The topology of defibrillation

We describe how Art Winfree's ideas about phase singularities can be used to understand the response of cardiac tissue with a random preexisting pattern of reentrant waves (fibrillation) to a large brief current stimulus. This discussion is organized around spatial dimension, beginning with a discussion of reentry on a periodic ring, followed by reentry in a two-dimensional planar domain (spiral waves), and ending with consideration of three-dimensional reentrant patterns (scroll waves). In all cases, we show how reentrant activity is changed by the application of a shock, describing conditions under which defibrillation is successful or not. Using topological arguments we draw the general conclusion that with a generic placement of stimulating electrodes, large-scale virtual electrodes do not give an adequate explanation for the mechanism of defibrillation.     

Structural Heterogeneity Modulates Effective Refractory Period: A Mechanism of Focal Arrhythmia Initiation

Reductions in electrotonic loading around regions of structural and electrophysiological heterogeneity may facilitate capture of focal triggered activity, initiating reentrant arrhythmias. How electrotonic loading, refractoriness and capture of focal ectopics depend upon the intricate nature of physiological structural anatomy, as well as pathological tissue remodelling, however, is not well understood. In this study, we performed computational bidomain simulations with anatomically-detailed models representing the rabbit left ventricle. We used these models to quantify the relationship between local structural anatomy and spatial heterogeneity in action potential (AP) characteristics, electrotonic currents and effective refractory periods (ERPs) under pacing and restitution protocols. Regions surrounding vessel cavities, in addition to tissue surfaces, had significantly lower peak downstream electrotonic currents than well coupled myocardium ( vs A/cm²), with faster maximum AP upstroke velocities ( vs mV/ms), although noticeably very similar APDs ( vs ms) and AP restitution properties. Despite similarities in APDs, ERPs in regions of low electrotonic load in the vicinity of surfaces, intramural vessel cavities and endocardial structures were up to ms shorter compared to neighbouring well-coupled tissue, leading to regions of sharp ERP gradients. Consequently, focal extra-stimuli timed within this window of ERP heterogeneity between neighbouring regions readily induced uni-directional block, inducing reentry. Most effective induction sites were within channels of low ERPs between large vessels and epicardium. Significant differences in ERP driven by reductions in electrotonic loading due to fine-scale physiological structural heterogeneity provides an important mechanism of capture of focal activity and reentry induction. Application to pathological ventricles, particularly myocardial infarction, will have important implications in anti-arrhythmia therapy.     

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.     

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.     

Relevance of ventricular electrical dispersion to arrhythmogenesis in ischemic myocardium--a simulation study

A computer simulation method was used to study the possible role of electrical dispersion induced by regional ischemia in the mechanisms underlying cardiac arrhythmias. Ischemic cells were simulated by considering the three major component conditions of acute ischemia (elevated extracellular K+ concentration, acidosis and anoxia) at the level of ionic currents and ionic concentrations. An ischemic area was introduced into a homogeneous healthy tissue to create a localized inhomogeneity. The constructed models were solved using the operator splitting and adaptive time step methods. The numerical experiments showed that action potential durations (APDs) of ischemic cells did not change with beats of shorter or longer cycle length. The smaller percentage increase of slow component of the delayed rectifier K+ current, I(ks), and smaller outward Na+-Ca2+ exchange current were found to be the ionic mechanisms underlying the decreased rate dependence in ischemic cells. The results suggest that ischemia flattens the APD restitution curve; however, the dispersion of refractory period can be greatly increased by a premature beat in the constructed inhomogeneous sheet. This demonstrates that the dispersion of refractoriness rather than APD by a premature beat contributes to reentrant tachyarrhythmias in the locally ischemic tissue.     

Effects of early afterdepolarizations on reentry in cardiac tissue: a simulation study

Early afterdepolarizations (EADs) are classically generated at slow heart rates when repolarization reserve is reduced by genetic diseases or drugs. However, EADs may also occur at rapid heart rates if repolarization reserve is sufficiently reduced. In this setting, spontaneous diastolic sarcoplasmic reticulum (SR) Ca release can facilitate cellular EAD formation by augmenting inward currents during the action potential plateau, allowing reactivation of the window L-type Ca current to reverse repolarization. Here, we investigated the effects of spontaneous SR Ca release-induced EADs on reentrant wave propagation in simulated one-, two-, and three-dimensional homogeneous cardiac tissue using a version of the Luo-Rudy dynamic ventricular action potential model modified to increase the likelihood of these EADs. We found: 1) during reentry, nonuniformity in spontaneous SR Ca release related to subtle differences in excitation history throughout the tissue created adjacent regions with and without EADs. This allowed EADs to initiate new wavefronts propagating into repolarized tissue; 2) EAD-generated wavefronts could propagate in either the original or opposite direction, as a single new wave or two new waves, depending on the refractoriness of tissue bordering the EAD region; 3) by suddenly prolonging local refractoriness, EADs caused rapid rotor displacement, shifting the electrical axis; and 4) rapid rotor displacement promoted self-termination by collision with tissue borders, but persistent EADs could regenerate single or multiple focal excitations that reinitiated reentry. These findings may explain many features of Torsades des pointes, such as perpetuation by focal excitations, rapidly changing electrical axis, frequent self-termination, and occasional degeneration to fibrillation.     

Intracellular calcium dynamics at the core of endocardial stationary spiral waves in Langendorff-perfused rabbit hearts

In vitro models of sustained monomorphic ventricular tachycardia (MVT) are rare and do not usually show spiral reentry on the epicardium. We hypothesized that MVT is associated with the spiral wave in the endocardium and that this stable reentrant propagation is supported by a persistently elevated intracellular calcium (Ca(i)) transient at the core of the spiral wave. We performed dual optical mapping of transmembrane potential (V(m)) and Ca(i) dynamics of the right ventricular (RV) endocardium in Langendorff-perfused rabbit hearts (n = 12). Among 64 induced arrhythmias, 55% were sustained MVT (>10 min). Eighty percent of MVT showed stationary spiral waves (>10 cycles, cycle length: 128 +/- 14.6 ms) in the endocardial mapped region, anchoring to the anatomic discontinuities. No reentry activity was observed in the epicardium. During reentry, the amplitudes of V(m) and Ca(i) signals were higher in the periphery and gradually decreased toward the core. At the core, maximal V(m) and Ca(i) amplitudes were 42.95 +/- 5.89% and 43.95 +/- 9.46%, respectively, of the control (P < 0.001). However, the trough of the V(m) and Ca(i) signals at the core were higher than those in the periphery, indicating persistent V(m) and Ca(i) elevations during reentry. BAPTA-AM, a calcium chelator, significantly reduced the maximal Ca(i) transient amplitude and prevented sustained MVT and spiral wave formation in the mapped region. These findings indicate that endocardial spiral waves often anchor to anatomic discontinuities causing stable MVT in normal rabbit ventricles. The spiral core is characterized by diminished V(m) and Ca(i) amplitudes and persistent V(m) and Ca(i) elevations during reentry.     

Reentrant waves in a ring of embryonic chick ventricular cells imaged with a Ca2+ sensitive dye

According to the classic model initially formulated by Mines, reentrant cardiac arrhythmias may be associated with waves circulating in a ring geometry. This study was designed to study the dynamics of reentry in a ring geometry of cardiac tissue culture. Reentrant calcium waves in rings of cultured embryonic chick cardiac myocytes were imaged using a macroscope to monitor the fluorescence of intracellular Calcium Green-1 dye. The rings displayed a variety of stable rhythms including pacemaker activity and spontaneous reentry. Waves originating from a localized pacemaker could lead to reentry as a consequence of unidirectional block. In addition, more complex patterns were observed due to the interactions between reentrant and pacemaker rhythms. These rhythms included instances in which pacemakers accelerated the reentrant rhythm, and instances in which the excitation was blocked in the vicinity of pacemakers. During reentrant activity an appropriately timed electrical stimulus could induce resetting of activity or cause complete annihilation of the propagating waves. This experimental preparation reveals many spontaneously occuring complex rhythms. These complex rhythms are hypothesized to reflect interactions between spontaneous pacemakers, wave propagation, refractory period, and overdrive suppression. This preparation may serve as a useful model system to further investigate complex dynamics arising during reentrant rhythms in cardiac 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.     

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.     

Vulnerable window for conduction block in a one-dimensional cable of cardiac cells, 2: multiple extrasystoles

Unidirectional conduction block of premature extrasystoles can lead to initiation of cardiac reentry, causing lethal arrhythmias including ventricular fibrillation. Multiple extrasystoles are often more effective at inducing unidirectional conduction block and reentry than a single extrasystole. Since the substrate for conduction block is spatial dispersion of refractoriness, in this study we investigate how the first extrasystole modulates this dispersion to influence the "vulnerable window" for conduction block by subsequent extrasystoles, particularly in relation to action potential duration restitution and conduction velocity restitution properties. Using a kinematic model to represent wavefront-waveback interactions and simulations with the Luo-Rudy model in a one-dimensional cable of cardiac cells, we show that in homogeneous tissue, a premature extrasystole can create a large dispersion of refractoriness leading to conduction block of a subsequent extrasystole. In heterogeneous tissue, however, a premature extrasystole can either reduce or enhance the dispersion of refractoriness depending on its propagation direction with respect to the previous beat. With multiple extrasystoles at random coupling intervals, vulnerability to conduction block is proportional to their number. In general, steep action potential duration restitution and broad conduction velocity restitution promote dispersion of refractoriness in response to multiple extrasystoles, and thus enhance vulnerability to conduction block. These restitution properties also promote spatially discordant alternans, a setting which is particularly prone to conduction block. The equivalent dispersion of refractoriness created dynamically in homogeneous tissue by spatially discordant alternans is more likely to cause conduction block than a comparable degree of preexisting dispersion in heterogeneous tissue.     

Repolarisation and vulnerability to re-entry in the human heart with short QT syndrome arising from KCNQ1 mutation--a simulation study

Idiopathic short QT syndrome (SQTS) is a recently identified, genetically heterogeneous condition characterised by abbreviated QT intervals and an increased susceptibility to arrhythmia and sudden death. This simulation study identifies mechanisms by which cellular electrophysiological changes in the SQT2 (slow delayed rectifier, I_Ks, -linked) SQTS variant increases arrhythmia risk. The channel kinetics of the V307L mutation of the KCNQ1 subunit of the I_Ks channel were incorporated into human ventricular action potential (AP) models and into 1D and 2D transmural tissue simulations. Incorporating the V307L mutation into simulations reproduced defining features of the SQTS: abbreviation of the QT interval, and increases in T wave amplitude and T_peak–T_end duration. In the single-cell model, the V307L mutation abbreviated ventricular cell AP duration at 90% repolarisation (APD₉₀) and increased the maximal transmural voltage heterogeneity (δV) during APs; this resulted in augmented transmural heterogeneity of APD₉₀ and of the effective refractory period (ERP). In the intact tissue model, the vulnerable window for unidirectional conduction block was also increased. In 2D tissue the V307L mutation facilitated and maintained reentrant excitation. Thus, in SQT2 increases in transmural heterogeneity of APD, δV, ERP and an increased vulnerable window for unidirectional conduction block generate an electrical substrate favourable to reentrant arrhythmia.     

Synchronization of Early Afterdepolarizations and Arrhythmogenesis in Heterogeneous Cardiac Tissue Models

Early afterdepolarizations (EADs) are linked to both triggered arrhythmias and reentrant arrhythmias by causing premature ventricular complexes (PVCs), focal excitations, or heterogeneous tissue substrates for reentry formation. However, a critical number of cells that synchronously exhibit EADs are needed to result in arrhythmia triggers and substrates in tissue. In this study, we use mathematical modeling and computer simulations to investigate EAD synchronization and arrhythmia induction in tissue models with random cell-to-cell variations. Our major observations are as follows. Random cell-to-cell variations in action potential duration without EAD presence do not cause large dispersion of refractoriness in well-coupled tissue. In the presence of phase-2 EADs, the cells may synchronously exhibit the same number of EADs or no EADs with a very small dispersion of refractoriness, or synchronize regionally to result in large dispersion of refractoriness. In the presence of phase-3 EADs, regional synchronization leads to propagating EADs, forming PVCs in tissue. Interestingly, even though the uncoupled cells exhibit either no EAD or only a single EAD, when these cells are coupled to form a tissue, more than one PVC can occur. When the PVCs occur at different locations and time, multifocal arrhythmias are triggered, with the foci shifting in space and time in an irregular manner. The focal arrhythmias either spontaneously terminate or degenerate into reentrant arrhythmias due to heterogeneities and spatiotemporal chaotic dynamics of the foci.     

The pinwheel experiment revisited: effects of cellular electrophysiological properties on vulnerability to cardiac reentry

In normal heart, ventricular fibrillation can be induced by a single properly timed strong electrical or mechanical stimulus. A mechanism first proposed by Winfree and coined the "pinwheel experiment" emphasizes the timing and strength of the stimulus in inducing figure-of-eight reentry. However, the effects of cellular electrophysiological properties on vulnerability to reentry in the pinwheel scenario have not been investigated. In this study, we extend Winfree's pinwheel experiment to show how the vulnerability to reentry is affected by the graded action potential responses induced by a strong premature stimulus, action potential duration (APD), and APD restitution in simulated monodomain homogeneous two-dimensional tissue. We find that a larger graded response, longer APD, or steeper APD restitution slope reduces the vulnerable window of reentry. Strong graded responses and long APD promote tip-tip interactions at long coupling intervals, causing the two initiated spiral wave tips to annihilate. Steep APD restitution promotes wave front-wave back interaction, causing conduction block in the central common pathway of figure-of-eight reentry. We derive an analytical treatment that shows good agreement with numerical simulation results.     

Electrotonic influences on action potential duration dispersion in small hearts: a simulation study

Intrinsic spatial variations in repolarization currents in the heart can produce spatial gradients in action potential duration (APD) that serve as possible sites for conduction block and the initiation of reentrant activity. In well-coupled myocardium, however, electrotonic influences at the stimulus site and wavefront collision sites act to modulate any intrinsic heterogeneity in APD. These effects alter APD gradients over an extent larger than that suggested by the length constant associated with propagation and, thus, are hypothesized to play a greater role in smaller hearts used as experimental models of human disease. This study uses computer simulation to investigate how heart size, tissue properties, and the spatial assignment of cell types affect functional APD dispersion. Simulations were carried out using the murine ventricular myocyte model of Pandit et al. or the Luo-Rudy mammalian model in three-dimensional models of mouse and rabbit ventricular geometries. Results show that the spatial extent of the APD dispersion is related to the dynamic changes in transmembrane resistance during recovery. Also, because of the small dimensions of the mouse heart, electrotonic effects on APD primarily determine the functional dispersion of refractoriness, even in the presence of large intrinsic cellular heterogeneity and reduced coupling. APD dispersion, however, is found to increase significantly when the heart size increases to the size of a rabbit heart, unmasking intrinsic cell types.     

Electrophysiological heterogeneity and stability of reentry in simulated cardiac tissue

Generation of wave break is a characteristic feature of cardiac fibrillation. In this study, we investigated how dynamic factors and fixed electrophysiological heterogeneity interact to promote wave break in simulated two-dimensional cardiac tissue, by using the Luo-Rudy (LR1) ventricular action potential model. The degree of dynamic instability of the action potential model was controlled by varying the maximal amplitude of the slow inward Ca(2+) current to produce spiral waves in homogeneous tissue that were either nearly stable, meandering, hypermeandering, or in breakup regimes. Fixed electrophysiological heterogeneity was modeled by randomly varying action potential duration over different spatial scales to create dispersion of refractoriness. We found that the degree of dispersion of refractoriness required to induce wave break decreased markedly as dynamic instability of the cardiac model increased. These findings suggest that reducing the dynamic instability of cardiac cells by interventions, such as decreasing the steepness of action potential duration restitution, may still have merit as an antifibrillatory strategy.     

Vulnerable window for conduction block in a one-dimensional cable of cardiac cells, 1: single extrasystoles

Spatial dispersion of refractoriness, which is amplified by genetic diseases, drugs, and electrical and structural remodeling during heart disease, is recognized as a major factor increasing the risk of lethal arrhythmias and sudden cardiac death. Dispersion forms the substrate for unidirectional conduction block, which is required for the initiation of reentry by extrasystoles or rapid pacing. In this study, we examine theoretically and numerically how preexisting gradients in refractoriness control the vulnerable window for unidirectional conduction block by a single premature extrasystole. Using a kinematic model to represent wavefront-waveback interactions, we first analytically derived the relationship (under simplified conditions) between the vulnerable window and various electrophysiological parameters such as action potential duration gradients, refractoriness barriers, conduction velocity restitution, etc. We then compared these findings to numerical simulations using the kinematic model or the Luo-Rudy action potential model in a one-dimensional cable of cardiac cells. The results from all three methods agreed well. We show that a critical gradient in action potential duration for conduction block can be analytically derived, and once this critical gradient is exceeded, the vulnerable window increases proportionately with the refractory barrier and is modulated by conduction velocity restitution and gap junctional conductance. Moreover, the critical gradient for conduction block is higher for an extrasystole traveling in the opposite direction from the sinus beat than for one traveling in the same direction (e.g., an epicardial extrasystole versus an endocardial extrasystole).     

Effects of simulated ischemia on spiral wave stability

Regional hyperkalemia during acute myocardial ischemia is a major factor promoting electrophysiological abnormalities leading to ventricular fibrillation (VF). However, steep action potential duration restitution, recently proposed to be a major determinant of VF, is typically decreased rather than increased by hyperkalemia and acute ischemia. To investigate this apparent contradiction, we simulated the effects of regional hyperkalemia and other ischemic components (anoxia and acidosis) on the stability of spiral wave reentry in simulated two-dimensional cardiac tissue by use of the Luo-Rudy ventricular action potential model. We found that the hyperkalemic "ischemic" area promotes wavebreak in the surrounding normal tissue by accelerating the rate of spiral wave reentry, even after the depolarized ischemic area itself has become unexcitable. Furthermore, wavebreak and fibrillation can be prevented if the dynamical instability of the normal tissue is reduced significantly by targeting electrical restitution properties, suggesting a novel therapeutic approach.     

Effects of Na(+) and K(+) channel blockade on vulnerability to and termination of fibrillation in simulated normal cardiac tissue

Na(+) and K(+) channel-blocking drugs have anti- and proarrhythmic effects. Their effects during fibrillation, however, remain poorly understood. We used computer simulation of a two-dimensional (2-D) structurally normal tissue model with phase I of the Luo-Rudy action potential model to study the effects of Na(+) and K(+) channel blockade on vulnerability to and termination of reentry in simulated multiple-wavelet and mother rotor fibrillation. Our main findings are as follows: 1) Na(+) channel blockade decreased, whereas K(+) channel blockade increased, the vulnerable window of reentry in heterogeneous 2-D tissue because of opposing effects on dynamical wave instability. 2) Na(+) channel blockade increased the cycle length of reentry more than it increased refractoriness. In multiple-wavelet fibrillation, Na(+) channel blockade first increased and then decreased the average duration or transient time () of fibrillation. In mother rotor fibrillation, Na(+) channel blockade caused peripheral fibrillatory conduction block to resolve and the mother rotor to drift, leading to self-termination or sustained tachycardia. 3) K(+) channel blockade increased dynamical instability by steepening action potential duration restitution. In multiple-wavelet fibrillation, this effect shortened because of enhanced wave instability. In mother rotor fibrillation, this effect converted mother rotor fibrillation to multiple-wavelet fibrillation, which then could self-terminate. Our findings help illuminate, from a theoretical perspective, the possible underlying mechanisms of termination of different types of fibrillation by antiarrhythmic drugs.     

Electrophysiological and Structural Remodeling in Heart Failure Modulate Arrhythmogenesis. 2D Simulation Study

BackgroundHeart failure is operationally defined as the inability of the heart to maintain blood flow to meet the needs of the body and it is the final common pathway of various cardiac pathologies. Electrophysiological remodeling, intercellular uncoupling and a pro-fibrotic response have been identified as major arrhythmogenic factors in heart failure.ObjectiveIn this study we investigate vulnerability to reentry under heart failure conditions by incorporating established electrophysiological and anatomical remodeling using computer simulations.MethodsThe electrical activity of human transmural ventricular tissue (5 cm×5 cm) was simulated using the human ventricular action potential model Grandi et al. under control and heart failure conditions. The MacCannell et al. model was used to model fibroblast electrical activity, and their electrotonic interactions with myocytes. Selected degrees of diffuse fibrosis and variations in intercellular coupling were considered and the vulnerable window (VW) for reentry was evaluated following cross-field stimulation.ResultsNo reentry was observed in normal conditions or in the presence of HF ionic remodeling. However, defined amount of fibrosis and/or cellular uncoupling were sufficient to elicit reentrant activity. Under conditions where reentry was generated, HF electrophysiological remodeling did not alter the width of the VW. However, intermediate fibrosis and cellular uncoupling significantly widened the VW. In addition, biphasic behavior was observed, as very high fibrotic content or very low tissue conductivity hampered the development of reentry. Detailed phase analysis of reentry dynamics revealed an increase of phase singularities with progressive fibrotic components.ConclusionStructural remodeling is a key factor in the genesis of vulnerability to reentry. A range of intermediate levels of fibrosis and intercellular uncoupling can combine to favor reentrant activity.