Meta-analyses of European populations has successfully identified genetic variants in over 100 loci associated with lipid levels, but our knowledge in other ethnicities remains limited. To address this, we performed dense genotyping of ∼2,000 candidate genes in 7,657 African Americans, 1,315 Hispanics and 841 East Asians, using the IBC array, a custom ∼50,000 SNP genotyping array. Meta-analyses confirmed 16 lipid loci previously established in European populations at genome-wide significance level, and found multiple independent association signals within these lipid loci. Initial discovery and in silico follow-up in 7,000 additional African American samples, confirmed two novel loci: rs5030359 within ICAM1 is associated with total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) (p = 8.8×10−7 and p = 1.5×10−6 respectively) and a nonsense mutation rs3211938 within CD36 is associated with high-density lipoprotein cholesterol (HDL-C) levels (p = 13.5×10−12). The rs3211938-G allele, which is nearly absent in European and Asian populations, has been previously found to be associated with CD36 deficiency and shows a signature of selection in Africans and African Americans. Finally, we have evaluated the effect of SNPs established in European populations on lipid levels in multi-ethnic populations and show that most known lipid association signals span across ethnicities. However, differences between populations, especially differences in allele frequency, can be leveraged to identify novel signals, as shown by the discovery of ICAM1 and CD36 in the current report.

Background

Smoking tobacco reduces lung function. African Americans have both lower lung function and decreased metabolism of tobacco smoke compared to European Americans. African ancestry is also associated with lower pulmonary function in African Americans. We aimed to determine whether African ancestry modifies the association between smoking and lung function and its rate of decline in African Americans.

Methodology/Principal Findings

We evaluated a prospective ongoing cohort of 1,281 African Americans participating in the Health, Aging, and Body Composition (Health ABC) Study initiated in 1997. We also examined an ongoing prospective cohort initiated in 1985 of 1,223 African Americans in the Coronary Artery Disease in Young Adults (CARDIA) Study. Pulmonary function and tobacco smoking exposure were measured at baseline and repeatedly over the follow-up period. Individual genetic ancestry proportions were estimated using ancestry informative markers selected to distinguish European and West African ancestry. African Americans with a high proportion of African ancestry had lower baseline forced expiratory volume in one second (FEV1) per pack-year of smoking (−5.7 ml FEV1/ smoking pack-year) compared with smokers with lower African ancestry (−4.6 ml in FEV1/ smoking pack-year) (interaction P value  = 0.17). Longitudinal analyses revealed a suggestive interaction between smoking, and African ancestry on the rate of FEV1 decline in Health ABC and independently replicated in CARDIA.

Conclusions/Significance

African American individuals with a high proportion of African ancestry are at greater risk for losing lung function while smoking.

The prevalence of hypertension in African Americans (AAs) is higher than in other US groups; yet, few have performed genome-wide association studies (GWASs) in AA. Among people of European descent, GWASs have identified genetic variants at 13 loci that are associated with blood pressure. It is unknown if these variants confer susceptibility in people of African ancestry. Here, we examined genome-wide and candidate gene associations with systolic blood pressure (SBP) and diastolic blood pressure (DBP) using the Candidate Gene Association Resource (CARe) consortium consisting of 8591 AAs. Genotypes included genome-wide single-nucleotide polymorphism (SNP) data utilizing the Affymetrix 6.0 array with imputation to 2.5 million HapMap SNPs and candidate gene SNP data utilizing a 50K cardiovascular gene-centric array (ITMAT-Broad-CARe [IBC] array). For Affymetrix data, the strongest signal for DBP was rs10474346 (P= 3.6 × 10−8) located near GPR98 and ARRDC3. For SBP, the strongest signal was rs2258119 in C21orf91 (P= 4.7 × 10−8). The top IBC association for SBP was rs2012318 (P= 6.4 × 10−6) near SLC25A42 and for DBP was rs2523586 (P= 1.3 × 10−6) near HLA-B. None of the top variants replicated in additional AA (n = 11 882) or European-American (n = 69 899) cohorts. We replicated previously reported European-American blood pressure SNPs in our AA samples (SH2B3, P= 0.009; TBX3-TBX5, P= 0.03; and CSK-ULK3, P= 0.0004). These genetic loci represent the best evidence of genetic influences on SBP and DBP in AAs to date. More broadly, this work supports that notion that blood pressure among AAs is a trait with genetic underpinnings but also with significant complexity.

Background

Data are sparse describing factors associated with development of prolonged QRS duration (QRSd) from young adulthood to middle age.

Methods

We analyzed 12-lead electrocardiograms (ECGs) from the Coronary Artery Risk Development in Young Adults (CARDIA) study over 20 years. We performed logistic regression to examine associations of baseline (Year 0) or average (Year 0 to Year 20) risk factors with incident prolonged QRSd (QRS > 100 msec).

Results

We included 2,537 participants (57.2% women, 44.7% black, mean age 25 years); 292 (11.5%) developed incident QRSd >100 msec by Year 20. In univariate analyses, baseline covariates associated with incident QRSd prolongation included white race, male sex, ECG-LVMI, and baseline QRSd. Similar results were observed after multivariable adjustment.

Conclusion

We found no long-term associations of modifiable risk factors with incident QRSd >100 msec. Men, whites, and those with higher ECG-LVMI and QRSd in young adulthood are at increased risk for incident prolonged QRSd by middle age.

Background

A low cardiovascular disease (CVD) risk profile (untreated cholesterol < 200 mg/dl, untreated blood pressure < 120/<80 mmHg, never smoking, and no history of diabetes and myocardial infarction) in middle age is associated with markedly better health outcomes in older age, but few middle aged adults have this low risk profile. We examined whether adopting a healthy lifestyle throughout young adulthood is associated with presence of the low CVD risk profile in middle age.

Methods and Results

The CARDIA study sample consisted of 3,154 black and white participants aged 18 to 30 years at Year 0 (Y0, 1985-86) who attended the Year 0, 7 and 20 (Y0, Y7 and Y20) examinations. Healthy lifestyle factors (HLFs) defined at Y0, Y7 and Y20 included: 1) Average BMI < 25 kg/m2; 2) No or moderate alcohol intake; 3) higher healthy diet score; 4) higher physical activity score; and 5) Never smoking. Mean age (25 years) and percentage of women (56%) were comparable across groups defined by number of HLFs. The age-, sex- and race-adjusted prevalences of low CVD risk profile at Y20 were 3.0%, 14.6%, 29.5%, 39.2% and 60.7% for people with 0 or 1, 2, 3, 4, and 5 HLFs, respectively (p-trend <0.0001). Similar graded relationships were observed for each sex-race group (all p-trend<0.0001).

Conclusions

Maintaining a healthy lifestyle throughout young adulthood is strongly associated with low CVD risk profile in middle age. Public health and individual efforts are needed to improve adoption and maintenance of healthy lifestyles in young adults.

Background

Few studies to date have described the prevalence of electrocardiographic (ECG) abnormalities in a biracial middle-aged cohort.

Methods and Results

Participants underwent measurement of traditional risk factors and 12-lead ECGs coded using both Minnesota Code (MC) and Novacode (NC) criteria. Among 2585 participants, of whom 57% were women and 44% were black (mean age 45 years), the prevalence of major and minor abnormalities were significantly higher (all P<0.001) among black men and women compared to whites. These differences were primarily due to higher QRS voltage and ST/T wave abnormalities among blacks. There was also a higher prevalence of Q waves (MC 1-1, 1-2, 1-3) than described by previous studies. These racial differences remained after multivariate adjustment for traditional cardiovascular (CV) risk factors.

Conclusions

Black men and women have a significantly higher prevalence of ECG abnormalities, independent of traditional CV risk factors, than whites in a contemporary cohort middle-aged participants.

Background

Religious involvement has been associated with improved health outcomes but greater obesity in older adults. No longitudinal study of young adults has examined the prospective association of religious involvement with incident cardiovascular risk factors (RFs) and subclinical disease (subCVD).

Methods

We included 2433 participants of the CARDIA study, aged 20 to 32 in 1987 when religiosity was assessed, who were followed for 18 years. Multivariable-adjusted regression models were fitted to assess prospective associations of frequency of religious participation at baseline with incidence of RFs and prevalence of subCVD after 18 years’ follow up.

Results

High frequency of religious participation was associated with a significantly greater incidence of obesity in unadjusted models (RR 1.57, 95% CI 1.14 – 1.73) and demographic-adjusted models (RR 1.34, 95% CI 1.09 – 1.65) but not after additional adjustment for baseline RFs (RR 1.17, 95% CI 0.97 – 1.41). When religious participation was treated dichotomously, any religious participation, compared with none, was associated with significantly lower subCVD.

Conclusions

Frequent religious participants are more likely to become obese between young adulthood and middle age; this association is confounded by demographic and other factors. Nonetheless, young adults with frequent participation may represent an opportunity for obesity prevention.

Background

Data are sparse regarding the long-term association of favorable levels of all major cardiovascular disease risk factors (RFs) (ie, low risk [LR]) with ankle-brachial index (ABI).

Methods and Results

In 2007–2010, the Chicago Healthy Aging Study reexamined a subset of participants aged 65 to 84 years from the Chicago Heart Association Detection Project in Industry cohort (baseline examination, 1967–1973). RF groups were defined as LR (untreated blood pressure ≤120/≤80 mm Hg, untreated serum cholesterol <200 mg/dL, body mass index <25 kg/m2, not smoking, no diabetes) or as 0 RFs, 1 RF, or 2+ RFs based on the presence of blood pressure ≥140/≥90 mm Hg or receiving treatment, serum cholesterol ≥240 mg/dL or receiving treatment, body mass index ≥30 kg/m2, smoking, or diabetes. ABI at follow-up was categorized as indicating PAD present (≤0.90), as borderline PAD (0.91 to 0.99), or as normal (1.00 to 1.40). We included 1346 participants with ABI ≤1.40. After multivariable adjustment, the presence of fewer baseline RFs was associated with a lower likelihood of PAD at 39-year follow-up (P for trend is <0.001). Odds ratios (95% CIs) for PAD in persons with LR, 0 RFs, or 1 RF compared with those with 2+ RFs were 0.14 (0.05 to 0.44), 0.28 (0.13 to 0.59), and 0.33 (0.16 to 0.65), respectively; findings were similar for borderline PAD (P for trend is 0.005). The association was mainly due to baseline smoking status, cholesterol, and diabetes. Remaining free of adverse RFs or improving RF status over time was also associated with PAD.

Conclusions

LR profile in younger adulthood (ages 25 to 45) is associated with the lowest prevalence of PAD and borderline PAD 39 years later.

Context

Type 2 diabetes in normal weight (body mass index [BMI] <25kg/m2) adults is an intriguing representation of the metabolically obese normal weight phenotype with unknown mortality consequences.

Objective

To minimize the influence of diabetes duration and voluntary weight loss on mortality, we tested the association of weight status with mortality in adults with new onset diabetes.

Design

Pooled analysis of five longitudinal cohort studies: Atherosclerosis Risk in Communities Study, 1990–2006; Cardiovascular Health Study, 1992–2008; Coronary Artery Risk Development in Young Adults, 1987–2011; Framingham Offspring Study, 1979–2007; Multi-Ethnic Study of Atherosclerosis, 2002–2011. Participants contributed 27,125 person-years of follow-up.

Setting

2,625 participants with incident diabetes

Participants

Men and women (age>40 years) who developed incident diabetes based on fasting glucose ≥ 126 mg/dL or newly-initiated diabetes medication and who had concurrent measurements of body mass index (BMI). Participants were classified as normal weight if their BMI was 18.5 to 24.99kg/m2 or overweight/obese if BMI≥25 kg/m2.

Main Outcome Measures

Total, cardiovascular, and non-cardiovascular mortality

Results

The proportion of adults who were normal weight at the time of incident diabetes ranged from 9–21% (overall=12%). Over follow-up, 449 participants died, 178 from cardiovascular causes and 253 from non-cardiovascular causes (18 were not classified). The rate of total, cardiovascular and non-cardiovascular mortality was higher in normal weight participants (248.8, 99.8, and 198.1 per 10,000 person-years, respectively) than overweight/obese participants (152.1, 67.8, and 87.9 per 10,000 person-years, respectively). Following adjustment for demographic characteristics and blood pressure, lipids, waist circumference and smoking status, hazard ratios comparing normal weight participants to overweight/obese participants for total, cardiovascular, and non-cardiovascular mortality were 2.08 (95% confidence interval [CI]: 1.52, 2.85), 1.52 (95% CI: 0.89, 2.58) and 2.32 (95% CI: 1.55, 3.48), respectively.

Conclusions

Adults who are normal weight at the time of incident diabetes have higher mortality than adults who are overweight or obese.

Background. Changes in retinal microvascular caliber, which occur prior to onset of retinopathy, may indicate presence of kidney damage.

Methods. This study examined the association between retinal arteriolar [central retinal artery equivalent (CRAE)] and venular caliber [central retinal venule equivalent (CRVE)] and presence of albuminuria (micro- or macroalbuminuria) among participants of the Multi-Ethnic Study of Atherosclerosis (MESA), a cohort of adults aged 45–84 years without baseline clinical cardiovascular disease. During the second MESA exam, digital fundus photography was completed in 5897 participants who provided spot urine specimens. Albuminuria was defined by spot urine albumin/creatinine ratios ≥30 mg/g. Multivariable adjusted odds of albuminuria by quintiles of CRAE and CRVE were determined using logistic regression. Analyses were repeated after stratifying by presence of type 2 diabetes.

Results. Albuminuria was noted in 11.5% (n = 675) and included 584 subjects with microalbuminuria and 91 with macroalbuminuria. A significant U-shaped pattern was seen with higher prevalence of albuminuria across quintile extremes in CRAE (15.7, 8.8 and 10.6% in CRAE Quintiles 1, 3 and 5, respectively; P <0.0001). After adjustment for covariates, both narrower CRAE [odds ratios (OR) 1.55; 95% confidence interval (CI) 1.17–2.04, Quintile 1 versus 3) and wider CRAE (OR 1.44; 95% CI 1.07–1.93, Quintile 5 versus 3) were significantly associated with albuminuria. Associations appeared substantially stronger in adults with than without type 2 diabetes but the interaction term for diabetes and CRAE on presence of albuminuria did not meet statistical significance (P = 0.3). No association was noted between CRVE quintiles and albuminuria.

Conclusions. Albuminuria is associated with narrower and wider arteriolar caliber. Future studies should determine whether variation in arteriolar caliber predicts incident albuminuria and whether associations are mediated by hypertension and diabetes. Such information could further clarify early microvascular processes in the pathogenesis of kidney disease.

The authors studied the incremental value of adding serum cystatin C or creatinine to the Framingham risk score variables (FRSVs) for the prediction of incident cardiovascular disease (CVD) among 6,653 adults without clinical CVD utilizing the Multi-Ethnic Study of Atherosclerosis (2000–2008). CVD events included coronary heart disease, heart failure, stroke, and peripheral arterial disease. Variables were transformed to yield optimal prediction of 6-year CVD events in sex-stratified models with FRSVs alone, FRSVs + cystatin C, and FRSVs + creatinine. Risk prediction in the 3 models was assessed by using the C statistic, and net reclassification improvement was calculated. The mean ages were 61.9 and 64.6 years for individuals with and without diabetes, respectively. After 6 years of follow-up, 447 (7.2%) CVD events occurred. In the total cohort, no significant change in the C statistic was noted with FRSVs + cystatin C and FRSVs + creatinine compared with FRSVs alone, and net reclassification improvement for CVD risk was extremely small and not significant with the addition of cystatin C or creatinine to FRSVs. Similar findings were noted after stratifying by baseline presence of diabetes. In conclusion, the addition of cystatin C or serum creatinine to FRSVs does not improve CVD risk prediction among adults without clinical CVD.

Background

Dyslipidemia causes coronary heart disease in middle-aged and elderly adults, but the consequences of lipid exposure during young adulthood are unclear.

Objective

To assess whether exposure to non-optimal lipids during young adulthood causes atherosclerotic changes that persist into middle age

Design

We estimated time-averaged cumulative exposure to lipids between ages 20-35 years using repeated serum lipid measures collected over 20 years by the Coronary Artery Risk Development in Young Adults (CARDIA) Study, and related this to coronary calcium measured later in life (45±4 years).

Setting

Four US cities

Participants

Black and white men and women recruited at age 18-30 in 1985-6

Measurements

Low- and high-density lipoprotein cholesterol (LDL and HDL) and triglycerides; coronary calcium

Results

Of 3258 participants, 2824 (87%) were exposed to non-optimal levels of LDL (≥100 mg/dl), HDL (<60 mg/dl) or triglyceride (≥150 mg/dl) during young adulthood. Coronary calcium prevalence two decades later was 8% in participants who maintained optimal LDL levels <70 mg/dl, and 44% in participants with LDL >160 mg/dl (p<.001). The association was similar across race and gender, and strongly graded, with odds ratios for coronary calcium of 1.5 (95% confidence interval 0.7-3.3) for LDL 70-99 mg/dl, 2.4 (1.1-5.3) for 100-129, 3.3 (1.3-7.8) for 130-159 and 5.6 (2.0-16) for ≥160 compared with LDL <70 mg/dl after adjustment for lipid exposure after age 35 and other coronary risk factors. After excluding lipid-lowering medication users and participants with clinically abnormal lipids, both LDL and HDL were independently associated with coronary calcium.

Limitations

Coronary calcium, although a strong predictor of future coronary heart disease, is not a clinical outcome.

Conclusions

Non-optimal LDL and HDL cholesterol at commonly observed levels during young adulthood are independently associated with coronary atherosclerosis two decades later.

Objectives

To determine whether poor lower extremity nerve function is associated with more adverse calf muscle characteristics and greater functional impairment in people with and without peripheral arterial disease (PAD).

Design

Cross-sectional

Setting

Three Chicago-area medical centers

Participants

413 participants with PAD (ankle-brachial index (ABI) <0.90) and 271 participants without PAD.

Measurements

Electrodiagnostic testing of the peroneal nerve was performed. Calf muscle cross-sectional area and percent fat were measured using computed tomography at 66.7% of the distance between the distal and proximal tibia. 6-minute walk performance was measured.

Results

Adjusting for age, sex, race, ABI, leg symptoms, smoking, physical activity, comorbidities, and other covariates, lower peroneal nerve conduction velocity (NCV) was associated with lower calf muscle area (1st quartile: 5571.1 mm2, 4th quartile: 4770.3 mm2, p-value<0.001) and poorer 6-minute walk distance (1st quartile: 989.2 ft, 4th quartile: 1210.8 ft, p-value<0.001) in non-diabetic PAD participants. Lower peroneal NCV was associated with lower calf muscle area (1st quartile: 5166.0 mm2, 4th quartile: 6003.8 mm2, p-value=0.014) and poorer 6-minute walk distance (1st quartile: 866.4 ft, 4th quartile: 1082.5 ft, p-value=0.012) in diabetic PAD participants as well. Among non-PAD participants, lower peroneal NCV was not associated with lower calf muscle area but was associated with poorer 6-minute walk distance in non-diabetic participants only (1st quartile 1317.0 ft, 4th quartile 1570.4 ft; p-trend<0.001).

Conclusion

Lower peroneal nerve function is associated with smaller calf muscle area in individuals with PAD and greater functional impairment in individuals with PAD. Future study is needed to determine whether improving peroneal NCV prevents loss of calf muscle and functional decline in PAD.

Objectives

Long-chain omega-3 polyunsaturated fatty acids (LCω3PUFAs), selenium (Se) and mercury (Hg) are three important components in fish. The cardioprotective effect of LCω3PUFA intake has been recognized; however, the hypothesis that this benefit may be greatest with high Se and low Hg levels has not been investigated.

Design

A cohort of 4,508 American adults aged 18–30, without hypertension at baseline in 1985, were enrolled. Six follow-ups were conducted at exams in 1987, 1990, 1992, 1995, 2000 and 2005. Diet was assessed by a validated interviewer-administered quantitative food frequency questionnaire at exams in 1985, 1992 and 2005. Incident hypertension was defined as first occurrence at any follow-up examination of systolic blood pressure ≥ 140 mmHg, diastolic blood pressure ≥ 90 mmHg, or taking anti-hypertensive medication. Toenail clippings were collected in 1987, and Se and Hg levels were quantified by instrumental neutron-activation analysis.

Result

Participants in the highest LCω3PUFAintake quartile had a significantly lower incidence of hypertension (Hazard Ratio: 0.65; 95% CI: 0.53–0.79; Ptrend<0.01) compared to those in the lowest quartile after adjustment for potential confounders. Docosahexaenoic acid showed a greater inverse association than eicosapentaenoic acid. The inverse association of LCω3PUFA intake with hypertension appeared more pronounced at higher Se and lower Hg levels, although interaction tests were statistically non-significant.

Conclusions

Out findings indicated that LCω3PUFA intake was inversely associated with incidence of hypertension. The prior hypothesis that the potential anti-hypertensive effect of LCω3PUFA intake varies depending on joint levels of Se and Hg received modest support, and cannot be ruled out.

Higher levels of inflammation are associated with adverse outcomes in persons with lower extremity peripheral arterial disease (PAD). This study evaluated associations of physical activity during daily life with levels of inflammatory biomarkers, D-dimer, and homocysteine in persons with PAD. Participants were 244 men and women (mean age 74.4 years ± 8.2) with PAD (ankle brachial index (ABI) < .90). C reactive protein (CRP), Interleukin-6 (IL-6), soluble Intracellular Adhesion Molecule-1 (sICAM-1), soluble Vascular Cellular Adhesion Molecule-1 (sVCAM-1), D-dimer, and homocysteine were assessed at study entry. Physical activity was objectively assessed via a vertical accelerometer, which participants wore continuously for 7 days. After adjusting for age, sex, race, body mass index, smoking, comorbidities, ABI, and other potential confounders, higher physical activity levels were associated linearly and significantly with lower levels of all measured circulating biomarkers: sVCAM-1 (p trend = 0.001); D-Dimer (p trend = 0.005); homocysteine (p trend = 0.006); IL-6 (p trend = 0.010); CRP, (p trend = 0.028); sICAM-1 (p trend = 0.033). In conclusion, higher levels of physical activity were associated independently with lower levels of inflammatory markers, homocysteine, and D-dimer in PAD patients.

Admixture mapping based on recently admixed populations is a powerful method to detect disease variants with substantial allele frequency differences in ancestral populations. We performed admixture mapping analysis for systolic blood pressure (SBP) and diastolic blood pressure (DBP), followed by trait-marker association analysis, in 6303 unrelated African-American participants of the Candidate Gene Association Resource (CARe) consortium. We identified five genomic regions (P< 0.001) harboring genetic variants contributing to inter-individual BP variation. In follow-up association analyses, correcting for all tests performed in this study, three loci were significantly associated with SBP and one significantly associated with DBP (P< 10−5). Further analyses suggested that six independent single-nucleotide polymorphisms (SNPs) contributed to the phenotypic variation observed in the admixture mapping analysis. These six SNPs were examined for replication in multiple, large, independent studies of African-Americans [Women's Health Initiative (WHI), Maywood, Genetic Epidemiology Network of Arteriopathy (GENOA) and Howard University Family Study (HUFS)] as well as one native African sample (Nigerian study), with a total replication sample size of 11 882. Meta-analysis of the replication set identified a novel variant (rs7726475) on chromosome 5 between the SUB1 and NPR3 genes, as being associated with SBP and DBP (P< 0.0015 for both); in meta-analyses combining the CARe samples with the replication data, we observed P-values of 4.45 × 10−7 for SBP and 7.52 × 10−7 for DBP for rs7726475 that were significant after accounting for all the tests performed. Our study highlights that admixture mapping analysis can help identify genetic variants missed by genome-wide association studies because of drastically reduced number of tests in the whole genome.

Background

Whereas it is well established that plasma lipid levels have substantial heritability within populations, it remains unclear how many of the genetic determinants reported in previous studies (largely performed in European American cohorts) are relevant in different ethnicities.

Methodology/Principal Findings

We tested a set of ∼50,000 polymorphisms from ∼2,000 candidate genes and genetic loci from genome-wide association studies (GWAS) for association with low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) in 25,000 European Americans and 9,000 African Americans in the National Heart, Lung, and Blood Institute (NHLBI) Candidate Gene Association Resource (CARe). We replicated associations for a number of genes in one or both ethnicities and identified a novel lipid-associated variant in a locus harboring ICAM1. We compared the architecture of genetic loci associated with lipids in both African Americans and European Americans and found that the same genes were relevant across ethnic groups but the specific associated variants at each gene often differed.

Conclusions/Significance

We identify or provide further evidence for a number of genetic determinants of plasma lipid levels through population association studies. In many loci the determinants appear to differ substantially between African Americans and European Americans.

Objectives

By examining the distribution of CAC across FRS strata in a large, multi-ethnic, community-based sample of men and women, we sought to determine if lower risk persons could potentially benefit from CAC screening.

Background

The 10-year Framingham risk scores (FRS) and coronary artery calcium (CAC) are predictors of coronary heart disease (CHD). CAC ≥300 is associated with the highest risk for CHD even in low risk (FRS <10%) persons; however expert groups have suggested CAC screening only in intermediate risk (FRS 10–20%) groups.

Methods

We included 5660 MESA participants. The number needed to screen [number of people that need to be screened to detect one person with CAC above the specified cut-point (NNS)] was used to assess the yield of screening for CAC. CAC prevalence was compared across FRS strata using chi-square tests.

Results

CAC >0, ≥100 and ≥300 were present in 46.4%, 20.6% and 10.1% of participants, respectively. Prevalence and amount of CAC increased with higher FRS. CAC ≥300 was observed in 1.7% and 4.4% of those with FRS 0–2.5% and 2.6–5%, respectively (NNS =59.7 and 22.7). Likewise, CAC ≥300 was observed in 24% and 30% of those with FRS 15.1–20% and >20%, respectively (NNS =4.2 and 3.3). Trends were similar when stratified by age, gender and race/ethnicity.

Conclusions

Our study suggests that in very low risk individuals (FRS ≤5%), the yield of screening and probability of identifying persons with clinically significant levels of CAC is low, but becomes greater in low and intermediate risk persons (FRS 5.1–20%).

Background

Data on selenium (Se) levels in American young adults, especially in African Americans, are lacking.

Objective

This study presented toenail Se distributions in American young adults of both genders, including both Caucasians and African Americans; and explored potential predictors of toenail Se levels.

Data and Methods

Data from the Coronary Artery Risk Development in Young Adults study among 4252 American young adults, aged 20-32 in 1987 was used to examine toenail Se levels by instrumental neutron-activation analysis. The distribution of Se levels was described and multivariable linear regression was used to examine potential modifiers of toenail Se concentration within ethnicity-gender subgroups.

Results

The geometric mean of toenail Se in this cohort was 0.844 μg/g (95% CI, 0.840-0.849 μg/g) and the median was 0.837 μg/g (95% CI, 0.833-0.844 μg/g). Median levels from lowest to highest quintile were 0.691, 0.774, 0.838, 0.913 and 1.037 μg/g, respectively. Se levels varied geographically, and were generally in accordance with its concentrations in local soil. Males, African Americans, current smokers, heavy drinkers and less educated participants were more likely to have low Se levels.

Conclusion

This study suggests that toenail Se levels vary geographically depending on soil Se concentrations. In addition to gender, ethnicity and education level, smoking status and alcohol consumption are two important indicators of Se status since they are modifiable lifestyle factors. Findings from this study might aid public health professionals in identifying people at relatively high or low Se levels, so that chronic disease prevention efforts can be directed toward these subgroups.

OBJECTIVE

To examine whether sleep duration and quality are associated with fasting glucose, fasting insulin, or estimated insulin resistance in a community-based sample of early middle-aged adults.

RESEARCH DESIGN AND METHODS

This was an ancillary study to the Coronary Artery Risk Development in Young Adults (CARDIA) Study. Habitual sleep duration and fragmentation were estimated from 6 days of wrist actigraphy collected in 2003–2005. Insomnia was defined as self-reported difficulty falling asleep or waking up in the night three or more times per week plus average sleep efficiency of <80% based on actigraphy. Fasting blood samples to measure glucose and insulin were collected after the sleep measures during the CARDIA clinical examination in 2005–2006. Insulin resistance was estimated using the homeostatic model assessment (HOMA) method. Analyses were cross-sectional and stratified by the presence of diabetes.

RESULTS

There was no association between sleep measures and fasting glucose, insulin, or HOMA in the 115 subjects without diabetes. Among the 40 subjects with diabetes, after adjustment for covariates, 10% higher sleep fragmentation was associated with a 9% higher fasting glucose level, a 30% higher fasting insulin level, and a 43% higher HOMA level. Insomnia was associated with a 23% higher fasting glucose level, a 48% higher fasting insulin level, and an 82% higher HOMA level.

CONCLUSIONS

The observed association between poor sleep quality and higher glucose, insulin, and estimated insulin resistance among subjects with diabetes warrants further examination of the effect of sleep disturbances on glucose control in type 2 diabetes.

We determined whether persistently high levels of interleukin-6 (IL-6) or soluble vascular adhesion molecule (sVCAM-1) are associated with faster functional decline, compared to fluctuating or persistently low biomarker levels, among 255 participants with peripheral arterial disease (PAD). Participants underwent baseline and at least two annual follow-up measures of IL-6 and sVCAM-1. Participants were categorized as follows: Category 1- annual levels of IL-6 (or sVCAM-1) were in the lowest tertile for at least three study visits. Category 3- annual levels of IL-6 (or sVCAM-1) were in the highest tertile for at least three visits. Category 2- levels of IL-6 (or sVCAM-1) did not meet criteria for Groups 1 or 3. Six-minute walk, fastest paced four meter walking velocity, and the short physical performance battery (SPPB) were measured annually. Results were adjusted for age, sex, race, comorbidities, statins, physical activity, the ankle brachial index, and other confounders. Across IL-6 categories, average annual declines in six minute walk performance were Category 1: -21.4 feet, Category 2:-49.2 feet, and Category 3:-76.8 feet (p trend = 0.013) and average annual declines in the SPPB score were -0.18, -0.45, and -0.62, respectively (p trend = 0.022). Similar associations of IL-6 categories with decline in fastest paced walking velocity were observed (p trend = 0.034). There were no significant associations of sVCAM-1 categories with functional decline. In conclusion, among PAD participants, persistently high IL-6 levels are associated with faster functional decline compared to those with fluctuating or persistently low IL-6 levels.

Background

The clinical significance of magnetic resonance imaged (MRI) plaque characteristics in the superficial femoral artery (SFA) is not well established. We studied associations of the ankle brachial index (ABI) and leg symptoms with MRI-measured plaque area and percent lumen area in the SFA in participants with and without lower extremity peripheral arterial disease (PAD).

Methods and Results

Four hundred twenty-seven participants (393 with PAD) underwent plaque imaging of the first 30 millimeters of the SFA. Twelve 2.5 millimeter cross-sectional images of the SFA were obtained. Outcomes were normalized plaque area, adjusted for artery size (0–1 scale, 1=greatest plaque), and lumen area, expressed as a percent of the total artery area. Adjusting for age, sex, race, smoking, statins, cholesterol, and other covariates, lower ABI values were associated with higher normalized mean plaque area (ABI < 0.50:0.79; ABI 0.50 to 0.69:0.73; ABI 0.70 to 0.89:0.65; ABI 0.90 to 0.99:0.62; ABI 1.00 to 1.09:0.48; ABI 1.10–1.30:0.47 (P trend <0.001)) and smaller mean percent lumen area (P trend<0.001). Compared to PAD participants with intermittent claudication, asymptomatic PAD participants had lower normalized mean plaque area (0.72 vs. 0.65, p=0.005) and larger mean percent lumen area (0.30 vs. 0.36, p=0.01), adjusting for the ABI and other confounders.

Conclusions

Lower ABI values are associated with greater MRI-measured plaque burden and smaller lumen area in the first 30 millimeters of the SFA. Compared to PAD participants with claudication, asymptomatic PAD participants have smaller plaque area and larger lumen area in the SFA.

Even among asymptomatic people at low risk (<10%) by Framingham Risk Score (FRS), high coronary artery calcium (CAC) scores signify higher predicted risk of coronary heart disease (CHD) events. We sought to determine non-invasive factors (without radiation exposure) significantly associated with CAC in low-risk, asymptomatic persons. In a cross-sectional analysis, we studied 3046 participants from MESA at low 10-year predicted risk (FRS <10%) for CHD events. Multivariable logistic regression was used to assess the association of novel markers with presence of any CAC (CAC >0) and advanced CAC (CAC ≥ 300). CAC >0 and CAC ≥ 300 were present in 30% and 3.5% of participants, respectively. Factor VIIIc, fibrinogen and sICAM were each associated with CAC presence (P ≤ 0.02); and C-reactive protein, D-dimer and carotid intima-media thickness (CIMT) with advanced CAC (P ≤ 0.03). The base model combining traditional risk factors had excellent discrimination for advanced CAC (C-statistic, 0.808). Addition of the 2 best-fit models combining biomarkers plus/minus CIMT improved the c-statistics to 0.822 and 0.820, respectively. All 3 models calibrated well, but were similar in estimating individual risk probabilities for advanced CAC (prevalence = 9.97%, 10.63% and 10.10% in the highest quartiles of predicted probabilities versus 0.26%, 0.26% and 0.26% in the lowest quartiles, respectively). In conclusion, in low risk individuals, traditional risk factors alone predicted advanced CAC with high discrimination and calibration. Biomarker combinations +/− CIMT were also significantly associated with advanced CAC, but improvement in prediction and estimation of clinical risk were modest compared to traditional risk factors alone.

BACKGROUND

Associations of decline in functional performance with clinically-important outcomes in patients with peripheral arterial disease (PAD) are unknown.

OBJECTIVES

We hypothesized that greater two-year decline in office-based functional performance measures would be associated with greater mobility loss and mortality in people with PAD.

METHODS

440 men and women with PAD completed the six-minute walk test and measures of walking velocity at baseline and annually for two years. Participants were categorized into tertiles according to their functional decline between baseline and two-year follow-up and were followed annually after the functional change assessment. Cox proportional hazard models were used to assess relations between the two-year change in functional performance with later mortality and mobility loss, adjusting for age, sex, race, the ankle brachial index, comorbidities, and other confounders.

RESULTS

One hundred two participants (23.2%) died during a median follow-up of 44.5 months after functional change was assessed. Of 319 participants without baseline mobility disability, 60 (18.8%) developed mobility loss after functional change was assessed. Participants in the tertile with greatest six-minute walk decline had the highest subsequent mobility loss (Hazard Ratio (HR)=3.50, 95% Confidence Interval (CI)=1.56–7.85, p=0.002), all-cause mortality (HR=2.16, 95% CI=1.28–3.64, p=0.004), and cardiovascular disease (CVD) mortality (HR=2.45, 95% CI=1.08–5.54, p=0.031), compared to those with the smallest six-minute walk decline. Greater declines in fastest paced four-meter walking velocity were associated with higher mobility loss (P trend=0.018), all-cause mortality (P trend=0.01) and CVD mortality (P trend=0.004).

CONCLUSION

PAD participants with declining functional performance are at increased risk for later mobility loss and mortality.

Background

The role of strength training in peripheral arterial disease (PAD) is unclear. Benefits of supervised treadmill exercise in PAD patients without intermittent claudication (IC) are not established.

Objective

To determine whether supervised treadmill exercise and lower extremity resistance training, respectively, improve functional performance compared to a control group in PAD persons with and without IC.

Design

Randomized controlled clinical trial performed between 4/1/04 and 8/19/08.

Participants

156 people with PAD (ankle brachial index ≤ 0.95), including 81.4% without IC.

Measurements

Primary outcomes were six-minute walk performance and the short physical performance battery (SPPB). Additional outcomes were brachial artery flow-mediated dilation (FMD), treadmill walking performance, the Walking Impairment Questionnaire (WIQ), and the Short-Form 36 Physical Functioning score (SF-36 PF).

Interventions

Three parallel arms: supervised treadmill exercise, supervised lower extremity resistance training, and a control group.

Results

Compared to control, the treadmill exercise group increased six-minute walk distance (+35.9 meters, 95% confidence interval (CI), +15.3 to +56.5; P <0.001), while the resistance trained group did not improve (+12.4 meters, 95% CI, −8.42 to +33.3; P=0.24). Neither exercise group improved the SPPB. Compared to control, treadmill exercise improved brachial artery FMD (+1.53%, 95% CI, +0.35 to +2.70, P=0.018), time on treadmill (+3.44 minutes, 95% CI, +2.05 to +4.84; P<0.001), the WIQ distance score P=0.015), and the SF-36 PF score (P=0.02). Compared to control, resistance training improved time on treadmill (+1.98 minutes, 95% CI, +0.56 to +3.39; P=0.007), the WIQ distance score (P=0.02), the WIQ stair climbing score (P=0.02), and the SF-36 PF score (P=0.04).

Conclusion

Supervised treadmill exercise improved six-minute walk distance, treadmill walking performance, brachial artery FMD, and quality of life, but not the SPPB, in PAD participants with and without classic IC symptoms. Resistance training improved treadmill walking performance, quality of life, and stair climbing ability in patients with PAD.