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Cardiovascular Research 2006 71(1):88-96; doi:10.1016/j.cardiores.2006.02.028
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Copyright © 2006, European Society of Cardiology

IKr contributes to the altered ventricular repolarization that determines long-term cardiac memory

Maria N. Obreztchikova1, Kornelis W. Patberg1, Alexei N. Plotnikov, Nazira Ozgen, Irina N. Shlapakova, Andrew V. Rybin, Eugene A. Sosunov, Peter Danilo, Jr., Evgeny P. Anyukhovsky, Richard B. Robinson and Michael R. Rosen*

Center for Molecular Therapeutics, Department of Pharmacology and Pediatrics, College of Physicians and Surgeons of Columbia University, 630 West 168 Street, PH 7West-321, New York, NY 10032, United States

* Corresponding author. Tel.: +1 212 305 8754; fax: +1 212 305 8351. Email address: mrr1{at}columbia.edu

Objective Cardiac memory (CM) is characterized by an altered T-wave morphology, which reflects altered repolarization gradients. We hypothesized that the delayed rectifier currents, IKr and IKs, might contribute to these repolarization changes.

Methods We studied conscious, chronically instrumented dogs paced from the postero-lateral left ventricular (LV) wall at rates 5–10% faster than sinus rate for 3weeks. ECGs during sinus rhythm were recorded on days 0, 7, 14 and 21 of pacing. Within 3weeks, CM achieved steady state, hearts were excised, and epicardial and endocardial tissues and myocytes were studied.

Results In unpaced controls, action potential duration to 50% and 90% repolarization (APD) in epicardium was shorter than in endocardium (P<0.05); in CM epicardial APD increased at CL≥500ms, while endocardial APD was either unchanged or decreased such that the transmural gradient seen in controls diminished (P<0.05). A transmural IKr gradient occurred in controls (epicardium>endocardium, P<0.05) and was reversed in CM. No IKs transmural gradient was found in controls, while in CM endocardial IKs was greater than epicardial at greater than +50mV. Canine ERG (cERG) mRNA and protein in epicardium>endocardium in controls (P<0.05), and this difference was lost in CM. Expression levels of KCNQ1 and KCNE1 protein were similar in all groups.

Conclusions A transcriptionally induced change in epicardial IKr contributes to the altered ventricular repolarization that characterizes CM.

KEYWORDS Arrhythmias (mechanisms); K-channel; ECG

1 Contributed equally as first author.

Time for primary review 22 days


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