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.