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1.  Erectile Dysfunction in Type 2 Diabetic Men: Relationship to Exercise Fitness and Cardiovascular Risk Factors in the Look AHEAD Trial 
The journal of sexual medicine  2009;6(5):1414-1422.
Introduction
Determinants of erectile dysfunction in diabetic men have not been adequately investigated as potential mediators of change.
Aim
To determine the prevalence and correlates of erectile dysfunction (ED) in overweight men with type 2 diabetes in the multicenter, Look AHEAD trial (Action for Health in Diabetes).
Main Outcome Measures
International Index of Erectile Function (IIEF), self-reported use of phosphodiesterase type 5 inhibitors, laboratory measures of adiposity, cardiometabolic parameters, and exercise fitness.
Methods
Male participants aged 45–75 in the Look AHEAD trial in a committed relationship were recruited for an ongoing study of sexual function and diabetes. Eligible participants completed the IIEF questionnaire and provided updated information on use of medical treatments for sexual dysfunction. Baseline sexual function results for participants in the male ancillary study are reported here; intervention data and results for female participants are presented elsewhere.
Results
A total of 373 eligible male participants completed all sexual function questionnaires, of whom 263 (68.7%) were sexually active at the time of the study. Almost half (49.8%) of the men reported mild or moderate degrees of ED, and 24.8% had complete ED. Among sexually active participants, 42.6% had sought medical help for their problem, and 39.7% reported use of ED medications. ED was significantly associated with age (odds ratio [OR] = 1.05; confidence interval [CI]: 1.01–1.10) baseline HbA1c (OR = 1.31; CI: 1.05–1.63), hypertension history (OR = 2.41; CI: 1.34–4.36), and metabolic syndrome (OR = 3.05, CI: 1.31–7.11). Of note, cardiorespiratory fitness was found to be protective of ED in a multivariable analysis (OR = 0.61; P < 0.001).
Conclusions
ED is prevalent in this sample of obese, type 2 diabetic men in the Look AHEAD study. Cardiovascular risk factors were highly associated with ED in this population, and cardiorespiratory fitness was protective in this analysis.
doi:10.1111/j.1743-6109.2008.01209.x
PMCID: PMC4951185  PMID: 19192106
Type 2 Diabetes; Erectile Dysfunction; Phosphodiesterase Type 5 Inhibitors; Physical Activity
2.  Anti-Mullerian Hormone (AMH) is Associated with Natural Menopause in a Population-Based Sample: The CARDIA Women’s Study 
Maturitas  2015;81(4):493-498.
Objective
AMH is associated with menopausal timing in several studies. In contrast to prior studies that were restricted to women with regular cycles, our objective was to examine this association in women with either regular or irregular menstrual cycles.
Methods
CARDIA is a longitudinal, population-based study that recruited adults ages 18–30 when it began in 1985–86. AMH was measured in serum stored in 2002–03. Natural menopause was assessed by survey in 2005–06 and 2010–11.
Results
Among 716 premenopausal women, median [25th, 75th] AMH was 0.77 [0.22–2.02] ng/dL at a median age of 42 [39–45] years. Twenty-nine percent of the women (n=207) reported natural menopause during 9 years of follow up. In fully adjusted discrete-time hazard models, a 0.5 ng/dL AMH decrement was associated with higher risk of menopause (p<0.001). Hazard ratios varied with time since AMH measurement. The HR (95% CI) for menopause was 8.1 (2.5–26.1) within 0–3 years and 2.3 (1.7–3.3) and 1.6 (1.3–2.1) for 3–6 and 6–9 years, respectively. When restricted to women with regular menses, results were similar (e.g., HR=6.1; 95% CI: 1.9–20.0 for 0–3 years).
Conclusion
AMH is independently associated with natural menopause. AMH appears most useful in identifying women at risk of menopause in the near future (within 3 years of AMH measurement).
doi:10.1016/j.maturitas.2015.06.026
PMCID: PMC4515384  PMID: 26139426
Anti-Mullerian Hormone; Menopause; Ovarian Aging; Ovarian Reserve; FSH; CARDIA
3.  The Look AHEAD Trial: Implications for Lifestyle Intervention in Type 2 Diabetes Mellitus 
Given the array of adverse health consequences of obesity, including increased risk for type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD), the Look AHEAD trial (N=5,145) was conducted to test the hypothesis that an intensive lifestyle intervention (ILI) for weight loss would achieve significantly greater reductions in CVD morbidity and mortality than a control condition of diabetes support and education (DSE) among participants with T2DM. A number of significant and long-term improvements were observed for ILI, including body weight, physical fitness and physical function, glucose control, quality-of-life (QoL), and healthcare costs. However, ILI did not significantly reduce CVD-related morbidity/mortality (i.e., CVD death, non-fatal MI, non-fatal stroke, hospitalized angina) after nearly 10 years of follow-up. There was a suggestion of heterogeneity of response based on the history of prior CVD at baseline (p=0.06). Despite the overall lack of CVD risk reduction, ILI remains important for care of patients with T2DM, particularly when accompanied by medication management. In particular, ILI may be an appealing option for patients wanting to minimize medication intensification. Also, ILI carries with it other potential benefits important to patients (e.g., improvements in physical functioning and QoL). Based on data from other trials, intensive medication management, such as tight glycemic control, is not without potential risks, which should be weighed in making treatment decisions. Future research is needed to determine if results observed in this trial would be replicated among younger patients, those without established T2DM, and/or those with no pre-existing CVD.
doi:10.1016/j.pcad.2015.04.002
PMCID: PMC4501472  PMID: 25936906
cardiovascular disease; type 2 diabetes mellitus; weight loss; lifestyle intervention
4.  Is Surgical Menopause Associated With Future Levels of Cardiovascular Risk Factor Independent of Antecedent Levels? 
American Journal of Epidemiology  2015;182(12):991-999.
In the present study, we compared changes in risk factors for cardiovascular disease (CVD) before and after natural menopause (NM), hysterectomy with at least 1 ovary conserved (HOC), or hysterectomy with bilateral oophorectomy (HBSO). Data were obtained from women 18–30 years of age who were enrolled in the Coronary Artery Risk Development in Young Adults Study (1985–2011). Piecewise linear mixed models were used to examine changes in CVD risk factors from baseline to the index visit (the first visit after the date of NM or hysterectomy) and after index visit until the end of follow-up. During 25 years of follow-up, 1,045 women reached menopause (for NM, n = 588; for HOC, n = 304; and for HBSO, n = 153). At baseline, women with either type of hysterectomy had less favorable values for CVD risk factors. When comparing the annual rates of change of all CVD risk factors from baseline until the index visit to those from the index visit to the end of follow-up, we saw a small increase in rate of change for high-density lipoprotein cholesterol (β = 0.28 mg/dL; P = 0.002) and a decrease for triglycerides (β =−0.006 mg/dL; P = 0.027) for all groups. Hysterectomy was not associated with risk factors for CVD after accounting for baseline values. However, antecedent young-adult levels of CVD risk factors were strong predictors of levels of postmenopausal risk factors.
doi:10.1093/aje/kwv162
PMCID: PMC4751238  PMID: 26628512
cardiovascular disease; hysterectomy; oophorectomy; surgical menopause; women's health
5.  Patterns of Co-existing MRI Lesions and Incident Knee Osteoarthritis: The MOST Study 
Objective
To identify patterns of co-existing lesions on MRI in knees free of radiographic osteoarthritis and to examine their relation to incident disease.
Methods
From a prospective cohort study, the Multicenter Osteoarthritis Study, one knee per subject without radiographic osteoarthritis in both tibiofemoral and patellofemoral joints at baseline was selected and followed up to 84-months. We used a novel approach, latent class analysis, to group the constellation of MRI lesions in each joint, i.e., cartilage damage, bone marrow lesion, meniscal tear, meniscal extrusion, synovitis, and effusion, to a manageable number of subgroups. The association of these subgroups with incident radiographic osteoarthritis in the same joint was assessed using logistic regression.
Results
Among 885 eligible knees (mean age 60.5 years, 203 with incident disease in the tibiofemoral joint, 64 in the patellofemoral joint), four latent subgroups were identified in the tibiofemoral joint described briefly as: minimal lesions, mild lesions, moderate lesions (but limited meniscal lesions), and severe lesions. The odds ratios of incident disease in the tibiofemoral joint were 1.0, 5.6, 1.8, and 5.0, respectively. A similar set of four subgroups was identified in the patellofemoral joint, except that the fourth subgroup had limited meniscal lesions. The odds ratios of incident disease in the patellofemoral joint were 1.0, 3.8, 5.1, and 13.7, respectively.
Conclusion
Different patterns of co-existing MRI lesions were identified that have different implications for risk of knee osteoarthritis. Meniscal damage seemed to play a different role in the development of incident disease in the tibiofemoral versus patellofemoral joints.
doi:10.1002/art.39436
PMCID: PMC4661091  PMID: 26414125
knee osteoarthritis; magnetic resonance imaging; latent class analysis; incidence
6.  The Association of Fruit and Vegetable Consumption During Early Adulthood With the Prevalence of Coronary Artery Calcium After 20 Years of Follow-Up: The CARDIA Study 
Circulation  2015;132(21):1990-1998.
Background
The relationship between intake of fruits and vegetables (F/V) during young adulthood and coronary atherosclerosis later in life is unclear.
Methods and Results
We studied participants of the Coronary Artery Risk Development in Young Adults (CARDIA) study, a cohort of young, healthy black and white individuals at baseline (1985–1986). Intake of F/V at baseline was assessed using a semi-quantitative interview administered diet history and CAC was measured at year 20 (2005–2006) using computed tomography. We used logistic regression to adjust for relevant variables and estimate the adjusted odds ratios (OR) and 95% confidence intervals (CI) across energy-adjusted, sex-specific tertiles of total servings of F/V per day. Among our sample (n=2,506), the mean (SD) age at baseline was 25.3 (3.5) years and 62.7% were female. After adjustment for demographics and lifestyle variables, higher intake of F/V was associated with a lower prevalence of CAC: OR (95% CI) =1.00 (reference), 0.78 (0.59–1.02), and 0.74 (0.56–0.99), from the lowest to the highest tertile of F/V, p-value for trend <0.001. There was attenuation of the association between F/V and CAC after adjustment for other dietary variables but the trend remained significant: OR (95% CI): 1.00 (reference), 0.84 (0.63–1.11), and 0.92 (0.67–1.26), p-value for trend <0.002].
Conclusions
In this longitudinal cohort study, higher intake of F/V during young adulthood was associated with lower odds of prevalent CAC after 20 years of follow-up. Our results reinforce the importance of establishing a high intake of F/V as part of a healthy dietary pattern early in life.
doi:10.1161/CIRCULATIONAHA.114.012562
PMCID: PMC4659718  PMID: 26503880
Epidemiology; Nutrition; Diet; Coronary Disease; Atherosclerosis; Imaging
7.  Do Short Spurts of Physical Activity Benefit Cardiovascular Health? The CARDIA Study 
Background
For optimal health benefits moderate to vigorous intensity physical activity (MVPA) is recommended in sustained bouts lasting ≥ 10 minutes. However, short spurts of MVPA lasting < 10 minutes are more common in everyday life. It is unclear whether short spurts of MVPA further protect against the development of hypertension and obesity in middle-aged adults beyond bouted MVPA.
Methods
Objectively measured physical activity was collected in the Coronary Artery Risk Development in Young Adults (CARDIA) study at the 20-year (2005–2006) examination, and blood pressure and BMI were collected at the 20-year and 25-year (2010–2011) examinations. Time spent in MVPA was classified as either bouted MVPA, i.e., ≥ 10 continuous minutes or short spurts of MVPA, i.e., < 10 continuous minutes. To examine the association of short spurts of MVPA with incident hypertension and obesity over five years, we calculated risk ratios (RR) adjusted for bouted MVPA and potential confounders.
Results
Among 1,531 and 1,251 participants without hypertension and obesity, respectively at Year 20 (Age 45.2 ±3.6, 57.3% Women, BMI 29.0 ± 7.0), 14.8% and 12.1% developed hypertension and obesity by Year 25. Study participants in the highest tertile of short spurts of MVPA were 31% less likely to develop hypertension 5 years later (RR=0.69 [0.49, 0.96]) compared with those in the lowest tertile. There was no statistically significant association of short spurts of MVPA with incident obesity.
Conclusion
These findings support the notion that accumulating short spurts of MVPA protects against the development of hypertension, but not obesity in middle-aged adults.
doi:10.1249/MSS.0000000000000662
PMCID: PMC4573767  PMID: 25785930
Physical activity; cohort study; obesity; hypertension
8.  Association of Fitness With Incident Dyslipidemias Over 25 Years in the Coronary Artery Risk Development in Young Adults Study 
Introduction
Few studies have examined the longitudinal associations of fitness or changes in fitness on the risk of developing dyslipidemias. This study examined the associations of: (1) baseline fitness with 25-year dyslipidemia incidence; and (2) 20-year fitness change on dyslipidemia development in middle age in the Coronary Artery Risk Development in young Adults (CARDIA) study.
Methods
Multivariable Cox proportional hazards regression models were used to test the association of baseline fitness (1985–1986) with dyslipidemia incidence over 25 years (2010–2011) in CARDIA (N=4,898). Modified Poisson regression models were used to examine the association of 20-year change in fitness with dyslipidemia incidence between Years 20 and 25 (n=2,487). Data were analyzed in June 2014 and February 2015.
Results
In adjusted models, the risk of incident low high-density lipoprotein cholesterol (HDL-C), high triglycerides, and high low-density lipoprotein cholesterol (LDL-C) was significantly lower, by 9%, 16%, and 14%, respectively, for each 2.0-minute increase in baseline treadmill endurance. After additional adjustment for baseline trait level, the associations remained significant for incident high triglycerides and high LDL-C in the total population and for incident high triglycerides in both men and women. In race-stratified models, these associations appeared to be limited to whites. In adjusted models, change in fitness did not predict 5-year incidence of dyslipidemias, whereas baseline fitness significantly predicted 5-year incidence of high triglycerides.
Conclusions
Our findings demonstrate the importance of cardiorespiratory fitness in young adulthood as a risk factor for developing dyslipidemias, particularly high triglycerides, during the transition to middle age.
doi:10.1016/j.amepre.2015.04.022
PMCID: PMC4615297  PMID: 26165197
9.  Multiple pathways from the neighborhood food environment to increased body mass index through dietary behaviors: A structural equation-based analysis in the CARDIA study 
Health & place  2015;36:74-87.
Objectives
To examine longitudinal pathways from multiple types of neighborhood restaurants and food stores to BMI, through dietary behaviors.
Methods
We used data from participants (n=5114) in the United States-based Coronary Artery Risk Development in Young Adults study and a structural equation model to estimate longitudinal (1985–86 to 2005–06) pathways simultaneously from neighborhood fast food restaurants, sit-down restaurants, supermarkets, and convenience stores to BMI through dietary behaviors, controlling for socioeconomic status (SES) and physical activity.
Results
Higher numbers of neighborhood fast food restaurants and lower numbers of sit-down restaurants were associated with higher consumption of an obesogenic fast food-type diet. The pathways from food stores to BMI through diet were inconsistent in magnitude and statistical significance.
Conclusions
Efforts to decrease the numbers of neighborhood fast food restaurants and to increase the numbers of sit-down restaurant options could influence diet behaviors. Availability of neighborhood fast food and sit-down restaurants may play comparatively stronger roles than food stores in shaping dietary behaviors and BMI.
doi:10.1016/j.healthplace.2015.09.003
PMCID: PMC4791952  PMID: 26454248
Geographic information systems; Neighborhood food environment; Longitudinal study; Diet; Structural equation model; Body mass index
10.  No association between daily walking and structural changes in people at risk of or with mild knee osteoarthritis. Prospective data from the Multicenter Osteoarthritis Study 
The Journal of rheumatology  2015;42(9):1685-1693.
Objective
We investigated the association between objectively measured daily walking and knee structural change, defined either as radiographic worsening or as cartilage loss, in people at risk of or with knee osteoarthritis (OA).
Methods
Participants from the Multicenter Osteoarthritis (MOST) study with Kellgren and Lawrence (KL) grades 0–2 and daily walking (measured with the StepWatch) at the 60-month visit, were included. Participants had fixed flexion weight bearing radiographs and knee magnetic resonance images (MRIs) at 60 and 84 months. Radiographic worsening was read in both knees using the OARSI grading, and MRIs were read for one knee using WORMS semiquantitative scoring. Odds ratios (OR) and 95% confidence intervals (CI) were calculated comparing those in the middle tertile against the lowest and highest tertiles of daily walking using logistic regression models and generalized estimating equations. Data on walking with moderate to vigorous intensity (minutes with >100 steps/min/day) was associated to structural change using multivariate and logistic regression models.
Results
The 1179 study participants (59% females) were 67.0 (±7.6) years, with a mean (±SD) body mass index of 29.8 (±5.3) kg/m2 who walked 6981 (±2630) steps/day. After adjusting for confounders, we found no significant associations between daily walking and radiographic worsening or cartilage loss. More time spent walking at a moderate to vigorous intensity was not associated with either radiographic worsening or cartilage loss.
Conclusion
Results from the MOST study indicated no association between daily walking and structural changes over two years in people at risk of or with mild knee OA.
doi:10.3899/jrheum.150071
PMCID: PMC4558377  PMID: 26077404
physical activity; osteoarthritis; structural changes; MRI
11.  Associations between Nonalcoholic Fatty Liver Disease and Subclinical Atherosclerosis in Middle-Aged Adults: The Coronary Artery Risk Development in Young Adults Study 
Atherosclerosis  2014;235(2):599-605.
Objective
Non-alcoholic fatty liver disease (NAFLD) is an obesity-related condition associated with cardiovascular mortality. Yet, whether or not NAFLD is independently related to atherosclerosis is unclear. In a population-based cross-sectional sample of middle-aged adults free from liver or heart disease, we tested the hypothesis that NAFLD is associated with subclinical atherosclerosis (coronary artery (CAC) and abdominal aortic calcification (AAC)) independent of obesity.
Methods
Participants from the Coronary Artery Risk Development in Young Adults study with CT quantification of liver fat, CAC and AAC were included (n=2,424). NAFLD was defined as liver attenuation ≤ 40 Hounsfield Units after exclusion of other causes of liver fat. CAC and AAC presence was defined as Agatston score > 0.
Results
Mean participant age was 50.1±3.6 years, (42.7% men, 50.0% black) and BMI was 30.6±7.2 kg/m2. The prevalence of NAFLD, CAC, and AAC was 9.6%, 27.1%, and 51.4%. NAFLD participants had increased prevalence of CAC (37.9% vs. 26.0%, p<0.001) and AAC (65.1% vs. 49.9%, p<0.001). NAFLD remained associated with CAC (OR, 1.33; 95% CI, 1.001–1.82) and AAC (OR, 1.74; 95% CI, 1.29–2.35) after adjustment for demographics and health behaviors. However, these associations were attenuated after additional adjustment for visceral adipose tissue (CAC OR, 1.05; 95% CI, 0.74–1.48, AAC OR=1.20; 95% CI, 0.86–1.67). There was no interaction by race or sex.
Conclusion
In contrast to prior research, these findings suggest that obesity attenuates the relationship between NAFLD and subclinical atherosclerosis. Further studies evaluating the role of NAFLD duration on atherosclerotic progression and cardiovascular events are needed.
doi:10.1016/j.atherosclerosis.2014.05.962
PMCID: PMC4124046  PMID: 24956534
calcium; cardiovascular diseases; epidemiology; imaging; liver; obesity; risk factors
12.  Effect of an Intensive Lifestyle Intervention on Atrial Fibrillation Risk in Individuals with Type 2 Diabetes: the Look AHEAD Randomized Trial 
American heart journal  2015;170(4):770-777.e5.
Background
Obesity is associated with higher risk of atrial fibrillation (AF), but the impact of behavioral weight loss interventions on atrial fibrillation (AF) risk in persons with diabetes is unknown. We addressed this question in the Look AHEAD randomized trial.
Methods and Results
5067 overweight or obese individuals 45-76 years old with type 2 diabetes without prevalent AF were randomized to either an intensive lifestyle intervention (ILI) designed to achieve and maintain weight loss through caloric reduction and increased physical activity or to a diabetes support and education (DSE) usual care group. AF was ascertained from electrocardiograms at study exams and hospitalization discharge summaries. Multivariable Cox models were used to estimate the intention to treat effect of the intervention adjusting for baseline covariates. During a mean follow-up of 9.0 years, 294 incident AF cases were identified. Rates of AF were comparable in the ILI and DSE groups (6.1 and 6.7 cases per 1,000 person-years, respectively, p=0.42). The intervention did not affect AF incidence (multivariable hazard ratio [HR] 0.99, 95% confidence interval [CI] 0.77, 1.28). Similarly, neither weight loss nor improvement in physical fitness during the first year of the intervention were significantly associated with AF incidence: multivariable HR (95%CI) comparing top versus bottom quartile were 0.70 (0.41, 1.18) for weight loss and 0.88 (0.55, 1.43) for physical fitness improvement.
Conclusion
In a large randomized trial of overweight and obese individuals with type 2 diabetes, an ILI that induced modest weight loss did not reduce the risk of developing AF.
doi:10.1016/j.ahj.2015.07.026
PMCID: PMC4576158  PMID: 26386801
atrial fibrillation; prevention; weight loss; type 2 diabetes; randomized trial
13.  Risk of Mortality According to Body Mass Index and Body Composition Among Postmenopausal Women 
American Journal of Epidemiology  2015;182(7):585-596.
Obesity, often defined as a body mass index (BMI; weight (kg)/height (m)2) of 30 or higher, has been associated with mortality, but age-related body composition changes can be masked by stable BMI. A subset of Women's Health Initiative participants (postmenopausal women aged 50–79 years) enrolled between 1993 and 1998 who had received dual-energy x-ray absorptiometry scans for estimation of total body fat (TBF) and lean body mass (LBM) (n = 10,525) were followed for 13.6 (standard deviation, 4.6) years to test associations between BMI, body composition, and incident mortality. Overall, BMI ≥35 was associated with increased mortality (adjusted hazard ratio (HR) = 1.45, 95% confidence interval (CI): 1.16, 1.82), while TBF and LBM were not. However, an interaction between age and body composition (P < 0.001) necessitated age stratification. Among women aged 50–59 years, higher %TBF increased risk of death (HR = 2.44, 95% CI: 1.38, 4.34) and higher %LBM decreased risk of death (HR = 0.41, 95% CI: 0.23, 0.74), despite broad-ranging BMIs (16.4–69.1). However, the relationships were reversed among women aged 70–79 years (P < 0.05). BMI did not adequately capture mortality risk in this sample of postmenopausal women. Our data suggest the clinical utility of evaluating body composition by age group to more robustly assess mortality risk among postmenopausal women.
doi:10.1093/aje/kwv103
PMCID: PMC4715226  PMID: 26350478
body fat; body mass index; death; lean body mass; menopause
14.  Transitions in Metabolic Risk and Long‐Term Cardiovascular Health: Coronary Artery Risk Development in Young Adults (CARDIA) Study 
Background
Despite evidence suggesting that early metabolic dysfunction impacts cardiovascular disease risk, current guidelines focus on risk assessments later in life, missing early transitions in metabolic risk that may represent opportunities for averting the development of cardiovascular disease.
Methods and Results
In 4420 young adults in the Coronary Artery Risk Development in Young Adults (CARDIA) study, we defined a “metabolic” risk score based on components of the Third Report of the Adult Treatment Panel's definition of metabolic syndrome. Using latent class trajectory analysis adjusted for sex, race, and time‐dependent body mass index, we identified 6 distinct metabolic trajectories over time, specified by initial and final risk: low‐stable, low‐worsening, high‐stable, intermediate‐worsening, intermediate‐stable, and high‐worsening. Overall, individuals gained weight over time in CARDIA with statistically but not clinically different body mass index trend over time. Dysglycemia and dyslipidemia over time were highest in initially high or worsening trajectory groups. Divergence in metabolic trajectories occurred in early adulthood (before age 40), with 2 of 3 individuals experiencing an increase in metabolic risk over time. Membership in a higher‐risk trajectory (defined as initially high or worsening over time) was associated with greater prevalence and extent of coronary artery calcification, left ventricular mass, and decreased left ventricular strain at year 25. Importantly, despite similar rise in body mass index across trajectories over 25 years, coronary artery calcification and left ventricular structure and function more closely tracked risk factor trajectories.
Conclusions
Transitions in metabolic risk occur early in life. Obesity‐related metabolic dysfunction is related to subclinical cardiovascular phenotypes independent of evolution in body mass index, including coronary artery calcification and myocardial hypertrophy and dysfunction.
doi:10.1161/JAHA.116.003934
PMCID: PMC5121498  PMID: 27737876
epidemiology; metabolic syndrome; obesity; risk factor; Epidemiology; Risk Factors; Lifestyle
15.  Serum Urate Association with Hypertension in Young Adults: Analysis from the Coronary Artery Risk Development in Young Adults Cohort 
Annals of the rheumatic diseases  2012;72(8):1321-1327.
Objective
To determine if serum urate concentration is associated with development of hypertension in young adults.
Methods
Retrospective cohort analysis from 4752 participants with available serum urate and without hypertension at baseline from the Coronary Artery Risk Development in Young Adults (CARDIA) Study; a mixed race (African-American and White) cohort established in 1985 with 20 years of follow-up data for this analysis. Associations between baseline serum urate concentration and incident hypertension (defined as a blood pressure greater or equal to 140/90 or being on antihypertensive drugs) were investigated in sex-stratified bivariate and multivariable Cox-proportional analyses.
Results
Mean age (standard deviation) at baseline was 24.8 (3.6) years for men and 24.9 (3.7) years for women. Compared with the referent category, we found a greater hazard of developing hypertension starting at 345 μmol/L (5.8 mg/ dL) of serum urate for men and 214 μmol/L (3.6 mg/dL) for women. There was a 25% increase in the hazard of developing hypertension in men (HR1.25 [95% CI 1.15-1.36]) per each mg/dL increase in serum urate but no significant increase in women (HR 1.06 [95%CI 0.97-1.16]).
Conclusions
We found a significant independent association between higher serum urate concentrations and the subsequent hazard of incident hypertension, even at concentrations below the conventional hyperuricemia threshold of 404 μmol/L (6.8 mg/dL).
doi:10.1136/annrheumdis-2012-201916
PMCID: PMC4428756  PMID: 22984170
health services research; hypertension; epidemiology
16.  Body Shape, Adiposity Index, and Mortality in Postmenopausal Women: Findings from the Women’s Health Initiative 
Obesity (Silver Spring, Md.)  2016;24(5):1061-1069.
Objective
Studies evaluating the relationship between body mass index (BMI) and mortality demonstrate a U-shaped association. To expand, this study evaluated the relationship between adiposity indices, a body shape index (ABSI) and body adiposity index (BAI), and mortality in 77,505 postmenopausal women.
Methods
A prospective cohort analysis was conducted in the Women’s Health Initiative to ascertain the independent relationships between adiposity indices and mortality in order to inform on the clinical usefulness of alternate measures of mortality risk. ABSI (waist circumference (cm)/[BMI2/3 × height (cm)1/2]), BAI (hip circumference (cm)/[height (m)1.5] − 18), weight, BMI, and waist circumference (WC) were evaluated in relation to mortality risk using adjusted Cox proportional hazards regression models.
Results
ABSI showed a linear association with mortality (HR, 1.37; 95% CI, 1.28–1.47 for quintile 5 vs. 1) while BMI and BAI had U-shaped relationships with HR of 1.30; 95% CI, 1.20–1.40 for obesity II/III BMI and 1.06, 95% CI, 0.99–1.13 for BAI. Higher WC (HR, 1.21; 95% CI, 1.13–1.29 for quintile 5 vs. 1) showed relationships similar to BMI.
Conclusions
ABSI appears to be a clinically useful measure for estimating mortality risk, perhaps more so than BAI and BMI in postmenopausal women.
doi:10.1002/oby.21461
PMCID: PMC5014350  PMID: 26991923
17.  Recruitment and Screening for the Testosterone Trials 
Background.
We describe the recruitment of men for The Testosterone (T) Trials, which were designed to determine the efficacy of T treatment.
Methods.
Men were eligible if they were ≥65 years, had an average of two morning total T values <275ng/dL with neither value >300ng/mL, and had symptoms and objective evidence of mobility limitation, sexual dysfunction, and/or low vitality. Men had to be eligible for and enroll in at least one of these three main trials (physical function, sexual function, vitality).
Results.
Men were recruited primarily through mass mailings in 12 U.S. communities: 82% of men who contacted the sites did so in response to mailings. Men who responded were screened by telephone to ascertain eligibility. Of 51,085 telephone screens, 53.5% were eligible for further screening. Of 23,889 initial screening visits (SV1), 2,781 (11.6%) men were eligible for the second screening visit (SV2), which 2,261 (81.3%) completed. At SV2, 931 (41.2%) men met the criteria for one or more trials, the T level criterion and had no other exclusions. Of these, 790 (84.6%) were randomized; 99 (12.5%) in all three trials and 348 (44%) in two trials. Their mean age was 72 years and mean body mass index (BMI) was 31.0kg/m2. Mean (standard deviation) total T (ng/dL) was 212.0 (40.0).
Conclusion:
Despite the telephone screening to enrollment ratio of 65 to 1, we met the recruitment goals for each trial. Recruitment of symptomatic older men with low testosterone levels is difficult but feasible.
doi:10.1093/gerona/glv031
PMCID: PMC4861649  PMID: 25878029
Testosterone treatment; Recruitment; Hypogonadal men; Physical function; Vitality; Sexual function; Randomized clinical trials.
18.  Association of nonalcoholic fatty liver disease with subclinical myocardial remodeling and dysfunction: A population-based study 
Hepatology (Baltimore, Md.)  2015;62(3):773-783.
Background
Nonalcoholic fatty liver disease (NAFLD) and heart failure (HF) are obesity-related conditions with high cardiovascular mortality. Whether NAFLD is independently associated with subclinical myocardial remodeling or dysfunction among the general population is unknown.
Methods
We performed a cross-sectional analysis of 2,713 participants from the multicenter, community-based Coronary Artery Risk Development in Young Adults (CARDIA) study who underwent concurrent computed tomography (CT) quantification of liver fat and comprehensive echocardiography with myocardial strain measured by speckle tracking during the Year-25 examination (age 43-55 years, 58.8% women, 48.0% black). NAFLD was defined as liver attenuation ≤ 40 Hounsfield units after excluding other causes of liver fat. Subclinical left ventricular (LV) systolic dysfunction was defined using values of absolute peak global longitudinal strain (GLS). Diastolic dysfunction was defined using Doppler and tissue Doppler imaging markers.
Results
The prevalence of NAFLD was 10.0%. Participants with NAFLD had lower early diastolic relaxation (e’) velocity (10.8±2.6 vs. 11.9±2.8 cm/s), higher LV filling pressure (E/e’ ratio, 7.7±2.6 vs. 7.0±2.3) and worse absolute GLS (14.2±2.4% vs. 15.2±2.4%) than non-NAFLD (p<0.0001 for all). When adjusted for HF risk factors or body mass index, NAFLD remained associated with subclinical myocardial remodeling and dysfunction (p<0.01). The association of NAFLD with e’ velocity (β= -0.36[SE=0.15] cm/s, p=0.02), E/e’ ratio (β= 0.35[0.16], p=0.03) and GLS (β= -0.42[0.18]%, p=0.02) was attenuated after controlling for visceral adipose tissue. Effect modification by race and sex was not observed.
Conclusions
NAFLD is independently associated with subclinical myocardial remodeling and dysfunction, and provides further insight into a possible link between NAFLD and heart failure.
doi:10.1002/hep.27869
PMCID: PMC4549239  PMID: 25914296
heart failure; epidemiology; echocardiography; NAFLD; obesity; CARDIA
19.  Quality Control and Reproducibility in M-mode, Two-dimensional, and Speckle Tracking Echocardiography Acquisition and Analysis: The CARDIA Study, Year-25 Examination Experience 
Echocardiography (Mount Kisco, N.Y.)  2014;32(8):1233-1240.
Introduction
Few large studies describe quality control procedures and reproducibility findings in cardiovascular ultra-sound, particularly in novel techniques such as Speckle Tracking (STE). We evaluate the echocardiography assessment performance in the CARDIA study Y25 examination (2010-2011) and report findings from a quality control and reproducibility program conducted to assess Field Center image acquisition and Reading Center (RC) accuracy.
Methods
The CARDIA Y25 examination had 3,475 echocardiograms performed in 4 US Field Centers and analyzed in a Reading Center, assessing standard echocardiography (LA dimension, aortic root, LV mass, LV end-diastolic volume [LVEDV], ejection fraction [LVEF]), and STE (2- and 4-chamber longitudinal, circumferential, and radial strains). Reproducibility was assessed using intra-class correlation coefficients (ICC), coefficients of variation (CV), and Bland-Altman plots.
Results
For standard echocardiography reproducibility, LV mass and LVEDV consistently had CV above 10% and aortic root below 6%. Intra-sonographer aortic root and LV mass had the most robust values of ICC in standard echocardiography. For STE, the number of properly tracking segments was above 80% in short-axis and 4-chamber and 58% in 2-chamber. Longitudinal strain parameters were the most robust and radial strain showed the highest variation. Comparing Field Centers with Echo RC STE readings, mean differences ranged from 0.4% to 4.1% and ICC from 0.37 to 0.66, with robust results for longitudinal strains.
Conclusion
Echocardiography image acquisition and reading processes in the CARDIA study were highly reproducible, including robust results for STE analysis. Consistent quality control may increase the reliability of echocardiography measurements in large cohort studies.
doi:10.1111/echo.12832
PMCID: PMC4426079  PMID: 25382818
Echocardiography; reproducibility; speckle tracking echocardiography; quality control
20.  Functional Impairment Is a Risk Factor for Knee Replacement in the Multicenter Osteoarthritis Study 
Background
Debilitating pain associated with knee osteoarthritis (OA) often leads patients to seek and complete total knee arthroplasty (TKA). To date, few studies have evaluated the relation of functional impairment to the risk of TKA, despite the fact that OA is associated with functional impairment.
Questions/purposes
The purpose of our study was to (1) evaluate whether function as measured by WOMAC physical function subscale was associated with undergoing TKA; and (2) whether any such association varied by sex.
Methods
The National Institutes of Health-funded Multicenter Osteoarthritis Study (MOST) is an observational cohort study of persons aged 50 to 79 years with or at high risk of symptomatic knee OA who were recruited from the community. All eligible subjects with complete data were included in this analysis. Our study population sample consisted of 2946 patients with 5796 knees; 1776 (60%) of patients were women. We performed a repeated-measures analysis using baseline WOMAC physical function score to predict the risk of TKA from baseline to 30 months and WOMAC score at 30 months to predict risk of incident TKA from 30 months to 60 months. We used generalized estimating equations to account for the correlation between two knees within an individual and across the two periods. We calculated relative risk (RR) of TKA over 30 months by WOMAC function using a score of 0 to 5 as the referent in multiple binomial regressions with log link.
Results
Those with the greatest functional impairment (WOMAC scores 40–68; 62 TKAs in 462 knee periods) had 15.5 times (95% confidence interval [CI], 7.6–31.8; p < 0.001) the risk of undergoing TKA over 30 months compared with the referent group (12 TKAs in 3604 knee periods), adjusting for basic covariates, and 5.9 times (95% CI, 2.8–12.5; p < 0.001) the risk after further adjusting for knee pain severity. At every level of functional limitation, the RR for TKA for women was higher than for men, but interaction with sex did not reach significance after adjustment for covariates including ipsilateral pain (p = 0.138).
Conclusions
Baseline physical function appears to be an important element in patients considering TKA. Future studies should examine whether interventions to improve function can reduce the need for TKA.
Level of Evidence
Level III, observational cohort study.
doi:10.1007/s11999-015-4211-3
PMCID: PMC4488226  PMID: 25754756
21.  Systolic Blood Pressure Control Among Individuals With Type 2 Diabetes: A Comparative Effectiveness Analysis of Three Interventions 
American Journal of Hypertension  2015;28(8):995-1009.
BACKGROUND
The relative effectiveness of 3 approaches to blood pressure control—(i) an intensive lifestyle intervention (ILI) focused on weight loss, (ii) frequent goal-based monitoring of blood pressure with pharmacological management, and (iii) education and support—has not been established among overweight and obese adults with type 2 diabetes who are appropriate for each intervention.
METHODS
Participants from the Action for Health in Diabetes (Look AHEAD) and the Action to Control Cardiovascular Risk in Diabetes (ACCORD) cohorts who met criteria for both clinical trials were identified. The proportions of these individuals with systolic blood pressure (SBP) <140mm Hg from annual standardized assessments over time were compared with generalized estimating equations.
RESULTS
Across 4 years among 480 Look AHEAD and 1,129 ACCORD participants with baseline SBPs between 130 and 159mm Hg, ILI (OR = 1.46; 95% CI = [1.18–1.81]) and frequent goal-based monitoring with pharmacotherapy (OR = 1.51; 95% CI = [1.16–1.97]) yielded higher rates of blood pressure control compared to education and support. The intensive behavioral-based intervention may have been more effective among individuals with body mass index >30kg/m2, while frequent goal-based monitoring with medication management may be more effective among individuals with lower body mass index (interaction P = 0.047).
CONCLUSIONS
Among overweight and obese adults with type 2 diabetes, both ILI and frequent goal-based monitoring with pharmacological management can be successful strategies for blood pressure control.
CLINICAL TRIALS REGISTRY
clinicaltrials.gov identifiers NCT00017953 (Look AHEAD) and NCT00000620 (ACCORD).
doi:10.1093/ajh/hpu292
PMCID: PMC4506323  PMID: 25666468
blood pressure; blood pressure control; blood pressure monitoring; comparative effectiveness; diabetes; hypertension; lifestyle intervention; obesity.
22.  Baseline radiographic osteoarthritis and semi-quantitatively assessed meniscal damage and extrusion and cartilage damage on MRI is related to quantitatively defined cartilage thickness loss in knee osteoarthritis: The Multicenter Osteoarthritis Study 
Objectives
To provide a comprehensive simultaneous relation of various semiquantitative knee OA MRI features as well as the presence of baseline radiographic OA to quantitative longitudinal cartilage loss.
Methods
We studied Multicenter OA Study (MOST) participants from a longitudinal observational study that included quantitative MRI measurement of cartilage thickness. These subjects also had Whole Organ MRI Score (WORMS) scoring of cartilage damage, bone marrow lesions (BMLs), meniscal pathology, and synovitis, as well as baseline radiographic evaluation for Kellgren and Lawrence (KL) grading. Knee compartments were classified as progressors when exceeding thresholds of measurement variability in normal knees. All potential risk factors of cartilage loss were dichotomized into “present” (score ≥2 for cartilage, ≥1 for others) or “absent”. Differences in baseline scores of ipsi-compartmental risk factors were compared between progressor and non-progressor knees by multivariable logistic regression, adjusting for age, sex, body mass index, alignment axis (degrees) and baseline KL grade. Odds ratios (OR) and 95% CIs were calculated for medial (MFTC) and lateral (LFTC) cartilage loss. Cartilage loss across both compartments was studied using Generalized Estimating Equations.
Results
196 knees of 196 participants were included (age 59.8±6.3 years [mean±SD], BMI 29.5±4.6, 62% women). For combined analyses of MFTC and LFTC, baseline factors related to cartilage loss were radiographic OA (KL grade ≥2: aOR 4.8 [2.4-9.5], cartilage damage (aOR 2.3 [1.2-4.4]), meniscal damage (aOR 3.9 [2.1-7.4]) and extrusion (aOR 2.9 [1.6-5.3]), all in the ipsilateral compartment, but not BMLs or synovitis.
Conclusion
Baseline radiographic OA and semiquantitatively assessed MRI-detected cartilage damage, meniscal damage and extrusion, but not BMLs or synovitis is related to quantitatively measured ipsicompartmental cartilage thinning over 30 months.
doi:10.1016/j.joca.2015.06.017
PMCID: PMC4957527  PMID: 26162806
meniscus; effusion; synovitis; cartilage; semiquantitative; quantitative
23.  Vascular risk factors, cerebrovascular reactivity, and the default-mode brain network 
NeuroImage  2015;115:7-16.
Cumulating evidence from epidemiologic studies implicates cardiovascular health and cerebrovascular function in several brain diseases in late life. We examined vascular risk factors with respect to a cerebrovascular measure of brain functioning in subjects in mid-life, which could represent a marker of brain changes in later life. Breath-hold functional MRI (fMRI) was performed in 541 women and men (mean age 50.4 years) from the Coronary Artery Risk Development in Young Adults (CARDIA) Brain MRI sub-study. Cerebrovascular reactivity (CVR) was quantified as percentage change in blood-oxygen level dependent (BOLD) signal in activated voxels, which was mapped to a common brain template and log-transformed. Mean CVR was calculated for anatomic regions underlying the default-mode network (DMN) - a network implicated in AD and other brain disorders - in addition to areas considered to be relatively spared in the disease (e.g. occipital lobe), which were utilized as reference regions. Mean CVR was significantly reduced in the posterior cingulate/precuneus (β = -0.063, 95% CI: - 0.106, -0.020), anterior cingulate (β = -0.055, 95% CI: -0.101, -0.010), and medial frontal lobe (β = -0.050, 95% CI: -0.092, -0.008) relative to mean CVR in the occipital lobe, after adjustment for age, sex, race, education, and smoking status, in subjects with pre-hypertension/hypertension compared to normotensive subjects. By contrast, mean CVR was lower, but not significantly, in the inferior parietal lobe (β = -0.024, 95% CI: -0.062, 0.014) and the hippocampus (β = -0.006, 95% CI: -0.062, 0.050) relative to mean CVR in the occipital lobe. Similar results were observed in subjects with diabetes and dyslipidemia compared to those without these conditions, though the differences were non-significant. Reduced CVR may represent diminished vascular functionality for the DMN for individuals with prehypertension/ hypertension in mid-life, and may serve as a preclinical marker for brain dysfunction in later life.
doi:10.1016/j.neuroimage.2015.04.039
PMCID: PMC4469180  PMID: 25917517
Alzheimer's disease; neurophysiology; vascular risk factors
24.  Marriage and parenthood in relation to obesogenic neighborhood trajectories: The CARDIA Study 
Health & place  2015;34:229-240.
Marriage and parenthood are associated with weight gain and residential mobility. Little is known about how obesity-relevant environmental contexts differ according to family structure. We estimated trajectories of neighborhood poverty, population density, and density of fast food restaurants, supermarkets, and commercial and public physical activity facilities for adults from a biracial cohort (CARDIA, n=4,174, aged 25–50) over 13 years (1992–93 through 2005–06) using latent growth curve analysis. We estimated associations of marriage, parenthood, and race with the observed neighborhood trajectories. Married participants tended to live in neighborhoods with lower poverty, population density, and availability of all types of food and physical activity amenities. Parenthood was similarly but less consistently related to neighborhood characteristics. Marriage and parenthood were more strongly related to neighborhood trajectories in whites (versus blacks), who, in prior studies, exhibit weaker associations between neighborhood characteristics and health. Greater understanding of how interactive family and neighborhood environments contribute to healthy living is needed.
doi:10.1016/j.healthplace.2015.05.005
PMCID: PMC4496281  PMID: 26093081
Built environment; Geographic Information Systems; Longitudinal Study; Life Course; Obesity
25.  DETERMINANTS OF AORTIC ROOT DILATATION AND REFERENCE VALUES AMONG YOUNG ADULTS OVER A 20-YEAR PERIOD: THE CORONARY ARTERY RISK DEVELOPMENT IN YOUNG ADULTS (CARDIA) STUDY 
Hypertension  2015;66(1):23-29.
Aortic size increases with age, but factors related to such dilatation in healthy young adult population have not been studied. We aim to evaluate changes in aortic dimensions and its principal correlates among young adults over a 20-year time period. Reference values for aortic dimensions in young adults by echocardiography are also provided.
Healthy CARDIA study participants aged 23–35 years in 1990–91 (n=3051) were included after excluding 18 individuals with significant valvular dysfunction. Aortic root diameter by M-mode echocardiography at Year-5 (43.7% men; age 30.2±3.6y) and Year-25 CARDIA exams were obtained. Univariable and multivariable analyses were performed to assess associations of aortic root diameter with clinical data at Years-5 and -25. Aortic root diameter from Year-5 was used to establish reference values of aortic root diameter in healthy young adults.
Aortic root diameter at Year-25 was greater in men (33.3±3.7 vs 28.7±3.4mm, p<0.001) and in whites (30.9±4.3 vs 30.5±4.1, p=0.006). On multivariable analysis, aortic root diameter at Year-25 was positively correlated with male gender, white ethnicity, age, height, weight, 20-year gain in weight, active smoking at baseline and 20-year increase in diastolic, systolic and mean arterial pressure. A figure showing the estimated 95th percentile of aortic root diameter by age and body surface area stratified by race and gender is provided.
This study demonstrates that smoking, blood pressure, and increase in body weight are the main modifiable correlates of aortic root dilation during young adulthood. Our study also provides reference values for aortic root diameter in young adults.
doi:10.1161/HYPERTENSIONAHA.115.05156
PMCID: PMC4465858  PMID: 25941347
Ascending Aorta; Aortic Diseases; Aortic Aneurysm; Echocardiography; Epidemiology

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