ATX-II Effects on the Apparent Location of M Cells in a Computational Model of a Human Left Ventricular Wedge

• Published in: Journal of cardiovascular electrophysiology Vol. 17; no. s1; pp. S86 - S95
• Main Authors: DOS SANTOS, RODRIGO WEBER, OTAVIANO CAMPOS, FERNANDO, NEUMANN CIUFFO, LEANDRO, NYGREN, ANDERS, GILES, WAYNE, KOCH, HANS
• Format: Journal Article
• Language: English
• Published: 350 Main Street , Malden , MA 02148-5018 , USA , and 9600 Garsington Road , Oxford OX4 2DQ , UK Blackwell Publishing Inc 01.05.2006
• Subjects: Action Potentials - drug effects; Action Potentials - physiology; bidomain cardiac model; Cardiotonic Agents - pharmacology; Cnidarian Venoms - pharmacology; Computer Simulation; Electric Stimulation; Heart Conduction System - drug effects; Heart Conduction System - physiology; Heart Ventricles - drug effects; human left ventricle action potential; Humans; Ion Channel Gating - drug effects; Ion Channel Gating - physiology; late Na+ current; M cell; Membrane Potentials - drug effects; Membrane Potentials - physiology; Models, Cardiovascular; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - physiology; Sodium - metabolism; Sodium Channels - drug effects; Sodium Channels - physiology; T-wave; transmural conduction; Ventricular Function
• ISSN: 1045-3873; 1540-8167
• DOI: 10.1111/j.1540-8167.2006.00389.x

Introduction: The apparent location of the myocytes (M cells) with the longest action potential duration (APD) in a canine left ventricular (LV) wedge have been reported to shift after application of a sea anemone toxin, ATX‐II. This toxin slows inactivation of INa and thus prolongs APD. Thus, M cells may exhibit dynamic functional states, rather than being a static, anatomically discrete, myocyte population. In this study, we attempted to further define and understand this phenomenon using a mathematical model of the human ventricular myocyte action potential incorporated into an in silico “wedge” preparation. Our simulations demonstrate that even under conditions of a fixed population and ratio of epicardial, M, and endocardial myocytes, the apparent anatomical position (transmural location) of the myocytes with the longest APD can shift following ATX‐II treatment. This arises because the ATX‐II effect, modeled as a small increase in the late or persistent Na+ current, and consequent prolongation of APD significantly changes the electrotonic interactions between ventricular myocytes in this LV wedge preparation. Methods and Results: This LV wedge model is based on bidomain equations. It corresponds to a rectangular tissue immersed in a passive and isotropic medium that represents the superfusion bath. In this theoretical work, the three known different and discrete populations of myocytes in the human left ventricle have been included: the epicardial, M, and endocardial cells. The effects of ATX‐II on INa were simulated by altering the voltage‐dependent steady‐state inactivation of the parameters h (fast gate) and j (slow gate). As a result, in these ATX‐II simulations a persistent late Na+ current was generated in all three types of ventricular myocytes. However, the APDs were prolonged in a heterogeneous pattern. Our simulations demonstrate that after the ATX‐II effects develop, alterations in transmural electrotonic interactions can produce changes in the transmural location of myocytes with the longest APD. Conclusions: The combination of intercellular electrotonic interactions, which tend to reduce and smooth out the discrete transmural APD variations, and the heterogeneous effects of ATX‐II, which preferentially prolong the APD of M cells, can shift the location of the ventricular myocytes. This shift results in significantly altered transmural patterns of action potential durations, which would be expected to change localized refractory period and excitability. These cellular changes give rise to alterations in the corresponding surface electrograms and may change the overall substrates for conduction and rhythm disturbances.