Background
Common carotid artery intima-media thickness (IMT), a measure of atherosclerosis, varies between peak systole and end-diastole. This difference might affect cardiovascular risk assessment.
Methods
IMT measurements of the right and left common carotid arteries were synchronized with an electrocardiogram, using the R wave for end-diastole and the T wave for peak systole. IMT was measured in 2,930 members of the Framingham Offspring Study. Multivariate regression models were generated with end-diastolic IMT, peak systolic IMT, and change in IMT as dependent variables and Framingham risk factors as independent variables. End-diastolic IMT estimates were compared with the upper quartile of IMT on the basis of normative data obtained at peak systole.
Results
The average age of the study population was 57.9 years. The average difference in IMT during the cardiac cycle was 0.037 mm (95% confidence interval, 0.035–0.038 mm). End-diastolic IMT and peak systolic IMT had similar associations with Framingham risk factors (total R 2 = 0.292 vs 0.275) and were significantly associated with all risk factors. In a fully adjusted multivariate model, thinner IMT at peak systole was associated with pulse pressure ( P < .0001), low-density lipoprotein cholesterol ( P = .0064), age ( P = .046), and no other risk factors. Performing end-diastolic IMT measurements while using upper quartile peak systolic IMT normative data led to inappropriately increasing by 42.1% the number of individuals in the fourth IMT quartile (high cardiovascular risk category).
Conclusion
The difference in IMT between peak systole and end diastole is associated with pulse pressure, low-density lipoprotein cholesterol, and age. In this study, the mean IMT difference during the cardiac cycle led to an overestimation by 42.1% of individuals at high risk for cardiovascular disease.
Common carotid artery intima-media thickness (cIMT) is an ultrasound marker of incident cardiovascular disease. Carotid IMT measurements are most often done on ultrasound images of the carotid artery acquired at end-diastole.
Small studies have shown that IMT changes during the cardiac cycle, with IMT decreasing as the artery diameter increases during systole.
Current strategies recommending the use of carotid IMT for cardiovascular risk assessment indicate that individuals be classified as at high risk if their IMT is above the 75% percentile at end-diastole. A review of recommended normative data shows inconsistent synchronization of IMT measurements with the cardiac cycle. In addition, reference is often made to normative data derived from the Atherosclerosis Risk in Communities (ARIC) study, in which IMT was measured in 12,629 of 15,800 participants in whom it was attempted. The ARIC common carotid artery IMT measurements, although often referred to as the best source for IMT normative data, were acquired at peak systole.
We hypothesized that IMT measurements made at peak systole and end-diastole have similar associations with Framingham risk factors and studied this hypothesis in members of the Framingham Offspring Study cohort who were free of prevalent cardiovascular disease. We also hypothesized that IMT measured at end-diastole may overclassify individuals into a high cardiovascular disease risk category when referenced against normative IMT data acquired at peak systole.
Methods
Subject Population and Measurement of Risk Factors
The Framingham Offspring Study cohort was constituted in 1970 and included 2,483 men and 2,641 women, selected by virtue of being the offspring and spouses of the original Framingham Heart Study participants. At inception, ages ranged from 5 to 70 years. Examination cycle 1 was conducted between 1971 and 1975, cycle 2 from 1979 to 1983, cycle 3 from 1983 to 1987, cycle 4 from 1987 to 1991, cycle 5 from 1991 to 1995, and cycle 6 from 1995 to September 1998. The total number of individuals seen during the cycle 6 clinic visit was 3,532, of whom 1,657 were men and 1,875 were women. Carotid ultrasound data were acquired from 1,593 men and 1,784 women (corresponding to 95.6% of participants [3,377 of 3,532] seen at examination cycle 6). We further restricted our analyses to individuals free of prevalent cardiovascular disease (according to the Framingham Heart Study definition ) and with complete risk factor data as well as both peak systolic and end-diastolic carotid IMT measurements (2,930 of 3,377 individuals with carotid ultrasound examinations [86.8%]) All participants provided informed consent, and the institutional review board of the Boston Medical Center approved the study protocol.
During the clinic visit, a medical history was obtained and a physical examination was performed. The cardiovascular risk factors relevant to this study were the components of the Framingham risk score (systolic blood pressure, cigarette smoking status, total serum cholesterol, high-density lipoprotein cholesterol, and diabetes), to which was added diastolic pressure to calculate pulse pressure. Treatment for hypertension was determined from the medical history.
Blood pressure was determined from the average of two resting readings taken by a physician using a 14-cm blood pressure cuff on the right arm. Smoking status was based on a self-reported history of cigarette smoking. All lipid analyses were performed at the Framingham Heart Study laboratory according to the Standardization Program of the Centers for Disease Control and Prevention and the National Heart, Lung, and Blood Institute Lipid Research Clinics. The presence of diabetes was based on a history of diabetes, either current or previous fasting glucose ≥126 mg/dl, or current or previous use of antihyperglycemic medication.
Ultrasound Studies
Ultrasound studies were acquired (Toshiba SSH-140A; Toshiba Medical Systems, Tustin, CA) according to a standard protocol using a high-resolution linear-array 7.5-MHz transducer at the level of the common carotid artery, at a frame rate of 32 Hz. The images were acquired with the participant’s head rotated 45° opposite to the side being imaged, with the transducer held 45° from the vertical. Images were centered below the common carotid artery bulb, the edge of the bulb to the left of the image, in an area free of plaque. The image scale was set at 140 pixels/cm. A continuous series of images lasting 3 sec were first acquired and stored in the memory of the ultrasound device and on Hi8 videotape (EV C100; Sony Corporation, Park Ridge, NJ). The acquired series of images were then slowly replayed in the ultrasound device’s playback mode and reviewed. A frame counter highlighted the position of the stored image with respect to the synchronously acquired electrocardiogram. The first image to be acquired was centered on the T wave. The sonographer was allowed to select the image with the largest systolic expansion if located within two frames of the T wave. The image was directly digitized into a Macintosh IIci (Apple Corporation, Cupertino, CA) with a PixelBuffer digitizing board (Perceptics Corporation, Knoxville, TN) and stored on a write-once, read-many drive (Pioneer Electronics, Long Beach, CA) using customized software. The process was then repeated, this time with the sonographer selecting an image with the frame marker on the R wave of the electrocardiographic tracing and with the sonographer confirming that this corresponded to the smallest diameter. The selected images were also recorded on videotape in addition to the dynamic video sequence.
A certified reader reviewed all images and performed IMT measurements using an offline and blinded process whereby the reader made continuous tracings of the key arterial wall interfaces (lumen-intima and media-adventitia). The images were analyzed at least 1 week after their acquisition. Custom-designed software displayed the images from the optical disks through the Macintosh computer onto a 19-inch screen. The reader activated a series of tools that permitted review of the images, their grading as to quality, and the drawing of lines at the key wall interfaces (lumen-intima and media-adventitia). An automated algorithm then determined the mean IMT values by processing the positions of these lines. Image quality was scored on a Likert-type scale ranging from 1 to 5, with 5 representing the best quality image possible, with all key interfaces visualized and traceable, and 1 representing uninterpretable (visualization of one interface or less). On the basis of the availability of ultrasound devices and sonographers, carotid ultrasound studies were acquired from 3,377 individuals (1,593 men and 1,784 women). Final numbers reflect the availability of Framingham risk factor data, the absence of prevalent disease, and IMT measurements at both end-diastole and peak systole ( n = 2,930). Reproducibility was assessed by replicate (interreader) measurements as part of the certification process in 37 randomly selected participants. The interreader Pearson’s correlation coefficients between replicate readings for mean CCA end-diastolic IMT was 0.94, whereas it was 0.93 for the mean CCA IMT at peak systole.
The videotaped study was replayed at the time of image analysis to help identify key anatomic landmarks. The videotape record had to be used to redigitize the images in 16 (of 2,930) participants because of poor quality of the images stored on the optical disks.
Statistical Analysis
The mean (and standard deviation) values of continuous variables, Framingham risk factors, peak systolic IMT, end-diastolic IMT, and change in IMT between diastole and systole (end-diastolic IMT to peak systolic IMT) are presented. Dichotomous variables are presented as percentages.
Multivariate regression models were fitted for peak systolic IMT and end-diastolic IMT as dependent variables with age, gender, smoking, diabetes, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein cholesterol, and pulse pressure.
We generated a parsimonious model using multivariate linear regression with the difference in IMT between diastole and systole as the outcome, forcing age and gender into the model.
The cumulative distribution of IMT measurements made at peak systole was used as normative data. This was done because peak systole was used to measure IMT in the ARIC study. Interquartile ranges of IMT were calculated. The IMT values obtained at end-diastole were matched against these normative values. The percentage overestimation of individuals at increased risk (upper quartile of normative IMT values) was calculated as the percentage increase of individuals within the upper quartile.
All analyses were run using SAS version 9.1 (SAS Institute Inc., Cary, NC), and two-sided P value < .05 were considered statistically significant.
Results
The mean age of our population was 57.9 years, with 55.3% women ( Table 1 ). The mean end-diastolic IMT was 0.595 ± 0.131 mm, and the mean peak systolic IMT was 0.558 ± 0.123 mm. The mean difference was 0.037 ± 0.053 mm, indicating a thinner wall thickness at peak systole when the artery is maximally dilated.
| Variable | Value |
|---|---|
| Age (y) | 57.9 ± 9.6 |
| Men/women | 44.7% (1,310)/55.3% (1,620) |
| LDL cholesterol (mg/dl) | 127.8 ± 33.3 |
| High-density lipoprotein cholesterol (mg/dl) | 52.0 ± 16.0 |
| Systolic pressure (mm Hg) | 127.8 ± 18.7 |
| Diastolic pressure (mm Hg) | 75.6 ± 9.4 |
| Pulse pressure (mm Hg) | 52.2 ± 15.4 |
| Treated blood pressure (yes/no) | 24.4% (714)/75.6% (2,216) |
| Smoker (yes/no) | 14.8% (433)/85.2% (2,497) |
| Diabetes (yes/no) | 8.4% (246)/91.6% (2,684) |
| Common carotid artery IMT diastole (mm) | 0.595 ± 0.131 |
| Common carotid artery IMT systole (mm) | 0.558 ± 0.123 |
| Difference in IMT (mm) | 0.037 ± 0.053 |
For the right common carotid artery, mean image quality scores were 4.12 ± 0.71 for end-diastolic images and 4.13 ± 0.70 for peak systolic images. On the left, mean scores were 4.02 ± 0.74 for end-diastolic images and 4.04 ± 0.75 for peak systolic images.
Multivariate-Adjusted Associations between End Diastole and End Systole
IMT and all Framingham risk factors were similar ( Table 2 ), with all risk factors being significantly associated with the respective IMT values. The overall model for predicting IMT from Framingham risk factors explained 29.2% of the variability for end-diastolic IMT and 27.5% for peak systolic IMT. The overall predicted variability for the models did not change after pulse pressure was substituted for systolic and diastolic pressure ( Table 3 ).
| Variable | Peak systolic IMT | End-diastolic IMT | ||
|---|---|---|---|---|
| β | P | β | P | |
| Sex (female) | −0.044 | <.0001 | −0.043 | <.0001 |
| Age | 0.0042 | <.0001 | 0.0045 | <.0001 |
| LDL cholesterol | 0.00019 | .0018 | 0.00027 | <.0001 |
| High-density lipoprotein cholesterol | −0.00065 | <.0001 | −0.00067 | <.0001 |
| Systolic pressure | 0.0013 | <.0001 | 0.0016 | <.0001 |
| Diastolic pressure | −0.0012 | <.0001 | −0.0017 | <.0001 |
| Diabetes (yes) | 0.023 | .0016 | 0.022 | .0036 |
| Smoker (yes) | 0.029 | <.0001 | 0.032 | <.0001 |
| Blood pressure treatment (yes) | 0.012 | .013 | 0.015 | .0042 |
| Variable | Peak systolic IMT | End-diastolic IMT | ||
|---|---|---|---|---|
| β | P | β | P | |
| Sex (female) | −0.045 | <.0001 | −0.043 | <.0001 |
| Age | 0.0042 | <.0001 | 0.0045 | <.0001 |
| LDL cholesterol | 0.00019 | .0014 | 0.00027 | <.0001 |
| High-density lipoprotein cholesterol | −0.00065 | <.0001 | −0.00067 | <.0001 |
| Pulse pressure | 0.0013 | <.0001 | 0.0016 | <.0001 |
| Diabetes (yes) | 0.023 | .0016 | 0.023 | .0036 |
| Smoker (yes) | 0.029 | <.0001 | 0.032 | <.0001 |
| Blood pressure treatment (yes) | 0.013 | .010 | 0.015 | .0037 |
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