Although mutations in cardiac sodium and potassium channel genes are associated with congenital long QT syndrome (LQTS), a "modifier" role of the sympathetic nervous system was proposed to explain the distinct severity of the disease. We evaluated cardiac sympathetic innervation using [11C]hydroxyephedrine ([11C]HED) and positron emission tomography (PET) in genotyped LQTS patients. H215O and [11C]HED PET studies were performed in 11 patients (5 symptomatic) and 8 controls. Perfusion and [11C]HED images were depicted as 36-sector polar maps. Sectorial values of perfusion (H2O%), absolute (HEDRet) and relative retention (HED%Ret) of [11C]HED, and the ratio of HED%Ret to H2O% (HED%Ret/H2O%) were calculated. Normal databases were obtained from controls. Sectorial values below 2SD database values were defined as "outside sectors." Controls and patients showed similar sectorial perfusion. Sectorial HEDRet did not differ between groups, but means of HED%Ret were lower in three sectors for patients (P < 0.05). Three sectors from 3 controls had HED%Ret below 2SD, whereas 36 sectors in 9 patients were outside sectors (P < 0.01). In patients, average HED%Ret/H2O% was lower in 9 sectors (P < 0.05 vs. controls); 2 outside sectors were found in controls, but 43 outside sectors were found in patients (P < 0.01), 77% of them in the 5 symptomatic patients. Heterogeneous [11C]HED retention was localized in the septal, anterior, and lateral walls. Most LQTS patients showed a localized and decreased pattern of [11C]HED retention. The larger number of heterogeneous sectors in symptomatic patients suggests that sympathetic function could play an amplifier role for severity of the disease.