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1.  Regional Left Ventricular Myocardial Dysfunction as a Predictor of Incident Cardiovascular Events 
We sought to examine the prognostic value of subclinical left ventricular (LV) regional myocardial dysfunction (RMD) measured by magnetic resonance imaging (MRI) among asymptomatic individuals.
LV RMD, defined as segmental impairment in systolic wall thickening, predicts adverse events in patients with established cardiovascular disease. MRI is highly accurate for detecting subtle RMD, of which the prognostic significance in a large multiethnic asymptomatic population is not known.
We used MRI to evaluate baseline regional LV myocardial function and prospectively followed a multiethnic (African American, Caucasian, Chinese, and Hispanic) population-based sample of 4,510 men and women without cardiovascular disease for a mean of 4.6 years. Regional myocardial dysfunction was defined as the presence of impaired systolic wall thickening (<10th percentile of segment-specific population distribution) in ≥2 contiguous LV segments within any given coronary artery territory.
Baseline prevalence of RMD was 25.6%. Heart failure developed in 34 (1.0%) and 30 (2.6%) participants without and with RMD, respectively (p < 0.001). After adjustment for demographics and traditional risk factors, RMD remained independently associated with incident heart failure (hazard ratio [HR]: 2.62; 95% confidence interval [CI]: 1.56 to 4.39; p < 0.001). The relationship persisted after further adjustment for biomarkers of reported association with cardiovascular disease and indexes of global LV systolic dysfunction and hypertrophy (HR: 1.80; 95% CI: 1.02 to 3.20; p = 0.044). Similarly, RMD independently conferred an increased risk for hard coronary events (myocardial infarction or death from coronary heart disease; HR: 1.75; 95% CI: 1.06 to 2.89; p = 0.029), the composite of hard coronary events and stroke (HR: 1.72; 95% CI: 1.16 to 2.56; p = 0.005), and all atherosclerotic cardiovascular events (HR: 1.50; 95% CI: 1.09 to 2.07; p = 0.012).
Among an asymptomatic multiethnic American cohort, RMD is an independent predictor beyond traditional risk factors and global LV assessment for incident heart failure and atherosclerotic cardiovascular events. The clinical utility of early recognition of this subclinical phenotype deserves further investigation.
PMCID: PMC4124734  PMID: 21511109
epidemiology; heart failure; magnetic resonance imaging; myocardial dysfunction; prognosis
2.  N-terminal Pro-B-Type Natriuretic Peptide, Left Ventricular Mass, and Incident Heart Failure: Multi-Ethnic Study of Atherosclerosis 
Circulation. Heart failure  2012;5(6):727-734.
Elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) is associated with clinically overt heart failure (HF). However, whether it provides additive prognostic information for incident HF beyond traditional risk factors and left ventricular (LV) mass index among multi-ethnic asymptomatic individuals has not yet been determined. We studied the associations of plasma NT-proBNP and magnetic resonance imaging defined LV mass index with incident HF in an asymptomatic multi-ethnic population.
Methods and Results
A total of 5597 multi-ethnic participants without clinically apparent cardiovascular disease underwent baseline measurement of NT-proBNP and were followed for 5.5±1.1 years. Among them, 4163 also underwent baseline cardiac magnetic resonance imaging. During follow-up, 111 participants experienced incident HF. Higher NT-proBNP was significantly associated with incident HF, independent of baseline age, sex, ethnicity, systolic blood pressure, diabetes mellitus, smoking, estimated glomerular filtration rate, medications (anti-hypertensive and statin), LV mass index, and interim myocardial infarction (hazard ratio: 1.95 per 1U log NT-proBNP increment, 95% CI 1.54–2.46, P<0.001). This relationship held among different ethnic groups, non-Hispanic whites, African-Americans, and Hispanics. Most importantly, NT-proBNP provided additive prognostic value beyond both traditional risk factors and LV mass index for predicting incident HF (integrated discrimination index=0.046, P<0.001; net reclassification index; 6-year risk probability categorized by <3%, 3–10%, >10% =0.175, P=0.019; category-less net reclassification index=0.561, P<0.001).
Plasma NT-proBNP provides incremental prognostic information beyond traditional risk factors and the magnetic resonance imaging-determined LV mass index for incident symptomatic HF in an asymptomatic multi-ethnic population.
Clinical Trial Registration
URL: Unique identifier: NCT00005487.
PMCID: PMC4124746  PMID: 23032197
N-terminal pro-B-type natriuretic peptide; heart failure; left ventricular mass
3.  Association of Endothelial and Oxidative Stress with Metabolic Syndrome and Subclinical Atherosclerosis: Multi-Ethnic Study of Atherosclerosis 
A cluster of metabolic abnormalities termed metabolic syndrome (MetS) is associated with vascular endothelial dysfunction and oxidative internal milieu. We examined whether the association of MetS with subclinical atherosclerosis is explained by biomarkers of endothelial damage and oxidative stress.
MESA is a population based study of 45-84 year old individuals of four US ethnicities without clinical cardiovascular disease. A random sample of 997 MESA participants had data on the following biomarkers: von Willebrand Factor, soluble intercellular adhesion molecule-1 (sICAM1), CD40 ligand, soluble thrombomodulin, E-selectin, and oxidized LDL (oxLDL). We examined whether the associations of MetS with B-mode ultrasound-defined common and internal carotid intimal medial thickness (IMT) and coronary artery calcium (CAC) measured using computerized tomography were explained by the biomarkers using multiple regression methods.
MetS was associated with higher levels of each of the biomarkers (p<0.001, CD40L suggestive association p=0.004), with greater IMT (p<0.001), and with greater extent of CAC in those in whom CAC was detectable (p=0.01). The association of MetS with measures of subclinical atherosclerosis remained unchanged after adjustment for the biomarkers. After adjusting for MetS, oxLDL was suggestively associated with greater prevalence of detectable CAC (p=0.005) and thicker internal carotid IMT (p=0.002), while sICAM-1was significantly associated with greater prevalence of detectable CAC (p=0.001).
The association of MetS with subclinical atherosclerosis was independent of its association with biomarkers of endothelial damage and oxidative stress, suggesting that metabolic abnormalities and oxidative endothelial damage may lead to atherosclerotic disease through distinct mechanisms.
PMCID: PMC3130805  PMID: 21505504
Metabolic syndrome; biomarkers; coronary artery atherosclerosis; carotid arteries
4.  Fibrinogen and Left Ventricular Myocardial Systolic Function: The Multi-Ethnic Study of Atherosclerosis 
American heart journal  2010;160(3):479-486.
Increasing evidence suggests that elevated plasma fibrinogen is associated with incident heart failure. However, the underlying pathophysiological mechanisms have not been well elucidated.
We examined the relationship between plasma fibrinogen level and peak systolic mid-wall circumferential strain(Ecc) at the base, mid-cavity and apex of the left ventricle measured by magnetic resonance imaging myocardial tagging in 1,096 participants without clinical cardiovascular disease enrolled in the Multi-Ethnic Study of Atherosclerosis(MESA).
After adjustment for demographics, established risk factors and body-mass-index, elevated fibrinogen was independently associated with reductions in absolute Ecc indicative of impaired systolic function in all regions(all P=0.015). The relationships were consistently significant upon further adjustment for measures of atherosclerosis(all P≤0.024), and were modestly attenuated with regional heterogeneity after additional adjustment for other inflammatory biomarker and N-terminal pro-brain-natriuretic peptide. In this fully-adjusted model, every one-standard deviation(74mg/dL) increment in plasma fibrinogen was independently associated with a reduction in left ventricular absolute Ecc of 0.29%(95%CI=0.03%–0.59%, P=0.048) at the base, 0.22%(95%CI=0.006%–0.43%, P=0.044) at mid-cavity, 0.20%(95%CI=−0.035%–0.43%, P=0.097) at the apex, and 0.24%(95%CI=0.05–0.43, P=0.015) overall.
Among asymptomatic individuals without clinical cardiovascular disease, elevated fibrinogen is independently associated with impaired myocardial systolic function. These findings support roles of inflammation, procoagulation and hyperviscosity underlying hyperfibrinogenemia in the pathogenesis of incipient myocardial dysfunction.
PMCID: PMC2937158  PMID: 20826256
epidemiology; heart failure; myocardial function; fibrinogen; hyperviscosity; hypercoagulability; magnetic resonance imaging
5.  Differences in the Incidence of Congestive Heart Failure by Ethnicity 
Archives of internal medicine  2008;168(19):2138-2145.
The relationship between incident congestive heart failure (CHF) and ethnicity as well as racial/ethnic differences in the mechanisms leading to CHF have not been demonstrated in a multiracial, population-based study. Our objective was to evaluate the relationship between race/ethnicity and incident CHF.
The Multi-Ethnic Study of Atherosclerosis (MESA) is a cohort study of 6814 participants of 4 ethnicities: white (38.5%), African American (27.8%), Hispanic (21.9%), and Chinese American (11.8%). Participants with a history of cardiovascular disease at baseline were excluded. Cox proportional hazards models were used for data analysis.
During a median follow-up of 4.0 years, 79 participants developed CHF (incidence rate: 3.1 per 1000 person-years). African Americans had the highest incidence rate of CHF, followed by Hispanic, white, and Chinese American participants (incidence rates: 4.6, 3.5, 2.4, and 1.0 per 1000 person-years, respectively). Although risk of developing CHF was higher among African American compared with white participants (hazard ratio, 1.8; 95% confidence interval, 1.1-3.1), adding hypertension and/or diabetes mellitus to models including ethnicity eliminated statistical ethnic differences in incident CHF. Moreover, African Americans had the highest proportion of incident CHF not preceded by clinical myocardial infarction (75%) compared with other ethnic groups (P = .06).
The higher risk of incident CHF among African Americans was related to differences in the prevalence of hypertension and diabetes mellitus as well as socioeconomic status. The mechanisms of CHF also differed by ethnicity; interim myocardial infarction had the least influence among African Americans, and left ventricular mass increase had the greatest effect among Hispanic and white participants.
PMCID: PMC3038918  PMID: 18955644
6.  Coronary Vessel Wall Evaluation by Magnetic Resonance Imaging in the Multi-Ethnic Study of Atherosclerosis: Determinants of Image Quality 
Coronary artery wall magnetic resonance imaging (MRI) has been developed to assess coronary lumen diameter and wall thickness. The purpose of this study was to evaluate the physiological parameters that affect the measures of coronary wall thickness using black-blood MRI pulse sequences.
Eighty-seven participants (38 men and 49 women) of the Multi-Ethnic Study of Atherosclerosis were enrolled in the coronary artery wall MRI study. Cine 4-chamber imaging was used to determine the coronary artery rest period. Free-breathing whole-heart magnetic resonance angiography with motion adaptor navigator was performed to localize the coronary arteries in 64 participants. Cross-sectional free-breathing black-blood images were acquired using electrocardiogram-gated, turbo spin echo sequence. Imaging parameters were as follows: repetition time = 2 R-R intervals, time to echo = 33 milliseconds, echo train length = 13, bandwidth = 305 Hz/pixel, matrix = 416 × 416, field of view = 420 × 420 mm, and slice thickness = 4 to 5 mm.
Imaging was completed in 215 (92%) of 234 coronary segments; 9 participants had incomplete scans. Mean age was 62.6 ± 8.4 years (range, 45–81 years). Mean body mass index was 29.2 ± 5.9 kg/m2. A higher proportion of images with quality of “good” was seen in the right coronary artery (40.5%) compared to the left main and left anterior descending coronary arteries (31.9% and 26.4%, respectively). There was a very good agreement between observers in the image quality scores (κ = 0.79, P < 0.001). Lower heart rate, male sex, and longer coronary rest period were associated with higher image quality score (P < 0.05). Signal-to-noise ratio was higher in participants with Agatston calcium score of more than 10 in the right coronary and left main arteries (48.5 vs 69.7, P = 0.001; and 53.4 vs 61.6, P = 0.032, respectively).
Improved depiction of the coronary artery wall with MRI is related to coronary rest period and atherosclerotic plaque burden as measured by calcium score and inversely related to heart rate. Because longer coronary artery rest periods are associated with improved image quality both for angiography with MRI and coronary artery wall imaging, heart rate–lowering methods in association with these techniques appear to be a logical application.
PMCID: PMC3037090  PMID: 19188777
coronary; magnetic resonance imaging; image quality; MRI; cardiac
7.  Common Genetic Variation, Residential Proximity to Traffic Exposure, and Left Ventricular Mass: The Multi-Ethnic Study of Atherosclerosis 
Environmental Health Perspectives  2010;118(7):962-969.
Elevated left ventricular mass (LVM) is a strong predictor of negative cardiovascular outcomes, including heart failure, stroke, and sudden cardiac death. A relationship between close (< 50 m compared with > 150 m) residential proximity to major roadways and higher LVM has previously been described, but the mechanistic pathways that are involved in this relationship are not known. Understanding genetic factors that influence susceptibility to these effects may provide insight into relevant mechanistic pathways.
We set out to determine whether genetic polymorphisms in genes affecting vascular and autonomic function, blood pressure, or inflammation influence the relationship between traffic proximity and LVM.
This was a cross-sectional study of 1,376 genotyped participants in the Multi-Ethnic Study of Atherosclerosis, with cardiac magnetic resonance imaging performed between 2000 and 2002. The impact of tagged single-nucleotide polymorphisms (tagSNPs) and inferred haplotypes in 12 candidate genes (ACE, ADRB2, AGT, AGTR1, ALOX15, EDN1, GRK4, PTGS1, PTGS2, TLR4, VEGFA, and VEGFB) on the relationship between residential proximity to major roadways and LVM was analyzed using multiple linear regression, adjusting for multiple potential confounders.
After accounting for multiple testing and comparing homozygotes, tagSNPs in the type 1 angiotensin II receptor (AGTR1, rs6801836) and arachidonate 15-lipoxygenase (ALOX15, rs2664593) genes were each significantly (q < 0.2) associated with a 9–10% difference in the association between residential proximity to major roadways and LVM. Participants with suboptimal blood pressure control demonstrated stronger interactions between AGTR1 and traffic proximity.
Common polymorphisms in genes responsible for vascular function, inflammation, and oxidative stress appear to modify associations between proximity to major roadways and LVM. Further understanding of how genes modify effects of air pollution on CVD may help guide research efforts into specific mechanistic pathways.
PMCID: PMC2920916  PMID: 20308035
AGTR1; ALOX15; cardiac structure; cardiac MRI; gene-environment interactions; left ventricular mass; traffic, air pollution
8.  Relation of Aortic Wall Thickness and Distensibility to Cardiovascular Risk Factors (From the Multi-Ethnic Study of Atherosclerosis [MESA]) 
The American journal of cardiology  2008;102(4):491-496.
To determine the relationship between aortic wall thickness (WT) and distensibility with traditional cardiovascular risk factors in the Multi-Ethnic Study of Atherosclerosis (MESA) cohort; 1053 participants of the MESA study with cardiac MRI were consecutively selected for measurement of aortic wall thickness and distensibility. Double inversion recovery fast spin echo images of the thoracic aorta were obtained to measure average and maximum WT. Aortic distensibility (AD) was measured at the same level using a gradient echo cine sequence. Both average and maximum WT were positively correlated with increasing age, and AD was inversely related to age (p<0.01). Compared to normotensive participants, those with hypertension had significantly greater mean average WT (2.45 mm vs. 2.23 mm, p<0.01), maximum WT (3.61 mm vs. 3.41 mm, p<0.01) and lower AD (0.15 vs. 0.2 mm Hg−1, p<0.01), respectively. In multiple regression analysis, older age and hypertension were significantly associated with higher mean average WT, while older age, male gender, and higher blood pressure were associated with higher mean maximum WT. AD was inversely related to older age, hypertension, current smoker status, African-American ethnicity and lower HDL-cholesterol (HDL-c) levels. In conclusion, in the MESA cohort, older age and higher blood pressure were associated with higher aortic wall thickness and lower aortic distensibilility. Decreased aortic distensibility was further associated with current smoking, African American ethnicity and higher HDL-c levels.
PMCID: PMC2586608  PMID: 18678312
9.  Obesity and hypertension in an Iranian cohort study; Iranian women experience higher rates of obesity and hypertension than American women 
BMC Public Health  2006;6:158.
Once considered as the main public health problem in developed countries, obesity has become a major problem throughout the world and developing countries, like Iran, are joining the global obesity pandemic. We determined the prevalence of overweight, obesity, and hypertension in a large cohort of Iranians and compared age-adjusted rates with the rates in the US.
Golestan Cohort Study is a population-based study of 8,998 men and women, aged 35-81 years, from urban and rural areas. Anthropometric parameters were measured by interviewers. Prevalence rates were directly adjusted to the 2000 United States standard population.
The age-adjusted prevalence rates of overweight (BMI ≥ 25 kg/m2) and obesity (BMI ≥ 30 kg/m2) in this Iranian population were 62.2% and 28.0%, respectively. Both overweight and obesity were more common in women than men. Age-adjusted prevalence of overweight was significantly higher in Iranian women compared to the American women (68.6% vs. 61.6%), while the age-adjusted prevalence of obesity is closer in these two populations (34.9% vs. 33.2%). Iranian men—compared to American men—had significantly lower age-adjusted prevalence of overweight (53.7% vs. 68.8%) and obesity (16.2% vs. 27.5%). Age-adjusted prevalence of hypertension was higher in Iranian women than American women (35.7% vs. 30.5%). Diabetes mellitus was reported in 6.2% of participants. Mean waist-to-hip ratio (WHR) among women was 0.96. Smoking rates in men and women were 33.2% and 2.2%, respectively.
The prevalence of obesity, overweight, and hypertension in Iran is as high as the US. However, Iranian women are more obese than American women and Iranian men are less obese than their American counterparts. This discrepancy might be due to the low rate of smoking among Iranian women. Iranian women have higher mean WHR than what WHO has defined in 19 other populations.
PMCID: PMC1533819  PMID: 16784543
10.  Lutein supplementation in retinitis pigmentosa: PC-based vision assessment in a randomized double-masked placebo-controlled clinical trial [NCT00029289] 
BMC Ophthalmology  2006;6:23.
There is no generally accepted medical or surgical treatment to stop the progressive course of retinitis pigmentosa. Previous studies have suggested lutein as a potential treatment with positive effects on macular pigment density. The objective of this study was to examine the effect of lutein supplementation on preservation of visual function in patients with retinitis pigmentosa (RP)
In a double-masked randomized placebo-controlled phase I/II clinical trial with a cross-over design, 34 adult patients with RP were randomized to two groups. One group, consisted of 16 participants, received lutein supplementation (10 mg/d for 12 wks followed by 30 mg/d) for the first 24 weeks and then placebo for the following 24 weeks, while the other group included 18 participants for whom placebo (24 weeks) was administered prior to lutein. Visual acuity, contrast sensitivity, and central visual field were measured at different illumination levels at baseline and every week using a PC-based test at home.
For visual acuity (VA) at normal illumination level, treatment with lutein reduced logMAR, i.e. improved VA, but this effect was not statistically significant. The changes in normal (100%), low (4%), and very low (0.1%) illumination log CS were not statistically significant (p-values: 0.34, 0.23, and 0.32, respectively). Lutein had a statistically significant effect on visual field (p-value: 0.038) and this effect increased in the model assuming a 6-week delay in effect of lutein. Comparing the development of vision measures against the natural loss expected to occur over the course of 48 weeks, most measures showed reduced decline, and these reductions were significant for normal illumination VA and CS.
These results suggest that lutein supplementation improves visual field and also might improve visual acuity slightly, although these results should be interpreted cautiously. As a combined phase I and II clinical trial, this study demonstrated the efficacy and safety of lutein supplementation.
PMCID: PMC1522015  PMID: 16759390
11.  Nonalcoholic fatty liver disease in developing countries 
PMCID: PMC4316043  PMID: 15968747
12.  Clinical and histological features of nonalcoholic steatohepatitis in Iranian patients 
BMC Gastroenterology  2003;3:27.
Although several studies have been performed on risk factors and natural course of NASH, it seems that NASH tends to be more than a disease confined to strict boundaries. The objective of this study was to assess the clinical and paraclinical features and risk factors for non-alcoholic steatohepatitis (NASH) patients in an Iranian population
Patients with histologically confirmed NASH who had elevated liver aminotransaminases, negative serologic markers of viral or autoimmune hepatitis and no findings in favor of metabolic liver disease were enrolled. A careful history was taken regarding alcohol intake.
53 patients consisting of 32 male and 21 female entered the study. The mean age was 37.8 ± 11.3 years. Twenty-six patients (55.3%) were overweight, 15 (31.9%) obese, 40 (75.5%) dyslipidemic, and three patients (5.7%) were diabetic. Liver biopsy showed mild steatosis in 35.7%, moderate steatosis in 53.6%, and severe forms in 10.7%. In 80.2% of patients, portal inflammation was present, and 9.4% had cirrhosis. The amount of increase in liver enzymes bore no relationship with fibrosis, portal inflammation, and degree of steatosis.
The patients in our study showed a male predominancy and were somewhat younger than other studies.
PMCID: PMC270051  PMID: 14561231
Nonalcoholic steatohepatitis; liver biopsy; Nonalcoholic Fatty liver disease; steatosis; obesity; Epidemiology

Results 1-12 (12)