Role of Computed Tomography in Cardiac Electrophysiology.

With the increasing prevalence of arrhythmias, the use of electrophysiology (EP) procedures has increased. Recent advancements in computed tomography (CT) technology have expanded its use in pre-assessments and post-assessments of EP procedures. CT provides high-resolution images, is noninvasive, and is widely available. This article highlights the strengths and weaknesses of cardiac CT in EP.

Economic analyses in cardiac electrophysiology: from clinical efficacy to cost utility.

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.

The effect of back massage with frankincense and myrrh oil before the cardiac electrophysiological procedure on back pain intensity and comfort: A single-blind randomized controlled trial.

CONTEXT: 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. OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Optogenetic Modulation of Arrhythmia Triggers: Proof-of-Concept from Computational Modeling.

Introduction: Early afterdepolarizations (EADs) are secondary voltage depolarizations associated with reduced repolarization reserve (RRR) that can trigger lethal arrhythmias. Relating EADs to triggered activity is difficult to study, so the ability to suppress or provoke EADs would be experimentally useful. Here, we use computational simulations to assess the feasibility of subthreshold optogenetic stimulation modulating the propensity for EADs (cell-scale) and EAD-associated ectopic beats (organ-scale). Methods: We modified a ventricular ionic model by reducing rapid delayed rectifier potassium (0.25-0.1 × baseline) and increasing L-type calcium (1.0-3.5 × baseline) currents to create RRR conditions with varying severity. We ran simulations in models of single cardiomyocytes and left ventricles from post-myocardial infarction patient MRI scans. Optogenetic stimulation was simulated using either ChR2 (depolarizing) or GtACR1 (repolarizing) opsins. Results: In cell-scale simulations without illumination, EADs were seen for 164 of 416 RRR conditions. Subthreshold stimulation of GtACR1 reduced EAD incidence by up to 84.8% (25/416 RRR conditions; 0.1 µW/mm2); in contrast, subthreshold ChR2 excitation increased EAD incidence by up to 136.6% (388/416 RRR conditions; 50 µW/mm2). At the organ scale, we assumed simultaneous, uniform illumination of the epicardial and endocardial surfaces. GtACR1-mediated suppression (10-50 µW/mm2) and ChR2-mediated unmasking (50-100 µW/mm2) of EAD-associated ectopic beats were feasible in three distinct ventricular models. Conclusions: Our findings suggest that optogenetics could be used to silence or provoke both EADs and EAD-associated ectopic beats. Validation in animal models could lead to exciting new experimental regimes and potentially to novel anti-arrhythmia treatments. Supplementary Information: The online version contains supplementary material available at 10.1007/s12195-023-00781-z.

lifex-ep: a robust and efficient software for cardiac electrophysiology simulations.

BACKGROUND: Simulating the cardiac function requires the numerical solution of multi-physics and multi-scale mathematical models. This underscores the need for streamlined, accurate, and high-performance computational tools. Despite the dedicated endeavors of various research teams, comprehensive and user-friendly software programs for cardiac simulations, capable of accurately replicating both normal and pathological conditions, are still in the process of achieving full maturity within the scientific community. RESULTS: This work introduces [Formula: see text]-ep, a publicly available software for numerical simulations of the electrophysiology activity of the cardiac muscle, under both normal and pathological conditions. [Formula: see text]-ep employs the monodomain equation to model the heart's electrical activity. It incorporates both phenomenological and second-generation ionic models. These models are discretized using the Finite Element method on tetrahedral or hexahedral meshes. Additionally, [Formula: see text]-ep integrates the generation of myocardial fibers based on Laplace-Dirichlet Rule-Based Methods, previously released in Africa et al., 2023, within [Formula: see text]-fiber. As an alternative, users can also choose to import myofibers from a file. This paper provides a concise overview of the mathematical models and numerical methods underlying [Formula: see text]-ep, along with comprehensive implementation details and instructions for users. [Formula: see text]-ep features exceptional parallel speedup, scaling efficiently when using up to thousands of cores, and its implementation has been verified against an established benchmark problem for computational electrophysiology. We showcase the key features of [Formula: see text]-ep through various idealized and realistic simulations conducted in both normal and pathological scenarios. Furthermore, the software offers a user-friendly and flexible interface, simplifying the setup of simulations using self-documenting parameter files. CONCLUSIONS: [Formula: see text]-ep provides easy access to cardiac electrophysiology simulations for a wide user community. It offers a computational tool that integrates models and accurate methods for simulating cardiac electrophysiology within a high-performance framework, while maintaining a user-friendly interface. [Formula: see text]-ep represents a valuable tool for conducting in silico patient-specific simulations.

The Role of TRPM4 in Cardiac Electrophysiology and Arrhythmogenesis.

The transient receptor potential melastatin 4 (TRPM4) channel is a non-selective cation channel that activates in response to increased intracellular Ca2+ levels but does not allow Ca2+ to pass through directly. It plays a crucial role in regulating diverse cellular functions associated with intracellular Ca2+ homeostasis/dynamics. TRPM4 is widely expressed in the heart and is involved in various physiological and pathological processes therein. Specifically, it has a significant impact on the electrical activity of cardiomyocytes by depolarizing the membrane, presumably via Na+ loading. The TRPM4 channel likely contributes to the development of cardiac arrhythmias associated with specific genetic backgrounds and cardiac remodeling. This short review aims to overview what is known so far about the TRPM4 channel in cardiac electrophysiology and arrhythmogenesis, highlighting its potential as a novel therapeutic target to effectively prevent and treat cardiac arrhythmias.

Effects of hydroxychloroquine on atrial electrophysiology in in silico wild-type and PITX2+/- atrial cardiomyocytes.

BACKGROUND: Hydroxychloroquine (HCQ) is commonly used in the treatment of autoimmune diseases and increases the risk of QT interval prolongation. However, it is unclear how HCQ affects atrial electrophysiology and the risk of atrial fibrillation (AF). METHODS: We quantitatively examined the potential atrial arrhythmogenic effects of HCQ on AF using a computational model of human atrial cardiomyocytes. We measured atrial electrophysiological markers after systematically varying HCQ concentrations. RESULTS: The HCQ concentrations were positively correlated with the action potential duration (APD), resting membrane potential, refractory period, APD alternans threshold, and calcium transient alternans threshold (p < 0.05). By contrast, HCQ concentrations were inversely correlated with the maximum upstroke velocity and calcium transient amplitude (p < 0.05). When the therapeutic concentration (Cmax) of HCQ was applied, HCQ increased APD90 by 1.4% in normal sinus rhythm, 1.8% in wild-type AF, and 2.6% in paired-like homeodomain transcription factor 2 (PITX2)+/- AF, but did not affect the alternans thresholds. The overall in silico results suggest no significant atrial arrhythmogenic effects of HCQ at Cmax, instead implying a potential antiarrhythmic role of low-dose HCQ in AF. However, at an HCQ concentration of fourfold Cmax, a rapid pacing rate of 4 Hz induced prominent APD alternans, particularly in the PITX2+/- AF model. CONCLUSION: Our in silico analysis suggests a potential antiarrhythmic role of low-dose HCQ in AF. Concomitant PITX2 mutations and high-dose HCQ treatments may increase the risk of AF, and this potential genotype/dose-dependent arrhythmogenic effect of HCQ should be investigated further.

Portable low-cost macroscopic mapping system for all-optical cardiac electrophysiology.

Significance: All-optical cardiac electrophysiology enables the visualization and control of key parameters relevant to the detection of cardiac arrhythmias. Mapping such responses in human induced pluripotent stem-cell-derived cardiomyocytes (hiPSC-CMs) is of great interest for cardiotoxicity and personalized medicine applications. Aim: We introduce and validate a very low-cost compact mapping system for macroscopic all-optical electrophysiology in layers of hiPSC-CMs. Approach: The system uses oblique transillumination, low-cost cameras, light-emitting diodes, and off-the-shelf components (total < $ 15 , 000 ) to capture voltage, calcium, and mechanical waves under electrical or optical stimulation. Results: Our results corroborate the equivalency of electrical and optogenetic stimulation of hiPSC-CMs, and V m - [ Ca 2 + ] i similarity in conduction under pacing. Green-excitable optical sensors are combinable with blue optogenetic actuators (chanelrhodopsin2) only under very low green light ( < 0.05 mW / mm 2 ). Measurements in warmer culture medium yield larger spread of action potential duration and higher conduction velocities compared to Tyrode's solution at room temperature. Conclusions: As multiple optical sensors and actuators are combined, our results can help handle the "spectral congestion" and avoid parameter distortion. We illustrate the utility of the system for uncovering the action of cellular uncoupling agents and show extensibility to an epi-illumination mode for future imaging of thicker native or engineered tissues.

The effect of sex and age on ex vivo cardiac electrophysiology: insight from a guinea pig model.

Highlighting the importance of sex as a biological variable, we recently reported sex differences in guinea pig in vivo electrocardiogram (ECG) measurements. However, substantial inconsistencies exist in this animal model, with conflicting reports of sex-specific differences in cardiac electrophysiology observed in vivo and in vitro. Herein, we evaluated whether sexual dimorphism persists in ex vivo preparations, using an isolated intact heart preparation. Pseudo-ECG recordings were collected in conjunction with dual optical mapping of transmembrane voltage and intracellular calcium from Langendorff-perfused hearts. In contrast to our in vivo results, we did not observe sex-specific differences in ECG parameters collected from isolated hearts. Furthermore, we observed significant age-specific differences in action potential duration (APD) and Ca2+ transient duration (CaD) during both normal sinus rhythm (NSR) and in response to dynamic pacing but only a modest sex-specific difference in CaD30. Similarly, the alternans fluctuation coefficient, conduction velocity during sinus rhythm or in response to pacing, and electrophysiology parameters (atrioventricular nodal effective refractory period, Wenckebach cycle length) were comparable between males and females. Results of our study suggest that the observed sex-specific differences in in vivo ECG parameters from guinea pigs are diminished in ex vivo isolated heart preparations, although age-specific patterns are prevalent. To assess sex as a biological variable in cardiac electrophysiology, a comprehensive approach may be necessary using both in vitro measurements from cardiomyocyte or intact heart preparations with secondary follow-up in vivo studies.NEW & NOTEWORTHY We evaluated whether the guinea pig heart has intrinsic sex-specific differences in cardiac electrophysiology. Although we observed sex-specific differences in in vivo ECGs, these differences did not persist ex vivo. Using a whole heart model, we observed similar APD, CaD, conduction velocity, and alternans susceptibility in males and females. We conclude that sex-specific differences in guinea pig cardiac electrophysiology are likely influenced by the in vivo environment and less dependent on the intrinsic electrical properties of the heart.

An inner-outer subcycling algorithm for parallel cardiac electrophysiology simulations.

This paper explores cardiac electrophysiological simulations of the monodomain equations and introduces a novel subcycling time integration algorithm to exploit the structure of the ionic model. The aim of this work is to improve upon the efficiency of parallel cardiac monodomain simulations by using our subcycling algorithm in the computation of the ionic model to handle the local sharp changes of the solution. This will reduce the turnaround time for the simulation of basic cardiac electrical function on both idealized and patient-specific geometry. Numerical experiments show that the proposed approach is accurate and also has close to linear parallel scalability on a computer with more than 1000 processor cores. Ultimately, the reduction in simulation time can be beneficial in clinical applications, where multiple simulations are often required to tune a model to match clinical measurements.

Efficient time splitting schemes for the monodomain equation in cardiac electrophysiology.

Approximating the fast dynamics of depolarization waves in the human heart described by the monodomain model is numerically challenging. Splitting methods for the PDE-ODE coupling enable the computation with very fine space and time discretizations. Here, we compare different splitting approaches regarding convergence, accuracy, and efficiency. Simulations were performed for a benchmark problem with the Beeler-Reuter cell model on a truncated ellipsoid approximating the left ventricle including a localized stimulation. For this configuration, we provide a reference solution for the transmembrane potential. We found a semi-implicit approach with state variable interpolation to be the most efficient scheme. The results are transferred to a more physiological setup using a bi-ventricular domain with a complex external stimulation pattern to evaluate the accuracy of the activation time for different resolutions in space and time.

Advances in Cardiac Electrophysiology.

Despite the global COVID-19 pandemic, during the past 2 years, there have been numerous advances in our understanding of arrhythmia mechanisms and diagnosis and in new therapies. We increased our understanding of risk factors and mechanisms of atrial arrhythmias, the prediction of atrial arrhythmias, response to treatment, and outcomes using machine learning and artificial intelligence. There have been new technologies and techniques for atrial fibrillation ablation, including pulsed field ablation. There have been new randomized trials in atrial fibrillation ablation, giving insight about rhythm control, and long-term outcomes. There have been advances in our understanding of treatment of inherited disorders such as catecholaminergic polymorphic ventricular tachycardia. We have gained new insights into the recurrence of ventricular arrhythmias in the setting of various conditions such as myocarditis and inherited cardiomyopathic disorders. Novel computational approaches may help predict occurrence of ventricular arrhythmias and localize arrhythmias to guide ablation. There are further advances in our understanding of noninvasive radiotherapy. We have increased our understanding of the role of His bundle pacing and left bundle branch area pacing to maintain synchronous ventricular activation. There have also been significant advances in the defibrillators, cardiac resynchronization therapy, remote monitoring, and infection prevention. There have been advances in our understanding of the pathways and mechanisms involved in atrial and ventricular arrhythmogenesis.

Guidelines for assessment of cardiac electrophysiology and arrhythmias in small animals.

Cardiac arrhythmias are a major cause of morbidity and mortality worldwide. Although recent advances in cell-based models, including human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM), are contributing to our understanding of electrophysiology and arrhythmia mechanisms, preclinical animal studies of cardiovascular disease remain a mainstay. Over the past several decades, animal models of cardiovascular disease have advanced our understanding of pathological remodeling, arrhythmia mechanisms, and drug effects and have led to major improvements in pacing and defibrillation therapies. There exist a variety of methodological approaches for the assessment of cardiac electrophysiology and a plethora of parameters may be assessed with each approach. This guidelines article will provide an overview of the strengths and limitations of several common techniques used to assess electrophysiology and arrhythmia mechanisms at the whole animal, whole heart, and tissue level with a focus on small animal models. We also define key electrophysiological parameters that should be assessed, along with their physiological underpinnings, and the best methods with which to assess these parameters.

Uremic toxins in chronic kidney disease highlight a fundamental gap in understanding their detrimental effects on cardiac electrophysiology and arrhythmogenesis.

Chronic kidney disease (CKD) and cardiovascular disease (CVD) have an estimated 700-800 and 523 million cases worldwide, respectively, with CVD being the leading cause of death in CKD patients. The pathophysiological interplay between the heart and kidneys is defined as the cardiorenal syndrome (CRS), in which worsening of kidney function is represented by increased plasma concentrations of uremic toxins (UTs), culminating in dialysis patients. As there is a high incidence of CVD in CKD patients, accompanied by arrhythmias and sudden cardiac death, knowledge on electrophysiological remodeling would be instrumental for understanding the CRS. While the interplay between both organs is clearly of importance in CRS, the involvement of UTs in pro-arrhythmic remodeling is only poorly investigated, especially regarding the mechanistic background. Currently, the clinical approach against potential arrhythmic events is mainly restricted to symptom treatment, stressing the need for fundamental research on UT in relation to electrophysiology. This review addresses the existing knowledge of UTs and cardiac electrophysiology, and the experimental research gap between fundamental research and clinical research of the CRS. Clinically, mainly absorbents like ibuprofen and AST-120 are studied, which show limited safe and efficient usability. Experimental research shows disturbances in cardiac electrical activation and conduction after inducing CKD or exposure to UTs, but are scarcely present or focus solely on already well-investigated UTs. Based on UTs data derived from CKD patient cohort studies, a clinically relevant overview of physiological and pathological UTs concentrations is created. Using this, future experimental research is stimulated to involve electrophysiologically translatable animals, such as rabbits, or in vitro engineered heart tissues.

Effects of dexmedetomidine on cardiac electrophysiology in patients undergoing general anesthesia during perioperative period: a randomized controlled trial.

BACKGROUND: Dexmedetomidine has controversial influence on cardiac electrophysiology. The aim of this study was to explore the effects of dexmedetomidine on perioperative cardiac electrophysiology in patients undergoing general anesthesia. METHODS: Eighty-one patients were randomly divided into four groups: groups D1, D2, D3 receiving dexmedetomidine 1, 1, 0.5 µg/kg over 10 min and 1, 0.5, 0.5 µg/kg/h continuous infusion respectively, and control group (group C) receiving normal saline. Twelve-lead electrocardiograms were recorded at the time before dexmedetomidine/normal saline infusion (T1), loading dose finish (T2), surgery ending (T6), 1 h (T7) after entering PACU, 24 h (T8), 48 h (T9), 72 h (T10) and 1 month (T11) postoperatively. Cardiac circulation efficiency (CCE) were also recorded. RESULTS: Compared with group C, QTc were significantly increased at T2 in groups D1 and D2 while decreased at T7 and T8 in group D3 (P < 0.05), iCEB were decreased at T8 (P < 0.05). Compared with group D1, QTc at T2, T6, T7, T9 and T10 and iCEB at T8 were decreased, and CCE at T2-T4 were increased in group D3 significantly (P < 0.05). Compared with group D2, QTc at T2 and iCEB at T8 were decreased and CCE at T2 and T3 were increased in group D3 significantly (P < 0.05). CONCLUSIONS: Dexmedetomidine at a loading dose of 0.5 µg/kg and a maintenance dose of 0.5 µg/kg/h can maintain stability of cardiac electrophysiology during perioperative period and has no significant adverse effects on CCE. TRIAL REGISTRATION: ClinicalTrials.gov NCT04577430 (Date of registration: 06/10/2020).

Virtual Reality Hypnosis in the Electrophysiology Lab: When Human Treatments Are Better than Virtual Ones.

Aims: Virtual reality hypnosis (VRH) has been used successfully in various clinical settings to decrease anxiety and the sensation of pain. We aimed to investigate the feasibility and safety of VRH in patients undergoing electrophysiology and pacing procedures under conscious sedation. Methods: During a two-month period, VRH support was proposed and accepted by 25 patients undergoing electrophysiological procedures. Data were compared with a control group (n = 61) enrolled during the following three-month period. Both groups underwent the measurement of the duration of intervention, the consumption of analgesics and hypnotics, and their pain and comfort using a validated visual analogue scale (VAS 0−10). Results: The baseline characteristics were comparable in both groups, including age. There were no differences in procedure duration (46 (±29) vs. 56 (±32) min, p = 0.18) or in hypnotic/antalgic consumption (midazolam 1.95 (±1.44) vs. 2.00 (±1.22) mg, p = 0.83; sufentanyl 3.78 (±2.87) vs. 3.58 (±2.48) µg, p = 0.9) between the control and VRH groups. In a multivariate analysis, the use of VRH was independently associated with lower comfort during the procedure assessed by postoperative visual analogue scale (OR 15.00 [95% CI 4.77−47.16], p < 0.01). There was no influence of VRH use on pain or drug consumption. Conclusions: In our experience, compared with VRH, human care is preferable during procedures in electrophysiology lab to improve the comfort of the patient. VRH has no influence on pain or drug consumption.

Artificial Intelligence and Machine Learning in Cardiac Electrophysiology.

Cardiac electrophysiology requires the processing of several patient-specific data points in real time to provide an accurate diagnosis and determine an optimal therapy. Expanding beyond the traditional tools that have been used to extract information from patient-specific data, machine learning offers a new set of advanced tools capable of revealing previously unknown data patterns and features. This new tool set can substantially improve the speed and level of confidence with which electrophysiologists can determine patient-specific diagnoses and therapies. The ability to process substantial amounts of data in real time also paves the way to novel techniques for data collection and visualization. Extended realities such as virtual and augmented reality can now enable the real-time visualization of 3-dimensional images in space. This enables improved preprocedural planning and intraprocedural interventions. Machine learning supplemented with novel visualization technologies could substantially improve patient care and outcomes by helping physicians to make more informed patient-specific decisions. This article presents current applications of machine learning and their use in cardiac electrophysiology.

Holographic optogenetic stimulation with calcium imaging as an all optical tool for cardiac electrophysiology.

All optical approaches to control and read out the electrical activity in a cardiac syncytium can improve our understanding of cardiac electrophysiology. Here, we demonstrate optogenetic stimulation of cardiomyocytes with high spatial precision using light foci generated with a ferroelectric spatial light modulator. Computer generated holograms binarized by bidirectional error diffusion create multiple foci with more even intensity distribution compared with thresholding approach. We evoke the electrical activity of cardiac HL1 cells expressing the channelrhodopsin-2 variant, ChR2(H134R) using single and multiple light foci and at the same time visualize the action potential using a calcium sensitive indicator called Cal-630. We show that localized regions in the cardiac monolayer can be stimulated enabling us to initiate signal propagation from a precise location. Furthermore, we demonstrate that probing the cardiac cells with multiple light foci enhances the excitability of the cardiac network. This approach opens new applications in manipulating and visualizing the electrical activity in a cardiac syncytium.