Original Article
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
INTRODUCTION
A
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 [1]. The advent of high-resolution ultrasound
Journal of Hypertension
technology has enabled researchers to evaluate atherosclerosis noninvasively at an early, subclinical stage [2]. 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’ [10]. 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 [11], more curved [12] 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 [13], limiting the amount of anatomical asymmetry [11]. The link between arterial geometry and atherosclerosis, mediated through changes in local haemodynamics and shear stress, has long been recognized [14]. 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
www.jhypertension.com
1429
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Bossuyt et al.
The ASKLEPIOS study protocol, methodology and baseline population characteristics have been described elsewhere in detail [15].
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).
Study population
RESULTS
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) [10]. 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 [18]. 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
www.jhypertension.com
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
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Atherosclerosis: influence of body side TABLE 1. Baseline characteristics of the ASKLEPIOS Study population Variable
Women (n ¼ 1301; 51.5%)
Men (n ¼ 1223; 48.5%)
45.7 (40.8–51.1) 25.1 4.7 80.5 11.3 13.5 20.7 7.3
45.9 (41.2–50.9) 26.5 3.7 93.8 10.4 17.3 19.2 11.8
123 14 78 10 45 9 72 10
131 13 82 10 48 7 68 12
214 36 71 17 125 33 79 (59–112) 1.1/6.9
219 38 56 14 137 34 104 (75–155) 2.1/14.5
17.7/21.8 8.1 (2.4–17.7) 66.0
24.1/34.3 11.3 (4.8–22.2) 53.6
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 0.9 mm Plaque TOD
Women (n ¼ 1301)
All (n ¼ 2524)
P
Left
Right
Left
Right
Left
Right
Body side
Sex
Sidesex
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
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
INTRODUCTION
A
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 [1]. The advent of high-resolution ultrasound
Journal of Hypertension
technology has enabled researchers to evaluate atherosclerosis noninvasively at an early, subclinical stage [2]. 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’ [10]. 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 [11], more curved [12] 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 [13], limiting the amount of anatomical asymmetry [11]. The link between arterial geometry and atherosclerosis, mediated through changes in local haemodynamics and shear stress, has long been recognized [14]. 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
www.jhypertension.com
1429
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Bossuyt et al.
The ASKLEPIOS study protocol, methodology and baseline population characteristics have been described elsewhere in detail [15].
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).
Study population
RESULTS
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) [10]. 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 [18]. 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
www.jhypertension.com
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
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Atherosclerosis: influence of body side TABLE 1. Baseline characteristics of the ASKLEPIOS Study population Variable
Women (n ¼ 1301; 51.5%)
Men (n ¼ 1223; 48.5%)
45.7 (40.8–51.1) 25.1 4.7 80.5 11.3 13.5 20.7 7.3
45.9 (41.2–50.9) 26.5 3.7 93.8 10.4 17.3 19.2 11.8
123 14 78 10 45 9 72 10
131 13 82 10 48 7 68 12
214 36 71 17 125 33 79 (59–112) 1.1/6.9
219 38 56 14 137 34 104 (75–155) 2.1/14.5
17.7/21.8 8.1 (2.4–17.7) 66.0
24.1/34.3 11.3 (4.8–22.2) 53.6
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 0.9 mm Plaque TOD
Women (n ¼ 1301)
All (n ¼ 2524)
P
Left
Right
Left
Right
Left
Right
Body side
Sex
Sidesex
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
