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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

  • Hongwei Jin
    Correspondence
    Address reprint requests and correspondence: Dr. Hongwei Jin
    Affiliations
    Tufts Medical Center, Tufts University School of Medicine, Boston, Massachusetts

    Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts
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  • Charles M. Welzig
    Affiliations
    Tufts Medical Center, Tufts University School of Medicine, Boston, Massachusetts

    Departments of Neurology, Physiology and Biomedical Engineering, Medical College of Wisconsin, Milwaukee, Wisconsin
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  • Mark Aronovitz
    Affiliations
    Tufts Medical Center, Tufts University School of Medicine, Boston, Massachusetts

    Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts
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  • Farzad Noubary
    Affiliations
    Tufts Medical Center, Tufts University School of Medicine, Boston, Massachusetts

    Tufts Clinical and Translational Science Institute, Boston, Massachusetts
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  • Robert Blanton
    Affiliations
    Tufts Medical Center, Tufts University School of Medicine, Boston, Massachusetts

    Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts

    Cardiovascular Division, Cardiovascular Center, Department of Medicine, Tufts Medical Center, Boston, Massachusetts
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  • Bo Wang
    Affiliations
    Tufts Medical Center, Tufts University School of Medicine, Boston, Massachusetts

    Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts
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  • Mohammad Rajab
    Affiliations
    Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts

    Department of Internal Medicine, Virginia Commonwealth University Medical Center, Richmond, Virginia
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  • Alfred Albano
    Affiliations
    Tufts Medical Center, Tufts University School of Medicine, Boston, Massachusetts

    Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts

    Spectrum Health, Grand Rapids, Michigan
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  • Mark S. Link
    Affiliations
    Tufts Medical Center, Tufts University School of Medicine, Boston, Massachusetts

    Tufts Clinical and Translational Science Institute, Boston, Massachusetts

    UT Southwestern Medical Center, Dallas, Texas
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  • Sami F. Noujaim
    Affiliations
    Tufts Medical Center, Tufts University School of Medicine, Boston, Massachusetts

    Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts

    Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, Tampa, Florida
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  • Ho-Jin Park
    Correspondence
    Ho-Jin Park
    Affiliations
    Tufts Medical Center, Tufts University School of Medicine, Boston, Massachusetts

    Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts
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  • Jonas B. Galper
    Correspondence
    Dr. Jonas B. Galper, Molecular Cardiology Research Institute, Tufts Medical Center, 750 Washington St, Boston, MA 02111.
    Affiliations
    Tufts Medical Center, Tufts University School of Medicine, Boston, Massachusetts

    Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts

    Cardiovascular Division, Cardiovascular Center, Department of Medicine, Tufts Medical Center, Boston, Massachusetts
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      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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