A three-dimensional human atrial model with fiber orientation. Electrograms and arrhythmic activation patterns relationship

The most common sustained cardiac arrhythmias in humans are atrial tachyarrhythmias, mainly atrial fibrillation. Areas of complex fractionated atrial electrograms and high dominant frequency have been proposed as critical regions for maintaining atrial fibrillation; however, there is a paucity of data on the relationship between the characteristics of electrograms and the propagation pattern underlying them. In this study, a realistic 3D computer model of the human atria has been developed to investigate this relationship. The model includes a realistic geometry with fiber orientation, anisotropic conductivity and electrophysiological heterogeneity. We simulated different tachyarrhythmic episodes applying both transient and continuous ectopic activity. Electrograms and their dominant frequency and organization index values were calculated over the entire atrial surface. Our simulations show electrograms with simple potentials, with little or no cycle length variations, narrow frequency peaks and high organization index values during stable and regular activity as the observed in atrial flutter, atrial tachycardia (except in areas of conduction block) and in areas closer to ectopic activity during focal atrial fibrillation. By contrast, cycle length variations and polymorphic electrograms with single, double and fragmented potentials were observed in areas of irregular and unstable activity during atrial fibrillation episodes. Our results also show: 1) electrograms with potentials without negative deflection related to spiral or curved wavefronts that pass over the recording point and move away, 2) potentials with a much greater proportion of positive deflection than negative in areas of wave collisions, 3) double potentials related with wave fragmentations or blocking lines and 4) fragmented electrograms associated with pivot points. Our model is the first human atrial model with realistic fiber orientation used to investigate the relationship between different atrial arrhythmic propagation patterns and the electrograms observed at more than 43000 points on the atrial surface.This work was partially supported by the Plan Nacional de Investigacion Cientifica, Desarrollo e Innovacion Tecnologica, Ministerio de Ciencia e Innovacion of Spain (TEC2008-02090), by the Plan Avanza (Accion Estrategica de Telecomunicaciones y Sociedad de la Informacion), Ministerio de Industria Turismo y Comercio of Spain (TSI-020100-2010-469), by the Programa Prometeo 2012 of the Generalitat Valenciana and by the Programa de Apoyo a la Investigacion y Desarrollo de la Universitat Politecnica de Valencia (PAID-06-11-2002). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Tobón Zuluaga, C.; Ruiz Villa, CA.; Heidenreich, E.; Romero Pérez, L.; Hornero, F.; Saiz Rodríguez, FJ. (2013). A three-dimensional human atrial model with fiber orientation. Electrograms and arrhythmic activation patterns relationship. PLoS ONE. 8(2):1-13. https://doi.org/10.1371/journal.pone.0050883S11382Ho SY, Sanchez-Quintana D, Anderson RH (1998) Can anatomy define electric pathways? In: International Workshop on Computer Simulation and Experimental Assessment of Electrical Cardiac Function, Lausanne, Switzerland. 77–86.Tobón C (2009) Evaluación de factores que provocan fibrilación auricular y de su tratamiento mediante técnicas quirúrgicas. Estudio de simulación. Master Thesis Universitat Politècnica de València.Ruiz C (2010) Estudio de la vulnerabilidad a reentradas a través de modelos matemáticos y simulación de la aurícula humana. Doctoral Thesis Universitat Politècnica de València.Tobón C (2010) Modelización y evaluación de factores que favorecen las arritmias auriculares y su tratamiento mediante técnicas quirúrgicas. Estudio de simulación. Doctoral Thesis Universitat Politècnica de València.Henriquez, C. S., & Papazoglou, A. A. (1996). Using computer models to understand the roles of tissue structure and membrane dynamics in arrhythmogenesis. Proceedings of the IEEE, 84(3), 334-354. doi:10.1109/5.486738Grimm, R. A., Chandra, S., Klein, A. L., Stewart, W. J., Black, I. W., Kidwell, G. A., & Thomas, J. D. (1996). Characterization of left atrial appendage Doppler flow in atrial fibrillation and flutter by Fourier analysis. American Heart Journal, 132(2), 286-296. doi:10.1016/s0002-8703(96)90424-xMaleckar, M. M., Greenstein, J. L., Giles, W. R., & Trayanova, N. A. (2009). K+ current changes account for the rate dependence of the action potential in the human atrial myocyte. American Journal of Physiology-Heart and Circulatory Physiology, 297(4), H1398-H1410. doi:10.1152/ajpheart.00411.200

Electrophysiologic effects of chronic amiodarone therapy and hypothyroidism, alone and in combination, on guinea pig ventricular myocytes

Amiodarone is a widely used antiarrhythmic drug, the mechanisms of action of which remain incompletely understood. Indirect evidence suggests that the class III properties of amiodarone may be mediated by cardiac antithyroid effects. We sought to determine whether the effects of chronic amiodarone on repolarization in guinea pig hearts can be attributed to an antithyroid action by studying the changes in dofetilide-sensitive rapid (I(Kr)) and dofetilide-resistant slow (I(Ks)) delayed rectifier currents, inward rectifier K+ current (I(K1)), and action potentials of ventricular myocytes from five groups of guinea pigs: control, hypothyroid, amiodarone- treated for 7 days, hypothyroid plus amiodarone, and vehicle (dimethyl sulfoxide) treated. I(Ks) was reduced by amiodarone (to 61% of control, P < .05, at 50 mV) but was more strongly reduced by hypothyroidism (to 35% of control, P < .01, 50 mV). Amiodarone significantly reduced I(Kr) and I(K1) (by 55 and 64% at 10 mV and -50 mV, respectively), which were unaffected by hypothyroidism. Amiodarone alone and hypothyroidism alone had similar action potential-prolonging actions. Hypothyroid animals treated with amiodarone showed a combination of ionic effects (strong I(Ks) reduction, similar to hypothyroidism alone; reduced I(Kr) and I(K1), similar to amiodarone alone), along with action potential prolongation significantly greater than that caused by either intervention alone. We conclude that chronic amiodarone and hypothyroidism have different effects on ionic currents and that their combination prolongs action potential duration to a greater extent than either alone in guinea pig hearts, suggesting that the class III actions of amiodarone are not mediated by a cardiac hypothyroid state.link_to_subscribed_fulltex

Electrophysiological mechanisms by which hypothyroidism delays repolarization in guinea pig hearts

Thyroid hormone is known to exert important effects on cardiac repolarization, but the underlying mechanisms are poorly understood. We investigated the electrophysiological mechanisms of differences in repolarization between control guinea pigs and hypothyroid animals (thyroidectomy plus 5-propyl-2-thiouracil). Hypothyroidism significantly prolonged the rate-corrected Q-T interval in vivo and action potential duration (APD) of isolated ventricular myocytes. Whole cell voltage-clamp studies showed no change in current density or kinetics of L-type Ca2+ current, inward rectifier K+ current, or Na+ current in hypothyroid hearts. Dofetilide-resistant current (I(Ks)) step current densities were smaller by ~65%, and tail current densities were reduced by 80% in myocytes from hypothyroid animals compared with controls. The ratio of delayed rectifier step current at +50 mV to tail current at -40 mV was significantly larger in hypothyroid cells for test pulses from 60- to 4,200-ms duration, reflecting a smaller I(Ks). Dofetilide-sensitive current (I(Kr)) densities were not significantly changed. I(Ks) half-activation voltage shifted to more positive voltages in hypothyroidism (29.5 ± 2.2 vs. 21.3 ± 2.7 mV in control, P < 0.01), whereas I(Kr) voltage dependence was unchanged. We conclude that hypothyroidism delays repolarization in the guinea pig ventricle by decreasing I(Ks), a novel and potentially important mechanism for thyroid regulation of cardiac electrophysiology.link_to_subscribed_fulltex

Electrophysiologic effects of chronic amiodarone therapy and hypothyroidism, alone and in combination, on guinea pig ventricular myocytes

Amiodarone is a widely used antiarrhythmic drug, the mechanisms of action of which remain incompletely understood. Indirect evidence suggests that the class III properties of amiodarone may be mediated by cardiac antithyroid effects. We sought to determine whether the effects of chronic amiodarone on repolarization in guinea pig hearts can be attributed to an antithyroid action by studying the changes in dofetilide-sensitive rapid (I(Kr)) and dofetilide-resistant slow (I(Ks)) delayed rectifier currents, inward rectifier K+ current (I(K1)), and action potentials of ventricular myocytes from five groups of guinea pigs: control, hypothyroid, amiodarone- treated for 7 days, hypothyroid plus amiodarone, and vehicle (dimethyl sulfoxide) treated. I(Ks) was reduced by amiodarone (to 61% of control, P < .05, at 50 mV) but was more strongly reduced by hypothyroidism (to 35% of control, P < .01, 50 mV). Amiodarone significantly reduced I(Kr) and I(K1) (by 55 and 64% at 10 mV and -50 mV, respectively), which were unaffected by hypothyroidism. Amiodarone alone and hypothyroidism alone had similar action potential-prolonging actions. Hypothyroid animals treated with amiodarone showed a combination of ionic effects (strong I(Ks) reduction, similar to hypothyroidism alone; reduced I(Kr) and I(K1), similar to amiodarone alone), along with action potential prolongation significantly greater than that caused by either intervention alone. We conclude that chronic amiodarone and hypothyroidism have different effects on ionic currents and that their combination prolongs action potential duration to a greater extent than either alone in guinea pig hearts, suggesting that the class III actions of amiodarone are not mediated by a cardiac hypothyroid state.link_to_subscribed_fulltex

Effects of the chromanol 293B, a selective blocker of the slow, component of the delayed rectifier K+ current, on repolarization in human and guinea pig ventricular myocytes

Objectives: The slow component of the delayed rectifier K+ current (I(Ks)) is believed to be important in cardiac repolarization, and may be a potential target for antiarrhythmic drugs, but its study has been limited by a lack of specific blockers. The chromanol derivate 293B blocks currents expressed by mink and not HERG in Xenopus oocytes, but little is known about its effects on native currents and action potentials. We aimed to establish the effects of 293B on K+, Na+ and Ca2+ currents and action potentials in human and guinea pig cardiomyocytes. Methods: Whole-cell patch clamp techniques were applied to assess the effects of 293B on isolated myocytes at 36°C. Results: Delayed rectifier current (I(K)) elicited by pulses to + 60 mV from a holding potential of -50 mV in guinea pig myocytes was strongly inhibited by 293B (maximum inhibition 96.9 ± 0.8%; 50% inhibitory concentration, EC50, 1.02 μM), but I(K) during pulses to - 10 mV was unaffected (3.9 ± 8.4% inhibition at 50 μM). Half-activation voltages, current-voltage relations, and current densities of drug-resistant and drug- sensitive I(K) correspond to those of I(Kr) and I(Ks) respectively. Inward rectifier K+ current, Na+ current and L-type Ca2+ current were unaffected by 293B. Transient outward current in human ventricular myocytes was inhibited by 293B at an EC50 of 24 μM, less than one twentieth the potency for I(Ks) inhibition in guinea pig myocytes. While dofetilide prolonged action potential duration (APD) with strong reverse use dependence, 293B prolonged guinea pig and human ventricular APD to a similar fractional extent at all frequencies. Conclusions: 293B is a selective I(Ks) blocker, and the frequency dependence of APD prolongation caused by this I(Ks) blocker is different from that caused by I(Kr) blockade: 293B may be an interesting tool to study the physiologic role of I(Ks) and the antiarrhythmic potential of I(Ks) blockade.link_to_subscribed_fulltex

Transmembrane I(Ca) contributes to rate-dependent changes of action potentials in human ventricular myocytes

The mechanism of action potential abbreviation caused by increasing rate in human ventricular myocytes is unknown. The present study was designed to determine the potential role of Ca2+ current (I(Ca)) in the rate-dependent changes in action potential duration (APD) in human ventricular cells. Myocytes isolated from the right ventricle of explanted human hearts were studied at 36°C with whole cell voltage and current-clamp techniques. APD at 90% repolarization decreased by 36 ± 4% when frequency increased from 0.5 to 2 Hz. Equimolar substitution of Mg2+ for Ca2+ significantly decreased rate-dependent changes in APD (to 6 ± 3%, P < 0.01). Peak I(Ca) was decreased by 34 ± 3% from 0.5 to 2 Hz (P < 0.01), and I(Ca) had recovery time constants of 65 ± 12 and 683 ± 39 ms at -80 mV. Action potential clamp demonstrated a decreasing contribution of I(Ca) during the action potential as rate increased. The rate-dependent slow component of the delayed rectifier K+ current (I(Ks)) was not observed in four cells with an increase in frequency from 0.5 to 3.3 Hz, perhaps because the I(Ks) is so small that the increase at a high rate could not be seen. These results suggest that reduction of Ca2+ influx during the action potential accounts for most of the rate-dependent abbreviation of human ventricular APD.link_to_subscribed_fulltex