Dataset Information

Transmural IK(ATP) heterogeneity as a determinant of activation rate gradient during early ventricular fibrillation: mechanistic insights from rabbit ventricular models.

ABSTRACT: Activation rate (AR) gradients develop during ventricular fibrillation (VF), with the highest AR on the surface near Purkinje system (PS) terminals (endocardium in humans and rabbits and epicardium in pigs). The application of glibenclamide to block adenosine triphosphate (ATP)-sensitive potassium current (IK(ATP)) before VF induction eliminates transmural AR gradients and prevents the induction of sustained arrhythmia. It remains unclear whether the PS, which is resistant to ischemia, is also a factor in AR heterogeneity.To dissect IK(ATP) and PS contributions to AR gradients during VF by using detailed computer simulations.We constructed rabbit ventricular models with either subendocardial or subepicardial PS terminals. Physiologically relevant IK(ATP) gradients were implemented, and early VF was induced and observed.Prominent AR gradients were observed only in models with large IK(ATP) gradients. The critical underlying factor of AR gradient maintenance was refractoriness in low-IK(ATP) regions, which blocked the propagation of action potentials from high-IK(ATP) regions. The PS played no role in transmural AR gradient maintenance, but did cause local spatial heterogeneity of AR on the surface adjacent to terminals. Simulated glibenclamide application during VF led to spontaneous arrhythmia termination within a few seconds in most cases, which builds on previous experimental findings of anti-VF properties of glibenclamide pretreatment.Differential IK(ATP) across the ventricular wall is an important factor underlying AR gradients during VF; thus, higher epicardial AR in pigs is most likely due to an abundance of epicardial IK(ATP). For terminating early VF, our results suggest that IK(ATP) modulation is a stronger target than Purkinje ablation.

SUBMITTER: Boyle PM

PROVIDER: S-EPMC3826179 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Transmural IK(ATP) heterogeneity as a determinant of activation rate gradient during early ventricular fibrillation: mechanistic insights from rabbit ventricular models.

Boyle Patrick M PM Massé Stéphane S Nanthakumar Kumaraswamy K Vigmond Edward J EJ

Heart rhythm 20130812 11

<h4>Background</h4>Activation rate (AR) gradients develop during ventricular fibrillation (VF), with the highest AR on the surface near Purkinje system (PS) terminals (endocardium in humans and rabbits and epicardium in pigs). The application of glibenclamide to block adenosine triphosphate (ATP)-sensitive potassium current (IK(ATP)) before VF induction eliminates transmural AR gradients and prevents the induction of sustained arrhythmia. It remains unclear whether the PS, which is resistant to ...[more]

PMID: 23948344

Similar Datasets

Project description:AimsCardiac electrophysiological heterogeneity includes: (i) regional differences in action potential (AP) waveform, (ii) AP waveform differences in cells isolated from a single region, (iii) variability of the contribution of individual ion currents in cells with similar AP durations (APDs). The aim of this study is to assess intra-regional AP waveform differences, to quantify the contribution of specific ion channels to the APD via drug responses and to generate a population of mathematical models to investigate the mechanisms underlying heterogeneity in rabbit ventricular cells.Methods and resultsAPD in ∼50 isolated cells from subregions of the LV free wall of rabbit hearts were measured using a voltage-sensitive dye. When stimulated at 2 Hz, average APD90 value in cells from the basal epicardial region was 254 ± 25 ms (mean ± standard deviation) in 17 hearts with a mean interquartile range (IQR) of 53 ± 17 ms. Endo-epicardial and apical-basal APD90 differences accounted for ∼10% of the IQR value. Highly variable changes in APD occurred after IK(r) or ICa(L) block that included a sub-population of cells (HR) with an exaggerated (hyper) response to IK(r) inhibition. A set of 4471 AP models matching the experimental APD90 distribution was generated from a larger population of models created by random variation of the maximum conductances (Gmax) of 8 key ion channels/exchangers/pumps. This set reproduced the pattern of cell-specific responses to ICa(L) and IK(r) block, including the HR sub-population. The models exhibited a wide range of Gmax values with constrained relationships linking ICa(L) with IK(r), ICl, INCX, and INaK.ConclusionModelling the measured range of inter-cell APDs required a larger range of key Gmax values indicating that ventricular tissue has considerable inter-cell variation in channel/pump/exchanger activity. AP morphology is retained by relationships linking specific ionic conductances. These interrelationships are necessary for stable repolarization despite large inter-cell variation of individual conductances and this explains the variable sensitivity to ion channel block.

Project description:Ventricular fibrillation (VF) is a lethal condition that affects millions worldwide. The mechanism underlying VF is unstable reentrant electrical waves rotating around lines called filaments. These complex spatio-temporal patterns can be studied using both experimental and numerical methods. Computer simulations provide unique insights including high resolution dynamics throughout the heart and systematic control of quantities such as fiber orientation and cellular kinetics that are not feasible experimentally. Here we study filament dynamics using two bi-ventricular 3-D high-resolution rabbit heart geometries, one with detailed fine structure and another without fine structure. We studied filament dynamics using anisotropic and isotropic conductivities, and with four cellular action potential models with different recovery kinetics. Spiral wave dynamics observed in isotropic two-dimensional sheets were not predictive of the behavior in the whole heart. In 2-D the four cell models exhibited stable reentry, meandering spiral waves, and spiral-wave breakup. In the whole heart with fine structure, all simulation results exhibited complex dynamics reminiscent of fibrillation observed experimentally. In the whole heart without fine structure, anisotropy acted to destabilize filament dynamics although the number of filaments was reduced compared to the heart with structure. In addition, in isotropic hearts without structure the two cell models that exhibited meandering spiral waves in 2-D, stabilized into figure-of-eight surface patterns. We also studied the sensitivity of filament dynamics to computer system configuration and initial conditions. After large simulation times, different macroscopic results sometimes occurred across different system configurations, likely due to a lack of bitwise reproducibility. The study conclusions were insensitive to initial condition perturbations, however, the exact number of filaments over time and their trends were altered by these changes. In summary, we present the following new results. First, we provide a new cell model that resembles the surface patterns of VF in the rabbit heart both qualitatively and quantitatively. Second, filament dynamics in the whole heart cannot be predicted from spiral wave dynamics in 2-D and we identified anisotropy as one destabilizing factor. Third, the exact dynamics of filaments are sensitive to a variety of factors, so we suggest caution in their interpretation and their quantitative analyses.

Project description: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.

Dataset Information

Transmural IK(ATP) heterogeneity as a determinant of activation rate gradient during early ventricular fibrillation: mechanistic insights from rabbit ventricular models.

Publications

Transmural IK(ATP) heterogeneity as a determinant of activation rate gradient during early ventricular fibrillation: mechanistic insights from rabbit ventricular models.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets