Under resting conditions, the failing heart shifts fuel use towards greater glucose and lower free fatty acids oxidation. We hypothesized that chronic metabolic abnormalities in patients with dilated cardiomyopathy (DCM) are associated with the absence of the normal increase in myocardial glucose uptake and maintenance of cardiac mechanical efficiency in response to pacing stress. In 10 DCM and in 6 control subjects, we measured coronary flow by intravascular ultrasonometry and sampled arterial and coronary sinus blood. Myocardial metabolism was determined at baseline, during atrial pacing at 130 bpm, and at 15 minutes of recovery, by infusing ³H-oleate and ¹³C-lactate and measuring transmyocardial artero-venous differences of oxygen and metabolites. At baseline, DCM patients showed depressed coronary flow, reduced uptake and oxidation of FFA and preferential utilization of carbohydrates. During pacing glucose uptake increased by 106% in controls, but did not change from baseline in DCM. Lactate release increased by 122% in DCM but not in controls. Cardiac mechanical efficiency in DCM was not different compared to controls at baseline, but was 34% lower during stress. Fatty acid uptake and oxidation did not change with pacing in either group. Our results show that in DCM there is preferential utilization of carbohydrates which is associated with reduced flow and oxygen consumption at rest and an impaired ability to increase glucose uptake during stress. These metabolic abnormalities might contribute to progressive cardiac deterioration and represent a target for therapeutic strategies aimed at modulating cardiac substrate utilization.