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1.  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
2.  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
3.  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
4.  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
5.  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
6.  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
7.  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
8.  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
9.  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
10.  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
11.  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
12.  Cardiovascular Health through Young Adulthood and Cognitive Functioning in Midlife 
Annals of neurology  2013;73(2):170-179.
To examine the association between overall cardiovascular health as recently defined by the American Heart Association in young adulthood to middle-age and cognitive function in midlife. Overall ideal cardiovascular health incorporates 7 metrics, including the avoidance of overweight or obesity, a healthful diet, nonsmoking, and physical activity, total cholesterol, blood pressure, and fasting glucose at goal levels.
This analysis of the Coronary Artery Risk Development in Young Adults (CARDIA) Study, a multicenter community-based study with 25 years of follow-up, included 2,932 participants aged 18 to 30 years at baseline (Year 0) who attended follow-up exams at Years 7 and 25. Cardiovascular health metrics were measured at each examination. The Digit Symbol Substitution Test (DSST), modified Stroop Test, and Rey Auditory Verbal Learning Test (RAVLT) were completed at Year 25.
A greater number of ideal cardiovascular metrics in young adulthood and middle-age was independently associated with better cognitive function in midlife (p-trend<0.01, for all). Specifically, each additional ideal metric was associated with 1.32 more symbols on the DSST (95% CI: 0.93 to 1.71), a 0.77-point lower interference score on the Stroop Test (−1.03 to −0.45), and 0.12 more words on the RAVLT (0.04 to 0.20). Participants who had ≥5 ideal metrics at a greater number of the 3 examinations over the 25-year period exhibited better performance on each cognitive test in middle-age (p-trend<0.01, for all).
Ideal cardiovascular health in young adulthood and its maintenance to middle-age is associated with better psychomotor speed, executive function, and verbal memory in midlife.
PMCID: PMC3608821  PMID: 23443990
13.  Association of early adult modifiable cardiovascular risk factors with left atrial size over a 20-year follow-up period: the CARDIA study 
BMJ Open  2014;4(1):e004001.
We investigate how early adult and 20-year changes in modifiable cardiovascular risk factors (MRF) predict left atrial dimension (LAD) at age 43–55 years.
The Coronary Artery Risk Development in Young Adults (CARDIA) study enrolled black and white adults (1985–1986). We included 2903 participants with echocardiography and MRF assessment in follow-up years 5 and 25. At years 5 and 25, LAD was assessed by M-mode echocardiography, then indexed to body surface area (BSA) or height. Blood pressure (BP), body mass index (BMI), heart rate (HR), smoking, alcohol use, diabetes and physical activity were defined as MRF. Associations of MRF with LAD were assessed using multivariable regression adjusted for age, ethnicity, gender and year-5 left atrial (LA) size.
The participants were 30±4 years; 55% white; 44% men. LAD and LAD/height were modest but significantly higher over the follow-up period, but LAD/BSA decreased slightly. Increased baseline and 20-year changes in BP were related to enlargement of LAD and indices. Higher baseline and changes in BMI were also related to higher LAD and LAD/height, but the opposite direction was found for LAD/BSA. Increase in baseline HR was related to lower LAD but not LAD indices, when only baseline covariates were included in the model. However, baseline and 20-year changes in HR were significantly associated to LA size.
In a biracial cohort of young adults, the most robust predictors for LA enlargement over a 20-year follow-up period were higher BP and BMI. However, an inverse direction was found for the relationship between BMI and LAD/BSA. HR showed an inverse relation to LA size.
PMCID: PMC3902509  PMID: 24384901
Cardiology; Epidemiology
14.  Maintaining a High Physical Activity Level Over 20 Years and Weight Gain 
JAMA : the journal of the American Medical Association  2010;304(23):10.1001/jama.2010.1843.
Data supporting physical activity guidelines to prevent long-term weight gain are sparse, particularly during the period when the highest risk of weight gain occurs.
To evaluate the relationship between habitual activity levels and changes in body mass index (BMI) and waist circumference over 20 years.
Design, Setting, and Participants
The Coronary Artery Risk Development in Young Adults (CARDIA) study is a prospective longitudinal study with 20 years of follow-up, 1985-86 to 2005-06. Habitual activity was defined as maintaining high, moderate, and low activity levels based on sex-specific tertiles of activity scores at baseline. Participants comprised a population-based multi-center cohort (Chicago, Illinois; Birmingham, Alabama; Minneapolis, Minnesota; and Oakland, California) of 3554 men and women aged 18 to 30 years at baseline.
Main Outcome Measures
Average annual changes in BMI and waist circumference
Over 20 years, maintaining high levels of activity was associated with smaller gains in BMI and waist circumference compared with low activity levels after adjustment for race, baseline BMI, age, education, cigarette smoking status, alcohol use, and energy intake. Men maintaining high activity gained 2.6 fewer kilograms (+ 0.15 BMI units per year; 95 % confidence interval [CI] 0.11-0.18 vs +0.20 in the lower activity group; 95% CI, 0.17-0.23) and women maintaining higher activity gained 6.1 fewer kilograms (+0.17 BMI units per year; 95 % CI, 0.12-0.21 vs. +0.30 in the lower activity group; 95 % CI, 0.25-0.34). Men maintaining high activity gained 3.1 fewer centimeters in waist circumference (+0.52 cm per year; 95 % CI, 0.43-0.61 cm vs 0.67 cm in the lower activity group; 95 % CI, 0.60-0.75) and women maintaining higher activity gained 3.8 fewer centimeters (+0.49 cm per year; 95 % CI, 0.39-0.58 vs 0.67 cm in the lower activity group; 95 % CI, 0.60-0.75).
Maintaining high activity levels through young adulthood may lessen weight gain as young adults transition to middle age, particularly in women.
PMCID: PMC3864556  PMID: 21156948
15.  G Protein-Coupled Receptor 124 (GPR124) Gene Polymorphisms and Risk of Brain Arteriovenous Malformation 
Translational stroke research  2012;3(4):418-427.
Abnormal endothelial proliferation and angiogenesis may contribute to brain arteriovenous malformation (BAVM) formation. G protein-coupled receptor 124 (GPR124) mediates embryonic CNS angiogenesis; thus we investigated the association of single nucleotide polymorphisms (SNPs) and haplotypes in GPR124 with risk of BAVM. Ten tagging SNPs spanning 39 kb of GPR124 were genotyped in 195 Caucasian BAVM patients and 243 Caucasian controls. SNP and haplotype association with risk of BAVM was screened using χ2 analysis. Associated variants were further evaluated using multivariable logistic regression, adjusting for age and sex. The minor alleles of 3 GPR124 SNPs adjacent to exon 2 and localized to a 16 kb region of high linkage disequilibrium were associated with reduced risk of BAVM (rs7015566 A, P=0.001; rs7823249 T, P=0.014; rs12676965 C, P=0.007). SNP rs7015566 (intron 1) remained associated after permutation testing (additive model P=0.033). Haplotype analysis revealed a significant overall association (χ2=12.55, 4 df, P=0.014); 2 haplotypes (ATCC, P=0.006 and GGCT, P=0.008) were associated with risk of BAVM. We genotyped a known synonymous SNP (rs16887051) in exon 2, however genotype frequency did not differ between cases and controls. Sequencing of conserved GPR124 regions revealed a novel indel polymorphism in intron 2. Immunohistochemistry confirmed GPR124 expression in the endothelium with no qualitative difference in expression between BAVM cases and controls. SNP rs7015566 mapping to intron 1 of GPR124 was associated with BAVM susceptibility among Caucasians. Future work is focused on investigating this gene region.
PMCID: PMC3544200  PMID: 23329986
Angiogenesis; Genetics; Intracerebral hemorrhage; Risk factor; Vascular malformation
16.  Recent Trauma and Acute Infection as Risk Factors for Childhood Arterial Ischemic Stroke 
Annals of neurology  2012;72(6):850-858.
Trauma and acute infection have been associated with stroke in adults, and are prevalent exposures in children. We hypothesized that these environmental factors are independently associated with childhood arterial ischemic stroke (AIS).
In a case-control study nested within a cohort of 2.5 million children (≤ 19 years old) enrolled in an integrated health care plan (1993–2007), childhood AIS cases (n=126) were identified from electronic records and confirmed through chart review. Age- and facility-matched controls (n=378) were randomly selected from the cohort. Exposures were determined from review of medical records prior to the stroke diagnosis, or the same date for the paired controls; time windows were defined a priori.
A medical encounter for head or neck trauma within the prior 12 weeks was an independent risk factor for childhood AIS (odds ratio [OR] 7.5, 95% confidence interval [CI] 2.9, 19.3), present in 12% of cases (1.6% of controls). Median time from trauma to stroke was 0.5 days (interquartile range 0, 2 days); post-hoc redefinition of trauma exposure (prior 1 week) was more strongly associated with AIS: OR 39 (95% CI 5.1, 298). A medical encounter for a minor acute infection (prior 4 weeks) was also an independent risk factor (OR 4.6, 95% CI 2.6, 8.2), present in 33% of cases (13% of controls). No single infection type predominated. Only two cases had exposure to trauma and infection.
Trauma and acute infection are common independent risk factors for childhood AIS, and may be targets for stroke prevention strategies.
PMCID: PMC3539242  PMID: 23280836
17.  Correlates of heart rate recovery over 20 years in a population sample 
Medicine and science in sports and exercise  2012;44(2):10.1249/MSS.0b013e31822cb190.
Slow heart rate recovery (HRR) from a graded exercise treadmill test (GXT) is a marker of impaired parasympathetic reactivation that is associated with elevated mortality. Our objective was to test whether demographic, behavioral or coronary heart disease (CHD) risk factors during young adulthood were associated with the development of slow HRR.
Participants from the Coronary Artery Risk Development in Young Adults study underwent symptom-limited maximal GXT using a modified Balke protocol at baseline (1985–86) and 20-year follow-up (2005–06) examinations. HRR was calculated as the difference between peak heart rate (HR) and HR two-minutes following cessation of the GXT. Slow HRR was defined as 2-minute HRR < 22 beats·min−1.
In 2,730 participants who did not have slow HRR at baseline, mean HRR was 44 beats*min−1 (SD = 11) at baseline and declined to 40 beats·min−1 (SD=12) in 2005–06; slow HRR developed in 5% (n=135) of the sample by 2005–06. Female sex, black race, fewer years of education, obesity, cigarette smoking, higher depressive symptoms, higher fasting glucose, hypertension, metabolic syndrome and physical inactivity and low fitness were each associated with incident slow HRR. In a multivariable model higher BMI, larger waist, low education, fasting glucose and current smoking remained significantly associated with incident slow HRR. Increasing BMI (per SD higher) over follow-up and incident hypertension, diabetes and metabolic syndrome (in the subsets of participants who were free from those conditions at baseline), were each associated with a significantly elevated odds of incident slow HRR.
On average, HRR declines with aging; however, the odds of having slow HRR in early middle age is significantly associated with traditional CHD risk factors.
PMCID: PMC3838873  PMID: 21796053
Epidemiology; Cardiovascular Disease; Exercise; Autonomic Nervous System
18.  A Genome-Wide Investigation of Copy Number Variation in Patients with Sporadic Brain Arteriovenous Malformation 
PLoS ONE  2013;8(10):e71434.
Brain arteriovenous malformations (BAVM) are clusters of abnormal blood vessels, with shunting of blood from the arterial to venous circulation and a high risk of rupture and intracranial hemorrhage. Most BAVMs are sporadic, but also occur in patients with Hereditary Hemorrhagic Telangiectasia, a Mendelian disorder caused by mutations in genes in the transforming growth factor beta (TGFβ) signaling pathway.
To investigate whether copy number variations (CNVs) contribute to risk of sporadic BAVM, we performed a genome-wide association study in 371 sporadic BAVM cases and 563 healthy controls, all Caucasian. Cases and controls were genotyped using the Affymetrix 6.0 array. CNVs were called using the PennCNV and Birdsuite algorithms and analyzed via segment-based and gene-based approaches. Common and rare CNVs were evaluated for association with BAVM.
A CNV region on 1p36.13, containing the neuroblastoma breakpoint family, member 1 gene (NBPF1), was significantly enriched with duplications in BAVM cases compared to controls (P = 2.2×10−9); NBPF1 was also significantly associated with BAVM in gene-based analysis using both PennCNV and Birdsuite. We experimentally validated the 1p36.13 duplication; however, the association did not replicate in an independent cohort of 184 sporadic BAVM cases and 182 controls (OR = 0.81, P = 0.8). Rare CNV analysis did not identify genes significantly associated with BAVM.
We did not identify common CNVs associated with sporadic BAVM that replicated in an independent cohort. Replication in larger cohorts is required to elucidate the possible role of common or rare CNVs in BAVM pathogenesis.
PMCID: PMC3789669  PMID: 24098321
19.  High critical care usage due to pediatric stroke 
Neurology  2012;79(5):420-427.
To measure intensive care unit (ICU) admission, intubation, decompressive craniotomy, and outcomes at discharge in a large population-based study of children with ischemic and hemorrhagic stroke.
In a retrospective study of all children enrolled in a Northern Californian integrated health care plan (1993–2003), we identified cases of symptomatic childhood stroke (age >28 days through 19 years) from inpatient and outpatient electronic diagnoses and radiology reports, and confirmed them through chart review. Data regarding stroke evaluation, management, and outcomes at discharge were abstracted. Intensive care unit (ICU) admission, intubation, and decompressive neurosurgery rates were measured, and multivariate logistic regression was used to identify predictors of critical care usage and outcomes at discharge.
Of 256 cases (132 hemorrhagic and 124 ischemic), 61% were admitted to the ICU, 32% were intubated, and 11% were treated with a decompressive neurosurgery. Rates were particularly high among children with hemorrhagic stroke (73% admitted to the ICU, 42% intubated, and 19% received a decompressive neurosurgery). Altered mental status at presentation was the most robust predictor for all 3 measures of critical care utilization. Neurologic deficits at discharge were documented in 57%, and were less common after hemorrhagic than ischemic stroke: 48% vs 66% (odds ratio 0.5, 95% confidence interval 0.3–0.8). Case fatality was 4% overall, 7% among children admitted to the ICU, and was similar between ischemic and hemorrhagic stroke.
ICU admission is frequent after childhood stroke and appears to be justified by high rates of intubation and surgical decompression.
PMCID: PMC3405247  PMID: 22744664
20.  Fasting Insulin Level Is Positively Associated With Incidence of Hypertension Among American Young Adults 
Diabetes Care  2012;35(7):1532-1537.
Although hyperinsulinemia, a surrogate of insulin resistance, may play a role in the pathogenesis of hypertension (HTN), the longitudinal association between fasting insulin level and HTN development is still controversial. We examined the relation between fasting insulin and incidence of HTN in a large prospective cohort.
A prospective cohort of 3,413 Americans, aged 18–30 years, without HTN in 1985 (baseline) were enrolled. Six follow-ups were conducted in 1987, 1990, 1992, 1995, 2000, and 2005. Fasting insulin and glucose levels were assessed by a radioimmunoassay and hexokinase method, respectively. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% CIs of incident HTN (defined as the initiation of antihypertensive medication, systolic blood pressure ≥140 mmHg, or diastolic blood pressure ≥90 mmHg).
During the 20-year follow-up, 796 incident cases were identified. After adjustment for potential confounders, participants in the highest quartile of insulin levels had a significantly higher incidence of HTN (HR 1.85 [95% CI 1.42–2.40]; Ptrend < 0.001) compared with those in the lowest quartile. The positive association persisted in each sex/ethnicity/weight status subgroup. A similar dose-response relation was observed when insulin-to-glucose ratio or homeostatic model assessment of insulin resistance was used as exposure.
Fasting serum insulin levels or hyperinsulinemia in young adulthood was positively associated with incidence of HTN later in life for both men and women, African Americans and Caucasians, and those with normal weight and overweight. Our findings suggested that fasting insulin ascertainment may help clinicians identify those at high risk of HTN.
PMCID: PMC3379592  PMID: 22511258
21.  Association of SNPs from 17 Candidate Genes with Baseline Symptom-Limited Exercise Test Duration and Decrease in Duration over 20 Years: The CARDIA Fitness Study 
It is not known if the genes involved with endurance performance during young adulthood are also involved with changes in performance. We examined the associations of gene variants with symptom-limited exercise test duration at baseline and decrease in duration over 20 years.
Methods and Results
3,783 (1,835 Blacks 1,948 Whites) and 2,335 (1,035 Blacks 1,300 Whites) participants from CARDIA were included in the baseline and 20 year models, respectively. 217 SNPs in Blacks and 171 SNPs in Whites from 17 genes were genotyped. In Blacks, five SNPs in the ATP1A2, HIF1A, NOS3, and PPARGC1A loci tended to be associated (p<0.05) with baseline duration in a multivariate regression model. Blacks (n=99) with at least four of the most-favorable genotypes at these loci had approximately two minutes longer baseline duration than those with only two such genotypes (P<0.0001). In Whites, the HIF1A rs1957757 and PPARGC1A rs3774909 markers tended to be associated with baseline duration, but the association of a multimarker construct of the most-favorable genotypes at both SNPs with baseline duration was not statistically significant. In Whites, four SNPs in the AGT, AMPD1, ANG, and PPARGC1A loci tended to be associated with decrease in exercise duration over 20 years, and those (n=40) with all four favorable genotypes had 0.8 min less decline in duration compared to those with none or one (n=232) (P<0.0001).
In multimarker constructs, alleles at genes related to skeletal muscle Na+/K+ transport, hypoxia, and mitochondrial metabolism are associated with symptom-limited exercise test duration over time in adults.
PMCID: PMC3595020  PMID: 20952631
cardiorespiratory fitness; genotype; prospective study
22.  Association of Increased Upper Trunk and Decreased Leg Fat With 2-h Glucose in Control and HIV-Infected Persons 
Diabetes Care  2011;34(11):2448-2453.
Changes in body fat distribution and abnormal glucose metabolism are common in HIV-infected patients. We hypothesized that HIV-infected participants would have a higher prevalence of impaired glucose tolerance (IGT) compared with control subjects.
A total of 491 HIV-infected and 187 control participants from the second examination of the Study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM) underwent glucose tolerance testing (GTT). Multivariable regression was used to identify factors associated with GTT parameters.
The prevalence of impaired fasting glucose (IFG) (>110 mg/dL) was similar in HIV-infected and control participants (21 vs. 25%, P = 0.23). In those without IFG, the prevalence of IGT was slightly higher in HIV-infected participants compared with control subjects (13.1 vs. 8.2%, P = 0.14) and in HIV+ participants with lipoatrophy versus without (18.1 vs. 11.5%, P = 0.084). Diabetes detected by GTT was rare (HIV subjects 1.3% and control subjects 0%, P = 0.65). Mean 2-h glucose levels were 7.6 mg/dL higher in the HIV-infected participants (P = 0.012). Increased upper trunk subcutaneous adipose tissue (SAT) and decreased leg SAT were associated with 2-h glucose and IGT in both HIV-infected and control participants. Adjusting for adipose tissue reduced the estimated effects of HIV. Exercise, alcohol use, and current tenofovir use were associated with lower 2-h glucose levels in HIV-infected participants.
In HIV infection, increased upper trunk SAT and decreased leg SAT are associated with higher 2-h glucose. These body fat characteristics may identify HIV-infected patients with normal fasting glucose but nonetheless at increased risk for diabetes.
PMCID: PMC3198295  PMID: 21926283
23.  Fish oil, selenium, and mercury in relation to incidence of hypertension: a 20-year follow-up study 
Journal of internal medicine  2011;270(2):175-186.
Long-chain omega-3 polyunsaturated fatty acids (LCω3PUFAs), selenium (Se) and mercury (Hg) are three important components in fish. The cardioprotective effect of LCω3PUFA intake has been recognized; however, the hypothesis that this benefit may be greatest with high Se and low Hg levels has not been investigated.
A cohort of 4,508 American adults aged 18–30, without hypertension at baseline in 1985, were enrolled. Six follow-ups were conducted at exams in 1987, 1990, 1992, 1995, 2000 and 2005. Diet was assessed by a validated interviewer-administered quantitative food frequency questionnaire at exams in 1985, 1992 and 2005. Incident hypertension was defined as first occurrence at any follow-up examination of systolic blood pressure ≥ 140 mmHg, diastolic blood pressure ≥ 90 mmHg, or taking anti-hypertensive medication. Toenail clippings were collected in 1987, and Se and Hg levels were quantified by instrumental neutron-activation analysis.
Participants in the highest LCω3PUFAintake quartile had a significantly lower incidence of hypertension (Hazard Ratio: 0.65; 95% CI: 0.53–0.79; Ptrend<0.01) compared to those in the lowest quartile after adjustment for potential confounders. Docosahexaenoic acid showed a greater inverse association than eicosapentaenoic acid. The inverse association of LCω3PUFA intake with hypertension appeared more pronounced at higher Se and lower Hg levels, although interaction tests were statistically non-significant.
Out findings indicated that LCω3PUFA intake was inversely associated with incidence of hypertension. The prior hypothesis that the potential anti-hypertensive effect of LCω3PUFA intake varies depending on joint levels of Se and Hg received modest support, and cannot be ruled out.
PMCID: PMC3070957  PMID: 21205024
omega-3 polyunsaturated fatty acids; selenium; mercury; hypertension; effect modification
24.  Urgent Neurology Consultation from the Emergency Department for Transient Ischemic Attack 
PMCID: PMC3005542  PMID: 20825839
Transient Ischemic Attack; Referral and Consultation; Emergency Medicine; Stroke
25.  Imaging Data Reveal a Higher Pediatric Stroke Incidence than Prior U.S. Estimates 
Prior annualized estimates of pediatric ischemic stroke incidence have ranged from 0.54 to 1.2 per 100,000 U.S. children, but relied purely on diagnostic code searches to identify cases. We sought to obtain a new estimate using both diagnostic code searches and searches of radiology reports, and to assess the relative value of these two strategies.
Using the population of 2.3 million children (<20 years old) enrolled in a Northern Californian managed care plan (1993–2003), we performed electronic searches of (1) in-patient and out-patient diagnoses for ICD-9 codes suggestive of stroke and cerebral palsy (CP) and (2) radiology reports for keywords suggestive of infarction. Cases were confirmed through chart review. We calculated sensitivities and positive predictive values (PPV) for the two search strategies.
We identified 1,307 potential cases from the ICD-9 code search, and 510 from the radiology search. A total of 205 ischemic stroke cases were confirmed, yielding an ischemic stroke incidence of 2.4 per 100,000 person-years. The radiology search had a higher sensitivity (83%) than the ICD-9 code search (39%), although both had low PPV’s. For perinatal stroke, the sensitivity of the stroke ICD-9 codes alone was 12%, versus 57% for stroke and CP codes combined; the radiology search was again the most sensitive (87%).
Our incidence estimate doubles that of prior U.S. reports, a difference at least partially explained by our use of radiology searches for case identification. Studies relying purely on ICD-9 code searches may underestimate childhood ischemic stroke rates, particularly for neonates.
PMCID: PMC3387270  PMID: 19762687
Stroke; ischemic; Child; Neonatal; Incidence

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