Dynamic clamping human and rabbit atrial calcium current: narrowing I (CaL) window abolishes early afterdepolarizations

KEY POINTS: Early‐afterdepolarizations (EADs) are abnormal action potential oscillations and a known cause of cardiac arrhythmias. Ventricular EADs involve reactivation of a Ca(2+) current (I (CaL)) in its ‘window region’ voltage range. However, electrical mechanisms of atrial EADs, a potential cause of atrial fibrillation, are poorly understood. Atrial cells were obtained from consenting patients undergoing heart surgery, as well as from rabbits. I (CaL) was blocked with nifedipine and then a hybrid patch clamp/mathematical‐modelling technique, ‘dynamic clamping’, was used to record action potentials at the same time as injecting an artificial, modifiable, I (CaL) (I (CaL,D‐C)). Progressively widening the I (CaL,D‐C) window region produced EADs of various types, dependent on window width. EAD production was strongest upon moving the activation (vs. inactivation) side of the window. EADs were then induced by a different method: increasing I (CaL,D‐C) amplitude and/or K(+) channel‐blockade (4‐aminopyridine). Narrowing of the I (CaL,D‐C) window by ∼10 mV abolished these EADs. Atrial I (CaL) window narrowing is worthy of further testing as a potential anti‐atrial fibrillation drug mechanism. ABSTRACT: Atrial early‐afterdepolarizations (EADs) may contribute to atrial fibrillation (AF), perhaps involving reactivation of L‐type Ca(2+) current (I (CaL)) in its window region voltage range. The present study aimed (i) to validate the dynamic clamp technique for modifying the I (CaL) contribution to atrial action potential (AP) waveform; (ii) to investigate the effects of widening the window I (CaL) on EAD‐propensity; and (iii) to test whether EADs from increased I (CaL) and AP duration are supressed by narrowing the window I (CaL). I (CaL) and APs were recorded from rabbit and human atrial myocytes by whole‐cell‐patch clamp. During AP recording, I (CaL) was inhibited (3 µm nifedipine) and replaced by a dynamic clamp model current, I (CaL,D‐C) (tuned to native I (CaL) characteristics), computed in real‐time (every 50 µs) based on myocyte membrane potential. I (CaL,D‐C)‐injection restored the nifedipine‐suppressed AP plateau. Widening the window I (CaL,D‐C), symmetrically by stepwise simultaneous equal shifts of half‐voltages (V (0.5)) of I (CaL,D‐C) activation (negatively) and inactivation (positively), generated EADs (single, multiple or preceding repolarization failure) in a window width‐dependent manner, as well as AP alternans. A stronger EAD‐generating effect resulted from independently shifting activation V (0.5) (asymmetrical widening) than inactivation V (0.5); for example, a 15 mV activation shift produced EADs in nine of 17 (53%) human atrial myocytes vs. 0 of 18 from inactivation shift (P < 0.05). In 11 rabbit atrial myocytes in which EADs were generated either by increasing the conductance of normal window width I (CaL,D‐C) or subsequent 4‐aminopyridine (2 mm), window I (CaL,D‐C) narrowing (10 mV) abolished EADs of all types (P < 0.05). The present study validated the dynamic clamp for I (CaL), which is novel in atrial cardiomyocytes, and showed that EADs of various types are generated by widening (particularly asymmetrically) the window I (CaL), as well as abolished by narrowing it. Window I (CaL) narrowing is a potential therapeutic mechanism worth pursuing in the search for improved anti‐AF drugs.