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.
cardiorespiratory fitness; genotype; prospective study
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.
RESEARCH DESIGN AND METHODS
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.
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.
omega-3 polyunsaturated fatty acids; selenium; mercury; hypertension; effect modification
Transient Ischemic Attack; Referral and Consultation; Emergency Medicine; Stroke
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.
Stroke; ischemic; Child; Neonatal; Incidence
Brain arteriovenous malformations (BAVM) are high-flow vascular lesions prone to intracranial hemorrhage (ICH). Abnormal angiogenesis is a key characteristic of BAVM tissue. Angiopoietin-like 4 (ANGPTL4), a secreted glycoprotein, is thought to be involved in angiogenesis and required for proper postnatal blood vessel partitioning. We investigated whether common single nucleotide polymorphisms (SNPs) in ANGPTL4 were associated with risk of BAVM or ICH.
Methods and Results
We conducted a case-control study of 216 Caucasian BAVM cases and 246 healthy controls, and a secondary case-only analysis, comparing 83 ruptured (ICH) with 133 unruptured BAVM cases at presentation. Four tagSNPs in ANGPTL4 captured variation over a 10-kb region (rs2278236, rs1044250, rs11672433, and rs1808536) and were tested for association with BAVM or ICH. The minor allele (A) of rs11672433 (exon 6, Pro389Pro) was associated with an increased risk of BAVM (p = 0.006), which persisted after adjusting for multiple comparisons (p = 0.03). After adjustments for age and sex, carriers of the minor allele (A) remained at higher risk for BAVM compared to noncarriers (odds ratio, OR = 1.56; 95% confidence interval, CI = 1.01–2.41; p = 0.046) and risk of BAVM was increased with increasing copy of the minor A allele (OR = 1.49, 95% CI = 1.03–2.15; ptrend = 0.03). Five common haplotypes (frequency >1%) were inferred; overall haplotype distribution differed between BAVM cases and controls (χ2 = 12.2, d.f. = 4, p = 0.02). Neither SNPs (p > 0.05) nor haplotype distribution (χ2 = 1.1, d.f. = 4, p = 0.89) were associated with risk of ICH among BAVM cases.
A synonymous SNP in ANGPTL4 and haplotypes carrying it are associated with risk of BAVM but not with ICH presentation in BAVM cases.
Arteriovenous malformations; Cerebrovascular disorders; Epidemiology; Genetics; Intracranial hemorrhage
The association of SNPs from seven candidate genes, including genotype-by-baseline fitness and genotype-by-baseline body mass index (BMI) interactions, with incident hypertension over 20 years was investigated in 2663 participants (1301 blacks, 1362 whites) of the Coronary Artery Risk Development in Young Adults Study (CARDIA) Study. Baseline cardiorespiratory fitness was determined from duration of a modified Balke treadmill test. A total of 98 SNPs in blacks and 89 SNPs in whites from seven candidate genes were genotyped. Participants that became hypertensive (295 blacks and 146 whites) had significantly higher blood pressure and BMI (both races), and lower fitness (blacks only) at baseline than those who remained normotensive. Markers at the PPARGC1A and BDKRB2 genes were nominally associated with greater risk of hypertension, while one marker each at the BDKRB2 and NOS3 genes were nominally associated with lower risk. The association of baseline fitness with risk of hypertension was nominally modified by genotype at markers within the ACE, AGT, BDKRB2, and NOS3 genes in blacks and the BDKRB2, EDN1, and PPARGC1A genes in whites. BDKRB2 rs4900318 showed nominal interactions with baseline fitness on the risk of hypertension in both races. The association of baseline BMI with risk of hypertension was nominally modified by GNB3 rs2301339 genotype in whites. None of the above associations were statistically significant after correcting for multiple testing. We found that SNPs in these candidate genes did not modify the association between baseline fitness or BMI and risk of hypertension in CARDIA participants.
cardiorespiratory fitness; gene-environment interaction; blood pressure; genotype
This study examined prepregnancy cardiometabolic risk factors and gestational diabetes mellitus (GDM) in subsequent pregnancies. The authors selected 1,164 women without diabetes before pregnancy who delivered 1,809 livebirths between 5 consecutive examinations from 1985 to 2006 in the Coronary Artery Risk Development in Young Adults (CARDIA) Study. The authors measured prepregnancy cardiometabolic risk factors and performed multivariate repeated-measures logistic regression to compute the odds of GDM adjusted for race, age, parity, birth order, and other covariates. Impaired fasting glucose (100–125 vs. <90 mg/dL), elevated fasting insulin (>15–20 and >20 vs. <10 μU/mL), and low levels of high-density lipoprotein cholesterol (<40 vs. >50 mg/dL) before pregnancy were directly associated with GDM: The odds ratios = 4.74 (95% confidence interval (CI): 2.14, 10.51) for fasting glucose, 2.19 (95% CI: 1.15, 4.17) for middle insulin levels and 2.36 (95% CI: 1.20, 4.63) for highest insulin levels, and 3.07 (95% CI: 1.62, 5.84) for low levels of high-density lipoprotein cholesterol among women with a negative family history of diabetes; all P < 0.01. Among overweight women, 26.7% with 1 or more cardiometabolic risk factors developed GDM versus 7.4% with none. Metabolic impairment exists before GDM pregnancy in nondiabetic women. Interconceptual metabolic screening could be included in routine health assessments to identify high-risk women for GDM in a subsequent pregnancy and to potentially minimize fetal exposure to metabolic abnormalities that program future disease.
cohort studies; diabetes, gestational; lipids; longitudinal studies; obesity; preconception care; pregnancy; risk factors
We sought to replicate the association between the kinesin-like protein 6 (KIF6) Trp719Arg polymorphism (rs20455) and clinical coronary artery disease (CAD).
Recent prospective studies suggest that carriers of the 719Arg allele in KIF6 are at increased risk of clinical CAD compared with non-carriers.
The KIF6 Trp719Arg polymorphism (rs20455) was genotyped in nineteen case-control studies of non-fatal CAD either as part of a genome-wide association study or in a formal attempt to replicate the initial positive reports.
Over 17 000 cases and 39 000 controls of European descent as well as a modest number of South Asians, African Americans, Hispanics, East Asians, and admixed cases and controls were successfully genotyped. None of the nineteen studies demonstrated an increased risk of CAD in carriers of the 719Arg allele compared with non-carriers. Regression analyses and fixed effect meta-analyses ruled out with high degree of confidence an increase of ≥2% in the risk of CAD among European 719Arg carriers. We also observed no increase in the risk of CAD among 719Arg carriers in the subset of Europeans with early onset disease (<50 years of age for males and <60 years for females) compared with similarly aged controls as well as all non-European subgroups.
The KIF6 Trp719Arg polymorphism was not associated with the risk of clinical CAD in this large replication study.
kinesin-like protein 6; KIF6; coronary artery disease; myocardial infarction; polymorphism
Lower extremity fat mass (LEFM) has been shown to be favorably associated with glucose metabolism. However, it is not clear whether this relationship is similar across varying levels of obesity. We hypothesized that lower amounts of LEFM is associated with higher insulin resistance (IR) and this association may vary according to weight status. Participants with available measures were examined from the Coronary Artery Risk Development in Young Adults study (CARDIA), a multi-center longitudinal study of the etiology of atherosclerosis in black and white men and women aged 38–50 years old in 2005–2006 (n = 1,579). The homeostasis model assessment of IR (HOMAIR) was calculated to estimate IR, regional adiposity was measured using dual energy X-ray absorptiometry (DXA), and weight status was defined according to BMI categories. Obese and overweight participants exhibited higher IR, total fat mass (FM), trunk FM (TFM), and LEFM compared to normal weight participants. After controlling for age, height, race, study center, education, smoking, and cardiorespiratory fitness (CRF), greater LEFM was significantly associated with higher IR only in normal weight men and women. Further adjustment for TFM revealed that lower LEFM was significantly associated with higher IR in overweight and obese men and women and the positive association in normal weight individuals was attenuated. These results suggest that excess adiposity in the lower extremities may attenuate the metabolic risk observed at a given level of abdominal adiposity in overweight and obese individuals. Weight status presents additional complexity since the metabolic influence of adipose tissue may not be homogenous across anatomic regions or level of obesity.
To determine the prevalence of illicit drug use and the impact on HIV treatment.
Multivariable regression of cross-sectional data from 1163 HIV-infected and 294 controls from the Study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM).
An analysis of (1) prevalence of specific illicit drug use (ever, current), (2) being on HAART among those with an indication and (3) current HIV RNA and CD4 cell count among HAART users.
Median age was 42 years, approximately 50% were non-Caucasian and 33% were women. Eighty-six percent of HIV-infected and 67% of controls reported ever using illicit drugs (P <0.0001); 28% of HIV-infected and 16% of controls reported current use (P = 0.0001). In adjusted models, current cocaine use and past heroin use were associated with not currently being on HAART. Among HAART users, those reporting past heroin use were as likely to have an undetectable HIV viral load as those who had never used heroin. Current and past cocaine use and current heroin use was associated with lower odds of undetectable HIV RNA. Past amphetamine use was associated with having an undetectable HIV. Similar results were seen for CD4 lymphocyte counts.
Illicit drug use in the US is common, although far fewer report current use than past use. Among HIV-infected patients, understanding of the type of illicit drugs used and whether drug use was in the past or ongoing is important, because of their differential effects on HIV treatment outcomes.
amphetamines; cocaine; heroin; HIV; street drugs; viral load
Microalbuminuria is associated with increased risk of cardiovascular disease and mortality. The objective of the study was to evaluate if HIV infection was an independent risk factor for microalbuminuria.
The relationship between HIV infection and microalbuminuria was assessed using subjects enrolled in the study of Fat Redistribution and Metabolic Change in HIV Infection, which consists of HIV-positive and control men and women. Participants with proteinuria (dipstick ≥1+) were excluded.
Microalbuminuria (urinary albumin/creatinine ratio, ACR>30 mg/g) was present in 11% of HIV infected, and 2% of control participants (P<0.001); a fivefold odds after multivariate adjustment (odds ratio, 5.11; 95% confidence interval, 1.97–13.31; P=0.0008). Several cardiovascular risk factors were associated with higher ACR in HIV participants: insulin resistance (HOMA>4; 32%, P<0.0001), systolic blood pressure (21%, P=0.01 for 120–140 versus <120 mmHg, and 43%, P <0.06 for >140 versus <120 mmHg), and family history of hypertension (17%, P=0.03). Higher CD4 cell count was associated with lower albumin/creatinine ratio (−24%, P=0.009 for 200–400 versus <200 cells/ml and −26%, P=0.005 for >400 versus <200 cells/ml).
HIV infection had a strong and independent association with microalbuminuria, the severity of which was predicted by markers of insulin resistance, hypertension, and advanced HIV infection. These associations warrant further investigation, as the increased prevalence of microalbuminuria in HIV infection may be a harbinger of future risk of cardiovascular and kidney diseases.
Microalbuminuria; kidney; urine protein; insulin resistance; lipodystrophy
Although studies have reported a high prevalence of end-stage renal disease in human immunodeficiency virus (HIV)-infected individuals, little is known about moderate impairments in kidney function. Cystatin C measurement may be more sensitive than creatinine for detecting impaired kidney function in persons with HIV.
We evaluated kidney function in the Fat Redistribution and Metabolic Change in HIV Infection (FRAM) cohort, a representative sample of 1008 HIV-infected persons and 290 controls from the Coronary Artery Risk Development in Young Adults (CARDIA) study in the United States.
Cystatin C level was elevated in HIV-infected individuals; the mean±SD cystatin C level was 0.92±0.22 mg/L in those infected with HIV and 0.76±0.15 mg/L in controls (P<.001). In contrast, both mean creatinine levels and estimated glomerular filtration rates appeared similar in HIV-infected individuals and controls (0.87±0.21 vs 0.85±0.19 mg/dL [to convert to micromoles per liter, multiply by 88.4] [P=.35] and 110±26 vs 106±23 mL/min/1.73 m2 [P=.06], respectively). Persons with HIV infection were more likely to have a cystatin C level greater than 1.0 mg/L (OR, 9.8; 95% confidence interval, 4.4-22.0 [P<.001]), a threshold demonstrated to be associated with increased risk for death and cardiovascular and kidney disease. Among participants with HIV, potentially modifiable risk factors for kidney disease, hypertension, and low high-density lipoprotein concentration were associated with a higher cystatin C level, as were lower CD4 lymphocyte count and coinfection with hepatitis C virus (all P<.001).
Individuals infected with HIV had substantially worse kidney function when measured by cystatin Clevel compared with HIV-negative controls, whereas mean creatinine levels and estimated glomerular filtration rates were similar. Cystatin C measurement could be a useful clinical tool to identify HIV-infected persons at increased risk for kidney and cardiovascular disease.
The natural history of Chiari I malformation in children remains unclear.
In this population-based retrospective cohort study, we searched radiology reports from all head and spine MRI scans (n=5248) performed among 741, 815 children under age 20 within Kaiser Northern California, 1997–1998, for Chiari I. We reviewed medical records and imaging studies to determine clinical and radiographic predictors of significant neurologic symptoms defined as moderate to severe headache, neck pain, vertigo or ataxia.
The 51 patients identified with Chiari I represented 1% of children who had head or spine MRI scans performed during the study period. Headache (55%) and neck pain (12%) were the most common symptoms. Syringomyelia was present in 6 patients (12%) at time of initial diagnosis; no new syrinxes developed during follow-up. Older age at time of diagnosis was associated with increased risk of headache (OR 1.3, 95% CI 1.1–1.5) and significant neurologic symptoms (OR 1.2, 95% CI 1.04–1.4).
Chiari I, an under-recognized cause of headaches in children, is also frequently discovered incidentally in children without symptoms. Larger and longer-term studies are needed to determine the prognosis and optimal treatment of pediatric Chiari I.
The Study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM), initiated in 2000, investigates the prevalence and correlates of changes in fat distribution, insulin resistance, and dyslipidemia among human immunodeficiency virus (HIV)-infected men and women compared with a population-based group of control men and women. Between June 2000 and September 2002, 1,480 participants (1,183 HIV-infected persons and 297 controls) were enrolled in FRAM. Measurements taken included whole-body magnetic resonance imaging for quantification of regional fat, anthropometric measurements, central laboratory analysis of metabolites, and assessment of symptoms, sociodemographic factors, and lifestyle. Similar measurements were repeated among FRAM participants 4 years later (FRAM 2) for investigation of the progression of fat distribution changes, insulin resistance, and hyperlipidemia. In FRAM 2, which is ongoing, investigators are also determining the associations of subclinical cardiovascular disease, as measured by carotid intimal-medial wall thickness, with HIV infection, fat distribution changes, insulin resistance, and other proatherogenic changes in serum lipid levels. The demographic characteristics of HIV-infected FRAM men and women were comparable to those reported from a national random sampling of HIV-infected men and women receiving medical care in the United States. The representativeness of the FRAM sample increases its value as a resource for studies on fat distribution, metabolic changes, and atherosclerosis in HIV infection.
body fat distribution; dyslipidemias; HIV infections; insulin resistance; lipodystrophy; metabolism
Visceral obesity is associated with insulin resistance, but the association of other regional adipose depots with insulin resistance is not understood. In HIV infection, buffalo hump (upper trunk fat) is associated, but the association of upper trunk fat with insulin resistance has not been examined in controls. To determine the independent association of adipose depots other than visceral with insulin resistance, we performed a cross-sectional analysis of controls and HIV-infected subjects in the Fat Redistribution and Metabolic Change in HIV Infection (FRAM) study, who had measurements of glucose, insulin, and adipose tissue volumes by whole-body magnetic resonance imaging. We studied 926 HIV-positive persons from 16 academic medical center clinics and trials units with demographic characteristics representative of US patients with HIV infection and 258 FRAM controls from the population-based Coronary Artery Risk Development in Young Adults study. We measured visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) volume in the legs, arms, lower trunk (back and abdomen), and upper trunk (back and chest) and assessed their association with the homeostasis model of assessment (HOMA) and HOMA >4 by stepwise multivariable analysis. The prevalence of HOMA >4 as a marker of insulin resistance was 28% among controls compared with 37% among HIV-infected subjects (P = 0.005). Among controls, those in the highest tertile of upper trunk SAT volume had an odds ratio (OR) of 9.0 (95% confidence interval [CI]: 2.4 to 34; P = 0.001) for having HOMA >4 compared with the lowest tertile, whereas in HIV-positive subjects, the OR was lower (OR = 2.09, 95% CI: 1.36 to 3.19; P = 0.001). Among controls, the highest tertile of VAT volume had an OR of 12.1 (95% CI: 3.2 to 46; P = 0.0002) of having HOMA >4 compared with the lowest tertile, whereas in HIV-positive subjects, the OR was 3.12 (95% CI: 2.0 to 4.8; P < 0.0001). After adjusting for VAT and upper trunk SAT, the association of other SAT depots with HOMA >4 did not reach statistical significance. Thus, VAT and upper trunk SAT are independently associated with insulin resistance in controls and in HIV-infected persons.
buffalo hump; fat distribution; insulin resistance; lipodystrophy; visceral obesity
Background and Purpose
Gender differences in carotid endarterectomy (CEA) rates after transient ischemic attack (TIA) are not well studied, though some reports suggest that eligible men are more likely to have CEA than women after stroke.
We retrospectively identified all patients diagnosed with TIA and ≥70% carotid stenosis on ultrasound in 2003-2004 from 19 emergency departments. Medical records were abstracted for clinical data, 90-day follow-up events including stroke, cardiovascular events or death, CEA within 6 months, and post-operative 30-day outcomes. We assessed gender as a predictor of CEA and its complications, adjusting for demographic and clinical variables, as well as time to CEA between groups.
Of 299 patients identified, 47% were women. Women were older with higher presenting SBP and less likely to smoke or to have CAD or diabetes. Fewer women (36.4%) had CEA than men (53.8%) (p=0.004). Reasons for withholding surgical treatment were similar in women and men, and there were no differences in follow-up stroke, CV event, postoperative complications or death. Time to CEA was also significantly delayed in women.
Women with severe carotid stenosis and recent TIA are less likely to undergo CEA than men, and surgeries are more delayed.
 Epidemiology;  Carotid Stenosis;  Carotid endarterectomy;  Transient Ischemic Attacks
Background and Purpose
We propose to study possible differences in the associations between risk factors for cardiovascular disease (myocardial infarction and stroke) and Carotid Intima-Media thickness (IMT) measurements made at three different levels of the carotid bifurcation. Methods: Cross-sectional study of a cohort of Whites and African Americans of both genders with mean age 45 years. Traditional cardiovascular risk factors were determined in cohort members. Carotid IMT was measured from high-resolution B-mode ultrasound images at three levels: the common carotid artery (CCA), the carotid artery bulb (Bulb) and the internal carotid artery (ICA). Associations with risk factors were evaluated by multivariate linear regression analyses.
Of 3258 who underwent carotid IMT measurements, CCA, Bulb, and ICA IMT were measured at all three separate levels in 3023 (92.7%). A large proportion of the variability of CCA IMT was explained by cardiovascular risk factors (26.8%) but less so for the Bulb (11.2%) and ICA (8.0%). Carotid IMT was consistently associated with age, LDL-cholesterol, smoking and hypertension in all segments. Associations with fasting glucose and diastolic blood pressure were stronger for CCA than for the other segments. Hypertension, diabetes and current smoking had qualitatively stronger associations with Bulb IMT, and LDL cholesterol with ICA IMT. Conclusion: In our cohort of relatively young white and African-American men and women, a greater proportion of the variability in common carotid IMT can be explained by traditional cardiovascular risk factors than for the carotid artery bulb and internal carotid arteries.
Carotid Intimal Medial Thickness; Risk Factors; Carotid Ultrasound
Systematic differences between readers or equipment in imaging studies are not uncommon; failure to account for such differences when using Carotid Ultrasonography may introduce bias into associations between carotid intima media thickness (cIMT) and outcomes. We demonstrate the impact of this source of systematic measurement error (SME) using data on 5,521 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) and 661 participants from the Study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM). Participants were between 37 and 78 years old. Two outcomes were considered: (1) the effect of HIV infection on cIMT (between study) and (2) the association of cIMT with cardiovascular events (within study). All estimates were adjusted for demographics (age, gender, and ethnicity) and for traditional cardiovascular disease risk factors (smoking, blood pressure, diabetes and cholesterol). When comparing the FRAM and MESA cohorts to estimate the association of HIV infection on common cIMT, accounting for machine and reader variability (between study variability) reduced the difference associated with HIV infection from +0.080 mm (95% Confidence Interval (CI):0.065–0.095) to +0.037 mm (95% CI:0.003 to 0.072) while internal cIMT declined from +0.254 mm (95% CI:0.205–0.303) to +0.192 mm (95% CI:0.076–0.308). Attenuation of the association between cIMT and cardiovascular endpoints occurred when within study reader variability was not accounted for. The effect of SME due to use of multiple readers or machines is most important when comparisons are made between two different study populations. Within-cohort measurement error dilutes the association with events.
Carotid intima media thickness; Measurement error; Bias; Carotid ultrasonography
HIV infection and antiretroviral therapy are associated with dyslipidemia, but the association between regional adipose tissue depots and lipid levels is not defined.
The association of MRI-measured visceral (VAT) and regional subcutaneous adipose tissue (SAT) volume with fasting lipid parameters was analyzed by multivariable linear regression in 737 HIV-infected and 145 control men from the study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM).
HIV-infected men had higher median triglycerides (TG) (170mg/dl vs. 107mg/dl, p<0.0001), lower high density lipoprotein (HDL-C) (38mg/dl vs. 46mg/dl, p<0.0001) and lower low density lipoprotein (LDL-C) (105mg/dl vs. 125mg/dl, p<0.0001) than controls. After adjustment, greater VAT was associated with higher TG and lower HDL-C in both HIV-infected and control men, while greater leg SAT was associated with lower TG in HIV-infected men with a similar trend in controls. More upper trunk SAT was associated with higher LDL-C and lower HDL-C in controls, while more lower trunk SAT was associated with higher TG in controls. After adjustment, HIV infection remained strongly associated (p<0.0001) with higher TG (+76%, CI: 53, 103), lower LDL-C (−19%, CI: −25,−12), and lower HDL-C (−18%, CI: −22,−12).
HIV-infected men are more likely than controls to have higher TG and lower HDL-C, which promote atherosclerosis, but also lower LDL-C. Less leg SAT and more VAT are important factors associated with high TG and low HDL-C in HIV-infected men. The reduced leg SAT in HIV-infected men with lipoatrophy places them at increased risk for pro-atherogenic dyslipidemia.
High-density lipoprotein cholesterol (HDL-C) levels in premenopausal and postmenopausal women are differentially affected by exogenous sex hormones depending on their apolipoprotein E (apo E) genotype. Because endogenous sex hormones markedly increase during pregnancy, we examined whether HDL-C declines after a first birth varied by apo E polymorphisms.
In 1147 nulliparas (416 black, 731 white), fasting blood samples (nonpregnant) were drawn at baseline and at follow-up years 5, 7, and 10. Time-dependent pregnancy groups included 0 pregnancies (P0), 1+ short pregnancy (P1+), 1 birth (B1), 2 or more births (B2+). ApoE groups by alleles identified with a phenotype method included E4 (4/3 and 4/4), E3 (3/3), and E2 (2/2 and 3/2). Differences in adjusted mean HDL-C changes among pregnancy groups and ApoE groups were examined using repeated measures multiple linear regression.
HDL-C declines associated with parity (one or more births) depended on ApoE group (ApoE*Pregnancy Interaction; p < 0.002). For B1 and B2+ vs. P0, HDL-C declines were −2.4 to −2.7 mg/dl in E4 and −3.4 to −4.1 mg/dl in E3. In E2, HDL-C declines were −6.6 mg/dl for one birth, and −11.5 mg/dl for two or more births, each relative to the 0 pregnancies (P0) group (linear trend, p < 0.001).
The degree to which childbearing adversely affects long-term HDL-C declines varies by apo E phenotype, based on a method that accurately classifies genotype. Our findings show that 2/2 and 3/2 genotypes are associated with larger parity-related HDL-C declines than 3/3, 4/3, and 4/4 genotypes.
Fitness and physical activity are each inversely associated with the development of hypertension. We tested whether fitness and physical activity were independently associated with the 20-year incidence of hypertension in 4618 men and women. Hypertension was determined in participants who had systolic blood pressure (SBP)≥140 mmHg or diastolic blood pressure (DBP) ≥90 mmHg or who reported antihypertensive medication use. Fitness was estimated based on the duration of a symptom-limited graded exercise treadmill test and physical activity was self-reported. The incidence rate of hypertension was 13.8 per 1000 person-years (n=1022). Both baseline fitness (hazard ratio [HR]=0.63, 95% confidence interval [CI]: 0.56, 0.70 per standard deviation [SD; 2.9 minutes]) and physical activity (HR=0.86, 95% CI: 0.79, 0.84 per SD [297 exercise units]) were inversely associated with incident hypertension when included jointly in a model that also adjusted for age, sex, race, baseline smoking status, SBP, alcohol intake, HDL cholesterol, dietary fiber, dietary sodium, fasting glucose and BMI. The magnitude of association between physical activity and hypertension was strongest among participants in the high fitness (HR= 0.80, 95% CI: 0.68, 0.94) category, whereas the magnitude of association between fitness and hypertension was similar across tertiles of physical activity. The estimated proportion of hypertension cases that could be prevented if participants moved to a higher fitness category (i.e., preventive fraction) was 34% and varied by race and sex group. Fitness and physical activity are each associated with incident hypertension, and low fitness may account for a substantial proportion of hypertension incidence.
epidemiology; exercise; ethnicity; risk factors; special populations
Estimating risk of intracranial hemorrhage (ICH) for patients with unruptured brain arteriovenous malformations (AVMs) in the natural course is essential for assessing risks and benefits of treatment. Traditionally, the survival period starts at the time of diagnosis and ends at ICH, but most patients are quickly censored because of treatment. Alternatively, a survival period from birth to first ICH, censoring at the date of diagnosis, has been proposed. The authors quantitatively compared these 2 timelines using survival analysis in 1,581 Northern California brain AVM patients (2000–2007). Time-shift analysis of the birth-to-diagnosis timeline and maximum pseudolikelihood identified the point at which the 2 survival curves overlapped; the 95% confidence interval was determined using bootstrapping. Annual ICH rates per 100 patient-years were similar for both the birth-to-diagnosis (1.27, 95% confidence interval (CI): 1.18, 1.36) and the diagnosis-to-ICH (1.17, 95% CI: 0.89, 1.53) timelines, despite differences in curve morphology. Shifting the birth-to-diagnosis timeline an optimal amount (10.3 years, 95% CI: 3.3, 17.4) resulted in similar ICH survival curves (P = 0.979). These results suggest that the unconventional birth-to-diagnosis approach can be used to analyze risk factors for natural history risk in unruptured brain AVM patients, providing greater statistical power. The data also suggest a biologic change around age 10 years influencing ICH rate.
arteriovenous malformations; intracranial hemorrhages; risk factors; survival analysis
COPD is a major cause of disability, but little is known about how disability develops in this condition.
We analyzed data from the FLOW (Function, Living, Outcomes, and Work) Study which enrolled 1,202 Kaiser Permanente Northern California members with COPD at baseline and re-evaluated 1,051 subjects at 2 year follow-up. We tested the specific hypothesis that the development of specific non-respiratory impairments (abnormal body composition and muscle strength) and functional limitations (decreased lower extremity function, poor balance, mobility-related dyspnea, reduced exercise performance, and decreased cognitive function) will determine the risk of disability in COPD, after controlling for respiratory impairment (FEV1 and oxygen saturation). The Valued Life Activities Scale was used to assess disability in terms of a broad range of daily activities. The primary disability outcome measure was defined as an increase in the proportion of activities that cannot be performed of 3.3% or greater from baseline to 2-year follow-up (the estimated minimal important difference). Multivariable logistic regression was used for analysis.
Respiratory impairment measures were related to an increased prospective risk of disability (multivariate OR 1.75; 95% CI 1.26 to 2.44 for 1 litre decrement of FEV1 and OR 1.57 per 5% decrement in oxygen saturation; 95% CI 1.13 to 2.18). Non-respiratory impairment (body composition and lower extremity muscle strength) and functional limitations (lower extremity function, exercise performance, and mobility-related dyspnea) were all associated with an increased longitudinal risk of disability after controlling for respiratory impairment (p<0.05 in all cases). Non-respiratory impairment and functional limitations were predictive of prospective disability, above-and-beyond sociodemographic characteristics, smoking status, and respiratory impairment (area under the receiver operating characteristic curve increased from 0.65 to 0.75; p<0.001).
Development of non-respiratory impairment and functional limitations, which reflect the systemic nature of COPD, appear to be critical determinants of disablement. Prevention and treatment of disability require a comprehensive approach to the COPD patient.
Although COPD is a common cause of death and disability, little is known about the effects of socioeconomic status (SES) and race-ethnicity on health outcomes.
We aimed to determine the independent impacts of SES and race-ethnicity on COPD severity status, functional limitations, and acute exacerbations of COPD among patients with access to health care. Data were used from the FLOW cohort study of 1,202 Kaiser Permanente Northern California Medical Care Plan members with COPD.
Lower educational attainment and household income were consistently related to greater disease severity, poorer lung function, and greater physical functional limitations in cross-sectional analysis. Black race was associated with greater COPD severity, but these differences were no longer apparent after controlling for SES variables and other covariates (comorbidities, smoking, body mass index, and occupational exposures). Both lower education and income were independently related to a greater prospective risk of acute COPD exacerbation (HR 1.5; 95% CI 1.01 to 2.1; and HR 2.1; 95% CI 1.4 to 3.4, respectively).
Low SES is a risk factor for a broad array of adverse COPD health outcomes. Clinicians and disease management programs should consider SES as a key patient-level marker of risk for poor outcomes.