The main findings of the present study are as follows: In a large sample of Caucasian patients referred for cardiovascular risk assessment, we compared the left and the right common carotid artery IMT measurements, and assessed whether age, gender and cardiovascular risk factors have differential effects on the left versus the right common carotid artery IMT. We found that the left common carotid artery IMT was larger than the right, but not in the young (< 30 years) or the elderly (> 69 years), and that this side difference was less in women than in men. In addition, the determinants of the left common carotid artery IMT differed from those of the right. In addition to age and gender, the left common carotid IMT was associated with dyslipidaemia (protective) and diabetes mellitus, whereas the right common carotid artery IMT was correlated with hypertension. The apparent protective effect of dyslipdaemia was a reflection of the high prevalence of statin use (in accordance with current therapeutic practice, all patients diagnosed with dyslipidaemia were receiving lipid lowering medication [statins]).

The finding of a larger left compared to right common carotid artery IMT in the present study is consistent with previous reports of side differences in carotid IMT in various populations [8,9,10,11,12,13,14,15,16]. Moreover, our data support a former study indicating an impact of age on the presence of side differences in measurements of carotid artery IMT [9]. In this regard, our report of a greater left versus right carotid artery IMT in healthy individuals aged between 30 and 69 years, but no differences in those less than 30 or greater than 69 years of age is similar to that of Luo et al. [9] who reported a greater left versus right carotid artery IMT in healthy individuals aged between 35 and 65 years of age [9]. However, we extend these findings by reporting that gender, in addition to age, impacts on the side differences in carotid artery IMT. Similar to a previous report in a healthy Argentinean population [14], we report a greater difference in left versus right carotid IMT in men compared to in women, and that gender impacts on the effects of age on the differences between left and right carotid artery IMT.

Reasons for the impact of age on side differences in carotid artery IMT have been speculated. It has been suggested the side differences are not present in the young as it takes time for cardiovascular risk factors to have an impact on carotid artery IMT [13]. In addition, the increase in prevalence of cardiovascular risk factors with age may also play a role. However, this does not explain the lack of side differences in carotid artery IMT after the age of 65 years (present study) [9], and the presence of side differences in carotid artery IMT in a prior study in youth [23].

Reasons for the impact of gender on the effects of age on side differences in carotid artery IMT are unclear. However, in the present study, the men had a greater prevalence of hypertension and diabetes mellitus, and the left common carotid artery IMT was associated with diabetes mellitus in men but not in women. Indeed, the greater carotid artery IMT in men compared to in women [8, 24,25,26], has been attributed to a greater prevalence of cardiovascular risk factors in men. These data suggest that the reporting of measurements on both the left and the right common carotid artery IMT is particularly pertinent in men.

A theoretical suggestion for side differences in carotid artery IMT, is the dissimilarity in the anatomical origins of the carotid arteries from the aorta. In this regard, the left carotid artery comes directly off the aortic arch, whereas the right carotid artery originates from the innominate artery which is an extension of the ascending aorta. Consequently, blood flow velocity and oscillating shear forces, which are strong determinants of intimal thickening, are greater in the left compared to the right carotid artery [16]. In comparison, Luo et al. [9] showed that the right carotid artery IMT was associated with haemodynamic parameters (blood flow velocity); whereas the left carotid artery IMT correlated better with blood biochemical indices such as blood cholesterol (total and LDL-cholesterol) and blood glucose levels. We extend these findings by showing that independent of age and gender, the right common carotid artery IMT was associated with hypertension; while the left common carotid artery IMT was associated with diabetes mellitus and dyslipidaemia. Moreover, we show that the right common carotid IMT was consistently associated with hypertension irrespective of gender; whereas the left common carotid artery IMT was associated with diabetes mellitus in men and dyslipidaemia in women. The lack of association of the number of risk factors with either right or left carotid artery IMT, could be attributed to the apparent protective impact of dyslipidaemia on carotid artery IMT. In other words, the positive association of either hypertension with right or diabetes with left carotid artery IMT, is offset by the negative association of dyslipidaemia with carotid artery IMT. Although metabolic syndrome has been associated with carotid artery IMT in both normotensive and hypertensive participants [29], in meta-analyses [30], and in longitudinal studies [31, 32], whether metabolic syndrome is associated differentially with right versus left carotid IMT needs to be assessed in future studies.

There are several limitations to the present study. As the present study was cross-sectional in design, the relationships noted may not be cause and effect and may be attributed to residual confounding. Further studies evaluating the long-term impact of haemodynamic and biochemical cardiovascular risk factors on left versus right carotid artery IMT are therefore required. Second, we employed a combination of manual and semi-automated measurements of carotid artery IMT. However, it has previously been reported that the method of measurement of carotid artery IMT has no impact on the presence versus absence of side differences in carotid artery IMT [13, 15]. In addition, although automated echo-tracking is advantageous as it lowers the variability between readers [33], in the current study all of the IMT measurements were performed by the same investigator (BS). Third, data on lipid lowering and anti-hypertensive therapy were not available, and hence could not be included in the models. However, most patients were receiving lipid lowering therapy (74.5% had dyslipidaemia and were receiving lipid lowering agents as per current clinical practise). It is possible that therapy could be a determinant of IMT. Indeed, the negative relationship observed between dyslipidaemia and IMT is likely a reflection of the high prevalence of lipid lowering therapy. Bearing in mind the relationship between hypertension and right carotid artery IMT, and between diabetes and left carotid artery IMT in the current study, it is possible that anti-hypertensive therapy may influence the progression of right carotid artery IMT, and anti-diabetic agents may influence the progression of left carotid artery IMT. However, future studies should investigate the impact of current therapy on left versus right carotid artery IMT. Four, due to the low prevalence of data from other population groups, the present study was only conducted in Caucasian participants. Hence, whether the results are translatable to all populations is unknown. Nevertheless, our data are supported in part by similar findings in an Argentinean population [14], and in a Chinese population [9]. Lastly, the smaller sample sizes of individuals less than 30 years and older than 69 years of age, may in-part explain the lack of differences between left and right carotid artery IMT within these age groups. However, our findings support those previously reported in a Chinese population [9], where no side differences in IMT were observed in individuals less than 35 or more than 65 years of age, and the sample sizes for these groups were similar to the group aged 56 to 65 years where side differences were noted [9].

The presence of side differences in common carotid artery IMT and the differential effects of cardiovascular risk factors on the right compared to the left carotid artery IMT are of clinical relevance. Disparities in the prognostic ability of the right versus the left carotid artery IMT have previously been reported [21, 34,35,36]. In patients with coronary artery disease, the right carotid artery IMT (hazard ratio [HR] 18.31, p < 0.0001) predicted cardiovascular outcomes, but not the left carotid artery IMT (HR 3.81, p = 0.11). Furthermore, the predictive ability of the right carotid artery IMT was independent of confounders in multivariate analyses (HR 17.07, p = 0.007) [21]. As the patients had coronary artery disease, the cardiovascular outcomes were predominantly cardiac in origin (27% cardiac death, 73% acute coronary syndrome). In a community-based study of the elderly, a 0.3 mm increase in right carotid artery IMT was a better predictor of all-cause mortality (right IMT: relative risk [RR] = 3.33, p = 0.0053; left IMT: RR = 1.65, p = 0.022) and cardiovascular mortality (right IMT: RR = 2.89, p = 0.038; left IMT = 2.35, p = 0.043) [34], than the same increase in left carotid artery IMT. One third of the deaths in this study were cardiovascular, being either myocardial infarction or stroke. The superior predictive ability of the right carotid artery IMT over the left carotid artery IMT, may be attributed to its relationship with hypertension. In the current study, the right, but not the left, carotid artery IMT was associated with hypertension. In addition, both borderline hypertension and isolated systolic hypertension are associated with increases in the right, but not the left, carotid artery IMT [35, 36]. These data would suggest that the right carotid artery IMT is more sensitive to haemodynamic cardiovascular risk factors and consequently better predicts clinical events than the left carotid artery IMT. The differential power of the right and left carotid artery IMT in predicting vascular events, depending on the patients baseline characteristics and pathogenesis, is important to consider in the interests of personalised and precision medicine.

In conclusion, in a large sample of Caucasian patients referred for cardiovascular risk assessment, we show that age, gender and cardiovascular risk factors have differential effects on the left versus the right common carotid artery IMT. In this regard, the left common carotid artery IMT was larger than the right, but not in the young (< 30 years) or the elderly (> 69 years), and this side difference was less in women than in men. In addition to age and gender, the left common carotid IMT was associated with dyslipidaemia and diabetes mellitus, whereas the right common carotid artery IMT was associated with hypertension. These data suggest that there may be subgroups, such as men and those aged 30 to 69 years, where reporting on the left and right carotid artery IMT as opposed to the average is particularly pertinent. Moreover, in the present study, only 25% of participants had increased IMT on both the left and the right sides. As the left and right common carotid artery IMT may exhibit different prognostic values in patients with stable coronary artery disease [21], our data highlight the importance of assessing common carotid artery IMT on both sides of the body.