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Background: Inflammation plays a fundamental role in atherothrombosis. Yet, whether direct inhibition of inflammation will reduce the occurrence of adverse cardiovascular outcomes is not known., Design: The Cardiovascular Inflammation Reduction Trial (CIRT) (ClinicalTrials.govNCT01594333) will randomly allocate 7,000 patients with prior myocardial infarction (MI) and either type 2 diabetes or the metabolic syndrome to low-dose methotrexate (target dose 15-20 mg/wk) or placebo over an average follow-up period of 3 to 5 years. Low-dose methotrexate is a commonly used anti-inflammatory regimen for the treatment of rheumatoid arthritis and lacks significant effects on lipid levels, blood pressure, or platelet function. Both observational and mechanistic studies suggest that low-dose methotrexate has clinically relevant antiatherothrombotic effects. The CIRT primary end point is a composite of nonfatal MI, nonfatal stroke, and cardiovascular death. Secondary end points are all-cause mortality, coronary revascularization plus the primary end point, hospitalization for congestive heart failure plus the primary end point, all-cause mortality plus coronary revascularization plus congestive heart failure plus the primary end point, incident type 2 diabetes, and net clinical benefit or harm. CIRT will use standardized central methodology designed to ensure consistent performance of all dose adjustments and safety interventions at each clinical site in a manner that protects the blinding to treatment but maintains safety for enrolled participants., Summary: CIRT aims to test the inflammatory hypothesis of atherothrombosis in patients with prior MI and either type 2 diabetes or metabolic syndrome, conditions associated with persistent inflammation. If low-dose methotrexate reduces cardiovascular events, CIRT would provide a novel therapeutic approach for the secondary prevention of heart attack, stroke, and cardiovascular death., (Copyright © 2013 Mosby, Inc. All rights reserved.)

Background: Animal data suggest that natriuretic peptides play an important role in energy metabolism, but prospective studies evaluating a relationship between these peptides and type 2 diabetes mellitus (T2DM) in humans are few and results are conflicting., Methods: We used a prospective case-cohort approach (n = 491 T2DM cases, n = 561 reference subcohort) within the Women's Health Study to evaluate baseline N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations and the risk of incident T2DM. We also tested for associations between 4 common variants in the natriuretic peptide A and B genes (NPPA and NPPB) and NT-proBNP concentrations (n = 458) and incident T2DM (n = 1372 cases among 22 607 women)., Results: Case subjects had higher median baseline body mass index (29.4 vs 25.0 kg/m(2), P < 0.001) and lower baseline median (interquartile range) NT-proBNP concentrations [46.8 ng/L (26.1-83.2) vs 66.7 ng/L (39.3-124.7), P < 0.001]. In proportional hazards models adjusting for established diabetes risk factors, women in the highest quartile of baseline NT-proBNP concentration (≥ 117.4 ng/L) had a 49% reduction in risk of T2DM [hazard ratio (HR) 0.51, 0.30-0.86, P = 0.01] relative to those in the lowest quartile. Two of the 4 tested variants in NPPA and NPPB (rs632793, rs198389) were associated with increased NT-proBNP concentrations and reduced risk of T2DM. For example, each copy of the minor allele of rs632793 was associated with increased NT-proBNP [β (SE) = 0.201 (0.063), P < 0.01] and decreased T2DM risk (HR 0.91, 0.84-0.989, P = 0.026)., Conclusions: NT-proBNP concentrations that are high, but still within the reference interval, associate with reduced risk of incident diabetes in women and support a favorable role for natriuretic peptides in the prevention of T2DM.

Background: Symptoms of psychological distress and depression have been associated with risk of ventricular arrhythmias and sudden cardiac death. Their relationship with atrial arrhythmias, however, is less well studied., Methods and Results: We sought to assess the long-term relations between psychological distress and risk of atrial fibrillation (AF) in the Women's Health Study of female health professionals. We measured psychological symptoms with the Mental Health Inventory-5. Incident AF was assessed annually and verified through medical records. Among 30 746 women without history of cardiovascular disease or AF, 771 cases of AF occurred during a median follow-up of 125 months (interquartile range, 117-130 months). Global psychological distress was not associated with AF risk in age-stratified (P=0.61 for linear trend) or multivariable proportional-hazards models that included antidepressant use (P=0.34). A proxy measure for depression, consisting of Mental Health Inventory-5 score <53, antidepressant use, or both, was also not associated with AF risk in multivariable models (hazard ratio=0.99; 95% confidence interval, 0.78-1.25; P=0.93). In post hoc analyses of individual symptoms from the Mental Health Inventory-5, positive affect, "feeling happy some/a good bit of the time," was associated with reduced risk of AF (hazard ratio=0.69; 95% confidence interval, 0.49-0.99; P=0.04); other depressive and anxious symptoms were not., Conclusions: In this prospective study of women without known cardiovascular disease, global psychological distress and specific depressive symptoms were unrelated to AF risk. (J Am Heart Assoc. 2012;1:e001107 doi: 10.1161/JAHA.112.001107.).

Context: The risks associated with new-onset atrial fibrillation (AF) among middle-aged women and populations with a low comorbidity burden are poorly defined., Objectives: To examine the association between incident AF and mortality in initially healthy women and to evaluate the influence of associated cardiovascular comorbidities on risk., Design, Setting, and Participants: Between 1993 and March 16, 2010, 34,722 women participating in the Women's Health Study underwent prospective follow-up. Participants were 95% white, older than 45 years (median, 53 [interquartile range {IQR}, 49-59] years), and free of AF and cardiovascular disease at baseline. Cox proportional hazards models with time-varying covariates were used to determine the risk of events among women with incident AF. Secondary analyses were performed among women with paroxysmal AF., Main Outcome Measures: Primary outcomes included all-cause, cardiovascular, and noncardiovascular mortality. Secondary outcomes included stroke, congestive heart failure, and myocardial infarction., Results: During a median follow-up of 15.4 (IQR, 14.7-15.8) years, 1011 women developed AF. Incidence rates per 1000 person-years among women with and without AF were 10.8 (95% confidence interval [CI], 8.1-13.5) and 3.1 (95% CI, 2.9-3.2) for all-cause mortality, 4.3 (95% CI, 2.6-6.0) and 0.57 (95% CI, 0.5-0.6) for cardiovascular mortality, and 6.5 (95% CI, 4.4-8.6) and 2.5 (95% CI, 2.4-2.6) for noncardiovascular mortality, respectively. In multivariable models, hazard ratios (HRs) of new-onset AF for all-cause, cardiovascular, and noncardiovascular mortality were 2.14 (95% CI, 1.64-2.77), 4.18 (95% CI, 2.69-6.51), and 1.66 (95% CI, 1.19-2.30), respectively. Adjustment for nonfatal cardiovascular events potentially on the causal pathway to death attenuated these risks, but incident AF remained associated with all mortality components (all-cause: HR, 1.70 [95% CI, 1.30-2.22]; cardiovascular: HR, 2.57 [95% CI, 1.63-4.07]; and noncardiovascular: HR, 1.42 [95% CI, 1.02-1.98]). Among women with paroxysmal AF (n = 656), the increase in mortality risk was limited to cardiovascular causes (HR, 2.94; 95% CI, 1.55-5.59)., Conclusion: Among a group of healthy women, new-onset AF was independently associated with all-cause, cardiovascular, and noncardiovascular mortality, with some of the risk potentially explained by nonfatal cardiovascular events.

Background: Physical activity (PA) is well known to reduce the risk of cardiovascular disease. We hypothesized that regular PA, possibly acting through reductions in blood pressure and body mass index (BMI), would reduce the risk of incident atrial fibrillation (AF) in women., Methods and Results: We prospectively followed 34 759 women who reported their leisure-time PA levels for the occurrence of AF. We estimated energy expenditure in metabolic equivalent (MET)-h/wk and validated self-reported AF with medical records. The mean (SD) age of the 34 759 participants was 54.6 (7.0) years, the mean BMI was 26.0 (5.0) kg/m(2), 26.5% had hypertension, and the median (IQR) PA was 8.4 (2.8, 20.4) MET-h/wk. After a median of 14.4 years of observation, 968 women had development of AF. In age-, cholesterol-, smoking-, alcohol-, diabetes-, and race-adjusted models, increasing quintiles of PA were associated with reduced risks of AF (hazard ratio for extreme quintiles, 0.82; 0.66 to 1.01; P trend=0.007 over quintiles). Although this association was not substantially different after adjusting for hypertension (0.87; 0.70 to 1.07; P trend 0.02), it was attenuated after adjustment for BMI (0.99; 0.80 to 1.23; P trend=0.22). Women who achieved the federal government's recommendation of 7.5 MET-h/wk of PA were at reduced risk of AF compared with those who did not (0.86; 0.75 to 0.98; P=0.03). This association was also attenuated by BMI (0.96; 0.84 to 1.10; P=0.57)., Conclusions: In middle-aged women, physical activity was associated with a modestly reduced risk of AF. However, this relationship was no longer significant after controlling for body mass index.

Background: Recent genome-wide association studies have identified common variants associated with high-density lipoprotein cholesterol (HDL-C). Whether these associations are modified by physical activity, which increases HDL-C levels and reduces the risk of cardiovascular disease, is uncertain., Methods and Results: In a prospective cohort study of 22 939 apparently healthy US women of European ancestry, we selected 58 single nucleotide polymorphisms (SNPs) in 9 genes that demonstrated genome-wide association (P<5×10(-8)) with HDL-C levels and sought evidence of effect modification according to levels of physical activity. Physical activity modified the effects on HDL-C of 7 SNPs at 3 loci, and the strongest evidence of effect was observed for rs10096633 at lipoprotein lipase (LPL), rs1800588 at hepatic lipase (LIPC), and rs1532624 at cholesteryl ester transfer protein (CETP) (each P-interaction<0.05). The per-minor-allele increase in HDL-C for rs1800588 at LIPC and rs1532624 at CETP was greater in active than inactive women, whereas the reverse was observed for rs10096633 at LPL. Minor-allele carrier status at the LPL SNP was associated with a reduced risk of myocardial infarction in active (hazard ratio, 0.51; 95% confidence interval 0.30-0.86) but not among inactive women (hazard ratio 1.13; 95% confidence interval 0.79 to 1.61; P-interaction=0.007). By contrast, carrier status at the CETP SNP was associated with a reduced risk of myocardial infarction regardless of activity level (hazard ratio, 0.72; 95% confidence interval, 0.57 to 0.92; P-interaction=0.71). No association between LIPC SNP carrier status and myocardial infarction risk was noted., Conclusions: The effects of common variants in the LPL, LIPC, and CETP genes on HDL-C levels are modified by physical activity. For a common variant in LPL, the impact on myocardial infarction varied by activity level, whereas the effects of a common variant in CETP on myocardial infarction risk did not.

Background: It is somewhat controversial whether caffeine consumption is associated with an increased risk of developing atrial fibrillation (AF)., Objective: We prospectively assessed the relation between caffeine intake and incident AF., Design: A total of 33,638 initially healthy women who participated in the Women's Health Study and who were gt 45 y of age and free of cardiovascular disease and AF at baseline were prospectively followed for incident AF from 1993 to 2 March 2009. All women provided information on caffeine intake via food-frequency questionnaires at baseline and in 2004., Results: During a median follow-up of 14.4 y (interquartile range: 13.8-14.8 y), 945 AF events occurred. Median caffeine intakes across increasing quintiles of caffeine intake were 22, 135, 285, 402, and 656 mg/d, respectively. Age-adjusted incidence rates of AF across increasing quintiles of caffeine intake were 2.15, 1.89, 2.01, 2.24, and 2.04 events, respectively, per 1000 person-years of follow-up. In Cox proportional hazards models updated in 2004 by using time-varying covariates, the corresponding multivariable-adjusted hazard ratios (95% CI) were 1.0, 0.88 (0.72, 1.06), 0.78 (0.64, 0.95), 0.96 (0.79, 1.16), and 0.89 (0.73, 1.09) (P for linear trend: 0.45). None of the individual components of caffeine intake (coffee, tea, cola, and chocolate) were significantly associated with incident AF., Conclusions: In this large cohort of initially healthy women, elevated caffeine consumption was not associated with an increased risk of incident AF. Therefore, our data suggest that elevated caffeine consumption does not contribute to the increasing burden of AF in the population. This trial was registered at clinicaltrials.gov as NCT00000479.

Aims: To assess the joint influence of inflammatory biomarkers on the risk of incident atrial fibrillation (AF) in women., Methods and Results: We performed a prospective cohort study among women participating in the Women's Health Study. All women were free of AF at study entry and provided a baseline blood sample assayed for high-sensitivity C-reactive protein, soluble intercellular adhesion molecule-1, and fibrinogen. To evaluate the joint effect of these three biomarkers, an inflammation score was created that ranged from 0 to 3 and reflected the number of biomarkers in the highest tertile per individual. During a median follow-up of 14.4 years, 747 of 24,734 women (3.0%) experienced a first AF event. Assessed individually, all three biomarkers were associated with incident AF, even after adjustment for traditional risk factors. When combined into an inflammation score, a strong and independent relationship between inflammation and incident AF emerged. Across increasing inflammation score categories, there were 1.66, 2.22, 2.73, and 3.25 AF events per 1000 person-years of follow-up. The corresponding hazard ratios (95% confidence intervals) across inflammation score categories were 1.0, 1.22 (1.00-1.49), 1.32 (1.06-1.65), and 1.59 (1.22-2.06) (P for linear trend 0.0006) after multivariable adjustment., Conclusion: In this large-scale prospective study among women without a history of cardiovascular disease, markers of systemic inflammation were significantly related to AF even after controlling for traditional risk factors.

Background: We examined whether a hypertension risk prediction model based on clinical characteristics and blood biomarkers might improve on risk prediction based on current blood pressure alone., Methods: A prospective cohort of 14,822 normotensive women aged 45 years and older were followed over 8 years beginning in 1992 for the development of hypertension. Among a randomly selected two-thirds sample (N=9427), hypertension prediction models were developed using 52 potential predictors and compared with a model based on blood pressure alone. Each prediction model was validated in the remaining one third (N=5395)., Results: In the development cohort, the best prediction model for incident hypertension included age, blood pressure, ethnicity, body mass index, total grain intake, apolipoprotein B, lipoprotein(a), and C-reactive protein (Bayes Information Criteria [BIC]=8788). Although this model was superior to a model based on blood pressure alone (BIC=8957), it was only marginally better than a simplified model including age, blood pressure, ethnicity, and body mass index (BIC=8820). In the validation cohort, the simplified model demonstrated adequate calibration, a c-index similar to that of the best model (0.703 vs 0.705), and when compared with the model based on blood pressure alone, reclassified 1499 participants to hypertension risk categories that proved to be closer to observed risk in all but one instance., Conclusion: In this prospective cohort of initially normotensive women, a model based on readily available clinical information predicted incident hypertension better than a model based on blood pressure alone.

Background: Published reports of a relationship between lipids and incident venous thromboembolism (VTE) are conflicting., Objectives: To clarify the relationship between lipids and VTE risk in healthy women, including potential effect modification by hormone therapy (HT)., Patients/methods: Among 27 081 initially healthy women followed prospectively for incident VTE, we measured a full panel of lipid biomarkers, including total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides and apolipoproteins A-I (apo A-I) and B(100)., Results: During a median follow-up of 11.4 years, VTE occurred in 355 women. We observed no relationship between any of the lipids and VTE risk. However, when unprovoked VTE was considered separately (n=161), both HDL-C and apo A-I were positively associated with risk. Fully adjusted hazard ratios (HR) and 95% confidence intervals (CI) for extreme tertiles of HDL-C and apo A-I were 1.75 (1.13-2.73) and 1.70 (1.10-2.62), respectively. After stratifying by HT use, this relationship was present only among HT users; the HRs for unprovoked VTE for extreme tertiles of HDL-C and apo A-I were 3.58 (1.69-7.58) and 2.88 (1.29-6.42) among users, but only 0.79 (0.39-1.62) and 0.89 (0.50-1.57) among non-users. The interactions were statistically significant (each Pinteraction<0.05)., Conclusions: We observed little evidence that lipid levels predict risk of incident VTE among non-users of HT. High levels of HDL-C and apo A-I associate with unprovoked VTE risk among HT users. This observation likely reflects prothrombotic effects of HT that are concomitant with HDL-C and apo A-I levels, rather than direct effects of those lipids.

Objective: Elevated levels of interleukin (IL)-18 have been implicated in the development of atherosclerosis in animals. Data in humans are less clear, and data in women are particularly scarce., Methods and Results: In a prospective nested case-control study of initially healthy women, we measured baseline plasma IL-18 levels in 253 participants who subsequently developed cardiovascular disease (CVD) and in 253 healthy age- and smoking-matched controls. IL-18 levels were higher at baseline among those who developed CVD (274.1pg/mL versus 233.8pg/mL, P<0.001), and were associated with future CVD (relative risk (RR) for highest versus lowest quartile 2.53; 95% CI, 1.47-4.35, P<0.001). While that risk was attenuated after adjustment for traditional cardiovascular risk factors (RR 1.60; 95% CI, 0.77-3.34, P=0.13), those with IL-18 levels at or above a threshold of the 90th percentile (442pg/mL) remained at elevated risk after adjustment (RR 2.40; 95% CI, 1.05-5.56, P=0.04). Levels of IL-18 above this threshold modify the fully adjusted risk of future CVD conferred by elevated levels of total cholesterol (P(interaction)=0.02)., Conclusions: In this population of apparently healthy women, IL-18 levels associate with increased risk of cardiovascular disease, but that risk is attenuated in models adjusting for traditional cardiovascular risk factors. Very high levels of IL-18 interact with hypercholesterolemia to alter CVD risk.

Background: Current guidelines suggest consideration of initial combination therapy for patients with stage 2 hypertension, but rates of hypertension treatment and control in clinical practice vary according to age, race, sex, and body mass index (BMI)., Objective: This was a prespecified subgroup analysis of one of the primary efficacy end points-mean change in systolic blood pressure (SBP) at 6 weeks -in a previously published community-based, randomized, open-label trial comparing valsartan monotherapy with valsartan/hydrochlorothiazide (HCTZ) combination therapy as initial treatment for high-risk patients with stage 2 hypertension., Methods: Eligible participants with stage 2 hypertension (SBP >or=160 mm Hg and/or diastolic blood pressure [DBP] >or=100 mm Hg) were treated with valsartan 160 mg/d or valsartan/HCTZ 160/12.5 mg/d for 2 weeks, followed by forced titration to valsartan 320 mg/d or valsartan/HCTZ 320/12.5 mg/d for an additional 4 weeks. In addition to the primary blood pressure end point (change in SBP at 6 weeks), secondary blood pressure end points at 6 weeks included changes in DBP and the proportion of patients achieving a blood pressure control threshold of <140/90 mm Hg (<130/80 mm Hg for patients with diabetes), as recommended by the Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7). The subgroups of interest were women, blacks, Hispanics, the elderly (age >or=65 years), patients with diabetes, smokers, and lean, overweight, and obese subjects (BMI <25, 25-<30, and =30 kg/m(2), respectively)., Results: The randomized trial included 1668 patients (756 [45.3%] female, 392 [23.5%] black, 109 [6.5%] Hispanic, 220 [13.2%] elderly, 970 of 1641 [59.1%] obese, 166 [10.0%] with diabetes, 467 [28.0%] smokers) with stage 2 hypertension. Among those allocated to combination therapy compared with monotherapy, the mean (SD) change in SBP at 6 weeks was -27.4 (18.5) and -19.3 (17.7) mm Hg in women, -21.4 (17.6) and -12.6 (18.5) mm Hg in black subjects, -21.7 (17.6) and -16.3 (16.5) mm Hg in Hispanic subjects, -25.5 (20.2) and -16.9 (17.9) mm Hg in the elderly, and -23.6 (18.1) and -15.9 (16.2) mm Hg in obese subjects. With the exception of the results for Hispanics, all comparisons of combination therapy and monotherapy were statistically significant (Por=65 years (43.9% vs 24.5%; P=0.004), overweight subjects (49.0% vs 31.2%; P<0.001), and obese subjects (41.4% vs 26.0%; P<0.001). In the entire study cohort, patients assigned to combination therapy had a significantly higher incidence of dizziness compared with those assigned to monotherapy (8.5% vs 4.7%; P=0.002); however, there was no statistically significant difference in the frequency of adverse events between treatment groups in the prespecified subgroups., Conclusions: Across various subgroups of patients with stage 2 hypertension, combination therapy was consistently associated with a significantly greater reduction in SBP than monotherapy. With the exception of a significantly greater increase in dizziness compared with monotherapy, combination therapy was well tolerated.

Objective: To evaluate the association between total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol to HDL-C ratio, and non-HDL-C with the risk of ischemic stroke in a large cohort of apparently healthy women., Methods: Prospective cohort study among 27,937 US women aged > or =45 years participating in the Women's Health Study who provided baseline blood samples. Stroke occurrence was self-reported and confirmed by medical record review. We categorized plasma lipid measurements into quintiles. We used Cox proportional hazards models to evaluate the association between lipids and risk of ischemic stroke., Results: During 11 years of follow-up, 282 ischemic strokes occurred. All lipid levels were strongly associated with increased risk of ischemic stroke in age-adjusted models. The association attenuated particularly for HDL-C after adjustment for potential confounders. For the comparison of the highest to the lowest quintile, the multivariable-adjusted hazard ratios (95% CI; p for trend across mean quintile values) of ischemic stroke were 2.27 (1.43, 3.60; p(trend) < 0.001) for total cholesterol; 1.74 (1.14, 2.66; p(trend) = 0.003) for LDL-C; 0.78 (0.52, 1.17; p(trend) = 0.27) for HDL-C; 1.65 (1.06, 2.58; p(trend) = 0.02) for the total cholesterol to HDL-C ratio; and 2.45 (1.54, 3.91; p(trend) < 0.001) for non-HDL-C., Conclusions: In this large cohort of apparently healthy women, total cholesterol, low-density lipoprotein cholesterol, the total cholesterol to high-density lipoprotein cholesterol ratio, and non-high-density lipoprotein cholesterol were significantly associated with increased risk of ischemic stroke.

Background: The clinical significance of heparin/platelet factor 4 (PF4) antibodies in subjects undergoing cardiac surgery has not been systematically studied. We prospectively investigated whether the presence of heparin/PF4 antibodies would predict clinical thrombosis in this population., Methods: In 299 patients scheduled for cardiac surgery between October 2003 and March 2005, the heparin/PF4 antibodies and platelet count were measured immediately prior to, and 5 days after, surgery. The patients were followed up at 30 days for thrombotic complications., Results: The prevalence of the heparin/PF4 antibodies was 4.3% (13 of 299) prior to surgery and increased more than fivefold to 22.4% (62 of 277) postoperatively (p < 0.0001). Thromboembolic events occurred in 8.8% of patients with negative antibody and in 6.3% of patients with positive antibody (p = 0.77). Of the 62 patients with positive heparin/PF4 antibodies postoperatively, 22 (35.5%) were treated with a nonheparin anticoagulant. There was a trend toward higher rates of thromboembolic events in subjects who were thrombocytopenic compared with those who were not (17.1% and 6.7%, respectively, p = 0.06), regardless of antibody status. Two out of 8 patients (25%) with both thrombocytopenia and a positive antibody (clinical heparin-induced thrombocytopenia [HIT]) suffered a thromboembolic event, compared with 17 of 222 (7.7%) without clinical HIT (p = 0.13)., Conclusions: The high prevalence of antibodies to the heparin/PF4 complex after cardiac surgery and the low rate of thromboembolic complications in this population suggest that the antibody alone does not confer an increased risk of thrombotic complications. Monitoring for thrombocytopenia is recommended.

Objectives: We sought to determine the relative strength of high-sensitivity C-reactive protein (hs-CRP) and lipid levels as markers for future ischemic stroke compared with coronary heart disease (CHD) in women., Background: Although hs-CRP and lipid levels are established risk determinants for vascular disease, the relative strength of these biomarkers for ischemic stroke compared with CHD is uncertain., Methods: Among 15,632 initially healthy women who were followed for a 10-year period, we compared hs-CRP, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), high-density lipoprotein cholesterol (HDL-C), apolipoproteins A-I and B100, and lipid ratios as determinants of ischemic stroke compared with CHD., Results: After adjustment for age, smoking status, blood pressure, diabetes, and obesity, the hazard ratios (HRs) and 95% confidence intervals (CIs) for the third versus the first tertile for future ischemic stroke compared with CHD were, respectively, 1.91 (95% CI 1.13 to 3.21) and 2.26 (95% CI 1.64 to 3.12) for TC, 1.29 (95% CI 0.83 to 2.02) and 2.09 (95% CI 1.53 to 2.85) for LDL-C, 0.57 (95% CI 0.36 to 0.92) and 0.38 (95% CI 0.27 to 0.52) for HDL-C, 1.72 (95% CI 1.03 to 2.86) and 2.93 (95% CI 2.04 to 4.21) for non-HDL-C, and 2.76 (95% CI 1.51 to 5.05) and 1.66 (95% CI 1.17 to 2.34) for hs-CRP. Of the lipid ratios, that of TC to HDL-C had the largest HR for both future ischemic stroke and CHD (HR 1.95 [95% CI 1.16 to 3.26] and 4.20 [95% CI 2.79 to 6.32], respectively)., Conclusions: In this large prospective cohort of initially healthy women, lipid levels are significant risk determinants for ischemic stroke, but with a magnitude of effect smaller than that observed for CHD. High-sensitivity CRP associates more closely with ischemic stroke than with CHD. Concomitant evaluation of lipid levels and hs-CRP may improve risk assessment for stroke as well as CHD. (The Women's Health Study; http://www.clinicaltrials.gov/ct/show/NCT00000479/; NCT00000479).

A substantial proportion of patients who undergo cardiac catheterization develop antibodies directed against the heparin/platelet factor 4 (PF4) complex after the procedure, which have been implicated in the pathogenesis of heparin-induced thrombocytopenia. This study attempted to identify factors that predicted the development of these antibodies in a prospective cohort study. Antiheparin/PF4 antibody titers were measured at baseline and again 5 +/- 2 days after cardiac catheterization by enzyme-linked immunosorbent assay. A total of 311 patients who underwent cardiac catheterization were included in the analysis. Of these, 25 (8.0%) developed positive antibody levels after catheterization. Patients who had positive antibody test results after catheterization had significantly greater baseline antiheparin/PF4 antibody titers compared with those whose titers remained low (optical density 0.227 vs 0.158, p < 0.001). In a logistic regression model, greater baseline antibody titers, a history of heparin exposure, and a lower platelet count at enrollment were the strongest predictors of conversion to positive antiheparin/PF4 antibody titers after cardiac catheterization. It is possible to identify patients at high risk for developing elevated titers of antiheparin/PF4 antibodies on the basis of their baseline clinical characteristics.

Background: Heparin is ubiquitously used in cardiac catheterization but predisposes to the development of heparin-induced thrombocytopenia. The objective was to examine prospectively the prevalence of anti-platelet factor 4 (PF4)/heparin antibodies and heparin-induced thrombocytopenia in the population undergoing cardiac catheterization., Methods: This is a prospective study of 500 consecutive patients presenting for cardiac catheterization at our institution who were enrolled over the course of 1 year. Anti-PF4/heparin antibodies and concurrent platelet counts were measured at catheterization and 5 days thereafter. Thrombotic complications were assessed 30 days after the procedure via telephone interview. All patients presenting for cardiac catheterization at our institution were screened. Inclusion criteria were (a) males and nonpregnant females with age >18 years and (b) patients scheduled to undergo cardiac catheterization. Patients with a known history of heparin-induced thrombocytopenia, with documented bleeding or hypercoagulability, and those at high risk for bleeding were excluded., Results: Of 500 patients, 15 (3%) had anti-PF4/heparin antibodies before catheterization. After catheterization, the prevalence of anti-PF4/heparin antibodies increased to 10.1% (36 of 357) of the patients. Overall rates of thrombotic complications were low (4 of 445, 0.9%) and did not correlate with anti-PF4/heparin antibody status. Patients with an initial positive test for anti-PF4/heparin antibodies were more likely to have prior coronary disease (73.3% vs 45.2%; P < .05). Patients who developed anti-PF4/heparin antibodies after catheterization were more likely to have increased length of stay (3.7 vs 2.4 days; P = .02). The platelet count at the time of catheterization was lower in the cohort of patients who developed the second positive anti-PF4/heparin antibody test versus patients without a second positive antibody test (mean values of 191,800/microL vs 222,300/microL; P = .008)., Conclusions: The prevalence of antibodies to PF4/heparin is low in the population presenting for cardiac catheterization. However, a significant proportion of patients develop antibodies to PF4/heparin after a small exposure to heparin during catheterization. Clinically significant thrombotic complications were rare and did not correlate with antibody status.