Action Potential Duration Restitution Curve Research Articles

Abstract 454: Plasticizer Interaction With the Heart: Chemicals Used in Plastic Medical Devices Can Interfere With Cardiac Electrophysiology

Background: Phthalates are employed as plasticizers in the manufacturing of flexible, plastic medical products. Patients can be subjected to high phthalate exposure through contact with plastic medical devices. We aimed to investigate the cardiac safety and biocompatibility of mono-2-ethylhexyl phthalate (MEHP), a phthalate with documented exposure in intensive care patients. Methods and Results: Optical mapping of transmembrane voltage and pacing studies were performed on isolated, Langendorff-perfused rat hearts to assess cardiac electrophysiology after MEHP exposure compared with controls. MEHP dose was chosen based on reported blood concentrations following an exchange transfusion procedure. 30-min exposure to MEHP increased the atrioventricular node (147 vs. 107msec) and ventricular (117 vs. 77.5msec) effective refractory periods, compared with controls. Optical mapping revealed prolonged action potential duration (APD) at slower pacing cycle lengths, akin to reverse use-dependence. The plateau phase of the APD restitution curve steepened and became monophasic in MEHP-exposed hearts (0.18 vs. 0.06 slope). APD lengthening occurred during late-phase repolarization resulting in triangulation (70.3 vs. 56.6 msec). MEHP-exposure also slowed epicardial conduction velocity (35 vs. 60 cm/sec), which may be partly explained by inhibition of Na v 1.5 (874 μM and 231 μM IC50, fast and late sodium current). Conclusions: This study highlights the impact of acute MEHP exposure, using a clinically-relevant dose, on cardiac electrophysiology in the intact heart. Heightened clinical exposure to plasticized medical products may have cardiac safety implications – given that action potential triangulation and electrical restitution modifications are a risk factor for early after depolarizations and cardiac arrhythmias.

Plasticizer Interaction With the Heart: Chemicals Used in Plastic Medical Devices Can Interfere With Cardiac Electrophysiology.

Background:Phthalates are used as plasticizers in the manufacturing of flexible, plastic medical products. Patients can be subjected to high phthalate exposure through contact with plastic medical devices. We aimed to investigate the cardiac safety and biocompatibility of mono-2-ethylhexyl phthalate (MEHP), a phthalate with documented exposure in intensive care patients.Methods:Optical mapping of transmembrane voltage and pacing studies were performed on isolated, Langendorff-perfused rat hearts to assess cardiac electrophysiology after MEHP exposure compared with controls. MEHP dose was chosen based on reported blood concentrations after an exchange transfusion procedure.Results:Thirty-minute exposure to MEHP increased the atrioventricular node (147 versus 107 ms) and ventricular (117 versus 77.5 ms) effective refractory periods, compared with controls. Optical mapping revealed prolonged action potential duration at slower pacing cycle lengths, akin to reverse use dependence. The plateau phase of the action potential duration restitution curve steepened and became monophasic in MEHP-exposed hearts (0.18 versus 0.06 slope). Action potential duration lengthening occurred during late-phase repolarization resulting in triangulation (70.3 versus 56.6 ms). MEHP exposure also slowed epicardial conduction velocity (35 versus 60 cm/s), which may be partly explained by inhibition of Nav1.5 (874 and 231 µmol/L half-maximal inhibitory concentration, fast and late sodium current).Conclusions:This study highlights the impact of acute MEHP exposure, using a clinically relevant dose, on cardiac electrophysiology in the intact heart. Heightened clinical exposure to plasticized medical products may have cardiac safety implications—given that action potential triangulation and electrical restitution modifications are a risk factor for early after depolarizations and cardiac arrhythmias.

Interventricular Differences in Action Potential Duration Restitution Contribute to Dissimilar Ventricular Rhythms in ex vivo Perfused Hearts.

Background: Dissimilar ventricular rhythms refer to the occurrence of different ventricular tachyarrhythmias in the right and left ventricles or different rates of the same tachyarrhythmia in the two ventricles.Objective: We investigated the inducibility of dissimilar ventricular rhythms, their underlying mechanisms, and the impact of anti-arrhythmic drugs (lidocaine and amiodarone) on their occurrence.Methods: Ventricular tachyarrhythmias were induced with burst pacing in 28 Langendorff-perfused Sprague Dawley rat hearts (14 control, 8 lidocaine, 6 amiodarone) and bipolar electrograms recorded from the right and left ventricles. Fourteen (6 control, 4 lidocaine, 4 amiodarone) further hearts underwent optical mapping of transmembrane voltage to study interventricular electrophysiological differences and mechanisms of dissimilar rhythms.Results: In control hearts, dissimilar ventricular rhythms developed in 8/14 hearts (57%). In lidocaine treated hearts, there was a lower cycle length threshold for developing dissimilar rhythms, with 8/8 (100%) hearts developing dissimilar rhythms in comparison to 0/6 in the amiodarone group. Dissimilar ventricular tachycardia (VT) rates occurred at longer cycle lengths with lidocaine vs. control (57.1 ± 7.9 vs. 36.6 ± 8.4 ms, p < 0.001). The ratio of LV:RV VT rate was greater in the lidocaine group than control (1.91 ± 0.30 vs. 1.76 ± 0.36, p < 0.001). The gradient of the action potential duration (APD) restitution curve was shallower in the RV compared with LV (Control - LV: 0.12 ± 0.03 vs RV: 0.002 ± 0.03, p = 0.015), leading to LV-to-RV conduction block during VT.Conclusion: Interventricular differences in APD restitution properties likely contribute to the occurrence of dissimilar rhythms. Sodium channel blockade with lidocaine increases the likelihood of dissimilar ventricular rhythms.

The effects of interleukin 17A on left stellate ganglion remodeling are mediated by neuroimmune communication in normal structural hearts

BackgroundIt is reported interleukin (IL)-17A, a classical proinflammatory cytokine, is implicated in neuroimmune-associated remodeling in neural plasticity and pathological conditions. However, the effect of IL-17A on left stellate ganglion (LSG) remodeling remains unclear. ObjectiveThis study was performed to determine whether exogenous IL-17A promotes LSG remodeling and destabilize ventricular electrophysiological properties (EPs) in normal canines. Methods24 beagles were randomly allocated into three groups. In the first group, animals were subjected to 0.1 ml phosphate buffer saline (PBS) microinjection of into LSG (n = 8), an equivalent IL-17A was administrated in the second group (n = 8), and an equivalent anti-IL-17A mAb plus IL-17A was administrated in the third group (n = 8). The ventricular EPs, neural function and activity of the LSG were determined at baseline and 30 min after administration. In the end, LSG tissues were collected. ResultsCompared with the control group, the experimental group had a significantly shorter effective refractory period (ERP) and action potential duration (APD)90, an increased ERP, APD90, Smax dispersion, and APD alternans cycle length; and steepened APD restitution curves. In addition, IL-17A enhanced the neural function and activity of the LSG, upregulated the expressions of neuropeptides and proinflammatory cytokines and cells. And all these effects were attenuated by anti-IL-17A mAb. Importantly, IL-17 receptor A (IL-17R-A) was detected in sympathetic neurons in the LSG. ConclusionIL-17A promoted LSG remodeling by regulating the neural inflammation response. It did so by binding to IL-17R-A, resulting in unstable ventricular electrophysiology in normal structural hearts.

Vagus nerve stimulation reduces ventricular arrhythmias and increases ventricular electrical stability.

Transcutaneous stimulation of the auricular branch of the vagus nerve (AB-VNS) is a potentially noninvasive, inexpensive, and safe approach for vagus nerve stimulation that suppresses the induction and duration of atrial fibrillation and reduces sympathetic nerve outflow in healthy humans. Researchers have not determined whether AB-VNS affects ventricular arrhythmias. To evaluate the antiarrhythmic effects of noninvasive AB-VNS on ventricular arrhythmias induced by myocardial infarction (MI). Twelve beagle dogs were randomly divided into the following two groups: a AB-VNS group (coronary artery occlusion and noninvasive AB-VNS) and a control group (coronary artery occlusion but without AB-VNS). We examined spontaneous ventricular arrhythmias, ventricular electrophysiological properties, and cardiac function in conscious dogs. Morphology, fibrosis, and ultrastructures were also assessed. AB-VNS significantly reduced the occurrence of spontaneous ventricular arrhythmias, including isolated premature ventricular complexes, ventricular couplets, ventricular bigeminy, ventricular trigeminy, and ventricular tachycardia. AB-VNS effectively increased ventricular electrical stability, including significantly prolonged ventricular effective refractory periods, decreased the dispersion of effective refractory period, enhanced the ventricular fibrillation threshold, and decreased the maximum slope of the monophasic action potential duration restitution curve. AB-VNS treatments alleviate ventricular interstitial fibrosis after MI. However, cardiac function was not improved, and MI-induced ultrastructural changes in the myocardium were not reversed by 4weeks of AB-VNS. In addition, AB-VNS for 4weeks resulted in mild mitochondrial swelling within the neuronal axons of the auricular vagus fiber. Noninvasive AB-VNS reduces the occurrence of spontaneous ventricular arrhythmias in conscious dogs with MI. AB-VNS increases ventricular electrical stability and alleviates ventricular interstitial fibrosis induced by MI.

Transient outward K+ current can strongly modulate action potential duration and initiate alternans in the human atrium.

Efforts to identify the mechanisms for the initiation and maintenance of human atrial fibrillation (AF) often focus on changes in specific elements of the atrial "substrate," i.e., its electrophysiological properties and/or structural components. We used experimentally validated mathematical models of the human atrial myocyte action potential (AP), both at baseline in sinus rhythm (SR) and in the setting of chronic AF, to identify significant contributions of the Ca2+-independent transient outward K+ current ( Ito) to electrophysiological instability and arrhythmia initiation. First, we explored whether changes in the recovery or restitution of the AP duration (APD) and/or its dynamic stability (alternans) can be modulated by Ito. Recent reports have identified disease-dependent spatial differences in expression levels of the specific K+ channel α-subunits that underlie Ito in the left atrium. Therefore, we studied the functional consequences of this by deletion of 50% of native Ito (Kv4.3) and its replacement with Kv1.4. Interestingly, significant changes in the short-term stability of the human atrial AP waveform were revealed. Specifically, this K+ channel isoform switch produced discontinuities in the initial slope of the APD restitution curve and appearance of APD alternans. This pattern of in silico results resembles some of the changes observed in high-resolution clinical electrophysiological recordings. Important insights into mechanisms for these changes emerged from known biophysical properties (reactivation kinetics) of Kv1.4 versus those of Kv4.3. These results suggest new approaches for pharmacological management of AF, based on molecular properties of specific K+ isoforms and their changed expression during progressive disease. NEW & NOTEWORTHY Clinical studies identify oscillations (alternans) in action potential (AP) duration as a predictor for atrial fibrillation (AF). The abbreviated AP in AF also involves changes in K+ currents and early repolarization of the AP. Our simulations illustrate how substitution of Kv1.4 for the native current, Kv4.3, alters the AP waveform and enhances alternans. Knowledge of this "isoform switch" and related dynamics in the AF substrate may guide new approaches for detection and management of AF.

Arrhythmogenic β-adrenergic signaling in cardiac hypertrophy: The role of small-conductance calcium-activated potassium channels via activation of CaMKII

Sustained ventricular arrhythmias (SVAs) lead to sudden cardiac death, for which β- adrenoreceptor blockers are effective. We hypothesized that electrophysiological changes and arrhythmias by β- adrenoreceptor stimulation are crucially related to activation of small-conductance calcium-activated potassium (SK) channels via the increase in Ca2+/calmodulin-dependent protein kinase II (CaMKII) activity. We used normotensive Wistar-Kyoto (WKY) rats and spontaneous hypertensive rats (SHRs). The latter served as a model of left ventricular hypertrophy. We performed dual optical mapping of action potentials and Ca2+ transients, and the effects of isoproterenol and apamin, an SK channel blocker, were evaluated in the Langendorff-perfused hearts. Action potential duration was abbreviated by isoproterenol (100 nM) in both WKY rats and SHRs. In contrast, the CaMKII activity was increased by isoproterenol only in SHRs. In the presence of isoproterenol, apamin prolonged the action potential duration only in SHRs (n = 10, from 116.6 ± 5.05 ms to 125.4 ± 3.80 ms, P = 0.011), which was prevented by KN-93, a CaMKII inhibitor. Increase in Ca2+ transients and shortening of Ca2+ transient duration by isoproterenol were similarly observed in both animals, which was not affected by apamin. Apamin reduced the isoproterenol-induced SVAs and maximal slope of action potential duration restitution curve specifically in SHRs. In conclusion, β- adrenoreceptor stimulation creates arrhythmogenic substrates via the CaMKII-dependent activation of SK channels in cardiac hypertrophy.

Complexity reduction in human atrial modeling using extended Kalman filter.

Human atrial tissue electrophysiology is modeled upon biophysical details obtained from cellular level measurements. Data collected for this purpose typically represent a unique state of the tissue. As reproducing dynamic cases such as subject-varied and/or disorder-varied electrophysiological properties is in question, such complex models are typically hard to use. Hence, there is a need for simpler yet biophysically accurate and mathematically tractable models to be used for case-specific reproductions and simulations. In this study, a scheme for parameter estimation of a phenomenological cardiac model to match a targeted behavior generated from a complex model is used. Specifically, an algorithm incorporating extended Kalman filter (EKF) into the scheme is proposed. Its performance is then compared to that of particle swarm optimization (PSO) and sequential quadratic programming (SQP), algorithms that have been widely used for parameter optimization. Both robustness and adaptability performance of the algorithms are tested through various designs. For this, reproducing action potential (AP) waveforms of varying remodeling states of atrial fibrillation (AF) at different stimulus protocols was targeted. Also, randomly generated initial parameter sets are included in the tests. In addition, AP duration (APD) restitution curve (RC) is used for a multiscale evaluation of fitting performance. Finally, wavefront propagation on 2D of a selected AF remodeling state using parameter solutions from each of the algorithms is simulated for a qualitative evaluation. In general, PSO yielded superior performances than EKF and SQP with respect to fitting AP waveforms. Considering both AP and APD RC, however, EKF yielded the best accuracies. Also, more accurate spiral wave reentry is obtained with EKF. Overall, EKF algorithm yielded the best performance in robustness and adaptability. Graphical Abstract.

Electrical stimulation-based renal nerve mapping exacerbates ventricular arrhythmias during acute myocardial ischaemia.

Blood pressure elevation in response to transient renal nerve stimulation (RNS) has been used to determine the ablation target and endpoint of renal denervation. This study aimed to evaluate the safety of transient RNS in canines with normal or ischaemic hearts. In ten normal (Group 1) and six healed myocardial infarction (HMI) (Group 2) canines, a large-tip catheter was inserted into the left or right renal artery to perform transient RNS. The left stellate ganglion neural activity (LSGNA) and ventricular electrophysiological parameters were measured at baseline and during transient RNS. In another 20 acute myocardial infarction (AMI) canines, RNS (Group 3, n = 10) or sham RNS (Group 4, n = 10) was intermittently (1 min ON and 4 min OFF) performed for 1 h following AMI induction. The LSGNA and AMI-induced ventricular arrhythmias were analysed. In normal and HMI canines, although transient RNS significantly increased the LSGNA and facilitated the action potential duration (APD) alternans, it did not induce any ventricular arrhythmias and did not change the ventricular effective refractory period, APD or maximum slope of the APD restitution curve. In AMI canines, transient RNS significantly exacerbated LSG activation and promoted the incidence of ventricular arrhythmias. Transient RNS did not increase the risk of ventricular arrhythmias in normal or HMI hearts, but it significantly promoted the occurrence of ventricular arrhythmias in AMI hearts. Therefore, electrical stimulation-based renal nerve mapping may be unsafe in AMI patients and in patients with a high risk for malignant ventricular arrhythmias.

Targeted ablation of cardiac sympathetic neurons improves ventricular electrical remodelling in a canine model of chronic myocardial infarction.

The purpose of this study was to evaluate the cardiac electrophysiologic effects of targeted ablation of cardiac sympathetic neurons (TACSN) in a canine model of chronic myocardial infarction (MI). Thirty-eight anaesthetized dogs were randomly assigned into the sham-operated, MI, and MI-TACSN groups, respectively. Myocardial infarction-targeted ablation of cardiac sympathetic neuron was induced by injecting cholera toxin B subunit-saporin compound in the left stellate ganglion (LSG). Five weeks after surgery, the cardiac function, heart rate variability (HRV), ventricular electrophysiological parameters, LSG function and neural activity, serum norepinephrine (NE), nerve growth factor (NGF), and brain natriuretic peptide (BNP) levels were measured. Cardiac sympathetic innervation was determined with immunofluorescence staining of growth associated protein-43 (GAP43) and tyrosine hydroxylase (TH). Compared with MI group, TACSN significantly improved HRV, attenuated LSG function and activity, prolonged corrected QT interval, decreased Tpeak-Tend interval, prolonged ventricular effective refractory period (ERP), and action potential duration (APD), decreased the slopes of APD restitution curves, suppressed the APD alternans, increased ventricular fibrillation threshold, and reduced serum NE, NGF, and BNP levels. Moreover, the densities of GAP43 and TH-positive nerve fibres in the infarcted border zone in the MI-TACSN group were lower than those in the MI group. Targeted ablation of cardiac sympathetic neuron attenuates sympathetic remodelling and improves ventricular electrical remodelling in the chronic phase of MI. These data suggest that TACSN may be a novel approach to treating ventricular arrhythmias.

Real-Time Closed Loop Diastolic Interval Control Prevents Cardiac Alternans in Isolated Whole Rabbit Hearts.

Cardiac alternans, a beat-to-beat alternation in action potential duration (APD), can lead to fatal arrhythmias. During periodic pacing, changes in diastolic interval (DI) depend on subsequent changes in APD, thus enhancing cardiac instabilities through a 'feedback' mechanism. Recently, an anti-arrhythmic Constant DI pacing protocol was proposed and shown to be effective in suppressing alternans in 0D and 1D in silico studies. However, previousexperimental validation of Constant DI pacingin the heart has been unsuccessful due to the spatio-temporal complexity of 2D cardiac tissue and the technical challenges in its real-time implementation. Here, we developed a novel closed loop system to detect T-waves from real-time ECG data, enabling successful implementation of Constant DI pacing protocol, and performed high-resolution optical mapping experiments on isolated whole rabbit hearts to validate its anti-arrhythmic effects. The results were compared with: (1) Periodic pacing (feedback inherent) and (2) pacing with heart rate variability (HRV) (feedback modulation) introduced by using either Gaussian or Physiological patterns. We observed that Constant DI pacingsignificantly suppressed alternans in the heart, while maintaining APD spatial dispersion and flattening the slope of the APD restitution curve, compared to traditional Periodic pacing. In addition, introduction of HRV in Periodicpacing failed to prevent cardiac alternans, and was arrhythmogenic.

Computational Cardiac Modeling Reveals Mechanisms of Ventricular Arrhythmogenesis in Long QT Syndrome Type 8: CACNA1C R858H Mutation Linked to Ventricular Fibrillation.

Functional analysis of the L-type calcium channel has shown that the CACNA1C R858H mutation associated with severe QT interval prolongation may lead to ventricular fibrillation (VF). This study investigated multiple potential mechanisms by which the CACNA1C R858H mutation facilitates and perpetuates VF. The Ten Tusscher-Panfilov (TP06) human ventricular cell models incorporating the experimental data on the kinetic properties of L-type calcium channels were integrated into one-dimensional (1D) fiber, 2D sheet, and 3D ventricular models to investigate the pro-arrhythmic effects of CACNA1C mutations by quantifying changes in intracellular calcium handling, action potential profiles, action potential duration restitution (APDR) curves, dispersion of repolarization (DOR), QT interval and spiral wave dynamics. R858H “mutant” L-type calcium current (ICaL) augmented sarcoplasmic reticulum calcium content, leading to the development of afterdepolarizations at the single cell level and focal activities at the tissue level. It also produced inhomogeneous APD prolongation, causing QT prolongation and repolarization dispersion amplification, rendering R858H “mutant” tissue more vulnerable to the induction of reentry compared with other conditions. In conclusion, altered ICaL due to the CACNA1C R858H mutation increases arrhythmia risk due to afterdepolarizations and increased tissue vulnerability to unidirectional conduction block. However, the observed reentry is not due to afterdepolarizations (not present in our model), but rather to a novel blocking mechanism.

Restitution slope is principally determined by steady-state action potential duration.

AimsThe steepness of the action potential duration (APD) restitution curve and local tissue refractoriness are both thought to play important roles in arrhythmogenesis. Despite this, there has been little recognition of the apparent association between steady-state APD and the slope of the restitution curve. The objective of this study was to test the hypothesis that restitution slope is determined by APD and to examine the relationship between restitution slope, refractoriness and susceptibility to VF.Methods and resultsExperiments were conducted in isolated hearts and ventricular myocytes from adult guinea pigs and rabbits. Restitution curves were measured under control conditions and following intervention to prolong (clofilium, veratridine, bretylium, low [Ca]e, chronic transverse aortic constriction) or shorten (catecholamines, rapid pacing) ventricular APD. Despite markedly differing mechanisms of action, all interventions that prolonged the action potential led to a steepening of the restitution curve (and vice versa). Normalizing the restitution curve as a % of steady-state APD abolished the difference in restitution curves with all interventions. Effects on restitution were preserved when APD was modulated by current injection in myocytes pre-treated with the calcium chelator BAPTA-AM – to abolish the intracellular calcium transient. The non-linear relation between APD and the rate of repolarization of the action potential is shown to underpin the common influence of APD on the slope of the restitution curve. Susceptibility to VF was found to parallel changes in APD/refractoriness, rather than restitution slope.Conclusion(s)Steady-state APD is the principal determinant of the slope of the ventricular electrical restitution curve. In the absence of post-repolarization refractoriness, factors that prolong the action potential would be expected to steepen the restitution curve. However, concomitant changes in tissue refractoriness act to reduce susceptibility to sustained VF. Dependence on steady-state APD may contribute to the failure of restitution slope to predict sudden cardiac death.

Molsidomine Attenuates Ventricular Electrical Remodeling and Arrhythmogenesis in Rats With Chronic β-Adrenergic Receptor Activation Through the NO/cGMP/PKG Pathway.

This study investigated the effects and associated underlying mechanisms of molsidomine, a nitric oxide (NO) donor, on cardiac electrical remodeling and ventricular tachycardias (VTs) induced by chronic isoprenaline (ISO) stimulation in rats. The rats were randomly divided into groups that were treated with saline (control group), ISO (ISO group), ISO + molsidomine (ISO + M group), and ISO + molsidomine + the soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, ISO + M + O group) for 14 days. An electrophysiological study was performed to assess cardiac repolarization, action potential duration restitution, and the induction of action potential duration alternans and VTs in vitro. The properties of the Ca transients, Ca handling-related proteins, and NO/guanosine 3'5'-cyclic monophosphate (cGMP)/protein kinase G (PKG) pathway were examined. Compared with the control group, chronic ISO stimulation prolonged the cardiac repolarization, decreased the Ca transient alternans and action potential duration alternans thresholds, and increased the maximum slope (Smax) of the action potential duration restitution curve and incidence of VTs in vitro. All these effects were attenuated by molsidomine treatment (P < 0.05). Moreover, molsidomine activated cGMP/PKG signaling and stabilized the expression of calcium handling-related proteins compared with the ISO group. However, the protective effects of molsidomine were partially inhibited by ODQ. Our results suggest that molsidomine stabilizes calcium handling and attenuates cardiac electrical remodeling and arrhythmogenesis in rats with chronic β-adrenergic receptor activation. These effects are at least partially mediated by the activation of NO/cGMP/PKG pathway.

Pro-arrhythmogenic effects of CACNA1C G1911R mutation in human ventricular tachycardia: insights from cardiac multi-scale models.

Mutations in the CACNA1C gene are associated with ventricular tachycardia (VT). Although the CACNA1C mutations were well identified in patients with cardiac arrhythmias, mechanisms by which cardiac arrhythmias are generated in such genetic mutation conditions remain unclear. In this study, we identified a novel mechanism of VT resulted from enhanced repolarization dispersion which is a key factor for arrhythmias in the CACNA1C G1911R mutation using multi-scale computational models of the human ventricle. The increased calcium influx in the mutation prolonged action potential duration (APD), produced steepened action potential duration restitution (APDR) curves as well as augmented membrane potential differences among different cell types during repolarization, increasing transmural dispersion of repolarization (DOR) and the spatial and temporal heterogeneity of cardiac electrical activities. Consequentially, the vulnerability to unidirectional conduction block in response to a premature stimulus increased at tissue level in the G1911R mutation. The increased functional repolarization dispersion anchored reentrant excitation waves in tissue and organ models, facilitating the initiation and maintenance of VT due to less meandering rotor tip. Thus, the increased repolarization dispersion caused by the G1911R mutation is a primary factor that may primarily contribute to the genesis of cardiac arrhythmias in Timothy Syndrome.

Global alternans instability and its effect on non-linear wave propagation: dynamical Wenckebach block and self terminating spiral waves

The main mechanism of formation of reentrant cardiac arrhythmias is via formation of waveblocks at heterogeneities of cardiac tissue. We report that heterogeneity and the area of waveblock can extend itself in space and can result formation of new additional sources, or termination of existing sources of arrhythmias. This effect is based on a new form of instability, which we coin as global alternans instability (GAI). GAI is closely related to the so-called (discordant) alternans instability, however its onset is determined by the global properties of the APD-restitution curve and not by its slope. The APD-restitution curve relates the duration of the cardiac pulse (APD) to the time interval between the pulses, and can easily be measured in an experimental or even clinical setting. We formulate the conditions for the onset of GAI, study its manifestation in various 1D and 2D situations and discuss its importance for the onset of cardiac arrhythmias.

Biophysical Modeling Predicts Ventricular Tachycardia Inducibility and Circuit Morphology: A Combined Clinical Validation and Computer Modeling Approach.

Computational modeling of cardiac arrhythmogenesis and arrhythmia maintenance has made a significant contribution to the understanding of the underlying mechanisms of arrhythmia. We hypothesized that a cardiac model using personalized electro-anatomical parameters could define the underlying ventricular tachycardia (VT) substrate and predict reentrant VT circuits. We used a combined modeling and clinical approach in order to validate the concept. Non-contact electroanatomic mapping studies were performed in 7 patients (5 ischemics, 2 non-ischemics). Three ischemic cardiomyopathy patients underwent a clinical VT stimulation study. Anatomical information was obtained from cardiac magnetic resonance imaging (CMR) including high-resolution scar imaging. A simplified biophysical mono-domain action potential model personalized with the patients' anatomical and electrical information was used to perform in silico VT stimulation studies for comparison. The personalized in silico VT stimulations were able to predict VT inducibility as well as the macroscopic characteristics of the VT circuits in patients who had clinical VT stimulation studies. The patients with positive clinical VT stimulation studies had wider distribution of action potential duration restitution curve (APD-RC) slopes and APDs than the patient with a negative VT stimulation study. The exit points of reentrant VT circuits encompassed a higher percentage of the maximum APD-RC slope compared to the scar and non-scar areas, 32%, 4%, and 0.2%, respectively. VT stimulation studies can be simulated in silico using a personalized biophysical cardiac model. Myocardial spatial heterogeneity of APD restitution properties and conductivity may help predict the location of crucial entry/exit points of reentrant VT circuits.

Receptor for Advanced Glycation End Products Suppressed Arrhythmia by Reducing Infarct Size and Fibrosis in Ischemia Reperfusion Rat Model

Background and Objectives: The role of the receptor for advanced glycation end products (RAGE) blockers in the arrhythmogenic effect after myocardial infarction remains unclear. In this study, we evaluated the anti-arrhythmogenic effects of RAGE in an ischemia reperfusion (IR) model. Subject and Methods: IR was performed by ligation of the left anterior descending artery for 1 h in 8-week-old male Sprague-Dawley rats. A RAGE-siRNA polyplex combined with a polyethyleneiminemodified with deoxycholic acid (PEI-DA) was delivered to the heart. Rats were randomly divided into the following four groups: 1) control (sham operation, n=10), 2) IR (IR only, n=11), 3) IR+siRAGE (IR and RAGE-siRNA injection, n=10), and 4) IR+scRNA (IR and scrambled siRNA injection, n=9). Results: In the IR group, 6 (55%) of 11 rats died suddenly at 46 ± 14 min after acute myocardial infarction. However, no rats died in the control or IR+siRAGE groups. The IR+siRAGE group showed a better survival rate than the IR group (p=0.03). IR+siRAGE prevented arrhythmia (10% vs. 50%, p=0.02) compared with IR only. In Langendorff-perfused rat hearts, the IR+siRAGE group showed decreased action potential duration (121 ± 10, vs. 162 ± 60 ms, p=0.001), maximum slope of the action potential duration restitution curve (0.34 ± 0.09 vs. 1.14 ± 0.26, p<0.001), and inducible ventricular tachycardia (0% vs. 71%, p=0.01) compared to the IR group. However, these protective effects were not observed in the IR+scRNA group. The IR+siRAGE group showed significantly reduced infarct size and fibrosis compared to the IR group. Conclusion: RAGE-siRNA polyplexes combined with polyethyleneimine-modified with deoxycholic acid suppressed arrhythmia by reducing infarct size and fibrosis in a rat IR model.

Sympathetic denervation of heart and kidney induces similar effects on ventricular electrophysiological properties.

We aimed to investigate whether sympathetic denervation of the heart and kidney had similar effects on ventricular effective refractory period (ERP) and action potential duration (APD) restitution properties in a canine model. Twenty-four anaesthetised open-chest dogs (17-20 kg) were assigned to a sham operation group (n=8), a cardiac sympathetic denervation group (CSD, n=8) or a renal sympathetic denervation group (RSD, n=8). CSD was performed by ablating the caudal half of the LSG and T2-T4 thoracic sympathetic ganglia, while RSD was performed by ablating four sites on the adventitial surface of each renal artery. The ventricular electrophysiological properties were determined at four time points: baseline, 0 min, 30 min, and 60 min after interventions. The results showed that, when compared to the control group at the time point of 60 min after interventions, both CSD and RSD significantly reduced heart rate, prolonged the QT interval and ventricular ERP and APD, decreased the ERP dispersion and the slopes of APD restitution curves, and suppressed the APD alternans without affecting blood pressure and corrected QT interval. However, there were no significant differences in these parameters between CSD and RSD groups at the same time point. This study showed that sympathetic denervation of the heart and kidney induced similar electrophysiological effects in ventricles.

Analytical description of the slope of the APD-restitution curve to assess the interacting contribution of conduction and repolarization dynamics.

The restitution of the action potential duration (APDR) is a mechanism whereby cardiac excitation and relaxation adapt to changes in heart rate. Several studies, mainly carried out in-vitro and in-silico, have demonstrated that a steep APDR curve is associated with increased vulnerability to fatal arrhythmias. However, the mechanisms that link the steepness of the APDR curve to arrhythmogenesis remain undetermined. Although APDR is known to interact with conduction dynamics, few studies have focused on these interactions. In this paper, an analytical expression of the slope of the APDR is derived. This expression explicitly describes the dependency of the slope of the APDR curve on the activation time and/or conduction velocity changes. The study of this expression shows that conduction dynamics are among the main determinants of the slope of the APDR curve. A small absolute increment in the steepness of the activation time restitution slope can cause the steepness of the APDR slope to dramatically increase. Theoretically, the APDR slope quickly diverges to infinity when the increase in activation time matches the decrease in the pacing interval. High density epicardial mapping performed in a patient undergoing open heart surgery, shows excellent agreement between measures of the slope of the APDR curve and its analytical prediction (linear correlation > 0.95). The in-vivo recordings suggest that activation time restitution is the main determinant of the slope of the APDR curve.