Effects of maintained cell coupling during myocardial ischemia - A theoretical model explaining experimental effects of the gap junction opener AAP10

Seidel, Thomas, Prof. Dr. Dhein, Stefan. Heart Centre Leipzig Clinic for Cardiac Surgery, Struempellstr. 39, 04289 Leipzig, Germany.

Background: Altered electrophysiological behaviour of ischemic cardiac tissue is known to be a main cause of arrhythmia. Yet, the complexity of the observed phenomena is not fully understood. Therefore, we developed a 2-dimensional mathematical computer model of cardiac tissue for simulating action potential propagation. It gives the opportunity to simulate normal and pathological conditions as well as effects of pharmacological drugs.

Methods: The model combines the Luo-Rudy-II and the Priebe-Beuckelmann model and includes models of Na+/H+-exchange, of I(K.ATP) and simulates extracellular K+-diffusion. For integration an approximate factorization implicit (AFI) method was used.

In this study, our aim was to investigate the effects of gap junction openers, e.g. AAP10, on parameters which are known to be critical for the development of arrhythmia during acute regional ischemia.

Results: In our model, regional ischemia involved gap junction uncoupling and resulted in regionally enhanced dispersion (40ms vs 7ms in control), and reduced longitudinal and transverse conduction velocities (29cm/s and 16cm/s vs 49cm/s and 19cm/s in control) as well as shortened action potential duration (APD) together with elevated extracellular K+ (up to 15mmol/l vs 5mmol/l in control) and enhanced intracellular Na+ and Ca++. In contrast, when maintaining high cellular coupling during ischemia, we obtained a significantly increased APD homogeneity and less dispersion, higher conduction velocity and, in certain areas a paradoxically decreased number of activated cells which can be explained by current-source-current-sink phenomena. Our data support recent experimental findings and substantiate the antiarrhythmic effects of GJ openers during acute myocardial ischemia.

Conclusion: The simulation shows that maintaining gap junction coupling alone is able to attenuate ischemia-induced APD dispersion and conduction slowing.