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Serum adiponectin inversely correlates with the extent of coronary artery disease (CAD).To investigate the clinical significance of measuring high molecular weight (HMW) adiponectin in addition to total adiponectin from different samples (peripheral veins and ostia of coronary arteries) in patients with CAD.We studied 134 patients; 57 with acute coronary syndrome (ACS), 44 with stable angina and 33 healthy patients. Total and HMW adiponectin were measured in the coronary ostia and peripheral veins simultaneously. Venous levels of lipid profile, C-reactive protein, tumour necrosis factor-α, interleukin-6 and insulin were measured.Mean levels of HMW adiponectin in the coronary ostia were significantly correlated with the venous levels of total (r = 0.33, P = 0.002) and HMW (r = 0.37, P = 0.002) adiponectin. Mean levels of total and HMW adiponectin were lower in CAD patients versus controls (6.9 ± 0.5 versus 7.9 ± 0.7 μg/ml, P = 0.3 and 1.9 ± 0.2 versus 3.1 ± 0.3 μg/ml, P = 0.003). In the coronary ostia, levels of HMW adiponectin were higher in ACS than those with stable angina (1.1 ± 0.1 versus 0.8 ± 0.1 μg/ml, P = 0.2). In patients with CAD, levels of ostial adiponectin (total and HMW) were significantly lower in diabetic than non-diabetic patients (6.5 ± 0.8 versus 9.4 ± 1.1 μg/ml, P = 0.04 and 0.8 ± 0.12 versus 1.2 ± 0.1 μg/ml, P = 0.03). Mean levels of venous adiponectin (total and HMW) were non-significantly lower in diabetic patients (5.9 ± 0.7 versus 7.7 ± 0.7, P = 0.12 and 1.8 ± 0.4 versus 1.9 ± 0.1, P = 0.8).Measurement of HMW adiponectin and its ratio to total adiponectin may be a better marker for CAD than total adiponectin levels. Ostial levels of adiponectin in ACS may indicate re-distribution of adiponectin molecules towards the acute lesions. The low HMW adiponectin levels in diabetes mellitus may in part explain the worse outcome of CAD in diabetics.