Image-Based Tools and Analysis for Human RVOT/RV Structures.

The right-ventricular (RV) outflow tract (RVOT) and the transition to the RV free wall are recognized sources of arrhythmia in human hearts. However, we do not fully understand myocardial tissue structures in this region. Human heart tissue was processed for optical clarity, labelled with wheat-germ agglutin (WGA) and anti-Cx43, and imaged on a custom-built line scanning confocal microscope. The 3D images were analyzed for myocyte gross structures and cell morphology. There were regions of high organization as well as rapid changes to more heterogeneous regions. Preliminary cell segmentations were used to estimate cell morphology. Observed RVOT/RV structure is consistent with known arrhythmic substrates.Clinical Relevance- New views of human tissue structure enable clearer clinical understanding of arrhythmogenic activation pathways and targets for invasive treatment such as RF ablation.

Mechanisms of pulmonary arterial hypertension-induced atrial fibrillation: insights from multi-scale models of the human atria.

This study aimed to use multi-scale atrial models to investigate pulmonary arterial hypertension (PAH)-induced atrial fibrillation mechanisms. The results of our computer simulations revealed that, at the single-cell level, PAH-induced remodelling led to a prolonged action potential (AP) (ΔAPD: 49.6 ms in the right atria (RA) versus 41.6 ms in the left atria (LA)) and an increased calcium transient (CaT) (ΔCaT: 7.5 × 10-2 µM in the RA versus 0.9 × 10-3 µM in the LA). Moreover, heterogeneous remodelling increased susceptibility to afterdepolarizations, particularly in the RA. At the tissue level, we observed a significant reduction in conduction velocity (CV) (ΔCV: -0.5 m s-1 in the RA versus -0.05 m s-1 in the LA), leading to a shortened wavelength in the RA, but not in the LA. Additionally, afterdepolarizations in the RA contributed to enhanced repolarization dispersion and facilitated unidirectional conduction block. Furthermore, the increased fibrosis in the RA amplified the likelihood of excitation wave breakdown and the occurrence of sustained re-entries. Our results indicated that the RA is characterized by increased susceptibility to afterdepolarizations, slow conduction, reduced wavelength and upregulated fibrosis. These findings shed light on the underlying factors that may promote atrial fibrillation in patients with PAH.

Multimodal imaging shows fibrosis architecture and action potential dispersion are predictors of arrhythmic risk in spontaneous hypertensive rats.

Hypertensive heart disease (HHD) increases risk of ventricular tachycardia (VT) and ventricular fibrillation (VF). The roles of structural vs. electrophysiological remodelling and age vs. disease progression are not fully understood. This cross-sectional study of cardiac alterations through HHD investigates mechanistic contributions to VT/VF risk. Risk was electrically assessed in Langendorff-perfused, spontaneously hypertensive rat hearts at 6, 12 and 18 months, and paced optical membrane voltage maps were acquired from the left ventricular (LV) free wall epicardium. Distributions of LV patchy fibrosis and 3D cellular architecture in representative anterior LV mid-wall regions were quantified from macroscopic and microscopic fluorescence images of optically cleared tissue. Imaging showed increased fibrosis from 6 months, particularly in the inner LV free wall. Myocyte cross-section increased at 12 months, while inter-myocyte connections reduced markedly with fibrosis. Conduction velocity decreased from 12 months, especially transverse to the myofibre direction, with rate-dependent anisotropy at 12 and 18 months, but not earlier. Action potential duration (APD) increased when clustered by age, as did APD dispersion at 12 and 18 months. Among 10 structural, functional and age variables, the most reliably linked were VT/VF risk, general LV fibrosis, a measure quantifying patchy fibrosis, and non-age clustered APD dispersion. VT/VF risk related to a quantified measure of patchy fibrosis, but age did not factor strongly. The findings are consistent with the notion that VT/VF risk is associated with rate-dependent repolarization heterogeneity caused by structural remodelling and reduced lateral electrical coupling between LV myocytes, providing a substrate for heterogeneous intramural activation as HHD progresses. KEY POINTS: There is heightened arrhythmic risk with progression of hypertensive heart disease. Risk is related to increasing left ventricular fibrosis, but the nature of this relationship has not been quantified. This study is a novel systematic characterization of changes in active electrical properties and fibrotic remodelling during progression of hypertensive heart disease in a well-established animal disease model. Arrhythmic risk is predicted by several left ventricular measures, in particular fibrosis quantity and structure, and epicardial action potential duration dispersion. Age alone is not a good predictor of risk. An improved understanding of links between arrhythmic risk and fibrotic architectures in progressive hypertensive heart disease aids better interpretation of late gadolinium-enhanced cardiac magnetic resonance imaging and electrical mapping signals.

Simplifying the Process of Going From Cells to Tissues Using Statistical Mechanics.

The value of digital twins for prototyping controllers or interventions in a sandbox environment are well-established in engineering and physics. However, this is challenging for biophysics trying to seamlessly compose models of multiple spatial and temporal scale behavior into the digital twin. Two challenges stand out as constraining progress: (i) ensuring physical consistency of conservation laws across composite models and (ii) drawing useful and timely clinical and scientific information from conceptually and computationally complex models. Challenge (i) can be robustly addressed with bondgraphs. However, challenge (ii) is exacerbated using this approach. The complexity question can be looked at from multiple angles. First from the perspective of discretizations that reflect underlying biophysics (functional tissue units) and secondly by exploring maximum entropy as the principle guiding multicellular biophysics. Statistical mechanics, long applied to understanding emergent phenomena from atomic physics, coupled with the observation that cellular architecture in tissue is orchestrated by biophysical constraints on metabolism and communication, shows conceptual promise. This architecture along with cell specific properties can be used to define tissue specific network motifs associated with energetic contributions. Complexity can be addressed based on energy considerations and finding mean measures of dependent variables. A probability distribution of the tissue's network motif can be approximated with exponential random graph models. A prototype problem shows how these approaches could be implemented in practice and the type of information that could be extracted.

Impulse Data Models for the Inverse Problem of Electrocardiography.

OBJECTIVE: To develop, train and test neural networks for predicting heart surface potentials (HSPs) from body surface potentials (BSPs). The method re-frames traditional inverse problems of electrocardiography into regression problems, constraining the solution space by decomposing signals with multidimensional Gaussian impulse basis functions. METHODS: Impulse HSPs were generated with single Gaussian basis functions at discrete heart surface locations and projected to corresponding BSPs using a volume conductor torso model. Both BSP (inputs) and HSP (outputs) were mapped to regular 2D surface meshes and used to train a neural network. Predictive capabilities of the network were tested with unseen synthetic and experimental data. RESULTS: A dense full connected single hidden layer neural network was trained to map body surface impulses to heart surface Gaussian basis functions for reconstructing HSP. Synthetic pulses moving across the heart surface were predicted from the neural network with root mean squared error of 9.1±1.4%. Predicted signals were robust to noise up to 20 dB and errors due to displacement and rotation of the heart within the torso were bounded and predictable. A shift of the heart 40 mm toward the spine resulted in a 4% increase in signal feature localization error. The set of training impulse function data could be reduced, and prediction error remained bounded. Recorded HSPs from in-vitro pig hearts were reliably decomposed using space-time Gaussian basis functions. Activation times calculated from predicted HSPs for left-ventricular pacing had a mean absolute error of 10.4±11.4 ms. Other pacing scenarios were analyzed with similar success. CONCLUSION: Impulses from Gaussian basis functions are potentially an effective and robust way to train simple neural network data models for reconstructing HSPs from decomposed BSPs. SIGNIFICANCE: The HSPs predicted by the neural network can be used to generate activation maps that non-invasively identify features of cardiac electrical dysfunction and can guide subsequent treatment options.

It's clearly the heart! Optical transparency, cardiac tissue imaging, and computer modelling.

Recent developments in clearing and microscopy enable 3D imaging with cellular resolution up to the whole organ level. These methods have been used extensively in neurobiology, but their uptake in other fields has been much more limited. Application of this approach to the human heart and effective use of the data acquired present challenges of scale and complexity. Four interlinked issues need to be addressed: 1) efficient clearing and labelling of heart tissue, 2) fast microscopic imaging of human-scale samples, 3) handling and processing of multi-terabyte 3D images, and 4) extraction of structural information in computationally tractable structure-based models of cardiac function. Preliminary studies show that each of these requirements can be achieved with the appropriate application and development of existing technologies.

Cardiac Conduction Velocity, Remodeling and Arrhythmogenesis.

Cardiac electrophysiological disorders, in particular arrhythmias, are a key cause of morbidity and mortality throughout the world. There are two basic requirements for arrhythmogenesis: an underlying substrate and a trigger. Altered conduction velocity (CV) provides a key substrate for arrhythmogenesis, with slowed CV increasing the probability of re-entrant arrhythmias by reducing the length scale over which re-entry can occur. In this review, we examine methods to measure cardiac CV in vivo and ex vivo, discuss underlying determinants of CV, and address how pathological variations alter CV, potentially increasing arrhythmogenic risk. Finally, we will highlight future directions both for methodologies to measure CV and for possible treatments to restore normal CV.

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

OBJECTIVE: 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. METHODS: 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. CONCLUSION: 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. SIGNIFICANCE: These findings demonstrate how an abstract heart model can be used for device validation and to design personalized treatment.

Closing the Loop: Validation of Implantable Cardiac Devices With Computational Heart Models.

OBJECTIVE: Cardiovascular Implantable Electronic Devices (CIEDs) are used extensively for treating life-threatening conditions such as bradycardia, atrioventricular block and heart failure. The complicated heterogeneous physical dynamics of patients provide distinct challenges to device development and validation. We address this problem by proposing a device testing framework within the in-silico closed-loop context of patient physiology. METHODS: We develop an automated framework to validate CIEDs in closed-loop with a high-level physiologically based computational heart model. The framework includes test generation, execution and evaluation, which automatically guides an integrated stochastic optimization algorithm for exploration of physiological conditions. CONCLUSION: The results show that using a closed loop device-heart model framework can achieve high system test coverage, while the heart model provides clinically relevant responses. The simulated findings of pacemaker mediated tachycardia risk evaluation agree well with the clinical observations. Furthermore, we illustrate how device programming parameter selection affects the treatment efficacy for specific physiological conditions. SIGNIFICANCE: This work demonstrates that incorporating model based closed-loop testing of CIEDs into their design provides important indications of safety and efficacy under constrained physiological conditions.

Cardiac intramural electrical mapping reveals focal delays but no conduction velocity slowing in the peri-infarct region.

Altered electrical behavior alongside healed myocardial infarcts (MIs) is associated with increased risk of sudden cardiac death. However, the multidimensional mechanisms are poorly understood and described. This study characterizes, for the first time, the intramural spread of electrical activation in the peri-infarct region of chronic reperfusion MIs. Four sheep were studied 13 wk after antero-apical reperfusion infarction. Extracellular potentials (ECPs) were recorded in a ~20 × 20-mm2 region adjacent to the infarct boundary (25 plunge needles <0.5-mm diameter with 15 electrodes at 1-mm centers) during multisite stimulation. Infarct geometry and electrode locations were reconstructed from magnetic resonance images. Three-dimensional activation spread was characterized by local activation times and interpolated ECP fields (n = 191 records). Control data were acquired in 4 non-infarcted sheep (n = 96 records). Electrodes were distributed uniformly around 15 ± 5% of the intramural infarct boundary. There were marked changes in pacing success and ECP morphology across a functional border zone (BZ) ±2 mm from the boundary. Stimulation adjacent to the infarct boundary was associated with low-amplitude electrical activity within the BZ and delayed activation of surrounding myocardium. Bulk tissue depolarization occurred 3.5-14.6 mm from the pacing site for 39% of stimuli with delays of 4-37 ms, both significantly greater than control (P < 0.0001). Conduction velocity (CV) adjacent to the infarct was not reduced compared with control, consistent with structure-only computer model results. Insignificant CV slowing, irregular stimulus-site specific activation delays, and obvious indirect activation pathways strongly suggest that the substrate for conduction abnormalities in chronic MI is predominantly structural in nature.NEW & NOTEWORTHY Intramural in vivo measurements of peri-infarct electrical activity were not available before this study. We use pace-mapping in a three-dimensional electrode array to show that a subset of stimuli in the peri-infarct region initiates coordinated myocardial activation some distance from the stimulus site with substantial associated time delays. This is site dependent and heterogeneous and occurs for <50% of ectopic stimuli in the border zone. Furthermore, once coordinated activation is initiated, conduction velocity adjacent to the infarct boundary is not significantly different from control. These results give new insights to peri-infarct electrical activity and do not support the widespread view of uniform electrical remodeling in the border zone of chronic myocardial infarcts, with depressed conduction velocity throughout.

Resonant model-A new paradigm for modeling an action potential of biological cells.

Organ level simulation of bioelectric behavior in the body benefits from flexible and efficient models of cellular membrane potential. These computational organ and cell models can be used to study the impact of pharmaceutical drugs, test hypotheses, assess risk and for closed-loop validation of medical devices. To move closer to the real-time requirements of this modeling a new flexible Fourier based general membrane potential model, called as a Resonant model, is developed that is computationally inexpensive. The new model accurately reproduces non-linear potential morphologies for a variety of cell types. Specifically, the method is used to model human and rabbit sinoatrial node, human ventricular myocyte and squid giant axon electrophysiology. The Resonant models are validated with experimental data and with other published models. Dynamic changes in biological conditions are modeled with changing model coefficients and this approach enables ionic channel alterations to be captured. The Resonant model is used to simulate entrainment between competing sinoatrial node cells. These models can be easily implemented in low-cost digital hardware and an alternative, resource-efficient implementations of sine and cosine functions are presented and it is shown that a Fourier term is produced with two additions and a binary shift.

Shift of leading pacemaker site during reflex vagal stimulation and altered electrical source-to-sink balance.

KEY POINTS: Vagal reflexes slow heart rate and can change where the heartbeat originates within the sinoatrial node (SAN). The mechanisms responsible for this process - termed leading pacemaker (LP) shift - have not been investigated fully. We used optical mapping to measure the effects of baroreflex, chemoreflex and carbachol on pacemaker entrainment and electrical conduction across the SAN. All methods of stimulation triggered shifts in LP site from the central SAN to one or two caudal pacemaker regions. These shifts were associated with reduced current generation capacity centrally and increased electrical load caudally. Previous studies suggest LP shift is a rate-dependent phenomenon whereby acetylcholine slows central pacemaker rate disproportionately, enabling caudal cells that are less acetylcholine sensitive to assume control. However, our findings indicate the LP region is defined by both pacemaker rate and capacity to drive activation. Shifts in LP site provide an important homeostatic mechanism for rapid switches in heart rate. ABSTRACT: Reflex vagal activity causes abrupt heart rate slowing with concomitant caudal shifts of the leading pacemaker (LP) site within the sinoatrial node (SAN). However, neither the mechanisms responsible nor their dynamics have been investigated fully. Therefore, the objective of this study was to elucidate the mechanisms driving cholinergic LP shift. Optical maps of right atrial activation were acquired in a rat working heart-brainstem preparation during baroreflex and chemoreflex stimulation or with carbachol. All methods of stimulation triggered shifts in LP site from the central SAN to caudal pacemaker regions, which were positive for HCN4 and received uniform cholinergic innervation. During baroreflex onset, the capacity of the central region to drive activation declined with a decrease in amplitude and gradient of optical action potentials (OAPs) in the surrounding myocardium. Accompanying this decline, there was altered entrainment in the caudal SAN as shown by decreased conduction velocity, OAP amplitude, gradient and activation time. Atropine abolished these responses. Chemoreflex stimulation produced similar effects but central capacity to drive activation was preserved before the LP shift. In contrast, carbachol produced a prolonged period of reduced capacity to drive and altered entrainment. Previous studies suggest LP shift is a rate-dependent phenomenon whereby acetylcholine slows central pacemaker rate disproportionately, enabling caudal cells that are less acetylcholine sensitive to assume control. Our findings indicate that cholinergic LP shifts are also determined by altered electrical source-to-sink balance in the SAN. We conclude that the LP region is defined by both rate and capacity to drive atrial activation.

Quantitative descriptions of extended volume cardiac tissue architecture from multiple large hearts.

The arrangement of cardiac cells into strand and sheet-like structures within the heart wall, confers important electrical properties onto heart tissue. Unraveling cardiomyocyte architecture in both healthy and diseased hearts is fundamental to understanding the mechanisms generating normal rhythm and arrhythmia. We analyzed five extended volume serial image stacks of normal pig left ventricular tissue. Analysis included: (1) reconstruction of original tissue volume and shape with non-linear correction maps; (2) segmentation and higher-order descriptions, areas and orientations of laminar structures through the heart wall; (3)computation of fiber directions; (4) computation of tissue connectivity using a shell filter. These measures contributed to a deeper and more objective understanding of cardiac tissue structures and their spatial variation than previously possible.

A machine learning approach to reconstruction of heart surface potentials from body surface potentials.

Invasive cardiac catheterisation is a precursor to ablation therapy for ventricular tachycardia. Invasive cardiac diagnostics are fraught with risks. Decades of research has been conducted on the inverse problem of electrocardiography, which can be used to reconstruct Heart Surface Potentials (HSPs) from Body Surface Potentials (BSPs), for non-invasive cardiac diagnostics. State of the art solutions to the inverse problem are unsatisfactory, since the inverse problem is known to be ill-posed. In this paper we propose a novel approach to reconstructing HSPs from BSPs using a Time-Delay Artificial Neural Network (TDANN). We first design the TDANN architecture, and then develop an iterative search space algorithm to find the parameters of the TDANN, which results in the best overall HSP prediction. We use recorded BSPs and HSPs from individuals suffering from serious cardiac conditions to validate our TDANN. The results are encouraging, in that the predicted and recorded HSPs have an average correlation coefficient of 0.7 under diseased conditions.

A Parametric Computational Model of the Action Potential of Pacemaker Cells.

OBJECTIVE: A flexible, efficient, and verifiable pacemaker cell model is essential to the design of real-time virtual hearts that can be used for closed-loop validation of cardiac devices. A new parametric model of pacemaker action potential is developed to address this need. METHODS: The action potential phases are modeled using hybrid automaton with one piecewise-linear continuous variable. The model can capture rate-dependent dynamics, such as action potential duration restitution, conduction velocity restitution, and overdrive suppression by incorporating nonlinear update functions. Simulated dynamics of the model compared well with previous models and clinical data. CONCLUSION: The results show that the parametric model can reproduce the electrophysiological dynamics of a variety of pacemaker cells, such as sinoatrial node, atrioventricular node, and the His-Purkinje system, under varying cardiac conditions. SIGNIFICANCE: This is an important contribution toward closed-loop validation of cardiac devices using real-time heart models.

An intracardiac electrogram model to bridge virtual hearts and implantable cardiac devices.

Virtual heart models have been proposed to enhance the safety of implantable cardiac devices through closed loop validation. To communicate with a virtual heart, devices have been driven by cardiac signals at specific sites. As a result, only the action potentials of these sites are sensed. However, the real device implanted in the heart will sense a complex combination of near and far-field extracellular potential signals. Therefore many device functions, such as blanking periods and refractory periods, are designed to handle these unexpected signals. To represent these signals, we develop an intracardiac electrogram (IEGM) model as an interface between the virtual heart and the device. The model can capture not only the local excitation but also far-field signals and pacing afterpotentials. Moreover, the sensing controller can specify unipolar or bipolar electrogram (EGM) sensing configurations and introduce various oversensing and undersensing modes. The simulation results show that the model is able to reproduce clinically observed sensing problems, which significantly extends the capabilities of the virtual heart model in the context of device validation.

Development of 3-D Intramural and Surface Potentials in the LV: Microstructural Basis of Preferential Transmural Conduction.

INTRODUCTION: Extracellular potentials measured on the heart surfaces are used to infer events that originate deep within the heart wall. We have reconstructed intramural potentials in three dimensions for the first time, and compare these with epicardial and endocardial surface potentials and cardiac microstructure. METHODS AND RESULTS: Extracellular potentials from intramural point stimulation were measured from a high density 3-D electrode array in the in vivo pig LV. MR and extended volume imaging were used to register electrode locations and characterize fiber and laminar orientations throughout the recording volume. Measured potentials were compared with predictions of tissue-specific bidomain computer activation models. Positive potentials recorded in the LV wall preceded the depolarization wavefront as it spread in the fiber direction. Transverse to this, passive and active potentials spread preferentially in the laminar direction (anisotropy ratio ∼1.6:1). Epicardial surface potentials reflect initial intramural propagation at the stimulus location, but endocardial potentials do not, particularly adjacent to papillary muscles. Measured 3-D potentials were consistently better captured by computer models that incorporate three distinct conductivities aligned with local microstructural axes, but the preferential spread of potentials in the laminar direction was not fully predicted. CONCLUSIONS: This study provides evidence for preferential transmural conduction and raises questions about the extent to which intramural electrical events can be inferred from endocardial potentials.

A novel retractable laparoscopic device for mapping gastrointestinal slow wave propagation patterns.

BACKGROUND: Gastric slow waves regulate peristalsis, and gastric dysrhythmias have been implicated in functional motility disorders. To accurately define slow wave patterns, it is currently necessary to collect high-resolution serosal recordings during open surgery. We therefore developed a novel gastric slow wave mapping device for use during laparoscopic procedures. METHODS: The device consists of a retractable catheter constructed of a flexible nitinol core coated with Pebax. Once deployed through a 5-mm laparoscopic port, the spiral head is revealed with 32 electrodes at 5 mm intervals. Recordings were validated against a reference electrode array in pigs and tested in a human patient. RESULTS: Recordings from the device and a reference array in pigs were identical in frequency (2.6 cycles per minute; p = 0.91), and activation patterns and velocities were consistent (8.9 ± 0.2 vs 8.7 ± 0.1 mm s-1; p = 0.2). Device and reference amplitudes were comparable (1.3 ± 0.1 vs 1.4 ± 0.1 mV; p = 0.4), though the device signal-to-noise ratio was higher (17.5 ± 0.6 vs 12.8 ± 0.6 dB; P < 0.0001). In the human patient, corpus slow waves were recorded and mapped (frequency 2.7 ± 0.03 cycles per minute, amplitude 0.8 ± 0.4 mV, velocity 2.3 ± 0.9 mm s-1). CONCLUSION: In conclusion, the novel laparoscopic device achieves high-quality serosal slow wave recordings. It can be used for laparoscopic diagnostic studies to document slow wave patterns in patients with gastric motility disorders.

Functional physiology of the human terminal antrum defined by high-resolution electrical mapping and computational modeling.

High-resolution (HR) mapping has been used to study gastric slow-wave activation; however, the specific characteristics of antral electrophysiology remain poorly defined. This study applied HR mapping and computational modeling to define functional human antral physiology. HR mapping was performed in 10 subjects using flexible electrode arrays (128-192 electrodes; 16-24 cm2) arranged from the pylorus to mid-corpus. Anatomical registration was by photographs and anatomical landmarks. Slow-wave parameters were computed, and resultant data were incorporated into a computational fluid dynamics (CFD) model of gastric flow to calculate impact on gastric mixing. In all subjects, extracellular mapping demonstrated normal aboral slow-wave propagation and a region of increased amplitude and velocity in the prepyloric antrum. On average, the high-velocity region commenced 28 mm proximal to the pylorus, and activation ceased 6 mm from the pylorus. Within this region, velocity increased 0.2 mm/s per mm of tissue, from the mean 3.3 ± 0.1 mm/s to 7.5 ± 0.6 mm/s (P < 0.001), and extracellular amplitude increased from 1.5 ± 0.1 mV to 2.5 ± 0.1 mV (P < 0.001). CFD modeling using representative parameters quantified a marked increase in antral recirculation, resulting in an enhanced gastric mixing, due to the accelerating terminal antral contraction. The extent of gastric mixing increased almost linearly with the maximal velocity of the contraction. In conclusion, the human terminal antral contraction is controlled by a short region of rapid high-amplitude slow-wave activity. Distal antral wave acceleration plays a major role in antral flow and mixing, increasing particle strain and trituration.

Hybrid automata models of cardiac ventricular electrophysiology for real-time computational applications.

Virtual heart models have been proposed for closed loop validation of safety-critical embedded medical devices, such as pacemakers. These models must react in real-time to off-the-shelf medical devices. Real-time performance can be obtained by implementing models in computer hardware, and methods of compiling classes of Hybrid Automata (HA) onto FPGA have been developed. Models of ventricular cardiac cell electrophysiology have been described using HA which capture the complex nonlinear behavior of biological systems. However, many models that have been used for closed-loop validation of pacemakers are highly abstract and do not capture important characteristics of the dynamic rate response. We developed a new HA model of cardiac cells which captures dynamic behavior and we implemented the model in hardware. This potentially enables modeling the heart with over 1 million dynamic cells, making the approach ideal for closed loop testing of medical devices.