Common carotid arterial interadventitial distance (diameter) as an indicator of the damaging effects of age and atherosclerosis, a cross-sectional study of the Atherosclerosis Risk in Community Cohort Limited Access Data (ARICLAD), 1987–89

Because of its accessibility, the common carotid artery (CCA) is often evaluated using B-mode ultrasound to assess atherosclerosis severity [1–3]. Ultrasound, animal, and anatomic studies indicate arterial diameters are associated with hemodynamic factors [4–7] and with vascular damage [8, 9]. Several studies have suggested that arterial wall area, or arterial diameter in conjunction with wall thickness, may provide useful information for understanding atherosclerosis progression, vascular injury, or vascular vulnerability [2, 8, 10–15]. However, the relationship between arterial wall thickness and diameter is not likely to be simple since both physiologic and pathological processes can contribute to diameter differences [13]. For example multiple factors such as gender [16], physiologic response to shear stress[17] as well as plaque characteristics [8, 9] are known to be associated with arterial diameter. So, many factors could potentially impact the relationship between age and diameter. While many studies have evaluated associations of risk factors or vascular characteristics with arterial diameter [8, 9, 11, 18–23], fewer studies have attempted to separate the effects of age and atherosclerosis on arterial diameter. The Bruneck study found that age was related to CCA diameter only in persons within the upper 50^th percentile of wall thickness [11] while a small study of 69 male subjects screened for the absence of atherosclerosis and its risk factors found that diameter did increase significantly with age [13].

This study extends previous studies of B-mode ultrasound CCA by estimating optimal B-mode ultrasound right CCA diameters (interadventitial distances) within a low-risk subset from a bi-racial population sample of both men and women; by determining whether atherosclerosis severity measures were effect modifiers of the age-CCA diameter relationship; and by estimating the effect of age among diseased, high risk, and low risk populations from the same population sample.

Of the 9,109 participants with right CCA diameter B-mode ultrasound measurements, 8,528 participants had adequate information for classification of disease severity and 8,163 participants had data for risk adjustment. Among persons with data from all 6 carotid sites (right or left, internal, bifurcation, and CCA), 36% were found to have plaque or shadowing (evidence of calcification) of at least 1 site. The low risk, high risk, and pre-existing disease groups were comprised of 1,397, 6175 and 591 participants respectively.

Age-diameter relationships: separate models adjusting to young-age risk levels

Results were similar when the relationship between age and diameter was determined for each subset in separate analyses (Figure 1). Betas for covariates were determined in linear regression models for each subset. Each stratified analysis was then adjusted to the means/proportions for the covariates of persons who were 45 to 50 years old in the respective subsets. Older age was associated with larger diameters in all subsets regardless of the level of adjustment, but the effect of age was reduced by risk factor adjustment in all subsets (slopes decreased after adjustment). Diameters for the pre-existing disease and high risk groups were larger than the low risk group, regardless of the level of adjustment. After risk factor adjustment, there was little difference between the slopes for the pre-existing disease and high risk groups (pre-existing disease: 0.028 mm/year; high risk group: 0.027 mm/year), but both groups continued to have slightly greater slopes than the low risk group (0.020 mm/year).

This study provides estimates for the effect of age on the right CCA diameter in both low and high risk populations. As an estimate of optimal right CCA diameters for middle-aged adults, the study provides age-, gender- and height-specific estimates for right CCA diameters from a low risk subset of the ARICLAD. Our findings of a significant, positive association between age and CCA diameter among a low risk population, with a larger effect among persons with atherosclerotic disease or high levels of risk factors, suggest that arterial remodeling may indicate duration of exposure among persons with atherosclerosis or elevated risk factors and duration of "normal" stresses among persons with low risk factor levels.

That atherosclerosis and atherosclerotic risk factors are associated with arterial diameter is well recognized [7, 20, 29, 32], and recent studies have suggested arterial remodelling frequently occurs in association with vulnerable plaques [8, 9, 14]. So, associations between age and arterial diameter may not reflect the contribution of age itself, but instead, an increase in prevalence and/or severity of atherosclerosis or its risk factors with increasing age. The prospective Bruneck study, comprised of a random sample of men and women 40 to 85 years old, found a statistically significant increase in CCA diameter with age for persons in the highest 50^th percentile of wall thickness, but a much smaller and non-significant diameter increase among persons with thinner CCA walls [11]. Similarly, our study found a larger effect of age on CCA diameter in persons with pre-existing atherosclerotic disease or high cardiovascular risk factor levels compared to low risk persons (e.g. without atherosclerotic disease and with low CVD risk factor levels). In our study, the greater effect of age on the CCA diameter in the higher risk groups was driven by the presence of atherosclerotic plaques. In contrast to the Bruneck study, our study found a significant positive association between age and CCA diameter even in the low risk subset. A number of differences between the studies could explain the discrepant findings: our study evaluated cross-sectional data and the Bruneck study evaluated prospective data; our study was of the right CCA and the Bruneck study combined right and left CCA; different criteria were used to define the low risk groups; and the study populations were different. However, qualitatively, results from the two studies are similar. CCA did increase with age in the Bruneck study low risk group, just not significantly so. Another study evaluated 69 male patients and athletes, aged 16–75, who were selected for the absence of major atherosclerotic risk factors and plaque [13]. In this convenience sample, age was a strong independent predictor of CCA diastolic diameter. Each ten years of increasing age was associated with a 0.17 mm larger CCA diameter [13], which is similar to the estimate in persons without atherosclerotic plaques (0.02 mm/year) and identical to the risk factor adjusted estimate from our low risk subset (0.017 mm/year). These findings support an effect for aging that is separate from that of clinically identifiable atherosclerosis and which appears to be relatively uniform in middle aged populations without major risk factors.

The significant interactions between both atherosclerosis severity measures and age in models predicting CCA diameter are consistent with age being a marker for length of exposure to the damaging risk factor effects. However, a significant interaction persisted only between age and plaques after adjustment for risk factors suggesting that much of the greater age effect in the pre-existing disease and high risk groups occur because of the effect of atherosclerotic damage evidenced by the presence of plaques.

The low risk subset was selected so that subjects had risk factor values lower than those typically used to identify cardiovascular risk. The reduction in the parameter estimate for age's impact on CCA diameter in the low risk group after adjusting for continuous atherosclerotic risk factors, indicates that even risk factor levels not commonly classified as detrimental can impact CCA diameters. This is not surprising given previous findings for BP [33]. Thus, at least part of the CCA diameter differences seen with older age in this low risk group was likely due to higher (though still normal) atherosclerosis risk factor levels at older ages. The persistence of a significant, positive association between age and CCA diameter in the low risk population, even after adjustment for atherosclerotic risk factors, suggests that damage or weakening of the arterial wall associated with aging also contributes to diameter enlargement. Since the primary goal of the ARIC ultrasound examination was not to identify plaques, we cannot exclude the possibility that some of the CCA diameter enlargement, even in the low risk group, was due to underlying atherosclerosis which was not identified.

This difference in diameters among the low risk group and higher risk groups has important implications for defining normal values in general. Since the prevalence of obesity and associated risk factors is high in many populations [34–36], using population based samples could result in incorrect estimations of optimal values for CCA diameter and other risk factors influenced by obesity. Thus, persons at risk could be misclassified as being normal, and the possibility of misclassification could be largest in populations with the greatest obesity and risk.

Because the study is cross-sectional in design, the associations that were identified do not necessarily indicate a causal mechanism. The division into low risk, high risk and pre-existing disease groups is somewhat arbitrary; and so, results could reflect differences because of the ages represented within the risk groups. However, given that substantial proportions of all age categories 45–49, 50–54, 55–59, and 60–64 were represented within each risk group, age differences are unlikely to be driving the findings. Persons who had missing information leading to their exclusion in the current study were different in a number of ways from the persons available for study. However, since the associations for age and CCA diameter were quantitatively similar to those reported by for a smaller "normal" male population and qualitatively similar to those reported in a prospective study [11, 13], our results are likely to provide reasonable estimates for the differences that would be found in populations with disparate atherosclerotic risk.

In conclusion, consistent with our hypothesis and previous studies, our cross-sectional results indicate that persons with pre-existing atherosclerotic disease or atherosclerosis risk factors have larger diameters than persons without those attributes. More importantly, we also found that the impact of each year of older age on CCA diameter was significantly larger among populations with pre-existing cardiovascular disease and among persons with high risk factor levels or plaques compared to those at low risk of atherosclerotic disease and we were able to quantify the expected effect. Future investigations should consider the relationship between age, length of risk factor exposure, diameter, wall thickness, plaque, and disease development to better understand the progression of atherosclerosis and development of cardiovascular disease.

The authors have no conflicts of interest to disclose. Neither the interpretation nor presentation of the data was influenced by personal or financial relationship with other people or organizations.