Few prospective studies have explored the association between renal function and risk of incident atrial fibrillation (AF) in apparently healthy populations. A total of 24,746 women participating in the Women’s Health Study who were free of cardiovascular disease (CVD), AF and provided a blood sample at baseline were prospectively followed for incident AF from 1993 to 2010. AF events were confirmed by medical chart review. Estimated glomerular filtration rate (eGFR) was calculated from baseline creatinine using the Chronic Kidney Disease – Epidemiology equation. Cox models were used to estimate hazard ratios (HR) and 95% CI for incident AF across eGFR categories controlling for AF risk factors. During 15.4 years (median) of follow-up, 786 incident AF events occurred. The multivariable-adjusted HR for incident AF across eGFR categories (<60, 60–74.9, 75–89, and ≥ 90 ml/min/1.73 m2) were:1.36 (1.00–1.84), 0.90 (0.71–1.14), 0.99 (0.84–1.18) and 1.00, respectively, without evidence of a linear association (P for trend, 0.48). Similarly, there was no significant curvilinear association (P quadratic, 0.10) in multivariable analysis across categories. As compared to women with an eGFR ≥ 60 ml/min/1.73 m2, the 1008 women with an eGFR < 60 ml/min/1.73 m2 had a multivariable adjusted HR for AF of 1.39 (1.04–1.86, p value 0.03). In conclusion, no significant linear or curvilinear relationship was observed between incident AF and less severe impairment of renal function in this large prospective cohort of women. However, a significant elevation in AF risk was observed at a threshold eGFR of < 60 ml/min/1.73 m2.
atrial fibrillation; renal function
Venous thromboembolism (VTE) and cardiovascular disease (CVD) share some risk factors, including obesity, yet it is unclear how dietary patterns associated with reduced risk of CVD relate to risk of VTE.
To compare relationships of adherence to a DASH-style diet with risks of CVD and VTE.
We confirmed by medical record review 1094 incident cases of CVD and 675 incident VTEs during mean follow-up of 14.6 years in 34,827 initially healthy participants in the Women’s Health Study who completed at baseline a 133-item food frequency questionnaire scored for adherence to a DASH diet. We compared estimated associations of dietary patterns with CVD and VTE from proportional hazards models in a competing risk framework.
Initial analyses adjusted for age, energy intake, and randomized treatments found 36–41% reduced hazards of CVD among women in the top two quintiles of DASH score relative to those in the bottom quintile (Ptrend<0.001). In multivariate analysis, women in the top two quintiles had 12–23% reduced hazards of CVD relative to women in the bottom quintile (Ptrend=0.04). Analyses restricted to coronary events found more variable 10–33% reduced hazards in the top two quintiles (Ptrend=0.09). In contrast, higher DASH scores were unrelated to risk of VTE with a 1% reduced hazard for the top vs. bottom quintile (Ptrend=0.95).
An apparently strong association of adherence to the DASH diet with incidence of CVD was attenuated upon control for confounding variables. Adherence to the DASH diet was not associated with risk of VTE in women.
Increasing evidence supports a role for inflammation in promoting atrial fibrillation (AF) and statins have anti-inflammatory effects that may be relevant for the prevention of AF. However, studies of statin therapy and incident AF have yielded mixed results and not focused on individuals with an underlying pro-inflammatory response. We studied whether high-sensitivity C-reactive protein is associated with incident AF and whether treatment with rosuvastatin is associated with a lower incidence of AF compared with placebo.
Methods and results
We randomized men and women with LDL cholesterol <130 mg/dL and high-sensitivity C-reactive protein ≥2 mg/L to receive either rosuvastatin 20 mg daily or placebo. Atrial fibrillation was determined from treatment-blind adverse event reports. Among 17 120 participants without prior history of arrhythmia, each increasing tertile of baseline high-sensitivity C-reactive protein was associated with a 36% increase in the risk of developing AF (95% CI: 1.16–1.60; P-trend < 0.01). Allocation to rosuvastatin when compared with placebo was associated with a 27% reduction in the relative risk of developing AF during the trial period; specifically, AF was reported among 138 participants in the placebo group and 100 in the rosuvastatin group (incidence rate 0.78 vs. 0.56/100 person-years, HR: 0.73, 95% CI: 0.56–0.94, P = 0.01). The exclusion of participants who developed a major cardiovascular event prior to the report of AF yielded similar results.
Within the JUPITER trial cohort of individuals selected for underlying inflammation, increasing levels of high-sensitivity C-reactive protein were associated with an increased risk of incident AF and random allocation to rosuvastatin significantly reduced that risk.
C-reactive protein; Atrial fibrillation; Statins
Prior studies found inverse associations between high-density-lipoprotein cholesterol (HDL-C) or apolipoprotein A-1 with cardiovascular disease (CVD). Whether this is consistent across levels of low-density-lipoprotein cholesterol (LDL-C) or total atherogenic particle burden (apolipoprotein B100) is less well studied, particularly in women.
To determine the association between HDL-C or apolipoprotein A-1 with CVD across a range of LDL-C or apolipoprotein B100.
Prospective cohort study.
The Women’s Healthy Study, a cohort of US female health professionals.
26,861 initially healthy women, age ≥ 45 years at study entry (1992–1995), followed for a mean of approximately 11 years.
Baseline lipids were measured directly, and apolipoproteins with immunoassays. Outcomes were incident total CVD (N=929), coronary events (N=602), and stroke (N=319).
In multivariable analyses, HDL-C and apolipoprotein A-1 were inversely associated with CVD and coronary events but not stroke. Adjusted coronary hazard ratios (HRs) for decreasing quintiles of HDL-C were 1.00, 1.23 (95% CI, 0.85–1.78), 1.42 (CI, 0.98–2.06), 1.90 (CI, 1.33–2.71), and 2.19 (CI, 1.51–3.19), P for linear trend<0.001; and for apolipoprotein A-1 1.00, 0.98 (CI, 0.71–1.35), 1.02 (CI, 0.72–1.44), 1.37 (CI, 0.98–1.90), and 1.58 (CI, 1.14–2.20), P for linear trend=0.005. Consistent inverse associations were found for HDL-C with coronary events across a range of LDL-C, including among women with low LDL-C. No associations were noted for HDL-C or apolipoprotein A-1 among women with low apolipoprotein B100 (<90 mg/dL).
Population of low risk women, small numbers of events in the lowest apolipoprotein B100 stratum, single baseline measurements, and potential residual confounding.
Consistent inverse associations were found for HDL-C with incident coronary events among women with a range of LDL-C. Among women with low total atherogenic particle burden (apolipoprotein B100<90 mg/dL), few events occurred and no associations were seen.
To identify women who benefit from aspirin 100 mg on alternate days for primary prevention of vascular events by using treatment effect prediction based on individual patient characteristics.
Methods and results
Randomized controlled trial data from the Women's Health Study were used to predict treatment effects for individual women in terms of absolute risk reduction for major cardiovascular events (i.e. myocardial infarction, stroke, or cardiovascular death). Predictions were based on existing risk scores, i.e. Framingham (FRS), and Reynolds (RRS), and on a newly developed prediction model. The net benefit of different aspirin treatment-strategies was compared: (i) treat no one, (ii) treat everyone, (iii) treatment according to the current guidelines (i.e. selective treatment of women >65 years of age or having >10% FRS), and (iv) prediction-based treatment (i.e. selective treatment of patients whose predicted treatment effect exceeds a given decision threshold). The predicted reduction in 10-year absolute risk for major cardiovascular events was <1% in 97.8% of 27 939 study subjects when based on the refitted FRS, in 97.0% when based on the refitted RRS, and in 90.0% when based on the newly developed model. Of the treatment strategies considered, only prediction-based treatment using the newly developed model and selective treatment of women >65 years of age yielded more net benefit than treating no one, provided that the 10-year number-willing-to-treat (NWT) to prevent one cardiovascular event was above 50.
Aspirin was ineffective or even harmful in the majority of patients. Age was positively related to treatment effect, whereas current smoking and baseline risk for cardiovascular events were not. When the NWT is 50 or lower, the aspirin treatment strategy that is associated with optimal net benefit in primary prevention of vascular events in women is to treat none.
Trial registration information: Clinicaltrials.gov identifier number: NCT00000479.
Aspirin; Primary prevention; Treatment effect prediction; Net benefit
Adiponectin is linked to reduced diabetes risk and may be anti-atherogenic, yet clinical data show no consistent relationship with incident cardiovascular events, especially among women. To our knowledge, no prior prospective studies have evaluated adiponectin, including high-molecular-weight (HMW) adiponectin, and incident peripheral artery disease (PAD).
Methods & Results
We evaluated the relationship of total, HMW and the HMW-to-total adiponectin ratio with incident symptomatic PAD in a prospective, nested case-control study conducted within the Women’s Health Study (n=110 cases, n=230 controls, frequency matched in strata defined by five-year age categories, smoking, fasting status and follow-up time; median cohort follow-up=13.2 yrs). Baseline median levels of HMW and total adiponectin were significantly lower in women developing PAD than those remaining event-free(HMW: 3.3 vs. 3.8 μg/mL, P=0.0005; total: 5.6 vs. 7.4 μg/mL, P<0.0001). The ratio did not differ significantly between groups. Age-adjusted PAD odds ratios (95% CI) across tertiles were 1.0, 0.66 (0.39–1.13) and 0.40 (0.22–0.74)for HMW and 1.0, 0.74 (0.43–1.25) and 0.35 (0.18–0.65) for total adiponectin (P-trend=0.004 and 0.001, respectively). Results were similar after adjustment for traditional cardiovascular risk factors, use of post-menopausal hormone therapy, high-sensitivity C-reactive protein, soluble intercellular adhesion molecule-1, leptin, hemoglobin A1c and fasting insulin [adjusted OR and 95% CI for HMW: 1.0, 0.62 (0.29–1.34), 0.30 (0.12–0.74); total: 1.0, 0.46 (0.22–1.00), 0.30 (0.12–0.76 );Ptrend=0.01 for both].
Total and HMW adiponectin are inversely associated with incident PAD among initially healthy women. These prospective data support a protective role for this adipokine in peripheral atherosclerosis development.
adiponectin; biomarker; epidemiology; peripheral artery disease; women
Inflammatory markers such as high-sensitivity C-reactive protein (hsCRP) are associated with an increased risk of cardiovascular events and with the severity of peripheral arterial disease. The effects of inflammation on the development of vein graft disease remain speculative. We hypothesized that high levels of inflammatory markers would identify patients at increased risk for adverse events (graft failure, major cardiovascular events) after lower extremity bypass surgery.
Patients (n = 91) scheduled to undergo lower extremity bypass using autogenous vein were enrolled into a prospective study at two institutions. Exclusion criteria included the presence of major infection. A baseline plasma sample was obtained on the morning of lower extremity bypass. Biomarkers for inflammation included hsCRP, fibrinogen, and serum amyloid A (SAA). Values between patients with and without critical limb ischemia were compared. Proportions of events among dichotomized populations (upper limit of normal of each laboratory assay) were compared by log-rank test.
Of the patients undergoing lower extremity bypass, 69% were men, 53% were diabetic, 81% were smokers, and their mean ankle-brachial index was 0.51 ± 0.19. The indication for lower extremity bypass was critical limb ischemia in 55%. There were no perioperative deaths and two early graft occlusions. During a mean follow-up of 342 days (range, 36–694 days) there were four deaths, 27 graft-related events, and 10 other cardiovascular events. No relationships were found between events and demographics, comorbidities, baseline ankle-brachial index, or statin use. High-sensitivity CRP (P = .005), fibrinogen (P < .001), and SAA (P = .0001) levels were associated with critical limb ischemia at presentation. Among patients with an elevated hsCRP (>5 mg/L) immediately before surgery, major postoperative vascular events occurred in 60% (21/35), compared with a 32% (18/56) rate in those with a baseline CRP <5 mg/L (P = .004, log-rank test). On multivariable analysis, only elevated hsCRP correlated with adverse graft-related or cardiovascular events (P = .018).
The inflammatory biomarkers of hsCRP, fibrinogen, and SAA correlate with peripheral arterial disease severity at presentation in patients undergoing lower extremity bypass. Patients with elevated hsCRP are at increased risk for postoperative vascular events, most of which are related to the vein graft. These findings suggest a potential relationship between inflammation and outcomes after lower extremity vein bypass surgery.
Inflammation predicts risk of cardiovascular disease (CVD) events, but the relation of drugs that directly target inflammation with CVD risk is not established. Methotrexate is a disease-modifying anti-rheumatic drug broadly used for treatment of chronic inflammatory disorders. We performed a systematic review and meta-analysis of evidence for relationships of methotrexate with CVD occurrence. Cohorts, case-control studies or randomized trials were included if they reported an association between methotrexate and CVD risk. Inclusions/exclusions were independently adjudicated, and all data were extracted in duplicate. Pooled effects were calculated using inverse-variance-weighted meta-analysis. Of 694 identified publications, 10 observational studies, in which methotrexate was administered among patients with rheumatoid arthritis, psoriasis, or polyarthritis met inclusion criteria. Methotrexate was associated with 21% lower risk of total CVD (n=10 studies, 95% CI=0.73-0.87, p<0.001), and 18% lower risk of myocardial infarction (n=5, 95% CI=0.71-0.96, p=0.01), without evidence for statistical between-study heterogeneity (p=0.30, p=0.33, respectively). Among prespecified sources of heterogeneity explored, stronger associations were observed in studies that adjusted for underlying disease severity (RR=0.64, 95% CI=0.43-0.96, p<0.01), and for other concomitant medication (RR=0.73, 95% CI=0.63-0.84, p<0.001). Publication bias was potentially evident (funnel plot, Begg’s test, p=0.06); excluding studies with extreme risk estimates did not, however, alter results (RR=0.81, 95% CI=0.74-0.89). In conclusion, methotrexate use is associated with lower risk of CVD among patients with chronic inflammation. These findings suggest that a direct treatment of inflammation may reduce CVD risk.
systematic review; meta-analysis; methotrexate; inflammation; cardiovascular disease
It is unclear whether models which include hemoglobin A1c (HbA1c) levels only for diabetic patients improve ability to predict cardiovascular disease (CVD) risk when compared to the currently recommended classification of diabetes as a cardiovascular risk equivalent.
24,674 women (including 685 diabetic participants at baseline) and 11,280 men (including 563 diabetic participants at baseline) were followed prospectively for CVD. 125 CVD events occurred in diabetic women (666 in non-diabetic women) and 170 events occurred in diabetic men (1382 in non-diabetic men). Models for CVD risk were generated separately for men and women using the traditional CVD risk factors with the addition of a term for HbA1c levels only for diabetic individuals. In diabetic participants, the resulting predicted risks were compared to classification of diabetes as a cardiovascular risk equivalent (10-year CVD-risk of at least 20%).
In women, the models including HbA1c levels in diabetic participants improved the c-statistic by 0.177 (p <0.001) over the risk equivalence model and showed improved reclassification (NRI of 26.7%, p = 0.001). In men, the improvements were more modest but still statistically significant (c-statistic change of 0.039, p=0.015; NRI of 9.2%, p= 0.042). Including HbA1c levels also improved prediction over a dichotomous term for diabetes in women (NRI of 11.8%, p = 0.033) but not in men.
In both women and men with baseline diabetes, we observed significant improvements in predictive ability of CVD risk using models incorporating HbA1c levels compared to classification of diabetes as a cardiovascular risk equivalent.
Leukocyte telomere length shortening has recently been associated with type 2 diabetes Mellitus (T2D). Whether this observation was modulated by genetic variation within the telomere-pathway genes remains elusive. To date, no prospective epidemiological data on the relationship of telomere-pathway gene variation with T2D are available.
The association between 150 tagging-SNPs (tSNPs) of 11 telomere-pathway genes (TERC, UCP1, TERT, POT1, TNKS, TERF1, TNKS2, TEP1, ACD, TERF2 and TERF2IP) and incident T2D was investigated in 22,715 Caucasian female participants of the prospective Women’s Genome Health Study. All were free of known cardiovascular disease, cancer and diabetes at baseline. During a 13-year follow-up period, 1,445 participants developed an incident T2D. Multivariable Cox regression analysis was performed to investigate the relationship between genotypes and T2D risk assuming an additive genetic model. Haplotype block analysis was also performed.
A total of eleven tSNPs within TERF1, TNKS, TEP1, ACD, and TERF2 were associated with T2D risk (all p-uncorrected <0.050). Further investigation using the haplotype-block analysis again revealed an association of several prespecified haplotypes of TERF1, and TEP1 with T2D risk (all p-uncorrected <0.040).
If corroborated in other prospective studies, the present findings suggest that genetic variation within the telomere-pathway gene loci examined may be useful predictor for T2D risk assessment.
Inflammation, as measured by the circulating inflammatory marker high sensitivity C-reactive protein (hsCRP), has been associated with cardiovascular disease. However, data regarding CRP and risk of colorectal cancer have been conflicting. The Adenoma Prevention with Celecoxib (APC) trial demonstrated that the anti-inflammatory drug celecoxib prevents recurrence of colorectal adenoma but increases risk of cardiovascular events. We examined if serum hsCRP modified these results.
We measured hsCRP from serum specimens provided at study entry by patients enrolled in the APC trial. Patients were stratified according to use of low-dose aspirin, randomized to receive three years of treatment with placebo, 200-mg-bid celecoxib, or 400-mg-bid celecoxib, and underwent follow-up colonoscopies at Year 1 and 3.
Among 1,680 patients, the estimated three-year cumulative incidence of adenoma was 42% for patients with hsCRP <1mg/L, compared with 43% (RR=1.02; 95% confidence interval (CI)=0.85–1.22) for hsCRP 1–3mg/L, and 41% (RR=1.1; CI=0.90–1.34) for hsCRP >3mg/L. The effect of celecoxib on adenoma recurrence did not vary among patients with high (>3mg/L) compared with low (≦3mg/L) hsCRP. However, among patients with high hsCRP, the RR of cardiovascular events compared with placebo was 2.27 (95%CI=0.72–7.14) for those randomized to celecoxib 200-mg-bid and 3.28 (CI=1.09–9.91) for 400-mg-bid. In contrast, among patients with low hsCRP, the corresponding RRs were 0.99 (CI=0.53–1.83) and 1.11 (CI=0.61–2.02).
HsCRP may predict risk of celecoxib-associated cardiovascular toxicity, but not adenoma recurrence or celecoxib treatment efficacy. Patients with low hsCRP may be a subgroup with a favorable risk-benefit profile for celecoxib chemoprevention.
Adenoma; celecoxib; c-reactive protein; inflammation; chemoprevention
Prospective data regarding risk factors for peripheral artery disease (PAD) are sparse, especially among women; the relative contribution of systolic versus diastolic blood pressure control for incident PAD has not been well-studied. We evaluated the association of self-reported blood pressure control with incident symptomatic PAD in middle-aged and older women.
We examined the relationship between reported hypertension and incident confirmed symptomatic PAD (n=178) in 39,260 female health professionals aged ≥45 years without known vascular disease at baseline. Median follow-up was 13.3 years. Women were grouped according to presence of reported isolated diastolic (IDH), isolated systolic (ISH), or combined systolic-diastolic hypertension (SDH) using cut-points of 90 and 140 mmHg for diastolic and systolic blood pressure, respectively. SBP and DBP were modeled as continuous and categorical exposures. Multivariable-adjusted hazard ratios (HRs), including adjustment for CV risk factors, were derived from Cox proportional hazards models.
Adjusted HRs compared to women without reported hypertension were 1.0 (0.4–2.8) for IDH, 2.0 (1.3–3.1) for ISH, and 2.8 (1.8–4.5) for SDH. There was a 43% increased adjusted risk per 10 mmHg of reported SBP (95% CI 27–62%) and a gradient in risk according to SBP category (<120, 120–139, 140–159, and ≥160 mmHg); HRs were 1.0, 2.3, 4.3, and 6.6 (p-trend<0.001), respectively. Reported DBP, while individually predictive in models excluding SBP, was not predictive after adjustment for SBP.
These prospective data suggest a strong prognostic role for uncontrolled blood pressure and, particularly, uncontrolled systolic blood pressure in the development of peripheral atherosclerosis in women.
hypertension; peripheral artery disease; women
Very low levels of cardiac troponin T associate with increased risk of cardiovascular death in patients with stable chronic coronary disease. Whether high-sensitivity cardiac troponin T (hsTnT) levels associate with adverse cardiovascular outcomes in individuals without cardiovascular disease (CVD) has not been well studied.
Methods and Results
Utilizing two complementary study designs, we evaluated the relationship between baseline cardiac troponin and incident CVD events among diabetic and non-diabetic participants in the Women’s Health Study (median follow-up 12.3 years). All diabetic women with blood specimens were included in a cohort study (n=512 diabetic women, n=65 events) and non-diabetic women were sampled for inclusion in a case-cohort analysis (n=564 comprising the subcohort, n=479 events). HsTnT was detectable (≥0.003 μg/L) in 45.5% of diabetic women and 30.3% of non-diabetic women (P<0.0001). In models adjusted for traditional risk factors and hemoglobin A1c, detectable hsTnT was associated with subsequent CVD (myocardial infarction, stroke, cardiovascular death) in diabetic women (adjusted HR 1.79, 95% CI 1.04-3.07, P=0.036), but not non-diabetic women (adjusted HR 1.13, 95% CI 0.82-1.55, P=0.46). Further adjustment for NT-proBNP and estimated renal function did not substantially alter this relationship among diabetic women (HR 1.76, 95% CI 1.00-3.08, P=0.0499), which appeared to be driven by a threefold increase in CVD death that was not observed in non-diabetic women.
Very low but detectable levels of cardiac troponin T associate with total CVD and CVD death in women with diabetes. Among healthy non-diabetic women, detectable compared to undetectable troponin was not associated with CVD events.
Primary prevention; cardiovascular disease risk factors; troponin; diabetes mellitus type 2; women
The detrimental effects of smoking on risk of myocardial infarction and stroke are well documented, but less information is available regarding peripheral artery disease (PAD), particularly among women.
To prospectively assess the association of current smoking status, cumulative smoking exposure and smoking cessation with incident symptomatic PAD in women
Prospective cohort study
U.S. female health care professionals in the Women's Health Study
39825 women free of cardiovascular disease were prospectively followed for a median of 12.7 years.
Incident symptomatic PAD (n=178). Cox proportional hazards models were used to compare PAD risk among never (n=20336) and former smoking (n=14263) women, women who smoked <15 cigarettes/day (n=1967) and women who smoked ≥15 cigarettes/day (n=3259).
Age-adjusted incidences across smoking categories were 0.12, 0.34, 0.95 and 1.63 per 1000 person-years of follow-up. Multivariable adjustment had little impact on this risk gradient; adjusted hazard ratios (HRs) (95% confidence intervals (CIs)) were 3.14 (2.01–4.90), 8.93 (5.02–15.89) and 16.95 (10.77–26.67) compared with never-smokers. Additional adjustment for high sensitivity C-reactive protein and soluble intercellular adhesion molecule 1 among women with available blood samples (n=28314, 117 events) attenuated risk estimates with HRs of 5.58 (2.61–11.93) and 9.52 (5.17–7.53) for women smoking <15 and ≥15 cigarettes/day, respectively. We found a strong dose-response relationship for lifetime exposure such that the fully adjusted HR’s for 0 (reference), <10, 10–30 and ≥30 pack years were 2.52 (1.49–4.25), 6.75 (4.33–10.52) and 11.09 (6.94–17.72). Compared to current smokers, the adjusted HRs (95% CIs) for smoking abstinence of <10 years, 10–20 years, >20 years and lifelong abstinence were 0.39 (0.24–0.66), 0.28 (0.17–0.46), 0.16 (0.10–0.26) and 0.08 (0.05–0.12).
The use of symptomatic PAD as the primary a priori end point excludes asymptomatic disease.
Among initially healthy women, smoking is a potent risk factor for symptomatic PAD, an effect partially explained by subclinical inflammation. Smoking cessation substantially reduces PAD risk, but an increased occurrence of PAD persists even among former smokers who maintain abstinence.
Primary Funding Source
National Heart, Lung, and Blood Institute and National Cancer Institute
Peripheral artery disease; cardiovascular disease; smoking; inflammation; women
We determined whether persistently high levels of interleukin-6 (IL-6) or soluble vascular adhesion molecule (sVCAM-1) are associated with faster functional decline, compared to fluctuating or persistently low biomarker levels, among 255 participants with peripheral arterial disease (PAD). Participants underwent baseline and at least two annual follow-up measures of IL-6 and sVCAM-1. Participants were categorized as follows: Category 1- annual levels of IL-6 (or sVCAM-1) were in the lowest tertile for at least three study visits. Category 3- annual levels of IL-6 (or sVCAM-1) were in the highest tertile for at least three visits. Category 2- levels of IL-6 (or sVCAM-1) did not meet criteria for Groups 1 or 3. Six-minute walk, fastest paced four meter walking velocity, and the short physical performance battery (SPPB) were measured annually. Results were adjusted for age, sex, race, comorbidities, statins, physical activity, the ankle brachial index, and other confounders. Across IL-6 categories, average annual declines in six minute walk performance were Category 1: -21.4 feet, Category 2:-49.2 feet, and Category 3:-76.8 feet (p trend = 0.013) and average annual declines in the SPPB score were -0.18, -0.45, and -0.62, respectively (p trend = 0.022). Similar associations of IL-6 categories with decline in fastest paced walking velocity were observed (p trend = 0.034). There were no significant associations of sVCAM-1 categories with functional decline. In conclusion, among PAD participants, persistently high IL-6 levels are associated with faster functional decline compared to those with fluctuating or persistently low IL-6 levels.
Inflammation; physical functioning; peripheral arterial disease; intermittent claudication
Evidence from observational studies have raised the possibility that statin treatment reduces the incidence of certain bacterial infections, particularly pneumonia. We analyzed data from a randomized controlled trial of rosuvastatin to examine this hypothesis.
We analyzed data from the randomized, double-blind, placebo-controlled JUPITER trial (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin). In this trial, 17 802 healthy participants (men 50 years and older and women 60 and older) with a low-density lipoprotein (LDL) cholesterol level below 130 mg/dL (3.4 mmol/L) and a high-sensitivity C-reactive protein level of 2.0 mg/L or greater were randomly assigned to receive either rosuvastatin or placebo. We evaluated the incidence of pneumonia on an intention-to-treat basis by reviewing reports of adverse events from the study investigators, who were unaware of the treatment assignments.
Among 17 802 trial participants followed for a median of 1.9 years, incident pneumonia was reported as an adverse event in 214 participants in the rosuvastatin group and 257 in the placebo group (hazard ratio [HR] 0.83, 95% confidence interval [CI] 0.69–1.00). In analyses restricted to events occurring before a cardiovascular event, pneumonia occurred in 203 participants given rosuvastatin and 250 given placebo (HR 0.81, 95% CI 0.67–0.97). Inclusion of recurrent pneumonia events did not modify this effect (HR 0.81, 95% CI 0.67–0.98), nor did adjustment for age, sex, smoking, metabolic syndrome, lipid levels and C-reactive protein level.
Data from this randomized controlled trial support the hypothesis that statin treatment may modestly reduce the incidence of pneumonia.
(ClinicalTrials.gov trial register no. NCT0023968.)
Islet amyloid polypeptide (IAPP) gene variation has recently been implicated in type 2 diabetes mellitus (T2D). However, to date, no prospective epidemiological data are available.
The association between 10 IAPP tag-single nucleotide polymorphisms (tSNPs) and incident T2D was investigated in 22,715 Caucasian participants of the prospective Women’s Genome Health Study. All were free of known cardiovascular disease, cancer, and diabetes at baseline. During a 13-year follow-up period, 1,445 participants developed an incident T2D. Multivariable Cox regression analysis was performed to investigate the relationship between genotypes and T2D risk. Haplotype-based analysis was also performed.
No evidence for an association of any of the tSNPs tested or haplotypes thereof with T2D risk.
If corroborated in other large, prospective studies, the present findings further suggest that the IAPP gene locus may not be useful predictor for T2D risk assessment.
IAPP; Diabetes; Gene; risk factor
Cardiovascular inflammation is a key contributor to the development of atherosclerosis and the prediction of cardiovascular events among healthy women. An emerging literature suggests biomarkers of inflammation vary by geography of residence at the state-level, and are associated with individual-level socioeconomic status. Associations between cardiovascular inflammation and state-level socioeconomic conditions have not been evaluated. The study objective is to estimate whether there are independent associations between state-level socioeconomic conditions and individual-level biomarkers of inflammation, in excess of individual-level income and clinical covariates among healthy women.
The authors examined cross-sectional multilevel associations among state-level socioeconomic conditions, individual-level income, and biomarkers of inflammation among women (n = 26,029) in the Women's Health Study, a nation-wide cohort of healthy women free of cardiovascular diseases at enrollment. High sensitivity C-reactive protein (hsCRP), soluble intercellular adhesion molecule-1 (sICAM-1) and fibrinogen were measured between 1993 and 1996. Biomarker levels were examined among women within quartiles of state-level socioeconomic conditions and within categories of individual-level income.
The authors found that favorable state-level socioeconomic conditions were correlated with lower hsCRP, in excess of individual-level income (e.g. state-level real per capital gross domestic product fixed effect standardized Βeta coefficient [Std B] -0.03, 95% CI -0.05, -0.004). Individual-level income was more closely associated with sICAM-1 (Std B -0.04, 95% CI -0.06, -0.03) and fibrinogen (Std B -0.05, 95% CI -0.06, -0.03) than state-level conditions.
We found associations between state-level socioeconomic conditions and hsCRP among healthy women. Personal household income was more closely associated with sICAM-1 and fibrinogen than state-level socioeconomic conditions. Additional research should examine these associations in other cohorts, and investigate what more-advantaged states do differently than less-advantaged states that may influence levels of cardiovascular inflammation among healthy women.
C-reactive protein; Geography; Income; Inflammation; Multilevel analysis; Poverty; Socioeconomic factors; Women's health
By guiding initial warfarin dose, pharmacogenetic (PGx) algorithms may improve the safety of warfarin initiation. However, once INR response is known, the contribution of PGx to dose refinements is uncertain. This study sought to develop and validate clinical and PGx dosing algorithms for warfarin dose refinement on days 6–11 after therapy initiation.
Materials and Methods
An international sample of 2,022 patients at 13 medical centers on 3 continents provided clinical, INR, and genetic data at treatment days 6–11 to predict therapeutic warfarin dose. Independent derivation and retrospective validation samples were composed by randomly dividing the population (80%/20%). Prior warfarin doses were weighted by their expected effect on S-warfarin concentrations using an exponential-decay pharmacokinetic model. The INR divided by that “effective” dose constituted a treatment response index.
Treatment response index, age, amiodarone, body surface area, warfarin indication, and target INR were associated with dose in the derivation sample. A clinical algorithm based on these factors was remarkably accurate: in the retrospective validation cohort its R2 was 61.2% and median absolute error (MAE) was 5.0 mg/week. Accuracy and safety was confirmed in a prospective cohort (N=43). CYP2C9 variants and VKORC1-1639 G→A were significant dose predictors in both the derivation and validation samples. In the retrospective validation cohort, the PGx algorithm had: R2= 69.1% (P<0.05 vs. clinical algorithm), MAE= 4.7 mg/week.
A pharmacogenetic warfarin dose-refinement algorithm based on clinical, INR, and genetic factors can explain at least 69.1% of therapeutic warfarin dose variability after about one week of therapy.
warfarin; VKORC1; CYP2C9; pharmacogenetic
Variation in the fat mass and obesity-associated (FTO) gene is associated with obesity. The extent to which separate and combined effects of physical activity and caloric intake modify this association remains unclear.
RESEARCH DESIGN AND METHODS
FTO polymorphism rs8050136 was measured, and physical activity, caloric intake, and anthropometrics were self-reported in 21,675 apparently healthy Caucasian women.
The effect of the risk allele (A) on BMI was larger among inactive or higher intake women, with additive effects of inactivity and high intake on the associated genetic risk. Specifically, each A allele was associated with mean BMI difference of +0.73 (SE 0.08) kg/m2 among inactive women (≤median, 8.8 MET-hours/week), compared with +0.31 (0.06) kg/m2, P < 0.0001, among active women (>8.8 MET-hours/week). Similarly, each A allele was associated with mean BMI difference of +0.65 (0.07) among high intake women (>median, 1,679 kcals/day), compared with +0.38 (0.07) kg/m2, P = 0.005, among low intake women (≤1,679 kcals/day). Among inactive/high intake women, each A allele was associated with mean BMI difference of +0.97 (0.11) kg/m2 vs. +0.22 (0.08) kg/m2 among inactive/low intake women, P < 0.0001. Among inactive/high intake women, each A allele carried increased risk of obesity (odds ratio 1.39, 95% CI 1.27–1.52) and diabetes (odds ratio 1.36, 95% CI 1.07–1.73).
In this study, lifestyle factors modified the genetic risk of FTO on obesity phenotypes, particularly among women who were both inactive and had high intake. Healthier lifestyle patterns blunted but did not completely eliminate the associated genetic risk.
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 (CVD), is uncertain.
Methods and Results
In a prospective cohort study of 22,939 apparently healthy Caucasian US women, 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 (PA). PA modified the effects on HDL-C of 7 SNPs at 3 loci, and the strongest evidence of effect was observed for rs10096633 at LPL, rs1800588 at LIPC and rs1532624 at 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 MI in active (Hazard Ratio [HR] 0.42, 95% Confidence Interval [CI] 0.23–0.76) but not amongst inactive women (HR 1.10, 95% CI 0.83–1.44; P-interaction=0.007). By contrast, carrier status at the CETP SNP was associated with a reduced risk of MI regardless of activity level (HR 0.72, 95% CI 0.57–0.92; P-interaction=0.71). No association between LIPC SNP carrier status and MI risk was noted
The effects of common variants in the LPL, LIPC and CETP genes on HDL-C levels are modified by PA. For a common variant in LPL, the impact on MI varied by activity level, while the effects of a common variant in CETP on MI risk did not.
genomic studies; HDL cholesterol; myocardial infarction; exercise
Candidate genes associated with telomere-length maintenance, an important molecular marker for biological aging, represent potential risk predictors for cardiovascular disease (CVD). To date, no prospective data are available.
The associations between 154 tag-single nucleotide polymorphisms (tSNPs) of 11 telomere-associated candidate genes (TERT, POT1, TNKS, TERF1, TNKS2, UCP2, TEP1, ACD, TERF2, TERF2IP, TERC) were investigated in 23,294 Caucasian participants of the Women’s Genome Health Study. All were free of known CVD and cancer at baseline. The primary outcome measure was a composite CVD endpoint (incident ischemic stroke, myocardial infarction (MI), or death due to ischemic CVD); other measures were incident MI, and ischemic stroke. During follow-up, 1178 total incident CVD, 315 incident MI cases, and 323 incident ischemic stroke events were identified. Multivariable Cox regression analysis and a haplotype-based approach were performed to investigate the relationship between genotypes/haplotypes and CVD risk assuming an additive model.
In a marker-by-marker analysis, 7 (TEP1, TNKS, ACD), 11 (TEP1, ACD, TERT), and 24 (TEP1, TNKS, TERT, TERF2IP, TNKS2, UCP2) SNPs were associated -at the level of p<0.05- with total CVD, MI, and ischemic stroke risk, respectively. Further analysis using a haplotype-based approach showed similar findings. Although, none remained significant after correction of multiple testing, the false discovery rate analysis revealed 28% of the nominally significant SNPs with true associations in relation to ischemic stroke risk.
The present large prospective study encourages further investigation of the biological role of telomere-associated pathway genes in the pathogenesis and early assessment of vascular events.
High sensitivity C-reactive protein (hsCRP) and family history independently associate with future cardiovascular events and have been incorporated into risk prediction models for women (the Reynolds Risk Score for women). However, no cardiovascular risk prediction algorithm incorporating these variables currently exists for men.
Methods and Results
Among 10,724 initially healthy American non-diabetic men who were followed prospectively over a median period of 10.8 years, we compared the test characteristics of global model fit, discrimination, calibration, and reclassification in two prediction models for incident cardiovascular events, one based on age, blood pressure, smoking status, total cholesterol, and high-density lipoprotein cholesterol (traditional model), and the other based on these risk factors as well as hsCRP and parental history of myocardial infarction before age 60 years (Reynolds Risk Score for men). 1,294 cardiovascular events accrued during study follow-up. Compared to the traditional model, the Reynolds Risk Score had better global fit (likelihood ratio test P<0.001), a superior (lower) Bayes Information Criterion, and a larger C-index (P<0.001). For the endpoint of all cardiovascular events, the Reynolds Risk Score for men reclassified 17.8 percent [1,904/10,724] of the study population (and 20.2 percent [1,342/6,884] of those at 5 to 20 percent 10-year risk) into higher- or lower-risk categories with markedly improved accuracy among those reclassified. For this model comparison, the net reclassification index (NRI) was 5.3 percent and the clinical net reclassification index (CNRI) was 14.2 percent (both P-values<0.001). In models based on the ATP-III preferred endpoint of coronary heart disease and limited to men not taking lipid-lowering therapy, 16.7 percent of the study population (and 20.1 percent of those at 5 to 20 percent 10-year risk) were reclassified to higher- or lower-risk groups, again with significantly improved global fit, larger C-index (P<0.001), and markedly improved accuracy among those reclassified. For this model, NRI was 8.4 percent and CNRI 15.8 percent (both P-values <0.001).
As previously shown in women, a prediction model in men that incorporates hsCRP and parental history significantly improves global cardiovascular risk prediction.
prediction; prevention; inflammation; C-reactive protein; family history
This study examines C-reactive protein (CRP) levels predict cardiovascular events (CVE) among hormone therapy (HT) users and non-users.
CRP levels are higher in women who use oral HT than in non-users; however, whether the same CRP cutpoints determine increased cardiovascular risk remains unanswered.
CRP was measured at baseline in 10,953 HT users and 15,838 non-users in the Women’s Health Study. In HT non-users and users, Cox-proportional hazard models adjusted for age, cardiovascular risk factors, BMI, and menopausal status were constructed using AHA/CDC-recommended CRP cut-points for low, average, and high cardiovascular risk as well as HT non-user-and user-derived quantiles of CRP to predict incident cardiovascular events(CVE).
CVE risk increased with lnCRP for both HT users and non-users. After adjusting for cardiovascular risk factors including lipids, the multivariable relative risk (RR) per log unit of CRP was 1.27 (95% CI, 1.13 to 1.44) for HT non-users and 1.22 (95% CI, 1.07 to 1.40) for HT users. In order to compare the risk associated with AHA/CDC CRP categories across HT use groups, we fit a model in which non-users with CRP <1 mg/L were the reference group. After adjusting for other risk factors including lipids, HT users with CRP ≥3 had a RR of 1.93 (1.38–2.69) while non-users had a RR of 1.92 (1.35–2.72).
CRP predicts CVE in a linear relationship among both HT users and non-users. CRP levels ≥3 mg/L were associated with increased cardiovascular risk in both non-users and HT users.
cardiovascular diseases; prevention; risk factors; hormones; C-reactive protein