Abstract:
Background and objectives: Type 2 diabetes is associated with the development of diastolic dysfunction and can progress to overt heart failure if left untreated. 2D speckle tracking echocardiography has been proposed as a useful tool for cardiac functional evaluation. However, to date its application in characterising diastolic dysfunction in rodent models of diabetes has been limited. The first goal of this study was to use speckle tracking echocardiography to evaluate diastolic function in a high fat diet-induced mouse model of type 2 diabetes. Unpublished data from the Mellor, et al. lab has identified that diastolic dysfunction in diabetes may be linked to cardiac glycogen accumulation. The second goal of this study was to investigate the relationship between cardiac glycogen and diastolic myocardial mechanics in diabetic hearts. In conjunction with establishing a high throughput in-vitro model for investigating cardiomyocyte glycogen dysregulation in diabetic conditions. Methods: C57Bl/6J mice were fed either a control or high fat diet for 20 weeks followed by m-mode, doppler and 2D speckle tracking echocardiography. Glycogen was measured using a glycogen absorbance assay and a protein lowry assay for standardisation. H9c2 cells were exposed to high (40mM) or control (20mM) glucose for 96hrs prior to glycogen measurement. Results: 1) Mild cardiac remodelling was observed in obese diabetic mice, evidenced by increased systolic left ventricular anterior and posterior wall thickness (14% and 12% increase respectively). 2) Conventional doppler imaging measures of diastolic dysfunction (E/e’, 35% increase) were associated with marked changes in diastolic myocardial wall deformation and kinetics in obese diabetic mice 3) Unexpectedly, cardiac glycogen was unchanged in obese diabetic mice. Preliminary investigations revealed that isoflurane anaesthesia may influence cardiac glycogen levels (39% decrease). 4) H9c2 cells are validated as a high-throughput in-vitro model of glycogen dysregulation in diabetic conditions (104% glycogen increase, 40mM vs 20mM glucose). Conclusion: This study provides the first evidence that type 2 diabetes alters diastolic myocardial wall deformation parameters, and that speckle tracking echocardiography is a more sensitive approach in measuring diastolic function than doppler imaging. This study also provides evidence validating the use of H9c2 cells to examine the molecular mechanisms of glycogen accumulation in the cardiac setting.