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.


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.


CONCLUSIONS
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.
Dong
Deli
D
Cardiovascular Research Group, Department of Medicine, University of Calgary, 3330 Hospital Drive N.W., Calgary, Alberta, Canada T2N 4N1.
Duan
Yanjun
Y
Guo
Jiqing
J
Roach
Dan E
DE
Swirp
Shauni L
SL
Wang
Li
L
Lees-Miller
J P
JP
Sheldon
R S
RS
Molkentin
Jeffery D
JD
Duff
Henry J
HJ
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000503:physiopathology; D019703:Calcineurin / Q000502:physiology*; D065095:Calcineurin Inhibitors; D016572:Cyclosporine / Q000627:therapeutic use; D016757:Death, Sudden, Cardiac / Q000209:etiology*; D004562:Electrocardiography; D005260:Female; D006329:Heart Conduction System; D017379:Hypertrophy, Left Ventricular / Q000503:physiopathology / Q000517:prevention & control; D008133:Long QT Syndrome / Q000503:physiopathology; D051379:Mice; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism*; D015996:Survival Rate
D065095:Calcineurin Inhibitors; D015221:Potassium Channels; D016572:Cyclosporine; D019703:Calcineurin