Background
The metabolic syndrome (MetS) is linked to increased levels of vascular damage [
1], cardiovascular morbidity and cardiovascular mortality [
2‐
4]. A survey of the most recent evidence estimated that cardiovascular disease risk is increased ~2-fold in both men and women with MetS [
2]. Non-invasive carotid ultrasound techniques can potentially be used to test the validity of this relationship at a much earlier pre-clinical stage. Furthermore, these surrogate measurements of cardiovascular disease may assess a patient's risk and be used in the evaluation of novel treatments [
5].
The commonly used measurement to assess carotid "atherosclerosis" is intima media thickness (IMT). Recently, however, newer measurements such as assessment of plaque area or total plaque volume (TPV) have been suggested to represent a potentially more powerful approach, since these measurements in higher dimensions evaluate plaque burden in the carotid system and hold great sensitivity and discrimination [
6‐
8]. IMT and TPV, however, are not interchangeable. Their correlation is only moderate (
r < 0.7) and these different ultrasound-derived measures of carotid artery morphology likely represent distinct attributes of atherosclerosis [
9,
10]. As more research is needed to provide a complete understanding of how these ultrasound traits relate to cardiovascular disease stages and endpoints we have evaluated two carotid ultrasound measurements, namely IMT and TPV, in a Canadian Oji-Cree population with one of the highest MetS prevalence rates in the world [
11].
Discussion
We found: 1) elevated carotid IMT for subjects with MetS in comparison to those without MetS (P = 0.039); 2) no significant difference in carotid TPV for subjects with MetS, adjusting for age and sex; and, 3) a trend towards increasing IMT with increasing numbers of MetS components. The results suggest that IMT has a stronger and more consistent relationship with MetS than does TPV.
Our results are consistent with previous studies of IMT which have also found a significant association between increased carotid artery thickening and MetS diagnosis. In the largest study to date, the Atherosclerosis Risk in Communities (ARIC) study (N = 12,178), MetS was significantly associated with both an increased risk of coronary heart disease and also with increased IMT. The observed difference between those with and without MetS was relatively small (747
vs 704 μm), but highly significant (
P < 0.0001), even after adjustment for age, sex, and race/study [
20]. Similarly in an Austrian study (N = 1,588), IMT was found to be significantly higher in subjects with MetS (
P < 0.0005) [
21]. The observed difference in IMT between those with and without MetS was more pronounced in females than in males, indicating a potentially stronger relationship between MetS and atherosclerosis in females [
21].
One distinctive feature of our study was the relatively younger age of our Oji-Cree sample, which may be affected by a lesser degree of measurable disease progression. Interestingly we observed a difference in IMT of ~70 μm between those with and without MetS, greater than the difference observed in the ARIC study, yet similar to the values observed for the middle-aged females in the Austrian study. Observing this degree of IMT for subjects with MetS among the relatively young Oji-Cree collective is consistent with the high prevalence of both type 2 diabetes and coronary heart disease that have been observed in this population [
14,
22].
While a significant difference was found for IMT, no significant difference was found for TPV between subjects with MetS and subjects without MetS, although TPV tended to be greater among subjects with MetS. The absence of statistical significance following adjustment for age and sex is undoubtedly related to the small number of subjects and the proportion of individuals without measurable plaque (TPV ≤ 0.01 mm
3 for 31% of subjects), but it may also be because of the relative insensitivity of carotid TPV as a surrogate marker for atherosclerosis (i.e. greater intra- and inter- operator variation) or because patients with MetS have increased IMT rather than increased plaque. Previous studies have reported that the correlation between IMT and TPV is only modest (
r < 0.7), indicating that these measures likely represent distinct attributes of atherosclerosis [
7,
9,
10]. This is understandable, considering that the measurement of IMT is based on a single defined location near to the transition between the common carotid and bulb regions, whereas the measurement of TPV involves the whole carotid system, and thus disparities can arise depending on whether or not plaque happens to be present in this designated area. When measured in the same subjects, these ultrasound traits have been shown to have distinct relationships with individual risk factors [
9], diabetes [
7], and genetic determinants [
23,
24]. TPV may better reflect the later stages of plaque formation and the total disease burden, especially among subjects with diabetes [
7,
9], whereas IMT, correlating more closely with hypertension and age [
9], may reflect wall hyperplasia or hypertrophy related to hypertension. This considered, it may be that IMT would capture vascular disease burden more effectively in MetS-affected subjects, considering that both systolic and diastolic blood pressure are key components of the MetS definition.
A limitation of our study and others is the lack of prospective data to determine the relationship between MetS and the progression of carotid ultrasound traits. A prospective study of 316 Swedish middle-aged men found that IMT was greater at baseline and also after three years in subjects with MetS, while no significant change was observed for subjects with no MetS risk factors [
25]. Further prospective studies such as these, analyzing the use of ultrasound measures for detecting disease progression, would be potentially valuable for future MetS research.
In addition, it would have been beneficial if our study evaluated additional, more general populations, to determine if this pattern of positive association for IMT and no association for TPV is typical or simply a unique observation for the Oji-Cree. The Oji-Cree study group was also not just a typical population, in that the prevalence of diabetes was >50% for the MetS subjects. Considering the distinctiveness of the carotid ultrasound trait measures, it is indeed highly likely that there will also be distinct relationships observed depending on the population studied.
Conclusion
Our study of the relationship between MetS and carotid atherosclerosis has, to the best of our knowledge, evaluated IMT and TPV in parallel, for the first time. For this study group, the observations show that standard IMT measurement captures an increased disease burden among individuals with MetS, while the TPV measurement appears somewhat less strongly related and less informative. This supports previous reports of increased carotid ultrasound analytes for persons with MetS, but additionally, this study indicates that TPV may not be as valuable a surrogate marker of vascular disease burden in MetS, though this is likely dependent on the characteristics of the study population.
Ultrasound measurements are, however, only surrogate markers for risk of arterial occlusion. What would be of great interest is to know which test correlates more closely with outcome. This is an important step for future studies. Though increased TPV was not a significant hallmark for those with MetS in this study, it still, nonetheless, is a distinct ultrasound trait which may be shown to be an important preclinical marker for arterial occlusion risk.
Acknowledgements
The authors gratefully acknowledge Maria DiCicco for performing the ultrasound scans, and also would like to recognize the chief, council and community members of Sandy Lake First Nation and the Sandy Lake community surveyors, whose partnership and co-operation was essential in the design and implementation of this project.
Supported by the Jacob J. Wolfe Distinguished Medical Research Chair, the Edith Schulich Vinet Canada Research Chair (Tier I) in Human Genetics, a Career Investigator award from the Heart and Stroke Foundation of Ontario, and operating grants from the Canadian Institutes for Health Research, the Heart and Stroke Foundation of Ontario, the Ontario Research and Development Challenge Fund (Project #0507) and by Genome Canada.
Competing interests
The author(s) declare that they have no competing interests.
Authors' contributions
RLP participated in the design of the study, analysis of the data, and writing of the manuscript. KZA and AAH calculated the total plaque volume and intima-media thickness measurements, respectively, and assisted with manuscript revisions. MM coordinated the data collection. JDS, AF, BZ, SBH, and AJGH provided patients and data for the study, and assisted with manuscript revisions. RAH participated in the design of the study and writing of the manuscript. All authors read and approved the final manuscript.