What have we learned from mathematical models of defibrillation and postshock arrhythmogenesis? Application of bidomain simulations.
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Biomedical subjects
Blanca Rodríguez
Publications and source records attributed to Blanca Rodríguez.
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.
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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.
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Differences between left and right ventricular chamber geometry affect cardiac vulnerability to electric shocks.
Although effects of shock strength and waveform on cardiac vulnerability to electric shocks have been extensively documented, the contribution of ventricular anatomy to shock-induced polarization and postshock propagation and thus, to shock outcome, has never been quantified; this is caused by lack of experimental methodology capable of mapping 3-D electrical activity. The goal of this study was to use optical imaging experiments and 3-D bidomain simulations to investigate the role of structural differences between left and right ventricles in vulnerability to electric shocks in rabbit hearts. The ventricles were paced apically, and uniform-field, truncated-exponential, monophasic shocks of reversed polarity were applied over a range of coupling intervals (CIs) in experiment and model. Experiments and simulations revealed that reversing the direction of externally-applied field (RV- or LV- shocks) alters the shape of the vulnerability area (VA), the 2-D grid encompassing episodes of arrhythmia induction. For RV- shocks, VA was nearly rectangular indicating little dependence of postshock arrhythmogenesis on CI. For LV- shocks, the probability of arrhythmia induction was higher for longer than for shorter CIs. The 3-D simulations demonstrated that these effects stem from the fact that reversal of field direction results in relocation of the main postshock excitable area from LV wall (RV- shocks) to septum (LV- shocks). Furthermore, the effect of septal (but not LV) excitable area in postshock propagation was found to strongly depend on preshock state. Knowledge regarding the location of the main postshock excitable area within the 3-D ventricular volume could be important for improving defibrillation efficacy.
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Effects of pinacidil on reentrant arrhythmias generated during acute regional ischemia: a simulation study.
Many experimental studies have pointed out the controversy involving the arrhythmogenic effects of potassium channel openers (KCOs) in ischemia. KCOs activate the ATP-sensitive potassium current [IK(ATP)], resulting in action potential duration (APD) shortening, especially under pathological conditions such as ischemia. Acute myocardial ischemia leads to electrophysiological inhomogeneities in APD, conduction velocity, and refractoriness, which provide the substrate for reentry initiation and maintenance and may lead to malignant arrhythmias. The aim of this work is to analyze the effect of the KCO pinacidil on vulnerability to reentry during acute regional ischemia using computer simulations. We use a two-dimensional virtual heart tissue with implementation of acute regional ischemia conditions. Membrane kinetics are represented by a modified version of Luo-Rudy (phase II) action potential model that incorporates the effect of pinacidil on IK(ATP). The vulnerable window (VW) for reentry is quantified for different doses of pinacidil. Our results show that for doses below 3 micromol/l the VW widens with increasing pinacidil concentration, whereas for higher doses of pinacidil the VW decreases, becoming zero for concentrations above 10 micromol/l. The ionic mechanisms involved in this behavior are explored. This study demonstrates that the effect of pinacidil on arrhythmogenesis is strongly dose-dependent, and that high doses of pinacidil exert a strong antiarrhythmic effect.
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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.
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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.
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Rhizoctonia solani, an elicitor of 6-pentyl-alpha-pyrone production by Trichoderma harzianum in a two liquid phases, extractive fermentation system.
6-pentyl-alpha-pyrone (6PP) production by Trichoderma harzianum, in an extractive fermentation system, was elicitated by Rhizoctonia solani. The extent of 6PP elicitation was related to the state of Rhizoctonia and to the Trichoderma inoculum type. The use of non-viable Rhizoctonia solani mycelium in mycelium-inoculated Trichoderma harzianum culture, yielded the maximal 6PP production (474 mg l(-1)) compared to control cultures (147 mg l(-1)) and decreased the process time from 192 to 96 h.
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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
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