Hemorheological alterations in carotid artery stenosis

1 Introduction

Carotid artery stenosis (CAS) that is defined by a stenosis of ≥50% in the region of the bifurcation of the extracranial internal carotid artery is one of the main risk factors of ischemic stroke [16]. Even asymptomatic CAS may refer to generalized atherosclerosis. Based on previous findings, hemorheological parameters can indicate the extent of coronary and cerebral atherosclerosis [14]. Hemorheological parameters can also correlate with the degree of CAS, both in symptomatic and asymptomatic patients [1, 10].

In chronic cerebrovascular disorders chronic hyperviscosity and increased fibrinogen level are present, furthermore impaired deformability and elevated RBC aggregation were also found [11, 15]. Previous studies in the past 30 years suggest that altered hemorheology can correlate with the degree of carotid artery stenosis; hematocrit, plasma fibrinogen concentration, plasma viscosity, whole blood viscosity, and RBC aggregation can also be involved [14]. Other publications have investigated asymptomatic patients to reveal the possible link between rheology and stenosis, and to assess the role of rheology in early atherosclerosis, although these findings have remained controversial. While plasma viscosity was found as a possible marker of atherosclerosis and carotid thickening [13], and some findings have supposed RBC aggregation and fibrinogen can promote plaque formation [4], others have suggested hemorheological parameters have only a minor role in early atherosclerosis [12].

It is not clear whether alterations in blood rheology are the late consequences of cerebrovascular events or the markers of carotid atherosclerosis. This study investigates the relationship among hemorheological parameters, stenosis and atherosclerosis both in symptomatic and asymptomatic cerebrovascular patients.

2 Subjects and methods

3 Results

In routine laboratory examinations cholesterol and LDL were significantly higher in asymptomatic patients than in symptomatic patients and also in the non-stenotic group compared to the stenotic group. Albumin was reduced in the asymptomatic group and hemoglobin was increased in smokers, but there were no differences in fibrinogen level or other routine laboratory tests (Table 2).

Table 3 shows the hemorheological parameters of the stenotic and non-stenotic groups. Hematocrit was not different between non-stenotic and stenotic group, neither between asymptomatic and symptomatic group, while in asymptomatic patients non-stenotic group had significantly lower Hct level than stenotic group. Whole blood viscosity (at every shear rates) was higher in stenotic group than in non-stenotic group, and also in symptomatic group compared to asymptomatic group. During subgroup analysis we found that non-stenotic patients without cerebrovascular event had significantly lower viscosity than both asymptomatic patients with stenosis and symptomatic patients with (at all shear rates) or without (only at certain shear rates) stenosis. Plasma viscosity was significantly lower in asymptomatic patients compared to symptomatic patients. In the asymptomatic non-stenotic group PV was significantly lower than in the symptomatic non-stenotic group, and also than in the symptomatic stenotic group. Red blood cell aggregation was higher in the stenotic group than in the non-stenotic group according to t1/2. Worse red blood cell deformability (EI from 0.3 to 16.87 shear stresses and SS_1/2) was found in the symptomatic group compared to the asymptomatic group. Subgroup analysis showed RBC deformability of asymptomatic non-stenotic patients better than deformability of the three other groups.

Table 4 represents data of the CAS subgroups. Elevated PV and impaired red blood cell deformability were found in the evolving AS and the CAS groups compared to the negative group. There was no difference between non-negative groups, neither between the moderate and the severe CASgroup.

In current smokers Hct and WBV (at all shear rates) were significantly higher than in current non-smokers. These differences were detected only between the never smoking group and the present smoking group. In the symptomatic subgroup Hct and WBV were significantly elevated, and interestingly red blood cell deformability (EI at 1.69–0.3 Pa and SS_1/2) was impaired in non-smokers. In the asymptomatic group beside increased Hct and PV, deteriorated red blood cell aggregation was observed in current smokers. In the stenotic group we found Hct, PV, and WBC (at all shear rates) higher in smokers. There were no differences in the non-stenotic group(Table 5).

4 Discussion

Several researches have investigated the connection between hemorheological parameters and stenosis of carotid arteries, but methods of hemorheological measurements and patient classification according to stenosis were different. We decided to compare clinically significant stenosis to non–significant stenosis.

Previous investigations have described the changes in hemorheology in stenosis among chronic cerebrovascular patients: increased hematocrit [6, 14] was found; whole blood viscosity, plasma viscosity [11, 14], and red blood cell aggregation were also elevated [1, 14]. In acute stroke no differences were found in hematocrit and WBV either, but plasma viscosity was higher in patients who had severe CAS as well [8]. Our results are similar to these findings although we investigated a mixed population, not only symptomatic patients.

We observed reduced red blood cell deformability, elevated whole blood and plasma viscosity in symptomatic patients compared to asymptomatic patients. Others found higher hematocrit, fibrinogen, and RBC aggregation as well, not visible in our results, however our asymptomatic patients were age-matched controls who had cardiovascular risk factors, while controls in these studies were younger healthy volunteers [11, 14].

Evaluation of the effect of stenosis and cerebrovascular event in history based on subgroup analysis suggests that while PV is altered only with symptoms and Hct only with stenosis, changes in WBV and red blood cell deformability can be signs both of them. But it is still unclear whether altered hemorheology is a consequence of cerebrovascular events or the presence of deteriorated hemorheological parameters can lead to stroke or TIA, which remain worsened after the events.

Further subgroup analysis demonstrated no correlation between rheology and degree of stenosis, severe and moderate stenosis could not be separated by these factors. Nevertheless, plasma viscosity and red blood cell deformability were worse than in the negative group not just in CAS groups but in evolving atherosclerosis as well, which can imply the possible role of these factors in atherosclerosis formation. Prior findings proposed red blood cell deformability and fibrinogen level as potential markers of atherosclerotic plaque formation in patients 3 month after acute stroke [12] and suggested that plasma fibrinogen concentration may predict the progression of stenosis [4, 9]. Other studies found correlation between hematocrit and intima-media thickness [9], and between plasma viscosity and early phase atherosclerosis [9, 10], while another investigation indicated IMT related plasma viscosity and reduced red blood cell filterability having minor relevance, and explained differences in fibrinogen level by smoking [10].

Smoking causes hemorheological disturbances like increased Hct, WBV, PV, fibrinogen, deteriorated red blood cell aggregation, and deformability [3, 14]. Our results suggest that present smoking is a relevant factor in hemorheology, but smoking history does not have a significant role despite a recent finding implied that past smoking has a relevant effect too [3]. Smoking worsened Hct and whole blood viscosity, furthermore plasma viscosity was higher in the asymptomatic and stenotic subgroup, and red blood cell aggregation was increased only in asymptomatic patients. Surprisingly, red blood cell deformability was deteriorated in nonsmokers among symptomatic patients. Only age can explain this discrepancy: nonsmokers were significantly (p = 0.006) older than smokers (nonsmokers 64.6±6 years vs. smokers 59.0±4 years), while there were differences neither in sex, stenosis, chronic diseases, nor in drug therapy.

In routine laboratory examinations cholesterol and LDL were significantly higher in asymptomatic patients than in symptomatic patients and also in the non-stenotic group compared to the stenotic group; it can be explained by the fact that most of the non-stenotic patients with no history of cerebrovascular event were poorly medicalized receiving lipid lowering agents in about 50%.

Our research indicate that hemorheological parameters could be affected by stenotic carotid artery, furthermore clinically significant stenosis and the history of a cerebrovascular event themselves have a remarkable role. Even though we suppose that these factors cannot be suitable markers, presence of atherosclerosis may be detected.