Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SFMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout.
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.
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.
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.
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.
We studied associations of magnetic resonance imaging measurements of plaque area and relative percent lumen reduction in the proximal superficial femoral artery with functional performance among participants with peripheral arterial disease.
The clinical significance of directly imaged plaque characteristics in lower extremity arteries is not well established.
A total of 454 participants with an ankle brachial index <1.00 underwent magnetic resonance cross-sectional imaging of the proximal superficial femoral artery and completed a 6-min walk test, measurement of 4-m walking velocity at usual and fastest pace, and measurement of physical activity with a vertical accelerometer.
Adjusting for age, sex, race, body mass index, smoking, statin use, comorbidities, and other covariates, higher mean plaque area (1st quintile [least plaque]: 394 m, 2nd quintile: 360 m, 3rd quintile: 359 m, 4th quintile: 329 m, 5th quintile [greatest plaque]: 311 m; p trend <0.001) and smaller mean percent lumen area (1st quintile [greatest plaque]: 319 m, 2nd quintile: 330 m, 3rd quintile: 364 m, 4th quintile: 350 m, 5th quintile: 390 m; p trend <0.001) were associated with shorter distance achieved in the 6-min walk test. Greater mean plaque area was also associated with slower usual-paced walking velocity (p trend = 0.006) and slower fastest-paced 4-m walking velocity (p trend = 0.003). Associations of mean plaque area and mean lumen area with 6-min walk distance remained statistically significant even after additional adjustment for the ankle brachial index and leg symptoms.
Among participants with peripheral arterial disease, greater plaque burden and smaller lumen area in the proximal superficial femoral artery are associated independently with poorer functional performance, even after adjusting for the ankle brachial index and leg symptoms.
atherosclerotic plaque intermittent claudication; peripheral arterial disease; physical functioning
We investigate how early adult and 20-year changes in modifiable cardiovascular risk factors (MRF) predict left atrial dimension (LAD) at age 43–55 years.
The Coronary Artery Risk Development in Young Adults (CARDIA) study enrolled black and white adults (1985–1986). We included 2903 participants with echocardiography and MRF assessment in follow-up years 5 and 25. At years 5 and 25, LAD was assessed by M-mode echocardiography, then indexed to body surface area (BSA) or height. Blood pressure (BP), body mass index (BMI), heart rate (HR), smoking, alcohol use, diabetes and physical activity were defined as MRF. Associations of MRF with LAD were assessed using multivariable regression adjusted for age, ethnicity, gender and year-5 left atrial (LA) size.
The participants were 30±4 years; 55% white; 44% men. LAD and LAD/height were modest but significantly higher over the follow-up period, but LAD/BSA decreased slightly. Increased baseline and 20-year changes in BP were related to enlargement of LAD and indices. Higher baseline and changes in BMI were also related to higher LAD and LAD/height, but the opposite direction was found for LAD/BSA. Increase in baseline HR was related to lower LAD but not LAD indices, when only baseline covariates were included in the model. However, baseline and 20-year changes in HR were significantly associated to LA size.
In a biracial cohort of young adults, the most robust predictors for LA enlargement over a 20-year follow-up period were higher BP and BMI. However, an inverse direction was found for the relationship between BMI and LAD/BSA. HR showed an inverse relation to LA size.
Cross-sectional and prospective studies have linked cardiovascular events and traditional risk factors (TRFs) with higher plasma fibrinogen levels. In a young cohort, we sought to determine longitudinal associations between changes in/development of TRFs and fibrinogen levels over 13 years.
We included 2525 adults from the CARDIA study, aged 25-37 with fibrinogen and TRFs measured at year 7 (study baseline; 1992-1993); and year 20 (follow-up). Multiple linear regressions were used to compare mean changes in fibrinogen to TRFs.
Mean fibrinogen increased by 71mg/dL vs. 70mg/dL (p=NS) in black vs. white men, and 78mg/dL vs. 68mg/dL (p<0.05) in black vs. white women, respectively over 13 years. After multivariable adjustments, fibrinogen generally rose with increasing BMI (p<0.001; all sex/race groups), LDL-cholesterol, log triglycerides and diastolic blood pressure; and fell with increasing HDL-cholesterol and physical activity. 13-year increase in fibrinogen for persons who quit smoking or became non-obese were comparable (p=NS) to that of never-smokers and never-obese persons.
Among young black and white men and women with few baseline cardiovascular risk factors, fibrinogen tracked longitudinally with changes in TRFs over 13 years through middle-age. There was a strong inverse longitudinal relationship between modifiable risk factors (weight loss/smoking cessation) and 13-year change in fibrinogen. Our study helps provide some insight into the role of fibrinogen as a disease marker in the associations between fibrinogen and CVD.
Fibrinogen; risk factors; cardiovascular disease prevention; obesity; smoking; sex; race
The authors sought to determine the prevalence, prospective risk markers, and prognosis associated with diastolic dysfunction in the Coronary Artery Risk Development in Young Adults (CARDIA) Study. The CARDIA Study cohort includes approximately equal proportions of white and black men and women. The authors collected data on risk markers at year 0 (1985–1986), and echocardiography was done at year 5 when the participants were 23–35 years of age. Participants were followed for 20 years (through 2010) for a composite endpoint of all-cause mortality, myocardial infarction, heart failure, and stroke. Diastolic function was defined according to a validated hierarchical classification algorithm. In the 2,952 participants included in the primary analysis, severe diastolic dysfunction was present in 1.1% and abnormal relaxation was present in 9.3%. Systolic blood pressure at year 0 was associated with both severe diastolic dysfunction and abnormal relaxation 5 years later, whereas exercise capacity and pulmonary function abnormalities were associated only with abnormal relaxation 5 years later. After multivariate adjustment, the hazard ratios for the composite endpoint in participants with severe diastolic dysfunction and abnormal relaxation were 4.3 (95% confidence interval: 2.0, 9.3) and 1.6 (95% confidence interval: 1.1, 2.5), respectively. Diastolic dysfunction in young adults is associated with increased morbidity and mortality, and the identification of prospective risk markers associated with diastolic dysfunction could allow for targeted primary prevention efforts.
CARDIA study; clinical outcomes; diastolic dysfunction; left ventricle
The expanding overweight and obesity epidemic notwithstanding, little is known about their long-term effect on health-related quality of life (HRQoL). The main objective of this study was to investigate whether overweight (body mass index [BMI] 25–<30 kg/m2) and obese (BMI ≥ 30 kg/m2) young adults have poorer HRQoL 20 years later.
The authors studied 3014 participants in the Coronary Artery Risk Development in Young Adults (CARDIA) study, a longitudinal, community-dwelling, biracial cohort from four cities. BMI was measured at baseline and 20 years later. HRQoL was assessed via the physical component summary (PCS) and the mental component summary (MCS) scores of the Medical Outcomes Study 12-Item Short Form Health Survey at year 20. Higher PCS or MCS scores indicate better HRQoL.
Mean year 20 PCS score was 52.2 for normal weight participants at baseline, 50.3 for overweight, and 46.4 for obese (P-trend <0.001). This relation persisted after adjustment for baseline demographics, general health, and physical and behavioral risk factors and after further adjustment for 20-year changes in risk factors. No association was observed for MCS scores (P-trend 0.43).
Overweight and obesity in early adulthood are adversely associated with self-reported physical HRQoL, but not mental HRQoL 20 years later.
Data supporting physical activity guidelines to prevent long-term weight gain are sparse, particularly during the period when the highest risk of weight gain occurs.
To evaluate the relationship between habitual activity levels and changes in body mass index (BMI) and waist circumference over 20 years.
Design, Setting, and Participants
The Coronary Artery Risk Development in Young Adults (CARDIA) study is a prospective longitudinal study with 20 years of follow-up, 1985-86 to 2005-06. Habitual activity was defined as maintaining high, moderate, and low activity levels based on sex-specific tertiles of activity scores at baseline. Participants comprised a population-based multi-center cohort (Chicago, Illinois; Birmingham, Alabama; Minneapolis, Minnesota; and Oakland, California) of 3554 men and women aged 18 to 30 years at baseline.
Main Outcome Measures
Average annual changes in BMI and waist circumference
Over 20 years, maintaining high levels of activity was associated with smaller gains in BMI and waist circumference compared with low activity levels after adjustment for race, baseline BMI, age, education, cigarette smoking status, alcohol use, and energy intake. Men maintaining high activity gained 2.6 fewer kilograms (+ 0.15 BMI units per year; 95 % confidence interval [CI] 0.11-0.18 vs +0.20 in the lower activity group; 95% CI, 0.17-0.23) and women maintaining higher activity gained 6.1 fewer kilograms (+0.17 BMI units per year; 95 % CI, 0.12-0.21 vs. +0.30 in the lower activity group; 95 % CI, 0.25-0.34). Men maintaining high activity gained 3.1 fewer centimeters in waist circumference (+0.52 cm per year; 95 % CI, 0.43-0.61 cm vs 0.67 cm in the lower activity group; 95 % CI, 0.60-0.75) and women maintaining higher activity gained 3.8 fewer centimeters (+0.49 cm per year; 95 % CI, 0.39-0.58 vs 0.67 cm in the lower activity group; 95 % CI, 0.60-0.75).
Maintaining high activity levels through young adulthood may lessen weight gain as young adults transition to middle age, particularly in women.
Individuals living in primary care health professional shortage areas (PC-HPSA) often have difficulty obtaining medical care; however, no previous studies have examined association of PC-HPSA residence with prevalence of CVD risk factors.
Methods and Results
To examine this question, the authors used data from the Multi-Ethnic Study of Atherosclerosis baseline exam (2000–2002). Outcomes included the prevalence of diabetes, hypertension, hyperlipidemia, smoking and obesity as well as the awareness and control of diabetes, hypertension, and hyperlipidemia. Multivariable Poisson models were used to examine the independent association of PC-HPSA residence with each outcome. Models were sequentially adjusted for demographics, acculturation, socioeconomic status, access to health care and neighborhood socioeconomic status. Similar to the national average, 16.7% of MESA participants lived in a PC-HPSA. In unadjusted analyses, prevalence rates of diabetes (14.8% vs 11.0%), hypertension (48.2% vs 43.1%), obesity (35.7% vs 31.1%) and smoking (15.5% vs 12.1%) were significantly higher among residents of PC-HPSAs. There were no significant differences in the awareness or control of diabetes, hypertension, or hyperlipidemia. After adjustment, residence in a PC-HPSA was not independently associated with CVD risk factor prevalence, awareness or control.
This study suggests that increased prevalence of CVD risk factors in PC-HPSAs are explained by the demographic and socioeconomic characteristics of their residents. Future interventions aimed at increasing the number of primary care physicians may not improve cardiovascular risk without first addressing other factors underlying healthcare disparities.
epidemiology; prevention; risk factors
Slow heart rate recovery (HRR) from a graded exercise treadmill test (GXT) is a marker of impaired parasympathetic reactivation that is associated with elevated mortality. Our objective was to test whether demographic, behavioral or coronary heart disease (CHD) risk factors during young adulthood were associated with the development of slow HRR.
Participants from the Coronary Artery Risk Development in Young Adults study underwent symptom-limited maximal GXT using a modified Balke protocol at baseline (1985–86) and 20-year follow-up (2005–06) examinations. HRR was calculated as the difference between peak heart rate (HR) and HR two-minutes following cessation of the GXT. Slow HRR was defined as 2-minute HRR < 22 beats·min−1.
In 2,730 participants who did not have slow HRR at baseline, mean HRR was 44 beats*min−1 (SD = 11) at baseline and declined to 40 beats·min−1 (SD=12) in 2005–06; slow HRR developed in 5% (n=135) of the sample by 2005–06. Female sex, black race, fewer years of education, obesity, cigarette smoking, higher depressive symptoms, higher fasting glucose, hypertension, metabolic syndrome and physical inactivity and low fitness were each associated with incident slow HRR. In a multivariable model higher BMI, larger waist, low education, fasting glucose and current smoking remained significantly associated with incident slow HRR. Increasing BMI (per SD higher) over follow-up and incident hypertension, diabetes and metabolic syndrome (in the subsets of participants who were free from those conditions at baseline), were each associated with a significantly elevated odds of incident slow HRR.
On average, HRR declines with aging; however, the odds of having slow HRR in early middle age is significantly associated with traditional CHD risk factors.
Epidemiology; Cardiovascular Disease; Exercise; Autonomic Nervous System
Physical performance is a major determinant of health in older adults, and is related to lifestyle factors. Dietary fiber has multiple health benefits. It remains unclear whether fiber intake is independently linked to superior physical performance. We aimed to assess the association between dietary fiber and physical performance in older adults.
This was a cross-sectional study conducted with community-dwelling adults aged 55 years and older (n=2680) from the ongoing Healthy Aging Longitudinal Study (HALST) in Taiwan 2008-2010. Daily dietary fiber intake was assessed using a validated food frequency questionnaire. Physical performance was determined objectively by measuring gait speed, 6-minute walk distance, timed “up and go” (TUG), summary performance score, hand grip strength.
Adjusting for all potential confounders, participants with higher fiber intake had significantly faster gait speed, longer 6-minute walk distance, faster TUG, higher summary performance score, and higher hand grip strength (all P <.05). Comparing with the highest quartile of fiber intake, the lowest quartile of fiber intake was significantly associated with the lowest sex-specific quartile of gait speed (adjusted OR, 2.18 in men [95% CI, 1.33-3.55] and 3.65 in women [95% CI, 2.20-6.05]), 6-minute walk distance (OR, 2.40 in men [95% CI, 1.38-4.17] and 4.32 in women [95% CI, 2.37-7.89]), TUG (OR, 2.42 in men [95% CI, 1.43-4.12] and 3.27 in women [95% CI, 1.94-5.52]), summary performance score (OR, 2.12 in men [95% CI, 1.19-3.78] and 5.47 in women [95% CI, 3.20-9.35]), and hand grip strength (OR, 2.64 in men [95% CI, 1.61-4.32] and 4.43 in women [95% CI, 2.62-7.50]).
Dietary fiber intake was independently associated with better physical performance.
Background and purpose
Carotid intima-media thickness (CIMT) is a subclinical marker of cardiovascular disease (CVD). Recent studies suggest that shorter sleep duration is a risk factor for CVD, but there is limited evidence regarding this association using high-quality, objective assessments of sleep. The aim of this study is to determine whether sleep duration is associated with CIMT.
The study used an observational cohort consisting of 617 black and white middle-aged healthy participants (37–52 y; 58% female) in the Coronary Artery Risk Development in Young Adults (CARDIA) Study. Multivariable-adjusted linear regression analyses were performed. Sleep duration was measured using wrist actigraphy monitors. CIMT was calculated using the average of 20 measurements of the mean common carotid, bulb and internal CIMT, which was assessed using ultrasound images.
After adjusting for covariates, one hour of longer sleep duration was associated with 0.026 mm less CIMT among men (p=0.02, 95% CI -0.047, -0.005), and 0.001 mm less CIMT among women (p=0.91, 95% CI -0.020, 0.022). Segment-specific analyses indicated that the carotid bulb was a key driver of the observed association.
Shorter objectively assessed sleep duration was associated with greater CIMT among men but not women.
Sleep; carotid intima-media thickness; atherosclerosis; cardiovascular disease
People with lower extremity peripheral artery disease (PAD) have greater functional impairment and faster functional decline than those without PAD. We describe methods for the Group Oriented Arterial Leg Study (GOALS), an ongoing randomized controlled clinical trial designed to determine whether a Group-Mediated Cognitive Behavioral (GMCB) intervention improves functional performance in PAD participants, compared to a health education control condition. In GOALS, PAD participants are randomized to either an intervention or a health education control condition in a parallel design. Both conditions consist of weekly group sessions with other PAD participants. In the intervention, cognitive behavioral techniques are used to assist participants in setting and adhering to home-based walking exercise goals. Participants are encouraged to walk for exercise at home at least five days per week. In the control condition, participants receive lectures on health-related topics. After six months of on-site weekly sessions, participants are transitioned to telephone follow-up for another six months. Participants in the intervention are asked to continue home walking exercise. The primary outcome is change in six-minute walk performance between baseline and six-month follow-up. Secondary outcomes include change in six-minute walk performance at 12-month follow-up, and change in treadmill walking performance, the Walking Impairment Questionnaire, quality of life, and physical activity at six and 12-month follow-up. In conclusion, if our group-mediated cognitive behavioral intervention is associated with improved walking performance in individuals with PAD, results will have major public health implications for the large and growing number of people with PAD.
Peripheral artery disease; intermittent claudication; clinical trial; exercise
Prolonged QRS duration (QRSd) on the electrocardiogram (ECG) has been associated with cardiac structural and functional abnormalities by echocardiography and an increased risk of heart failure (HF). Data are sparse on these relationships in middle-aged and elderly individuals free of baseline cardiovascular disease with respect to cardiac magnetic resonance imaging (MRI). We sought to determine whether QRSd is associated with incident HF and measures of cardiac structure and function by cardiac MRI.
Methods and results
We analysed baseline ECGs in the Multi-Ethnic Study of Atherosclerosis (MESA) to determine whether QRSd >100 ms was associated with incident HF. We adjusted for demographic and clinical risk factors, as well as MRI measures of left ventricular (LV) structure and function. Among 4591 eligible participants (51% women; 39% white; mean age 61 years), 75 developed incident HF over a mean follow-up of 7.1 years. QRSd >100 ms was significantly associated with MRI measures of cardiac structure and function, as well as incident HF, even after adjustment for demographic covariates [hazard ratio (HR) 2.10, 95% confidence interval (CI) 1.29–3.42; P = 0.003] and clinical risk factors (HR 1.86, 95% CI 1.14–3.03; P = 0.01). With further adjustment for individual LV structural measures, findings were attenuated to non-significance. Separate adjustment for LV functional measures yielded only mild attenuation.
In middle-aged and older adults without cardiovascular disease, a QRSd >100 ms was significantly associated with incident HF. After adjustment for LV structural measures, the association was attenuated to non-significance, suggesting that prolonged QRSd is potentially a useful marker of LV structure that may predispose to HF risk.
Electrocardiogram; Heart failure; Magnetic resonance imaging; QRS duration
The purpose of this study was to assess the prevalence and distribution of coronary artery calcium (CAC) across Framingham Risk Score (FRS) strata and therefore determine FRS levels at which asymptomatic, young to early middle-age individuals could potentially benefit from CAC screening.
High CAC burden is associated with increased risk of coronary events beyond the FRS. Expert panel recommendations for CAC screening are based on data obtained in middle-age and older individuals.
We included 2,831 CARDIA (Coronary Artery Risk Development in Young Adults) study participants with an age range of 33 to 45 years. The number needed to screen ([NNS] number of people in each FRS stratum who need to be screened to detect 1 person with a CAC score above the specified cut point) was used to assess the yield of screening for CAC. CAC prevalence was compared across FRS strata using a chi-square test.
CAC scores >0 and ≥100 were present in 9.9% and 1.8% of participants, respectively. CAC prevalence and amount increased across higher FRS strata. A CAC score >0 was observed in 7.3%, 20.2%, 19.1%, and 44.8% of individuals with FRSs of 0 to 2.5%, 2.6% to 5%, 5.1% to 10%, and >10%, respectively (NNS = 14, 5, 5, and 2, respectively). A CAC score of ≥100 was observed in 1.3%, 2.4%, and 3.5% of those with FRSs of 0 to 2.5%, 2.6% to 5%, and 5.1% to 10%, respectively (NNS = 79, 41, and 29, respectively), but in 17.2% of those with an FRS >10% (NNS = 6). Similar trends were observed when findings were stratified by sex and race.
In this young to early middle-age cohort, we observed concordance between CAC prevalence/amount and FRS strata. Within this group, the yield of screening and possibility of identifying those with a high CAC burden (CAC score of ≥100) is low in those with an FRS of ≤10%, but considerable in those with an FRS >10%.
coronary artery calcium; coronary heart disease; Framingham Risk Score; number needed to screen; risk factors
The association between measures of arterial compliance and peripheral arterial disease (PAD) is unclear. Early changes in arterial wall compliance could be a useful marker of patients at high risk for developing lower extremity atherosclerosis.
We used linear and logistic regression models on baseline data from 2803 female and 2558 male participants in the Multi-Ethnic Study of Atherosclerosis (MESA) to study associations between tonometry-derived baseline measures of arterial compliance (large artery compliance [C1] and small artery compliance [C2]) and the baseline ankle-brachial index (ABI), as well as change in the ABI over approximately 3 years of follow up.
In cross-sectional analyses, lower C1 and C2 values, indicating poorer arterial compliance, were associated with lower ABI. There were significant linear trends across strata of ABI, especially in C2 which ranged from 3.7ml/mmHg × 100 (95% confidence interval (CI) 3.3 to 4.2) in women with an ABI < 0.90 to 4.2ml/mmHg × 100 (95% CI 4.1 to 4.3 p<0.001) in women with ABI 1.10 - <1.40. Similar significant trends (p<0.001) were seen in men. In prospective analyses, those with the lowest tertile of C2 values at baseline had a greater multivariable-adjusted odds for decline in ABI of ≥ 0.15 over 3 years compared to those with the highest C2 values at baseline (OR 1.80 95% CI 1.23–2.64).
We observed that less compliant arteries were significantly associated with low ABI in cross-sectional analysis and with greater decline in ABI over time.
Ankle-Brachial Index; Arterial Compliance; Peripheral Arterial Disease
Sex hormones are thought to play an important role in the pathophysiology of depressive disorders in women. This study assessed the associations of total testosterone (T), bioavailable T, estradiol (E2), dehydroepiandrosterone (DHEA) and sex hormone binding globulin (SHBG) with depressive symptoms stratified on postmenopausal stage to determine whether associations were strongest for early postmenopausal women.
Women (N=1824) free of depressive symptoms at baseline (2000–2002) in the Multi-Ethnic Study of Atherosclerosis were categorized into tertiles of years postmenopause: T1, 0–10 years; T2, 11–20 years; and T3, 21–58 years. Multivariable-adjusted relative risks (RR) and 95% confidence intervals were computed for the incidence of depressive symptoms, as defined by a score of 16 or higher on the Center for Epidemiologic Studies Depression scale at examination 3 (2004–2005).
In analysis including all sex hormones, the RRs for incident depressive symptoms associated with 1 unit higher log(total T) was 0.57 (p=0.13), log(E2) was 0.78 (p=0.04), log(SHBG) was 1.84 (p=0.003) and log(DHEA) was 1.45 (p=0.08) in T1. Without adjustment for SHBG, the RR for log(bioavailable T) was 0.16 (p=0.04). However, in T2 and T3, there were no meaningful associations of hormone or SHBG levels with incident depressive symptoms. When stratified by HT use, results were consistent for HT users but attenuated for HT non-users.
In women early postmenopause, sex hormones were associated with incident depressive symptoms.
sex hormones; CES-D; depression; testosterone; estradiol; SHBG
Systemic inflammation has been linked to the development of heart failure in population studies including MESA (Multi-Ethnic Study of Atherosclerosis) but little evidence exists regarding potential mechanism of this relationship. In this study, we used longitudinal MRI follow-up analysis to examine whether C-reactive protein (CRP) levels relate to progressive myocardial functional deterioration as a potential mechanism of incident heart failure.
Regional myocardial functional data from MESA participants who had baseline CRP measurement and also underwent tagged cardiac MRI both at baseline and at five-year follow-up were analyzed. Left ventricular (LV) midwall and mid-slice peak circumferential strain (Ecc), of which a more negative value denotes stronger regional myocardial function, was measured. Ecc change was calculated as the difference between baseline and follow-up Ecc.
During the follow-up period, participants (n=785) with elevated CRP experienced a decrease in strain, independent of age, gender and ethnicity (B=0.081; ΔEcc change per 1mg/L CRP change, 95% CI 0.036–0.126, p<0.001, Model 1), and additionally beyond systolic blood pressure, heart rate, diabetes, smoking status, body mass index, current medication and glomerular filtration rate (B=0.099, 0.052–0.145, p<0.001, Model 2). The relationship remained statistically significant after further adjustment for LV mass, coronary calcium score and interim clinical coronary events (B=0.098, 0.049–0.147, p<0.001, Model 3).
Higher CRP levels are related to progressive myocardial functional deterioration independent of subclinical atherosclerosis and clinical coronary events in asymptomatic individuals without previous history of heart disease.
inflammation; myocardial function; magnetic resonance imaging
While much prior research has focused on identifying the roles of
major regulatory systems in health risks, the concept of allostatic load
(AL) focuses on the importance of a more multi-systems view of health risks.
How best to operationalize allostatic load, however, remains the subject of
To test a hypothesized meta-factor model of allostatic load composed
of a number of biological system factors, and to investigate model
invariance across sex and ethnicity.
Subjects & Methods
Biological data from 782 men and women, aged 32–47, from the
Oakland, CA and Chicago, IL sites of the Coronary Artery Risk Development in
Young Adults Study (CARDIA) were collected as part of the Year 15 exam in
2000. These include measures of blood pressure, metabolic parameters
(glucose, insulin, lipid profiles, and waist circumference), markers of
inflammation (interleukin-6, C-reactive protein, and fibrinogen), heart rate
variability, sympathetic nervous system activity (12 hr urinary
norepinephrine and epinephrine) and hypothalamic-pituitary-adrenal axis
activity (diurnal salivary free cortisol).
A “meta-factor” model of AL as an aggregate measure
of six underlying latent biological subfactors was found to fit the data,
with the meta-factor structure capturing 84% of variance of all
pairwise associations among biological subsystems. There was little evidence
of model variance across sex and/or ethnicity.
These analyses extend work operationalizing AL as a multi-systems
index of biological dysregulation, providing initial support for a model of
AL as a meta-construct of inter-relationships among multiple biological
regulatory systems, that varies little across sex or ethnicity.
biological risk; allostatic load; gender; ethnicity; CARDIA
To examine long-term associations between change in alcohol-consumption status and cessation of alcohol use, and fibrinogen levels in a large, young, biracial cohort.
Analysis of covariance models were used to analyse participants within the Coronary Artery Risk Development in Young Adults Study (CARDIA) cohort who had fibrinogen and alcohol use data at year 7 (1992–1993; ages 25–37) and year 20 examinations.
4 urban US cities.
2520 men and women within the CARDIA cohort.
Main outcome measures
13-year changes in alcohol use related to changes in fibrinogen.
Over 13 years, mean fibrinogen increased by 71 vs 70 mg/dL (p=NS) in black men (BM) versus white men (WM), and 78 vs 68 mg/dL (p<0.05) in black women (BW) versus white women (WW), respectively. Compared with never-drinkers, there were smaller longitudinal increases in fibrinogen for BM, BW and WW (but a larger increase in WM) who became or stayed drinkers, after multivariable adjustment. For BM, WM and WW, fibrinogen increased the most among persons who quit drinking over 13 years (p<0.001 for WM (fibrinogen increase=86.5 (7.1) (mean (SE))), compared with never-drinkers (fibrinogen increase=53.1 (5.4)).
In this young cohort, compared with the participants who never drank, those who became/stayed drinkers had smaller increases, while those who quit drinking had the highest increase in fibrinogen over 13 years of follow-up. The results provide a novel insight into the mechanism for the established protective effect of moderate alcohol intake on cardiovascular disease outcomes.
Epidemiology; Preventive Medicine
Although hyperinsulinemia, a surrogate of insulin resistance, may play a role in the pathogenesis of hypertension (HTN), the longitudinal association between fasting insulin level and HTN development is still controversial. We examined the relation between fasting insulin and incidence of HTN in a large prospective cohort.
RESEARCH DESIGN AND METHODS
A prospective cohort of 3,413 Americans, aged 18–30 years, without HTN in 1985 (baseline) were enrolled. Six follow-ups were conducted in 1987, 1990, 1992, 1995, 2000, and 2005. Fasting insulin and glucose levels were assessed by a radioimmunoassay and hexokinase method, respectively. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% CIs of incident HTN (defined as the initiation of antihypertensive medication, systolic blood pressure ≥140 mmHg, or diastolic blood pressure ≥90 mmHg).
During the 20-year follow-up, 796 incident cases were identified. After adjustment for potential confounders, participants in the highest quartile of insulin levels had a significantly higher incidence of HTN (HR 1.85 [95% CI 1.42–2.40]; Ptrend < 0.001) compared with those in the lowest quartile. The positive association persisted in each sex/ethnicity/weight status subgroup. A similar dose-response relation was observed when insulin-to-glucose ratio or homeostatic model assessment of insulin resistance was used as exposure.
Fasting serum insulin levels or hyperinsulinemia in young adulthood was positively associated with incidence of HTN later in life for both men and women, African Americans and Caucasians, and those with normal weight and overweight. Our findings suggested that fasting insulin ascertainment may help clinicians identify those at high risk of HTN.
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.
Sex Hormones; epidemiology; waist to hip ratio
To determine whether higher body mass index (BMI) is associated with more adverse lower extremity muscle characteristics at baseline and more adverse changes in muscle over time among participants with lower extremity peripheral arterial disease (PAD).
Longitudinal, observational study.
Academic medical center in Chicago.
Participants were 425 men and women with PAD and 261 without PAD.
Computed Tomography was used to measure calf muscle characteristics at baseline and every two years. Knee extension isometric strength, power, and six-minute walk were measured at baseline and annually. Baseline BMI categories were ideal (20-25 kg/m2), overweight (>25-30 kg/m2), and obese (>30 kg/m2). Analyses adjust for age, race, gender, ankle brachial index (ABI), comorbidities, and other covariates.
At baseline, among participants with PAD, higher BMI was associated with greater calf muscle area (ideal BMI: 5181 mm2, overweight: 5513 mm2, obese: 5695 mm2, p trend=0.0009), higher calf muscle percent fat (6.38%, 10.28%, 17.44% respectively, p trend<0.0001), lower calf muscle density (p trend<0.0001), and higher isometric knee extension strength (p trend=0.015). Among participants with PAD, higher BMI was associated with greater declines in calf muscle area p trend=0.030) and greater increases in calf muscle percent fat (p trend=0.023). Among participants without PAD, there were no significant associations of baseline BMI with changes in lower extremity muscle outcomes over time.
Among PAD participants, higher BMI is associated with greater calf muscle area at baseline. However, higher BMI is associated with more adverse calf muscle density and percent fat at baseline and greater declines in calf muscle area over time.