More than 16 million people are afflicted with diabetes mellitus in the United States, and its long-term complications account for over 15% of the total U.S. health care costs. Nearly all the morbidity from diabetes is related to cardiovascular dysfunction with diabetic subjects exhibiting a 4-5 times increased risk of developing CHF. Successful early detection of abnormal myocardial function in diabetics may help in the development of therapeutic strategies to prevent or delay progression to overt cardiac disease. The advantage of magnetic resonance imaging, in concert with a technique called tagging to identify intramural patterns of fiber strain, is that the effects of three-dimensional forces acting at a cellular level in the heart can be elucidated. In particular, the twisting motion of the ventricle referred to as torsion reflects the underlying shearing motion of individual planes of myofibrils which generates wall thickening and ventricular ejection. The applicants hypothesize that disruption of the ability of the heart fibers to shear, due to protein cross-linking from advanced glycation end products, will play a role in both systolic and diastolic dysfunction in this entity.
The aims of the study are to show (1) that increased stiffness of the myocardium of diabetics is a major cause of diastolic dysfunction and will be manifest as a decreased rate of ventricular untwisting, (2) that early systolic twist will be also abnormal due to increased stiffness in both compensated and decompensated diabetic hearts, (3) that treatment with cross-link inhibitors or inhibitors of fibrosis can reduce myocardial dysfunction, and (4) that the degree of stiffness of the myocardium and resulting inability to shear is related to exposure to glycemia as assessed by direct measurement of advanced glycation end-products in experimental animals and glycosylated hemoglobin (HbA1c) levels in patients. Diabetic rats (n = 140) and patients (n = 120) will be studied. Ventricular twist will be determined using MR tagging and results compared to traditional measures of diastolic and systolic function, glycosylated hemoglobin levels, advanced glycosylation end products and other clinical sequelae typically associated with advanced diabetes such as retinopathy, renal dysfunction, and autonomic neuropathy.