Syncope in patients with advanced heart failure is a sign of poor prognosis. The cause of syncope in patients with dilated cardiomyopathy (DC) is not fully recognized and may remain elusive even after standardized evaluation. The purpose of the present study was to examine the implication of neurally mediated mechanisms in the pathophysiology of syncopal episodes in patients with DC. Twenty-six patients (21 men, 5 women; mean age 59 +/- 2 years, range 38 to 79) with DC and left ventricular ejection fractions <or=40% were included in the study. Thirteen patients with unexplained syncope or presyncope and a control group of 13 patients without unexplained syncope underwent head-up tilt tests with clomipramine challenge. The 2 groups were matched with regard to age, gender, and left ventricular ejection fractions, and there were no major differences in terms of medication. Heart rate variability analysis and plethysmography of forearm flow were performed during the tilt tests. Blood samples were also drawn for catecholamine measurements. In the group with histories of unexplained syncope, the head-up tilt test results were positive in 11 patients (84.6%). Sympathetic and parasympathetic heart rate indexes were markedly stimulated, while catecholamine concentrations and blood flow changes indicated sympathetic withdrawal during tilting. In the control group, the head-up tilt test results were negative in 12 patients (92.3%). In conclusion, neurally mediated mechanisms seem to be implicated in the pathophysiology of syncope in patients with DC and should therefore be considered in the differential diagnosis of syncopal episodes of unexplained origin.