HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Free via Open Access: OA OA Full Text Full Text (PDF) OA All Versions of this Article: 578/1/99    most recent jphysiol.2006.118133v1 Services Email this article to a friend Similar articles in this journal 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 Thomas, G. Articles by Huang, C. L.-H. Search for Related Content PubMed PubMed Citation Articles by Thomas, G. Articles by Huang, C. L.-H. Related Collections Cardiovascular

¹ Section of Cardiovascular Biology, Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1QW, UK
² Physiological Laboratory, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK

Mutations within KCNE1 encoding a transmembrane protein which coassembles with K⁺ channels mediating slow K⁺, I_Ks, currents are implicated in cardiac action potential prolongation and ventricular arrhythmogenicity in long QT syndrome 5. We demonstrate the following potentially arrhythmogenic features in simultaneously recorded, left ventricular, endocardial and epicardial monophasic action potentials from Langendorff-perfused murine KCNE1–/– hearts for the first time. (1) Prolonged epicardial (57.1 ± 0.5 ms cf. 36.1 ± 0.07 ms in wild-type (WT), P < 0.001; n = 5) and endocardial action potential duration at 90% repolarication (APD₉₀) (54.4 ± 2.4 ms cf. 48.5 ± 0.3 ms, P < 0.05; n = 5). (2) Negative transmural repolarization gradients (APD₉₀: endocardial minus epicardial APD₉₀) (–2.5 ± 2.4 ms, compared with 12.4 ± 1.1 ms in WT, P < 0.001; n = 5). (3) Frequent epicardial early afterdepolarizations (EADs) and spontaneous ventricular tachycardia (VT) in 4 out of 5 KCNE1–/– hearts but not WT (n = 5). EADs were especially frequent following temporary cessations of ventricular pacing. (4) Monomorphic VT lasting 1.36 ± 0.2 s in 5 out of 5 KCNE1–/– hearts, following premature stimuli but not WT (n = 5). (5) Epicardial APD alternans. Perfusion of KCNE1–/– hearts with 1 µM nifedipine induced potentially anti-arrhythmic changes including: (1) restored epicardial APD₉₀ (from 57.1 ± 0.5 ms to 42.3 ± 0.4 ms, P < 0.001; n = 5); (2) altered APD₉₀ to values (11.2 ± 2.6) close to WT (P > 0.05; n = 5); (3) EAD suppression during both spontaneous activity and following cessation of ventricular pacing (n = 5) to give similar features to WT controls (n = 5); (4) suppression of programmed electrical stimulation-induced VT; and (5) suppression of APD alternans. These findings suggest arrhythmic effects of reduced outward currents expected in KCNE1–/– hearts and their abolition by antagonism of inward L-type Ca²⁺ current.

(Received 28 July 2006; accepted after revision 2 November 2006; first published online 9 November 2006)
Corresponding author C. L.-H. Huang: Physiological Laboratory, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK. Email: clh11{at}cam.ac.uk