On Quantifying Plaque Size and Intima-Media Thickness in Carotid and Femoral Arteries
Comments on Results From a Prospective Ultrasound Study in Patients With Familial Hypercholesterolemia
The aim of the present analysis in an ongoing observational study was to evaluate the possibility of measuring plaque size in ultrasound images from carotid and femoral arteries and the usefulness of quantitative plaque measurements in such a prospective study. Twenty-five patients with carotid plaques were identified in a group of patients with familial hypercholesterolemia (n=50) compared with 7 subjects in a low-risk control group (n=47). Only 20 of the 32 recorded plaques were accessible for quantitative follow-up measurements of area, base length, and thickness, which represents only 21% of all subjects investigated. In contrast, paired observations of intima-media thickness in the common carotid artery were available in 98% and in the carotid bulb in 87% of the subjects investigated. In those with paired observations of plaque area available, the data indicated a close relationship between the 2-year change recorded in plaque area and the 2-year change in intima-media thickness measured in a 10-mm-long predefined section of the carotid bulb (r=.81, P<.001, n=19). The corresponding relationship between change in plaque area and change in a 10-mm-long section of the common carotid artery was r=.38 and P<.05 (n=20). Quantitative measurements of plaques in the femoral arteries were also performed, but the results from these measurements were in most cases judged not to be useful. However, measurements of intima-media thickness in a 15-mm-long predefined section of the common femoral artery may be performed in a reproducible way in most patients. We conclude that the usefulness of plaque area measurements in prospective studies of the carotid artery seems limited because plaques available for quantitative measurements are present in only a small proportion of subjects. However, reproducible measurements of intima-media thickness in a predefined section of the carotid bulb are achievable in most subjects, and our data indicate that the changes recorded over time in the carotid bulb closely mirror changes occurring in the size of atherosclerotic plaques within the carotid artery region. In addition, present data indicate that measurements of intima-media thickness in the common carotid artery complement measurements performed in the carotid artery bulb in the study of early atherosclerosis.
- Received July 6, 1995.
- Revision received January 29, 1996.
Until recently knowledge of atherosclerotic disease in human arteries was based principally on autopsy findings and contrast angiography in selected patient groups and was therefore insufficient in many ways. The development of the B-mode ultrasound technique has made it possible to noninvasively study early atherosclerotic changes in large superficial arteries by measuring the I-M complex. The thickness of the carotid I-M complex has been related to cardiovascular risk factors in cross-sectional studies1 and the occurrence of coronary heart disease.2 3 An increased carotid I-M thickness as a risk factor for coronary heart disease has also been prospectively studied.4 Several preventive trials have reported results from cholesterol-lowering treatment in which the studied variable was common carotid I-M thickness5 6 or different scores of I-M thickness measured in the common carotid artery, the carotid bulb, and the internal carotid artery.7 8 When the studied variable has been maximum I-M thickness, the measurement must often have been performed on atherosclerotic plaques. Few attempts have been made, however, to perform a more detailed quantification of the plaque regarding its extension in a two-dimensional image,9 and in no study has there been a critical analysis of the value of quantitative measurements of plaque extension in ultrasound images from prospective studies.
The aim of the present analysis in an ongoing observational study10 was to evaluate, during 2 years of follow-up, the possibility of measuring the I-M area of atherosclerotic plaques in two-dimensional ultrasound images from carotid and femoral arteries and to evaluate the usefulness of quantitative plaque measurements in such a prospective study compared with measurements of I-M thickness in predefined sections of the carotid and femoral arteries.
Thirty men and 23 women with heterozygous FH were recruited from the lipid clinic of the Sahlgrenska Hospital, Gothenburg, Sweden, to participate in an observational study of the effects of cholesterol-lowering treatment. The specific criteria used for diagnosis of FH have been described in detail previously.11
The control group (n=53) was recruited from a representative population sample in Gothenburg. FH patients and control subjects were matched for sex, age, height, and weight11 ; all control subjects had serum cholesterol levels <6.5 mmol/L.
The FH patients were followed up at the lipid clinic and examined with ultrasound at the Wallenberg Laboratory. Several articles, including results from the first 3 years of follow-up, are available.10 11 12 One FH patient and 1 control subject died during the first 3 years of follow-up. All living patients and control subjects were asked to participate in a continued follow-up. One control subject had moved to another country and 1 to another part of Sweden; 2 patients and 3 control subjects were for other reasons unable or unwilling to visit the laboratory. For the present analysis 50 of the FH patients and 47 of the control subjects agreed to an additional 2-year follow-up. The anthropometric data for patients and control subjects are presented in Table 1⇓.
The FH patients had taken part in an observational study of lipid-lowering treatment for 3 years prior to the present follow-up.10 During the continued 2-year follow-up in the present study all but two of the patients had pharmacological cholesterol-lowering treatment: 26% had cholestyramine, 36% pravastatin, 6% simvastatin, and 28% a combination of lipid-lowering drugs. None of the control subjects had lipid-lowering treatment during follow-up.
Resting blood pressure was measured phonographically in the right arm after about 30 minutes of supine rest after the ultrasound examination. A heart-sound microphone was placed over the brachial artery, and an automatically inflated and deflated standard cuff (Bouche-Brecht) was used. Cuff pressure, Korotkoff sounds, and an electrocardiographic signal (lead II) were simultaneously recorded on a Mingograph (Siemens-Elema). Blood pressure was calculated to the nearest 1 mm Hg and was the mean of two recordings.13
Information on smoking habits was obtained by a self-administered questionnaire at baseline and checked with an interview at the 5-year follow-up. The total number of years of smoking was multiplied by the average number of cigarettes smoked daily (“cigarette-years”).
Blood samples for serum cholesterol and triglyceride levels and lipoprotein fractions were drawn after a fasting period of 10 to 12 hours. Cholesterol and triglyceride levels were determined by using fully enzymatic techniques.14 15 HDL cholesterol was determined after precipitation of apoB-containing lipoproteins with manganese chloride and heparin.16 LDL cholesterol was calculated as described by Friedewald et al.17
Examination was performed with an ultrasound scanner (Acuson 128) with a linear transducer and a transducer aperture of 38 mm. All baseline registrations (for both patient and control groups) were made with a 5-MHz transducer and all follow-up registrations with a 7-MHz transducer. (The 7-MHz transducer was not available at the baseline investigation.) The same transducer was used for the carotid artery and femoral artery registrations. In a methodological substudy, a comparison of the 5- and 7-MHz transducers showed similar mean values for I-M thickness (0.92±0.38 and 0.91±0.40 mm, respectively; r=.98, n=32). The electrocardiographic signal (lead II) was simultaneously recorded to synchronize the image capture with the top of the R wave to minimize variability during the cardiac cycle.18
The right carotid artery was scanned at the level of the bifurcation. The examination included ≈2 cm of the common carotid artery, the carotid bulb, and 1 cm of the internal and external arteries. The femoral artery was examined distally to the inguinal ligament, at the site where the artery divides into the superficial femoral artery and the profound femoral artery. The femoral artery was scanned ≈4 cm proximal and 1 cm distal to the flow divider. If a plaque was present, a frozen B-mode image of the thickest part of the plaque in the longitudinal view (visually judged and guided by both longitudinal and transverse scannings) was recorded on videotape. The procedure was repeated three times to achieve three separate images for analysis. A short sequence of real-time images was also recorded to assist in the interpretation of the frozen images. Pulsed Doppler was used to provide information on blood flow velocity.
Images for I-M thickness measurements were recorded from the carotid bulb, the common carotid artery, and the common femoral artery. At the position of the thickest part of the far wall (visually judged), a frozen longitudinal image was recorded on videotape. This procedure was repeated three times to achieve three separate images for analysis (see below). A short sequence of real-time images was also recorded on videotape to assist in the interpretation of the frozen images.
A study protocol was completed immediately after the examination, including a drawing of the vessel topography and a description of the probe angle when recording the images of the carotid and femoral arteries. These earlier protocols were only used to guide the transducer position at the follow-up examinations and did not give any information on I-M thickness or plaque occurrence.
Measurement of I-M Thickness and Lumen Diameter
The ultrasound images from the videotape were analyzed by using a computerized analyzing system.19 I-M thickness was defined as the distance from the leading edge of the lumen-intima interface to the leading edge of the media-adventitia interface of the far wall. The measurement of I-M thickness in the carotid artery was made along a 10-mm-long section in the common carotid artery and in the carotid bulb (Fig 1⇓). About 10 boundary points were marked along each echo interface by using a digitizer table and a mouse. Between these marked points the echo interfaces were interpolated by the computer, so that 100 boundary points were analyzed for each 10-mm section. The computer program calculated the average and maximum thicknesses (IMTmean and IMTmax) along the 10-mm-long section. Mean and minimum lumen diameters of the common carotid artery (LDmean and LDmin) were defined by the distance between the leading edge of the intima-lumen interface of the near wall and the lumen-intima interface of the far wall.11 An estimate of the mean cross-sectional area of the I-M complex was calculated as the difference between the total area inside the adventitia and the lumen area18 :|<|\pi|>|(|<|[|>|LD_|<|mean|>|/2|<|]|>||<|+|>|IMT_|<|mean|>|)^|<|2|>||<|-|>||<|\pi|>|(LD_|<|mean|>|/2)^|<|2|>|Cross-sectional I-M area was not calculated in patients with plaques present in the common carotid artery (n=3).
Measurements in the common femoral artery were made in a similar way as for the carotid artery, but along a 15-mm-long section proximal to the bifurcation.12
The mean of three separately analyzed images in the common carotid artery, the carotid bulb, and the common femoral artery, respectively, was used in the analyses. All images from the 3- and 5-year follow-up investigations were analyzed after the last 5-year visit and in a blinded manner with regard to the group to which the images belonged. This was done to avoid a possible drift in reading by the laboratory technologist (see “Variability Studies”).
A plaque was defined as a distinct area with an I-M thickness more than 50% thicker than neighboring sites.12 A quantitative analysis of plaques was performed during the 2 years of continued follow-up (3 to 5 years). All plaques in the near and far walls were recorded, but quantitative measurements were performed only on far-wall plaques (leading edge principle).20 If several plaques were present, measurements were performed on the largest plaque. Examinations at both 3 and 5 years were analyzed separately and in a blinded manner with regard to the group to which the images belonged. Each carotid plaque was recorded in a protocol that noted its location in the different carotid sections and whether it was located in the near or far wall. Similar descriptions were made for the femoral plaques.
Measurement of Plaque Size
A quantitative measurement was performed to estimate the size of the largest plaque in the far wall of the carotid and femoral arteries. The analysis system that was used for the measurement of I-M thickness was also used in this analysis. The contour of the plaque was outlined on the image, and the analyzing program calculated the area of the plaque (Fig 1⇑). The maximum thickness of the plaque was measured as the distance from the leading edge of the lumen-intima interface to the leading edge of the media-adventitia interface. As a third estimation of the extension of the plaque, the base of the plaque along the media-adventitia interface was marked to define the maximal length of the plaque in the longitudinal section. All measurements were performed on three images, and the mean of these was calculated.
Most of the examinations and all analyses of I-M thickness and plaque occurrence were performed by the same investigator. Seventeen FH patients and 18 control subjects were examined on two different occasions within 7 to 14 days to estimate intraobserver variability. The CV for recording and measurements in the common carotid artery was 10.6% for mean I-M thickness and 10.4% for maximum I-M thickness.12 The corresponding figures for measurements in the carotid bulb were 13.2% and 17.0%. Measurements of mean and maximum I-M thickness in the common femoral artery had CVs of 11.9% and 14.4%, respectively.12
Rereading of images from 50 subjects was performed by one investigator, with approximately 1 year between the first and second reading. Mean difference between the two readings in mean common carotid I-M thickness was 0.02±0.04 mm (P<.01; 95% CI, 0.01 to 0.04 mm; CV=3.8%). The corresponding figure for mean I-M thickness measured in the carotid bulb was 0.03±0.05 mm (P<.01; 95% CI, 0.01 to 0.05 mm; CV=3.8%). For mean femoral I-M thickness the mean difference between the first and second readings was 0±0.11 mm (NS; CV=6.9%). These data and those of others21 illustrate that a small drift may occur, even with a very experienced reader, when readings are done a long time apart.
The CVs calculated for rereading of plaques (20 from the 3-year and 20 from the 5-year follow-up) used in paired measurements in the present study were 19.5% for plaque area, 20.4% for plaque base, and 5.6% for plaque thickness.
All statistics were analyzed by using SPSS for Windows 6.1. In the variability study, means and SDs for differences between the two examinations were calculated. Intraobserver error(s) was calculated according to the formula s=SD/√2. The CV describes the difference as a percentage of the pooled mean value (x̄) and was calculated according to the formulaCV|<|=|>|\frac|<|s|<|\cdot|>|100|>||<||<|\bar|<|x|>||>||>| %Because the two groups by definition differed in serum lipid levels, these were not formally tested, but 95% CIs for each of these variables in the two groups have been given. Net difference was defined as the difference between the change observed within the control group and the change observed within the FH group between the baseline value and the value recorded at the follow-up investigation. For comparison between groups, the Mann-Whitney U test was used, and a t-distributed variable was used to calculate 95% CIs for differences. A nonparametric Spearman's rank correlation test was used in the correlation analysis with the relationship illustrated with Pearson's correlation coefficient (r). The proportions of smokers (never, past, or current) were compared by testing with a χ2 test. A value of P<.05 (two sided) was regarded as significant.
Table 1⇑ presents anthropometric data and some other characteristics in the two study groups at the 5-year follow-up. No significant differences were observed between the groups for any of the variables, but there was a nonsignificant tendency for somewhat more past smokers in the FH group.
Serum Lipid and Lipoprotein Levels
During the earlier 3-year follow-up, the LDL cholesterol of the FH group decreased 32% compared with the low-risk control group.10 No further significant change during the 2 years of continued follow-up was recorded. After 5 years of follow-up, total and LDL cholesterol levels and the LDL/HDL ratio were still higher in the FH group than in the control group (see 95% CIs, Table 2⇓). Serum triglyceride levels were also higher in the FH group, but for HDL cholesterol 95% CIs in the two groups overlapped.
Plaque Occurrence in the Carotid Artery
Altogether, 32 subjects with plaques in the carotid artery were identified at the 3-year follow-up: 7 (15%) in the control group (n=47) and 25 (51%) in the FH group (n=49). After 5 years of follow-up the corresponding figures were 12 subjects (26%) in the control group and 28 patients (57%) in the FH group. The majority of plaques were located in the carotid bulb (72%; Fig 2⇓).
Availability of Paired Observations
Only 20 of the 32 recorded plaques (63%) at the 3-year follow-up were accessible for quantitative follow-up measurements: 4 were in the control group and 16 in the FH group, which represents 21% of all subjects investigated (Fig 3⇓). Five of the plaques were not measurable because they were located in the near wall and the other seven because of difficulties with delineating the contour of the plaque.
Paired observations regarding changes in common carotid I-M thickness during the continued 2-year follow-up were obtained in 98% of the subjects investigated (n=97, Table 3⇓). The corresponding figure for the carotid bulb was 87% and for common femoral I-M thickness 92% (Table 3⇓).
Quantitative Measurements of Plaques in the Carotid Artery
Plaques in the FH group were nonsignificantly larger than plaques in the control group in area, base, and thickness (Table 4⇓). Net differences between the two groups in 2-year changes were not calculated because of the low number of plaques in the control group. The plaques available for paired analysis were mainly located in the carotid bulb (Fig 2⇑). The relationship between the change observed in mean I-M thickness in a predefined 10-mm-long section of the carotid bulb and the change in plaque area observed over the 2-year continued follow-up period is shown in Fig 4⇓ (top). The correlation coefficient was r=.81, P<.001, n=19. (In one patient the measurement of I-M thickness in the carotid bulb was not correctly performed at the 5-year follow-up due to a calibration error; this patient was excluded from the analysis.) The correlation coefficient for the relationship between the change observed in mean common carotid I-M thickness and the change in plaque area observed during 2 years was r=.38, P<.05, n=20 (Fig 4,⇓ bottom).
No significant correlation was found between the change in carotid bulb I-M thickness and the change in common carotid I-M thickness, nor was there any significant correlation between the change observed in carotid I-M thickness and the change in femoral I-M thickness.
Plaque Occurrence in the Femoral Artery
Thirteen (28%) of the control subjects (n=46) had femoral plaques at the 3-year follow-up compared with 31 (65%) of the FH patients (n=48). After 5 years of follow-up the corresponding figures were 13 (28%) and 32 (67%), respectively.
Quantitative measurements of plaques in the femoral arteries were also performed, but the results from these measurements were in most cases judged not to be useful. One of the difficulties with the measurements was that the femoral plaques often extended along several centimeters of the far wall of the common femoral artery, and uncertainty arose as to whether it should be regarded as one or several plaques. Another problem was that the femoral artery is often a curved vessel, and if the plaque extended along several centimeters it was difficult to get the whole plaque structure perpendicular to the ultrasound beam.
I-M Thickness During 5 Years of Follow-up
The mean I-M thickness of a 10-mm-long predefined section of the common carotid artery in the FH patients at baseline was 0.84±0.22 mm, and after 5 years of cholesterol-lowering therapy, 0.83±0.22 mm (mean difference, −0.01 mm, NS). The corresponding figure in the control group at baseline was 0.70±0.14 mm and after 5 years, 0.77±0.18 mm (mean difference, 0.07 mm; P<.001; 95% CI, 0.04 to 0.10 mm). There was a net difference of −0.08 mm (P<.01; 95% CI, −0.13 to −0.03 mm) when comparing changes in mean common carotid artery I-M thicknesses in the FH and control groups (Fig 5,⇓ top).
Mean I-M thickness of a 15-mm-long predefined section of the common femoral artery in the FH patients at baseline was 1.12±0.48 mm, and after 5 years of cholesterol-lowering therapy, 1.38±0.66 mm (mean difference, 0.26 mm; P<.01; 95% CI, 0.12 to 0.40 mm). The corresponding figure in the control group at baseline was 0.83±0.39 mm, and after 5 years, 0.96±0.49 mm (mean difference, 0.14 mm; P<.01; 95% CI, 0.05 to 0.22 mm). The net difference (0.12 mm) between the groups in mean femoral I-M thickness was not significant (Fig 5⇑).
This study was performed to evaluate in a 2-year prospective study the possibility of measuring the I-M area of atherosclerotic plaques in two-dimensional ultrasound images from carotid and femoral arteries and to evaluate the usefulness of these kinds of measurements in such prospective studies. The results indicate that the value of plaque area measurements in two-dimensional images from carotid and femoral arteries seems limited compared with measurements of I-M thickness in predefined sections of carotid and femoral arteries. This is because plaques available for quantitative measurements are only present in a small proportion of all subjects.
The development of atherosclerosis in carotid arteries typically begins with an increased I-M thickness in the bifurcation area, ie, in the proximal part of the internal carotid artery and the carotid bulb. The majority of carotid plaques were also localized to the carotid bulb (72%). Only 20 of the 32 identified carotid plaques at the 3-year follow-up however were accessible for paired quantitative measurements; this represents only 21% of all subjects investigated. In comparison, the availability of measuring mean and maximum I-M thickness in a predefined section of the carotid bulb was 87% of all investigated subjects in the continued 2-year follow-up. A simultaneous reading procedure of baseline and follow-up scannings would probably slightly diminish problems with the relatively high CV of carotid plaque area measurements. However, this procedure would also diminish blindness. Quantitative measurements of plaques in the femoral artery were judged to be unreliable.
The thickness of the I-M complex in the common carotid artery is often used as a key variable in ultrasound studies of atherosclerosis. Good-quality images of the far wall of the straight part of the common carotid artery are easy to obtain and may be achieved in nearly every case. An increased thickness of the I-M complex in the common carotid artery, however, does not necessarily indicate atherosclerosis,22 although several ultrasound studies have suggested that an increased I-M complex in the common carotid artery may be regarded as an early sign of atherosclerotic disease.1 2 11 The same close relationship that was recorded between change in plaque area and change in carotid bulb I-M thickness during the 2-year follow-up was not seen between change in plaque area and change in common carotid I-M thickness. One may speculate that this is because measurements of I-M thickness in the common carotid artery represent earlier changes in the arterial wall than changes present in atherosclerotic plaques and the carotid bulb.
Measurements of I-M thickness are used in pathophysiological studies of the local atherosclerotic process, but increased I-M thickness is also used as a marker of generalized atherosclerosis, including coronary atherosclerosis. The association between carotid I-M thickness and coronary atherosclerosis is still unclear, although several studies have been performed.23 24 One of the problems with these studies is that different methods are used when measuring degree of atherosclerosis in peripheral and coronary arteries. In ultrasound studies of carotid arteries I-M thickness is the main variable studied, while with coronary angiography stenosis is measured and not wall thickness. According to Glagov et al,22 large increases in wall thickness may be seen both in carotid and coronary arteries before a decrease in lumen diameter and stenosis development occur. Therefore it is not to be expected that ultrasound findings and findings from coronary angiography will necessarily be similar during the early development of atherosclerosis.
After 3 years of cholesterol-lowering therapy the FH patients showed a decrease in common carotid I-M thickness compared with the low-risk control group.10 However, the same favorable change in I-M thickness that was recorded in the carotid artery after 3 years of follow-up was not seen in the femoral artery.10 These results were confirmed after 5 years of cholesterol-lowering therapy (Fig 5⇑). Other groups also report a decrease in carotid I-M thickness after cholesterol-lowering therapy.5 6 7 8 25 Of interest is that two of these studies report a reduced rate of progression in the common carotid artery but no effect on the rate of progression in the bifurcation area.7 25 These data indicate that changes recorded in the carotid bulb may be of a somewhat different nature than those in the common carotid artery.
In the beginning of this observational study we did not have the experience to record high-quality images from the carotid bulb that would permit measurement of the I-M complex from this section of the artery. During the 2 years of continued follow-up, however, good-quality images with satisfactory reproducibility were recorded from this part of the artery. At the end of the study, in spite of the seemingly beneficial effect observed in the common carotid artery, mean I-M thickness was still thicker in all three studied arterial segments in FH patients than in control subjects. The percentage difference in mean I-M thickness between the two study groups in the common carotid artery was 9%, in the carotid bulb 27%, and in the common femoral artery 46%, which may indicate that these three arterial segments are in different stages of atherosclerotic disease.
In ultrasound studies of early atherosclerosis, it is important that a main variable can be studied in the majority of subjects investigated. The results from the present study indicate that the value of plaque area measurements in two-dimensional ultrasound images from the carotid artery seems limited, mainly because this variable can be studied in only a small proportion of all subjects. Even in a high-risk group, such as the FH patients in the present study, only half the subjects had a plaque in the carotid artery. These plaques were not all located in the far wall and in addition, measurements were missing because of difficulties in delineating the contour of the plaque. Plaque area measurements, however, may have a value if one of the inclusion criteria in a study is a measurable plaque located in the far wall of the carotid artery.
Reproducible measurements of I-M thickness in a predefined section of the carotid bulb are achievable in most subjects, and our data indicate that the changes recorded over time in the carotid bulb closely mirror changes that occur in the size of atherosclerotic plaques within the carotid artery region. Furthermore, one might speculate that measurements of I-M thickness in the common carotid artery may give information on the early changes in atherosclerotic disease that would differ from the information achieved from measurements in the carotid artery bulb. The value of plaque area measurements in two-dimensional images of the femoral artery also seems very limited. However, measurements of I-M thickness in a 15-mm-long predefined section of the common femoral artery may be performed in a reproducible way in most patients. Furthermore, a semiquantitative visual scoring of plaque occurrence in both carotid and femoral arteries has been used in ultrasound studies12 26 27 and may be useful as a complement to I-M thickness measurements.
In conclusion, valuable and reproducible measurements of I-M thickness in predefined sections of the common carotid artery, the carotid bulb, and the common femoral artery may be achieved in the majority of studied subjects. Furthermore, the data indicate that these three regions may complement each other in the study of atherosclerotic disease. Further studies are needed to clarify what possible differences in the pathophysiology and morphology of atherosclerotic disease are represented by an increased I-M thickness in the different arterial segments.
Selected Abbreviations and Acronyms
|CV||=||coefficient of variation|
This study was supported by grants from the Swedish Heart-Lung Foundation, the Swedish Medical Research Council (project B94-27X-10880-01A), and the Astra/Hässle Cardiovascular Research Laboratories, Mölndal, Sweden. Anders Odén of the Department of Mathematics, Göteborg University, Gothenburg, was the statistical consultant.
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