Abstract 20209: Spontaneous Post Myocardial Infarction Arrhythmia is Potentiated by Calcium Alternans in Type I Diabetic Akita Mice

Abstract

Introduction: Myocardial infarction (MI) is the most common cause of mortality in diabetes. Diabetics have been shown to be twice as likely to die suddenly from MI out of hospital compared to non diabetic patients. The mechanism of sudden death in the diabetic population is unclear. Here we use the Akita Type I diabetic mouse as an animal model for the study of post MI ventricular tachycardia arrhythmias (VT) and the role of abnormalities of Ca2+ homeostasis in the pathogenesis of post MI VT. Methods: To determine the effect of MI on the incidence of VT, EKG transmitters were implanted into WT and Akita mice. MIs were generated by permanent ligation of the left coronary artery resulting in infarctions affecting more than 30% of the LV as demonstrated by echocardiographic analysis and TTC staining. Dual calcium-voltage optical mapping was performed on the isolated Langendorf heart after MI. Left ventricular myocytes were isolated for calcium imaging studies. Sarcomere shortening and Ca2+transients were measured by Ionoptix system and Ca2+ sparks by confocal microscopy. Results: Compared to WT, Akita diabetic mice developed a high incidence of non sustained and sustained VT in the first 30h post MI peaking at 18 h. Epicardial optical mapping demonstrated pacing induced: Ca2+ alternans which was most marked in the peri-infarction zone of Akitas and VT also originating in the peri-infarction zone in the Akita mice, but not in WT. Single cardiomyocytes from Akita displayed both contractile and Ca2+ alternans when pacing rate was increased above 3Hz, but none in cells from WT mice. Ca2+ imaging studies were performed to determine whether alterations in Sacroplasmic reticulum(SR) Ca2+ function contributes to Ca2+ alternans. In Akita myocytes, Ca2+ transient decay time( Tau) was significantly increased ( 0.171±0.01s, N=23 ) compared to WT(0.139±0.007s, N=20, P<0.05), The frequency of spontaneous Ca2+ sparks in Akita mocytes increased from 0.043 ± 0.003 sparks/100μm/s (N=23) in the WT to 0.266 ± 0.023 sparks/100μm/s ( P<0.05, N=36). Conclusions: The type 1 diabetic Akita mice demonstrate a high incidence of spontaneous post MI VT associated with pronounced Ca2+ alternans in the peri-infarction zone and abnormalities of Ca2+ homeostasis.