Associations of Extracranial Carotid Atherosclerosis Progression With Coronary Status and Risk Factors in Patients With and Without Coronary Artery Disease
Background— Intimal medial thickness of the extracranial carotid arteries (IMT) is related to coronary artery disease (CAD) and CAD risk factors. Few studies have explored the association of risk factors with progression of IMT, and none have evaluated their associations with IMT progression specifically in patients with and without CAD.
Methods and Results— We used coronary angiography to identify 280 patients equally divided between men and women and those with either ≥50% coronary artery stenosis or no CAD. Risk factors were measured at baseline and IMT was measured at baseline and yearly for 3 years in 241 of these individuals. Baseline risk factors and CAD status were related to IMT progression. IMT of patients with CAD progressed 3 times faster than that of patients with no CAD (mean±SEM, 33.7±7.4 versus 8.9±7.1 μm/year; P=0.02), and CAD status and high-density lipoprotein (HDL) cholesterol were independently associated with IMT progression. Male sex, increased waist to hip ratio, cigarette smoking, increased triglycerides, and decreased HDL cholesterol were associated with increased progression in CAD patients.
Conclusions— Patients with CAD have more rapid progression of IMT than CAD-free controls, and risk factors are related to progression in them.
Received June 13, 2002; revision received August 2, 2002; accepted August 2, 2002.
Age, sex, hypertension, smoking, diabetes, LDL and HDL cholesterol, as well as coronary status have been associated with extracranial carotid disease,1–3⇓⇓ and investigators have suggested that they impact disease progression. Although direct quantification of the influence of risk factors on carotid intimal medial thickness (IMT) progression is more accurate than inference from cross-sectional studies, it also represents a greater technological challenge, because IMT changes slowly. Several epidemiological investigations have reported on IMT progression.4–19⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓ However, previous investigations have not compared progression in patients with and without coronary artery disease (CAD). It is likely that patients with angiographic evidence for CAD would experience more rapid progression of carotid IMT than CAD-free individuals. To test this, we quantified baseline risk factors and progression rates of extracranial carotid IMT over 3 years in 241 patients with angiographically defined coronary status.
Patients, Clinical Evaluation, and Study Design
Equal numbers of male and female patients were enrolled in this study, as described previously.20–23⇓⇓⇓ They consisted of 139 controls free of any evidence of CAD at coronary angiography and 141 cases with obstructive CAD manifest by at least 1 coronary artery with 50% or more stenosis. Approximately 70% of controls underwent cardiac catheterization because of chest pain and 20% because of valvular heart disease.23
Trained interviewers collected pertinent medical history and risk factor profiles from all participants within 6 to 8 weeks after angiography. Clinic coordinators also measured height, weight, and blood pressure. Blood was drawn for laboratory analyses. Hypertension was defined by history of the disease, a systolic blood pressure >150 mm Hg, or a diastolic blood pressure >90 mm Hg. Diabetes was defined by history of the disease or by a fasting plasma glucose level of >140 mg/dL. Smoking status was recorded as the number of pack years smoked. Plasma concentrations of lipids and lipoproteins were measured using Center for Disease Control–standardized methods.20–23⇓⇓⇓ Apolipoprotein E polymorphism and lipoprotein (a) were determined, as described previously.22 B-mode ultrasound was used to quantify IMT of the extracranial carotid arteries, as described below. Subsequently, patients completed a brief health, risk factor, and medication use questionnaire and underwent repeat B-mode ultrasound evaluation on a yearly basis for 3 years (total of 4 examinations).
Of the 280 individuals who were originally enrolled, 256 (91%) returned for at least one follow-up visit. Use of lipid-altering therapy at baseline was an exclusion from participation in the study. This likely resulted in exclusion of a few markedly hyperlipidemic participants from the baseline examination (before 1993). However, at study end, 19% of cases but only 4% of controls who returned for follow-up were treated with lipid-altering therapy. Because lipid-altering therapy has been shown in several clinical trials to retard the progression of extracranial carotid IMT,1 analysis for this study excluded all visits after participants began taking lipid-altering therapy. We similarly excluded visits when participants were taking antioxidants because of suggestions that this therapy might similarly influence IMT progression.24 These decisions excluded 72 visits in a total of 32 participants from the database. We also censored follow-up visits for 1 individual after carotid endarterectomy. All these decisions pared the analysis database to 241 individuals (86% of the original cohort) with an average of 2.80 of 3 planned annual follow-up visits. Risk factors and baseline IMT of the extracranial carotid arteries of the subset of the population in this cohort study were not statistically different from those of the overall population evaluated at baseline.
The ultrasound machine used was a Biosound 2000 II, s.a. with an 8-MHZ annular array transducer (Biosound, Indianapolis). The patient’s head position, sonographer position, scanning angles, and scanning angle sequence were all standardized. The extracranial carotid artery was evaluated at 3 1-cm segments, the common carotid, the carotid bifurcation, and the internal carotid artery. In longitudinal arterial images, the distances between the interfaces generated from the boundaries between adventitia/media, intima/lumen on the near wall, and the interfaces from lumen/intima, media/adventitia on the far wall were identified as the IMT. The right and left carotid arteries were scanned as circumferentially as possible to search for the thickest IMT on both near and far walls for each segment. The scan was recorded on a super VHS videotape and reviewed offline. While reviewing the image tape, the reader selected the most appropriate frame showing the thickest IMT for each site of the carotid artery (which was used for analysis20–23⇓⇓⇓).
Baseline characteristics of CAD cases and controls were compared using t tests and χ2 tests. IMT progression was described by fitting mixed models to the longitudinal data using maximum likelihood.25 In these models, IMT measurements from each wall segment were included and blocked within subjects. Progression of IMT over time was modeled with a fixed effect; random intercepts terms were included to describe subject-specific differences. The use of fixed, rather than random, effects for IMT progression may inflate type I error rates if IMT progressions are heterogeneous26; however, we found little difference in the results in our analyses from the two approaches and chose to avoid models in which explicit distributions must be assumed for any heterogeneity. For simplicity, correlations among arterial sites and longitudinal measurements of IMT from individual segments were modeled with compound symmetry covariance structure. This approach, rather than using unstructured covariance matrices, slightly decreased the efficiency of comparisons but seemed to provide more stable estimates. This general approach of using maximum likelihood and mixed models protects against biases related to missing measurements.27 Differences in the progression rates between CAD cases and controls were contrasted using Wald tests.25
Baseline characteristics of the 241 participants contributing to our analyses are presented in Table 1 according to CAD status at enrollment. On average, individuals with CAD were older, less likely to be African American, and more likely to have hypertension, diabetes, lower HDL cholesterol, higher LDL cholesterol and triglycerides, and higher lipoprotein (a).
Table 2 summarizes cross-sectional IMT at enrollment and IMT progression for individuals with and without CAD. At enrollment, average IMT was ≈10% greater in individuals with CAD compared with CAD-free controls (P<0.0001), and significant case-control differences in mean IMT were apparent at each segment and arterial wall (all P<0.0001). Among cases, longitudinal analyses demonstrated significant carotid IMT progression (confidence interval excludes 0) for the aggregate mean of all sites as well as at both near and far arterial walls and at the common and bifurcation segments. Among controls, carotid IMT progression was significant only at the common segment. Individuals with CAD had 3-fold greater progression rates of IMT compared with those free of CAD (33.7 versus 8.9 μm/year; P=0.02). At baseline, the aggregate mean IMT was more variable among individuals with CAD (SD=439 μm) compared with those without CAD (SD=256 μm). This trend held for subsets of sites, as well. Standard deviations of average IMT at the common, bifurcation, and internal segments for CAD versus CAD-free individuals were 289 versus 174 μm, 660 versus 424 μm, and 612 versus 370 μm, respectively. Similarly, the progression of aggregate IMT was more variable among individuals with CAD. The standard deviation of fitted slopes of aggregate IMT over time was 143 μm/year for individuals with CAD versus 72 μm/year for those who were CAD-free. This trend also held within each segment: 85 versus 44 μm/year (common), 210 versus 112 μm/year (bifurcation), and 241 versus 103 μm/year (internal).
Table 3 examines relationships between baseline risk factors and IMT progression for the entire cohort. IMT progression related most strongly to ordered pack years smoking (P=0.04) and ordered HDL cholesterol (P=0.04). The associations of sex and waist/hip ratio with progression were of borderline significance (P=0.09). To test whether sex, pack years of smoking, and HDL cholesterol might partly explain differences in progression rates between individuals with and without CAD, we entered these factors as covariates in models in which we reassessed differences in progression rates associated with CAD status. After adjustment for sex, smoking, and HDL cholesterol, individuals with CAD had fitted progression rates that were 21.2±10.3 μm/year greater than those without CAD (P=0.04). After control for CAD status, HDL cholesterol remained related to progression (P=0.01). No other risk factor entered a model to predict IMT progression that contained CAD status and HDL cholesterol.
Table 3 also explores associations of risk factors with progression in CAD cases and controls. Among controls, only younger age was associated with increased progression. Male sex, waist to hip ratio, pack years of smoking, lower HDL cholesterol, and higher triglycerides were associated with more rapid progression in CAD cases. Because the association of HDL cholesterol with progression might be confounded by associations of HDL cholesterol with sex and of sex with progression, we carried out an additional sex-specific analysis of associations of HDL cholesterol with progression in patients with CAD. In this analysis, there was no association of HDL cholesterol with progression in female CAD patients, but progression rates in male CAD patients were 84.7±18.0, 46.2±21.6, 8.4±28.9, and 2.5±32.4 μm/year for the lowest to the highest quartile of HDL cholesterol (P<0.006 for trend).
Progression of IMT in Individuals With and Without CAD
Intimal-medial thickness of the extracranial carotid arteries of CAD cases has been previously shown to exceed that of controls in cross-sectional analysis.1–3⇓⇓ We observed faster IMT progression rates in CAD cases (33.7 μm/year) than in controls (8.9 μm/year). As a qualitative comparator, we also estimated progression from cross-sectional analyses of the associations of IMT with age in the same population at baseline (not presented) to determine how well the estimated progression rates compared with those actually observed. We inferred progression rates of 20.6 and 10.4 μm/year for cases and controls, respectively. Thus, the progression rates inferred from the cross-sectional analyses are qualitatively comparable to those directly measured for controls, but they underestimate progression for cases, as would be expected if older fast progressors were underrepresented in the CAD group at baseline. The progression rate in controls observed and inferred from cross-sectional baseline data in this study (10 μm/year) is similar to that inferred in a previous review that included other healthy populations.3 One prior publication demonstrated more rapid carotid IMT progression in patients with CAD compared with those without significant CAD.4 However, in that study IMT was quantified as the sum of carotid IMT from various sites and cannot be compared with the now more widely used mean maximum IMT (as in the present communication).
Associations of Risk Factors With Progression of IMT
Several epidemiologic studies have explored the associations of risk factors with progression of extracranial carotid IMT in healthy populations. Cigarette smoking,5–8⇓⇓⇓ dyslipidemia,5,6,8–10⇓⇓⇓⇓ blood pressure,6,8,11,12⇓⇓⇓ factors related to thrombosis and thrombolysis,5,6,8,13⇓⇓⇓ alcohol,14 diabetes control,15 Chlamydia,16 lutein,17 cardiorespiratory fitness,18 and psychosocial factors19 have all been related to progression. Clinical trials indicate that reduction of LDL cholesterol,1 antioxidant vitamins,24 angiotensin-converting enzyme inhibition, 28 and β-blocker treatment29 retard progression of IMT.
In the present study population, CAD status was the most significant correlate of IMT progression. In addition, cigarette smoking and reduced HDL cholesterol were the only risk factors that were associated with greater IMT progression. After control for CAD status, only reduced HDL cholesterol remained associated with faster progression.
The lack of an association of many risk factors with IMT progression in the overall cohort obscured the fact that sex, waist to hip ratio, smoking, HDL cholesterol, and triglycerides were related to IMT progression in CAD cases. Low HDL cholesterol was associated with more rapid progression of carotid IMT in male but not female CAD patients. Because control status was associated with overall attenuated progression, the power to detect the impact of risk factors on progression in the control group was similarly reduced, and we cannot precisely discuss the relative impact of risk factors on progression in them compared with cases. Nonetheless, the data are consistent with a hypothesis that the impact of risk factors on progression is quantitatively greater in patients with CAD than in those free of CAD. It is possible that the discrepancy between the apparent impact of risk factors on progression in asymptomatic population-based samples5–14⇓⇓⇓⇓⇓⇓⇓⇓⇓ and the lack of effect in our controls partly reflects the presence of individuals with subclinical disease and more rapid progression in apparently healthy populations (see below).
Strengths and Limitations of This Investigation
Reed and Yano30 have previously described the limitations of studies where case and control status were identified at angiography. Angiographically defined controls are a unique population referred for catheterization to evaluate chest pain, valvular heart disease, and heart failure. They also differ from clinically asymptomatic individuals because of objective exclusion of obstructive coronary disease.31 For these reasons, risk factor profiles in them may not be precisely representative of those in clinically asymptomatic populations.
The primary prespecified outcome for this study was progression of the aggregate measure of IMT. An alternate approach would have been to focus on the common carotid alone. Separate analysis of influence of risk factors on progression of the common carotid IMT (data not presented) showed only an association of smoking with progression in the entire cohort and in those with CAD, and it is possible that risk factors may have a differential impact on progression of different segments.
Strengths of the study, however, were its single-center nature, the accurate assessment of IMT, and precise definition of case/control status. We excluded patients with mildly obstructive CAD (<50% stenosis) by design because of the likelihood that they had underlying CAD.31
A single measurement of vascular structure better reflects past risk factor exposure than present risk burden (and thus future risk). By way of example, the Framingham investigators observed stronger associations of carotid disease with time-integrated risk factor levels than with concurrently measured risk factors.32 On the other hand, progression of a stable marker of atherosclerosis may be a better index of future CAD risk.33 Our data support the likelihood of large differences in progression in patients with CAD compared with CAD-free controls. It is unlikely that this technique could provide a specific or sensitive clinical predictor of incident CAD for an individual patient; however, additional studies of the ability of change in IMT to predict clinical events in subsets of symptomatic as well as asymptomatic individuals are needed.
This study was supported by grant NHLBI RO1 HL35333 and General Clinical Research Center Grant MO1 RR-07122.
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- ↵Hodis HN, Mack WJ, Dunn M, et al. Intermediate-density lipoproteins and progression of carotid arterial wall intima-media thickness. Circulation. 1997; 95: 2022–2026.
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- ↵Zureik M, Touboul PJ, Bonithon-Kopp C, et al. Cross-sectional and 4-year longitudinal associations between brachial pulse pressure and common carotid intima-media thickness in a general population: the EVA study. Stroke. 1999; 30: 550–555.
- ↵Lakka TA, Salonen R, Kaplan GA, et al. Blood pressure and the progression of carotid atherosclerosis in middle-aged men. Hypertension. 1999; 34: 51–56.
- ↵Cortellaro M, Baldassarre D, Cofrancesco E, et al. Relation between hemostatic variables and increase of common carotid intima-media thickness in patients with peripheral arterial disease. Stroke. 1996; 27: 450–454.
- ↵Kauhanen J, Kaplan GA, Goldberg DE, et al. Pattern of alcohol drinking and progression of atherosclerosis. Arterioscler Thromb Vasc Biol. 1999; 19: 3001–3006.
- ↵Yamasaki Y, Kodama M, Nishizawa H, et al. Carotid intima-media thickness in Japanese type 2 diabetic subjects: predictors of progression and relationship with incident coronary heart disease. Diabetes Care. 2000; 23: 1310–1315.
- ↵Sander D, Winbeck K, Klingelhofer J, et al. Enhanced progression of early carotid atherosclerosis is related to Chlamydia pneumoniae (Taiwan acute respiratory) seropositivity. Circulation. 2001; 103: 1390–1395.
- ↵Dwyer JH, Navab M, Dwyer KM, et al. Oxygenated carotenoid lutein and progression of early atherosclerosis: the Los Angeles atherosclerosis study. Circulation. 2001; 103: 2922–2927.
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- ↵Espeland MA, Tang R, Terry JG, et al. Associations of risk factors with segment specific intimal-medial thickness of the extracranial carotid artery. Stroke. 1999; 30: 1047–1055.
- ↵Crouse JR, Craven TE, Hagaman AP, et al. Association of coronary disease with segment specific intimal medial thickening of the extracranial carotid artery. Circulation. 1995; 92: 1141–1147.
- ↵Terry JG, Howard G, Mercuri M, et al. Apo E and segment specific atherosclerosis of the extracranial carotid arteries in cases with coronary disease and coronary disease free controls. Stroke. 1996; 27: 1755–1759.
- ↵Craven TE, Ryu JE, Espeland MA, et al. Evaluation of the associations between carotid artery atherosclerosis and coronary artery stenosis: a case control study. Circulation. 1990; 82: 1230–1242.
- ↵Azen SP, Qian D, Mack WJ, et al. Effect of supplementary antioxidant vitamin intake on carotid arterial wall intima-media thickness in a controlled clinical trial of cholesterol lowering. Circulation. 1996; 94: 2369–2272.
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