[show abstract][hide abstract] ABSTRACT: 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.).
Canadian Medical Association Journal 03/2012; 184(7):E367-72. · 6.47 Impact Factor
[show abstract][hide abstract] ABSTRACT: Although lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) levels are associated with cardiovascular events, Lp-PLA(2) is physically linked to LDL cholesterol (LDL-C). Whether measures of Lp-PLA(2) mass or activity continue to predict risk after LDL-C reduction by statin therapy is uncertain.
Lp-PLA(2) mass concentration and activity were evaluated at baseline and after treatment in the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial comparing rosuvastatin 20 mg to placebo among 17 802 men and women without cardiovascular disease or diabetes at study entry. The relationships of Lp-PLA(2) mass and activity with risk of future vascular events were evaluated in the placebo and rosuvastatin groups.
Before randomization, levels of Lp-PLA(2) mass and activity correlated moderately with each other and with LDL-C. The magnitude of these correlations increased after statin therapy. Rosuvastatin reduced Lp-PLA(2) mass by 33.8%, Lp-PLA(2) activity by 33.2%, and LDL-C by 48.7% (all P < 0.0001). Among those study participants allocated to placebo, increasing quartiles of Lp-PLA(2) activity (P(trend) = 0.04) but not Lp-PLA(2) mass (P(trend) = 0.92) were associated with incident cardiovascular events after adjustment for LDL-C and conventional risk factors. Comparable analyses conducted among those allocated to rosuvastatin revealed no significant relationship between Lp-PLA(2) levels and subsequent vascular events. The ability of rosuvastatin to reduce vascular events was not significantly modified by baseline Lp-PLA(2) level.
Among JUPITER trial participants allocated to placebo, levels of Lp-PLA(2) activity, but not mass, were associated with cardiovascular risk. However, Lp-PLA(2) no longer predicted risk or modified clinical outcomes when participants were treated with rosuvastatin.
[show abstract][hide abstract] ABSTRACT: Framingham-based and Reynolds Risk scores for cardiovascular disease (CVD) prediction have not been directly compared in an independent validation cohort.
We selected a case-cohort sample of the multiethnic Women's Health Initiative Observational Cohort, comprising 1722 cases of major CVD (752 myocardial infarctions, 754 ischemic strokes, and 216 other CVD deaths) and a random subcohort of 1994 women without prior CVD. We estimated risk using the Adult Treatment Panel III (ATP-III) score, the Reynolds Risk Score, and the Framingham CVD model, reweighting to reflect cohort frequencies. Predicted 10-year risk varied widely between models, with ≥10% risk in 6%, 10%, and 41% of women with the ATP-III, Reynolds, and Framingham CVD models, respectively. Calibration was adequate for the Reynolds model, but the ATP-III and Framingham CVD models overestimated risk for coronary heart disease and major CVD, respectively. After recalibration, the Reynolds model demonstrated improved discrimination over the ATP-III model through a higher c statistic (0.765 versus 0.757; P=0.03), positive net reclassification improvement (NRI; 4.9%; P=0.02), and positive integrated discrimination improvement (4.1%; P<0.0001) overall, excluding diabetics (NRI=4.2%; P=0.01), and in white (NRI=4.3%; P=0.04) and black (NRI=11.4%; P=0.13) women. The Reynolds (NRI=12.9%; P<0.0001) and ATP-III (NRI=5.9%; P=0.0001) models demonstrated better discrimination than the Framingham CVD model.
The Reynolds Risk Score was better calibrated than the Framingham-based models in this large external validation cohort. The Reynolds score also showed improved discrimination overall and in black and white women. Large differences in risk estimates exist between models, with clinical implications for statin therapy.
[show abstract][hide abstract] ABSTRACT: Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10(-8)-1.2×10(-43)). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3×10(-4)). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p = 4.3×10(-3), n = 22,044), increased triglycerides (p = 2.6×10(-14), n = 93,440), increased waist-to-hip ratio (p = 1.8×10(-5), n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4×10(-3), n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL-cholesterol concentrations (p = 4.5×10(-13), n = 96,748) and decreased BMI (p = 1.4×10(-4), n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance.
[show abstract][hide abstract] ABSTRACT: In statin trials, each 20 mg/dL reduction in cholesterol results in a 10-15% reduction of annual incidence rates for vascular events. However, interindividual variation in low-density lipoprotein cholesterol (LDL-C) response to statins is wide and may partially be determined on a genetic basis.
A genome-wide association study of LDL-C response was performed among a total of 6989 men and women of European ancestry who were randomly allocated to either rosuvastatin 20 mg daily or placebo. Single nucleotide polymorphisms (SNPs) for genome-wide association (P<5×10(-8)) with LDL-C reduction on rosuvastatin were identified at ABCG2, LPA, and APOE, and a further association at PCSK9 was genome-wide significant for baseline LDL-C and locus-wide significant for LDL-C reduction. Median LDL-C reductions on rosuvastatin were 40, 48, 51, 55, 60, and 64 mg/dL, respectively, among those inheriting increasing numbers of LDL-lowering alleles for SNPs at these 4 loci (P trend=6.2×10(-20)), such that each allele approximately doubled the odds of percent LDL-C reduction greater than the trial median (odds ratio, 1.9; 95% confidence interval, 1.8-2.1; P=5.0×10(-41)). An intriguing additional association with sub-genome-wide significance (P<1×10(-6)) was identified for statin related LDL-C reduction at IDOL, which mediates posttranscriptional regulation of the LDL receptor in response to intracellular cholesterol levels. In candidate analysis, SNPs in SLCO1B1 and LDLR were confirmed as associated with LDL-C lowering, and a significant interaction was observed between SNPs in PCSK9 and LDLR.
Inherited polymorphisms that predominantly relate to statin pharmacokinetics and endocytosis of LDL particles by the LDL receptor are common in the general population and influence individual patient response to statin therapy.
[show abstract][hide abstract] ABSTRACT: In randomized trials, statins reduce plasma levels of C-reactive protein (CRP) and low-density lipoprotein cholesterol (LDL-C), and the magnitude of event reduction relates to on-treatment levels of both. However, whether different mechanisms underlie statin-induced CRP and LDL-C reduction is unknown.
We performed a study to evaluate potential genetic determinants of CRP response using genome-wide genetic data from a total of 6766 participants of European ancestry randomly allocated to 20 mg/d of rosuvastatin or placebo in the JUPITER trial. Among 3386 rosuvastatin-allocated individuals, both CRP and LDL-C levels were reduced by 50% after 12 months of therapy (P<0.001 for both) and essentially uncorrelated (r(2)<0.03). No variants in the 3 genes (ABCG2, LPA, and APOE) that previously showed genome-wide association with LDL-C reduction in this cohort and none of the candidate single-nucleotide polymorphisms associated with LDL-C reduction were associated with rosuvastatin-induced CRP change after multiple testing correction. Among candidate single-nucleotide polymorphisms selected from prior genetic analyses of baseline CRP, CRP reduction was associated with rs2794520 in CRP (mean, -3.5% [SE, 2.0%] change in CRP per minor allele; P=6.4×10(-4)) and with rs2847281 in PTPN2 (mean, 3.7% [SE, 1.9%] change in CRP per minor allele; P=7.4×10(-4)). These associations remained significant after multiple testing correction but were not significant in a formal test of interaction. Neither variant was associated with rosuvastatin-induced LDL-C reduction or with CRP reduction among 3380 placebo-allocated JUPITER participants.
The genetic determinants of rosuvastatin-induced CRP reduction differ from, and are largely independent of, the major pharmacogenetic determinants of rosuvastatin-induced LDL-C reduction. This supports the hypothesis that differing pathways may mediate the anti-inflammatory and lipid-lowering properties of statin therapy.
[show abstract][hide abstract] ABSTRACT: Few epidemiologic studies have examined the potential cardiovascular mechanisms of tomato-based food products, the primary dietary source of lycopene. We examined the cross-sectional association between tomato-based food product intake and coronary biomarkers in the Women's Health Study. Tomato-based food products (tomatoes, tomato juice, tomato sauce, pizza) were summed from a semiquantitative FFQ and multiple risk factors ascertained. Plasma from baseline blood samples were assayed for lipids, lipoproteins, hemoglobin A1c, C-reactive protein, fibrinogen, soluble intracellular adhesion molecule-1, and creatinine. A total of 27,261 women aged ≥45 y who were free of cardiovascular disease and cancer provided relevant data for this study. Tomato-based food product intake was modest, with 84% of women consuming <1 serving/d, but those with greater intake had healthier lifestyle and dietary habits. Women consuming ≥10 compared with <1.5 servings/wk of tomato-based food products had significant but clinically modest improvements in total cholesterol (TC) (5.38 vs. 5.51 mmol/L; P = 0.029), the TC:HDL cholesterol ratio (4.08 vs. 4.22; P = 0.046), and hemoglobin A1c (5.02 vs. 5.13%; P < 0.001) in multivariable models. Considering clinical cutpoints, women consuming ≥10 compared with <1.5 servings/wk were 31% (95% CI = 6%, 50%), 40% (95% CI = 13%, 59%), and 66% (95% CI = 20%, 86%) less likely to have elevated TC (≥6.21 mmol/L), LDL cholesterol (≥4.14 mmol/L), and hemoglobin A1c (≥6%), respectively. Other coronary biomarkers were unassociated with tomato-based food products. In conclusion, women consuming ≥10 compared with <1.5 servings/wk of tomato-based food products had clinically modest but significant improvements in TC, the TC:HDL cholesterol ratio, and hemoglobin A1c but not other coronary biomarkers.
Journal of Nutrition 02/2012; 142(2):326-33. · 4.20 Impact Factor
[show abstract][hide abstract] ABSTRACT: Migraine is a common and debilitating neurovascular disorder with a complex envirogenomic aetiology. Numerous studies have demonstrated a preponderance of women affected with migraine and previous pedigree linkage studies in our laboratory have identified susceptibility loci on chromosome Xq24-Xq28. In this study we have used the genetic isolate of Norfolk Island to further analyse the X chromosome for migraine susceptibility loci.An association approach was employed to analyse 14,124 SNPs spanning the entire X chromosome. Genotype data from 288 individuals comprising a large core-pedigree, of which 76 were affected with migraine, were analysed. Although no SNP reached chromosome-wide significance (empirical α = 1 × 10(-5)) ranking by P-value revealed two primary clusters of SNPs in the top 25. A 10 SNP cluster represents a novel migraine susceptibility locus at Xq12 whilst a 11 SNP cluster represents a previously identified migraine susceptibility locus at Xq27. The strongest association at Xq12 was seen for rs599958 (OR = 1.75, P = 8.92 × 10(-4)), whilst at Xq27 the strongest association was for rs6525667 (OR = 1.53, P = 1.65 × 10(-4)). Further analysis of SNPs at these loci was performed in 5,122 migraineurs from the Women's Genome Health Study and provided additional evidence for association at the novel Xq12 locus (P<0.05).Overall, this study provides evidence for a novel migraine susceptibility locus on Xq12. The strongest effect SNP (rs102834, joint P = 1.63 × 10(-5)) is located within the 5'UTR of the HEPH gene, which is involved in iron homeostasis in the brain and may represent a novel pathway for involvement in migraine pathogenesis.
PLoS ONE 01/2012; 7(5):e37903. · 3.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: To newly identify loci for age at natural menopause, we carried out a meta-analysis of 22 genome-wide association studies (GWAS) in 38,968 women of European descent, with replication in up to 14,435 women. In addition to four known loci, we identified 13 loci newly associated with age at natural menopause (at P < 5 × 10(-8)). Candidate genes located at these newly associated loci include genes implicated in DNA repair (EXO1, HELQ, UIMC1, FAM175A, FANCI, TLK1, POLG and PRIM1) and immune function (IL11, NLRP11 and PRRC2A (also known as BAT2)). Gene-set enrichment pathway analyses using the full GWAS data set identified exoDNase, NF-κB signaling and mitochondrial dysfunction as biological processes related to timing of menopause.
[show abstract][hide abstract] ABSTRACT: 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.
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.
European Heart Journal 12/2011; 33(4):531-7. · 14.10 Impact Factor
[show abstract][hide abstract] ABSTRACT: Prior studies have found inverse associations between high-density lipoprotein cholesterol (HDL-C) or apolipoprotein A-I levels and cardiovascular disease (CVD). Whether this observation is consistent across low-density lipoprotein cholesterol (LDL-C) levels or total atherogenic particle burden (apolipoprotein B100) is less well-studied, particularly in women.
To determine the association between HDL-C or apolipoprotein A-I level and CVD across a range of LDL-C and apolipoprotein B100 values.
Prospective cohort study.
The Women's Health Study, a cohort of U.S. female health professionals.
26,861 initially healthy women, aged 45 years or older at study entry (1992-1995), who were followed for a mean of approximately 11 years.
Baseline lipids were measured directly, and apolipoproteins were measured 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-I levels were inversely associated with CVD and coronary events but not stroke. Adjusted coronary hazard ratios for decreasing quintiles of HDL-C were 1.00 (reference), 1.23 (95% CI, 0.85 to 1.78), 1.42 (CI, 0.98 to 2.06), 1.90 (CI, 1.33 to 2.71), and 2.19 (CI, 1.51 to 3.19) (P for linear trend < 0.001); corresponding hazard ratios for apolipoprotein A-I were 1.00 (reference), 0.98 (CI, 0.71 to 1.35), 1.02 (CI, 0.72 to 1.44), 1.37 (CI, 0.98 to 1.90), and 1.58 (CI, 1.14 to 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 values, including among women with low LDL-C levels. No associations were noted for HDL-C or apolipoprotein A-I among women with low apolipoprotein B100 values (<0.90 g/L).
Participants were at low risk for CVD, the number of events in the lowest apolipoprotein B100 stratum was small, only a single baseline measurement was obtained, and residual confounding may have occurred.
Consistent inverse associations were found for HDL-C with incident coronary events among women with a range of LDL-C values. Among women with low total atherogenic particle burden (apolipoprotein B100 level <0.90 g/L), few events occurred and no associations were seen.
Merck & Co. and the National Heart, Lung, and Blood Institute and National Cancer Institute, National Institutes of Health.
Annals of internal medicine 12/2011; 155(11):742-50. · 13.98 Impact Factor
[show abstract][hide abstract] ABSTRACT: Circulating levels of soluble intercellular adhesion molecule-1, soluble P-selectin, and soluble E-selectin have been associated with variation at the ABO locus. To evaluate these associations and the effect sizes, we performed a meta-analysis with new and previous reported data for polymorphism rs579459.
Compared with major allele homozygotes, heterozygotes and minor allele homozygotes had 4.6% (95% CI, 3.4%-5.8%, P=7.3 × 10(-14)) and 7.2% (95% CI, 4.7%-9.7%, P=1.5 × 10(-8)), respectively, lower soluble intercellular adhesion molecule-1 levels (n=33 671). An allele dose-dependent association also was observed for soluble P-selectin (n=4921) with heterozygotes and minor allele homozygotes having 11.5% (95% CI, 7.2%-15.8%, P=1.7 × 10(-7)) and 18.6% (95% CI, 9.1%-28.1%, P=1.2 × 10(-4)), respectively, lower levels than in major allele homozygotes. A larger effect size, again consistent with an additive genetic model, was seen for soluble E-selectin (n=2860) whose level was 25.6% (95% CI, 19.0%-32.2%, P=2.1 × 10(-14)) lower in heterozygotes and 43.3% (95% CI, 36.9%-49.3%, P=4.3 × 10(-42)) lower in minor allele homozygotes than in major allele homozygotes.
The data support the association of variation at the ABO locus with soluble intercellular adhesion molecule-1, soluble P-selectin, and soluble E-selectin levels.
[show abstract][hide abstract] ABSTRACT: Adiponectin is linked to reduced diabetes risk and may be antiatherogenic, 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).
We evaluated the relationship of total adiponectin, HMW adiponectin, 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 5-year age categories, smoking, fasting status, and follow-up time; median cohort follow-up=13.2 years). Baseline median levels of HMW and total adiponectin were significantly lower in women developing PAD than in those remaining event free (HMW: 3.3 versus 3.8 μg/mL, P=0.0005; total: 5.6 versus 7.4 μg/mL, P<0.0001). The ratio did not differ significantly between groups. Age-adjusted PAD odds ratios (95% confidence intervals) 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 postmenopausal hormone therapy, high-sensitivity C-reactive protein, soluble intercellular adhesion molecule-1, leptin, hemoglobin A(1c), and fasting insulin (adjusted odds ratio and 95% confidence interval 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]; P(trend)=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.
[show abstract][hide abstract] ABSTRACT: Few prospective studies have explored the association between renal function and risk for 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 and AF and provided blood samples 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 (CKD-EPI) equation. Cox models were used to estimate hazard ratios and 95% confidence intervals (CIs) for incident AF across eGFR categories controlling for AF risk factors. During a median of 15.4 years of follow-up, 786 incident AF events occurred. The multivariate-adjusted hazard ratios for incident AF across eGFR categories (<60, 60 to 74.9, 75 to 89, and ≥90 ml/min/1.73 m(2)) were 1.36 (95% CI 1.00 to 1.84), 0.90 (95% CI 0.71 to 1.14), 0.99 (95% CI 0.84 to 1.18) and 1.00, respectively, without evidence of a linear association (P for trend = 0.48). Similarly, there was no significant curvilinear association (quadratic p = 0.10) in multivariate analysis across categories. Compared to women with eGFRs ≥60 ml/min/1.73 m(2), the 1,008 women with eGFRs <60 ml/min/1.73 m(2) had a multivariate-adjusted hazard ratio for AF of 1.39 (95% CI 1.04 to 1.86, p = 0.03). In conclusion, no significant linear or curvilinear relation 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 m(2).
The American journal of cardiology 11/2011; 109(4):538-42. · 3.58 Impact Factor
[show abstract][hide abstract] ABSTRACT: AIMS 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. CONCLUSION 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.
European Heart Journal 11/2011; 32(23):2962-9. · 14.10 Impact Factor
[show abstract][hide abstract] ABSTRACT: Although statin therapy is known to increase concentrations of PCSK9, whether this effect is related to the magnitude of LDL reduction is uncertain. This study was undertaken to understand the extent of this effect and examine the relationship between PCSK9 and LDL cholesterol (LDL-C) reduction.
We measured plasma PCSK9 concentrations by ELISA at baseline and at 1 year in 500 men and 500 women participating in the Justification for Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial that randomly allocated participants to rosuvastatin 20 mg daily or placebo. We also evaluated rs11591147, a single nucleotide polymorphism known to have an impact on plasma PCSK9 concentrations.
At baseline, median (interquartile range) PCSK9 concentrations were higher in women [73 (62-90)] ng/mL than in men [69 (57-81) ng/mL] (P<0.005). During 1 year, there was no change in PCSK9 concentrations in the placebo arm, suggesting stability in time. In contrast, the rosuvastatin increased PCSK9 by 35% in women [101 (82-117) ng/mL] and 28% in men [89 (71-109) ng/mL] (P<0.0001). Among those allocated to rosuvastatin, greater reductions in LDL-C were associated with greater increases in PCSK9 on both absolute and relative scales (r=-0.15, P<0.0005). Furthermore PCSK9 (rs11591147) did not alter the magnitude of LDL-C reduction associated with rosuvastatin use.
In this randomized trial, rosuvastatin increased plasma concentration of PCSK9 in proportion to the magnitude of LDL-C reduction; the LDL-C response to statin could not be inferred by PCSK9 concentrations.
[show abstract][hide abstract] ABSTRACT: Inflammation contributes to all phases of the atherothrombotic process, and patients with elevated inflammatory biomarkers such as high-sensitivity C-reactive protein (hsCRP) have increased vascular risk. Yet, it remains unknown whether direct inhibition of inflammation will reduce cardiovascular event rates.
The CANTOS will evaluate whether interleukin-1β (IL-1β) inhibition as compared with placebo can reduce rates of recurrent myocardial infarction, stroke, and cardiovascular death among stable patients with coronary artery disease who remain at high vascular risk due to persistent elevations of hsCRP (>2 mg/L) despite contemporary secondary prevention strategies. Canakinumab is a human monoclonal antibody that selectively neutralizes IL-1β, a proinflammatory cytokine that plays multiple roles in the atherothrombotic process and that undergoes activation by the nucleotide-binding leucine-rich repeat-containing pyrin receptor 3 inflammasome, a process promoted by cholesterol crystals. Canakinumab significantly reduces systemic C-reactive protein and other inflammatory biomarker levels, is generally well tolerated, and is currently indicated for the treatment of inherited IL-1β driven inflammatory diseases such as the Muckle-Wells syndrome. In a multinational collaborative effort using an event-driven intention-to-treat protocol, CANTOS will randomly allocate 17,200 stable postmyocardial infarction patients with persistent elevation of hsCRP to either placebo or to canakinumab at doses of 50, 150, or 300 mg every 3 months, administered subcutaneously. All participants will be followed up over an estimated period of up to 4 years for the trial primary end point (nonfatal myocardial infarction, nonfatal stroke, cardiovascular death) as well as for other vascular events, total mortality, adverse events, and specific clinical end points associated with inflammation including new onset diabetes, venous thrombosis, and atrial fibrillation.
If positive, CANTOS would confirm the inflammatory hypothesis of atherothrombosis and provide a novel cytokine-based therapy for the secondary prevention of cardiovascular disease and new-onset diabetes.
American heart journal 10/2011; 162(4):597-605. · 4.65 Impact Factor
[show abstract][hide abstract] ABSTRACT: Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 × 10(-8) to P = 2.3 × 10(-13)) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP.
[show abstract][hide abstract] ABSTRACT: Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.