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(Circulation. 2001;104:2728.)
© 2001 American Heart Association, Inc.

Basic Science Reports

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

Arie O. Verkerk, PhD; Marieke W. Veldkamp, PhD; Antonius Baartscheer, PhD; Cees A. Schumacher, BSc; Corinne Klöpping, MD; Antoni C.G. van Ginneken, PhD; Jan H. Ravesloot, PhD

From the Department of Physiology (A.O.V., A.C.G.v.G., J.H.R.) and the Experimental and Molecular Cardiology Group (M.W.V., A.B., C.A.S., A.C.G.v.G.), Academic Medical Center, University of Amsterdam, and the Department of Cardiac Transplantation, University Medical Center, Utrecht (C.K.), the Netherlands.

Correspondence to Arie Verkerk, Department of Physiology, Academic Medical Center, Meibergdreef 15, 1105 AZ Amsterdam, the Netherlands. E-mail a.o.verkerk{at}amc.uva.nl

Background— Animal studies have shown that the Ca²⁺-activated Cl^- current (I_Cl(Ca)) and the Na⁺/Ca²⁺ 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_tis 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⁺/Ca²⁺ 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.

Key Words: arrhythmia • heart failure • ion channels • sodium • calcium

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