Action Potential Duration Restitution Properties Research Articles

Interpretable machine learning of action potential duration restitution properties in single-cell models of atrial cardiomyocyte

Action potential duration (APD) restitution curve and its maximal slope (Smax) reflect single cell-level instability for inducing chaotic heart rhythms. Conventional parameter sensitivity analysis often fails to describe nonlinear relationships between ion channel parameters and electrophysiological phenotypes, such as Smax. We explored the parameter-phenotype mapping in in silico atrial cell models through interpretable machine learning (ML) approaches. We generated a population of 5,000 single-cell atrial cell models by log-uniformly sampling parameter combinations with the Sobol sequence scheme.

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.

Dynamic Action Potential Restitution Contributes to Mechanical Restitution in Right Ventricular Myocytes From Pulmonary Hypertensive Rats.

We investigated the steepened dynamic action potential duration (APD) restitution of rats with pulmonary artery hypertension (PAH) and right ventricular (RV) failure and tested whether the observed APD restitution properties were responsible for negative mechanical restitution in these myocytes. PAH and RV failure were provoked in male Wistar rats by a single injection of monocrotaline (MCT) and compared with saline-injected animals (CON). Action potentials were recorded from isolated RV myocytes at stimulation frequencies between 1 and 9 Hz. Action potential waveforms recorded at 1 Hz were used as voltage clamp profiles (action potential clamp) at stimulation frequencies between 1 and 7 Hz to evoke rate-dependent currents. Voltage clamp profiles mimicking typical CON and MCT APD restitution were applied and cell shortening simultaneously monitored. Compared with CON myocytes, MCT myocytes were hypertrophied; had less polarized diastolic membrane potentials; had action potentials that were triggered by decreased positive current density and shortened by decreased negative current density; APD was longer and APD restitution steeper. APD90 restitution was unchanged by exposure to the late Na+-channel blocker (5 μM) ranolazine or the intracellular Ca2+ buffer BAPTA. Under AP clamp, stimulation frequency-dependent inward currents were smaller in MCT myocytes and were abolished by BAPTA. In MCT myocytes, increasing stimulation frequency decreased contraction amplitude when depolarization duration was shortened, to mimic APD restitution, but not when depolarization duration was maintained. We present new evidence that the membrane potential of PAH myocytes is less stable than normal myocytes, being more easily perturbed by external currents. These observations can explain increased susceptibility to arrhythmias. We also present novel evidence that negative APD restitution is at least in part responsible for the negative mechanical restitution in PAH myocytes. Thus, our study links electrical restitution remodeling to a defining mechanical characteristic of heart failure, the reduced ability to respond to an increase in demand.

Abstract 12610: Renal Sympathetic Denervation Modulates Ventricular Electrophysiology and Arrhythmogenesis

Introduction: Previous studies suggest that renal sympathetic nerves can modulate central sympathetic tone. Recently, a beneficial effect of renal sympathetic denervation (RSD) has been seen in patients with different settings of ventricular electrical storm. However, the effect of RSD on ventricular electrophysiology remains unclear. Methods: Twenty-eight adult mongrel dogs were included in the present study. Eighteen dogs were subjected to RSD which was performed by ablating the adventitial surface of the renal artery. In Group 1 (n=8), programmed stimulation was performed before and after RSD to determinate ventricular effective refractory period (ERP) and action potential duration (APD) restitution properties. In Group 2 (n=10), acute myocardial ischemia (AMI) was induced by ligating the proximal left anterior descending coronary artery after the performance of RSD and the incidence of ventricular arrhythmia (VA) was calculated during 1-hour recording. In another 10 dogs (Group 3), AMI was induced and VA was measured with sham RSD. Results: In Group 1, RSD significantly prolonged ventricular ERP and APD, reduced the maximum slope (Smax) of the restitution curve and suppressed APD alternans at each site (Fig. 1A, C, E). RSD also significantly decreased the spatial dispersions of ERP, APD and Smax (Fig. 1B, D, F). The occurrence of spontaneous VA during 1-h AMI in Group 2 was significantly lower than that in Group 3 (Tab. 1). Conclusions: RSD significantly prolongs ventricular ERP and APD, attenuates APD restitution properties and reduces the incidence of ischemia-induced VA, suggesting that RSD may exert an anti-arrhythmic role for VA.

Systematic characterization of the ionic basis of rabbit cellular electrophysiology using two ventricular models

Several mathematical models of rabbit ventricular action potential (AP) have been proposed to investigate mechanisms of arrhythmias and excitation-contraction coupling. Our study aims at systematically characterizing how ionic current properties modulate the main cellular biomarkers of arrhythmic risk using two widely-used rabbit ventricular models, and comparing simulation results using the two models with experimental data available for rabbit. A sensitivity analysis of AP properties, Ca2+ and Na+ dynamics, and their rate dependence to variations (±15% and ±30%) in the main transmembrane current conductances and kinetics was performed using the Shannon et al. (2004) and the Mahajan et al. (2008a,b) AP rabbit models. The effects of severe transmembrane current blocks (up to 100%) on steady-state AP and calcium transients, and AP duration (APD) restitution curves were also simulated using both models. Our simulations show that, in both virtual rabbit cardiomyocytes, APD is significantly modified by most repolarization currents, AP triangulation is regulated mostly by the inward rectifier K+ current (IK1) whereas APD rate adaptation as well as [Na+]i rate dependence is influenced by the Na+/K+ pump current (INaK). In addition, steady-state [Ca2+]i levels, APD restitution properties and [Ca2+]i rate dependence are strongly dependent on INaK, the L-Type Ca2+ current (ICaL) and the Na+/Ca2+ exchanger current (INaCa), although the relative role of these currents is markedly model dependent. Furthermore, our results show that simulations using both models agree with many experimentally-reported electrophysiological characteristics. However, our study shows that the Shannon et al. model mimics rabbit electrophysiology more accurately at normal pacing rates, whereas Mahajan et al. model behaves more appropriately at faster rates. Our results reinforce the usefulness of sensitivity analysis for further understanding of cellular electrophysiology and validation of cardiac AP models.

Abnormal Action Potential Duration Restitution Property in the Right Ventricular Outflow Tract in Brugada Syndrome

Although patients with Brugada syndrome (BS) are at risk of ventricular fibrillation (VF) and ensuing death, the action potential duration (APD) restitution properties of the right ventricular outflow tract (RVOT) in patients with BS remain undetermined. Endocardial monophasic action potentials (MAPs) were obtained from 16 patients with BS and 17 control patients. MAPs were recorded from the RVOT in all patients. The MAP duration at 90% repolarization (MAPD(90)), effective refractory period (ERP), and maximum slope of the APD restitution curve were obtained. VF was induced with up to 3 extrastimuli from the RV apex or RVOT. There was no difference in MAPD(90) between the 2 groups, but the ERP was significantly shorter in patients with BS than in control patients (210.7+/-10.5 vs 223.8+/-13.4 ms, P=0.008). MAPD at the shortest diastolic interval was significantly shorter in patients with BS than in control patients (149.9+/-19.9 vs 179.8+/-13.7 ms, P<0.001). The maximum slope of the APD restitution curve was steeper in patients with BS than in control patients (2.90+/-1.29 vs 1.38+/-0.41, P<0.001). The shorter ERP, shorter MAPD at the shortest diastolic interval and steeply sloped APD restitution curve in the RVOT appear to be related to the inducibility of VF in patients with BS.

Whole heart action potential duration restitution properties in cardiac patients: a combined clinical and modelling study

Steep action potential duration (APD) restitution has been shown to facilitate wavebreak and ventricular fibrillation. The global APD restitution properties in cardiac patients are unknown. We report a combined clinical electrophysiology and computer modelling study to: (1) determine global APD restitution properties in cardiac patients; and (2) examine the interaction of the observed APD restitution with known arrhythmia mechanisms. In 14 patients aged 52-85 years undergoing routine cardiac surgery, 256 electrode epicardial mapping was performed. Activation-recovery intervals (ARI; a surrogate for APD) were recorded over the entire ventricular surface. Mono-exponential restitution curves were constructed for each electrode site using a standard S1-S2 pacing protocol. The median maximum restitution slope was 0.91, with 27% of all electrode sites with slopes<0.5, 29% between 0.5 and 1.0, and 20% between 1.0 and 1.5. Eleven per cent of restitution curves maintained slope>1 over a range of diastolic intervals of at least 30 ms; and 0.3% for at least 50 ms. Activation-recovery interval restitution was spatially heterogeneous, showing regional organization with multiple discrete areas of steep and shallow slope. We used a simplified computer model of 2-D cardiac tissue to investigate how heterogeneous APD restitution can influence vulnerability to, and stability of re-entry. Our model showed that heterogeneity of restitution can act as a potent arrhythmogenic substrate, as well as influencing the stability of re-entrant arrhythmias. Global epicardial mapping in humans showed that APD restitution slopes were organized into regions of shallow and steep slopes. This heterogeneous organization of restitution may provide a substrate for arrhythmia.

Regional differences in APD restitution can initiate wavebreak and re-entry in cardiac tissue: A computational study

BackgroundRegional differences in action potential duration (APD) restitution in the heart favour arrhythmias, but the mechanism is not well understood.MethodsWe simulated a 150 × 150 mm 2D sheet of cardiac ventricular tissue using a simplified computational model. We investigated wavebreak and re-entry initiated by an S1S2S3 stimulus protocol in tissue sheets with two regions, each with different APD restitution. The two regions had a different APD at short diastolic interval (DI), but similar APD at long DI. Simulations were performed twice; once with both regions having steep (slope > 1), and once with both regions having flat (slope < 1) APD restitution.ResultsWavebreak and re-entry were readily initiated using the S1S2S3 protocol in tissue sheets with two regions having different APD restitution properties. Initiation occurred irrespective of whether the APD restitution slopes were steep or flat. With steep APD restitution, the range of S2S3 intervals resulting in wavebreak increased from 1 ms with S1S2 of 250 ms, to 75 ms (S1S2 180 ms). With flat APD restitution, the range of S2S3 intervals resulting in wavebreak increased from 1 ms (S1S2 250 ms), to 21 ms (S1S2 340 ms) and then 11 ms (S1S2 400 ms).ConclusionRegional differences in APD restitution are an arrhythmogenic substrate that can be concealed at normal heart rates. A premature stimulus produces regional differences in repolarisation, and a further premature stimulus can then result in wavebreak and initiate re-entry. This mechanism for initiating re-entry is independent of the steepness of the APD restitution curve.

The simplified FitzHugh-Nagumo model with action potential duration restitution: Effects on 2D wave propagation

A modification of the simplified FitzHugh-Nagumo (FN) equations is proposed for introducing a residual component of the slow variable, which determines the restitution of action potential duration (APD) also known as the interval-excitation duration relationship. The three-step-wise approximation of ϵ( E) which is widely used in current publications is replaced in a new model by a four-step approximation. This change is used for studying by computer simulation the effects of APD restitution properties independently of the APD and refractory period on 2D wave propagation in an isotropic matrix (made by 128 × 128 nodes). The method for fitting the model to the given experimental restitution data (obtained from myocardial cells) is presented. The computer simulations implemented on a massively parallel computer (Connection Machine) showed at least three important qualitative distinctions in behavior which demonstrate the effect of APD restitution: changes in the speed and wavelength of propagated waves with the period of stimulation, non-stationary propagation of spiral waves, and site-specific induction of spiral waves with premature stimulation not on the tail of the previous wave. Quantitative effects of differing restitution properties are expressed in the size and location of a window of vulnerability in 2D excitable media. These windows are characterized by the appearance of single and double spiral waves in response to premature stimulation applied inside the window. Thus the APD restitution incorporated in the FN model produces a significant effect on the formation and propagation of spiral waves.