Inference of intramural wavefront orientation from optical recordings in realistic whole-heart models.
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Action Potentials↗
Biomedical subjects
Natalia Trayanova
Publications and source records attributed to Natalia Trayanova.
What have we learned from mathematical models of defibrillation and postshock arrhythmogenesis? Application of bidomain simulations.
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Animals↗
Defibrillation of the heart: insights into mechanisms from modelling studies.
Despite its critical role in restoring cardiac rhythm and thus in saving human life, cardiac defibrillation remains poorly understood. Further mechanistic inquiry is hampered by the inability of presently available experimental techniques to resolve, with sufficient accuracy, electrical behaviour confined to the depth of the ventricles. The objective of this review article is to demonstrate that realistic 3-D simulations of the ventricular defibrillation process in close conjunction with experimental observations are capable of bringing a new level of understanding of the electrical events that ensue from the interaction between fibrillating myocardium and applied shock. The article does this by reviewing the results of two studies, one on vulnerability to electric shocks and another on defibrillation. An overview of the modelling tools used in these studies is also provided.
Action Potentials↗
Synthesis of voltage-sensitive optical signals: application to panoramic optical mapping.
Fluorescent photon scattering is known to distort optical recordings of cardiac transmembrane potentials; however, this process is not well quantified, hampering interpretation of experimental data. This study presents a novel model, which accurately synthesizes fluorescent recordings over the irregular geometry of the rabbit ventricles. Using the model, the study aims to provide quantification of fluorescent signal distortion for different optical characteristics of the preparation and of the surrounding medium. A bi-domain representation of electrical activity is combined with finite element solutions to the photon diffusion equation simulating both the excitation and emission processes, along with physically realistic boundary conditions at the epicardium, which allow simulation of different experimental setups. We demonstrate that distortion in the optical signal as a result of fluorescent photon scattering is truly a three-dimensional phenomenon and depends critically upon the geometry of the preparation, the scattering properties of the tissue, the direction of wavefront propagation, and the specifics of the experimental setup. Importantly, we show that in an anatomically accurate model of ventricular geometry and fiber orientation, the morphology of the optical signal does not provide reliable information regarding the intramural direction of wavefront propagation. These findings underscore the potential of the new model in interpreting experimental data.
Animals↗
Myocardial ischemia lowers precordial thump efficacy: an inquiry into mechanisms using three-dimensional simulations.
BACKGROUND: Precordial thump is the first International Liaison Committee on Resuscitation-prescribed procedure for advanced life support in witnessed cardiac arrest. Success rates vary and, according to clinical evidence, are significantly reduced under ischemic conditions. OBJECTIVES: The purpose of this study was to elucidate the mechanisms involved in termination of ventricular tachycardia (VT) by precordial thump and its decreased rate of success in ischemia using a three-dimensional realistic model of electrical behavior in the rabbit ventricles. METHODS: The electrophysiologic effect of precordial thump was represented by recruitment of mechanosensitive channels in the regions affected by precordial thump. In normoxia, precordial thump opened cation nonselective stretch-activated channels (SAC-NS, reversal potential -20 mV). In ischemia, precordial thump was assumed to additionally activate ATP-sensitive K+ (K(ATP)) channels (reversal potential -95 mV). Ten randomly selected cases of VT were used, and for each case the effect of precordial thump on VT was examined for normoxia and under ischemic conditions of varying severity. RESULTS: Precordial thump was found to have a 60% success rate in normoxia and 30% in ischemia. Results demonstrate that precordial thump-induced SAC-NS opening in normoxia reduced heterogeneity in transmembrane potential by partially repolarizing excited tissue and depolarizing resting myocardium, potentially causing foci of excitation that eradicate the excitable gap, thus facilitating VT termination. Decreased precordial thump efficacy in ischemia was caused by recruitment of K(ATP), which diminished the depolarizing effect of SAC-NS on resting tissue and caused pronounced action potential shortening, thus facilitating establishment of reentry. CONCLUSION: This study provides mechanistic insight into precordial thump mechanisms and its reduced clinical utility in patients with myocardial ischemia.
Animals↗
Three-dimensional models of individual cardiac histoanatomy: tools and challenges.
There is a need for, and utility in, the acquisition of data sets of cardiac histoanatomy, with the vision of reconstructing individual hearts on the basis of noninvasive imaging, such as MRI, enriched by reference to detailed atlases of serial histology obtained from representative samples. These data sets would be useful not only as a repository of knowledge regarding the specifics of cardiac histoanatomy, but could form the basis for generation of individualized high-resolution cardiac structure-function models. The current article presents a step in this general direction: it illustrates how whole-heart noninvasive imaging can be combined with whole-heart histology in an approach to achieve automated construction of histoanatomically detailed models of cardiac 3D structure and function at hitherto unprecedented resolution and accuracy (based on 26.4 x 26.4 x 24.4 microm MRI voxel size, and enriched by histological detail). It provides an overview of the tools used in this quest and outlines challenges posed by the approach in the light of applications that may benefit from the availability of such data and tools.
Animals↗
Modeling cardiac ischemia.
Myocardial ischemia is one of the main causes of sudden cardiac death, with 80% of victims suffering from coronary heart disease. In acute myocardial ischemia, the obstruction of coronary flow leads to the interruption of oxygen flow, glucose, and washout in the affected tissue. Cellular metabolism is impaired and severe electrophysiological changes in ionic currents and concentrations ensue, which favor the development of lethal cardiac arrhythmias such as ventricular fibrillation. Due to the burden imposed by ischemia in our societies, a large body of research has attempted to unravel the mechanisms of initiation, sustenance, and termination of cardiac arrhythmias in acute ischemia, but the rapidity and complexity of ischemia-induced changes as well as the limitations in current experimental techniques have hampered evaluation of ischemia-induced alterations in cardiac electrical activity and understanding of the underlying mechanisms. Over the last decade, computer simulations have demonstrated the ability to provide insight, with high spatiotemporal resolution, into ischemic abnormalities in cardiac electrophysiological behavior from the ionic channel to the whole organ. This article aims to review and summarize the results of these studies and to emphasize the role of computer simulations in improving the understanding of ischemia-related arrhythmias and how to efficiently terminate them.
Action Potentials↗
Differences between left and right ventricular anatomy determine the types of reentrant circuits induced by an external electric shock. A rabbit heart simulation study.
Despite the fact that elucidating the mechanisms of cardiac vulnerability to electric shocks is crucial to understanding why defibrillation shocks fail, important aspects of cardiac vulnerability remain unknown. This research utilizes a novel anatomically based bidomain finite-element model of the rabbit ventricles to investigate the effect of shock polarity reversal on the reentrant activity induced by an external defibrillation-strength shock in the paced ventricles. The specific goal of the study is to examine how differences between left and right ventricular chamber anatomy result in differences in the types of reentrant circuits established by the shock. Truncated exponential monophasic shocks of duration 8 ms were delivered via two external electrodes at various timings. Vulnerability grids were constructed for shocks of reversed polarity (referred to as RV- or LV- when either the RV or the LV electrode is a cathode). Our results demonstrate that reversing electrode polarity from RV- to LV- changes the dominant type of post-shock reentry: it is figure-of-eight for RV- and quatrefoil for LV- shocks. Differences in secondary types of post-shock arrhythmia also occur following shock polarity reversal. These effects of polarity reversal are primarily due to the fact that the LV wall is thicker than the RV, resulting in a post-shock excitable gap that is predominantly within the LV wall for RV- shocks and in the septum for LV- shocks.
Animals↗
In pursuit of the elusive culprit.
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Animals↗
Mechanisms of myocardial capture and temporal excitable gap during spiral wave reentry in a bidomain model.
BACKGROUND: Recent studies have demonstrated that regional capture during cardiac fibrillation is associated with an elevated capture threshold. It is typically assumed that the temporal excitable gap (capture window) during fibrillation reflects the size of the spatial excitable gap (excitable tissue between fibrillation waves). Because capture threshold is high, virtual electrode polarization is expected to be involved in the process. However, little is known about the underlying mechanisms of myocardial capture during fibrillation. METHODS AND RESULTS: To clarify these issues, we conducted altogether 3168 simulations of single spiral wave capture in a bidomain sheet. Unipolar stimuli of strengths 4, 8, 16, and 24 mA and 2-ms duration were delivered at 99 locations in the sheet. We found that cathode-break rather than cathode-make excitation was the dominant mechanism of myocardial capture. When the stimulation site was located diagonally with respect to the core (upper left or lower right if the spiral wave rotates counterclockwise), the cathode-break excitation easily invaded the spatial excitable gap and resulted in a successful capture as a result of the formation of virtual anodes in the direction of the myocardial fibers. Thus, the spatial distribution of the temporal excitable gap did not reflect the spatial excitable gap. CONCLUSIONS: The areas exhibiting wide temporal excitable gaps were areas in which the cathode-break excitation wave fronts easily invaded the spatial excitable gap via the virtual anodes. This study provides mechanistic insight into myocardial capture.
Atrial Fibrillation↗
Effect of acute global ischemia on the upper limit of vulnerability: a simulation study.
The goal of this modeling research is to provide mechanistic insight into the effect of altered membrane kinetics associated with 5-12 min of acute global ischemia on the upper limit of cardiac vulnerability (ULV) to electric shocks. We simulate electrical activity in a finite-element bidomain model of a 4-mm-thick slice through the canine ventricles that incorporates realistic geometry and fiber architecture. Global acute ischemia is represented by changes in membrane dynamics due to hyperkalemia, acidosis, and hypoxia. Two stages of acute ischemia are simulated corresponding to 5-7 min (stage 1) and 10-12 min (stage 2) after the onset of ischemia. Monophasic shocks are delivered in normoxia and ischemia over a range of coupling intervals, and their outcomes are examined to determine the highest shock strength that resulted in induction of reentrant arrhythmia. Our results demonstrate that acute ischemia stage 1 results in ULV reduction to 0.8A from its normoxic value of 1.4A. In contrast, no arrhythmia is induced regardless of shock strength in acute ischemia stage 2. An investigation of mechanisms underlying this behavior revealed that decreased postshock refractoriness resulting mainly from 1) ischemic electrophysiological substrate and 2) decrease in the extent of areas positively-polarized by the shock is responsible for the change in ULV during stage 1. In contrast, conduction failure is the main cause for the lack of vulnerability in acute ischemia stage 2. The insight provided by this study furthers our understanding of mechanisms by which acute ischemia-induced changes at the ionic level modulate cardiac vulnerability to electric shocks.
Action Potentials↗
Induction of ventricular arrhythmias following mechanical impact: a simulation study in 3D.
Commotio cordis, mechanical induction of heart rhythm disturbances, including sudden cardiac death, in the absence of corresponding structural damage, has been reported with increasing frequency in young individuals participating in sporting activities. Recently, the electrophysiological changes during c. cordis have been attributed to mechano-electric feedback, and particularly, to the recruitment of stretch-activated ion channels. The underlying mechanisms, however, by which a mechanical impact results in ventricular fibrillation, remain unknown. This study employs a 3D realistic model of rabbit ventricular geometry and fiber orientation to elucidate the electrophysiological mechanisms involved in arrhythmia induction following acute mechanical stimulation of the heart. Impact effects are modeled through stretch-activated ion channel activation in a 3D region of the ventricles representing the impact profile. Both cation-nonselective and potassium-selective stretch-activated ion channels are recruited upon mechanical impact. The impact is administered at various coupling intervals following pacing at the apex. To aid in the interpretation of results, the effect of mechanical stimulation on single cell action potentials is also examined. The results demonstrate that the region of impact is characterized by different types of cellular responses, including generation of a new action potential, shortening, or lengthening of action potential duration. The impact induces sustained reentry only when (1) a new activation is elicited by mechanical stimulation (caused by activation of cation-nonselective stretch-activated ion channels), and (2) upon return to the original region of impact, this activation does not encounter an extension of action potential duration (prevented by activation of potassium-selective stretch-activated ion channels).
Action Potentials↗
Effect of stretch-activated channels on defibrillation efficacy.
OBJECTIVES: This study aims to explore whether defibrillation threshold elevation could be caused by sustained recruitment of stretch-activated channels (SACs) and, if so, what are the underlying mechanisms. BACKGROUND: Clinical studies have demonstrated that patients with dilated and overloaded ventricles have elevated defibrillation threshold. Prolonged ventricular stretch has been suggested as a possible factor in defibrillation threshold elevation; however, its role remains unclear. METHODS: A two-dimensional finite-element bidomain model of ventricular defibrillation was used in the study. Retaining the geometrical parameters in the model, defibrillation dose-response curves were constructed with and without SACs to isolate the effect of stretch on shock outcome. RESULTS: Simulations demonstrate that SAC activation leads to flattening of dose-response curve and increases in defibrillation threshold and effective dose for defibrillation by 31.4% and 18.8%, respectively. Examination of the electrophysiologic properties associated with sustained SAC recruitment pinpointed the main mechanisms responsible for the decrease in defibrillation efficacy. The lower conduction velocity of the shock-induced break excitations and the more positive transmembrane potential at the end of the effective refractory period in the tissue with SACs are proposed as main reasons for defibrillation threshold elevation. CONCLUSIONS: Demonstrating the contribution of SACs to defibrillation threshold elevation identifies SACs as an attractive pharmaceutical target to reduce defibrillation threshold in patients with dilated cardiomyopathy.
Cardiomyopathy, Dilated↗
The effect of vagally induced dispersion of action potential duration on atrial arrhythmogenesis.
OBJECTIVE: The purpose of this study is to ascertain the effects of spatially variable ACh distributions on arrhythmogenesis in a morphologically realistic computer model of canine atria. BACKGROUND: Vagal stimulation releases acetylcholine (ACh), which causes a dose-dependent reduction in action potential duration (APD) in the atria. Due to the nonuniform distribution of nerve endings, APD dispersion may result, which has been shown to play a role in the breakup of activity. METHODS: Reentry was initiated in a computationally efficient, morphologically realistic computer model of the atria. Discrete regions corresponding to ACh release sites, referred to as islands, were assigned shortened APDs in an ACh-dependent fashion. Island APD was varied as well as the basal APD. The window of vulnerability for ectopic beat-induction of sustained reentry was determined for both left atrial(LA) and right atrial (RA) stimulation. The resulting reentries were categorized based on type and location. RESULTS: 1) Atrial geometry severely restricts the formation of reentrant circuits. 2) Wave fractionation only occurred for large differences between island and basal APD. 3) Small ACh concentration differences produced stable figure-of-8 reentrant patterns. 4) Large islands displayed more wave breakup but could sometimes anchor reentries. CONCLUSIONS: Large APD gradients produced by ACh heterogeneity can lead to a breakdown of organized activity.
Acetylcholine↗
Cardiac vulnerability to electric shocks during phase 1A of acute global ischemia.
OBJECTIVES: The purpose of this study is to characterize the changes in vulnerability to electric shocks during phase 1A of global ischemia in the rabbit ventricles and to determine the mechanisms responsible for these changes. BACKGROUND: Mechanisms responsible for the changes in cardiac vulnerability over the course of ischemia phase 1A remain poorly understood. The lack of understanding results from the rapid ischemic change in cardiac electrophysiologic properties, which renders experimental evaluation of vulnerability difficult. METHODS: To examine dynamic changes in vulnerability to electric shocks over the course of acute global ischemia phase 1A, this study used a three-dimensional anatomically accurate bidomain model of ischemic rabbit ventricles. Monophasic shocks are applied at various coupling intervals to construct vulnerability grids in normoxia and at various stages of ischemia phase 1A. RESULTS: Our simulations demonstrate that 2 to 3 minutes after the onset of ischemia, the upper limit of vulnerability remains at its normoxic value (12.75 V/cm); however, arrhythmias are induced at shorter coupling intervals. As ischemia progresses, the upper limit of vulnerability decreases, reaching 6.4 V/cm in the advanced stage of ischemia phase 1A, and the vulnerable window shifts towards longer coupling intervals. CONCLUSIONS: Changes in the upper limit of vulnerability result from an increase in the spatial extent of the shock-end excitation wavefronts and the slower recovery from shock-induced positive polarization. Shifts in the vulnerable window stem from decreases in local repolarization times and the occurrence of postshock conduction failure caused by prolonged postrepolarization refractoriness.
Action Potentials↗
Spiral wave control by a localized stimulus: a bidomain model study.
INTRODUCTION: It has been reported that electrical stimulation can control spiral wave (SW) reentry. However, previous research does not account for the effects of stimulus-induced virtual electrode polarization (VEP) and the ensuing cathode-break (CB) excitation. The aim of the present study was to examine the interaction of VEP with SW reentry in a bidomain model of electrical stimulation and thus provide insight into the mechanistic basis of SW control. METHODS AND RESULTS: We conducted 3,168 simulations of localized stimulation during SW reentry in an anisotropic bidomain sheet. Unipolar cathodal 2-ms stimuli of strengths 4, 8, 16, and 24 mA were delivered at 99 locations in the sheet. The interaction between stimulus-induced VEP and SW reentry resulted in 1 of 3 possible outcomes: SW shift, SW breakup, or no effect. SW shift, which could be instrumental in SW termination at an anatomic or functional line of block, resulted from CB rather than cathode-make excitation. Stimulus timing, site, and strength all were important factors in VEP-mediated SW control. Furthermore, we found that the number of episodes of SW shift across the fibers was more sensitive to stimulus strength than that of SW shift along the fibers. SW shift can be explained by the interaction between the four VEP-induced wavebreaks and the wavebreak of the SW, ultimately resulting in termination of the original SW and the survival of one of the VEP-induced wavebreaks. This establishes a new SW reentry. CONCLUSION: This study provides new mechanistic insight into SW control.
Atrial Fibrillation↗
Upper limit of vulnerability in a defibrillation model of the rabbit ventricles.
The goal of this modeling study is to investigate the mechanisms responsible for the upper and lower limits of vulnerability (ULV and LLV) to re-entry induced by electric shocks within the three-dimensional volume of the heart. We use a geometrically accurate rabbit ventricular model with realistic fiber architecture that also includes the blood in the cavities and a perfusing bath. The shocks are delivered over a range of strengths and coupling intervals via two large mesh electrodes located at the vertical boundaries of the perfusing bath. Our results demonstrate that shock-induced virtual electrode polarization (VEP) in the midmyocardium is weaker and more complex than VEP on the surfaces, where only 2 areas, one of positive and one of negative polarization, are induced. Transmural views of the ventricles show that, in all cases, tissue in the LV free wall and in the septum is deexcited by the shock providing an excitable path for wavefront propagation. Conversely, the RV free wall myocardium is depolarized after the end of the shock. The evolution of postshock electrical activity in the RV free wall plays a critical role in determining the outcome of the shock. In all cases, a wavefront starts in the apex at the site of largest transmembrane voltage gradient between oppositely polarized areas. For shocks of strength above the LLV, the postshock refractoriness of the RV free wall produces the unidirectional block necessary for reentry induction. If shock strength is below the ULV, the RV free wall recovers in time to provide the reentrant pathway. In contrast, for shocks of strength above the ULV, the postshock excitable gap in the LV free wall and in the septum is depolarized before the RV free wall recovers. Therefore, both ventricles are refractory and reentry is not induced
Animals↗
Phase singularities and termination of spiral wave reentry.
INTRODUCTION: Recent defibrillation studies show that electric fields interact with reentrant activity in myocardial tissue through virtual electrode polarization (VEP). This study focuses on determining how VEP relates to the creation and survival of postshock phase singularities in cardiac tissue and demonstrating that interactions between VEP and preshock tissue state engender the probabilistic nature of defibrillation. METHODS AND RESULTS: We constructed a two-dimensional tissue model representing a ventricular cross-section with fiber architecture and surrounding bath. We initiated spiral wave reentry and subjected the tissue to a monophasic shock. We estimated the shock success probability for a given strength by testing 16 coupling intervals throughout a single rotation of the wavefront. Over a range of shock strengths, our model exhibits dose-response behavior similar to experimental defibrillation efficacy curves. At the 50% effective strength (ED50), successful termination of reentry depends upon the interaction between preshock excitable gap and postshock phase singularities. We also found that increasing the stimulus strength toward ED50 increases the number of postshock singularities, whereas further strength increases above ED50 decrease the number of singularities. CONCLUSION: Our results show for the first time that a computational model can account for the probabilistic nature of defibrillation as VEP interacts with the dynamics of an ongoing reentrant wavefront. Further, we demonstrate that success of a shock depends on the annihilation of the phase singularities that arise after any strong stimulus. Our findings imply that VEP completely overrides the preshock tissue state in shocks that are highly likely to defibrillate (ED95).
Biophysical Phenomena↗