Cardiac cells stimulated with an axial current-like waveform reproduce electrophysiological properties of tissue fibers

Background and objective: In silico electrophysiological models are generally validated by comparing simulated results with experimental data. When dealing with single-cell and tissue scales simultaneously, as occurs frequently during model development and calibration, the effects of inter-cellular coupling should be considered to ensure the trustworthiness of model predictions. The hypothesis of this paper is that the cell-tissue mismatch can be reduced by incorporating the effects of conduction into the single-cell stimulation current. Methods: Five different stimulation waveforms were applied to the human ventricular O'Hara-Rudy cell model. The waveforms included the commonly used monophasic and biphasic (symmetric and asymmetric) pulses, a triangular waveform and a newly proposed asymmetric waveform (stimulation A) that resembles the transmembrane current associated with AP conduction in tissue. A comparison between single-cell and fiber simulated results was established by computing the relative difference between the values of AP-derived properties at different scales, and by evaluating the differences in the contributions of ionic conductances to each evaluated property. As a proof of the benefit, we investigated multi-scale differences in the simulation of the effects induced by dofetilide, a selective IKr blocker with high torsadogenic risk, on ventricular repolarization at different pacing rates. Results: Out of the five tested stimulation waveforms, stimulation A produced the closest correspondence between cell and tissue simulations in terms of AP properties at steady-state and under dynamic pacing and of ionic contributors to those AP properties. Also, stimulation A reproduced the effects of dofetilide better than the other alternative waveforms, mirroring the ’beat-skipping’ behavior observed at fast pacing rates in experiments with human tissue. Conclusions: The proposed stimulation current waveform accounts for inter-cellular coupling effects by mimicking cell excitation during AP conduction. The proposed waveform improves the correspondence between simulation scales, which could improve the trustworthiness of single-cell simulations without adding computational cost. © 202

Circadian modulation on T-wave alternans activity in chronic heart failure patients

Average TWA activity has been shown to be an independent predictor of sudden cardiac death (SCD) in chronic heart failure (CHF) patients. However, the influence of circadian rhythms on TWA remains understudied. In this work, we assessed circadian TWA changes in a CHF population and evaluated whether the prognostic value of TWA indices is sensitive to the circadian pattern. Holter ECG recordings from 626 consecutive CHF patients (52 SCD) were analyzed. The index of average alternans (IAA), quantifying the average TWA level, was measured in 4 consecutive 6-hour intervals using a multilead fully-automated method. Survival analysis was performed considering SCD as an independent endpoint. IAA changed along the day, with statistically significant lower values during the night than during daytime. This pattern is similar to the one observed in the mean heart rate (HR). However, a low correlation (r=.18) was found between IAA and HR in windows of 128 beats. After dichotomization of patients based on the third quartile of IAA indices, IAA indices computed between hours 06-12 (IAA06-12) and 18-24 (IAA18-24) successfully predicted SCD (Hazard Ratio, HaR:2.34(1.33-4.13)per µV, andHaR:1.87(1.04-3.36) per µV, respectively). In conclusion, circadian variation should be considered for SCD risk prediction

Investigación in silico sobre el papel de los canales SK en miocitos ventriculares de pacientes con insuficiencia cardiaca

En este trabajo se presenta la extensión de un modelo computacional electrofisiológico de miocito ventricular humano para representar la actividad de los canales SK en condiciones de insuficiencia cardiaca. Las simulaciones realizadas con el modelo permiten reproducir evidencias experimentales acerca del papel de estos canales en la actividad eléctrica ventricular

Sudden cardiac death and pump failure death prediction in chronic heart failure by combining ECG and clinical markers in an integrated risk model

BACKGROUND: Sudden cardiac death (SCD) and pump failure death (PFD) are common endpoints in chronic heart failure (CHF) patients, but prevention strategies are different. Currently used tools to specifically predict these endpoints are limited. We developed risk models to specifically assess SCD and PFD risk in CHF by combining ECG markers and clinical variables. METHODS: The relation of clinical and ECG markers with SCD and PFD risk was assessed in 597 patients enrolled in the MUSIC (MUerte Súbita en Insuficiencia Cardiaca) study. ECG indices included: turbulence slope (TS), reflecting autonomic dysfunction; T-wave alternans (TWA), reflecting ventricular repolarization instability; and T-peak-to-end restitution (ΔαTpe) and T-wave morphology restitution (TMR), both reflecting changes in dispersion of repolarization due to heart rate changes. Standard clinical indices were also included. RESULTS: The indices with the greatest SCD prognostic impact were gender, New York Heart Association (NYHA) class, left ventricular ejection fraction, TWA, ΔαTpe and TMR. For PFD, the indices were diabetes, NYHA class, ΔαTpe and TS. Using a model with only clinical variables, the hazard ratios (HRs) for SCD and PFD for patients in the high-risk group (fifth quintile of risk score) with respect to patients in the low-risk group (first and second quintiles of risk score) were both greater than 4. HRs for SCD and PFD increased to 9 and 11 when using a model including only ECG markers, and to 14 and 13, when combining clinical and ECG markers. CONCLUSION: The inclusion of ECG markers capturing complementary pro-arrhythmic and pump failure mechanisms into risk models based only on standard clinical variables substantially improves prediction of SCD and PFD in CHF patients

DENIS: Solving cardiac electrophysiological simulations with volunteer computing.

Cardiac electrophysiological simulations are computationally intensive tasks. The growing complexity of cardiac models, together with the increasing use of large ensembles of models (known as populations of models), make extensive simulation studies unfeasible for regular stand-alone computers. To address this problem, we developed DENIS, a cardiac electrophysiology simulator based on the volunteer computing paradigm. We evaluated the performance of DENIS by testing the effect of simulation length, task deadline, and batch size, on the time to complete a batch of simulations. In the experiments, the time to complete a batch of simulations did not increase with simulation length, and had little dependence on batch size. In a test case involving the generation of a population of models, DENIS was able to reduce the simulation time from years to a few days when compared to a stand-alone computer. Such capacity makes it possible to undertake large cardiac simulation projects without the need for high performance computing infrastructure

Multilead analysis of T-wave alternans in the electrocardiogram

Las alternancias de onda T (TWA) se definen como una alteración en la morfología de la repolarización que se repite cada dos latidos. Este fenómeno cardíaco está relacionado con el riesgo de sufrir arritmias ventriculares malignas que pueden conducir a la muerte súbita cardíaca. La amplitud de las TWA puede ser muy baja, del orden de los microvoltios, resultando indetectables a simple vista en el ECG, lo que dificulta en gran medida su detección. El objetivo de esta tesis es desarrollar estrategias de análisis multiderivacional que mejoren la detección y la cuantificación de TWA en el ECG, y que aumenten el valor clínico de las TWA como índice de riesgo

Limitations in electrophysiological model development and validation caused by differences between simulations and experimental protocols

Models of ion channel dynamics are usually built by fitting isolated cell experimental values of individual parameters while neglecting the interaction between them. Another shortcoming regards the estimation of ionic current conductances, which is often based on quantification of Action Potential (AP)-derived markers. Although this procedure reduces the uncertainty in the calculation of conductances, many studies evaluate electrophysiological AP-derived markers from single cell simulations, whereas experimental measurements are obtained from tissue preparations. In this work, we explore the limitations of these approaches to estimate ion channel dynamics and maximum current conductances and how they could be overcome by using multiscale simulations of experimental protocols. Four human ventricular cell models, namely ten Tusscher and Panfilov (2006), Grandi et al. (2010), O'Hara et al. (2011), and Carro et al. (2011), were used. Two problems involving scales from ion channels to tissue were investigated: 1) characterization of L-type calcium voltage-dependent inactivation ICa,L; 2) identification of major ionic conductance contributors to steady-state AP markers, including APD90, APD75, APD50, APD25, Triangulation and maximal and minimal values of V and dV/dt during the AP (Vmax, Vmin, dV/dtmax, dV/dtmin). Our results show that: 1) ICa,Linactivation characteristics differed significantly when calculated from model equations and from simulations reproducing the experimental protocols. 2) Large differences were found in the ionic currents contributors to APD25, Triangulation, Vmax, dV/dtmaxand dV/dtminbetween single cells and 1D-tissue. When proposing any new model formulation, or evaluating an existing model, consistency between simulated and experimental data should be verified considering all involved effects and scales

The Role of Purkinje Automaticity as an Arrhythmia Mechanism in Hyperkalaemia

Conference paper: Violeta Monasterio, Jesús Carro, Esther Pueyo, José F Rodríguez. Computing in Cardiology 2015; 42:873-876