Background and Purpose
Recent evidence suggests that atherosclerosis is an inflammatory condition. Serum levels of inflammatory markers may serve as measures of the severity of atherosclerosis and risk of stroke. We sought to determine whether tumor necrosis factor-α (TNF-α) and TNF receptor levels are associated with carotid plaque thickness.
The Northern Manhattan Stroke Study is a community-based study of stroke risk factors. For this cross-sectional analysis, inflammatory marker levels, including TNF-α and TNF receptors 1 and 2, were measured by immunoassay in stroke-free community subjects undergoing carotid duplex Doppler ultrasound. Maximal carotid plaque thickness (MCPT) was measured for each subject. Analyses were stratified by age <70 and ≥70 years. Simple and multiple linear regression analyses were used to calculate the association between marker levels and MCPT. Multiple logistic regression was used to calculate odds ratios and 95% CIs for the association of inflammatory markers with MCPT ≥1.5 mm (>75th percentile), after adjustment for demographic and potential medical confounding factors.
The mean age of the 279 subjects was 67.6±8.5 years; 49% were men; 63% were Hispanic, 17% black, and 17% white. Mean values for TNF-α and its receptors were as follows: TNF-α, 1.88±3.97 ng/mL; TNF receptor 1, 2.21±0.99 ng/mL; and TNF receptor 2, 4.85±2.23 ng/mL. Mean MCPT was elevated in those in the highest quartiles compared with lowest quartiles of TNF receptor 1 and 2 (1.24 versus 0.79 mm and 1.23 versus 0.80 mm, respectively). Among those aged <70 years, TNF receptor 1 and 2 were associated with an increase in MCPT (mean difference=0.36 mm, P=0.01 for TNF receptor 1 and mean difference=0.10 mm, P=0.04 for TNF receptor 2). After adjustment for sex, race-ethnicity, hypertension, diabetes mellitus, LDL cholesterol, smoking, and body mass index, associations remained (mean difference=0.36 mm, P=0.001 for TNF receptor 1 and mean difference=0.09 mm, P=0.051 for TNF receptor 2). There was no association for TNF receptors in those aged ≥70 years old and no association for TNF-α in either age group. Among those aged ≥70 years, each unit increase in TNF receptor level increased the odds of the participant’s having MCPT ≥1.5 mm (adjusted odds ratio=4.7; 95% CI, 1.7 to 15.4 for TNF receptor 1; odds ratio=1.9; 95% CI, 1.3 to 2.9 for TNF receptor 2).
Relative elevation in TNF receptor levels, but not TNF-α, is associated with carotid atherosclerosis among individuals aged <70 years in this multiethnic, urban population. Chronic subclinical infection or inflammation may account for this association, and modification of these inflammatory pathways may provide a novel approach to stroke prevention.
atherosclerosis; cerebrovascular disorders; epidemiology; risk factors
Impaired vascular function occurs early in atherogenesis. Brachial flow mediated dilatation (FMD) is a non-invasive measure of vascular function and may be an important marker of preclinical atherosclerosis. Data on the association between FMD and carotid plaque in multi-ethnic populations are limited. The objective of this study was to determine whether endothelial dysfunction is independently associated with carotid plaque in a community of northern Manhattan.
In the population-based Northern Manhattan Study (NOMAS), high-resolution B-mode ultrasound images of the brachial and carotid arteries were obtained in 643 stroke-free subjects (mean age 66 years; 55% women; 65% Caribbean-Hispanic, 17% African-American, 16% Caucasian). Brachial FMD was measured during reactive hyperemia. Maximum carotid plaque thickness (MCPT) was measured at the peak plaque prominence.
The mean brachial FMD was 5.78 ± 3.83 %. Carotid plaque was present in 339 (53%) subjects. The mean MCPT was 1.68 ± 0.82 mm, and the 75th percentile was 2.0 mm. Reduced FMD was significantly associated with increased MCPT. After adjusting for demographics, vascular risk factors, and education, each percent of FMD decrease was associated with a significant 0.02 mm increase in MCPT (p = 0.028). In a dichotomous adjusted model, blunted FMD was associated with an increased risk of MCPT ≥ 2.0 mm (OR, 1.11 for every 1% decrease in FMD; 95% CI, 1.03–1.19).
Decreased brachial FMD is independently associated with carotid plaque. Non-invasive evaluation of endothelial dysfunction may be a useful marker of preclinical atherosclerosis and help to individualize cardiovascular risk assessment beyond traditional risk factors.
Background and purpose: Moderate alcohol intake has been associated with better cognitive performance, implicating vascular and neurodegenerative processes. Few studies to clarify the importance of vascular disease have included direct measures of atherosclerosis or minority populations at higher risk of vascular disease and dementia.
Methods: The Northern Manhattan Study includes stroke-free community based Hispanic (54%), black (25%), and white (22%) participants. We performed a cross-sectional study of alcohol intake and performance on the Mini Mental State Exam (MMSE) in subjects with sonographic measurement of maximal carotid plaque thickness (MCPT) and adjusted for sociodemographic and vascular risk factors.
Results: The median MMSE score was 27 (interquartile range 24-29; N=2,215). Reported alcohol intake was divided into four groups: never (N=509), past (N=494), <1 drink/week (N=300), 1/week to ≤2 drinks/day (N=796), and >2 drinks/day (N=116). Drinking up to 2 drinks/day was associated with better performance on the MMSE (OR=1.19; 95% CI=1.10-1.26) compared to never drinkers in women (P=<0.0001) but not in men, adjusting for sociodemographic and vascular risk factors. MCPT (mean 1.1 mm; SD 1.2 mm) was not associated with alcohol intake and did not mediate the relationship between alcohol and cognition.
Conclusions: Moderate alcohol consumption was independently associated with better cognitive performance in women from this multiethnic sample. Carotid plaque was not a mediator of this association suggesting alcohol may impact cognition through a separate vascular or degenerative pathway.
cognition; carotid diseases; alcohol intake
Common infections may be associated with stroke risk, though no single infection is likely a major independent predictor.
To determine the association between a composite measure of serologies to common infections (Chlamydia pneumoniae, Helicobacter pylori, cytomegalovirus, Herpes Simplex Virus 1 and 2) and stroke risk in a prospective cohort study.
Prospective cohort followed longitudinally for median 8 years.
Randomly selected stroke-free participants from a multiethnic urban community.
Northern Manhattan Study (NOMAS).
Main Outcome measure
Incident stroke and other vascular events.
All five infectious serologies were available from baseline samples in 1625 participants (mean age 68.5 ± 10.1 years; 64.9% women). Cox proportional hazards models were used to estimate associations of each positive serology with stroke. Individual parameter estimates were then combined into a weighted index of infectious burden (IB) and used to calculate hazard ratios and confidence intervals (HR, 95% CI) for association with risk of stroke and other outcomes, adjusted for risk factors. Each individual infection was positively though not significantly associated with stroke risk after adjusting for other risk factors. The IB index was associated with an increased risk of all strokes (adjusted HR per standard deviation 1.39, 95% CI 1.02–1.90) after adjusting for demographics and risk factors. Results were similar after excluding those with coronary disease (adjusted HR 1.50, 95% CI 1.05–2.13) and adjusting for inflammatory biomarkers.
A quantitative weighted index of infectious burden was associated with risk of first stroke in this cohort. Future studies are needed to confirm these findings and to further define optimal measures of IB as a stroke risk factor.
Assess the association of vitamin D deficiency and indices of mineral metabolism with subclinical carotid markers that predict cardiovascular events.
203 community-dwelling adults (Northern Manhattan Study, age: 68±11, 50–93 yrs) had serum measurements (calcium, phosphorus, 25-hydroxyvitamin D [25OHD], 1,25-dihydroxyvitamin D, PTH) and carotid ultrasound (plaque presence, number, maximal carotid plaque thickness [MCPT], intima-media thickness [IMT]).
Adjusting for cardiovascular risk factors, plaque number was associated with phosphorus levels (β=0.39 per unit increase; p=0.02) and calcium-phosphorus product (β=0.36 per 10 unit increase; p=0.03). In those with plaque (N=116; 57%), the association of plaque number with phosphorus and calcium-phosphorus product persisted. In addition, 25OHD was inversely associated with both IMT (β= −0.01 per 10 ng/ml increase; p=0.05) and MCPT (β= −0.10 per 10 ng/ml increase; p=0.03). In a model containing traditional cardiac risk factors and indices of mineral metabolism, 25OHD accounted for 13% of the variance in both IMT and MCPT. Calcium, PTH, and 1,25-dihydroxyvitamin D levels were not associated with carotid measures.
After adjusting for cardiovascular risk factors and renal function, serum phosphorus and calcium-phosphorus product were associated with greater burden of subclinical carotid atherosclerosis. Low 25OHD levels were associated with increased IMT and MCPT in those with plaque, and 25OHD contributed in a robust manner to the variance in both. These results confirm and extend data on the association of low vitamin D levels with subclinical carotid atherosclerosis. The precise nature of this association and the optimum levels of vitamin D for vascular health remain to be elucidated.
Vitamin D deficiency; parathyroid hormone; carotid plaque; IMT; atherosclerosis
Carotid atherosclerosis is a known biomarker associated with future vascular disease. The risk associated with small, nonstenotic carotid plaques is less clear. The objective of this study was to examine the association between maximum carotid plaque thickness and risk of vascular events in an urban multiethnic cohort.
As part of the population-based Northern Manhattan Study, carotid plaque was analyzed among 2,189 subjects. Maximum carotid plaque thickness was evaluated at the cutoff level of 1.9 mm, a prespecified value of the 75th percentile of the plaque thickness distribution. The primary outcome measure was combined vascular events (ischemic stroke, myocardial infarction, or vascular death).
Carotid plaque was present in 1,263 (58%) subjects. After a mean follow-up of 6.9 years, vascular events occurred among 319 subjects; 121 had fatal or nonfatal ischemic stroke, 118 had fatal or nonfatal myocardial infarction, and 166 died of vascular causes. Subjects with maximum carotid plaque thickness greater than 1.9 mm had a 2.8-fold increased risk of combined vascular events in comparison to the subjects without carotid plaque (hazard ratio, 2.80; 95% CI, 2.04–3.84). In fully adjusted models, this association was significant only among Hispanics. Approximately 44% of the low-risk individuals by Framingham risk score had a 10-year vascular risk of 18.3% if having carotid plaque.
Maximum carotid plaque thickness is a simple and noninvasive marker of subclinical atherosclerosis associated with increased risk of vascular outcomes in a multiethnic cohort. Maximum carotid plaque thickness may be a simple and nonexpensive tool to assist with vascular risk stratification in preventive strategies and a surrogate endpoint in clinical trials.
Helicobacter pylori is now incriminated in the pathogenesis
To examine the importance of H. pylori infection as a
cardiovascular disease (CVD) risk factor.
Two hundred five patients (128 with H. pylori infection
[HP-seropositive] and 77 without) had a baseline assessment
for other potential CVD risk factors and were followed prospectively for 10
years (1999–2008). They were assessed on a monthly basis for the
outcomes of carotid plaque, angina pectoris, myocardial infarction, and
stroke. In the HP-seropositive group, male sex and quartile 4 for IgG
anti-H. pylori antibodies (anti-HP Ab) were correlated
with traditional CVD risk factors, stroke, myocardial infarction, and angina
At the baseline assessment, the levels of carotid intima-media thickness,
blood fibrinogen, total cholesterol, fasting plasma glucose, and uric acid
were higher in H. pylori-infected patients than in the
uninfected group. Serum HDL-cholesterol was significantly lower in the
HP-seropositive group. Men had higher levels of IgG anti-HP Ab, waist
circumference, blood pressure, uric acid, and total cholesterol than women.
Within the HP-seropositive group, individuals in quartile 4 for IgG anti-HP
Ab had higher rates of elevated fibrinogen, diabetes mellitus, low
high-density lipoprotein cholesterol, arterial hypertension, and high total
cholesterol than those in quartile 1. After adjusting for traditional CVD
risk factors, H. pylori infection was the only independent
predictor of incident carotid plaque (multivariate odds ratio
[OR] = 2.3, 95% confidence interval
[CI]: 1.2–7.2; P < 0.0001) and
incident acute stroke (multivariate OR = 3.6, 95% CI:
1.4–8.2; P < 0.0001). Within the HP-seropositive
group and after adjusting for traditional CVD risk factors, male sex was the
only independent predictor of incident angina pectoris (multivariate OR
= 3.5, 95% CI: 1.6–16; P <
0.0001), incident acute stroke (multivariate OR = 3.2, 95%
CI: 1.4–28; P < 0.0001), and acute myocardial
infarction (multivariate OR = 7.2, 95% CI: 3.1–18;
P < 0.0001).
Our study provides evidence for an association among known CVD risk factors,
carotid plaque, stroke, and H. pylori infection. Among
infected individuals, there is a significant association among severity of
HP-seropositivity, male sex, and CVD. The eradication of H.
pylori infection may therefore reduce the emerging burden of
CVD in Africa.
Helicobacter pylori; stroke; myocardial infarction; cardiovascular disease; carotid plaque; Africans
YKL-40 has been demonstrated to be related to atherosclerosis, but its role in predicting plaque status and the outcome of carotid atherosclerosis (CAS) caused by CagA-positive helicobacter pylori remains unclear. This study was aimed to investigate the role of YKL-40 in predicting the outcome of carotid atherosclerosis with CagA-positive Helicobacter pylori infection.
The serum concentrations of YKL-40, C-reaction protein in 310 patients undergoing color Duplex assessment of carotid atherosclerosis were recorded and divided into 3 groups according to the infectious statuses of helicobacter pylori. We also examined serum YKL-40, C-reaction protein and the plaque morphology in animal model of carotid atherosclerosis with different types of helicobacter pylori infection.
Overexpression of YKL-40 was only found in carotid atherosclerosis group with CagA-positive helicobacter pylori infection; C-reaction protein failed to distinguish different infectious statuses of helicobacter pylori infection. In patients with CagA-positive helicobacter pylori infection, elevated YKL-40 expression was accompanied by more severe clinical symptoms. We also confirmed similar findings in rabbit model of carotid atherosclerosis with CagA-positive helicobacter pylori infection. We found that in 7 rabbits treated with anti-helicobacter pylori therapy, the serum YKL-40 level decreased and the plaque became more stable.
Our findings suggested that increased serum YKL-40 level indicates plaque instability and more severe clinical symptoms of carotid atherosclerosis with CagA-positive helicobacter pylori infection. Compared with C-reaction protein, YKL-40 seems to be a more specific predictor of plaque status and outcome of carotid atherosclerosis with CagA-positive helicobacter pylori infection.
We previously showed that the burden of Chlamydia pneumoniae in carotid plaques was significantly associated with plaque interleukin (IL)-6, and serum IL-6 and C-reactive protein (CRP), suggesting that infected plaques contribute to systemic inflammatory markers in patients with stroke risk. Since lipoprotein-associated phospholipase A2 (Lp-PLA2) mediates inflammation in atherosclerosis, we hypothesized that serum Lp-PLA2 mass and activity levels and plaque Lp-PLA2 may be influenced by plaque C. pneumoniae infection.
Forty-two patients underwent elective carotid endarterectomy. Tissue obtained at surgery was stained by immunohistochemistry for Lp-PLA2 grade, macrophages, IL-6, C. pneumoniae and CD4+ and CD8+ cells. Serum Lp-PLA2 activity and mass were measured using the colorimetric activity method (CAM™) and ELISA, respectively. Serum homocysteine levels were measured by HPLC. Eleven (26.2%) patients were symptomatic with transient ischemic attacks. There was no correlation between patient risk factors (smoking, coronary artery disease, elevated cholesterol, diabetes, obesity, hypertension and family history of genetic disorders) for atherosclerosis and serum levels or plaque grade for Lp-PLA2. Plaque Lp-PLA2 correlated with serum homocysteine levels (p = 0.013), plaque macrophages (p<0.01), and plaque C. pneumoniae (p<0.001), which predominantly infected macrophages, co-localizing with Lp-PLA2.
The significant association of plaque Lp-PLA2 with plaque macrophages and C. pneumoniae suggests an interactive role in accelerating inflammation in atherosclerosis. A possible mechanism for C. pneumoniae in the atherogenic process may involve infection of macrophages that induce Lp-PLA2 production leading to upregulation of inflammatory mediators in plaque tissue. Additional in vitro and in vivo research will be needed to advance our understanding of specific C. pneumoniae and Lp-PLA2 interactions in atherosclerosis.
To evaluate the association between carotid intima-media thickness (CIMT) and the presence of aortic arch plaques (AP) in a community-based cohort.
Large AP are associated with ischemic stroke. CIMT is a marker of subclinical atherosclerosis and a strong predictor of cardiovascular disease and stroke. The association between CIMT and AP has been studied in stroke patients, but not in the general population. Aim of this study was to investigate this association in an elderly asymptomatic cohort, and the possibility to use CIMT to predict the presence or absence of large AP.
Stroke-free control subjects from the Aortic Plaque and Risk of Ischemic Stroke (APRIS) Study underwent transesophageal echocardiography and high-resolution B-mode ultrasound of the carotid arteries. CIMT was measured at the common carotid artery, bifurcation and internal carotid artery. The association between CIMT and AP was analyzed by multivariate regression models. Positive and negative predictive values of CIMT for large (≥ 4 mm) AP were calculated.
Among 138 subjects, large AP was present in 35 (25.4%) subjects. Only CIMT at the bifurcation was associated with large AP after adjustment for atherosclerotic risk factors (p=0.007). Positive and negative predictive value for AP ≥ 4 mm of CIMT at the bifurcation above the 75th percentile (≥ 0.95 mm) were 42% and 80%, respectively. Negative predictive value increased to 87% when the median CIMT value (0.82 mm) was used.
CIMT at the bifurcation is independently associated with AP ≥ 4 mm. Its strong negative predictive value for large arch plaque indicates that CIMT may be used as an initial screening test to exclude severe arch atherosclerosis in the general population.
Background and Purpose
Sex differences have been recognized in stroke risk; however, the sex-dependent genetic contribution to stroke is unclear. We sought to examine the sex-dependent associations between genes involved in lipid metabolism and carotid atherosclerotic plaque, a subclinical precursor of stroke.
For the Genetic Determinant of Subclinical Carotid Disease study, 287 Dominicans ascertained through the Northern Manhattan Study (NOMAS) were examined for carotid plaque using high-resolution ultrasound. Sixty-four single nucleotide polymorphisms (SNPs) in eleven lipid-related genes were genotyped. Plaque presence and plaque sub-phenotypes, including multiple, thick, irregular and calcified plaque, were analyzed. First, the interaction between each SNP and sex was evaluated for association with each plaque phenotype using multiple logistic regression and controlling for age, smoking, and the main effects of sex and SNP. For SNPs with suggestive evidence for interaction with sex (p<0.1 for the interaction term), stratification analysis by sex was performed to evaluate the sex-specific association between the SNP and plaque phenotypes.
The most compelling finding is with the missense SNP rs11053646 (K167N) in the OLR1 gene, which encodes lectin-like oxidized LDL receptor. Stratification analysis revealed a strong association between rs11053646 and all plaque phenotypes in women (OR=2.44~5.86, p=0.0003~0.0081) but not in men (OR=0.85~1.22 p=0.77~0.92).
Genetic variation in genes involved in lipid metabolism may have sex-dependent effects on carotid plaque burden. Our findings provide a plausible biological basis underlying the sex difference in cardiovascular risk.
OLR1; candidate genes; carotid plaque; sex; lipids
Atherosclerosis is related to various cardiovascular and cerebrovascular events like cerebral infarction. Recurrence of ischemic stroke is specifically related to atherosclerotic load as determined by the presence of carotid atheromatous plaques and its echogenicity.
This study was to evaluate the association of recurrence of stroke with echogenic characteristics of carotid plaque in ischemic stroke patients.
Materials and Methods:
Carotid sonography using high-resolution 7.5 MHz along with gray-scale technique was done in each ischemic stroke patient to find the occurrence of plaque and its echogenicity according to Mannheim Carotid Intima-Media Thickness Consensus (2004-2006). Followup of patient done to know the recurrence of stroke during 6-month duration and its association with plaque echogenicity.
A significant association found between the presence of plaque and known cerebrovascular risk factors. Also significant association found between recurrence of stroke and echolucent character of carotid plaque in bivariate analysis (P = 0.0028).
Recurrence of stroke is related to advanced stage of atherosclerosis that is specified by carotid plaque and its characteristics. It will help us to identify groups of patients at different risk for stroke and planning better strategies to prevent such events.
Carotid ultrsonography; Cerebrovascular diseases; Echogenic plaque; Ischemic stroke
The prevalence of carotid bruits and the utility of auscultation for predicting carotid stenosis are not well known. We aimed to establish the prevalence of carotid bruits and the diagnostic accuracy of auscultation for detection of hemodynamically significant carotid stenosis, using carotid duplex as the gold standard.
The Northern Manhattan Study (NOMAS) is a prospective multiethnic community-based cohort designed to examine the incidence of stroke and other vascular events and the association between various vascular risk factors and subclinical atherosclerosis. Of the stroke-free cohort (n=3298), 686 were examined for carotid bruits and underwent carotid duplex. Main outcome measures included prevalence of carotid bruits and sensitivity, specificity, positive predictive value, negative predictive value and accuracy of auscultation for prediction of ipsilateral carotid stenosis.
Among 686 subjects with a mean age of 68.2 ± 9.4 years, the prevalence of ≥60% carotid stenosis as detected by ultrasound was 2.2% and the prevalence of carotid bruits was 4.1%. For detection of carotid stenosis, sensitivity of auscultation was 56%, specificity was 98%, positive predictive value was 25%, negative predictive value was 99% and overall accuracy was 97.5%.
In this ethnically diverse cohort, the prevalence of carotid bruits and hemodynamically significant carotid stenosis was low. Sensitivity and positive predictive value were also low, and the 44% false-negative rate suggests that auscultation is not sufficient to exclude carotid stenosis. While the presence of a bruit may still warrant further evaluation with carotid duplex, ultrasonography may be considered in high-risk asymptomatic patients, irrespective of findings on auscultation.
Carotid bruit; auscultation; vascular ultrasonography; carotid stenosis
Shear stress gradients and inflammation have been causally associated with atherosclerosis development in carotid bifurcation regions. The mechanism underlying higher levels of carotid intima-media thickness observed among HIV-infected individuals remains unknown.
Methods and Results
We measured carotid intima-media thickness progression and development of plaque in the common carotid, bifurcation region, and internal carotid artery in 300 HIV-infected persons and 47 controls. The median duration of follow-up was 2.4 years. When all segments were included, the rate of intima-media thickness progression was greater in HIV-infected subjects compared with controls after adjustment for traditional risk factors (0.055 vs. 0.024 mm/year, P=0.016). Rate of progression was also greater in the bifurcation region (0.067 vs. 0.025 mm/year, P=0.042) whereas differences were smaller in the common and internal regions. HIV-infected individuals had a greater incidence of plaque compared with controls in the internal (23% vs. 6.4%, P=0.0037) and bifurcation regions (34% vs. 17%, P=0.014). Among HIV-infected individuals, the rate of progression in the bifurcation region was more rapid compared with the common carotid, internal, or mean intima-media thickness; in contrast, progression rates among controls were similar at all sites. Baseline hsCRP was elevated in HIV-infected persons and was a predictor of progression in the bifurcation region.
Atherosclerosis progresses preferentially in the carotid bifurcation region in HIV-infected individuals. hsCRP, a marker of inflammation, is elevated in HIV and is associated with progression in the bifurcation region. These data are consistent with a model in which the interplay between hemodynamic shear stresses and HIV-associated inflammation contribute to accelerated atherosclerosis. (J Am Heart Assoc. 2012;1:jah3-e000422 doi: 10.1161/JAHA.111.000422.)
Clinical Trial Registration
URL: http://clinicaltrials.gov. Unique identifier: NCT01519141
AIDS; carotid arteries; inflammation; atherosclerosis
The features of carotid atherosclerosis in ketosis-onset diabetes have not been investigated. Our aim was to evaluate the prevalence and clinical characteristics of carotid atherosclerosis in newly diagnosed Chinese diabetic patients with ketosis but without islet-associated autoantibodies.
In total, 423 newly diagnosed Chinese patients with diabetes including 208 ketosis-onset diabetics without islet-associated autoantibodies, 215 non-ketotic type 2 diabetics and 79 control subjects without diabetes were studied. Carotid atherosclerosis was defined as the presence of atherosclerotic plaques in any of the carotid vessel segments. Carotid intima-media thickness (CIMT), carotid atherosclerotic plaque formation and stenosis were assessed and compared among the three groups based on Doppler ultrasound examination. The clinical features of carotid atherosclerotic lesions were analysed, and the risk factors associated with carotid atherosclerosis were evaluated using binary logistic regression in patients with diabetes.
The prevalence of carotid atherosclerosis was significantly higher in the ketosis-onset diabetic group (30.80%) than in the control group (15.2%, p=0.020) after adjusting for age- and sex-related differences, but no significant difference was observed in comparison to the non-ketotic diabetic group (35.8%, p=0.487). The mean CIMT of the ketosis-onset diabetics (0.70±0.20 mm) was markedly higher than that of the control subjects (0.57±0.08 mm, p<0.001), but no significant difference was found compared with the non-ketotic type 2 diabetics (0.73±0.19 mm, p=0.582) after controlling for differences in age and sex. In both the ketosis-onset and the non-ketotic diabetes, the prevalence of carotid atherosclerosis was markedly increased with age (both p<0.001) after controlling for sex, but no sex difference was observed (p=0.479 and p=0.707, respectively) after controlling for age. In the ketosis-onset diabetics, the presence of carotid atherosclerosis was significantly associated with age, hypertension, low-density lipoprotein cholesterol and mean CIMT.
The prevalence and risk of carotid atherosclerosis were significantly higher in the ketosis-onset diabetics than in the control subjects but similar to that in the non-ketotic type 2 diabetics. The characteristics of carotid atherosclerotic lesions in the ketosis-onset diabetics resembled those in the non-ketotic type 2 diabetics. Our findings support the classification of ketosis-onset diabetes as a subtype of type 2 diabetes.
Ketosis-prone diabetes; Type 2 diabetes; Atherosclerosis; Carotid arteries; Epidemiology
Besides the established factors "presence of symptoms" and
"degree of stenosis", plaque echolucency is considered to be
associated with increased risk of stroke in patients with carotid
artery disease. An evaluation was carried out as to whether the
prevalence and number of microembolic signals (MES) detected by
transcranial Doppler ultrasound were higher in patients with echolucent
carotid plaques. One hundred and
five patients with carotid
artery stenosis from 20%-99% or occlusion underwent clinical
investigations, duplex ultrasound of the carotid arteries, and a 1 hour
recording from the middle cerebral artery downstream to the carotid
artery pathology using the four gate technique. The presence of MES was
more frequent and the number greater in symptomatic patients (21 out of
64 patients (33%); mean number of MES in all 64 patients 3.1) than in
asymptomatic patients (four out of 41 patients (10%); mean number of
MES in all 41 patients 0.3) (p=0.007, and p=0.006, respectively).
Echogenicity of the lesions did not affect either number or presence of
MES. Positivity for MES and the number of MES increased with increasing degree of stenosis (both p=0.002). Four out of 12 patients with carotid
artery occlusion showed MES. No MES could be detected in carotid artery
stenosis below 80%. There was a decline in positivity of MES and of
the number of MES with the time after the ischaemic event. After 80 days or more after the index event, only one patient showed MES. In conclusion, increasing degree of stenosis and presence of symptoms
similarly affect macroembolic and microembolic risk. Thus MES may be a
surrogate parameter for risk of stroke. The presence of MES in a few
asymptomatic patients suggests that clinically silent circulating
microemboli may give additional information on the pending embolic
potential of carotid artery stenoses. Echolucency of the plaque was not
related to an increased number of MES.
The SNP rs11628722 in the SERPINA9 gene was previously associated with incident ischemic stroke in the Atherosclerosis Risk in Communities (ARIC) study. Centerin, the protein encoded by SERPINA9, is involved in maturation and maintenance of naïve B cells, which play a role in atherogenesis. We investigated whether 21 tag SNPs in the SERPINA9 gene are associated with features of carotid artery atherosclerotic plaque measured by magnetic resonance imaging (MRI). Carotid MRI data were obtained from 1,282 European Americans and 341 African Americans of the ARIC Carotid MRI study, which recruited participants from ARIC by a stratified sampling plan that over-sampled participants with carotid intima-media thickening. Five MRI measures, focused on carotid wall volume, wall thickness, and lipid core, were analyzed. Genetic associations between the MRI measurements and each of the 21 SNPs were analyzed in linear regression models with adjustment for sample weights and traditional risk factors. Rs11628722 was tested a priori. In African Americans, rs11628722 was significantly associated with carotid wall volume (p < 0.05). Among the other 20 SNPs, adjusted for multiple testing, rs4905204, which encodes an Ala to Val amino acid change, was significantly associated with maximum wall thickness (p < 0.000625) and suggestively associated with total wall volume (p < 0.0026) in European Americans. In conclusion, SNPs in the SERPINA9 gene showed race-specific associations with characteristics of carotid atherosclerotic plaques. Replications in other populations are needed to validate findings of this study and to establish the SERPINA9 gene as a candidate in the etiology of carotid atherosclerosis.
SERPINA9 gene; carotid atherosclerosis; MRI; genetic association
Background and Purpose
Carotid intima-media thickness (IMT) is a surrogate marker of subclinical atherosclerosis and a strong predictor of stroke and myocardial infarction. The object of this study was to determine the association between carotid IMT and 702 single nucleotide polymorphisms in 145 genes.
B-mode carotid ultrasound was performed among 408 Hispanics from the Northern Manhattan Study. The common carotid artery IMT and bifurcation IMT were phenotypes of interest. Genetic effects were evaluated by the multivariate regression model adjusting for traditional vascular risk factors. For each individual, we calculated a gene risk score (GRS) defined as the total number of the significant single nucleotide polymorphisms in different genes. Subjects were then divided into 3 GRS categories using the 2 cutoff points: mean GRS ±1 SD.
We identified 6 significant single nucleotide polymorphisms in 6 genes for common carotid artery IMT and 7 single nucleotide polymorphisms in 7 genes for bifurcation IMT using the probability value of 0.005 as the significant level. There were no common significant genes for both phenotypes. The most significant genes were the tissue plasminogen activator (P=0.0005 for common carotid artery IMT) and matrix metallopeptidase-12 genes (P=0.0004 for bifurcation IMT). Haplotype analysis did not yield a more significant result. Subjects with GRS ≥9 had significantly increased IMT than those with GRS ≤5 (P<0.001). GRS was an independent predictor of both common carotid artery IMT (P=2.3×10−9) and bifurcation MT (P=7.2×10−8).
Multiple genes contributed to the variation in carotid IMT. IMT in different carotid segments may be regulated by different sets of susceptibility genes.
atherosclerosis; carotid intima-media thickness; genetics; polymorphism
Background and Purpose
The coexistence of carotid atherosclerosis in ischemic stroke patients with small-vessel disease (SVD) or intracranial large-vessel disease (ICLVD) was investigated using carotid duplex ultrasonography, and whether its coexistence affected the clinical prognosis was determined.
Ischemic stroke patients with SVD or ICLVD were enrolled (n=103). Risk factors, demographic data, and National Institutes of Health Stroke Scale (NIHSS) scores were obtained for all of the subjects. Early neurological progression was defined by an increase in NIHSS score during the first 7 days. Carotid ultrasonography was performed to measure the intima-media thickness (IMT) and carotid plaques.
Among the 103 patients who were retrospectively enrolled in this study (56 with SVD and 47 with ICLVD), 66 (64.1%) had an atherosclerotic plaque and 23 (22.3%) had increased IMT. Increased IMT was observed more frequently in ICLVD than in SVD [15/47 (31.9%) vs. 8/56 (14.3%), p=0.032]. An atherosclerotic plaque was observed on subsequent carotid ultrasonographic examination in 28 (50%) of the 56 patients whose computed tomography angiography scans of the neck vessels were interpreted as normal. There was no association between presence of atherosclerotic change and early neurologic progression (p=0.94).
A coexisting atherosclerotic plaque or increased IMT was observed in 71.8% of patients with SVD or ICLVD. Whether the coexistence of carotid atherosclerotic change with either of these conditions affects the clinical prognosis remains to be elucidated.
small-vessel disease; intracranial large-vessel disease; atherosclerosis; plaque; stroke
We examined the cross-sectional relationships of subclinical atherosclerosis – expressed by carotid intimal–medial thickness and coronary calcification – with antibodies to Chlamydia pneumoniae, Helicobacter pylori, cytomegalovirus, herpes simplex virus, hepatitis A virus, and pathogen burden (number of positive pathogens). A random sample of 1056 individuals chosen from 5030 Multi-Ethnic Study of Atherosclerosis cohort participants were included. After multiple adjustment, no associations were found between atherosclerosis measures and either individual pathogens or pathogen burden. Interactions with inflammatory and endothelial function markers, demographic factors, BMI, high-density lipoprotein, diabetes, and smoking were also explored. The only interaction that was large, qualitative, statistically significant (P < 0.05) and in the expected direction was that between hepatitis A virus and soluble intercellular adhesion molecule-1 with regard to Agatston calcium score: the difference between hepatitis A virus-positive and hepatitis A virus-negative participants was −86 units in participants with soluble intercellular adhesion molecule-1 below the median, and +162 units in those with soluble intercellular adhesion molecule-1 equal or above the median. However, given the number of interactions that were explored, these results must be interpreted cautiously.
Findings from the present analyses do not provide support for an infectious etiology for subclinical atherosclerosis. However, the study’s limitations, which include its cross-sectional design and insufficient statistical power, suggest that inferences from its findings should be made cautiously.
atherosclerosis; infections; pathogens
Rheumatoid arthritis (RA) patients have increased mortality and morbidity as a result of cardiovascular and cerebrovascular disease. What is not clear, however, is either how early accelerated atherosclerosis begins in RA or how soon risk factors must be rigorously controlled. Furthermore, given the strong relationship of vascular disease to RA mortality and of inflammation to the accelerated atherosclerosis associated with RA, it is important to evaluate indices that could serially and noninvasively quantify atherosclerotic disease in RA patients. The carotid intima-media thickness (cIMT) and plaque, measured by ultrasound, correlate closely with direct measurement of the local and systemic atherosclerotic burden. To investigate the presence of subclinical atherosclerosis in the early stages of RA, the cIMT and plaque were measured using carotid duplex scanning in 40 RA patients with disease duration < 12 months and in 40 control subjects matched for age, sex and established cardiovascular risk factors. Patients with RA had significantly higher average cIMT values and more plaque than the control group (cIMT 0.64 ± 0.13 mm versus 0.58 ± 0.09 mm, respectively; P = 0.03). In RA patients, the cIMT was predicted by age and C-reactive protein level at first presentation to the clinic (R2 = 0.64). C-reactive protein was associated with age of disease onset and history of smoking. Since inflammation has been shown to predate onset of clinical RA, the accelerated atherogenic process related to inflammation may precede RA symptom onset.
We sought to identify clinical and/or plaque characteristics that affect atherosclerotic disease progression and arterial remodeling in the carotid artery with subclinical stenosis.
Increasing severity of stenosis has been associated with a higher risk of stroke. Factors that drive subclinical lesions to become stenotic plaques remain ambiguous. Carotid magnetic resonance imaging (MRI) has been validated with histology to accurately quantify in vivo arterial morphology and plaque composition.
A total of 67 asymptomatic participants with 16% to 49% carotid stenosis as demonstrated by duplex ultrasonography were imaged at 1.5-T with a carotid MRI protocol at baseline and at 18-month follow-up. Clinical and/or intra-arterial metrics with a significant association with change in plaque burden during multivariate analysis were evaluated for effects on lumen, wall, and total vessel volume.
From multiple regression analysis, intraplaque hemorrhage (IPH) (p < 0.001) and statin therapy (p = 0.015) were identified as key determinants of change in plaque burden. The group with IPH compared with the group without IPH demonstrated luminal narrowing, with a mean ± SD decrease in lumen volume (−24.9 ± 21.1 mm3/year vs. −0.5 ± 26.9 mm3/year; p = 0.005), a larger increase in wall volume (44.1 ± 36.1 mm3/year vs. 0.8 ± 34.5 mm3/year; p < 0.001), and no difference in total vessel volume (19.3 ± 27.4 mm3/year vs. 0.4 ± 42.4 mm3/year; p = 0.15). The nonstatin group compared with the statin group demonstrated outward remodeling, with an increase in wall volume (22.4 ± 35.6 mm3/year3/year vs. 0.9 ± 38.0 mm3/year; p = 0.026) and total vessel volume (19.2 ± 36.9 mm3/year vs. −4.9 ± 40.4 mm3/year; p = 0.019) and no difference in lumen volume (−5.8 ± 26.6 mm3/year vs. −3.2 ± 29.5 mm3/year; p = 0.72).
IPH may represent an indication of accelerated plaque growth and impending luminal compromise in the subclinical carotid artery. Statin therapy may stabilize lesions by slowing or halting lesion progression. This phase of plaque stenosis (16% to 49%) may be a critical stage for intrinsic and extrinsic factors to affect the atherosclerotic disease process.
atherosclerosis; carotid arteries; magnetic resonance imaging; remodeling
Chromosome 9p21 has recently been shown to be a risk region for a broad range of vascular diseases. Since carotid intima-media thickness (IMT) and plaque are independent predictors for vascular diseases, the association between 9p21 and these two phenotypes was investigated.
Carotid segment-specific IMT and plaques were obtained in 1083 stroke- and myocardial infarction-free volunteers. We tested the genotypes and haplotypes of key single nucleotide polymorphisms (SNPs) on chromosome 9p21 for the associations with carotid IMT and plaque. Multivariate permutation analyses demonstrated that carriers of the T allele of SNP rs1333040 were significantly associated with thicker common carotid artery (CCA) IMT (p = 0.021) and internal carotid artery (ICA) IMT (p = 0.033). The risk G allele of SNP rs2383207 was associated with ICA IMT (p = 0.007). Carriers of the C allele of SNP rs1333049 were found to be significantly associated with thicker ICA IMT (p = 0.010) and the greater risk for the presence of carotid plaque (OR = 1.57 for heterozygous carriers; OR = 1.75 for homozygous carriers). Haplotype analysis showed a global p value of 0.031 for ICA IMT and 0.115 for the presence of carotid plaque. Comparing with the other haplotypes, the risk TGC haplotype yielded an adjusted p value of 0.011 and 0.017 for thicker ICA IMT and the presence of carotid plaque respectively. Further analyzing the data separated by sex, the results were significant only in men but not in women.
Chromosome 9p21 had a significant association with carotid atherosclerosis, especially ICA IMT. Furthermore, such genetic effect was in a gender-specific manner in the Han Chinese population.
Genetic variation in coagulation and fibrinolysis may affect the development of subclinical atherosclerosis modifying the risk of stroke and cardiovascular disease. However, data on the relationship between subclinical atherosclerosis and genes involved in the coagulation system are sparse. The objective of this study is to examine the association between single nucleotide polymorphisms (SNPs) in coagulation system genes and subclinical carotid plaque phenotypes.
From the Genetic Determinants of Subclinical Carotid Disease study, 287 Dominicans were examined for carotid plaque presence, thickness, and surface irregularity by high-resolution B-mode carotid ultrasound. Logistic regression was used to test for association between 101 SNPs in 23 coagulation system genes and plaque phenotypes while controlling for age, sex, smoking, hypertension, dyslipidemia, and diabetes. Within gene haplotypes and interactions between genes were examined. A follow-up of SNPs in moderate to high (r2>0.25) linkage disequilibrium (LD) with those implicated in the discovery analysis (p≤0.01) was performed in an independent sample of 301 Dominicans.
The prevalence of carotid plaque (47% discovery; 46% follow-up) as well as the mean age (65±8 discovery; 65±9 follow-up) of the participants was similar in both datasets. Two genes (vWF and THBS1) were associated (p≤0.01) with plaque size and surface irregularity. In followup, 5 SNPs in vWF were associated (p≤0.05) with plaque size. SERPINE1 was an additional gene of interest in the haplotype and interaction analyses.
Variation in the vWF, THBS1, and SERPINE1 gene may play an important role in the pathogenesis of atherosclerotic plaque.
candidate genes; carotid plaque; coagulation system; single nucleotide polymorphism; subclinical atherosclerosis
Sirtuins (SIRTs) and mitochondrial uncoupling proteins (UCPs) have been implicated in cardiovascular diseases through the control of reactive oxygen species production. This study sought to investigate the association between genetic variants in the SIRT and UCP genes and carotid plaque.
In a group of 1018 stroke-free subjects from the Northern Manhattan Study with high-definition carotid ultrasonography and genotyping, we investigated the associations of 85 single nucleotide polymorphisms (SNPs) in the 11 SIRT and UCP genes with the presence and number of carotid plaques, and evaluated interactions of SNPs with sex, smoking, diabetes and hypertension as well as interactions between SNPs significantly associated with carotid plaque.
Overall, 60% of subjects had carotid plaques. After adjustment for demographic and vascular risk factors, T-carriers of the SIRT6 SNP rs107251 had an increased risk for carotid plaque (odds ratio, OR = 1.71, 95% CI = 1.23–2.37, Bonferroni-corrected p = 0.03) and for a number of plaques (rate ratio, RR = 1.31, 1.18–1.45, Bonferroni-corrected p = 1.4×10−5), whereas T-carriers of the UCP5 SNP rs5977238 had an decreased risk for carotid plaque (OR = 0.49, 95% CI = 0.32–0.74, Bonferroni-corrected p = 0.02) and plaque number (RR = 0.64, 95% CI = 0.52–0.78, Bonferroni-corrected p = 4.9×10−4). Some interactions with a nominal p≤0.01 were found between sex and SNPs in the UCP1 and UCP3 gene; between smoking, diabetes, hypertension and SNPs in UCP5 and SIRT5; and between SNPs in the UCP5 gene and the UCP1, SIRT1, SIRT3, SIRT5, and SIRT6 genes in association with plaque phenotypes.
We observed significant associations between genetic variants in the SIRT6 and UCP5 genes and atherosclerotic plaque. We also found potential effect modifications by sex, smoking and vascular risk factors of the SIRT/UCP genes in the associations with atherosclerotic plaque. Further studies are needed to validate our observations.