Individual participant time-to-event data from multiple prospective epidemiologic studies enable detailed investigation into the predictive ability of risk models. Here we address the challenges in appropriately combining such information across studies. Methods are exemplified by analyses of log C-reactive protein and conventional risk factors for coronary heart disease in the Emerging Risk Factors Collaboration, a collation of individual data from multiple prospective studies with an average follow-up duration of 9.8 years (dates varied). We derive risk prediction models using Cox proportional hazards regression analysis stratified by study and obtain estimates of risk discrimination, Harrell's concordance index, and Royston's discrimination measure within each study; we then combine the estimates across studies using a weighted meta-analysis. Various weighting approaches are compared and lead us to recommend using the number of events in each study. We also discuss the calculation of measures of reclassification for multiple studies. We further show that comparison of differences in predictive ability across subgroups should be based only on within-study information and that combining measures of risk discrimination from case-control studies and prospective studies is problematic. The concordance index and discrimination measure gave qualitatively similar results throughout. While the concordance index was very heterogeneous between studies, principally because of differing age ranges, the increments in the concordance index from adding log C-reactive protein to conventional risk factors were more homogeneous.
C index; coronary heart disease; D measure; individual participant data; inverse variance; meta-analysis; risk prediction; weighting
Background The extent to which adult height, a biomarker of the interplay of genetic endowment and early-life experiences, is related to risk of chronic diseases in adulthood is uncertain.
Methods We calculated hazard ratios (HRs) for height, assessed in increments of 6.5 cm, using individual–participant data on 174 374 deaths or major non-fatal vascular outcomes recorded among 1 085 949 people in 121 prospective studies.
Results For people born between 1900 and 1960, mean adult height increased 0.5–1 cm with each successive decade of birth. After adjustment for age, sex, smoking and year of birth, HRs per 6.5 cm greater height were 0.97 (95% confidence interval: 0.96–0.99) for death from any cause, 0.94 (0.93–0.96) for death from vascular causes, 1.04 (1.03–1.06) for death from cancer and 0.92 (0.90–0.94) for death from other causes. Height was negatively associated with death from coronary disease, stroke subtypes, heart failure, stomach and oral cancers, chronic obstructive pulmonary disease, mental disorders, liver disease and external causes. In contrast, height was positively associated with death from ruptured aortic aneurysm, pulmonary embolism, melanoma and cancers of the pancreas, endocrine and nervous systems, ovary, breast, prostate, colorectum, blood and lung. HRs per 6.5 cm greater height ranged from 1.26 (1.12–1.42) for risk of melanoma death to 0.84 (0.80–0.89) for risk of death from chronic obstructive pulmonary disease. HRs were not appreciably altered after further adjustment for adiposity, blood pressure, lipids, inflammation biomarkers, diabetes mellitus, alcohol consumption or socio-economic indicators.
Conclusion Adult height has directionally opposing relationships with risk of death from several different major causes of chronic diseases.
Height; cardiovascular disease; cancer; cause-specific mortality; epidemiological study; meta-analysis
To assess whether markers of acculturation (birthplace, number of U.S. generations) and socioeconomic status (SES) are associated with carotid artery plaque, internal carotid intima-media thickness (IMT), and albuminuria, in four racial/ethnic groups.
Using Multi-Ethnic Study of Atherosclerosis data (n = 6,716; age: 45-84) and race-specific binomial regression models, we computed prevalence ratios, adjusted for demographics and traditional cardiovascular risk factors.
The adjusted U.S. to foreign-born prevalence ratio (99% CI) for carotid plaque was 1.20 (0.97, 1.39) in Whites, 1.91 (0.94, 2.94) in Chinese, 1.62 (1.28, 2.06) in Blacks, and 1.23 (1.15, 1.31) in Hispanics. Greater carotid plaque prevalence was also found among Whites, Blacks, and Hispanics with more generations of US residence (p<0.001). Lower educational attainment and/or income were associated with greater carotid plaque prevalence in Whites and Blacks. Similar associations were observed with IMT. There was also some evidence of an inverse association between albuminuria and SES, in Whites and Hispanics.
Greater U.S. acculturation and lower SES were associated with a higher prevalence of carotid plaque and IMT, while little association was found with albuminuria.
Lp(a); venous thrombosis; pulmonary embolus; risk factors; prospective study; epidemiology
How 9p21 variation affects risk of cardiovascular disease is unclear, so we assessed whether 9p21 variants are associated with arterial elasticity or retinal microvascular findings.
In the prospective Multi-Ethnic Study of Atherosclerosis (MESA) we assessed 378 SNPs in the 9p21 locus. Within four ethnic groups, we used an additive genetic model to relate the 9p21 SNPs to five vascular phenotypes: small and large elasticity derived from radial diastolic pulse contour analysis; Young’s elastic modulus from carotid artery ultrasound measurements; and the diameter of the central retinal arteries and veins.
In neither ethnic-specific nor pooled data was there any statistically significant association between any of the 9p21 SNPs and any of the five vascular phenotypes.
Our study does not support an association of 9p21 variation with arterial elasticity or retinal microvascular abnormalities.
Prospective study; 9p21 SNP; retinal microvascular abnormalities; arterial elasticity
The association of individual fatty acids with ischemic stroke has not been thoroughly studied, and results have been inconsistent. Few prospective studies have systematically explored the association of biomarkers of fatty acid intake with stroke. The aim of this study was to explore which individual plasma fatty acids would be associated with higher risk of ischemic stroke among whites.
We studied 3,870 white men and women from the Minneapolis field center of the Atherosclerosis Risk in Communities (ARIC) Study, aged 45–64 at baseline (1987–89) who had plasma cholesterol ester (CE) and phospholipid (PL) fatty acids measured. Participants were followed through 2008 for incident ischemic stroke. Hazard ratios (HRs) with 95% confidence intervals (CIs) across quartiles of each fatty acid, measured as the percentage of total fatty acids, were calculated using Cox proportional hazards model.
During a maximum of 22-years of follow-up, we identified 168 cases of ischemic stroke. After adjustment for age and sex, plasma levels of saturated fatty acids were associated positively: HR (95%CI) of the highest quartile vs the lowest quartile for CE fraction was 1.93 (1.23–3.04), p for trend =0.01 and that for PL fraction was 1.64 (1.05–2.57), p for trend =0.03. There was also a positive linear association with monounsaturated fatty acids, especially with palmitoleic acid: HR (95%CI) of the highest quartile vs the lowest quartile for CE fraction was 1.86 (1.20–2.87), p for trend =0.003 for CE; and those for PL fraction was 1.52 (0.99–2.34), p for trend =0.005. No associations of ω-3 and ω-6 polyunsaturated fatty acids with ischemic stroke were observed, but linoleic acid was inversely and nonlinearly associated with ischemic stroke: HR (95%CI) of the highest quartile vs the lowest quartile for CE fraction was 0.64 (0.43–0.97), p for trend =0.13 and that for PL fraction was 0.69 (0.45–1.05), p for trend =0.24. These associations were generally unchanged after adjustment for cardiovascular risk factors.
In this US cohort of whites, we found significant positive associations of plasma saturated and monounsaturated fatty acids, especially of palmitoleic acid, with ischemic stroke. We also found an inverse nonlinear association between linoleic acid and ischemic stroke.
longitudinal study; epidemiology; fat; biomarkers; risk factors
Plasma lipoprotein-associated phospholipase A2 (Lp-PLA2) is an inflammatory marker associated positively with atherothrombotic risk. Whether Lp-PLA2 is related to risk of venous thromboembolism (VTE) is incompletely studied.
We assessed Lp-PLA2 activity in 10,687 Atherosclerosis Risk in Communities (ARIC) Study participants and followed them a median of 8.3 years (from 1996–98 through 2005) for VTE occurrence (n = 226).
There was no significant association between baseline Lp-PLA2 quartiles and risk of VTE, neither overall nor stratified as provoked or unprovoked. Adjusted for other risk factors, the hazard ratios (95% confidence interval) of total VTE across quartiles of Lp-PLA2 were 1.0 (reference), 0.95 (0.64, 1.42), 1.03 (0.69, 1.56), and 1.26 (0.83, 1.91). In the subset of participants with LDL-cholesterol ≥ 130 mg/dL, hazard ratios of total VTE were 1.00, 1.39 (0.44, 4.44), 2.45 (0.84, 7.11), and 2.84 (0.99, 8.14).
Our study does not support the overall hypothesis that elevated Lp-PLA2 contributes to VTE occurrence in the general population. However, in the presence of high LDL-cholesterol there was some evidence that Lp-PLA2 may increase VTE risk.
lipoprotein-associated phospholipase A2; prospective study; pulmonary embolism; venous thromboembolism
Height is inversely associated with incident coronary disease and total stroke, but few studies have examined the association between height and intraparenchymal hemorrhage. We hypothesized height would be inversely associated with incident intraparenchymal hemorrhage in the combined cohorts of the Atherosclerosis Risk in Communities Study and the Cardiovascular Health Study.
Data on Caucasian and African American participants were used to estimate the association of height at baseline with incident intraparenchymal hemorrhage verified by MD review of medical records and imaging reports. Sex-specific Cox proportional hazards regression models were used to calculate hazard ratios.
A total of 20,983 participants initially free of stroke (11,788 women, 9,195 men) were followed for an average of 15.9 years (SD = 5.1 years). Incident intraparenchymal hemorrhage occurred in 115 women and 73 men. Sex, but not age, race, study or blood pressure, modified the association, p = 0.03. After adjustment for risk factors (age, systolic blood pressure, triglycerides, LDL-cholesterol, fibrinogen and race), among women, height was significantly inversely associated with incident intraparenchymal hemorrhage [hazard ratio per standard deviation (6.3 cm) = 0.81, 95% CI (0.66 – 0.99)], p = 0.04. The hazard ratio (95% CI) for tertile 3 versus 1 in women was 0.63 (0.37–1.08). Among men, height was not linearly associated with incident intraparenchymal hemorrhage [hazard ratio per standard deviation (6.7 cm) = 1.09, 95% CI (0.84 – 1.40)], p = 0.52.
This large prospective study provides evidence that shorter height may be a risk factor for incident intraparenchymal hemorrhage in women.
Background and Purpose
Increased levels of plasma troponins and natriuretic peptides are associated with increased risk of cardiovascular disease, but only limited information exists on these biomarkers and stroke occurrence. In a prospective epidemiological study, we tested the hypothesis that high-sensitivity troponin T (TnT) and N-terminal pro B-type natriuretic peptide (NT-proBNP) are associated positively with incidence of stroke.
The Atherosclerosis Risk in Communities (ARIC) Study measured plasma TnT and NT-proBNP in 10,902 men or women initially free of stroke and followed them for a mean of 11.3 years for stroke occurrence (n=507).
Both biomarkers were associated positively with total stroke, nonlacunar ischemic, and especially, cardioembolic stroke, but not with lacunar or hemorrhagic stroke. For example, after adjustment for prevalent risk factors and cardiac diseases, the hazard ratios (95% confidence intervals) for jointly high values of TnT and NT-proBNP (versus neither biomarker high) were 2.70 (1.92, 3.79) for total stroke and 6.26 (3.40, 11.5) for cardioembolic stroke. Associations with stroke appeared somewhat stronger for NT-proBNP than TnT. Strikingly, approximately 58% of cardioembolic strokes occurred in the highest quintile of pre-stroke NT-proBNP, and 32% of cardioembolic strokes occurred in participants who had both NT-proBNP in the highest quintile and were known by ARIC to have atrial fibrillation sometime before their cardioembolic stroke occurrence.
In the general population, elevated plasma TnT and NT-proBNP concentrations are associated with increased risk of cardioembolic and other nonlacunar ischemic strokes.
epidemiology; natriuretic peptides; risk factors; stroke; troponins
To evaluate the associations of high sensitivity Troponin T (Hs-TnT), N-terminal pro-brain natriuretic peptide (NT-proBNP), and high sensitivity C-reactive protein (Hs-CRP) with mortality from any cause, cardiovascular disease (CVD), coronary heart disease (CHD), stroke, cancer, and respiratory disease in the Atherosclerosis Risk in Communities (ARIC) cohort.
11193 participants aged 54-74 years, initially free of the conditions being studied, had biomarkers measured and were followed for a mean of 9.9 years.
Hazard ratios (HR), adjusted for multiple risk factors, for mortality in participants in the highest Hs-TnT category compared to those with undetectable levels were: total 3.42 (95% Confidence Interval: 2.75-4.26), CVD 7.34 (4.64-11.6), CHD 6.06 (2.91-12.6), stroke 3.31 (1.26-8.66), cancer 1.60 (1.08-2.38) and respiratory 3.85 (1.39-10.7). Comparing the highest NT-proBNP quintile to those in the lowest quintile, the adjusted HRs for mortality were: total 3.05 (2.46-3.77), CVD 7.48 (4.67-12.0), CHD 4.07 (2.07-7.98) and stroke 10.4 (2.26-47.7). Comparing extreme Hs-CRP quintiles, the adjusted HRs for mortality were: total 1.61 (1.32-1.97), CVD 1.76 (1.19-2.62) and respiratory 3.36 (1.34-8.45). Having multiple markers elevated simultaneously greatly increased cause-specific mortality risks.
Greater levels of Hs-TnT, NT-proBNP and Hs-CRP are associated with increased risk of death, not just from cardiovascular disease but also from some non-cardiovascular causes.
biomarkers; troponin T; B natriuretic peptide; C- reactive protein; mortality
This study evaluated the prevalence of ideal cardiovascular (CV) health in the Atherosclerosis Risk in Communities Study and determined its relationship with prevalent retinopathy, wider retinal venular diameters, and narrower arteriolar diameters, which are risk markers for subclinical cerebrovascular disease and are associated with increased stroke and coronary heart disease (CHD) morbidity and mortality.
Methods and Results
We used gradings of fundus photography measurements from the Atherosclerosis Risk in Communities Study to examine the association of retinopathy and retinal arteriolar and venular calibers to the number of ideal CV health metrics. Prevalent retinopathy showed a graded relationship with the CV health categories and number of ideal CV health metrics present: retinopathy prevalence was 2.1% among those with ≥5 ideal CV health metrics compared with 13.1% among those with zero ideal CV health metrics (odds ratio [CI]), 4.8 [2.5 to 8.9]). Central retinal venule equivalent and central retinal arteriolar equivalent diameters also showed graded relationships with CV health categories and number of ideal CV health metrics: after adjustment for age, race, sex, and education, mean central retinal venular equivalent was 187.8 μm (95% CI, 186.9 to 188.6 μm) among those with ≥5 ideal CV health metrics compared with 201.1 μm (95% CI, 199.1 to 203.1 μm) among those with zero ideal CV health metrics. Mean central retinal arteriolar equivalent was 163.8 μm (95% CI, 163.0 to 164.5 μm) among those with ≥5 ideal CV health metrics compared with 157.9 μm (95% CI, 156.1 to 159.7 μm) among those with zero ideal CV health metrics.
Few adults had ideal cardiovascular health. Those with the best level of health were less likely to have retinopathy signs, wide retinal venules, and narrow retinal arterioles, which are associated with increased stroke and coronary heart disease risk.
cardiovascular diseases; cardiovascular health metrics; cerebrovascular circulation; epidemiology; risk factors
To determine whether the 9p21 SNP association with coronary heart disease is modified by other classical or novel risk markers.
The 9p21 SNP (rs10757274) and multiple risk markers were measured in the Atherosclerosis Risk in Communities Study, and incident coronary disease events were ascertained. Effect modification (interaction) of the 9p21 SNP with risk markers was tested in Cox proportional hazard regression models.
The incidence rates of coronary heart disease per 1000 person-years were 14.4, 17.0, and 18.7 for AA, AG, and GG genotypes, yielding hazard ratios of 1.0, 1.20 (95% CI = 1.07-1.36), and 1.34 (95% CI = 1.16-1.53). There was no meaningful evidence of an interaction (all p-interaction > 0.04) between 9p21 SNP and any of 14 other risk markers for coronary heart disease. These included novel markers not previously explored for 9p21 interaction (e.g., cardiac troponin T and N-terminal pro-brain natriuretic peptide).
Our study extends evidence that the 9p21 SNP association with coronary heart disease is not modified by classical or novel risk markers. Our findings therefore rule out additional plausible pathways by which 9p21 might have increased coronary heart disease risk.
coronary disease; prospective study; 9p21 SNP
Cardiovascular risk prediction models based on classical risk factors identified in epidemiologic cohort studies are useful in primary prevention of cardiovascular disease in individuals. This article briefly reviews aspects of cardiovascular risk prediction in the United States and efforts to evaluate novel risk factors. Even though many novel risk markers have been found to be associated with cardiovascular disease, few appear to improve risk prediction beyond the powerful, classical risk factors. A recent US consensus panel concluded that clinical measurement of certain novel markers for risk prediction was reasonable, namely, hemoglobin A1c (in all adults), microalbuminuria (in patients with hypertension or diabetes), and C-reactive protein, lipoprotein-associated phospholipase, coronary calcium, carotid intima-media thickness, and ankle/brachial index (in patients deemed to be at intermediate cardiovascular risk, based on traditional risk factors).
risk factors; coronary disease; cardiovascular disease; epidemiology
To determine whether the burden of leukoaraiosis and the number of brain infarcts, defined by MRI, are prospectively and independently associated with intraparenchymal hemorrhage (IPH) incidence in a pooled population-based study.
Among 4,872 participants initially free of clinical stroke in the Atherosclerosis Risk in Communities (ARIC) Study and the Cardiovascular Health Study (CHS), we assessed white matter grade (range 0–9), reflecting increasing leukoaraiosis, and brain infarcts using MRI. Over a median of 13 years of follow-up, 71 incident, spontaneous IPH events occurred.
After adjustment for other IPH risk factors, the hazard ratios (95% confidence intervals) across white matter grades 0–1, 2, 3, and 4–9 were 1.00, 1.68 (0.86–3.30), 3.52 (1.80–6.89), and 3.96 (1.90–8.27) (p for trend <0.0001). These hazard ratios were weakened only modestly (p for trend = 0.0003) with adjustment for MRI-defined brain infarcts. The IPH hazard ratios for 0, 1, 2, or ≥3 MRI-defined brain infarcts were 1.00, 1.97 (1.10–3.54), 2.00 (0.83–4.78), and 3.12 (1.31–7.43) (p for trend = 0.002), but these were substantially attenuated when adjusted for white matter grade (p for trend = 0.049).
Greater MRI-defined burden of leukoaraiosis is a risk factor for spontaneous IPH. Spontaneous IPH should be added to the growing list of potential poor outcomes in people with leukoaraiosis.
Background and Purpose
Carotid intima-media thickness (IMT) and electrocardiographic left ventricular hypertrophy (ECG-LVH) are two subclinical cardiovascular disease measures associated with increased risk of total and ischemic strokes. Increased IMT and ECG-LVH also may reflect end-organ hypertensive effects. Information is scant on the associations of these subclinical measures with intracerebral hemorrhage (ICH). We hypothesized that greater carotid IMT and the presence of ECG-LVH would be independently associated with increased ICH incidence.
Among 18,155 participants initially free of stroke in the Atherosclerosis Risk in Communities Study (ARIC) and the Cardiovascular Health Study (CHS), we assessed carotid IMT, carotid plaque, and ECG-LVH. Over a median of 18 years of follow-up, 162 incident ICH events occurred.
After adjustment for other ICH risk factors, carotid IMT was associated positively with incidence of ICH in both ARIC and CHS. The risk was lowest in study-specific quartile 1, elevated 1.6 to 2.6-fold in quartiles 2–3, and elevated 2.5 to 3.7-fold in quartile 4 (p<0.05 for both studies). In CHS, having a carotid plaque was associated with a 2-fold (95% CI = 1.1–3.4) greater ICH risk than having no plaque, but only 1.2-fold (95% CI = 0.76–2.0) greater ICH risk in ARIC. ECG-LVH carried a hazard ratio of ICH of 1.7 (95% CI = 0.77–3.7) in CHS and 2.8 (95% CI = 1.2–6.4) in ARIC.
Our data suggest that people with carotid atherosclerosis and possibly LVH are at increased risk not only of ischemic stroke but also of ICH.
atherosclerosis; left ventricular hypertrophy; intracerebral hemorrhage; prospective study; risk factors
To testthe hypothesis that inflammation measured by white blood cell count (WBC) and C-reactive protein (CRP) is associated positively with incident heart failure (HF).
Using the Atherosclerosis Risk in Communities (ARIC) Study, we conducted separate Cox proportional hazards regression analyses for WBC (measured 1987 to 1989) and CRP (measured 1996 to 1998) in relation to subsequent heart failure occurrence. A total of 14,485 and 9,978 individuals were included in the WBC and CRP analyses, respectively.
There were 1647 participants that developed HF during follow up after WBC assessment and 613 developed HF after CRP assessment. After adjustment for demographic variables and traditional HF risk factors, the hazard ratio (95% CI)for incident HF across quintiles of WBC was 1.0, 1.10 (0.9-1.34), 1.27(1.05-1.53), 1.44(1.19-1.74), and 1.62(1.34-1.96) (p trend <0.001); hazard ratio across quintiles of CRP was 1.0, 1.03 (0.68-1.55), 0.99 (0.66-1.51), 1.40 (0.94-2.09) and 1.70 (1.14-2.53) (p trend 0.002). Granulocytes appeared to drive the relation between WBCs and heart failure [hazard ratios across quintiles: 1.0, 0.93(0.76-1.15), 1.26 (1.04-1.53), 1.67(1.39-2.01) and 2.19 (1.83-2.61) (p trend <0.0001)], while lymphocytes or monocytes were not related.
Greater levels of WBC (especially granulocytes) and CRP are associated with increased risk of heart failure in middle-aged adults, independent of traditional risk factors.
Prospective Study; Risk Factors; Heart Failure; Inflammation; C-Reactive Protein; Leukocytes; Granulocytes
To estimate the prevalence of ideal cardiovascular health and its relation to incident cardiovascular disease (CVD).
An American Heart Association committee recently set a goal to improve the cardiovascular heath of Americans by 20% by 2020. The committee developed definitions of “ideal,” “intermediate,” or “poor” cardiovascular health for adults and children based on seven CVD risk factors or health behaviors.
We used data from the Atherosclerosis Risk in Communities (ARIC) Study cohort, aged 45–64 years, to estimate the prevalence of ideal cardiovascular health in 1987–89 and the corresponding incidence rates of CVD. Incident CVD comprised stroke, heart failure, myocardial infarction, or fatal coronary disease.
Among 12,744 participants initially free of CVD, only 0.1% had ideal cardiovascular health, 17.4% had intermediate cardiovascular health, and 82.5% had poor cardiovascular health. CVD incidence rates through 2007 showed a graded relation with the ideal, intermediate, and poor categories and with the number of ideal health metrics present: rates were one tenth as high in those with six ideal health metrics (3.9 per 1,000 person-years) compared with zero ideal health metrics (37.1 per 1,000 person-years).
In this community-based sample, few adults in 1987–9 had ideal cardiovascular health by the new AHA definition. Those who had the best levels of cardiovascular health nevertheless sustained relatively few events. Clearly, to achieve the AHA goal of improving cardiovascular health by 20% by 2020, we will need to redouble nationwide primordial prevention efforts at the population and individual levels.
epidemiology; risk factors; cardiovascular disease; stroke; coronary disease
Background and Purpose
Understanding associations of carotid atherosclerosis with stroke subtypes may contribute to more effective prevention of stroke.
Between 1987 and 1989, 13,560 men and women aged 45 to 64 years and free of clinical stroke, took part in the first examination of the Atherosclerosis Risk in Communities study. Incident strokes were ascertained by hospital surveillance.
During an average follow up of 15.7-years, 82 incident hemorrhagic and 621 incident ischemic strokes (131 lacunar, 358 nonlacunar, and 132 cardioembolic strokes) occurred. The incidence rates of hemorrhagic and ischemic strokes were greater across higher carotid intima-media thickness (IMT) levels. Although this positive association was observed for all stroke subtypes, the age-, sex-, and race-adjusted risk ratios (RR) were higher for cardioembolic and nonlacunar strokes than for hemorrhagic and lacunar strokes. Compared with participants in the lowest quintile (<0.61mm), the adjusted RRs for those in the highest quintile (≥0.85mm) of IMT were 2.55 (95%CI, 1.09 to 5.94) for hemorrhagic, 2.89 (95%CI, 1.50 to 5.54) for lacunar, 3.61 (95%CI, 2.33 to 5.99) for nonlacunar, and 6.12 (95%CI, 2.71 to 13.9) for cardioembolic stroke. The RRs were attenuated by additional adjustment for covariates, but remained statistically significant for nonlacunar and cardioembolic strokes (p for trend <0.001, respectively). The association between carotid IMT and lacunar stroke was somewhat stronger in African Americans than in whites (P for interaction = 0.07).
Carotid atherosclerosis was associated with increased risk of all stroke subtypes, but the association of carotid atherosclerosis with stroke may vary by subtypes.
Brain Infarction; Carotid artery; Epidemiology; Intima-media thickness; Stroke subtypes
D-dimer, a fibrin degradation product, is related to risk of cardiovascular disease and venous thromboembolism. Genetic determinants of D-dimer are not well characterized; notably, few data have been reported for African American (AA), Asian, and Hispanic populations.
Materials and Methods
We conducted a large-scale candidate gene association study to identify variants in genes associated with D-dimer levels in multi-ethnic populations. Four cohorts, comprising 6,848 European Americans (EAs), 2,192 AAs, 670 Asians, and 1,286 Hispanics in the NHLBI Candidate Gene Association Resource (CARe) consortium, were assembled. Approximately 50,000 genotyped SNPs in 2,000 cardiovascular disease gene loci were analyzed by linear regression, adjusting for age, sex, study site, and principal components in each cohort and ethnic group. Results across studies were combined within each ethnic group by meta-analysis.
Twelve SNPs in coagulation factor V (F5) and 3 SNPs in the fibrinogen alpha chain (FGA) were significantly associated with D-dimer level in EAs with p < 2.0×10−6. The signal for the most associated SNP in F5 (rs6025, F5 Leiden) was replicated in Hispanics (p = 0.023), while that for the top functional SNP in FGA (rs6050) was replicated in AAs (p = 0.006). No additional SNPs were significantly associated with D-dimer.
Our study replicated previously reported associations of D-dimer with SNPs in F5 (F5-Leiden) and FGA in EAs; we demonstrated replication of the association of D-dimer with FGA rs6050 in AAs and the F5-Leiden variant in Hispanics.
D-dimer; genetic association study; CARe consortium; single nucleotide polymorphisms
Background. The incidence of venous thromboembolism (VTE) is increased with severe kidney disease, but whether less-severe chronic kidney disease (CKD) increases the risk of VTE is less certain.
Methods. We studied this in a prospective cohort of 10 700 whites and African Americans, aged 53–75 years, attending Visit 4 (1996–98) of the Atherosclerosis Risk in Communities Study. Estimated glomerular filtration rate (eGFR) values were estimated from prediction equations based on serum creatinine (eGFRcreat) or cystatin C (eGFRcys). Normal kidney function was defined as eGFR ≥90 ml/min/1.73 m2, mildly decreased kidney function as eGFR between 60 and 89 ml/min/1.73 m2 and Stage 3 to 4 CKD as eGFR between 15 and 59 ml/min/1.73 m2. VTE occurrence (n = 228) was ascertained over a median of 8.3 years.
Results. For eGFRcys, the age-, race- and sex-adjusted hazard ratios of total VTE were 1.0, 1.40 and 1.94 (P trend = 0.003) for normal kidney function, mildly impaired kidney function and Stage 3 to 4 CKD, respectively. These respective hazard ratios were moderately attenuated to 1.0, 1.26 and 1.60 (P trend = 0.04) with adjustment for hormone replacement therapy, diabetes and body mass index. Associations between CKD based on eGFRcys and VTE were slightly stronger for idiopathic VTE than for secondary VTE. In contrast, CKD based on eGFRcreat was not associated with total VTE occurrence.
Conclusions. Stage 3 to 4 CKD, based on eGFRcys but not eGFRcreat, was associated with an approximately 1.6-fold increased risk of VTE.
chronic kidney disease; prospective study; pulmonary embolism; venous thromboembolism
Background and purpose
Although low glomerular filtration rate (GFR) and albuminuria are associated with increased risk of stroke, few studies compared their contribution to risk of ischemic versus hemorrhagic stroke separately. We contrasted the association of these kidney measures with ischemic versus hemorrhagic stroke.
We pooled individual participant data from four community-based cohorts: three from the United States and one from The Netherlands. GFR was estimated by using both creatinine and cystatin C, and albuminuria was quantified by urinary albumin-to-creatinine ratio (ACR). Associations of eGFR and ACR were compared for each stroke type (ischemic vs. intraparenchymal hemorrhagic) using study-stratified Cox-regression.
Amongst 29,595 participants (mean age 61 [SD 12.5] years, 46% males, 17% black), 1,261 developed stroke (12% hemorrhagic) during 280,549 person-years. Low eGFR was significantly associated with increased risk of ischemic, but not hemorrhagic, stroke risk, while high ACR was associated with both stroke types. Adjusted HRs for ischemic and hemorrhagic stroke at eGFR of 45 (vs. 95) ml/min/1.73m2 were 1.30 (95% CI, 1.01–1.68) and 0.92 (0.47–1.81), respectively. In contrast, the corresponding HR for ACR 300 (vs. 5) mg/g were 1.62 (1.27–2.07) for ischemic and 2.57 (1.37–4.83) for hemorrhagic stroke, with significantly stronger association with hemorrhagic stroke (P =0.04). For hemorrhagic stroke, the association of elevated ACR was of similar magnitude as that of elevated systolic blood pressure.
Whereas albuminuria showed significant association with both stroke types, the association of decreased eGFR was only significant for ischemic stroke. The strong association of albuminuria with both stroke types warrants clinical attention and further investigations.
We hypothesized that serum magnesium (Mg) is associated with increased risk of sudden cardiac death (SCD).
The Atherosclerosis Risk in Communities (ARIC) Study assessed risk factors and levels of serum Mg in a cohort of 45–64 year olds in 1987–1989 (n = 14,232). After an average of 12 years of follow-up we observed 264 cases of SCD, as determined by physician review of all suspected cases. We used proportional hazards regression to evaluate the association of serum Mg with risk of SCD.
Individuals in the highest quartile of serum Mg were at significantly lower risk of SCD in all models. This association persisted after adjustment for potential confounding variables, with an almost 40% reduced risk of SCD (HR=0.62, 95% CI=0.42–0.93) in quartile 4 vs. 1 of serum Mg observed in the fully-adjusted model.
This study suggests that low levels of serum Mg may be an important predictor of SCD, and warrants further research into the effectiveness of Mg supplementation for those considered to be at high risk for SCD.
sudden cardiac death; magnesium; cohort study
To document the incidence, case-fatality, and recurrence of venous thromboembolism (VTE) in women, and to explore the relation of demographic, lifestyle, and anthropometric factors to VTE incidence.
In 1986 Iowa women aged 55–69 completed a mailed survey. These data were linked to Medicare data for 1986–2004 (n=40,377) to identify hospitalized VTE cases. Cox regression adjusted for age, education, smoking status, physical activity, and BMI.
2,137 women developed VTE, yielding an incidence rate of 4.04/1,000 person-years. The 28-day case-fatality was 7.7% and the 1-year recurrence, 3.4%. Educational attainment and age-at-menopause were inversely associated with VTE, as was physical activity, prior to BMI adjustment. The risk of secondary (particularly cancer-related) VTE was increased in smokers compared with never smokers. BMI, waist circumference, waist-hip-ratio height, and diabetes were positively associated with VTE risk. Hormone replacement therapy use was associated with increased risk of idiopathic VTE, while parity was unrelated.
VTE is a significant source of morbidity and mortality in older women. Risk was elevated among women who were smokers, physically inactive, overweight, and diabetic, indicating that lifestyle contributes to VTE risk.
The incidence of venous thromboembolism (VTE) is increased in patients with albuminuria. However, whether a low serum albumin concentration is associated with increased risk of VTE has been a matter of controversy. We determined the association of serum albumin with VTE incidence in two large, prospective, population-based cohorts: the Atherosclerosis Risk in Communities (ARIC) Study (n = 15,300) and the Cardiovascular Health Study (CHS) (n = 5,400). Validated VTE occurrence (n=462 in ARIC and n=174 in CHS) was ascertained during follow-up. In both studies, after adjustment for age, sex, race, use of hormone replacement therapy, estimated GFR, history of cancer, and diabetes, serum albumin tended to be associated inversely with VTE. The adjusted hazard ratio per standard deviation lower albumin was 1.18 (95% CI = 1.08, 1.31) in ARIC and 1.10 (95% CI = 0.94, 1.29) in CHS. The hazard ratio for albumin below (versus above) the fifth percentile was 1.28 (95% CI = 0.90, 1.84) in ARIC and 1.80 (95% CI = 1.11, 2.93) in CHS. In conclusion, low serum albumin was a modest marker of increased VTE risk. The observed association likely does not reflect cause and effect, but rather that low serum albumin reflects a hyperinflammatory or hypercoagulable state. Whether this association has clinical relevance warrants further study.
albumin; prospective study; pulmonary embolism; venous thrombosis
Numerous studies have established that hormone replacement therapy increases the risk of venous thromboembolism (VTE), but an association of endogenous estrogen exposure with the incidence of VTE is not fully established. Using a prospective design combining the Atherosclerosis Risk in Communities and the Cardiovascular Health Study cohort, we studied the 12-year risk of VTE in relation to hormone replacement therapy use, age at menopause, parity number, and type of menopause in 8,236 post-menopausal women. There were no significant associations of age at menopause, parity number, or type of menopause with incidence of VTE. Women currently using hormone replacement had a 1.6-times higher multivariate-adjusted rate ratio (RR) of VTE compared with those without hormone use in the time-dependent model (RR=1.60, 95% CI, 1.06-2.36; Population attributable fraction=6.7%, 95%CI, 1.0-10.3). When we excluded women with 1-year or more duration of hormone therapy at baseline, the associations was stronger (RR=2.02, 95%CI, 1.31-3.12). The multivariate-adjusted RRs of VTE for current users tended to be higher in those with idiopathic VTE (RR=2.40, 95%CI, 1.40-4.12) than those with secondary VTE (RR=1.08, 95%CI, 0.63-1.85). Hormone replacement therapy is associated with increased risk of VTE, but reproductive history markers of endogenous estrogen exposure were not associated with VTE.
Epidemiology; Hormone therapy; Menopause; Risk factors; Venous thrombosis