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

Abstract

Background Animal studies have shown that the Ca 2+ -activated Cl − current ( I Cl(Ca) ) and the Na + /Ca 2+ exchange current ( I Na/Ca ) contribute to the transient inward current ( I ti ). I ti is responsible for the proarrhythmic delayed afterdepolarizations (DADs). We investigated the ionic mechanism of I ti 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. I ti s were elicited in the presence of 1 μmol/L norepinephrine by trains of repetitive depolarizations from −80 to +50 mV. DADs were induced in the presence of 1 μmol/L norepinephrine at a stimulus frequency of 1 Hz. I ti 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 I ti or DAD amplitude. This excludes an important role for I Cl(Ca) . Blockade of Na + /Ca 2+ exchange by substitution of all extracellular Na + by Li + , conversely, completely inhibited I ti . In rabbit, I Cl(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, I ti and DADs in human ventricular cells from failing hearts consist only of I Na/Ca . In rabbits, heart failure per se does not alter I Cl(Ca) density, suggesting that I Cl(Ca) may also be absent during DADs in nonfailing human ventricular cells.