A Longitudinal Study of Carotid Plaque and Risk of Ischemic Cardiovascular Disease in the Chinese Population

Transcription

1 A Longitudinal Study of Carotid Plaque and Risk of Ischemic Cardiovascular Disease in the Chinese Population Wuxiang Xie, MD, Yangfeng Wu, MD, PhD, Wei Wang, MD, Dong Zhao, MD, Lirong Liang, PhD, MD, Miao Wang, MD, Ying Yang, MD, Jiayi Sun, MD, Ping Shi, MD, and Yong Huo, MD, Beijing, China Background: The aim of this study was to investigate the role of carotid plaque in predicting ischemic cardiovascular risk, which has been intensively reported in Western populations but not yet in the Chinese population, in which the cardiovascular disease profile is significantly different. Methods: Cox proportional-hazards regression was used to analyze associations between the presence of carotid plaque and the number of segments of carotid arteries with plaque (total plaque score) and the risk for subsequent ischemic cardiovascular disease (ICVD) events, including ischemic stroke and coronary heart disease, in 3,258 Chinese men and women aged 38 to 79 years at baseline. During 5 years of follow-up, 137 ICVD events were identified. Results: The person-year incidence was 10.6 per 1,000 for ICVD, 6.7 per 1,000 for ischemic stroke, and 4.4 per 1,000 for coronary heart disease. After adjustment for conventional cardiovascular risk factors, the risk for ICVD was significantly associated with the presence of carotid plaque (hazard ratio, 1.49; 95% confidence interval [CI], ) and total plaque score (hazard ratio per 1-score increase, 1.25; 95% CI, ). Further analysis showed that the multivariate-adjusted hazard ratio of ICVD associated with plaque in common carotid arteries was 1.90 (95% CI, ) and that with plaque in bifurcations was 1.26 (95% CI, ). The results of separate analyses for ischemic stroke and coronary heart disease paralleled those for ICVD. The addition of total plaque score to the risk prediction model resulted in a significant improvement in risk estimation when measured by net reclassification improvement index. Conclusions: Carotid plaque adds significant additional information for predicting the risk for ICVD events in the Chinese population. (J Am Soc Echocardiogr 2011;24: ) Keywords: Carotid plaque, Ischemic cardiovascular disease, Chinese It has been demonstrated that several noninvasive measures of carotid atherosclerosis, such as intima-media thickness, total area of plaque, and plaque calcification, can predict cardiovascular From the Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, Beijing, China (W.X., Y.W.); the Department of Epidemiology, Beijing Institute of Heart, Lung and Blood Vessel Disease, Beijing Anzhen Hospital, Capital Medical University, Beijing, China (W.W., D.Z., M.W., J.S.); Beijing Chaoyang Hospital, Capital Medical University, Beijing, China (L.L.); the Department of Cardiology, Peking University First Hospital, Beijing, China (Y.Y., Y.H.); and Shijingshan Chronic Disease Prevention and Control Institute, Shijingshan Center for Disease Prevention and Control, Beijing, China (P.S.). This study was supported by the People s Republic of China Ministry of Science and Technology and the Ministry of Health through the 10th and 11th National Five-Year Plan Projects (contracts 2001BA703B01 and 2006BAI01A02). Reprint requests: Yangfeng Wu, MD, PhD, Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, No. 38, Xueyuan Road, Haidian District, Beijing, , China ( wuyf@ bjmu.edu.cn) /$36.00 Copyright 2011 by the American Society of Echocardiography. doi: /j.echo disease. 1-3 However, these measures are difficult to perform, because they are complicated and time-consuming, requiring specialized training and a high-resolution ultrasound scanner. Therefore, a simple, safe, inexpensive, and effective ultrasound marker is urgently needed, especially for community prevention. The presence of carotid plaque has been reported to increase the risk for cardiovascular disease in Western populations in longitudinal studies. 4-8 Nevertheless, the predictive ability of carotid plaque in assessing the risk for cardiovascular disease remains unclear in the Chinese population, which accounts for one fifth of the world s population. It has been reported that the pattern of cardiovascular disease is significantly different in the Chinese population, in which stroke rather than coronary heart disease (CHD) is the predominant type of cardiovascular disease. 9 In addition, most previous studies have focused on the number, area, composition, and surface morphology of carotid plaques; few have addressed the differences of carotid plaques in different locations in predicting the risk for cardiovascular disease. Hence, we conducted a prospective cohort study in a middle-aged and elderly Chinese population to investigate the relationship between baseline carotid plaque and subsequent ischemic stroke and CHD and whether the association is affected by the location of plaque. 729

2 730 Xie et al Journal of the American Society of Echocardiography July 2011 Abbreviations CCA = Common carotid artery CHD = Coronary heart disease CI = Confidence interval HR = Hazard ratio ICVD = Ischemic cardiovascular disease MONICA = Multinational Monitoring of Trends and Determinants in Cardiovascular Disease NRI = Net reclassification improvement TPS = Total plaque score METHODS Study Population The study population was composed of two cohorts in Beijing, one rural (Shijingshan district cohort) and one urban (Peking University community cohort). The former was taken from the study population of the third survey of the People s Republic of China/United States of America Collaborative Study of Cardiovascular & Cardiopulmonary Epidemiology in 1993 and ,11 This cohort consisted of a cluster random sample of 2,313 participants from all 11 rural communities in Beijing s Shijingshan district. Of the 2,313 participants, 39 died, 268 had histories of stroke or/and CHD, and the other 2,006 were all invited to take part in this study in 2002 or in In total, 1,734 participants who were free of cardiovascular diseases and gave consent underwent carotid ultrasound measurements. The second cohort, comprising 1,985 participants living an urban community in Beijing, was part of the Chinese Multi-Provincial Cohort Study cohort, which was set up in 1992 to evaluate cardiovascular risk factors. 12 A total of 1,541 surviving participants free of stroke and CHD were enrolled for the baseline carotid artery ultrasound examination in Of these 3,275 men and women in total, 17 individuals were excluded because of missing baseline laboratory results or blood pressure data. Four hundred seventy-four participants who were lost to follow-up were considered to be censored, and half of the period from baseline to the next follow-up assessment was used in the analysis as the time variable for these participants. In this study, we used data from the 3,258 eligible participants (1,342 men and 1,916 women) aged 38 to 79 years. The Fuwai Hospital Ethics Committee and Anzhen Hospital Ethics Committee approved the baseline examination, and the Peking University Health Science Center Ethics Committee approved the follow-up examination. Written informed consent was obtained from all participants for all examinations. Conventional Risk Factor Measurements All the conventional cardiovascular risk factors measurements were included in the baseline assessment following standard protocols. 11,13 Briefly, weight and height were measured with participants wearing light indoor clothing and no shoes; two consecutive blood pressure readings were taken in the right arm with a mercury sphygmomanometer, and the means were used for analysis; and a 12-hour fasting blood sample was collected and blood lipids, serum total cholesterol, and high-density lipoprotein cholesterol were measured according to the standardized protocol of the National Heart, Lung, and Blood Institute and the Centers for Disease Control and Prevention. Twelve-hour fasting glucose was measured using an enzymatic method (SmithKline Instruments, Inc., Sunnyvale, CA). Current smoking was defined as having smoked at least one cigarette per day for at least the past 1 year. Hypertension was defined as mean systolic blood pressure $ 140 mm Hg and/or mean diastolic blood pressure $ 90 mm Hg or the current use of antihypertensive drugs for 2 weeks. Diabetes mellitus was defined as a fasting blood glucose level $ 7.0 mmol/l or current use of insulin or oral hypoglycemic medication. Body mass index was calculated in units of kilograms per square meter. Carotid Ultrasound Protocol The measurements and definitions of carotid plaque were the same at baseline for the two cohorts. Carotid plaque was measured for its presence in each segment of both the right and left common carotid arteries (CCAs) and bifurcations, in magnified longitudinal views. A carotid plaque was defined as a thickness of $1.5 mm measured from the media-adventitia interface to the intima-lumen interface or a focal raised lesion of $0.5 mm with or without flow disturbance, according to the consensus statement from the American Society of Echocardiography 14 and the Mannheim consensus 15 (Figure 1). The total plaque score (TPS), defined as the total number of segments with plaque, ranged from 0 to 4. Reproducibility studies of ultrasound assessment of carotid plaque have been published elsewhere. 16,17 For the rural cohort, we randomly selected 20 participants from the cohort and invited them to attend the reproducibility study. For the presence or absence of plaque at the same segment (sample size, 80 segments), interobserver agreement was associated with a k value of 0.70 and intraobserver agreement with a k value of For the urban cohort, the reproducibility study was performed in a random sample of 30 subjects (sample size, 120 segments) from the cohort, and the corresponding k values were 0.67 and Event Follow-Up Procedures and Diagnostic Criteria After the baseline ultrasound examination in 2002, the rural cohort was resurveyed in 2005 and then in 2007; the urban cohort was resurveyed in 2004 and then in Follow-up of cardiovascular events was conducted in 2005 or 2004 and 2007, respectively. Follow-up data for CHD and stroke events were first collected by investigators using a standardized form at each follow-up survey via face-to-face interviews (82.8%). If participants were absent, the investigators completed the forms via telephone (17.2%). Suspected events were further investigated with a doctor s revisit to the patient or family, or the hospital if applicable, to collect clinical data needed for diagnosis (including symptoms, personal history, electrocardiograms, enzyme tests, brain computed tomographic scans, or autopsy findings). The vital information for assessing events was provided by patients or family members (86%), primary care physicians (10%), and relatives or friends (4%). If a participant died or reported an incidence of cardiovascular events during the follow-up, the participant s death certificate, hospital records including medical history, findings from physical and laboratory examinations, discharge diagnosis, and autopsy findings if applicable were reviewed and abstracted by a trained staff member using a standard form. The final diagnosis was made by the independent adjudication committees by reviewing medical history information and death certificates with the prespecified criteria from the World Health Organization Multinational Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA) project 18 and the Collaborative Study of Cardiovascular & Cardiopulmonary Epidemiology. 11 CHD was defined as the occurrence of first nonfatal or fatal myocardial infarction and hospitalization for unstable angina pectoris during follow-up. Criteria used to define myocardial infarction were adapted from diagnostic criteria developed by the Collaborative

3 Journal of the American Society of Echocardiography Volume 24 Number 7 Xie et al 731 Figure 1 Measurement of carotid plaque using B-mode ultrasound. (Top) Focal carotid plaque. (Bottom) Nonfocal intimamedia thickening. Study of Cardiovascular & Cardiopulmonary Epidemiology and have been described in detail elsewhere. 11 Hospitalized angina was defined as new-onset ischemic chest pain or worsening of angina requiring hospitalization, and stable angina pectoris was not included as CHD in the present study. During the follow-up period, the incidence of first stroke was defined using the MONICA criteria 18 : rapidly developing signs of focal (or global) disturbance of cerebral function lasting >24 hours (unless interrupted by surgery or death), with no apparent nonvascular cause. The definition of ischemic stroke included cerebral thrombosis and cerebral embolism. Intracerebral hemorrhage, subarachnoid hemorrhage, transient ischemic attacks, and silent brain infarctions (cases without clinical symptoms or signs) were not included; neither were events associated with trauma, blood disease, or malignancy. All of the patients with stroke underwent morphologic evaluation using brain computed tomography. The incidence of ischemic cardiovascular disease (ICVD) was defined as the composite of CHD or ischemic stroke. If an individual had more than one event, the first event was used, and if an individual had both CHD and ischemic stroke, only one was counted as an ICVD event. Statistical Analysis Statistical analysis was based on the pooled study population of the two cohorts, and a total of 3,258 participants (1,342 men and 1,916 women) were eligible for analysis. Differences in means and percentages of baseline characteristics between participants who did and did not have new ICVD events during the follow-up period were tested using t tests and c 2 tests. After testing for the assumption of proportionality, we used the Cox proportional hazards models to estimate the hazard ratios (HRs) of new events in relation to the presence of carotid plaque. The TPS was analyzed both as a continuous variable (per 1-score increase) and as a categorical variable in different models. In addition, we used the same strategy to examine the locations of plaque (only CCAs, only bifurcations, and both) in relation to the risk for ICVD events. All analyses were done with no adjustment, adjustment for age and sex, and in addition for cohort (rural vs urban), diabetes mellitus (yes or no), hypertension (yes or no), body mass index, current smoking status (yes or no), and total and high-density lipoprotein cholesterol levels. To explore whether TPS could provide additional value for predicting risk after accounting for conventional risk factors, we fit two models using backward stepwise regression (backward: likelihood ratio; removal: 0.10): one without and the other with TPS. We compared the goodness of fit between the two models using the log-likelihood function, suggested by Cook. 19 We used the area under the receiver operating characteristic curve (c-statistic) to compare the discriminative abilities of the two models. Equality of the c-statistic was tested using the algorithm suggested by Hanley and McNeil. 20 In addition, considering the incapability of the c-statistic to detect the difference induced by the addition of a novel risk factor to a conventional model, we also compared the two models by using the net reclassification improvement (NRI) index proposed by Pencina et al. 21 to evaluate the added predictive value of TPS. This method requires that there exist a priori meaningful risk categories. The National Cholesterol Education Program Adult Treatment Panel III classified persons into low-risk, intermediate-risk, and high-risk categories of CHD, designated as <6%, 6% to 20%, and >20% 10-year CHD risk, respectively. 22 Accordingly, in this study, reclassification tables were constructed separately for participants who did and did not develop events, using <3%, 3% to 10% and >10% 5-year ICVD risk categories. The 5-year risk for ICVD was calculated using the formula suggested by the Framingham investigators. 23 Statistical analyses were performed using SPSS version 13.0 (SPSS, Inc., Chicago, IL). All analyses were two sided with P values <.05 considered to indicate statistical significance. RESULTS Baseline Characteristics During a mean follow-up period of 4 years (12,901 person-years in total), there were 87 new cases of ischemic stroke (42 in men and 45 in women) and 57 of CHD (23 in men and 34 in women), and a total of 137 participants had new ICVD events (63 in men and 74 in women). The incidence rate was 6.7 per 1,000 person-years for ischemic stroke (8.0 in men and 5.9 in women), 4.4 per 1,000 person-years for CHD (4.4 in men and 4.4 in women), and 10.6 per 1,000 person-years for ICVD events (12.0 in men and 9.7 in women). Table 1 describes the baseline characteristics of the study participants. The means of age, systolic blood pressure, highdensity lipoprotein cholesterol, fasting blood glucose, and TPS and the prevalence of current smoking, hypertension, and plaque in the CCA, bifurcation, and any carotid artery were all significantly higher in patients with new ICVD events than in those without.

4 732 Xie et al Journal of the American Society of Echocardiography July 2011 Table 1 Baseline characteristics of study participants with and without new ICVD events during follow-up Variable ICVD (n = 137) No ICVD (n = 3,121) P* Age (y) <.001 Men 46.0% 41.0%.244 Rural cohort 64.2% 52.3%.006 Current smoking 32.1% 23.8%.026 Body mass index (kg/m 2 ) Systolic blood pressure (mm Hg) <.001 Diastolic blood pressure (mm Hg) Serum total cholesterol (mmol/l) High-density lipoprotein cholesterol (mmol/l) Fasting blood glucose (mmol/l) Hypertension 65.0% 50.2% <.001 Diabetes 13.9% 9.6%.101 Plaque in common carotid artery 14.6% 5.4% <.001 Plaque in bifurcation 36.5% 23.3% <.001 Plaque in any carotid artery 41.6% 25.2% <.001 TPS <.001 *P values are given for the difference between those with and without ICVD using t tests or c 2 tests. Figure 2 Prevalence of carotid plaque (percentage) and mean TPS by sex and age group. Ninety-five percent CIs of prevalence and means are presented. (Left) The prevalence of carotid plaque and the 95% CIs are shown; P values for trends were calculated using linear-by-linear association c 2 tests, and P values for comparison between men and women were calculated using c 2 tests. (Right) The mean TPS and the 95% CIs are shown; P values for trends were calculated using linear regression analysis, and P values for comparison between men and women were calculated using t tests. Age and Sex Distribution of Carotid Plaque Figure 2 shows that the prevalence of carotid plaque increased with increasing age group (P for trend <.001) in both men and women. Before age 60 years, women s prevalence was significantly lower than men s (P <.001; Figure 2). However, after age 60, the difference in prevalence between women and men was no longer significant (P >.05; Figure 2). The results for mean TPS also showed the same trends as for plaque prevalence (Figure 2). Association of Baseline Carotid Plaque and Risk for ICVD The presence of carotid plaque, without considering its location, was significantly associated with risk for new ICVD events (multivariable adjusted HR, 1.49; 95% confidence interval [CI], ; Table 2). Figure 3 shows that the incidence of ischemic stroke, CHD, and ICVD increased with increasing TPS in both the rural and urban cohorts. Further analysis showed that the HR for ICVD associated with TPS was 2.20 (95% CI, ) for the highest category compared with the lowest category after multivariate adjustment (Table 2). Cox proportional-hazards models using TPS as a continuous variable also showed significant associations with new ICVD events. The ageadjusted and sex-adjusted HR associated with a change of 1 score in TPS was 1.45 (95% CI, ) and remained significant after further adjustment for other risk factors (multivariate-adjusted HR, 1.25; 95% confidence interval, ), although it was slightly reduced in magnitude. Types of ICVD and Their Associations With Carotid Plaque The same analyses as above were conducted for ischemic stroke and CHD separately (Table 2). The results for both ischemic stroke and

5 Journal of the American Society of Echocardiography Volume 24 Number 7 Xie et al 733 Table 2 HRs and 95% CIs of ICVD events, ischemic stroke, and CHD in relation to carotid plaque indexes HR (95% CI) Carotid plaque index Events/sample size Unadjusted Age and sex adjusted Multivariate adjusted* ICVD events Presence of plaque in any carotid arteries No 80/2, Yes 57/ ( ) 1.86 ( ) 1.49 ( ) P < TPS 0 80/2, / ( ) 1.56 ( ) 1.28 ( ) 2 21/ ( ) 1.98 ( ) 1.46 ( ) 3 and 4 9/ ( ) 3.57 ( ) 2.20 ( ) Per 1 score increase 137/3, ( ) 1.45 ( ) 1.25 ( ) P for trend <.001 < Ischemic stroke Presence of plaque in any carotid arteries No 53/2, Yes 34/ ( ) 1.68 ( ) 1.29 ( ) P TPS 0 53/2, / ( ) 1.43 ( ) 1.08 ( ) 2 11/ ( ) 1.52 ( ) 1.20 ( ) 3 and 4 7/ ( ) 4.18 ( ) 2.45 ( ) Per 1 score increase 87/3, ( ) 1.45 ( ) 1.22 ( ) P for trend < CHD Presence of plaque in any carotid arteries No 30/2, Yes 27/ ( ) 2.33 ( ) 1.86 ( ) P < TPS 0 30/2, / ( ) 1.92 ( ) 1.61 ( ) 2 11/ ( ) 2.90 ( ) 2.29 ( ) 3 and 4 3/ ( ) 3.33 ( ) 2.40 ( ) Per 1 score increase 57/3, ( ) 1.54 ( ) 1.35 ( ) P for trend < *Adjusted for age, sex, cohort, diabetes mellitus, hypertension, body mass index, current smoking status, and total and high-density lipoprotein cholesterol levels. CHD generally showed the same trends as for ICVD, except that some associations were no longer statistically significant. were 1.21 (95% CI, ), 2.21 (95% CI, ), and 2.33 (95% CI, ) for the three groups, respectively (Table 3). Location of Carotid Plaque and Its Association With Risk for ICVD Table 3 gives the HRs of ICVD associated with the presence of plaque in different locations, which were 3.03 (95% CI, ) for plaque in the CCA and 2.01 (95% CI, ) for plaque in the bifurcation. Adjustment for age and sex and further for other conventional cardiovascular risk factors reduced the size of HRs, and only that for plaque presence in CCA remained statistically significant. We further divided participants into four categories according to plaque locations: no plaque, only in the bifurcation, only in the CCA, and in both the bifurcation and the CCA. With reference to participants with no plaque, the multivariate-adjusted HRs of ICVD Added Value of TPS in Predicting Risk for ICVD First, we fit two models, one without and the other with TPS (Table 4). The results clearly indicated that TPS was independently associated with risk for ICVD events and thus showed its additional value in prediction of ICVD risk. To test this additional value, we first compared the c-statistics (0.742 [95% CI, ] for the model without TPS vs [95% CI, ] for the model with TPS) between the receiver operating characteristic curves for the two models, but there was no statistically significant difference (P =.424). We then used the log-likelihood function to compare the difference in goodness of fit between the two models, and the test resulted in a c 2 value of (P <.05). We further used the NRI method to evaluate the added value of TPS (Table 5). The NRI index was estimated at 0.105

6 734 Xie et al Journal of the American Society of Echocardiography July 2011 Figure 3 Unadjusted incidence of ischemic stroke (IS), CHD, and ICVD in relation to TPS. Table 3 Location of carotid plaque and its association with the risk for subsequent ICVD events HR (95% CI) Carotid plaque index ICVD events/sample size Unadjusted Age and sex adjusted Multivariate adjusted* Presence of plaque in CCA No 117/3, Yes 20/ ( ) 2.37 ( ) 1.90 ( ) P < Presence of plaque in bifurcation No 87/2, Yes 50/ ( ) 1.69 ( ) 1.26 ( ) P < Presence of plaque in CCA and bifurcation No plaque 80/2, Only in bifurcation 37/ ( ) 1.59 ( ) 1.21 ( ) Only in CCA 7/ ( ) 2.56 ( ) 2.21 ( ) Both 13/ ( ) 2.90 ( ) 2.33 ( ) P <.001 < *Adjusted for age, sex, cohort, diabetes mellitus, hypertension, body mass index, current smoking status, and total and high-density lipoprotein cholesterol levels. (95% CI, ; Z = 3.18; P =.001), indicating an improvement of 10.5% in the prediction of ICVD risk. DISCUSSION Primary Findings The present study demonstrated that the presence of carotid plaque was significantly associated with the subsequent incidence of ICVD events, and a dose-response relationship existed between risk for ICVD and TPS. The same findings was reported previously in only two large-scale and population-based prospective studies, one in the Netherlands and the other in the United States. 5,7,8 In the Rotterdam Study, the age-adjusted and sex-adjusted HR of myocardial infarction was 2.45 (95% CI, ) for the participants with carotid plaque scores $ 3 compared with those without plaque. 7 The risk for stroke gradually increased with increasing number of carotid plaques after multivariate adjustment (HR per plaque increase, 1.13; 95% CI, ). 5 In the Northern Manhattan Study, the unadjusted HRs of ischemic stroke, myocardial infarction, and vascular death were 1.79 (95% CI, ), 2.87 (95% CI, ), and 3.28 (95% CI, ), respectively, for participants with carotid plaque compared with those without plaque. 8 Furthermore, we found that plaque in the CCA may carry a higher risk than plaque in the bifurcation. The first explanation to consider is that the means of age and total cholesterol and the prevalence of hypertension were all significantly higher in participants with plaque only in the CCA than in those with plaque only in the bifurcation (data not shown). We also found that most other traditional risk factors were also at higher levels in those with plaque only in the CCA, though the differences were not significant, because of low statistical power. These findings indicate that plaque in the CCA could better reflect the risk levels of traditional risk factors and hence could better predict the risk for future ICVD. The second explanation for this observation is that the special anatomic structure of bifurcation makes it much easier to be affected by plaque than other places of carotid artery. The formation of plaque in the bifurcation may be due largely to local hemodynamic factors rather than systemic atherosclerosis and thus reflect more local changes In contrast, the presence of plaque in the CCA may largely represent the process and degree of systemic atherosclerosis and thus reflect more systemic changes. In our study, plaques were more often present in the bifurcation than in the CCA (23.8% vs 5.8%), similar to the findings of previous studies. 29,30 Hence, we hypothesized that the presence of plaque in the CCA is more directly reflect systemic atherosclerosis than plaque in the

7 Journal of the American Society of Echocardiography Volume 24 Number 7 Xie et al 735 Table 4 Regression coefficients and HRs for associated baseline factors from Cox regression analyses Total (n = 3,258) Men (n = 1,342) Women (n = 1,916) Baseline variable b HR (95% CI) P b HR (95% CI) P b HR (95% CI) P Model without TPS Age ( ) < ( ) ( ).007 Cohort (rural/urban) ( ) ( ) ( ).031 Systolic blood pressure ( ) < ( ) ( ).007 Current smoking ( ) ( ) ( ).124 High-density lipoprotein cholesterol ( ) ( ) ( ).893 Fasting blood glucose ( ) ( ) ( ).041 Model with TPS Age ( ) ( ) ( ).033 Cohort (rural/urban) ( ) ( ) ( ).093 Systolic blood pressure ( ) < ( ) ( ).011 Current smoking ( ) ( ) ( ).179 High-density lipoprotein cholesterol ( ) ( ) ( ).710 Fasting blood glucose ( ) ( ) ( ).033 TPS ( ) ( ) ( ).027 Table 5 Contribution of TPS to reclassification of 5-year ICVD risk among participants who experienced ICVD events and those who did not experience ICVD events in follow-up Model with TPS Model without TPS Class of 5-year risk <3% 3% 10% >10% Total Participants who experienced ICVD events <3% 69 9 [ 0 [ 78 3% 10% 2 Y 42 8 [ 52 >10% 0 Y 1 Y 6 7 Total Participants who did not experience ICVD events <3% 2, [ 0 [ 2,408 3% 10% 96 Y [ 677 >10% 0 Y 16 Y Total 2, ,121 NRI = [( )/137] + [( )/3,121] = bifurcation and thus is more associated with cardiovascular risk. This hypothesis needs to be confirmed in larger study samples and in other populations. The Pattern of ICVD in Chinese Subjects The pattern of ICVD in Chinese subjects is very different from that in Caucasian populations. Our results show that ischemic stroke was much more prevalent than CHD in both men and women. The Collaborative Study of Cardiovascular & Cardiopulmonary Epidemiology also found this pattern: among Chinese men, the observed 10-year incidence rates of ischemic stroke and CHD were 32.3& and 13.5&, respectively; among women, the same rates were 21.5& and 7.8&. 13 The Sino-MONICA project, aiming to monitor incidence rates of cardiovascular disease and their trends in different provinces of China, indicated that the incidence of stroke was significantly greater than the incidence of CHD in both men and women in all provinces. 9 In Caucasian populations, CHD is a more common manifestation of ICVD, especially in men. The Atherosclerosis Risk in Communities study reported that the incidence rates of ischemic stroke and CHD in men were 17.2& ( ) 31 and 34.9& ( ), 32 respectively. In women, the same rates were 11.4& ( ) 31 and 13.1& ( ). 32 Different patterns may indicate different risk profiles and pathogenesis. Whether atherosclerosis really plays an important role in ICVD events is still largely unknown in the Chinese general population. This large-scale cohort study will fill the gaps in some degree. Prevalence of Carotid Plaque Our results show that the prevalence of plaque increased with increasing age group in both men and women. Before the age of 60 years, women s prevalence was significantly lower than men s. However, after age 60, the difference in prevalence between women and men was not significant. The prevalence of plaque increased rapidly after age 60 in women, which may indicate that a natural menopause has an unfavorable effect on atherosclerosis. In this study, the overall prevalence of carotid plaque was 25.8% in 3,258 participants (mean age, 59 years). Compared with the previous

8 736 Xie et al Journal of the American Society of Echocardiography July 2011 population-based studies, we found that the overall prevalence of carotid plaque was considerably lower in the Chinese population. The Paroi Arterielle et Risque Cardiovasculaire in Asia Africa/Middle East and Latin America study, which investigated the atherosclerosis in Asia (China, Hong Kong, Korea, and Singapore), reported that the prevalence of carotid plaque in Asia was 23% (1,031 persons; mean age, 50 years), similar to our results. 33 In European countries, the British Regional Heart Study found that the prevalence of carotid plaque in 425 men and 375 women (mean age, 66 years) was 57%, 6 and the Rotterdam Study showed that the same prevalence was 58% in 6,389 participants (mean age, 69 years). 7 Similarly, in the United States, the Northern Manhattan Study found that carotid plaque was present in 58% of participants after surveying 2,189 persons (mean age, 68 years). 8 We realize that the population samples are quite different, as the mean ages in the two studies conducted in Asia are much lower than in the three studies in Europe and the United States. It is well known that age is one of the most important risk factor of atherosclerosis, and we suggest that this factor could explain most of the difference observed in the prevalence of carotid plaque (in this study, the prevalence was 45% in participants aged >70 years). Moreover, we note that the definitions of carotid plaque were different among the studies mentioned above, so comparison of these study results should consider this limitation. Third, we did not measure plaque in the internal carotid artery and hence were not able to compare plaque in the internal carotid artery and that in the CCA and the bifurcation in their ability to predict the ICVD risk. Last, we did not measured the number of plaques and the intimamedia thickness for all study participants at baseline, because of resource constrains, which limited our ability to provide more sophisticated data on carotid atherosclerosis. CONCLUSIONS In our study, carotid plaque provided important additional information about future risk for ICVD events in the Chinese general population and represents a simple and inexpensive screening tool to estimate cardiovascular risk for preventive strategies. Plaque in the CCA may bear more clinical significance than that in the bifurcation in predicting subsequent ICVD risk. ACKNOWLEDGMENT We deeply appreciate the participation of our colleagues and especially the contribution of the research participants in these studies. The Added Value of TPS in Predicting the Risk for ICVD We used three methods to detect the additional value of TPS in the prediction of ICVD risk: the test for the difference of c-statistics, the c 2 test for improvement in goodness of fit, and the NRI method developed by Pencina et al. 21 In our study, the additional value of TPS could not be demonstrated by the c-statistic test. However, both the test for the improvement in goodness of fit and the NRI showed a statistically significant difference between the models with and without TPS. We believe that this is probably because the additional contribution is small, and the NRI method and the test for goodness of fit are more sensitive than c-statistics to detect small additional values. In fact, the NRI index was only 0.105, implying that TPS improved the risk prediction of ICVD by only 10.5%, which is additional to conventional risk factors. Other Findings Our study also showed that carotid plaque was a stronger predictor of CHD than of ischemic stroke, which is supported by the results of the Northern Manhattan Study. 8 It is very interesting that some other cohort studies and meta-analyses found the opposite for carotid intimamedia thickness The differences between the heart and brain may influence the presence and extent of atherosclerotic lesions that give rise to symptoms, but the detailed reasons remain unknown. Limitations Our study had some limitations that must be addressed. First, 474 participants (13.4%) were lost to follow-up, and the results showed that these subjects had a higher risk for cardiovascular disease than those who were not lost to follow-up (data not shown). Whether or not these 474 participants were included in the analyses as censored data, the results were similar. This is a limitation that affects the ability to generalize the findings of our study to broader populations. Second, separate models were not developed and tested for men and women, because of the low statistical power. REFERENCES 1. Spence JD, Eliasziw M, DiCicco M, Hackam DG, Galil R, Lohmann T. Carotid plaque area: a tool for targeting and evaluating vascular preventive therapy. Stroke 2002;33: Hunt KJ, Evans GW, Folsom AR, Sharrett AR, Chambless LE, Tegeler CH, et al. Acoustic shadowing on B-mode ultrasound of the carotid artery predicts ischemic stroke: the Atherosclerosis Risk in Communities (ARIC) study. Stroke 2001;32: O Leary DH, Polak JF, Kronmal RA, Manolio TA, Burke GL, Wolfson SK Jr. Cardiovascular Health Study Collaborative Research Group. Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. N Engl J Med 1999; 340: Stork S, van den Beld AW, von Schacky C, Angermann CE, Lamberts SW, Grobbee DE, et al. Carotid artery plaque burden, stiffness, and mortality risk in elderly men: a prospective, population-based cohort study. Circulation 2004;110: Hollander M, Bots ML, Del Sol AI, Koudstaal PJ, Witteman JC, Grobbee DE, et al. Carotid plaques increase the risk of stroke and subtypes of cerebral infarction in asymptomatic elderly: the Rotterdam study. Circulation 2002;105: Ebrahim S, Papacosta O, Whincup P, Wannamethee G, Walker M, Nicolaides AN, et al. Carotid plaque, intima media thickness, cardiovascular risk factors, and prevalent cardiovascular disease in men and women: the British Regional Heart Study. Stroke 1999;30: van der Meer IM, Bots ML, Hofman A, del Sol AI, van der Kuip DA, Witteman JC. Predictive value of noninvasive measures of atherosclerosis for incident myocardial infarction: the Rotterdam Study. Circulation 2004; 109: Rundek T, Arif H, Boden-Albala B, Elkind MS, Paik MC, Sacco RL. Carotid plaque, a subclinical precursor of vascular events: the Northern Manhattan Study. Neurology 2008;70: Wu Z, Yao C, Zhao D, Wu G, Wang W, Liu J, et al. Sino-MONICA project: a collaborative study on trends and determinants in cardiovascular diseases in China, part i: morbidity and mortality monitoring. Circulation 2001;103: Vollmer WM, Tsai R, Wu Y, Li YH, Johnson LR, Williams OD, et al. Patterns of lung function in asymptomatic nonsmoking men and women in the People s Republic of China. Ann Epidemiol 2002;12:

9 Journal of the American Society of Echocardiography Volume 24 Number 7 Xie et al An epidemiological study of cardiovascular and cardiopulmonary disease risk factors in four populations in the People s Republic of China. Baseline report from the P.R.C.-U.S.A. Collaborative Study. Circulation 1992;85: Liu J, Hong Y, D Agostino RB Sr., Wu Z, Wang W, Sun J, et al. Predictive value for the Chinese population of the Framingham CHD risk assessment tool compared with the Chinese Multi-Provincial Cohort Study. JAMA 2004;291: Wu Y, Liu X, Li X, Li Y, Zhao L, Chen Z, et al. Estimation of 10-year risk of fatal and nonfatal ischemic cardiovascular diseases in Chinese adults. Circulation 2006;114: Stein JH, Korcarz CE, Hurst RT, Lonn E, Kendall CB, Mohler ER, et al. Use of carotid ultrasound to identify subclinical vascular disease and evaluate cardiovascular disease risk: a consensus statement from the American Society of Echocardiography Carotid Intima-Media Thickness Task Force Endorsed by the Society for Vascular Medicine. J Am Soc Echocardiog 2008; 21: Touboul PJ, Hennerici MG, Meairs S, Adams H, Amarenco P, Desvarieux M, et al. Mannheim intima-media thickness consensus. Cerebrovasc Dis 2004;18: Lu M, Wu L, Shi P, Kang S, Shi L, Wu Y. Hypertension and subclinical carotid atherosclerosis in a suburban general population in China. J Hypertens 2004;22: Wang W, Zhao D, Hou L, Li Z, Yong Q, Sun H, et al. The association of baseline blood pressure level and its 10 year change with carotid atherosclerosis in 1331 cohort subjects. Chin J Cardiol 2004;32: Truelsen T, Mahonen M, Tolonen H, Asplund K, Bonita R, Vanuzzo D. Trends in stroke and coronary heart disease in the WHO MONICA project. Stroke 2003;34: Cook NR. Use and misuse of the receiver operating characteristic curve in risk prediction. Circulation 2007;115: Hanley JA, McNeil BJ. A method of comparing the areas under receiver operating characteristic curves derived from the same cases. Radiology 1983;148: Pencina MJ, D Agostino RB Sr., D Agostino RB Jr., Vasan RS. Evaluating the added predictive ability of a new marker: from area under the ROC curve to reclassification and beyond. Stat Med 2008;27: Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285: D Agostino RB Sr., Grundy S, Sullivan LM, Wilson P. Validation of the Framingham coronary heart disease prediction scores: results of a multiple ethnic groups investigation. JAMA 2001;286: Schulz UG, Rothwell PM. Sex differences in carotid bifurcation anatomy and the distribution of atherosclerotic plaque. Stroke 2001;32: Fisher M, Fieman S. Geometric factors of the bifurcation in carotid atherogenesis. Stroke 1990;21: Frangos SG, Gahtan V, Sumpio B. Localization of atherosclerosis: role of hemodynamics. Arch Surg 1999;134: Zarins CK, Giddens DP, Bharadvaj BK, Sottiurai VS, Mabon RF, Glagov S. Carotid bifurcation atherosclerosis. Quantitative correlation of plaque localization with flow velocity profiles and wall shear stress. Circ Res 1983;53: Glagov S, Zarins C, Giddens DP, Ku DN. Hemodynamics and atherosclerosis. Insights and perspectives gained from studies of human arteries. Arch Pathol Lab Med 1988;112: Rubba P, Panico S, Bond MG, Covetti G, Celentano E, Iannuzzi A, et al. Site-specific atherosclerotic plaques in the carotid arteries of middleaged women from southern Italy: associations with traditional risk factors and oxidation markers. Stroke 2001;32: Fabris F, Zanocchi M, Bo M, Fonte G, Poli L, Bergoglio I, et al. Carotid plaque, aging, and risk factors. A study of 457 subjects. Stroke 1994;25: Chambless LE, Folsom AR, Clegg LX, Sharrett AR, Shahar E, Nieto FJ, et al. Carotid wall thickness is predictive of incident clinical stroke: the Atherosclerosis Risk in Communities (ARIC) study. Am J Epidemiol 2000;151: Chambless LE, Heiss G, Folsom AR, Rosamond W, Szklo M, Sharrett AR, et al. Association of coronary heart disease incidence with carotid arterial wall thickness and major risk factors: the Atherosclerosis Risk in Communities (ARIC) study, Am J Epidemiol 1997;146: Touboul PJ, Hernandez-Hernandez R, Kucukoglu S, Woo KS, Vicaut E, Labreuche J, et al. Carotid artery intima media thickness, plaque and Framingham cardiovascular score in Asia, Africa/Middle East and Latin America: the PARC-AALA study. Int J Cardiovasc Imaging 2007;23: Bots ML, Hoes AW, Koudstaal PJ, Hofman A, Grobbee DE. Common carotid intima-media thickness and risk of stroke and myocardial infarction: the Rotterdam Study. Circulation 1997;96: Hollander M, Hak AE, Koudstaal PJ, Bots ML, Grobbee DE, Hofman A, et al. Comparison between measures of atherosclerosis and risk of stroke: the Rotterdam Study. Stroke 2003;34: Lorenz MW, Markus HS, Bots ML, Rosvall M, Sitzer M. Prediction of clinical cardiovascular events with carotid intima-media thickness: a systematic review and meta-analysis. Circulation 2007;115: Simon A, Megnien JL, Chironi G. The value of carotid intima-media thickness for predicting cardiovascular risk. Arterioscler Thromb Vasc Biol 2010;30:182-5.