85
S
troke is a leading cause of death and disability worldwide.
1The global burden of stroke has increased in the past 25
years and will continue to increase in the coming years.
1A
bet-ter understanding of stroke risk factors can aid in development
of more effective preventive strategies.
Arterial remodeling, defined as the change in structural
arterial properties through time in response to atherogenic
or adverse hemodynamic alterations in the arterial
envi-ronment,
2is manifested by carotid diameter enlargement.
Processes that may lead to carotid arterial diameter
enlarge-ment include atherosclerosis (ie, thickening of the intima),
3blood pressure–related media thickening,
4,5and arterial
stiff-ening.
6In addition, carotid diameter enlargement may lead
to an increase in circumferential wall stress.
7A larger carotid
diameter has, therefore, been hypothesized as an important
predictor of stroke.
8Some previous studies,
8–14but not all,
15,16have shown that
a larger carotid artery diameter is associated with a higher
incidence of cardiovascular events (see Table S1 in the
online-only Data Supplement
). However, most of these studies
9,10,12,14did not investigate incident stroke as a separate outcome, and
some failed to correct for important potential confounders,
such as prior cardiovascular disease (CVD),
8,9,13blood
pres-sure,
9,10and heart rate.
8–13,15,16In addition, it is not known whether the association
between carotid diameter enlargement and stroke could be
Received March 26, 2018; first decision April 4, 2018; revision accepted April 19, 2018.From the Departments of Epidemiology (S.S., M.K., O.H.F., M.A.I.), Internal Medicine (F.M.-R.), Neurology (M.A.I.), and Radiology (M.A.I.), Erasmus Medical Center, Rotterdam, the Netherlands; Department of Internal Medicine and Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, the Netherlands (T.T.v.S., C.D.A.S.); Inserm U970, HEGP, AP-HP, Université Paris-Descartes, France (T.T.v.S., S.L., P.B.); Department of Pharmacology, Georges Pompidou European Hospital, Paris, France (S.L., P.B.); Department of Nephrology, Hôpital Manhès, Paris, France (G.M.L.); and Centre d’Investigations Préventives et Cliniques (IPC Center), Paris, France (B.P.).
*These authors contributed equally to this work.
The online-only Data Supplement is available with this article at http://hyper.ahajournals.org/lookup/suppl/doi:10.1161/HYPERTENSIONAHA. 118.11253/-/DC1.
Correspondence to Coen D.A. Stehouwer, Department of Medicine, Maastricht University Medical Centre, Prof. Debyelaan 25, 6229HX Maastricht, the Netherlands. E-mail cda.stehouwer@mumc.nl
Abstract—Carotid arterial diameter enlargement is a manifestation of arterial remodeling and may be a risk factor for
cardiovascular disease (CVD). We evaluated the association between carotid artery diameter and risk of stroke, coronary
heart disease, CVD, and all-cause mortality and explored whether the associations could be explained by processes
involved in arterial remodeling, that is, blood pressure–related media thickening, arterial stiffness, arterial wall stress, and
atherosclerosis. We included 4887 participants (mean age 67±9 years; 54% women) from 4 cohort studies: Rotterdam
Study, NEPHROTEST, Hoorn Study, and a study by Blacher et al. Common carotid artery properties were measured using
echotracking. Incident cases were recorded based on medical records. We used Cox proportional hazard models adjusting
for cardiovascular risk factors and estimates of processes underlying arterial remodeling. During follow-up (mean, 11
years), 379 (8%) individuals had a stroke, 516 had a (11%) coronary heart disease, 807 had a (17%) CVD, and 1486 (30%)
had died. After adjustment for cardiovascular risk factors, individuals in the highest tertile of carotid diameter (diameter
>8 mm) compared with those in the lowest tertile (diameter <7 mm) had a higher incidence of stroke (hazard ratio, 1.5;
95% confidence interval, 1.1–2.0). From all estimates of processes underlying arterial remodeling, adjustment for carotid
intima-media thickness attenuated this association (hazard ratio after adjustment for intima-media thickness, 1.2; 95%
confidence interval, 0.9–1.6). Larger carotid diameter was associated with risk of CVD and mortality but not clearly
with coronary heart disease risk. We showed that a larger carotid diameter is associated with incident stroke, CVD, and
mortality. Carotid intima-media thickness, a measure of blood pressure–related media thickening, partially explained the
association with stroke incidence. (Hypertension. 2018;72:85-92. DOI: 10.1161/HYPERTENSIONAHA.118.11253.)
•
Online Data Supplement
Key Words: atherosclerosis
◼ carotid artery, common ◼ cohort studies ◼ mortality ◼ risk ◼ stroke
Common Carotid Artery Diameter and Risk of
Cardiovascular Events and Mortality
Pooled Analyses of Four Cohort Studies
Sanaz Sedaghat,* Thomas T. van Sloten,* Stéphane Laurent, Gérard M. London,
Bruno Pannier, Maryam Kavousi, Francesco Mattace-Raso, Oscar H. Franco, Pierre Boutouyrie,
M. Arfan Ikram, Coen D.A. Stehouwer
© 2018 American Heart Association, Inc.
Hypertension is available at http://hyper.ahajournals.org DOI: 10.1161/HYPERTENSIONAHA.118.11253
explained by processes involved in arterial diameter
enlarge-ment, notably blood pressure–related media thickening,
4,5arterial stiffening,
6increased wall stress,
7and atherosclerosis.
3These processes may act as a confounder, an antecedent, or
a mediator.
17Previous studies
11,13,15that investigated the role
of carotid intima-media thickness (IMT; a measure of blood
pressure–related media thickening or carotid atherosclerosis)
in the link between arterial diameter enlargement and risk of
CVD did not find that carotid IMT affected this association. In
addition, the roles of arterial stiffness and carotid wall stress
(CWS) in the association between arterial diameter
enlarge-ment and risk of CVD have not been investigated.
We combined individual-level data from 4 studies to
evaluate the association between carotid diameter and
inci-dent stroke. In addition, we evaluated whether this
associa-tion could be explained by carotid IMT (measured adjacent to
carotid plaques, and, therefore, a measure of blood pressure–
related media thickening), arterial stiffness, CWS, or carotid
plaques. Finally, we evaluated the association between carotid
diameter and the incidence of other outcomes than stroke,
including coronary heart disease (CHD), any CVD event, and
all-cause mortality.
Methods
Data are available based on the policies of the included studies, in which data are available on request subject to approval. The detailed
information on the systematic review is provided in the online-only
Data Supplement.
Population
We included individual-level data of all prospective cohort studies in humans (of any age) that investigated the association between carotid diameter and incident stroke, CHD events or total cardiovas-cular events, and all-cause mortality, and had measured carotid artery properties, together with brachial or local pulse pressure (PP), and carotid-femoral pulse wave velocity (cfPWV). Studies that had mea-sured carotid artery properties, but not cfPWV, were not included in the present analysis. The studies included were the RS (Rotterdam
Study),18 NEPHROTEST study,12 Hoorn Study,6 and a study by
Blacher et al10 and comprised a total of 4887 individuals. The
pres-ent study extends our individual participant data meta-analysis on the association between carotid stiffness and incident stroke and other
cardiovascular events19 that used the same eligibility criteria and
included similar studies.
Rotterdam Study
RS is a prospective, population-based cohort study of determinants of several chronic diseases in individuals >55 years. In brief, the cohort started in 1990, consisting of 7983 participants aged ≥55 years living in Ommoord, a district of Rotterdam in the Netherlands (RS-I). In 2000, the first extension of the RS (RS-II) started, adding 3011 new participants who had become 55 years of age or had moved into the study district. All participants visited the research center every 3 to 4
years.18 For this study, we included 3984 participants with available
data for carotid assessment, which took place at the third visit of RS-I and the first visit of RS-II. The median follow-up duration was 10.5 years for RS-I and 9.5 years for RS-II.
NEPHROTEST Study
A prospective hospital-based cohort that started in 2000, enrolling patients who had diagnoses of stages 2 through 5 chronic kidney disease and were referred for extensive work-up by 2 nephrology departments. All patients had to be >18 years of age, not on dialysis,
and without a kidney transplant.12,20 A subset of 168 participants with
available data on carotid diameter was included in this study. The median follow-up duration was 5.5 years.
Hoorn Study
The Hoorn Study is a population-based cohort study of glucose metabolism and CVD risk among the inhabitants of the municipality of Hoorn in the Netherlands. For the present study, we used data from the 2000 Hoorn study examination. In this study, individuals were included (n=579) who had type 2 diabetes mellitus (24.6%), impaired glucose metabolism (29.5%), or normal glucose metabolism (45.8%)
and in whom data on carotid diameter were available.6,21,22 The median
follow-up duration was 7.7 years.
Blacher
It is a prospective cohort study (n=156) that started in 1995 at the F.H. Manhès Hospital, Fleury-Mérogis, France. Patients were included who had been on hemodialysis for at least 3 months and had had no
clinical CVD during the 6 months preceding entry in the study.10 The
median follow-up duration was 5.1 years.
Carotid Arterial Properties Assessment
Diameter, Distensibility Coefficient, IMT, and Wall Stress
Information on the measurements per study is provided in the
online-only Data Supplement (Table S2) and has been described previously.19 In short, common carotid arterial properties were determined in plaque-free areas by ultrasound using echotracking. Echotracking is considered the gold standard measurement technique to assess carotid
artery properties.8 The carotid distensibility coefficient was calculated
according to the following equation: (2∆D×D+∆D2)/(PP×D2), 10–3/
kPa, where D is arterial diameter, ∆D is distension, and PP is brachial PP (calculated as systolic minus diastolic blood pressure). Lower carotid distensibility represents greater carotid stiffness. Carotid IMT was determined adjacent to the presence of any plaques and was cal-culated as the average of left and right common carotid IMT. Pulsatile and mean CWS were calculated as follows: pulsatile CWS was cal-culated as PP×(lumen diameter/2/IMT), kPa. In addition, mean CWS was calculated as mean arterial pressure×([lumen diameter/2]/IMT),
kPa.23 Lumen diameter was calculated as D−(2×IMT), mm.
Carotid-Femoral Pulse Wave Velocity
cfPWV was measured as previously described8 according to recent
guidelines (Table S2).24
Carotid Plaques
Presence of carotid plaques was determined by ultrasound in the common, internal, and bifurcation sites of the carotid artery. Plaques were defined as a focal widening relative to adjacent segments, with protrusion into the lumen composed of either only calcified deposits or a combination of calcified and noncalcified material.
Outcome Definitions
Information on the occurrence of cardiovascular events was acquired through automated linkage with general practitioners’ database or
local hospital discharge forms.12,25,26 Stroke events included nonfatal
and fatal cerebral infarctions and intracerebral hemorrhage. CHD events included nonfatal and fatal acute myocardial infarction, coro-nary artery bypass grafting, and percutaneous corocoro-nary intervention. Any cardiovascular events (CVD) included stroke, CHD events, and congestive heart failure. All-cause mortality included death from any cause. Data were available on stroke, CHD and any CVD events, and all-cause mortality in the Rotterdam and Hoorn studies, on incident any CVD events and all-cause mortality in the NEPHROTEST study,
and on all-cause mortality in the study of Blacher et al.10 Further
details on the outcome definitions are provided in the online-only
Data Supplement (Tables S3 and S4).
Statistical Analyses
Missing values on covariates were imputed using the expectation
max-imization method (single imputation)27 for each cohort separately. We
calculated incident cardiovascular event and mortality rates accord-ing to tertiles of carotid diameter. The association between carotid diameter and outcomes was evaluated using Cox regression models.
We performed the analyses in 2 steps. First, we did a meta-analysis with results from each cohort with random effect methods. Second, we performed pooled analyses adjusting for the cohort variable. We performed the analyses in 4 models: we first adjusted the analyses for age and sex (model 1); additionally adjusted for systolic blood pres-sure and heart rate (model 2); additionally adjusted for other cardio-vascular risk factors, including body mass index, smoking, diabetes mellitus, history of CVD, triglycerides, and total cholesterol/HDL (high-density lipoprotein) ratio (model 3); and finally additionally adjusted for use of antihypertensive and lipid-modifying medication (model 4). The proportionality assumption was met for all analyses.
We modeled carotid diameter both on a categorical (tertiles) and a continuous scale (per SD) because previous studies have reported a
nonlinear association between arterial diameter and vascular events.28
In addition, we explored the presence of nonlinear associations be-tween carotid diameter and outcomes using restricted cubic splines with 3 knots at the 10th, 50th, and 90th percentiles, but we did not observe significant nonlinearity (Figure S1).
To evaluate whether the association between carotid diameter and outcomes could be explained by blood pressure–related media thickening, arterial stiffness, wall stress, or atherosclerosis, we, ad-ditionally, adjusted the analyses for carotid IMT, cfPWV, carotid dis-tensibility, CWS, and carotid plaques.
Furthermore, we evaluated whether associations differed according to sex, kidney function (estimated glomerular filtration rate [eGFR] <60
versus eGFR ≥60 mL/min per 1.73 meter2), diabetes mellitus, and prior
CVD. Finally, we repeated the analyses after excluding participants with
an eGFR <60 mL/min per 1.73 meter2, diabetes mellitus, or prior CVD.
All analyses were done using R statistical software version 3.4.2.
Results
Table 1 shows baseline characteristics of the total population
and across tertiles of carotid diameter; Table 2 shows these
for each cohort separately. Participants had an average age of
67±9 years, and 54% were women. Participants with a larger
carotid diameter were older and had higher levels of
cardiovas-cular risk factors compared with those with a smaller carotid
diameter (Table 1). During follow-up (mean, 10 years), 379
strokes, 516 CHD, and 807 CVD cases were identified, and
1486 individuals died. Incidence rates of stroke, CHD, any
CVD, and all-cause mortality according to tertiles of carotid
diameter are presented in Figure S2.
Table 3 shows pooled associations of carotid diameter
(tertiles and per SD) with incident stroke and other
cardio-vascular outcomes and mortality; Figure S3 shows results
of the individual studies. Individuals in the highest tertile
of carotid diameter (diameter >8 mm) compared with those
in the lowest tertile (diameter <7 mm) had a higher risk of
developing stroke (hazard ratio [HR], 1.90; 95% confidence
interval [CI], 1.42–2.54; Table 3; model 1). Adjustment for
age, sex, systolic blood pressure, and heart rate did not
mate-rially change this association (Table 3; model 2). Additional
adjustment for other cardiovascular risk factors and
medi-cation use attenuated this association, but the association
Table 1. Baseline Characteristics of the Total Population and According to Tertiles of Carotid Diameter
Characteristics
Total Population (n=4887)
Carotid Diameter Tertiles, mm Lowest (<7.3; n=1628) Middle (7.3–8.1; n=1630) Highest (≥8.1; n=1629) Age, y 67.4 (9.1) 64.2 (8.7) 67.5 (8.7) 70.4 (8.8) Female 2623 (53.7) 1197 (73.5) 898 (55.1) 528 (32.4)
Body mass index, kg/m2 26.7 (3.9) 26.1 (3.9) 26.9 (4.0) 27.1 (3.7)
Systolic arterial pressure, mm Hg 142.4 (21.5) 135.1 (19.3) 142.6 (19.9) 149.5 (22.6)
Heart rate, bpm 70.8 (11.9) 71.4 (11.2) 71.0 (11.9) 69.7 (12.4)
Total cholesterol, mmol/L 5.7(1.0) 5.9 (1.0) 5.8 (1.0) 5.6 (1.0)
HDL cholesterol, mmol/L 1.4 (0.4) 1.5 (0.4) 1.4 (0.4) 1.3 (0.4) Triglycerides, mmol/L 1.5 (0.8) 1.5 (0.7) 1.6 (0.8) 1.6 (0.8) Current smokers 921 (18.8) 274 (16.8) 274 (16.8) 373 (22.9) Diabetes mellitus 660 (13.5) 140 (8.6) 228 (14.0) 292 (17.9) Previous CVD* 812 (17.2) 160 (10.1) 246 (15.5) 406 (26.0) Antihypertensive medication 1807 (37.0) 446 (27.4) 589 (36.1) 772 (47.2) Lipid-modifying medication* 712 (15.0) 208 (13.2) 243 (15.3) 261 (16.7)
Carotid intima-media thickness, mm 0.8 (0.1) 0.7 (0.1) 0.8 (0.1) 0.9 (0.1)
Carotid-femoral pulse wave velocity, m/s 12.5 (3.2) 11.5 (2.7) 12.6 (3.1) 13.6 (3.5)
Carotid distensibility, 10–3/kPa 11.8 (5.0) 13.6 (5.3) 11.7 (4.6) 10.1 (4.5)
Pulsatile carotid wall stress, kPa 30.8 (9.7) 26.9 (7.3) 30.5 (8.2) 35.1 (11.3)
Mean carotid wall stress, kPa 45.9 (11.5) 42.1 (9.2) 45.4 (10.1) 50.4 (13.3)
Presence of carotid plaque† 2702 (71.1) 784 (58.9) 906 (70.6) 1012 (85.4)
Significant P values indicate a difference across the carotid diameter strata.
Continuous variables are presented as mean (SD) and categorical variables as number (%). CVD indicates cardiovascular disease; and HDL, high-density lipoprotein.
*These variables were not available in the study of Blacher et al.10
†This variable was available in 3800 individuals.
remained statistically significant (HR, 1.48; 95% CI, 1.09–
2.00; Table 3; model 4). Larger carotid diameter was also
associated with risk of any CVD event, and all-cause
mortal-ity, independently of potential confounders. HRs comparing
individuals in the highest tertile to those in the lowest tertile
were 1.33 (95% CI, 1.08–1.64) for any CVD event and 1.28
(95% CI, 1.10–1.48) for all-cause mortality, respectively
(Table 3; model 4). There was no statistically significant
difference in the risk of CHD events between individuals in
the highest tertile of carotid diameter and those in the
low-est tertile (HR, 1.21; 95% CI, 0.93–1.57; Table 3; model 4).
Results for carotid diameter modeled on a continuous scale
(per SD) were qualitatively similar (Table 3).
The Figure and Figure S4 show the association between
carotid diameters and all outcomes adjusted for carotid IMT,
cfPWV, carotid distensibility, pulsatile and mean CWS, and
carotid plaques. From all potential factors involved in
arte-rial remodeling, adjustment for carotid IMT most clearly
attenuated the association with stroke (HR comparing those
in the highest tertile to those in the lowest tertile after
adjust-ment for IMT, 1.17; 95% CI, 0.85–1.62; corresponding to a
decrease of 26%), as well as for CVD (HR comparing those
in the highest tertile to those in the lowest tertile after
adjust-ment for IMT, 1.09; 95% CI, 0.87–1.36; corresponding to a
decrease of 22%). We did not observe any differences in the
association between carotid diameter and any of the outcomes
according to sex, an eGFR of 60 mL/min per 1.73 meter
2,
dia-betes mellitus, or prior CVD (P interaction>0.05). In addition,
results did not materially change after excluding individuals
with an eGFR <60 mL/min per 1.73 meter
2, diabetes mellitus,
or prior CVD (Table S5).
Discussion
The present study showed that a larger carotid diameter was
independently associated with a higher incidence of stroke. In
addition, a larger carotid diameter was associated with incident
Table 2. Baseline Characteristics of the Participants in Different Cohorts
Characteristics Rotterdam Study I (n=2069) Rotterdam Study II (n=1915) NEPHROTEST (n=168) Hoorn Study (n=579) Blacher et al10 (n=156) Age, y 71.7 (6.8) 63.91 (7.5) 59.3 (14.4) 69.6 (5.5) 53.7 (15.3) Female 1186 (57.3) 1039 (54.3) 42 (25.0) 293 (50.6) 63 (40.4)
Body mass index, kg/m2 26.6 (3.7) 27.0 (3.9) 25.4 (4.5) 27.0 (3.4) 23.9 (4.3)
Systolic blood pressure, mm Hg 142.8 (20.9) 142.0 (21.2) 133.9 (21.9) 142.3 (20.7) 150.8 (29.2)
Heart rate, bpm 73.5 (12.1) 71.0 (11.1) 65.1 (10.9) 62.3 (9.2) 68.9 (10.3)
Total cholesterol, mmol/L 5.8 (0.9) 5.8 (0.9) 4.7 (1.1) 5.8 (1.0) 4.9 (1.1)
HDL cholesterol, mmol/L 1.4 (0.4) 1.4 (0.4) 1.2 (0.4) 1.4 (0.4) 1.0 (0.4) Triglycerides, g/L 1.5 (0.7) 1.6 (0.8) 1.5 (0.8) 1.5 (0.7) 1.9 (0.9) Current smokers 351 (17.0) 370 (19.3) 42 (25.0) 86 (14.9) 72 (46.2) Diabetes mellitus 282 (13.6) 206 (10.8) 23 (13.7) 133 (23.0) 16 (10.3) Previous CVD 297 (14.4) 178 (9.3) 47 (28.0) 290 (50.1) NA Antihypertensive medication 800 (38.7) 526 (27.5) 154 (91.7) 199 (34.4) 128 (82.1) Lipid-modifying medication* 287 (13.9) 235 (12.3) 99 (58.9) 91 (15.7) NA
Carotid intima-media thickness, mm 0.9 (0.1) 0.8 (0.1) 0.8 (0.1) 0.9 (0.2) 0.8 (0.1)
Carotid-femoral pulse wave velocity, m/s 13.4 (3.0) 12.5 (2.9) 11.6 (3.1) 10.2 (3.5) 10.9 (2.8)
Carotid distensibility, 10–3/kPa 10.5 (4.3) 13.0 (4.8) 15.3 (7.8) 10.9 (4.2) 13.7 (8.1)
Pulsatile carotid wall stress, kPa 29.1 (8.8) 31.3 (8.5) 34.3 (13.4) 32.4 (11.2) 39.0 (6.8)
Mean carotid wall stress, kPa 43.5 (10.8) 46.1 (9.3) 53.6 (15.6) 48.9 (14.2) 59.2 (14.5)
Presence of carotid plaque 1304 (69.1) 1398 (73.1) NA NA NA
Carotid diameter, mm 7.9 (1.2) 7.6 (0.9) 7.8 (1.1) 7.9 (1.1) 7.9 (1.1)
Incidence rate Stroke,* per 1000 pyrs (95% CI)
10.9 (9.6–12.4) 5.1 (4.1–6.1) NA 9.8 (7.0–13.3) NA
Incidence rate CHD,* per 1000 pyrs (95% CI)
15.1 (13.4–16.9) 10.6 (9.1–12.3) NA 14.3 (12.5–16.2) NA
Incidence rate any CVD,* per 1000 pyrs (95% CI)
22.8 (20.6–25.2) 14.3 (12.5–16.2) 42.1 (29.3–58.6) 36.0 (30.2–42.7) NA
Incidence rate all mortality,*per 1000 pyrs (95% CI)
44.3 (41.6–47.1) 18.2 (16.5–20.1) 23.7 (14.9–35.9) 22.6 (18.3–27.7) 75.7 (57.7–97.7)
CHD indicates coronary heart disease; CI, confidence interval; CVD, cardiovascular disease; HDL, high-density lipoprotein; NA, not applicable; and pyrs, person years. *A total of 146 participants had missing data on incident stroke, 150 on CVD, and 107 on CHD.
any CVD event, and all-cause mortality, but not clearly with
incident CHD. These associations were partly explained by
carotid IMT, but not by arterial stiffness, mean or pulsatile
CWS, or carotid plaques.
We combined data from 4 cohorts covering a population
with a large risk spectrum, including apparently healthy
indi-viduals and indiindi-viduals with diabetes mellitus and chronic
kidney disease, to evaluate the association between carotid
diameter and incident stroke. The present findings agree with
and extend previous studies
8,9,11,13,15,16(summarized in Table
S1) reporting an association between larger carotid diameter
and incident cardiovascular events. However, previous studies
failed to correct for important potential confounders, such as
prior CVD,
8,9,13blood pressure,
9and heart rate.
8,9,13,15,16The use
of individual participant data from 4 cohort studies enabled
us to do a comprehensive range of additional analyses with
enhanced power, including adjustments for a large number of
potential confounders. Furthermore, we were able to evaluate
the role of carotid IMT, stiffness, and wall stress in the
asso-ciation between carotid diameter and stroke.
The main finding of the present study is that larger
carotid diameter was associated with a higher incidence of
stroke. This relationship was attenuated after adjustment for
carotid IMT but not arterial stiffness or CWS. After
adjust-ments for all potential confounders, carotid IMT explained
26% of the association between carotid diameter and
inci-dent stroke when individuals in the highest tertile of carotid
diameter were compared with those in the lowest tertile.
Previous population-based studies
11,13,15did not find a
mod-erating effect of carotid IMT. However, these studies had
lower statistical power when compared with the present
study because they had a smaller sample size
15or included
individuals with a lower cardiovascular risk
13,15,16compared
with the present study. The present study included older
indi-viduals and higher risk populations with a greater variation
in IMT and carotid diameter values.
The fact that the association between carotid diameter and
stroke risk was attenuated by carotid IMT can be interpreted
in 2 ways, which are not mutually exclusive. First, carotid
diameter enlargement may reflect the compensatory
remodel-ing of the vascular wall in response to local mean and pulsatile
blood pressure (ie, thickening of the media).
4,5This may serve
to normalize circumferential wall stress.
4,5In this scenario,
carotid IMT confounds the association between carotid
diam-eter and stroke, and failure to adjust for carotid IMT leads
to an overestimation of this association. Second, increased
carotid IMT may also be an antecedent of carotid diameter
enlargement. In this scenario, adjustment for carotid IMT
gives an underestimation of the association between carotid
diameter and stroke.
Table 3. Associations Between Carotid Diameter and Incident Cardiovascular Events and All-Cause Mortality
Models
Hazard Ratio (95% Confidence Interval)
Stroke CHD Any CVD All-Cause Mortality
n=4417/379 Events n=4456/516 Events n=4581/807 Events n=4887/1606 Events
Carotid diameter
Model 1 Per SD increase 1.11 (1.06–1.17) 1.17 (1.10–1.24) 1.18 (1.13–1.24) 1.09 (1.06–1.13)
Lowest tertile (reference) 1 1 1 1
Middle tertile 1.29 (0.97–1.73) 1.36 (1.06–1.74) 1.40 (1.15–1.71) 1.21 (1.05–1.39)
Highest tertile 1.90 (1.42–2.54) 1.53 (1.19–1.97) 1.75 (1.43–2.14) 1.51 (1.31–1.75)
Model 2 Per SD increase 1.08 (1.02–1.14) 1.16 (1.08–1.23) 1.16 (1.10–1.23) 1.09 (1.06–1.12)
Lowest tertile (reference) 1 1 1 1
Middle tertile 1.19 (0.89–1.59) 1.30 (1.02–1.67) 1.29 (1.06–1.58) 1.19 (1.03–1.37)
Highest tertile 1.59 (1.18–2.15) 1.40 (1.08–1.82) 1.50 (1.22–1.84) 1.47 (1.28–1.71)
Model 3 Per SD increase 1.07 (1.01–1.14) 1.10 (1.03–1.19) 1.13 (1.06–1.19) 1.07 (1.04–1.11)
Lowest tertile (reference) 1 1 1 1
Middle tertile 1.19 (0.89–1.60) 1.24 (0.96–1.59) 1.25 (1.03–1.53) 1.16 (1.00–1.34)
Highest tertile 1.52 (1.13–2.06) 1.23 (0.95–1.61) 1.37 (1.11–1.69) 1.32 (1.14–1.54)
Model 4 Per SD increase 1.07 (1.00–1.14) 1.08 (0.99–1.16) 1.11 (1.04–1.17) 1.07 (1.03–1.10)
Lowest tertile (reference) 1 1 1 1
Middle tertile 1.18 (0.88–1.58) 1.22 (0.95–1.56) 1.22 (0.99–1.49) 1.14 (0.99–1.31)
Highest tertile 1.48 (1.09–2.00) 1.21 (0.93–1.57) 1.33 (1.08–1.64) 1.28 (1.10–1.48)
Model 1: Adjusted for age, sex, and cohort.
Model 2: Adjusted for model 1+ systolic blood pressure and heart rate.
Model 3: Adjusted for model 2+ body mass index, smoking, diabetes mellitus, history of cardiovascular disease, triglycerides, and total cholesterol/HDL cholesterol ratio.
Model 4: Adjusted for model 3+ use of antihypertensive and lipid-modifying medication. CHD indicates coronary heart disease; CVD, cardiovascular disease; and HDL, high-density lipoprotein.
At least part of the association between carotid
diam-eter and incident stroke remained unexplained after taking
into account the carotid IMT, suggesting the possibility that
carotid diameter enlargement may directly lead to stroke. An
enlarged artery may be less capable to effectively control
lev-els of endothelial shear stress.
29,30Arterial segments exposed
to high endothelial shear stress tend to undergo vessel lumen
enlargement, whereas those segments exposed to low shear
stress will undergo vessel lumen narrowing.
31This mechanism
may be impaired in already enlarged arteries,
29,30leading to
endothelial injury and a higher thrombogenicity of the arterial
wall,
31which may lead to vascular events.
28This study does not support the hypotheses that carotid
diameter is associated with stroke because of associations
with arterial stiffening, increased CWS, or presence of carotid
plaques as adjustment for carotid distensibility, cfPWV, CWS,
or carotid plaques did not attenuate the association between
carotid diameter and stroke. For CWS, we cannot exclude the
possibility that this is related to a relatively large
measure-ment error in the calculation of this estimate because it
com-bines measurement errors of diameter, IMT, and PP, which are
contained in the equation.
32In accordance, pulsatile and mean
CWS were not associated with incident stroke or any other
outcome in the present study (data not shown), and no
previ-ous study has demonstrated any such association.
Carotid diameter was associated with incident stroke,
inci-dent any CVD event, and all-cause mortality, but not clearly
with CHD, although the 95% CI of the effect estimate for
CHD does not exclude the possibility of an association with
CHD. This observation is in line with the results from the
IMPROVE study (Carotid Intima Media Thickness [IMT] and
IMT-Progression as Predictors of Vascular Events in a High
Risk European Population).
15Carotid atherosclerosis, which
is reflected as carotid diameter enlargement, may directly
lead to cerebrovascular events. In addition, carotid diameter
enlargement may directly lead to stroke, but not CHD, because
of local endothelial injury and a higher thrombogenicity of the
carotid wall.
This study has several limitations. First, (unavoidable)
sur-vival bias may have led to an underestimation of the
associa-tions observed. Second, we were not able to make a distinction
between stroke types (ie, ischemic or hemorrhagic), in part,
because data on ischemic versus hemorrhagic stroke were not
available in all studies. In addition, the definition of stroke
differed across studies with 1 study including both ischemic
and hemorrhagic and the other study only ischemic stroke.
Therefore, it is unclear whether carotid diameter enlargement
increases the risk of specific stroke type, and this issue needs
further study. Third, we used brachial PP instead of local
PP to calculate carotid stiffness and wall stress indices. This
may have led to an underestimation of the explained effect
by carotid stiffness and wall stress of the association between
carotid diameter and stroke. However, previous studies
19,26suggest that calculation of carotid stiffness and wall stress
using brachial PP is as accurate as using local PP in relatively
older populations, such as the study populations included in
the present analysis (mean age of included cohort studies
ranged between 54 and 72 years). Third, we observed
mod-erate heterogeneity between estimates from studies probably
because of the differences between the included participants
in each study. Adjustment for potential cardiovascular risk
factors eliminated, however, a large part of the heterogeneity.
In conclusion, a larger carotid diameter is
indepen-dently associated with incident stroke, and this association
is explained partly by carotid IMT. This suggests that larger
carotid diameter, a manifestation of arterial remodeling, is
associated with incident stroke in part because it reflects blood
pressure–related media thickening. A larger carotid diameter
was also associated with a higher risk of any cardiovascular
event and mortality but not clearly with incident CHD.
Figure. Association between carotid diameter (tertiles) and risk of cardiovascular events and all-cause mortality. All associations are adjusted for age, sex, cohort, systolic blood pressure, heart rate, body mass index, smoking, diabetes mellitus, history of cardiovascular disease (CVD), antihypertensive medication, lipid-modifying medication, triglycerides, and total cholesterol/HDL (high-density lipoprotein) cholesterol ratio. In addition, results are additionally adjusted for carotid intima-media thickness (IMT), carotid-femoral pulse wave velocity (cfPWV), carotid distensibility (CD), pulsatile and mean carotid wall stress (CWS), and presence of carotid plaques. CHD indicates coronary heart disease; and HR, hazard ratio.
Perspectives
Carotid diameter enlargement is associated with a higher
stroke incidence, in part because of atherosclerosis and blood
pressure–related media thickening. Some part of the
associa-tion between carotid diameter and incident stroke remained
unexplained after taking into account the effects of carotid
IMT. This suggests that larger carotid diameter, a
manifesta-tion of arterial remodeling, is associated with incident stroke,
in part because it reflects blood pressure–related media
thick-ening. Our findings emphasize the need for additional
evi-dence to establish these associations. In particular, studies are
needed to identify potential biological pathways underpinning
the independent association between carotid diameter and
incident stroke, to explore whether modern intensive medical
therapy will improve arterial remodeling, and eventually to
determine the effect of targeted preventive interventions.
Sources of Funding
T. Van Sloten and C.D.A. Stehouwer are supported by the European Regional Development Fund as part of OP-ZUID, the province of Limburg, the Department of Economic Affairs of the Netherlands (grant 31O.041), Stichting the Weijerhorst, the Pearl String Initiative Diabetes, the Cardiovascular Centre Maastricht, Cardiovascular Research Institute Maastricht, School for Nutrition, Toxicology and Metabolism, Stichting Annadal, and Health Foundation Limburg. M. Kavousi is supported by the VENI grant (91616079) from The Netherlands Organization for Health Research and Development (ZonMw). O.H. Franco works in ErasmusAGE, a center for aging research across the life course funded by Nestlé Nutrition (Nestec, Ltd); Metagenics, Inc; and AXA. S. Laurent, G.M. London, B. Pannier, and P. Boutouyrie are supported by Assistance Publique Hopitaux de Paris, Paris Descartes University, and National Institute for Health and Medical Research (INSERM). The Hoorn Study was supported by grants from the Netherlands Organization for Health Research and Development, the Netherlands Heart Foundation, and the Dutch Diabetes Foundation. The NEPHROTEST study was sup-ported by grants from Programme Hospitalier de Recherche Clinique, French Ministry of Health; and INSERM. The Rotterdam Study is supported by the Erasmus MC, and Erasmus University Rotterdam; the Netherlands Organisation for Scientific Research; the ZonMw; the Research Institute for Diseases in the Elderly; the Netherlands Genomics Initiative; the Ministry of Education, Culture and Science; the Ministry of Health Welfare and Sports; the European Commission (DG XII); and the Municipality of Rotterdam.
Disclosures
None.References
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What Is New?
•
Few studies have evaluated the association of carotid diameterenlarge-ment, a manifestation of arterial remodeling, and incident stroke, cardio-vascular events, and mortality.
•
It has not been investigated whether any association between carotiddiameter enlargement and stroke can be explained by atherosclerosis, blood pressure–related media thickening, arterial stiffening, or increased wall stress.
What Is Relevant?
•
A better understanding of stroke risk factors can aid in the developmentof more effective preventive strategies.
Summary
The present study is the first to show that carotid diameter en-largement is associated with a higher incidence of stroke, inde-pendently of a large number of potential confounders (eg, prior cardiovascular disease and blood pressure). This association is, in part, explained by carotid intima-media thickness, a measure of blood pressure–related media thickening, but not by arterial stiffening, increased wall stress or carotid plaques. A larger ca-rotid diameter was also associated with risk of any cardiovascular events and all-cause mortality but not clearly with incident coro-nary heart disease.
