Three‐dimensional mechanisms of increased vulnerability to electric shocks in myocardial infarction: Altered virtual electrode polarizations and conduction delay in the peri‐infarct zone

Defibrillation is known to be less efficient in infarcted than in healthy hearts. In a rabbit model of myocardial infarction, altered 3D distribution of virtual electrodes and propagation delay in the peri-infarct zone caused increased vulnerability to electric shocks in infarcted hearts. The infarct scar alone – without the presence of a peri-infarct zone – did not cause an increase in vulnerability. The results help us to understand the mechanisms of increased vulnerability and decreased defibrillation efficacy in infarcted hearts. Abstract Defibrillation efficacy is decreased in infarcted hearts, but the mechanisms by which infarcted hearts are more vulnerable to electric shocks than healthy hearts remain poorly understood. The goal of this study was to provide insight into the 3D mechanisms for the increased vulnerability to electric shocks in infarcted hearts. We hypothesized that changes in virtual electrode polarizations (VEPs) and propagation delay through the peri-infarct zone (PZ) were responsible. We developed a microanatomically detailed rabbit ventricular model with chronic myocardial infarction from magnetic resonance imaging and enriched the model with data from optical mapping experiments. We further developed a control model without the infarct. The simulation protocol involved apical pacing followed by biphasic shocks. Simulation results from both models were compared. The upper limit of vulnerability (ULV) was 8 V cm−1 in the infarction model and 4 V cm−1 in the control model. VEPs were less pronounced in the infarction model, providing a larger excitable area for postshock propagation but smaller transmembrane potential gradients to initiate new wavefronts. Initial post-shock transmural activation occurred at a later time in the infarction model, and the PZ served to delay propagation in subsequent beats. The presence of the PZ was found to be responsible for the increased vulnerability. Myocardial infarction (MI) as a consequence of coronary artherosclerosis is the underlying cause of up to 80% of ventricular tachyarrhythmias leading to sudden cardiac death (SCD) (Huikuri et al. 2001). Defibrillation, the application of a strong electric shock to the heart, is the only known way of terminating these disturbances in heart rhythm and, thus, preventing SCD. The use of shocks to treat malignant cardiac arrhythmias is associated with a host of adverse effects that include cellular injury from electroporation (Tung et al. 1994; Al-Khadra et al. 2000), cardiac conduction disturbances (Eysmann et al. 1986), mechanical dysfunction (Tung et al. 1994; Tokano et al. 1998; Mollerus Larsen et al. 2011), and pain and psychological trauma (Maisel, 2006). Better understanding the mechanisms of defibrillation, and specifically in infarcted hearts, is likely to lead to an optimization of the delivery of defibrillation in patients with MI. Indeed, research on defibrillation mechanisms has focused predominantly on the healthy heart (Dixon et al. 1987; Efimov et al. 1998; Rodriguez et al. 2005; Ashihara et al. 2008), with limited insights under the conditions of MI. It has been shown experimentally that vulnerability to shock-induced ventricular tachycardia (VT) increases in the infarcted rabbit heart (Li et al. 2005). However, the 3D mechanisms responsible for the increased vulnerability to electric shocks in MI remain unknown, and the interaction of the electric shock with the electrophysiological and structural substrate of MI in the depth of the ventricular wall is poorly understood. A key component of the distinct electrophysiological substrate of MI is the border or peri-infarct zone (PZ). Tissue in the PZ is electrically and structurally remodelled. This leads to abnormal cell-to-cell coupling, increased anisotropy, and changes in ion channel properties, all of which can form a substrate for reentry (for review, see Nattel et al. 2007). It is, therefore, likely that the remodelled tissue of the PZ could also play a role in the substrate for post-shock arrhythmia formation and maintenance. Post-shock arrhythmogenesis results from the specific distribution of virtual electrode polarization (VEP; depolarizing and hyperpolarizing changes in membrane potential in response to the applied electric field) established at the end of the shock (Rodriguez et al. 2005; Ashihara et al. 2008; Constantino et al. 2010); VEP is a function of the electrophysiological state and the structure of the tissue (Trayanova et al. 1998a; Trayanova, 2001). Hence, electrically and structurally remodelled tissue in the PZ along with the infarct scar is expected to establish a specific 3D VEP distribution and subsequent post-shock propagation patterns that could result in post-shock arrhythmogenesis significantly different from that in the healthy heart. The goal of this study is to ascertain the mechanisms for the increased vulnerability to external electric shocks observed experimentally in infarcted rabbit hearts (Li et al. 2005) and to test the hypotheses that it is due to (1) altered 3D distribution and magnitude of VEPs in the zone of infarct, altering the immediate post-shock transmural propagation, and (2) subsequent propagation delay in the PZ. The 3D activity in the rabbit ventricles both during and after external electric shocks needs to be analysed in order to achieve the aim of the study and test these hypotheses. Because current optical mapping techniques cannot resolve electrical activity in the depth of the ventricular wall, we use an established computer modelling approach here, in which the model is enriched with experimental data. A detailed description of the methods can be found in the online Supplemental Material in Supplementary Methods. A brief description is below. The animal protocol was approved by the Washington University Institutional Animal Care and Use Committee. Details on anaesthesia and killing of the animal involved in this study can be found in a previous publication (Li et al. 2005). A New Zealand White rabbit at 7.5 weeks post-infarction was used to gather the needed input for the computational model of the same heart. Ex-vivo optical mapping studies were performed according to established protocols (Li et al. 2009; Ripplinger et al. 2009) (for details see Supplementary Methods). The infarcted rabbit heart subsequently underwent high-resolution (61 μm × 61 μm × 60 μm) magnetic resonance imaging (MRI) and diffusion tensor MRI (DTMRI) to acquire data for model generation; a representative long-axis slice of the MR image stack is shown in Figure 1A. From the MRI scans, a highly detailed finite-element geometric model of the rabbit ventricles was constructed, following the model generation pipeline developed recently (Vadakkumpadan et al. 2009, 2010). The scar and PZ were segmented from the healthy myocardium (Fig. 1B) (McDowell et al. 2011). The segmented images were used to generate the finite element mesh of the ventricles using the meshing package Tarantula (CAE Software Solutions, Eggenburg, Austria); the methodology is described in (Prassl et al. 2009). Each element of the 3 million node mesh (average edge length 135 μm) was assigned a fibre orientation based on the primary eigenvector and a sheet normal orientation based on the tertiary eigenvector of the diffusion tensor as obtained from the DTMRI data (Fig. 1C) (Scollan et al. 1998). The model A, ex-vivo MRI scan of the rabbit heart with healed myocardial infarction. B, left panel, anterior view of the ventricles submerged in a perfusing bath and placed between plate electrodes (blue, grounding electrode; red, shock The infarct scar is shown in the PZ is shown in The on the the of the pacing The the highly detailed structure of the scar and the PZ. The left the details of the computational panel, anterior view of the ventricles by of by are shown in anterior view of the fibre in the The membrane of the ventricular in the normal of the ventricles were by the et al. model of the rabbit ventricular potential et al. The model and the in the PZ were in with experimental to PZ electrophysiological and structural can be found in Supplementary et al. A control rabbit ventricular model was also developed the and in the ventricles were to the used for healthy The model was used to the role of the PZ and infarct scar in post-shock In order to the infarct scar without the remodelled PZ cause an increased vulnerability to electric we an model that did the infarct but that the and conduction of healthy tissue in the area of the PZ. We to this model as the model. we a model the infarct and was as scar in order to increased scar the zone of lead to increased vulnerability. we only the were in the PZ but was and the PZ was remodelled in of but were not models were used to or alone cause an increase in vulnerability. the and fibre orientation were experimentally in this and the model was the to be assigned to the model are not known for the rabbit heart. in tissue lead to conduction and post-shock activation we used experimental data to the model and experimental activation patterns and the of as described in Supplementary were used in previous studies by (Rodriguez et al. 2005; et al. et al. following pacing at of were between optical mapping and computer for × on the of the same rabbit heart. the the activation and patterns for the were between and model (Fig. in in in in in in of the ventricles in the and in the model. the activation patterns between and model, the 3D rabbit ventricular model was used to the shock-induced in the depth of the ventricular wall not by using the protocols below. the model with experimental data the rabbit heart. × analysed in the experimental and pacing activation A, left B, arrhythmias following electric shocks could not be in the model with the as described This is with experimental results from infarcted rabbit hearts, could not be without the of (Li et al. 2009; Ripplinger et al. 2009). in the model was decreased by by the A in the effects of on et al. The ventricles were at the at a of which was the that did not or Supplementary for shocks for electrode of both and et al. were at and shock in order to the vulnerability to electric shocks. The upper limit of vulnerability (ULV) was as the shock that a A post-shock arrhythmia was or more post-shock were observed (Li et al. 2005; Ashihara et al. The were in the infarction and control of VEPs as the between the transmembrane potential shock was and the (Trayanova et al. and post-shock propagation patterns were between infarction and control models in order to the mechanisms responsible for changes in in MI and to test hypotheses. The applied electric was to as the left ventricular electrode was the the electrode was the the shock was to as (Rodriguez et al. 2006). was as the of the applied electric Figure 3 the shock-induced vulnerability for the computational infarction and control models following biphasic and shocks. The for shocks was 8 V cm−1 in the infarction model and 4 V cm−1 in the control model, the for shocks was 4 V cm−1 in infarction and V cm−1 in In the of mechanisms responsible for the in MI we without of with the was in the infarction model than in control of the of the applied electric following biphasic shocks. to post-shock to post-shock of post-shock the the A, vulnerability after shocks for the infarction model. B, vulnerability after shocks for the control model. vulnerability after shocks for the infarction model. vulnerability after shocks for the control model. Figure 4 the and the shock of the infarction and control models to an electric shock with a shock of V applied at a of This shock in post-shock arrhythmia in the infarcted heart, in control it only in potential of the in the of Figure are shown in Supplementary Figure for this electrode polarization following a V cm−1 shock at a of of the with the scar shown in and the PZ in A, The in the PZ was and conduction was in the PZ. left panel, between infarction and control models as control infarction White control was to infarction control was than infarction and control was than infarction B, was less in the infarction model panel, between infarction and control as control infarction tissue was in the infarction model left panel, between infarction and control as control infarction were smaller gradients to the and and in the to the PZ in the infarction model. panel, between infarction and control models infarction was in the infarction model than in specifically in the area of the PZ and in the the on the left the between infarction and as in control in the infarction to decreased in the PZ – in the PZ was to in the control heart at to the PZ × – activation of the ventricles by the apical pacing in the infarction model than in control This propagation in less tissue at in the PZ and in the in the infarction model as to In the this was further by the caused by the leading to a of in the PZ and in the in control × in Figure the distribution of and the depolarizing and membrane effects of the electric The on the the in between infarction and control control It is from the that VEPs were less in infarction than in control in the PZ and on the by the was in the area of the and in the same area in the control ventricles × on was shock-induced in the healthy tissue than in the PZ. potential at a node in healthy tissue on the a node in the PZ to the and a node in the PZ this and are shown in Supplementary Figure and described in Supplementary Figure the distribution of post-shock and is both by state and shock-induced in between the infarction and control models infarction are in the on the was in the PZ and in the same area in control × Tissue in the PZ and on the was less in infarction than in control in providing less of an for post-shock propagation in Figure the that by the shock can current to The on the the in gradients between infarction and were smaller in the infarction model than in control in to the and as as in in the to the PZ on the of the was in infarction than in control in The smaller post-shock gradients in the infarction model provide a as to to post-shock propagation into of the after the shock are shown in Figure The in the the the followed by the The immediate activation of the following the shock after shock in the infarction model and post-shock in It in the the gradients were larger in control than in infarction in propagation in the infarction model was to control and from with gradients on the and the that were also in with gradients in both infarction and control models in wall, and in did not of a of excitable tissue Figure the of the post-shock as the of that were at the were smaller in infarction to control by that the activation was in infarction. post-shock propagation following a V cm−1 shock at a of A, activation The ventricles are shown in an anterior the scar is shown in and the PZ is in of B, the of that were at The were larger after the shock in the control model but in the infarction model larger after the delay of excitable of the of along with the of were excitable in the infarction model than in control However, the propagation of the shock-induced was in the infarction model than in The delay in the post-shock activation in the infarction model the tissue with more time to from the The post-shock excitable for the after the shock is in Figure of between infarction and control shown as The larger excitable in the infarction model is by of the current less and, therefore, more post-shock in infarction to control (Fig. This excitable in the infarction model propagation through the from the that the activation in the occurred after the immediate post-shock activation in the in the infarcted but in control time the of the the in the infarcted ventricles increased due to the propagation, larger than in control after post-shock area in delay in the peri-infarct zone following a V cm−1 shock at a of A, activation post-shock of the with the scar shown in and the PZ in The to an of conduction in the infarct by the B, post-shock activation are shown as was in the infarction model, but not in activation after the shock are shown in Figure was in and the infarct in this time were at the same in both models at but after only of the were in the infarcted ventricles the the of the control and after the was in the PZ and in the same area in control × a post-shock conduction in the PZ. The delay in post-shock activation of the along with the subsequent propagation through the in the infarcted ventricles in tissue the the of the post-shock conduction was in and in Figure after the which that the arrhythmia was in the infarction model. In on the the only tissue in the after post-shock and, therefore, for activation for the post-shock conduction and propagation delay was observed in the infarction model, but not in shown propagation delay in the PZ an role in in the infarction model. However, it or not the remodelled PZ alone caused the increased vulnerability to electric shocks in the infarction model, or the infarct scar also to the The vulnerability for the PZ model following shocks is shown in Figure The for the PZ model was to the of the control model V the presence of the infarct scar alone did not increase vulnerability to electric shocks. The role of the peri-infarct zone in vulnerability to electric shocks A, vulnerability after shocks for the PZ model. B, anterior of the with the scar shown in in between infarction and PZ models and between control and PZ models after a V cm−1 shock at with between infarction and PZ models were larger than with between control and PZ models of in between infarction and PZ models and between control and PZ models activation for the PZ model following a V cm−1 shock at of the scar shown in Figure in between the infarction and the PZ models and between the control and the PZ models In the area of the in the the on the and the was increased in the PZ model to the infarction model the on the to the infarct scar and on the was decreased in the PZ model to control of in between infarction and PZ and between control and PZ models are shown in Figure It is from the that between infarction and PZ were larger than between control and PZ Figure transmural activation for the PZ model. these to in the of and it is that the post-shock propagation was between the control and PZ that the in between control and PZ did not result in different post-shock propagation as propagation through the infarct was not in the PZ model to propagation through the same area in as is by of the in the PZ and control models at both and after the The and the models arrhythmia after a 4 V cm−1 but not after a V cm−1 the model the a V cm−1 shock to arrhythmia in the model. results that the of the infarct alone the changes in the PZ without increased vulnerability to electric in the PZ did cause an increased The presence of the scar alone the scar the zone of infarct, the as in the was not to cause VEP changes and to delay propagation, and did not increase vulnerability. it was the in the PZ that was responsible for the vulnerability of infarcted hearts to electric shocks by altering VEP and gradients and by propagation This study insights into the 3D mechanisms that increased vulnerability to electric shocks in infarcted hearts and that could infarcted hearts to defibrillation the to electric shocks in infarcted hearts was increased for biphasic of both magnitude of the and increased magnitude of the VEPs in infarcted hearts in the formation of a larger post-shock excitable to healthy hearts. gradients in infarcted hearts smaller for post-shock propagation and caused a post-shock delay in the PZ during post-shock propagation for the increase in excitable which in reentry The presence of the PZ but not of the scar alone caused increased vulnerability to electric shocks. provide insights into the defibrillation mechanisms in the of increased vulnerability to electric shocks into increased defibrillation This is of arrhythmia with electric shocks vulnerability to electric and defibrillation are by the same mechanisms et al. et al. et al. Rodriguez et al. 2005; Ashihara et al. 2008), also by the between and et al. understanding the mechanisms of vulnerability to electric shocks a to understand the mechanisms of defibrillation and arrhythmogenesis by shocks. the vulnerability to electric shocks by computational is also a to the mechanisms by which an electric shock with the 3D ventricles than by defibrillation In view of the that the study used a high-resolution model of the rabbit computational vulnerability to electric shocks than defibrillation in these The rabbit model of infarction a recently pipeline for the of models (Vadakkumpadan et al. 2009, 2010). The model infarct scar and PZ and fibre the model distinct scar and with previous studies that shown the presence of a between infarct scar and normal of of remodelled and scar tissue et al. modelling approach this zone as a with remodelled electrophysiological in decreased This is as by simulation studies that a of myocardium and scar results in a in et al. 2010). and fibre in model were from MRI and DTMRI The model used et al. it was based on data to cellular in the remodelled PZ. The model was enriched with experimental data from the same heart that was used for model The model in this study the to model delivery of electric shocks in the structurally remodelled to model vulnerability to electric shocks in the ventricles were limited to only (Rodriguez et al. the of infarction on vulnerability to shocks and on defibrillation been and study found an increase in defibrillation and current at the of infarction et al. In the study by et al. hearts with healed were found to but not less to ventricular et al. that the presence of infarction was not found to the and In a optical mapping et al. in rabbit hearts with healed infarction, an increase in the for shocks. We that the was in infarction than in control for biphasic the for defibrillation shocks – which are biphasic in – in infarction than in et al. that post-shock arrhythmias in the infarcted rabbit heart from in the and leading to on the the also VEPs the infarct Ripplinger et al. and et al. in infarcted rabbit hearts, was by at the infarct in the infarct and, on the edge of the infarct et al. 2009). results the of the PZ in post-shock arrhythmia in the along with the altered propagation through the PZ. of these mechanisms the state that the was less in infarction to The in the model was to the in the control model This that the in state between the control and infarction models were caused by electrophysiological and conduction delay in the and not by a conduction the In – remodelled – altered the in the PZ. The changes in state and tissue in changes in with results from previous studies (Trayanova et al. the remodelled and distribution conduction in the which in post-shock propagation VEP and altered post-shock propagation in increased vulnerability to electric shocks in infarcted hearts. We further that the presence of an infarct scar alone did not increase vulnerability – the scar was to the of the infarct – and did not post-shock Indeed, the scar alone did not cause a in VEP to and post-shock propagation patterns were between the control model and the model with the scar but without the PZ the remodelled PZ was the for increased vulnerability in infarcted hearts. It has been shown that is after infarction et al. and that in the infarction area is but time et al. we did not a specific distribution of and in model, we in the which could from the results that only in the PZ increases the only or a scar the infarct zone without PZ not increase we that different of or distribution in the PZ not a on vulnerability to electric shocks. The model used in this study did not the This was based on the by et al. that the an role in post-shock but not in arrhythmogenesis caused by electric shocks. et al. that the the defibrillation mechanisms after but that the was not involved in defibrillation mechanisms after specific in this study as activation and gradients be on the and of the infarct as as on the specific of the PZ. the mechanisms altered propagation the increase in vulnerability in infarcted hearts of the specific infarct This model a of an infarcted rabbit heart (Li et al. 2005; et al. 2008), which in is a model for infarction in hearts the heart, the rabbit heart both an and an PZ (Li et al. 2005). the of plate electrodes a shock electrode use in vulnerability and defibrillation studies and is an established et al. Ashihara et al. 2008; et al. it defibrillation electric in the of the heart is to specific as the likely be different for electrode but we that the vulnerability in infarction, VEP changes in infarction, propagation delay through the remain in these and of the and and the computational studies and was responsible for the optical mapping Washington University in and of performed the computer and to the of the computational studies the for use in University and at and and analysed the data the or it for the and and the approved the of the is a of a of the of at the of This study was by of to by and to and by to and to and of was not involved in this Supplementary Figure Figure Figure The is not responsible for the or of by the than be to the for the