Action Potential Duration Restitution Research Articles

Abstract 18867: A Novel Light-Sensitive Ex-Vivo Rat Atrial Anatomical Model for Studying Atrial Arrhythmias and Cardioversion

Introduction: Atrial arrhythmias, including atrial fibrillation (AF), contribute to significant morbidity and mortality. However, the lack of suitable tissue models in small animals hampers our understanding of the underlying mechanisms. Optogenetic actuators offer precise and reversible stimulation with high spatiotemporal resolution, presenting a unique opportunity to investigate atrial arrhythmias. Hypothesis: Our aim was to develop a light-sensitive ex-vivo anatomical model in rats for studying atrial arrhythmias and to utilize this model for optimizing optogenetic stimulation and cardioversion strategies. Methods: We injected purified AAV particles containing the transgenic light-sensitive channel (CoChR) into 5-day-old Wistar rats, followed by an 8-10 week period for atrial growth. The atria were then isolated, flattened, and affixed to a custom-made silicon plate. Superfusion with oxygenated Tyrode's solution and loading with Di-4-ANBDQBS allowed for high-resolution optical mapping. Atrial arrhythmias were induced through targeted tachypacing combined with carbamylcholine treatment. Additionally, we compared different optical and pharmacological treatment strategies to evaluate their efficacy in modulating atrial arrhythmias. Results: Immunostaining confirmed atrial expression of CoChR. Optical mapping revealed a functional syncytium with sinus node activation and propagation throughout the atria. Pacing at increasing frequencies resulted in a relatively flattened action potential duration restitution curve. Successful induction of reentrant arrhythmias was achieved. Additionally, we demonstrated the feasibility of optogenetic actuators for atrial pacing, modulation of spontaneous activity, and optical termination of arrhythmias. Conclusions: The developed optogenetic superfused atria model provides a valuable platform for studying atrial electrophysiology and modeling reentrant arrhythmias. Furthermore, it enables the optimization of optogenetic stimulation and cardioversion strategies. This integrated approach enhances our understanding of atrial arrhythmias and holds promise for the development of novel therapeutic interventions.

Local Control Model of a Human Ventricular Myocyte: An Exploration of Frequency-Dependent Changes and Calcium Sparks.

Calcium (Ca2+) sparks are the elementary events of excitation-contraction coupling, yet they are not explicitly represented in human ventricular myocyte models. A stochastic ventricular cardiomyocyte human model that adapts to intracellular Ca2+ ([Ca2+]i) dynamics, spark regulation, and frequency-dependent changes in the form of locally controlled Ca2+ release was developed. The 20,000 CRUs in this model are composed of 9 individual LCCs and 49 RyRs that function as couplons. The simulated action potential duration at 1 Hz steady-state pacing is ~0.280 s similar to human ventricular cell recordings. Rate-dependence experiments reveal that APD shortening mechanisms are largely contributed by the L-type calcium channel inactivation, RyR open fraction, and [Ca2+]myo concentrations. The dynamic slow-rapid-slow pacing protocol shows that RyR open probability during high pacing frequency (2.5 Hz) switches to an adapted "nonconducting" form of Ca2+-dependent transition state. The predicted force was also observed to be increased in high pacing, but the SR Ca2+ fractional release was lower due to the smaller difference between diastolic and systolic [Ca2+]SR. Restitution analysis through the S1S2 protocol and increased LCC Ca2+-dependent activation rate show that the duration of LCC opening helps modulate its effects on the APD restitution at different diastolic intervals. Ultimately, a longer duration of calcium sparks was observed in relation to the SR Ca2+ loading at high pacing rates. Overall, this study demonstrates the spontaneous Ca2+ release events and ion channel responses throughout various stimuli.

PO-01-143 HYPOTHERMIA-INDUCED J-WAVES AND ARRHYTHMIAS ARE ASSOCIATED WITH AN EXACERBATION OF REPOLARIZATION RATHER THAN CONDUCTION HETEROGENEITY IN HUMAN HEARTS

The cardiac effects of hypothermia have been studied for many years since the initial discovery of the electrocardiographic J-wave in a case of accidental hypothermia. However, the precise mechanisms underlying the origin of the hypothermic J-wave and associated arrhythmias in man are still debated. A limited number of ex vivo animal studies have focused on the transmural repolarization dispersion, but do not provide global mapping of ventricular activation and repolarization heterogeneities. To map hypothermia-induced electrophysiological changes at a tissue level and study the mechanisms of initiation and maintenance of arrhythmias. Optical mapping experiments were performed on isolated right ventricles (RV) from pigs (N=7) and humans obtained through our organ donation program (N=3 control subjects; N=1 SCN5A BrS-associated mutant subject). Epi- and endocardial (EPI and ENDO) action potential conduction and repolarization properties were assessed at different pacing frequencies and arrhythmias were mapped and quantified at baseline (37°C), during severe hypothermia (29°C), and after a return to normothermia. Hypothermia induced a reversible prolongation of global action potential duration at 80% of repolarization (APD80) in pigs (EPI: +27%, ENDO: +21%; p<0.01) and humans (+45% in both EPI and ENDO), an increase in APD80 dispersion, and steepness of APD restitution curve. Repolarization time dispersion was increased in both species (pigs: +94%, p<0.001 in EPI and +79%, p<0.05 in ENDO; humans: +97% in EPI and +14% in ENDO). The total activation time was significantly prolonged in pigs (EPI: +58%, p<0.001; ENDO: +46%, p<0.01) but not in humans. Arrhythmogenicity was further increased in human ventricles (+43% of spontaneous arrhythmias in pigs versus +100% in humans), which always displayed defibrillation-resistant arrhythmias. In the carrier of a SCN5A mutant, hypothermia additionally potentiated epicardial localized conductive disorders already detected at baseline. Our results indicate that, in humans, and contrary to pigs, the hypothermic J-wave and associated arrhythmogenesis result more from an exacerbation of repolarization rather than conduction heterogeneity. Pre-existing localized conduction heterogeneities within pathological hearts can however contribute to the J-wave phenotype during hypothermia.

Sex differences in electrophysiology of the intact atria.

Atrial fibrillation (AF) is the most common cardiac arrhythmia and is associated with electrophysiological and calcium (Ca) handling remodeling. Though AF affects both sexes, there is disparity in the onset, presentation, treatment efficacy and outcomes of the disease: males develop AF earlier, but females experience abnormal symptoms, treatment side effects, and increased risk of mortality. Treatment success likely depends on the underlying arrhythmogenic substrate. However, sex-related differences in AF pathophysiology are currently unclear, complicated by sparse knowledge about how even the healthy atria differs between males and females. As such, this study aims to investigate sex differences in electrophysiology, Ca handling and arrhythmia susceptibility in the intact atria. Hearts were extracted from young (3-4 month) rabbits and optically mapped using voltage (RH237) and Ca-sensitive (Rhod-2 AM) indicators. Signals from the atria were isolated with minimal ventricular interference by covering all tissue beneath the coronary sulcus. Electrical stimulation was performed via a pacing electrode on the right atrium. Rapid pacing and premature stimuli protocols were performed to examine baseline electrophysiology and arrhythmia susceptibility that was further tested with pharmacological intervention with carbachol (0.5 µM). Females had longer action potential duration at 25% repolarization (APD25) but no difference in APD50, APD80 or Ca transient duration (CaTD50 or CaTD80) vs. males. There was similarly no difference in the pacing thresholds for emergence of alternans between sexes; however, females had steeper APD and CaTD restitution. Despite this, arrhythmia vulnerability was greater in males, with sustained reentry observed following application of carbachol and rapid pacing in 66% of animals. Our data suggests that males are more susceptible to reentrant arrhythmias due to innate differences in electrophysiology that may include autonomic modulation. Future work will focus on potential sex differences in the age-associated remodeling that predisposes to AF.

Data-driven, patient-specific simulations of long-term heart rate variability and cardiac alternans formation.

Individuals suffering from chronic heart failure (CHF) have a greater risk for death mediated by ventricular arrhythmias, which may be related to changes in heart rate. Heart rate constantly fluctuates from beat-to-beat on a timescale ranging from seconds to hours under physiological conditions, termed heart rate variability (HRV). Individuals with CHF have reduced HRV and faster heart rates, both of which influence the formation of pro-arrhythmic alternans, a beat-to-beat alternation in the action potential duration (APD) and intracellular calcium (Ca) levels. It is unclear how long-term changes in heart rate influence alternans and arrhythmia formation. We obtained sequences of RR intervals (time between successive R waves in an electrocardiogram) from individuals with normal sinus rhythm (NSR) and CHF from a Physionet database. These RR-sequences are used to define the pacing period for a discrete-time coupled map model of APD and intracellular Ca cycling for a single cardiac myocyte, modified to account for human heart rates and pathological Ca-remodeling in CHF. These modifications include fitting human ventricular myocyte APD restitution parameters, including a new term for Ca leak from the sarcoplasmic reticulum (SR), and scaling SR Ca-related parameters. Importantly, this minimal model enables simulation of long-term trends, on the order of 24 hours, in large populations. We find that the alternations in APD and Ca vary over time, such that there are periods with both small and large beat-to-beat differences in both populations. However, the CHF population tends to have a larger alternations magnitude, demonstrating that CHF-associated heart rates promotes more pro-arrhythmic phenomena. Future work will extend this methodology to determine what statistical properties govern the CHF RR-sequences, and further to test to what extent pro-arrhythmic alternans depends on CHF-related changes in heart rate or remodeling.

Spatially discordant alternans occurring when cardiac tissue is paced alternatively from two sites.

Cardiac alternans are a precursor to arrhythmias. Spatially discordant alternans (SDA) in ventricles are especially arrhythmogenic as they can lead to ventricular tachycardia and fibrillation. Bidirectional ventricular tachycardia (BVT) is one of the rare arrhythmias. However, the underlying mechanism is still not clear. The normal electrical activity generated by the sinoatrial node propagates as an action potential wave in the heart. BVT occurs when the route of conduction changes in every other beat. In this study, we investigated the mechanism of BVT using mathematical models of cardiac tissue. The two-dimensional tissue was paced from two sites at a constant pacing cycle length. The stimulation site alternated every pacing cycle. We measured electrical alternans, which are defined as an alternating sequence of the action potential durations. We varied parameters in the model such as the distance between two sites and the pacing cycle length. We found that alternans amplitude was significantly amplified when the tissue was paced alternatively from two sites. SDA was formed even at slow heart rates. The alternans amplitude increased with the distance between the pacing sites. The nodal line was formed in the middle of the two pacing sites. This is arrhythmogenic since it can easily lead to a wave break that may initiate a spiral wave. Fast pacing with steep APD restitution is another mechanism of SDA. However, the nodal line is parallel to the wavefront. When tissue is paced rapidly and alternatively from two sites, APD distribution becomes more complex. Our study demonstrates that alternans can be formed by alternating pacing from two sites that mimics BVT.

Spiral- and scroll-wave dynamics in mathematical models for canine and human ventricular tissue with varying Potassium and Calcium currents

We conduct a systematic, direct-numerical-simulation (DNS) study, in mathematical models for ventricular tissue, of the dependence of spiral- and scroll-wave dynamics on GKr, the maximal conductance of the delayed rectifier Potassium current (IKr) channel, and the parameter γCao, which determines the magnitude and shape of the current ICaL for the L-type calcium-current channel, in both square and anatomically realistic, whole-ventricle simulation domains. We study canine and human models. In the former, we use a canine-ventricular geometry, with fiber-orientation details, obtained from diffusion-tensor-magnetic-resonance-imaging (DTMRI) data; and we employ the physiologically realistic Hund-Rudy-Dynamic (HRD) model for a canine ventricular myocyte. To focus on the dependence of spiral- and scroll-wave dynamics on GKr and γCao, we restrict ourselves to an HRD-model parameter regime, which does not produce spiral- and scroll-wave instabilities because of other, well-studied causes like a very sharp action-potential-duration-restitution (APDR) curve or early after depolarizations (EADs) at the single-cell level. We find that spiral- or scroll-wave dynamics are affected predominantly by a simultaneous change in ICaL and IKr from their original values in the model, rather than by a change in any one of these currents; other currents do not have such a large effect on these wave dynamics in this parameter regime of the HRD model. In particular, we examine spiral-wave dynamics for ten different values of GKr and ten different values of γCao in our 2D DNSs. For our 3D DNSs in an anatomically realistic domain, we chose 16 parameter sets. In the parameter regime we begin with, the system displays broken spiral or scroll states with S1–S2 initial conditions (see below). We show that, by simultaneously increasing GKr and reducing γCao, we can get to a parameter regime in which the system displays single, stable rotating spirals or scroll waves. We obtain stability diagrams (or phase diagrams) in the GKr−γCao plane; and we find that these diagrams are significantly different in our 2D and 3D studies. In the 3D case, the geometry of the domain itself supports the confinement of the scroll waves and makes them more stable compared to their spiral-wave counterparts in our flat, 2D simulation domain. Thus, a combination of functional and geometrical mechanisms produce different dynamics for 3D scroll waves and their 2D spiral-wave counterparts. In particular, the former do not break easily because, in an anatomically realistic ventricular geometry, they are not easily absorbed at boundaries, nor do they break near boundaries. We have also carried out a comparison of our HRD results with their counterparts for the human-ventricular TP06 model; and we have found important differences between wave dynamics in these two models. The region in parameter space, where we obtain broken spiral or scroll waves in the HRD model is the region of stable rotating waves in the TP06 model; the default parameter values produce broken waves in the HRD model, but stable scrolls in the TP06 model. In both these models, to make a transition, (most simply, from broken-wave to stable-scroll states) we must simultaneously increase IKr and decrease ICaL; a modification of only one of these currents is not enough to effect this transition. Furthermore, the converse, i.e., an increase in ICaL along with a decrease in IKr does not yield any interesting dynamical transitions in the HRD model, for, in this range of currents, this model does not sustain spiral or scroll waves or broken waves.

In-silico drug trials for precision medicine in atrial fibrillation: From ionic mechanisms to electrocardiogram-based predictions in structurally-healthy human atria.

Atrial fibrillation (AF) inducibility, sustainability and response to pharmacological treatment of individual patients are expected to be determined by their ionic current properties, especially in structurally-healthy atria. Mechanisms underlying AF and optimal cardioversion are however still unclear. In this study, in-silico drug trials were conducted using a population of human structurally-healthy atria models to 1) identify key ionic current properties determining AF inducibility, maintenance and pharmacological cardioversion, and 2) compare the prognostic value for predicting individual AF cardioversion of ionic current properties and electrocardiogram (ECG) metrics. In the population of structurally-healthy atria, 477 AF episodes were induced in ionic current profiles with both steep action potential duration (APD) restitution (eliciting APD alternans), and high excitability (enabling propagation at fast rates that transformed alternans into discordant). High excitability also favored 211 sustained AF episodes, so its decrease, through prolonged refractoriness, explained pharmacological cardioversion. In-silico trials over 200 AF episodes, 100 ionic profiles and 10 antiarrhythmic compounds were consistent with previous clinical trials, and identified optimal treatments for individual electrophysiological properties of the atria. Algorithms trained on 211 simulated AF episodes exhibited >70% accuracy in predictions of cardioversion for individual treatments using either ionic current profiles or ECG metrics. In structurally-healthy atria, AF inducibility and sustainability are enabled by discordant alternans, under high excitability and steep restitution conditions. Successful pharmacological cardioversion is predicted with 70% accuracy from either ionic or ECG properties, and it is optimal for treatments maximizing refractoriness (thus reducing excitability) for the given ionic current profile of the atria.

Interpretable machine learning of action potential duration restitution kinetics in single-cell models of atrial cardiomyocytes

Action potential duration (APD) restitution curve and its maximal slope (Smax) reflect single cell-level dynamic instability for inducing chaotic heart rhythms. However, conventional parameter sensitivity analysis often fails to describe nonlinear relationships between ion channel parameters and electrophysiological phenotypes, such as Smax. We explored the parameter–phenotype mapping in a population of 5000 single-cell atrial cell models through interpretable machine learning (ML) approaches. Parameter sensitivity analyses could explain the linear relationships between parameters and electrophysiological phenotypes, including APD90, resting membrane potential, Vmax, refractory period, and APD/calcium alternans threshold, but not for Smax. However, neural network models had better prediction performance for Smax. To interpret the ML model, we evaluated the parameter importance at the global and local levels by computing the permutation feature importance and the local interpretable model-agnostic explanations (LIME) values, respectively. Increases in ICaL, INCX, and IKr, and decreases in IK1, Ib,Cl, IKur, ISERCA, and Ito are correlated with higher Smax values. The LIME algorithm determined that INaK plays a significant role in determining Smax as well as Ito and IKur. The atrial cardiomyocyte population was hierarchically clustered into three distinct groups based on the LIME values and the single-cell simulation confirmed that perturbations in INaK resulted in different behaviors of APD restitution curves in three clusters. Our combined top-down interpretable ML and bottom-up mechanistic simulation approaches uncovered the role of INaK in heterogeneous behaviors of Smax in the atrial cardiomyocyte population.

Estimation of Parameters for an Archetypal Model of Cardiomyocyte Membrane Potentials

Contemporary realistic mathematical models of single-cell cardiac electrical excitation are immensely detailed. Model complexity leads to parameter uncertainty, high computational cost and barriers to mechanistic understanding. There is a need for reduced models that are conceptually and mathematically simple but physiologically accurate. To this end, we consider an archetypal model of single-cell cardiac excitation that replicates the phase-space geometry of detailed cardiac models, but at the same time has a simple piecewise-linear form and a relatively low-dimensional configuration space. In order to make this archetypal model practically applicable, we develop and report a robust method for estimation of its parameter values from the morphology of single-stimulus action potentials derived from detailed ionic current models and from experimental myocyte measurements. The procedure is applied to five significant test cases and an excellent agreement with target biomarkers is achieved. Action potential duration restitution curves are also computed and compared to those of the target test models and data, demonstrating conservation of dynamical pacing behaviour by the fine-tuned archetypal model. An archetypal model that accurately reproduces a variety of wet-lab and synthetic electrophysiology data offers a number of specific advantages such as computational efficiency, as also demonstrated in the study. Open-source numerical code of the models and methods used is provided.

Ablation and antiarrhythmic drug effects on PITX2 +/- deficient atrial fibrillation: A computational modeling study.

IntroductionAtrial fibrillation (AF) is a heritable disease, and the paired-like homeodomain transcription factor 2 (PITX2) gene is highly associated with AF. We explored the differences in the circumferential pulmonary vein isolation (CPVI), which is the cornerstone procedure for AF catheter ablation, additional high dominant frequency (DF) site ablation, and antiarrhythmic drug (AAD) effects according to the patient genotype (wild-type and PITX2+/− deficient) using computational modeling.MethodsWe included 25 patients with AF (68% men, 59.8 ± 9.8 years of age, 32% paroxysmal AF) who underwent AF catheter ablation to develop a realistic computational AF model. The ion currents for baseline AF and the amiodarone, dronedarone, and flecainide AADs according to the patient genotype (wild type and PITX2+/− deficient) were defined by relevant publications. We tested the virtual CPVI (V-CPVI) with and without DF ablation (±DFA) and three virtual AADs (V-AADs, amiodarone, dronedarone, and flecainide) and evaluated the AF defragmentation rates (AF termination or changes to regular atrial tachycardia (AT), DF, and maximal slope of the action potential duration restitution curves (Smax), which indicates the vulnerability of wave-breaks.ResultsAt the baseline AF, mean DF (p = 0.003), and Smax (p < 0.001) were significantly lower in PITX2+/− deficient patients than wild-type patients. In the overall AF episodes, V-CPVI (±DFA) resulted in a higher AF defragmentation relative to V-AADs (65 vs. 42%, p < 0.001) without changing the DF or Smax. Although a PITX2+/− deficiency did not affect the AF defragmentation rate after the V-CPVI (±DFA), V-AADs had a higher AF defragmentation rate (p = 0.014), lower DF (p < 0.001), and lower Smax (p = 0.001) in PITX2+/− deficient AF than in wild-type patients. In the clinical setting, the PITX2+/− genetic risk score did not affect the AF ablation rhythm outcome (Log-rank p = 0.273).ConclusionConsistent with previous clinical studies, the V-CPVI had effective anti-AF effects regardless of the PITX2 genotype, whereas V-AADs exhibited more significant defragmentation or wave-dynamic change in the PITX2+/− deficient patients.

Mechanism of carvedilol induced action potential and calcium alternans

ABSTRACT Carvedilol is a nonspecific β-blocker clinically used for the treatment of cardiovascular diseases but has also been shown to have profound effects on excitation-contraction coupling and Ca signaling at the cellular level. We investigate the mechanism by which carvedilol facilitates Ca transient (CaT) and action potential duration (APD) alternans in rabbit atrial myocytes. Carvedilol lowered the frequency threshold for pacing-induced CaT alternans and facilitated alternans in a concentration-dependent manner. Carvedilol prolonged the sarcoplasmic reticulum (SR) Ca release refractoriness by significantly increasing the time constant τ of recovery of SR Ca release; however, no changes in L-type calcium current recovery from inactivation or SR Ca load were found after carvedilol treatment. Carvedilol enhanced the degree of APD alternans nearly two-fold. Carvedilol slowed the APD restitution kinetics and steepened the APD restitution curve at the pacing frequency (2 Hz) where alternans were elicited. No effect on the CaT or APD alternans ratios was observed in experiments with a different β-blocker (metoprolol), excluding the possibility that the carvedilol effect on CaT and APD alternans was determined by its β-blocking properties. These data suggest that carvedilol contributes to the generation of CaT and APD alternans in atrial myocytes by modulating the restitution of CaT and APD.

BS-516-02 OPTICAL MAPPING OF EXPLANTED HUMAN HEARTS ENABLES REFINED IONIC MODELS OF ACTION POTENTIAL AND CONDUCTION VELOCITY RESTITUTION CURVES FOR ARRHYTHMIA SIMULATION

Dynamics and stability of electrical waves in the heart has been attributed to the action potential duration (APD) restitution curve, which is a measure of how the tissue responds to a given cycle length (CL) and the conduction velocity (CV). The restitution curves have been used to investigate how changes in stimulation CL can lead to the induction of alternans and arrhythmias. Only few restitution curves are available from clinical measurements in human hearts, and they were generated using monophasic action potential measurements or from single human cardiomyocytes. To obtain APD and CV restitution curves from explanted human hearts with optical mapping, and take advantage of the experimental data to refine the dynamics of an ionic model, which can be valuable for arrhythmia simulation studies. Optical mapping of membrane potentials was performed on explanted human hearts (n=2 from recipient patients and n=1 from a rejected donor) at high resolutions (256x256 pixels, at 500 Hz) and a large field of view of 8 x 8 cm2. Action potential was measured across the anterior epicardial RV and LV and the endocardium LV, paced at CLs from 3 sec and shorter, until conduction block or VF induction. APD and CV restitution were obtained across the mapped tissue. Optical voltage signals were obtained by pacing the heart at different CLs (Panel A). APDs and CVs were calculated, and restitution curves for APD and CV were calculated for different regions in the hearts. APD alternans, between even and odd beats, were observed and quantified (panels B and C). A human ventricular cardiomyocyte model was fitted to the experimentally obtained APD and CV restitution curves to reproduce AP duration (APD restitution) and conduction velocity (CV restitution) at all CLs. The resultant ionic model recapitulates the experimental data including the bifurcation period and magnitude of alternans as well as the wave propagations. Optical mapping of action potential from explanted human hearts were used to refine the dynamics of an ionic model of human ventricular myocytes. The refined model reproduced the experimental wave propagations at all CLs, including alternans. Our study presents a clinically relevant in silico model to study the induction and dynamics of arrhythmias in whole heart simulations.

PO-705-01 ACTION POTENTIAL RESTITUTION CURVES OBTAINED FROM FULL EXPLANTED HUMAN HEARTS

Much of dynamics and stability of electrical waves in the heart is attributed to action potential restitution curve. These curves have been used to investigate how changes in periods of stimulation can lead to the induction of alternans and the initiation of electrically driven arrhythmias. To date, there have been only obtained a few restitution curves from clinical measurements in human hearts using MAPs, or from single human cardiac cells. To obtain the first in tissue action potential duration (APD) restitution curves across large areas of human cardiac tissue. We studied three arterially-perfused whole explanted human hearts (two from recipient patient and one from a rejected donor) using simultaneous voltage and calcium optical mapping at high spatial and temporal resolutions (256x256 pixels, at 500 Hz) and a large field of view of 6-10 cm2. Voltage was measured across the anterior epicardial RV and LV tissue and the endocardium LV, paced at cycle lengths from 3 second down up to conduction block or induction of VF. We use optical mapping to obtain the voltage signal from a large region of the epicardium and quantify the action potential from each pixel (Panel A) to obtain their APD as a function of cycle length (Panel B) across space (as large as 10cm2). We quantify in detail, for the first time, the bifurcation to period doubling (the period of stimulation at which alternans develops) in human hearts across space which appear at or below 600ms (Panel C). For each pacing cycle length we quantify the values of APD dispersion across the tissue and how much they shift during alternans, between even and odd beats as in Panel D, which shows the shortest period of stimulation before VF induction (346ms for heart 1). APD dispersion across the tissue can vary by up to 100 ms and shift the majority of the values by up to 20ms. Optical mapping of explanted hearts is a powerful tool to quantify the dispersion of voltage and action potential duration across tissue. We present the first quantification of the action potential restitution curve for a large range of period of stimulation including the initiation and window of periods for alternans of action potential which is associated with the development of T-wave alternans.

A Parameter Representing Missing Charge Should Be Considered when Calibrating Action Potential Models.

Computational models of the electrical potential across a cell membrane are longstanding and vital tools in electrophysiology research and applications. These models describe how ionic currents, internal fluxes, and buffering interact to determine membrane voltage and form action potentials (APs). Although this relationship is usually expressed as a differential equation, previous studies have shown it can be rewritten in an algebraic form, allowing direct calculation of membrane voltage. Rewriting in this form requires the introduction of a new parameter, called Γ0 in this manuscript, which represents the net concentration of all charges that influence membrane voltage but are not considered in the model. Although several studies have examined the impact of Γ0 on long-term stability and drift in model predictions, there has been little examination of its effects on model predictions, particularly when a model is refit to new data. In this study, we illustrate how Γ0 affects important physiological properties such as action potential duration restitution, and examine the effects of (in)correctly specifying Γ0 during model calibration. We show that, although physiologically plausible, the range of concentrations used in popular models leads to orders of magnitude differences in Γ0, which can lead to very different model predictions. In model calibration, we find that using an incorrect value of Γ0 can lead to biased estimates of the inferred parameters, but that the predictive power of these models can be restored by fitting Γ0 as a separate parameter. These results show the value of making Γ0 explicit in model formulations, as it forces modellers and experimenters to consider the effects of uncertainty and potential discrepancy in initial concentrations upon model predictions.

Simulation of atrial fibrillation in a non-ohmic propagation model with dynamic gap junctions.

Gap junctions exhibit nonlinear electrical properties that have been hypothesized to be relevant to arrhythmogenicity in a structurally remodeled tissue. Large-scale implementation of gap junction dynamics in 3D propagation models remains challenging. We aim to quantify the impact of nonlinear diffusion during episodes of arrhythmias simulated in a left atrial model. Homogenization of conduction properties in the presence of nonlinear gap junctions was performed by generalizing a previously developed mathematical framework. A monodomain model was solved in which conductivities were time-varying and depended on transjunctional potentials. Gap junction conductances were derived from a simplified Vogel-Weingart model with first-order gating and adjustable time constant. A bilayer interconnected cable model of the left atrium with 100 μm resolution was used. The diffusion matrix was recomputed at each time step according to the state of the gap junctions. Sinus rhythm and atrial fibrillation episodes were simulated in remodeled tissue substrates. Slow conduction was induced by reduced coupling and by diffuse or stringy fibrosis. Simulations starting from the same initial conditions were repeated with linear and nonlinear gap junctions. The discrepancy in activation times between the linear and nonlinear diffusion models was quantified. The results largely validated the linear approximation for conduction velocities >20 cm/s. In very slow conduction substrates, the discrepancy accumulated over time during atrial fibrillation, eventually leading to qualitative differences in propagation patterns, while keeping the descriptive statistics, such as cycle lengths, unchanged. The discrepancy growth rate was increased by impaired conduction, fibrosis, conduction heterogeneity, lateral uncoupling, fast gap junction time constant, and steeper action potential duration restitution.

Anti-atrial Fibrillation Effects of Pulmonary Vein Isolation With or Without Ablation Gaps: A Computational Modeling Study.

BackgroundAlthough pulmonary vein isolation (PVI) gaps contribute to recurrence after atrial fibrillation (AF) catheter ablation, the mechanism is unclear. We used realistic computational human AF modeling to explore the AF wave-dynamic changes of PVI with gaps (PVI-gaps).MethodsWe included 40 patients (80% male, 61.0 ± 9.8 years old, 92.5% persistent AF) who underwent AF catheter ablation to develop our realistic computational AF model. We compared the effects of a complete PVI (CPVI) and PVI-gap (2-mm × 4) on the AF wave-dynamics by evaluating the dominant frequency (DF), spatial change of DF, maximal slope of the action potential duration restitution curve (Smax), and AF defragmentation rate (termination or change to atrial tachycardia), and tested the effects of additional virtual interventions and flecainide on ongoing AF with PVI-gaps.ResultsCompared with the baseline AF, CPVIs significantly reduced extra-PV DFs (p < 0.001), but PVI-gaps did not. COV-DFs were greater after CPVIs than PVI-gaps (p < 0.001). Neither CPVIs nor PVI-gaps changed the mean Smax. CPVIs resulted in higher AF defragmentation rates (80%) than PVI-gaps (12.5%, p < 0.001). In ongoing AF after PVI-gaps, the AF defragmentation rates after a wave-breaking gap ablation, extra-PV DF ablation, or flecainide were 60.0, 34.3, and 25.7%, respectively (p = 0.010).ConclusionCPVIs effectively reduced the DF, increased its spatial heterogeneity in extra-PV areas, and offered better anti-AF effects than extra-PV DF ablation or additional flecainide in PVI-gap conditions.

Restitution Slope Affects the Outcome of Dominant Frequency Ablation in Persistent Atrial Fibrillation: CUVIA-AF2 Post-Hoc Analysis Based on Computational Modeling Study.

IntroductionAlthough the dominant frequency (DF) localizes the reentrant drivers and the maximal slope of the action potential duration (APD) restitution curve (Smax) reflects the tendency of the wave-break, their interaction has never been studied. We hypothesized that DF ablation has different effects on atrial fibrillation (AF) depending on Smax.MethodsWe studied the DF and Smax in 25 realistic human persistent AF model samples (68% male, 60 ± 10 years old). Virtual AF was induced by ramp pacing measuring Smax, followed by spatiotemporal DF evaluation for 34 s. We assessed the DF ablation effect depending on Smax in both computational modeling and a previous clinical trial, CUVIA-AF (170 patients with persistent AF, 70.6% male, 60 ± 11 years old).ResultsMean DF had an inverse relationship with Smax regardless of AF acquisition timing (p < 0.001). Virtual DF ablations increased the defragmentation rate compared to pulmonary vein isolation (PVI) alone (p = 0.015), especially at Smax <1 (61.5 vs. 7.7%, p = 0.011). In post-DF ablation defragmentation episodes, DF was significantly higher (p = 0.002), and Smax was lower (p = 0.003) than in episodes without defragmentation. In the post-hoc analysis of CUVIA-AF2, we replicated the inverse relationship between Smax and DF (r = −0.47, p < 0.001), and we observed better rhythm outcomes of clinical DF ablations in addition to a PVI than of empirical PVI at Smax <1 [hazard ratio 0.45, 95% CI (0.22–0.89), p = 0.022; log-rank p = 0.021] but not at ≥ 1 (log-rank p = 0.177).ConclusionWe found an inverse relationship between DF and Smax and the outcome of DF ablation after PVI was superior at the condition with Smax <1 in both in-silico and clinical trials.

Interpretable machine learning of action potential duration restitution properties in single-cell models of atrial cardiomyocyte

Action potential duration (APD) restitution curve and its maximal slope (Smax) reflect single cell-level instability for inducing chaotic heart rhythms. Conventional parameter sensitivity analysis often fails to describe nonlinear relationships between ion channel parameters and electrophysiological phenotypes, such as Smax. We explored the parameter-phenotype mapping in in silico atrial cell models through interpretable machine learning (ML) approaches. We generated a population of 5,000 single-cell atrial cell models by log-uniformly sampling parameter combinations with the Sobol sequence scheme.

Effects of dynamic change of action potential on evolution behavior of spiral wave

It is observed in cardiac patients that the steepnesses of action potential duration (APD) restitution curve of cardiomyocytes in different regions of the ventricle are significantly different from region to region. However, the steep APD restitution curve can either lead the spiral wave to break up and set up the ventricular fibrillation in certain conditions or result in no breakup of spiral wave in other conditions. The relationship between the dynamic behavior of spiral wave and steep APD restitution curve is still not completely clear. Therefore, further research is needed. In this paper, a two-dimensional excitable medium cellular automata model is used to study the influences of the APD restitution curves with different steepnesses on the dynamic behavior of spiral wave. Numerical simulation results show that the steep APD restitution curve can stabilize the meandering spiral wave, causing the stable spiral wave to roam or break, and even to disappear. When the total average slope of APD restitution curve is greater than 1, it is observed that spiral wave may be still stable or meandering. When the total average slope of APD restitution curve is much smaller than 1, the breakup of spiral waves may occur. Three types of spiral wave breakups are observed. They are the Doppler instability, Eckhaus instability, and APD alternation. The Doppler instability and Eckhaus instability are related to the total average slope of APD restitution curve greater than 1, and the spiral wave breakup caused by APD alternans may occur when the total average slope of APD restitution curve is much smaller than 1. When the total average slope of APD restitution curve is greater than 1, the phenomena that spiral waves disappear by meandering out of the system boundary and conduction barriers are observed. In addition, we also find that increasing cellular APD is beneficial to preventing spiral wave from breaking up. The physical mechanisms behind those phenomena are heuristically analyzed.