Int J Cardiovasc Imaging (2014) 30:759–768 DOI 10.1007/s10554-014-0399-7
ORIGINAL PAPER
Association of conventional risk factors for cardiovascular disease with IMT in middle-aged and elderly Chinese Han-mei Wang • Tian-cheng Chen • Shuang-quan Jiang • Yu-jie Liu • Jia-wei Tian
Received: 8 November 2013 / Accepted: 6 March 2014 / Published online: 14 March 2014 Ó Springer Science+Business Media Dordrecht 2014
Abstract To study the association between known risk factors for cardiovascular disease and intima-media thickness (IMT) in the carotid and popliteal arteries in middleaged and elderly Chinese adults. 686 middle aged and elderly Chinese adults from the China Da Qing Diabetes Prevention Study who had full clinical, laboratory, ultrasound examination results were enrolled in the study. Common carotid artery (CCA) and popliteal artery (PA) IMT were obtained using high resolution ultrasound machine. Pearson’s or Spearman’s correlation analysis and logistic regression analysis were used to determine association between risk factors [age, gender, tobacco smoking, body mass index (BMI), diabetes mellitus (DM), systolic blood pressure (SBP), diastolic blood pressure (DBP), total cholesterol, total triglyceride, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol, glycosylated hemoglobin (HbA1c)] and CCA- or PA–IMT. The age range of the study population was 45–87 years, 384 of them (56 %) were women. The prevalence of high blood pressure and DM was 60.6 and 68.8 %, respectively. Participants in DM group tended to be older, had greater value for SBP, HbA1c and PA–IMT, but smaller value for DBP than those in control group. Smoke status, BMI, blood H. Wang S. Jiang Y. Liu J. Tian (&) Department of Ultrasound, Second Affiliated Hospital of Harbin Medical University, No. 148, Baojian Road, Nangang District, Harbin 150086, China e-mail: [email protected] H. Wang Department of Echocardiography, Daqing Oilfield General Hospital, Daqing, China T. Chen Department of Epidemiology and Biostatistics, Public Health School, Harbin Medical University, Harbin, China
lipids and CCA–IMT were not statistically different between groups. Pearson’s or Spearman’s rank correlation analysis showed that CCA–IMT had a positive correlation with age, gender, DM, SBP, BMI and HbA1c, negative correlation with HDL-C. PA–IMT showed a positive correlation with age, gender and SBP. Univariate logistic regression analysis showed that elevation of age, SBP, BMI, HbA1c and having DM were significant predictors of CCA–IMT thickening, so was reduction of HDL-C. Risk factors that predicted significant thickening of PA–IMT were age, gender, tobacco smoking. After adjusted for age and gender, except HDL-C, the other four risk factors (SBP, BMI, HbA1c and having DM) that predicted CCAIMT thickening remained significant; however none of the risk factors predicted PA–IMT thickening after adjusted for age and gender. The current results provide evidence that CCA–IMT is a superior marker for atherosclerosis compared with PA–IMT. Aggressive control of SBP, HbA1c and proper control of weight may postpone thickening of CCA–IMT. Keywords Intima-media thickness Risk factor Ultrasonography Carotid artery Popliteal artery
Introduction With increasing incidence of cardiovascular disease (CVD) and stroke in the population, it is important to identify high-risk patients with subclinical manifestation of disease which will benefit from early and aggressive therapy. Carotid intima-medial thickness (IMT), as measured by high-resolution B mode ultrasound, is a simple and noninvasive imaging test assessing structural changes in the arterial wall, and has been widely used as an intermediate,
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preclinical phenotype of atherosclerotic disease [1]. In a systematic review and meta-analysis, eight observational population-based studies were examined and showed a significant association of IMT with risk factors for CVD [2]. Data in this respect is as yet limited in China. In the present paper, we investigated the association between known risk factors for CVD and IMT in the carotid and popliteal artery in a middle-aged and elderly Chinese population. We also discussed the value of IMT in clinical practice.
Subjects and methods Study population The study population came from China Da Qing Diabetes Prevention Study (CDQDPS) [3], a large-scale follow up study which began in 1986. The initial aim of the CDQDPS was to examine the effect of different lifestyle interventions in the progression of impaired glucose tolerance (IGT). The result was reported in Lancet in 2008 [4]. In the follow up study in 2009 and 2010, carotid and popliteal ultrasound examinations were added to assess structural changes of the arteries in the participants. Two of the sonographers (J.H and W.H.M) from Daqing Oilfield General Hospital were formally trained in ultrasound scanning and reading at Medstar Health Research Institute in Phoenix and Washington D. C. USA. Figure 1 shows the participant flow in the CDQDPS from the initial study to the last follow-up. In 1986, 582 participants with IGT, 630 with diabetes mellitus (DM), and 523 non-DM controls (CON) from 33 clinics in Da Qing city were recruited. Till 2009 and 2010, 95 participants were lost to follow-up, 611 died; the remaining participants were followed up over the 23 years. Numbers
95 lost
28
In 1986
100
523 CON
174
32
582 IGT
317
In 2009
355 CON
38
33
33 IGT
337
630 DM
302
261
78
641 DM
Fig. 1 Participant flow in the CDQDPS from the first to the last examination. CON, group of non-diabetes mellitus controls; IGT, group of patients with impaired glucose tolerance; DM, group of patients with diabetes mellitus
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Clinical and laboratory examinations For each participant, height, weight was measured to the nearest 0.1 cm and 0.1 kg, respectively. Body mass index (BMI) was calculated as weight in kilograms divided by the square of height in meters (kg/m2). Overweight was defined as 28 kg/m2 [ BMI C 24 kg/m2, while obesity was defined as BMI C 28 kg/m2 [5]. Blood samples were drawn after a 12-h overnight fast to determine blood lipids [total cholesterol (TC), total triglyceride (TG), high-density lipoprotein cholesterol (HDLC), low-density lipoprotein cholesterol (LDL-C), and glycosylated hemoglobin (HbA1c)]. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) at the right upper arm were measured and recorded by trained nurses using standard mercury sphygmomanometers in quietly seated participants after C5-min of rest [6]. If the first SBP was C140 mmHg or the first DBP was C90 mmHg, the measurement was repeated. The second reading was used in the analyses. Hypertension [high blood pressure (HBP)] was defined as SBP of C140 mmHg and/or DBP of C90 mmHg, or current use of anti-hypertensive agents [7]. Pre-hypertension was defined as 140 mmHg [ SBP C 120 mmHg and/or 90 mmHg [ DBP C 80 mmHg [8]. The presence of DM was defined by self-reported diagnosis of diabetes plus evidence of raised glucose levels in the medical record, taking oral hypoglycemic medications, or abnormal fasting glucose and oral glucose tolerance tests [9]. Tobacco smoking status was based on a self-reported history of cigarette smoking. Ultrasound studies
611 dead
35
in the three groups were 33 patients with IGT, 641 with DM and 355 non-DM controls, respectively. Written informed consent was obtained from each participant. The study was approved by the Ethics Committee of Daqing Oilfield General Hospital.
Ultrasound scanning and analysis protocol in this study followed Phase 5 operations manual of the Strong Heart Study (SHS) [10]. B-mode ultrasonography of the common carotid artery (CCA) and popliteal artery (PA) was performed by three trained sonographers using Philips iE33 ultrasound machine (Holland), equipped with L11-3 linear array transducer. During CCA–IMT scanning, the participants took a supine position with the neck slightly extended and the head rotated contra-laterally to the side. During PA–IMT measurement, the participants took a prone position with knees flexed slightly. After the carotid or popliteal arteries were
Int J Cardiovasc Imaging (2014) 30:759–768 Fig. 2 a Site to measure carotid IMT. Longitudinal view of distal common carotid artery (CCA) and carotid bifurcation (Bulb) of the left carotid artery. IMT was measured in the far wall of distal CCA, approximately 1 cm to the bifurcation, free from plaque. Site to measure CCA–IMT in this image is between the two blue bars. b B-mode guided M-mode ultrasound to measure CCA-IMT. IMT was defined as the distance between 2 parallel echogenic lines corresponding to the blood–intima and media– adventitia interface on the far wall. In this image, IMT was measured on the far wall of distal CCA; measurements from three cardiac cycles should be averaged. Time to measure IMT is at end diastole (approximately at the end of the QRS complex when the lumen has a minimum diameter). c Local magnifying (ZOOM function) of M-mode image to measure CCA–IMT. The IMT was enlarged in ZOOM function, which provides better recognition of the echo interface. In this image, IMT was also performed on three cardiac cycles at end diastole
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a Name of the participant
Bulb
CCA
b Name of the participant
c Name of the participant
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located by transverse scans, the probe was rotated 90° to obtain and record a longitudinal image of the anterior and posterior wall (Fig. 2a). The ultrasound beam was carefully adjusted to be as perpendicular to the vessels as possible. Two-dimensionally (B-mode) guided M-mode images of the distal CCA or mid PA were obtained. Gain settings were optimized to limit ‘‘blossoming’’ of brighter interfaces. Images and cine-loops on the longitudinal view of distal CCA and mid PA were obtained with simultaneous electrocardiogram (ECG) and recorded on videotapes for offline analysis. All the images on videotapes were reviewed and measured by an experienced sonographer (W.H.M), who was totally blinded to clinical status of the study participants. IMT was defined as the distance from the leading edge of the first echogenic line (lumen–intima interface) to the leading edge of the second line (media-adventitia interface) on the far wall of CCA (posterior wall) or PA (anterior wall). The simultaneous ECG was used to time IMT measurements at end diastole (approximately at the end of the QRS complex when the lumen has a minimum diameter) (Fig. 2b). CCA–IMT measurement was taken in both arteries approximately 1 cm proximal to the carotid artery bifurcation in an area free of plaque. PA–IMT measurement was taken in both arteries at the site of the popliteal fossa in an area free of plaque. If plaque was present in the selecting site, the adjacent wall was selected; if there was still plaque, the corresponding near wall was measured. IMT was most commonly measured from B-mode guided M-mode images. If clear M-mode images were difficult to acquire, then B-mode images were used instead. Although spatial resolution is comparable with the two techniques, temporal resolution is far superior with M-mode imaging, thereby facilitating standardization of measurements at the time of end diastole. ZOOM function (local magnifying) was also used to better determine the lumen interface, and acquire measurements more accurately (Fig. 2c). All measurements were performed on 3 cardiac cycles and then averaged on each side. Statistical analysis Continuous variables were given as mean ± standard deviation (SD), and compared by unpaired t test or Satterthwaite t’ test according to distribution and variance of the data. Categorical variables were expressed as absolute numbers with the percentage of subjects in parentheses, and compared using Chi square analysis. Pearson’s or Spearman’s rank correlation analyses were used to assess bivariate correlation between each risk factor and IMT for continuous variables, while Pearson’s Chi square test was used to compare groups regarding categorical variables. Binary logistic regression analyses were performed to
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identify predictor variables for thickened IMT. Odds ratios (ORs) were given to assess the strength of association between risk factors and IMT. An IMT C 0.9 mm was considered thickened in performing these analyses [11, 12]. Two-sided P values below 0.05 were considered statistical significance. All statistical analyses were performed using SAS, version 9.0 (SAS Institute, Cary, NC). To observe intra-reader variation, 30 cases were randomly selected for a second measurement about 2 months apart from the initial reading. Spearman’s rank correlation analysis was used. The correlation coefficient of intrareader variation is 0.92.
Results Basic characteristics Among the 1,029 participants (CON: 355, IGT: 33 and DM: 641), 44 moved outside the Daqing city; they were interviewed by telephone, and examined by their local health provider. For the 985 participants living in the city, 79 were interviewed at home, of whom 58 took physical Table 1 Characteristics of the study population with and without diabetes mellitus CON (n = 214)
DM (n = 472)
P value
Age (years)
63.43 ± 7.59
64.97 ± 7.18
0.011*
Female, n (%)
115 (53.74)
269 (56.99)
0.464
SBP (mmHg)
137.05 ± 19.63
146.86 ± 19.20
0.000*
DBP (mmHg)
82.80 ± 10.09
79.04 ± 10.84
0.000*
HBP, n (%)
101 (47.20)
315(66.74)
0.000*
BMI (kg/m2)
25.58 ± 3.59
25.62 ± 3.44
0.915
Smoker, n (%)
81 (37.85)
154 (32.63)
0.157
TC (mmol/L)
5.014 ± 0.95
5.041 ± 1.16
0.790
TG (mmol/L)
1.880 ± 1.13
1.916 ± 1.33
0.767
LDL-C (mmol/L)
3.000 ± 0.794
3.007 ± 0.923
0.930 0.591
HDL-C(mmol/L)
1.273 ± 0.282
1.257 ± 0.329
HbA1c (%)
5.914 ± 0.652
8.142 ± 0.731
0.000*
CCA–IMT left (mm)
0.764 ± 0.168
0.792 ± 0.180
0.071
CCA–IMT right (mm)
0.770 ± 0.177
0.782 ± 0.173
0.433
PA–IMT left (mm)
0.769 ± 0.186
0.817 ± 0.214
0.013*
PA–IMT right (mm)
0.768 ± 0.189
0.818 ± 0.198
0.007*
All values are the mean ± SD or the number with the percentage of subjects in parentheses. P values represent the comparison between control and diabetes mellitus group by unpaired-t, Satterthwaite t’-test or Chi square test CON control group, DM diabetes mellitus group, SBP systolic blood pressure, DBP diastolic blood pressure, HBP high blood pressure, BMI body mass index, TC total cholesterol, TG total triglyceride, HDL- or LDL-C high- or low-density lipoprotein cholesterol, HbA1c glycosylated hemoglobin, IMT intima-media thickness, CCA common carotid artery, PA popliteal artery *P \ 0.05 (statistically significant)
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and laboratory examination, but didn’t take ultrasound examination. The remainder (906) were interviewed and examined at Da Qing Oilfield General Hospital. Number of participants in the IGT group (25) was too small to analyze, therefore were excluded for analysis. Images that could not provide high quality to ensure accurate measurement of IMT were also excluded (85 cases). Some video disks couldn’t work after several times’ reading and could not be evaluated (59 cases). Participants with partial clinical or laboratory information were also excluded (51 cases). The final study population included 472 DM patients and 214 non-DM participants. Demographic and clinical data of 686 participants are summarized in Table 1. The age range of the study population was 45–87 years, 384 of them (56 %) were women. The prevalence of hypertension and DM were high in this study population (60.6 and 68.8 %, respectively). Participants in DM group tended to be older, had greater value for SBP and HbA1c, but smaller value for DBP than those in CON group. Smoke status, BMI and blood lipids were not statistically different between groups. Participants in DM group had greater value for PA–IMT than the CON group on both sides, while CCA-IMT was not statistically different between the two groups. Pearson or Spearman correlation analysis Correlation or contingency coefficients of all risk factors with CCA- or PA–IMT are shown in Table 2. CCA-IMT had a positive correlation with age, gender, DM, SBP, BMI and HbA1c, negative correlation with HDL-C. Age showed the highest correlation coefficient (0.3025) among the risk factors, followed by SBP (0.2761). PA–IMT showed a positive correlation with age, gender and SBP. Age was also the strongest predictor for PA–IMT (r = 0.2986). Correlation or contingency coefficient of each risk factor was lower than 0.4, indicating the magnitude of these associations is rather weak.
763 Table 2 Correlation of each risk factor with CCA- and PA–IMT Risk factors
CCA–IMT r/C
PA–IMT P value
r/C
P value
Age (years)
0.3025
0.000*
0.2986
Gender
0.1178
0.023*
0.1933
0.001*
Smoke
0.0475
0.659
0.0998
0.217
DM
0.1294
0.012*
SBP (mmHg)
0.2761
0.000*
-0.013 0.1874
0.000*
0.823 0.001*
DBP (mmHg)
0.0421
0.420
0.0679
0.235
BMI (kg/m2)
0.1652
0.001*
0.0544
0.338
0.0657
0.248
HbA1c (%)
0.1902
0.000*
TC (mmol/L)
0.0336
0.518
TG (mmol/L)
0.0499
0.336
0.0086
0.880
LDL-C (mmol/L)
0.0657
0.206
-0.0295
0.604
0.003*
-0.1065
0.060
HDL-C (mmol/L)
-0.153
-0.035
0.541
r, Pearson’s or spearman’s correlation coefficient C, Pearson’s contingency coefficient Abbreviations as in Table 1 *P \ 0.05
3.818 and 5.881 for SBP between 120 and 139 mmHg and C 140 mmHg compared to SBP \ 120 mmHg, respectively]; followed by BMI (OR 2.612 for BMI C 28 kg/m2 compared to BMI \ 24 kg/m2). However, none of the risk factors predicted PA–IMT thickening any more after adjusting for age and gender (data not shown). In secondary analysis, associations of risk factors with CCA-IMT on the left and right side were evaluated separately (Table 4). Different power of effect was observed for elevation of SBP to predict CCA–IMT thickening on different side: the power of SBP between 120 and 139 mmHg had a 2.06-fold greater risk of developing CCA-IMT thickening on the left side than that on the right side (OR 6.249 vs 3.033); for SBP C 140 mmHg, the predictive power for developing CCA-IMT thickening was 1.17-fold higher on the left than on the right side (OR 6.419 vs 5.489).
Logistic regression analysis
Discussion
In univariate binary logistic regression, elevation of age, SBP, BMI, HbA1c and having DM were significant predictors of CCA-IMT thickening, so was reduction of HDLC. Risk factors that predicted significant thickening of PA– IMT were age, gender, tobacco smoking. Odds ratios (ORs) of each risk factor compared with the reference value are listed in Table 3. After adjusting for age and gender, except HDL-C, the other four risk factors (SBP, BMI, HbA1c and having diabetes mellitus) that predicted significant CCA-IMT thickening remained in the model (Table 4). The strongest predictor of CCA-IMT thickening was SBP [odds ratio (OR):
IMT is considered as a comprehensive picture of all alterations caused by multiple risk factors over time, which reflects atherosclerosis in the arterial walls. Traditional CVD risk factors have shown a positive association with CCA–IMT in epidemiological studies of patients and general population [13, 14]. In this study, we tested the association between traditional CVD risk factors and CCAand PA–IMT in a group of middle aged and elderly Chinese participants with high incidence of hypertension and DM. Risk factors predicting thickening of CCA-IMT in this study are age, DM, SBP, BMI, HDL-C and HbA1c.
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764 Table 3 Unadjusted risk factors associated with thickening of CCA- or PA–IMT
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Explanatory variables
CCA–IMT OR (95 % CI)
PA–IMT P value
OR (95 % CI)
P value
Age (years) \65
1
C65
1.986 (1.109–3.027)
1 0.0103*
2.277 (1.384–3.792)
0.0016*
Gender Women
1
Men
1.514 (0.646–2.448)
1 0.0874
2.379 (1.453–3.897)
0.0008*
Smoke (ciga/d) 0
1
C1
1.114 (0.682–1.789)
0.6725
1 1.510 (0.743–3.062)
0.2568
C10
1.353 (0.841–2.175)
0.2124
1.805 (1.011–3.223)
0.0483*
TC (mmol/L) \5.18
1
C5.18
1.366 (0.800–2.331)
0.2528
0.845 (0.474–1.506)
0.8232
C6.19
1.292 (0.650–2.568)
0.4645
0.921 (0.452–1.878)
0.5794
1
TG (mmol/L) \1.76
1
C1.76
0.944 (0.481–1.851)
0.8657
0.620 (0.225–1.328)
0.7943
C2.26
0.788 (0.451–1.377)
0.4033
1.127 (0.656–2.025)
0.6218
1
HDL-C (mmol/L) \1.55
1
C1.55
0.554 (0.209–0.994)
1 0.0323*
0.587 (0.289–1.191)
0.2188
LDL-C (mg/dL) \130
1
C130
1.059 (0.631–1.928)
0.8493
0.497 (0.237–1.042)
0.0637
C160
1.562 (0.773–3.218)
0.2272
1.219 (0.584–2.578)
0.5988
1 1.945 (1.218–3.027)
0.0136*
1 1.193 (0.736–1.933)
0.1761
1
DM No Yes SBP (mmHg) \120
1
C120
4.069 (1.174–14.096)
0.0269*
1.366 (0.504–3.712)
0.5594
C140
4.917 (1.459–16.565)
0.0102*
2.453 (0.931–6.481)
0.1368
1
DBP (mmHg) \80
1
C80
1.071 (0.614–1.868)
0.7327
0.877 (0.496–1.549)
0.1860
C90
1.412 (0.792–2.591)
0.2375
1.313 (0.706–2.445)
0.5576
1
2
BMI (kg/m ) \24
1
C24
1.192 (0.670–2.121)
0.5510
0.888 (0.501–1.575)
0.6847
C28
2.643 (1.431–4.881)
0.0019*
0.990 (0.498–1.965)
0.9765
0.4631 0.6763
1
HbA1c (%) OR odds ratio, CI confidence interval *P \ 0.05
\7 C7
1 1.975 (1.138–3.427)
0.0197*
1 1.242 (0.697–2.213)
C9
2.219 (1.184–4.159)
0.0333*
0.998 (0.479–2.079)
Because determinants of CCA–IMT were both age- and gender-dependent [15], we further controlled the two factors in the logistic regression analysis. After adjusting for
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age and gender, CCA–IMT is still predicted by SBP, DM, BMI and HbA1c, with SBP having the greatest OR value, indicating that SBP is the strongest predictor of CCA–IMT
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765
Table 4 Statistically significant risk factors associated with thickening of CCA–IMT on each side adjusted for age and gender Explanatory variables
CCA–IMT OR (95 % CI)
Left CCA–IMT P value
OR (95 % CI)
0.0183*
2.137 (1.298–3.520)
Right CCA–IMT P value
OR (95 % CI)
0.0029*
1.705 (1.054–2.759)
P value
DM No
1
Yes
1.908 (1.189–2.939)
1
1 0.0297*
SBP (mmHg) \120
1
C120
3.818 (1.071–15.58)
0.0473*
6.249 (1.415–27.60)
0.0156*
3.033 (0.862–10.699)
0.0838
C140 BMI (kg/m2)
5.881 (1.514–22.62)
0.0103*
6.419 (1.483–27.78)
0.0129*
5.489 (1.620–18.604)
0.0063*
\24
1
C24
1.127 (0.623–2.036)
0.6929
1.218 (0.679–2.186)
0.5082
1.616 (0.897–2.912)
0.1104
C28
2.612 (1.395–4.890)
0.0027*
2.268 (1.207–4.263)
0.0110*
2.759 (1.456–5.229)
0.0019*
1
1
1
1
HbA1c (%) \7
1
C7
1.983 (1.136–3.461)
0.0162*
2.111 (1.199–3.716)
0.0097*
1.781 (1.026–3.091)
0.0403*
C9
2.004 (1.029–3.905)
0.0438*
2.515 (1.302–4.858)
0.0061*
1.813 (0.942–3.492)
0.0751
1
1
*P \ 0.05
thickening. This result is consistent with other investigations [16, 17]. Mechanisms by which hypertension predisposes to atherosclerosis may include endothelial dysfunction, hyperinsulinemia, hemodynamic stress and multiple metabolic alterations [16]. With the development of atherosclerosis, vascular wall becomes less elastic and more rigid, which in turn elevates SBP of the patient, a vicious cycle is thus formed. We notice that in addition to patients with systolic hypertension (SBP C 140 mmHg), participants with systolic pre-hypertension (SBP between 120 and 139 mmHg) can as well predict thickening of CCA–IMT, suggesting an aggressive control of SBP is necessary to postpone the process of CCA–IMT thickening. Another interesting phenomenon revealed from this study is that left sided CCA–IMT was more influenced by elevation of SBP compared to the opposite side, since the OR values are much higher on left side than those on the right side (OR 6.249 vs 3.033 and 6.419 vs 5.489 for SBP between 120 and 139 mmHg and SBP C 140 mmHg, respectively). The power of SBP in predicting CCA-IMT thickening on left side is 2.06- and 1.17-fold higher than that on the right side. One possible explanation may be that left CCA originates directly from aortic arch, which means left CCA is usually under higher wall shear stress than right CCA, which lead to a higher proneness of developing atherosclerosis. DM is a well known risk factor for atherosclerosis and is associated with aggressive vascular abnormalities. The alterations in vascular homeostasis due to endothelial and smooth muscle cell dysfunction are the main features of diabetic vasculopathy favoring a pro-inflammatory/
thrombotic state which ultimately leads to atherothrombosis [18]. HbA1c has been accepted as the best marker for diabetic microvascular complications [19]. It is associated closely with advanced glycation end products (AGEs), which are widespread in the diabetic vascular system and contribute to the development of atherosclerosis through the formation of bridging between molecules in the basement membrane of the extracellular matrix by joining the receptor for advanced AGEs [20]. In the present study, we found having DM or a greater value of HbA1c are predictive of CCA–IMT thickening, and a well controlled level of HbA1c (\7 %) is suggestive to lower the risk of CCA–IMT thickening. Obesity is a complex disorder leading to alterations in lipid metabolism, insulin resistance, deregulation of hormonal axes, oxidative stress, systemic inflammation and ectopic fat distribution, which ultimately leads to development of atherosclerosis [17]. In this study, we found obesity (BMI C 28 kg/m2) is associated with thickening of CCA–IMT, while overweight (28 kg/m2 [ BMI C 24 kg/ m2) is not, suggesting that weight control is also necessary to prevent obesity in order to maintain lower speed of progression of CCA–IMT. Popliteal artery is the second most-common site of aneurysm after the aorta and appears particularly susceptible to calcium accumulation; arterial tortuosity and reduced distensibility with age [21–23]. But to our knowledge, there are limited previous studies which observed PA–IMT. In this study, we followed the Phase 5 protocol of Strong Heart Study to measure PA–IMT as well as to measure CCA-IMT. In our study, PA–IMT thickening
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is predicted by age, gender, tobacco smoking, but is not associated with blood pressure, blood lipids, DM or obesity. After adjustment for age and gender, PA–IMT thickening is not predicted by any risk factors any more, suggesting that PA–IMT is not a marker for atherosclerosis. One possible explanation of the inconformity of atherosclerotic changes shown in CCA and PA in this study might lies in the histology difference of the arteries. The distending pressure of aortic systolic pressure in the large elastic-type arteries (aorta and carotid) is a key determinant of the degenerative changes that characterize accelerated aging and hypertension. In contrast, muscular peripheral arteries, such as brachial and popliteal arteries, are less influenced by these changes [24]. In our study, CCA–IMT seems a superior marker for atherosclerosis compared with PA–IMT, since it is positively associated with a number of traditional CVD risk factors, including blood pressure, DM and obesity. Whether increased CCA–IMT itself reflects local and generalized atherosclerosis and thus is predictive of future CVD is still a subject of debate. Anatomy-pathologic studies showed that CCA–IMT mainly represents hypertensive medial hypertrophy or thickening of smooth muscles in the media, whereas atherosclerosis is largely an intimal process [25]. Age-related thickening of intimal and medial layers of CCA also occurs in the absence of overt atherosclerosis [26]. In our study, we also found that the main predictors of CCAIMT are age and SBP, which is consistent with other research [17]. A recent large meta-analysis of 18 case– control and cohort studies evaluated the value of CCA–IMT and plaque in the screening for coronary heart disease, and showed no benefit of IMT as a screening tool, since the discrimination between affected and unaffected individuals was insufficient [27]. Similarly, another recent meta-analysis of 41 randomized trials showed that regression or slowed progression of CCA–IMT with cardiovascular drugs did not affect the risk of cardiovascular events [28]. And also, compared to carotid plaque, a distinctive phenotype of atherosclerosis, CCA–IMT didn’t show increase in chronic inflammatory diseases despite markedly premature subclinical (and clinical) atherosclerosis manifest by focal plaque [29, 30]. As a result, unlike blood pressure and LDL-C, which are already FDA-approved surrogate markers of cardiovascular disease, CCA–IMT is still awaiting its final approval and validation by the FDA. The current guideline for the use of CCA–IMT in assessment of cardiovascular risk in asymptomatic adults gives carotid IMT class IIa rank with a level B for evidence for asymptomatic adults at intermediate risk. An appropriate indication for the use of IMT is for individuals without CVD with intermediate risk, older, and individuals with metabolic syndrome. The testing of low-risk or very high-risk CVD individuals as well
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as serial IMT testing is considered inappropriate use of this method [31, 32].
Limitations DM and hypertension were highly prevalent in our study population, which is not consistent with the general population. This is because the participants in this study came from a 23 year follow-up study, but not from a community random sampling one. DM and hypertension are both CVD risk factors and are associated with atherosclerosis; the high prevalence of these two factors in this study didn’t seem to influence the results. Computer-aided software (Qlab, Philips) which can analyze IMT automatically is also available in our echo lab, but we measured IMT manually for the following reasons: (a) one of the purposes of this study is to discuss the clinical value of IMT in evaluating subclinical atherosclerosis, thus a simple, rapid and reliable manner of detection is highly recommended in daily clinical practice. The time-consuming, off-line analyzing by computer-aided software is obviously contradicted to this need; (b) the computerized system depends highly on image quality; the automated tracked borders sometimes are not precise if image quality is not good enough, thus need to be manually traced and read; (c) the mixture of automated and manually read results may produce systemic error in data analysis, which is a huge defect of this method. In our study, echo images were read by a single and well trained sonographer, which avoided inter-observer variation. Intra-observer variation was also acceptable (correlation coefficient 0.92).
Conclusions The current results provide evidence that CCA–IMT is a superior marker for atherosclerosis compared with PA– IMT. Aggressive control of SBP, HbA1c and proper control of weight may be suggested to postpone thickening of CCA–IMT. Acknowledgments This study was partially funded by CDC/WHO Cooperative Agreement number U58/CCU424123-01-02. The authors gratefully thank Doctor Hong Jin, Xin Li and Li Pang from Department of Echocardiography of Da Qing Oilfield General Hospital for their help in image collection. Conflict of interest
None.
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ORIGINAL PAPER
Association of conventional risk factors for cardiovascular disease with IMT in middle-aged and elderly Chinese Han-mei Wang • Tian-cheng Chen • Shuang-quan Jiang • Yu-jie Liu • Jia-wei Tian
Received: 8 November 2013 / Accepted: 6 March 2014 / Published online: 14 March 2014 Ó Springer Science+Business Media Dordrecht 2014
Abstract To study the association between known risk factors for cardiovascular disease and intima-media thickness (IMT) in the carotid and popliteal arteries in middleaged and elderly Chinese adults. 686 middle aged and elderly Chinese adults from the China Da Qing Diabetes Prevention Study who had full clinical, laboratory, ultrasound examination results were enrolled in the study. Common carotid artery (CCA) and popliteal artery (PA) IMT were obtained using high resolution ultrasound machine. Pearson’s or Spearman’s correlation analysis and logistic regression analysis were used to determine association between risk factors [age, gender, tobacco smoking, body mass index (BMI), diabetes mellitus (DM), systolic blood pressure (SBP), diastolic blood pressure (DBP), total cholesterol, total triglyceride, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol, glycosylated hemoglobin (HbA1c)] and CCA- or PA–IMT. The age range of the study population was 45–87 years, 384 of them (56 %) were women. The prevalence of high blood pressure and DM was 60.6 and 68.8 %, respectively. Participants in DM group tended to be older, had greater value for SBP, HbA1c and PA–IMT, but smaller value for DBP than those in control group. Smoke status, BMI, blood H. Wang S. Jiang Y. Liu J. Tian (&) Department of Ultrasound, Second Affiliated Hospital of Harbin Medical University, No. 148, Baojian Road, Nangang District, Harbin 150086, China e-mail: [email protected] H. Wang Department of Echocardiography, Daqing Oilfield General Hospital, Daqing, China T. Chen Department of Epidemiology and Biostatistics, Public Health School, Harbin Medical University, Harbin, China
lipids and CCA–IMT were not statistically different between groups. Pearson’s or Spearman’s rank correlation analysis showed that CCA–IMT had a positive correlation with age, gender, DM, SBP, BMI and HbA1c, negative correlation with HDL-C. PA–IMT showed a positive correlation with age, gender and SBP. Univariate logistic regression analysis showed that elevation of age, SBP, BMI, HbA1c and having DM were significant predictors of CCA–IMT thickening, so was reduction of HDL-C. Risk factors that predicted significant thickening of PA–IMT were age, gender, tobacco smoking. After adjusted for age and gender, except HDL-C, the other four risk factors (SBP, BMI, HbA1c and having DM) that predicted CCAIMT thickening remained significant; however none of the risk factors predicted PA–IMT thickening after adjusted for age and gender. The current results provide evidence that CCA–IMT is a superior marker for atherosclerosis compared with PA–IMT. Aggressive control of SBP, HbA1c and proper control of weight may postpone thickening of CCA–IMT. Keywords Intima-media thickness Risk factor Ultrasonography Carotid artery Popliteal artery
Introduction With increasing incidence of cardiovascular disease (CVD) and stroke in the population, it is important to identify high-risk patients with subclinical manifestation of disease which will benefit from early and aggressive therapy. Carotid intima-medial thickness (IMT), as measured by high-resolution B mode ultrasound, is a simple and noninvasive imaging test assessing structural changes in the arterial wall, and has been widely used as an intermediate,
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preclinical phenotype of atherosclerotic disease [1]. In a systematic review and meta-analysis, eight observational population-based studies were examined and showed a significant association of IMT with risk factors for CVD [2]. Data in this respect is as yet limited in China. In the present paper, we investigated the association between known risk factors for CVD and IMT in the carotid and popliteal artery in a middle-aged and elderly Chinese population. We also discussed the value of IMT in clinical practice.
Subjects and methods Study population The study population came from China Da Qing Diabetes Prevention Study (CDQDPS) [3], a large-scale follow up study which began in 1986. The initial aim of the CDQDPS was to examine the effect of different lifestyle interventions in the progression of impaired glucose tolerance (IGT). The result was reported in Lancet in 2008 [4]. In the follow up study in 2009 and 2010, carotid and popliteal ultrasound examinations were added to assess structural changes of the arteries in the participants. Two of the sonographers (J.H and W.H.M) from Daqing Oilfield General Hospital were formally trained in ultrasound scanning and reading at Medstar Health Research Institute in Phoenix and Washington D. C. USA. Figure 1 shows the participant flow in the CDQDPS from the initial study to the last follow-up. In 1986, 582 participants with IGT, 630 with diabetes mellitus (DM), and 523 non-DM controls (CON) from 33 clinics in Da Qing city were recruited. Till 2009 and 2010, 95 participants were lost to follow-up, 611 died; the remaining participants were followed up over the 23 years. Numbers
95 lost
28
In 1986
100
523 CON
174
32
582 IGT
317
In 2009
355 CON
38
33
33 IGT
337
630 DM
302
261
78
641 DM
Fig. 1 Participant flow in the CDQDPS from the first to the last examination. CON, group of non-diabetes mellitus controls; IGT, group of patients with impaired glucose tolerance; DM, group of patients with diabetes mellitus
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Clinical and laboratory examinations For each participant, height, weight was measured to the nearest 0.1 cm and 0.1 kg, respectively. Body mass index (BMI) was calculated as weight in kilograms divided by the square of height in meters (kg/m2). Overweight was defined as 28 kg/m2 [ BMI C 24 kg/m2, while obesity was defined as BMI C 28 kg/m2 [5]. Blood samples were drawn after a 12-h overnight fast to determine blood lipids [total cholesterol (TC), total triglyceride (TG), high-density lipoprotein cholesterol (HDLC), low-density lipoprotein cholesterol (LDL-C), and glycosylated hemoglobin (HbA1c)]. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) at the right upper arm were measured and recorded by trained nurses using standard mercury sphygmomanometers in quietly seated participants after C5-min of rest [6]. If the first SBP was C140 mmHg or the first DBP was C90 mmHg, the measurement was repeated. The second reading was used in the analyses. Hypertension [high blood pressure (HBP)] was defined as SBP of C140 mmHg and/or DBP of C90 mmHg, or current use of anti-hypertensive agents [7]. Pre-hypertension was defined as 140 mmHg [ SBP C 120 mmHg and/or 90 mmHg [ DBP C 80 mmHg [8]. The presence of DM was defined by self-reported diagnosis of diabetes plus evidence of raised glucose levels in the medical record, taking oral hypoglycemic medications, or abnormal fasting glucose and oral glucose tolerance tests [9]. Tobacco smoking status was based on a self-reported history of cigarette smoking. Ultrasound studies
611 dead
35
in the three groups were 33 patients with IGT, 641 with DM and 355 non-DM controls, respectively. Written informed consent was obtained from each participant. The study was approved by the Ethics Committee of Daqing Oilfield General Hospital.
Ultrasound scanning and analysis protocol in this study followed Phase 5 operations manual of the Strong Heart Study (SHS) [10]. B-mode ultrasonography of the common carotid artery (CCA) and popliteal artery (PA) was performed by three trained sonographers using Philips iE33 ultrasound machine (Holland), equipped with L11-3 linear array transducer. During CCA–IMT scanning, the participants took a supine position with the neck slightly extended and the head rotated contra-laterally to the side. During PA–IMT measurement, the participants took a prone position with knees flexed slightly. After the carotid or popliteal arteries were
Int J Cardiovasc Imaging (2014) 30:759–768 Fig. 2 a Site to measure carotid IMT. Longitudinal view of distal common carotid artery (CCA) and carotid bifurcation (Bulb) of the left carotid artery. IMT was measured in the far wall of distal CCA, approximately 1 cm to the bifurcation, free from plaque. Site to measure CCA–IMT in this image is between the two blue bars. b B-mode guided M-mode ultrasound to measure CCA-IMT. IMT was defined as the distance between 2 parallel echogenic lines corresponding to the blood–intima and media– adventitia interface on the far wall. In this image, IMT was measured on the far wall of distal CCA; measurements from three cardiac cycles should be averaged. Time to measure IMT is at end diastole (approximately at the end of the QRS complex when the lumen has a minimum diameter). c Local magnifying (ZOOM function) of M-mode image to measure CCA–IMT. The IMT was enlarged in ZOOM function, which provides better recognition of the echo interface. In this image, IMT was also performed on three cardiac cycles at end diastole
761
a Name of the participant
Bulb
CCA
b Name of the participant
c Name of the participant
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located by transverse scans, the probe was rotated 90° to obtain and record a longitudinal image of the anterior and posterior wall (Fig. 2a). The ultrasound beam was carefully adjusted to be as perpendicular to the vessels as possible. Two-dimensionally (B-mode) guided M-mode images of the distal CCA or mid PA were obtained. Gain settings were optimized to limit ‘‘blossoming’’ of brighter interfaces. Images and cine-loops on the longitudinal view of distal CCA and mid PA were obtained with simultaneous electrocardiogram (ECG) and recorded on videotapes for offline analysis. All the images on videotapes were reviewed and measured by an experienced sonographer (W.H.M), who was totally blinded to clinical status of the study participants. IMT was defined as the distance from the leading edge of the first echogenic line (lumen–intima interface) to the leading edge of the second line (media-adventitia interface) on the far wall of CCA (posterior wall) or PA (anterior wall). The simultaneous ECG was used to time IMT measurements at end diastole (approximately at the end of the QRS complex when the lumen has a minimum diameter) (Fig. 2b). CCA–IMT measurement was taken in both arteries approximately 1 cm proximal to the carotid artery bifurcation in an area free of plaque. PA–IMT measurement was taken in both arteries at the site of the popliteal fossa in an area free of plaque. If plaque was present in the selecting site, the adjacent wall was selected; if there was still plaque, the corresponding near wall was measured. IMT was most commonly measured from B-mode guided M-mode images. If clear M-mode images were difficult to acquire, then B-mode images were used instead. Although spatial resolution is comparable with the two techniques, temporal resolution is far superior with M-mode imaging, thereby facilitating standardization of measurements at the time of end diastole. ZOOM function (local magnifying) was also used to better determine the lumen interface, and acquire measurements more accurately (Fig. 2c). All measurements were performed on 3 cardiac cycles and then averaged on each side. Statistical analysis Continuous variables were given as mean ± standard deviation (SD), and compared by unpaired t test or Satterthwaite t’ test according to distribution and variance of the data. Categorical variables were expressed as absolute numbers with the percentage of subjects in parentheses, and compared using Chi square analysis. Pearson’s or Spearman’s rank correlation analyses were used to assess bivariate correlation between each risk factor and IMT for continuous variables, while Pearson’s Chi square test was used to compare groups regarding categorical variables. Binary logistic regression analyses were performed to
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identify predictor variables for thickened IMT. Odds ratios (ORs) were given to assess the strength of association between risk factors and IMT. An IMT C 0.9 mm was considered thickened in performing these analyses [11, 12]. Two-sided P values below 0.05 were considered statistical significance. All statistical analyses were performed using SAS, version 9.0 (SAS Institute, Cary, NC). To observe intra-reader variation, 30 cases were randomly selected for a second measurement about 2 months apart from the initial reading. Spearman’s rank correlation analysis was used. The correlation coefficient of intrareader variation is 0.92.
Results Basic characteristics Among the 1,029 participants (CON: 355, IGT: 33 and DM: 641), 44 moved outside the Daqing city; they were interviewed by telephone, and examined by their local health provider. For the 985 participants living in the city, 79 were interviewed at home, of whom 58 took physical Table 1 Characteristics of the study population with and without diabetes mellitus CON (n = 214)
DM (n = 472)
P value
Age (years)
63.43 ± 7.59
64.97 ± 7.18
0.011*
Female, n (%)
115 (53.74)
269 (56.99)
0.464
SBP (mmHg)
137.05 ± 19.63
146.86 ± 19.20
0.000*
DBP (mmHg)
82.80 ± 10.09
79.04 ± 10.84
0.000*
HBP, n (%)
101 (47.20)
315(66.74)
0.000*
BMI (kg/m2)
25.58 ± 3.59
25.62 ± 3.44
0.915
Smoker, n (%)
81 (37.85)
154 (32.63)
0.157
TC (mmol/L)
5.014 ± 0.95
5.041 ± 1.16
0.790
TG (mmol/L)
1.880 ± 1.13
1.916 ± 1.33
0.767
LDL-C (mmol/L)
3.000 ± 0.794
3.007 ± 0.923
0.930 0.591
HDL-C(mmol/L)
1.273 ± 0.282
1.257 ± 0.329
HbA1c (%)
5.914 ± 0.652
8.142 ± 0.731
0.000*
CCA–IMT left (mm)
0.764 ± 0.168
0.792 ± 0.180
0.071
CCA–IMT right (mm)
0.770 ± 0.177
0.782 ± 0.173
0.433
PA–IMT left (mm)
0.769 ± 0.186
0.817 ± 0.214
0.013*
PA–IMT right (mm)
0.768 ± 0.189
0.818 ± 0.198
0.007*
All values are the mean ± SD or the number with the percentage of subjects in parentheses. P values represent the comparison between control and diabetes mellitus group by unpaired-t, Satterthwaite t’-test or Chi square test CON control group, DM diabetes mellitus group, SBP systolic blood pressure, DBP diastolic blood pressure, HBP high blood pressure, BMI body mass index, TC total cholesterol, TG total triglyceride, HDL- or LDL-C high- or low-density lipoprotein cholesterol, HbA1c glycosylated hemoglobin, IMT intima-media thickness, CCA common carotid artery, PA popliteal artery *P \ 0.05 (statistically significant)
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and laboratory examination, but didn’t take ultrasound examination. The remainder (906) were interviewed and examined at Da Qing Oilfield General Hospital. Number of participants in the IGT group (25) was too small to analyze, therefore were excluded for analysis. Images that could not provide high quality to ensure accurate measurement of IMT were also excluded (85 cases). Some video disks couldn’t work after several times’ reading and could not be evaluated (59 cases). Participants with partial clinical or laboratory information were also excluded (51 cases). The final study population included 472 DM patients and 214 non-DM participants. Demographic and clinical data of 686 participants are summarized in Table 1. The age range of the study population was 45–87 years, 384 of them (56 %) were women. The prevalence of hypertension and DM were high in this study population (60.6 and 68.8 %, respectively). Participants in DM group tended to be older, had greater value for SBP and HbA1c, but smaller value for DBP than those in CON group. Smoke status, BMI and blood lipids were not statistically different between groups. Participants in DM group had greater value for PA–IMT than the CON group on both sides, while CCA-IMT was not statistically different between the two groups. Pearson or Spearman correlation analysis Correlation or contingency coefficients of all risk factors with CCA- or PA–IMT are shown in Table 2. CCA-IMT had a positive correlation with age, gender, DM, SBP, BMI and HbA1c, negative correlation with HDL-C. Age showed the highest correlation coefficient (0.3025) among the risk factors, followed by SBP (0.2761). PA–IMT showed a positive correlation with age, gender and SBP. Age was also the strongest predictor for PA–IMT (r = 0.2986). Correlation or contingency coefficient of each risk factor was lower than 0.4, indicating the magnitude of these associations is rather weak.
763 Table 2 Correlation of each risk factor with CCA- and PA–IMT Risk factors
CCA–IMT r/C
PA–IMT P value
r/C
P value
Age (years)
0.3025
0.000*
0.2986
Gender
0.1178
0.023*
0.1933
0.001*
Smoke
0.0475
0.659
0.0998
0.217
DM
0.1294
0.012*
SBP (mmHg)
0.2761
0.000*
-0.013 0.1874
0.000*
0.823 0.001*
DBP (mmHg)
0.0421
0.420
0.0679
0.235
BMI (kg/m2)
0.1652
0.001*
0.0544
0.338
0.0657
0.248
HbA1c (%)
0.1902
0.000*
TC (mmol/L)
0.0336
0.518
TG (mmol/L)
0.0499
0.336
0.0086
0.880
LDL-C (mmol/L)
0.0657
0.206
-0.0295
0.604
0.003*
-0.1065
0.060
HDL-C (mmol/L)
-0.153
-0.035
0.541
r, Pearson’s or spearman’s correlation coefficient C, Pearson’s contingency coefficient Abbreviations as in Table 1 *P \ 0.05
3.818 and 5.881 for SBP between 120 and 139 mmHg and C 140 mmHg compared to SBP \ 120 mmHg, respectively]; followed by BMI (OR 2.612 for BMI C 28 kg/m2 compared to BMI \ 24 kg/m2). However, none of the risk factors predicted PA–IMT thickening any more after adjusting for age and gender (data not shown). In secondary analysis, associations of risk factors with CCA-IMT on the left and right side were evaluated separately (Table 4). Different power of effect was observed for elevation of SBP to predict CCA–IMT thickening on different side: the power of SBP between 120 and 139 mmHg had a 2.06-fold greater risk of developing CCA-IMT thickening on the left side than that on the right side (OR 6.249 vs 3.033); for SBP C 140 mmHg, the predictive power for developing CCA-IMT thickening was 1.17-fold higher on the left than on the right side (OR 6.419 vs 5.489).
Logistic regression analysis
Discussion
In univariate binary logistic regression, elevation of age, SBP, BMI, HbA1c and having DM were significant predictors of CCA-IMT thickening, so was reduction of HDLC. Risk factors that predicted significant thickening of PA– IMT were age, gender, tobacco smoking. Odds ratios (ORs) of each risk factor compared with the reference value are listed in Table 3. After adjusting for age and gender, except HDL-C, the other four risk factors (SBP, BMI, HbA1c and having diabetes mellitus) that predicted significant CCA-IMT thickening remained in the model (Table 4). The strongest predictor of CCA-IMT thickening was SBP [odds ratio (OR):
IMT is considered as a comprehensive picture of all alterations caused by multiple risk factors over time, which reflects atherosclerosis in the arterial walls. Traditional CVD risk factors have shown a positive association with CCA–IMT in epidemiological studies of patients and general population [13, 14]. In this study, we tested the association between traditional CVD risk factors and CCAand PA–IMT in a group of middle aged and elderly Chinese participants with high incidence of hypertension and DM. Risk factors predicting thickening of CCA-IMT in this study are age, DM, SBP, BMI, HDL-C and HbA1c.
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764 Table 3 Unadjusted risk factors associated with thickening of CCA- or PA–IMT
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Explanatory variables
CCA–IMT OR (95 % CI)
PA–IMT P value
OR (95 % CI)
P value
Age (years) \65
1
C65
1.986 (1.109–3.027)
1 0.0103*
2.277 (1.384–3.792)
0.0016*
Gender Women
1
Men
1.514 (0.646–2.448)
1 0.0874
2.379 (1.453–3.897)
0.0008*
Smoke (ciga/d) 0
1
C1
1.114 (0.682–1.789)
0.6725
1 1.510 (0.743–3.062)
0.2568
C10
1.353 (0.841–2.175)
0.2124
1.805 (1.011–3.223)
0.0483*
TC (mmol/L) \5.18
1
C5.18
1.366 (0.800–2.331)
0.2528
0.845 (0.474–1.506)
0.8232
C6.19
1.292 (0.650–2.568)
0.4645
0.921 (0.452–1.878)
0.5794
1
TG (mmol/L) \1.76
1
C1.76
0.944 (0.481–1.851)
0.8657
0.620 (0.225–1.328)
0.7943
C2.26
0.788 (0.451–1.377)
0.4033
1.127 (0.656–2.025)
0.6218
1
HDL-C (mmol/L) \1.55
1
C1.55
0.554 (0.209–0.994)
1 0.0323*
0.587 (0.289–1.191)
0.2188
LDL-C (mg/dL) \130
1
C130
1.059 (0.631–1.928)
0.8493
0.497 (0.237–1.042)
0.0637
C160
1.562 (0.773–3.218)
0.2272
1.219 (0.584–2.578)
0.5988
1 1.945 (1.218–3.027)
0.0136*
1 1.193 (0.736–1.933)
0.1761
1
DM No Yes SBP (mmHg) \120
1
C120
4.069 (1.174–14.096)
0.0269*
1.366 (0.504–3.712)
0.5594
C140
4.917 (1.459–16.565)
0.0102*
2.453 (0.931–6.481)
0.1368
1
DBP (mmHg) \80
1
C80
1.071 (0.614–1.868)
0.7327
0.877 (0.496–1.549)
0.1860
C90
1.412 (0.792–2.591)
0.2375
1.313 (0.706–2.445)
0.5576
1
2
BMI (kg/m ) \24
1
C24
1.192 (0.670–2.121)
0.5510
0.888 (0.501–1.575)
0.6847
C28
2.643 (1.431–4.881)
0.0019*
0.990 (0.498–1.965)
0.9765
0.4631 0.6763
1
HbA1c (%) OR odds ratio, CI confidence interval *P \ 0.05
\7 C7
1 1.975 (1.138–3.427)
0.0197*
1 1.242 (0.697–2.213)
C9
2.219 (1.184–4.159)
0.0333*
0.998 (0.479–2.079)
Because determinants of CCA–IMT were both age- and gender-dependent [15], we further controlled the two factors in the logistic regression analysis. After adjusting for
123
age and gender, CCA–IMT is still predicted by SBP, DM, BMI and HbA1c, with SBP having the greatest OR value, indicating that SBP is the strongest predictor of CCA–IMT
Int J Cardiovasc Imaging (2014) 30:759–768
765
Table 4 Statistically significant risk factors associated with thickening of CCA–IMT on each side adjusted for age and gender Explanatory variables
CCA–IMT OR (95 % CI)
Left CCA–IMT P value
OR (95 % CI)
0.0183*
2.137 (1.298–3.520)
Right CCA–IMT P value
OR (95 % CI)
0.0029*
1.705 (1.054–2.759)
P value
DM No
1
Yes
1.908 (1.189–2.939)
1
1 0.0297*
SBP (mmHg) \120
1
C120
3.818 (1.071–15.58)
0.0473*
6.249 (1.415–27.60)
0.0156*
3.033 (0.862–10.699)
0.0838
C140 BMI (kg/m2)
5.881 (1.514–22.62)
0.0103*
6.419 (1.483–27.78)
0.0129*
5.489 (1.620–18.604)
0.0063*
\24
1
C24
1.127 (0.623–2.036)
0.6929
1.218 (0.679–2.186)
0.5082
1.616 (0.897–2.912)
0.1104
C28
2.612 (1.395–4.890)
0.0027*
2.268 (1.207–4.263)
0.0110*
2.759 (1.456–5.229)
0.0019*
1
1
1
1
HbA1c (%) \7
1
C7
1.983 (1.136–3.461)
0.0162*
2.111 (1.199–3.716)
0.0097*
1.781 (1.026–3.091)
0.0403*
C9
2.004 (1.029–3.905)
0.0438*
2.515 (1.302–4.858)
0.0061*
1.813 (0.942–3.492)
0.0751
1
1
*P \ 0.05
thickening. This result is consistent with other investigations [16, 17]. Mechanisms by which hypertension predisposes to atherosclerosis may include endothelial dysfunction, hyperinsulinemia, hemodynamic stress and multiple metabolic alterations [16]. With the development of atherosclerosis, vascular wall becomes less elastic and more rigid, which in turn elevates SBP of the patient, a vicious cycle is thus formed. We notice that in addition to patients with systolic hypertension (SBP C 140 mmHg), participants with systolic pre-hypertension (SBP between 120 and 139 mmHg) can as well predict thickening of CCA–IMT, suggesting an aggressive control of SBP is necessary to postpone the process of CCA–IMT thickening. Another interesting phenomenon revealed from this study is that left sided CCA–IMT was more influenced by elevation of SBP compared to the opposite side, since the OR values are much higher on left side than those on the right side (OR 6.249 vs 3.033 and 6.419 vs 5.489 for SBP between 120 and 139 mmHg and SBP C 140 mmHg, respectively). The power of SBP in predicting CCA-IMT thickening on left side is 2.06- and 1.17-fold higher than that on the right side. One possible explanation may be that left CCA originates directly from aortic arch, which means left CCA is usually under higher wall shear stress than right CCA, which lead to a higher proneness of developing atherosclerosis. DM is a well known risk factor for atherosclerosis and is associated with aggressive vascular abnormalities. The alterations in vascular homeostasis due to endothelial and smooth muscle cell dysfunction are the main features of diabetic vasculopathy favoring a pro-inflammatory/
thrombotic state which ultimately leads to atherothrombosis [18]. HbA1c has been accepted as the best marker for diabetic microvascular complications [19]. It is associated closely with advanced glycation end products (AGEs), which are widespread in the diabetic vascular system and contribute to the development of atherosclerosis through the formation of bridging between molecules in the basement membrane of the extracellular matrix by joining the receptor for advanced AGEs [20]. In the present study, we found having DM or a greater value of HbA1c are predictive of CCA–IMT thickening, and a well controlled level of HbA1c (\7 %) is suggestive to lower the risk of CCA–IMT thickening. Obesity is a complex disorder leading to alterations in lipid metabolism, insulin resistance, deregulation of hormonal axes, oxidative stress, systemic inflammation and ectopic fat distribution, which ultimately leads to development of atherosclerosis [17]. In this study, we found obesity (BMI C 28 kg/m2) is associated with thickening of CCA–IMT, while overweight (28 kg/m2 [ BMI C 24 kg/ m2) is not, suggesting that weight control is also necessary to prevent obesity in order to maintain lower speed of progression of CCA–IMT. Popliteal artery is the second most-common site of aneurysm after the aorta and appears particularly susceptible to calcium accumulation; arterial tortuosity and reduced distensibility with age [21–23]. But to our knowledge, there are limited previous studies which observed PA–IMT. In this study, we followed the Phase 5 protocol of Strong Heart Study to measure PA–IMT as well as to measure CCA-IMT. In our study, PA–IMT thickening
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766
is predicted by age, gender, tobacco smoking, but is not associated with blood pressure, blood lipids, DM or obesity. After adjustment for age and gender, PA–IMT thickening is not predicted by any risk factors any more, suggesting that PA–IMT is not a marker for atherosclerosis. One possible explanation of the inconformity of atherosclerotic changes shown in CCA and PA in this study might lies in the histology difference of the arteries. The distending pressure of aortic systolic pressure in the large elastic-type arteries (aorta and carotid) is a key determinant of the degenerative changes that characterize accelerated aging and hypertension. In contrast, muscular peripheral arteries, such as brachial and popliteal arteries, are less influenced by these changes [24]. In our study, CCA–IMT seems a superior marker for atherosclerosis compared with PA–IMT, since it is positively associated with a number of traditional CVD risk factors, including blood pressure, DM and obesity. Whether increased CCA–IMT itself reflects local and generalized atherosclerosis and thus is predictive of future CVD is still a subject of debate. Anatomy-pathologic studies showed that CCA–IMT mainly represents hypertensive medial hypertrophy or thickening of smooth muscles in the media, whereas atherosclerosis is largely an intimal process [25]. Age-related thickening of intimal and medial layers of CCA also occurs in the absence of overt atherosclerosis [26]. In our study, we also found that the main predictors of CCAIMT are age and SBP, which is consistent with other research [17]. A recent large meta-analysis of 18 case– control and cohort studies evaluated the value of CCA–IMT and plaque in the screening for coronary heart disease, and showed no benefit of IMT as a screening tool, since the discrimination between affected and unaffected individuals was insufficient [27]. Similarly, another recent meta-analysis of 41 randomized trials showed that regression or slowed progression of CCA–IMT with cardiovascular drugs did not affect the risk of cardiovascular events [28]. And also, compared to carotid plaque, a distinctive phenotype of atherosclerosis, CCA–IMT didn’t show increase in chronic inflammatory diseases despite markedly premature subclinical (and clinical) atherosclerosis manifest by focal plaque [29, 30]. As a result, unlike blood pressure and LDL-C, which are already FDA-approved surrogate markers of cardiovascular disease, CCA–IMT is still awaiting its final approval and validation by the FDA. The current guideline for the use of CCA–IMT in assessment of cardiovascular risk in asymptomatic adults gives carotid IMT class IIa rank with a level B for evidence for asymptomatic adults at intermediate risk. An appropriate indication for the use of IMT is for individuals without CVD with intermediate risk, older, and individuals with metabolic syndrome. The testing of low-risk or very high-risk CVD individuals as well
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as serial IMT testing is considered inappropriate use of this method [31, 32].
Limitations DM and hypertension were highly prevalent in our study population, which is not consistent with the general population. This is because the participants in this study came from a 23 year follow-up study, but not from a community random sampling one. DM and hypertension are both CVD risk factors and are associated with atherosclerosis; the high prevalence of these two factors in this study didn’t seem to influence the results. Computer-aided software (Qlab, Philips) which can analyze IMT automatically is also available in our echo lab, but we measured IMT manually for the following reasons: (a) one of the purposes of this study is to discuss the clinical value of IMT in evaluating subclinical atherosclerosis, thus a simple, rapid and reliable manner of detection is highly recommended in daily clinical practice. The time-consuming, off-line analyzing by computer-aided software is obviously contradicted to this need; (b) the computerized system depends highly on image quality; the automated tracked borders sometimes are not precise if image quality is not good enough, thus need to be manually traced and read; (c) the mixture of automated and manually read results may produce systemic error in data analysis, which is a huge defect of this method. In our study, echo images were read by a single and well trained sonographer, which avoided inter-observer variation. Intra-observer variation was also acceptable (correlation coefficient 0.92).
Conclusions The current results provide evidence that CCA–IMT is a superior marker for atherosclerosis compared with PA– IMT. Aggressive control of SBP, HbA1c and proper control of weight may be suggested to postpone thickening of CCA–IMT. Acknowledgments This study was partially funded by CDC/WHO Cooperative Agreement number U58/CCU424123-01-02. The authors gratefully thank Doctor Hong Jin, Xin Li and Li Pang from Department of Echocardiography of Da Qing Oilfield General Hospital for their help in image collection. Conflict of interest
None.
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