Interaction of genetic predisposition and environmental factors in the pathogenesis of idiopathic orthostatic intolerance

Background: The hemodynamic and autonomic abnormalities in idiopathic ortho static intolerance (IOI) have been studied extensively. However, the mechan isms underlying these abnormalities are not understood. If genetic predispo sition were important in the pathogenesis of IOI, monozygotic twins of pati ents with IOI should have similar hemodynamic and autonomic abnormalities. Methods: We studied two patients with IOI and their identical twins. Both s iblings in the first twin pair had orthostatic symptoms, significant orthos tatic tachycardia, increased plasma norepinephrine levels with standing, an d a greater than normal decrease in systolic blood pressure with trimethaph an infusion. Results: Both siblings had a normal response of plasma renin a ctivity to upright posture. In the second twin pair, only one sibling had s ymptoms of orthostatic intolerance, an orthostatic tachycardia, and raised plasma catecholamines with standing. The affected sibling had inappropriate ly low plasma renin activity with standing and was 8-fold more sensitive to the presser effect of phenylephrine than the unaffected sibling. Conclusio ns: We conclude that in same patients, IOI seems to be strongly influenced by genetic factors. In others, however, IOI may be mainly caused by nongene tic factors. These findings suggest that IOI is heterogenous, and that both genetic and environmental factors contribute individually or collectively to create the IOI phenotype.