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CLINICAL RESEARCH: DIABETIC CARDIOMYOPATHY

Altered Myocardial Substrate Metabolism and Decreased Diastolic Function in Nonischemic Human Diabetic Cardiomyopathy

Studies With Cardiac Positron Emission Tomography and Magnetic Resonance Imaging

Luuk J. Rijzewijk, MD^_*, Rutger W. van der Meer, MD, PhD, Hildo J. Lamb, MD, PhD, Hugo W.A.M. de Jong, PhD, Mark Lubberink, PhD, Johannes A. Romijn, MD, PhD^||, Jeroen J. Bax, MD, PhD^¶, Albert de Roos, MD, PhD, Jos W. Twisk, PhD, Robert J. Heine, MD, PhD^_*, Adriaan A. Lammertsma, PhD, Johannes W.A. Smit, MD, PhD^|| and Michaela Diamant, MD, PhD^_*,_*

^_* Diabetes Center, VU University Medical Center, Amsterdam, the Netherlands
Department of Nuclear Medicine and PET Research, VU University Medical Center, Amsterdam, the Netherlands
Department of Clinical Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, the Netherlands
Department of Radiology, Leiden University Medical Center, Leiden, the Netherlands
^|| Department of Endocrinology, Leiden University Medical Center, Leiden, the Netherlands
^¶ Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands

Manuscript received October 21, 2008; revised manuscript received April 17, 2009, accepted April 23, 2009.

^_* Reprint requests and correspondence: Dr. Michaela Diamant, Diabetes Center, VU University Medical Center, P.O. Box 7057, 1007 MB Amsterdam, the Netherlands (Email: m.diamant{at}vumc.nl).

Objectives: This study was designed to evaluate myocardial substrate and high-energy phosphate (HEP) metabolism in asymptomatic men with well-controlled, uncomplicated type 2 diabetes with verified absence of cardiac ischemia, and age-matched control subjects, and to assess the association with myocardial function.

Background: Metabolic abnormalities, particularly an excessive exposure of the heart to circulating nonesterified fatty acids and myocardial insulin resistance are considered important contributors to diabetic cardiomyopathy in animal models of diabetes. The existence of myocardial metabolic derangements in uncomplicated human type 2 diabetes and their possible contribution to myocardial dysfunction still remain undetermined.

Methods: In 78 insulin-naive type 2 diabetes men (age 56.5 ± 5.6 years, body mass index 28.7 ± 3.5 kg/m², glycosylated hemoglobin A_1c 7.1 ± 1.0%; expressed as mean ± SD) without cardiac ischemia and 24 normoglycemic control subjects (age 54.5 ± 7.1 years, body mass index 27.0 ± 2.5 kg/m², glycosylated hemoglobin A_1c 5.3 ± 0.2%), we assessed myocardial left ventricular (LV) function by magnetic resonance imaging, and myocardial perfusion and substrate metabolism by positron emission tomography using H₂ ¹⁵O, carbon ¹¹C-palmitate, and 18-fluorodeoxyglucose 2-fluoro-2-deoxy-D-glucose. Cardiac HEP metabolism was assessed by phosphorous P 31 magnetic resonance spectroscopy.

Results: In patients, compared with control subjects, LV diastolic function (E/A ratio: 1.04 ± 0.25 vs. 1.26 ± 0.36, p = 0.003) and myocardial glucose uptake (260 ± 128 nmol/ml/min vs. 348 ± 154 nmol/ml/min, p = 0.015) were decreased, whereas myocardial nonesterified fatty acid uptake (88 ± 31 nmol/ml/min vs. 68 ± 18 nmol/ml/min, p = 0.021) and oxidation (85 ± 30 nmol/ml/min vs. 63 ± 19 nmol/ml/min, p = 0.007) were increased. There were no differences in myocardial HEP metabolism or perfusion. No association was found between LV diastolic function and cardiac substrate or HEP metabolism.

Conclusions: Patients versus control subjects showed impaired LV diastolic function and altered myocardial substrate metabolism, but unchanged HEP metabolism. We found no direct relation between cardiac diastolic function and parameters of myocardial metabolism.

Key Words: diabetes mellitus • cardiomyopathy • metabolism • magnetic resonance imaging • tomography • positron emission

Abbreviations and Acronyms   ATP = adenosine triphosphate   BMI = body mass index   CAD = coronary artery disease   CMR = cardiac magnetic resonance   DCM = diabetic cardiomyopathy   18FDG = 18-fluorodeoxyglucose 2-fluoro-2-deoxy-D-glucose   HbA1c = glycosylated hemoglobin A1c   HEP = high-energy phosphate   LV = left ventricular   LVM = left ventricular mass   MFAE = myocardial fatty acid esterification   MFAO = myocardial fatty acid oxidation   MFAU = myocardial fatty acid uptake   MMRglu = myocardial metabolic rate of glucose uptake   NEFA = nonesterified fatty acid   PCr = phosphocreatine   PET = positron emission tomography   [31P]-MRS = phosphorus-31 magnetic resonance spectroscopy   T2DM = type 2 diabetes mellitus

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