The Journal for Vascular Ultrasound 32(3):129–132, 2008

Common Carotid Intimal-medial Thickness Is

Associated with Coronary In-stent Restenosis
Gregory T. Jones;1 A. M. van Rij;1 G. B. Hill;1 G. T. Wilkins;2 M. J. A. Williams2

ABSTRACT Introduction.—Coronary artery in-stent restenosis (ISR) consists of a rapid vascu-

lar smooth muscle cell proliferation after stent placement. This study tested the hypothesis that
carotid artery intimal thickening may be associated with susceptibility to coronary ISR.
Methods.—Coronary stent treated patients with (ISR, n = 81) and without (ISR-free, n = 163)
ISR were examined along with age- and gender-matched vascular disease-free controls (n = 200).
All participants underwent bilateral carotid duplex ultrasound assessment and cardiovascular
risk factor evaluation. Multiple logistic regressions were used to determine the independence of
any risk associations with either coronary artery disease or ISR.
Results.—Maximal carotid intimal medial thickness was independently associated with symp-
tomatic coronary ISR, with an adjusted odds ratio of 3.4 (95% confidence interval, 1.5–7.7, p <
0.005 for carotid intimal medial thickness >1 mm). Atherosclerosis within the carotid bifurcation
and internal carotid artery, as measured by carotid stenosis scores, was significantly greater in
both coronary artery patient groups compared with vascular disease-free controls but was not
associated with ISR.
Conclusions.—Intimal thickening within the common carotid artery may represent a distinct
pathological process from that which occurs within the carotid bifurcation and internal carotid
arteries. Changes in common carotid IMT appears to represent an independent risk indicator for
symptomatic coronary ISR.

Introduction insertion were recruited retrospectively from the

Dunedin Hospital Cardiology Clinical database. A
Coronary bare metal in-stent restenosis (ISR) is
group of 81 consecutive patients with a history of
characterized by smooth muscle cellular migration
symptomatic, angiographically proven, in-stent reste-
and proliferation around the stent strut. Although
nosis (ISR CAD) were compared with a consecutive
drug-eluting stents have significantly reduced this
series of 163 patients who were angina free for more
problem, it still remains a clinical entity, albeit in a
than 1 year after their stent placement (ISR-free CAD).
smaller group of patients. A number of demographic
The ISR CAD group included patients who had un-
and clinical risk factors for ISR have been identified,
dergone repeat percutaneous intervention or coronary
including waist-to-hip ratio, low-level chronic sys-
artery bypass surgery for ISR and were then free of
temic inflammation, preinterventional lesion charac-
symptoms and cardiovascular events for at least 6
teristics, and the number, diameter, and length of
months. The vast majority (96.9%) of patients were of
stents inserted.1–3
European ethnicity, with the remainder being New
Common carotid artery (CCA) intimal medial thick-
Zealand Mâori (2.3%) or Asian (0.6%).
ening4 shares histopathological similarities with coro-
Coronary angiograms in all patients were analyzed
nary ISR,5 which are distinct from that of atheroscle-
by an experienced cardiologist, with the extent of coro-
rotic plaques. The a priori hypothesis of this study was
nary artery disease expressed as the number of vessel
that carotid artery intimal thickening, particularly
territories (left anterior descending, left circumflex, and
with the common carotid segment, may be associated
right coronary arteries) with one or more stenoses of
with the occurrence of coronary ISR.
ⱖ50% of the vessel normal reference diameter using
visual assessment of lesion severity. CAD extent was
Methods
expressed as single-, double-, or triple-vessel CAD.
Patients with angiographically proven coronary ar- The American College of Cardiology/American Heart
tery disease (CAD) and coronary bare-metal stent Association (AHA/ACC) classification6 was used to
evaluate the morphology of coronary lesions at the
index coronary angiogram. Follow-up angiography
From the Sections of 1Surgery and 2Medicine, University of was analyzed in the restenosis group with the defini-
Otago, Dunedin, New Zealand.
Address correspondence to: Gregory T. Jones, Vascular Research tion of restenosis being diameter stenosis ⱖ50% of the
Group, Section of Surgery, University of Otago, PO Box 913, Dunedin, vessel reference diameter by visual assessment at the
New Zealand. E-mail: greg.jones@otago.ac.nz site of the lesion treated with the stent observed in at
130 JONES ET AL. JVU 32(3)

least one of multiple projections. The single most se-
vere view was used to categorize the pattern of reste-
nosis as proposed by Mehran et al.7 for classification
of in-stent restenotic lesions.
A group of 200 elderly control subjects (97.1% Eu-
ropean) was recruited from the same geographical re-
gion as the CAD cohort. These patients had no history
of ischemic heart disease, peripheral vascular disease,
ischemic stroke, or abdominal aortic aneurysm.
A detailed record of each individual’s current medi-
cations, body mass index, waist-to-hip ratio, and risk
factor history, including previous history of hyperten-
sion, hyperlipidemia, diabetes, other vascular dis-
eases, and smoking history, was collected from all par-
ticipants. One smoking pack year was defined as 20
cigarettes (1 pack) per day for 1 year. All subjects gave
written informed consent before they were recruited
into this study, and the investigation conformed to the
principles outlined in the Declaration of Helsinki.
All 444 participants underwent carotid duplex ul-
trasound (7–12 MHz; ATL, Philips Medical Systems)
assessment. Bilateral far-wall common carotid intimal-
medial thicknesses (cIMTs) were measured 1 cm proxi-
mal from the bifurcation, in accordance with the Mann-
heim carotid IMT consensus statement.8 The presence
of carotid stenoses, within the internal carotid arteries
(ICA), was assessed using the Australasian Society for
Ultrasound in Medicine clinical protocol (D14)9 for
color duplex ultrasound extracranial carotid disease
(carotid stenosis score). In brief, each patient was bi-
laterally scored for degree of stenosis as (0) no steno-
sis, (1) <15%. (2) 16–49%, (3) 50–69%, (4) 70–79%, (5)
80–99%, or (6) occluded.
Statistical analysis was performed with StatView
version 5.01 (SAS Institute, Cary, NC). Each patient’s
maximal cIMT or carotid stenosis score values were
used for subsequent statistical analysis. Because the
cIMT was not normally distributed, this variable was
assessed with the Mann-Whitney U-test. Maximal
CCA IMT >1 mm was applied as the binary cut-off for
abnormal arterial wall thickening as per previous
studies.10–12 Binary cIMT and carotid stenosis scores
were assessed with the Chi-squared test.
Multiple logistic regressions were used to test the
interactive effects of other variables on the observed
association between cIMT and in-stent restenosis. Sig-
nificant or suggestive (p < 0.15) confounders of either
patient group, cIMT, or carotid stenosis scores were
identified and included in the winnowed model (waist
circumference, plasma high sensitivity C-reactive pro-
tein [hs-CRP], extent of coronary disease, AHA/ACC
lesion classification, total stent(s) length, number of
sites stented, and average stent diameter).
Results are expressed as means ± one standard
deviation, except non-Gaussian variables, which are
expressed as medians and interquartile range. Odds
ratios are expressed with 95% confidence intervals. A
p value <0.05 was considered significant.
Results
Demographic differences between ISR CAD and
ISR-free CAD patients included coronary disease se-
verity, coronary lesion score, stent characteristics
(length, diameter, and number of segments), medica-
tions and plasma hs-CRP levels (Tables 1 and 2). Vas-
cular disease-free controls had lower rates of hyper-
tension, hypercholesterolemia, diabetes, smoking,
body mass index, and plasma hs-CRP along with
greater plasma high-density lipoprotein-cholesterol
levels compared with both coronary disease groups
(Table 1).
Maximal common cIMT were significantly greater in
ISR patients compared with either ISR-free (p < 0.03) or
vascular disease-free controls (p < 0.0008). However,
there was no difference between the disease-free con-
trols and the ISR-free CAD patients. Similarly, the per-
centage of ISR patients with cIMT >1 mm was signifi-
cantly greater than in the ISR-free or control groups
(Table 2).
Calcium channel antagonist (p < 0.005) and nitrate
(p < 0.02) medication were used more frequently in

Table 1
Demographic Characteristics of Controls and CAD Groups
Control, ISR-free CAD, ISR CAD, p Value, Control p Value, ISR Free CAD
n = 200 n = 163 n = 81 vs. CAD vs. CAD ISR
Age, years 67.3 ± 6.3 63.8 ± 9.1 62.5 ± 9.0 <0.001 NSD
Gender, % male 77.6 68.7 67.9 NSD NSD
Hypertension, % 22.2 43.8 42.5 <0.001 NSD
Hypercholesterolemia, % 27.8 50.6 43.8 <0.001 NSD
Diabetes, % 2.0 16.0 15.0 <0.001 NSD
Smoking history, pack years 8.0 ± 14.3 20.1 ± 27.0 20.1 ± 24.6 <0.0001 NSD
HDL cholesterol, mmol/L 1.3 ± 0.4 1.2 ± 0.4 1.1 ± 0.3 <0.01 NSD
hsCRP, mg/mL, median (IQR) 1.2 (0.3–2.1) 1.9 (0.3–3.2) 2.5 (2.0–4.0) <0.001 <0.06
Body mass index 25.8 ± 3.8 27.9 ± 4.4 28.8 ± 4.4 <0.0001 NSD
Waist circumference (cm) 95.8 ± 10.8 96.7 ± 11.6 99.1 ± 12.6 NSD vs. ISR-free NSD
<0.0006 vs. ISR

Data are presented as means ± 1 SD or median with interquartile ranges (IQR).

CAD = coronary artery disease; HDL = high-density lipoprotein; hsCRP = high-sensitivity C-reactive protein; ISR = in-stent
restenosis; NSD = no significant difference.
2008 CAROTID IMT IS INCREASED IN CORONARY IN-STENT RESTENOSIS 131

Table 2
Demographic Characteristics of Controls and CAD Groups
p Value,
Control, ISR-free CAD, ISR CAD, p Value, ISR Free CAD
n = 200 n = 163 n = 81 Control vs. CAD vs. CAD ISR
Maximal cIMT (mm), 0.8 (0.7–0.9) 0.8 (0.65–0.95) 1.0 (0.8–1.2) NSD <0.03
median, IQR
Mean ± 1 SD 0.8 ± 0.3 0.9 ± 0.4 1.1 ± 0.9
Maximal cIMT ⱖ1 mm, % 24.2 27.6 50.6 NSD vs. ISR-free <0.0005
<0.0001 vs. CAD ISR
Carotid Stenosis Score, % 98.0, 2.0, 0 92.5, 5.0, 2.5 93.9, 5.5, 0.6 <0.03 NSD
0–1, 2–3, 4–6

Data are presented as means ± 1 SD or median with interquartile ranges (IQR). Maximal carotid intima media thickness
(cIMT) was able to significantly differentiate between in-stent restenosis (ISR) and ISR-free coronary artery disease (CAD)
patients. Carotid stenosis scores were significant greater in CAD versus controls but not significant different (NSD) between
ISR and ISR-free CAD patients.

ISR CAD subjects (Table 3) and, therefore, were included
in the logistic regression model. The univariant odds
ratio for maximal cIMT >1 mm was 2.7 (95% confi-
dence interval, 1.5–4.7, p < 0.0006) and when adjusted
for confounding risk factors (CAD severity, index
AHA/ACC lesion score, number of sites stented, stent
length, stent diameter, waist circumference, hsCRP
and medications.) this remained significant at 3.4 (95%
CI, 1.5–7.7, p < 0.005).
In contrast, carotid stenosis scores, an indicator of
atherosclerotic burden within the carotid bifurcation,
was not significantly different between CAD groups
but was higher in both CAD groups compared with
the vascular disease-free controls (Table 2).
Discussion
A number of demographic and clinical markers
have been implicated as risk factors for coronary
ISR.1–3 These confounding parameters were therefore
included in the multiple logistic analyses used to de-
termine the independence of any risk associations be-
tween carotid ultrasound measurements and coronary
ISR. To our knowledge, this is the first study to dem-
onstrate an independent association between cIMT
and coronary artery ISR.
Lacroix and colleagues13 investigated whether cIMT
was associated with events (death, nonfatal myocar-
dial infarction, the recurrence of angina, hospitaliza-
tion for heart failure, new positive exercise test) after
percutaneous coronary angioplasty. They demon-
strated, in a univariate analysis, that coronary patients
with CCA IMT >0.7 mm had an increased risk of car-
diac events after coronary angioplasty compared with
those with cIMT <0.7 mm (p = 0.03). Although no
evidence of independent association appeared to be
observed by multivariate analysis and angioplasty re-
stenosis was not directly assessed, this study did at
least indicate that cIMT may be linked to postinter-
ventional outcome events.
Although abnormal carotid and femoral artery wall
thickening has been linked with the severity of coro-
nary artery disease the inclusion of measures within
the carotid bifurcation appears to be a key component
of these risk associations.11 Recently, age-adjusted in-
travascular ultrasound measurements of both coro-
nary percentage of atheromatous volume and coro-
nary IMT have been shown to significantly correlate

Table 3
Angiographic and Clinical Features of CAD Patients
ISR-free CAD, ISR CAD, p
n = 163 n = 81 Value
CAD severity, % 1, 2, 3 vessels diseased 44.7, 36.4, 18.9 39.0, 27.3, 33.7 <0.06
Index AHA/ACC lesion score, % A, B1, B2, C 14.5, 37.7, 33.3, 14.5 11.3, 31.3, 18.7, 38.7 <0.0004
Total stent length inserted, mm 22.1 ± 11.2 29.9 ± 17.3 <0.0008
Average stent diameter, mm 3.2 ± 0.5 3.0 ± 0.6 <0.06
Number of sites stented 1.2 ± 0.5 1.4 ± 0.7 <0.07
Medications
Ca2+ antagonists, % treated 21.8 36.0 <0.03
Fibrates, % treated 8.4 12.0 NSD
Nitrates, % treated 20.7 42.9 <0.0007
Statins, % treated 93.7 93.7 NSD

Data are presented as percentages or means ± 1 SD. Significant difference between both clinical and angiographic criteria
were noted between ISR and ISR-free coronary disease patients, as previously reported.1,2
AHA/ACC = American Heart Association/American College of Cardiology; CAD = coronary artery disease; ISR = in-stent
restenosis.
132 JONES ET AL.
with carotid bifurcation IMT but not common carotid
IMT,14 indicating that the carotid atherosclerotic bur-
den is the associative factor. Although variance in IMT
at difference carotid artery sites has been well re-
ported, these have largely been attributed to localized
differences in temporal phases of the same (atheroscle-
rotic) process.
We propose an alternative interpretation based on
differences in the underlying localized pathogenic
processes within distinct carotid segments. Although
changes in cIMT are largely associated with a fibro-
muscular intimal thickening, these changes appear
pathophysiologically distinct from the fibro fatty ath-
erosclerotic lesions known to be localized within the
neighboring carotid bifurcation.4 In this study, mea-
surements of carotid bifurcation stenosis appeared to
be associated with systemic atherosclerosis, as indi-
cated by increased carotid bifurcation stenosis scores
in both CAD groups compared with healthy controls.
This result appears consistent with recent coronary
investigations in which the authors used intravascular
ultrasound.14 In contrast, cIMT was only significantly
increased in those CAD patients with a history of ISR.
The composition of coronary ISR is distinct from that
of de novo atherosclerotic lesions, with ISR being hy-
percellular and having relatively low numbers of mac-
rophages.5 We suggest that ISR and cIMT may share
pathogenic similarities distinct from that of systemic
atherosclerosis.
In conclusion, maximal cIMT is significantly in-
creased in patients with coronary artery bare metal
ISR. This association appears to be independent of
known demographic and clinical confounders of ISR
and warrants further investigation to determine the
predictive power of this non-invasive assessment tool.
Acknowledgment. This study was funded with a Grant-in-aid from
the Dunedin Heart Unit Trust.
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