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An increasing electromechanical window is a predictive marker of ventricular fibrillation in anesthetized rabbit with ischemic heart.

ABSTRACT: The QTc interval is widely used in Safety Pharmacological studies to predict arrhythmia risk, and the electromechanical window (EMW) and short-term variability of QT intervals (STVQT) have been studied as new biomarkers for drug-induced Torsades de Pointes (TdP). However, the use of EMW and STVQT to predict ventricular fibrillation (VF) has not been elucidated. This study aimed to evaluate EMW and STVQT to predict VF in anesthetized rabbit model of VF. VF was induced by ligation of the left anterior descending and a descending branch of the left circumflex coronary arteries in a sample population of rabbits (n=18). VF was developed 55.6% (10/18). In rabbit with VF, the EMW was significantly higher than in rabbits without VF (96.3 ± 15.6 ms and 49.5 ± 5.6 ms, respectively, P<0.05). STVQT had significantly increased before the onset of VF in rabbits that experienced VF, but not in rabbits that did not experience VF (11.7 ± 1.8 ms and 3.7 ± 0.4 ms, respectively, P<0.05). The EMW and STVQT had better predictive power for VF with higher sensitivity and specificity than the QTc measure. The result suggested that the increasing of EMW, as well as the elevation of STVQT, can potentially be used as biomarkers for predicting of VF.

SUBMITTER: Limprasutr V

PROVIDER: S-EPMC5955749 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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An increasing electromechanical window is a predictive marker of ventricular fibrillation in anesthetized rabbit with ischemic heart.

Limprasutr Vudhiporn V Pirintr Prapawadee P Kijtawornrat Anusak A Hamlin Robert L RL

Experimental animals 20171121 2

The QTc interval is widely used in Safety Pharmacological studies to predict arrhythmia risk, and the electromechanical window (EMW) and short-term variability of QT intervals (STVQT) have been studied as new biomarkers for drug-induced Torsades de Pointes (TdP). However, the use of EMW and STVQT to predict ventricular fibrillation (VF) has not been elucidated. This study aimed to evaluate EMW and STVQT to predict VF in anesthetized rabbit model of VF. VF was ind ...[more]

PMID: 29162767

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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

An increasing electromechanical window is a predictive marker of ventricular fibrillation in anesthetized rabbit with ischemic heart.

Publications

An increasing electromechanical window is a predictive marker of ventricular fibrillation in anesthetized rabbit with ischemic heart.

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