QRS/T-wave and calcium alternans in a type I diabetic mouse model for spontaneous postmyocardial infarction ventricular tachycardia: A mechanism for the antiarrhythmic effect of statins.

Background: The incidence of sudden arrhythmic death is markedly increased in diabetics.

Objective: The purpose of this study was to develop a mouse model for postmyocardial infarction (post-MI) ventricular tachycardia (VT) in the diabetic heart and determine the mechanism of an antiarrhythmic effect of statins.

Methods: ECG transmitters were implanted in wild-type (WT), placebo, and pravastatin-treated type I diabetic Akita mice. MIs were induced by coronary ligation, and Ca transients were studied by optical mapping, and Ca transients and sparks in left ventricular myocytes (VM) by the Ionoptix system and confocal microscopy.

Results: Burst pacing of Akita mouse hearts resulted in rate-related QRS/T-wave alternans, which was attenuated in pravastatin-treated mice. Post-MI Akita mice developed QRS/T-wave alternans and VT at 2820 ± 879 beats per mouse, which decreased to 343 ± 115 in pravastatin-treated mice (n = 13, P <.05). Optical mapping demonstrated pacing-induced VT originating in the peri-infarction zone and Ca alternans, both attenuated in hearts of statin-treated mice. Akita VM displayed Ca alternans, and triggered activity as well as increased Ca transient decay time (Tau), Ca sparks, and cytosolic Ca and decreased SR Ca stores all of which were in part reversed in cells from statin treated mice. Homogenates of Akita ventricles demonstrated decreased SERCA2a/PLB ratio and increased ratio of protein phosphatase (PP-1) to the PP-1 inhibitor PPI-1 which were reversed in homogenates of pravastatin-treated Akita mice.

Conclusion: Pravastatin decreased the incidence of post-MI VT and Ca alternans in Akita mouse hearts in part by revering abnormalities of Ca handling via the PP-1/PPI-1 pathway.