Carotid Atherosclerosis Progression Study Research Articles

PP.21.39] CAROTID INTIMA-MEDIA THICKNESS SCREENING ADDS VALUE IN A CANADIAN COHORT

Objective: Carotid Intima-Media Thickness (CIMT) is an independent risk factor for sub-clinical atherosclerosis. Despite evidence to support its use, CIMT is not currently reimbursed by the Ontario government payment plan. We accessed CIMT in a cohort of patients who chose to pay for the test. The objective is to see if CIMT will add predictive value to traditional risk assessment in this contemporary Canadian cohort. Design and method: We analyzed the first sequential 1,969 patients in a private pay clinic with CIMT from 19 December 2013-29 October 2014. CIMT values were calculated using a Panasonic Healthcare Co. CardioHealth Station bilateral B-mode ultrasound and compared to traditional Framingham Risk Scores (FRS). The CIMT measures considered were mean intima-media thickness (both left and right side) and risk percentiles (low<25%; medium 25–75%; high>75%). The CIMT risk percentiles are based on the original Carotid Atherosclerosis Progression Study (CAPS) database. Results: Of the 1,969 patients, 995 (51%) were classified as low risk, 579 (29%) were classified as moderate risk, and 395 (20%) were classified as high risk for future CV events based on CIMT data. We compared traditional FRS with CIMT results. FRS was only available for 288 of the high CIMT patients (73%). Of these 288 patients, 139 (48%) were considered low risk by traditional FRS. Of the 139 patients who were misclassified by Framingham's (low FRS, high CIMT) 30% of the patients were women; the average age in this group of patients was 51. Ongoing, multi-variant analysis is under way to look for predictors of CIMT values.Conclusions: In a contemporary Canadian cohort FRS has limitations in classifying cardio-vascular disease risk. This was seen in a relatively young population, many of whom were women. Consideration should be given to adopting more widespread use of CIMT screening. This has implications for patient management and funding of such preventive strategies.

Cardiovascular risk in lupus nephritis: Do renal disease-related and other traditional risk factors play a role?

This study was performed to evaluate the prevalence of thickened carotid intima media thickness (CIMT) in a Sri Lankan cohort of lupus nephritis (LN) patients and to identify associations between traditional cardiovascular disease (CVD) and LN-related risk factors with increased CIMT. Consecutive patients with biopsy-proven LN were evaluated for conventional CVD risk factors, renal parameters and extent of organ involvement in this cross-sectional study. Current disease activity and damage were assessed by the British Isles Lupus Activity Group (BILAG) score and the Systemic Lupus International Collaborative Clinics/American College of Rheumatology (SLICC/ACR) damage index, respectively. CIMT was assessed by B Mode grey scale ultrasonography. Increased CIMT was defined as CIMT more than the 75th percentile based on cutoffs from the "Carotid Atherosclerosis Progression Study." Forty patients (98% female), with a mean age of 38 years (age range of 20-50) and of South Asian descent, were evaluated. The mean duration of disease of 6.15 years (SD = 4.66). The overall prevalence of cardiovascular events was low and included previous acute coronary syndromes in 7.5%, stable angina in 5%, cerebrovascular accidents in 7.5% and transient ischemic attacks in 2.5% of the patients; 72.5% had hypertension (HTN) [mean blood pressure (BP) 140/80 mm Hg]; 32.5% had dyslipidemias (mean serum cholesterol 5.9; SD = 5.6) and 25% had diabetes (mean blood sugar 103.7; SD = 15.6). Forty percent were obese and 20% were overweight (Asian cutoffs). Increased CIMT (57.5%) and atherosclerotic plaques (15.36%) indicated a high CVD risk in this cohort. Diabetes (P = 0.016), HTN (P = 0.002), dyslipidemia (P = 0.002) and obesity (P = 0.048) were associated with thickened CIMT. The only LN-related risk factor associated with thickened CIMT (P <0.05) was the SLICC/ACR damage index. The independent predictors of thickened CIMT determined by logistic regression analysis were HTN and dyslipidemia.

Prediction of asymptomatic carotid artery stenosis in the general population: identification of high-risk groups.

Because of a low prevalence of severe carotid stenosis in the general population, screening for presence of asymptomatic carotid artery stenosis (ACAS) is not warranted. Possibly, for certain subgroups, screening is worthwhile. The present study aims to develop prediction rules for the presence of ACAS (>50% and >70%). Individual participant data from 4 population-based cohort studies (Malmö Diet and Cancer Study, Tromsø Study, Carotid Atherosclerosis Progression Study, and Cardiovascular Health Study; totaling 23 706 participants) were pooled. Multivariable logistic regression was performed to determine which variables predict presence of ACAS (>50% and >70%). Calibration and discrimination of the models were assessed, and bootstrapping was used to correct for overfitting. Age, sex, history of vascular disease, systolic and diastolic blood pressure, total cholesterol/high-density lipoprotein ratio, diabetes mellitus, and current smoking were predictors of stenosis (>50% and >70%). The calibration of the model was good confirmed by a nonsignificant Hosmer and Lemeshow test for moderate (P=0.59) and severe stenosis (P=0.07). The models discriminated well between participants with and without stenosis, with an area under the receiver operating characteristic curve corrected for over optimism of 0.82 (95% confidence interval, 0.80-0.84) for moderate stenosis and of 0.87 (95% confidence interval, 0.85-0.90) for severe stenosis. The regression coefficients of the predictors were converted into a score chart to facilitate practical application. A clinical prediction rule was developed that allows identification of subgroups with high prevalence of moderate (>50%) and severe (>70%) ACAS. When confirmed in comparable cohorts, application of the prediction rule may lead to a reduction in the number needed to screen for ACAS.

AB0671 Cardiovascular risk in systemic lupus erythematosus: Do renal risk factors play a part?

BackgroundSystemic lupus erythematosus (SLE) is associated with a high risk of cardiovascular disease (CVD). In addition to traditional risk factors, SLE disease related factors such as renal dysfunction are postulated...

Clinical usefulness of carotid ultrasound to improve stroke risk assessment: ten-year results from the Carotid Atherosclerosis Progression Study (CAPS)

To prevent strokes it is essential to correctly classify people according to their risk of stroke. The aim of the present study was to assess whether carotid ultrasound improves the stroke risk prediction in asymptomatic individuals. The baseline visit of the Carotid Atherosclerosis Progression Study (CAPS) included assessment of conventional risk factors and carotid ultrasound. During the 10-year follow-up of 4995 subjects, strokes, transient ischaemic attacks (TIA) and deaths were recorded. We assessed the additional usefulness of carotid ultrasound compared to the Framingham Stroke Risk Score (FSRS) with reclassification statistics using four risk categories. Most risk models were not improved by carotid ultrasound. For individual stroke prediction, intima-media thickness (IMT) or plaque of the internal carotid arteries were more useful than common carotid or bifurcational IMT. The model predicting 'any stroke or death' was significantly improved when ultrasound parameters were included - 339 subjects (7.2%) were reclassified to another risk category (122 were shifted to a higher, 217 to a lower risk category); 182 (53.7%) were correctly reclassified. The net reclassification improvement (NRI) was 7.7% (p = 0.029) and the integrated discrimination improvement (IDI) was 0.73% (p = 0.023). When carotid ultrasound is not restricted to the common carotid artery but includes the internal carotid segments, the inclusion of ultrasound data into stroke risk models may improve the risk classification of individuals. Further validation in primary prevention cohorts is warranted.

Thickened carotid intima media thickness and carotid atherosclerosis among lupus nephritis patients: the role of traditional and lupus-specific factors

The objectives of this study were to investigate the frequency of thickened carotid intima media thickness (CIMT) and atherosclerosis among lupus nephritis (LN) patients and to study their associated risk factors. In this cross-sectional study, carotid ultrasonography was performed on consecutive LN patients to determine CIMT and presence of carotid plaques. CIMT was considered to be abnormally thickened if it was more than the 75th percentile matched for age and sex from the 'Carotid Atherosclerosis Progression Study'. The association between thickened CIMT with traditional cardiovascular risk factors and lupus characteristics were examined. A total of 83 patients with the mean age of 33.6 ± 10 years were recruited. Fourteen patients (16.9%) had thickened CIMT and three (3.6%) had carotid plaques. On univariate analysis, traditional risk factors significantly associated with thickened CIMT (P < 0.05) were patient's current age, diabetes mellitus and waist circumference. Meanwhile, a lower serum C4 levels and higher serum C-reactive protein levels were the lupus-specific factors associated with thickened CIMT (P < 0.05, P < 0.05 and P < 0.01, respectively). In logistic regression analysis, the independent predictors of thickened CIMT were age of diagnosis, lower serum C4 levels and waist circumference (P < 0.05). More lupus specific factors were independently associated with thickened CIMT, suggesting that a multi-targeted approach of treatment addressing both the lupus and traditional cardiovascular risks are very important. Larger prospective studies of these special risk factors are indicated.

Adiponectin Level as a Consequence of Genetic Variation, but Not Leptin Level or Leptin

The adipocytokines adiponectin and leptin have been suggested as risk factors for cardiovascular disease, including stroke, acting through atherosclerosis. However, studies have provided conflicting results in underpowered cohorts with some suggesting that the leptin:adiponectin ratio is a better predictor of risk. We examined these associations with carotid intima-media thickness (IMT), a marker of early atherosclerosis and arterial remodeling and an independent predictor of stroke. We also examined association between genetic variants in the leptin and adiponectin genes and IMT. Adiponectin and leptin levels were determined in 990 individuals from the community Carotid Atherosclerosis Progression Study. Five variants in the gene encoding adiponectin and 7 in the gene encoding leptin were genotyped and their effects on circulating levels assessed. Both were then correlated with IMT. Adiponectin levels negatively correlated with IMT (-0.079, P=0.013). There was no correlation between leptin levels or leptin:adiponectin ratio and IMT. Two variants in the ADIPOQ gene encoding adiponectin were associated with altered adiponectin levels, 1 of which (rs266729) was associated with IMT. There was also an interaction with body mass index (P=0.019) with the association being present in obese subjects (P=0.02). Our results support a causal role for adiponectin in early carotid IMT and suggest it may act through interaction with obesity. In contrast, we found no evidence of a role for leptin and no evidence that leptin:adiponectin ratio is a better predictor of risk that adiponectin levels alone.

Prevalence of Asymptomatic Carotid Artery Stenosis in the General Population: An Individual Participant Data Meta-Analysis

Conclusion: The prevalence of severe asymptomatic internal carotid artery (ICA) stenosis in the general population ranges from 0% to 3.1%. Summary: The authors sought to determine the prevalence of moderate and severe asymptomatic ICA stenosis using information from four population-based cohort studies. They used pooled cohort data to analyze prevalence of moderate and severe asymptomatic ICA stenosis by age and sex. This was an individual participant data meta-analysis of 23,706 participants from four population-based studies: the Malmo Diet and Cancer Study, Tromoso, Carotid Atherosclerosis Progression Study, and the Cardiovascular Health Study. Moderate asymptomatic ICA stenosis was defined as >50% to 69% stenosis. Severe stenosis was defined as >70% stenosis. Moderate asymptomatic ICA stenosis had a prevalence ranging from 0.2% (95% CI, 0.0%-0.4%) in men aged <50 years to 7.5% (95% CI, 5.2%-10.5%) in men aged ≥80 years. In women, prevalence of asymptomatic ICA stenosis ranged from 0% (95% CI, 0%-0.2%) to 5% (95% CI, 3.1%-7.5%). Severe asymptomatic ICA stenosis ranged from 0.1% to 3.1% (95% CI, 0.0%-0.3%) in men aged <50 years and from 1.7% to 5.3% in men aged >80. In women, the prevalence of severe asymptomatic ICA stenosis increases from 0% (95% CI, 0.0%-0.2%) in those aged <50 years to 0.9% (95% CI, 0.3%-2.4%) in those aged <80 years, respectively. Comment: Screening for asymptomatic ICA stenosis has not been endorsed by the US Preventative Health Services Task Force. There are no data here that will lead to a change in their opinion. Up to age 70 years, the prevalence of high-grade asymptomatic carotid stenosis is <2%. No comorbidity increases that prevalence beyond 2%. Given the relatively benign natural history of asymptomatic ICA stenosis, it seems highly unlikely from these data that screening for asymptomatic high-grade ICA stenosis can be clinically effective or cost-effective in any patient subgroup.

Is carotid intima media thickness useful for individual prediction of cardiovascular risk? Ten-year results from the Carotid Atherosclerosis Progression Study (CAPS)

Carotid intima media thickness (cIMT) is an intermediate phenotype of early atherosclerosis that independently predicts vascular events. It is often suggested that cIMT be used as a screening tool to select subjects with an elevated event risk. Whether cIMT adds information to traditional risk models has so far received little investigation. The 10-year follow-up of 4904 subjects from the Carotid Atherosclerosis Progression Study (CAPS) without pre-existing vascular disease included cardiovascular events and total mortality. Using Cox models and reclassification statistics, we investigated the usefulness of cIMT in individual risk prediction beyond the Framingham and the SCORE models, using risk strata of 0-5, 5-10, 10-20, and >or=20% over 10 years. Carotid intima media thickness was significantly and independently predictive for cardiovascular events. Compared with a model using the Framingham risk factors, a second model that included the common carotid-IMT led to the reclassification of 357 subjects (8.1%). In 107 subjects (30.0%), this reclassification was correct as confirmed with the actual outcome over 10 years. Net reclassification improvement was -1.41% (P = NS); integrated discrimination improvement was 0.04% (P = NS). More subjects were shifted to lower than to higher risk categories by the inclusion of cIMT. Analyses including other endpoint definitions, other carotid segments, and the SCORE risk model for baseline prediction did not result in consistently better risk prediction with cIMT. Despite cIMT being predictive for cardiovascular endpoints, it did not consistently improve the risk classification of individuals. Carotid intima media thickness may not be useful for the risk stratification of individuals in the general population.

Prevalence of Asymptomatic Carotid Artery Stenosis in the General Population

In the discussion on the cost-effectiveness of screening, precise estimates of severe asymptomatic carotid stenosis are vital. Accordingly, we assessed the prevalence of moderate and severe asymptomatic carotid stenosis by age and sex using pooled cohort data. We performed an individual participant data meta-analysis (23 706 participants) of 4 population-based studies (Malmö Diet and Cancer Study, Tromsø, Carotid Atherosclerosis Progression Study, and Cardiovascular Health Study). Outcomes of interest were asymptomatic moderate (> or =50%) and severe carotid stenosis (> or =70%). Prevalence of moderate asymptomatic carotid stenosis ranged from 0.2% (95% CI, 0.0% to 0.4%) in men aged <50 years to 7.5% (5.2% to 10.5%) in men aged > or =80 years. For women, this prevalence increased from 0% (0% to 0.2%) to 5.0% (3.1% to 7.5%). Prevalence of severe asymptomatic carotid stenosis ranged from 0.1% (0.0% to 0.3%) in men aged <50 years to 3.1% (1.7% to 5.3%) in men aged > or =80. For women, this prevalence increased from 0% (0.0% to 0.2%) to 0.9% (0.3% to 2.4%). The prevalence of severe asymptomatic carotid stenosis in the general population ranges from 0% to 3.1%, which is useful information in the discussion on the cost-effectiveness of screening.

Genetic Variation in the Leukotriene Pathway and Carotid Intima-Media Thickness

The recent finding that genetic variation in the leukotriene biosynthesis pathway may confer an increased risk of ischemic stroke and atherosclerosis has implicated the leukotriene family as potential mediators of cardiovascular disease. Using a 2-stage replication design, we have examined whether polymorphisms in 8 genes related to this pathway are associated with early atherosclerosis and remodeling as measured by carotid artery intima-media thickness. We assessed 969 individuals from the Carotid Atherosclerosis Progression Study (CAPS), a community based study of normal subjects, for 39 variants in the leukotriene pathway. Significant associations and gene-environment interactions were found for 21 variants in the initial cohort and were examined in the next 1905 consecutive cases from the same CAPS population. No replicable association between any individual polymorphism and carotid intima-media thickness itself was present after correction for multiple testing. A single gene-environment interaction was replicated between rs17222814 on bifurcation intima-media thickness and alcohol consumption exceeding 30 grams per day. The genetic variants we examined in the leukotriene biosynthesis pathway have little effect on early atherosclerosis and remodeling risk as determined by carotid intima-media thickness. Our study cannot exclude them as being risk factors for more advanced stages in the atherosclerotic process.

Influence of Inflammatory Variables on Intima-Media Thickness

To the Editor: The increase of carotid intima-media thickness (IMT) is a validated marker for atherosclerotic progression,1 and it has been related to a higher incidence of cardiovascular events.2 However, data focusing on its determinants are scarce. Lorenz et al3 reported the relationship between C-reactive protein (CRP) and the progression of carotid IMT in a population-based study. We have studied the influence of inflammatory markers in the development of atherosclerosis (baseline and IMT increase/decrease) in Human Immunodeficiency Virus (HIV)–infected patients (n=141).4,5 We performed a standardized protocol for …

Toll-like Receptor Polymorphisms and Carotid Artery Intima-Media Thickness

Inflammation is a key mechanism in atherosclerosis. Variation in genes encoding inflammatory responses may therefore influence atherosclerosis risk possibly through interaction with chronic infections and proinflammatory environmental risk factors such as smoking, diabetes, and obesity. The Toll-like receptor family (TLRs) genes TLR2 and TLR4, both involved in the inflammatory process, are potential candidates and TLR-4 has been previously associated with cardiovascular disease, although other studies have failed to confirm this.A total of 3000 individuals from the prospective community-based Carotid Atherosclerosis Progression Study (CAPS) were genotyped for single nucleotide polymorphisms: TLR2 (Arg753Gln, -16934 A/T) and TLR4 (D299G, T399I). Associations were determined with common carotid artery intima-media thickness (IMT) at baseline and also progression of IMT over the 3-year follow-up period. Gene-environment interactions with high sensitive C-reactive protein, smoking, body mass index, and diabetes were determined.There was no association between single nucleotide polymorphisms or haplotypes in either TLR4 or TLR2 and either baseline IMT or progression of IMT over the 3-year follow up. There were no interactions among the three proinflammatory risk factors. No genotype or haplotype was associated with high sensitive C-reactive protein.In this large community population, we found no evidence for genetic variation in these two TLRs being risk factors for increased IMT either directly or through interaction with proinflammatory risk factors. We were unable to confirm associations with the TLR4 polymorphisms reported in previous smaller studies.

Carotid intimal-media thickening indicates a higher vascular risk across a wide age range: prospective data from the Carotid Atherosclerosis Progression Study (CAPS)

Background and Purpose—Carotid intima-media thickness (IMT) is an independent predictor of vascular events in age groups 45 years. However, there is little information about the predictive value of IMT in younger individuals. Methods—In the Carotid Atherosclerosis Progression Study (CAPS; n 5056; age range 19 to 90 years; mean age 50.1 years), common carotid artery (CCA) IMT, bifurcation IMT, internal carotid artery IMT and vascular risk factors were evaluated at baseline. The incidence of stroke, myocardial infarction (MI), and death was determined prospectively. Data for younger ( 50 years; n 2436) and older subjects ( 50 years; n 2620) were analyzed separately using Cox proportional hazard regression models. Results—During a mean follow-up period of 4.2 years, there were 228 cases of MI, 107 strokes, and 50 deaths. IMT at all carotid segments was highly predictive of all end points (eg, hazard rate ratios [HRRs] per 1 SD CCA-IMT increase were 1.43 [95% CI: 1.35 to 1.51] for MI, 1.47 [1.35 to 1.60] for stroke, and 1.45 [1.38 to 1.52] for MI, stroke or death; all P 0.0001). Even after adjustment for age, sex, and vascular risk factors, the predictive value of CCA-IMT and bifurcation IMT remained significant for MI and the combined end point. For the latter, the HRRs were considerably higher in the younger than in the older age group (eg, HRR per 0.1 mm CCA-IMT was 1.34 [1.16 to 1.55] vis-a-vis 1.10 [1.05 to 1.15]; P 0.011 for age-IMT interaction). Conclusions—Carotid IMT independently predicts future vascular events. Its predictive value is at least as high in younger subjects as in older subjects. (Stroke. 2006;37:87-92.)

Toll Receptor Polymorphisms and Carotid Artery Intima-Media Thickness

Inflammation is a key mechanism in atherosclerosis. Variation in genes encoding inflammatory responses may therefore influence atherosclerosis risk possibly through interaction with chronic infections and proinflammatory environmental risk factors such as smoking, diabetes, and obesity. The Toll-like receptor family (TLRs) genes TLR2 and TLR4, both involved in the inflammatory process, are potential candidates and TLR-4 has been previously associated with cardiovascular disease, although other studies have failed to confirm this. A total of 3000 individuals from the prospective community-based Carotid Atherosclerosis Progression Study (CAPS) were genotyped for single nucleotide polymorphisms: TLR2 (Arg753Gln, -16934 A/T) and TLR4 (D299G, T399I). Associations were determined with common carotid artery intima-media thickness (IMT) at baseline and also progression of IMT over the 3-year follow-up period. Gene-environment interactions with high sensitive C-reactive protein, smoking, body mass index, and diabetes were determined. There was no association between single nucleotide polymorphisms or haplotypes in either TLR4 or TLR2 and either baseline IMT or progression of IMT over the 3-year follow up. There were no interactions among the three proinflammatory risk factors. No genotype or haplotype was associated with high sensitive C-reactive protein. In this large community population, we found no evidence for genetic variation in these two TLRs being risk factors for increased IMT either directly or through interaction with proinflammatory risk factors. We were unable to confirm associations with the TLR4 polymorphisms reported in previous smaller studies.

Carotid Intima-Media Thickening Indicates a Higher Vascular Risk Across a Wide Age Range

Carotid intima-media thickness (IMT) is an independent predictor of vascular events in age groups >45 years. However, there is little information about the predictive value of IMT in younger individuals. In the Carotid Atherosclerosis Progression Study (CAPS; n=5056; age range 19 to 90 years; mean age 50.1 years), common carotid artery (CCA) IMT, bifurcation IMT, internal carotid artery IMT and vascular risk factors were evaluated at baseline. The incidence of stroke, myocardial infarction (MI), and death was determined prospectively. Data for younger (<50 years; n=2436) and older subjects (> or =50 years; n=2620) were analyzed separately using Cox proportional hazard regression models. During a mean follow-up period of 4.2 years, there were 228 cases of MI, 107 strokes, and 50 deaths. IMT at all carotid segments was highly predictive of all end points (eg, hazard rate ratios [HRRs] per 1 SD CCA-IMT increase were 1.43 [95% CI: 1.35 to 1.51] for MI, 1.47 [1.35 to 1.60] for stroke, and 1.45 [1.38 to 1.52] for MI, stroke or death; all P<0.0001). Even after adjustment for age, sex, and vascular risk factors, the predictive value of CCA-IMT and bifurcation IMT remained significant for MI and the combined end point. For the latter, the HRRs were considerably higher in the younger than in the older age group (eg, HRR per 0.1 mm CCA-IMT was 1.34 [1.16 to 1.55] vis-à-vis 1.10 [1.05 to 1.15]; P=0.011 for age-IMT interaction). Carotid IMT independently predicts future vascular events. Its predictive value is at least as high in younger subjects as in older subjects.