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Arterial Wall Thickness inFamilial Hypercholesterolemia

Ultrasound Measurement of Intima-Media Thicknessin the Common Carotid Artery

Inger Wendelhag, Olov Wiklund, and John Wikstrand

B-mode ultrasound was used to noninvasively determine wall thickness and lumen diameter in thecommon carotid artery in patients with familial hypercholesterolemia (n=53) and in a controlgroup (n=53). The controls were matched for sex, age, height, and weight, and all had a serumcholesterol level below 6.5 mmol/1. The study was performed to evaluate whether the patients hada thicker arterial wall compared with that of the control group. Wall thickness was determined asthe combined intima-media thickness of the far wall and is presented as the mean and maximumthickness of a 10-mm-long section of the common carotid artery. The difference between the groupswas 0.13 mm in mean wall thickness (p<0.001; 95% confidence interval, 0.07-0.18 mm) and 0.20mm in maximum wall thickness (p<0.001; 95% confidence interval, 0.09-023 mm). Fifty of thesubjects were examined twice to estimate the interobserver variability. The coefficients of variationfor mean and maximum wall thickness were 102% and 8.9%, respectively. The two study groupswere well matched and differed only in lipid levels. Thus, there is reason to believe that thedifference in wall thickness can be explained by the background of familial hypercholesterolemiaand the increased cholesterol levels. {Arteriosclerosis and Thrombosis 1992; 12:70-77)

During recent years, noninvasive methodshave been developed to study the extent ofclinical atherosclerotic disease in the ca-

rotid arteries.1 B-mode (two-dimensional) medicalultrasound also seems to be a promising method forstudies of the early, silent phases of atheroscleroticdisease in the arterial wall.2 However, only largearteries like the carotid and femoral arteries arepresently amenable to investigation. The arterial wallchanges in these vessels are meant to be used asindicators for general atherosclerosis, including cor-onary atherosclerosis.

Familial hypercholesterolemia is a common inher-ited disease characterized by elevated low densitylipoprotein (LDL) cholesterol levels and tendon xan-thomas. These patients are at a high risk for coronaryheart disease.3

New drugs are available to lower plasma lipopro-tein levels. With B-mode ultrasound, it is possible toperform repeated examinations and study the

From the Wallenberg Laboratory for Cardiovascular Research,Sahlgrenska Hospital, Gothenburg University, Gothenburg, Sweden.

Supported by grants from the Swedish Heart-Lung Foundation,the Swedish Medical Research Council (project 4531), and theAstra Cardiovascular Research Laboratories, Molndal, Sweden.

Address for correspondence: John Wikstrand, Wallenberg Lab-oratory, Sahlgrenska Hospital, S-413 45 Gothenburg, Sweden.

Received June 20, 1991; accepted September 5, 1991.

changes in vessel wall morphology over time. Hence,an important role of the method would be to evaluatethe effect of cholesterol lowering on the atheroscle-rotic process. However, a prerequisite for the designof such studies is more information about the meth-od's sensitivity and variability.

Earlier studies of in vitro experiments have shownthat it is possible to measure lumen diameter and thecombined intima-media thickness of the far wall in thecommon carotid artery.4 Several studies of selectedpatient material have also been published,5"8 but noneof the studies published so far has dealt exclusively withpatients with familial hypercholesterolemia.

The aim of this study was to evaluate whetherpatients with familial hypercholesterolemia have athicker arterial wall in the common carotid arterycompared with that of a sex- and age-matchedcontrol group.

MethodsStudy Groups

A group of patients (n=53) with heterozygousfamilial hypercholesterolemia was recruited from thelipid clinic of the Sahlgrenska Hospital, Gothenburg,Sweden, to participate in the present study of ultra-sound examination of the carotid artery. This groupwill be referred to as the "hypercholesterolemicgroup." The diagnosis of familial hypercholesterol-

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Wendelhag et al Arterial Wall Thickness in Hypercholesterolemia 71

TABLE 1. Inclusion Criteria for the B-Mode Ultrasound Study

Al Serum cholesterol >9Oth percentile of the population

A2 Serum triglycerides <3.0 mmol/1

A3 High density lipoprotein cholesterol <2.0 mmol/1

Bl Tendon xanthomata in patient

B2 Tendon xanthomata in one first-degree or twosecond-degree relatives

B3 Assay of receptor expression on fibroblasts consistent withreceptor deficiency

B4 One first-degree or two second-degree relatives withhyperlipoproteinemia type IIA, according to Al-3

B5 At least two first-degree or second-degree relatives withcoronary heart disease before age 50 years (men) or 60years (women) (myocardial infarction, angina pcctoris, orsudden death)

The presence of Al plus Bl, B2, or B3, or Al-3 plus B4 or B5was required.

emia was defined as described in Table I.9 Patientswere 30 men and 23 women with a mean age of 52.8years (range, 20-72 years) (Table 2). Premenopausalwomen were excluded, as were patients with diabe-tes, hepatic dysfunction, severe hypertension, or ex-cessive obesity. The patients were examined after atleast 8 weeks of a wash-out period from previoustreatment with a lipid-lowering drug. During thisperiod, the patients were given dietary advice.

A control group with serum cholesterol levelsbelow 6.5 mmol/1 was recruited from a representativepopulation sample in Gothenburg. To each patientwith hypercholesterolemia a subject was matchedwith regard to sex, age, height (±10 cm), and weight(±7 kg). Age matching was within ±5 years except intwo cases ( -6 and +7 years) (Table 2). For technicalreasons, high-quality images from the common ca-rotid artery were missing for two patient-controlpairs. Therefore, all data are presented for 51 pairs.

In the hypercholesterolemic group, 14 patients hadhad a myocardial infarction and one had had astroke. In the control group, two subjects had had a

TABLE 2. Anthropometric Data, Blood Pressure, Heart Rate, andSmoking Habits of Study Participants

Variable

Age (yr)

Body height (m)

Body weight (kg)

BMI (kg/m2)

SBP (mm Hg)

DBP (mm Hg)

HR (beats per minute)

Never smoked (%)

Past smoker (%)

Current smoker (%)

Total cigarette-years

Controlgroup

("=51)

52.8±11.8

173±8

72.6±12.4

24.2±3.5

125±17

74±10

63 + 10

57

22

22

10,970

Familialhypercholesterolemia

group (n°51)

52.2+12.1

173±10

74.1 ± 13.7

24.7±3.8

124+16

77±10

61 + 10

33

43

24

10,420

Values arc mean±SD.BMI, body mass index; SBP/DBP,

blood pressure; HR, heart rate.systolic/diastolic arterial

myocardial infarction and none had had a stroke.Eight patients with hypercholesterolemia and fivecontrol subjects were being treated for hypertensionat the time of examination.

Blood PressureResting blood pressure was measured phono-

graphically in the right arm after about 30 minutes ofsupine rest, in connection with the ultrasound exam-ination.10 A heart-sound microphone was placed overthe brachial artery, and an automatically inflated anddeflated standard cuff (Bouche-Brecht, FRG) wasused. Cuff pressure, Korotkoff sounds, and an elec-trocardiographic signal (lead II) were simultaneouslyrecorded on a Mingograph (Siemens-Elema, Swe-den). Blood pressure was calculated to the nearest 1mm Hg and was the mean of two recordings.10

SmokingInformation on smoking habits was obtained by a

self-administered questionnaire. The total number ofyears of smoking was multiplied by the averagenumber of cigarettes smoked daily. The product wascalled "cigarette-years."

Biochemical AnalysisBlood samples for total serum cholesterol, serum

triglycerides, and lipoprotein fractions were drawnafter a fasting period of 10-12 hours. Cholesterol andtriglyceride levels were determined by fully enzy-matic techniques by using a Gilford System 3500Autoanalyzer (Gilford Instruments Inc., Oberlin,Ohio).11'12 High density lipoprotein (HDL) choles-terol was determined after precipitation of apolipo-protein (apo) B-containing lipoproteins with manga-nese chloride and heparin.13 LDL cholesterol wascalculated as described by Friedewald et al.14

Apos A-I, B, and E were analyzed by using frozensamples stored at -80°C. Apo A-I concentrationswere measured by a rate-nephelometric method.15

Apo B and apo E levels were determined by elec-troimmunoassay.16'17 Levels of lipoprotein(a) weredetermined by radioimmunoassay (Pharmacia Diag-nostics, Uppsala, Sweden).18

Carotid UltrasonographyExamination was performed with an ultrasound

scanner (Acuson 128, Mountain View, Calif.)equipped with a linear 5- or 7-MHz transducer. Thetransducer aperture was 38 mm.

Subjects were examined in a supine position with thehead turned to the left while resting on a speciallydesigned firm cushion that was positioned at a 45°angle. The ultrasound transducer was placed over theright carotid artery at the level of the bifurcation. Theelectrocardiographic signal (lead II) was simultane-ously recorded to synchronize the image capture to thetop of the R wave (end diastole). The common carotidartery close to the bifurcation was scanned longitudi-nally, starting with the transducer placed anteriorly andmedially of the artery and with the beam directed



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72 Arteriosclerosis and Thrombosis Vol 12, No 1 January 1992

FIGURE 1. Upper panel: Ultrasound image of thecommon carotid artery in a subject in the controlgroup. Arrow indicates the beginning of the carotidbulb. Lower panel: Ultrasound image of the samesection in a patient with familial hypercholesterol-emia. Observe the increase in wall thickness indicatedby the unfilled arrow in the lower image.

through the vessel. The artery was then scanned bymoving the transducer in a lateral direction. At theposition of best visibility of the wall structures, threeimages were captured from the common carotid arteryjust proximal to the carotid bulb (Figure 1). The imagecapture was performed by "freezing" the continuousregistrations at end diastole by electrocardiographictriggering, with subsequent recording on videotape.

Measurement of Wall Thickness and Lumen DiameterThe ultrasound images from the videotape were

analyzed by a computerized analyzing system.19 Allanalyses were performed in a blinded manner withregard to the group to which the images belonged.Wall thickness was defined as the distance from theleading edge of the lumen-intima interface of the farwall to the leading edge of the media-adventitiainterface of the far wall. Lumen diameter was de-fined by the distance between the leading edges ofthe intima-lumen interface of the near wall and thelumen-intima interface of the far wall.19 The mea-surements were made in the common carotid arteryalong a 10-mm-long section proximal to the carotidbulb. The computer program calculated the mini-mum, maximum, and mean values of intima-mediathickness and lumen diameter. Three frozen imagesfrom the same section of the artery were measured,and the mean of these was calculated.

Interobserver Variability

To estimate the interobserver variability, a total of50 subjects, 26 from the hypercholesterolemic groupand 24 control subjects, underwent the ultrasoundexamination twice on the same day performed by twoindependent observers who were blinded with regardto the results of the other observer. Arterial wallthickness and lumen diameter from the two exami-nations were measured by each observer blinded withregard to the results of the other observer and also tothe group from which the images came. For technicalreasons, high-quality images were missing for threesubjects.

The correlation coefficient between two indepen-dent observers was r=0.83 for mean wall thicknessand r=0.89 for maximum wall thickness. Correlationcoefficients were r=0.96 for mean lumen diameterand r=0.95 for minimum lumen diameter. The coef-ficient of variation for mean wall thickness was 10.2%and for maximum wall thickness, 8.9%. For meanand minimum lumen diameter, the coefficients ofvariation were 2.8% and 3.0%, respectively.19

Statistical Analysis

MINITAB software in a PDP 11-34 computer wasused in the statistics. Two-sided nonparametric testswere used. Because matching was performed andthere was a significant relation among the 51 pairs inmean wall thickness of the common carotid artery



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TABLE 3. Serum Lipids and LJpoprotein Levels of Study Participants

Variable

Serum cholesterol (mmol/1)Serum triglycerides (mmol/1)HDL cholesterol (mmol/1)LDL cholesterol (mmol/1)Apo A-I (g/l)Apo E (g/l)Apo B (g/l)Lp(a) (mg/1)

ControlMean+SD'

5.64+0.921.36±0.821.44±0.393.65+0.821.53+0.33

0.054+0.0131.08+0.28

59 (7-1,040)

group (n=51)

95% CI

5.38-5.901.03-1.451.31-1.533.39-3.851.42-1.61

0.050-0.0581.00-1.15

Familial hypercholesterolemiagroup

Mean±SD

9.56±1.791.64±0.741.33±0.377.43 ±1.861.40±0.31

0.060±0.0161.88±0.40

230(25-1,244)

("=51)

95% CI

8.90-9.981.38-1.831.23-1.436.81-7.861.30-1.49

0.056-0.0641.72-1.97

CI, confidence interval; HDL, high density lipoprotein; LDL, low density lipoprotein; apo, apolipoprotein; Lp{a),lipoprotein(a).

'For Lp(a), values are median and range.

(r=0.48, n=51,p=0.00l), the hypothesis of no differ-ence in distributions between the groups was testedwith Wilcoxon's test for paired data. Furthermore,95% confidence intervals for differences were calcu-lated. Because the two groups, by definition, differedin serum lipids, these were not formally tested, but95% confidence intervals for each of these variablesin the two groups have been given.

The proportions of smokers (never, past, or cur-rent) in the two groups were compared by testingwith Fisher's test for paired comparisons. The otherproportions (wall thickness) were tested with McNe-mar's test. Limits for abnormality in the studiedvariables were arbitrarily set at the second highestvalue of the control group.

In the reproducibility study, means and standarddeviations (SDs) for differences between the twoobservers were calculated. The SD of the interob-server error (s) was then calculated according to theformula

s=SD/-\/2

The coefficient of variation (CV) describes the dif-ference as a percentage of the pooled mean values(x) and was calculated according to the formula

sxl00%cv=-

ResultsThe two study groups were very similar in anthro-

pometric data, blood pressure, and heart rate (Table2). The proportion of current smokers was the samein the two groups, but there was a tendency (NS) forsomewhat greater numbers of past smokers in thegroup with familial hypercholesterolemia. Smokingexposure calculated as total cigarette-years was verysimilar in the two groups (Table 2).

Serum Lipld and Lipoprotein Levels

Total and LDL cholesterol and apo B levels werehigher in the hypercholesterolemic group compared

with the control group (see 95% confidence intervals,Table 3). For serum triglycerides, HDL cholesterol,and apo A-I, 95% confidence intervals in the twogroups overlapped.

Lumen Diameter and Wall ThicknessThe mean and maximum wall thicknesses (intima-

media of the far wall) of a 10-mm-long section of thecommon carotid artery were significantly thicker in thehypercholesterolemic group than in the control group(/?<0.001; Table 4 and Figures 2 and 3). The meandifference in thickness between the groups was 0.13mm for mean wall thickness (95% confidence interval,0.07-0.18 mm) and 0.20 mm for maximum wall thick-ness (95% confidence interval, 0.09-0.23 mm). Meanand minimum lumen diameters were significantlysmaller in the hypercholesterolemic group than in thecontrol group (p<0.05; Table 4). The mean differencebetween the groups was 0.21 mm for mean lumendiameter (95% confidence interval, 0.01-0.48 mm)and 0.24 mm for minimum lumen diameter (95%confidence interval, 0.05-0.48 mm).

The proportion of mean wall thickness >1.0 mmand the proportion of maximum wall thickness >1.3mm were significantly higher in the hypercholester-olemic group compared with the control group(p<0.05; Figures 2 and 3).

The ratio between mean wall thickness and meanlumen diameter (relative wall thickness) was signifi-cantly higher in the hypercholesterolemic group com-pared with the control group (/?<0.001; Table 4).

Wall Thickness and Serum Lipid andLipoprotein Levels

The two study groups were analyzed together, andthe correlation coefficients for the relations betweenarterial wall thickness and serum lipid and lipopro-tein levels are presented in Table 5. Mean wallthickness was significantly correlated to total serumcholesterol (r=0.32, /?<0.001), to LDL cholesterol(r=0.30, p<0.01), and to apo B (r=0.32, p<0.01;Table 5 and Figure 4).



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TABLE 4. Arterial Wall Thickness (Intima-Media of the Far Wall) and Lumen Diameter in the Common CarotidArtery of Study Participants

Variable

Wall thicknessMean (mm)Maximum (mm)

Lumen diameterMean (mm)Minimum (mm)

Wall thickness to lumen diameter ratioMean

Controlgroup(«=51)

0.72±0.130.90±0.17

6.09+0.715.82±0.68

0.12±0.02

Familialhypercholesterolemia

group (n=51)

0.85±0.22*1.10±0.36*

5.88±0.66t5.58±0.56t

0.14±0.03*

Meandifference

between groups

0.130.20

-0.21-0.24

0.025

95% CI formean

difference

0.07-0.180.09-0.23

-0.48—0.01-0.48—0.05

0.016-0.033

Values are mean±SD.CI, confidence interval.•p<0.001, tp<0.05.

Wall Thickness and AgeThe relation between arterial wall thickness and

age was statistically significant. The correlation coef-ficient was r=0.48 (/?<0.001) in the hypercholester-olemic group and r=0.49 in the control group(p< 0.001). If the two groups were combined in theanalysis, the correlation coefficient was r=0.43(/?<0.001; Figure 5). The slope of the regression linerelating age to wall thickness was 0.009 mm/yr in the

hypercholesterolemic group and 0.005 mm/yr in thecontrol group (p=0.20).

Wall Thickness and Gender

Table 6 shows that men and women differed withregard to both age and smoking habits. Therefore, ameaningful analysis of any gender differences couldnot be performed.

No Control group (n=51)

10-

Hl-

x=0.72mm SD=0.13>1.0mm=2/51=3.9%

0.5 1.0 1.5Mean wall thickness (mm)

No Familial Hypercholesterolemia (n=51)20-i

10-

Hl-

x=0.85mm*"SD = 0.22>1.0mm=9/51 = 17.5%

FIGURE 2. Bar graphs of distribution of mean wallthickness (intima-media of the far wall) in the commoncarotid artery in the two study groups. Dashed linesindicate limits for abnormality. SD, standard deviation.*p<0.05, ***p<0.001.

0.5 1.0 1.5Mean wall thickness (mm)



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No Control group (n=51)

10-

7/-

x=0.90mm SD=0.17>1.3mm = 1/51=2.0%

1.0 1.5 2.0 2.5Maximum wall thickness (mm)

No20i

Familial Hypercholesterolemia (n=51)

1 0 -

x=1.10mm*** SD=0.36>1.3mm = 10/51 = 19.6%*

1.0 1.5 2.0 2.5Maximum wall thickness (mm)

FIGURE 3. Bar graphs of distribu-tion of maximum wall thickness (in-tima -media of the far wall) in thecommon carotid artery in the twostudy groups. Dashed lines indicatelimits for abnormality. SD, standarddeviation. *p<0.05, ***p<0.001.

Wall Thickness and SmokingAnalysis of wall thickness in the different smoking

habit groups (never, past, or current) was not per-formed because the gender distribution was differentin these groups. However, in the control group alinear correlation analysis revealed no relation be-tween cigarette-years and wall thickness (r=0.13),

whereas in the hypercholesterolemic group the rvalue was 0.27 (p<0.05).

Discussion

This study was performed in part to evaluatewhether the B-mode ultrasound method was capableof measuring in detail the wall thickness of the

TABLE 5. Correlation Coefficients for the Relation Between Arte-rial Wall Thickness (Intima-Media of the Far Wall) and SerumLipid and Lipoprotein Levels

Variable

Serum cholesterol (mmol/l)Serum triglycerides (mmol/l)HDL cholesterol (mmol/l)LDL cholesterol (mmol/l)Apo A-I (g/I)Apo E (g/l)Apo B (g/l)Lp(a) (mg/l)

Hypercholesterolemicgroup+control (« = 102)

correlation vs.Mean wall

thickness (r)

0.32*0.050.03

0.30t0.010.180.32t0.16

Maximum wallthickness (r)

0.32*0.14

-0.010.29f

-0.04-0.15

0.34*0.17

HDL, high density lipoprotein; LDL, low density lipoprotein;apo, apolipoprotein; Lp(a), lipoprotein(a).

*p<0.001, tp<0.01.

Intima-mediathickness(mm)2.0-1

1.5 -

1 . 0 -

0.5 -

• FHo Controlsr=0.32 (p<0.01)n = 100

1 .0 2 .0 3.0Apo B (g/l)

FIGURE 4. Scatterplot of relation between apolipoprotein(apo) B and mean wall thickness in all subjects, familialhypercholesterolemic patients (FH; %) and controls (o).



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Intlma-medlathlcknass(mm)2.0-1

1 .5

1 . 0

0.5

4/A-

• - F H°— Controlsr=0.43 (p<0.001)n = 102

20 30 40 50 60 70 80Ag« (yaars)

FIGURE 5. Scatterplot of relation between age and meanwall thickness in all subjects, familial hypercholesterolemicpatients (FH; •) and controls (o).

common carotid artery. The results showed an in-creased arterial wall thickness in patients with het-erozygous familial hypercholesterolemia comparedwith a control group. Interobserver variability wasstudied and was found to be quite satisfactory whenmeasuring both intima-media thickness and lumendiameter.

The presence of intima-media thickening, how-ever, is not necessarily atherosclerosis.20 Hemody-namic changes, for example, an increase in walltension in the vessel, may lead to intimal thickening.This thickening of the intima may be diffuse instraight arteries, but in the carotid bifurcation wherethere are areas with low wall shear stress, there isoften a focal intimal thickening. However, becauseblood pressure or heart rate did not differ betweenthe groups, there is no reason to believe that walltension or shear stress would differ. Hence, the

difference in the intima-media between the groups isprobably not explained by hemodynamic factors.

The two study groups were matched for sex, age,height, and weight. Exposure to smoking was similar.The only observed difference between the groups wasin serum cholesterol, LDL, and apo B. A relationbetween extent of atherosclerosis and LDL or apo Bhas been shown in several studies.21-22 Consequently,the increased intima-media thickness may possiblybe seen as an expression of early atheroscleroticdisease.

The intima-media thickness increased with age inboth groups, and the findings may indicate a higherincrease in wall thickness in the hypercholester-olemic group. This observation is well in line with theearly development of atherosclerosis in these pa-tients. A relation was also found between wall thick-ness and cigarette-years in the hypercholesterolemicgroup but not in the control group. One may specu-late that the higher the cholesterol level, the greaterthe importance of smoking as a risk factor.

No previous data are available on arterial wallthickness in a well-defined group of patients withfamilial hypercholesterolemia, although Poli et al5

have performed a similar study of hypercholester-olemic patients. They also found a significant in-crease in arterial wall thickness compared with thatin a control group.

Further studies are ongoing to evaluate the prog-ress of atherosclerotic disease with time in patientswith familial hypercholesterolemia. The presentstudy showed a highly statistically significant differ-ence between the two study groups, and reproduc-ibility was quite satisfactory. Hence, it should bepossible to perform prospective studies in groups ofpatients like the present one. Data from prospectivestudies of patients with familial hypercholesterolemiaare needed to calculate sample sizes for randomized

TABLE 6. Anthropometric Data, Blood Pressure, Heart Rate, and Smoking Habits in Men and Women

Variable

Age(yr)Body height (m)Body weight (kg)BMI (kg/m2)SBP (mm Hg)DBP (mm Hg)HR (beats per minute)Total serum cholesterolNever smoked (%)Past smoker (%)Current smoker (%)Total cigarette-years

Control

Men(n=30)

47.8±12.3178±5

76.5±13.024.3 ±3.3122±1371±965±11

5.58±1.0250

20

30

8,750

group

Women("=21)

59.8±6.5166±6

67.0±13.224.1 ±3.9129±2178±962±8

5.73±0.7867

24

10

2,240

Familial

Men(n=30)

46.9±12.1179±7

78.8±13.124.6±3.5120±1575 ±1058±9

8.96±1.6920

53

27

8,220

hypercholesterolemiagroup

Women("=21)

59.8±7.1165±6

67.7±12.025.0±4.4129±1577±1064±10

10.47±1.6157

24

19

2,070

Values are mean±SD.BMI, body mass index; SBP/DBP, systolic/diastolic arterial blood pressure; HR, heart rate.



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clinical trials whose aim is to prevent or postponeprogression of the disease.

However, it should be borne in mind that theintima-media thickness of the carotid artery is usedonly as a sunogate variable for coronary atheroscle-rosis. The relation between this variable and coro-nary atherosclerosis or clinical disease has yet to beproven. Future long-term prospective studies, there-fore, must also address the issue of how changes inthe carotid and femoral arteries are correlated withcoronary atherosclerosis and its sequelae, myocardialinfarction and sudden death.

AcknowledgmentsThe statistical consultant for this study was Anders

Od6n, Department of Mathematics, GothenburgUniversity, Gothenburg. We thank Lars Wilhelmsenand Alekka Tsippogianni for letting us use theMONICA file for selection of controls and NancyBarrheden for valuable help.

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I Wendelhag, O Wiklund and J Wikstrandintima-media thickness in the common carotid artery.

Arterial wall thickness in familial hypercholesterolemia. Ultrasound measurement of

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