Cardiac vulnerability to electric shocks during phase 1A of acute global ischemia

doi:10.1016/j.hrthm.2004.08.018

Heart Rhythm

Volume 1, Issue 6, December 2004, Pages 695-703

https://doi.org/10.1016/j.hrthm.2004.08.018 Get rights and content

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.

Introduction

Understanding cardiac vulnerability to electric shocks has long been considered a route to understanding arrhythmogenesis by failed defibrillation shocks.1, 2, 3, 4, 5 Although the majority of patients who undergo defibrillation suffer from coronary disease, research on shock-induced arrhythmogenesis has focused mostly on normal hearts (see, for instance, references 1, 2, 3) and rarely on hearts with ischemic disease.4, 5 This is due to the fact that during ischemia, myocardial electrophysiologic properties change rapidly.6 This renders experimental evaluation of arrhythmogenesis difficult: tissue state varies from shock to shock in during the course of a single experiment.4, 5 Therefore, changes in cardiac vulnerability to electric shocks over the course of ischemia phase 1A remain poorly understood.

Simulations of postshock electrical events in a realistic model of the normal ventricles have afforded significant insights into the mechanisms of shock-induced arrhythmogenesis2, 7 by providing information, with a high spatiotemporal resolution, regarding shock-induced electrical behavior within the myocardial depth not currently accessible by experimental techniques. The present study extends this approach to arrhythmogenesis in the acutely ischemic ventricles. The goal is to characterize the changes in vulnerability to electric shocks during phase 1A of global ischemia and to determine the mechanisms responsible for these changes. This study focuses on global ischemia as an important step4, 5 in understanding the mechanisms that underlie vulnerability to electric shocks following an ischemic event associated with coronary heart disease.

Because break-excitations secondary to shock-induced virtual electrode polarization underlie postshock activity in the myocardium,1, 2, 3, 8, 9, 10 we hypothesize that dynamic changes in ionic currents and concentrations over the course of ischemia phase 1A affect the characteristics of break-excitation wavefronts and their propagation, thus altering the vulnerable window and the upper limit of vulnerability (ULV) to electric shocks. The present research tests this hypothesis.

Section snippets

Computational model

We used the anatomically accurate finite-element bidomain rabbit ventricular model (Figure 1) described previously.2, 7 Numerical aspects regarding ventricular discretization and finite-element solver can be found in previous publications by our group.11, 12

Global ischemia was implemented by assigning the same (ischemic) membrane dynamics to every cell in the rabbit ventricles. Ionic currents were represented by an ischemic version8 of the Luo-Rudy dynamic model13, 14 modified for

Electrical activity in acute global ischemia

Figure 2 illustrates the effect of increasing ischemia severity on action potential morphology (panel A), APD and V_rest (panel B), ERP and postrepolarization refractoriness period (panel C), and on the maps of activation and repolarization times (panel D). Note that because action potential morphology and ERP are the same for each cell (per our implementation of global ischemia), changes in the parameters shown in panels A, B, and C over the course of acute ischemia refer to any ventricular

Discussion

This study uses for the first time a sophisticated computer model of ventricular electrophysiology to provide mechanistic insight into the dynamic changes in cardiac vulnerability to electric shocks during phase 1A of acute global ischemia. Our results demonstrate that ULV diminishes as ischemia progresses, whereas the range of CIs comprising the vulnerable window shifts as a function of ischemia severity. Altogether the ventricles become less vulnerable to electric shocks as global ischemia

Acknowledgment

The authors thank Dr. J.M. Ferrero Jr. (Universidad Politécnica de Valencia, Spain) for helpful comments and suggestions.

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Mathematical modeling of the cardiac electrophysiology, and its simulation, is a great tool to understand the biological mechanisms that drive the observed response under physiological and pathological conditions. Modeling the electric activity of the heart, considering the structural complexities inherent to its tissue and having to account for the complex electric behavior of the cardiac cells, represents a great challenge. The cardiac electrophysiology is a multiscale problem that makes a numerical solution difficult, requiring temporal and spatial resolutions of 0.1 ms and 0.2 mm, respectively, for accurate simulations. This means models with millions of degrees of freedom that need to be solved for a thousand time steps. The solution to this problem requires the use of algorithms with higher levels of parallelism in multicore platforms. In this regard, the newer programmable graphic processing units (GPU) have become valid alternatives due to their tremendous computational horsepower. This chapter presents results obtained with novel electrophysiology simulation software entirely developed in compute unified device architecture. The software implements fully explicit and semiimplicit solvers for the monodomain model, using operator splitting and the finite element method for space discretization. Performance is compared with classical multicore message passing interface (MPI)-based solvers operating on dedicated high-performance computer clusters. Results obtained with the GPU-based solver show enormous potential for this technology, with accelerations of more than 50 times for three-dimensional (3D) problems. This technology has been applied to study proarrhythmic mechanisms during acute ischemia. In particular, how hyperkalemia affects the vulnerability window to reentry has been investigated as well as the reentry patterns in the heterogeneous substrate caused by acute regional ischemia using an anatomically and biophysically detailed human biventricular model. A 3D geometrically and anatomically accurate regionally ischemic human heart model was created. The ischemic region was located in the inferolateral and posterior side of the left ventricle, mimicking the occlusion of the circumflex artery, and the presence of a washed-out zone not affected by ischemia at the endocardium has been incorporated. Realistic heterogeneity and fiber anisotropy have also been considered in the model. A human highly electrophysiological detailed action potential model has been adapted to make it suitable for modeling ischemic conditions (hyperkalemia, hypoxia, and acidic conditions) by introducing a formulation of the adenosine triphosphate-sensitive K⁺ current. The model predicts the generation of sustained reentrant activity in the form of a single and a double circus around a blocked area within the ischemic zone for K⁺ concentrations bellow 9 mM, with the reentrant activity associated with ventricular tachycardia in all cases. Results suggest the washed-out zone as a potential proarrhythmic substrate factor helping to establish sustained ventricular tachycardia. In addition, the implemented solver can be used to study proarrhythmic mechanisms during apnea by extending the hypoxia and hyperkalemia to the whole cardiac organ.
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Ventricular tachycardia and ventricular fibrillation are two types of cardiac arrhythmias that usually occur during acute ischemia and frequently lead to sudden death. Pro-arrhythmic mechanisms related to acute ischemia have been extensively investigated, although often in animal models rather than in human. In this work, we investigate how hyperkalemia affects the vulnerable window to reentry and the reentry patterns in the heterogeneous substrate caused by acute regional ischemia using an anatomically and biophysically detailed human biventricular model. The ischemic region was located in the inferolateral and posterior side of the left ventricle, mimicking the occlusion of the circumflex artery, and includes a wash-out zone not affected by ischemia located in the endocardium. Realistic heterogeneity and fiber anisotropy have been considered in the model. An electrophysiologically detailed human action potential model has been modified to simulate ischemic conditions. The model predicts the generation of sustained reentrant activity in the form of single and double circuits around an area of block within the ischemic zone for K⁺ concentrations below 9 mM, with the reentrant activity corresponding to ventricular tachycardia in all cases. Our results also suggest that the wash-out zone is a potential pro-arrhythmic factor that favors sustained ventricular tachycardia.
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The VEPs elicited the formation of wavefronts that propagated through excitable gaps and led to successful defibrillation (Bishop et al., 2012). Rabbit ventricular models have also been used to elucidate the mechanisms of defibrillation in ischemic and infarcted hearts (Rantner et al., 2012; Rodriguez et al., 2004b, 2004c). Rodriguez et al. used the UCSD rabbit ventricle model to examine the role of electrophysiological remodeling during different phases of global acute ischemia in determining success or failure of defibrillation shocks (Rodriguez et al., 2004a, 2004b; Rodriguez and Trayanova, 2003).
Current understanding of cardiac electrophysiology has been greatly aided by computational work performed using rabbit ventricular models. This article reviews the contributions of multiscale models of rabbit ventricles in understanding cardiac arrhythmia mechanisms. This review will provide an overview of multiscale modeling of the rabbit ventricles. It will then highlight works that provide insights into the role of the conduction system, complex geometric structures, and heterogeneous cellular electrophysiology in diseased and healthy rabbit hearts to the initiation and maintenance of ventricular arrhythmia. Finally, it will provide an overview on the contributions of rabbit ventricular modeling on understanding the mechanisms underlying shock-induced defibrillation.
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Cardiac imaging is routinely used to evaluate cardiac tissue properties prior to therapy. By integrating the structural information with electrophysiological data from e.g. electroanatomical mapping systems, knowledge of the properties of the cardiac tissue can be further refined. However, as in other clinical modalities, electrophysiological data are often sparse and noisy, and this results in high levels of uncertainty in the estimated quantities. In this study, we develop a methodology based on Bayesian inference, coupled with a computationally efficient model of electrical propagation to achieve two main aims: (1) to quantify values and associated uncertainty for different tissue conduction properties inferred from electroanatomical data, and (2) to design strategies to optimize the location and number of measurements required to maximize information and reduce uncertainty. The methodology is validated in an in silico study performed using simulated data obtained from a human image-based ventricular model, including realistic fibre orientation and a transmural scar. We demonstrate that the method provides a simultaneous description of clinically-relevant electrophysiological conduction properties and their associated uncertainty for various levels of noise. By using the developed methodology to investigate how the uncertainty decreases in response to added measurements, we then derive an a priori index for placing electrophysiological measurements in order to optimize the information content of the collected data. Results show that the derived index has a clear benefit in minimizing the uncertainty of inferred conduction properties compared to a random distribution of measurements, reducing the number of required measurements by over 50% in several of the investigated settings. This suggests that the methodology presented in this work provides an important step towards improving the quality of the spatiotemporal information obtained using electroanatomical mapping.

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: This work was supported by AHA Established Investigator Award to Dr. Trayanova, National Institutes of Health (NIH) Grant HL063195 to Dr. Trayanova, Pre-NPEBC NIH grant P20EB001432 (Tulane Center for Computational Sciences), and grants from the Whitaker and Keck Foundations to Dr. Eason. For this work, Dr. Rodríguez was awarded first prize in the Young Investigator Award Competition at the NASPE–Heart Rhythm Society Meeting in 2004; thus, a portion of this work was published previously in abstract form.23

View full text

Cardiac vulnerability to electric shocks during phase 1A of acute global ischemia

Objectives

Background

Methods

Results

Conclusions

Introduction

Section snippets

Computational model

Electrical activity in acute global ischemia

Discussion

Acknowledgment

J Am Coll Cardiol

Virtual electrode-induced phase singularitya basic mechanism of defibrillation failure

Circ Res

Upper limit of vulnerability in a defibrillation model of the rabbit ventricles

J Electrocardiol

Concepts of ventricular defibrillation

Phil Trans R Soc Lond

Mechanisms of shock-induced arrhythmogenesis during acute global ischemia

Am J Physiol Heart Circ Physiol

Cardiac ionic currents and acute ischemiafrom channels to arrhythmias

Physiol Rev

Computer simulations of cardiac defibrillationA look inside the heart

Comput Visual Sci

Effect of acute global ischemia on the upper limit of vulnerabilitya simulation study

Am J Physiol Heart Circ Physiol

Effect of shock-induced changes in transmembrane potential on reentrant waves and outcome during cardioversion of isolated rabbit hearts

J Cardiovasc Electrophysiol

Success and failure of the defibrillation shockinsights from a simulation study

J Cardiovasc Electrophysiol

Termination of reentry by a long-lasting AC shock in a slice of canine hearta computational study

J Cardiovasc Electrophysiol