Increased Sensitivity to Ischemia in an Early Diabetic Cardiomyopathy: The Role of Calcium Handling

Abstract

Diabetic cardiomyopathy is characterized by early-onset diastolic dysfunction and late-onset systolic dysfunction. However, little is known about the mechanisms underlying the response of the diabetic myocardium to ischemia.Aim - To study the left ventricular (LV) dysfunction and the role of calcium handling in infarcted diabetic mice in an early stage of diabetic cardiomyopathy.Methods and Results - A cohort of male diabetic db/db and age-matched nondiabetic control mice at 10 wk of age was randomly assigned into Sham and myocardial infarction (MI) groups. MI was induced by coronary ligation. Standard echocardiography and tissue Doppler imaging were performed by high-resolution in-vivo imaging system, and diastolic sarcoplasmic reticulum (SR) calcium leak was measured in isolated cardiomyocytes using fluorescence microscope. One month after MI, 75% of the nondiabetic mice survived vs. 55% of the MI diabetic mice (p=0.04). A significant LV dilatation was observed in MI diabetic mice compared to nondiabetic (p=0.03). Peak systolic tissue velocity (Sm) was 28% lower in MI diabetic mice than in nondiabetic group (nondiabetic: 19±1 vs. 17±2mm/s; diabetic: 18±2 vs. 13±2∗mm/s, ∗p=0.05, for Sham and MI, respectively). Peak early diastolic tissue velocity (Em) was decreased in both Sham and MI diabetic mice (17±2∗ and 16±4∗ vs. 25±3 and 25±4 mm/s, ∗p<0.05, respectively). Diastolic SR calcium leak was unchanged in 10-wk diabetic mice compared with nondiabetic mice. However, a significant increase diastolic SR calcium leak was observed in MI diabetic mice relative to MI nondiabetic mice.Conclusion - The altered calcium homeostasis is an important determinant of sensitivity to ischemia and of loss of the ventricular function in the early stage of diabetic heart disease in diabetic mice.