Hongwei Jin1, Charles M Welzig2, Mark Aronovitz3, Farzad Noubary4, Robert Blanton5, Bo Wang3, Mohammad Rajab6, Alfred Albano7, Mark S Link8, Sami F Noujaim9, Ho-Jin Park10, Jonas B Galper11. 1. Tufts Medical Center, Tufts University School of Medicine, Boston, Massachusetts; Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts. Electronic address: HJin@tuftsmedicalcenter.org. 2. Tufts Medical Center, Tufts University School of Medicine, Boston, Massachusetts; Departments of Neurology, Physiology and Biomedical Engineering, Medical College of Wisconsin, Milwaukee, Wisconsin. 3. Tufts Medical Center, Tufts University School of Medicine, Boston, Massachusetts; Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts. 4. Tufts Medical Center, Tufts University School of Medicine, Boston, Massachusetts; Tufts Clinical and Translational Science Institute, Boston, Massachusetts. 5. 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. 6. Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts; Department of Internal Medicine, Virginia Commonwealth University Medical Center, Richmond, Virginia. 7. Tufts Medical Center, Tufts University School of Medicine, Boston, Massachusetts; Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts; Spectrum Health, Grand Rapids, Michigan. 8. Tufts Medical Center, Tufts University School of Medicine, Boston, Massachusetts; Tufts Clinical and Translational Science Institute, Boston, Massachusetts; UT Southwestern Medical Center, Dallas, Texas. 9. 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. 10. Tufts Medical Center, Tufts University School of Medicine, Boston, Massachusetts; Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts. Electronic address: HPark@tuftsmedicalcenter.org. 11. 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. Electronic address: JGalper@tuftsmedicalcenter.org.
Abstract
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.
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 Akitamice. 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 Akitamice 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.
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