This is an application for designation as a Regional Clinical Center (RCC) of the Heart Failure (HF) Clinical Research Network. The participants are a diverse group of institutions in Northern New England, New York and Quebec, including the University of Vermont/Fletcher Allen Health Care (the sponsoring institution), Albany/St. Peter's Medical Centers, Catholic Medical Center, Dartmouth-Hitchcock Medical Center, McGill Medical Center and Univ. of Massachusetts Medical Center. The proposed RCC has a tertiary care catchment population over 6,000,000 and over 3,500 hospital beds. In 2004, over 2300 new patients with HF were seen, and over 180 follow-up patients with HF were seen weekly. The RCC also includes cardiologists in private practice in Vermont and New York who are committed to enrolling patients from rural areas who rarely participate in clinical trials. Key personnel have extensive experience in planning and management of multi-center trials and local PIs at each institution are experienced participants. Various collaborative activities are planned to maintain a vibrant regional network. The two proposed projects for the RCC share a. common theme, type 2 diabetes mellitus (DM) as a risk factor for and mechanism of HF. Project #1 is a placebo-controlled, randomized trial of a thiazalodinedione to treat diastolic dysfunction (DD), a common and early manifestation of diabetic cardiomyopathy. Secondary outcomes are systolic dysfunction and changes in blood levels of pro-inflammatory and pro-fibrotic biomarkers. Project #2 employs methods we have developed to study "skinned" strips of myocardium obtained during cardiac surgery as well as from endstage, explanted hearts. By using surgical biopsies, we can examine non-end stage disease states that can cause HF and delineate disease-specific elements of pathophysiology and drug effects. We will use these methods to determine the in vitro, disease-specific effects of the drug Alagebrium, a breaker of advanced glycation end-product (AGE) associated collagen cross-links, on passive stiffness in patients with DM, hypertension (HTN) and DM + HTN. AGEs are thought to cause increased myocardial and vascular stiffness in these patients. Results will be correlated with pre-operative DD and assessment of AGEs by immuno electronmicroscopy. The studies we propose for our RCC have potential to reduce the risk of HF in patients with DM. Biopsy studies will improve understanding of pathophysiology and drug effects and mechanisms. (End of Abstract)