Congestive heart failure is a leading cause of morbidity and mortality in the United States and diabetes has been recognized as a major risk factor for the development of this disease. However, there is a lack of consensus regarding the existence of a diabetes-specific cardiomyopathy as well as the importance of vascular and non-vascular alterations in the development of diabetes-related cardiac disease. We recently demonstrated a transient decrease in cardiac phosphocreatine (PCr)/ATP with handgrip stress, indicative of ischemia, in women with chest pain but no artery disease. The most likely explanation for these results was the presence of microvascular disease. Thus, given the sensitivity of changes in bioenergetics to ischemia and the lack of any direct, non-invasive measurements of microvascular disease, we will use 31P-NMR spectroscopy to evaluate the effects of diabetes on cardiac metabolism. Specifically, we will test the hypothesis that patients with diabetes will exhibit reversible, exercise-induced decreases in PCr/ATP and PCr/inorganic phosphate consistent with an imbalance in energy supply and demand. Furthermore, we propose that these changes will be present only in those diabetic patients with evidence of systematic microvascular disease and will be accompanied by evidence of contractile dysfunction as assessed by cine MRI. Finally we anticipate that the observation of metabolic functional abnormalities will be predictive of short- and long-term outcomes. We will test these hypotheses by determining the effects of handgrip exercise on cardiac bioenergetics and cardiac function in diabetic patients with and without evidence of systematic microvascular disease. We will also evaluate the utility of abnormal cardiac bioenergetics and function as predictors for the development of overt cardiac disease in patients with diabetes. Cardiac bioenergetics will be assessed using 31P-NMR spectroscopy at 4.1T and cardiac function will be measured using cine MRI at 1.5T. Type 1 diabetic patients aged 40 and under with a duration of diabetes greater than 10 years will be studied and grouped based on the presence or absence of systemic microangiopathy. These studies will enable us to assess whether the presence of microvessel disease is a prerequisite for the development of cardiac dysfunction in diabetic patients. This investigation will provide an unprecedented insight into the impact of diabetes on cardiac function and bioenergetics in humans. This will provide valuable information for the development of novel therapeutic interventions and improved management of diabetic patients with cardiac disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Diagnostic Radiology Study Section (RNM)
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Buxton, Denis B
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University of Southern California
Internal Medicine/Medicine
Schools of Medicine
Los Angeles
United States
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Wenger, Nanette K; Arnold, Anita; Bairey Merz, C Noel et al. (2018) Hypertension Across a Woman's Life Cycle. J Am Coll Cardiol 71:1797-1813
Bairey Merz, C Noel; Pepine, Carl J; Walsh, Mary Norine et al. (2017) Ischemia and No Obstructive Coronary Artery Disease (INOCA): Developing Evidence-Based Therapies and Research Agenda for the Next Decade. Circulation 135:1075-1092
Thurston, Rebecca C; Johnson, B Delia; Shufelt, Chrisandra L et al. (2017) Menopausal symptoms and cardiovascular disease mortality in the Women's Ischemia Syndrome Evaluation (WISE). Menopause 24:126-132
Doyle, Mark; Pohost, Gerald M; Bairey Merz, C Noel et al. (2016) Use of bio-informatics assessment schema (BIAS) to improve diagnosis and prognosis of myocardial perfusion data: results from the NHLBI-sponsored women's ischemia syndrome evaluation (WISE). Cardiovasc Diagn Ther 6:424-431
Wenger, Nanette K; Ferdinand, Keith C; Bairey Merz, C Noel et al. (2016) Women, Hypertension, and the Systolic Blood Pressure Intervention Trial. Am J Med 129:1030-6
Park, Seong-Mi; Merz, C Noel Bairey (2016) Women and Ischemic Heart Disease: Recognition, Diagnosis and Management. Korean Circ J 46:433-42
Bairey Merz, C Noel; Elboudwarej, Omeed; Mehta, Puja (2015) The autonomic nervous system and cardiovascular health and disease: a complex balancing act. JACC Heart Fail 3:383-385
Agrawal, Shilpa; Van Eyk, Jennifer; Sobhani, Kimia et al. (2015) Sex, Myocardial Infarction, and the Failure of Risk Scores in Women. J Womens Health (Larchmt) 24:859-61
Bairey Merz, C Noel (2014) Sex, death, and the diagnosis gap. Circulation 130:740-2
Doyle, Mark; Pohost, Gerald M; Merz, C Noel Bairey et al. (2013) Improved diagnosis and prognosis using Decisions Informed by Combining Entities (DICE): results from the NHLBI-sponsored Women's Ischemia Syndrome Evaluation (WISE). Cardiovasc Diagn Ther 3:216-27

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