Reentrant Wave Research Articles

Quantifying the frequency modulation in electrograms during simulated atrial fibrillation in 2D domains

Atrial fibrillation (AF) affects millions of people in the world, causing increased morbidity and mortality. Treatment involves antiarrhythmic drugs and catheter ablation, showing high success for paroxysmal AF but challenges for persistent AF. Experimental evidence suggests reentrant waves and rotors contribute to AF substrates. Ablation procedures rely on electroanatomical maps and electrogram (EGM) signals; however, current methods used in clinical practice lack consideration for time–frequency varying EGM components. The fractional Fourier transform (FrFT) can be adopted to capture time-varying frequency components, thereby enhancing the comprehension of arrhythmogenic substrates during AF for improved ablation strategies. To this end, a FrFT-based algorithm is developed to characterize non-stationary components in EGM signals from simulated AF episodes. The proposed algorithm comprises a pre-processing step to enhance the coarser features of the EGM waveform, a windowing process for dynamic assessment of the EGM, and a FrFT order optimization stage that seeks compact signal representations in fractional Fourier domains. The resulting order is related to the rate of frequency change in the signal, making it a useful indicator for frequency-modulated components. The FrFT-based algorithm is implemented on EGM signals from AF simulations in 2D domains representing a region of the atrial tissue. Consequently, the computed optimum FrFT orders are used to build maps that are spatially correlated to the underlying propagation dynamics of the simulated AF episode. The results evince that the extreme values in the optimum orders map pinpoint the localization of fibrillatory mechanisms, generating EGM activation waveforms with varying frequency content over time.

Experimental studies of spiral wave teleportation in a light sensitive Belousov-Zhabotinsky system.

Cardiac arrythmias are a form of heart disease that contributes toward making heart disease a significant cause of death globally. Irregular rhythms associated with cardiac arrythmias are thought to arise due to singularities in the heart tissue that generate reentrant waves in the underlying excitable medium. A normal approach to removing such singularities is to apply a high voltage electric shock, which effectively resets the phase of the cardiac cells. A concern with the use of this defibrillation technique is that the high-energy shock can cause lasting damage to the heart tissue. Various theoretical works have investigated lower-energy alternatives to defibrillation. In this work, we demonstrate the effectiveness of a low-energy defibrillation method in an experimental 2D Belousov-Zhabotinsky (BZ) system. When implemented as a 2D spatial reaction, the BZ reaction serves as an effective analog of general excitable media and supports regular and reentrant wave activity. The defibrillation technique employed involves targeted low-energy perturbations that can be used to "teleport" and/or annihilate singularities present in the excitable BZ medium.

Polycystin-1 loss of function increases susceptibility to atrial fibrillation through impaired DNA damage response.

The increasing prevalence of atrial fibrillation (AF) and chronic kidney diseases highlights the need for a deeper comprehension of the molecular mechanisms linking them. Mutations in PKD1, the gene encoding Polycystin-1 (PKD1 or PC1), account for 85% of autosomal dominant polycystic kidney disease (ADPKD) cases. This disease often includes cardiac complications such as AF. In cardiomyocytes, PC1 deletion reduces hypertrophic response to pressure overload but promotes baseline ventricular dysfunction, while deletion in fibroblasts ameliorates post-myocardial infarction fibrosis. Despite its known cardiac impact, the role of PC1 in atrial cardiomyocytes and arrhythmias is less understood. Here, we sought to investigate the role of PC1 in AF. We used intracardiac programmed stimulation and optical mapping to evaluate AF inducibility in two mouse models, Pkd1 R3277C, which recapitulates human ADPKD progression, and cardiomyocyte-specific Pkd1 deletion, and their respective controls. Isolated adult mouse atrial cardiomyocytes, human iPSC-derived atrial cardiomyocytes (hiPSC-aCM), and HL-1 cells served as in vitro cellular models. Molecular mechanisms were evaluated using optical mapping and molecular and biochemical approaches. Loss-of-function PC1 mutations significantly increased AF susceptibility in vivo and facilitated local reentry in ex vivo left atrial appendages. Comprehensive in vitro experiments supported a direct effect of PC1 in atrial cardiomyocytes. PC1-deficient monolayers exhibited increased arrhythmic events, escalating into reentrant spiral waves post-tachypacing. Transcriptomics analysis revealed PC1-dependent regulation of DNA repair, with PC1 deficiency leading to increased DNA damage under stress. PARP1 inhibitors or nicotinamide riboside, which counteract DNA damage-related metabolic consequences, reduced in vitro arrhythmias PC1-deficient monolayers. Overexpression of the C-terminus of PC1 had the opposite effects in DNA repair genes, suggesting its regulatory effects in atrial cardiomyocytes through retinoblastoma/E2F. Analyses of human atrial tissue from non-ADPKD patients showed reduced levels of mature PC1, suggesting a broader relevance of impaired PC1 in AF. Impaired PC1 increases in vivo AF inducibility under programmed electrical stimulation and promotes in vitro arrhythmias in hiPSC-aCM and HL-1 cells. Our findings indicate that PC1 protects against DNA damage to reduce AF susceptibility.

Systematic in-silico evaluation of fibrosis effects on re-entrant wave dynamics in atrial tissue.

Despite the key role of fibrosis in atrial fibrillation (AF), the effects of different spatial distributions and textures of fibrosis on wave propagation mechanisms in AF are not fully understood. To clarify these aspects, we performed a systematic computational study to assess fibrosis effects on the characteristics and stability of re-entrant waves in electrically-remodelled atrial tissues. A stochastic algorithm, which generated fibrotic distributions with controlled overall amount, average size, and orientation of fibrosis elements, was implemented on a monolayer spheric atrial model. 245 simulations were run at changing fibrosis parameters. The emerging propagation patterns were quantified in terms of rate, regularity, and coupling by frequency-domain analysis of correspondent synthetic bipolar electrograms. At the increase of fibrosis amount, the rate of reentrant waves significantly decreased and higher levels of regularity and coupling were observed (p < 0.0001). Higher spatial variability and pattern stochasticity over repetitions was observed for larger amount of fibrosis, especially in the presence of patchy and compact fibrosis. Overall, propagation slowing and organization led to higher stability of re-entrant waves. These results strengthen the evidence that the amount and spatial distribution of fibrosis concur in dictating re-entry dynamics in remodeled tissue and represent key factors in AF maintenance.

'Trapped re-entry' as source of acute focal atrial arrhythmias.

Diseased atria are characterized by functional and structural heterogeneities, adding to abnormal impulse generation and propagation. These heterogeneities are thought to lie at the origin of fractionated electrograms recorded during sinus rhythm (SR) in atrial fibrillation (AF) patients and are assumed to be involved in the onset and perpetuation (e.g. by re-entry) of this disorder. The underlying mechanisms, however, remain incompletely understood. Here, we tested whether regions of dense fibrosis could create an electrically isolated conduction pathway (EICP) in which re-entry could be established via ectopy and local block to become 'trapped'. We also investigated whether this could generate local fractionated electrograms and whether the re-entrant wave could 'escape' and cause a global tachyarrhythmia due to dynamic changes at a connecting isthmus. To precisely control and explore the geometrical properties of EICPs, we used light-gated depolarizing ion channels and patterned illumination for creating specific non-conducting regions in silico and in vitro. Insight from these studies was used for complementary investigations in virtual human atria with localized fibrosis. We demonstrated that a re-entrant tachyarrhythmia can exist locally within an EICP with SR prevailing in the surrounding tissue and identified conditions under which re-entry could escape from the EICP, thereby converting a local latent arrhythmic source into an active driver with global impact on the heart. In a realistic three-dimensional model of human atria, unipolar epicardial pseudo-electrograms showed fractionation at the site of 'trapped re-entry' in coexistence with regular SR electrograms elsewhere in the atria. Upon escape of the re-entrant wave, acute arrhythmia onset was observed. Trapped re-entry as a latent source of arrhythmogenesis can explain the sudden onset of focal arrhythmias, which are able to transgress into AF. Our study might help to improve the effectiveness of ablation of aberrant cardiac electrical signals in clinical practice.

Transition mechanisms from atrial flutter to atrial fibrillation during anti-tachycardia pacing therapy.

Atrial anti-tachycardia pacing (aATP) has been shown to be effective for the termination of atrial tachyarrhythmias, but its success rate is still not high enough. The main objective of this study was to investigate the mechanisms of atrial flutter (AFL) termination by aATP and the transition from AFL to atrial fibrillation (AF) during aATP. We developed a multi-scale model of the human atrium based on magnetic resonance images and examined the atrial electrophysiology of AFL during aATP with a ramp protocol. In successful cases of aATP, paced excitation entered the excitable gap and collided with the leading edge of the reentrant wave front. Furthermore, the excitation propagating in the opposite direction collided with the trailing edge of the reentrant wave to terminate AFL. The second collision was made possible by the distribution of the wave propagation velocity in the atria. The detailed analysis revealed that the slowing of propagation velocity occurred at the exit of the sub-Eustachian isthmus, probably due to source-sink mismatch. During the transition from AFL to AF, the excitation collided with the refractory zone of the preceding wave and broke into multiple wave fronts to induce AF. A similar observation was made for the transition from AF to sinus rhythm. In both cases, the complex anatomy of the atria played an essential role. The complex anatomy of atria plays an essential role in the maintenance of stable AFL and its termination by aATP, which were revealed by the realistic three-dimensional simulation model.

Nonpharmacological Approach to Managing Atrial Fibrillation: A Review

Background: AF's global prevalence underscores its significance as a cardiac rhythm disorder that disrupts atrial activity, impairing normal cardiac function. Over five decades of study have illuminated the pathophysiological mechanisms underlying AF, including insights into re-entrant waves and macro-reentrant circuits. The emergence of non-uniform conduction patterns and bidirectional block regions has further enriched our understanding. Risk factors contributing to AF development encompass cardiovascular conditions, advanced age, and atrial structural changes. With its implications on stroke risk and cardiovascular health, AF has become a growing public health concern. The focus on AF epidemiology has expanded, with attention on the relationship between left atrial size and AF development. Individuals with larger left atria exhibit a heightened risk. Additionally, the elevated stroke risk associated with AF has been consistently documented.&#x0D; To optimize clinical management, distinctions are drawn between chronic and paroxysmal AF, as well as the presence of structural heart disease. Mapping techniques have revealed insights into "atrial remodeling" and AF pathology. In managing AF, controlling heart rate, preventing clot formation, and restoring sinus rhythm are principal objectives. This article categorizes AF into acute, chronic, stable, or unstable forms, tailoring management approaches accordingly. While pharmacological interventions have shown efficacy, their limitations drive the exploration of nonpharmacological strategies. Approaches range from medications to cardioversion, including electrical and pharmacological methods.&#x0D; Objective: This paper aimed to provide a comprehensive exploration of non-pharmacological approaches to AF management.&#x0D; Methodology: This paper employed a structured methodology. This method involved a literature review, data synthesis, and critical analysis. During the literature review phase, we systematically searched electronic databases (PubMed, MEDLINE, Embase, and Google Scholar) for studies published from 1960 to 2023. Specific keywords and phrases such as "atrial fibrillation," "non-pharmacological interventions," "electrical cardioversion," "catheter ablation," "lifestyle modifications," "autonomic modulation," "left atrial appendage closure," and "exercise" were used. Our inclusion criteria encompassed studies addressing various non-pharmacological approaches for AF management, including observational studies and randomized controlled trials.&#x0D; Result: The initial stage of our study involved the identification of a substantial number of relevant studies. We conducted a thorough literature search across multiple databases, using specific search terms and criteria relevant to our research topic. This comprehensive search yielded a total of 1,200 studies. After applying these stringent filtering criteria, we were left with 350 studies. To further refine our final sample and categorize the studies according to type, we conducted a detailed review of the remaining 350 studies. We categorized them into various types based on study design, methodology, and focus. We then also excluded studies with duplicate ideas and finally included 103 studies that addressed the objective of our research plan. (See reference list [1-103]).&#x0D; Conclusion: This reviewed a number of non-pharmacological approaches including electrical cardioversion, catheter ablation, lifestyle modifications, autonomic modulation, left atrial appendage closure, and exercise, the paper delves into each method's advantages, potential risks, techniques, and efficacy. By offering this extensive overview, the article contributes to the expanding repository of knowledge on non-pharmacological approaches for AF management. These approaches offer potential for unique management of atrial fibrillations or in addition to pharmacologic management, may improve patient survivability or reduce complication outcomes.&#x0D; In the management of Atrial fibrillation, choice between rhythm and rate control, lifestyle modifications, and patient adherence to treatment plans are critical factors influencing outcomes are factors to consider. Emerging therapies offer promise, but timely diagnosis, individualized care, and ongoing monitoring remain essential to improving AF patients' overall prognosis.

Right atrial collision time (RACT): A novel marker of propensity for typical atrial flutter.

The risk of typical atrial flutter (AFL) is increased proportionately to right atrial (RA) size or right atrial scarring that results in reduced conduction velocity. These characteristics result in propagation of a flutter wave by ensuring the macro re-entrant wave front does not meet its refractory tail. The time taken to traverse the circuit would take account of both of these characteristics and may provide a novel marker of propensity to develop AFL. Our goal was to investigate right atrial collision time (RACT) as a marker of existing typical AFL. This single-centre, prospective study recruited consecutive typical AFL ablation patients that were in sinus rhythm. Controls were consecutive electrophysiology study patients >18 years of age. While pacing the coronary sinus (CS) ostium at 600 ms, a local activation time map was created to locate the latest collision point on the anterolateral right atrial wall. This RACT is a measure of conduction velocity and distance from CS to a collision point on the lateral right atrial wall. Ninety-eight patients were included in the analysis, 41 with atrial flutter and 57 controls. Patients with atrial flutter were older, 64.7 ± 9.7 versus 52.4 ± 16.8 years (<.001), and more often male (34/41 vs. 31/57 [.003]). The AFL group mean RACT (132.6 ± 17.3 ms) was significantly longer than that of controls (99.1 ± 11.6 ms) (p < .001). A RACT cut-off of 115.5 ms had a sensitivity and specificity of 92.7% and 93.0%, respectively for diagnosis of atrial flutter. A ROC curve indicated an AUC of 0.96 (95% CI: 0.93-1.0, p < .01). RACT is a novel and promising marker of propensity for typical AFL. This data will inform larger prospective studies.

Generation of cardiac digital twins based on noninvasive cardiac mapping

Abstract Funding Acknowledgements Type of funding sources: Other. Main funding source(s): Generalitat Valenciana Grants Ministerio de Ciencia, Innovación y Universidades Background Personalized cardiac digital twins have been proposed as a clinical tool to plan ablation strategies during cardiac arrhythmias. However, these personalization frameworks normally rely on invasive recordings which limits their clinical applicability. Electrocardiographic Imaging (ECGI) is a mapping technique that allows the reconstruction of global cardiac activity non-invasively. Purpose Evaluate the applicability of ECGI as a non-invasive tool for the planification of ablation strategies based on personalized digital twins. Methods Cardiac digital twins generated from endocardial or ECGI mapping were compared in a patient with Atrial Flutter prescribed for cardiac ablation. Endocardial mapping was obtained in the right atrium by using electroanatomical mappings. ECGI was recorded during the ablation procedure with a mapping system of 128 body surface recordings. For the cardiac digital twin based on endocardial mapping, the reentrant circuit around the tricuspid valve was reproduced based on the activation time maps obtained with the electroanatomical mapping system. Total activation time of both atria was personalized based on the duration of the F-waves on the ECG since the left atrium was not endocardialy mapped. For the cardiac digital twin based on the ECGI, activation times obtained in both left and right atrium were used to set-up the personalized model. From both approaches, computed torso potentials were calculated. The correlation with real body surface recordings was compared. To further evaluate the fidelity of the models, the efficacy of the ablation strategy performed on the real patient was evaluated over the digital twins. Results Both digital twins, the one based on endocardial mapping, and the one based on ECGI were compared. Regarding dynamics of the model, both models reproduced the reentrant circuit around the tricuspid valve. Interestingly, only the ECGI digital twin reproduced a reentrant wave around the right pulmonary veins. When endocardial map was used for the personalization, a median conduction velocity (CV) of 90.5 cm/s was obtained for the right atrium and 174.7 cm/s for the left; whereas when ECGI was used, the median CV were 104.2 cm/s at the right and 129.1 cm/s at the left atrium. The ability to reproduce body surface ECGs of both digital twins demonstrated that the one based on endocardial mapping obtained a low correlation of 0.13, whereas the ECGI digital twin increase the correlation up to 0.66. Regarding the ablation outcome, ablation terminated the arrhythmia only in the cardiac digital twin based on ECGI. Conclusion The possibility to generate cardiac digital twins based on non-invasive ECGI mapping has been demonstrated. This opens the door to obtaining personalized cardiac digital twins before endocardial interventions which can be used to plan ablation procedures.

PO-01-180 MECHANISMS OF PULMONARY ARTERIAL HYPERTENSION-INDUCED ATRIAL FIBRILLATION IN THE RIGHT HEART: INSIGHTS FROM MULTI-SCALE MODELS OF THE HUMAN ATRIA

Pulmonary arterial hypertension (PAH) is one of the common conditions primarily affecting the right heart and promoting atrial fibrillation (AF), but the mechanisms are poorly understood. This study aimed to use multi-scale atrial models to investigate mechanisms by which right atrial (RA) remodeling facilitates and perpetuates atrial arrhythmias. We have developed single-cell-to-tissue-level computer models to mimic control and disease conditions by incorporating the most recent experimental data on PAH-induced electrical and structural remodeling (Hiram et al., JACC, 2019). The effects of PAH-induced remodeling in both RA and left atria (LA) on action potential duration (APD), calcium transient (CaT), conduction velocity (CV), and dynamics of re-entrant excitation waves were assessed using the multi-scale computer models. Our computer simulation results suggested that at the single cell level, although PAH-induced remodeling prolonged action potential (ΔAPD: 49.6 ms in the RA vs. 41.6 ms in the LA) and increased calcium transient (ΔCaT: 7.5e-2 μM in the RA vs. 0.9e-3 μM in the LA), heterogeneous remodeling increased susceptibility to afterdepolarizations only in the RA (Fig. A). At the tissue level, dramatically reduced CV (ΔCV: -0.5 m/s in the RA vs. -0.05 m/s in the LA) abbreviated wavelength inthe RA but not inthe LA. In addition, afterdepolarizations in the RA increased repolarization dispersion and promoted unidirectional conduction block (Fig B). Finally, the upregulated fibrosis increased the chance of breakdown of excitation waves and sustained reentries in in the RA (Fig C). These results demonstrated that PAH-induced AF is mainly in RA not LA, due to a higher degree of cardiac remodeling. RA remodeling increases arrhythmias risk due to elevated susceptibility to afterdepolarizations, reduced wavelength, increased repolarization heterogeneity and upregulation of fibrosis, which together facilitate initiation and maintenance of re-entrant circuits in the right heart.

Computational analysis of arrhythmogenesis in KCNH2 T618I mutation-associated short QT syndrome and the pharmacological effects of quinidine and sotalol

Short QT syndrome (SQTS) is a rare but dangerous genetic disease. In this research, we conducted a comprehensive in silico investigation into the arrhythmogenesis in KCNH2 T618I-associated SQTS using a multi-scale human ventricle model. A Markov chain model of IKr was developed firstly to reproduce the experimental observations. It was then incorporated into cell, tissue, and organ models to explore how the mutation provided substrates for ventricular arrhythmias. Using this T618I Markov model, we explicitly revealed the subcellular level functional alterations by T618I mutation, particularly the changes of ion channel states that are difficult to demonstrate in wet experiments. The following tissue and organ models also successfully reproduced the changed dynamics of reentrant spiral waves and impaired rate adaptions in hearts of T618I mutation. In terms of pharmacotherapy, we replicated the different effects of a drug under various conditions using identical mathematical descriptions for drugs. This study not only simulated the actions of an effective drug (quinidine) at various physiological levels, but also elucidated why the IKr inhibitor sotalol failed in SQT1 patients through profoundly analyzing its mutation-dependent actions.

Direct observation of a stable spiral wave reentry in ventricles of a whole human heart using optical mapping for voltage and calcium.

From the studies of Gordon Moe in the 1960s, functional reentry has been investigated as a mechanism for tachycardia and fibrillation; however, it was not until 1990 that optical mapping (OM) experiments using sheep hearts verified the existence of reentrant spiral waves.1 Eventually, it was shown that electromechanical 3-dimensional vortex filaments drive cardiac fibrillation.2 To date, only multiple complex and short-lived reentrant waves have been recorded using OM on human ventricles.3 The presence of single spiral waves in human ventricles has only been demonstrated using low-resolution intracardiac electrocardiograms (ECGs).

Mechanisms of ventricular arrhythmias elicited by coexistence of multiple electrophysiological remodeling in ischemia: A simulation study.

Myocardial ischemia, injury and infarction (MI) are the three stages of acute coronary syndrome (ACS). In the past two decades, a great number of studies focused on myocardial ischemia and MI individually, and showed that the occurrence of reentrant arrhythmias is often associated with myocardial ischemia or MI. However, arrhythmogenic mechanisms in the tissue with various degrees of remodeling in the ischemic heart have not been fully understood. In this study, biophysical detailed single-cell models of ischemia 1a, 1b, and MI were developed to mimic the electrophysiological remodeling at different stages of ACS. 2D tissue models with different distributions of ischemia and MI areas were constructed to investigate the mechanisms of the initiation of reentrant waves during the progression of ischemia. Simulation results in 2D tissues showed that the vulnerable windows (VWs) in simultaneous presence of multiple ischemic conditions were associated with the dynamics of wave propagation in the tissues with each single pathological condition. In the tissue with multiple pathological conditions, reentrant waves were mainly induced by two different mechanisms: one is the heterogeneity along the excitation wavefront, especially the abrupt variation in conduction velocity (CV) across the border of ischemia 1b and MI, and the other is the decreased safe factor (SF) for conduction at the edge of the tissue in MI region which is attributed to the increased excitation threshold of MI region. Finally, the reentrant wave was observed in a 3D model with a scar reconstructed from MRI images of a MI patient. These comprehensive findings provide novel insights for understanding the arrhythmic risk during the progression of myocardial ischemia and highlight the importance of the multiple pathological stages in designing medical therapies for arrhythmias in ischemia.

Rotors anchored by refractory islands drive torsades de pointes in an experimental model of electrical storm.

Electrical storm (ES) is a life-threatening emergency in patients at high risk of ventricular tachycardia/ventricular fibrillation (VF), but the pathophysiology and molecular basis are poorly understood. The purpose of this study was to explore the electrophysiological substrate for experimental ES. A model was created by inducing chronic complete atrioventricular block in defibrillator-implanted rabbits, which recapitulates QT prolongation, torsades des pointes (TdP), and VF episodes. Optical mapping revealed island-like regions with action potential duration (APD) prolongation in the left ventricle, leading to increased spatial APD dispersion, in rabbits with ES (defined as ≥3 VF episodes/24 h). The maximum APD and its dispersion correlated with the total number of VF episodes invivo. TdP was initiated by an ectopic beat that failed to enter the island and formed a reentrant wave and perpetuated by rotors whose centers swirled in the periphery of the island. Epinephrine exacerbated the island by prolonging APD and enhancing APD dispersion, which was less evident after late Na+ current blockade with 10 μM ranolazine. Nonsustained ventricular tachycardia in a non-ES rabbit heart with homogeneous APD prolongation resulted from multiple foci with an electrocardiographic morphology different from TdP driven by drifting rotors in ES rabbit hearts. The neuronal Na+-channel subunit NaV1.8 was upregulated in ES rabbit left ventricular tissues and expressed within the myocardium corresponding to the island location in optically mapped ES rabbit hearts. The NaV1.8 blocker A-803467 (10 mg/kg, intravenously) attenuated QT prolongation and suppressed epinephrine-evoked TdP. A tissue island with enhanced refractoriness contributes to the generation of drifting rotors that underlies ES in this model. NaV1.8-mediated late Na+ current merits further investigation as a contributor to the substrate for ES.

Individual Contributions of Cardiac Ion Channels on Atrial Repolarization and Reentrant Waves: A Multiscale In-Silico Study.

The excitation, contraction, and relaxation of an atrial cardiomyocyte are maintained by the activation and inactivation of numerous cardiac ion channels. Their collaborative efforts cause time-dependent changes of membrane potential, generating an action potential (AP), which is a surrogate marker of atrial arrhythmias. Recently, computational models of atrial electrophysiology emerged as a modality to investigate arrhythmia mechanisms and to predict the outcome of antiarrhythmic therapies. However, the individual contribution of atrial ion channels on atrial action potential and reentrant arrhythmia is not yet fully understood. Thus, in this multiscale in-silico study, perturbations of individual atrial ionic currents (INa, Ito, ICaL, IKur, IKr, IKs, IK1, INCX and INaK) in two in-silico models of human atrial cardiomyocyte (i.e., Courtemanche-1998 and Grandi-2011) were performed at both cellular and tissue levels. The results show that the inhibition of ICaL and INCX resulted in AP shortening, while the inhibition of IKur, IKr, IKs, IK1 and INaK prolonged AP duration (APD). Particularly, in-silico perturbations (inhibition and upregulation) of IKr and IKs only minorly affected atrial repolarization in the Grandi model. In contrast, in the Courtemanche model, the inhibition of IKr and IKs significantly prolonged APD and vice versa. Additionally, a 50% reduction of Ito density abbreviated APD in the Courtemanche model, while the same perturbation prolonged APD in the Grandi model. Similarly, a strong model dependence was also observed at tissue scale, with an observable IK1-mediated reentry stabilizing effect in the Courtemanche model but not in the Grandi atrial model. Moreover, the Grandi model was highly sensitive to a change on intracellular Ca2+ concentration, promoting a repolarization failure in ICaL upregulation above 150% and facilitating reentrant spiral waves stabilization by ICaL inhibition. Finally, by incorporating the previously published atrial fibrillation (AF)-associated ionic remodeling in the Courtemanche atrial model, in-silico modeling revealed the antiarrhythmic effect of IKr inhibition in both acute and chronic settings. Overall, our multiscale computational study highlights the strong model-dependent effects of ionic perturbations which could affect the model’s accuracy, interpretability, and prediction. This observation also suggests the need for a careful selection of in-silico models of atrial electrophysiology to achieve specific research aims.

Rotor Localization and Phase Mapping of Cardiac Excitation Waves Using Deep Neural Networks.

The analysis of electrical impulse phenomena in cardiac muscle tissue is important for the diagnosis of heart rhythm disorders and other cardiac pathophysiology. Cardiac mapping techniques acquire local temporal measurements and combine them to visualize the spread of electrophysiological wave phenomena across the heart surface. However, low spatial resolution, sparse measurement locations, noise and other artifacts make it challenging to accurately visualize spatio-temporal activity. For instance, electro-anatomical catheter mapping is severely limited by the sparsity of the measurements, and optical mapping is prone to noise and motion artifacts. In the past, several approaches have been proposed to create more reliable maps from noisy or sparse mapping data. Here, we demonstrate that deep learning can be used to compute phase maps and detect phase singularities in optical mapping videos of ventricular fibrillation, as well as in very noisy, low-resolution and extremely sparse simulated data of reentrant wave chaos mimicking catheter mapping data. The self-supervised deep learning approach is fundamentally different from classical phase mapping techniques. Rather than encoding a phase signal from time-series data, a deep neural network instead learns to directly associate phase maps and the positions of phase singularities with short spatio-temporal sequences of electrical data. We tested several neural network architectures, based on a convolutional neural network (CNN) with an encoding and decoding structure, to predict phase maps or rotor core positions either directly or indirectly via the prediction of phase maps and a subsequent classical calculation of phase singularities. Predictions can be performed across different data, with models being trained on one species and then successfully applied to another, or being trained solely on simulated data and then applied to experimental data. Neural networks provide a promising alternative to conventional phase mapping and rotor core localization methods. Future uses may include the analysis of optical mapping studies in basic cardiovascular research, as well as the mapping of atrial fibrillation in the clinical setting.

Interactive 3D Human Heart Simulations on Segmented Human MRI Hearts.

Understanding cardiac arrhythmic mechanisms and developing new strategies to control and terminate them using computer simulations requires realistic physiological cell models with anatomically accurate heart structures. Furthermore, numerical simulations must be fast enough to study and validate model and structure parameters. Here, we present an interactive parallel approach for solving detailed cell dynamics in high-resolution human heart structures with a local PC's GPU. In vitro human heart MRI scans were manually segmented to produce 3D structures with anatomically realistic electrophysiology. The Abubu.js library was used to create an interactive code to solve the OVVR human ventricular cell model and the FDA extension of the model in the human MRI heart structures, allowing the simulation of reentrant waves and investigation of their dynamics in real time. Interactive simulations of a physiological cell model in a detailed anatomical human heart reveals propagation of waves through the fine structures of the trabeculae and pectinate muscle that can perpetuate arrhythmias, thereby giving new insights into effects that may need to be considered when planning ablation and other defibrillation methods.

A Multi-Scale Computational Model for the Rat Ventricle: Construction, Parallelization, and Applications

BackgroundCardiovascular diseases are the top killer of human beings. The ventricular arrhythmia, as a type of malignant cardiac arrhythmias, typically leads to death if not treated within minutes. The multi-scale virtual heart provides an idealized tool for exploring the underlying mechanisms, by means of incorporating abundant experimental data at the level of ion channels and analyzing the subsequent pathological changes at organ levels. However, there are few studies on building a virtual heart model for rats—a species most widely used in experiments. ObjectiveTo build a multi-scale computational model for rats, with detailed methodology for the model construction, computational optimization, and its applications. MethodsFirst, approaches for building multi-scale models ranging from cellular to 3-D organ levels are introduced, with detailed descriptions of handling the ventricular myocardium heterogeneity, geometry processing, and boundary conditions, etc. Next, for dealing with the expensive computational costs of 3-D models, optimization approaches including an optimized representation and a GPU-based parallelization method are introduced. Finally, methods for reproducing of some key phenomenon (e.g., electrocardiograph, spiral/scroll waves) are demonstrated. ResultsThree types of heterogeneity, including the transmural heterogeneity, the interventricular heterogeneity, and the base-apex heterogeneity are incorporated into the model. The normal and reentrant excitation waves, as well as the corresponding pseudo-ECGs are reproduced by the constructed ventricle model. In addition, the temporal and spatial vulnerability to reentry arrhythmias are quantified based on the evaluation experiments of vulnerable window and the critical length. ConclusionsThe constructed multi-scale rat ventricle model is able to reproduce both the physiological and the pathological phenomenon in different scales. Evaluation experiments suggest that the apex is the most susceptible area to arrhythmias. The model can be a promising tool for the investigation of arrhythmogenesis and the screening of anti-arrhythmic drugs.

Post myocardial infarction ionic remodelling promotes repolarisation dispersions and abnormalities in acute and chronic stages

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Wellcome Trust Background Sudden cardiac death after a myocardial infarction (MI) was reported in both the acute stage and the chronic stage with the development of heart failure (HF). Around 50% of these deaths were due to ventricular tachyarrhythmia which is related to the temporal dispersion of repolarisation caused by the post-MI remodelling of ionic currents. While variable extent of ionic current changes was observed in multiple animal species in different post-MI phases, the proarrhythmic effects of such remodelling in post infarction human hearts is not fully explored. Purpose The goal of this study is to explore the proarrhythmic effects of post-MI ionic remodelling in human ventricular myocyte models of electrophysiology for both the acute and the chronic stages. Methods The ToR-ORd human ventricular cellular model was used as the baseline model, and a new formulation of the calcium activated potassium current was implemented. We constructed and calibrated a population of 253 human ventricular cell models (POM) to represent electrophysiological variability of normal zone (NZ) myocytes. For the acute phase, three types of border zone (BZ) remodelling (Acute BZ1-3) were introduced based on dog experimental data collected within one week after infarction. For the chronic phase with the development of HF, BZ (Chronic BZ) and one type of remote zone (RZ) remodelling (Chronic RZ1) were introduced based on minipig data collected 5 months post-MI. Another type of RZ remodelling (Chronic RZ2) was introduced based on experimental data from failing human hearts. The cellular models were paced at cycle lengths of 1000ms, 500ms, 400ms and 300ms for 500 beats before the analysis of repolarization abnormalities. Results For both the acute and the chronic stages post-MI, the extent of repolarisation dispersion between BZ and the corresponding NZ and RZ varied from 2ms up to 120ms, and largely depended on the level of potassium current remodelling. A weaker calcium transient was always observed in the BZ. Early after depolarisations (EADs) and repolarisation failure (RF) were observed in the chronic stages, caused by the reactivation of L-type calcium current due to the augmentation of late sodium current and the inhibition of hERG current. Beat-to-beat repolarization alternans was observed in both the acute and the chronic stages, with the key ionic mechanisms being the inhibition of SERCA activity and the slower calcium release due to enhanced CaMKII. Conclusions Post-MI ionic remodelling of the acute and chronic stages can cause a substantial dispersion of repolarisation in human hearts by inducing the prolongation of action potential durations, EADs, RFs, and alternans, providing substrates for the generation and maintenance of lethal reentrant waves. Abstract Figure. BZ and RZ ionic current remodelling

Modelling Study on Acetylcholine Regulation to the Pacemaker Ability of the Sinoatrial Tissue in Hearts

As an important neurotransmitter, acetylcholine (Ach) is closely related with dysfunction of sinoatrial node (SAN), but many questions about its effects on electrophysiological behaviors of SAN are still unclear. In this paper based on the dynamic model of rabbit SAN and atrial cells while considering Ach activated inward rectifying K+ current, other Ach-adjusted ionic currents, and heterogeneity of SAN as well, a two-dimensional tissue model was developed. Computer simulation studies found that slowing of the firing rates caused by Ach could reach above 300%. Upstroke velocity of the central cell is over 3 times greater than that of the peripheral cell, thus presenting more sensitivity to Ach and easier property of sinus pause. Additionally, when Ach distributed nonuniformly, the leading pacemaker site would shift to where the maximum concentration gradient of Ach was. Moreover, the reentrant wave produced at atrial tachycardia could invade into the SAN and suppress its spontaneous firing. The greater the Ach concentration, the easier the suppression is.