Conduction Velocity Restitution Research Articles

Autonomic modulation impacts conduction velocity dynamics and wavefront propagation in the left atrium.

Atrial fibrosis and autonomic remodelling are proposed pathophysiological mechanisms in atrial fibrillation (AF). Their impact on conduction velocity (CV) dynamics and wavefront propagation was evaluated. Local activation times (LATs), voltage, and geometry data were obtained from patients undergoing ablation for persistent AF. LATs were obtained at three pacing intervals (PIs) in sinus rhythm (SR). LATs were used to determine CV dynamics and their relationship to local voltage amplitude. The impact of autonomic modulation- pharmacologically and with ganglionated plexi (GP) stimulation, on CV dynamics, wavefront propagation, and pivot points (change in wavefront propagation of ≥90°) was determined in SR. Fifty-four patients were included. Voltage impacted CV dynamics whereby at non-low voltage zones (LVZs) (≥0.5 mV) the CV restitution curves are steeper [0.03 ± 0.03 m/s ΔCV PI 600-400 ms (PI1), 0.54 ± 0.09 m/s ΔCV PI 400-250 ms (PI2)], broader at LVZ (0.2-0.49 mV) (0.17 ± 0.09 m/s ΔCV PI1, 0.25 ± 0.11 m/s ΔCV PI2), and flat at very LVZ (<0.2 mV) (0.03 ± 0.01 m/s ΔCV PI1, 0.04 ± 0.02 m/s ΔCV PI2). Atropine did not change CV dynamics, while isoprenaline and GP stimulation resulted in greater CV slowing with rate. Isoprenaline (2.7 ± 1.1 increase/patient) and GP stimulation (2.8 ± 1.3 increase/patient) promoted CV heterogeneity, i.e. rate-dependent CV (RDCV) slowing sites. Most pivot points co-located to RDCV slowing sites (80.2%). Isoprenaline (1.3 ± 1.1 pivot increase/patient) and GP stimulation (1.5 ± 1.1 increase/patient) also enhanced the number of pivot points identified. Atrial CV dynamics is affected by fibrosis burden and influenced by autonomic modulation which enhances CV heterogeneity and distribution of pivot points. This study provides further insight into the impact of autonomic remodelling in AF.

Spontaneous Repolarization Alternans Causes VT/VF Rearrest That Is Suppressed by Preserving Gap Junctions

BackgroundVentricular tachycardia (VT)/ventricular fibrillation (VF) rearrest after successful resuscitation is common, and survival is poor. A mechanism of VT/VF, as demonstrated in ex vivo studies, is when repolarization alternans becomes spatially discordant (DIS ALT), which can be enhanced by impaired gap junctions (GJs). However, in vivo spontaneous DIS ALT–induced VT/VF has never been demonstrated, and the effects of GJ on DIS ALT and VT/VF rearrest are unknown. ObjectivesThis study aimed to determine whether spontaneous VT/VF rearrest induced by DIS ALT occurs in vivo, and if it can be suppressed by preserving Cx43-mediated GJ coupling and/or connectivity. MethodsWe used an in vivo porcine model of resuscitation from ischemia-induced cardiac arrest combined with ex vivo optical mapping in porcine left ventricular wedge preparations. ResultsIn vivo, DIS ALT frequently preceded VT/VF and paralleled its incidence at normal (37°C, n = 9) and mild hypothermia (33°C, n = 8) temperatures. Maintaining GJs in vivo with rotigaptide (n = 10) reduced DIS ALT and VT/VF incidence, especially during mild hypothermia, by 90% and 60%, respectively (P < 0.001; P < 0.013). Ex vivo, both rotigaptide (n = 5) and αCT11 (n = 7), a Cx43 mimetic peptide that promotes GJ connectivity, significantly reduced DIS ALT by 60% and 100%, respectively (P < 0.05; P < 0.005), and this reduction was associated with reduced intrinsic heterogeneities of action potential duration rather than changes in conduction velocity restitution. ConclusionsThese results provide the strongest in vivo evidence to date suggesting a causal relationship between spontaneous DIS ALT and VT/VF in a clinically realistic scenario. Furthermore, our results suggest that preserving GJs during resuscitation can suppress VT/VF rearrest.

PITX2c impairment electrical remodeling increases susceptibility to atrial fibrillation

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): the National Research Foundation of Korea (NRF) grants funded by the Korea government (MSIT), the Korean Fund for Regenerative Medicine (KFRM) grant funded by the Korea government Background Functional mutations in the PITX2 (Paired-like homeodomain transcription factor 2) gene cause genetically inherited atrial fibrillation (AF). PITX2 is known to plays a pivotal role in regulating the expression of distinct ion channels, beta-adrenergic stimulation, cell-cell coupling and resulting in AF due to abnormal calcium abnormalities and electrical remodeling. However, the pathophysiological mechanisms linking impaired PITX2 with AF are still to be explored. This study was performed to generate PITX2c knockout human iPSC atrial cardiomyocytes (hiPSC-atrial CM), which are useful tools for arrhythmia modeling, and evaluate the mechanism of PITX2 deficiency leading to AF. Methods We generated a PITX2 knock-out iPSC line using a CRISPR/Cas9-based genome editing system. hiPSCs were electroporated with Cas9/sgRNA ribonucleoprotein (RNP) complexes. PITX2c knock-out hiPSC-CMs differentiated into atrial cardiomyocytes based on the manipulation of retinoic acid signaling. For the three-dimensional (3D) culture model, cells were plated in the spherical plate 5D. Electrophysiological properties and oxidative stress were assessed in PITX2c-deficient cardiomyocytes. Proarrhythmic effects of the PITX2c knock-out were quantified with AP morphology, AP duration (APD) restitution, wavelength (WL) and conduction velocity (CV) restitution using microelectrode arrays (MEA). Results We demonstrated that atrial-specific differentiated hiPSC-CMs expressed atrial-specific genes and the properties of action potentials were like those of human atrial cardiomyocytes. In addition, both 2D and 3D PITX2c knock-out atrial hiPSC-CMs showed signs of APD shortening and reduced wavelength (WL) and increased conduction velocity (CV) restitution (P&amp;lt;0.05). Next, a functional assessment of calcium homeostasis has shown that PITX2c causes atrial arrhythmias by impairing calcium handling genes (SERCA2a, RyR2, PLN). We then demonstrated that miR-374a-5p and miR-374b-5p could be involved in pathophysiological functions as therapeutic candidates when affinity for PITX2 was based on the upper context score percentile (&amp;gt; 99). Conclusions This study provides an understanding of electrical remodeling by PITX2c loss-of-function mutations and suggests the potential therapeutic candidates by miR-374a-5p and miR-374b-5p, thus helping to understand the mechanism of PITX2 deficiency leading to atrial fibrillation.

BS-454195-1 ADRENERGIC MODULATION OF CONDUCTION DURING CARDIAC STRESS IS MEDIATED BY CALCIUM CHANNEL AUTOREGULATION OF INTERCALATED DISC NANODOMAINS

During stress, adrenergic signaling enhances cardiac conduction, although the mechanisms are not fully understood. Reducing extracellular calcium in the heart widens an intercalated disc (ID) nanodomain adjacent to gap junctions known as the perinexus. Under acute cardiac stress, the perinexus adaptively remodels; preventing this response by experimentally changing calcium levels slows conduction and increases arrhythmia risk. This raises the question of whether myocytes autoregulate calcium-mediated ID adhesion to stabilize conduction during cardiac stress. The cardiac voltage gated calcium channel (Cav1.2) is a primary source of calcium influx and a key target during adrenergic signaling. Expression of Cav1.2 within the ID has not been described. To test the hypothesis that Cav1.2 is expressed in the ID and autoregulates myocyte adhesion and conduction in the adrenergic response to cardiac stress. Ex vivo guinea pig hearts were Langendorff-perfused and ventricular tissue harvested for microscopy. Cav1.2 cellular localization was quantified by spinning disk confocal microscopy (n=5), conduction velocity (CV) was measured by optical mapping (n=9), and ID ultrastructure was quantified from transmission electron micrographs (n=17). Cav1.2 function was modulated by perfusion with the β-adrenergic agonist isoproterenol (Iso, 0.6μM), the Cav1.2 agonist BayK8644 (BayK, 0.5μM), or the Cav1.2 antagonist verapamil (Ver, 2μM). Super resolution confocal microscopy demonstrated that 2.5% of total Cav1.2 signal co-occurred with connexin43 and N-cadherin. At baseline, CV slowed at shorter CLs (150 vs 300ms = 4% slower), consistent with CV restitution. Treatment with Iso increased both Wp (20.2 vs 17.0 nm at baseline) and CV (300ms: 113% of baseline). Iso reversed CV restitution such that CV increased by 4%. Activation of Cav1.2 by BayK widened Wp to the same degree as Iso (20.1 vs 20.2 nm). Verapamil prevented both the Iso-induced increase in Wp (17.0 nm) and CV (93.9% of baseline), and exacerbated CV restitution. A subpopulation of Cav1.2 was identified within the ID. Adrenergic stimulation widened perinexal width, increased conduction, and reversed CV restitution. Blocking Cav1.2 prevented the adrenergic-mediated change in perinexal structure and conduction. Thus, Cav1.2 function regulates ID ultrastructure and may serve as an adaptive response to enhance conduction during conditions of acute cardiac stress.

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.

An Automata-Based Cardiac Electrophysiology Simulator to Assess Arrhythmia Inducibility

Personalized cardiac electrophysiology simulations have demonstrated great potential to study cardiac arrhythmias and help in therapy planning of radio-frequency ablation. Its application to analyze vulnerability to ventricular tachycardia and sudden cardiac death in infarcted patients has been recently explored. However, the detailed multi-scale biophysical simulations used in these studies are very demanding in terms of memory and computational resources, which prevents their clinical translation. In this work, we present a fast phenomenological system based on cellular automata (CA) to simulate personalized cardiac electrophysiology. The system is trained on biophysical simulations to reproduce cellular and tissue dynamics in healthy and pathological conditions, including action potential restitution, conduction velocity restitution and cell safety factor. We show that a full ventricular simulation can be performed in the order of seconds, emulate the results of a biophysical simulation and reproduce a patient’s ventricular tachycardia in a model that includes a heterogeneous scar region. The system could be used to study the risk of arrhythmia in infarcted patients for a large number of scenarios.

A computationally efficient dynamic model of human epicardial tissue.

We present a new phenomenological model of human ventricular epicardial cells and we test its reentry dynamics. The model is derived from the Rogers-McCulloch formulation of the FitzHugh-Nagumo equations and represents the total ionic current divided into three contributions corresponding to the excitatory, recovery and transient outward currents. Our model reproduces the main characteristics of human epicardial tissue, including action potential amplitude and morphology, upstroke velocity, and action potential duration and conduction velocity restitution curves. The reentry dynamics is stable, and the dominant period is about 270 ms, which is comparable to clinical values. The proposed model is the first phenomenological model able to accurately resemble human experimental data by using only 3 state variables and 17 parameters. Indeed, it is more computationally efficient than existing models (i.e., almost two times faster than the minimal ventricular model). Beyond the computational efficiency, the low number of parameters facilitates the process of fitting the model to the experimental data.

CVAR-Seg: An Automated Signal Segmentation Pipeline for Conduction Velocity and Amplitude Restitution.

BackgroundRate-varying S1S2 stimulation protocols can be used for restitution studies to characterize atrial substrate, ionic remodeling, and atrial fibrillation risk. Clinical restitution studies with numerous patients create large amounts of these data. Thus, an automated pipeline to evaluate clinically acquired S1S2 stimulation protocol data necessitates consistent, robust, reproducible, and precise evaluation of local activation times, electrogram amplitude, and conduction velocity. Here, we present the CVAR-Seg pipeline, developed focusing on three challenges: (i) No previous knowledge of the stimulation parameters is available, thus, arbitrary protocols are supported. (ii) The pipeline remains robust under different noise conditions. (iii) The pipeline supports segmentation of atrial activities in close temporal proximity to the stimulation artifact, which is challenging due to larger amplitude and slope of the stimulus compared to the atrial activity.Methods and ResultsThe S1 basic cycle length was estimated by time interval detection. Stimulation time windows were segmented by detecting synchronous peaks in different channels surpassing an amplitude threshold and identifying time intervals between detected stimuli. Elimination of the stimulation artifact by a matched filter allowed detection of local activation times in temporal proximity. A non-linear signal energy operator was used to segment periods of atrial activity. Geodesic and Euclidean inter electrode distances allowed approximation of conduction velocity. The automatic segmentation performance of the CVAR-Seg pipeline was evaluated on 37 synthetic datasets with decreasing signal-to-noise ratios. Noise was modeled by reconstructing the frequency spectrum of clinical noise. The pipeline retained a median local activation time error below a single sample (1 ms) for signal-to-noise ratios as low as 0 dB representing a high clinical noise level. As a proof of concept, the pipeline was tested on a CARTO case of a paroxysmal atrial fibrillation patient and yielded plausible restitution curves for conduction speed and amplitude.ConclusionThe proposed openly available CVAR-Seg pipeline promises fast, fully automated, robust, and accurate evaluations of atrial signals even with low signal-to-noise ratios. This is achieved by solving the proximity problem of stimulation and atrial activity to enable standardized evaluation without introducing human bias for large data sets.

Stability of spatially discordant repolarization alternans in cardiac tissue.

Cardiac alternans, a period-2 behavior of excitation and contraction of the heart, is a precursor of ventricular arrhythmias and sudden cardiac death. One form of alternans is repolarization or action potential duration alternans. In cardiac tissue, repolarization alternans can be spatially in-phase, called spatially concordant alternans, or spatially out-of-phase, called spatially discordant alternans (SDA). In SDA, the border between two out-of-phase regions is called a node in a one-dimensional cable or a nodal line in a two-dimensional tissue. In this study, we investigate the stability and dynamics of the nodes and nodal lines of repolarization alternans driven by voltage instabilities. We use amplitude equation and coupled map lattice models to derive theoretical results, which are compared with simulation results from the ionic model. Both conduction velocity restitution induced SDA and non-conduction velocity restitution induced SDA are investigated. We show that the stability and dynamics of the SDA nodes or nodal lines are determined by the balance of the tensions generated by conduction velocity restitution, convection due to action potential propagation, curvature of the nodal lines, and repolarization and coupling heterogeneities. Our study provides mechanistic insights into the different SDA behaviors observed in experiments.

P920Understanding arrhythmia mechanisms in patients with atrial septal defects

Abstract Background Atrial arrhythmias represent a major cause of morbidity and hospitalization in patients with atrial septal defects (ASD). Optimum treatment strategies are unknown since the mechanisms of arrhythmia are undefined in this cohort. Purpose We investigated whether percutaneous ASD closure reduces atrial arrhythmias and subsequently examined the electrical and structural changes underpinning arrhythmogenesis in ASD patients. Methods Meta-analysis was used to study the effect of closure on arrhythmias. Bi-atrial electrical dysfunction was assessed through invasive measurement of atrial voltage, refractory periods (ERP) over three drive trains (600, 450 and 300ms) and local conduction velocity (CV) with subsequent assessment of ERP and CV restitution. Structural remodelling was assessed through non-invasive quantification of fibrosis using cardiac MRI (CMR). Origin of ectopy was evaluated invasively using isoprenaline infusion and non-invasively using 24-hour Holter monitoring. Comparison was made to normal heart controls. Results Meta-analysis Meta-analysis of 25 studies found that percutaneous closure was associated with a weak reduction in atrial arrhythmias only in patients &amp;gt;40 years old (OR 0.777, 95% CI 0.616-0.979, P = 0.032). Electrical Remodelling On invasive assessment (21 ASDs; 21 controls), proportion of right atrial low voltage (&amp;lt;0.5mV) and scar (&amp;lt;0.05mV) was greater in ASD vs control patients (P = 0.02 and P = 0.039). In ASD patients, these parameters were greater in the right atrium vs the left atrium (P = 0.002 and P = 0.01). Right atrial ERP restitution slopes were steeper in ASD vs control patients (P = 0.016). Maximum right atrial CV and CV restitution slopes were greater in ASD vs control patients (P= 0.005 and P &amp;lt; 0.001 respectively) and CV decrement occurred at longer coupling intervals in the right atrium in ASD patients (P = 0.015). Structural Remodelling On CMR assessment (36 ASDs; 36 controls), bi-atrial fibrosis was greater in ASD vs control patients (P &amp;lt; 0.001). In ASD patients right atrial fibrosis was burden greater in patients with vs without atrial arrhythmias (P = 0.034). Arrhythmia Triggers On 24-hour Holter monitoring and during invasive isoprenaline infusion right and left atrial ectopy was equally prevalent in ASD vs control patients. Conclusion This study highlights the importance of right atrial electrical dysfunction to the occurrence of arrhythmias in ASD patients with extensive right atrial remodelling (fibrosis, low voltage, steeper ERP and CV restitution) seen in ASD patients compared to normal heart controls. From the results of the meta-analysis it appears that percutaneous closure alone is insufficient to treat arrhythmias in ASD patients. Given the predominance of right atrial remodelling, right-sided ablation as an adjunct to conventional left-sided ablation should be investigated as a strategy to treat atrial arrhythmias in these patients. Abstract Figure.

PITX2 upregulation increases the risk of chronic atrial fibrillation in a dose-dependent manner by modulating IKs and ICaL -insights from human atrial modelling.

BackgroundFunctional analysis has shown that the paired-like homeodomain transcription factor 2 (PITX2) overexpression associated with atrial fibrillation (AF) leads to the slow delayed rectifier K+ current (IKs) increase and the L-type Ca2+ current (ICaL) reduction observed in isolated right atrial myocytes from chronic AF (CAF) patients. Through multiscale computational models, this study aimed to investigate the functional impact of the PITX2 overexpression on atrial electrical activity.MethodsThe well-known Courtemanche-Ramirez-Nattel (CRN) model of human atrial action potentials (APs) was updated to incorporate experimental data on alterations in IKs and ICaL due to the PITX2 overexpression. These cell models for sinus rhythm (SR) and CAF were then incorporated into homogeneous multicellular one-dimensional (1D), two-dimensional (2D), and three-dimensional (3D) tissue models. The proarrhythmic effects of the PITX2 overexpression were quantified with ion current profiles, AP morphology, AP duration (APD) restitution, conduction velocity restitution (CVR), wavelength (WL), vulnerable window (VW) for unidirectional conduction block, and minimal substrate size required to induce re-entry. Dynamic behaviors of spiral waves were characterized by measuring lifespan (LS), tip patterns and dominant frequencies.ResultsThe IKs increase and the ICaL decrease arising from the PITX2 overexpression abbreviated APD and flattened APD restitution (APDR) curves in single cells. It reduced WL and increased CV at high excitation rates at the 1D tissue level. Although it had no effects on VW for initiating spiral waves, it decreased the minimal substrate size necessary to sustain re-entry. It also stabilized and accelerated spiral waves in 2D and 3D tissue models.ConclusionsElectrical remodeling (IKs and ICaL) due to the PITX2 overexpression increases susceptibility to AF due to increased tissue vulnerability, abbreviated APD, shortened WL and altered CV, which, in combination, facilitate initiation and maintenance of spiral waves.

Spatially Discordant Repolarization Alternans in the Absence of Conduction Velocity Restitution

Spatially discordant alternans (SDA) of action potential duration (APD) has been widely observed in cardiac tissue and is linked to cardiac arrhythmogenesis. Theoretical studies have shown that conduction velocity restitution (CVR) is required for the formation of SDA. However, this theory is not completely supported by experiments, indicating that other mechanisms may exist. In this study, we carried out computer simulations using mathematical models of action potentials to investigate the mechanisms of SDA in cardiac tissue. We show that when CVR is present and engaged, such as fast pacing from one side of the tissue, the spatial pattern of APD in the tissue undergoes either spatially concordant alternans or SDA, independent of initial conditions or tissue heterogeneities. When CVR is not engaged, such as simultaneous pacing of the whole tissue or under normal/slow heart rates, the spatial pattern of APD in the tissue can have multiple solutions, including spatially concordant alternans and different SDA patterns, depending on heterogeneous initial conditions or pre-existing repolarization heterogeneities. In homogeneous tissue, curved nodal lines are not stable, which either evolve into straight lines or disappear. However, in heterogeneous itssue, curved nodal lines can be stable, depending on their initial locations and shapes relative to the structure of the heterogeneity. Therefore, CVR-induced SDA and non-CVR-induced SDA exhibit different dynamical properties, which may be responsible for the different SDA properties observed in experimental studies and arrhythmogenesis in different clinical settings.

Proarrhythmia in the p.Met207Val PITX2c-Linked Familial Atrial Fibrillation-Insights From Modeling.

Functional analysis has shown that the p.Met207Val mutation was linked to atrial fibrillation and caused an increase in transactivation activity of PITX2c, which caused changes in mRNA synthesis related to ionic channels and intercellular electrical coupling. We assumed that these changes were quantitatively translated to the functional level. This study aimed to investigate the potential impact of the PITX2c p.Met207Val mutation on atrial electrical activity through multiscale computational models. The well-known Courtemanche-Ramirez-Nattel (CRN) model of human atrial cell action potentials (APs) was modified to incorporate experimental data on the expected p.Met207Val mutation-induced changes in ionic channel currents (INaL, IKs, and IKr) and intercellular electrical coupling. The cell models for wild-type (WT), heterozygous (Mutant/Wild type, MT/WT), and homozygous (Mutant, MT) PITX2c cases were incorporated into homogeneous multicellular 1D and 2D tissue models. Effects of this mutation-induced remodeling were quantified as changes in AP profile, AP duration (APD) restitution, conduction velocity (CV) restitution and wavelength (WL). Temporal and spatial vulnerabilities of atrial tissue to the genesis of reentry were computed. Dynamic behaviors of re-entrant excitation waves (Life span, tip trajectory and dominant frequency) in a homogeneous 2D tissue model were characterized. Our results suggest that the PITX2c p.Met207Val mutation abbreviated atrial APD and flattened APD restitution curves. It reduced atrial CV and WL that facilitated the conduction of high rate atrial excitation waves. It increased the tissue's temporal vulnerability by increasing the vulnerable window for initiating reentry and increased the tissue spatial vulnerability by reducing the substrate size necessary to sustain reentry. In the 2D models, the mutation also stabilized and accelerated re-entrant excitation waves, leading to rapid and sustained reentry. In conclusion, electrical and structural remodeling arising from the PITX2c p.Met207Val mutation may increase atrial susceptibility to arrhythmia due to shortened APD, reduced CV and increased tissue vulnerability, which, in combination, facilitate initiation and maintenance of re-entrant excitation waves.

Spatiotemporal correlation uncovers characteristic lengths in cardiac tissue.

Complex spatiotemporal patterns of action potential duration have been shown to occur in many mammalian hearts due to period-doubling bifurcations that develop with increasing frequency of stimulation. Here, through high-resolution optical mapping experiments and mathematical modeling, we introduce a characteristic spatial length of cardiac activity in canine ventricular wedges via a spatiotemporal correlation analysis, at different stimulation frequencies and during fibrillation. We show that the characteristic length ranges from 40 to 20cm during one-to-one responses and it decreases to a specific value of about 3cm at the transition from period-doubling bifurcation to fibrillation. We further show that during fibrillation, the characteristic length is about 1cm. Another significant outcome of our analysis is the finding of a constitutive phenomenological law obtained from a nonlinear fitting of experimental data which relates the conduction velocity restitution curve with the characteristic length of the system. The fractional exponent of 3/2 in our phenomenological law is in agreement with the domain size remapping required to reproduce experimental fibrillation dynamics within a realistic cardiac domain via accurate mathematical models.

Cardiac Electrical Modeling for Closed-Loop Validation of Implantable Devices.

Evaluating and testing cardiac electrical devices in a closed-physiologic-loop can help design safety, but this is rarely practical or comprehensive. Furthermore, in silico closed-loop testing with biophysical computer models cannot meet the requirements of time-critical cardiac device systems, while simplified models meeting time-critical requirements may not have the necessary dynamic features. We propose a new high-level (abstracted) physiologically-based computational heart model that is time-critical and dynamic. The model comprises cardiac regional cellular-electrophysiology types connected by a path model along a conduction network. The regional electrophysiology and paths are modeled with hybrid automata that capture non-linear dynamics, such as action potential and conduction velocity restitution and overdrive suppression. The hierarchy of pacemaker functions is incorporated to generate sinus rhythms, while abnormal automaticity can be introduced to form a variety of arrhythmias such as escape ectopic rhythms. Model parameters are calibrated using experimental data and prior model simulations. Regional electrophysiology and paths in the model match human action potentials, dynamic behavior, and cardiac activation sequences. Connected in closed loop with a pacing device in DDD mode, the model generates complex arrhythmia such as atrioventricular nodal reentry tachycardia. Such device-induced outcomes have been observed clinically and we can establish the key physiological features of the heart model that influence the device operation. These findings demonstrate how an abstract heart model can be used for device validation and to design personalized treatment.

Mechanistic insight into spontaneous transition from cellular alternans to arrhythmia-A simulation study.

Cardiac electrical alternans (CEA), manifested as T-wave alternans in ECG, is a clinical biomarker for predicting cardiac arrhythmias and sudden death. However, the mechanism underlying the spontaneous transition from CEA to arrhythmias remains incompletely elucidated. In this study, multiscale rabbit ventricular models were used to study the transition and a potential role of INa in perpetuating such a transition. It was shown CEA evolved into either concordant or discordant action potential (AP) conduction alternans in a homogeneous one-dimensional tissue model, depending on tissue AP duration and conduction velocity (CV) restitution properties. Discordant alternans was able to cause conduction failure in the model, which was promoted by impaired sodium channel with either a reduced or increased channel current. In a two-dimensional homogeneous tissue model, a combined effect of rate- and curvature-dependent CV broke-up alternating wavefronts at localised points, facilitating a spontaneous transition from CEA to re-entry. Tissue inhomogeneity or anisotropy further promoted break-up of re-entry, leading to multiple wavelets. Similar observations have also been seen in human atrial cellular and tissue models. In conclusion, our results identify a mechanism by which CEA spontaneously evolves into re-entry without a requirement for premature ventricular complexes or pre-existing tissue heterogeneities, and demonstrated the important pro-arrhythmic role of impaired sodium channel activity. These findings are model-independent and have potential human relevance.

A work flow to build and validate patient specific left atrium electrophysiology models from catheter measurements.

Biophysical models of the atrium provide a physically constrained framework for describing the current state of an atrium and allow predictions of how that atrium will respond to therapy. We propose a work flow to simulate patient specific electrophysiological heterogeneity from clinical data and validate the resulting biophysical models. In 7 patients, we recorded the atrial anatomy with an electroanatomical mapping system (St Jude Velocity); we then applied an S1-S2 electrical stimulation protocol from the coronary sinus (CS) and the high right atrium (HRA) whilst recording the activation patterns using a PentaRay catheter with 10 bipolar electrodes at 12 ± 2 sites across the atrium. Using only the activation times measured with a PentaRay catheter and caused by a stimulus applied in the CS with a remote catheter we fitted the four parameters for a modified Mitchell-Schaeffer model and the tissue conductivity to the recorded local conduction velocity restitution curve and estimated local effective refractory period. Model parameters were then interpolated across each atrium. The fitted model recapitulated the S1-S2 activation times for CS pacing giving a correlation ranging between 0.81 and 0.98. The model was validated by comparing simulated activations times with the independently recorded HRA pacing S1-S2 activation times, giving a correlation ranging between 0.65 and 0.96. The resulting work flow provides the first validated cohort of models that capture clinically measured patient specific electrophysiological heterogeneity.

Stochastic Pacing Inhibits Spatially Discordant Cardiac Alternans

Depressed heart rate variability is a well-established risk factor for sudden cardiac death in survivors of acute myocardial infarction and for those with congestive heart failure. Although measurements of heart rate variability provide a valuable prognostic tool, it is unclear whether reduced heart rate variability itself is proarrhythmic or if it simply correlates with the severity of autonomic nervous system dysfunction. In this work, we investigate a possible mechanism by which heart rate variability could protect against cardiac arrhythmia. Specifically, in numerical simulations, we observe an inverse relationship between the variance of stochastic pacing and the occurrence of spatially discordant alternans, an arrhythmia that is widely believed to facilitate the development of cardiac fibrillation. By analyzing the effects of conduction velocity restitution, cellular dynamics, electrotonic coupling, and stochastic pacing on the nodal dynamics of spatially discordant alternans, we provide intuition for this observed behavior and propose control strategies to inhibit discordant alternans.

A conduction velocity adapted eikonal model for electrophysiology problems with re-excitability evaluation.

Computational models of heart electrophysiology achieved a considerable interest in the medical community as they represent a novel framework for the study of the mechanisms underpinning heart pathologies. The high demand of computational resources and the long computational time required to evaluate the model solution hamper the use of detailed computational models in clinical applications. In this paper, we present a multi-front eikonal algorithm that adapts the conduction velocity (CV) to the activation frequency of the tissue substrate. We then couple the eikonal new algorithm with the Mitchell-Schaeffer (MS) ionic model to determine the tissue electrical state. Compared to the standard eikonal model, this model introduces three novelties: first, it evaluates the local value of the transmembrane potential and of the ionic variable solving an ionic model; second, it computes the action potential duration (APD) and the diastolic interval (DI) from the solution of the MS model and uses them to determine if the tissue is locally re-excitable; third, it adapts the CV to the underpinning electrophysiological state through an analytical expression of the CV restitution and the computed local DI. We conduct series of simulations on a 3D tissue slab and on a realistic heart geometry and compare the solutions with those obtained solving the monodomain equation. Our results show that the new model is significantly more accurate than the standard eikonal model. The proposed model enables the numerical simulation of the heart electrophysiology on a clinical time scale and thus constitutes a viable model candidate for computer-guided radio-frequency ablation.

Effects of pharmacological gap junction and sodium channel blockade on S1S2 restitution properties in Langendorff-perfused mouse hearts

Gap junctions and sodium channels are the major molecular determinants of normal and abnormal electrical conduction through the myocardium, however, their exact contributions to arrhythmogenesis are unclear. We examined conduction and recovery properties of regular (S1) and extrasystolic (S2) action potentials (APs), S1S2 restitution and ventricular arrhythmogenicity using the gap junction and sodium channel inhibitor heptanol (2 mM) in Langendorff-perfused mouse hearts (n=10). Monophasic action potential recordings obtained during S1S2 pacing showed that heptanol increased the proportion of hearts showing inducible ventricular tachycardia (0/10 vs. 5/8 hearts (Fisher’s exact test, P < 0.05), prolonged activation latencies of S1 and S2 APs, thereby decreasing S2/S1 activation latency ratio (ANOVA, P < 0.05) despite prolonged ventricular effective refractory period (VERP). It did not alter S1 action potential duration at 90% repolarization (APD90) but prolonged S2 APD90 (P < 0.05), thereby increasing S2/S1 APD90 ratio (P < 0.05). It did not alter maximum conduction velocity (CV) restitution gradient or maximum CV reductions but decreased the restitution time constant (P < 0.05). It increased maximal APD90 restitution gradient (P < 0.05) without altering critical diastolic interval or maximum APD90 reductions. Pro-arrhythmic effects of 2 mM heptanol are explicable by delayed conduction and abnormal electrical restitution. We concluded that gap junctions modulated via heptanol (0.05 mM) increased arrhythmogenicity through a delay in conduction, while sodium channel inhibition by a higher concentration of heptanol (2 mM) increased arrhythmogenicity via additional mechanisms, such as abnormalities in APDs and CV restitution.