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This Article Full Text Full Text (PDF) All Versions of this Article: 295/1/H97    most recent 01032.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Guo, D. Articles by Yan, G.-X. Search for Related Content PubMed PubMed Citation Articles by Guo, D. Articles by Yan, G.-X.

Calcium-activated chloride current contributes to action potential alternations in left ventricular hypertrophy rabbit

¹Main Line Health Heart Center, Wynnewood, ²Department of Pathology, Microbiology and Immunology, Philadelphia College of Osteopathic Medicine, Philadelphia, and ³Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania

Submitted 7 September 2007 ; accepted in final form 25 April 2008

T-wave alternans, characterized by a beat-to-beat change in T-wave morphology, amplitude, and/or polarity on the ECG, often heralds the development of lethal ventricular arrhythmias in patients with left ventricular hypertrophy (LVH). The aim of our study was to examine the ionic basis for a beat-to-beat change in ventricular repolarization in the setting of LVH. Transmembrane action potentials (APs) from epicardium and endocardium were recorded simultaneously, together with transmural ECG and contraction force, in arterially perfused rabbit left ventricular wedge preparation. APs and Ca²⁺-activated chloride current (I_Cl,Ca) were recorded from left ventricular myocytes isolated from normal rabbits and those with renovascular LVH using the standard microelectrode and whole cell patch-clamping techniques, respectively. In the LVH rabbits, a significant beat-to-beat change in endocardial AP duration (APD) created beat-to-beat alteration in transmural voltage gradient that manifested as T-wave alternans on the ECG. Interestingly, contraction force alternated in an opposite phase ("out of phase") with APD. In the single myocytes of LVH rabbits, a significant beat-to-beat change in APD was also observed in both left ventricular endocardial and epicardial myocytes at various pacing rates. APD alternans was suppressed by adding 1 µM ryanodine, 100 µM 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS), and 100 µM 4-acetamido-4'-isothiocyanostilbene-2,2'-disulfonic acid (SITS). The density of the Ca²⁺-activated chloride currents (I_Cl,Ca) in left ventricular myocytes was significantly greater in the LVH rabbits than in the normal group. Our data indicate that abnormal intracellular Ca²⁺ fluctuation may exert a strong feedback on the membrane I_Cl,Ca, leading to a beat-to-beat change in the net repolarizing current that manifests as T-wave alternans on the ECG.

T-wave alternans