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Purpose: An elevated plasma homocysteine level has been identified as an independent risk factor for atherosclerosis. Whether this represents a marker for vascular disease or a direct effect on the vasculature remains unclear. Because vascular smooth muscle cells (VSMCs) play an integral role in the atherosclerotic process, we studied the effect of homocysteine on human infragenicular VSMC proliferation and the role of folic acid in reversing the homocysteine effect. Methods: Human infragenicular VSMCs harvested from amputation specimens were studied. Various cell groups were exposed to physiologic (6.25 @mmol/L and 12.5 @mmol/L) and pathologic (25 @mmol/L to 500 @mmol/L) concentrations of homocysteine. Similar groups were simultaneously exposed to 20 nmol/L of folic acid. Cell counts and DNA synthesis, as reflected by [methyl-^3H]-thymidine incorporation, were performed at 6 days and 24 hours, respectively. Additional groups were exposed to various combinations of folic acid (20 nmol/L), vitamin B"6 (145 nmol/L), and vitamin B"1"2 (0.45 nmol/L) in the presence of homocysteine (25, 50, and 250 @mmol/L). Results: Homocysteine resulted in a dose-dependent increase in DNA synthesis and cell proliferation. Cell counts increased significantly at homocysteine concentrations ranging from 25 @mmol/L to 500 @mmol/L (P < .05), with a maximal increase of 98% at 500 @mmol/L of homocysteine. The addition of 20 nmol/L folic acid resulted in significant inhibition of cell proliferation at all homocysteine concentrations studied (P < .001). Maximal inhibition of 70% occurred in the cells exposed to 50 @mmol/L of homocysteine. The increases in [methyl-^3H]-thymidine incorporation ranged from 36% at 6 @mmol/L homocysteine to a maximum of 247% at 500 @mmol/L homocysteine. All increases were statistically significant (P < .05). The addition of 20 nmol/L folic acid resulted in significant inhibition of DNA synthesis (P < .002). Vitamins B"6 and B"1"2 did not demonstrate significant antiproliferative properties. Conclusion: A possible role of homocysteine in the formation of atherosclerotic lesions is through a direct proliferative effect on VSMCs in a dose-dependent fashion. Folic acid intake at levels available in dietary supplements may prove protective in hyperhomocysteinemia-induced atherosclerosis. Vitamins B"6 and B"1"2 alone do not appear to exhibit a substantial inhibitory effect in the setting of elevated homocysteine levels. (J Vasc Surg 1999;30:1121-8.)

Purpose: High-dose external radiotherapy used in the treatment of head and neck carcinoma has been implicated as a risk factor for accelerated atherosclerotic disease of the carotid arteries. However, how radiotherapy affects atherosclerotic disease is controversial, and little data exist to demonstrate a strong relationship between radiotherapy and progressive carotid disease. Methods: We performed a retrospective chart review of 69 patients (all men) who underwent duplex ultrasound scanning examinations for carotid disease between 1993 and 1998. Twenty-three patients had received high-dose radiotherapy for the treatment of head and neck carcinoma within the past 12 years (group 1; mean age, 67.8 years), and 46 patients were randomly selected as age-matched control subjects (group 2; mean age, 68.3 years). The mean radiation dose was 6060 +/- 182 rads, and the average interval between radiotherapy and ultrasound scanning was 6.5 +/- 1.8 years. There was no significant difference between the two groups in the presence of these comorbidities: diabetes mellitus, coronary artery disease, hypertension, tobacco use, hypercholesterolemia, peripheral vascular disease, or stroke. Similarly, there was no difference in the indications for the duplex scanning studies. Results: Five of the 23 patients in group 1 (21.7%) were found to have advanced carotid disease (70% to 99% stenosis); four patients were symptomatic, three patients went on to endarterectomy, and one patient was awaiting surgery. Two of the 46 patients in the control group (4%) had advanced carotid disease. One patient was symptomatic, and both patients underwent endarterectomy. A significant difference in the prevalence of advanced disease between the two groups was noted (P = .037). Sixteen patients who survived irradiation underwent a second duplex scanning study and had evidence of progressive disease with significant increases in peak systolic velocities. Conclusion: High-dose radiotherapy to the head and neck region may be a significant risk factor for accelerated carotid atherosclerotic disease. Routine carotid duplex surveillance may be warranted in this high-risk patient population. (J Vasc Surg 1999;30:1045-51.)