10
Clinical Investigation
Carotid Arteriosclerosis in Identical Twins
Discordant for Cigarette Smoking
Arto Haapanen, MD, Markku Koskenvuo, MD, Jaakko Kaprio, MD,
Y. Antero Kesaniemi, MD, and Kauko Heikkila, LicPhil
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From a nationwide twin panel, identical twin pairs with highest discordance in cigarette
smoking were selected for a study of arteriosclerosis (49 pairs with a mean age of 52 years).
Smoking history was obtained in 1975, 1981, and 1986. The mean life-long smoking dose of the
smoking cotwins was 20 package-years. The smoking and nonsmoking cotwins had similar
systolic and diastolic blood pressures, total plasma cholesterol level, body mass index, and some
psychosocial factors; the only difference was found in use of alcohol, which was greater among
smoking cotwins. Duplex sonography of carotid arteries was performed. Carotid artery stenoses
(narrowing of area of the lumen with 15-60%o) were found in nine pairs: in nine smoking twins
and in two of their nonsmoking cotwins (p=0036). The total area of carotid plaques was 3.2
times larger in smoking cotwins (p< 0.001). The thickness of the inner layer of carotid arteries
was more marked in smoking cotwins (p<0.001). The size of plaques and the degree of inner
layer thickening correlated with the dose of smoking (NS). The association of smoking with
carotid arteriosclerosis was highly significant even after the adjustment for age, total plasma
cholesterol level, diastolic blood pressure, and body mass index in multiple logistic regression
analyses. (Circulation 1989;80:10-16)
S moking is associated with arteriosclerotic
lesions. The relation has been most consistently shown in the abdominal aorta and in
major arteries of the lower limbs, but in coronary
arteries, the relation has been less consistently
shown.4,9-11 There are only a few reports on the
relation between smoking and atherosclerosis in
cerebral arteries.12 In contrast to other epidemiologic evidence, studies of smoking-discordant twin
pairs have not shown differences in manifest coronary heart disease in the smoking and nonsmoking
cotwins.'3-19 These findings have suggested to critics that the association of smoking and coronary
heart disease is noncausal.20-22 Studies of mortality
among smoking-discordant pairs found only a slightly
increased risk of death in the smoking cotwin
compared with the nonsmoking cotwin.7,23 ThereFrom the Department of Public Health, University of Turku
(M.K.), the Department of Public Health, University of Helsinki
(J.K., K.H.); Seinajoki Central Hospital (A.H.), and Department
of Internal Medicine, University of Oulu (Y.A.K.), Finland.
Supported by grants from The Council For Tobacco ResearchUSA, Inc, Medical Council of the Academy of Finland, the
Sigrid Juselius Foundation, and the Astra Company in Finland;
performed under a contract with the Finnish Life Insurance
Companies.
Address for correspondence: Markku Koskenvuo, MD, Department of Public Health, Lemminkaisenkatu 1, 20520 Turku,
Finland.
Received May 19, 1988; revision accepted March 14, 1989.
fore a study of the incidence of ischemic heart
disease in smoking-discordant twin pairs was undertaken in Finland in 1975; from 208 ischemic heart
disease-free identical male pairs discordant for
cigarette smoking, during a 6-year follow-up, 16
smoking cotwins and three nonsmoking cotwins
died or were hospitalized because of ischemic
heart disease.24 This result raised the question,
"Was the increased ischemic heart disease risk
associated with arteriosclerosis among the smoking cotwins?" Therefore, we decided to study
noninvasively the carotid arteriosclerosis of identical twin pairs discordant for smoking.
Methods
Subjects
The Finnish Twin Cohort comprises all Finnish
sex-matched twin pairs born before 1958 and alive
in 1967. A questionnaire was mailed in 1975 to
determine zygosity and to obtain data on healthrelated variables. The overall response rate was
89%. A second questionnaire study was carried out
in 1981, and the response rate was 84%. The validity of zygosity was studied in a subsample of 104
pairs. The agreement of diagnosis from the questionnaires and 11 blood markers was 100%, and the
estimated probability of misclassification was 1.7%.25
Smoking was defined by the following criteria. 1)
Nonsmokers. Never smokers: life-long dose of cig-
Haapanen et
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arettes less than five packages (i.e., 100 cigarettes)
and a report of "never daily smoking." Occasional
smokers: a report of "never daily smoking." 2)
Smokers. Exsmokers: a report of daily smoking in
the past. Current smokers: a report of current daily
smoking.
The questionnaire included questions on whether
diabetes mellitus had been diagnosed by a physician. The reported use of alcohol (amount of beer,
wine, and hard liquor consumed separately each
month) was converted to grams of absolute alcohol.
Questions were included on the use of coffee,
physical activity, marital status, education, and
hostility.26
In 1986, 78 identical pairs (61 male and 17 female
pairs) with the highest discordance in the life-long
dose of cigarette smoking were invited to Seinajoki
Central Hospital. Smoking history was obtained
from the 1975 and 1981 questionnaires and checked
by the interview in 1986, and the life-long smoking
dose of smokers was calculated by multiplying the
mean number of cigarettes smoked daily and the
number of years of smoking (by using the age of
starting, possible quitting, and years without smoking). The life-long dose of smoking was calculated
as package-years (i.e., smoking of one package
each day during a year).
Twenty-eight (36%) pairs refused or did not
respond, 16 (26%) male and 12 (71%) female pairs.
The mean age of the participants was 52 years, and
that of the nonparticipants was 58 years. The participant and nonparticipant male pairs did not differ
in the life-long dose of smoking, but the participant
female smokers had smoked more than the nonparticipants. For the nonparticipants, the distances of
their homes from the Seinajoki hospital were more
than 200 miles in 19 pairs. Forty-five male and five
female pairs were examined. One male pair was
excluded from the analyses because a heavy smoking history was found in both cotwins. The mean
age was 52 years (range, 31-77 years). The distribution of the smoking cotwins by the life-long
smoking dose was > 29 package-years (n = 7), 20-29
(n= 16), 10-19 (n=16), and < 10 (n= 10). The mean
package-years of smoking cotwins was 19.7. In the
nonsmoking cotwin group, 47 were nonsmokers,
and two were exsmokers. The smoking doses of the
two exsmokers were 7 and 1 package-years. The
discordance in smoking of these two pairs was 19
and 17 package-years. Urine cotinine was measured
in 10 pairs: all smoking cotwins were positive, but
their nonsmoking cotwins showed no trace of
smoking.27
Blood pressure was measured in the sitting position from the left arm with a standard cuff and a
mercury manometer. Total plasma cholesterol level
was determined from fasting blood samples.28 No
statistical differences were found between smoking
and nonsmoking cotwins in the following variables:
body mass index, systolic and diastolic blood pressures, total plasma cholesterol level, prevalence of
al Carotid Arteriosclerosis in Twins
11
TABLE 1. Blood Pressure, Body Mass Index, Plasma Lipids,
Prevalence of Diabetes Mellitus and Some Psychosocial Factors in
Smoking and Nonsmoking Cotwins of 49 Identical Pairs Discordant for Cigarette Smoking
Nonsmoking
Variable
Systolic blood
pressure (mm Hg)
Diastolic blood
pressure (mm Hg)
Body mass index
(kg/M2)
cotwins
Smoking
cotwins
p
137+16.3
132±16.4
NS
94±+11.3
92±11.9
NS
26.4±3.2
25.5±3.1
NS
5.88±1.13
5.95±1.32
NS
2.1
NS
NS
NS
NS
NS
Total cholesterol
(mmol/l)
Reported diabetes
diagnosed by a
physician (%)
Blue collar work (%)
Sport training (yr)
Education (yr)
Married (%)
Reported use of coffee
4.3
45.8
1.7+2.1
8.1+2.7
93.6
54.3
1.2±1.8
8.0+2.0
89.4
NS
5.4±3.7
5.6±2.7
(cups/day)
Reported use of
alcohol (g/mo as
<0.05
460±405
absolute alcohol)
258±413
Hostility score (range,
6.6±2.7
NS
6.6±2.8
3-15)
Values are mean-SD.
p values by intrapair difference and its SD. NS isp>0.05.
diabetes mellitus, use of coffee, physical activity,
marital status, education, and self-rating of hostility
(Table 1). The reported use of alcohol consumption
was almost two times higher among smoking cotwins
(p<0.05) (Table 1).
Duplex sonography was performed in all cases by
one of the authors (A.H.). Carotid variables were
estimated without the knowledge of smoking history. A Technicare Autosector (Englewood, Colorado) with a 7.5-MHz real time transducer and a
pulsed Doppler was used. Hard copies of real time
images were made for longitudinal sections of common carotid arteries and transverse sections of
carotid bifurcations. If the bifurcation had less than
15% stenosis (an arbitrary limit of decrease of
lumen area), the condition was classified as a "nonstenosis," and in case the decrease was more than
15%, it was classified as a "stenosis." The decrease
of lumen area was computer-calculated from the
"intact" and stenosed intimal lines in the transverse section. Doppler spectra from common and
internal carotid arteries were additionally used,29'30
but no significant discrepancy between real time
image and Doppler spectra was observed in any of
the cases. The dimensions of the plaques and the
inner surface thicknesses were measured with a
ruler on the hard copy (by attempting to use 0.25mm increments) 2 months after the clinical examination by one of the authors (A.H.) without knowing the smoking status: 1) the size and the number
12
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TABLE 2. Carotid Arteriosclerosis in 49 Identical Twin Pairs Discordant for Cigarette Smoking
Arteriosclerosis
Nonsmoking cotwins
Smoking cotwins
Individuals with stenotic (15-60%)
carotid arteries (n)
2
9
2
10
Stenotic carotid arteries (n)
Degree of stenosis
0.43±1.9
3.00±6.8
Mean±SD (%)
n
49
49
Individuals with echogenic carotid
40
47
plaques (n)
Echogenic carotid plaques per person
excluding persons with carotid
stenosis
1.90+0.70
1.23±0.85
Mean±SD
47
n
40
Area of carotid plaques (per artery)
2.24±2.4
7.15±8.5
Mean±SD (mm2)
49
49
n
Inner layer thickening (per artery)
0.69±0.3
0.91±0.3
Mean+SD (mm)
n
48
49
p
<0.05
<0.05
<0.05
NS
<0.001
<0.001
<0.001
Carotid stenosis (15-60%) was found in nine from 49 pairs including two pairs concordant for carotid stenosis.
p values by intrapair difference and its SD. NS, p>0.05.
of the echogenic plaques from the transverse section of both carotid bifurcations and 2) the thickness
of the inner surface of the vessel wall at the thickest
site of both common carotid arteries from the
longitudinal section. The bright line along the inner
margin of the artery wall and the sonolucent line
beneath this echogenic line were included in this
measurement. For clarification of intraobserver and
interobserver variation of the measurements, we
have conducted a separate study of 26 individuals
(52 carotid arteries) in the same manner as in the
study of twin pairs. The assessments were made on
the same hard copies by two independent observers.
The interobserver agreement of the assessments of
inner layer thickening was 73% when classified with
accuracy of 0.25 mm and was 83% when classified
with accuracy of 0.5 mm. The agreement of the
assessments of the summed area of echogenic plaques
was 88% when classified with an accuracy of 5 mm2.
The corresponding values for the intraobserver agreement were 83%, 96%, and 88%.
The area of echogenic carotid plaques correlated
highly significantly (p<0.001) with age (r=0.36),
with the degree of carotid stenosis (r=0.89), and
with the inner layer thickening (r=0.59).
Statistical Analysis
Data were missing for cholesterol levels in two
smokers and for inner layer thickening in one nonsmoker. Statistical difference between smokers and
nonsmokers was tested with Student's t test and the
intrapair difference and its standard deviation. Confidence limits of 95% for ratios were calculated by
Fisher's method. Conditional logistic regression models were used in multivariate analysis; relative risks
and their confidence limits were calculated using
the /3-coefficient and its SEM.
Results
Carotid artery stenosis (narrowing of area of the
lumen of 15% or more) was found in nine pairs: in
nine smoking cotwins and in two nonsmoking
cotwins (p=0.036) (Table 2). An example of carotid
stenosis is shown in Figure 1. In addition, minor
plaques in the carotid bifurcation were found in 38
of 49 smoking cotwins and in 38 of 49 nonsmoking
cotwins. The mean number of echogenic plaques
for each person (excluding persons with carotid
stenosis) was 1.90 (SD=0.70) for smokers and 1.23
(SD=0.85) for nonsmokers (p<0.001). The mean
area of all carotid plaques was 3.2 times larger in
smoking cotwins than in nonsmoking cotwins
(p<0.001) (Table 2). The thickness of the inner
layer of carotid arteries was more marked in smoking cotwins (p<0.001) (Table 2). An example of
inner layer thickening is shown in Figure 2.
The area of carotid plaques of the smoking cotwins
compared with that of the nonsmoking cotwins had
the following ratios with an increase in smoking
dose: 2.66 (for the subgroup in which the smoking
cotwins had smoked less than 10 package-years),
3.15 (10-19 package-years), 3.49 (20-29 packageyears), and 3.57 (>29 package-years). Correspondingly, the ratios for the degree of inner layer thickening were 1.25, 1.27, 1.40, and 1.46. Those two
trends, however, were statistically nonsignificant.
The distribution of individuals by the total area of
carotid plaques, smoking, and plasma cholesterol
level is given in Table 3, and the distribution of
carotid arteries by inner layer thickening, smoking,
and serum cholesterol level is given in Table 4.
Haapanen et al Carotid Arteriosclerosis in Twins
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FIGURE 1. Longitudinal section ofreal time image ofleft carotid bifurcation of a 53-year-old monozygotic twin pair with
a smoking discordance of 7package-years (7 vs. 0). Panel A: Nonsmoking cotwin. An echogenic plaque is in the dorsal
aspect of the bifurcation. Panel B: Smoking cotwin has clearly greater plaques in the bifurcation.
Inner layer thickening was more marked among
smokers than among nonsmokers in both subgroups
of individuals: those with serum cholesterol levels
above 6.0 mmol/l and those below it. The corresponding difference for the size of echogenic plaques
was significant only in individuals with cholesterol
levels above 6.0 mmol/l.
The association of smoking and carotid arteriosclerosis was also tested by a conditional logistic
model with dichotomized variables. Age-adjusted
relative risk (odds ratio calculated from the regression coefficient of the logistic model) of all indicators
of carotid arteriosclerosis was significantly increased
among smoking cotwins even after the adjustment of
total plasma cholesterol level, diastolic blood pressure, and body mass index (Table 5).
Discussion
The validity of zygosity diagnosis was satisfactory for epidemiologic purposes because the overall
probability of misclassification was 1.7% by blood
tests in a subsample.25 A high proportion (89%) of
the twins responded to questionnaire studies. Fifty
of seventy-eight selected pairs (64%) participated in
FIGURE 2. Longitudinal section of real time image ofleft common carotid artery of a 54-year-old monozygotic twin pair
with a smoking discordance of 21 package-years (21 vs. 0). Panel A: Nonsmoking cotwin. Panel B: Smoking cotwin. Note
difference in the thickness of the so-called "echogenic line" of the artery.
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TABLE 3. Distribution of Individuals by the Size of Carotid
Plaques, Cigarette Smoking, and Plasma Cholesterol
Cholesterol (mmol/l)
Total size of echogenic
Nonsmokers
Smokers
carotid plaques (both
>6.0
<6.0
>6.0
<6.0
sides) (mm2)
1
5
4
1
0
2
2
0-<1
14
3
6
10
1-<5
4
3
10
5
5-< 10
4
2
2
15
6
10-<
1
1
15-<20
1
1
1
20-<30
2
1
30-<40
2
40-<60
1
1
80-<90
22
27
21
26
n
9.7
5.4
2.4
2.1
Mean (mm2)
95% confidence limits 5.0-14.4 2.2-8.6 1.1-3.8 1.1-3.1
Proportion of those
with plaque size
27
11
57
18
.10mm2(%)
the clinical examination. The relatively low participation rate was not surprising because the study
involved long travel in most cases. The nonparticipants were mainly twin pairs over 60 years old.
Therefore, arteriosclerotic changes were probably
more frequent among nonparticipants than among
participants. The mean life-long smoking dose of
smoking cotwins corresponded to smoking one package each day for 20 years. The corresponding dose
of the same-aged Finnish current male smokers was
28 package-years.31 The life-long dose of smoking of
the current sample was clearly lower than that of
the age- and sex-matched Finnish population. Thus,
our results probably underestimate the real effect of
smoking on carotid arteriosclerosis in the age- and
sex-matched Finnish population.
Duplex carotid ultrasonography has been used
for the screening of carotid arteriosclerosis.32,33 The
TABLE 4. Distribution of Carotid Arteries by Inner Layer Thickening, Cigarette Smoking, and Plasma Cholesterol
Cholesterol (mmol/l)
Degree of
carotid inner
Smokers
Nonsmokers
><
layerthmcken<ng6.
>6.0
<6.0
> 6.0
<6.0
(0.5 mm)
6
6
5
5
0-<0.5
27
32
23
10
0.5-<1.0
14
22
9
1.0-< 1.5
19
1
2
6
1.5-<2.0
1
2
>2.0
52
44
52
42
n
0.71
0.67
0.99
0.84
Mean (mm)
95% confidence
0.85-1.13 0.75-0.93 0.62-0.80 0.61-0.73
limits
Proportion of
those with
inner layer
thickening
19
11
2
36
>1.5 mm (%)
layerothickningr
duplex sonography of carotid arteries is an operatordependent examination. In carotid stenosis over
50%, the sensitivity of duplex sonography was 9194%, and the specificity was 85-89% according to
previous studies.34-38 Recently, a Finnish population study39 that used high-resolution ultrasonography to assess carotid atherosclerosis as in our study
reported that the agreement of reassessment was
89.8% when carotid arteriosclerosis was classified
into four groups. In our study, the reliability of
intraobserver and interobserver variation was clarified by the high correlation between reassessments
and the assessments made by two independent
observers and by the highly significant intercorrelations of the three different measurements of carotid
arteriosclerosis.
The so-called "echogenic line" is a frequent
finding in the real time image of carotid arteries in
persons over 30 years of age, and it seems to
correspond to the surface of the intima.3040 The
sonolucent line typically seen beneath the echogenic
TABLE 5. Age-Adjusted Odds Ratios (and 95% Confidence Limits) for Carotid Arteriosclerosis by Cigarette Smoking in Univariate Models
and in Multivariate Models Adjusted for Plasma Cholesterol, Diastolic Blood Pressure, and Body Mass Index in 49 Identical
Smoking-Discordant Twin Pairs
Model
Univariate
Current and exsmokers (vs. nonsmokers)
95% confidence limit
Carotid stenosis >15%
(n=11/98)
5.99
(1.19-30.3)
Arteriosclerotic endpoint
Total area of
Carotid inner
carotid
layer thickening
.1.2 mm
plaques > 10
(n=21/97)
mm2 (n=26/98)
3.97
(1.36-11.6)
5.91
1.76-19.8)
Either of those
changes
(n=34198)
6.21
(2.13-18.1)
Multivariate
Current and exsmokers (vs. nonsmokers)
6.96
6.37
3.91
6.24
95% confidence limit
(1.79-27.1)
(2.08-19.5)
(1.29-11.9)
(1.15-33.8)
Four univariate and four multivariate logistic regression models with dichotomized variables; cut-off points: 6.0 mmol/l for total
cholesterol, 100 mm Hg foi diastolic blood pressure, and 26 for body mass index.
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intimal reflection probably represents the composite of intima and media sandwiched between the
strong reflections from the intimal surface and the
adventitial layer.40
A great deal of data of the causes of arteriosclerosis has been accumulated, but direct information
is lacking on how smoking and other risk factors are
related to the cellular and molecular factors.41-45
Smoking is associated with development of arteriosclerotic lesions in abdominal aorta and in major
arteries of the lower limbl-8 and in coronary
arteries.4,9-11 The relation between smoking and
cerebral atherosclerosis has not been so widely
studied, and the reported results have shown only a
weak association.12 Smoking seems to be a significant risk factor for ischemic heart disease but not a
strong and consistent risk factor for stroke.46-48
Smoking cotwins were slightly leaner than their
nonsmoking twin partners, but the smoking and
nonsmoking cotwins had similar blood pressures,
serum cholesterol levels, prevalence of diabetes
mellitus, use of coffee, physical activity, education,
marital status, and aggressive behavior. Smoking
cotwins consumed more alcohol than nonsmoking
cotwins. Numerous epidemiologic and biochemical
reports, however, suggest that the use of alcohol
has an antiatherogenic effect. The higher consumption of alcohol of the smoking cotwins possibly
masks the atherogenic effect of smoking found in
our sample. In other studies on identical twin pairs
discordant for smoking, smoking and nonsmoking
cotwins also had similar serum cholesterol levels49
and psychosocial characteristics.50 Some nontwin
studies of smoking and serum lipids, however, have
shown that plasma high-density lipid cholesterol
levels tend to be lower in smokers than in
nonsmokers.5' 5 The discrepancy between the
results of studies of twins and nontwins may be
explained in two ways: 1) twins are "overmatched"; that is, a smoker and his nonsmoking
cotwin are more similar than an average smoker and
nonsmoker with respect to the factors affecting
serum high-density lipid cholesterol; 2) the proportion of heavy smokers was low in identical twins
discordant for smoking in reported samples.
The association of smoking with carotid arteriosclerosis was significant also after adjustment for
age, total plasma cholesterol level, diastolic blood
pressure, and body mass index. The sample was
small for subgrouping by the smoking dose, but the
results showed a nonsignificant trend between smoking dose and degree of carotid arteriosclerosis.
Conclusions
Our results seem to indicate that smoking is a
strong factor in the development of carotid arteriosclerosis independent of genetic factors, blood pressure, serum cholesterol level, body mass index, and
a number of other potential confounding factors
(diabetes, use of coffee and alcohol, physical activ-
15
ity, education, marital status, and hostility) in a
population with a high serum cholesterol level.
Earlier studies of twins on smoking and coronary
heart disease13-19 showed no or little difference
between smoking and nonsmoking cotwins. These
unexpected findings supported proponents20-22 of a
noncausal hypothesis for the association between
smoking and atherosclerosis and coronary heart
disease. Recent data on the 21-year follow-up of the
Swedish smoking-discordant twin pairs55 and the
12-year follow-up of the Finnish sample56 show that
the smoking twins are at a significantly higher risk
of coronary heart disease than their nonsmoking
cotwins. The earlier negative results were probably
due to the low level of smoking discordance and the
small power of the studies. These new mortality
studies and the results of our present study strongly
support a causal role of smoking in the development
of atherosclerosis.
Acknowledgments
We are indebted to Mrs. Ulla Kulmala-Grahn,
RN, Eila Voipio, RN, Mr. Jussi Vilpponen, RN,
Mrs. Leena Saikko, and Mrs. Irma Piri for technical
and secretarial assistance, and to Reino Raninen,
MD, for the reassessment of carotid data.
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KEY WORDS * carotid inner layer thickening
duplex
sonography * serum cholesterol * diastolic blood pressure
carotid arteriosclerosis * identical twins * cigarette smoking
Carotid arteriosclerosis in identical twins discordant for cigarette smoking.
A Haapanen, M Koskenvuo, J Kaprio, Y A Kesäniemi and K Heikkilä
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Circulation. 1989;80:10-16
doi: 10.1161/01.CIR.80.1.10
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