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

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 I-tof was significantly reduced in TG versus WT and CsA reversed this effect. While I-tos and I-Kslow were also reduced in TG, CsA does not reverse this change because long-term in vivo CsA treatment of WT also reduces I-tos and I-Kslow To assess whether the decreased 'repolarization reserve' contributed to arrhythmogenesis, the residual I-Kr was blocked by dofetilide precipitating pleomorphic ventricular tachycardias. Conclusion: Since the downregulation of I-tof was observed with overexpression of calcineurin and was also reversed by the calcineurin inhibitor CsA, we conclude that downregulation of I-tof is a consequence of calcineurin overexpression. (C) 2003 European Society of Cardiology. Published by Elsevier Science B.V. All rights reserved.