Overexpressing calcineurin (CN) in transgenic mouse heart results in massive cardiac hypertrophy followed by sudden death. Sudden deaths are caused by abrupt transitions from sinus rhythm to heart block (asystole) in CN mice. Preliminary studies showed decreased dv/dt_max of phase 0 of the action potential. Accordingly, the hypothesis was tested that decreased activity of the sodium channel contributes to heart block. Profound decreases in activity of I_Na paralleled the changes in action potential characteristics. Progressive age-dependent decreases were observed such that at 42-50 days of life, little sodium channel function exists. However, this was not paralleled by decreased protein expression as assessed by immunocytochemistry or by Western blot. Since calcineurin can interact with the ryanodine receptor, we assessed whether chronic in vitro treatment with BAPTA-AM, thapsigargin and ryanodine could rescue the decrease of I_Na. All of these treatments rescued I_Na to levels indistinguishable from wildtype. The non-specific PKC inhibitor bisindolylmaleimide-I also rescued the decrease of I_Na. To assess whether decreased sodium channel activity contributes to sudden death in vivo, response to encainide (20 mg/kg) was assessed: 6/10 young calcineurin mice died due to asystole whereas 0/10 wildtype mice died (p < 0.01). Moreover, encainide produced exaggerated prolongation of the QRS width in sinus beats before the heart block. Catacholamine tone appears necessary to support life in older calcineurin mice because propranolol (1 mg/kg) triggered asystolic death in 5/6 calcineurin mice. Conclusion: Decrease in Na channel activity is in the common final pathway to asystole in calcineurin mice.