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1.  Excess Body Mass Index- and Waist Circumference-Years and Incident Cardiovascular Disease: The CARDIA Study 
Obesity (Silver Spring, Md.)  2015;23(4):879-885.
Determine the influence of the total cumulative exposure to excess overall and abdominal adiposity on the incidence of cardiovascular disease (CVD).
Prospective study of 4,061 white and black adults without CVD at baseline in 1985-86 (age 18-30 years) from the multicenter, community-based CARDIA study. Time-varying excess body mass index (BMI) and waist circumference (WC)-years were calculated as products of the degree and duration of excess overall (BMI ≥25 kg/m2) and abdominal adiposity [WC >94 cm (men) and >80 cm (women)], respectively, collected at up to eight examinations.
During a median of 24.8 years, there were 125 incident CVD, 62 coronary heart disease (CHD), and 33 heart failure (HF) events. Adjusted hazard ratios for CVD, CHD, and HF for each additional 50 excess BMI-years were 1.20 (1.08, 1.34), 1.25 (1.07, 1.46), and 1.45 (1.23, 1.72), respectively. For each 50 excess WC-years, these hazard ratios were 1.10 (1.04, 1.18), 1.13 (1.03, 1.24), and 1.22 (1.11, 1.34), respectively. Akaike information criterion values were lowest in models containing time-varying excess BMI- or WC-years than those including time-varying BMI or WC only.
Excess BMI- and WC-years are predictors of the risk of CVD and may provide a better indicator of the cumulative exposure to excess adiposity than BMI or WC only.
PMCID: PMC4380633  PMID: 25755157
cardiovascular risk; obesity; adiposity; central obesity
2.  A community-based, case-control study of childhood stroke risk associated with congenital heart disease 
Background and Purpose
A better understanding of the stroke risk factors in children with congenital heart disease (CHD) could inform stroke prevention strategies. We analyzed pediatric stroke associated with CHD in a large community-based, case-control study.
From 2.5 million children (< 20 years) enrolled in a Northern California integrated healthcare plan, we identified ischemic and hemorrhagic strokes and randomly selected age and facility-matched stroke-free controls (3 per case). We determined exposure to CHD (diagnosed prior to stroke) and used conditional logistic regression to analyze stroke risk.
CHD was identified in 15/412 cases (4%) versus 7/1,236 controls (0.6%). Children (28 days – 20 years) with CHD had 19-fold (Odds Ratio [OR] 19; 95% Confidence Interval [CI] 4.2, 83) increased stroke risk compared to controls. History of CHD surgery was associated with >30-fold increased risk of stroke (OR 31; CI 4, 241 compared to controls). After excluding peri-operative strokes, a history of CHD surgery still increased childhood stroke risk (OR 13; CI 1.5, 114). The majority of children with stroke and CHD were outpatient at the time of stroke, and almost half the cases who underwent cardiac surgery had their stroke >5 years after the most recent procedure. An estimated 7% of ischemic and 2% of hemorrhagic childhood strokes in the population were attributable to CHD.
CHD is an important childhood stroke risk factor. Children who undergo CHD surgery remain at elevated risk outside of the peri-operative period, and would benefit from optimized long-term stroke prevention strategies.
PMCID: PMC4308424  PMID: 25516197
congenital heart disease; pediatric stroke; epidemiology
3.  Early Adult to Midlife Cardiovascular Risk Factors and Cognitive Function 
Circulation  2014;129(15):1560-1567.
Studies have linked midlife and late-life cardiovascular risk factors (CVRFs) to cognitive function, yet little is known about CVRF exposure in early adulthood and subsequent cognitive function. In addition, most studies rely on single assessments of CVRFs, which may not accurately reflect long-term exposure. We sought to determine the association between cumulative exposure to CVRFs from early to middle adulthood and cognitive function at midlife.
Methods and Results
In a prospective study of 3381 adults (age, 18–30 years at baseline) with 25 years of follow-up, we assessed cognitive function at year 25 (2010–2011) with the Digit Symbol Substitution Test, Stroop Test, and Rey Auditory Verbal Learning Test analyzed with standardized z scores. The primary predictor was 25-year cumulative exposure estimated by areas under the curve for resting systolic and diastolic blood pressures, fasting blood glucose, and total cholesterol. Higher cumulative systolic and diastolic blood pressures and fasting blood glucose were consistently associated with worse cognition on all 3 tests. These associations were significant primarily for exposures above recommended guidelines; cognitive test z scores were between 0.06 and 0.30 points less, on average, for each 1-SD increase in risk factor area under the curve after adjustment for age, race, sex, and education (P<0.05 for all). Fewer significant associations were observed for cholesterol.
Cumulative exposure to CVRFs from early to middle adulthood, especially above recommended guidelines, was associated with worse cognition in midlife. The meaning of this association and whether it warrants more aggressive treatment of CVRFs earlier in life require further investigation.
PMCID: PMC4700881  PMID: 24687777
blood pressure; cholesterol; cognition; glucose; risk factors
4.  Apolipoprotein E ε2 Is Associated with New Hemorrhage Risk in Brain Arteriovenous Malformations 
Neurosurgery  2006;58(5):838-843.
Patients with brain arteriovenous malformation (AVM) are at life-threatening risk of intracranial hemorrhage (ICH). Identification of genetic variants associated with increased new ICH risk would facilitate risk stratification and guide therapeutic intervention.
Brain AVM patients evaluated at University of California, San Francisco or Kaiser Permanente Northern California were followed longitudinally. Primary outcome was new ICH after diagnosis; censoring events were any AVM treatment or last follow-up examination. The association of ApoE ε2 and ε4 genotype with new ICH was evaluated by Kaplan-Meier survival analysis and further characterized via a Cox proportional hazards model.
We genotyped 284 brain AVM patients (50% women; 57% Caucasian; median follow-up time, 0.3 yr) including 18 patients with a history of new ICH). ApoE ε2, but not ApoE ε4 genotype, was associated with new ICH (P = 0.0052). ApoE ε2 carriers had fivefold increased risk of new ICH (hazard ratio, 5.09; 95% confidence interval, 1.46–17.7; P = 0.010; Cox proportional hazards model adjusting for race/ethnicity and clinical presentation). Subset analysis in the largest homogenous ethnic subcohort (Caucasians) confirmed the increased risk of new ICH in ApoE ε2 carriers (hazard ratio, 8.71; 95% confidence interval, 1.4–53.9; P = 0.020; multivariate model adjusting for clinical presentation).
ApoE genotype may influence the risk of ICH in the natural course of brain AVM. The identification of genetic predictors of ICH risk may facilitate estimation of AVM natural history risk and individualize clinical decision-making and therapeutic recommendations.
PMCID: PMC4648360  PMID: 16639317
Cerebral hemorrhage; Genetic epidemiology; Vascular malformations
5.  A Multisite Study of Long-term Remission and Relapse of Type 2 Diabetes Mellitus following Gastric Bypass 
Obesity surgery  2013;23(1):93-102.
Gastric bypass has profound effects on glycemic control in adults with type 2 diabetes mellitus. The goal of this study was to examine the long-term rates and clinical predictors of diabetes remission and relapse among patients undergoing gastric bypass.
We conducted a retrospective cohort study of adults with uncontrolled or medication-controlled type 2 diabetes who underwent gastric bypass from 1995 to 2008 in three integrated health care delivery systems in the United States. Remission and relapse events were defined by diabetes medication use and clinical laboratory measures of glycemic control.
We identified 4,434 adults with uncontrolled or medication-controlled type 2 diabetes who had gastric bypass. Overall, 68.2% (95% CI: 66%, 70%) experienced an initial complete diabetes remission within five years after surgery. Among these, 35.1% (95% CI: 32%, 38%) redeveloped diabetes within five years. The median duration of remission was 8.3 years. Significant predictors of complete remission and relapse were poor preoperative glycemic control, insulin use, and longer diabetes duration. Weight trajectories after surgery were significantly different for never remitters, relapsers, and durable remitters (p=0.03).
Gastric bypass surgery is associated with durable remission of type 2 diabetes in many but not all severely obese diabetic adults, and about one-third experience a relapse within five years of initial remission. More research is needed to understand the mechanisms of diabetes relapse, the optimal timing of surgery in effecting a durable remission, and the relationship between remission duration and incident microvascular and macrovascular events.
PMCID: PMC4641311  PMID: 23161525
gastric bypass; diabetes; remission; relapse
6.  Comparative Effectiveness of Bariatric Surgery versus Nonsurgical Treatment of Type 2 Diabetes among Severely Obese Adults 
Although all weight-loss approaches may improve insulin sensitivity in type 2 diabetes, bariatric surgery is believed to be the only reliable means of achieving diabetes remission. We conducted a retrospective cohort study to compare rates of diabetes remission, relapse and all-cause mortality among severely obese individuals with diabetes who underwent bariatric surgery versus nonsurgically treated individuals. Severely obese adults with uncontrolled or medication-controlled diabetes who underwent bariatric surgery or received usual medical care from 2005 to 2008 in three health care delivery systems in the United States were eligible. Diabetes status was identified using pharmacy, laboratory, and diagnosis information from electronic medical records. A propensity approach and exclusion criteria identified 1395 adults with diabetes who had bariatric surgery and 62322 who did not. Most procedures were Roux-en-Y gastric bypass (72.0% laparoscopic; 8.2% open); 4.4% were gastric banding, 2.4 % sleeve gastrectomy, and 13.2% were other procedures. At two years, bariatric subjects experienced significantly higher diabetes remission rates [73.7% (95% CI: 70.6, 76.5)] compared to nonsurgical subjects [6.9% (95%CI: 6.9, 7.1)]. Age, site, duration of diabetes, hemoglobin A1c level, and intensity of diabetes medication treatment were significantly associated with remission. Bariatric subjects also experienced lower relapse rates than nonsurgical subjects (adjusted HR: 0.19; 95% CI: 0.15 to 0.23) with no higher risk of death (adjusted HR: 0.54; 95% CI: 0.22 to 1.30). We conclude that bariatric surgery can effectively induce remission of diabetes among most severely obese adults, and this treatment approach appears to be superior to nonsurgical treatment in inducing diabetes remission.
PMCID: PMC4632526  PMID: 24306153
bariatric surgery; diabetes; remission; comparative effectiveness
7.  Common variants on 9p21.3 are associated with brain arteriovenous malformations with accompanying arterial aneurysms 
To investigate whether previously reported 9p21.3 single nucleotide polymorphisms (SNPs) are associated with risk of brain arteriovenous malformations (BAVMs), which often have accompanying arterial aneurysms. Common variants in the 9p21.3 locus have been reported to be associated with multiple cardiovascular phenotypes, including coronary artery disease and intracranial aneurysms (rs10757278 and rs1333040).
We used data from 338 BAVM cases participating in the University of California, San Francisco-Kaiser Brain AVM Study Project and 504 healthy controls to evaluate genotypes for seven common SNPs (minor allele frequency>0.05) that were imputed using 1000 Genomes Phase 1 European data (R2>0.87). Association with BAVM was tested using logistic regression adjusting for age, sex and the top three principal components of ancestry. Subgroup analysis included 205 BAVM cases with aneurysm data: (a) 74 BAVM with aneurysm vs. 504 controls, and (b) 131 BAVM without aneurysm vs. 504 controls.
We observed suggestive association with BAVM and rs10757278-G (OR=1.23, 95% CI=0.99–1.53, P=0.064) and rs1333040-T (OR=1.27, 95% CI=1.01–1.58, P=0.04). For rs10757278-G, the association was stronger in BAVM cases with aneurysm (OR=1.52, 95% CI=1.03–2.22, P=0.032) than in BAVM without aneurysm (OR=0.98, 95% CI=0.72–1.34, P=0.91). Similar patterns of effects were observed for rs1333040 and for other SNPs in linkage disequilibrium (r2>0.8) with rs10757278.
Common 9p21.3 variants showed similar effect sizes for association with BAVM as previously reported for aneurysmal disease. The association with BAVM appears to be explained by known associations with aneurysms, suggesting that BAVM associated aneurysms share similar vascular pathology mechanisms with other aneurysm types.
PMCID: PMC4201968  PMID: 24777168
cerebral arteriovenous malformations; intracranial aneurysms; genetic association studies
8.  Healthy Lifestyle Change and Subclinical Atherosclerosis in Young Adults: Coronary Artery Risk Development in Young Adults (CARDIA) Study 
Circulation  2014;130(1):10-17.
The benefits of healthy habits are well-established, but it is unclear whether making health behavior changes as an adult can still alter coronary artery disease risk.
Methods and Results
The Coronary Artery Risk Development in Young Adults (CARDIA) prospective cohort study (n = 3538) assessed 5 healthy lifestyle factors (HLFs) among young adults between ages 18–30 (Year 0 baseline) and 20 years later (Year 20): not overweight/obese, low alcohol intake, healthy diet, physically active, nonsmoker. We tested whether change from Year 0 to 20 in a continuous composite HLF score (HLF change; range: −5 to +5) is associated with subclinical atherosclerosis [coronary artery calcification (CAC) and carotid intima-media thickness (IMT)] at Year 20, after adjustment for demographics, medications, and baseline HLFs. By Year 20, 25·3% of the sample improved (HLF change ≥ +1); 40·4% deteriorated (had fewer HLFs); 34·4% stayed the same; 19·2% had CAC (>0). Each increase in HLFs was associated with reduced odds of detectable CAC (OR = .85, 95% CI: .74 – .98) and lower IMT (carotid bulb β = −.024, p = 0.001), and each decrease in HLFs was predictive to a similar degree of greater odds of CAC (OR = 1.17, 95% CI: 1.02 – 1.33) and greater IMT (β = +.020, p < 0.01).
Healthy lifestyle changes during young adulthood are associated with decreased, and unhealthy lifestyle changes with increased risk for subclinical atherosclerosis in middle age.
PMCID: PMC4615574  PMID: 24982115
epidemiology; follow-up studies; risk factors; prevention; behavior modification
9.  Practice variation in neuroimaging to evaluate dizziness in the ED✰,✰✰ 
The appropriate role of neuroimaging to evaluate emergency department (ED) patients with dizziness is not established by guidelines or evidence.
We identified all adults with a triage complaint of dizziness who were evaluated at 20 EDs of a large Northern California integrated health care program in 2008. Using comprehensive medical records, we captured all head computed tomographies (CTs) or brain magnetic resonance images (MRIs) completed at presentation or within 2 days and all stroke diagnoses within 1 week. We assessed variation in neuroimaging use by site using a random-effects logistic model to account for differences in patient- (demographic and vascular risk factors) and site-level factors (volume, % patients with dizziness, and % patients with dizziness admitted) and linear regression to assess the relationship between neuroimaging rates and stroke diagnosis rates by site.
Of 378 992 patients seen in 2008, 20 795 (5.5%) had at least one ED visit for dizziness. Overall, 5585 patients (26.9%) had a head CT and 652 (3.1%) had a brain MRI. Between 21.8% and 32.8% of ED patients with dizziness at each site had a head CT (P < .001). For brain MRI, the range was 0.8% to 6.2%—a nearly 8-fold variation (P < .001) that persisted after adjustment for patient- and site-level factors. Higher neuroimaging rates did not translate into higher stroke diagnoses rates, with 0.7% to 2.5% of patients with dizziness diagnosed with stroke by site.
The use of neuroimaging for ED patients with dizziness varies substantially without an associated improvement in stroke diagnosis, which is identified only rarely.
PMCID: PMC4560264  PMID: 21570240
10.  Timing and number of minor infections as risk factors for childhood arterial ischemic stroke 
Neurology  2014;83(10):890-897.
In a population-based case-control study, we examined whether the timing and number of minor infections increased risk of childhood arterial ischemic stroke (AIS).
Among 102 children with AIS and 306 age-matched controls identified from a cohort of 2.5 million children in a large integrated health care plan (1993–2007), we abstracted data on all medical visits for minor infection within the 2 years prior to AIS or index date for pairwise age-matched controls. We excluded cases of AIS with severe infection (e.g., sepsis, meningitis). Using conditional logistic regression, we examined the effect of timing and total number of minor infections on stroke risk.
After adjusting for known pediatric stroke risk factors, the strongest association between infection and AIS was observed for infectious visits ≤3 days prior to stroke (odds ratio [OR] 12.1, 95% confidence interval [CI] 2.5, 57, p = 0.002). Respiratory infections represented 80% of case infections in that time period. Cases had more infectious visits, but not significantly so, for all time periods ≥4 days prior to the stroke. A greater cumulative number of infectious visits over 2 years did not increase risk of AIS.
Minor infections appear to have a strong but short-lived effect on pediatric stroke risk, while cumulative burden of infection had no effect. Proposed mechanisms for the link between minor infection and stroke in adults include an inflammatory-mediated prothrombotic state and chronic endothelial injury. The transient effect of infection in children may suggest a greater role for a prothrombotic mechanism.
PMCID: PMC4153847  PMID: 25142897
11.  Left atrial dimension and traditional cardiovascular risk factors predict 20-year clinical cardiovascular events in young healthy adults: the CARDIA study 
We investigated whether the addition of left atrial (LA) size determined by echocardiography improves cardiovascular risk prediction in young adults over and above the clinically established Framingham 10-year global CV risk score (FRS).
Methods and results
We included white and black CARDIA participants who had echocardiograms in Year-5 examination (1990–91). The combined endpoint after 20 years was incident fatal or non-fatal cardiovascular disease: myocardial infarction, heart failure, cerebrovascular disease, peripheral artery disease, and atrial fibrillation/flutter. Echocardiography-derived M-mode LA diameter (LAD; n = 4082; 149 events) and 2D four-chamber LA area (LAA; n = 2412; 77 events) were then indexed by height or body surface area (BSA). We used Cox regression, areas under the receiver operating characteristic curves (AUC), and net reclassification improvement (NRI) to assess the prediction power of LA size when added to calculated FRS or FRS covariates. The LAD and LAA cohorts had similar characteristics; mean LAD/height was 2.1 ± 0.3 mm/m and LAA/height 9.3 ± 2.0 mm2/m. After indexing by height and adjusting for FRS covariates, hazard ratios were 1.31 (95% CI 1.12, 1.60) and 1.43 (95% CI 1.13, 1.80) for LAD and LAA, respectively; AUC was 0.77 for LAD and 0.78 for LAA. When LAD and LAA were indexed to BSA, the results were similar but slightly inferior. Both LAD and LAA showed modest reclassification ability, with non-significant NRIs.
LA size measurements independently predict clinical outcomes. However, it only improves discrimination over clinical parameters modestly without altering risk classification. Indexing LA size by height is at least as robust as by BSA. Further research is needed to assess subgroups of young adults who may benefit from LA size information in risk stratification.
PMCID: PMC4215562  PMID: 24534011
Left atrial size; Cardiovascular events; Echocardiography; Young adults
12.  Cardiorespiratory fitness and cognitive function in middle age 
Neurology  2014;82(15):1339-1346.
To investigate whether greater cardiorespiratory fitness (CRF) is associated with better cognitive function 25 years later.
We studied 2,747 participants in the community-based Coronary Artery Risk Development in Young Adults Study of black and white men and women aged 18 to 30 years at recruitment in 1985–1986 (baseline year 0). Symptom-limited maximal treadmill test durations at years 0 and 20 provided measures of CRF. Cognitive tests at year 25 measured verbal memory (Rey Auditory Verbal Learning Test [RAVLT]), psychomotor speed (Digit Symbol Substitution Test [DSST]), and executive function (Stroop Test).
Per minute of baseline CRF, the RAVLT was 0.12 words recalled higher (standard error [SE] = 0.03, p < 0.0001), the DSST was 0.92 digits higher (SE = 0.13, p < 0.0001), and the Stroop Test score was 0.52 lower (better performance, SE = 0.11, p < 0.0001), after accounting for race, sex, age, education, and clinical center. Compared with the lowest quartile of CRF, each cognitive test was 21% to 34% of an SD better in the highest CRF quartile. Further adjustment for lifestyle and clinical measures attenuated coefficients for RAVLT and DSST slightly, while the coefficient predicting the Stroop Test lost more than half its value (p = 0.07). Analysis in the subset of 1,957 participants who also completed the year-20 treadmill test showed that 20-year change in CRF was positively associated only with DSST (p < 0.001).
Better verbal memory and faster psychomotor speed at ages 43 to 55 years were clearly associated with better CRF 25 years earlier.
PMCID: PMC4001190  PMID: 24696506
13.  Framingham Score and LV Mass predict Events in Young Adults: CARDIA Study 
International journal of cardiology  2014;172(2):350-355.
Framingham risk score (FRS) underestimates risk in young adults. LV mass (LVM) relates to cardiovascular disease (CVD), with unclear value in youth. In a young biracial cohort, we investigate how FRS predicts CVD over 20 years and the incremental value of LVM. We also explore the predictive ability of different cut-points for hypertrophy.
We assessed FRS and echocardiography-derived LVM (indexed by BSA or height2.7) from 3980 African-American and white CARDIA participants (1990-1991); and followed over 20 years for a combined endpoint: cardiovascular death; nonfatal myocardial infarction, heart failure, cerebrovascular disease, and peripheral artery disease. We assessed the predictive ability of FRS for CVD and also calibration, discrimination, and net reclassification improvement for adding LVM to FRS.
Mean age was 30±4 years, 46% males, and 52% white. Event incidence (n = 118) across FRS groups was, respectively, 1.3%, 5.4%, and 23.1% (p<0.001); and was 1.4%, 1.3%, 3.7%, and 5.4% (p<0.001) across quartiles of LVM (cut-points 117g, 144g, and 176g). LVM predicted CVD independently of FRS, with the best performance in normal weight participants. Adding LVM to FRS modestly increased discrimination and had a statistically significant reclassification. The 85th percentile (≥116 g/m2 for men; ≥96 g/m2 for women) showed event prediction more robust than currently recommended cut-points for hypertrophy.
In a biracial cohort of young adults, FRS and LVM are helpful independent predictors of CVD. LVM can modestly improve discrimination and reclassify participants beyond FRS. Currently recommended cut-points for hypertrophy may be too high for young adults.
PMCID: PMC4068332  PMID: 24507735
young adults; cardiovascular risk; left ventricular hypertrophy; echocardiography
14.  Race–Ethnic and Sex Differences in Left Ventricular Structure and Function: The Coronary Artery Risk Development in Young Adults (CARDIA) Study 
We investigated race–ethnic and sex‐specific relationships of left ventricular (LV) structure and LV function in African American and white men and women at 43 to 55 years of age.
Methods and Results
The Coronary Artery Risk Development in Young Adults (CARDIA) Study enrolled African American and white adults, age 18 to 30 years, from 4 US field centers in 1985–1986 (Year‐0) who have been followed prospectively. We included participants with echocardiographic assessment at the Year‐25 examination (n=3320; 44% men, 46% African American). The end points of LV structure and function were assessed using conventional echocardiography and speckle‐tracking echocardiography. In the multivariable models, we used, in addition to race–ethnic and gender terms, demographic (age, physical activity, and educational level) and cardiovascular risk variables (body mass index, systolic blood pressure, diastolic blood pressure, heart rate, presence of diabetes, use of antihypertensive medications, number of cigarettes/day) at Year‐0 and ‐25 examinations as independent predictors of echocardiographic outcomes at the Year‐25 examination (LV end‐diastolic volume [LVEDV]/height, LV end‐systolic volume [LVESV]/height, LV mass [LVM]/height, and LVM/LVEDV ratio for LV structural indices; LV ejection fraction [LVEF], Ell, and Ecc for systolic indices; and early diastolic and atrial ratio, mitral annulus early peak velocity, ratio of mitral early peak velocity/mitral annulus early peak velocity; ratio, left atrial volume/height, longitudinal peak early diastolic strain rate, and circumferential peak early diastolic strain rate for diastolic indices). Compared with women, African American and white men had greater LV volume and LV mass (P<0.05). For LV systolic function, African American men had the lowest LVEF as well as longitudinal (Ell) and circumferential (Ecc) strain indices among the 4 sex/race–ethnic groups (P<0.05). For LV diastolic function, African American men and women had larger left atrial volumes; African American men had the lowest values of Ell and Ecc for diastolic strain rate (P<0.05). These race/sex differences in LV structure and LV function persisted after adjustment.
African American men have greater LV size and lower LV systolic and diastolic function compared to African American women and to white men and women. The reasons for these racial‐ethnic differences are partially but not completely explained by established cardiovascular risk factors.
PMCID: PMC4392424  PMID: 25770024
echocardiography; left ventricular function; left ventricular mass; speckle‐tracking echocardiography
15.  Relation of Left Ventricular Mass at Age 23 to 35 years to Global Left Ventricular Systolic Function 20 Years Later (From the Coronary Artery Risk Development in Young Adults Study) 
The American journal of cardiology  2013;113(2):377-383.
Left ventricular (LV) mass and LV ejection fraction (EF) are major independent predictors of future cardiovascular disease. The association of LV mass with future LVEF in younger populations has not been studied. We investigated the relation of LV mass index (LVMI) at age 23 to 35 years to LV function after 20 years of follow-up in the Coronary Artery Risk Development in Young Adults (CARDIA) Study. CARDIA is a longitudinal study that enrolled young adults in 1985–1986. We included participants with echocardiographic examinations at both years-5 and -25. LVMI and LVEF were assessed using M-mode echocardiography at year-5 and using both M-mode and 2-dimensional images at year-25. Statistical analytic models assessed the correlation between LVMI and LV functional parameters both cross-sectionally and longitudinally. A total of 2,339 participants were included. The mean LVEF at year-25 was 62%. Although there was no cross-sectional correlation between LVMI and LVEF at year-5, there was a small, but statistically significant negative correlation between LVMI at year-5 and LVEF 20 years later (r = −0.10, p < 0.0001); this inverse association persisted for LVMI in the multivariable model. High LVMI was an independent predictor of systolic dysfunction (LVEF < 50%) 20 years later (odds ratio 1.46, p = 0.0018). In conclusion, we have shown that LVMI in young adulthood in association with chronic risk exposure impacts systolic function in middle age; the antecedents of heart failure may occur at younger ages than previously thought.
PMCID: PMC3901209  PMID: 24176073
left ventricular mass; left ventricular ejection fraction; echocardiography; left ventricular remodeling
16.  Improved Blood Pressure Control Associated With a Large-Scale Hypertension Program 
JAMA  2013;310(7):699-705.
Hypertension control for large populations remains a major challenge.
To describe a large-scale hypertension program in northern California and to compare rates of hypertension control of the program to statewide and national estimates.
Design, Setting, and Patients
The Kaiser Permanente Northern California (KPNC) Hypertension program included a multi-faceted approach to blood pressure control. Patients identified with hypertension within an integrated health care delivery system in northern California from 2001–2009 were included. The comparison group included insured patients in California between 2006–2009 who were included in the Healthcare Effectiveness Data and Information Set (HEDIS) commercial measurement by California health insurance plans participating in the National Committee for Quality Assurance (NQCA) quality measure reporting process. A secondary comparison group was the reported national mean NCQA HEDIS commercial rates of hypertension control from 2001–2009 from health plans that participated in the NQCA HEDIS quality measure reporting process.
Main Outcome Measure
Hypertension control as defined by NCQA HEDIS.
The KPNC hypertension registry established in 2001 included 349,937 patients and grew to 652,763 by 2009. The NCQA HEDIS commercial measurement for hypertension control increased from 44% to 80% during the study period. In contrast, the national mean NCQA HEDIS commercial measurement increased modestly from 55.4% to 64.1%. California mean NCQA HEDIS commercial rates of hypertension were similar to those reported nationally from 2006–2009. (63.4% to 69.4%).
Conclusion and Relevance
Among adults diagnosed with hypertension, implementation of a large-scale hypertension program was associated with a significant increase in hypertension control compared with state and national control rates.
PMCID: PMC4270203  PMID: 23989679
Hypertension; Single pill combination Therapy; Angiotensin Enzyme Converting Inhibitor; Hydrochlorothiazide; Quality
17.  HIV/HCV coinfection ameliorates the atherogenic lipoprotein abnormalities of HIV infection 
AIDS (London, England)  2014;28(1):49-58.
Higher levels of small low-density lipoprotein (LDL) and lower levels of high-density lipoprotein (HDL) subclasses have been associated with increased risk of cardiovascular disease. The extent to which HIV infection and HIV/HCV coinfection are associated with abnormalities of lipoprotein subclasses is unknown.
Lipoprotein subclasses were measured by nuclear magnetic resonance (NMR) spectroscopy in plasma samples from 569 HIV-infected and 5948 control participants in the FRAM, CARDIA and MESA studies. Multivariable regression was used to estimate the association of HIV and HIV/HCV coinfection with lipoprotein measures with adjustment for demographics, lifestyle factors, and waist-to-hip ratio.
Relative to controls, small LDL levels were higher in HIV-monoinfected persons (+381 nmol/L, p<.0001), with no increase seen in HIV/HCV coinfection (−16.6 nmol/L). Levels of large LDL levels were lower (−196 nmol/L, p<.0001) and small HDL were higher (+8.2 μmol/L, p<.0001) in HIV-monoinfection with intermediate values seen in HIV/HCV-coinfection. Large HDL levels were higher in HIV/HCV-coinfected persons relative to controls (+1.70 μmol/L, p<.0001), whereas little difference was seen in HIV-monoinfected persons (+0.33, p=0.075). Within HIV-infected participants, HCV was associated independently with lower levels of small LDL (−329 nmol/L, p<.0001) and small HDL (−4.6 μmol/L, p<.0001), even after adjusting for demographic and traditional cardiovascular risk factors.
HIV-monoinfected participants had worse levels of atherogenic LDL lipoprotein subclasses compared with controls. HIV/HCV coinfection attenuates these changes, perhaps by altering hepatic factors affecting lipoprotein production and/or metabolism. The effect of HIV/HCV coinfection on atherosclerosis and the clinical consequences of low small subclasses remain to be determined.
PMCID: PMC4267724  PMID: 24136113
HIV infection; HCV infection; lipoproteins; cardiovascular disease
18.  Subclinical Atherosclerotic Calcification and Cognitive Functioning in Middle-Aged Adults: The CARDIA Study 
Atherosclerosis  2013;231(1):10.1016/j.atherosclerosis.2013.08.038.
Cardiovascular risk factors in middle-age are associated with cognitive impairment and dementia in older age. Less is known about the burden of calcified subclinical atherosclerosis and cognition, especially in midlife. We examined the association of coronary artery and abdominal aortic calcified plaque (CAC and AAC, respectively) with cognitive functioning in middle-aged adults.
This cross-sectional study included 2,510 black and white adults (age: 43–55 years) without heart disease or stroke who completed a year 25 follow-up exam (2010–11) as part of the Coronary Artery Risk Development in Young Adults Study. CAC and AAC were measured with non-contrast computed tomography. Cognition was assessed with the Digit Symbol Substitution Test (DSST) (psychomotor speed), Stroop Test (executive function), and Rey Auditory Verbal Learning Test (RAVLT) (verbal memory).
A greater amount of CAC and AAC was associated with worse performance on each test of cognitive function after adjustment for age, sex, race, education, and study center. Associations were attenuated, but remained significant for the DSST and RAVLT following additional adjustment for vascular risk factors, including adiposity, smoking, alcohol use, dyslipidemia, hypertension, and diabetes. Compared to participants without CAC or AAC, those with both CAC and AAC, but not CAC or AAC alone was associated with lower DSST scores (p<0.05).
In this community-based sample, greater subclinical atherosclerotic calcification was associated with worse psychomotor speed and memory in midlife. These findings underscore the importance of a life course approach to the study of cognitive impairment with aging.
PMCID: PMC3828555  PMID: 24125414
atherosclerosis; heart disease; calcium score; cognition; subclinical disease; risk factors
19.  Role of trauma and infection in childhood hemorrhagic stroke due to vascular lesions 
Neurology  2013;81(6):581-584.
Trauma and infection have been postulated as “triggers” for hemorrhage from underlying brain vascular lesions (arteriovenous malformations, cavernous malformations, and aneurysms) in pediatric hemorrhagic stroke. We decided to perform an association study examining these environmental risk factors.
In this case-control study nested within the cohort of 2.3 million children enrolled in a Northern California integrated health plan (1993–2004), we identified childhood hemorrhagic stroke cases through electronic searches of diagnostic and radiology databases, confirmed through chart review. Three age- and facility-matched controls per case were randomly selected from the study population. Exposure variables were measured using medical records documented before stroke diagnosis. Main outcome measure was hemorrhagic stroke.
Of 132 childhood, non-neonatal hemorrhagic stroke cases, 65 had underlying vascular lesions: 34 arteriovenous malformations, 16 cavernous malformations, and 15 aneurysms. A documented exposure to head and neck trauma in the prior 12 weeks was present in 3 cases (4.6%) with underlying vascular lesions, compared with no controls (p < 0.015). However, all 3 vascular lesions were aneurysms, and traumatic pseudoaneurysms were possible. Recent minor infection (prior 4 weeks) was present in 5 cases (7.7%) and 9 controls (4.6%) (p = 0.34).
Our observed association between trauma and hemorrhagic stroke with a vascular lesion may be explained by traumatic pseudoaneurysms. Neither recent head or neck trauma nor infection appeared to be a “trigger” for pediatric hemorrhagic stroke due to underlying vascular malformations.
PMCID: PMC3775687  PMID: 23825175
20.  Acute Seizures Predict Epilepsy After Childhood Stroke 
Annals of neurology  2013;74(2):249-256.
To determine incidence rates and predictors of epilepsy after childhood stroke and compare these to published estimates of 3–5% cumulative epilepsy incidence by five years post-stroke in adults.
In a retrospective population-based study of children with stroke (29 days−19 years) in an integrated health care system (1993–2007), post-stroke seizures were identified through electronic searches and confirmed by chart review. Stroke and seizure characteristics were abstracted from medical records. Survival analysis was used to determine rates and predictors of remote seizures and active epilepsy (anti-convulsant treatment for remote seizure within prior 6 months) at last follow-up.
From a population of 2.5 million children, we identified 305 stroke cases. Over a median follow-up of 4.1 years (interquartile range 1.8–6.8), 49 children had a first unprovoked remote seizure. The average annual incidence rate of first remote seizure was 4.4% (95% confidence interval [CI] 3.3, 5.8) with a cumulative risk of 16% (CI 12%, 21%) at 5 years and 33% (CI 23%, 46%) at 10 years post-stroke. The cumulative risk of active epilepsy was 13% (CI 9%, 18%) at five years and 30% (CI 20%, 44%) at 10 years. Acute seizures at the time of stroke predicted development of active epilepsy (hazard ratio [HR] 4.2, CI 2.2, 8.1). At last follow-up, one-third of the children with active epilepsy had a recent breakthrough seizure despite anti-convulsant usage.
Unlike adults, children are uniquely vulnerable to epilepsy after stroke. Children with acute seizures at the time of stroke are at particularly high risk.
PMCID: PMC3830669  PMID: 23613472
21.  Perceived weight discrimination in the CARDIA study: Differences by race, sex, and weight status 
Obesity (Silver Spring, Md.)  2013;22(2):530-536.
To examine self-reported weight discrimination and differences based on race, sex, and BMI in a biracial cohort of community-based middle-aged adults.
Design and Methods
We report on 3,466 participants (mean age=50 years, mean BMI=30 kg/m2) of the Coronary Artery Risk Development in Young Adults (CARDIA) Study who completed the 25-year examination of this epidemiological investigation in 2010–11. The sample included normal weight, overweight, and obese participants. CARDIA participants are distributed into four race-sex groups, with about half being African-American and half White. Participants completed a self-reported measure of weight discrimination.
Among overweight/obese participants, weight discrimination was lowest for White men (12.0%) and highest for White women (30.2%). The adjusted odds ratio (95% CI) for weight discrimination in those with class 2/3 obesity (BMI≥35 kg/m2) versus the normal-weight was most pronounced: African American men, 4.59(1.71–12.34); African American women, 7.82(3.57–17.13); White men, 6.99(2.27–21.49); and White women, 18.60(8.97–38.54). Being overweight (BMI=25–29.9 kg/m2) vs. normal weight was associated with increased discrimination in White women only: 2.10(1.11–3.96).
We provide novel evidence for a race-sex interaction on perceived weight discrimination, with White women more likely to report discrimination at all levels of overweight and obesity. Pychosocial mechanisms responsible for these differences deserve exploration.
PMCID: PMC3695009  PMID: 23512948
discrimination; obesity; weight; sex; race
22.  Long-term Plasma Lipid Changes Associated with a First Birth The Coronary Artery Risk Development in Young Adults Study 
American journal of epidemiology  2004;159(11):1028-1039.
Previous studies have reported declines in high density lipoprotein (HDL) cholesterol 1–2 years after pregnancy. In 1986–1996, the authors prospectively examined the association between childbearing and changes in fasting plasma lipids (low density lipoprotein, HDL, and total cholesterol; triglycerides) among 1,952 US women (980 Black, 972 White) in the Coronary Artery Risk Development in Young Adults study. Repeated-measures multiple linear regression was used to examine lipid changes over three time intervals (baseline to years 5, 7, and 10) in time-dependent follow-up groups: P0 (0 pregnancies), P1 (≥1 miscarriages/abortions), B1 (1 birth), and B2 (≥2 births). Means stratified by race and baseline parity (nulliparous or parous) were fully adjusted for study center, time, height, baseline diet, and other baseline and time-dependent covariates (age, smoking, education, weight, waist circumference, alcohol intake, oral contraceptive use, physical activity, short pregnancies). For both races, fully adjusted HDL cholesterol declines of −3 to −4 mg/dl were associated with a first birth versus no pregnancies during follow-up (p < 0.001). Higher-order births were not associated with greater declines in HDL cholesterol (B2 similar to B1, no association among women parous at baseline). In Whites, total and low density lipoprotein cholesterol declines were associated with follow-up births. HDL cholesterol declines of −3 to −4 mg/dl after a first birth persisted during the 10 years of follow-up independent of weight, central adiposity, and selected behavior changes.
PMCID: PMC4107869  PMID: 15155287
ethnic groups; lipids; lipoproteins; HDL cholesterol; parity; pregnancy
23.  Common polymorphisms of ALOX5 and ALOX5AP and risk of coronary artery disease 
Human genetics  2008;123(4):399-408.
Recent human genetic studies suggest that allelic variants of leukotriene pathway genes influence the risk of clinical and subclinical atherosclerosis. We sequenced the promoter, exonic, and splice site regions of ALOX5 and ALOX5AP and then genotyped 7 SNPs in ALOX5 and 6 SNPs in ALOX5AP in 1,552 cases with clinically significant coronary artery disease (CAD) and 1,583 controls from Kaiser Permanente including a subset of participants of the coronary artery risk development in young adults study. A nominally significant association was detected between a promoter SNP in ALOX5 (rs12762303) and CAD in our subset of white/European subjects (adjusted odds ratio per minor allele, log-additive model, 1.32; P = 0.002). In this race/ethnic group, rs12762303 has a minor allele frequency of 15% and is tightly linked to variation at the SP1 variable tandem repeat promoter polymorphism. However, the association between CAD and rs12762303 could not be reproduced in the atherosclerosis risk in communities study (hazard rate ratio per minor allele; 1.08, P = 0.1). Assuming a recessive mode of inheritance, the association was not significant in either population study but our power to detect modest effects was limited. No significant associations were observed between all other SNPs and the risk of CAD. Overall, our findings do not support a link between common allelic variation in or near ALOX5 or ALOX5AP and the risk of CAD. However, additional studies are needed to exclude modest effects of promoter variation in ALOX5 on the risk of CAD assuming a recessive mode of inheritance.
PMCID: PMC4023692  PMID: 18369664
24.  History of Gestational Diabetes Mellitus and Future Risk of Atherosclerosis in Mid‐life: The Coronary Artery Risk Development in Young Adults Study 
History of gestational diabetes mellitus (GDM) increases lifetime risk of type 2 diabetes (DM) and the metabolic syndrome (MetS), which increase risk of cardiovascular disease. It is unclear, however, whether GDM increases risk of early atherosclerosis independent of pre‐pregnancy obesity and subsequent metabolic disease.
Methods and Results
Of 2787 women (18 to 30 years) enrolled in the Coronary Artery Risk Development in Young Adults (CARDIA) study, we studied 898 (47% black) who were free of DM and heart disease at baseline (1985‐1986), delivered ≥1 post‐baseline births, reported GDM history, and had common carotid intima media thickness (ccIMT, mm) measured in 2005‐2006. We used multivariable linear regression to assess associations between GDM and ccIMT adjusted for race, age, parity, and pre‐pregnancy cardiometabolic risk factors. We assessed mediators (weight gain, insulin resistance, blood pressure), and effect modification by incident DM or MetS during the 20‐year period. Of the 898 women, 119 (13%) reported GDM (7.6 per 100 deliveries). Average age was 31 at last birth and 44 at ccIMT measurement for GDM and non‐GDM groups. Unadjusted mean ccIMT was 0.023 mm higher for GDM than non‐GDM groups (P=0.029), but pre‐pregnancy BMI attenuated the difference to 0.016 mm (P=0.109). In 777 women without subsequent DM or the MetS, mean ccIMT was 0.023 mm higher for GDM versus non‐GDM groups controlling for race, age, parity, and pre‐pregnancy BMI (0.784 versus 0.761, P=0.039). Addition of pre‐pregnancy insulin resistance index had minimal impact on adjusted mean net ccIMT difference (0.22 mm). Mean ccIMT did not differ by GDM status among 121 women who developed DM or the MetS (P=0.58).
History of GDM may be a marker for early atherosclerosis independent of pre‐pregnancy obesity among women who have not developed type 2 diabetes or the metabolic syndrome.
PMCID: PMC4187501  PMID: 24622610
atherosclerosis; gestational diabetes mellitus; pregnancy; prospective cohort studies; women
25.  Association of Electrocardiographically Determined Left Ventricular Mass With Incident Diabetes, 1985–1986 to 2010–2011 
Diabetes Care  2013;36(3):645-647.
Electrocardiographic indices reflecting left ventricular hypertrophy are associated with incident diabetes in clinical populations at risk for coronary heart disease. We tested whether electrocardiographically determined left ventricular mass was positively associated with incident diabetes in a population sample.
Coronary Artery Risk Development in Young Adults (CARDIA) study participants (n = 4,739) were followed from 1985–1986 to 2010–2011 for incident diabetes. Validated sex- and race-specific formulas were applied to standard electrocardiograms to determine left ventricular mass.
Over 25 years, 444 participants developed diabetes (9.4%). After adjustment for demographic, behavioral, and clinical covariates, participants in the highest quartile of left ventricular mass index (LVMI) were twice as likely to develop diabetes than participants in the lower three quartiles (hazard ratio 2.61 [95% CI 2.16–3.17]). Neither Cornell voltage nor Cornell voltage product was associated with incident diabetes in fully adjusted models.
Electrocardiographically determined LVMI may be a useful noninvasive marker for identifying adults at risk for diabetes.
PMCID: PMC3579342  PMID: 23160723

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