Action Potential Duration Gradients Research Articles

Amiodarone prevents wave front-tail interactions in patients with heart failure: an in silico study.

Amiodarone (AM) is an antiarrhythmic drug whose chronic use has proved effective in preventing ventricular arrhythmias in a variety of patient populations, including those with heart failure (HF). AM has both class III [i.e., it prolongs the action potential duration (APD) via blocking potassium channels) and class I (i.e., it affects the rapid sodium channel) properties; however, the specific mechanism(s) by which it prevents reentry formation in patients with HF remains unknown. We tested the hypothesis that AM prevents reentry induction in HF during programmed electrical stimulation (PES) via its ability to induce postrepolarization refractoriness (PRR) via its class I effects on sodium channels. Here we extend our previous human action potential model to represent the effects of both HF and AM separately by calibrating to human tissue and clinical PES data, respectively. We then combine these models (HF + AM) to test our hypothesis. Results from simulations in cells and cables suggest that AM acts to increase PRR and decrease the elevation of takeoff potential. The ability of AM to prevent reentry was studied in silico in two-dimensional sheets in which a variety of APD gradients (ΔAPD) were imposed. Reentrant activity was induced in all HF simulations but was prevented in 23 of 24 HF + AM models. Eliminating the AM-induced slowing of the recovery of inactivation of the sodium channel restored the ability to induce reentry. In conclusion, in silico testing suggests that chronic AM treatment prevents reentry induction in patients with HF during PES via its class I effect to induce PRR.NEW & NOTEWORTHY This work presents a new model of the action potential of the human, which reproduces the complex dynamics during premature stimulation in heart failure patients with and without amiodarone. A specific mechanism of the ability of amiodarone to prevent reentrant arrhythmias is presented.

Sex-specific repolarization heterogeneity in mouse left ventricle: Optical mapping combined with mathematical modeling predict the contribution of specific ionic currents.

Ventricular repolarization shows notable sex-specificity, with female sex being associated with longer QT-intervals in electrocardiography irrespective of the species studied. From a clinical point of view, women are at a greater risk for drug-induced torsade de pointes and symptomatic long-QT syndrome. Here, we present an optical mapping (OM) approach to reveal sex-specific action potential (AP) heterogeneity in a slice preparation of mouse hearts. Left ventricular epicardial repolarization in female versus male mice shows longer and, interindividually, more variable AP duration (APD), yielding a less prominent transmural APD gradient. By combining OM with mathematical modeling, we suggest a significant role of IKto,f and IKur in AP broadening in females. Other transmembrane currents, including INaL , only marginally affect basal APD. As in many cardiac pathophysiologies, increasing [Ca2+ ]i poses a risk for arrhythmia, the response of AP morphology to enhanced activation of L-type calcium channels (LTCC) was assessed in a sex-selective manner. Both APD and its variation increased significantly more in female versus male mice after pharmacological LTCC activation, which we hypothesize to be due to sex-specific INaL expression based on mathematical modeling. Altogether, we demonstrate a more delayed repolarization of LV epicardium, a leveled LV transmural APD gradient, and a more pronounced epicardial APD response to Ca2+ influx in females versus males. Mathematical modeling quantifies the relative contributions of selected ionic currents to sex-specific AP morphology under normal and pathophysiological conditions.

PO-01-205 COMPUTATIONAL MODELING UNCOVERS A UNIFYING MECHANISM LINKING CONDUCTION BLOCK TO VT LOCALIZATION AND STABILITY IN ARRHYTHMOGENIC CARDIOMYOPATHY

We recently showed in a murine model of arrhythmogenic cardiomyopathy (ACM) that VT was driven by discrete rotors deep within the RV. Mechanisms underlying the evolution of these RV-pinned rotors, however, remained unknown considering that the initial wavebreaks that preceded VT were at the LV/RV interface. We hypothesized that the unique spatial action potential duration (APD) profile (RV>LV) in ACM during rapid pacing and adrenergic stimulation, independent of other factors such as structural remodeling, is sufficient to explain the rapid evolution of wavebreaks into discrete rotors that efficiently translocate and stabilize in the RV to maintain VT. We developed 2D virtual sheets of mouse ventricular myocardium using isotropic cellular automaton models with realistic restitution properties that mimic experimentally measured LV to RV APD gradients in wildtype (WT) and ACM hearts (Fig A). VT rotors were induced by burst stimulus trains at increasing frequencies. VT threshold was defined as the duration of the burst stimulus train required to initiate stable VT. Rotors were localized in space and time using phase singularity (PS) analysis. To determine the relationship between spatial APD profile and rotor dynamics, we varied the steepness of the LV-to-RV APD gradient. Once induced, we examined rotor dynamics, speed of rotor drift, meander, stability and dominant frequency (DF). VT threshold was markedly decreased in ACM (2.9s) vs WT (14.5s) reflecting increased vulnerability. VT rotors were more readily induced when stimuli were applied from the zone of short versus long APD. While VT rotors were randomly distributed across homogeneous tissues, PS density analysis revealed exclusive localization of VT rotors within areas of increased APD in heterogeneous tissues (Fig B). Varying the slope of the APD gradient revealed divergent effects on forward drift and DF of VT rotors (Fig C). As the slope of the APD gradient steepened, the velocity of rotor forward drift to the RV increased exponentially while rotor DF decreased in a linear manner consistent with increased stability. Simulation of experimentally measured LV-to-RV APD gradient in ACM caused forward drift of multiple rotors at 2.18cm/sec before pinning within narrow RV loci. The unique spatial APD profile at early stages of ACM is sufficient to explain not only the initiation but also the translocation, dynamics and stability of VT rotors within the RV.

Electrophysiological characterization of a 19-years-old male marathon runner suffering a sudden cardiac death

1 in 50,000 of athletes suffers a cardiac student death (SCD) per year, more of them under 35 years of age. Around 25% of these patients had normal structure, implying that other electrical disorder cause these SCD. Determine the electrophysiological causes of a SCD of a young 19-years-old occurred during a marathon with any heart structural diseases. Pathologic left ventricle (PLV) (n = 1, male, 19-years-old) and control left ventricle (CLV) (n = 1, female, 56-years-old) were perfused and imaged using high resolution optical mapping and Di-4-ANEPPS like a dye. Endocardial and endocardial free wall and his bundle were paced to obtain activation time (AT), repolarization time (RT) and action-potential duration (APD). Purkinje-muscle junctions (PMJs) were determine like activation origins far from the his bundle pacing. Effective refractory period (ERP) was determined using S1S2S3S4 short-coupled pacing. The protocol was repeated after isoplenalie injection [500 nM] like β-adrenergic receptor agonist. His-ventricle activation at high frequency pacing was higher in PLV (143ms) than in control (84ms) and decrease in both at similar levels under ISO (≈60ms). APD gradient increase was observed in PLV near PMJs under ISO (from 3ms/mm to 40ms/mm) and any gradient was observed in the control one. Ectopic episodes were observed in PLV under ISO and 82% of the origins had less that 4 mm of distance with the PMJs. In PLV, the ERP in His-pacing is always lower (320, 260, 250 ms) than endocardial (350, 315, 285 ms) pacing but in CLV, the His-pacing ERP was always higher (320, 260, 240 ms) that endocardial pacing (280, 240, 220 ms). Ventricular fibrillation (VF) was observed in PLV after his bundle pacing at high frequency (more than 330 ms) and any VF was observed in CLV. During this VF, 76% of the focal activities had less than 4 mm of distance with the PMJs. Conduction system (CS) of the PLV shows high sensitivity to high frequency pacing and to presence of ISO. Ectopic episodes and APD gradient near PMJs may show the role of Purkinje network like arrhythmic source. Indeed, the shorter ERP during His-pacing than in the endocardium, give the possibility to produce a macro-re-entry in the conduction system and maintain the arrhythmia with focal activities. CS abnormalities likely played a critical role in arrhythmogenicity and maintenance of VF in this patient during sudden cardiac death.

The interplay of sex-specific electrophysiology and repolarization heterogeneity governs ventricular arrhythmia sustainability in women

Abstract Background The role of sex-specific electrophysiology in the development of lethal ventricular arrhythmia is poorly understood. Since female ventricles have a longer action potential duration (APD) than male ventricles, we hypothesized that female hearts are more vulnerable to sustained ventricular arrhythmia in the presence of known arrhythmogenic substrates. Purpose To determine if prolonged APD in females leads to sustained ventricular arrhythmia in the presence of left ventricular (LV) hypertrophy, diffuse fibrosis, and repolarization heterogeneity. Methods Magnetic resonance imaging (MRI) data were used to develop computational biventricular models of two aortic stenosis patients (male, 54 years; female, 64 years) before (LV hypertrophy) and 3 months after (regressed LV hypertrophy) aortic valve replacement (AVR). These patients were chosen since they exhibit reduced LV mass, less fibrosis, and no ventricular arrhythmias after AVR. The models were assigned sex-specific cellular electrophysiology and an apicobasal repolarization gradient derived from human data. Simulations of apical pacing with a cycle length (CL) of 750 ms were performed while APD at 90% repolarization (APD90) and repolarization time (activation time + APD90) were calculated. Reentrant arrhythmia was induced by rapidly pacing the LV with a 2 mm wide apicobasal line electrode at CL≤265 ms. The simulations were repeated in the presence of diffuse myocardial fibrosis derived from the MRI patient data, and repeated again with an apicobasal repolarization gradient reduced by ≈35%. Ventricular mass was calculated as the product of model volume and myocardial density. Results In hypertrophic ventricles with default apicobasal repolarization gradient, rapid pacing led to reentry that lasted longer in the female (>25 s) than in the male (1.0 s) ventricles. The duration of reentry increased in the presence of fibrosis in the male ventricles (male: 6.6 s; female >25 s) and decreased in the female ventricles when the apicobasal repolarization gradient was reduced (Figure). Sustained reentry (>25 s) was not observed in the ventricles with regressed hypertrophy, regardless of the presence of fibrosis or repolarization gradient. Average APD90 was longer in the female ventricles both before (male: 267±35 ms; female: 318±34 ms) and after (male: 272±35 ms; female: 328±38 ms) AVR. The female heart had lower myocardial mass than the male heart both before (280 vs. 406 g) and after AVR (227 vs. 310 g). Conclusion Longer APD and steeper apicobasal repolarization gradients in hypertrophic female ventricles resulted in sustained arrhythmia, despite their lower mass when compared to males. The absence of sustained reentry in the post-AVR models indicates a potential electrophysiological benefit of AVR and encourages future clinical studies to quantify sex-specific differences in spatial repolarization heterogeneity. Funding Acknowledgement Type of funding sources: Public grant(s) – EU funding. Main funding source(s): European Union's Horizon 2020 research and innovation program under the ERA-NET co-fund action No. 680969 with ANR (ERA-CVD SICVALVES) and Agence Nationale de la Recherche

A computational model of rabbit geometry and ECG: Optimizing ventricular activation sequence and APD distribution.

Computational modeling of electrophysiological properties of the rabbit heart is a commonly used way to enhance and/or complement findings from classic lab work on single cell or tissue levels. Yet, thus far, there was no possibility to extend the scope to include the resulting body surface potentials as a way of validation or to investigate the effect of certain pathologies. Based on CT imaging, we developed the first openly available computational geometrical model not only of the whole heart but also the complete torso of the rabbit. Additionally, we fabricated a 32-lead ECG-vest to record body surface potential signals of the aforementioned rabbit. Based on the developed geometrical model and the measured signals, we then optimized the activation sequence of the ventricles, recreating the functionality of the Purkinje network, and we investigated different apico-basal and transmural gradients in action potential duration. Optimization of the activation sequence resulted in an average root mean square error between measured and simulated signal of 0.074 mV/ms for all leads. The best-fit T-Wave, compared to measured data (0.038 mV/ms), resulted from incorporating an action potential duration gradient from base to apex with a respective shortening of 20 ms and a transmural gradient with a shortening of 15 ms from endocardium to epicardium. By making our model and measured data openly available, we hope to give other researchers the opportunity to verify their research, as well as to create the possibility to investigate the impact of electrophysiological alterations on body surface signals for translational research.

P532Endocardial pacing is less arrhythmogenic than conventional epicardial pacing when pacing in proximity to scar in patients with ischemic heart failure

Abstract Funding Acknowledgements WT 203148/Z/16/Z; MR/N011007/1; RE/08/003; PG/15/91/31812; PG/16/81/32441 Background Endocardial pacing has been shown to improve response to cardiac resynchronization therapy (CRT) in comparison to conventional epicardial pacing and the physiological activation, endocardium to epicardium, is proposed to make it less arrhythmogenic. However, the relative arrhythmic risk of endocardial and epicardial pacing has not been systematically investigated. Pacing in proximity to scar increases susceptibility to arrhythmogenesis during epicardial pacing. Whether this is also the case during endocardial pacing is currently unknown. Purpose We investigate 1) whether endocardial pacing is less arrhythmogenic than epicardial pacing, 2) whether pacing location relative to scar plays a role in arrhythmogenesis during endocardial pacing, and 3) whether these findings could be explained by the direction of the transmural action potential duration (APD) gradient. Methods We used computational models of ischemic heart failure and patient-specific (n = 24) left ventricular anatomy and scar morphology to simulate repolarization during endocardial and epicardial pacing. Pacing locations were selected 0.2-3.5cm from a scar. We ran simulations with a 20ms transmural APD gradient, as found in heart failure, from the epicardium to endocardium (physiological) and with this gradient inverted. We computed the volume of high (>3ms/mm) repolarization gradients (HRG) within 1cm around a scar, as a surrogate for arrhythmia risk, and analysed these with ANOVA and Tukey-Kramer post-hoc tests. Results Simulations with a physiological APD gradient predict that endocardial pacing creates a smaller (34%) volume of HRG around (1cm) a scar compared to epicardial pacing when pacing 0.2cm from scar (Figure 1-A). The volume of HRG decreases (P < 0.05) with distance from scar for epicardial pacing but not endocardial pacing (Figure 1-A). Inverting the transmural APD gradient, inverts the trend observed with a physiological gradient. In this case, the volume of HRG is unaffected by pacing location during epicardial pacing, whereas it decreases (19%) with the distance from scar for endocardial pacing. This is illustrated in the regions highlighted in yellow in Figure 1 for endocardial pacing at 0.2 and 3.5cm from a scar with a physiological (B) and an inverted (C) gradient. Conclusions Endocardial pacing is less arrhythmogenic (purpose 1) than conventional epicardial pacing when pacing in proximity to scar and is also less susceptible to pacing location relative to scar (purpose 2). The direction of the transmural APD gradient offers a mechanistic explanation for reduced susceptibility to arrhythmogenesis during endocardial pacing compared to epicardial pacing (purpose 3). Endocardial pacing is an attractive alternative to conventional epicardial pacing in patients with scar, as it allows pacing in proximity to scar while avoiding increasing arrhythmogenic risk in patients with ischemic heart failure. Abstract Figure.

Left ventricular endocardial pacing is less arrhythmogenic than conventional epicardial pacing when pacing in proximity to scar

BackgroundEpicardial pacing increases risk of ventricular tachycardia (VT) in patients with ischemic cardiomyopathy (ICM) when pacing in proximity to scar. Endocardial pacing may be less arrhythmogenic as it preserves the physiological sequences of activation and repolarization.ObjectiveThe purpose of this study was to determine the relative arrhythmogenic risk of endocardial compared to epicardial pacing, and the role of the transmural gradient of action potential duration (APD) and pacing location relative to scar on arrhythmogenic risk during endocardial pacing.MethodsComputational models of ICM patients (n = 24) were used to simulate left ventricular (LV) epicardial and endocardial pacing 0.2–3.5 cm from a scar. Mechanisms were investigated in idealized models of the ventricular wall and scar. Simulations were run with/without a 20-ms transmural APD gradient in the physiological direction and with the gradient inverted. Dispersion of repolarization was computed as a surrogate of VT risk.ResultsPatient-specific models with a physiological APD gradient predict that endocardial pacing decreases VT risk (34%; P <.05) compared to epicardial pacing when pacing in proximity to scar (0.2 cm). Endocardial pacing location does not significantly affect VT risk, but epicardial pacing at 0.2 cm compared to 3.5 cm from scar increases it (P <.05). Inverting the transmural APD gradient reverses this trend. Idealized models predict that propagation in the direction opposite to APD gradient decreases VT risk.ConclusionEndocardial pacing is less arrhythmogenic than epicardial pacing when pacing proximal to scar and is less susceptible to pacing location relative to scar. The physiological repolarization sequence during endocardial pacing mechanistically explains reduced VT risk compared to epicardial pacing.

The Effects of Mechanical Preload on Transmural Differences in Mechano-Calcium-Electric Feedback in Single Cardiomyocytes: Experiments and Mathematical Models.

Transmural differences in ventricular myocardium are maintained by electromechanical coupling and mechano-calcium/mechano-electric feedback. In the present study, we experimentally investigated the influence of preload on the force characteristics of subendocardial (Endo) and subepicardial (Epi) single ventricular cardiomyocytes stretched by up to 20% from slack sarcomere length (SL) and analyzed the results with the help of mathematical modeling. Mathematical models of Endo and Epi cells, which accounted for regional heterogeneity in ionic currents, Ca2+ handling, and myofilament contractile mechanisms, showed that a greater slope of the active tension–length relationship observed experimentally in Endo cardiomyocytes could be explained by greater length-dependent Ca2+ activation in Endo cells compared with Epi ones. The models also predicted that greater length dependence of Ca2+ activation in Endo cells compared to Epi ones underlies, via mechano-calcium-electric feedback, the reduction in the transmural gradient in action potential duration (APD) at a higher preload. However, the models were unable to reproduce the experimental data on a decrease of the transmural gradient in the time to peak contraction between Endo and Epi cells at longer end-diastolic SL. We hypothesize that preload-dependent changes in viscosity should be involved alongside the Frank–Starling effects to regulate the transmural gradient in length-dependent changes in the time course of contraction of Endo and Epi cardiomyocytes. Our experimental data and their analysis based on mathematical modeling give reason to believe that mechano-calcium-electric feedback plays a critical role in the modulation of electrophysiological and contractile properties of myocytes across the ventricular wall.

A model for human action potential dynamics in vivo

Computational modeling based on experimental data remains an important component in cardiac electrophysiological research, especially because clinical data such as human action potential (AP) dynamics are scarce or limited by practical or ethical concerns. Such modeling has been used to develop and test a variety of mechanistic hypotheses, with the majority of these studies involving the rate dependence of AP duration (APD) including APD restitution and conduction velocity (CV). However, there is very little information regarding the complex dynamics at the boundary of repolarization (or refractoriness) and reexcitability. Here, we developed a "minimal" ionic model of the human AP, based on in vivo human monophasic AP (MAP) recordings obtained during clinical programmed electrical stimulation (PES) to address the progressive decrease in AP take-off potential (TOP) and associated CV slowing seen during three tightly spaced extrastimuli. Recent voltage-clamp data demonstrating the effect of intracellular calcium on sodium current availability were incorporated and were required to reproduce large (>15 mV) elevations in take-off potential and progressive encroachment. Introducing clinically observed APD gradients into the model enabled us to replicate the dynamic response to PES in patients leading to conduction block and reentry formation for the positive, but not the negative, APD gradient. Finally, we modeled the dynamics of reentry and show that spiral waves follow a meandering trajectory with a period of ~180 ms. We conclude that our model reproduces a variety of electrophysiological behavior including the response to sequential premature stimuli and provides a basis for studies of the initiation of reentry in human ventricular tissue.NEW & NOTEWORTHY This work presents a new model of the action potential of the human which reproduces the complex dynamics during premature stimulation in patients.

Intra-tracheal gene delivery of aerosolized SERCA2a to the lung suppresses ventricular arrhythmias in a model of pulmonary arterial hypertension

BackgroundPulmonary arterial hypertension (PAH) results in right ventricular (RV) failure, electro-mechanical dysfunction and heightened risk of sudden cardiac death (SCD), although exact mechanisms and predisposing factors remain unclear. Because impaired chronotropic response to exercise is a strong predictor of early mortality in patients with PAH, we hypothesized that progressive elevation in heart rate can unmask ventricular tachyarrhythmias (VT) in a rodent model of monocrotaline (MCT)-induced PAH. We further hypothesized that intra-tracheal gene delivery of aerosolized AAV1.SERCA2a (AAV1.S2a), an approach which improves pulmonary vascular remodeling in PAH, can suppress VT in this model. ObjectiveTo determine the efficacy of pulmonary AAV1.S2a in reversing electrophysiological (EP) remodeling and suppressing VT in PAH. MethodsMale rats received subcutaneous injection of MCT (60 mg/kg) leading to advanced PAH. Three weeks following MCT, rats underwent intra-tracheal delivery of aerosolized AAV1.S2a (MCT + S2a, N = 8) or saline (MCT, N = 9). Age-matched rats served as controls (CTRL, N = 7). The EP substrate and risk of VT were determined using high-resolution optical action potential (AP) mapping ex vivo. The expression levels of key ion channel subunits, fibrosis markers and hypertrophy indices were measured by RT-PCR and histochemical analyses. ResultsOver 80% of MCT but none of the CTRL hearts were prone to sustained VT by rapid pacing (P < .01). Aerosolized gene delivery of AAV1.S2a to the lung suppressed the incidence of VT to <15% (P < .05). Investigation of the EP substrate revealed marked prolongation of AP duration (APD), increased APD heterogeneity, a reversal in the trans-epicardial APD gradient, and marked conduction slowing in untreated MCT compared to CTRL hearts. These myocardial EP changes coincided with major remodeling in the expression of K and Ca channel subunits, decreased expression of Cx43 and increased expression of pro-fibrotic and pro-hypertrophic markers. Intra-tracheal gene delivery of aerosolized AAV1 carrying S2a but not luciferase resulted in selective upregulation of the human isoform of SERCA2a in the lung but not the heart. This pulmonary intervention, in turn, ameliorated MCT-induced APD prolongation, reversed spatial APD heterogeneity, normalized myocardial conduction, and suppressed the incidence of pacing-induced VT. Comparison of the minimal conduction velocity (CV) generated at the fastest pacing rate before onset of VT or at the end of the protocol revealed significantly lower values in untreated compared to AAV1.S2a treated PAH and CTRL hearts. Reversal of EP remodeling by pulmonary AAV1.S2a gene delivery was accompanied by restored expression of key ion channel transcripts. Restored expression of Cx43 and collagen but not the pore-forming Na channel subunit Nav1.5 likely ameliorated VT by improving CV at rapid rates in PAH. ConclusionAerosolized AAV1.S2a gene delivery selectively to the lungs ameliorates myocardial EP remodeling and VT susceptibility at rapid heart rates. Our findings highlight for the first time the utility of a non-cardiac gene therapy approach for arrhythmia suppression.

Wavelength and Fibrosis Affect Phase Singularity Locations During Atrial Fibrillation.

The mechanisms underlying atrial fibrillation (AF), the most common sustained cardiac rhythm disturbance, remain elusive. Atrial fibrosis plays an important role in the development of AF and rotor dynamics. Both electrical wavelength (WL) and the degree of atrial fibrosis change as AF progresses. However, their combined effect on rotor core location remains unknown. The aim of this study was to analyze the effects of WL change on rotor core location in both fibrotic and non-fibrotic atria. Three patient specific fibrosis distributions (total fibrosis content: 16.6, 22.8, and 19.2%) obtained from clinical imaging data of persistent AF patients were incorporated in a bilayer atrial computational model. Fibrotic effects were modeled as myocyte-fibroblast coupling + conductivity remodeling; structural remodeling; ionic current changes + conductivity remodeling; and combinations of these methods. To change WL, action potential duration (APD) was varied from 120 to 240ms, representing the range of clinically observed AF cycle length, by modifying the inward rectifier potassium current (IK1) conductance between 80 and 140% of the original value. Phase singularities (PSs) were computed to identify rotor core locations. Our results show that IK1 conductance variation resulted in a decrease of APD and WL across the atria. For large WL in the absence of fibrosis, PSs anchored to regions with high APD gradient at the center of the left atrium (LA) anterior wall and near the junctions of the inferior pulmonary veins (PVs) with the LA. Decreasing the WL induced more PSs, whose distribution became less clustered. With fibrosis, PS locations depended on the fibrosis distribution and the fibrosis implementation method. The proportion of PSs in fibrotic areas and along the borders varied with both WL and fibrosis modeling method: for patient one, this was 4.2–14.9% as IK1 varied for the structural remodeling representation, but 12.3–88.4% using the combination of structural remodeling with myocyte-fibroblast coupling. The degree and distribution of fibrosis and the choice of implementation technique had a larger effect on PS locations than the WL variation. Thus, distinguishing the fibrotic mechanisms present in a patient is important for interpreting clinical fibrosis maps to create personalized models.

Compartmentalized Structure of the Moderator Band Provides a Unique Substrate for Macroreentrant Ventricular Tachycardia

Background Papillary muscles are an important source of ventricular tachycardia (VT). Yet little is known about the role of the right ventricular (RV) endocavity structure, the moderator band (MB). The aim of this study was to determine the characteristics of the MB that may predispose to arrhythmia substrates. Methods Ventricular wedge preparations with intact MBs were studied from humans (n=2) and sheep (n=15; 40-50 kg). RV endocardium was optically mapped, and electrical recordings were measured along the MB and septum. S1S2 pacing of the RV free wall, MB, or combined S1-RV S2-MB sites were assessed. Human (n=2) and sheep (n=4) MB tissue constituents were assessed histologically. Results The MB structure was remarkably organized as 2 excitable, yet uncoupled compartments of myocardium and Purkinje. In humans, action potential duration heterogeneity between MB and RV myocardium was found (324.6±12.0 versus 364.0±8.4 ms; P<0.0001). S1S2-MB pacing induced unidirectional propagation via MB myocardium, permitting sustained macroreentrant VT. In sheep, the incidence of VT for RV, MB, and S1-RV S2-MB pacing was 1.3%, 5.1%, and 10.3%. Severing the MB led to VT termination, confirming a primary arrhythmic role. Inducible preparations had shorter action potential duration in the MB than RV (259.3±45.2 versus 300.7±38.5 ms; P<0.05), whereas noninducible preparations showed no difference (312.0±30.3 versus 310.0±24.6 ms, respectively). Conclusions The MB presents anatomic and electrical compartmentalization between myocardium and Purkinje fibers, providing a substrate for macroreentry. The vulnerability to sustain VT via this mechanism is dependent on MB structure and action potential duration gradients between the RV free wall and MB.

Role of the Purkinje-Muscle Junction on the Ventricular Repolarization Heterogeneity in the Healthy and Ischemic Ovine Ventricular Myocardium.

Alteration of action potential duration (APD) heterogeneity contributes to arrhythmogenesis. Purkinje-muscle junctions (PMJs) present differential electrophysiological properties including longer APD. The goal of this study was to determine if Purkinje-related or myocardial focal activation modulates ventricular repolarization differentially in healthy and ischemic myocardium. Simultaneous epicardial (EPI) and endocardial (ENDO) optical mapping was performed on sheep left ventricular (LV) wedges with intact free-running Purkinje network (N = 7). Preparations were paced on either ENDO or EPI surfaces, or the free-running Purkinje fibers (PFs), mimicking normal activation. EPI and ENDO APDs were assessed for each pacing configuration, before and after (7 min) of the onset of no-flow ischemia. Experiments were supported by simulations. In control conditions, maximal APD was found at endocardial PMJ sites. We observed a significant transmural APD gradient for PF pacing with PMJ APD = 347 ± 41 ms and EPI APD = 273 ± 36 ms (p < 0.001). A similar transmural gradient was observed when pacing ENDO (49 ± 31 ms; p = 0.005). However, the gradient was reduced when pacing EPI (37 ± 20 ms; p = 0.005). Global dispersion of repolarization was the most pronounced for EPI pacing. In ischemia, both ENDO and EPI APD were reduced (p = 0.005) and the transmural APD gradient (109 ± 55 ms) was increased when pacing ENDO compared to control condition or when pacing EPI (p < 0.05). APD maxima remained localized at functional PMJs during ischemia. Local repolarization dispersion was significantly higher at the PMJ than at other sites. The results were consistent with simulations. We found that the activation sequence modulates repolarization heterogeneity in the ischemic sheep LV. PMJs remain active following ischemia and exert significant influence on local repolarization patterns.

Mechanisms linking T-wave alternans to spontaneous initiation of ventricular arrhythmias in rabbit models of long QT syndrome.

T-wave alternans (TWA) and T-wave lability (TWL) are precursors of ventricular arrhythmias in long QT syndrome; however, the mechanistic link remains to be clarified. Computer simulations show that action potential duration (APD) prolongation and slowed heart rates promote APD alternans and chaos, manifesting as TWA and TWL, respectively. Regional APD alternans and chaos can exacerbate pre-existing or induce de novo APD dispersion, which combines with enhanced ICa,L to result in premature ventricular complexes (PVCs) originating from the APD gradient region. These PVCs can directly degenerate into re-entrant arrhythmias without the need for an additional tissue substrate or further exacerbate the APD dispersion to cause spontaneous initiation of ventricular arrhythmias. Experiments conducted in transgenic long QT rabbits show that PVC alternans occurs at slow heart rates, preceding spontaneous intuition of ventricular arrhythmias. T-wave alternans (TWA) and irregular beat-to-beat T-wave variability or T-wave lability (TWL), the ECG manifestations of action potential duration (APD) alternans and variability, are precursors of ventricular arrhythmias in long QT syndromes. TWA and TWL in patients tend to occur at normal heart rates and are usually potentiated by bradycardia. Whether or how TWA and TWL at normal or slow heart rates are causally linked to arrhythmogenesis remains unknown. In the present study, we used computer simulations and experiments of a transgenic rabbit model of long QT syndrome to investigate the underlying mechanisms. Computer simulations showed that APD prolongation and slowed heart rates caused early afterdepolarization-mediated APD alternans and chaos, manifesting as TWA and TWL, respectively. Regional APD alternans and chaos exacerbated pre-existing APD dispersion and, in addition, APD chaos could also induce APD dispersion de novo via chaos desynchronization. Increased APD dispersion, combined with substantially enhanced ICa,L , resulted in a tissue-scale dynamical instability that gave rise to the spontaneous occurrence of unidirectionally propagating premature ventricular complexes (PVCs) originating from the APD gradient region. These PVCs could directly degenerate into re-entrant arrhythmias without the need for an additional tissue substrate or could block the following sinus beat to result in a longer RR interval, which further exacerbated the APD dispersion giving rise to the spontaneous occurrence of ventricular arrhythmias. Slow heart rate-induced PVC alternans was observed in experiments of transgenic LQT2 rabbits under isoproterenol, which was associated with increased APD dispersion and spontaneous occurrence of ventricular arrhythmias, in agreement with the theoretical predictions.

Chronic intermittent hypoxia promotes myocardial ischemia-related ventricular arrhythmias and sudden cardiac death

We investigated the effects of intermittent hypoxia (IH), such as that encountered in severe obstructive sleep apnea (OSA) patients, on the development and severity of myocardial ischemia-related ventricular arrhythmias. Rats were exposed to 14 days of IH (30 s at 5%O2 and 30 s at 21%O2, 8 h·day−1) or normoxia (N, similar air-air cycles) and submitted to a 30-min coronary ligature. Arterial blood pressure (BP) and ECG were recorded for power spectral analysis, ECG interval measurement and arrhythmia quantification. Left ventricular monophasic action potential duration (APD) and expression of L-type calcium (LTCC) and transient receptor potential (TRPC) channels were assessed in adjacent epicardial and endocardial sites. Chronic IH enhanced the incidence of ischemic arrhythmias, in particular ventricular fibrillation (66.7% vs. 33.3% in N rats, p < 0.05). IH also increased BP and plasma norepinephine levels along with increased low-frequency (LF), decreased high-frequency (HF) and increased LF/HF ratio of heart rate and BP variability. IH prolonged QTc and Tpeak-to-Tend intervals, increased the ventricular APD gradient and upregulated endocardial but not epicardial LTCC, TRPC1 and TRPC6 (p < 0.05). Chronic IH, is a major risk factor for sudden cardiac death upon myocardial ischemia through sympathoactivation and alterations in ventricular repolarization, transmural APD gradient and endocardial calcium channel expression.

Oxidative Stress Remodeling of Zebrafish Cardiac Electrical Gradients

In mammalian hearts, electrical gradients ensure well-orchestrated electrical stability and mechanical efficiency under physiological baseline. Regional heterogeneities of ion channels and/or calcium handling proteins establish gradients of activation, action potential duration (APD), and repolarization that are protective at baseline, but susceptible to disruptive remodeling in myocardial injuries and failure. However, in zebrafish hearts, physiological electrical gradients are unexplored. Considering the important application of zebrafish hearts in high-throughput screening for drug-induced cardiotoxicities (such as QT prolongation) and the role of the apicobasal APD and repolarization gradients in the inscription of the T wave and the QT interval, this study investigates the apicobasal electrical gradients in normal adult zebrafish and the arrhythmogenic impact of acute H2O2-induced oxidative stress. Following epicardial optical mapping of intact zebrafish hearts, apicobasal gradients of activation, repolarization, and APD under normal baseline vs. oxidative stress (H2O2, 100 μmol/L) condition were determined. At baseline, an apicobasal APD90 gradient was evident with longer APD90 in the apex due to earlier activation and later repolarization compared to the base (apex 198 ± 23 > base 121 ± 13 ms, n=5; P<0.0004). Acute H2O2 challenge abolished or reversed the apicobasal APD gradient and prolonged both apical and basal APDs (apex 352 ± 86 < base 401 ± 37 ms, n=4; NS). However, H2O2 remodeling impact was regionally heterogeneous, affecting the base more than apex. H2O2 impaired repolarization and induced occasional early after depolarizations and trigger activity. Given that the apicobasal APD and repolarization gradients in normal zebrafish are reverse those in normal humans, one should exert caution when extrapolating drug-induced QT prolongation in zebrafish to humans. Nonetheless, based on the human-like arrhythmogenic response of the zebrafish heart to acute H2O2 challenge, zebrafish constitutes a relevant model to investigate repolarization disorders associated with oxidative stress.

Fitting local repolarization parameters in cardiac reaction-diffusion models in the presence of electrotonic coupling

Background: Repolarization gradients contribute to arrhythmogenicity. In reaction–diffusion models of cardiac tissue, heterogeneities in action potential duration (APD) can be created by locally modifying an intrinsic membrane kinetics parameter. Electrotonic coupling, however, acts as a confounding factor that modulates APD dispersion.Method: We developed an algorithm based on a quasi-Newton method that iteratively adjusts the spatial distribution of a membrane parameter to reproduce a pre-defined target APD map in a coupled tissue. The method assumes that the relation between the adjustable parameter and APD is bijective in an isolated cell. Each iteration of the algorithm involved simulating the cardiac reaction–diffusion system with the updated parameter profile for one beat and extracting the APD map. The algorithm was extended to simultaneous estimation of two parameter profiles based on two APD maps at different repolarization thresholds.Results: The method was validated in 1D, 2D and 3D atrial tissues using synthetic target APD maps with controllable total variation and maximum APD gradient. The adjustable parameter was local acetylcholine concentration. The iterations converged provided that APD gradients were not too steep. Convergence was found to be faster 2–5 iterations) when the maximal gradient was less steep, when APD range was smaller and when tissue conductivity was reduced.Conclusion: This algorithm provides a tool to automatically generate arrhythmogenic substrates with controllable repolarization gradients and possibly incorporate experimental APD maps into computer models.

Proarrhythmic remodelling of the right ventricle in a porcine model of repaired tetralogy of Fallot

ObjectiveThe growing adult population with surgically corrected tetralogy of Fallot (TOF) is at risk of arrhythmias and sudden cardiac death. We sought to investigate the contribution of right ventricular (RV)...

Electrophysiology of Heart Failure Using a Rabbit Model: From the Failing Myocyte to Ventricular Fibrillation.

Heart failure is a leading cause of death, yet its underlying electrophysiological (EP) mechanisms are not well understood. In this study, we use a multiscale approach to analyze a model of heart failure and connect its results to features of the electrocardiogram (ECG). The heart failure model is derived by modifying a previously validated electrophysiology model for a healthy rabbit heart. Specifically, in accordance with the heart failure literature, we modified the cell EP by changing both membrane currents and calcium handling. At the tissue level, we modeled the increased gap junction lateralization and lower conduction velocity due to downregulation of Connexin 43. At the biventricular level, we reduced the apex-to-base and transmural gradients of action potential duration (APD). The failing cell model was first validated by reproducing the longer action potential, slower and lower calcium transient, and earlier alternans characteristic of heart failure EP. Subsequently, we compared the electrical wave propagation in one dimensional cables of healthy and failing cells. The validated cell model was then used to simulate the EP of heart failure in an anatomically accurate biventricular rabbit model. As pacing cycle length decreases, both the normal and failing heart develop T-wave alternans, but only the failing heart shows QRS alternans (although moderate) at rapid pacing. Moreover, T-wave alternans is significantly more pronounced in the failing heart. At rapid pacing, APD maps show areas of conduction block in the failing heart. Finally, accelerated pacing initiated wave reentry and breakup in the failing heart. Further, the onset of VF was not observed with an upregulation of SERCA, a potential drug therapy, using the same protocol. The changes introduced at the cell and tissue level have increased the failing heart’s susceptibility to dynamic instabilities and arrhythmias under rapid pacing. However, the observed increase in arrhythmogenic potential is not due to a steepening of the restitution curve (not present in our model), but rather to a novel blocking mechanism.