Medical Student Research Fellowship for Summer 2005

Mentor: Darren McGuire
Department: Cardiology/Internal Medicine
Room number: St Paul 9th Floor: HA9.133
Mail Code: MC 9047
Phone number: 214 645 7520
E-mail: darren.mcguire@utsouthwestern.edu

Two projects:

Project I title: Cardiovascular Effects of Rosiglitazone versus Placebo

Human subjects IRB approved project number (where applicable): 082004-017

Project Type: Patient-based research

Brief Description of Project:

PURPOSE: The primary objectives of this study are: 1) to determine if rosiglitazone treatment improves integrated cardiovascular performance in patients at risk for CHF (congestive heart failure) 2) to determine if treatment with rosiglitazaone decreases intracellular (ectopic) triglyceride (TG) deposition in cardiomyocytes using nuclear magnetic resonance (NMR) techniques, and how changes in intra-myocardial lipid content relate to changes in cardiac structure and function.
BACKGROUND: Cardiovascular disease (CVD), including congestive heart failure (CHF), accounts for over 75% of deaths among patients with diabetes. Thus, it is imperative to rigorously evaluate existing and emerging hypoglycemic therapies with regard to their cardiovascular consequences. The thiazolinedione (TZD) class of drugs, which includes rosiglitazone, are potent and selective agonists for the peroxisome proliferator-activated receptor (PPAR) and have emerged as a safe, effective and widely used treatment of hyperglycemia in type 2 diabetes. Through their effects on PPAR , TZDs have been shown to decrease hepatic gluconeogenesis, increase insulin sensitivity and lead to a transition of fat distribution from visceral to subcutaneous depots, a pattern that has been associated with lower cardiovascular risks. TZDs have also been shown to decrease ectopic, and possibly toxic, deposition of triglycerides in skeletal muscle and myocardium of animals and in skeletal muscle of humans that is associated with obesity and insulin resistance. Both in vitro and in vivo studies have revealed favorable pleiotropic effects of TZD on myocyte and ventricular structure and function. However, approximately 10% of patients taking TZDs develop peripheral edema, although it is unclear if this is related to impaired cardiac function. In addition, case reports exist of patients who have developed heart failure decompensation on the drug. These observations have led to a FDA warning regarding the use of TZDs in patients with or at high risk of developing CHF. Despite the high prevalence of CVD in patients with type 2 diabetes, the exact effects of TZDs on cardiac function remains unclear, and additional studies are needed to evaluate the effect of TZDs on cardiovascular performance, cardiac structure and myocardial triglyceride content in humans.
CONCISE SUMMARY OF PROJECT: This study is a multi-center, prospective, randomized, double-blind, placebo-controlled, parallel-group study. Subjects will be randomized in a 1:1 fashion to receive rosiglitazone 4mg or matching placebo once daily for one month followed by rosiglitazone 8 mg or matching placebo once daily for 5 months. One hundred five subjects will be enrolled in this study. Study participation will last 6 months, and involve one visit a month for 6 months. Vital signs, physical exam and blood work (3-4 tablespoons) will be performed at each visit. At Visits 1 and 5, skin-fold thickness, cardiopulmonary exercise testing, cardiac MRI, and magnetic resonance spectroscopy will be performed; KCCQ and PAR will be administered; and blood samples (3 tablespoons) will be collected, processed, and stored for subsequent analyses of biomarkers related to cardiovascular disease.

Project II le: TRIUMPH Registry of Patients with Acute Myocardial Infarction

Human subjects IRB approved project number (where applicable): Pending

Project Type: Patient-based research

Brief Description of Project:

The principal goal of this project is to better understand the relationship between race and outcomes of patients suffering from acute myocardial infarctions. The care and outcomes will be in the context of numerous other potentially influential factors, including genetic and metabolic determinants, clinical and non-clinical risk factors, the healthcare systems responsible for treating patients, and the care received. The TRIUMPH Registry is a multi-center observational registry and will include baseline interviews, chart abstractions, blood sample collection, and 1-, 6-, and 12-month follow-up contacts for three years.

Previous Research Activities or Publications with Medical Students:

Mentored 2 students last summer, who will both continue on the project they started this coming summer; co-mentored a 3rd student, with paper in preparation.

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