Effects of L-type calcium channel and human ether-a-go-go related gene blockers on the electrical activity of the human heart: a simulation study.

AIMS: Class III and IV drugs affect cardiac human ether-a-go-go related gene (IKr) and L-type calcium (ICaL) channels, resulting in complex alterations in repolarization with both anti- and pro-arrhythmic consequences. Interpretation of their effects on cellular and electrocardiogram (ECG)-based biomarkers for risk stratification is challenging. As pharmaceutical compounds often exhibit multiple ion channel effects, our goal is to investigate the simultaneous effect of ICaL and IKr block on human ventricular electrophysiology from ionic to ECG level. METHODS AND RESULTS: Simulations are conducted using a human body torso bidomain model, which includes realistic representation of human membrane kinetics, anatomy, and fibre orientation. A simple block pore model is incorporated to simulate drug-induced ICaL and IKr blocks, for drug dose = 0, IC50, 2× IC50, 10× IC50, and 30× IC50. Drug effects on human ventricular activity are quantified for different degrees and combinations of ICaL and IKr blocks from the ionic to the body surface ECG level. Electrocardiogram simulations show that ICaL block results in shortening of the QT interval, ST elevation, and reduced T-wave amplitude, caused by reduction in action potential duration and action potential amplitude during the plateau phase, and in repolarization times. In contrast, IKr block results in QT prolongation and reduced T-wave amplitude. When ICaL and IKr blocks are combined, the degree of ICaL block strongly determines QT interval whereas the effect of IKr block is more pronounced on the T-wave amplitude. CONCLUSION: Our simulation study provides new insights into the combined effect of ICaL and IKr blocks on human ventricular activity using a multiscale computational human torso model.

MODELO PARAMÉTRICO DE LA ACTIVIDAD ELÉCTRICA CELULAR CARDIACA ESTIMADO A PARTIR DE REGISTROS ELECTROCARDIOGRÁFICOS ESTÁNDARES / PARAMETRICAL MODEL OF CARDIAC CELL ELECTRICAL ACTIVITY ESTIMATED FROM STANDARD ELECTROCARDIOGRAM RECORDINGS

El presente trabajo tiene como objetivo principal relacionar la actividad eléctrica cardiaca celular con la actividad eléctrica cardiaca medida en una sola derivación del electrocardiograma (ECG), mediante un modelo paramétrico de potencial de acción (PA) celular, lo cual se llevó a cabo relacionando dinámicas conocidas, matemáticamente modelables, que existen a nivel de una célula cardiaca, a dinámicas que pueden ser encontradas en un registro ECG estándar. La principal dinámica celular a relacionar con el ECG es la conocida como curva de restitución celular en tres dimensiones, la cual relaciona la duración del potencial de acción celular (APD) con el intervalo diastólico que lo precede y con el mismo APD pero del ciclo cardiaco precedente. Curvas de restitución similares se encontraron en señales ECG registradas durante el test isométrico handgrip, relacionando el intervalo QT con el intervalo TQ que lo precede y con el intervalo QT del ciclo cardiaco precedente. Siguiendo esta similitud, un modelo paramétrico de curva de restitución, extraído de un modelo de PA a tres corrientes iónicas, es ajustado a la curva de restitución del ECG con el fin de estimar los parámetros del modelo de PA. Este modelo es finalmente simulado estimulándolo con un tren de impulsos de frecuencia igual a la frecuencia cardiaca del sujeto experimentado. Los resultados muestran que la curva de restitución obtenida experimentalmente a partir del ECG es similar a la obtenida a partir de la simulación del modelo de PA. Más aún, el APD simulado del modelo sigue de forma satisfactoria la variación en el tiempo del intervalo QT del sujeto experimentado. Esto abre nuevas perspectivas en el análisis de la actividad celular a partir de registros ECG estándar.

The main purpose of this paper is to relate cellular cardiac electrical activity with the cardiac electrical activity measured in only one electrocardiogram (ECG) lead, through a cellular action potential (AP) parametrical model. This is performed by relating known dynamics, which can be mathematically modeled, existing at a cardiac cell level, to dynamics which can be obtained from a standard ECG recording. The main cellular dynamic used for relating with the ECG is the one known as three dimensional cellular restitution curve, which relates the action potential duration (APD) with its preceding diastolic interval and with the APD of the preceding cardiac cycle. Similar restitution curves were found in ECG signals recorded under the isometric handgrip test by relating the QT interval with its preceding TQ interval and with the QT interval of the preceding cardiac cycle. Following this similarity, a parametrical restitution curve, derived from a three ionic current cellular AP model was fitted to the ECG restitution relation for AP model parameter estimation. This model is finally simulated by stimulating it with an impulse train of frequency similar to the heart rate of the tested subject. The results show that the restitution curve experimentally obtained from the ECG is similar to the one obtained from de AP model simulation. Moreover the simulated APD follows satisfactorily the QT interval time variation of the tested subject. This opens new perspectives for the analysis of cellular cardiac electrical activity from standard ECG recordings.