Smith T P, Cruz C P, Brown A T, Eidt J F, Moursi M M
Department of Surgery, Division of Vascular Surgery, Central Arkansas Veterans Health Care System, University of Arkansas for Medical Sciences, Little Rock 72205, USA.
J Vasc Surg. 2001 Sep;34(3):474-81. doi: 10.1067/mva.2001.117144.
Hyperhomocysteinemia has been implicated as a causative factor in intimal hyperplasia development. The addition of dietary folate in a hyperhomocysteinemia, carotid endarterectomy rat model is postulated to decrease plasma homocysteine levels and, in turn, reduce post-carotid endarterectomy intimal hyperplasia.
Each rat was fed one of six diets: (1) lab chow with no folate (n = 7), (2) lab chow with 10 mg/kg folate added (n = 3), (3) lab chow with 25 mg/kg folate added (n = 3), (4) a homocysteine diet with no folate (n = 7), (5) a homocysteine diet with 10 mg/kg folate added (n = 5), or (6) homocysteine diet with 25 mg/kg folate added (n = 5). Each rat then underwent an open carotid endarterectomy. In 2 weeks, intimal hyperplasia in the carotid artery was measured. Plasma homocysteine and folate levels were measured.
Plasma folate levels rose with folate administration. Plasma homocysteine in the lab chow group was 5.4 +/- 0.5 micromol/L and did not change with the addition of folate. In the homocysteine diet group, plasma homocysteine rose 10-fold over the lab chow group (51.9 +/- 6.5 vs 5.4 +/- 0.5, micromol/L, P <.0001). In the group fed a homocysteine diet with 10 mg/kg folate added, a significant decrease in plasma homocysteine was observed (17.5 +/- 8.5 vs 51.9 +/- 6.5, micromol/L, P =.0003). In the group fed a homocysteine diet with 25 mg/kg folate added, plasma homocysteine levels were further reduced to levels seen in the lab chow group (12.6 +/- 2.6 vs 5.4 +/- 0.5, micromol/L, P = not significant). The relationship between plasma folate and homocysteine was inverse (R = 0.39, P =.0036). Luminal stenosis due to intimal hyperplasia was minimal in lab chow groups and unaffected by folate. The homocysteine diet group demonstrated post-carotid endarterectomy luminal stenosis due to intimal hyperplasia (60.9% +/- 9.2%). In the group fed a homocysteine diet with 10 mg/kg folate added, intimal hyperplasia was reduced, compared with the homocysteine diet group (32.6% +/- 7.4% vs 60.9% +/- 9.2%, P =.009). In the group fed a homocysteine diet with 25 mg/kg folate added, intimal hyperplasia was reduced to lab chow group levels (10.8% +/- 0.8% vs 4.8% +/- 1.0%, P = not significant) and was reduced, compared with the group fed a homocysteine diet with 10 mg/kg folate added.
The use of folate in this hyperhomocysteinemia carotid endarterectomy model and the resultant attenuation of plasma homocysteine elevation and intimal hyperplasia development lend strong support to homocysteine being an independent etiologic factor in post-carotid endarterectomy intimal hyperplasia.
高同型半胱氨酸血症被认为是内膜增生发展的一个致病因素。在高同型半胱氨酸血症的颈动脉内膜切除术大鼠模型中添加膳食叶酸，推测可降低血浆同型半胱氨酸水平，进而减少颈动脉内膜切除术后的内膜增生。
每组大鼠喂食六种饮食之一：（1）不含叶酸的实验室常规饲料（n = 7），（2）添加10 mg/kg叶酸的实验室常规饲料（n = 3），（3）添加25 mg/kg叶酸的实验室常规饲料（n = 3），（4）不含叶酸的同型半胱氨酸饮食（n = 7），（5）添加10 mg/kg叶酸的同型半胱氨酸饮食（n = 5），或（6）添加25 mg/kg叶酸的同型半胱氨酸饮食（n = 5）。然后每组大鼠均接受开放性颈动脉内膜切除术。2周后，测量颈动脉的内膜增生情况。检测血浆同型半胱氨酸和叶酸水平。
随着叶酸的摄入，血浆叶酸水平升高。实验室常规饲料组的血浆同型半胱氨酸为5.4±0.5 μmol/L，添加叶酸后无变化。在同型半胱氨酸饮食组中，血浆同型半胱氨酸比实验室常规饲料组升高了10倍（51.9±6.5对5.4±0.5，μmol/L，P <.0001）。在添加10 mg/kg叶酸的同型半胱氨酸饮食组中，观察到血浆同型半胱氨酸显著降低（17.5±8.5对51.9±6.5，μmol/L，P =.0003）。在添加25 mg/kg叶酸的同型半胱氨酸饮食组中，血浆同型半胱氨酸水平进一步降至实验室常规饲料组的水平（12.6±2.6对5.4±0.5，μmol/L，P无统计学意义）。血浆叶酸和同型半胱氨酸之间呈负相关（R = 0.39，P =.0036）。实验室常规饲料组因内膜增生导致的管腔狭窄最小，且不受叶酸影响。同型半胱氨酸饮食组出现了因内膜增生导致的颈动脉内膜切除术后管腔狭窄（60.9%±9.2%）。在添加10 mg/kg叶酸的同型半胱氨酸饮食组中，与同型半胱氨酸饮食组相比，内膜增生有所减少（32.6%±7.4%对60.9%±9.2%，P =.009）。在添加25 mg/kg叶酸的同型半胱氨酸饮食组中，内膜增生降至实验室常规饲料组水平（10.8%±0.8%对4.8%±1.0%，P无统计学意义），且与添加10 mg/kg叶酸的同型半胱氨酸饮食组相比有所减少。
在这个高同型半胱氨酸血症颈动脉内膜切除术模型中使用叶酸，以及由此导致的血浆同型半胱氨酸升高和内膜增生发展的减弱，有力地支持了同型半胱氨酸是颈动脉内膜切除术后内膜增生的一个独立病因。
