1. Journal of Nuclear Cardiology | Official Journal of the American Society of Nuclear Cardiology Left Ventricular Metabolism, Function and Sympathetic Innervation in Men and Women with Type 1 Diabetes Claire S. Duvernoy, David M. Raffel, Scott D. Swanson, Mamta Jaiswal, Gisela Mueller, El-Sayed Ibrahim, Subramaniam Pennathur, Cynthia Plunkett, Jadranka Stojanovska, Morton B. Brown, and Rodica Pop-Busui University of Michigan, Ann Arbor, MI Copyright American Society of Nuclear Cardiology Rodica Pop-Busui, MDClaire S. Duvernoy, MD

2. BACKGROUND 1- Type 1 diabetes (T1DM) may lead to left ventricular (LV) dysfunction and cardiomyopathy in the absence of coronary artery disease (CAD) or hypertension. 2- A potential mechanism is cardiovascular autonomic neuropathy (CAN) with its associated sympathetic/parasympathetic imbalance, which may impair oxidative metabolism and LV efficiency. 3- Positron emission tomography can be used to assess myocardial sympathetic innervation, oxidative metabolism, and myocardial blood flow. 4- Our objectives were to evaluate associations between LV function, innervation, perfusion, and metabolism in young, otherwise healthy Type I diabetics at baseline compared with age-matched nondiabetic controls. Copyright American Society of Nuclear Cardiology Journal of Nuclear Cardiology | Official Journal of the American Society of Nuclear Cardiology

3. METHODS A.Study type: 1.Prospective, case control study of 45 subjects with T1DM and 10 age-matched healthy controls. All subjects had normal resting ECGs and normal exercise treadmill test results before enrolling in the study Inclusion criteria for diabetic subjects were: T1DM, age 18-65 years, minimum of 5 years and <20 years diabetes duration, no signs of microvascular complications, and normal EKG stress tests at baseline. B.Study endpoints: 1.Primary end point(s): To evaluate associations between LV function, innervation, perfusion, and metabolism in these subjects at baseline compared with age- matched nondiabetic controls, and to evaluate potential effects of glucose control and glucose variability. 2.Secondary end point(s): To assess whether gender differences in these parameters may explain gender differences in cardiovascular risk in T1DM C.Study variables: 1.LV sympathetic innervation -- [ 11 C]HED retention index; LV oxidative metabolism – kmono from [ 11 C]acetate PET studies; LV efficiency. Copyright American Society of Nuclear Cardiology Journal of Nuclear Cardiology | Official Journal of the American Society of Nuclear Cardiology

4. RESULTS Copyright American Society of Nuclear Cardiology Journal of Nuclear Cardiology | Official Journal of the American Society of Nuclear Cardiology Figure 1: k mono vs. [ 11 C]HED RI – Correlation between cardiac sympathetic innervation, assessed by [ 11 C]meta- hydroxyephedrine ( 11 C HED) as a global retention index (RI) and myocardial oxidative metabolism, assessed by the clearance rate of [ 11 C]acetate (k mono ), after adjustment for gender. Shown are the correlations for men in blue, and for women in red.

5. Copyright American Society of Nuclear Cardiology Journal of Nuclear Cardiology | Official Journal of the American Society of Nuclear Cardiology

6. CONCLUSIONS 1- Our findings provide insights into the relationship between LV sympathetic innervation, a measure of CAN, and substrate metabolism in type 1 diabetes. 2- Increased oxidative metabolism may be an early event in the natural history of diabetic cardiomyopathy. 3- Gender differences in myocardial blood flow and oxidative metabolism as well as sympathetic innervation may contribute to the adverse prognosis seen in diabetic women. Copyright American Society of Nuclear Cardiology Journal of Nuclear Cardiology | Official Journal of the American Society of Nuclear Cardiology