Background Carotid intima‐media thickness (IMT) is a measure of atherosclerosis and a predictor of vascular diseases. Traditional vascular risk factors and genetic variants do not completely explain the variation in carotid IMT. We sought to identify epigenetic factors that may contribute to the remaining carotid IMT variability. Methods and Results An epigenome‐wide association study was performed in 61 Dominican families with 769 individuals. A cytosine nucleotide that precedes a guanine nucleotide methylation in blood‐derived DNA was measured using the Human MethylationEPIC BeadChip. Linear mixed model analyses were performed regressing bifurcation carotid IMT (bIMT) on beta values for cytosine nucleotide that precedes a guanine nucleotide sites, adjusting for covariates, followed by differentially methylated region (DMR) analysis. One‐sample Mendelian randomization analysis was conducted to investigate causal associations between DMRs and bIMT. Twenty‐five DMRs were associated with bIMT (Sidak P <0.05), with the strongest DMR (Sidak P =2.45×10 −17 ) overlapping with the promoter of PM20D1 . All 11 cytosine nucleotides that precede a guanine nucleotide within the PM20D1 DMR were positively associated with bIMT ( P =0.0007–0.00006). Methylation of the PM20D1 DMR was associated with cis variants, including rs823154 (β=0.26; P =1.1×10 −121 ). As reported in GTEx (Genotype‐Tissue Expression project), rs823154 is an expression quantitative trait locus for PM20D1 in multiple tissues, including the aorta ( P =2.3×10 −60 ) and blood ( P =4.0×10 −73 ), suggesting that hypermethylation of the PM20D1 DMR directs lower expression of the gene. Mendelian randomization analysis supported a causal role for PM20D1 DMR in bIMT ( P =0.049). Conclusions Our study and previous expression quantitative trait locus studies provide converging evidence that reduced PM20D1 expression via hypermethylation of the promoter is associated with increased atherosclerosis.

Objective: Determine whether markers of carotid atherosclerosis are associated with cognitive function through the burden of white matter disease. Background: Atherosclerosis is a risk factor for cognitive decline. Ultrasonographic measures of carotid atherosclerosis (plaque and intima-media thickness) and MRI measures of small vessel disease (white matter hyperintensity volume) are subclinical markers of cerebrovascular disease that are associated with cognitive dysfunction. Design/Methods: We included 1290 subjects from the racially and ethnically diverse Northern Manhattan Study (age 64+/−8years, 60% women, 67% Hispanic, 18% Black, 15% White, education 10+/−5years). We assessed total plaque area (TPA) and intima-media thickness (cIMT) measures on carotid ultrasound and measures of white matter hyperintensity volume (WMHV) on MRI. Participants underwent neurocognitive evaluation to estimate global cognitive performance and domains of episodic memory, executive function, semantic memory, and processing speed. Associative mediation models were employed to determine if WMHV mediates the association of TPA and cIMT on global and domain-specific cognitive performance adjusting for age, sex, race, ethnicity, education, ApoE4 status, hypertension, hypercholesteremia, diabetes, and smoking. Results: Of the 1290 participants, 675 had carotid plaque (TPA 21+/−22mm2, cIMT 0.95+/−0.09mm, and WMHV 0.77+/−0.93% TIV). WMHV(log) mediated the association of TPA on global cognition [b(indirect-effect)=−0.001, p<0.05], episodic memory [b(indirect-effect)=−0.001, p<0.05], and processing speed [b(indirect-effect)=−0.001, p<0.05)] after adjustment. WMHV(log) volume mediated the association of cIMT on global cognition [b(indirect-effect)=−0.073, p<0.05], episodic memory [b(indirect-effect)=−0.112, p<0.05], and processing speed [b(indirect-effect)=−0.097, p<0.05] after adjustment. No associations were present for executive function and semantic memory. Conclusions: Ultrasound measures of extracranial carotid arteriosclerosis are related to intracranial MRI measures of small vessel disease and associated with cognitive performance. White matter hyperintensity volume may be an important factor in understanding the biological link between atherosclerosis and cognitive dysfunction in middle to older age population. More research is needed to better understand vascular imaging biomarkers of age-related cognitive dysfunction. Disclosure: Ms. Ariko has nothing to disclose. Ms. Aimagambetova has nothing to disclose. Ms. Gardener has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Intersocietal Accreditation Commission. Ms. Gardener has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Ellipse Analytics. Ms. Gardener has received personal compensation in the range of $10,000-$49,999 for serving as an Expert Witness for Baum Hedlund. Ms. Gardener has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant with A Green Slate Consulting. Bonnie Levin has nothing to disclose. Dr. Sun has nothing to disclose. Ms. Cabral has nothing to disclose. Carolina Gutierrez has nothing to disclose. Prof. Zhao has nothing to disclose. Noam Alperin has nothing to disclose. Dr. Elkind has received personal compensation for serving as an employee of American Heart Association. Dr. Elkind has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Atria Academy. The institution of Dr. Elkind has received research support from BMS-Pfizer Alliance for Eliquis. The institution of Dr. Elkind has received research support from Roche. Dr. Elkind has received publishing royalties from a publication relating to health care. Dr. Elkind has a non-compensated relationship as a Officer with American Heart Association that is relevant to AAN interests or activities. Dr. Elkind has received personal compensation for serving as an employee of American Heart Association. Dr. Elkind has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Atria Academy. The institution of Dr. Elkind has received research support from BMS-Pfizer Alliance for Eliquis. The institution of Dr. Elkind has received research support from Roche. Dr. Elkind has received publishing royalties from a publication relating to health care. Dr. Elkind has a non-compensated relationship as a Officer with American Heart Association that is relevant to AAN interests or activities. Dr. Gutierrez has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for Roetzel & Andress, JOHN ASTUNO, JR. L.L.C.. The institution of Dr. Gutierrez has received research support from NIH. Dr. Gutierrez has received publishing royalties from a publication relating to health care. Dr. Gutierrez has received publishing royalties from a publication relating to health care. An immediate family member of Dr. Wright has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Elsevier. An immediate family member of Dr. Wright has received personal compensation in the range of $5,000-$9,999 for serving as an Expert Witness for MARSHALL DENNEHY. The institution of an immediate family member of Dr. Wright has received research support from Oncospace. Dr. Wright has received publishing royalties from a publication relating to health care. An immediate family member of Dr. Wright has received personal compensation in the range of $500-$4,999 for serving as a surveyor with ASTRO. Dr. Sacco has received personal compensation in the range of $100,000-$499,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for American Heart Association. The institution of Dr. Sacco has received research support from NIH, NINDS, NCATS, NIMHD. The institution of Dr. Sacco has received research support from FL Department of Health. Dr. Sacco has received research support from University of Washington, Seattle. Dr. Sacco has received publishing royalties from a publication relating to health care. The institution of Dr. Rundek has received research support from NIH.

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 (β = −5.78, p = 0.007), obesity BMI (β = −6.92, p = 0.01), and greater levels of fasting glucose (β = −8.02, p = 0.02) and LDL dyslipidemia (β = −6.64, p = 0.005) were positively associated with lower minGSM, while presence of glucose lowering medication resulted in a significant inverse association (β = 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 (β = −0.44, p = 0.03) than in women (β = −0.20, p = 0.18), and in individuals not taking glucose lowering medication (β = −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.

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 beta=1.6; p=0.01, and -1.3; p=0.03, respectively) and being Black participant (beta=-4.6; p<0.01 and -2.9; p=0.04, respectively), while unfavorable left ICA angle was associated with being female (beta=-2.8; p=0.03) and increased diastolic blood pressure (per 10 mmHg increase beta=-2.1; p<0.01). Overall, studied factors explained less than 10% of the variance in ICA angle (left R-2 =0.07; right R-2 =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.

Background: Internal carotid artery (ICA) angle of origin is considered a contributor to atherogenesis because of its influence on hemodynamics. It is controversial if ICA angle variations are causal or consequential to carotid atherosclerosis or vascular risk factors. We aim to determine whether vascular risk factors underly ICA angle interindividual variations. Methods: The study included 1,111 stroke-free participants of the population-based Northern Manhattan Study (NOMAS) who underwent ICA angle estimation using B-mode carotid ultrasound (mean age 68.7±8.9 years; 41% were men, 60% Hispanic, 21% Black, and 18% White). Multivariable linear regression models were fit to assess the relationship of ICA angle to vascular risk factors. Results: ICA angle was significantly wider on the left compared to the right (26.6 ±15.5 degrees versus 18.6 ±12.9 degrees; p<0.001). In multivariate analyses, left ICA angle was correlated with age (B=0.07; p=0.03), female sex (B=0.09; p=0.004), Black race (B=0.11; p=0.02), and diastolic blood pressure (B=0.16; p<0.001), whereas right ICA angle was positively correlated with body mass index (B=0.07; p=0.04) and physical inactivity (B=0.08; p=0.02), and inversely correlated with low-density lipoprotein level (B=-0.1; p=0.004). Overall, these factors explained less than 5% of ICA angle variance (R 2 =0.0399 on the left; R 2 =0.0197 on the right). Conclusion: ICA angle variations are poorly explained by vascular risk factors at the population level. Our results suggest ICA angle is an independent feature that may predispose to atherogenesis.

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 (β [SE] = -5.1 [2.5] P < .05) in the BA. Short sleep was associated with increased PI (β [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.

Background: Factor XII (FXII) activation initiates the intrinsic (contact) coagulation pathway. It has been recently suggested that FXII could act as an autoimmunity mediator in multiple sclerosis (MS). FXII depositions nearby dentritic cells were detected in the central nervous system of MS patients and increased FXII activity has been reported in plasma of relapsing remitting and secondary progressive MS patients. FXII inhibition has been proposed to treat MS. Objective: To investigate in MS patients multiple FXII-related variables, including the circulating amount of protein, its pro-coagulant function, and their variation over time. To explore kinetic activation features of FXII in thrombin generation (TG). Methods: In plasma from 74 MS patients and 49 healthy subjects (HS), FXII procoagulant activity (FXII:c) and FXII protein (FXII:Ag) levels were assessed. Their ratio (FXII:ratio) values were derived. Intrinsic TG was evaluated by different triggers. Results: Higher FXII:Ag levels (p = 0.003) and lower FXII:ratio (p < 0.001) were detected in MS patients compared with HS. FXII variables were highly correlated over four time points, which supports investigation of FXII contribution to disease phenotype and progression. A significant difference over time was detected for FXII:c (p = 0.031). In patients selected for the lowest FXII:ratio, TG triggered by ellagic acid showed a trend in lower endogenous thrombin potential (ETP) in MS patients compared with HS (p = 0.042). Intrinsic triggering of TG by nucleic acid addition produced longer time parameters in patients than in HS and substantially increased ETP in MS patients (p = 0.004) and TG peak height in HS (p = 0.008). Coherently, lower FXII:ratio and longer lag time (p = 0.02) and time to peak (p = 0.007) point out a reduced response of FXII to activation in part of MS patients. Conclusion: In MS patients, factor-specific and modified global assays suggest the presence of increased FXII protein level and reduced function within the intrinsic coagulation pathway. These novel findings support further investigation by multiple approaches of FXII contribution to disease phenotype and progression.

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.

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 non-invasive 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.

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 (β = 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.

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.

Sirtuins (SIRTs) are a family of nicotinamide adenine dinucleotide (NAD+)-dependent deacetylases, 1 Dali-Youcef N. Lagouge M. Froelich S. Koehl C. Schoonjans K. Auwerx J. Sirtuins: the 'magnificent seven', function, metabolism and longevity. Ann Med. 2007; 39: 335-345 Crossref PubMed Scopus (361) Google Scholar and mitochondrial uncoupling proteins (UCPs) are a family of inner mitochondrial membrane proteins capable of driving the adenosine triphosphate (ATP)–synthase pathway via regulation of the proton electrochemical gradient. 2 Rousset S. Alves-Guerra M.C. Mozo J. et al. The biology of mitochondrial uncoupling proteins. Diabetes. 2004; 53: S130-S135 Crossref PubMed Google Scholar SIRTs and UCPs have been implicated in slowing vascular aging by reducing reactive oxygen species (ROS). 3 Della-Morte D. Ricordi C. Rundek T. The fountain of youth: role of sirtuins in aging and regenerative medicine. Regen Med. 2013; 8: 681-683 Crossref PubMed Scopus (7) Google Scholar Previously, we demonstrated a significant association between single-nucleotide polymorphisms (SNPs) in SIRT/UCP and risk for carotid plaque (CP), number of plaques, 4 Dong C. Della-Morte D. Wang L. et al. Association of the sirtuin and mitochondrial uncoupling protein genes with carotid plaque. PLoS One. 2011; 6: e27157 Crossref PubMed Scopus (48) Google Scholar and carotid intima media thickness (cIMT). 5 Della-Morte D. Dong C. Bartels S. et al. Association of the sirtuin and mitochondrial uncoupling protein genes with carotid intima-media thickness. Transl Res. 2012; 160: 389-390 Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar Carotid stiffness (STIFF) is a measure of the vessel wall's tendency to resist deformation by systolic blood pressure (BP) during the cardiac cycle and is considered to be biologically and genetically distinct phenotypes of atherosclerosis compared with CP and cIMT. 6 Rundek T. Brook R.D. Spence J.D. Letter by Rundek et al regarding article, "prediction of clinical cardiovascular events with carotid intima-media thickness: a systematic review and meta-analysis". Circulation. 2007; 116: e317 Crossref PubMed Scopus (18) Google Scholar , 7 Della-Morte D. Guadagni F. Palmirotta R. et al. Genetics of ischemic stroke, stroke-related risk factors, stroke precursors and treatments. Pharmacogenomics. 2012; 13: 595-613 Crossref PubMed Scopus (108) Google Scholar In the present study, we investigate the association between variations in the SIRT/UCP genes and STIFF and its components, systolic diameter (SD) and diastolic diameter (DD) in an urban and elderly multiethnic population.

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. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

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. (C) 2014 Published by Elsevier Ireland Ltd.

Reduced cerebrovascular perfusion has been associated with cognitive decline and dementia. However there are few data regarding the relation of cerebrovascular perfusion to domains of cognitive performance in non-demented population based samples due in part to feasibility issues and cost of P.E.T. or MRI. Transcranial Doppler (TCD) ultrasound provides an inexpensive, rapid, non-invasive technique for assessing cerebrovascular function. We examined the cross-sectional associations of TCD measures of blood flow velocities in arteries of the circle of Willis to cognitive performance in participants in the EAS cohort. Analyses included 97 non-demented, community residing elderly, age 3 70. TCD was performed by a trained ultrasound technician using a standardized and validated research protocol during the annual clinic visit which included neuropsychological testing and neurological exams. The group was 52% female, mean age 80.9 (±5.6) years, mean education 15 years. Cognitive domain evaluation included episodic memory (Free Recall from Free and Cued Selective Reminding Test-FR-FCSRT and WMS-R Logical Memory I subtest -LM), semantic memory (category fluency CF), executive function (WAIS-III digit symbol substitution test-DSST; Trail-Making Test-B TMT-B), and language (phonemic fluency-FAS). We computed the mean of right and left flow velocities (MFV) for each vessel. Spearman's correlation coefficients were used to examine the relation of MFV in the anterior (ACA_MFV), posterior (PCA_MFV) and middle (MCA_MFV) cerebral arteries to cognitive performance. Linear regression analyses were used to determine whether associations persisted after adjustment for age, sex and education. There was a consistent pattern showing a positive correlation between CF, DSST, TMT-B and FAS with ACA_MFV and PCA_MFV while memory tests were not correlated with MFV. The MCA-MFV was not correlated with any cognitive measures. The associations of ACA_MFV and PCA_MFV with cognition remained after adjustment for age sex, and education. Cerebral blood flow appears to be more highly correlated with performance on tests of executive function and language than with tests of episodic memory. This is consistent with prior information suggesting a link between vascular processes and frontal executive function. TCD may be useful for distinguishing persons at risk for amnestic versus non-amnestic mild cognitive impairment. Longitudinal data are needed to confirm this hypothesis.

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.

Background and Purpose: Carotid plaque (CP) and increased carotid artery stiffness (STIFF) are intermediate pre-clinical markers of atherosclerosis and important predictors of cardiovascular disease (CVD) and ischemic stroke (IS). This study sought to investigate the association between STIFF and carotid plaque burden (plaque number; total plaque area-TPA) in a multiethnic population-based cohort from the Northern Manhattan Study (NOMAS). Methods: We used multivariable-adjusted regression models to examine the independent associations of STIFF with plaque number (negative binomial regression) and TCAP (multinomial logistic regression) among 876 subjects with carotid ultrasound imaging assessments and free of stroke and myocardial infarction. Results: Prevalence of CP was 57%. Among those with plaque, the mean TPA was 22.61±23.00 mm 2 , median=14.83. The mean STIFF was 6.66±0.63. STIFF was positively associated with the number of carotid plaques in multivariable-adjusted models. An association was also suggested between STIFF and TPA, but it was attenuated slightly and lost statistical significance after adjusting for anti-hypertensive medication use and vascular risk factors. Conclusion: Exploring the possible interrelationships between the vascular structure and function may lead to a better understanding of the pathophysiology of atherosclerosis and better preventive treatments of vascular diseases.