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South Asian men have different patterns of coronary artery disease when compared with European men
International Journal of Cardiology 129 (2008) 406 – 413 www.elsevier.com/locate/ijcard
South Asian men have different patterns of coronary artery disease when compared with European men Therese Tillin a,⁎, Harshil Dhutia a , John Chambers a , Iqbal Malik a , Emma Coady a , Jamil Mayet a , Andrew R. Wright a , Jaspal Kooner a , Angela Shore b , Simon Thom a , Nish Chaturvedi a , Alun Hughes a a
International Centre for Circulatory Health, St Mary's Hospital, Hammersmith Hospital and Imperial College, 59 North Wharf Road, London W2 1LA, UK b Institute of Biomedical & Clinical Science, Peninsula Medical School, Exeter, UK Received 28 March 2007; received in revised form 6 June 2007; accepted 7 July 2007 Available online 26 November 2007
Abstract Background: To compare patterns of coronary artery disease in British South Asian and White European men. Methods: 41 South Asian and 42 European men (mean age 64 ± 9 years) with coronary artery disease were studied. All had similar symptoms. Vessel reference diameter and degree of stenosis were calculated using quantitative coronary angiography. Extent of atherosclerotic disease in the LAD was assessed using calcification scores (CAC) measured by multislice Computed Tomography. Fasting bloods and blood pressure were measured. The LAD was subdivided into four 2.5 cm segments for analysis. Results: Most atherosclerosis occurred in the proximal LAD segment, South Asian men had more proximal LAD stenosis than European men (50% vs. 37%, p = 0.036), but CAC scores were similar. South Asians with CAC scores in the lowest tertile (0–22 HU), had significantly narrower LAD diameters than Europeans (2.8 mm vs. 3.8 mm, p = 0.004, adjusted for body surface area and age). This ethnic difference was not explained by measured risk factors, including diabetes. In contrast, ethnic differences in LAD diameter were abolished in the upper tertiles of CAC scores (23–2416 HU) (South Asians: 3.0 mm, Europeans: 3.1 mm, p = 0.6). Calcification scores were negatively correlated with LAD diameter in Europeans (rho = − 0.38, p = 0.016) but not in South Asians (rho = − 0.06, p = 0.72). Conclusions: Increased LAD stenosis, despite equivalent levels of calcified disease, in South Asians is attributable to narrower arteries. Reduced LAD diameter is associated with advanced disease in Europeans but not in South Asians, indicative of ethnic differences in vascular remodelling. © 2007 Elsevier Ireland Ltd. All rights reserved. Keywords: South Asian; Atherosclerosis; Coronary artery disease; Coronary calcification; Vascular remodelling
1. Introduction People of South Asian descent worldwide have markedly elevated rates of coronary artery disease (CAD) compared with European origin populations [1–5]. Unfavourable risk factors, such as diabetes and dyslipidaemia, may account for only part of this elevated risk. In addition, although inhospital death rates may be declining in parallel with those of European origin populations [6], risk of subsequent death ⁎ Corresponding author. Tel.: +44 20 75943396; fax: +44 20 7594 3392. E-mail address: [email protected] (T. Tillin). 0167-5273/$ - see front matter © 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2007.07.129
and re-infarction remains greater in British South Asians post infarct [7,8], and South Asians have higher risk of mortality following coronary artery bypass grafting [9,10]. These observations are unexplained but may be due to adverse local patterns of atherosclerosis itself, or vessel responses to atheroma. In support of this hypothesis, South Asians in the UK have been reported to have a more proximal distribution of angiographic CAD in association with longer lesions than Caucasians [11]. In addition, a number of studies suggest that South Asians have smaller coronary arteries than Europeans, although some, but not all, report that the difference is explained by smaller body size [12–16]. However, it is not
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clear whether these unfavourable patterns in South Asians are simply due to their greater burden of atherosclerosis. Coronary artery calcification (CAC) score is a noninvasive measure that has been shown to correlate well with stenosis and other indicators of atherosclerosis in several ethnic groups [17,18] including Indian Asians [19]. It correlates with total plaque size histologically [20] and predicts future coronary events [21–24]. The combination of assessment of coronary artery calcification with angiography may provide additional information on plaque type, severity, and lumen patency.
Fasting bloods were taken for measurement of glucose, HbA1c, total and HDL cholesterol, triglycerides and insulin. Sitting systolic and diastolic blood pressures and heart rate were measured as the average of three readings using a validated automated device (Omron 705CP). Height, weight, waist, hip and thigh circumferences were measured. A summary score for physical activity was derived, based on responses to questions regarding daily walking, heavy lifting, cycling and other regular sport or physical activity.
2. Aims
All subjects underwent CT coronary artery calcification (CAC) scoring using either a Philips Mx8000 4-detector multislice CT scanner, or a Philips Mx8000 IDT 16-detector multislice CT scanner. Identical scanning parameters were used in all subjects to ensure no variation in data capture using the two scanners. Contiguous 3 mm sections covering the whole heart were acquired using prospective ECG gating during suspended inspiration. Scans were acquired with 120 kV, 140 mA s, field of view of 250 mm, and display matrix 512 × 512. Coronary artery calcification was quantified using proprietary software on a Philips MxView computer workstation, and calcification was defined as an area N1 mm2 of density N 130 Hounsfield Units (HU). The CAC score was calculated as the sum of all lesion scores. A single observer (ARW), masked to the identity of the participant made all coronary calcification measurements. A repeatability study of 20 scans showed a mean difference between cycles of 1 HU, with a coefficient of repeatability of 20 HU.
1. To address the following hypotheses: – South Asian men have smaller coronary arteries than European men at equivalent levels of atherosclerotic burden and these differences are not explained by differences in body size – South Asians have more proximal LAD disease than Europeans at equivalent levels of atherosclerotic burden. 2. To study ethnic group differences in LAD diameters as indicators of arterial remodelling responses to increasing atherosclerotic burden. 3. Methods Forty two European and 41 South Asian men with established coronary artery disease (CAD) were recruited from patients referred to cardiology clinics at St Mary's and Ealing Hospitals. Men with confirmed coronary artery disease (diagnosed on clinically indicated routine angiography by the presence of at least a 50% stenosis in one vessel and evidence of atherosclerosis elsewhere in the coronary arteries) were consecutively invited to take part in the study until at least 40 men were recruited to each ethnic group. This study was a planned addition to analyses of an already conducted study of ethnic group differences in lower limb atherosclerosis [25]; but excludes participants who formed a control group free of known CAD. The sample size was calculated to address the main study objectives [25]. Patients with unstable angina or severe co-morbidities or who had undergone previous coronary intervention procedures were excluded. The study was approved by the St Mary's Hospital local research ethics committee and all participants gave written informed consent.
3.2. Coronary calcification
3.3. Other measures of atherosclerosis Carotid and femoral intima-media thickness (IMT) measurements were performed in all subjects using B mode, colour and pulsed Doppler ultrasound with a HDI 5000 scanner (Philips Medical Systems) equipped with a 5 to 12 MHz broadband linear array transducer. 3.4. New analyses For this planned substudy, new analyses were performed to determine local calcification and the degree of proximal
3.1. Main study investigations Name recognition was used to identify migrants to the UK of South Asian origin (i.e. from India, Pakistan and Bangladesh). Participants were invited to attend St Mary's Hospital for investigation. Ethnic origin was confirmed with each participant, using both self assignment and country of birth of both parents. Baseline demographic, medical history and lifestyle data were collected.
Fig. 1. Diagram to illustrate angiographic measurements in one segment of the LAD.
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Table 1 Ethnic group characteristics (unadjusted) Europeans (n = 42)
South Asians (n = 41)
p value
Mean ± SD, median (25th,75th centiles) or % (number) Age: mean IHD duration based on recall/or date of angiography if no recall: years Diabetes (patient reported) prevalence Hypertension (patient reported), prevalence Systolic blood pressure: mm Hg Diastolic blood pressure: mm Hg Heart rate HbA1c: % Fasting glucose: mmol/l Fasting insulin: μU/l Triglycerides: mmol/l Total cholesterol: mmol/l HDL cholesterol: mmol/l LDL cholesterol: mmol/l Cholesterol: HDL ratio Creatinine (blood): μmol/l Weight: kg Height: cm Waist: cm BMI: kg/m2 Hip circumference: cm WHR Body surface area: m2 Current smoking Ex smoking Parental cardiovascular disease Physical activity score a Alcohol — drinks daily Lipid-lowering medication Blood pressure lowering medication Carotid lumen diameter: mm Carotid IMT: mm Femoral lumen diameter: mm Femoral IMT: mm
67.4 ± 8.6 0.50 (0.14, 1.20) 15 (6) 69 (29) 139 (130, 152) 82 (77, 85) 61 ± 9.3 6.0 ± 0.7 5.5 (5.1, 6.3) 49.3 (34.3, 82.3) 1.24 (0.90, 1.64) 4.2 (3.37, 4.69) 1.13 (1.0, 1.28) 2.28 (1.68, 2.92 3.73 (3.01, 4.3) 102 (92, 119) 85.7 ± 11.9 173.7 ± 6.8 102.9 ± 7.8 28.4 ± 3.7 105.8 ± 13.7 0.98 ± 0.08 2.03 ± 0.16 10 (4) 69 (13) 72 (26) 4.5 ± 1.1 25 (10) 88 (37) 88 (37) 6.68 ± 0.86 0.90 (0.74, 1.07) 8.20 ± 1.12 2.75 (2.18, 3.08)
61.1 ± 8.0 0.86 (0.20, 7.8) 38(15) 64 (25) 130 (122, 145) 79 (74, 82) 65 ± 10.6 6.8 ± 1.3 5.6 (5.2, 6.5) 64.4 (54.4, 87.8) 1.35 (1.00, 2.10) 3.87 (3.36, 4.57) 0.99 (0.88, 1.16) 2.04 (1.56, 2.63) 3.48 (3.2, 4.39) 100 (90, 115) 77.4 ± 10.2 168.8 ± 7.4 100.2 ± 8.61 27.2 ± 3.2 99.4 ± 5.9 1.01 ± 0.05 1.90 ± 0.15 8 (3) 40 (24) 77(26) 4.8 ± 1.3 11 (3) 85 (35) 95 (39) 6.14 ± 0.64 0.90 (0.74, 1.00) 7.47 ± 1.21 2.40 (0.86, 2.94)
0.004 0.230 0.019 0.53 0.006 0.11 0.13 0.001 0.37 0.10 0.35 0.55 0.047 0.52 0.52 0.54 0.001 0.002 0.14 0.11 0.007 0.053 b0.001 0.74 0.008 0.68 0.23 0.12 0.71 0.25 0.002 0.62 0.006 0.20
Data are mean ± SD, median (25th, 75th centile) or % (number). Statistical comparisons were made using students t, Wilcoxon rank sum and chi square tests respectively. a Physical activity score range 0–9 (9 = most active).
LAD disease. The LAD was chosen for detailed measurements due to its length and importance in supplying blood to the left ventricle and septum. Calcification has been found to be greater in the LAD than in other major coronary arteries and with greater levels of calcification in the proximal LAD artery compared to the rest of the artery [26]. For calcification scoring, the LAD was visualised in four 2.5 cm segments from its origin as a branch of the left coronary artery. Lesion scores were calculated by multiplying the areas in mm2 by an attenuating factor as described by Agatston et al. [27]. The CAC score was calculated as the sum of all lesion scores in each segment. A single observer (HD, supervised by a senior radiologist (ARW)), blinded to patient identity, ethnicity and other results, made all LAD calcification measurements. Intraobserver repeatability was estimated by Bland Altman analysis [28]. A study of 10 scans showed a mean difference
between cycles of 13HU, with a coefficient of repeatability of 44 HU. Quantitative coronary angiography (QCA), limited to the LAD, was performed without vasodilation using Medcon Quantitative Measurement QCA to analyse the original clinic diagnostic angiograms. Calibration of the system was based on catheter dimensions while unfilled with contrast medium. Within each of the four proximal 2.5 cm segments, the reference lumen diameter was determined by edge detection and averaged from the two orthogonal projections (Fig. 1). The degree of stenosis was calculated as a % of the total diameter of the artery and the lengths of lesions were measured for each of the four 2.5 cm segments of the LAD (Fig. 1). An experienced observer (JC) who was unaware of patient identity, ethnicity, clinical data or calcification profile of the cases performed the analysis. The mean intra-observer difference [28] in vessel diameter was − 0.20 mm (coefficient
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Table 2 Characteristics of left anterior descending (LAD) artery segments in European and South Asian men (age adjusted) European men
South Asian men
p for ethnic group
n = 42
n = 41
difference
LAD diameter, mm a Segment 1 (proximal) Segment 2 Segment 3 Segment 4
3.4 2.7 2.3 2.1
(3.1, 3.6) (2.5, 2.9) (2.1, 2.5) (1.9, 2.2)
2.9 2.6 2.2 1.9
(2.7, 3.1) (2.4, 2.8) (2.1, 2.5) (1.8, 2.0)
0.007 0.38 0.55 0.12
LAD diameter, mm Age and BSA adjusted a Segment 1 (proximal) Segment 2 Segment 3 Segment 4
3.3 2.7 2.2 2.1
(3.1, 3.5) (2.5, 2.9) (2.0, 2.4) (1.9, 2.3)
3.0 2.6 2.3 2.0
(2.8, 3.3) (2.4, 2.9) (2.1, 2.5) (1.8, 2.2)
0.13 0.79 0.79 0.76
(40.0, 119.5) (8.6, 26.2) (0, 0) (0, 0)
43.4 7.3 0 0
(25.0, 75.6) (4.1, 12.8) (0, 0) (0, 0)
0.76 0.24 1.00 1.00
(2, 7) (1, 4) (0, 0) (0, 0)
3 1 0 0
(2, (0, (0, (0,
0.35 0.001 1.00 1.00
LAD calcification score, HU Segment 1 (proximal)¥ Segment 2¥ Segment 3¥ Segment 4¥ Number of calcified lesions in LAD Segment 1 (proximal)† Segment 2† Segment 3† Segment 4†
69.2 15.0 0 0
4 3 0 0
5) 3) 0) 0)
% stenosis in LAD Segment 1 (proximal) Segment 2 Segment 3† Segment 4†
34.7 34.1 21.6 15.0
(25.4, 43.9) (25.6, 42.5) (0, 43.5) (0, 23.3)
52.3 27.2 16.1 0
(42.8, 61.8) (18.6, 35.7) (0, 28.8) (0, 20.7)
Length of LAD stenosis, mm Segment 1 (proximal) Segment 2 Segment 3† Segment 4†
9.3 10.5 15.1 15.5
(7.2, 11.4) (8.1, 12.9) (9.6, 22.6) (6, 14.4)
13.3 9.4 7.4 –
(7.2, 11.4) (6.8, 12.1) (7.2, 8.8)
0.012 0.29 0.59 b0.001
0.012 0.57 0.61 0.51
Data are age adjusted and presented as means (95% CI), except † = medians (interquartile range), ¥ = geometric mean of (CAC score +1) (95% CI). p values were calculated using the T statistic. a Reference diameter data were not available for 3 European and 3 South Asian men.
of repeatability = 0.68 mm) and the mean intra-observer difference in length of stenosis was 1 mm (coefficient of repeatability = 7.3 mm) and for degree of stenosis it was 0.3% (coefficient of repeatability = 12.5%). 3.5. Statistical analyses Data were markedly positively skewed for CAC scores in all segments. Coronary artery calcification scores were transformed using log (CAC score + 1) to approximate a Normal distribution. Log transformations were used to transform vessel reference diameters in each LAD segment. Other skewed data were transformed or analysed using nonparametric regression models (quantile regression). Body surface area (BSA) was calculated using the formula of Mosteller [29] (BSA = square root of (height (cm) × weight) / 3600). Duration of CHD was calculated by
subtracting date of diagnosis (participant recall or date of diagnostic angiography) from date of study visit. Age adjusted measures of central tendency (means, geometric means or medians) for LAD diameter, calcification and stenosis were calculated and comparisons were made between ethnic groups using p values based on the T statistic. LAD diameters and stenosis for each 2.5 cm segment were then calculated in each ethnic subgroup of men with equivalent levels of atherosclerosis; for this purpose, LAD segment CAC scores were grouped into tertiles in order to categorise levels of local coronary atherosclerotic disease burden. Tertiles were pre-specified to maximise power; however, additional confirmatory analyses were conducted in quartilised data. In addition, similar analyses were performed to examine ethnic group differences in common carotid artery diameters, stratifying by tertile of total CAC scores as an estimate of generalised atherosclerotic burden.
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Robust linear regression models were used to assess whether measured cardiovascular risk factors or measures of atherosclerosis at other sites explained any ethnic group differences in these associations. Tests for interactions between ethnicity and each risk factor were performed in the regression models. 4. Results 4.1. Ethnic group characteristics The South Asian men were on average 6years younger than the European men, but their duration of known coronary artery disease was longer. South Asian men consumed less alcohol, were less likely ever to have smoked, had more diabetes and higher HbA1c and fasting insulin levels. They were also shorter, with smaller body surface areas, but had higher body mass index (BMI) and waist hip ratios (WHR) than European men. Blood lipid profiles were similar between the two groups, with the exception of HDL cholesterol which was lower in South Asian men, however, most men in both ethnic groups were receiving lipidlowering medications. Approximately two-thirds of each group reported doctor diagnosed hypertension. (Table 1) and cardiac symptoms did not differ between ethnic groups. Physical activity levels did not differ by ethnicity. Compared with European men, South Asian men had significantly narrower carotid and femoral lumen diameters, similar carotid intima-media thickness (IMT) and less femoral IMT, although the latter difference was not statistically significant (Table 1).
contrast, South Asian men had less marked stenoses in segments 2–4 than European men, although these differences were not significant (Table 2). In the proximal segment, South Asian men had fewer, but significantly longer, stenotic lesions than the European men. In contrast, South Asians had shorter lesions in segments 2– 4, although there were few lesions beyond the proximal segment in either ethnic group (Table 2). The degree of stenosis and length of lesions weakly correlated with calcification scores in the proximal segment in European men (rho = 0.32, p = 0.05 and rho = 0.34, p = 0.04) but no significant correlations were observed in South Asian men (rho = 0.24, p = 0.16 and rho = 0.19, p = 0.28). 4.3. Left anterior descending artery reference diameter 4.3.1. All men European men had significantly larger proximal segment reference diameters than South Asian men (age adjusted: 3.4 mm vs 2.9 mm, p = 0.007), but there were no significant ethnic differences in reference diameter in the segments 2–4. This ethnic group difference in proximal segment diameter was attenuated but not abolished by further adjustment for BSA (Table 2). Proximal segment reference diameter was negatively correlated with proximal segment CAC score and number of calcified atherosclerotic lesions in European (rho = − 0.38, p = 0.016 and rho = − 0.43, p = 0.007), but not in South Asian men (rho = − 0.06, p = 0.72 and rho = 0.04, p = 0.81) and with physical activity score in South Asian men (rho = 0.32, p = − 0.05) but not in European men (rho = 0.11, p = 0.52).
4.2. Characteristics of atherosclerosis in the LAD Angiograms were missing for 3 (7%) European and 3 (7%) South Asian men, resulting in missing data on LAD stenosis and vessel diameter for these cases; in addition one South Asian and two European men had occlusion in the distal segments which prevented visualisation.
4.3.2. Stratified by atherosclerotic burden Since disease may influence LAD diameter we performed further analyses of ethnic group differences stratified by extent of local coronary artery disease (estimated by LAD segment
4.2.1. Coronary artery calcification score and calcified lesions 95% and 93% of Europeans and South Asians had CAC scores N0 in the proximal LAD segment (segment 1) and 81% and 68% Europeans and South Asians had CAC scores N 0 in the second segment. Calcification was undetectable in the segments 3–4 in either South Asians or Europeans. South Asians had lower CAC scores than Europeans in segments 1–2, although the differences were not statistically significant (Table 2). Europeans also had more calcified lesions in the proximal segment (age adjusted: 4.3 vs 3.3, p = 0.35) and in segment 2 (3 vs 1, p = 0.001) (Table 2). 4.2.2. Degree and length of stenosis in LAD on angiography South Asian men had significantly greater proximal stenoses than European men. This difference increased on adjustment for age and duration of coronary artery disease and was not explained by any other measured risk factors. In
Fig. 2. Diameter of proximal LAD subdivided by tertiles of calcification (CAC) score and after adjustment for age and body surface area.
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calcification score). The tertile of European men with least proximal disease (segment 1 CAC score b22 HU) had markedly larger vessel diameters than the tertile with most disease (segment 1 CAC score = 132–2416 HU) (3.8 mm vs 2.8 mm, p for trend = 0.038). The diameter of the proximal LAD in the tertile of South Asian men with least coronary artery disease was significantly less than in the same CACS tertile of European men (3.8 mm vs 2.8 mm, p = 0.016 adjusted for age and BSA), but, unlike European men, proximal LAD diameter did not decrease with increasing disease, but showed a small non-significant increase with increasing tertile of CAC score (Fig. 2). For all men in the lowest tertile of calcification score, proximal segment diameter was associated with age, duration of coronary artery disease and smoking status. However, adjustment for these variables did not alter the ethnic group difference in proximal segment vessel diameter (Table 3). Diabetes, fasting glucose and insulin, blood lipid levels, height, BSA and measures of obesity and physical activity were not associated with proximal segment diameter in men in the lowest tertile of CAC score. For men in the upper two tertiles of CAC score, proximal segment diameter was associated with BSA (age adjusted standardised beta coefficient for BSA = 0.36, p = 0.008) in both ethnic groups, with physical activity score in South Asian men (age adjusted standardised beta coefficient for physical activity score = − 0.43, p = 0.027) and with length of lesions in European men (age adjusted standardised beta coefficient for Table 3 B coefficients for ethnicity in robust linear regression models by tertile of LAD calcification score Adjustment
Standardised Beta coefficient for ethnicity (European men = reference group)
p value for ethnic group difference in association with proximal LAD diameter
Adjusted R2 value for model
Men in lowest tertile of LAD calcification score (0–22 HU), n = 26 Unadjusted − 0.52 0.007 24% Adjusted for Age − 0.64 0.003 28% Age + body − 0.82 0.008 37% surface area⁎ Age + duration of coronary − 0.42 0.002 51% artery disease Age + smoking status − 0.91 b0.001 57% (ever smoker) Men in upper tertiles of LAD calcification score (23–2416 HU), n = 51 Unadjusted − 0.08 0.18 4% Adjusted for Age⁎ − 0.23 0.14 5% Age⁎ + body surface area − 0.03 0.59 13% Age⁎ + physical activity − 0.19 0.26 14% score B coefficients are for log vessel diameter. Explanatory variables shown only if p b 0.10 (with exception of age⁎ and body surface area⁎ which were forced into some models). Dependent variable = proximal LAD diameter.
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length of stenosis = −0.52, p = 0.022). There were no other associations between proximal segment diameter and markers of atherosclerosis or risk factors, including blood lipid levels and use of lipid-lowering medication, in men in the upper tertiles of CAC score. None of these findings were altered when analyses were stratified by quartile of LAD CACS. In LAD segments 2–4, the absence of ethnic group differences in vessel diameter was unchanged on stratification by tertile of local CAC score. 4.4. Common carotid artery diameters stratified by atherosclerotic burden The ethnic group differences observed for common carotid artery diameters were also most marked in those in the lowest tertile of total CACS (age and BSA adjusted diameters South Asian men: 6.0 mm, European men: 6.6 mm, p = 0.073). There was no ethnic group difference in carotid artery diameters in men in the upper tertiles of total CACS (age and BSA adjusted diameters: 6.4 and 6.5 mm, p = 0.528). 5. Discussion Overall, South Asians had a greater degree of stenosis in the proximal LAD than Europeans. South Asian men also had fewer but longer lesions in the proximal segment, although the increased degree and length of stenosis in South Asian men was not associated with increased coronary calcification scores. However, in men with minimal local atherosclerosis, South Asians had significantly narrower proximal LADs than Europeans and this difference was unexplained by age, body size or other measured risk factors. This suggests that there may be ethnic differences in LAD size and this is consistent with the findings that South Asians also had smaller carotid and femoral artery diameters than Europeans. Interestingly, in men with more advanced atherosclerosis the ethnic group difference in proximal LAD diameter was abolished. In Europeans an increasing level of local atherosclerosis was associated with narrower proximal LAD reference diameters, but this relationship was not seen in South Asians. This might be explained by more inward remodelling of atherosclerosis as disease advances in Europeans compared with South Asians. In terms of atherosclerosis in the LAD, the largest ethnic group differences were observed in the most proximal 2.5 cm segment and there was little calcification or stenosis in the more distal segments in either group. It therefore seems likely that the increased degree of LAD stenosis, despite similar symptoms and CAC scores, in South Asian men is attributable to a narrower proximal LAD. Proximal segment LAD diameters in European men (3.8 mm) with lower levels of calcification in our study closely approximate those recorded by Dodge et al., who found that the mean diameter of the proximal LAD segment was 3.7 ± 0.4 mm in subjects with
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normal angiograms [30]. We found that adjustment for BSA attenuated, but did not wholly account for ethnic group differences. Our study differs from most previous studies in that we used local coronary calcification scores to stratify atherosclerotic burden rather than excluding people with angiographically determined disease. Coronary calcification has been shown to predict total plaque size assessed by histology [20], while degree of stenosis is highly dependent on coronary artery remodelling. Our findings suggest that European men undergo more inward remodelling in the LAD in response to advanced atherosclerosis. The negative correlation, albeit weak, between LAD diameter and length of stenosis in European men is consistent with this hypothesis. A similar relationship between narrower reference diameter and increased disease was not seen in South Asian men and one can speculate either that they do not inwardly remodel in response to advanced disease or that inward remodelling occurs at an earlier stage of disease progression than in European men. In view of the higher risk of coronary events in South Asian men the latter possibility seems more likely, but further studies using intra-vascular ultrasound (IVUS) may help to resolve this question. A recent pilot study using IVUS in 41 patients suggests that inward remodelling in coronary vessels may be associated with a more stable plaque phenotype than outward remodelling [31]. Our study may explain apparently contradictory findings of previous studies with regard to coronary artery size. Our findings of no significant ethnic difference in LAD diameter in men with the greatest atheromatous burden are in accord with those of Zindrou et al., who studied age, sex and BSA matched patients with severe disease selected to undergo coronary artery bypass grafting [13]. In contrast, Lip et al. [15] and Makaryus et al. [16] examined apparently normal angiograms, whilst Dhawan and Bray [14] studied disease-free segments from routine angiograms, however, these analyses were not stratified by atheromatous burden. Since it is known that the CT has higher sensitivity than angiography in identifying atheromatous lesions even in the absence of obstruction [32], our approach of stratifying local atheromatous burden by CAC score may be more sensitive in identifying groups of men with similar levels of local disease, and thus ethnic group differences which are present in men with low levels of atherosclerotic burden are less likely to be masked by heterogeneity of disease burden and potential differences in arterial remodelling. Our study has a number of limitations in terms of sample size, recruitment, and accuracy of measurements. This is a relatively small study and consequently caution is needed in interpretation of the effects of explanatory and interacting variables in multivariate and stratified models. We recruited a cardiology clinic-based sample and it is likely that there are ethnic group differences in health seeking behaviours. However, UK evidence suggests that South Asians in our communities seek treatment earlier [33] and that they receive similar levels of interventions [34,35]. Duration of coronary artery disease was difficult to quantify, as many participants
were unaware of their diagnosis until they underwent angiography. Known duration of coronary artery disease was slightly greater in South Asians, despite their younger age and could contribute to some observed differences. Measuring CAC score in four different segments necessitates length measurements as well as calcification scoring introducing additional potential for measurement error. However, intraobserver reproducibility for LAD calcification scores was acceptable and measurement errors are unlikely to introduce systematic misclassification since the observer was blinded to ethnicity and all other participant characteristics. 6. Conclusions In men with minimal atherosclerosis, British South Asians have significantly narrower proximal left anterior descending arteries than comparable Europeans even after adjustment for age and body size. South Asian men have a greater degree of LAD stenosis and fewer but longer calcified lesions than European men. This increased degree of LAD stenosis, despite equivalent levels of calcified disease, in South Asians is attributable to narrower arteries. European men exhibit a greater narrowing of the proximal LAD in association with more advanced atherosclerosis compared with South Asian men. These findings may be attributed to ethnic group differences in remodelling. Acknowledgements We would like to thank Shirley Featherston for performing the coronary CT scans, Sheila Raynor for technical assistance and Victor Anionwu, Metabolic Medicine, Imperial College London, for measuring insulin. This study was kindly supported by a grant from the British Heart Foundation. References [1] McKeigue PM, Miller GJ, Marmot MG. Coronary heart disease in south Asians overseas: a review. J Clin Epidemiol 1989;42 (7):597–609. [2] Balarajan R. Ethnicity and variations in the nation's health. Health Trends 1995;27(4):114–9. [3] Enas EA, Garg A, Davidson MA, Nair VM, Huet BA, Yusuf S. Coronary heart disease and its risk factors in first-generation immigrant Asian Indians to the United States of America. Indian Heart J 1996;48:343–53. [4] Anand SS, Yusuf S, Vuksan V, et al. Differences in risk factors, atherosclerosis, and cardiovascular disease between ethnic groups in Canada: the Study of Health Assessment and Risk in Ethnic groups (SHARE). Lancet 2000;356:279–84. [5] Goyal A, Yusuf S. The burden of cardiovascular disease in the Indian subcontinent. Indian J Med Res 2006;124:235–44. [6] Liew R, Sulfi S, Ranjadayalan K, Cooper J, Timmis AD. Declining case fatality rates for acute myocardial infarction in South Asian and white patients in the past 15years. Heart 2006;92:1030–4. [7] Wilkinson P, Sayer J, Laji K, et al. Comparison of case fatality in south Asian and white patients after acute myocardial infarction: observational study. BMJ 1996;312(7042):1330–3.
T. Tillin et al. / International Journal of Cardiology 129 (2008) 406–413 [8] Hughes LO, Raval U, Raftery EB. First myocardial infarctions in Asian and white men. BMJ 1989;298:1345–50. [9] Zindrou D, Bagger JP, Smith P, Taylor KM, Ratnatunga CP. Comparison of operative mortality after coronary artery bypass grafting in Indian subcontinent Asians versus Caucasians. Am J Cardiol 2001;88(3):313–6. [10] Brister SJ, Hamdulay Z, Verma S, Maganti M, Buchanan MR. Ethnic diversity: South Asian ethnicity is associated with increased coronary artery bypass grafting mortality. J Thorac Cardiovasc Surg 2007;133:150–4. [11] Dhawan J, Bray CL. Angiographic comparison of coronary artery disease between Asians and Caucasians. Postgrad Med J 1994;70 (827):625–30. [12] Sahni D, Jit I. Origin and size of the coronary arteries in the north-west Indians. Indian Heart J 1989;41(4):221–8. [13] Zindrou D, Taylor KM, Bagger JP. Coronary artery size and disease in UK South Asian and Caucasian men. Eur J Cardio thorac Surg 2006;29:492–5. [14] Dhawan J, Bray CL. Are Asian coronary arteries smaller than Caucasian? A study of angiographic coronary artery size estimation during life. Int J Cardiol 1995;49:267–9. [15] Lip GY, Rathore VS, Katira R, Watson RD, Singh SP. Do Indo-Asians have smaller coronary arteries? Postgrad Med J 1999;75(886):463–6. [16] Makaryus AN, Dhama B, Raince J, et al. Coronary artery diameter as a risk factor for acute coronary syndromes in Asian-Indians. Am J Cardiol 2005;96(6):778–80. [17] Kitamura A, Kobayashi T, Ueda K, et al. Evaluation of coronary artery calcification by multi-detector row computed tomography for the detection of coronary artery stenosis in Japanese patients. J Epidemiol 2005;15:187–93. [18] Haberl R, Becker A, Leber A, et al. Correlation of coronary calcification and angiographically documented stenoses in patients with suspected coronary artery disease: results of 1,764 patients. J Am Coll Cardiol 2001;37:451–7. [19] Shrivastava S, Agrawal V, Kasliwal RR, et al. Coronary calcium and coronary artery disease: an Indian perspective. Indian Heart J 2003;55 (4):344–8. [20] Simons DB, Schwartz RS, Edwards WD, Sheedy PF, Breen JF, Rumberger JA. Noninvasive definition of anatomic coronary artery disease by ultrafast computed tomographic scanning: a quantitative pathologic comparison study. J Am Coll Cardiol 1992;20(5):1118–26. [21] Keelan PC, Bielak LF, Ashai K, et al. Long-term prognostic value of coronary calcification detected by electron-beam computed tomography in patients undergoing coronary angiography. Circ 2001;104:412–7. [22] Arad Y, Spadaro LA, Goodman K, Newstein D, Guerci AD. Prediction of coronary events with electron beam computed tomography. J Am Coll Cardiol 2000;36:1253–60.
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[23] Pohle K, Ropers D, Maffert R, et al. Coronary calcifications in young patients with first, unheralded myocardial infarction: a risk factor matched analysis by electron beam tomography. Heart 2003;89 (6):625–8. [24] Farzaneh-Far A, Proudfoot D, Shanahan C, Weissberg PL. Vascular and valvar calcification: recent advances. Heart 2001;85(1):13–7. [25] Chaturvedi N, Coady E, Mayet J, et al. Indian Asian men have less peripheral arterial disease than European men for equivalent levels of coronary disease. Atheroscler 2007;193(1):204–12. [26] Kajinami K, Seki H, Takekoshi N, Mabuchi H. Noninvasive prediction of coronary atherosclerosis by quantification of coronary artery calcification using electron beam computed tomography: comparison with electrocardiographic and thallium exercise stress test results. J Am Coll Cardiol 1995;26:1209–21. [27] Agatston AS, Janowitz WR, Hildner FJ, Zusmer NR, Viamonte Jr M, Detrano R. Quantification of coronary artery calcium using ultrafast computed tomography. J Am Coll Cardiol 1990;15(4):827–32. [28] Bland JM, Altman DG. Statistical methods for assessing agreement between two methods of clinical measurement. Lancet 1986;1 (8476):307–10. [29] Mosteller RD. Simplified calculation of body-surface area. N Engl J Med 1987;317(17):1098. [30] Dodge Jr JT, Brown BG, Bolson EL, Dodge HT. Lumen diameter of normal human coronary arteries. Influence of age, sex, anatomic variation, and left ventricular hypertrophy or dilation. Circulation 1992;86(1):232–46. [31] Rodriguez-Granillo GA, Serruys PW, Garcia-Garcia HM, et al. Coronary artery remodelling is related to plaque composition. Heart 2006;92(3):388–91. [32] Budoff MJ, Achenbach S, Blumenthal RS, et al. Assessment of coronary artery disease by cardiac computed tomography: a scientific statement from the American Heart Association Committee on Cardiovascular Imaging and Intervention, Council on Cardiovascular Radiology and Intervention, and Committee on Cardiac Imaging, Council on Clinical Cardiology. Circulation 2006;114:1761–91. [33] Adamson J, Ben-Shlomo Y, Chaturvedi N, Donovan J. Ethnicity, socio-economic position and gender-do they affect reported health-care seeking behaviour? Soc Sci Med 2003;57(5):895–904. [34] Britton A, Shipley M, Marmot M, Hemingway H. Does access to cardiac investigation and treatment contribute to social and ethnic differences in coronary heart disease? Whitehall II prospective cohort study. BMJ 2004;329(7461):318. [35] Pollard TM, Carlin LE, Bhopal R, Unwin N, White M, Fischbacher C. Social networks and coronary heart disease risk factors in South Asians and Europeans in the UK. Ethn Health 2003;8(3):263–75.
South Asian men have different patterns of coronary artery disease when compared with European men Therese Tillin a,⁎, Harshil Dhutia a , John Chambers a , Iqbal Malik a , Emma Coady a , Jamil Mayet a , Andrew R. Wright a , Jaspal Kooner a , Angela Shore b , Simon Thom a , Nish Chaturvedi a , Alun Hughes a a
International Centre for Circulatory Health, St Mary's Hospital, Hammersmith Hospital and Imperial College, 59 North Wharf Road, London W2 1LA, UK b Institute of Biomedical & Clinical Science, Peninsula Medical School, Exeter, UK Received 28 March 2007; received in revised form 6 June 2007; accepted 7 July 2007 Available online 26 November 2007
Abstract Background: To compare patterns of coronary artery disease in British South Asian and White European men. Methods: 41 South Asian and 42 European men (mean age 64 ± 9 years) with coronary artery disease were studied. All had similar symptoms. Vessel reference diameter and degree of stenosis were calculated using quantitative coronary angiography. Extent of atherosclerotic disease in the LAD was assessed using calcification scores (CAC) measured by multislice Computed Tomography. Fasting bloods and blood pressure were measured. The LAD was subdivided into four 2.5 cm segments for analysis. Results: Most atherosclerosis occurred in the proximal LAD segment, South Asian men had more proximal LAD stenosis than European men (50% vs. 37%, p = 0.036), but CAC scores were similar. South Asians with CAC scores in the lowest tertile (0–22 HU), had significantly narrower LAD diameters than Europeans (2.8 mm vs. 3.8 mm, p = 0.004, adjusted for body surface area and age). This ethnic difference was not explained by measured risk factors, including diabetes. In contrast, ethnic differences in LAD diameter were abolished in the upper tertiles of CAC scores (23–2416 HU) (South Asians: 3.0 mm, Europeans: 3.1 mm, p = 0.6). Calcification scores were negatively correlated with LAD diameter in Europeans (rho = − 0.38, p = 0.016) but not in South Asians (rho = − 0.06, p = 0.72). Conclusions: Increased LAD stenosis, despite equivalent levels of calcified disease, in South Asians is attributable to narrower arteries. Reduced LAD diameter is associated with advanced disease in Europeans but not in South Asians, indicative of ethnic differences in vascular remodelling. © 2007 Elsevier Ireland Ltd. All rights reserved. Keywords: South Asian; Atherosclerosis; Coronary artery disease; Coronary calcification; Vascular remodelling
1. Introduction People of South Asian descent worldwide have markedly elevated rates of coronary artery disease (CAD) compared with European origin populations [1–5]. Unfavourable risk factors, such as diabetes and dyslipidaemia, may account for only part of this elevated risk. In addition, although inhospital death rates may be declining in parallel with those of European origin populations [6], risk of subsequent death ⁎ Corresponding author. Tel.: +44 20 75943396; fax: +44 20 7594 3392. E-mail address: [email protected] (T. Tillin). 0167-5273/$ - see front matter © 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2007.07.129
and re-infarction remains greater in British South Asians post infarct [7,8], and South Asians have higher risk of mortality following coronary artery bypass grafting [9,10]. These observations are unexplained but may be due to adverse local patterns of atherosclerosis itself, or vessel responses to atheroma. In support of this hypothesis, South Asians in the UK have been reported to have a more proximal distribution of angiographic CAD in association with longer lesions than Caucasians [11]. In addition, a number of studies suggest that South Asians have smaller coronary arteries than Europeans, although some, but not all, report that the difference is explained by smaller body size [12–16]. However, it is not
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clear whether these unfavourable patterns in South Asians are simply due to their greater burden of atherosclerosis. Coronary artery calcification (CAC) score is a noninvasive measure that has been shown to correlate well with stenosis and other indicators of atherosclerosis in several ethnic groups [17,18] including Indian Asians [19]. It correlates with total plaque size histologically [20] and predicts future coronary events [21–24]. The combination of assessment of coronary artery calcification with angiography may provide additional information on plaque type, severity, and lumen patency.
Fasting bloods were taken for measurement of glucose, HbA1c, total and HDL cholesterol, triglycerides and insulin. Sitting systolic and diastolic blood pressures and heart rate were measured as the average of three readings using a validated automated device (Omron 705CP). Height, weight, waist, hip and thigh circumferences were measured. A summary score for physical activity was derived, based on responses to questions regarding daily walking, heavy lifting, cycling and other regular sport or physical activity.
2. Aims
All subjects underwent CT coronary artery calcification (CAC) scoring using either a Philips Mx8000 4-detector multislice CT scanner, or a Philips Mx8000 IDT 16-detector multislice CT scanner. Identical scanning parameters were used in all subjects to ensure no variation in data capture using the two scanners. Contiguous 3 mm sections covering the whole heart were acquired using prospective ECG gating during suspended inspiration. Scans were acquired with 120 kV, 140 mA s, field of view of 250 mm, and display matrix 512 × 512. Coronary artery calcification was quantified using proprietary software on a Philips MxView computer workstation, and calcification was defined as an area N1 mm2 of density N 130 Hounsfield Units (HU). The CAC score was calculated as the sum of all lesion scores. A single observer (ARW), masked to the identity of the participant made all coronary calcification measurements. A repeatability study of 20 scans showed a mean difference between cycles of 1 HU, with a coefficient of repeatability of 20 HU.
1. To address the following hypotheses: – South Asian men have smaller coronary arteries than European men at equivalent levels of atherosclerotic burden and these differences are not explained by differences in body size – South Asians have more proximal LAD disease than Europeans at equivalent levels of atherosclerotic burden. 2. To study ethnic group differences in LAD diameters as indicators of arterial remodelling responses to increasing atherosclerotic burden. 3. Methods Forty two European and 41 South Asian men with established coronary artery disease (CAD) were recruited from patients referred to cardiology clinics at St Mary's and Ealing Hospitals. Men with confirmed coronary artery disease (diagnosed on clinically indicated routine angiography by the presence of at least a 50% stenosis in one vessel and evidence of atherosclerosis elsewhere in the coronary arteries) were consecutively invited to take part in the study until at least 40 men were recruited to each ethnic group. This study was a planned addition to analyses of an already conducted study of ethnic group differences in lower limb atherosclerosis [25]; but excludes participants who formed a control group free of known CAD. The sample size was calculated to address the main study objectives [25]. Patients with unstable angina or severe co-morbidities or who had undergone previous coronary intervention procedures were excluded. The study was approved by the St Mary's Hospital local research ethics committee and all participants gave written informed consent.
3.2. Coronary calcification
3.3. Other measures of atherosclerosis Carotid and femoral intima-media thickness (IMT) measurements were performed in all subjects using B mode, colour and pulsed Doppler ultrasound with a HDI 5000 scanner (Philips Medical Systems) equipped with a 5 to 12 MHz broadband linear array transducer. 3.4. New analyses For this planned substudy, new analyses were performed to determine local calcification and the degree of proximal
3.1. Main study investigations Name recognition was used to identify migrants to the UK of South Asian origin (i.e. from India, Pakistan and Bangladesh). Participants were invited to attend St Mary's Hospital for investigation. Ethnic origin was confirmed with each participant, using both self assignment and country of birth of both parents. Baseline demographic, medical history and lifestyle data were collected.
Fig. 1. Diagram to illustrate angiographic measurements in one segment of the LAD.
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Table 1 Ethnic group characteristics (unadjusted) Europeans (n = 42)
South Asians (n = 41)
p value
Mean ± SD, median (25th,75th centiles) or % (number) Age: mean IHD duration based on recall/or date of angiography if no recall: years Diabetes (patient reported) prevalence Hypertension (patient reported), prevalence Systolic blood pressure: mm Hg Diastolic blood pressure: mm Hg Heart rate HbA1c: % Fasting glucose: mmol/l Fasting insulin: μU/l Triglycerides: mmol/l Total cholesterol: mmol/l HDL cholesterol: mmol/l LDL cholesterol: mmol/l Cholesterol: HDL ratio Creatinine (blood): μmol/l Weight: kg Height: cm Waist: cm BMI: kg/m2 Hip circumference: cm WHR Body surface area: m2 Current smoking Ex smoking Parental cardiovascular disease Physical activity score a Alcohol — drinks daily Lipid-lowering medication Blood pressure lowering medication Carotid lumen diameter: mm Carotid IMT: mm Femoral lumen diameter: mm Femoral IMT: mm
67.4 ± 8.6 0.50 (0.14, 1.20) 15 (6) 69 (29) 139 (130, 152) 82 (77, 85) 61 ± 9.3 6.0 ± 0.7 5.5 (5.1, 6.3) 49.3 (34.3, 82.3) 1.24 (0.90, 1.64) 4.2 (3.37, 4.69) 1.13 (1.0, 1.28) 2.28 (1.68, 2.92 3.73 (3.01, 4.3) 102 (92, 119) 85.7 ± 11.9 173.7 ± 6.8 102.9 ± 7.8 28.4 ± 3.7 105.8 ± 13.7 0.98 ± 0.08 2.03 ± 0.16 10 (4) 69 (13) 72 (26) 4.5 ± 1.1 25 (10) 88 (37) 88 (37) 6.68 ± 0.86 0.90 (0.74, 1.07) 8.20 ± 1.12 2.75 (2.18, 3.08)
61.1 ± 8.0 0.86 (0.20, 7.8) 38(15) 64 (25) 130 (122, 145) 79 (74, 82) 65 ± 10.6 6.8 ± 1.3 5.6 (5.2, 6.5) 64.4 (54.4, 87.8) 1.35 (1.00, 2.10) 3.87 (3.36, 4.57) 0.99 (0.88, 1.16) 2.04 (1.56, 2.63) 3.48 (3.2, 4.39) 100 (90, 115) 77.4 ± 10.2 168.8 ± 7.4 100.2 ± 8.61 27.2 ± 3.2 99.4 ± 5.9 1.01 ± 0.05 1.90 ± 0.15 8 (3) 40 (24) 77(26) 4.8 ± 1.3 11 (3) 85 (35) 95 (39) 6.14 ± 0.64 0.90 (0.74, 1.00) 7.47 ± 1.21 2.40 (0.86, 2.94)
0.004 0.230 0.019 0.53 0.006 0.11 0.13 0.001 0.37 0.10 0.35 0.55 0.047 0.52 0.52 0.54 0.001 0.002 0.14 0.11 0.007 0.053 b0.001 0.74 0.008 0.68 0.23 0.12 0.71 0.25 0.002 0.62 0.006 0.20
Data are mean ± SD, median (25th, 75th centile) or % (number). Statistical comparisons were made using students t, Wilcoxon rank sum and chi square tests respectively. a Physical activity score range 0–9 (9 = most active).
LAD disease. The LAD was chosen for detailed measurements due to its length and importance in supplying blood to the left ventricle and septum. Calcification has been found to be greater in the LAD than in other major coronary arteries and with greater levels of calcification in the proximal LAD artery compared to the rest of the artery [26]. For calcification scoring, the LAD was visualised in four 2.5 cm segments from its origin as a branch of the left coronary artery. Lesion scores were calculated by multiplying the areas in mm2 by an attenuating factor as described by Agatston et al. [27]. The CAC score was calculated as the sum of all lesion scores in each segment. A single observer (HD, supervised by a senior radiologist (ARW)), blinded to patient identity, ethnicity and other results, made all LAD calcification measurements. Intraobserver repeatability was estimated by Bland Altman analysis [28]. A study of 10 scans showed a mean difference
between cycles of 13HU, with a coefficient of repeatability of 44 HU. Quantitative coronary angiography (QCA), limited to the LAD, was performed without vasodilation using Medcon Quantitative Measurement QCA to analyse the original clinic diagnostic angiograms. Calibration of the system was based on catheter dimensions while unfilled with contrast medium. Within each of the four proximal 2.5 cm segments, the reference lumen diameter was determined by edge detection and averaged from the two orthogonal projections (Fig. 1). The degree of stenosis was calculated as a % of the total diameter of the artery and the lengths of lesions were measured for each of the four 2.5 cm segments of the LAD (Fig. 1). An experienced observer (JC) who was unaware of patient identity, ethnicity, clinical data or calcification profile of the cases performed the analysis. The mean intra-observer difference [28] in vessel diameter was − 0.20 mm (coefficient
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Table 2 Characteristics of left anterior descending (LAD) artery segments in European and South Asian men (age adjusted) European men
South Asian men
p for ethnic group
n = 42
n = 41
difference
LAD diameter, mm a Segment 1 (proximal) Segment 2 Segment 3 Segment 4
3.4 2.7 2.3 2.1
(3.1, 3.6) (2.5, 2.9) (2.1, 2.5) (1.9, 2.2)
2.9 2.6 2.2 1.9
(2.7, 3.1) (2.4, 2.8) (2.1, 2.5) (1.8, 2.0)
0.007 0.38 0.55 0.12
LAD diameter, mm Age and BSA adjusted a Segment 1 (proximal) Segment 2 Segment 3 Segment 4
3.3 2.7 2.2 2.1
(3.1, 3.5) (2.5, 2.9) (2.0, 2.4) (1.9, 2.3)
3.0 2.6 2.3 2.0
(2.8, 3.3) (2.4, 2.9) (2.1, 2.5) (1.8, 2.2)
0.13 0.79 0.79 0.76
(40.0, 119.5) (8.6, 26.2) (0, 0) (0, 0)
43.4 7.3 0 0
(25.0, 75.6) (4.1, 12.8) (0, 0) (0, 0)
0.76 0.24 1.00 1.00
(2, 7) (1, 4) (0, 0) (0, 0)
3 1 0 0
(2, (0, (0, (0,
0.35 0.001 1.00 1.00
LAD calcification score, HU Segment 1 (proximal)¥ Segment 2¥ Segment 3¥ Segment 4¥ Number of calcified lesions in LAD Segment 1 (proximal)† Segment 2† Segment 3† Segment 4†
69.2 15.0 0 0
4 3 0 0
5) 3) 0) 0)
% stenosis in LAD Segment 1 (proximal) Segment 2 Segment 3† Segment 4†
34.7 34.1 21.6 15.0
(25.4, 43.9) (25.6, 42.5) (0, 43.5) (0, 23.3)
52.3 27.2 16.1 0
(42.8, 61.8) (18.6, 35.7) (0, 28.8) (0, 20.7)
Length of LAD stenosis, mm Segment 1 (proximal) Segment 2 Segment 3† Segment 4†
9.3 10.5 15.1 15.5
(7.2, 11.4) (8.1, 12.9) (9.6, 22.6) (6, 14.4)
13.3 9.4 7.4 –
(7.2, 11.4) (6.8, 12.1) (7.2, 8.8)
0.012 0.29 0.59 b0.001
0.012 0.57 0.61 0.51
Data are age adjusted and presented as means (95% CI), except † = medians (interquartile range), ¥ = geometric mean of (CAC score +1) (95% CI). p values were calculated using the T statistic. a Reference diameter data were not available for 3 European and 3 South Asian men.
of repeatability = 0.68 mm) and the mean intra-observer difference in length of stenosis was 1 mm (coefficient of repeatability = 7.3 mm) and for degree of stenosis it was 0.3% (coefficient of repeatability = 12.5%). 3.5. Statistical analyses Data were markedly positively skewed for CAC scores in all segments. Coronary artery calcification scores were transformed using log (CAC score + 1) to approximate a Normal distribution. Log transformations were used to transform vessel reference diameters in each LAD segment. Other skewed data were transformed or analysed using nonparametric regression models (quantile regression). Body surface area (BSA) was calculated using the formula of Mosteller [29] (BSA = square root of (height (cm) × weight) / 3600). Duration of CHD was calculated by
subtracting date of diagnosis (participant recall or date of diagnostic angiography) from date of study visit. Age adjusted measures of central tendency (means, geometric means or medians) for LAD diameter, calcification and stenosis were calculated and comparisons were made between ethnic groups using p values based on the T statistic. LAD diameters and stenosis for each 2.5 cm segment were then calculated in each ethnic subgroup of men with equivalent levels of atherosclerosis; for this purpose, LAD segment CAC scores were grouped into tertiles in order to categorise levels of local coronary atherosclerotic disease burden. Tertiles were pre-specified to maximise power; however, additional confirmatory analyses were conducted in quartilised data. In addition, similar analyses were performed to examine ethnic group differences in common carotid artery diameters, stratifying by tertile of total CAC scores as an estimate of generalised atherosclerotic burden.
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Robust linear regression models were used to assess whether measured cardiovascular risk factors or measures of atherosclerosis at other sites explained any ethnic group differences in these associations. Tests for interactions between ethnicity and each risk factor were performed in the regression models. 4. Results 4.1. Ethnic group characteristics The South Asian men were on average 6years younger than the European men, but their duration of known coronary artery disease was longer. South Asian men consumed less alcohol, were less likely ever to have smoked, had more diabetes and higher HbA1c and fasting insulin levels. They were also shorter, with smaller body surface areas, but had higher body mass index (BMI) and waist hip ratios (WHR) than European men. Blood lipid profiles were similar between the two groups, with the exception of HDL cholesterol which was lower in South Asian men, however, most men in both ethnic groups were receiving lipidlowering medications. Approximately two-thirds of each group reported doctor diagnosed hypertension. (Table 1) and cardiac symptoms did not differ between ethnic groups. Physical activity levels did not differ by ethnicity. Compared with European men, South Asian men had significantly narrower carotid and femoral lumen diameters, similar carotid intima-media thickness (IMT) and less femoral IMT, although the latter difference was not statistically significant (Table 1).
contrast, South Asian men had less marked stenoses in segments 2–4 than European men, although these differences were not significant (Table 2). In the proximal segment, South Asian men had fewer, but significantly longer, stenotic lesions than the European men. In contrast, South Asians had shorter lesions in segments 2– 4, although there were few lesions beyond the proximal segment in either ethnic group (Table 2). The degree of stenosis and length of lesions weakly correlated with calcification scores in the proximal segment in European men (rho = 0.32, p = 0.05 and rho = 0.34, p = 0.04) but no significant correlations were observed in South Asian men (rho = 0.24, p = 0.16 and rho = 0.19, p = 0.28). 4.3. Left anterior descending artery reference diameter 4.3.1. All men European men had significantly larger proximal segment reference diameters than South Asian men (age adjusted: 3.4 mm vs 2.9 mm, p = 0.007), but there were no significant ethnic differences in reference diameter in the segments 2–4. This ethnic group difference in proximal segment diameter was attenuated but not abolished by further adjustment for BSA (Table 2). Proximal segment reference diameter was negatively correlated with proximal segment CAC score and number of calcified atherosclerotic lesions in European (rho = − 0.38, p = 0.016 and rho = − 0.43, p = 0.007), but not in South Asian men (rho = − 0.06, p = 0.72 and rho = 0.04, p = 0.81) and with physical activity score in South Asian men (rho = 0.32, p = − 0.05) but not in European men (rho = 0.11, p = 0.52).
4.2. Characteristics of atherosclerosis in the LAD Angiograms were missing for 3 (7%) European and 3 (7%) South Asian men, resulting in missing data on LAD stenosis and vessel diameter for these cases; in addition one South Asian and two European men had occlusion in the distal segments which prevented visualisation.
4.3.2. Stratified by atherosclerotic burden Since disease may influence LAD diameter we performed further analyses of ethnic group differences stratified by extent of local coronary artery disease (estimated by LAD segment
4.2.1. Coronary artery calcification score and calcified lesions 95% and 93% of Europeans and South Asians had CAC scores N0 in the proximal LAD segment (segment 1) and 81% and 68% Europeans and South Asians had CAC scores N 0 in the second segment. Calcification was undetectable in the segments 3–4 in either South Asians or Europeans. South Asians had lower CAC scores than Europeans in segments 1–2, although the differences were not statistically significant (Table 2). Europeans also had more calcified lesions in the proximal segment (age adjusted: 4.3 vs 3.3, p = 0.35) and in segment 2 (3 vs 1, p = 0.001) (Table 2). 4.2.2. Degree and length of stenosis in LAD on angiography South Asian men had significantly greater proximal stenoses than European men. This difference increased on adjustment for age and duration of coronary artery disease and was not explained by any other measured risk factors. In
Fig. 2. Diameter of proximal LAD subdivided by tertiles of calcification (CAC) score and after adjustment for age and body surface area.
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calcification score). The tertile of European men with least proximal disease (segment 1 CAC score b22 HU) had markedly larger vessel diameters than the tertile with most disease (segment 1 CAC score = 132–2416 HU) (3.8 mm vs 2.8 mm, p for trend = 0.038). The diameter of the proximal LAD in the tertile of South Asian men with least coronary artery disease was significantly less than in the same CACS tertile of European men (3.8 mm vs 2.8 mm, p = 0.016 adjusted for age and BSA), but, unlike European men, proximal LAD diameter did not decrease with increasing disease, but showed a small non-significant increase with increasing tertile of CAC score (Fig. 2). For all men in the lowest tertile of calcification score, proximal segment diameter was associated with age, duration of coronary artery disease and smoking status. However, adjustment for these variables did not alter the ethnic group difference in proximal segment vessel diameter (Table 3). Diabetes, fasting glucose and insulin, blood lipid levels, height, BSA and measures of obesity and physical activity were not associated with proximal segment diameter in men in the lowest tertile of CAC score. For men in the upper two tertiles of CAC score, proximal segment diameter was associated with BSA (age adjusted standardised beta coefficient for BSA = 0.36, p = 0.008) in both ethnic groups, with physical activity score in South Asian men (age adjusted standardised beta coefficient for physical activity score = − 0.43, p = 0.027) and with length of lesions in European men (age adjusted standardised beta coefficient for Table 3 B coefficients for ethnicity in robust linear regression models by tertile of LAD calcification score Adjustment
Standardised Beta coefficient for ethnicity (European men = reference group)
p value for ethnic group difference in association with proximal LAD diameter
Adjusted R2 value for model
Men in lowest tertile of LAD calcification score (0–22 HU), n = 26 Unadjusted − 0.52 0.007 24% Adjusted for Age − 0.64 0.003 28% Age + body − 0.82 0.008 37% surface area⁎ Age + duration of coronary − 0.42 0.002 51% artery disease Age + smoking status − 0.91 b0.001 57% (ever smoker) Men in upper tertiles of LAD calcification score (23–2416 HU), n = 51 Unadjusted − 0.08 0.18 4% Adjusted for Age⁎ − 0.23 0.14 5% Age⁎ + body surface area − 0.03 0.59 13% Age⁎ + physical activity − 0.19 0.26 14% score B coefficients are for log vessel diameter. Explanatory variables shown only if p b 0.10 (with exception of age⁎ and body surface area⁎ which were forced into some models). Dependent variable = proximal LAD diameter.
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length of stenosis = −0.52, p = 0.022). There were no other associations between proximal segment diameter and markers of atherosclerosis or risk factors, including blood lipid levels and use of lipid-lowering medication, in men in the upper tertiles of CAC score. None of these findings were altered when analyses were stratified by quartile of LAD CACS. In LAD segments 2–4, the absence of ethnic group differences in vessel diameter was unchanged on stratification by tertile of local CAC score. 4.4. Common carotid artery diameters stratified by atherosclerotic burden The ethnic group differences observed for common carotid artery diameters were also most marked in those in the lowest tertile of total CACS (age and BSA adjusted diameters South Asian men: 6.0 mm, European men: 6.6 mm, p = 0.073). There was no ethnic group difference in carotid artery diameters in men in the upper tertiles of total CACS (age and BSA adjusted diameters: 6.4 and 6.5 mm, p = 0.528). 5. Discussion Overall, South Asians had a greater degree of stenosis in the proximal LAD than Europeans. South Asian men also had fewer but longer lesions in the proximal segment, although the increased degree and length of stenosis in South Asian men was not associated with increased coronary calcification scores. However, in men with minimal local atherosclerosis, South Asians had significantly narrower proximal LADs than Europeans and this difference was unexplained by age, body size or other measured risk factors. This suggests that there may be ethnic differences in LAD size and this is consistent with the findings that South Asians also had smaller carotid and femoral artery diameters than Europeans. Interestingly, in men with more advanced atherosclerosis the ethnic group difference in proximal LAD diameter was abolished. In Europeans an increasing level of local atherosclerosis was associated with narrower proximal LAD reference diameters, but this relationship was not seen in South Asians. This might be explained by more inward remodelling of atherosclerosis as disease advances in Europeans compared with South Asians. In terms of atherosclerosis in the LAD, the largest ethnic group differences were observed in the most proximal 2.5 cm segment and there was little calcification or stenosis in the more distal segments in either group. It therefore seems likely that the increased degree of LAD stenosis, despite similar symptoms and CAC scores, in South Asian men is attributable to a narrower proximal LAD. Proximal segment LAD diameters in European men (3.8 mm) with lower levels of calcification in our study closely approximate those recorded by Dodge et al., who found that the mean diameter of the proximal LAD segment was 3.7 ± 0.4 mm in subjects with
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normal angiograms [30]. We found that adjustment for BSA attenuated, but did not wholly account for ethnic group differences. Our study differs from most previous studies in that we used local coronary calcification scores to stratify atherosclerotic burden rather than excluding people with angiographically determined disease. Coronary calcification has been shown to predict total plaque size assessed by histology [20], while degree of stenosis is highly dependent on coronary artery remodelling. Our findings suggest that European men undergo more inward remodelling in the LAD in response to advanced atherosclerosis. The negative correlation, albeit weak, between LAD diameter and length of stenosis in European men is consistent with this hypothesis. A similar relationship between narrower reference diameter and increased disease was not seen in South Asian men and one can speculate either that they do not inwardly remodel in response to advanced disease or that inward remodelling occurs at an earlier stage of disease progression than in European men. In view of the higher risk of coronary events in South Asian men the latter possibility seems more likely, but further studies using intra-vascular ultrasound (IVUS) may help to resolve this question. A recent pilot study using IVUS in 41 patients suggests that inward remodelling in coronary vessels may be associated with a more stable plaque phenotype than outward remodelling [31]. Our study may explain apparently contradictory findings of previous studies with regard to coronary artery size. Our findings of no significant ethnic difference in LAD diameter in men with the greatest atheromatous burden are in accord with those of Zindrou et al., who studied age, sex and BSA matched patients with severe disease selected to undergo coronary artery bypass grafting [13]. In contrast, Lip et al. [15] and Makaryus et al. [16] examined apparently normal angiograms, whilst Dhawan and Bray [14] studied disease-free segments from routine angiograms, however, these analyses were not stratified by atheromatous burden. Since it is known that the CT has higher sensitivity than angiography in identifying atheromatous lesions even in the absence of obstruction [32], our approach of stratifying local atheromatous burden by CAC score may be more sensitive in identifying groups of men with similar levels of local disease, and thus ethnic group differences which are present in men with low levels of atherosclerotic burden are less likely to be masked by heterogeneity of disease burden and potential differences in arterial remodelling. Our study has a number of limitations in terms of sample size, recruitment, and accuracy of measurements. This is a relatively small study and consequently caution is needed in interpretation of the effects of explanatory and interacting variables in multivariate and stratified models. We recruited a cardiology clinic-based sample and it is likely that there are ethnic group differences in health seeking behaviours. However, UK evidence suggests that South Asians in our communities seek treatment earlier [33] and that they receive similar levels of interventions [34,35]. Duration of coronary artery disease was difficult to quantify, as many participants
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