and, vice versa, that increasing the preload acutely prolongs repolarization duration and increases electrical heterogeneity, particularly in aLQTS as compared to control.Our results substantiate the hypothesis that LQTS is an ‛electro‐mechanical', rather than a 'purely electrical', disease and suggest that acute MEC effects may play an additional role in LQT‐related arrhythmogenesis. [ABSTRACT FROM AUTHOR]

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 imagederived 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 (ESAC) 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 ESAC of −10 and −30 mV, SAC activated during the T-wave could cause depolarization of the SAC region which lead to reentry. For ESAC 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Rhythm control is a cornerstone of atrial fibrillation (AF) management. Shorter time between diagnosis of AF and receipt of catheter ablation is associated with greater rates of therapy success. Previous work considered diagnosis-to-ablation time as a binary or categorical variable and did not consider the unique risk profile of patients after a referral for ablation was made. The purpose of this study was to comprehensively assess the impact of diagnosis-to-ablation and referral-to-ablation time on postprocedural outcomes at a population level. This observational cohort study included patients who received catheter ablation to treat AF in Ontario, Canada. Patient demographics, medical comorbidities, AF diagnosis date, ablation referral date, and ablation date were collected. The primary outcomes of interest included a composite of death and hospitalization/emergency department visit for AF, heart failure, or ischemic stroke. Multivariable Cox models assessed the impact of diagnosis-to-ablation and referral-to-ablation times on the primary outcome. Our cohort included 7472 patients who received ablation for de novo AF between April 1, 2016, and March 31, 2022. Median [interquartile range] diagnosis-to-ablation time was 718 [399–1274] days and median referral-to-ablation time was 221 [117–363] days. Overall, 911 patients (12.2%) had the composite endpoint within 1 year of ablation. Increasing diagnosis-to-ablation time was associated with a greater incidence for the primary outcome (hazard ratio [HR]1.02; 95% confidence interval [CI] 1.01–1.02 per month). Increasing referral-to-ablation time did not impact the primary outcome (HR 1.00; 95% CI 0.98–1.01 per month). Delays between AF diagnosis and ablation referral may contribute to adverse postprocedural outcomes and provide an opportunity for health system quality improvements. [Display omitted] [ABSTRACT FROM AUTHOR]

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. This meta-analysis aimed to assess complication rates after modern electrophysiology procedures during the lifetime of the procedures. 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). 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). Despite an increase in cardiac electrophysiology procedures, procedural safety has improved over time. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Premature ventricular contraction (PVC) burden is a risk factor for heart failure and cardiovascular death in patients with structural heart disease. Long-term electrocardiographic monitoring can have a significant impact on PVC burden evaluation by further defining PVC distribution patterns. This study aimed to ascertain the optimal duration of electrocardiographic monitoring to characterize PVC burden and to understand clinical characteristics associated with frequent PVCs and nonsustained ventricular tachycardia in a large US cohort. Commercial data (iRhythm's Zio patch) from June 2011 to April 2022 were analyzed. Inclusion criteria were age >18 years, PVC burden ≥5%, and wear period ≥13 days. PVC burden cutoffs were determined on the basis of AHA/ACC/HRS guidelines for very frequent PVCs (10,000–20,000 during 24 hours). Patients were assigned to categories by PVC densities: low, <10%; moderate, 10% to <20%; and high, ≥20%. Mean measured error was assessed at baseline and daily until the wear period's end for overall PVC burden and different PVC densities. Analysis of 106,705 patch monitors revealed a study population with mean age of 70.6 ± 14.6 years (33.6% female). PVC burden was higher in male patients and those >65 years of age. PVC burden mean error decreased from 2.9% at 24 hours to 1.3% at 7 days and 0.7% at 10 days. Number of ventricular tachycardia episodes per patient increased with increasing PVC burden (P <.0001). Extending ambulatory monitoring beyond 24 hours to 7 days or more improves accuracy of assessing PVC burden. Ventricular tachycardia frequency and duration vary by initial PVC density, highlighting the need for prolonged cardiac monitoring. [ABSTRACT FROM AUTHOR]

(1) Background: The main factors and their interrelationships contributing to cardiac repolarization alternans (CRA) remain unclear. This study aimed to elucidate the calcium (Ca2+)-related mechanisms underlying myocardial ischemia (MI)-induced CRA. (2) Materials and Methods: CRA was induced using S1 stimuli for pacing in an in silico ventricular model with MI. The standard deviations of nine Ca2+-related subcellular parameters among heartbeats from 100 respective nodes with and without alternans were chosen as features, including the maximum systole and end-diastole and corresponding differences in the Ca2+ concentration in the intracellular region([Ca2+]i) and junctional sarcoplasmic reticulum ([Ca2+]jsr), as well as the maximum opening of the L-type Ca2+ current (ICaL) voltage-dependent activation gate (d-gate), maximum closing of the inactivation gate (ff-gate), and the gated channel opening time (GCOT). Feature selection was applied to determine the importance of these features. (3) Results: The major parameters affecting CRA were the differences in [Ca2+]i at end-diastole, followed by the extent of d-gate activation and GCOT among beats. (4) Conclusions: MI-induced CRA is primarily characterized by functional changes in Ca2+ re-uptake, leading to alternans of [Ca2+]i and subsequent alternans of ICaL-dependent properties. The combination of computational simulation and machine learning shows promise in researching the underlying mechanisms of cardiac electrophysiology. [ABSTRACT FROM AUTHOR]

The development of right ventricular hypertrophy (RVH) is a consequence of a large group of diseases that lead to increased pressure or volume load on the right ventricle. Electrocardiography (ECG) is a commonly used diagnostic method in clinical practice. This method allows for the identification of RVH signs in the early stages of examination. During the 20th century, more than 30 diagnostic criteria were developed. Several of these criteria are associated with worse prognosis, including increased mortality. Authors of international guidelines recommend the verification of criteria in local populations. Such studies have not been published in Russia, but according to data obtained from foreign researchers, the diagnostic properties of ECG criteria can vary significantly. In most cases, the criteria are characterized by low sensitivity and high specificity, which complicates early diagnosis of conditions leading to RVH development. It is proposed to increase the sensitivity of the method by using all the developed criteria or sets that include some of them. However, this approach may reduce the specificity of ECG diagnosis of RVH, and the selection of criteria for inclusion in diagnostic algorithms is not always based on scientific research data. This article analyzes the history of the development of RVH criteria, research data on their diagnostic capabilities, and ways to improve diagnostic algorithms.

Cardiac function is tightly regulated by the autonomic nervous system (ANS). Activation of the sympathetic nervous system increases cardiac output by increasing heart rate and stroke volume, while parasympathetic nerve stimulation instantly slows heart rate. Importantly, imbalance in autonomic control of the heart has been implicated in the development of arrhythmias and heart failure. Understanding of the mechanisms and effects of autonomic stimulation is a major challenge because synapses in different regions of the heart result in multiple changes to heart function. For example, nerve synapses on the sinoatrial node (SAN) impact pacemaking, while synapses on contractile cells alter contraction and arrhythmia vulnerability. Here, we present a multiscale neurocardiac modelling and simulator tool that predicts the effect of efferent stimulation of the sympathetic and parasympathetic branches of the ANS on the cardiac SAN and ventricular myocardium. The model includes a layered representation of the ANS and reproduces firing properties measured experimentally. Model parameters are derived from experiments and atomistic simulations. The model is a first prototype of a digital twin that is applied to make predictions across all system scales, from subcellular signalling to pacemaker frequency to tissue level responses. We predict conditions under which autonomic imbalance induces proarrhythmia and can be modified to prevent or inhibit arrhythmia. In summary, the multiscale model constitutes a predictive digital twin framework to test and guide high-throughput prediction of novel neuromodulatory therapy. KEY POINTS: A multi-layered model representation of the autonomic nervous system that includes sympathetic and parasympathetic branches, each with sparse random intralayer connectivity, synaptic dynamics and conductance based integrate-and-fire neurons generates firing patterns in close agreement with experiment. A key feature of the neurocardiac computational model is the connection between the autonomic nervous system and both pacemaker and contractile cells, where modification to pacemaker frequency drives initiation of electrical signals in the contractile cells. We utilized atomic-scale molecular dynamics simulations to predict the association and dissociation rates of noradrenaline with the β-adrenergic receptor. Multiscale predictions demonstrate how autonomic imbalance may increase proclivity to arrhythmias or be used to terminate arrhythmias. The model serves as a first step towards a digital twin for predicting neuromodulation to prevent or reduce disease.

The proposed mechanisms of sleep-dependent memory consolidation involve the overnight regulation of neural activity at both synaptic and whole-network levels. Now, there is a lack of in vivo data in humans elucidating if, and how, sleep and its varied stages balance neural activity, and if such recalibration benefits memory. We combined electrophysiology with in vivo two-photon calcium imaging in rodents as well as intracranial and scalp electroencephalography (EEG) in humans to reveal a key role for non-oscillatory brain activity during rapid eye movement (REM) sleep to mediate sleep-dependent recalibration of neural population dynamics. The extent of this REM sleep recalibration predicted the success of overnight memory consolidation, expressly the modulation of hippocampal-neocortical activity, favoring remembering rather than forgetting. The findings describe a non-oscillatory mechanism how human REM sleep modulates neural population activity to enhance long-term memory.

Abstract Aim Numerous recent reports have highlighted the association between mental disorders and electrocardiographic findings. The early repolarization pattern (ERP) on electrocardiogram has been linked with a history of suicide attempts and attention deficit hyperactivity disorder, and associations with impulsivity have also been reported. It is known that suicidal intent is more common at night. Patients who have a mental disorder and ERP may have a higher likelihood of impulsivity, potentially increasing the risk of suicide at night. Methods The subjects were 43 patients with a history of suicide attempts who had undergone electrocardiographic examination at Jikei University School of Medicine Kashiwa Hospital and received intervention from our department. Due to the diurnal variation in electrocardiographic findings, only patients who underwent the examination during the daytime were included. Patients' clinical backgrounds were compared according to the presence or absence of ERP, and the association between nocturnal suicide attempts and ERP was examined using multivariate analysis. Results The frequency of nocturnal suicidal behavior was 76.2% in patients with ERP and 31.8% in those without ERP, but the difference was not significant after Bonferroni correction. In the multivariate analysis, there was a significant association of ERP with nocturnal suicide attempts (p = 0.018). Conclusion The finding of an association between ERP and nocturnal suicide attempts indicates that ERP is a biological indicator that can predict nocturnal suicide attempts.

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 x 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. [ABSTRACT FROM AUTHOR]

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 β-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. [ABSTRACT FROM AUTHOR]

The complexity of cardiac electrophysiology, involving dynamic changes in numerous components across multiple spatial (from ion channel to organ) and temporal (from milliseconds to days) scales, makes an intuitive or empirical analysis of cardiac arrhythmogenesis challenging. Multiscale mechanistic computational models of cardiac electrophysiology provide precise control over individual parameters, and their reproducibility enables a thorough assessment of arrhythmia mechanisms. This review provides a comprehensive analysis of models of cardiac electrophysiology and arrhythmias, from the single cell to the organ level, and how they can be leveraged to better understand rhythm disorders in cardiac disease and to improve heart patient care. Key issues related to model development based on experimental data are discussed, and major families of human cardiomyocyte models and their applications are highlighted. An overview of organ-level computational modeling of cardiac electrophysiology and its clinical applications in personalized arrhythmia risk assessment and patient-specific therapy of atrial and ventricular arrhythmias is provided. The advancements presented here highlight how patient-specific computational models of the heart reconstructed from patient data have achieved success in predicting risk of sudden cardiac death and guiding optimal treatments of heart rhythm disorders. Finally, an outlook toward potential future advances, including the combination of mechanistic modeling and machine learning/artificial intelligence, is provided. As the field of cardiology is embarking on a journey toward precision medicine, personalized modeling of the heart is expected to become a key technology to guide pharmaceutical therapy, deployment of devices, and surgical interventions. [ABSTRACT FROM AUTHOR]

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 (R 2 = 0.84) and abolished in older adults (R 2 = 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. [ABSTRACT FROM AUTHOR]

Aim: Numerous recent reports have highlighted the association between mental disorders and electrocardiographic findings. The early repolarization pattern (ERP) on electrocardiogram has been linked with a history of suicide attempts and attention deficit hyperactivity disorder, and associations with impulsivity have also been reported. It is known that suicidal intent is more common at night. Patients who have a mental disorder and ERP may have a higher likelihood of impulsivity, potentially increasing the risk of suicide at night. Methods: The subjects were 43 patients with a history of suicide attempts who had undergone electrocardiographic examination at Jikei University School of Medicine Kashiwa Hospital and received intervention from our department. Due to the diurnal variation in electrocardiographic findings, only patients who underwent the examination during the daytime were included. Patients' clinical backgrounds were compared according to the presence or absence of ERP, and the association between nocturnal suicide attempts and ERP was examined using multivariate analysis. Results: The frequency of nocturnal suicidal behavior was 76.2% in patients with ERP and 31.8% in those without ERP, but the difference was not significant after Bonferroni correction. In the multivariate analysis, there was a significant association of ERP with nocturnal suicide attempts (p = 0.018). Conclusion: The finding of an association between ERP and nocturnal suicide attempts indicates that ERP is a biological indicator that can predict nocturnal suicide attempts. [ABSTRACT FROM AUTHOR]

Single ventricle patients, including those with hypoplastic left heart syndrome (HLHS), typically undergo three palliative heart surgeries culminating in the Fontan procedure. HLHS is associated with high rates of morbidity and mortality, and many patients develop arrhythmias, electrical dyssynchrony, and eventually ventricular failure. However, the correlation between ventricular enlargement and electrical dysfunction in HLHS physiology remains poorly understood. Here we characterize the relationship between growth and electrophysiology in HLHS using computational modeling. We integrate a personalized finite element model, a volumetric growth model, and a personalized electrophysiology model to perform controlled in silico experiments. We show that right ventricle enlargement negatively affects QRS duration and interventricular dyssynchrony. Conversely, left ventricle enlargement can partially compensate for this dyssynchrony. These findings have potential implications on our understanding of the origins of electrical dyssynchrony and, ultimately, the treatment of HLHS patients. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The incidence of perioperative arrhythmias is 4%~20% in noncardiac surgery and 10% ~ 30% in cardiothoracic surgery， with the incidence of perioperative arrhythmias in cardiac surgery patients as high as 90%. Perioperative arrhythmias can prolong hospitalization and increase morbidity and mortality during hospitalization. Studies have shown that aberrantly expressed microRNAs in cardiovascular diseases can participate in cardiac automaticity, excitability and conductivity by regulating ion channels, gap junction proteins, and intracellular Ca2+ handling proteins, thereby regulating cardiac electrophysiological homeostasis and arrhythmias. In this article, we will review the research progress of microRNAs and arrhythmias mainly from the perspective of cardiac electrophysiological imbalance. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

• Back pain is one of the most common problems experienced by patients due to, limitation of movement and immobilization of the affected leg after the electrophysiology study procedure. • The limitation of movement after the procedure negatively affects the comfort and satisfaction of patients. • Back massage with frankincense and myrrh oil increased overall comfort, physical comfort, the psychospiritual comfort. • Massage with frankincense and myrrh oil can be recommended as a complementary and integrative treatment to improve comfort in patients who are to undergo cardiac electrophysiological study. Back pain is one of the most common problems experienced by patients after the cardiac electrophysiological study procedure. In addition, limitation of movement after the procedure negatively affects the comfort and satisfaction of patients. The aim of this study was to determine the effect of back massage with frankincense and myrrh oil on back pain severity and comfort in patients who were to undergo cardiac electrophysiological study. This is a randomized controlled study with a pretest–posttest design. This study was conducted from October 2020 to March 2021, at the angio unit of a heart hospital at a university in Turkey. The study was completed with 30 patients in each group, a total of 90 people. Data were collected using a patient information form, a Visual Analogue Scale (VAS) and the General Comfort Questionnaire (GCQ). The intervention group and the placebo group received back massage with frankincense and myrrh essential oil and with jojoba fixed oil respectively. No intervention was applied to the control group. There was no statistically significant difference between the post-procedure VAS values according to the groups. Except for sociocultural comfort, there were significant differences between the groups in terms of GCQ total scores and subscales at the first and last follow-up. Back massage with frankincense and myrrh oil increased overall comfort, physical comfort, the psychospiritual comfort. Additional research with a rigorous design is needed to determine its effect on pain. [ABSTRACT FROM AUTHOR]

BackgroundThe 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.MethodsBased 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 (ESAC) 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.ResultsIn models with healthy tissue or fibrosis modeled solely as CV slowing, we observed two vulnerable periods of reentry: For ESAC of −10 and −30 mV, SAC activated during the T-wave could cause depolarization of the SAC region which lead to reentry. For ESAC 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).ConclusionStretch 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.

Multi-modal single cell RNA assays capture RNA content as well as other data modalities, such as spatial cell position or the electrophysiological properties of cells. Compared to dedicated scRNA-seq assays however, they may unintentionally capture RNA from multiple adjacent cells, exhibit lower RNA sequencing depth compared to scRNA-seq, or lack genome-wide RNA measurements. We present scProjection, a method for mapping individual multi-modal RNA measurements to deeply sequenced scRNA-seq atlases to extract cell type-specific, single cell gene expression profiles. We demonstrate several use cases of scProjection, including identifying spatial motifs from spatial transcriptome assays, distinguishing RNA contributions from neighboring cells in both spatial and multi-modal single cell assays, and imputing expression measurements of un-measured genes from gene markers. scProjection therefore combines the advantages of both multi-modal and scRNA-seq assays to yield precise multi-modal measurements of single cells.

Myocardial infarction (MI) and its associated complications including ventricular arrhythmias and heart failure are responsible for a significant incidence of morbidity and mortality worldwide. The ensuing cardiomyocyte loss results in neurohormone‐driven cardiac remodeling, which leads to chronic heart failure in MI survivors. Ivabradine is a heart rate modulation agent currently used in treatment of chronic heart failure with reduced ejection fraction. The canonical target of ivabradine is the hyperpolarization‐activated cyclic nucleotide‐gated channels (HCN) in cardiac pacemaker cells. However, in post‐MI hearts, HCN can also be expressed ectopically in non‐pacemaker cardiomyocytes. There is an accumulation of intriguing evidence to suggest that ivabradine also possesses cardioprotective effects that are independent of heart rate reduction. This review aims to summarize and discuss the reported cardioprotective mechanisms of ivabradine beyond heart rate modulation in myocardial infarction through various molecular mechanisms including the prevention of reactive oxygen species‐induced mitochondrial damage, improvement of autophagy system, modulation of intracellular calcium cycling, modification of ventricular electrophysiology, and regulation of matrix metalloproteinases. [ABSTRACT FROM AUTHOR]

T‐tubules (TT) form a complex network of sarcolemmal membrane invaginations, essential for well‐co‐ordinated excitation–contraction coupling (ECC) and thus homogeneous mechanical activation of cardiomyocytes. ECC is initiated by rapid depolarization of the sarcolemmal membrane. Whether TT membrane depolarization is active (local generation of action potentials; AP) or passive (following depolarization of the outer cell surface sarcolemma; SS) has not been experimentally validated in cardiomyocytes. Based on the assessment of ion flux pathways needed for AP generation, we hypothesize that TT are excitable. We therefore explored TT excitability experimentally, using an all‐optical approach to stimulate and record trans‐membrane potential changes in TT that were structurally disconnected, and hence electrically insulated, from the SS membrane by transient osmotic shock. Our results establish that cardiomyocyte TT can generate AP. These AP show electrical features that differ substantially from those observed in SS, consistent with differences in the density of ion channels and transporters in the two different membrane domains. We propose that TT‐generated AP represent a safety mechanism for TT AP propagation and ECC, which may be particularly relevant in pathophysiological settings where morpho‐functional changes reduce the electrical connectivity between SS and TT membranes. Key points: Cardiomyocytes are characterized by a complex network of membrane invaginations (the T‐tubular system) that propagate action potentials to the core of the cell, causing uniform excitation–contraction coupling across the cell.In the present study, we investigated whether the T‐tubular system is able to generate action potentials autonomously, rather than following depolarization of the outer cell surface sarcolemma.For this purpose, we developed a fully optical platform to probe and manipulate the electrical dynamics of subcellular membrane domains.Our findings demonstrate that T‐tubules are intrinsically excitable, revealing distinct characteristics of self‐generated T‐tubular action potentials.This active electrical capability would protect cells from voltage drops potentially occurring within the T‐tubular network. [ABSTRACT FROM AUTHOR]

Anaesthetists play a key role in the management of patients in the cardiac catheterization laboratory (cath lab), both for elective and emergency procedures. Safe and effective provision of anaesthesia relies on a thorough appreciation of the setup of the cath lab and an understanding of the ever-increasing range of procedures carried out in the angiography suite. This article provides an overview of general considerations for working in this challenging environment within the hospital, as well as outlining key cardiology subspecialties and their requisites for the anaesthetist: electrophysiology, structural, interventional, devices and mechanical circulatory support. [ABSTRACT FROM AUTHOR]

[Display omitted] • The healthcare system is a significant contributor to global warming. • Cardiac electrophysiology mainly uses high-tech single-use medical devices. • Worldwide complex supply chain for medical treatment, particularly medical devices. • The complex supply chain has led to device shortages. • Reprocessing of medical devices labelled single use could be part of the solution. • All stakeholders must engage sustainability efforts. Sustainability in healthcare, particularly within the domain of cardiac electrophysiology, assumes paramount importance for the near future. The escalating environmental constraints encountered necessitate a proactive approach. This position paper aims to raise awareness among physicians, spark critical inquiry and identify potential solutions to enhance the sustainability of our practice. Reprocessing of single-use medical devices has emerged as a potential solution to mitigate the environmental impact of electrophysiology procedures, while also offering economic advantages. However, reprocessing remains unauthorized in certain countries. In regions where it is possible, stringent regulatory standards must be adhered to, to ensure patient safety. It is essential that healthcare professionals, policymakers and manufacturers collaborate to drive innovation, explore sustainable practices and ensure that patient care remains uncompromised in the face of environmental challenges. Ambitious national/international programmes of disease prevention should be the cornerstone of the strategy. It is equally vital to implement immediate actions, as delineated in this position paper, to bring about tangible change quickly. [ABSTRACT FROM AUTHOR]

Background: The rapid delayed rectifier potassium current (IKr) is important for cardiac repolarization and is most often involved in drug-induced arrhythmias. However, accurately measuring this current can be challenging in human-induced pluripotent stem cell (hiPSC)-derived cardiomyocytes because of its small current density. Interestingly, the ion channel conducting IKr, hERG channel, is not only permeable to K+ ions but also to Cs+ ions when present in equimolar concentrations inside and outside of the cell.Methods: In this study, IhERG was measured from Chinese hamster ovary (CHO)-hERG cells and hiPSC-CM using either Cs+ or K+ as the charge carrier. Equimolar Cs+ has been used in the literature in manual patch-clamp experiments, and here, we apply this approach using automated patch-clamp systems. Four different (pre)clinical drugs were tested to compare their effects on Cs+- and K+-based currents.Results: Using equimolar Cs+ solutions gave rise to approximately ten-fold larger hERG conductances. Comparison of Cs+- and K+-mediated currents upon application of dofetilide, desipramine, moxifloxacin, or LUF7244 revealed many similarities in inhibition or activation properties of the drugs studied. Using equimolar Cs+ solutions gave rise to approximately ten-fold larger hERG conductances. In hiPSC-CM, the Cs+-based conductance is larger compared to the known K+-based conductance, and the Cs+ hERG conductance can be inhibited similarly to the K+-based conductance.Conclusion: Using equimolar Cs+ instead of K+ for IhERG measurements in an automated patch-clamp system gives rise to a new method by which, for example, quick scans can be performed on effects of drugs on hERG currents. This application is specifically relevant when such experiments are performed using cells which express small IKr current densities in combination with small membrane capacitances. [ABSTRACT FROM AUTHOR]

Significance: Radiofrequency ablation (RFA) procedures for atrial fibrillation frequently fail to prevent recurrence, partially due to limitations in assessing extent of ablation. Optical spectroscopy shows promise in assessing RFA lesion formation but has not been validated in conditions resembling those in vivo. Aim: Catheter-based near-infrared spectroscopy (NIRS) was applied to porcine hearts to demonstrate that spectrally derived optical indices remain accurate in blood and at oblique incidence angles. Approach: Porcine left atria were ablated and mapped using a custom-fabricated NIRS catheter. Each atrium was mapped first in phosphate-buffered saline (PBS) then in porcine blood. Results: NIRS measurements showed little angle dependence up to 60 deg. A trained random forest model predicted lesions with a sensitivity of 81.7%, a specificity of 86.1%, and a receiver operating characteristic curve area of 0.921. Predicted lesion maps achieved a mean structural similarity index of 0.749 and a mean normalized inner product of 0.867 when comparing maps obtained in PBS and blood. Conclusions: Catheter-based NIRS can precisely detect RFA lesions on left atria submerged in blood. Optical parameters are reliable in blood and without perpendicular contact, confirming their ability to provide useful feedback during in vivo RFA procedures. [ABSTRACT FROM AUTHOR]

The electrophysiological evolution of atrial fibrillation, the most common of rhythm disturbances of the heart, is compared with that of human behaviour, philosophy, and interpersonal relationships. The well-documented principles of cardiac arrhythmia pathophysiology--trigger, substrate, and remodelling apply in both situations. Atrial disease ultimately becomes irreversible and, in this respect, differs from human behaviour where permanent scarring of the mind does not occur allowing a clean slate to be applied with dismissal of pre-existing biases. Comprehension of cardiac electrophysiological principles together with psychology and philosophy could benefit human interaction even at a global level. [ABSTRACT FROM AUTHOR]

Hypothyroidism is the most frequent endocrine pathology. Although clinical or overt hypothyroidism has been traditionally associated to low T3 / T4 and high thyrotropin (TSH) circulating levels, other forms exist such as subclinical hypothyroidism, characterized by normal blood T3 / T4 and high TSH. In its different forms is estimated to affect approximately 10% of the population, especially women, in a 5:1 ratio with respect to men. Among its consequences are alterations in cardiac electrical activity, especially in the repolarization phase, which is accompanied by an increased susceptibility to cardiac arrhythmias. Although these alterations have traditionally been attributed to thyroid hormone deficiency, recent studies, both clinical trials and experimental models, demonstrate a fundamental role of TSH in cardiac electrical remodeling. Thus, both metabolic thyroid hormones and TSH regulate cardiac ion channel expression in many and varied ways. This means that the different combinations of hormones that predominate in different types of hypothyroidism (overt, subclinic, primary, central) can generate different forms of cardiac electrical remodeling. These new findings are raising the relevant question of whether serum TSH reference ranges should be redefined. [ABSTRACT FROM AUTHOR]

Cardiac electrophysiology is an evolving field that relies heavily on costly device- and catheter-based technologies. An increasing number of patients with heart rhythm disorders are becoming eligible for cardiac interventions, not least due to the rising prevalence of atrial fibrillation and increased longevity in the population. Meanwhile, the expansive costs of healthcare face finite societal resources, and a cost-conscious approach to new technologies is critical. Cost-effectiveness analyses support rational decision-making in healthcare by evaluating the ratio of healthcare costs to health benefits for competing therapies. They may, however, be subject to significant uncertainty and bias. This paper aims to introduce the basic concepts, framework, and limitations of cost-effectiveness analyses to clinicians including recent examples from clinical electrophysiology and device therapy. [ABSTRACT FROM AUTHOR]

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.

Amiodarone is a benzofuran-based class III antiarrhythmic agent frequently used for the treatment of atrial and ventricular arrhythmias. The primary target of class III antiarrhythmic drugs is the cardiac human ether-a-go-go-related gene (hERG) encoded channel, KCNH2, commonly known as HERG, that conducts the rapidly activating delayed rectifier potassium current (IKr). Like other class III antiarrhythmic drugs, amiodarone exerts its physiologic effects mainly through IKr blockade, delaying the repolarization phase of the action potential and extending the effective refractory period. However, while many class III antiarrhythmics, including sotalol and dofetilide, can cause long QT syndrome (LQTS) that can progress to torsade de pointes, amiodarone displays less risk of inducing this fatal arrhythmia. This review article discusses the arrhythmogenesis in LQTS from the aspects of the development of early afterdepolarizations (EADs) associated with Ca2+ current, transmural dispersion of repolarization (TDR), as well as reverse use dependence associated with class III antiarrhythmic drugs to highlight electropharmacological effects of amiodarone on the myocardium.

A common genetic risk factor for bipolar disorder is CACNA1C, a gene that is also critical for cardiac rhythm. The impact of CACNA1C mutations on bipolar patient cardiac rhythm is unknown. Here, we report the cardiac electrophysiological implications of a bipolar disorder–associated genetic risk factor in CACNA1C using patient induced pluripotent stem cell-derived cardiomyocytes. Results indicate that the CACNA1C bipolar disorder–related mutation causes cardiac electrical impulse conduction slowing mediated by impaired intercellular coupling via connexin 43 gap junctions. In vitro gene therapy to restore connexin 43 expression increased cardiac electrical impulse conduction velocity and protected against thioridazine-induced QT prolongation. Patients positive for bipolar disorder CACNA1C genetic risk factors may have elevated proarrhythmic risk for adverse events in response to psychiatric medications that slow conduction or prolong the QT interval. This in vitro diagnostic tool enables cardiac testing specific to patients with psychiatric disorders to determine their sensitivity to off-target effects of psychiatric medications.

BackgroundThe EnSite Precision™ cardiac mapping system (Abbott) is a catheter navigation and mapping system capable of displaying the three-dimensional (3D) position of conventional and sensor-enabled electrophysiology catheters, as well as displaying cardiac electrical activity as waveform traces and dynamic 3D maps of cardiac chambers. The EnSite Precision™ Observational Study (NCT-03260244) was designed to quantify and characterize the use of the EnSite Precision™ cardiac mapping system for mapping and ablation of cardiac arrhythmias in a real-world environment and evaluate procedural outcomes.MethodsA total of 1065 patients were enrolled at 38 centers in the USA and Canada between 2017 and 2018 and were followed for 12 months post procedure for arrhythmia recurrence, medication use, and quality-of-life changes. Eligible subjects were adults undergoing a cardiac electrophysiology mapping and radiofrequency ablation procedure using the EnSite Precision™ System.ResultsA final cohort of 925 patients (64.3 years of age, 30.2% female) were analyzed. The primary procedural indication was atrial flutter in 48.1% (445/925), atrial fibrillation in 46.5% (430/925), and other arrhythmias in 5% (50/925). Electroanatomic mapping was performed in 81.5% (754/925) of patients. Mapping was stable throughout 79.8% (738/925) of procedures with initial mapping time of 8.6 min (IQR 4.7-15.0). Average mapping efficiency created with AutoMap or TurboMap was 164.9 ± 365.7 used points per minute. Median number of mapping points collected and used was 1752.5 and 811.0, respectively. Only 335/925 (36.2%) required editing and 66.0% (221/335) of these patients required editing of less than 10 points. Fluoroscopy was utilized in most cases (n = 811/925, 87.4%) with fluoroscopy time of 11.0 min (IQR 6.0-18.0). Overall median procedure time was 101.0 min (IQR 59.0-152.0). Acute procedural success was high for both atrial fibrillation (n = 422/430, 98.1%) and atrial flutter (n = 434/445, 97.5%).ConclusionIn a real-world study analysis, use of the EnSite Precision™ mapping system was associated with high procedural stability, short mapping times, high point density requiring infrequent editing, low fluoroscopy time, and high prevalence of acute procedural success.

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.

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.

(1) Background: The main factors and their interrelationships contributing to cardiac repolarization alternans (CRA) remain unclear. This study aimed to elucidate the calcium (Ca2+)-related mechanisms underlying myocardial ischemia (MI)-induced CRA. (2) Materials and Methods: CRA was induced using S1 stimuli for pacing in an in silico ventricular model with MI. The standard deviations of nine Ca2+-related subcellular parameters among heartbeats from 100 respective nodes with and without alternans were chosen as features, including the maximum systole and end-diastole and corresponding differences in the Ca2+ concentration in the intracellular region([Ca2+]i) and junctional sarcoplasmic reticulum ([Ca2+]jsr), as well as the maximum opening of the L-type Ca2+ current (ICaL) voltage-dependent activation gate (d-gate), maximum closing of the inactivation gate (ff-gate), and the gated channel opening time (GCOT). Feature selection was applied to determine the importance of these features. (3) Results: The major parameters affecting CRA were the differences in [Ca2+]i at end-diastole, followed by the extent of d-gate activation and GCOT among beats. (4) Conclusions: MI-induced CRA is primarily characterized by functional changes in Ca2+ re-uptake, leading to alternans of [Ca2+]i and subsequent alternans of ICaL-dependent properties. The combination of computational simulation and machine learning shows promise in researching the underlying mechanisms of cardiac electrophysiology.

Background: Myocardial delivery of non-excitable cells--namely human mesenchymal stem cells (hMSCs) and c-kit+ cardiac interstitial cells (hCICs)--remains a promising approach for treating the failing heart. Recent empirical studies attempt to improve such therapies by genetically engineering cells to express specific ion channels, or by creating hybrid cells with combined channel expression. This study uses a computational modeling approach to test the hypothesis that custom hypothetical cells can be rationally designed to restore a healthy phenotype when coupled to human heart failure (HF) cardiomyocytes. Methods: Candidate custom cells were simulated with a combination of ion channels from non-excitable cells and healthy human cardiomyocytes (hCMs). Using a genetic algorithm-based optimization approach, candidate cells were accepted if a root mean square error (RMSE) of less than 50% relative to healthy hCM was achieved for both action potential and calcium transient waveforms for the cell-treated HF cardiomyocyte, normalized to the untreated HF cardiomyocyte. Results: Custom cells expressing only non-excitable ion channels were inadequate to restore a healthy cardiac phenotype when coupled to either fibrotic or nonfibrotic HF cardiomyocytes. In contrast, custom cells also expressing cardiac ion channels led to acceptable restoration of a healthy cardiomyocyte phenotype when coupled to fibrotic, but not non-fibrotic, HF cardiomyocytes. Incorporating the cardiomyocyte inward rectifier K+ channel was critical to accomplishing this phenotypic rescue while also improving single-cell action potential metrics associated with arrhythmias, namely resting membrane potential and action potential duration. The computational approach also provided insight into the rescue mechanisms, whereby heterocellular coupling enhanced cardiomyocyte L-type calcium current and promoted calcium-induced calcium release. Finally, as a therapeutically translatable strategy, we simulated delivery of hMSCs and hCICs genetically engineered to express the cardiomyocyte inward rectifier K+ channel, which decreased action potential and calcium transient RMSEs by at least 24% relative to control hMSCs and hCICs, with more favorable single-cell arrhythmia metrics. Conclusion: Computational modeling facilitates exploration of customizable engineered cell therapies. Optimized cells expressing cardiac ion channels restored healthy action potential and calcium handling phenotypes in fibrotic HF cardiomyocytes and improved single-cell arrhythmia metrics, warranting further experimental validation studies of the proposed custom therapeutic cells. [ABSTRACT FROM AUTHOR]