N. L. Smith

Association of cholesterol with stroke risk varies in stroke subtypes and patient subgroups

Objective: To perform a health maintenance organization–based case-control study to evaluate the association of total and high density lipoprotein (HDL) cholesterol with the risk of stroke subtypes and in patient subgroups. Methods: Cases had a confirmed incident ischemic stroke (n = 1,242) or hemorrhagic stroke (n = 313). Controls (n = 6,455) were identified in a companion myocardial infarction study. Risk of stroke was modeled using logistic regression. Results: The highest total cholesterol quintile was associated with an increased risk of ischemic stroke compared to the lowest quintile (OR = 1.6, 95% CI 1.3 to 2.0) with the strongest subtype associations for atherosclerotic stroke (OR = 3.2) and lacunar stroke (OR = 2.4). The highest HDL cholesterol quintile was associated with a decreased risk of ischemic stroke compared to the lowest quintile (OR = 0.8, CI 0.6 to 1.0). Subgroup analyses suggested that the total cholesterol association was more important for patients < 66 years of age and those with HDL < 50 mg/dL; the HDL association was more important for patients without diabetes or atrial fibrillation. The second through fourth total cholesterol quintiles were associated with a decreased risk of hemorrhagic stroke compared to the lowest quintile (OR = 0.7, CI 0.5 to 1.0). Conclusions: Higher total and lower HDL cholesterol levels were associated with increased risk of ischemic stroke, especially certain stroke subtypes and patient subgroups. The lowest levels of total cholesterol were associated with an increased risk of all hemorrhagic strokes.

Blood pressure control and risk of incident atrial fibrillation

BACKGROUND Atrial fibrillation (AF) is a common arrhythmia that affects more than 2 million people in the United States. We sought to determine whether the risk of incident AF among patients treated for hypertension differs by the degree of blood pressure control. METHODS A population-based, case-control study of 433 patients with verified incident AF and 899 controls was conducted to investigate the relationship between average achieved systolic (SBP) and diastolic (DBP) blood pressure and risk of AF. All patients were members of an integrated health-care delivery system and were pharmacologically treated for hypertension. Medical records were reviewed to confirm the diagnosis of new onset AF and to collect information on medical conditions, health behaviors, and measured blood pressures. Average achieved SBP and DBP were calculated from the three most recent outpatient blood pressure measurements. RESULTS Compared with the reference level of 120-129 mm Hg, for categories of average achieved SBP of <120, 130-139, 140-149, 150-159, 160-169, and > or =170 mm Hg, the odds ratios (ORs; 95% confidence interval (CI)) for incident AF were 1.99 (1.10, 3.62), 1.19 (0.78, 1.81), 1.40 (0.93, 2.09), 2.02 (1.30, 3.15), 2.27 (1.31, 3.93), and 1.84 (0.89, 3.80), respectively. Based on the population attributable fraction, we estimated that, among patients with treated hypertension, 17.2% (95% CI 4.3%, 28.3%) of incident AF was attributable to an average achieved SBP > or =140 mm Hg. CONCLUSION Among patients treated for hypertension, uncontrolled elevated SBP and SBP <120 mm Hg were associated with an increased risk of incident AF.

HMG-CoA reductase inhibitors and the risk of venous thrombosis among postmenopausal women

In addition to lowering blood lipid levels, statins (HMG CoA reductase inhibitors) inhibit platelet aggregation and maintain a favorable balance between prothrombotic and fibrinolytic mechanisms [1]. Perhaps these effects may account for the association of statins with a reduced risk of venous thrombosis [2,3]. Because different statins have different properties [4], the possibility that the risk of venous thrombosis varied by specific statin was also investigated. A population-based case–control study was conducted at Group Health Cooperative (GHC), a large health maintenance organization in western Washington state, USA. Cases were all postmenopausal women aged 30–89 years who had a first venous thrombosis between January 1, 1995 and December 31, 2000. This particular case-control study is one of several on-going case-control studies that share a single control group, which presents a stratified random sample of postmenopausal female Group Health members. For historical and sample-size reasons, the controls were frequency matched on age, calender year of identification, and treated hypertension status to distributions of myocardial infarction cases [5]. The index date for cases was the date of their first venous thrombosis, while for controls it was a random date during the calendar year in which they were selected to participate. We used GHC computerized pharmacy records to ascertain current use of lipid lowering medications at the index date, and categorized women into non-users of lipid lowering medications; statin users; and users of other lipid lowering medications, including bile-acid sequestrants, fibrates and niacins. Current use was defined as the receipt of at least one lipid lowering prescription prior to the index date with enough medications to last until the index date, assuming 80% compliance. Duration of use was calculated as the number of days that each prescription would last assuming 80% compliance and by summing this for each prescription since starting date. Simvastatin and pravastatin were used by 97.8% of the current statin users. Three women who used other statins (lovastatin or atorvastatin) and 17 women with chronic liver disease were excluded from the analysis. Women prescribed less than 40 mg of simvastatin were defined as low-dose users, and women prescribed 40 mg or more were defined as high-dose users. Included in this study were 465 postmenopausal women with a first venous thrombosis and 1962 controls. Venous thrombosis was objectively verified with a venogram, Doppler or Duplex study, a pulmonary angiography, lung scan with a high probability, or a computer tomography scan in 93% of all cases. Of the remaining 32 women, 13 died before any diagnostic test or treatment could be started and 19 women were treated with coumadin or had a vena cava filter after the diagnosis of venous thrombosis was clinically made. Deep vein thrombosis (DVT) in the leg occurred in 348 cases, a pulmonary embolism (PE) in 42, and 75 cases were diagnosed with both DVT and PE. At the index date, 4.5% of cases and 5.6% of controls were current users of statins. The median duration of statin use among cases was 435 (range 13–1751) days as compared to 354 (range 4–2505) days among control subjects. Among current users, 76.2% of cases and 85.5% of controls used simvastatin. Current statin users appeared to have a slightly lower risk of venous thrombosis than non-users after adjustment for the matching factors (OR 0.84; 95% CI 0.51–1.37) (Table 1). Adjustment for current estrogen use did not alter any of the odds ratios, in contrast to adjustment for vascular disease which decreased the risk. Further adjustment for weight and height or diabetes did not substantially effect the odds ratios. The reduced risk of venous thrombosis seemed to be confined to women using simvastatin as opposed to pravastatin and was found among both low-dose and high-dose users of simvastatin. Because of time trends in use direct comparison Correspondence: C.J.M. Doggen, Department of Clinical Epidemiology, Leiden University Medical Center C9-P, PO Box 9600, 2300 RC Leiden, the Netherlands. Tel.: +31 71 526 4037; fax: +31 71 526 6994; e-mail: C.J.M.Doggen@ lumc.nl

ABO genotype and risk of thrombotic events and hemorrhagic stroke

Summary.  Background: The non‐O alleles of the ABO genotype have been associated with an increased risk of thrombosis. Risk associated with the specific A1, A2 or B alleles is not well defined. Objectives: To examine the association of the ABO genotype with myocardial infarction (MI), ischemic stroke, hemorrhagic stroke, and venous thrombosis (VT). Patients and methods: We used data from two ongoing population‐based case–control studies of MI, stroke, and VT. Cases included hypertensive adults and postmenopausal women with incident non‐fatal MI (n = 1063), ischemic stroke (n = 469), and hemorrhagic stroke (n = 91), and postmenopausal women with incident non‐fatal VT (n = 504). Controls were frequency matched to cases on age, sex, hypertension status, and year of identification. ABO genotypes were determined using single‐nucleotide polymorphisms, and subjects were grouped by diplotype according to the presence of O1, O2, A11, A2 and B alleles. Logistic regression was used to test the association of diplotypes with risk of each outcome. Results: As compared with the O1O1 group, the A11 allele was associated with an increased risk of VT [odds ratio (OR) 1.79; 95% confidence interval (CI) 1.41–2.26] and MI (OR 1.23; 95% CI 1.05–1.44). The B allele was associated with an increased risk of VT (OR 1.82; 95% CI 1.29–2.57) and ischemic stroke (OR 1.59; 95% CI 1.17–2.17). The AB diplotype category was associated with a 2.7‐fold risk of VT (OR 2.70; 95% CI 1.73–4.21). No other associations reached significance. Conclusions: The VT and MI findings are confirmatory, and the ischemic stroke finding with the B allele is a novel finding and needs replication.

Cystatin C Concentration as a Predictor of Systolic and Diastolic Heart Failure

BACKGROUND Risk factors for heart failure (HF) may differ according to ejection fraction (EF). Higher cystatin C, a marker of kidney dysfunction, is associated with incident HF, but previous studies did not determine EF at diagnosis. We hypothesized that kidney dysfunction would predict diastolic HF (DHF) better than systolic HF (SHF) in the Cardiovascular Health Study. METHODS AND RESULTS Cystatin C was measured in 4453 participants without HF at baseline. Incident HF was categorized as DHF (EF > or = 50%) or SHF (EF < 50%). We compared the association of cystatin C with the risk for DHF and SHF, after adjustment for age, sex, race, medications, and HF risk factors. During 8 years of follow-up, 167 participants developed DHF and 206 participants developed SHF. After adjustment, sequentially higher quartiles of cystatin C were associated with risk for SHF (competing risks hazard ratios 1.0 [reference], 1.99 [95% confidence interval 1.14-3.48], 2.32 [1.32-4.07], 3.17 [1.82-5.50], P for trend < .001). The risk for DHF was apparent only at the highest cystatin C quartile (hazard ratios 1.0 [reference], 1.09 [0.62-1.89], 1.08 [0.61-1.93], and 1.83 [1.07-3.11]). CONCLUSIONS Cystatin C levels are linearly associated with the incidence of systolic HF, whereas only the highest concentrations of cystatin C predict diastolic HF.

Common hemostasis and inflammation gene variants and venous thrombosis in older adults from the Cardiovascular Health Study

Summary.  Background/Objectives: Age‐related changes in blood coagulation and fibrinolysis are associated with increased risk of thrombotic events. Inherited deficiencies of coagulation proteins, such as factor V (FV) Leiden and prothrombin G20210A, explain a small fraction of venous thromboembolic disease (VTE). Additional genetic factors are likely to underlie the etiology of VTE, some of which may become manifest at older ages. Methods: We tested 290 common SNPs within 51 thrombosis and inflammation genes for association with VTE in the Cardiovascular Health Study, a large, prospective cohort of older adults followed for up to 12 years. Results: There were 184 VTE events that occurred at mean age of 78 years. TagSNPs within four genes encoding FXIII subunit A (F13A), FVII activating protease (HABP2), protease activated receptor‐1 (F2R) and the urokinase receptor (PLAUR) showed the strongest evidence for association with VTE, with each gene having a global P‐value < 0.05 and at least one tagSNP false discovery rate (FDR) q‐value < 0.05. The rs3024409 variant allele of F13A1 was associated with 1.66‐fold increased risk of VTE, while the minor alleles of HABP2 rs6585234 and rs3862019, F2R rs253061 and rs153311, and PLAUR rs344782 were each associated with lower risk of VTE (hazard ratios in the range of 0.49–0.66). Consistent with the observed protective association for VTE risk, the HABP2 rs3862019 variant allele was also associated with lower activity levels of coagulation factors FVIII, FIX, FX and plasminogen. We also confirm previously reported associations between common variants of the coagulation FII, FV, FVIII, FXI, alpha‐fibrinogen and protein C genes and risk of VTE. Conclusions: These findings suggest that several novel common coagulation gene variants may be related to risk of VTE in older adults. Further studies in older adults are needed to validate these findings and assess functional molecular mechanisms.

Physical Activity and Incident Diabetes in American Indians The Strong Heart Study

The authors examined the association between total physical activity (leisure-time plus occupational) and incident diabetes among 1,651 American Indians who participated in the Strong Heart Study, a longitudinal study of cardiovascular disease and its risk factors among 13 American Indian communities in 4 states (North Dakota, South Dakota, Oklahoma, and Arizona). Discrete Cox models were used to examine the association between physical activity level (in tertiles), compared with no physical activity, and incident diabetes, after adjustment for potential confounders. During 10 years of follow-up (f1989-1999), 454 incident cases of diabetes were identified. Compared with participants who reported no physical activity, those who reported any physical activity had a lower risk of diabetes: Odds ratios were 0.67 (95% confidence interval (CI): 0.46, 0.99), 0.67 (95% CI: 0.45, 0.99), and 0.67 (95% CI: 0.45, 0.99) for increasing tertile of physical activity, after adjustment for age, sex, study site, education, smoking, alcohol use, and family history of diabetes. Further adjustment for body mass index and other potential mediators attenuated the risk estimates. These data suggest that physical activity is associated with a lower risk of incident diabetes in American Indians. This study identifies physical activity as an important determinant of diabetes among American Indians and suggests the need for physical activity outreach programs that target inactive American Indians.

Common VKORC1 variants are not associated with arterial or venous thrombosis

The vitamin K epoxide receptor complex subunit 1 (VKORC1) plays a crucial role in the regulation of several vitamin Kdependent proteins relevant to hemostasis and, perhaps, atherosclerosis [1]. Common polymorphisms and haplotypes of the VKORC1 gene have recently been shown to predict warfarin response [2,3] and arterial disease [4]. The latter findings have not yet been replicated in a population-based setting. Whether these variants are associated with venous disease in the general population is unknown. The goal of this study was to replicate the recent arterial thrombosis findings and determine whether these variants are additionally associated with venous thrombosis. Participants in this study formed part of three ongoing case– control studies of myocardial infarction (MI), stroke, and venous thrombosis (VT) at Group Health, a large healthcare delivery system based in western Washington State. All participants gave written informed consent. TheMI and stroke cases were either persons with pharmacologically treated hypertension or perimenopausal or postmenopausal women who had an incident non-fatal MI or ischemic stroke during 1995–2002 and were 30–79 years old [5,6]. VT cases were perimenopausal or postmenopausal women who experienced an incident deep vein thrombosis or pulmonary embolism during 1995–2002 and were 30–89 years old [7]. A common control group of randomly selected members of Group Health was frequency matched to MI cases on the basis of age, sex, and treated hypertension. Control participants were eligible for MI or stroke analyses if they did not have a priorMI or stroke, and were eligible for VT analyses if they did not have a prior deep vein thrombosis or pulmonary embolism. Data on characteristics prior to each participant s index date were collected from the Group Health outpatient record, and a venous blood sample was collected at an in-person interview. Single-nucleotide polymorphisms (SNPs) in the VKORC1 gene were identified through the resequencing efforts of SeattleSNPs (http://pga.gs.washington.edu; accessed 10 August 2007). Five tagSNPs (rs17708472, rs9934438, rs8050894, rs2359612 and rs7294) were initially selected and successfully genotyped on the Illumina BeadArray platform; 99.96% of genotypes were successfully called. These SNPs correspond to SeattleSNPs positions 6009, 6484, 6853, 7566, and 9041, respectively. According to SeattleSNPs data, three SNPs (rs9934438, rs8050894, and rs2359612) were in high linkage disequilibrium (r > 0.64); to avoid redundancy, only rs2359612 is presented in this analysis. All SNPs were in Hardy–Weinberg equilibrium. Haplotypes were inferred using PHASE 2.0. Odds ratios and 95% confidence intervals for the association between each SNP and outcome were calculated using logistic regression, and were adjusted for age, sex, treated hypertension, year of identification, and race (three categories). For haplotypes, estimates were derived from weighted logistic regression and robust standard errors, where weights corresponded to the probability for each possible inferred haplotype combination. The most common haplotype was arbitrarily selected as the reference. A Wald test was used to assess the global hypothesis that no haplotype had an association with the outcome that was significantly different from 1. The distribution of age, sex and treated hypertension across the case–control groups was consistent with the study design. The average age of study participants was 66 years for the MI and stroke studies and 68 years for the VT study. Caucasians comprised greater than 91% of the participants. Of the combined MI and stroke controls (n = 2686), MI cases (n = 856), and stroke cases (n = 368), men comprised 42%, Correspondence: Lucia A. Hindorff, Department of Epidemiology, University of Washington, Seattle, WA, USA. Tel.: +1 206 287 2808; fax: +1 206 287 2662; e-mail: lah@u. washington.edu

Body mass index and the risk of venous thrombosis among postmenopausal women

VIII inhibitors: predictors of success. Haematologica 2001; 86: 1186– 993. 6 Brackmann HH, Oldenberg J, Schwaab R. Immune tolerance for the treatment of FVIII inhibitors-twenty years of the Bonn protocol. Vox Sang 1996; 70: 30–5. 7 Freiburghaus C, Berntorp E, Ekman M, Gunnarsson M, Kjellberg BM, Nilsson IM. Tolerance induction using the Malmo treatment model 1982–1995. Haemophilia 1999; 1: 32–9. 8 Smith MP, Spence KJ, Waters EL, Beresford-Webb R, Mitchell MJ, Cuttler J, AlhaqA, Brown SA, SavidgeGF. Immune tolerance therapy for hemophilia A patients with acquired factor VIII alloantibodies: comprehensive analysis of experience at a single institution. Thromb Haemost 1999; 81: 35–8. 9 Rocino A, Papa ML, Salerno E, Capasso F, Miraglia E, DeBiasi R. Immune tolerance induction in hemophilia A patients with highresponding inhibitors to factor VIII: experience at a single institution. Haemophilia 2001; 7: 33–8.

Racial and ethnic differences in the risk of postpartum venous thromboembolism: a population-based, case-control study

Venous thromboembolism (VTE) is a major contributor of maternal morbidity and mortality. Whether maternal race/ethnicity is associated with the risk of postpartum VTE remains unclear.