OBJECTIVE: In this study, we tested the hypothesis that sympathetic over-activity may cause metabolic abnormalities and affect left ventricular (LV) structure and mass early in life. SUBJECTS AND SETTING: The study population consisted of 111 healthy adolescents and young adults living in Tecumseh, Michigan (USA). MAIN OUTCOME MEASURES: Correlations of LV mass and structure with several clinical variables in relation to the activity of the sympathetic nervous system. METHODS: Power spectrum density estimates of heart rate variability were calculated with an auto-regressive method, and subjects were divided by cluster analysis into two groups according to low-frequency and high-frequency components. LV data were obtained by echocardiographic assessment RESULTS: Subjects with signs of sympathetic over-activity (n = 38, group 1) had higher heart rate, blood pressure (BP), waist/hip ratio and cholesterol levels than the rest of the group (n = 73, group 2). In group 1 subjects, insulin emerged as the strongest univariate correlate of interventricular septum and posterior wall thicknesses (P< 0.001 for both) and of LV mass (P= 0.009). These relationships remained significant when body mass index was accounted for. By contrast, the marginal univariate relationship with diastolic BP did not remain significant in multivariate analysis. In group 2 subjects, BP was strongly correlated with LV wall thickness and mass both in univariate (P values from 0.03 to < 0.001) and multivariate analyses, while insulin was not. The interactive effect of sympathetic activity and insulin on echocardiographic data was confirmed by multivariate analyses performed in the subjects grouped together (P values from 0.02 to 0.001 for the sympathetic activity x insulin interaction term). CONCLUSIONS: In young subjects with heightened sympathetic activity and initial metabolic abnormalities, insulin is a strong determinant of LV wall thickness and geometry, while in subjects with normal autonomic nervous system activity, the main determinant of left ventricular size is the haemodynamic load.