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American Journal of Hypertension  2010;24(2):187-193.
The reasons for racial/ethnic disparities in hypertension prevalence in the U.S are poorly understood.
Using data from the Multi-Ethnic Study of Atherosclerosis (MESA), we investigated whether individual and neighborhood-level chronic stressors contribute to these disparities in cross-sectional analyses. The sample consisted of 2679 MESA participants (45–84yrs) residing in Baltimore, New York, and North Carolina. Hypertension was defined as systolic or diastolic blood pressure ≥140 or 90mmHg, or taking anti-hypertensive medications. Individual-level chronic stress was measured by self-reported chronic burden and perceived major and everyday discrimination. A measure of neighborhood (census tract) chronic stressors (i.e. physical disorder, violence) was developed using data from a telephone survey conducted with other residents of MESA neighborhoods. Binomial regression was used to estimate associations between hypertension and race/ethnicity before and after adjustment for individual and neighborhood stressors.
The prevalence of hypertension was 59.5% in African Americans (AA), 43.9% in Hispanics, and 42.0% in whites. Age and sex adjusted relative prevalences of hypertension (compared to whites) were 1.30 [95% Confidence Interval (CI): 1.22–1.38] for AA and 1.16 [95% CI: 1.04–1.31] for Hispanics. Adjustment for neighborhood stressors reduced these to 1.17 [95% CI: 1.11–1.22] and 1.09 [95% CI: 1.00–1.18] respectively. Additional adjustment for individual-level stressors, acculturation, income, education, and other neighborhood features only slightly reduced these associations.
Neighborhood chronic stressors may contribute to race/ethnic differences in hypertension prevalence in the U.S.
PMCID: PMC3319083  PMID: 20847728
neighborhoods; race; ethnicity; chronic stress; discrimination
2.  Endothelial dysfunction is associated with left ventricular mass (assessed using MRI) in an adult population (MESA) 
Journal of human hypertension  2010;25(1):25-31.
Brachial flow-mediated dilation (FMD) is a measure of endothelial nitric oxide bioavailability. Endothelial nitric oxide controls vascular tone and is likely to modify the ventricular muscle coupling mechanism. The association between left ventricular mass and FMD is not well understood. We assessed the association between left ventricular mass index (LVMI) and FMD in participants of the Multi-Ethnic Study of Atherosclerosis (MESA). MESA is a population-based study of 6814 adults free of clinical cardiovascular disease at baseline who were recruited from six US clinics. LVMI (left ventricular mass per body surface area) and FMD were measured in 2447 subjects. Linear regression analysis was used to evaluate the association. The subjects had a mean age of 61.2 ± 9.9 years, 51.2% females with 34.3% Caucasians, 21.6% Chinese, 19.4% African Americans and 24.7% Hispanics. The mean body mass index (BMI) was 27.4 ± 4.8 kg m−2, 9.4% had diabetes, 11% were current smokers and 38% hypertensives. The mean ± s.d. LVMI was 78.1 ± 15.9 g m−2 and mean ± s.d. FMD was 4.4% ± 2.8%. In univariate analysis, LVMI was inversely correlated with FMD (r = −0.20, P < 0.0001). In the multivariable analysis, LVMI was associated with FMD (β coefficient (se) = −0.50 (0.11), P < 0.001 (0.5 g m−2 reduction in LVMI per 1% increase in FMD)) after adjusting for age, gender, race/ethnicity, systolic blood pressure, diabetes mellitus, smoking, weight, statin use, antihypertensive medication use, high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol. The association between brachial flow mediated dilation and LVMI maybe independent of traditional CV risk factors in population based adults.
PMCID: PMC3037860  PMID: 20237502
left ventricular mass; endothelial function; brachial flow-mediated dilation; population
3.  Metabolic Syndrome, Endothelial Dysfunction, and Risk of Cardiovascular Events: the Northern Manhattan Study 
American heart journal  2008;156(2):405-410.
Metabolic syndrome (MetS) predisposes to cardiovascular disease. Endothelial dysfunction is thought to be an important factor in the pathogenesis of atherosclerosis. We tested the hypothesis that both MetS and endothelial dysfunction are vascular risk factors and provide additive prognostic values in predicting cardiovascular events in a multi-ethnic community sample.
The study population consisted of 819 subjects (467 female, mean age 66.5±8.8 years, 66% Hispanic) enrolled in the Northern Manhattan Study. MetS was defined using the revised Adult Treatment Panel III criteria. Brachial artery flow-mediated dilation (FMD) was measured using high-resolution ultrasound. Endothelial dysfunction was defined as FMD < 8.44% (lower three quartiles). Cox proportional hazards models were used to assess the effect of MetS and endothelial dysfunction on risk of cardiovascular events.
During 81±21 months of follow-up, events occurred in 84 subjects. MetS was independently associated with cardiovascular events in a multivariate model including cardiovascular risk factors (adjusted HR 2.08, 95% CI 1.27–3.40). Subjects with both MetS and endothelial dysfunction were at higher risk for cardiovascular events than those with either one of them alone (adjusted HR 2.60, 95% CI 1.14–5.92).
MetS is associated with incident cardiovascular events. Combined use of MetS and FMD identifies those who are at higher risk of cardiovascular events. MetS and non-invasive FMD testing can be used concurrently for cardiovascular risk prediction.
PMCID: PMC2597726  PMID: 18657678
4.  Retinal Vascular Caliber and Brachial Flow-Mediated Dilation 
Background and Purpose
Retinal vascular caliber changes have been shown to predict stroke, but the underlying mechanism of this association is unknown. We examined the relationship between retinal vascular caliber with brachial flow-mediated dilation (FMD), a measure of systemic endothelial function.
The Multi-Ethnic Study of Atherosclerosis (MESA) is a population-based study of persons 45 to 84 years of age residing in 6 US communities free of clinical cardiovascular disease at baseline. Brachial FMD data were collected at baseline (July 2000 to June 2002), and retinal vascular caliber was measured from digital retinal photographs at the second examination, immediately after the first (August 2002 to January 2004). Data were available for 2851 participants for analysis.
The mean brachial FMD was 4.39±2.79%. After adjusting for age and gender, brachial FMD was reduced in persons with wider retinal venular caliber (changes in FMD −0.25, 95% CI, −0.36, − 0.13; P<0.001, per SD increase in venular caliber). This relationship persists after adjusting for systolic blood pressure, serum total cholesterol, use of lipid-lowering and antihypertensive medication, body mass index, current smoking status, and hemoglobinA1C (−0.18; 95% CI −0.30, − 0.06; P=0.004, per SD increase in venular caliber). Brachial FMD was not associated with retinal arteriolar caliber.
Persons with wider retinal venules have reduced brachial FMD, independent of other vascular risk factors. This suggests that retinal venular caliber, previously shown to predict stroke, may be a marker of underlying systemic endothelial dysfunction.
PMCID: PMC2945294  PMID: 20508189
epidemiology; vasodilation; imaging; endothelial function
5.  Reduced Residual Renal Function is Associated with Endothelial Dysfunction in Patients Receiving Peritoneal Dialysis 
♦ Background: Endothelial dysfunction, which contributes to atherosclerosis and arteriosclerosis, commonly accompanies end-stage renal disease (ESRD). However, little is known about the role of residual renal function (RRF) in endothelial protection in ESRD patients. This study aimed to investigate the relationship between endothelial function and RRF in patients undergoing peritoneal dialysis (PD).
♦ Methods: This was a cross-sectional study involving 72 prevalent PD patients. Demographic and clinical data were recorded and residual glomerular filtration rate (GFR), Kt/V urea, and serum concentrations of inflammatory markers were measured. Endothelial function was assessed by brachial artery endothelium-dependent vasodilation [flow-mediated dilation (FMD)] to reactive hyperemia following 5 minutes of forearm ischemia.
♦ Results: In patients with FMD% above the median value (FMD > 2.41%), residual GFR was significantly higher compared to that in patients with FMD% below the median [1.50 (0 – 9.64) vs 0.48 (0 – 3.89) mL/min/1.73 m2, P = 0.026]. Correlation analyses revealed that residual GFR (ρ = 0.381, P = 0.001) and total Kt/V urea (γ = 0.408, P < 0.001) were positively correlated with FMD%, whereas PD duration (γ = –0.351, P = 0.003), high-sensitivity C-reactive protein (ρ = –0.345, P = 0.003), pulse pressure (γ = –0.341, P = 0.003), and age (γ = –0.403, P < 0.001) were inversely correlated with FMD%. In contrast, there was no correlation between peritoneal Kt/V urea and FMD%. In multivariate linear regression analysis adjusted for these factors, residual GFR was found to be an independent determinant of FMD% (β = 0.317, P = 0.017).
♦ Conclusion: This study shows that RRF is independently associated with endothelial dysfunction in ESRD patients on PD, suggesting that RRF may contribute to endothelial protection in these patients.
PMCID: PMC3525403  PMID: 20864603
Endothelial dysfunction; residual renal function
6.  Endothelial dysfunction is associated with carotid plaque: a cross-sectional study from the population based Northern Manhattan Study 
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.
PMCID: PMC1560160  PMID: 16916467
7.  Moderate alcohol consumption is associated with better endothelial function: a cross sectional study 
Moderate alcohol consumption is protective against coronary artery disease. Endothelial dysfunction contributes to atherosclerosis and the pathogenesis of cardiovascular disease. The effects of alcohol consumption on endothelial function may be relevant to these cardiovascular outcomes, but very few studies have examined the effect of alcohol consumption on endothelial function assessed by flow-mediated dilation (FMD) of the brachial artery in humans.
In the population-based Northern Manhattan Study (NOMAS), we performed a cross-sectional analysis of lifetime alcohol intake and brachial artery FMD during reactive hyperemia using high-resolution B-mode ultrasound images among 884 stroke-free participants (mean age 66.8 years, women 56.6%, Hispanic 67.4%, black 17.4%, and white 15.2%).
The mean brachial FMD was 5.7% and the median was 5.5%. Compared to non-drinkers, those who drank >1 drink/month to 2 drinks/day were more likely to have FMD above the median FMD (5.5%) (unadjusted OR 1.7, 95% CI 1.2–2.4, p = 0.005). In multivariate analysis, the relationship between moderate alcohol consumption and FMD remained significant after adjusting for multiple traditional cardiovascular risk factors, including sex, race-ethnicity, body mass index, diabetes mellitus, coronary artery disease, Framingham risk score, medication use (adjusted OR 1.8, 95%CI 1.1–3.0, p = 0.03). No beneficial effect on FMD was seen for those who drank more than 2 drinks/day.
In conclusion, consumption of up to 2 alcoholic beverages per day was independently associated with better FMD compared to no alcohol consumption in this multiethnic population. This effect on FMD may represent an important mechanism in explaining the protective effect of alcohol intake on cardiovascular disease.
PMCID: PMC2653471  PMID: 19228434
Idiopathic pulmonary arterial hypertension (IPAH) is a life-threatening disease manifested by progressive pulmonary vascular remodeling, compromised pulmonary blood flow and right heart failure. Most studies explore how pulmonary endothelial function modulates disease pathogenesis. We hypothesize that IPAH is a progressive panvasculopathy, affecting both pulmonary and systemic vascular beds, and that systemic endothelial dysfunction correlates with disease severity. Recent studies demonstrate systemic endothelial dysfunction in adults with pulmonary hypertension, however adults often have additional comorbidities affecting endothelial function. Systemic endothelial function has not been explored in children with IPAH.
This single-center, prospective, cross-sectional study examined brachial artery flow mediated dilation (FMD), a nitric oxide mediated, endothelial-dependent response, in children with IPAH and matched controls. FMD measurements were compared with clinical and echocardiographic measures of IPAH severity.
Thirteen patients and 13 controls were studied, ages 6–20 years old. FMD was decreased in IPAH subjects compared with controls (5.1 +/− 2.1% vs 9.7 +/− 2.0%; p<0.0001). In IPAH subjects, FMD correlated directly with cardiac index (R2=0.34, p=0.035), and inversely with tricuspid regurgitation velocity (R2=0.57, p=0.019) and right ventricular myocardial performance index (R2= 0.44, p=0.028).
The presence of systemic endothelial dysfunction in children with IPAH and its strong association with IPAH severity demonstrate that IPAH is a global vasculopathy. Although morbidity in IPAH is typically associated with pulmonary vascular disease, systemic vascular changes may also relate to disease pathogenesis and progression. Further study into shared mechanisms of systemic and pulmonary endothelial dysfunction may contribute to future therapies for IPAH.
PMCID: PMC3358491  PMID: 22440720
9.  Vascular Responses to Long- and Short-Term Exposure to Fine Particulate Matter 
This study evaluated the association of long- and short-term air pollutant exposures with flow-mediated dilation (FMD) and baseline arterial diameter (BAD) of the brachial artery using ultrasound in a large multicity cohort.
Exposures to ambient air pollution, especially long-term exposure to particulate matter <2.5 μm in aerodynamic diameter (PM2.5), are linked with cardiovascular mortality. Short-term exposure to PM2.5 has been associated with decreased FMD and vasoconstriction, suggesting that adverse effects of PM2.5 may involve endothelial dysfunction. However, long-term effects of PM2.5 on endothelial dysfunction have not been investigated.
FMD and BAD were measured by brachial artery ultrasound at the initial examination of the Multi-Ethnic Study of Atherosclerosis. Long-term PM2.5 concentrations were estimated for the year 2000 at each participant’s residence (n = 3,040) using a spatio-temporal model informed by cohort-specific monitoring. Short-term PM2.5 concentrations were based on daily central-site monitoring in each of the 6 cities.
An interquartile increase in long-term PM2.5 concentration (3 μg/m3) was associated with a 0.3% decrease in FMD (95% confidence interval [CI] of difference: −0.6 to −0.03; p = 0.03), adjusting for demographic characteristics, traditional risk factors, sonographers, and 1/BAD. Women, nonsmokers, younger participants, and those with hypertension seemed to show a greater association of PM2.5 with FMD. FMD was not significantly associated with short-term variation in PM2.5 (−0.1% per 12 μg/m3 daily increase [95% CI: −0.2 to 0.04] on the day before examination).
Long-term PM2.5 exposure was significantly associated with decreased endothelial function according to brachial ultrasound results. These findings may elucidate an important pathway linking air pollution and cardiovascular mortality.
PMCID: PMC3665082  PMID: 23103035
air pollution; atherosclerosis; cardiovascular mortality; endothelial function; flow-mediated dilation; traffic
10.  The Association Between A1C and Subclinical Cardiovascular Disease 
Diabetes Care  2009;32(9):1727-1733.
To test the hypothesis that A1C is associated with subclinical cardiovascular disease (CVD) in a population without evident diabetes, after adjusting for traditional CVD risk factors and BMI.
This was a cross-sectional study of 5,121 participants without clinically evident CVD or diabetes (fasting glucose ≥7.0 mmol/l or use of diabetes medication), aged 47–86 years, enrolled in the Multi-Ethnic Study of Atherosclerosis (MESA). Measurements included carotid intimal-medial wall thickness (CIMT) and coronary artery calcification (CAC). Results were adjusted for age, sex, ethnicity, smoking, systolic blood pressure, LDL cholesterol, HDL cholesterol, antihypertensive medication use, lipid-lowering medication use, and BMI.
Compared with those in the lowest quartile for A1C ([mean ± SD] 5.0 ± 0.2%), participants in the highest quartile (6.0 ± 0.3%) had higher adjusted mean values for common CIMT (0.85 vs. 0.87 mm, P = 0.003) and internal CIMT (1.01 vs. 1.08 mm, P = 0.003). A1C quartile was not associated with prevalence of CAC in the entire cohort (P = 0.27); however, the association was statistically significant in women (adjusted prevalence of CAC in lowest and highest A1C quartiles 37.5 vs. 43.0%, P = 0.01). Among those with some CAC, higher A1C quartile tended to be associated with higher CAC score, but the results were not statistically significant (adjusted P = 0.11).
In this multiethnic cohort, there were small, positive associations between A1C, common CIMT, and internal CIMT in the absence of clinically evident diabetes. An association between higher A1C and CAC prevalence was evident only in women.
PMCID: PMC2732160  PMID: 19549732
11.  Predictive Value of Brachial Flow-Mediated Dilation for Incident Cardiovascular Events in a Population-Based Study: The Multi-Ethnic Study of Atherosclerosis 
Circulation  2009;120(6):502-509.
Although brachial artery flow-mediated dilation (FMD) predicts recurrent cardiovascular events, its predictive value for incident cardiovascular disease (CVD) events in adults free of CVD is not well established. We assessed the predictive value of FMD for incident CVD events in the Multi Ethnic Study of Atherosclerosis (MESA).
Methods and Results
Brachial artery FMD was measured in a nested case- cohort sample of 3026 out of 6814 subjects (mean ± SD age 61.2 ± 9.9 years), in MESA, a population-based cohort study of adults free of clinical CV disease at baseline recruited at six clinic sites in the USA. The sample comprised 50.2% females, 34.3% Caucasian, 19.7% Chinese, 20.8% African Americans and 25.1% Hispanics. Probability-weighted Cox proportional hazard analysis was used to examine the association between FMD and five years of adjudicated incident CVD events, including incident myocardial infarction, definite angina, coronary revascularization (coronary artery bypass grafting, percutaneous transluminal coronary angioplasty or other revascularization), stroke, resuscitated cardiac arrest and CVD death.
Mean (SD) FMD of the cohort was 4.4 (2.8) %. In probability-weighted Cox models, FMD/unit SD was significantly associated with incident cardiovascular events in both the univariate(adjusted for age and gender) [hazard ratio; 0.79(95% CI, 0.65–0.97), p=0.01], after adjusting for the Framingham Risk Score (FRS) [hazard ratio; 0.80(95%CI, 0.62–0.97), p=0.025] and also in multivariable models [hazard ratio; 0.84(95%CI, 0.71–0.99), p=0.04] after adjusting for age, gender, diabetes mellitus, cigarette smoking status, systolic blood pressure, HDL, LDL, triglycerides, heart rate, statin use and blood pressure medication use. The c statistic (AUC) of FMD, FRS, FRS + FMD) were 0.65, 0.74 and 0.74 respectively. Compared with the FRS alone, the addition of FMD to the FRS net correctly re-classifies 52% of subjects with no incident CVD event, but net incorrectly reclassifies 23% of subjects with an incident CVD event; an overall net correct re-classification of 29% (p < 0.001).
Brachial FMD is a predictor of incident cardiovascular events in population based adults. Even though the addition of FMD to the FRS did not improve discrimination of subjects at risk of CVD events in ROC analysis, it did improve the classification of subjects as low, intermediate and high CVD risk compared to the FRS.
PMCID: PMC2740975  PMID: 19635967
Endothelial dysfunction; brachial flow-mediated dilation; incident cardiovascular event; healthy adults
12.  Stages of Systemic Hypertension and Blood Pressure as Correlates of Computed Tomography-Assessed Aortic Valve Calcium (From the Multi-Ethnic Study of Atherosclerosis) 
Hypertension has been identified as a risk factor for aortic valve calcium (AVC) but the magnitude of the risk relation with hypertension severity or whether age affects the strength of this risk association has not been studied. The relationship of hypertension severity, as defined by JNC-7 hypertension stages or blood pressure (BP), to CT-assessed AVC prevalence and severity was examined in 4,274 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) without treated hypertension. Analyses were stratified by age < or ≥ 65 years, were adjusted for common cardiovascular risk factors, and excluded those on antihypertensive medications. In age-stratified, adjusted analyses, Stage I/II hypertension was associated with prevalent AVC in those <65 but not in those ≥65 years of age [OR (95% CI): 2.31 (1.35, 3.94) vs. 1.33 (0.96, 1.85), P-interaction = 0.041]. Similarly, systolic BP and pulse pressure (PP) were more strongly associated with prevalent AVC in those <65 than those ≥65 years of age [OR (95% CI): 1.21 (1.08, 1.35) vs. 1.07 (1.01, 1.14) per 10 mmHg increase in systolic BP, Pinteraction = 0.006] and [OR (95% CI): 1.41 (1.21, 1.64) vs. 1.14 (1.05, 1.23) per 10 mmHg increase in PP]. No associations were found between either hypertension stage or BP and AVC severity. In conclusion, stage I/II hypertension, as well as higher systolic pressure and pulse pressure were associated with prevalent AVC. These risk associations were strongest in participants younger than age 65 years.
PMCID: PMC3032359  PMID: 21146685
Blood Pressure; Aortic Valve; Calcification
13.  Glycemic Associations With Endothelial Function and Biomarkers Among 5 Ethnic Groups: The Multi‐Ethnic Study of Atherosclerosis and the Mediators of Atherosclerosis in South Asians Living in America Studies 
The association of prediabetic states with endothelial dysfunction measured by flow‐mediated dilation (FMD) or endothelial biomarker levels remains controversial. We examined data from 5 ethnic groups to determine the association between glucose categories and FMD or endothelial biomarkers. We determined whether these associations vary by ethnic group or body mass index.
Methods and Results
We used data from 3516 participants from 5 race/ethnic groups with brachial FMD, endothelial biomarkers, and glucose category (normal, impaired fasting glucose [IFG], and diabetes) measures. There were significant ethnic differences in FMD, biomarker levels, and the prevalence of IFG and diabetes. However, all 5 ethnic groups showed similar patterns of higher FMD for the IFG group compared with the normal glucose and diabetes groups, which was most significant among whites and Asian Indians. Associations between glucose categories and endothelial biomarkers were more uniform, with the IFG and diabetes groups having higher biomarker levels than the normal glucose group. These associations did not change with further adjustment for fasting insulin levels. Whites with normal BMI had higher FMD values with higher glucose levels, but those with BMI in the overweight or obese categories had the inverse association (P for interaction=0.01).
The discordance of IFG being associated with higher FMD but more abnormal endothelial biomarker levels is a novel finding. This higher FMD for the IFG group was most notable in whites of normal BMI. The higher FMD among those with impaired fasting glucose may reflect differences in insulin signaling pathways between the endothelium and skeletal muscle.
PMCID: PMC3603246  PMID: 23525433
biomarkers; diabetes; endothelium; ethnicity; insulin resistance
14.  Endothelial dysfunction and hypertension in obstructive sleep apnea – Is it due to intermittent hypoxia? 
Obstructive sleep apnea (OSA) is a prevalent disorder causing hypertension. Endothelial dysfunction appears to underlie development of hypertension. It is not known whether hypoxia during sleep is necessarily the prerequisite process for endothelial dysfunction and hypertension in OSA. We therefore examined the relationship between endothelial-dependent vasodilatory capacity, hypoxia and circulating angiogenesis inhibitors in OSA.
Methods and results
We studies 95 subjects with and without OSA and hypertension. Endothelial-dependent vasodilation was assessed using brachial artery flow-mediated vasodilation method (FMD). Plasma angiogenesis inhibitors, endoglin (sEng) and fms-like tyrosine kinase-1 (sFlt-1), were measured using ELISA. The apnea–hypopnea indexes were 41 ± 5 and 48 ± 4 events/hr in normotensive OSA (N-OSA) and hypertensive OSA (H-OSA), respectively, indicating severe OSA. The sleep time spent with SaO2 < 90% (T < 90%) were 34 ± 8 and 40 ± 9 min, respectively. FMD was markedly impaired in H-OSA (8.0% ± 0.5) compared to N-OSA (13.5% ± 0.5, P < 0.0001), H-non-OSA (10.5% ± 0.8, P < 0.01), and N-non-OSA (16.1% ± 1.0, P < 0.0001). There was no correlation between T < 90% and FMD. Both OSA groups had elevated levels of sFlt-1 (62.4 ± 5.9 and 63.9 ± 4.7 pg/ml) compared to N-non-OSA (32.1 ± 6.5, P = 0.0008 and P = 0.0004, respectively) and H-non-OSA (41.2 ± 7.0, P < 0.05 and P = 0.03, respectively). In contrast, sEng was only elevated in H-OSA (4.20 ± 0.17 ng/ml) compared with N-OSA (3.64 ± 0.14, P = 0.01) and N-non-OSA (3.48 ± 0.20, P = 0.01). There was a modest but statistically significant inverse correlation between sEng and FMD in only H-OSA group (r = −0.38, P < 0.05).
These data show that patients with OSA and hypertension have marked impairment of FMD, independent of hypoxia exposure, which is associated with increased sEng.
PMCID: PMC3770209  PMID: 24027362
Angiogenesis inhibitors; Sleep apnea; Hypertension; Endothelial dysfunction
15.  Differences in Kidney Function and Incident Hypertension: The Multi-Ethnic Study of Atherosclerosis 
Annals of internal medicine  2008;148(7):501-508.
Kidney disease and hypertension commonly coexist, yet the direction of their association is still debated.
To evaluate whether early kidney dysfunction, measured by serum cystatin C levels and urinary albumin excretion, predates hypertension in adults without clinically recognized kidney or cardiovascular disease.
Observational cohort study using data from 2000 to 2005.
The MESA (Multi-Ethnic Study of Atherosclerosis), a community-based study of subclinical cardiovascular disease in adults age 45 to 84 years.
2767 MESA participants without prevalent hypertension, cardiovascular disease, or clinically recognized kidney disease (an estimated glomerular filtration rate <60 mL/min per 1.73 m2 or microalbuminuria).
Cystatin C was measured by using a nephelometer, and urinary albumin and creatinine were measured from a spot morning collection. The primary outcome was incident hypertension, defined as systolic blood pressure of at least 140 mm Hg, diastolic blood pressure of at least 90 mm Hg, or use of an antihypertensive medication.
During a median follow-up of 3.1 years, 19.7% of the cohort (545 participants) developed hypertension. After adjustment for established hypertension risk factors, each 15-nmol/L increase in cystatin C was associated with a statistically significant 15% greater incidence of hypertension (P = 0.017). The highest sex-specific quartile of urinary albumin–creatinine ratio was associated with a statistically insignificant 16% greater incidence of hypertension (P = 0.192) compared with the lowest quartile. No statistical evidence suggested a multiplicative interaction.
Unmeasured characteristics may have confounded observed associations of kidney markers with hypertension. Follow-up was relatively short. Hypertension that may have occurred between study visits or hypertension that was not captured by standard cuff measurements may have been missed.
Differences in kidney function, indicated by cystatin C levels, are associated with incident hypertension among individuals without clinical kidney or cardiovascular disease. These population-based findings complement experimental work implicating early kidney damage in the pathogenesis of essential hypertension.
PMCID: PMC3044648  PMID: 18378946
16.  Associations of Inflammatory Markers with Coronary Artery Calcification: Results from the Multi-Ethnic Study of Atherosclerosis 
Atherosclerosis  2009;209(1):226-229.
Inflammatory markers predict coronary heart disease (CHD). However, associations with coronary artery calcium (CAC), a marker of subclinical CHD, are not established.
We examined cross-sectional associations of C-reactive protein (CRP), interleukin-6 (IL-6) and fibrinogen with CAC presence (Agatston score > 0 by computed tomography) in 6,783 Multi-Ethnic Study of Atherosclerosis (MESA) participants.
In all participants, those in the highest, compared to lowest, quartile of CRP had a relative risk (RR, 95% confidence interval) of 1.13 (1.06-1.19; p<0.01) for CAC in age, sex and ethnicity adjusted models. For highest versus lowest quartiles, relative risks were 1.22 (1.15-1.30; p<0.01) for IL-6 and 1.18 (1.11-1.24; p<0.01) for fibrinogen. Adjusting for CHD risk factors (smoking, diabetes, blood pressure, obesity and dyslipidemia) attenuated RRs. RRs for CAC were 1.05 (0.99-1.12; p=0.63) for CRP, 1.12 (1.06-1.20; p<0.01) for IL-6 and 1.09 (1.02-1.16; p=0.01) for fibrinogen in multivariable adjusted models. Results were similar for men and women and across ethnic groups.
Inflammatory markers were weakly associated with CAC presence and burden in MESA. Our data support the hypothesis that inflammatory biomarkers and CAC reflect distinct pathophysiology.
PMCID: PMC2830357  PMID: 19766217
Atherosclerosis; Calcium; Inflammation; Population
17.  Seasonal variation of endothelium-dependent flow-mediated vasodilation measured in the same subjects 
Seasonal variation of flow-mediated vasodilation (FMD) remains controversial. A large cohort study showing that FMD was highest in summer and lowest in winter has been performed in a cross-sectional manner on different populations in different seasons, and the results for the same population were not compared.
FMD was compared between the cool season (14.4 ± 4.4°C) and warm season (28.8 ± 1.0°C) in the same 27 outpatients with hypertension, diabetes mellitus and/or hyperlipidemia.
The mean resting brachial artery diameter was significantly larger in the warm season than in the cool season. The maximal post-deflation brachial artery diameter was also significantly larger in the warm season than in the cool season. FMD, which was calculated from the resting diameter and the maximal diameter, was significantly higher in the warm season than in the cool season even when expressed as the relative value (4.74 ± 2.15 vs. 5.71 ± 2.17%, p=0.03) or absolute value (0.18 ± 0.08 vs, 0.23 ± 0.07 mm, p=0.008).
FMD was significantly higher in the warm season than in the cool season when the measurements were performed on the same subjects and a paired comparison was made.
PMCID: PMC3371618  PMID: 22720200
Flow-mediated vasodilation; seasonal variation
18.  Prevalence and Risk Factors for Epiretinal Membranes in a Multi-Ethnic United States Population 
Ophthalmology  2010;118(4):694-699.
To describe the prevalence of and risk factors for epiretinal membrane (ERM) in a multi-ethnic population and to evaluate possible racial/ethnic differences.
Cross-sectional study.
Participants of the Multi-Ethnic Study of Atherosclerosis (MESA), examined at the second visit of the MESA when retinal photography was performed.
Data on 5960 participants aged 45 to 84 years from MESA, including white, blacks, Hispanic and Chinese from six United States communities, were analysed. ERM was assessed from digital non-stereoscopic fundus photographs and defined as cellophane macular reflex (CMR) without retinal folds or pre-retinal macular fibrosis (PMF) with retinal folds. Risk factors were assessed from standardized interviews, clinical examinations, and laboratory investigations.
Main outcome measures
ERM prevalence by ethnic/racial group, and risk factors associated with ERM.
The prevalence of any ERM was 28.9%, of which 25.1% were CMR and 3.8% were PMF. The prevalence of ERM was significantly higher in Chinese (39.0%), compared to Hispanics (29.3%), whites (27.5%), and blacks (26.2%), p<0.001. In multivariable models, increasing age (odds ratio [OR] 1.19, 95% confidence intervals [CI], 1.06, 1.34, per year increase in age), diabetes (OR 1.92, 95% CI, 1.39, 2.65) and hypercholesterolemia (OR 1.33, 95% CI, 1.04, 1.69) were significantly associated with CMR.
This study showed that ERM was significantly more common in Chinese persons compared to whites, blacks and Hispanics. Risk factors for epiretinal membrane were increasing age, presence of diabetes and hypercholesterolemia.
PMCID: PMC3070851  PMID: 21035863
19.  Folic Acid Supplementation Improves Vascular Function in Professional Dancers With Endothelial Dysfunction 
To determine if folic acid supplementation improves vascular function (brachial artery flow-mediated dilation [FMD]) in professional dancers with known endothelial dysfunction.
Prospective cross-sectional study.
Academic institution in the Midwestern United States.
Twenty-two professional ballet dancers volunteered for this study.
Main Outcome Measures
Subjects completed a 3-day food record to determine caloric and micronutrient intake. Menstrual status was determined by interview and questionnaire. Endothelial function was determined as flow-induced vasodilation measured by high-frequency ultrasound of the brachial artery. A change in brachial diameter of <5% to hyperemic flow stimulus was defined a priori as endothelial dysfunction. Subjects with abnormal FMD took 10 mg of folic acid daily for 4 weeks, and FMD testing was then repeated. Serum whole blood was measured for folic acid levels before and after supplementation.
Sixty-four percent of dancers (n = 14) had abnormal brachial artery FMD (<5%) (mean ± standard deviation, 2.9% ± 1.5%). After 4 weeks of folic acid supplementation (10 mg/day), FMD improved in all the subjects (7.1% ± 2.3%; P < .0001).
This study reveals that vascular endothelial function improves in dancers after supplementation with folic acid (10 mg/day) for at least 4 weeks. This finding may have clinically important implications for future cardiovascular disease risk prevention.
PMCID: PMC3328806  PMID: 21715240
20.  Usefulness of Baseline Obesity to Predict Development of a High Ankle Brachial Index (From the Multi-Ethnic Study of Atherosclerosis) 
The American journal of cardiology  2011;107(9):1386-1391.
An abnormally high ankle brachial index (ABI) is associated with increased all-cause and cardiovascular mortality. The relationship of obesity to incident high-ABI has not been characterized. We investigated the hypothesis that increased obesity—quantified by body weight, BMI, waist circumference, and waist-to-hip-ratio—is positively associated with a high-ABI (ABI ≥ 1.3) and with mean ABI increases over a four year follow-up. Prevalence and incidence ratios for a high-ABI were obtained for 6540 and 5045 participants respectively in the Multi-Ethnic Study of Atherosclerosis (MESA), using log-binomial regression models adjusted for demographic, cardiovascular, and inflammatory/novel risk factors. Linear regression was used to analyze mean ABI change. Both prevalence and incidence of a high-ABI were significantly higher for the highest versus the lowest quartile of every baseline measure of obesity, with weight and BMI demonstrating the highest incidence ratios (2.7 and 2.4, respectively). All prevalence and incidence ratios were positive and graded across obesity quartiles, and were persistent in the subpopulation without diabetes. Among those with normal baseline ABI values, one MESA-standard deviation increase in every baseline measure of obesity was associated with significant increases in mean ABI values. In conclusion, we observed an independent, positive and graded association of increasing obesity to both prevalent and incident high-ABI, and to mean increases in ABI values over time. Weight and BMI seemed to be at least as strongly, if not more strongly, associated with a high-ABI than were measures of abdominal obesity.
PMCID: PMC3079000  PMID: 21377643
obesity; anthropometric measures; peripheral vascular disease; ankle-brachial index; epidemiology
21.  Chronic Stress and the Development of Early Atherosclerosis: Moderating Effect of Endothelial Dysfunction and Impaired Arterial Elasticity 
This study aims to explore the interactive effect of vital exhaustion (VE) and endothelial dysfunction on preclinical atherosclerosis, assessed by carotid intima-media thickness (IMT). Furthermore, interaction between VE and carotid elasticity is examined. Participants were 1,596 young healthy adults from the Cardiovascular Risk in Young Finns study. Endothelial dysfunction was measured by brachial flow-mediated dilatation (FMD), and carotid elasticity by carotid artery compliance (CAC). Significant interactions between FMD and VE, and between CAC and VE, for IMT were found in participants with the very lowest FMD and CAC. Thus, VE may be harmful if the endothelium is not working properly.
PMCID: PMC2800324  PMID: 20049236
chronic stress; vital exhaustion; intima-media thickness; flow-mediated dilatation; carotid artery compliance; atherosclerosis
22.  Diabetic Retinopathy and Endothelial Dysfunction in Patients with Type 2 Diabetes Mellitus 
Diabetes & Metabolism Journal  2013;37(4):262-269.
We investigated the relationship between endothelial dysfunction and diabetic retinopathy (DR) in patients with type 2 diabetes.
We used a cross-sectional design to examine 167 patients with type 2 diabetes mellitus. All patients underwent biochemical and ophthalmological examination. We assessed endothelial dysfunction by a flow-mediated vasodilation method of the brachial artery. Changes in vasodilation (flow-mediated vasodilatation, %FMD) were expressed as percent change over baseline values.
The mean±standard deviation of patient age was 54.1±8.6 years. The %FMD was significantly lower in patients with DR than without DR. The prevalence of retinopathy decreased across increasing tertiles of %FMD. After adjusting for patients' age, sex, diabetes duration, use of insulin, use of antihypertensive, antiplatelet, and lipid lowering medications, systolic blood pressure, fasting plasma glucose, 2-hour plasma glucose, glycated hemoglobin, and urinary albumin excretion, participants with a reduced %FMD were more likely to have DR (odds ratio, 11.819; 95% confidence interval, 2.201 to 63.461; P=0.004, comparing the lowest and highest tertiles of %FMD).
Endothelial dysfunction was associated with DR, which was most apparent when the endothelial dysfunction was severe. Our study provides insights into the possible mechanism of the influence of endothelial dysfunction on the development of DR.
PMCID: PMC3753491  PMID: 23991404
Diabetes mellitus, type 2; Diabetic retinopathy; Endothelial dysfunction; Flow-mediated vasodilation
23.  Association of Baseline Sex Hormone Levels with Baseline and Longitudinal Changes in Waist-to-Hip Ratio : Multi-Ethnic Study of Atherosclerosis 
Waist-to-hip ratio (WHR) is strongly associated with prevalent atherosclerosis. We analyzed the associations of baseline serum levels of testosterone (T), estradiol (E2), sex hormone binding globulin (SHBG), and dehydroepiandrosterone (DHEA) with WHR in the Multi-Ethnic Study of Atherosclerosis (MESA) cohort.
Baseline data was available for 3144 men and 2038 postmenopausal women, who were non-users of hormone therapy, who were 45–84 years of age, and of White, Chinese, Black or Hispanic racial/ethnic groups. Of these, 2708 men and 1678 women also had longitudinal measurements of WHR measured at the second and/or the third study visits (median follow-up 578 days, and 1135 days, respectively).
In cross-sectional analyses adjusted for age, race, and cardiovascular disease risk factors, T was negatively associated with baseline WHR in men, while in both sexes, E2 was positively associated and SHBG was negatively associated with WHR (all p<0.001). In longitudinal analyses, further adjusted for follow-up time and baseline WHR, baseline T was negatively associated with WHR at follow-up (p=0.001) in men, while in both sexes, E2 was positively associated (p=0.004), and SHBG was negatively associated with WHR (p<0.001). The longitudinal association of E2, but not T, was independent of SHBG. In both cross-sectional or longitudinal analyses, there were no associations between DHEA and WHR in either men or women.
Sex hormones are associated with WHR at baseline and also during follow-up above and beyond their baseline association. Future research is needed to determine if manipulation of hormones is associated with changes in central obesity.
PMCID: PMC3342434  PMID: 22270378
Sex Hormones; epidemiology; waist to hip ratio
24.  Hyperuricemia is independently associated with endothelial dysfunction in postmenopausal women but not in premenopausal women 
BMJ Open  2013;3(11):e003659.
The purpose of this study was to determine the relationships between uric acid, endothelial function and cardiovascular risk factors and to investigate whether menopausal status was associated with the relationship between uric acid and endothelial function in women.
Cross-sectional study.
3 general hospitals in Japan.
749 Japanese women aged 30–74 years recruited from people who underwent health-screening examinations with agreement for measurement of vascular function.
We measured serum concentrations of uric acid and flow-mediated vasodilation (FMD). Percentage of FMD (peak diameter−baseline diameter/baseline diameter) was used for analysis. Endothelial dysfunction was defined as FMD ≤4.90%, division point for the lowest tertile and the middle tertile of FMD. Menopause women were defined as participants without menstruation for over 1 year or participants with a history of hysterectomy or bilateral oophorectomy.
Of the 749 participants, 368 (49.1%) were premenopausal women and 381 (50.9%) were postmenopausal women. Age, body mass index, systolic blood pressure, total cholesterol, triglycerides, glucose, estimated glomerular filtration rate and Framingham risk score were significantly correlated with serum uric acid level. FMD showed a gradual decrease in accordance with the serum uric acid level in the entire study population (<4 mg/dL, 6.85±3.65%; 4 to <5 mg/dL, 6.79±3.60%; 5 to <6 mg/dL, 6.24±3.58%; ≥6 mg/dL, 5.27±3.18%; p=0.01). Multivariate analysis revealed that uric acid was a significantly independent risk factor for endothelial dysfunction in postmenopausal women (OR 1.23, 95% CI 1.01 to 1.50), but not in premenopausal women.
These findings suggest that uric acid can be used as a risk marker of endothelial dysfunction in a female population, and particularly as an independent risk factor in postmenopausal women but not in premenopausal women.
Registration number of the study
PMCID: PMC3822312  PMID: 24213096
Vascular Medicine; Pathology
25.  Sex-Specific Association of Age with Carotid Artery Distensibility: Multi-Ethnic Study of Atherosclerosis 
Journal of Women's Health  2012;21(5):516-520.
Older women have a higher prevalence of systolic hypertension than do men; however, whether or not this relates to arterial properties, such as distensibility coefficient (DC), is not known. We examined whether the association of carotid artery DC with age differed by sex in the Multi-Ethnic Study of Atherosclerosis (MESA).
B-mode ultrasound-measured carotid diameters and brachial pressures were obtained from 6359 participants (53% female, 38% white, 12% Chinese, 27% black, 22% Hispanic, aged 45–85 years) of the MESA baseline examination. The within-individual slopes of 2log(diameter) vs. blood pressure fit using mixed models (MM) are interpreted as the DC, and interaction terms are interpreted as differences in DC. The MM calculation allows for correction of the confounding caused by the association of age, sex, and race with blood pressure, the denominator in the calculation of DC.
DC was associated with age, sex, and race (all p<0.001). Women had a greater age-related lowering of DC compared to men (2.52×10−5 vs. 2.16×10−5/mm Hg lower DC per year of age, p=0.006). Mean diameter of carotid arteries was greater with age (p<0.001); this association also was significantly stronger in women compared to men (0.24% vs. 0.14% larger mean carotid diameter per year of age, p<0.001).
Greater stiffening and enlargement of arteries are seen in older women compared to older men. This implies that the afterload on the heart of older women is likely to be greater than that among older men.
PMCID: PMC3353825  PMID: 22393881

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