Arrhythmogenesis in heart cells involves reverse E–C coupling and reverse electrotonic conduction along T-tubules: Calcium Signaling and Excitation–Contraction in Cardiac, Skeletal and Smooth Muscle

Early afterdepolarization (EAD) is an aberrant cardiac afterpotential that underlies the development of life-threatening ventricular arrhythmias. It is believed that the development of EAD is caused by the reactivation of L-type Ca²⁺ current during the period of the action potential plateau; however, the cellular mechanisms that underlie the development of EAD is still controversial. One favorable alternative is the depolarizing reverse-mode operation of the Na⁺/Ca²⁺ exchanger, which is activated by aberrant Ca²⁺ release from the sarcoplasmic reticulum in the process of reverse E–C coupling. Since EADs develop preferentially in damaged heart cells with abnormal Ca²⁺-signaling, here I studied the causal link between the development of EADs and aberrant intracellular Ca²⁺ level ([Ca²⁺]_i) dynamics in mouse heart cells using the whole-cell clamp technique. My results show (1) the generation of EADs was preceded by the development of depolarizing membrane potential (V_m) fluctuation, (2) the depolarizing V_m fluctuation is associated with [Ca²⁺]_i elevation, suggesting an involvement of reverse E–C coupling via the Na⁺/Ca²⁺ exchanger, and (3) that extending the T-tubules’ length constant by decreasing the extracellular K⁺ level facilitated the development of the V_m fluctuation and EADs. Taken together, I conclude that EADs are caused by the depolarizing V_m fluctuation, which is induced locally in the T-tubule membrane by aberrant [Ca²⁺]_i elevation and is conducted back electrotonically along the T-tubules.