Asymmetry in prevalence of femoral but not carotid atherosclerosis Jelle Bossuyt a, Luc M. Van Bortel a, Tine L.M. De Backer a, Sandrien Van De Velde a, Majda Azermai a, Patrick Segers b, Marc De Buyzere c, Caroline Van daele c, Ernst Rietzschel c,d, on behalf of the Asklepios Investigators
Objective(s): Atherosclerotic disease is caused by a combination of systemic and local factors (e.g. geometry) affecting local flow conditions. In contrast to the carotid artery, at the iliac-femoral artery region, a large degree of bilateral asymmetry exists. Therefore, we aimed to determine the influence of body side on the prevalence of atherosclerosis (i.e. plaque and intima–media thickness; IMT) at the carotid and femoral arteries. Methods: Data were used from the ASKLEPIOS study, including 2524 apparently healthy individuals with a mean age of 46 years (range 35–55 years). Echographic images were obtained bilaterally of the carotid and femoral arteries. A single observer approach was used for the acquisition and quantification of plaques and IMT. Results: The carotid artery displays no significant left-right difference in IMT values nor plaque prevalence (right: 12.0 vs. left 13.3%; P ¼ 0.18). In contrast, for the femoral artery, the IMT distribution at the right common femoral artery is more skewed (P90 right: 1.11 mm, left 1.01 mm; P < 0.001), which is mirrored by a significantly higher plaque prevalence (right: 21.9 vs. left: 15.7%; P < 0.001). Conclusion: In the present study, atherosclerotic lesions are more prevalent at the right than at the left femoral artery. This finding highlights the possible role of local arterial geometry in the development of atherosclerosis and underscores the importance of the choice of body side when assessing vascular health. Keywords: atherosclerosis, atherosclerotic plaque, carotid artery, femoral artery Abbreviations: ATP III, Adult Treatment Panel III; CI, confidence interval; CVD, cardiovascular disease; IFG, Impaired fasting glycemia; IMT, Intima–media thickness; OR, odds ratio; SD, standard deviation; TOD, target organ damage
therosclerotic cardiovascular disease (CVD) remains the main cause of premature morbidity and mortality in the western world whilst rapidly also taking on epidemic proportions in the developing world . The advent of high-resolution ultrasound
Journal of Hypertension
technology has enabled researchers to evaluate atherosclerosis noninvasively at an early, subclinical stage . Measurements are usually performed at the carotid artery, but can also be done at the femoral artery. Both carotid [3,4] and femoral [5–7] arteries have been shown to carry independent prognostic information [8,9]. However, the fact that these arteries are paired raises the possibility to measure on left, right or both sides of the body, introducing unwanted variability. To date, consensus guidelines with regard to body side are either lacking (femoral artery), or confusing (carotid artery), as the Mannheim consensus document states that ‘[carotid] IMT values from the left and right side can be averaged although there is a significant difference between the left and right’ . Bilateral differences in the prevalence of atherosclerosis may be expected on the basis of an anatomical asymmetry, with left and right arteries following slightly different trajectories. In particular, the right iliofemoral trajectory has been shown to cover a significantly longer , more curved  path than its contralateral counterpart. In contrast, close to the measurement site, left and right carotid arteries run in a reasonably similar, almost parallel course , limiting the amount of anatomical asymmetry . The link between arterial geometry and atherosclerosis, mediated through changes in local haemodynamics and shear stress, has long been recognized . We hypothesized that if a left-right difference in arterial geometry indeed translates into an asymmetric distribution of atherosclerosis, then this effect should reveal itself at the population level. Therefore, our aim was to compare the prevalence of atherosclerosis (looking at both plaques and intima–media thickness, IMT) between the left and right carotid and femoral arteries, in a large population sample.
Journal of Hypertension 2014, 32:1429–1434 a Heymans Institute of Pharmacology, Clinical Pharmacology, bInstitute Biomedical Technology (IBiTech), Ghent University, cDepartment of Internal Medicine (Cardiovascular Diseases), Ghent University and Ghent University Hospital and dDepartment of Public Health, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
Correspondence to Jelle Bossuyt, Heymans Institute of Pharmacology, Ghent University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium. Tel: +32 9 332 00 42; fax: +32 9 332 88 00; e-mail: [email protected] Received 5 October 2013 Revised 11 March 2014 Accepted 11 March 2014 J Hypertens 32:1429–1434 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. DOI:10.1097/HJH.0000000000000205
The ASKLEPIOS study protocol, methodology and baseline population characteristics have been described elsewhere in detail .
average IMT over the observed segment) instead of maximal IMT, and when individuals with atherosclerosis at two or more locations were excluded (i.e. looking at ‘single-site atherosclerosis’, including only those individuals with a lesion at one single site).
MATERIALS AND METHODS
We recruited a cohort of 2524 apparently healthy, male and female volunteers aged 35–55 years at study initiation in October 2002. The individuals were randomly sampled from the twinned Belgian communities of Erpe-Mere and Nieuwerkerken, and were free from overt CVD. Exclusion criteria were clinical evidence of atherosclerotic or atherothrombotic disease; major concomitant illness; diabetes mellitus type 1 and 2 with proven clinical macro-vasculopathy or significant renal impairment; pregnancy; and inability to provide informed consent. The ethical committee of the Ghent University Hospital approved the study protocol.
Vascular imaging Individuals underwent ultrasonographic examination of the left and right carotid and femoral arteries (VIVID 7; GE Vingmed Ultrasound, Horton, Norway) [10,15–17]. Analysis of the ECG-gated cineloops was performed offline by a single, blinded, measurement-dedicated reader. Carotid and femoral arteries were scanned bilaterally for the presence of plaque (a focal protrusion >50% compared with adjacent sites with an absolute thickness >1.5 mm or with a protrusion into the lumen of >0.5 mm) . IMT was defined as the distance from the leading edge of the lumen-intima interface to the leading edge of the media-adventitia interface, measured in end diastole, at the far wall, proximal to the bifurcation [10,15– 17]. IMT corresponds with the maximum value over the observed segment. Intraobserver variability of IMT was 5%. Presence of plaque at an IMT-measuring site precludes IMT measurement at that site. This, together with difficult imaging (often related to obesity), resulted in missing IMT values in 8, 168 and 198 individuals for the right carotid, left femoral and right femoral arteries, respectively. IMT-values were categorized using cut-off values of 0.9 and 1.5 mm . The variable ‘vascular target organ damage’ (TOD) was defined as either IMT greater than 0.9 mm or presence of a plaque.
Demographics, anthropometric data, lifestyle and ultrasonographic data are provided in Table 1.
Intima–media thickness Median IMT was not significantly different between left and right carotid arteries. Quantile regression also revealed no significant differences for the 80th, 85th, 90th and 95th percentiles between right and left side (P > 0.05 for all percentiles). Median femoral artery IMT was identical for the left and right side. Comparison of upper percentiles, however, showed increasingly higher values at the right femoral artery (P < 0.05), indicating a more skewed distribution (Fig. 1). This effect was also demonstrated by the significantly higher number of individuals exceeding the 0.9 mm cut-off value for femoral artery IMT on the right side (Table 2).
Plaque prevalence A total of 303 and 335 plaques were found at the left and right carotid artery, respectively, revealing no significant influence of the body side (P ¼ 0.92). In contrast, at the level of the femoral artery, substantially more plaques were found on the right side (right: n ¼ 552, left: n ¼ 396), resulting in an OR significantly different from 1 (OR 1.53, 95% CI 1.28–1.83; P < 0.001). (Table 2) When cases of IMT greater than 1.5 mm but without significant protrusion into the lumen (>50% compared to adjacent sites or >0.5 mm) were also classified as plaques, these results were maintained (femoral artery: right: n ¼ 573, left: n ¼ 423; OR 1.51, 95% CI 1.27–1.81; P < 0.001; carotid artery: right: n ¼ 304: left: n ¼ 336; OR 1.01, 95% CI 0.82–1.25; P ¼ 0.92).
Target organ damage The combined phenotype, ‘TOD’, exhibits the same pattern as either plaque prevalence or intima-medial thickening alone, confirming the symmetrical and asymmetrical distributions at the carotid and femoral arteries, respectively. (Table 2)
Statistical analysis For continuous variables, median, 80th, 85th, 90th and 95th percentiles are reported. Distributions were compared between left and right side by performing quantile regression on median and individual percentile values. Categorical variables were summarized as absolute values and percentages. The influence of body side and (possible) confounding effect of sex was tested using logistic regression, adding side, sex and an interaction term (body sidesex) as fixed factors into the model. For each test, a P value of less than 0.05 was considered statistically significant. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were calculated. As a sensitivity analysis, we checked whether the results would be maintained when looking at mean IMT (i.e. the 1430
The influence of sex The prevalence of lesions was always higher in men than in women (P < 0.001). However, the modifying effect of sex was limited, as the interaction term (body sidesex) was significant only for carotid TOD (P ¼ 0.036), because of a reversed trend in men (right: n ¼ 310, left: n ¼ 335) compared with women (right: n ¼ 169, left: n ¼ 140). (Table 2)
Sensitivity analyses Single-site atherosclerosis When only taking into account individuals with atherosclerosis at a single site, the same pattern emerges: an almost identical number of lesions at right and left carotid arteries Volume 32 Number 7 July 2014
Age (years) BMI (kg/m2) Waist circumference (cm) Obesity, BMI 30 kg/m2 (%) Abdominal obesity, ATP III (%) Metabolic syndrome, ATP III (%) Haemodynamic parameters SBP (mmHg) DBP (mmHg) Pulse pressure (mmHg) Heart rate (bpm) Biochemical parameters Total cholesterol (mg/dl) HDL-cholesterol (mg/dl) LDL-cholesterol (mg/dl) Triglycerides (mg/dl) Diabetes mellitus/IFG (%) Lifestyle variables Smoking: Active/Ex (%) Pack-years, of ever smokers Leisure-time physical activity: None (%) Ultrasonographic measures Right carotid IMT (mm)a Left carotid IMT (mm)a Right femoral IMT (mm)a Left femoral IMT (mm)a
0.67 0.67 0.59 0.59
(0.60–0.76) (0.60–0.76) (0.51–0.71) (0.51–0.70)
0.71 0.73 0.72 0.71
(0.63–0.82) (0.63–0.83) (0.60–0.92) (0.60–0.87)
Cut-offs for abdominal obesity (Adult Treatment Panel, ATP III) are waist >88 cm (women)/>102 cm (men); Impaired fasting glycemia (IFG): glucose 100 and <126 mg/dl (diabetes). Data are mean SD or median (interquartile range) where appropriate. All variables, except age, were statistically different between men and women. a Maximum value over the observed segment.
(right: n ¼ 112, left: n ¼ 110; OR 1.02; 95% CI 0.78–1.33; P ¼ 0.89), in sharp contrast to the more than two-fold difference seen at the femoral arteries (right: n ¼ 207; left: n ¼ 94, OR 2.31, 95% CI 1.80–2.97; P < 0.001) (Fig. 2). This also indicates that by measuring both carotid arteries and only right, only left or none of the femoral arteries, 94 (4%), 207 (8%) and 474 (19%) individuals would be wrongly classified without TOD, respectively. Using mean intima–media thickness instead of maximal intima–media thickness When maximal IMT was replaced with mean IMT, this shifted IMT distributions towards lower values, reducing the total number of individuals exceeding the 0.9 mm cutoff value. However, this had no impact on our conclusions: P90 percentiles were again divergent for the femoral artery (right: 0.90 mm, left 0.85 mm; P < 0.05), while equal for the carotid artery (right: 0.75 mm, left 0.75 mm). Left-right distributions of TOD prevalence also remained unchanged when TOD was defined using mean instead of maximum IMT (femoral artery: left: n ¼ 488, right: n ¼ 633; P < 0.001; carotid artery: left: n ¼ 333, right: n ¼ 368; P ¼ 0.15) adding to the robustness of our findings.
DISCUSSION The present study investigated the influence of body side on the prevalence of atherosclerosis at the carotid and femoral arteries. Our main finding was that atherosclerosis, examined through maximal IMT and the presence of plaque, was distributed symmetrically at the carotid artery whereas asymmetrically at the femoral artery. For the Journal of Hypertension
carotid artery, these observations are in line with results from previous epidemiological studies, showing small  or insignificant  differences between both sides. With regard to the femoral artery, data are rather scarce but also tend to confirm our observations. Plaque thickness  and IMT  tend to be higher when measured on the right side. The results of this study also mirror anatomical features described in literature. The equal distribution of carotid artery atherosclerosis reflects the limited amount of morphological asymmetry between left and right side (at the level of the measurement location, proximal to the bifurcation), although the skewed distribution of femoral artery atherosclerosis can be explained by more pronounced differences in arterial anatomy. Moreover, the fact that the most frequently affected femoral artery is the one lying on the right side resonates with the current hemodynamic principles. It is now firmly established that regions of curvature, bifurcation or branching are associated with low longitudinal or high oscillatory shear stress, creating flow conditions that promote the development of atherosclerotic lesions [22–25]. Therefore, the higher prevalence of atherosclerosis seen at the right femoral artery may be explained by its generally more curved, bended nature. Although the anatomy of left and right carotid artery is also not completely comparable, particularly differing in terms of their origin, we speculate that the impact of this anatomical variability on the haemodynamics at the more distal measurement location is buffered by the relatively long straight segment in between. Indeed, at the common carotid artery, no bilateral difference is found in blood flow characteristics , including timing and velocity of the flow waveform , and shear stress distributions . In www.jhypertension.com
FIGURE 1 Cumulative distribution of maximal intima-media thickness at the carotid (a) and femoral (b) arteries. Left and right carotid artery IMT distributions largely overlap, although increasingly higher values are found at the right femoral artery compared with the left. Statistically significant (P < 0.05) differences between individual percentiles are indicated with an asterisk ().
addition, it can be speculated that the difference in vascular wall properties (the more elastic carotid and the more muscular femoral arteries), the more bent iliac-femoral
trajectory and the higher pressures at the femoral arteries in standing position might contribute to a possible difference in sensitivity to local atherogenic factors between the
TABLE 2. Prevalence of preclinical atherosclerosis in men, women and all individuals Carotid artery Men (n ¼ 1223)
IMT >0.9 mm Plaque TOD
Women (n ¼ 1301)
All (n ¼ 2524)
185 (15) 210 (17) 335 (27)
161 (13) 212 (17) 310 (25)
72 (6) 93 (7) 140 (11)
61 (5) 123 (9) 169 (13)
257 (10) 303 (12) 475 (19)
222 (9) 335 (13) 479 (19)
0.164 0.915 0.251
<0.001 <0.001 <0.001
0.952 0.101 0.036
Femoral artery Men (n ¼ 1223)
IMT >0.9 mm Plaque TOD
Women (n ¼ 1301)
All (n ¼ 2524)
241 (20) 280 (23) 402 (33)
292 (24) 382 (31) 508 (42)
113 (9) 116 (9) 195 (15)
137 (14) 170 (13) 250 (19)
354 (14) 396 (16) 597 (24)
429 (17) 552 (22) 758 (30)
0.013 <0.001 <0.001
<0.001 <0.001 <0.001
0.846 0.981 0.588
Vascular target organ damage (TOD) is defined as IMT 0.9 mm or presence of a plaque. Data are shown as absolute values and percentages, n (%). P values were obtained from logistic regression in all individuals, including body side, sex and an interaction term (body sidesex) as fixed factors.
Atherosclerosis: influence of body side Right carotid artery
Left carotid artery
112 61 36
75 Left femoral artery
Right femoral artery
FIGURE 2 Distribution of preclinical atherosclerosis in all individuals. Venn-diagram displaying all possible combinations of target organ damage distribution (TOD, IMT >0.9 mm or presence of a plaque), emphasizing cases of single-site atherosclerosis (bold).
common carotid and common femoral arteries. However, to provide more conclusive evidence for this hypothesis, information on the arterial anatomy on an individual basis is warranted. Instead, we had to base our assumptions on averaged anatomical data found in the literature, including our own MRI-based research in a different healthy population .
Study limitations As a general remark, we emphasize that this study was carried out in an apparently healthy population, exhibiting only preclinical signs of atherosclerosis. It remains to be established whether these lesions will actually become clinical later in life. Prospective studies are needed to show the clinical meaning of the difference of atherosclerosis in right and left femoral arteries. Other limitations of the study include the absence of bilateral diameter and flow measurements, and some limitations inherent to the noninvasive assessment of atherosclerosis. Ultrasound imaging provides only a two-dimensional view of the vessel wall and also fails to distinguish intimal from medial thickening . However, to deal with this latter point, we reported maximal (and not mean) IMT values, which may be considered to represent more closely the first signs of an atherosclerotic lesion [30,31]. In our study, the difference in maximal IMT values between left and right side was indeed closely mirrored by the difference in plaque prevalence, confirming this assumption. In addition, this study provides a systematic and robust measurement of atherosclerosis at the left and right carotid and femoral arteries, excluding any bias due to variations in operator, measurement device or other confounders. Although similar experiments have been repeatedly carried out on the carotid artery, this is the first study making a rigorous comparison of the prevalence of atherosclerosis between left and right femoral artery.
Implications A first implication of this study may relate to the guidelines for atherosclerosis imaging. For the carotid artery, our data Journal of Hypertension
provide additional support for the already widely accepted consensus advice of not taking into account the body side. For the femoral artery, guidelines are at present nonexisting, leaving operators free in their choice on which body side to measure upon. However, clinicians and researchers should be aware of the possibility that femoral artery atherosclerosis may more likely affect the right side of the body, as observed in our ASKLEPIOS population. A second implication may relate to the mechanisms responsible for the observed differences in atherosclerosis prevalence. Although unable to provide conclusive evidence for the causal role of anatomical asymmetries, our data do provide an interesting starting point for further research. In the future, also characterizing left-right differences in shear stress and blood flow patterns may yield more insight in the underlying processes behind this phenomenon, unravelling the critical anatomical features responsible for driving or protecting the development of an atherosclerotic lesion. In conclusion, in a healthy, middle-aged population sample, subclinical atherosclerosis is equally distributed between right and left carotid arteries. In contrast, the right femoral artery is significantly more affected than the left femoral artery. These results reflect general differences in anatomy between left and right side and therefore suggest a causal role for variations in local haemodynamics.
ACKNOWLEDGEMENTS The Asklepios study is indebted to F. Van Hoeke, B. Leydens, F. Brusselmans and the residents and general practitioners of Erpe-Mere and Nieuwerkerken for their help in completing the study. The Asklepios Study is supported by the Fund for Scientific Research – Flanders (FWO research grants G042703 and G083810N).
Conflicts of interest There are no conflicts of interest.
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Reviewers’ Summary Evaluations
Reviewer 2 In this population-based study, a byproduct of the ASKLEPIOS study, the authors establish the existence of a bilateral asymmetry in the prevalence of arteriosclerotic disease in the femoral arteries, the right side being more frequently affected than the left side, in sharp contrast with the symmetry observed at the level of the carotid artery. The study has been performed carefully. A notable strength is the relatively large sample. The results have some practical implication regarding the clinical detection of arteriosclerotic disease.
A major strength of this study is the large number of patients. The right/left difference in femoral IMT/plaque is attributed to a difference in anatomy between the right and left side, i.e. blood flow velocity pattern and shear stress. However, although at the carotid side the anatomy is not comparable between the right and left side, there is no significant difference in IMT/plaque. Which anatomical characteristics are responsible: curvature, diameter, branching, or sensitivity of the arterial wall structure to a given shear stress? A qualitative analysis of MRI measurements, which have been previously performed in 98 subjects by the authors (Bossuyt J et al. J Hypertens 2013), could help suggesting appropriate mechanisms.
There are conflicting results in the literature concerning the relationship between obesity and arterial stiffness, assessed by carotid-femoral pulse wave velocity (PWV). The discrepancies could be due to differences in carotid-femoral distance measu
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