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Cardiovascular Research 2004 64(3):488-495; doi:10.1016/j.cardiores.2004.08.005
© 2004 by European Society of Cardiology
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Copyright © 2004, European Society of Cardiology

Heart block in mice overexpressing calcineurin but not NF-AT3

Anne M. Gillis*, Katherine M. Kavanagh, Heather J. Mathison, Julie R. Somers, Shu Zhan and Henry J. Duff

The Cardiovascular Research Group and the Division of Cardiology, The University of Calgary and Foothills Medical Centre, Calgary, Alberta, Canada

* Corresponding author. Division of Cardiology, The University of Calgary, Health Sciences Hospital 1634, 3330 Hospital Drive N.W., Calgary, Alberta, Canada T2N 4N1. Tel.: +1 403 220 6841; fax: +1 403 270 0313. Email address: amgillis{at}ucalgary.ca

Objective: Overexpression of calcineurin causes cardiac hypertrophy and arrhythmic deaths. During disease development, sinus bradycardia followed by high degree atrioventricular (AV) block finally culminating in ventricular asystole has been observed over time in calcineurin hearts. AV block is associated with the development of pleomorphic ventricular tachycardia in mice and downregulation of potassium currents in ventricular myocytes. We tested the hypothesis that the abnormalities of AV block and propensity to ventricular tachycardia relate to overexpression of calcineurin independent of the development of hypertrophy.

Methods: Cardiac electrophysiologic properties were compared in isolated perfused hearts with ventricular hypertrophy due to overexpression of calcineurin or NF-AT3 and in their corresponding wild types at 15 or 30 days of age.

Results: Compared to wild-type hearts, significant prolongation of sinus node recovery times was noted in both NF-AT3 and calcineurin hearts. Compared to wild-type hearts, Wenckebach cycle length (WCL) and the left ventricular effective refractory period (LVERP) were significantly prolonged in the calcineurin hearts (p<0.05) but not NF-AT3 hearts. In calcineurin mice, left ventricular effective refractory period impinged on Wenckebach cycle length resulting in a significant correlation between left ventricular effective refractory period and Wenckebach cycle length (r2=0.56). No such correlation was observed for wild type or NF-AT3 hearts. At 30 days of development, ventricular tachycardia developed in 70% of calcineurin hearts compared to 0% wild-type hearts (p=0.003), whereas ventricular tachycardia was observed in 33% of NF-AT3 hearts and 10% of corresponding wild-type hearts (p=NS).

Conclusions: The prolonged ventricular refractoriness, seen only in calcineurin hearts, impinges on Wenckebach cycle length resulting in heart block and is associated with propensity to ventricular tachycardia.

KEYWORDS Hypertrophy; Sinus node; Transgenic animal models; Arrhythmias

Time for primary review 15 days


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