Improved algorithm for generating evenly-spaced streamlines from an orientation field on a triangulated surface.

BACKGROUND: Vector fields such as cardiac fiber orientation can be visualized on a surface using streamlines. The application of evenly-spaced streamline generation to the construction of interconnected cable structure for cardiac propagation models has more stringent requirements imperfectly fulfilled by current algorithms. METHOD: We developed an open-source C++/python package for the placement of evenly-spaced streamlines on a triangulated surface. The new algorithm improves upon previous works by more accurately handling streamline extremities, U-turns and limit cycles, by providing stronger geometrical guarantees on inter-streamline minimal distance, particularly when a high density of streamlines (up to 10µm spacing) is desired, and by making a more efficient parallel implementation available. The approach requires finding intersections between geometrical capsules and triangles to update an occupancy mask defined on the triangles. This enables fast streamline integration from thousands of seed points to identify optimal streamline placement. RESULTS: The algorithm was assessed qualitatively on different left atrial models of fiber orientation with varying mesh resolutions (up to 375k triangles) and quantitatively by measuring streamline lengths and distribution of inter-streamline minimal distance. The complexity and the computational performance of the algorithm were studied as a function of streamline spacing in relation to triangular mesh resolution. CONCLUSION: More accurate geometrical computations, attention to details and fine-tuning led to an algorithm more amenable to applications that require precise positioning of streamlines.

In Silico Human Cardiomyocyte Action Potential Modeling: Exploring Ion Channel Input Combinations.

In silico modeling offers an opportunity to supplement and accelerate cardiac safety testing. With in silico modeling, computational simulation methods are used to predict electrophysiological interactions and pharmacological effects of novel drugs on critical physiological processes. The O'Hara-Rudy's model was developed to predict the response to different ion channel inhibition levels on cardiac action potential duration (APD) which is known to directly correlate with the QT interval. APD data at 30% 60% and 90% inhibition were derived from the model to delineate possible ventricular arrhythmia scenarios and the marginal contribution of each ion channel to the model. Action potential values were calculated for epicardial, myocardial, and endocardial cells, with action potential curve modeling. This study assessed cardiac ion channel inhibition data combinations to consider when undertaking in silico modeling of proarrhythmic effects as stipulated in the Comprehensive in Vitro Proarrhythmia Assay (CiPA). As expected, our data highlight the importance of the delayed rectifier potassium channel (IKr) as the most impactful channel for APD prolongation. The impact of the transient outward potassium channel (Ito) inhibition on APD was minimal while the inward rectifier (IK1) and slow component of the delayed rectifier potassium channel (IKs) also had limited APD effects. In contrast, the contribution of fast sodium channel (INa) and/or L-type calcium channel (ICa) inhibition resulted in substantial APD alterations supporting the pharmacological relevance of in silico modeling using input from a limited number of cardiac ion channels including IKr, INa, and ICa, at least at an early stage of drug development.

QTc intervals at rest and during exercise assessed by group correction formulas in survivors of childhood acute lymphoblastic leukemia.

INTRODUCTION: Early signs of subclinical cardiac damage must be identified before they turn into clinical manifestations. Tailoring a formula is relevant for precise QTc evaluation in childhood acute lymphoblastic leukemia (ALL) survivors considering they are at risk of long-term cardiac problems. Therefore, we aim to develop group heart rate correction formulas for QT intervals in childhood ALL survivors at rest and during exercise, and to assess the applicability of these methods across a variety of risk groups exposed to diverse chemotherapy dosages. METHODS: Two hundred and fifty childhood ALL survivors in the PETALE study were classified into 3 groups depending on their prognostic risk group. ECG measurements (QT and RR intervals) were made at rest and during a cardiopulmonary exercise test. QT correction for heart rate was applied using 5 different formulas, which included 2 previously published formulas and 3 group-specific formulas for each sex. RESULTS: The QT/RR relation showed 2 different curves between rest and during exercise, which was worse for females. Group-specific QTc formulas allowed adequate heart rate-corrected QT interval, independently of the cumulative dose of doxorubicin received during treatment. Group-specific formulas showed significantly shorter QTc intervals than QTc from Bazett's formula. QTc (Bazett's formula) values surpassed the established clinical norm in 22 males (11%) and 22 females (11%), with a majority occurring during exercise, affecting 15 males (7.5%) and 10 females (5%). CONCLUSION: This study shows the applicability of personalized group correction of QT/RR data in childhood ALL survivors. Our comprehensive assessments (spanning rest, exercise, and recovery) is an effective approach for risk stratification of cardiac complications in childhood ALL survivors.

Intermittent nicotine access is as effective as continuous access in promoting nicotine seeking and taking in rats.

RATIONALE: Nicotine is a principal psychoactive agent in tobacco, contributing to tobacco's addictive potential. Preclinical studies on the effects of voluntary nicotine intake typically use self-administration procedures that provide continuous nicotine access during each self-administration session. However, many smokers consume cigarettes intermittently rather than continuously throughout each day. For drugs including cocaine and opioids, research in laboratory rats shows that intermittent intake can be more effective than continuous intake in producing patterns of drug use relevant to addiction. OBJECTIVE: We determined how intermittent versus continuous nicotine self-administration influences nicotine seeking and taking behaviours. METHODS: Female and male rats had continuous (i.e., Long Access; LgA, 6 h/day) or intermittent (IntA; 12 min ON, 60 min OFF, for 6 h/day) access to intravenous nicotine (15 µg/kg/infusion), for 12 daily sessions. We then assessed intake, responding for nicotine under a progressive ratio schedule of drug reinforcement and cue- and nicotine-induced reinstatement of drug seeking. We also estimated nicotine pharmacokinetic parameters during LgA and IntA self-administration. RESULTS: Overall, LgA rats took twice more nicotine than did IntA rats, yielding more sustained increases in estimated brain concentrations of the drug. However, the two groups showed similar motivation to seek and take nicotine, as measured using reinstatement and progressive ratio procedures, respectively. CONCLUSIONS: Intermittent nicotine use is just as effective as continuous use in producing addiction-relevant behaviours, despite significantly less nicotine exposure. This has implications for modeling nicotine self-administration patterns in human smokers and resulting effects on brain and behaviour.

Cardiac electrical abnormalities in childhood acute lymphoblastic leukemia survivors: a systematic review.

PURPOSE: The aim was to provide evidence about the prevalence, incidence, and risk factors of cardiac electrical abnormalities in childhood acute lymphoblastic leukemia (ALL) survivors. METHODS: We included all original studies reporting the incidence and/or prevalence of cardiac electrical abnormalities and/or risk factors associated with cardiac electrical abnormalities in childhood ALL survivors (< 21 years old at the time of their initial cancer diagnosis) who were post-treatment. Searches of the databases PubMed, Ovid MEDLINE(R) and Epub Ahead of Print, In-Process, In-Data-Review & Other Non-Indexed Citations, Daily and Versions(R), Ovid All EBM Reviews, Ovid Embase, and ISI Web of Science were completed in May 2023. The risk of bias was assessed using the standard JBI critical appraisal checklists. RESULTS: The 11 studies included in this review (N = 1,264 participants) evaluated various parameters, including different cardiac electrical abnormalities. Five studies reported heart rate abnormalities (0-68%), six reported repolarization disorders (0-30%), two reported depolarization disorders (0-1%), seven reported rhythm disturbances or abnormalities (0-100%), four reported conduction disorders (0-10%), and three reported unclassified abnormalities (1-38%). No risk factors were reported. CONCLUSIONS: Electrical heart problems have been observed in childhood ALL survivors after completion of treatment. Large prospective studies in childhood ALL survivors, clear definitions of cardiac electrical abnormalities, and comparison with a control group are warranted. IMPLICATIONS FOR CANCER SURVIVORS: Cardiac electrical abnormalities induced by chemotherapy-related cardiotoxicity in the growing population of childhood ALL survivors need to be better characterized to ensure better long-term follow-up and improve overall survival rate.

Vagus nerve stimulation parameters evoke differential neuronal responses in the locus coeruleus.

Vagus nerve stimulation (VNS) is used to treat drug-resistant epilepsy and depression, with additional applications under investigation. The noradrenergic center locus coeruleus (LC) is vital for VNS effects; however, the impact of varying stimulation parameters on LC activation is poorly understood. This study characterized LC activation across VNS parameters. Extracellular activity was recorded in rats' left LC while 11 VNS paradigms, utilizing variable frequencies and bursting characteristics, were pseudorandomly delivered to the left cervical vagus for five cycles. Neurons' change from baseline firing rate and timing response profiles were assessed. The proportion of neurons categorized as responders over 5 VNS cycles doubled in comparison to the first VNS cycle (p < 0.001) for all VNS paradigms, demonstrating an amplification effect. The percentage of positively consistent/positive responders increased for standard VNS paradigms with frequencies ≥10 Hz and for bursting paradigms with shorter interburst intervals and more pulses per burst. The synchrony between pairs of LC neurons increased during bursting VNS but not standard paradigms. Also, the probability of evoking a direct response during bursting VNS was higher with longer interburst intervals and a higher number of pulses per burst. Standard paradigms between 10-30 Hz best positively activates LC with consistency to VNS while the best bursting paradigm to increase activity was 300 Hz, seven pulses per burst separated by 1 s. Bursting VNS was effective in increasing synchrony between pairs of neurons, suggesting a common network recruitment originating from vagal afferents. These results indicate differential activation of LC neurons depending on the VNS parameters delivered.

The influence of exercise and postural changes on ventricular repolarization in the long QT syndrome: a systematic scoping review.

Current exercise recommendations make it difficult for long QT syndrome (LQTS) patients to adopt a physically active and/or athletic lifestyle. The purpose of this review is to summarize the current evidence, identify knowledge gaps, and discuss research perspectives in the field of exercise and LQTS. The first aim is to document the influence of exercise training, exercise stress, and postural change interventions on ventricular repolarization in LQTS patients, while the second aim is to describe electrophysiological measurements used to study the above. Studies examining the effects of exercise on congenital or acquired LQTS in human subjects of all ages were included. Systematic searches were performed on 1 October 2021, through PubMed (NLM), Ovid Medline, Ovid All EBM Reviews, Ovid Embase, and ISI Web of Science, and limited to articles written in English or French. A total of 1986 LQTS patients and 2560 controls were included in the 49 studies. Studies were mainly case-control studies (n = 41) and examined exercise stress and/or postural change interventions (n = 48). One study used a 3-month exercise training program. Results suggest that LQTS patients have subtype-specific repolarization responses to sympathetic stress. Measurement methods and quality were found to be very heterogeneous, which makes inter-study comparisons difficult. In the absence of randomized controlled trials, the current recommendations may have long-term risks for LQTS patients who are discouraged from performing physical activity, rendering its associated health benefits out of range. Future research should focus on discovering the most appropriate levels of exercise training that promote ventricular repolarization normalization in LQTS.

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

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

Acute effect of passive heat exposure on markers of cardiometabolic function in adults with type 2 diabetes mellitus.

Heat therapy is a promising strategy to improve cardiometabolic health. This study evaluated the acute physiological responses to hot water immersion in adults with type 2 diabetes mellitus (T2DM). On separate days in randomized order, 13 adults with T2DM [8 males/5 females, 62 ± 12 yr, body mass index (BMI): 30.1 ± 4.6 kg/m2] were immersed in thermoneutral (34°C, 90 min) or hot (41°C, core temperature ≥38.5°C for 60 min) water. Insulin sensitivity was quantified via the minimal oral model during an oral glucose tolerance test (OGTT) performed 60 min after immersion. Brachial artery flow-mediated dilation (FMD) and reactive hyperemia were evaluated before and 40 min after immersion. Blood samples were drawn to quantify protein concentrations and mRNA levels of HSP70 and HSP90, and circulating concentrations of cytokines. Relative to thermoneutral water immersion, hot water immersion increased core temperature (+1.66°C [+1.47, +1.87], P < 0.01), heart rate (+34 beats/min [+24, +44], P < 0.01), antegrade shear rate (+96 s-1 [+57, +134], P < 0.01), and IL-6 (+1.38 pg/mL [+0.31, +2.45], P = 0.01). Hot water immersion did not exert an acute change in insulin sensitivity (-0.3 dL/kg/min/µU/mL [-0.9, +0.2], P = 0.18), FMD (-1.0% [-3.6, +1.6], P = 0.56), peak (+0.36 mL/min/mmHg [-0.71, +1.43], P = 0.64), and total (+0.11 mL/min/mmHg × min [-0.46, +0.68], P = 0.87) reactive hyperemia. There was also no change in eHSP70 (P = 0.64), iHSP70 (P = 0.06), eHSP90 (P = 0.80), iHSP90 (P = 0.51), IL1-RA (P = 0.11), GLP-1 (P = 0.59), and NF-κB (P = 0.56) after hot water immersion. The physiological responses elicited by hot water immersion do not acutely improve markers of cardiometabolic function in adults with T2DM.NEW & NOTEWORTHY Heat therapy has been shown to improve markers of cardiometabolic health in preclinical and clinical studies. However, the effects of heat therapy in individuals with type 2 diabetes mellitus (T2DM) remain understudied. We examined the acute effect of hot water immersion on glucose tolerance, flow-mediated dilation, reactive hyperemia, inflammatory markers, and heat shock proteins in adults with T2DM. Hot water immersion did not acutely improve the markers studied.

Multiparameter optimization of nonuniform passive diffusion properties for creating coarse-grained equivalent models of cardiac propagation.

The arrhythmogenic role of discrete cardiac propagation may be assessed by comparing discrete (fine-grained) and equivalent continuous (coarse-grained) models. We aim to develop an optimization algorithm for estimating the smooth conductivity field that best reproduces the diffusion properties of a given discrete model. Our algorithm iteratively adjusts local conductivity of the coarse-grained continuous model by simulating passive diffusion from white noise initial conditions during 3-10 ms and computing the root mean square error with respect to the discrete model. The coarse-grained conductivity field was interpolated from up to 300 evenly spaced control points. We derived an approximate formula for the gradient of the cost function that required (in two dimensions) only two additional simulations per iteration regardless of the number of estimated parameters. Conjugate gradient solver facilitated simultaneous optimization of multiple conductivity parameters. The method was tested in rectangular anisotropic tissues with uniform and nonuniform conductivity (slow regions with sinusoidal profile) and random diffuse fibrosis, as well as in a monolayer interconnected cable model of the left atrium with spatially-varying fibrosis density. Comparison of activation maps served as validation. The results showed that after convergence the errors in activation time were < 1 ms for rectangular geometries and 1-3 ms in the atrial model. Our approach based on the comparison of passive properties (<10 ms simulation) avoids performing active propagation simulations (>100 ms) at each iteration while reproducing activation maps, with possible applications to investigating the impact of microstructure on arrhythmias.

Simulation of diffuse and stringy fibrosis in a bilayer interconnected cable model of the left atrium.

AIMS: The aim of this study is to design a computer model of the left atrium for investigating fibre-orientation-dependent microstructure such as stringy fibrosis. METHODS AND RESULTS: We developed an approach for automatic construction of bilayer interconnected cable models from left atrial geometry and epi- and endocardial fibre orientation. The model consisted of two layers (epi- and endocardium) of longitudinal and transverse cables intertwined-like fabric threads, with a spatial discretization of 100 µm. Model validation was performed by comparison with cubic volumetric models in normal conditions. Then, diffuse (n = 2904), stringy (n = 3600), and mixed fibrosis patterns (n = 6840) were randomly generated by uncoupling longitudinal and transverse connections in the interconnected cable model. Fibrosis density was varied from 0% to 40% and mean stringy obstacle length from 0.1 to 2 mm. Total activation time, apparent anisotropy ratio, and local activation time jitter were computed during normal rhythm in each pattern. Non-linear regression formulas were identified for expressing measured propagation parameters as a function of fibrosis density and obstacle length (stringy and mixed patterns). Longer obstacles (even below tissue space constant) were independently associated with prolonged activation times, increased anisotropy, and local fluctuations in activation times. This effect was increased by endo-epicardial dissociation and mitigated when fibrosis was limited to the epicardium. CONCLUSION: Interconnected cable models enable the study of microstructure in organ-size models despite limitations in the description of transmural structures.

Amphetamine maintenance therapy during intermittent cocaine self-administration in rats attenuates psychomotor and dopamine sensitization and reduces addiction-like behavior.

D-amphetamine maintenance therapy shows promise as a treatment for people with cocaine addiction. Preclinical studies using Long Access (LgA) cocaine self-administration procedures suggest D-amphetamine may act by preventing tolerance to cocaine's effects at the dopamine transporter (DAT). However, Intermittent Access (IntA) cocaine self-administration better reflects human patterns of use, is especially effective in promoting addiction-relevant behaviors, and instead of tolerance, produces psychomotor, incentive, and neural sensitization. We asked, therefore, how D-amphetamine maintenance during IntA influences cocaine use and cocaine's potency at the DAT. Male rats self-administered cocaine intermittently (5 min ON, 25 min OFF x10; 5-h/session) for 14 sessions, with or without concomitant D-amphetamine maintenance therapy during these 14 sessions (5 mg/kg/day via s.c. osmotic minipump). We then assessed responding for cocaine under a progressive ratio schedule, responding under extinction and cocaine-primed reinstatement of drug seeking. We also assessed the ability of cocaine to inhibit dopamine uptake in the nucleus accumbens core using fast scan cyclic voltammetry ex vivo. IntA cocaine self-administration produced psychomotor (locomotor) sensitization, strong motivation to take and seek cocaine, and it increased cocaine's potency at the DAT. D-amphetamine co-administration suppressed the psychomotor sensitization produced by IntA cocaine experience. After cessation of D-amphetamine treatment, the motivation to take and seek cocaine was also reduced, and sensitization of cocaine's actions at the DAT was reversed. Thus, treatment with D-amphetamine might reduce cocaine use by preventing sensitization-related changes in cocaine potency at the DAT, consistent with an incentive-sensitization view of addiction.

Observations on changes in ventricular repolarization following four weeks of exercise training in chronic heart failure patients.

OBJECTIVE: The aim of this study was to investigate the effects of exercise training on ventricular repolarization dynamicity and heart rate variability in chronic heart failure patients. DESIGN: A total of 22 chronic heart failure patients with reduced ejection fraction in sinus rhythm were included in the study. The patients were in NYHA classes II-III with an ejection fraction of 29.7 ± 7.7%. Before and after 4 weeks of aerobic exercise training, all patients performed a cardiopulmonary exercise test, a standard twelve-lead electrocardiogram and a 24 h Holter recording from which heart rate variability and ventricular repolarization dynamicity were assessed. RESULTS: We observed a significant decrease of QTpeak (p < .001) and QTend (p < .001) at RR intervals ranging from 600 to 1000 ms on 24 h QT/RR regressions after 4 weeks of exercise training. Our analyses revealed that short-term exercise training induced significant changes in the frequency and time domain HRV parameters on an overall time-period of 24 h. CONCLUSION: Four weeks of exercise training induced significant changes in ventricular repolarization dynamicity in chronic heart failure patients. In addition, short-term exercise training was enough to improve patients' heart rate variability.

Time resolution for wavefront and phase singularity tracking using activation maps in cardiac propagation models.

The dynamics of cardiac fibrillation can be described by the number, the trajectory, the stability, and the lifespan of phase singularities (PSs). Accurate PS tracking is straightforward in simple uniform tissues but becomes more challenging as fibrosis, structural heterogeneity, and strong anisotropy are combined. In this paper, we derive a mathematical formulation for PS tracking in two-dimensional reaction-diffusion models. The method simultaneously tracks wavefronts and PS based on activation maps at full spatiotemporal resolution. PS tracking is formulated as a linear assignment problem solved by the Hungarian algorithm. The cost matrix incorporates information about distances between PS, chirality, and wavefronts. A graph of PS trajectories is generated to represent the creations and annihilations of PS pairs. Structure-preserving graph transformations are applied to provide a simplified description at longer observation time scales. The approach is validated in 180 simulations of fibrillation in four different types of substrates featuring, respectively, wavebreaks, ionic heterogeneities, fibrosis, and breakthrough patterns. The time step of PS tracking is studied in the range from 0.1 to 10 ms. The results show the benefits of improving time resolution from 1 to 0.1 ms. The tracking error rate decreases by an order of magnitude because the occurrence of simultaneous events becomes less likely. As observed on PS survival curves, the graph-based analysis facilitates the identification of macroscopically stable rotors despite wavefront fragmentation by fibrosis.

Increased vulnerability of nigral dopamine neurons after expansion of their axonal arborization size through D2 dopamine receptor conditional knockout.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopamine (DA) neurons in the substantia nigra pars compacta (SNc). Rare genetic mutations in genes such as Parkin, Pink1, DJ-1, α-synuclein, LRRK2 and GBA are found to be responsible for the disease in about 15% of the cases. A key unanswered question in PD pathophysiology is why would these mutations, impacting basic cellular processes such as mitochondrial function and neurotransmission, lead to selective degeneration of SNc DA neurons? We previously showed in vitro that SNc DA neurons have an extremely high rate of mitochondrial oxidative phosphorylation and ATP production, characteristics that appear to be the result of their highly complex axonal arborization. To test the hypothesis in vivo that axon arborization size is a key determinant of vulnerability, we selectively labeled SNc or VTA DA neurons using floxed YFP viral injections in DAT-cre mice and showed that SNc DA neurons have a much more arborized axon than those of the VTA. To further enhance this difference, which may represent a limiting factor in the basal vulnerability of these neurons, we selectively deleted in mice the DA D2 receptor (D2-cKO), a key negative regulator of the axonal arbour of DA neurons. In these mice, SNc DA neurons have a 2-fold larger axonal arborization, release less DA and are more vulnerable to a 6-OHDA lesion, but not to α-synuclein overexpression when compared to control SNc DA neurons. This work adds to the accumulating evidence that the axonal arborization size of SNc DA neurons plays a key role in their vulnerability in the context of PD.

Visualization of interpolated atrial fiber orientation using evenly-spaced streamlines.

BACKGROUND: Mathematical models of electrical propagation in the atria necessitate the specification of fiber orientation, often visualized over the epicardial and endocardial surfaces. Clear graphical representation of an orientation field over a surface remain challenging, which hinders the comparison between published models. METHOD: A method for the placement of evenly-spaced streamlines over a triangulated surface is proposed. Streamlines tangent to an orientation field are integrated, starting from a set of seed points. Distribution of seed points can be either uniformly random or located in the vicinity of existing streamlines. Stopping conditions are designed to prevent streamlines from getting closer than a threshold referred to as the separation distance. At each iteration, the longest among candidate streamlines is kept. Streamlines are finally rendered on the surface as tubes. The outcome is assessed subjectively by visual inspection and objectively by measuring average streamline length and average lateral distance between streamlines. RESULTS: Fiber orientation fields are conveniently created by angle-based interpolation from fiber tracts manually drawn based on literature review. The zebra-like representation of evenly-spaced streamlines enables clear identification of local fiber orientation. The results show that streamline density can be controlled since the lateral distance between streamlines is guaranteed to vary between 1 and 2 times the separation distance. Average streamline length can be increased by using more seed points, which offers a trade-off between quality and speed. CONCLUSION: Evenly-spaced streamline visualization of fiber orientation facilitates the description and the comparison of fiber structure in computer models of the atria.

Simulated P wave morphology in the presence of endo-epicardial activation delay.

AIMS: Evidences of asynchrony between epicardial and endocardial activation in the atrial wall have been reported. We used a computer model of the atria and torso to investigate the consequences of such activation delay on P wave morphology, while controlling for P wave duration. METHODS AND RESULTS: We created 390 models of the atria based on the same geometry. These models differed by atrial wall thickness (from 2 to 3 mm), transmural coupling, and tissue conductivity in the endocardial and epicardial layers. Among them, 18 were in baseline, 186 had slower conduction in the epicardium layer and 186 in the endocardial layer. Conduction properties were adjusted in such a way that total activation time was the same in all models. P waves on a 16-lead system were simulated during sinus rhythm. Activation maps were similar in all cases. Endo-epicardial delay varied between -5.5 and 5.5 ms vs. 0 ± 0.5 ms in baseline. All P waves had the same duration but variability in their morphology was observed. With slower epicardial conduction, P wave amplitude was reduced by an average of 20% on leads V3-V5 and P wave area decreased by 50% on leads V1-V2 and by 40% on lead V3. Reversed, lower magnitude effects were observed with slower endocardial conduction. CONCLUSION: An endo-epicardial delay of a few milliseconds is sufficient to significantly alter P wave morphology, even if the activation map remains the same.

Phase singularity detection through phase map interpolation: Theory, advantages and limitations.

BACKGROUND: During a cardiac arrhythmia, reentrant waves rotate around critical points called phase singularities (PS). PS detection is relevant to the quantitative description of the dynamics and to the identification of potential targets for ablation. Phase interpolation techniques have been proposed to increase the accuracy of PS localization. Our aim is to provide a theoretical basis and a comparative analysis of these methods. METHOD: Different electrode configurations representing mapping systems or catheter multi-electrode arrays were considered: triangular mesh, regular square grid and circular arrays. Linear, spline and inverse squared distance interpolation were used to create a continuous map from discrete measurements of phase. Synthetic phase maps with a PS and background noise were generated. Monte-Carlo simulations were run over millions of realizations to estimate PS locations and calculate the false negative and false positive rates as a function of noise variance. RESULTS: Linear interpolation is shown to be exactly equivalent to the standard discrete approach without interpolation. Spline interpolation had lower false negative rate at the expense of a higher false positive rate in the presence of noise. Inverse squared distance interpolation reduced false positives and was more robust to noise but was more likely to fail to detect a PS. Phase interpolation decreased PS localization error down to 0.17 interelectrode distance. The error was largest when the PS was near an electrode. CONCLUSION: Phase interpolation methods offer additional flexibility to find the adequate trade-off between reducing false positives and false negatives.

In silico study of multicellular automaticity of heterogeneous cardiac cell monolayers: Effects of automaticity strength and structural linear anisotropy.

The biological pacemaker approach is an alternative to cardiac electronic pacemakers. Its main objective is to create pacemaking activity from added or modified distribution of spontaneous cells in the myocardium. This paper aims to assess how automaticity strength of pacemaker cells (i.e. their ability to maintain robust spontaneous activity with fast rate and to drive neighboring quiescent cells) and structural linear anisotropy, combined with density and spatial distribution of pacemaker cells, may affect the macroscopic behavior of the biological pacemaker. A stochastic algorithm was used to randomly distribute pacemaker cells, with various densities and spatial distributions, in a semi-continuous mathematical model. Simulations of the model showed that stronger automaticity allows onset of spontaneous activity for lower densities and more homogeneous spatial distributions, displayed more central foci, less variability in cycle lengths and synchronization of electrical activation for similar spatial patterns, but more variability in those same variables for dissimilar spatial patterns. Compared to their isotropic counterparts, in silico anisotropic monolayers had less central foci and displayed more variability in cycle lengths and synchronization of electrical activation for both similar and dissimilar spatial patterns. The present study established a link between microscopic structure and macroscopic behavior of the biological pacemaker, and may provide crucial information for optimized biological pacemaker therapies.