Goode G K, Heagerty A M
Department of Medicine, University of Manchester, England.
Circulation. 1995 Jun 15;91(12):2898-903. doi: 10.1161/01.cir.91.12.2898.
Studies in both animals and humans with raised lipid levels have demonstrated abnormalities in vascular function usually manifested by an impairment in endothelium-dependent vasorelaxation. This is believed to be an early event in atheroma formation. There are few data on the effects on vascular function in humans of lowering serum lipids. We conducted a study to investigate the effects of cholesterol reduction on the in vitro function of human peripheral small arteries in middle-aged patients with hypercholesterolemia.
Subcutaneous gluteal fat biopsies were taken from 18 hypercholesterolemic (HC) patients (mean +/- SEM serum total cholesterol, 9.7 +/- 0.57 mmol/L) and 16 age- and sex-matched control subjects (mean cholesterol, 4.69 +/- 0.18 mmol/L). Subcutaneous small arteries (internal diameter, < 330 microns) were dissected and mounted on a wire myograph for isometric tension measurements. The HC patients showed impaired relaxation to acetylcholine (10(-9) to 10(-6) mol/L) after preconstriction with the thromboxane A2 analogue U46619 (10(-6) mol/L, mean maximum relaxation, 42.9 +/- 5.4%) compared with control subjects (85.7 +/- 4.0%, P < .00001). Incubation with the nitric oxide substrate L-arginine (3 mmol/L) improved the endothelium-dependent vasorelaxation response to acetylcholine (70.9 +/- 6.0%, P < .01) in patients but not in control subjects. Also, there was a smaller but significant difference in responses to the endothelium-independent agent sodium nitroprusside (10(-9) to 10(-6) mol/L) between the HC group (mean maximum relaxation, 76.9 +/- 6.0%) and the control subjects (89.7 +/- 6%; P < .01). A total of 10 patients had a second gluteal skin biopsy and repeat functional studies after successful cholesterol-lowering therapy after a mean period of 9.9 +/- 4.7 months. A significant reduction in total and LDL cholesterol was achieved (5.29 +/- 0.2 and 3.23 +/- 0.21 mmol/L, respectively; P < .001). This restored vasorelaxation to control values in response to both acetylcholine (mean maximum relaxation, 83.3 +/- 3.8%; P < .0001) and sodium nitroprusside (87.9 +/- 4.8%, P < .01). Although both groups were normotensive, there were significantly higher blood pressures in the HC group compared with control subjects (139 +/- 4.1 versus 123 +/- 3.0 mm Hg systolic, P < .01; 84 +/- 1.3 versus 75 +/- 2.2 mm Hg diastolic, P < .01). There was no difference in initial blood pressures between the entire group of 18 and the 10 patients who had repeat biopsies. The blood pressures fell to control values after cholesterol reduction (129.33 +/- 4.93 mm Hg systolic and 72.33 +/- 2.93 diastolic mm Hg, P < .02 relative to pretreatment values).
These results demonstrate abnormalities of both endothelium-dependent and -independent relaxation in human peripheral small arteries that are normalized with effective lipid lowering. The changes in blood pressure may have been secondary to the improvement in vascular function.
对动物和血脂升高的人类的研究均表明，血管功能存在异常，通常表现为内皮依赖性血管舒张功能受损。这被认为是动脉粥样硬化形成过程中的早期事件。关于降低血脂对人类血管功能影响的数据较少。我们进行了一项研究，以调查降低胆固醇对中年高胆固醇血症患者外周小动脉体外功能的影响。
从18名高胆固醇血症（HC）患者（血清总胆固醇均值±标准误，9.7±0.57 mmol/L）和16名年龄及性别匹配的对照者（胆固醇均值，4.69±0.18 mmol/L）身上采集臀下皮下脂肪活检样本。解剖出皮下小动脉（内径<330微米），并安装在钢丝肌动描记器上进行等长张力测量。与对照者（85.7±4.0%，P<.00001）相比，HC患者在用血栓素A2类似物U46619（10^-6 mol/L）预收缩后，对乙酰胆碱（10^-9至10^-6 mol/L）的舒张反应受损（平均最大舒张率，42.9±5.4%）。用一氧化氮底物L-精氨酸（3 mmol/L）孵育可改善患者对乙酰胆碱的内皮依赖性血管舒张反应（70.9±6.0%，P<.01），而对照者无此改善。此外，HC组（平均最大舒张率，76.9±6.0%）与对照者（89.7±6%；P<.01）对非内皮依赖性药物硝普钠（10^-9至10^-6 mol/L）的反应存在较小但显著的差异。10名患者在平均9.9±4.7个月的成功降脂治疗后进行了第二次臀下皮肤活检和重复功能研究。总胆固醇和低密度脂蛋白胆固醇显著降低（分别为5.29±0.2和3.23±0.21 mmol/L；P<.001）。这使对乙酰胆碱（平均最大舒张率，83.3±3.8%；P<.0001）和硝普钠（87.9±4.8%，P<.01）的血管舒张反应恢复到对照值。尽管两组血压均正常，但HC组血压显著高于对照者（收缩压139±4.1对123±3.0 mmHg，P<.01；舒张压84±1.3对75±2.2 mmHg，P<.01）。18名患者的整个组与10名进行重复活检的患者的初始血压无差异。胆固醇降低后血压降至对照值（收缩压129.33±4.93 mmHg，舒张压72.33±2.93 mmHg，相对于治疗前值P<.02）。
这些结果表明，人类外周小动脉的内皮依赖性和非内皮依赖性舒张均存在异常，有效降低血脂可使其恢复正常。血压变化可能是血管功能改善的继发结果。
