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, Charles M. Welzig, Mark Aronovitz, Farzad Noubary, Robert Blanton, Bo Wang, Mohammad Rajab, Alfred Albano, Mark S. Link, Sami F. Noujaim, Ho Jin Park, Jonas B. Galper

Research output: Contribution to journalArticle

6 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1406-1416
Number of pages11
JournalHeart Rhythm
Volume14
Issue number9
DOIs
StatePublished - Sep 2017

Keywords

  • Akita mouse
  • Ca alternans
  • Ca handling proteins
  • Diabetes
  • Myocardial infarction
  • QRS/T-wave alternans
  • Statins
  • Ventricular tachycardia

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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    Jin, H., Welzig, C. M., Aronovitz, M., Noubary, F., Blanton, R., Wang, B., Rajab, M., Albano, A., Link, M. S., Noujaim, S. F., Park, H. J., & Galper, J. B. (2017). 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. Heart Rhythm, 14(9), 1406-1416. https://doi.org/10.1016/j.hrthm.2017.05.026