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 Ca2+ transients were studied by optical mapping, and Ca2+ 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 Ca2+ alternans, both attenuated in hearts of statin-treated mice. Akita VM displayed Ca2+ alternans, and triggered activity as well as increased Ca2+ transient decay time (Tau), Ca2+ sparks, and cytosolic Ca2+ and decreased SR Ca2+ 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 Ca2+ alternans in Akita mouse hearts in part by revering abnormalities of Ca2+ handling via the PP-1/PPI-1 pathway.
Keywords
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Article info
Publication history
Published online: May 15, 2017
Footnotes
This work was supported by National Institutes of Health (NIH) Grants R01HL074876 and R01HL087827 to Dr. Galper; Grant R21DK079622 to Dr. Park; NIH CTSA Award UL1TR001064 and American Heart Association Grant 13SDG17050021 to Dr. Jin; Grant RO1HL129136 to Dr Noujaim.
Drs. Jin and Welzig contributed equally to this work.
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