Ionic Mechanism of Delayed Afterdepolarizations in Ventricular Cells Isolated From Human End-Stage Failing Hearts

Background—Animal studies have shown that the Ca2+-activated Cl− current (ICl(Ca)) and the Na+/Ca2+ exchange current (INa/Ca) contribute to the transient inward current (Iti). Iti is responsible for the proarrhythmic delayed afterdepolarizations (DADs). We investigated the ionic mechanism of Iti and DADs in human cardiac cells. Methods and Results—Human ventricular cells were enzymatically isolated from explanted hearts of patients with end-stage heart failure and studied with patch-clamp methodology. Itis were elicited in the presence of 1 &mgr;mol/L norepinephrine by trains of repetitive depolarizations from −80 to +50 mV. DADs were induced in the presence of 1 &mgr;mol/L norepinephrine at a stimulus frequency of 1 Hz. Iti currents were inwardly directed over the voltage range between −110 and + 50 mV. Neither the Cl− channel blocker 4,4′-diisothiocyanatostilbene-2,2′-disulfonic acid nor changes in [Cl−]i affected Iti or DAD amplitude. This excludes an important role for ICl(Ca). Blockade of Na+/Ca2+ exchange by substitution of all extracellular Na+ by Li+, conversely, completely inhibited Iti. In rabbit, ICl(Ca) density in ventricular cells isolated from control hearts did not differ significantly from that in ventricular cells isolated from failing hearts. Conclusions—In contrast to many animal species, Iti and DADs in human ventricular cells from failing hearts consist only of INa/Ca. In rabbits, heart failure per se does not alter ICl(Ca) density, suggesting that ICl(Ca) may also be absent during DADs in nonfailing human ventricular cells.

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