Studies on antioxidant and lipid lowering effects on human microcirculation

Abstract

In previous work from this laboratory, vital microscopy was successfully used to study rnicrocirculatcry effects of hypercholesterolemia in a rabbit model. Hypercholesterolemia caused a dramatic depression of the blood flow velocity in the conjunctiva microvessels of the rabbits. In accordance with the contention that hypercholesterolemia is associated with oxidative stress that is of importance for the microcirculation, antioxidants were shown to have a clear preventive effect on the cholesterol- induced changes in the microcirculation.

It was considered to be of interest to study if similar effects by hypercholesterolemia and antioxidants might be demonstrated also in human microcirculation. A technique for computerized video capillary microscopy imaging was set up for evaluation of the microcirculation in the nailfold. In two of the studies, the flying-spot technique was primarily used for measurement of the blood cell flow velocity (CBV). In three of the studies the Capiflow system and the time to peak (TtP) after a brief arterial occlusion (PRH) were used. According to current concepts, the latter technique is a more reliable assessment. In an evaluation of the TtP method, the between-day variation was found to have a coefficient of variation of less than 13%, provided that the mean of at least two assessments were used.

Smoking is known to induce a considerable oxidative stress that would be expected to affect the microcirculation. In accordance with this, smoking a single cigarette caused a 40-50% decrease in microcirculatory blood flow velocity in 23 of 24 subjects studied. This change was reduced by more than 50% in the same subjects after intake of 2 g of vitamin C 2 h before smoking. Interestingly, intake of 1 g of vitamin C was without effect. Pretreatment for 2 weeks with N-acetylcysteine (200 mgx3 per day) also significantly reduced the smoking-induced effect on the microcirculation in a group of healthy volunteers with mixed smoking habits. The preventive effect of Nacetylcysteine was however considerably lower than the effect of the high dose of vitamin C.

Plasma apheresis offers a unique possibility to study effects in the microcirculation of abrupt changes in plasma lipid levels. We studied four patients regularly treated with LDL-apheresis every third week. In spite of a reduction of the cholesterol levels by almost 50%, there was no obvious change in time to peak at PRH registered prior to apheresis and two days later. The smoking- induced effect on TtP did not seem to he affected by the LDL-apheresis either. Essentially the same results were obtained when measuring the change in the diameter of the brachial artery (FMD) as a response to arterial occlusion and nitroglycerin. Thus the method used for evaluation of the microcirculation and that used for evaluation of conduit vessels showed concordant results.

Diabetes is known to be associated with a disturbed endothelial function and microcirculation. In a double blind cross over study on 17 patients with type 2 diabetes, microvascular reactivity was found to be markedly reduced. Treatment for 2 weeks with a daily dose of 1g x 3 of vitamin C did not significantly improve the vascular reactivity. A slight effect could however be demonstrated in capillary blood flow velocity.

It is concluded that it is possible to use capillary microscopy for evaluation of effects on the microcirculation in the nailfold, particularly in connection with acute studies. Patients with hypercholesterolemia and diabetes as well as volunteers inhaling cigarette smoke had a disturbed microcirculation, probably related to an oxidative stress. The most significant effects of antioxidants observed in the present work appeared in connection with acute oxidative stress (smoking) and a very high dose of the antioxidant (vitamin C).