Novel mapping techniques for rotor core detection using simulated intracardiac electrograms.

BACKGROUND: Catheter ablation is associated with limited success rates in patients with persistent atrial fibrillation (AF). Currently, existing mapping systems fail to identify critical target sites for ablation. Recently, we proposed and validated several techniques (multiscale frequency [MSF], Shannon entropy [SE], kurtosis [Kt], and multiscale entropy [MSE]) to identify pivot point of rotors using ex-vivo optical mapping animal experiments. However, the performance of these techniques is unclear for the clinically recorded intracardiac electrograms (EGMs), due to the different nature of the signals. OBJECTIVE: This study aims to evaluate the performance of MSF, MSE, SE, and Kt techniques to identify the pivot point of the rotor using unipolar and bipolar EGMs obtained from numerical simulations. METHODS: Stationary and meandering rotors were simulated in a 2D human atria. The performances of new approaches were quantified by comparing the "true" core of the rotor with the core identified by the techniques. Also, the performances of all techniques were evaluated in the presence of noise, scar, and for the case of the multielectrode multispline and grid catheters. RESULTS: Our results demonstrate that all the approaches are able to accurately identify the pivot point of both stationary and meandering rotors from both unipolar and bipolar EGMs. The presence of noise and scar tissue did not significantly affect the performance of the techniques. Finally, the core of the rotors was correctly identified for the case of multielectrode multispline and grid catheter simulations. CONCLUSION: The core of rotors can be successfully identified from EGMs using novel techniques; thus, providing motivation for future clinical implementations.

Global vs local control of cardiac alternans in a 1D numerical model of human ventricular tissue.

Cardiac alternans is a proarrhythmic state in which the action potential duration (APD) of cardiac myocytes alternate between long and short values and often occurs under conditions of rapid pacing of cardiac tissue. In the ventricles, alternans is especially dangerous due to the life-threatening risk of developing arrhythmias, such as ventricular fibrillation. Alternans can be formed in periodically paced tissue as a result of pacing itself. Recently, it has been demonstrated that this pacing-induced alternans can be prevented by performing constant diastolic interval (DI) pacing, in which DI is independent of APD. However, constant DI pacing is difficult to implement in experimental settings since it requires the real-time measurement of APD. A more practical way was proposed based on electrocardiograms (ECGs), which give an indirect measure of the global DI relaxation period through the TR interval assessment. Previously, we demonstrated that constant TR pacing prevented alternans formation in isolated Langendorff-perfused rabbit hearts. However, the efficacy of "local" constant DI pacing vs "global" constant TR pacing in preventing alternans formation has never been investigated. Thus, the purpose of this study was to implement an ECG-based constant TR pacing in a 1D numerical model of human ventricular tissue and to compare the dynamical behavior of cardiac tissue with that resulted from a constant DI pacing. The results showed that both constant TR and constant DI pacing prevented the onset of alternans until lower basic cycle length when compared to periodic pacing. For longer cable lengths, constant TR pacing was shown to exhibit greater control on alternans than constant DI pacing.

Cardiac spiral wave drifting due to spatial temperature gradients - A numerical study.

Cardiac rotors are believed to be a major driver source of persistent atrial fibrillation (AF), and their spatiotemporal characterization is essential for successful ablation procedures. However, electrograms guided ablation have not been proven to have benefit over empirical ablation thus far, and there is a strong need of improving the localization of cardiac arrhythmogenic targets for ablation. A new approach for characterize rotors is proposed that is based on induced spatial temperature gradients (STGs), and investigated by theoretical study using numerical simulations. We hypothesize that such gradients will cause rotor drifting due to induced spatial heterogeneity in excitability, so that rotors could be driven towards the ablating probe. Numerical simulations were conducted in single cell and 2D atrial models using AF remodeled kinetics. STGs were applied either linearly on the entire tissue or as a small local perturbation, and the major ion channel rate constants were adjusted following Arrhenius equation. In the AF-remodeled single cell, recovery time increased exponentially with decreasing temperatures, despite the marginal effect of temperature on the action potential duration. In 2D models, spiral waves drifted with drifting velocity components affected by both temperature gradient direction and the spiral wave rotation direction. Overall, spiral waves drifted towards the colder tissue region associated with global minimum of excitability. A local perturbation with a temperature of T = 28 °C was found optimal for spiral wave attraction for the studied conditions. This work provides a preliminary proof-of-concept for a potential prospective technique for rotor attraction. We envision that the insights from this study will be utilize in the future in the design of a new methodology for AF characterization and termination during ablation procedures.

Mechano-electric feedback effects in a three-dimensional (3D) model of the contracting cardiac ventricle.

Mechano-electric feedback affects the electrophysiological and mechanical function of the heart and the cellular, tissue, and organ properties. To determine the main factors that contribute to this effect, this study investigated the changes in the action potential characteristics of the ventricle during contraction. A model of stretch-activated channels was incorporated into a three-dimensional multiscale model of the contracting ventricle to assess the effect of different preload lengths on the electrophysiological behavior. The model describes the initiation and propagation of the electrical impulse, as well as the passive (stretch) and active (contraction) changes in the cardiac mechanics. Simulations were performed to quantify the relationship between the cellular activation and recovery patterns as well as the action potential durations at different preload lengths in normal and heart failure pathological conditions. The simulation results showed that heart failure significantly affected the excitation propagation parameters compared to normal condition. The results showed that the mechano-electrical feedback effects appear to be most important in failing hearts with low ejection fraction.

Termination of atrial spiral waves by traction into peripheral non 1:1 conducting regions - A numerical study.

Atrial ablation has been recently utilized to treat atrial fibrillation (AF) by isolation or destruction of arrhythmia drivers. In chronic or persistent AF patients these drivers often consist of one or few rotors at unknown locations, and several ablations are commonly conducted before arrhythmia is terminated. However, the irreversible damage done to the tissue may lead to AF recurrence. We propose an alternative strategy to terminate rotor activity by its attraction into a non 1:1 conducting region. The feasibility of the method was numerically tested in 2D models of chronic AF human atrial tissue. Left-to-right gradients of either acetylcholine (ACh) or potassium conductance were employed to generate regions of 1:1 and non 1:1 conduction, characterized by their dominant frequency (DF) ratios. Spiral waves were established in the 1:1 conducting region and raster scanning was employed using a stimulating probe to attract the spiral wave tip. The probe was then linearly moved towards the boundary between the two regions. Successful attraction of spiral waves to the probe was demonstrated when the probe was <8mm from the spiral wave tip. Maximal traction velocity without loss of anchoring increased in a non-linear way with increasing values of ACh. Success rate of spiral wave termination was over 90% for regional DF ratios of as low as 1:1.2. Given that normally much higher ratios are measured in physiological atrial tissues, we envision this technique to provide a feasible, safer alternative to ablation procedures performed in persistent AF patients.

The Multi-Domain Fibroblast/Myocyte Coupling in the Cardiac Tissue: A Theoretical Study.

Cardiac fibroblast proliferation and concomitant collagenous matrix accumulation (fibrosis) develop during multiple cardiac pathologies. Recent studies have demonstrated direct electrical coupling between myocytes and fibroblasts in vitro, and assessed the electrophysiological implications of such coupling. However, in the living tissues, such coupling has not been demonstrated, and only indirect coupling via the extracellular space is likely to exist. In this study we employed a multi-domain model to assess the modulation of the cardiac electrophysiological properties by neighboring fibroblasts assuming only indirect coupling. Numerical simulations in 1D and 2D human atrial models showed that extracellular coupling sustains a significant impact on conduction velocity (CV) and a less significant effect on the action potential duration. Both CV and the slope of the CV restitution increased with increasing fibroblast density. This effect was more substantial for lower extracellular conductance. In 2D, spiral waves exhibited reduced frequency with increasing fibroblast density, and the propensity of wavebreaks and complex dynamics at high pacing rates significantly increased.

Cardiac KATP channel modulation by 16Hz magnetic fields - A theoretical study.

Heart exposure to 16Hz magnetic fields (MFs) was shown to be cardio-protective for diseased hearts; still, the mechanism of this effect is unknown. We hypothesize that a possible one mechanism is an increased trans-membrane KATP channel open probability due to modulation of the degree of dissociation between K+ ions, having a resonance frequency of 16Hz, and the channel selectivity filter. The Fan-Makielski Markovian KATP channel model was adopted, and the MF bio-effect was manifested by modulating the open probability of the channel using the predictive MF bio-effect parameter based on Binhi's quantum mechanics model. The model was integrated in a ventricular single cell model and the MF effect on the calcium transients [Ca2+] was assessed. Periodic pacing (Cycle Length CL=1sec) was applied and a 16Hz or 32Hz MF was turned on at t=0 for 10min. MF exposure gradually decreased [Ca2+] due to KATP channel opening, more strongly at 16Hz. Additionally, a small negative diastolic shift was observed. These numerical results demonstrated similarity to published experimental data using similar 16Hz MF exposure. We conclude that 16Hz MF exposure increases the KATP channel open probability, lowering the cellular calcium load. Our model could be integrated in a tissue model to predict optimal MF parameters for future cardiac therapy devices.

Modulation of cardiac pacemaker inter beat intervals by sinoatrial fibroblasts -a numerical study.

The potential effect of sinoatrial fibroblasts on beat rate and variability of the cardiac pacemakers is not yet fully understood. Heterocellular coupling formation and fibroblast proliferation during diseased conditions may further signify the impact of those cells on sinoatrial node function. In this study we numerically modeled the impact of varying numbers of fibroblasts that are electrically coupled to a single pacemaker cell on several electrophysiological parameters. We employed cellular kinetics of the rabbit sinoatrial myocyte, and employed a range of potential gap junctional coupling between fibroblasts and myocytes. We show that increasing numbers of attached and coupled fibroblasts result in depolarization of the resting membrane potential of the pacemaker cell, as well as in attenuation in its action potential magnitude. We also demonstrate that the mean pacemaker inter-beat interval (IBI) was modulated in a non-linear, bi-phasic way by increasing numbers of attached fibroblasts, whereby an initial phase of decreasing IBIs was followed by a significant phase of exponentially increasing IBIs. These observations were more substantial for increased gap junctional coupling between the two cell types. We finally show that IBI variability exponentially increased with increasing numbers of attached and electrically coupled fibroblasts. Again, this effect was stronger with higher values of gap junctional coupling. We postulate that the last observation is related to the role of fibroblasts in amplifying membrane voltage fluctuations of attached myocytes.

A Genetic Algorithm Optimization Method for Mapping Non-Conducting Atrial Regions: A Theoretical Feasibility Study.

Atrial ablation has been recently utilized for curing atrial fibrillation. The success rate of empirical ablation is relatively low as often the exact locations of the arrhythmogenic sources remain elusive. Guided ablation has been proposed to improve ablation technique by providing guidance regarding the potential localization of the sources; yet to date no main technological solution has been widely adopted as an integral part of the ablation process. Here we propose a genetic algorithm optimization technique to map a major arrhythmogenic substance-non-conducting regions (NCRs). Excitation delays in a set of electrodes of known locations are measured following external tissue stimulation, and the spatial distribution of obstacles that is most likely to yield the measured delays is reconstructed. A forward problem module was solved to provide synthetic time delay measurements using a 2D human atrial model with known NCR distribution. An inverse genetic algorithm module was implemented to optimally reconstruct the locations of the now unknown obstacle distribution using the synthetic measurements. The performance of the algorithm was demonstrated for several distributions varying in NCR number and shape. The proposed algorithm was found robust to measurements with a signal-to-noise ratio of at least -20 dB, and for measuring electrodes separated by up to 3.2 mm. Our results support the feasibility of the proposed algorithm in mapping NCRs; nevertheless, further research is required prior to clinical implementation for incorporating more complex atrial tissue geometrical configurations as well as for testing the algorithm with experimental data.

Multiscale Interactions in a 3D Model of the Contracting Ventricle.

A biophysical detailed multiscale model of the myocardium is presented. The model was used to study the contribution of interrelated cellular mechanisms to global myocardial function. The multiscale model integrates cellular electrophysiology, excitation propagation dynamics and force development models into a geometrical fiber based model of the ventricle. The description of the cellular electrophysiology in this study was based on the Ten Tusscher-Noble-Noble-Panfilov heterogeneous model for human ventricular myocytes. A four-state model of the sarcomeric control of contraction developed by Negroni and Lascano was employed to model the intracellular mechanism of force generation. The propagation of electrical excitation was described by a reaction-diffusion equation. The 3D geometrical model of the ventricle, based on single fiber contraction was used as a platform for the evaluation of proposed models. The model represents the myocardium as an anatomically oriented array of contracting fibers with individual fiber parameters such as size, spatial location, orientation and mechanical properties. Moreover, the contracting ventricle model interacts with intraventricular blood elements linking the contractile elements to the heart's preload and afterload, thereby producing the corresponding pressure-volume loop. The results show that the multiscale ventricle model is capable of simulating mechanical contraction, pressure generation and load interactions as well as demonstrating the individual contribution of each ion current.

Interbeat interval modulation in the sinoatrial node as a result of membrane current stochasticity-a theoretical and numerical study.

A single isolated sinoatrial pacemaker cell presents intrinsic interbeat interval (IBI) variability that is believed to result from the stochastic characteristics of the opening and closing processes of membrane ion channels. To our knowledge, a novel mathematical framework was developed in this work to address the effect of current fluctuations on the IBIs of sinoatrial pacemaker cells. Using statistical modeling and employing the Fokker-Planck formalism, our mathematical analysis suggests that increased stochastic current fluctuation variance linearly increases the slope of phase-4 depolarization, hence the rate of activations. Single-cell and two-dimensional computerized numerical modeling of the sinoatrial node was conducted to validate the theoretical predictions using established ionic kinetics of the rabbit pacemaker and atrial cells. Our models also provide, to our knowledge, a novel complementary or alternative explanation to recent experimental observations showing a strong reduction in the mean IBI of Cx30 deficient mice in comparison to wild-types, not fully explicable by the effects of intercellular decoupling.

Detection of abnormal cardiac activity using principal component analysis--a theoretical study.

Electrogram-guided ablation has been recently developed for allowing better detection and localization of abnormal atrial activity that may be the source of arrhythmogeneity. Nevertheless, no clear indication for the benefit of using electrograms guided ablation over empirical ablation was established thus far, and there is a clear need of improving the localization of cardiac arrhythmogenic targets for ablation. In this paper, we propose a new approach for detection and localization of irregular cardiac activity during ablation procedures that is based on dimension reduction algorithms and principal component analysis (PCA). Using an 8×8 electrode array, our method produces manifolds that allow easy visualization and detection of possible arrhythmogenic ablation targets characterized by irregular conduction. We employ mathematical modeling and computer simulations to demonstrate the feasibility of the new approach for two well established arrhythmogenic sources for irregular conduction--spiral waves and patchy fibrosis. Our results show that the PCA method can differentiate between focal ectopic activity and spiral wave activity, as these two types of activity produce substantially different manifold shapes. Moreover, the technique allows the detection of spiral wave cores and their general meandering and drifting pattern. Fibrotic patches larger than 2 mm(2) could also be visualized using the PCA method, both for quiescent atrial tissue and for tissue exhibiting spiral wave activity. We envision that this method, contingent to further numerical and experimental validation studies in more complex, realistic geometrical configurations and with clinical data, can improve existing atrial ablation mapping capabilities, thus increasing success rates and optimizing arrhythmia management.

The interrelations among stochastic pacing, stability, and memory in the heart.

Low pacing variability in the heart has been clinically reported as a risk factor for lethal cardiac arrhythmias and arrhythmic death. In ia previous simulation study, we demonstrated that stochastic pacing sustains an antiarrhythmic effect by moderating the slope of the action potential duration (APD) restitution curve, by reducing the propensity of APD alternans, converting discordant to concordant alternans, and ultimately preventing wavebreaks. However, the dynamic mechanisms relating pacing stochasticity to tissue stability are not yet known. In this work, we develop a mathematical framework to describe the APD signal using an autoregressive stochastic model, and we establish the interrelations between stochastic pacing, cardiac memory, and cardiac stability, as manifested by the degree of APD alternans. Employing stability analysis tools, we show that increased stochasticity in the ventricular tissue activation sequence works to lower the maximal absolute eigenvalues of the stochastic model, thereby contributing to increased stability. We also show that the memory coefficients of the autoregressive model are modulated by pacing stochasticity in a nonlinear, biphasic way, so that for exceedingly high levels of pacing stochasticity, the antiarrhythmic effect is hampered by increasing APD variance. This work may contribute to establishment of an optimal antiarrhythmic pacing protocol in a future study.

Attraction of rotors to the pulmonary veins in paroxysmal atrial fibrillation: a modeling study.

Maintenance of paroxysmal atrial fibrillation (AF) by fast rotors in the left atrium (LA) or at the pulmonary veins (PVs) is not fully understood. To gain insight into this dynamic and complex process, we studied the role of the heterogeneous distribution of transmembrane currents in the PVs and LA junction (PV-LAJ) in the localization of rotors in the PVs. We also investigated whether simple pacing protocols could be used to predict rotor drift in the PV-LAJ. Experimentally observed heterogeneities in IK1, IKs, IKr, Ito, and ICaL in the PV-LAJ were incorporated into two- and pseudo three-dimensional models of Courtemanche-Ramirez-Nattel-Kneller human atrial kinetics to simulate various conditions and investigate rotor drifting mechanisms. Spatial gradients in the currents resulted in shorter action potential duration, minimum diastolic potential that was less negative, and slower upstroke and conduction velocity for rotors in the PV region than in the LA. Rotors under such conditions drifted toward the PV and stabilized at the shortest action potential duration and less-excitable region, consistent with drift direction under intercellular coupling heterogeneities and regardless of the geometrical constraint in the PVs. Simulations with various IK1 gradient conditions and current-voltage relationships substantiated its major role in the rotor drift. In our 1:1 pacing protocol, we found that among various action potential properties, only the minimum diastolic potential gradient was a rate-independent predictor of rotor drift direction. Consistent with experimental and clinical AF studies, simulations in an electrophysiologically heterogeneous model of the PV-LAJ showed rotor attraction toward the PV. Our simulations suggest that IK1 heterogeneity is dominant compared to other currents in determining the drift direction through its impact on the excitability gradient. These results provide a believed novel framework for understanding the complex dynamics of rotors in AF.

Stochastic pacing effect on cardiac alternans--simulation study of a 2D human ventricular tissue.

The physiological heart rate is not deterministic but rather varies in time; those variations are termed heart rate variability (HRV). It is well known that low HRV is often seen in patients prone to arrhythmias. The ability of HRV to predict arrhythmia events is traditionally attributed to an impaired balance between the autonomic sympathetic and parasympathetic tone. However, there is no concrete model that directly relates low HRV to the electrical conduction in the cardiac tissue and to arrhythmogenic dynamic properties. We simulated stochastic cardiac pacing with Gaussian distribution using 2D human ventricular tissue model. Conduction stabilization was obtained with stochastic pacing owing to reduced propensity of the appearance of action potential duration (APD) discordant alternans and reduced APD spatial heterogeneity.

Stochastic cardiac pacing increases ventricular electrical stability--a computational study.

The ventricular tissue is activated in a stochastic rather than in a deterministic rhythm due to the inherent heart rate variability (HRV). Low HRV is a known predictor for arrhythmia events and traditionally is attributed to autonomic nervous system tone damage. Yet, there is no model that directly assesses the antiarrhythmic effect of pacing stochasticity per se. One-dimensional (1D) and two-dimensional (2D) human ventricular tissues were modeled, and both deterministic and stochastic pacing protocols were applied. Action potential duration restitution (APDR) and conduction velocity restitution (CVR) curves were generated and analyzed, and the propensity and characteristics of action potential duration (APD) alternans were investigated. In the 1D model, pacing stochasticity was found to sustain a moderating effect on the APDR curve by reducing its slope, rendering the tissue less arrhythmogenic. Moreover, stochasticity was found to be a significant antagonist to the development of concordant APD alternans. These effects were generally amplified with increased variability in the pacing cycle intervals. In addition, in the 2D tissue configuration, stochastic pacing exerted a protective antiarrhythmic effect by reducing the spatial APD heterogeneity and converting discordant APD alternans to concordant ones. These results suggest that high cardiac pacing stochasticity is likely to reduce the risk of cardiac arrhythmias in patients.

Speckle-based configuration for simultaneous in vitro inspection of mechanical contractions of cardiac myocyte cells.

An optical lensless configuration for a remote noncontact measuring of mechanical contractions of a vast number of cardiac myocytes is proposed. All the myocytes were taken from rats, and the measurements were done in an in vitro mode. The optical method is based on temporal analysis of secondary reflected speckle patterns generated in lensless microscope configuration. The processing involves analyzing the movement and the change in the statistics of the secondary speckle patterns that are created on top of the cell culture when it is illuminated by a spot of laser beam. The main advantage of the proposed system is the ability to measure many cells simultaneously (∼1000 cells) and to extract the statistical data of their movement at once. The presented experimental results also include investigation of the effect of isoproteranol on cell contraction process.

Reconstruction of retrospective cardiac activity--numerical study in a single cell and in a linear strand.

Although computational modeling of the prospective electrical activity in the cardiac tissue is well established and robust, the retrospective extrapolation of this activity has not been explored to date. Here, we establish an algorithm for the backward-in-time extrapolation of electrical activity from measurements taken in the present. Using minimal human cardiac kinetic models and a modified Newton-Raphson algorithm, we demonstrate the feasibility of past activity reconstruction in a single cell and in a linear strand. In a single cell, reconstruction of state variables' shape, the action potential morphology, and the time of stimulation was successful for up to 1300 ms poststimulation and for data with signal-to-noise ratio levels higher than 40 dB. For linear strands, the action potential morphology was reconstructed for 500 ms poststimulation, and the reconstructed conduction velocity remained unaffected for signal-to-noise ratio levels higher than 50 dB. Moreover, tissue restitution properties due to various pacing rates were successfully reconstructed by the backward-in-time algorithm. These preliminary results demonstrate that past cardiac activity may be reconstructed from measurements in the present. We envision that this methodology could be implemented in future clinical applications, for example to trace the location and timing of ectopic foci during ablation procedures.