We investigated the association between plasma tHcy and IMT of the internal carotid artery/bifurcation (ICA/bulb) and the common carotid artery segment (CCA) of the extracranial artery, adjusting for other major risk factors for atherosclerosis. We observed a significant positive association between elevated tHcy levels and ICA/bulb-intima-media thickness (IMT) in individuals of all ages and in individuals 58 years old and older. The levels of circulating tHcy associated with increased ICA/bulb-IMT were similar to or higher than those associated with an increased risk for cardiovascular disease in other studies 33–37
. No significant positive association between tHcy levels and ICA/bulb-IMT was observed in individuals in the younger age group. It is possible that ICA/bulb-IMTs in the young age group were too low and less variable compared to those in the older age group to see a significant association with tHcy. No significant associations were observed between tHcy and the CCA-IMT segment after adjusting for important CVD risk factors.
Several other studies have investigated tHcy as a risk factor for increased IMT in the extracranial carotid artery 4–6, 19, 38
. However, in these studies, IMT was either measured only at the CCA or it was measured at two or three different segments of the artery (ICA, bulb, CCA) and the measures were then combined. No conclusions about segment specificity of the effect of high circulating tHcy can be drawn from these studies.
Studies relating cardiovascular risk factors (other than higher tHcy levels) with regard to IMT or plaque of the extracranial carotid artery have noted that the associations may vary according to the segment of the artery evaluated. Rubba et al. 39
, for example observed high body mass index (BMI) and systolic blood pressure (SBP) to be significantly associated with plaques in the common carotid artery in middle-aged women, while high LDL cholesterol levels and smoking were significantly associated with lesions at the bifurcation. In a study by Ebrahim et al. 40
systolic blood pressure and age were determinants of increased IMT at the common carotid artery in both men and women. Cigarette smoking was associated with increased IMT and plaques at the bifurcation. Results from these studies indicate that age, systolic blood pressure and BMI may be primarily associated with artery wall changes in the CCA segment, whereas smoking and higher LDL cholesterol may be risk factors that are associated with wall changes in the bifurcation segment. However, results are not completely consistent across various studies examining carotid artery segment-specific relations of these vascular risk factors.
Risk factors that are associated with wall changes at one specific segment might share common mechanisms leading to these changes, whereas changes at different segments might be a result of differing mechanisms associated with the specific structure of the artery segments. The artery segments differ in geometry, cellular composition and functions and are exposed differently to shear stress. The internal carotid artery is a muscular artery whereas the common carotid artery is an elastic artery 13
and the carotid wall at the level of the bifurcation contains more macrophages than the common carotid artery wall 41
It has been observed that atherosclerotic lesions occur mainly in the ICA/bulb segment and are rare in the CCA segment 24
. Therefore, our observed segment specific effect of higher circulating tHcy on the ICA/bulb segment may suggest that higher plasma tHcy levels are associated with plaque formation, rather than with wall thickening per se.
Several mechanisms for homocysteine as a risk factor for the development of atherosclerosis have been proposed, which include inducing endothelial dysfunction, supporting the oxidation of low-density lipoproteins initiating the lipid peroxidation cascade, and increasing vascular smooth-muscle cell proliferation via the activation of the transcription factor NFkB 42
. However, questions about specific mechanistic actions still remain 43
There are strengths and limitations to the present study. Major strengths of the study include the large number and broad age range of individuals, which allowed us to examine the associations in two age groups and at two different segments of the carotid artery, the inclusion of both men and women, and the rich data set that facilitated adjustment for a large number of potential confounders. A potential limitation of our study is the use of homocysteine levels from examination 5 and the use of IMT measurements from examination 6. This approach was prompted by the implementation of FDA-mandated folic acid fortification of enriched cereal grain products during the 6th
examination period at which the carotid IMT was assessed. The homocysteine levels respond rapidly to increased folic acid in fortified foods 22, 23
, but given the fairly short exposure times to mandatory fortification (as mentioned in the Methods section above, the median exposure time to fully implemented fortification was only 2 months), we do not believe that the increased folic acid would have any significant impact on IMT. IMT data from examination 5 were obtained by an older and less sensitive ultrasonography method and could therefore not be used in association with tHCY examination 5 data for the here presented analyses. Another limitation of our study is the cross-sectional nature of the association between tHcy and IMT as we are unable to demonstrate that a change in homocysteine levels would result in a reduced progression of ICA/bulb-IMT. Also, despite the high sensitivity of the B-mode ultrasonographic method used, it is not possible to differentiate the intima from the media layer of the artery. Therefore, it was not possible to technically distinguish between increased wall thickness and plaque per se. Further, it needs to be noted that although we observed these segment-specific associations between higher circulating tHcy and increased wall intima-media thickness, it is possible that tHcy is a risk marker for chronic disease rather than the cause for it 43
. In addition, our cohort consisted mainly of Caucasians of European ancestry. Thus, the presented findings therefore do not allow any conclusions with regard to the effect of race on the association, and the result may not apply to the general population.