Insights into diabetic cardiomyopathy from volume-overload stress

The nature of diabetic cardiomyopathy remains elusive, especially the reduction of systolic contractility that compounds fibrosis and diastolic stiffness. Some of the uncertainty relates to studies being done mainly under resting conditions. Systolic ventricular dysfunction in diabetes is most prominently expressed under stress. Ventricular dysfunction in metabolic and pressure-overload stress is associated with dysregulation of the transcription factor FoxO1, a central element in control of insulin signaling. A preliminary clinical database study has suggested that diabetic patients with moderate to severe mitral regurgitation have an accelerated increase in LV volume and mass compared with non-diabetic controls. To date, however, the interaction of diabetes and volume overload has not been studied in diabetic models. This pilot feasibility study would test the hypothesis that diabetes mellitus augments and accelerates the progression of systolic ventricular dysfunction and ventricular remodeling due to volume overload. This hypothesis will be tested in transgenic diabetic versus wild type rats, of a size most suitable for creation of an aortocaval fistula producing systemic volume overload. This procedure takes advantage of the skills of an experimental surgeon and laboratory resources at MGH for invasive hemodynamics and noninvasive imaging, in collaboration with Dr. Joseph Hill, whose group has studied FoxO1 and diabetic cardiomyopathy extensively. Readouts will include studies of FoxO1 and other molecules in the insulin signaling pathway along with insulin resistance. This study can increase our understanding of the mechanisms and therapeutic targets in diabetic ventricular dysfunction.,/p>

Lay summary: The heart muscle becomes weakened in diabetes, especially when the heart is stressed. This has been studied in stress caused by high-fat diet and high blood pressure, but not in the volume overload caused by leaking heart valves and other conditions. We will study the molecular changes caused by diabetes in volume overload to understand the mechanisms of heart muscle weakening and develop improved treatments and preventive measures to maintain normal heart function in diabetes.