Subjects

The study population consisted of 138 stroke-free control subjects (66 men and 72 women) aged 55 to 94 years from the Aortic Plaque and Risk of Ischemic Stroke (APRIS) study (funded by the National Institute of Neurological Disorders and Stroke, Bethesda, MD), a nested case-control study from the cohort of the Northern Manhattan Stroke Study (NOMAS). NOMAS is an ongoing, prospective, population-based epidemiologic study designed to determine stroke incidence, risk factors, and outcomes in a multiethnic urban population living in northern Manhattan. All individuals who were potential matches for APRIS subjects with strokes on the basis of age, sex, and race or ethnicity were requested to participate in the study.

As part of NOMAS, baseline data were collected through interviews by trained bilingual research assistants using standardized data collection instruments, review of medical records, and physical and neurologic examination by study physicians, and fasting blood was collected. Standardized questions were adapted from the Centers for Disease Control and Prevention’s Behavioral Risk Factor Surveillance System. Arterial hypertension was defined as systolic blood pressure ≥ 140 mm Hg or diastolic blood pressure ≥ 90 mm Hg on the basis of the mean of two readings, a patient’s self-report of a history of hypertension, or antihypertensive medication use. Diabetes mellitus was defined by a patient’s self-report of such history, insulin use, oral hypoglycemic use, or fasting glucose ≥ 126 mg/dL. Hypercholesterolemia was defined as total serum cholesterol > 240 mg/dL, a patient’s self-report of hypercholesterolemia, or the presence of lipid-lowering treatment. Smoking was defined by current use (within a current year) of cigars or cigarettes.

Informed consent was obtained from all subjects. The study was approved by the institutional review board of Columbia University Medical Center.

Detection of Aortic Plaques

Transesophageal echocardiography (TEE) was performed upon enrollment. TEE of the aorta was performed in a systematic fashion, as previously described, using a multiplane transducer. The aortic arch was defined as the portion of the aorta between the curve at the end of the ascending portion and the takeoff of the left subclavian artery. A plaque was defined as a discrete protrusion of the intimal surface of the vessel ≥2 mm in thickness, different in appearance and echogenicity from the adjacent intact intimal surface. The presence and location of any plaque was recorded on VHS videotapes and interpreted offline by a single experienced echocardiographer (M.R.D.) blinded to the duplex carotid sonographic findings. In cases of multiple plaques, the most advanced lesion was considered. Plaques were classified into small (>1 and ≤3.9 mm) or large (≥4 mm). An example of large arch plaque on TEE is shown in Figure 1 . Intraobserver variability for the chosen categorization was low (correlation coefficient, 0.95).

Example of large atherosclerotic plaque in the mid portion of the aortic arch by TEE. The maximum plaque thickness (0.5 cm) is measured perpendicular to the major axis of the vascular lumen.

Assessment of CIMT

CIMT was assessed using high-resolution B-mode carotid ultrasound (2D-Gateway, 7.5-MHz probe; Diasonics, Milpitas, CA) according to standardized scanning and reading protocols, as previously described. The CIMT scanning protocol consisted of the near and the far wall of the 3 carotid segments, defined as follows: (1) 10 to 20 mm proximal to the tip of the flow divider into the common carotid artery (CCA), (2) the carotid bifurcation (BIF) beginning at the tip of the flow divider and extending 10 mm proximal to the flow divider tip, and (3) the proximal 10 mm of the internal carotid artery. Measurements of intima-media thickness (IMT) were performed offline with the use of the M’Ath automatic computerized edge-tracking system (Canevas, Paris, France). The M’Ath program searches for the true wall boundaries using an intensity gradient detection algorithm. An example of IMT measurement is shown in Figure 2 . Reproducibility studies in our laboratory have been previously reported, with an interobserver correlation coefficient of 0.77 (percentage error, 10.6%) and an intraobserver correlation coefficient of 0.94 (percentage error, 5.6%). In each carotid segment, the mean distances between intima and media were measured outside the portion of plaques. The total CIMT was calculated as a composite measure (mean of the 12 carotid sites) that combined the near and far walls of the CCA IMT, the BIF IMT, and the internal carotid artery IMT of both sides of the neck.

CIMT measurements performed in the far wall of the right CCA (RCCAFW) by the automated computer-assisted edge detection software. Mean IMT in the RCCAFW was 0.656 ± 0.058 mm. Similarly, IMT in the carotid BIF and internal carotid artery was measured. Total CIMT is an average measure of IMT measured in all carotid arteries of the both side of the neck.

Statistical Analysis

Descriptive statistics were determined, and data are presented as mean ± SD for continuous variables and as proportions for categorical variables. Differences between proportions were assessed using the χ ² test, replaced by Fisher’s exact test when the expected cell count was <5. Differences between mean values were assessed using unpaired Student’s t tests.

The values of total CIMT and CIMT at the various carotid segments were analyzed. Multivariate logistic regression analysis was used to test the association between CIMT (the independent variable) and large aortic arch plaque (the dependent variable) after entering age, sex, and atherosclerotic risk factors as potential confounding factors in the model. Diabetes mellitus and hypercholesterolemia were significantly associated with aortic arch plaques in univariate analysis and therefore were entered as independent variables in the model, along with age and sex. Hypertension and smoking were not associated with large arch plaques and therefore were not included in the final model.

For CIMT significantly associated with arch plaques ≥ 4 mm in the multivariate analyses, positive and negative predictive values were calculated, using the 75th percentile and the median value of the total CIMT distribution.

Subject Characteristics

Demographics, cardiovascular risk factors, aortic arch plaque, and CIMT values for the study population are summarized in Table 1 .

The mean age of the study subjects was 66.3 ± 8.5 years, 52% were women, and the majority were Hispanics (55.8%). Sixty percent of the subjects had hypertension, 50% had hypercholesterolemia, 24% had diabetes mellitus, and 15% were current smokers.

Aortic arch plaques of any thickness were present in >60% of the study group, and large (≥4 mm) aortic arch plaques were present in 35 subjects (25.4%). Whites had a slightly higher prevalence of large plaques (35.3%) than Hispanics (26.0%) and blacks (21.4%), but the differences were not statistically significant. Subjects with large arch plaques had a significantly higher prevalence of hypercholesterolemia (68.6% vs 43.7%, P = .01) and a lower prevalence of diabetes mellitus (11.4% vs 28.2%, P < .05) than those with small or no plaques. The prevalence of hypertension and smoking was not significantly greater in subjects with large plaques.

The mean total CIMT was 0.74 ± 0.13 mm, and the highest mean CIMT was found in the carotid BIF (0.84 ± 0.18 mm; Table 1 ). Carotid plaque was present in 75 subjects (54.4%).

Correlation Between CIMT and Aortic Arch Atherosclerotic Plaques

Table 2 shows Spearman’s correlation coefficients for total CIMT and CIMT at different carotid sites (continuous variable) with the presence of any plaque or large plaque in the aortic arch.

Total CIMT and CIMT in the BIF were significantly associated with presence of both any aortic arch plaque and large aortic arch plaque. CIMT in the CCA was significantly correlated with the presence of aortic arch plaque of any thickness, but not with large aortic arch plaques.

A scatterplot of CIMT at the BIF and aortic plaque thickness is shown in Figure 3 .

Scatterplot of CIMT at the BIF and aortic arch plaque thickness.

The presence of carotid plaque was associated with large aortic plaque (34.7% vs 14.3%; odds ratio, 3.18; 95% confidence interval, 1.36-7.46; P = .008).

Association Between CIMT and Large Aortic Arch Plaques

The association between CIMT and large aortic arch plaques was tested in univariate and multivariate models adjusting for demographic variables and established risk factors for aortic atherosclerosis ( Table 3 ). Total CIMT was associated with large arch plaque in univariate analysis ( P = .02). The association was of borderline significance ( P = .05) after adjustment for age and sex and was no longer significant after adjustment for diabetes and hypercholesterolemia. In the analysis of CIMT in different carotid segments, only CIMT in the BIF remained significantly associated with large arch plaque in a fully adjusted model ( P = .007) and also after further adjustment for the presence of carotid plaque ( P < .03; data not shown).

Table 3

Association between carotid IMT and large aortic arch plaque (≥4 mm)

	Total CIMT		CCA IMT		BIF IMT		ICA IMT
Model	Estimate (SE)	P	Estimate (SE)	P	Estimate (SE)	P	Estimate (SE)	P
Unadjusted	3.39 (1.46)	.02	1.95 (1.18)	.10	3.38 (1.14)	.003	1.31 (1.55)	.40
Adjusted for age and sex	3.00 (1.51)	.05	1.65 (1.22)	.18	3.15 (1.16)	.007	0.73 (1.63)	.66
Age	0.03 (0.02)	.28	0.03 (0.02)	.20	0.02 (0.02)	.31	0.03 (0.02)	.15
Sex	0.17 (0.40)	.68	0.22 (0.40)	.58	0.19 (0.41)	.65	0.20 (0.40)	.61
Adjusted for age, sex, and risk factors	3.02 (1.63)	.06	1.30 (1.30)	.32	3.45 (1.27)	.007	0.87 (1.73)	.62
Age	0.03 (0.03)	.18	0.04 (0.03)	.11	0.03 (0.03)	.22	0.04 (0.03)	.08
Sex	0.26 (0.44)	.55	0.33 (0.43)	.45	0.22 (0.44)	.62	0.32 (0.43)	.45
Diabetes	−1.23 (0.61)	.04	−1.13 (0.60)	.06	−1.39 (0.62)	.03	−1.10 (0.60)	.07
High cholesterol	1.15 (0.46)	.01	1.18 (0.46)	.01	1.10 (0.47)	.02	1.26 (0.45)	.005

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