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(Circulation. 2004;110:489-495.)
© 2004 American Heart Association, Inc.

Original Articles

Cardiac Memory Evolves With Age in Association With Development of the Transient Outward Current

Alexei N. Plotnikov, MD^*; Eugene A. Sosunov, PhD^*; Kornelis W. Patberg, MD^*; Evgeny P. Anyukhovsky, PhD; Ravil Z. Gainullin, PhD; Iryna N. Shlapakova, MD; Ganga Krishnamurthy, MD; Peter Danilo, Jr, PhD; Michael R. Rosen, MD

From the Center for Molecular Therapeutics, Departments of Pharmacology and Pediatrics, College of Physicians and Surgeons of Columbia University, New York, NY.

Correspondence to Michael R. Rosen, MD, Gustavus A. Pfeiffer Professor of Pharmacology, Professor of Pediatrics, College of Physicians and Surgeons of Columbia University, Department of Pharmacology, 630 W 168 St, PH7West-321, New York, NY 10032. E-mail mrr1{at}columbia.edu

Received August 1, 2003; de novo received January 13, 2004; revision received March 16, 2004; accepted March 23, 2004.

Background— Calcium-insensitive transient outward current (I_to) is important to the development of cardiac memory (CM), which itself reflects the capacity of the heart to remodel electrophysiologically. We used cardiac pacing to test the hypothesis that CM evolution can be explained by developmental maturation of I_to.

Methods and Results— Acutely anesthetized dogs from 1 day old to adult were paced from the left ventricle (VP, n=29) or left atrial appendage (AP, n=12) to induce CM. T-wave vector displacement (TVD) obtained during VP was greater than with AP (adults, 0.39±0.06 mV; neonates, 0.04±0.01 mV; P<0.05). TVD began to increase at 40 days of age, reaching adult levels by 200 days. Microelectrode studies performed in 18 dogs (ages 3 to 94 days) after completing the CM protocol and 20 additional dogs (1 day old to adult) revealed that the epicardial action potential notch was absent in neonates, became apparent in the young, and was deepest in adults. The relationship between TVD and epicardial notch was such that as notch magnitude increased, TVD increased (r=–0.65, P<0.05). KChIP2 and Kv4.3 mRNA (measured via reverse transcription–polymerase chain reaction) also increased with age.

Conclusions— The inducibility of CM gradually increases with age in association with evolution of the epicardial action potential notch and mRNA expression for KChIP2 and Kv4.3. This suggests that the capacity of the heart to remodel electrophysiologically and to manifest memory during development depends in part on evolution of the determinants of I_to.

Key Words: electrocardiography • electrophysiology • ion channels • genes • pacing

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