Fellowship Mitov: Gender Specific mechanisms leading to elevated myocardial stiffness in type 1 diabetes

SPECIFIC AIMS Patients with diabetes are -3 times more likely to develop heart failure than patients who are not diabetic [5]. The earliest clinical sign of ventricular problems in human patients is left- ventricular diastolic dysfunction. This condition is characterized by slowed ventricular relaxation and increased myocardial stiffness and leads to a situation in which the ventricles do not fill properly with blood between contractions. The clinical dysfunction probably reflects changes in both the "active" (myosin-based) and "passive" (collagen, elastin and titin-based) molecular components of ventricular stiffness [38]. Clinical and epidemiological findings [27, 28, 31] show that the hearts of male and female patients respond differently during diabetes. Men with diabetes are twice as likely to develop heart failure than men without diabetes while diabetic women are five times more likely to develop heart failure than their non-diabetic controls [16]. The molecular mechanisms underlying the different disease progressions in men and women are currently unclear. The research proposed in this application will analyze a standard animal model of Type I diabetes (streptozotocin-injected rats) to provide new information about the development of diastolic dysfunction in males and females. Clinicians and scientists will be able to use this information to develop better treatment strategies for men and women with diabetes.