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Cardiovascular Research 2003 57(2):320-332; doi:10.1016/S0008-6363(02)00661-2
© 2003 by European Society of Cardiology
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Copyright © 2003, European Society of Cardiology

Overexpression of calcineurin in mouse causes sudden cardiac death associated with decreased density of K+ channels

Deli Dong, Yanjun Duan, Jiqing Guo, Dan E Roach, Shauni L Swirp, Li Wang, J.P Lees-Miller, R.S Sheldon, Jeffery D Molkentin and Henry J Duff*

Cardiovascular Research Group, Department of Medicine, University of Calgary, 3330 Hospital Drive N.W., Calgary, Alberta, Canada T2N 4N1

* Corresponding author. Tel.: +1-403-220-6841; fax: +1-403-270-0313. hduff{at}ucalgary.ca

Background: Overexpression of calcineurin in transgenic (TG) mice results in cardiac hypertrophy and unexpected deaths. Methods and results: None of the TG survived beyond 24 weeks (n=38) whereas all of the wildtype (WT, n=47) survived. Prolongation of repolarization preceded the development of sustained pleomorphic ventricular tachycardia and high degree atrioventricular block, which occurred during spontaneous sudden deaths. Since depolarization-activated K+ channels contribute dominantly to repolarization in mice, we hypothesized that the TG would decrease these K+ currents and that the in vivo administration of cyclosporin A (CsA), a calcineurin inhibitor, would reduce this effect. CsA reversed cardiac hypertrophy: capacitance measurements of WT left ventricular myocytes (127±7 pF; n=45) and CsA-treated TG (129±14 pF; n=17) were significantly lower than in placebo-treated TG (220±11 pF; n=41; P<0.001 by ANOVA). Independent of whether the data fit a bi- or a tri-exponential model, the density of Itof was significantly reduced in TG versus WT and CsA reversed this effect. While Itos and IKslow were also reduced in TG, CsA does not reverse this change because long-term in vivo CsA treatment of WT also reduces Itos and IKslow. To assess whether the decreased ‘repolarization reserve’ contributed to arrhythmogenesis, the residual IKr was blocked by dofetilide precipitating pleomorphic ventricular tachycardias. Conclusion: Since the downregulation of Itof was observed with overexpression of calcineurin and was also reversed by the calcineurin inhibitor CsA, we conclude that downregulation of Itof is a consequence of calcineurin overexpression.

KEYWORDS Tau1, relates to the IKslow component; Tau2, relates to the Itos component; Tau3, relates to the Itof component; TG, transgene; TGCsA, transgene treated with CsA; WT, wildtype; WTCsA, wildtype treated with CsA


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