Population

MESA comprises a multiethnic population of 6,814 men and women aged 45 to 84 years enrolled between July 2000 and August 2002 at six sites in the United States. The MESA cohort includes white, African American, Hispanic, and Chinese participants. Participants were excluded if they had physician diagnoses of myocardial infarction (MI), stroke, transient ischemic attack, heart failure, angina, or atrial fibrillation; histories of any cardiovascular procedure; weight > 300 lb; pregnancy; or any medical conditions that would prevent long-term participation. MESA protocols and all studies described herein have been approved by the institutional review boards of all collaborating institutions, and all participants gave informed consent.

Risk Factors and Anthropomorphic Variables

Age, sex, race/ethnicity, and medical history as well as medication use were self-reported. Current smoking was defined as self-report of one or more cigarettes in the past 30 days. Resting systolic and diastolic blood pressures were measured three times in the seated position using a Dinamap Pro 100 automated oscillometric sphygmomanometer (Critikon, Tampa, FL); the average of the last two measurements was used in these analyses.

Glucose and lipids were measured after a 12-hour fast. Serum glucose was measured by rate-reflectance spectrophotometry on the Vitros analyzer (Johnson & Johnson Clinical Diagnostics, Inc, Rochester, NY). Diabetes mellitus was determined according to the 2003 American Diabetes Association fasting criteria. Total cholesterol was measured using a cholesterol oxidase method (Roche Diagnostics GmbH, Mannheim, Germany), as was high-density lipoprotein (HDL) after precipitation of non-HDL cholesterol with magnesium/dextran.

The Framingham risk factors used in the analyses are the original risk factors determined for coronary heart disease (CHD) events (including angina) as reported by Wilson et al . : age, systolic blood pressure, total cholesterol, HDL cholesterol, smoking history, and diabetes, to which we added sex and race/ethnicity. We used the risk factors rather than calculated risk scores to circumvent calibration problems due to the diverse ethnic composition of our cohort. We also added use of blood pressure–lowering medication as part of the augmented Framingham risk score for CVD proposed by D’Agostino et al . in a sensitivity analysis.

Carotid Artery Measures

The results of the CCA measurements are part of a comprehensive protocol that acquired videotaped images from both sides of the neck and included imaging of the distal CCA (one view on each side) and the proximal internal carotid artery and bulb (three projections on each side). Details of the carotid artery evaluation have previously been described, and the acquisition protocol is the same one used in the Cardiovascular Health Study. The participants were imaged in the supine position with the head rotated 45° away from the side being imaged. The CCA was imaged with the beginning of the bulb shown on the image (to the left). A matrix-array probe (M12L; GE Medical Systems, Waukesha, WI) was used with the frequency set at 13 MHz, with two focal zones and a frame rate of 32 frames/sec.

All carotid artery measurements were blinded and made at the ultrasound reading center at Tufts Medical Center (Boston, MA). Videotapes were reviewed, and images were selected from a short cine recording lasting a few seconds. The readers were instructed to capture (digitize) a CCA image for IMT measurement such that the artery lumen had the smallest diameter during the cardiac cycle, the near and far walls had clear interfaces, and there was minimal degradation due to motion. Near and far wall common carotid IMT measurements were made of each CCA (one projection) using hand-drawn continuous tracings of the intima-lumen and media-adventitia interfaces ( Figure 1 ) that were processed with a previously described algorithm.

Representative image of the right common carotid artery. A reader has identified the near and far wall interfaces. The reader has then identified the beginning of the bulb (divergence of the outer wall of the artery) and drawn the interfaces to the right. The lines are color coded and, from the top of the image, are the near wall interfaces: periadventitia/adventitia ( red ), adventitia/media ( orange ), and intima/lumen ( yellow ). The far wall interfaces are the lumen/intima ( green ), media/adventitia ( blue ), and adventitia/periadventitia ( pink ) interfaces.

Far wall IMT was the mean of the far wall IMT of both the right and left common carotid arteries. Similarly, near wall IMT was the mean of the near wall IMT of both the right and left common carotid arteries. The mean IMT was the mean of all four CCA IMT values.

Outcomes

Events were identified during follow-up examinations and by telephone interview conducted every 9 to 12 months to inquire about all interim hospital admissions, cardiovascular outpatient diagnoses, and deaths. Copies were obtained of all death certificates and of all medical records for hospitalizations and outpatient cardiovascular diagnoses. The review process included all generated International Classification of Diseases, Ninth Revision, definitions, but the final adjudication of MESA end points was based on specific criteria applied to data obtained from medical records by two committee members or by the whole-study events committee in case of disagreement.

CHD events included MI, death due to CHD, resuscitated cardiac arrest, definite or probable angina followed by coronary revascularization, and definite angina not followed by coronary revascularization. Cases of coronary artery revascularization that did not have concurrent diagnoses of angina were not included, to minimize possible referral bias. “Hard” CVD events included MI, resuscitated cardiac event, stroke, and death due to CHD or stroke.

The diagnosis of MI was based on a combination of symptoms, electrocardiographic findings, and circulating cardiac biomarkers. Death was considered related to CHD if it occurred <28 days after a myocardial infarct, if the participant had experienced chest pain within the 72 hours preceding death, or if the participant had a history of CHD and died without documentation of any other cause of death. Resuscitated cardiac arrest included participants who successfully recovered from full cardiac arrest through cardiopulmonary resuscitation. Adjudicators graded the presence of angina on the basis of the following criteria: definite or probable angina required clear and definite documentation of symptoms without the development of MI. Definite angina also required objective evidence of reversible myocardial ischemia or obstructive coronary artery disease. Stroke was defined as a documented new-onset neurologic event lasting >24 hours or until death if death occurred in the first 24 hours.

Statistical Analyses

The mean (and SD) and median (and interquartile range) values of continuous variables and the percentage distribution of dichotomous variables as a percentage in each group are shown for the participants. We calculated the individual near and far wall IMT measurements for each individual and reported the difference as a mean and SD as well as median and interquartile range.

Reproducibility was assessed in two ways: (1) repeat image acquisitions and (2) the rereading of already acquired imaging studies. Blinded replicate scans were performed on 150 participants. Because of blinding, the same readers read most of the 150 repeat studies (144 of the 150 studies). Blinded rereads of 155 studies were also performed. The same readers (intrareader variability) read 78 of these cases and different readers (interreader variability) the remaining 77 cases. Reproducibility was calculated as Pearson correlation coefficients and 95% CIs.

Multivariate linear regression models were created with three separate outcomes: near wall IMT, far wall IMT, and mean IMT. The original Framingham risk factors were used as independent variables with the addition of race/ethnicity.

The main outcome was time to first CHD event. A baseline multivariate Cox proportional hazards model using robust error handling was created with the components of the Framingham risk score: age, systolic blood pressure, diabetes, HDL cholesterol, total cholesterol, and smoking, to which we added sex and race/ethnicity. To this model was added each of the three IMT metrics as continuous variables to create three new models for the estimation of hazard ratios (HRs). We used standardized values for systolic blood pressure, total and HDL cholesterol, as well as the IMT metrics to facilitate comparisons of the hazards ratios. Harrell’s C statistics were obtained for all of the Cox proportional hazards models. The predictive value of each model with a given IMT measurement was compared with the baseline model using the differences in Harrell’s C statistic. The proportional hazards assumption was verified using Schoenfeld residuals. Net reclassification improvement and incremental discrimination improvement were calculated as described by Pencina et al . Net reclassification improvement was calculated form the Framingham cut points of 6% and 20% at 10 years.

Kaplan-Meier curves were generated for illustrative purposes using unadjusted quartiles of near wall, far wall, and combined near and far wall IMT.

We performed a sensitivity analysis by using the difference between near wall and far wall IMT as a variable in the multivariate Cox proportional hazards models adjusted for risk factors, sex, and race/ethnicity. We also evaluated the predictive power of IMT measurements for incident “hard” CVD events in a sensitivity analysis.

Statistical analyses were performed using Stata version 11.2 (StataCorp LP, College Station, TX). The level of statistical significance was set at P ≤ .05. Net reclassification improvement and incremental discrimination improvement were calculated with the help of a Stata add-on from the Uppsala Clinical Research Center ( http://www.ucr.uu.se/en/index.php/epistat/program-code/306-nri-and-idi ).

Cross-Sectional Associations of Risk Factors with IMT

Results of the multivariate linear regression models are shown in Table 2 . All risk factors were significantly associated with the individual IMT measurements with the exception of current smoking. The respective coefficients for age, systolic blood pressure, HDL cholesterol, and diabetes in the three models were similar. Despite remaining significant in all cases, the standardized coefficients for total cholesterol varied from 0.037 for each change of 1 mm in near wall IMT to 0.055 for far wall IMT. Differences in the coefficients were also notable for sex, increasing from 0.03 for a change of 1 mm in near wall IMT to 0.045 for far wall IMT. Racial/ethnic differences were present, with Chinese participants having lower IMT values than whites and blacks having larger IMT values than whites. Overall, the best goodness of fit for risk factors was for mean IMT ( R ² = 0.31), followed by near wall IMT ( R ² = 0.26) and then far wall IMT ( R ² = 0.22).

Longitudinal Prediction of CHD Events by IMT

Results of Kaplan-Meir failure curves are plotted by quartile of IMT values in Figure 2 A for near wall IMT, Figure 2 B for far wall IMT, and Figure 2 C for mean IMT. Results for the multivariate Cox proportional hazards model that included all risk factors are shown to the left of Table 3 . Important predictors of CVD were increasing age, male sex, current smoking, increasing systolic blood pressure, presence of diabetes, lower HDL cholesterol, and elevated total cholesterol. There was a tendency for whites to have stronger associations with CHD than other ethnicities. The HR for near wall IMT was not significant (1.01; 95% CI, 0.92–1.11) for each increase of 0.19 mm, whereas the HRs for mean IMT (1.17; 95% CI, 1.08–1.28) and far wall IMT (1.21; 95% CI, 1.13–1.30) were significant for respective increases of 0.21 and 0.18 mm.

(A) Kaplan-Meier curves showing incident coronary heart disease events for the four quartiles of near wall intima-media thickness. Associations are significant (log-rank = 58, P < .0001). Values for the near wall quartiles are <0.65, 0.65 to 0.76, 0.76 to 0.89, and >0.89 mm. (B) Kaplan-Meier curves for far wall intima-media thickness. Note that the curves diverge earlier than for the near wall measurements in (A) and that the associations are stronger (log-rank = 140, P < .0001). Values for the far wall quartiles are <0.6, 0.6 to 0.71, 0.71 to 0.84, and >0.84 mm. (C) Kaplan-Meier curves showing incident coronary heart disease events for the four quartiles of mean near and far wall intima-media thickness. Associations are significant (log-rank = 140, P < .0001). Values for the intima-media thickness quartiles are <0.64, 0.64 to 0.74, 0.74 to 0.858, and >0.858 mm.

Table 3

Results of multivariate Cox proportional hazards models with time to first CHD event as outcome

Variables	Risk factors			Risk factors and near wall IMT			Risk factors and far wall IMT			Risk factors and mean of the far wall and near wall IMT
	HR	Lower 95% CL	Upper 95% CL	HR	Lower 95% CL	Upper 95% CL	HR	Lower 95% CL	Upper 95% CL	HR	Lower 95% CL	Upper 95% CL
Age	1.05	1.04	1.06	1.05	1.04	1.06	1.04	1.03	1.05	1.04	1.03	1.06
Sex (male)	2.06	1.68	2.54	2.06	1.67	2.54	1.97	1.60	2.43	1.98	1.61	2.45
Race/ethnicity
White (referent)	—	—	—	—	—	—	—	—	—	—	—	—
Chinese	0.58	0.41	0.80	0.58	0.41	0.80	0.59	0.42	0.82	0.60	0.43	0.83
African American	0.78	0.62	0.99	0.78	0.62	0.99	0.78	0.62	0.98	0.76	0.61	0.96
Hispanic	0.77	0.61	0.98	0.77	0.61	0.98	0.79	0.62	1.00	0.78	0.61	0.99
Diabetes (yes)	1.85	1.49	2.30	1.85	1.49	2.30	1.79	1.44	2.22	1.79	1.44	2.22
Smoker (yes)	1.66	1.29	2.14	1.66	1.28	2.14	1.65	1.28	2.12	1.64	1.27	2.11
Systolic blood pressure ∗	1.29	1.18	1.41	1.29	1.18	1.41	1.24	1.14	1.36	1.25	1.14	1.37
HDL cholesterol ∗	0.85	0.76	0.95	0.85	0.76	0.95	0.86	0.76	0.96	0.86	0.76	0.96
Total cholesterol ∗	1.14	1.04	1.25	1.14	1.04	1.25	1.13	1.03	1.25	1.14	1.03	1.25
IMT ∗				1.01 †	0.92	1.11	1.21	1.13	1.30	1.17	1.08	1.28

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