HYPERHOMOCYSTEINEMIA AFTER AN ORAL METHIONINE LOAD ACUTELY IMPAIRS ENDOTHELIAL FUNCTION IN HEALTHY-ADULTS

Background-Elevated plasma homocysteine is a risk factor for arteriosc lerosis, but a cause-and-effect relationship remains to be fully estab lished. Endothelial dysfunction, an early event in the atherogenic pro cess, has been shown to be associated with hyperhomocysteinemia in exp erimental and human studies. To further establish a direct relationshi p between changes in plasma homocysteine and endothelial dysfunction, we investigated whether moderate hyperhomocysteinemia induced by an or al methionine load would acutely impair flow-mediated endothelium-depe ndent vasodilatation in healthy adults. Methods and Results-Twenty-fou r healthy volunteers completed a randomized crossover study in which a n oral methionine load (0.1 g/kg) was administered on 1 of 2 study day s, 7 days apart. At each visit, plasma homocysteine and brachial arter y endothelium-dependent and -independent dilatation were measured at b aseline and at 4 hours. To further elucidate the temporal relationship between methionine, homocysteine, and endothelial function, an oral m ethionine load was administered in 10 subjects on a separate visit, an d the time courses of plasma methionine, homocysteine, and flow-mediat ed brachial artery dilatation were measured at baseline and after 1, 2 , 3, 4, and 8 hours, After oral methionine. plasma homocysteine increa sed from 7.9+/-2.0 mu mol/L at baseline to 23.1+/-5.4 mu mol/L at 4 ho urs (P<0.0001, n=24) and was associated with a decrease in flow-mediat ed brachial artery dilatation from 0.12+/-0.09 to 0.06+/-0.09 mm (P<0. 05). The time course of the impairment of flow-mediated vasodilatation mirrored the time course of the increase in homocysteine concentratio n, Conclusions-Oral methionine loading raises plasma homocysteine and impairs flow-mediated endothelium-dependent vasodilatation. This suppo rts the view that homocysteine may promote vascular disease by inducin g endothelial dysfunction.