Internal Carotid Artery Angle Variations are Poorly Explained by Vascular Risk Factors: The Northern Manhattan Study.

OBJECTIVES: The internal carotid artery (ICA) angle of origin may contribute to atherogenesis by altered hemodynamics. We aim to determine the contribution of vascular risk factors and arterial wall changes to ICA angle variations. METHODS: We analyzed 1,065 stroke-free participants from the population-based Northern Manhattan Study who underwent B-mode ultrasound (mean age 68.7±8.9 years; 59% women). ICA angle was estimated at the intersection between the common carotid artery and the ICA center line projections. Narrower external angles translating into greater carotid bifurcation bending were considered unfavorable. Linear regression models were fitted to assess the relationship between ICA angle and demographics, vascular risk factors, and arterial wall changes including carotid intima-media thickness (cIMT) and plaque presence. RESULTS: ICA angles were narrower on the left compared to the right side (153±15.4 degrees versus 161.4±12.7 degrees, p<0.01). Mean cIMT was 0.9±0.1 mm and 54.3% had at least one plaque. ICA angle was not associated with cIMT or plaque presence. Unfavorable left and right ICA angles were associated with advanced age (per 10-year increase ß=-1.6; p=0.01, and -1.3; p=0.03, respectively) and being Black participant (ß=-4.6; p<0.01 and -2.9; p=0.04, respectively), while unfavorable left ICA angle was associated with being female (ß=-2.8; p=0.03) and increased diastolic blood pressure (per 10 mmHg increase ß=-2.1; p<0.01). Overall, studied factors explained less than 10% of the variance in ICA angle (left R2=0.07; right R2=0.05). CONCLUSION: Only a small portion of ICA angle variation were explained by demographics, vascular risk factors and arterial wall changes. Whether ICA angle is determined by other environmental or genetic factors, and is an independent risk factor for atherogenesis, requires further investigation.

Association of Carotid Plaque Morphology and Glycemic and Lipid Parameters in the Northern Manhattan Study.

Low Gray-Scale Median (GSM) index is an ultrasonographic parameter of soft, lipid rich plaque morphology that has been associated with stroke and cardiovascular disease (CVD). We sought to explore the contribution of the modifiable and not-modifiable cardiovascular risk factors (RFs) to vulnerable plaque morphology measured by the low GSM index. A total of 1,030 stroke-free community dwelling individuals with carotid plaques present (mean age, 71.8 ± 9.1; 58% women; 56% Hispanic, 20% Non-Hispanic Black, 22% Non-Hispanic White) were assessed for minimum GSM (min GSM) using high-resolution B-mode carotid ultrasound. Multiple linear regression models were used to evaluate the association between RFs and minGSM after adjusting for sociodemographic characteristics. Within an individual, median plaque number was 2 (IQR: 1-3) and mean plaque number 2.3 (SD: 1.4). Mean minGSM was 78.4 ± 28.7 (IQR: 56-96), 76.3 ± 28.8 in men and 80 ± 28.5 in women; 78.7 ± 29.3 in Hispanics participants, 78.5 ± 27.2 in Non-Hispanic Black participants, and 78.2 ± 29 in Non-Hispanic white participants. In multivariable adjusted model, male sex (ß = -5.78, p = 0.007), obesity BMI (ß = -6.92, p = 0.01), and greater levels of fasting glucose (ß = -8.02, p = 0.02) and LDL dyslipidemia (ß = -6.64, p = 0.005) were positively associated with lower minGSM, while presence of glucose lowering medication resulted in a significant inverse association (ß = 7.68, p = 0.04). Interaction (with p for interaction <0.1) and stratification analyses showed that effect of age on minGSM was stronger in men (ß = -0.44, p = 0.03) than in women (ß = -0.20, p = 0.18), and in individuals not taking glucose lowering medication (ß = -0.33, p = 0.009). Our study has demonstrated an important contribution of glycemic and lipid metabolism to vulnerable, low density or echolucent plaque morphology, especially among men and suggested that use of glucose lowering medication was associated with more fibrose-stable plaque phenotype (greater GSM). Further research is needed to evaluate effects of medical therapies in individuals with vulnerable, low density, non-stenotic carotid plaques and how these effects translate to prevention of cerebrovascular disease.

Cerebral Hemodynamics in Sleep Apnea and Actigraphy-Determined Sleep Duration in a Sample of the Hispanic Community Health Study/ Study of Latinos.

STUDY OBJECTIVES: We sought to evaluate cerebral hemodynamics in obstructive sleep apnea (OSA) and actigraphy-defined short sleep duration using transcranial Doppler ultrasound (TCD) blood flow velocity in a subsample of Hispanics/Latinos without stroke and cardiovascular disease. METHODS: The sample consisted of consecutive participants at the Miami site of the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) with overnight home sleep testing and 7 days of wrist actigraphy in the Sueño sleep ancillary study. Ninety-five participants had sleep data and TCD determined cerebral hemodynamics. We evaluated the association between OSA (apnea-hypopnea index [AHI] ≥ 5 events/h) and short sleep duration (< 6.8 hours; sample median) with cerebral blood flow velocities (CBFV) and pulsatility index (PI) for the middle cerebral (MCA) and basilar arteries (BA). RESULTS: Median age was 48 years (range 20-64) with 71% females. Twenty-eight percent of the sample had OSA (AHI ≥ 5 events/h) with median AHI of 10.0 (range 5.0-51.7) events/h. In unadjusted analyses, participants with OSA had lower median CBFV in the BA (30.5 cm/s [interquartile range:10.2] versus 39.4 cm/s [13.3] P < .05), but not the MCA, whereas short sleepers had higher median vascular resistance in the MCA (PI = 0.92 [0.18] versus 0.86 [0.14] P < .05) and BA (PI = 1.0 [0.17] versus 0.93 [0.24] P < .05). After full adjustment, OSA was associated with decreased CBFV (ß [SE] = -5.1 [2.5] P < .05) in the BA. Short sleep was associated with increased PI (ß [SE] = 0.05 [0.02] P < .05) in the MCA. CONCLUSIONS: In this sample of Hispanic/Latinos, OSA was associated with decreased daytime blood flow velocity in the BA, whereas actigraphy-defined short sleep duration was associated with increased cerebrovascular pulsatility in the MCA.

Association Between Carotid Artery Function and Structure in the Northern Manhattan Study.

BACKGROUND AND PURPOSE: Carotid plaque (CP), carotid intima media thickness (cIMT), and stiffness (STIFF) are pre-clinical markers of atherosclerosis and predictors of cerebrovascular disease (CVD). We sought to investigate whether STIFF is a significant determinant of cIMT and CP, which may provide an insight into the mechanism by which STIFF adds to the risk of CVD. METHODS: We analyzed 876 stroke-free subjects from the Northern Manhattan Study with available ultrasound measures. To obtain the associations with STIFF, we performed multivariable-adjusted regression, negative binomial regression (for CP number), and multinomial logistic regression (for plaque area). RESULTS: The mean age was 64 ± 9 years; 63% women and 65% Caribbean Hispanics. The mean cIMT was 0.93 ± 0.9 mm, the mean diastolic diameter 6.24 ± 0.94 mm, and STIFF 8.6 ± 6.2 ln mmHg. Prevalence of CP was 57%, and the mean total plaque area was 22.6 ± 23.0 mm2. STIFF was positively associated with cIMT but not with CP. There was an association between diastolic diameter and thick plaque. For each millimeter increase in diastolic diameter, there was about a 20% increased risk of having thick plaque (vs. no plaque). In longitudinal analyses, each millimeter increase in diastolic diameter was associated with a 37% increased risk of incident plaque. CONCLUSION: Increased STIFF was associated with increased cIMT and carotid artery dilatation with greater plaque burden. Increased cIMT and plaque burden represent vascular remodeling likely resulting from the two different age-related mechanisms, one that includes diffuse wall thickening (cIMT) with STIFF and another that incorporates focal atherosclerosis (plaque) with luminal dilatation.

Subclinical Atherosclerosis Among Young and Middle-Aged Adults Using Carotid Intima-Media Thickness Measurements.

OBJECTIVES: The presence of atherosclerotic plaque in the carotid arteries is a strong predictor of cardiovascular disease (CVD). Research and data on CVD risk have been derived primarily from individuals aged 55 years or older, and assessment of CVD risk among young and middle-aged adults seldom has been studied. The use of ultrasonography to measure carotid intima-media thickness (IMT) and carotid plaque appears to have utility to detect subclinical atherosclerosis in asymptomatic adults. This study evaluated the presence of carotid plaque using ultrasonography among healthy young and middle-aged adults. METHODS: Participants were men and women recruited in Miami, Florida, and were 18 to 50 years old with no history of CVD. Participants underwent a general physical examination and carotid artery ultrasonography to evaluate carotid IMT and carotid plaque. RESULTS: From a total of 173 participants with a mean age of 34 years (standard deviation 8.9), 21.0% (95% confidence interval [CI] 15.0-27.2) were identified as having carotid plaque. IMT values ranged from 0.49 to 1.03 mm, with a mean value of 0.70 mm (standard deviation 0.09). In multivariable logistic regression older age (adjusted odds ratio [AOR] 1.08, 95% CI 1.01-1.16, P = 0.024) and cigarette smoking (AOR 2.67, 95% CI 1.02-7.00, P = 0.045) were associated with plaque, after controlling for IMT (AOR 2.55, 95% CI 1.40-4.65, P = 0.002). CONCLUSIONS: Traditional CVD risk factors such as those evaluated in this study may fail to provide adequate predictive value of carotid atherosclerosis in younger populations with no history of CVD, because the majority of traditional risk factors identified in previous research were not associated with carotid plaque in this young sample. Further research assessing nontraditional risk factors among asymptomatic individuals is required, and the evaluation of IMT as an intervention tool to detect CVD risk in these asymptomatic populations is warranted.

Cerebral Hemodynamics in the Elderly: A Transcranial Doppler Study in the Einstein Aging Study Cohort.

OBJECTIVES: We sought to describe the relationship between age, sex, and race/ethnicity with transcranial Doppler hemodynamic characteristics from major intracerebral arterial segments in a large elderly population with varying demographics. METHODS: We analyzed 369 stroke-free participants aged 70 years and older from the Einstein Aging Study. Single-gate, nonimaging transcranial Doppler sonography, a noninvasive sonographic technique that assesses real-time cerebrovascular hemodynamics, was used to interrogate 9 cerebral arterial segments. Individual Doppler spectra and cerebral blood flow velocities were acquired, and the pulsatility index and resistive index were calculated by the device's automated waveform-tracking function. Multiple linear regression models were used to examine the independent associations of age, sex, and race/ethnicity with transcranial Doppler measures, adjusting for hypertension, history of myocardial infarction or revascularization, and history of diabetes. RESULTS: Among enrolled participants, 303 individuals had at least 1 vessel insonated (mean age [SD], 80 [6] years; 63% women; 58% white; and 32% black). With age, transcranial Doppler measures of mean blood flow velocity were significantly decreased in the basilar artery (P = .001) and posterior cerebral artery (right, P = .003; left, P = .02). Pulsatility indices increased in the left middle cerebral artery (P = .01) and left anterior cerebral artery (P = .03), and the resistive index was increased in the left middle cerebral artery (P = .007) with age. Women had higher pulsatility and resistive indices compared to men in several vessels. CONCLUSIONS: We report a decreased mean blood flow velocity and weakly increased arterial pulsatility and resistance with aging in a large elderly stroke-free population. These referential trends in cerebrovascular hemodynamics may carry important implications in vascular diseases associated with advanced age, increased risk of cerebrovascular disease, cognitive decline, and dementia.

Sirtuin/uncoupling protein gene variants and carotid plaque area and morphology.

BACKGROUND: Sirtuins and uncoupling proteins have been implicated in cardiovascular diseases by controlling oxidative stress. AIMS: We sought to investigate the association of sirtuins and uncoupling proteins single nucleotide polymorphisms with total carotid plaque area and morphology measured by ultrasonographic gray scale median. METHODS: We analyzed 1356 stroke-free subjects (60% women, mean age = 68 ± 9 years) from the Northern Manhattan Study. Multiple linear regression models were used to evaluate the association of 85 single nucleotide polymorphisms in 11 sirtuins/uncoupling protein genes with total plaque area and gray scale median after controlling for demographics, vascular risk factors (RFs), and population stratification. We investigated effect modifications of these relationship by gender and RFs and performed stratified analysis if the interaction effect had P < 0·005. RESULTS: Among individuals with present plaque (55%), the mean total plaque area was 20·3 ± 20·8 mm(2) and gray scale median 90 ± 29. After adjustment, SIRT6 rs107251 was significantly associated with total plaque area (ß = 0·30 per copy of T allele increase, Bonferroni-corrected P = 0·005). T allele carriers of rs1430583 in UCP1 showed a decreased gray scale median in women but not in men. The minor allele carriers of rs4980329 and rs12363280 in SIRT3 had higher gray scale median in men but not in women. Variants in UCP3 gene were significantly associated with higher mean gray scale median in individuals with dyslipidemia. CONCLUSION: Our findings suggest that polymorphisms in SIRT6/UCP1 genes may be important for increased carotid plaque burden and echodensity, but translation of these findings to an individual risk of cerebrovascular events needs further investigation. Significant associations of rs1430583 in women, rs12363280 in men, and rs1685354 in those with dyslipidemia also deserve further investigations.

The relationship between carotid intima-media thickness and carotid plaque in the Northern Manhattan Study.

OBJECTIVE: Carotid intima-media thickness (cIMT) and carotid plaque (CP) are proposed biomarkers of subclinical atherosclerosis associated with stroke risk. Whether cIMT and CP are distinct phenotypes or single traits at different stages of atherosclerotic development is unclear. We explored the relationship between these markers in the population-based Northern Manhattan Study. METHODS: We used high-resolution ultrasound and validated imaging protocols to study the cross-sectional (N = 1788 stroke-free participants) and prospective relationship (N = 768 with follow-up scan; mean years between examinations = 3.5) between CP and cIMT measured in plaque-free areas. RESULTS: The mean age was 66 ± 9 (40% male, 19% black, 17% white, 61% Hispanic). The mean baseline cIMT was 0.92 ± 0.09 mm, 0.94 ± 0.09 mm among the 58% with prevalent plaque, 0.90 ± 0.08 mm among the 42% without prevalent plaque (p < 0.0001). Each 0.1 mm increase in baseline cIMT was associated with a 1.72-fold increased odds of plaque presence (95%CI = 1.50-1.97), increased plaque thickness (effect on the median = 0.46 mm, p < 0.0001), and increased plaque area (effect on the median = 3.45 mm(2), p < 0.0001), adjusting for demographics and vascular risk factors. Elevated baseline cIMT was associated with an increased risk of new plaque in any location at follow-up, but after adjusting for demographics and vascular risk factors this association was no longer present. No association was observed in carotid segment-specific analyses. CONCLUSION: Increased cIMT was associated with baseline prevalent plaque but did not predict incident plaque independent of other vascular risk factors. This finding suggests that increased cIMT is not an independent predictor of plaque development although these atherosclerotic phenotypes often coexist and share some common vascular determinants.

Genetic variants in LEKR1 and GALNT10 modulate sex-difference in carotid intima-media thickness: a genome-wide interaction study.

BACKGROUND: There is an established sex-difference in carotid artery intima-media thickness (cIMT), a recognized marker of subclinical atherosclerosis. However, the genetic underpinnings of sex-differences in gene-IMT associations are largely unknown. METHODS: With a multistage design using 731,037 single nucleotide polymorphisms (SNP), a genome wide interaction study was performed in a discovery sample of 931 unrelated Hispanics, followed by replication in 153 non-Hispanic whites and 257 non-Hispanic blacks. Assuming an additive genetic model, we tested for sex-SNP interactions on cIMT using regression analysis. RESULTS: We did not identify any genome-wide significant SNPs but identified 14 loci with suggestive significance. Specifically, SNP-by-sex interaction was found for rs7616559 within LEKR1 gene (P = 3.5E-06 in Hispanic discovery sample, P = 0.018 in White, and P = 1.3E-06 in combined analysis) and for rs2081015 located within GALNT10 gene (P = 4.5E-06 in Hispanic discovery sample, P = 0.042 in Blacks, and P = 5.3E-07 in combined analysis). For rs7616559 within LEKR1, men had greater cIMT than women in G allele carriers (beta ± SE: 0.044 ± 0.007, P = 4.2E-09 in AG carriers; beta ± SE: 0.064 ± 0.007, P = 6.2E-05 in GG carriers). For rs2081015 within GALNT10, men had greater cIMT than women in C allele carriers (beta ± SE: 0.022 ± 0.007, P = 0.002 in CT carriers; beta ± SE: 0.051 ± 0.008, P = 3.1E-10 in CC carriers). CONCLUSIONS: Our genome-wide interaction analysis reveals multiple loci that may modulate sex difference in cIMT. Of them, genetic variants on LEKR1 and GALNT10 genes have been associated with control of adiposity and weight. Given the consistent findings across different-ethnic groups, further studies are warranted to perform investigations of functional genetic variants in these regions.

Mediterranean diet and carotid atherosclerosis in the Northern Manhattan Study.

OBJECTIVE: Adherence to a Mediterranean-style diet (MeDi) may protect against clinical vascular events by reducing atherosclerosis, but data is limited. This is the first observational study of the association between MeDi adherence and carotid plaque thickness and area. METHODS: The study included 1374 participants of the population-based Northern Manhattan Study with diet assessed and carotid intima-media thickness (cIMT) and plaque measured using B-mode ultrasound (mean age 66 ± 9 years, 60% female, 60% Hispanic, 18% White, 19% Black). A MeDi adherence score (range = 0-9, 9 representing maximal adherence) was examined continuously and in quintiles (3/4/5/6-9 vs. 0-2). RESULTS: Mean cIMT = 0.9 ± 0.1 mm and 57% had plaque (median plaque thickness = 1.5 mm, 75th percentile = 2.2; median plaque area = 4.2 mm(2), 75th percentile = 15.8). There was no association between MeDi and cIMT or plaque presence. MeDi adherence was inversely associated with the 75th percentile of plaque thickness and median of plaque area in quantile regression analyses. These associations persisted after controlling for demographics, smoking, physical activity, and total energy consumption (effect of a 1-point increase in MeDi score on the 75th percentile of plaque thickness = -0.049 mm, p = 0.03; median of plaque area = -0.371 mm(2), p = 0.03), and when additionally controlling for vascular disease biomarkers, medication use, BMI, and previous cardiac disease. The protective associations appeared strongest for those with a MeDi score of 5 (4th quintile) vs. 0-2 (bottom quintile). Differential effects of a MeDi on plaque thickness and area across race/ethnic groups was suggested. CONCLUSIONS: Moderate and strict adherence to a MeDi may protect against a higher burden of carotid atherosclerotic plaque, which may mediate the protection against clinical vascular events. Efforts to improve adherence to a MeDi are critical to reducing the burden of atherosclerotic disease.

Traditional risk factors are not major contributors to the variance in carotid intima-media thickness.

BACKGROUND AND PURPOSE: Carotid intima-media thickness (cIMT) was a widely accepted ultrasound marker of subclinical atherosclerosis in the past. Although traditional risk factors may explain ≈50% of the variance in plaque burden, they may not explain such a high proportion of the variance in IMT, especially when measured in plaque-freel ocations. We aimed this study to identify individuals with cIMT unexplained by traditional risk factors for future environmental and genetic research. METHODS: As part of the Northern Manhattan Study, 1790 stroke-free individuals (mean age, 69±9 years; 60% women; 61% Hispanic; 19% black; 18% white) were assessed for cIMT using B-mode carotid ultrasound. Multiple linear regression models were evaluated: (1) incorporating prespecified traditional risk factors; and (2) including less traditional factors, such as inflammation biomarkers, adiponectin, homocysteine, and kidney function. Standardized cIMT residual scores were constructed to select individuals with unexplained cIMT. RESULTS: Mean total cIMT was 0.92±0.09 mm. The traditional model explained 11% of the variance in cIMT. Age (7%), male sex (3%), glucose (<1%), pack-years of smoking (<1%), and low-density lipoprotein cholesterol (<1%) were significant contributing factors. The model, including inflammatory biomarkers, explained 16% of the variance in cIMT. Adiponectin was the only additional significant contributor to the variance in cIMT. We identified 358 individuals (20%) with cIMT unexplained by the investigated risk factors. CONCLUSIONS: Vascular risk factors explain only a small proportion of variance in cIMT. Identification of novel genetic and environmental factors underlying unexplained subclinical atherosclerosis is of utmost importance for future effective prevention of vascular disease.

Cerebrovascular pulsatility in patients with sleep-disordered breathing.

PURPOSE: The aim of our study is to determine the association between the pulsatility index (PI), a surrogate of cerebral small vessel disease and sleep-disordered breathing (SDB). METHODS: We conducted a transcranial Doppler ultrasound (TCD) study of 19 consecutive patients free of stroke and cardiovascular disease, referred for the evaluation of SDB. TCD was performed by a certified technologist. Subsequent polysomnography was performed according to the practice parameters of the American Academy of Sleep Medicine. We evaluated the association between the apnea-hypopnea index (AHI), the oxygen nadir, the blood flow velocities, and the Gosling PI, for the middle cerebral artery. We performed Spearman's rank correlation and nonparametric regression to evaluate the relationship between AHI, oxygen levels, and the PI. RESULTS: Median age was 48 years (range 37-83), with 52 % male sex (n = 10), and median BMI of 29.9 (range 25-40.4). The median AHI was 16.4 (0.2-69). The median PI was 0.97 (0.72-1.89) cm/s. The PI correlated with the AHI (rho = 0.44; p = 0.004) and with age (rho = 0.57; p = 0.001). Nonparametric regression adjusting for age showed a positive association between the AHI and the PI (standardized estimate = 0.88; p = 0.002). There was no relation between the oxygen nadir and the PI. CONCLUSION: We observed increased PI in patients with SDB during wakefulness. The PI could potentially be an estimate of cerebral small vessel disease in patients with SDB and hence allow evaluating cerebral hemodynamics during wakefulness with a clinically relevant device.

Traditional cardiovascular risk factors explain the minority of the variability in carotid plaque.

BACKGROUND AND PURPOSE: Subclinical atherosclerotic plaque is an important marker of increased vascular risk. Identifying factors underlying the variability in burden of atherosclerotic carotid plaque unexplained by traditional vascular risk factors may help target novel preventive strategies. METHODS: As a part of the carotid substudy of the Northern Manhattan Study (NOMAS), 1790 stroke-free individuals (mean age, 69±9; 60% women; 61% Hispanic, 19% black, 18% white) were assessed for total plaque area (TPA) burden using 2-dimensional carotid ultrasound imaging. Multiple linear regression models were constructed. Model 1 used prespecified traditional risk factors: age, sex, low-density lipoprotein cholesterol, diabetes mellitus, pack-years of smoking, blood pressure, and treatment for blood pressure; and Model 2, an addition of socioeconomic and less traditional risk factors. The contributions of the components of the Framingham heart risk score and the NOMAS Global Vascular Risk Score to the TPA were explored. RESULTS: Prevalence of carotid plaque was 58%. Mean TPA was 13±19 mm2. Model 1 explained 19.5% of the variance in TPA burden (R2=0.195). Model 2 explained 21.9% of TPA burden. Similarly, the Framingham heart risk score explained 18.8% and NOMAS global vascular risk score 21.5% of the TPA variance. CONCLUSIONS: The variation in preclinical carotid plaque burden is largely unexplained by traditional and less traditional vascular risk factors, suggesting that other unaccounted environmental and genetic factors play an important role in the determination of atherosclerotic plaque. Identification of these factors may lead to new approaches to prevent stroke and cardiovascular disease.

Association of the sirtuin and mitochondrial uncoupling protein genes with carotid plaque.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Ethnic differences in carotid artery diameter and stiffness: the Northern Manhattan Study.

OBJECTIVE: Race/ethnic differences in carotid arterial function and structure exist among those with cerebrovascular disease, but whether differences persist among healthy populations is unknown. Our objective was to investigate differences in carotid artery diameter and stiffness between race/ethnic groups, and examine whether these race/ethnic differences were age-dependent. METHODS: Carotid diameters were assessed by B-mode ultrasound among 1536 participants from the Northern Manhattan Study (NOMAS), and carotid stiffness metrics were calculated. We used multivariable linear regression models to determine the relationship between race/ethnicity and both carotid arterial stiffness and carotid diastolic diameter. RESULTS: Mean participant age was 70 ± 9 years (Hispanics = 68 ± 8, blacks = 72 ± 9, and whites = 74 ± 9, p < 0.0001). Mean DDIAM was 6.2 ± 1.0mm (Hispanics = 6.2 ± 0.9 mm, blacks = 6.3 ± 1.0 mm, and whites = 6.3 ± 1.0 mm, p < 0.005) and mean STIFF was 8.7 ± 6.3 (Hispanics = 8.5 ± 5.7, blacks = 9.2 ± 6.2 and whites = 8.9 ± 6.9, p < 0.02). In a model that adjusted for sociodemographics and vascular risk factors including hypertension, diabetes, dislipidemia, renal function, physical acticity and a history of known coronary artery diseases; age was positively associated with greater DDIAM in Hispanics (p < 0.0001) but not among blacks or whites. Older age was associated with greater stiffness among Hispanics (p < 0.0001) and blacks (p < 0.003), but not among whites. CONCLUSIONS: We found race/ethnic differences in the association between age and arterial stiffness and diameter, including age-dependent arterial dilation observed in Hispanics that was not observed among blacks or whites.

Carotid plaque and candidate genes related to inflammation and endothelial function in Hispanics from northern Manhattan.

BACKGROUND AND PURPOSE: The genetic influence on carotid atherosclerotic plaque is mostly unknown. This study examines the association between carotid plaque and single nucleotide polymorphisms in selected genes implicated in inflammation and endothelial function. METHODS: A total of 43 genes (197 single nucleotide polymorphisms) involved in inflammation and endothelial function were interrogated in 287 Dominicans from the Northern Manhattan Study (mean age, 64±7 years; 58% women) who had undergone high-resolution B-mode ultrasound for examination of carotid plaque. Using an additive genetic model, multiple logistic regression analyses were conducted, a within-gene haplotype analysis was performed, and interactions between genes were examined. Results were validated in an independent set of 301 Dominicans. RESULTS: Carotid plaque was present in 143 (47%) participants. Nine genes had at least 1 single nucleotide polymorphism associated (P≤0.01) with carotid plaque phenotypes: TNF, NOS2A, IL6R, TNFSF4, PPARA, IL1A, TLR4, ITGA2, and HABP2. Single nucleotide polymorphisms in TNFSF4, PPARA, TLR4, ITGA2, and HABP2 were also implicated with the same carotid phenotype in the validation analysis. Haplotype analysis revealed an additional gene of interest, VCAM1. CONCLUSIONS: We report novel associations between variations in 10 genes involved in inflammation and endothelial function and carotid plaque phenotypes in a Dominican sample, with replication for 5 genes in an independent Dominican sample.

Carotid artery distensibility: a reliability study.

OBJECTIVE: Carotid distensibility (CD) is a measure of carotid artery elasticity that has been introduced as a risk factor for cardiovascular disease. Information regarding reproducibility of sonographic CD measures is limited. The objective of this study was to evaluate the inter-reader reliability of sonographic measurements of common carotid artery (CCA) diameters and derived metrics of CD. METHODS: Two independent readers (R1 and R2) measured the systolic diameter (SD) and diastolic diameter (DD) for the right CCA from the B/M-mode sonographic registrations among 118 subjects. The derived CD metrics (strain, elastic modulus [E], stiffness [beta], and CD) were calculated. The inter-reader type 3 intraclass correlation coefficients (ICC3,1) for carotid diameters were calculated. RESULTS: The mean SDs +/- standard deviation were 7.15 +/- 1.43 mm for R1 and 7.24 +/- 1.43 mm for R2. The mean DDs were 6.71 +/- 1.36 mm for R1 and 6.68 +/- 1.41 mm for R2. The mean differences of SD and DD between R1 and R2 were 0.08 +/- 0.40 mm (paired t test, P = .04) and 0.03 +/- 0.43 mm (paired t test, P = .46), respectively. Inter-reader type 3 intraclass correlation coefficients were 0.96 for SD and 0.95 for DD. We observed a significant association of demographics with carotid diameters but not with derived CD metrics or risk factors. CONCLUSIONS: Our results suggest good reproducibility of CCA diameters measured with B/M-mode sonography. However, very small changes in linear measurements of carotid diameters can have big effects on estimates of arterial mechanical properties such as strain and Young's modulus. The standard boundary identification methods may not be precise and reproducible enough for use in a clinical setting.