Loss of transverse-tubules promotes the development of ectopic activity in guinea-pig ventricle

Intracellular calcium cycling plays an important role in healthy and pathophysiological cardiac behavior. One such behavior is the development of ectopic activity, which is linked to rapid arrhythmias such as tachycardia and fibrillation. Calcium dynamics are strongly dependant on the function of the dyad; a restricted space which contains the L-type calcium channels and intracellular calcium release units. Dyads are observed in both the surface and T-tubular membrane. In this study, we use a stochastic mathematical model of the guinea-pig ventricle to investigate the effect of a loss of the T-tubular membrane on the dynamics of intracellular calcium cycling and its affect on membrane ion currents. It was demonstrated that in the presence of beta-stimulation, loss of T-tubules promotes significant triggered activity at the cellular level, which may develop into ectopic activity at the tissue level. The primary mechanism by which this occurs is two-fold: (1) increased activity of L-type calcium channels under beta-stimulation leads to large triggered and spontaneous intracellular calcium transients, promoting enhanced sodium-calcium exchanger activity; (2) a loss of the time-independent potassium channels raises the resting potential, allowing the threshold for activation of the fast sodium current to be surpassed.