Mechano-electric feedback and atrial fibrillation

Atrial fibrillation frequently occurs under conditions associated with atrial dilatation suggesting a role of mechano-electric feedback in atrial arrhythmogenesis. Although atrial arrhythmias may be due both to abnormal focal activity and reentrant mechanisms, the majority of sustained atrial arrhythmias have been ascribed to reentrant activity. Atrial stretch may contribute to focal arrhythmias by inducing afterdepolarizations and to reentrant arrhythmias by increasing the atrial surface, by shortening the refractory period and/or slowing the conduction velocity and by increasing their spatial dispersion. Experimental and clinical studies have demonstrated that changes in mechanical loading conditions may modulate the electrophysiological properties of the atria. These studies have, for the most part, involved the effects of acute stretch on atrial refractoriness. While studies in humans and intact animals yield divergent results due to the variety of loading conditions and neurohumoral influences, experimental studies in isolated preparations clearly show that atrial refractory period and action potential duration at early levels of repolarization shorten by acute atrial dilatation. Both experimental and human studies have shown that acute atrial stretch is arrhythmogenic and may induce triggered premature beats and atrial fibrillation.     

Increased vasodilator responsiveness to BRL 34915 in spontaneously hypertensive versus normotensive rats: contrast with nifedipine

The blood pressure-lowering potency and activity of BRL 34915, a new vasodilator and putative stimulator of potassium efflux from vascular smooth muscle, was investigated in conscious spontaneously hypertensive rats (SHR) and normotensive rats (NTR) after intravenous administration and compared with that of the calcium channel blocker, nifedipine. In SHR, BRL 34915 (3-100 micrograms/kg) or nifedipine (10-3000 micrograms/kg) produced similar reductions in mean arterial pressure of 58 +/- 3% and 55 +/- 3%, respectively. BRL 34915 (ED30% = 13.8 micrograms/kg) was 15.3 times more potent than nifedipine (ED30% = 207 micrograms/kg) in SHR. In contrast, only a 1.7-fold difference in potency was observed in NTR between BRL 34915 (ED30% = 123 micrograms/kg) and nifedipine (ED30% = 182 micrograms/kg). The potency ratio (ED30% NTR/ED30% SHR) for BRL 34915 was 8.83 whereas nifedipine had a ratio of 0.88, reflecting the greater responsiveness of the SHR to BRL 34915. Systemic hemodynamics were monitored in anesthetized SHR and NTR to determine the basis for the reductions in blood pressure. BRL 34915 (3-100 micrograms/kg iv) lowered mean arterial pressure in both groups solely by decreasing total peripheral vascular resistance, since no changes in cardiac output were observed. Relaxation responses were also obtained in phenylephrine-contracted isolated aortic strips from both strains of rat to ascertain whether differences in responsiveness existed at this level of the vasculature. No significant difference in the potency of BRL 34915 (3-10 microM) as a vasodilator was found in aortas from SHR or NTR. These results indicate that, unlike nifedipine, BRL 34915 is a more potent vasodepressor agent in SHR than in NTR and suggests that the potassium efflux stimulator may preferentially relax resistance vessels in the hypertensive rat.     

Comparison of effects of a potassium channel opener BRL34915, a specific potassium ionophore valinomycin and calcium channel blockers on endothelin-induced vascular contraction

The effects of a potassium (K+) channel opener BRL34915 and a specific K+ ionophore valinomycin on vasoconstriction induced by endothelin (ET) were compared with those of calcium (Ca2+) channel blockers, nicardipine and verapamil, using helical strips from rat thoracic aorta. ET induced potent and persistent contraction in control solution and similar but smaller contraction in Ca2+-free solution. BRL34915 and valinomycin inhibited the ET-induced contraction dose-dependently in control solution, but not in Ca2+-free solution. The ET-induced contraction was also inhibited by nicardipine and verapamil, though less strongly. On the other hand, high K+ (35 mM)-induced vasoconstriction was strongly inhibited by nicardipine and verapamil, but not by BRL34915 or valinomycin. These results support the idea that the extracellular Ca2+-dependent component of the ET-induced contraction may be mediated by Ca2+ influx by a route other than voltage-dependent Ca2+-channels.     

Leiurus quinquestriatus venom inhibits BRL 34915-induced 86Rb+ efflux from the rat portal vein

The effect of the crude venom of the Israeli scorpion Leiurus quinquestriatus hebraeus on the 86Rb+ efflux stimulated by the K+ channel opener BRL 34915 in the rat portal vein was examined. Applied alone, the venom greatly increased the spontaneous mechanical activity of and the concomitant 86Rb+ efflux from the vessel. When the excitability of the vein was suppressed by the dihydropyridine calcium antagonist, PN 200-110, the 86Rb+ efflux stimulated by BRL 34915 could be shown to be inhibited by the venom. From the concentration dependence of this inhibition an IC50 value of 0.17 +/- 0.01 mg/ml was estimated. This venom is thus the most potent blocker of BRL 34915-evoked 86Rb+ efflux reported so far.     

Effects of simulated ischaemia on the electrical activity of ventricular myocardium in the presence of antiarrhythmic drugs.

The effects of a nutrient solution simulating the 'ischaemic milieu' (combined hyperkalaemia, hypoxia and acidosis) on the electrical activity of rabbit isolated ventricular myocardium were examined in the absence and presence of antiarrhythmic drugs. In such a simulated ischaemia the resting membrane potential, the rate of depolarization (Vmax) and the action potential duration (APD) were all diminished with a resultant decrease in conduction and a shortening of the effective refractory period (ERP). Sotalol, a Class 3 antiarrhythmic drug (5 x 10(-6)-10(-5) M/l) afforded a marked protection against the "ischaemic" abbreviation of the ERP and APD. To a much lesser extent, the same applied to propafenone, a predominantly Class 1C antidysrhythmic agent (1.65-3.3 x 10(-6) M/l). The 'ischaemia'-induced depression of Vmax was increased considerably by propafenone and diminished slightly by sotalol. The results are in keeping with the efficacy of propafenone and sotalol in ventricular arrhythmias of ischaemic origin and also with the proposal that the major mechanism by which propafenone inhibits postinfarction ventricular arrhythmias is a further depression of ischaemic myocardial cells resulting in conduction block of the reentrant wave front.     

Spatiotemporal dynamics of reentrant ventricular tachycardias in canine myocardial infarction: pharmacological modulation

During the transition from a slow to rapid depolarization rhythm, rate-dependent sodium channel blockade develops progressively and increases from beat to beat under procainamide but more abruptly under lidocaine. We investigated the consequences of such differences on the dynamic course and stability of reentrant tachycardias at their onset. Procainamide and lidocaine were infused to equipotent plasma concentrations in canines with three-day-old myocardial infarction. We measured the activation times (ms) and maximum slopes of negative deflections in activation complexes (absolute value: /-dV/dt(max)/ in mV/ms) in 191 unipolar electrograms recorded from ischemically damaged subepicardial muscle during programmed stimulation inducing reentrant tachycardias. Procainamide caused a greater reduction in /-dV/dt(max)/ than did lidocaine in the responses to basic stimulation, and it favored the occurrence of cycle length prolongation at tachycardia onset as the /-dV/dt(max)/ decreased progressively in successive beats. This resulted in conduction block and tachycardia termination in three of eight preparations. In contrast, lidocaine caused a greater depression in /-dV/dt(max)/ in response to closely coupled extrastimuli, but /-dV/dt(max)/ remained constant or even improved thereafter, and none of the tachycardias terminated spontaneously under lidocaine (n = 9). However, the reentrant circuits remained spatially unstable, and lidocaine favored the occurrence of cycle length dynamics displaying constant or decreasing trends. This study supports the notion that cycle length dynamics at tachycardia onset are determined by the properties of the reentrant substrate and their pharmacological modulation.     

基于虚拟心脏的早期后除极导致室颤的仿真研究

为了分析早期后除极(early afterdepolarizations,EADs)诱发室颤的机理,本研究基于精细的浦肯野纤维网络与心室解剖数据,构建了一个三维心室电传导模型.基于该模型,模拟了产生早期后除极的电生理变化,探讨了三种心室细胞的早期后除极的易感性,分析了早期后除极易感细胞对折返波的影响,最后定量比较早期后除极诱发室颤的伪心电图的改变情况.实验结果表明:中间层细胞早期后除极易感性最强,中间层细胞早期后除极的产生能够导致折返波破裂,并且在心电图中表现为紊乱的不规则的颤动心律,这与之前在动物实验观察得到的现象一致,因此中间层细胞可能是一个诱发室颤的重要靶点.     

Cryothermal energy ablation of cardiac arrhythmias 2005: state of the art

At the time of antiarrhythmic surgery, cryothermal energy application by a hand-held probe was used to complement dissections and resections and permanently abolish the arrhythmogenic substrate. Over the last decade, significant engineering advances allowed percutaneous cryoablation based on catheters, apparently not very different from standard radiofrequency ablation catheters. Cryothermal energy has peculiar characteristics. In fact, it allows testing in a reversible way the effects of energy application at higher temperature, before producing a permanent lesion at -75 degrees C. Moreover, slow formation of the lesion allows timely discontinuation of the application, as soon as inadvertent modifications of normal atrioventricular conduction are observed during ablation in the proximity of atrioventricular node and His bundle, avoiding its permanent damage. Over the last years, percutaneous cryothermal ablation has been widely used for a variety of cardiac arrhythmias. From the data gathered, it is unlikely that cryoablation will replace standard ablation in unselected cases. Nevertheless, for the above mentioned peculiarities, cryothermal ablation has proved very effective and safe for ablation of arrhythmogenic substrates close to the normal conduction pathways, becoming the first choice method to ablate anteroseptal and midseptal accessory pathways. It can be also the best treatment for ablation of the slow pathway to abolish atrioventricular node reentrant tachycardia in pediatrics or when particular anatomy of the Koch's triangle is observed. Cryothermal ablation of the pulmonary veins for atrial fibrillation, although longer than radiofrequency ablation, is not associated with pulmonary vein stenosis and is expected to be less thrombogenic; new catheter designs for cryothermal ablation of this challenging arrhythmia are to be tested to assess their efficacy and clinical usefulness.     

Mechanoelectric feedback leads to conduction slowing and block in acutely dilated atria: a modeling study of cardiac electromechanics

Atrial fibrillation, a common cardiac arrhythmia, is promoted by atrial dilatation. Acute atrial dilatation may play a role in atrial arrhythmogenesis through mechanoelectric feedback. In experimental studies, conduction slowing and block have been observed in acutely dilated atria. In the present study, the influence of the stretch-activated current (I(sac)) on impulse propagation is investigated by means of computer simulations. Homogeneous and inhomogeneous atrial tissues are modeled by cardiac fibers composed of segments that are electrically and mechanically coupled. Active force is related to free Ca(2+) concentration and sarcomere length. Simulations of homogeneous and inhomogeneous cardiac fibers have been performed to quantify the relation between conduction velocity and I(sac) under stretch. In our model, conduction slowing and block are related to the amount of stretch and are enhanced by contraction of early-activated segments. Conduction block can be unidirectional in an inhomogeneous fiber and is promoted by a shorter stimulation interval. Slowing of conduction is explained by inactivation of Na(+) channels and a lower maximum upstroke velocity due to a depolarized resting membrane potential. Conduction block at shorter stimulation intervals is explained by a longer effective refractory period under stretch. Our observations are in agreement with experimental results and explain the large differences in intra-atrial conduction, as well as the increased inducibility of atrial fibrillation in acutely dilated atria.     

Effects of Na(+) channel and cell coupling abnormalities on vulnerability to reentry: a simulation study

The role of dynamic instabilities in the initiation of reentry in diseased (remodeled) hearts remains poorly explored. Using computer simulations, we studied the effects of altered Na(+) channel and cell coupling properties on the vulnerable window (VW) for reentry in simulated two-dimensional cardiac tissue with and without dynamic instabilities. We related the VW for reentry to effects on conduction velocity, action potential duration (APD), effective refractory period dispersion and restitution, and concordant and discordant APD alternans. We found the following: 1). reduced Na(+) current density and slowed recovery promoted postrepolarization refractoriness and enhanced concordant and discordant APD alternans, which increased the VW for reentry; 2). uniformly reduced cell coupling had little effect on cellular electrophysiological properties and the VW for reentry. However, randomly reduced cell coupling combined with decoupling promoted APD dispersion and alternans, which also increased the VW for reentry; 3). the combination of decreased Na(+) channel conductance, slowed Na(+) channel recovery, and cellular uncoupling synergistically increased the VW for reentry; and 4) the VW for reentry was greater when APD restitution slope was steep than when it was flat. In summary, altered Na(+) channel and cellular coupling properties increase vulnerability to reentrant arrhythmias. In remodeled hearts with altered Na(+) channel properties and cellular uncoupling, dynamic instabilities arising from electrical restitution exert important influences on the VW for reentry.     

The potassium channel opener BRL 38227 inhibits binding of [125I]-labelled endothelin-1 to rat cardiac membranes.

Binding of [125I]-labelled endothelin-1 (ET-1) to rat cardiac membranes and the effects of endothelin-1 (ET-1), endothelin-3 (ET-3), the calcium channel antagonist nifedipine, and both enantiomers of the potassium channel opener cromakalim (BRL 34915) on binding have been examined. Specific binding of [125I]-ET-1 was inhibited in a concentration dependent manner by both unlabelled ET-1 (10(-12)-10(-7) M) and ET-3 (10(-12)-10(-6) M). Nifedipine (10(-11)-10(-5) M) did not affect [125I]-ET-1 binding. However, BRL 38227 (10(-11)-10(-5) M), the biologically active isomer of cromakalim, significantly inhibited [125I]-ET-1 binding. The inactive isomer, BRL 38226 (10(-11)-10(-5) M) had no effect. These findings provide the first evidence for a stereospecific interaction between BRL 38227 and an ET-1 binding site in rat cardiac membranes.     

Increased vulnerability of human ventricle to re-entrant excitation in hERG-linked variant 1 short QT syndrome

The short QT syndrome (SQTS) is a genetically heterogeneous condition characterized by abbreviated QT intervals and an increased susceptibility to arrhythmia and sudden death. This simulation study identifies arrhythmogenic mechanisms in the rapid-delayed rectifier K(+) current (I(Kr))-linked SQT1 variant of the SQTS. Markov chain (MC) models were found to be superior to Hodgkin-Huxley (HH) models in reproducing experimental data regarding effects of the N588K mutation on KCNH2-encoded hERG. These ionic channel models were then incorporated into human ventricular action potential (AP) models and into 1D and 2D idealised and realistic transmural ventricular tissue simulations and into a 3D anatomical model. In single cell models, the N588K mutation abbreviated ventricular cell AP duration at 90% repolarization (APD(90)) and decreased the maximal transmural voltage heterogeneity (δV) during APs. This resulted in decreased transmural heterogeneity of APD(90) and of the effective refractory period (ERP): effects that are anticipated to be anti-arrhythmic rather than pro-arrhythmic. However, with consideration of transmural heterogeneity of I(Kr) density in the intact tissue model based on the ten Tusscher-Noble-Noble-Panfilov ventricular model, not only did the N588K mutation lead to QT-shortening and increases in T-wave amplitude, but δV was found to be augmented in some local regions of ventricle tissue, resulting in increased tissue vulnerability for uni-directional conduction block and predisposing to formation of re-entrant excitation waves. In 2D and 3D tissue models, the N588K mutation facilitated and maintained re-entrant excitation waves due to the reduced substrate size necessary for sustaining re-entry. Thus, in SQT1 the N588K-hERG mutation facilitates initiation and maintenance of ventricular re-entry, increasing the lifespan of re-entrant spiral waves and the stability of scroll waves in 3D tissue.     

Mechanisms of ventricular arrhythmias elicited by coexistence of multiple electrophysiological remodeling in ischemia: A simulation study

Myocardial ischemia, injury and infarction (MI) are the three stages of acute coronary syndrome (ACS). In the past two decades, a great number of studies focused on myocardial ischemia and MI individually, and showed that the occurrence of reentrant arrhythmias is often associated with myocardial ischemia or MI. However, arrhythmogenic mechanisms in the tissue with various degrees of remodeling in the ischemic heart have not been fully understood. In this study, biophysical detailed single-cell models of ischemia 1a, 1b, and MI were developed to mimic the electrophysiological remodeling at different stages of ACS. 2D tissue models with different distributions of ischemia and MI areas were constructed to investigate the mechanisms of the initiation of reentrant waves during the progression of ischemia. Simulation results in 2D tissues showed that the vulnerable windows (VWs) in simultaneous presence of multiple ischemic conditions were associated with the dynamics of wave propagation in the tissues with each single pathological condition. In the tissue with multiple pathological conditions, reentrant waves were mainly induced by two different mechanisms: one is the heterogeneity along the excitation wavefront, especially the abrupt variation in conduction velocity (CV) across the border of ischemia 1b and MI, and the other is the decreased safe factor (SF) for conduction at the edge of the tissue in MI region which is attributed to the increased excitation threshold of MI region. Finally, the reentrant wave was observed in a 3D model with a scar reconstructed from MRI images of a MI patient. These comprehensive findings provide novel insights for understanding the arrhythmic risk during the progression of myocardial ischemia and highlight the importance of the multiple pathological stages in designing medical therapies for arrhythmias in ischemia.     

The potassium channel opener cromakalim (BRL 34915) activates ATP-dependent K+ channels in isolated cardiac myocytes

In cardiac myocytes, cromakalim (BRL 34915), a potassium channel opener, activates a time-independent K+ current exhibiting poor voltage-sensitivity. This effect of cromakalim is antagonized by low concentrations of glibenclamide, a specific blocker of ATP-dependent K+ channels in cardiac cells. Direct recording of the activity of K+ channels in inside-out membrane patches, confirmed that cromakalim is a potent activator of ATP-dependent K+ channels in cardiac myocytes.     

Region [corrected] of slowed conduction acts as core for spiral wave reentry in cardiac cell monolayers

Pathophysiological heterogeneity in cardiac tissue is related to the occurrence of arrhythmias. Of importance are regions of slowed conduction, which have been implicated in the formation of conduction block and reentry. Experimentally, it has been a challenge to produce local heterogeneity in a manner that is both reversible and well controlled. Consequently, we developed a dual-zone superfusion chamber that can dynamically create a small (5 mm) central island of heterogeneity in cultured cardiac cell monolayers. Three different conditions were studied to explore the effect of regionally slowed conduction on wave propagation and reentry: depolarization by elevated extracellular potassium, sodium channel inhibition with lidocaine, and cell-cell decoupling with palmitoleic acid. Using optical mapping of transmembrane voltage, we found that the central region of slowed conduction always served as the core region around which a spiral wave formed and then revolved following a period of rapid pacing. Because of the localized slowing in the core region, we observed experimentally for the first time an S shape of the spiral wave front near its tip. These results indicate that a small region of slowed conduction can play a crucial role in the formation, anchoring, and modulation of reentrant spiral waves.     

Effect of atrial dilatation on the tendency of atrial arrhythmias

The arrhythmogenic effect of atrial dilatation was studied by electrophysiological investigations carried out on 24 dogs. Atrial distension was evoked by increasing the pressure in the right atrium (12 to 14 mm Hg) or by the balloon dilatation of the left atrium. Programmed electrical stimulation of the heart was used for the electrophysiological investigations. In addition to the superficial ECG leads also atrial and ventricular epicardial electrograms were obtained for the ECG recording. Acute atrial dilatation led to shortening of the atrial refractory period, whereas neither impulse conduction of the heart, nor pacemaker activity of the sinus node exhibited any alteration. Atrial dilatation resulted in pathological atrial irritability, and early or frequent atrial stimulation caused atrial tachycardia of shorter (non sustained) or longer (sustained) duration. Repetitive atrial extrasystoles in response to early stimuli could also frequently be observed during atrial dilatation. The obtained results indicate that atrial dilatation is arrhythmogenic and may lead to the development of atrial tachycardia.     

A model for human ventricular tissue

The experimental and clinical possibilities for studying cardiac arrhythmias in human ventricular myocardium are very limited. Therefore, the use of alternative methods such as computer simulations is of great importance. In this article we introduce a mathematical model of the action potential of human ventricular cells that, while including a high level of electrophysiological detail, is computationally cost-effective enough to be applied in large-scale spatial simulations for the study of reentrant arrhythmias. The model is based on recent experimental data on most of the major ionic currents: the fast sodium, L-type calcium, transient outward, rapid and slow delayed rectifier, and inward rectifier currents. The model includes a basic calcium dynamics, allowing for the realistic modeling of calcium transients, calcium current inactivation, and the contraction staircase. We are able to reproduce human epicardial, endocardial, and M cell action potentials and show that differences can be explained by differences in the transient outward and slow delayed rectifier currents. Our model reproduces the experimentally observed data on action potential duration restitution, which is an important characteristic for reentrant arrhythmias. The conduction velocity restitution of our model is broader than in other models and agrees better with available data. Finally, we model the dynamics of spiral wave rotation in a two-dimensional sheet of human ventricular tissue and show that the spiral wave follows a complex meandering pattern and has a period of 265 ms. We conclude that the proposed model reproduces a variety of electrophysiological behaviors and provides a basis for studies of reentrant arrhythmias in human ventricular tissue.     

Effects of Ibutilide on Inhibiting Heart Rate and Rapidly Terminating Atrial Flutter in Canine

Ibutilide is a newer class-III antiarrhythmic agent approved for clinical use. We sought to investigate its electrophysiological effects in canines and also the underlying mechanism of conversion of atrial flutter (AFL). For this purpose, 15 male mongrel dogs were anesthetized, intubated with tracheal tube, and heart was exposed and connected to electrodes. Electrophysiologic variables were measured with and without ibutilide (10-min infusion-dose: 0.10 mg/kg; 30-min later, maintaining dose: 0.01 mg/min) which included heart rate, conduction of intra- and inter-atrium, conduction ratio of isthmus, and ERP. Ibutilide had a significant inhibitory effect on sinus atrial node, peak response time was 20–30 min, and heart rate returned to the baseline after 2 h. One canine had 5 s sinus pause, and the other had 2:1 atrioventricular conduction post-administration. Atrial, ventricular, and pulmonary vein ERP was significantly prolonged (P < 0.05). No significant differences were observed regarding conduction of intra-atrium, inter-atrium, and isthmus. It was, therefore, concluded that ibutilide had suppressive effect on sinus atrial and atrioventricular nodes. Ibutilide rapidly terminated AFL due to the reentrant wave front’s inability to proceed as the refractory period was protracted and hence caused the whole excitable gap of the reentrant circuit to be affected by refractoriness.     

Effect of myocardial infarction and ischemia on induction of cardiac reentries and ventricular fibrillation

The present work is aimed at investigating the effects of myocardial infarction and ischemia on induction of ventricular fibrillation. Electrophysiologic effects of global and local ischemia (variation of the dispersion of refractory periods as well as conduction velocity) on initiation of reentry mechanisms was studied by means of computer simulations based on a cellular automata model of propagation of activation wave through a ventricular surface element. A local area of ischemia where effects of the dispersion of refractory periods are investigated is then simulated. This is made using a Gaussian distribution characterized by its mean and standard deviation. These simulations show that ischemia is capable of initiating reentry phenomena which propagate through the whole ventricle; they are responsible for ventricular fibrillation which causes sudden cardiac death, even when ischemia only involves limited parts of the myocardium. Statistical study of the probability of reentries as a function of both of the size of ischemic zones and the rate of dispersion of refractory periods shows that the latter parameter is of primary importance in triggering cardiac reentries.     

Investigating a Novel Activation-Repolarisation Time Metric to Predict Localised Vulnerability to Reentry Using Computational Modelling

Exit sites associated with scar-related reentrant arrhythmias represent important targets for catheter ablation therapy. However, their accurate location in a safe and robust manner remains a significant clinical challenge. We recently proposed a novel quantitative metric (termed the Reentry Vulnerability Index, RVI) to determine the difference between activation and repolarisation intervals measured from pairs of spatial locations during premature stimulation to accurately locate the critical site of reentry formation. In the clinic, the method showed potential to identify regions of low RVI corresponding to areas vulnerable to reentry, subsequently identified as ventricular tachycardia (VT) circuit exit sites. Here, we perform an in silico investigation of the RVI metric in order to aid the acquisition and interpretation of RVI maps and optimise its future usage within the clinic. Within idealised 2D sheet models we show that the RVI produces lower values under correspondingly more arrhythmogenic conditions, with even low resolution (8 mm electrode separation) recordings still able to locate vulnerable regions. When applied to models of infarct scars, the surface RVI maps successfully identified exit sites of the reentrant circuit, even in scenarios where the scar was wholly intramural. Within highly complex infarct scar anatomies with multiple reentrant pathways, the identified exit sites were dependent upon the specific pacing location used to compute the endocardial RVI maps. However, simulated ablation of these sites successfully prevented the reentry re-initiation. We conclude that endocardial surface RVI maps are able to successfully locate regions vulnerable to reentry corresponding to critical exit sites during sustained scar-related VT. The method is robust against highly complex and intramural scar anatomies and low resolution clinical data acquisition. Optimal location of all relevant sites requires RVI maps to be computed from multiple pacing locations.