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], 1.05–2.14) and total plaque score (hazard ratio per 1-score increase, 1.25; 95% CI, 1.04–1.50). Further analysis showed that the multivariate-adjusted hazard ratio of ICVD associated with plaque in common carotid arteries was 1.90 (95% CI, 1.15–3.13) and that with plaque in bifurcations was 1.26 (95% CI, 0.86–1.85). 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.
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 disease. 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. 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. 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.
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 1994. 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 2005. 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. A total of 1,541 surviving participants free of stroke and CHD were enrolled for the baseline carotid artery ultrasound examination in 2002.
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. 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 and the Mannheim consensus ( 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. 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 κ value of 0.70 and intraobserver agreement with a κ value of 0.78. 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 κ values were 0.67 and 0.72.
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 2007. 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 and the Collaborative Study of Cardiovascular & Cardiopulmonary Epidemiology.
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 Study of Cardiovascular & Cardiopulmonary Epidemiology and have been described in detail elsewhere. 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 : 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 χ 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. 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.
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. 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. 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.
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, high-density 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.
| Variable | ICVD ( n = 137) | No ICVD ( n = 3,121) | P ∗ |
|---|---|---|---|
| Age (y) | 61.6 ± 7.8 | 58.7 ± 8.3 | <.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 ) | 25.8 ± 3.6 | 25.5 ± 3.5 | .287 |
| Systolic blood pressure (mm Hg) | 142.4 ± 27.3 | 133.7 ± 20.7 | <.001 |
| Diastolic blood pressure (mm Hg) | 81.6 ± 13.6 | 80.4 ± 10.8 | .154 |
| Serum total cholesterol (mmol/L) | 5.15 ± 0.89 | 5.30 ± 1.00 | .073 |
| High-density lipoprotein cholesterol (mmol/L) | 1.23 ± 0.28 | 1.30 ± 0.31 | .009 |
| Fasting blood glucose (mmol/L) | 5.59 ± 2.11 | 5.23 ± 1.65 | .014 |
| 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 | 0.74 ± 1.06 | 0.40 ± 0.79 | <.001 |
∗ P values are given for the difference between those with and without ICVD using t tests or χ 2 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], 1.05–2.14; 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, 1.05–4.62) 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 age-adjusted and sex-adjusted HR associated with a change of 1 score in TPS was 1.45 (95% CI, 1.22–1.72) and remained significant after further adjustment for other risk factors (multivariate-adjusted HR, 1.25; 95% confidence interval, 1.04–1.50), although it was slightly reduced in magnitude.
| Carotid plaque index | Events/sample size | HR (95% CI) | ||
|---|---|---|---|---|
| Unadjusted | Age and sex adjusted | Multivariate adjusted ∗ | ||
| ICVD events | ||||
| Presence of plaque in any carotid arteries | ||||
| No | 80/2,416 | 1.00 | 1.00 | 1.00 |
| Yes | 57/842 | 2.23 (1.59–3.13) | 1.86 (1.30–2.64) | 1.49 (1.05–2.14) |
| P | <.001 | .001 | .014 | |
| TPS | ||||
| 0 | 80/2,416 | 1.00 | 1.00 | 1.00 |
| 1 | 27/443 | 1.79 (1.16–2.77) | 1.56 (1.01–2.43) | 1.28 (0.81–2.01) |
| 2 | 21/325 | 2.46 (1.52–3.99) | 1.98 (1.20–3.25) | 1.46 (0.87–2.45) |
| 3 and 4 | 9/74 | 4.64 (2.33–9.26) | 3.57 (1.76–7.22) | 2.20 (1.05–4.62) |
| Per 1 score increase | 137/3,258 | 1.59 (1.36–1.86) | 1.45 (1.22–1.72) | 1.25 (1.04–1.50) |
| P for trend | <.001 | <.001 | .018 | |
| Ischemic stroke | ||||
| Presence of plaque in any carotid arteries | ||||
| No | 53/2,416 | 1.00 | 1.00 | 1.00 |
| Yes | 34/842 | 1.97 (1.28–3.03) | 1.68 (1.07–2.62) | 1.29 (0.84–2.03) |
| P | .002 | .023 | .269 | |
| TPS | ||||
| 0 | 53/2,416 | 1.00 | 1.00 | 1.00 |
| 1 | 16/443 | 1.60 (0.92–2.80) | 1.43 (0.81-2.52) | 1.08 (0.60–1.95) |
| 2 | 11/325 | 1.86 (0.97-3.57) | 1.52 (0.78–2.98) | 1.20 (0.67–2.26) |
| 3 and 4 | 7/74 | 5.23 (2.38-11.53) | 4.18 (1.86-9.39) | 2.45 (1.05–5.77) |
| Per 1 score increase | 87/3,258 | 1.56 (1.28–1.90) | 1.45 (1.17–1.79) | 1.22 (0.97–1.53) |
| P for trend | <.001 | .001 | .091 | |
| CHD | ||||
| Presence of plaque in any carotid arteries | ||||
| No | 30/2,416 | 1.00 | 1.00 | 1.00 |
| Yes | 27/842 | 2.89 (1.72-4.87) | 2.33 (1.36–4.01) | 1.86 (1.05–3.30) |
| P | <.001 | .002 | .028 | |
| TPS | ||||
| 0 | 30/2,416 | 1.00 | 1.00 | 1.00 |
| 1 | 13/443 | 2.30 (1.20-4.41) | 1.92 (0.99-3.73) | 1.61 (0.82–3.18) |
| 2 | 11/325 | 3.67 (1.83-7.34) | 2.90 (1.41–5.95) | 2.29 (1.08–4.85) |
| 3 and 4 | 3/74 | 4.51 (1.37-14.83) | 3.33 (1.00–11.16) | 2.40 (0.81–7.73) |
| Per 1 score increase | 57/3,258 | 1.72 (1.35–2.19) | 1.54 (1.19–1.99) | 1.35 (1.03–1.78) |
| P for trend | <.001 | .001 | .035 | |
∗ Adjusted for age, sex, cohort, diabetes mellitus, hypertension, body mass index, current smoking status, and total and high-density lipoprotein cholesterol levels.
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 CHD generally showed the same trends as for ICVD, except that some associations were no longer statistically significant.
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, 1.88–4.86) for plaque in the CCA and 2.01 (95% CI, 1.42–2.86) 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 were 1.21 (95% CI, 0.80–1.85), 2.21 (95% CI, 1.02–4.85), and 2.33 (95% CI, 1.40–4.03) for the three groups, respectively ( Table 3 ).
| Carotid plaque index | ICVD events/sample size | HR (95% CI) | ||
|---|---|---|---|---|
| Unadjusted | Age and sex adjusted | Multivariate adjusted ∗ | ||
| Presence of plaque in CCA | ||||
| No | 117/3,068 | 1.00 | 1.00 | 1.00 |
| Yes | 20/190 | 3.03 (1.88–4.86) | 2.37 (1.46–3.86) | 1.90 (1.15–3.13) |
| P | <.001 | .001 | .008 | |
| Presence of plaque in bifurcation | ||||
| No | 87/2,483 | 1.00 | 1.00 | 1.00 |
| Yes | 50/775 | 2.01 (1.42–2.86) | 1.69 (1.18–2.41) | 1.26 (0.86–1.85) |
| P | <.001 | .005 | .235 | |
| Presence of plaque in CCA and bifurcation | ||||
| No plaque | 80/2,416 | 1.00 | 1.00 | 1.00 |
| Only in bifurcation | 37/652 | 1.86 (1.26–2.75) | 1.59 (1.07–2.38) | 1.21 (0.80–1.85) |
| Only in CCA | 7/67 | 3.24 (1.50–7.02) | 2.56 (1.17–5.60) | 2.21 (1.02–4.85) |
| Both | 13/123 | 3.74 (2.08–6.71) | 2.90 (1.60–5.28) | 2.33 (1.40–4.03) |
| P | <.001 | <.001 | .010 | |
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