Although epidemiologic data link biomarkers of cardiovascular risk with incident and prevalent coronary artery disease, exact anatomic relationships between biomarkers and coronary atherosclerosis as measured by coronary CT angiography remain unclear. Patients with acute chest pain who ultimately had no evidence of acute coronary syndrome underwent contrast-enhanced 64-slice coronary CT angiography to determine presence, extent and composition of coronary atherosclerotic plaque. We determined the differences in levels of blood biomarkers measured at the time of the CT scan between different CT-based atherosclerotic plaque groups. Among 313 patients (mean age: 51.6 ± 11 years, 62% male) high-sensitivity C-reactive protein (hs-CRP) and matrix metalloproteinase-2 were associated with the extent of calcified plaque (P = 0.03 and P<0.001), while hs-CRP and apolipoprotein A1 were associated with the extent of non-calcified plaque (P = 0.03 and P = 0.004; respectively). Despite a generally lower risk profile, subjects with exclusively non-calcified plaque had significantly higher levels of hs-CRP and oxidized low-density lipoprotein (P = 0.01 and P = 0.03; respectively) and lower levels of adiponectin (P = 0.03) when compared to subjects with calcified plaque (n = 130, 42%). Biomarkers reflecting inflammation, vascular remodeling, oxidation, and lipoprotein metabolism maybe associated with different patterns of coronary atherosclerosis as quantified by coronary CT angiography.

Background

Elevated soluble (s) E-selectin levels have been associated with various cardiovascular diseases. Recently, genetic variants in the ABO blood group have been related to E-selectin levels in a small cohort of patients with type 1 diabetes. We evaluated whether this association is reproducible in two large samples of Caucasians.

Methodology/ Principal Findings

Data of the present study was drawn from the population-based MONICA/KORA Augsburg study (n = 1,482) and the patients-based LURIC study (n = 1,546). A high-density genotyping array (50K IBC Chip) containing single-nucleotide polymorphisms (SNPs) from E-selectin candidate genes selected on known biology of E-selectin metabolism, mouse genetic studies, and human genetic association studies, was used for genotyping. Linear regression analyses with adjustment for age and sex (and survey in KORA) were applied to assess associations between gene variants and sE-selectin concentrations. A number of 12 SNPs (in KORA) and 13 SNPs (in LURIC), all from the ABO blood group gene, were significantly associated with the log-transformed concentration of E-selectin. The strongest association was observed for rs651007 with a change of log-transformed sE-selectin per one copy of the minor allele of −0.37 ng/ml (p = 1.87×10−103) in KORA and −0.35 ng/ml (p = 5.11×10−84) in LURIC. Inclusion of rs651007 increased the explained sE-selectin variance by 0.256 in KORA and 0.213 in LURIC. All SNPs had minor allele frequencies above 20% showing a substantial gene variation.

Conclusions/ Significance

Our findings in two independent samples indicate that the genetic variants at the ABO locus affect sE-selectin levels. Since distinct genome-wide association studies linked the ABO gene with myocardial infarction (MI) in the presence of coronary atherosclerosis and with coronary artery disease, these findings may not only enhance our understanding of adhesion molecule biology, but may also provide a focus for several novel research avenues.

Objective

The association between blood glucose and carotid intima-media thickness (CIMT) is considered to be established knowledge. We aimed to assess whether associations between different measures of glycaemia and CIMT are actually independent of anthropometric variables and metabolic risk factors. Moreover, we checked published studies for the adjustment for shared risk factors of blood glucose and CIMT.

Methods

Fasting glucose, 2-hour glucose, HbA1c, and CIMT were measured in 31-81-years-old participants of the population-based Cooperative Health Research in the Region of Augsburg (KORA) F4 study in Southern Germany (n = 2,663). CIMT was assessed according to the Rotterdam protocol. Linear and logistic regression models with adjustment for age, sex, anthropometric measures, hypertension, and dyslipidaemia were fitted to assess the association between continuous measures of glycaemia, and categories of glucose regulation, respectively, with CIMT.

Results

We found a 0.10 mm increase (95%-confidence interval: 0.08–0.12) in CIMT in subjects with compared to subjects without diabetes in crude analysis. This increase was not significant in age-sex adjusted models (p = 0.17). Likewise, neither impaired fasting glucose (p = 0.22) nor impaired glucose tolerance (p = 0.93) were associated with CIMT after adjustment for age, sex, and waist circumference. In multivariable adjusted models, age, sex, hypertension, waist circumference, HDL and LDL cholesterol, but neither fasting glucose nor 2-hour glucose nor HbA1c were associated with elevated CIMT. Literature findings are inconclusive regarding an independent association of glucose levels and CIMT.

Conclusion

CIMT is highly dependent on traditional cardiovascular risk factors, but no relationships between blood glucose and CIMT were found after adjustment for age, sex, and anthropometric variables.

OBJECTIVE

To assess the association between serum 25-hydroxyvitamin D (25-OHD) and incident type 2 diabetes and to determine whether the association is mediated by subclinical inflammation.

RESEARCH DESIGN AND METHODS

Using a case-cohort design, baseline levels of 25-OHD were measured in 416 case subjects with incident type 2 diabetes and 1,267 noncase subjects selected from a source population of 7,936 middle-aged participants in the population-based Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA)/Cooperative Health Research in the Region of Augsburg (KORA) study.

RESULTS

A significant inverse association was observed between serum 25-OHD and incident type 2 diabetes after adjustment for diabetes risk factors and season. The hazard ratio (HR) and 95% CI comparing tertile extremes was 0.63 (0.44–0.90) (Ptrend = 0.010). Further adjustment for C-reactive protein, interleukin-6, soluble intercellular adhesion molecule-1, and interferon-γ–inducible protein-10 attenuated this association by 16% (HR 0.73 [0.50–1.05], P = 0.090).

CONCLUSIONS

Vitamin D status is inversely related to type 2 diabetes risk and our data suggest that this association may be partially mediated by subclinical inflammation.

Background

So far it is unclear whether the association between serum uric acid (SUA), inflammatory cytokines and risk of atherosclerosis is causal or an epiphenomenon. The aim of the project is to investigate the independent prognostic relationship of inflammatory markers and SUA levels with adverse cardiovascular outcomes in a patient population with stable coronary heart disease (CHD).

Methods

SUA, C-reactive protein (CRP) and interleukin (IL)-6 were measured at baseline in a cohort of 1,056 patients aged 30–70 years with CHD. Cox proportional hazards model was used to determine the prognostic value of these markers on a combined CVD endpoint during eight year follow-up after adjustment for covariates.

Results

For 1,056 patients with stable coronary heart disease aged 30–70 years (mean age 58.9 years, SD 8.0) follow-up information and serum measurements were complete and n = 151 patients (incidence 21.1 per 1000 patients years) experienced a fatal or non-fatal CVD event during follow-up (p-value = 0.05 for quartiles of SUA, p = 0.002 for quartiles of CRP, p = 0.13 for quartiles of IL-6 in Kaplan-Meier analysis). After adjustment for age, gender and hospital site the hazard ratio (HR) for SUA increased from 1.37 to 1.65 and 2.27 in the second, third, and top quartile, when compared to the bottom one (p for trend <0.0005). The HR for CRP increased from 0.85 to 0.98 and 1.64 in the respective quartiles (p for trend 0.02). After further adjustment for covariates SUA still showed a clear statistically significant relationship with the outcome (p for trend 0.045), whereas CRP did not (p for trend 0.10).

Conclusion

The data suggest that compared to inflammatory markers such as CRP and IL-6 serum uric acid levels may predict future CVD risk in patients with stable CHD with a risk increase even at levels considered normal.

Background

More accurate coronary heart disease (CHD) prediction, specifically in middle-aged men, is needed to reduce the burden of disease more effectively. We hypothesised that a multilocus genetic risk score could refine CHD prediction beyond classic risk scores and obtain more precise risk estimates using a prospective cohort design.

Methods

Using data from nine prospective European cohorts, including 26,221 men, we selected in a case-cohort setting 4,818 healthy men at baseline, and used Cox proportional hazards models to examine associations between CHD and risk scores based on genetic variants representing 13 genomic regions. Over follow-up (range: 5–18 years), 1,736 incident CHD events occurred. Genetic risk scores were validated in men with at least 10 years of follow-up (632 cases, 1361 non-cases). Genetic risk score 1 (GRS1) combined 11 SNPs and two haplotypes, with effect estimates from previous genome-wide association studies. GRS2 combined 11 SNPs plus 4 SNPs from the haplotypes with coefficients estimated from these prospective cohorts using 10-fold cross-validation. Scores were added to a model adjusted for classic risk factors comprising the Framingham risk score and 10-year risks were derived.

Results

Both scores improved net reclassification (NRI) over the Framingham score (7.5%, p = 0.017 for GRS1, 6.5%, p = 0.044 for GRS2) but GRS2 also improved discrimination (c-index improvement 1.11%, p = 0.048). Subgroup analysis on men aged 50–59 (436 cases, 603 non-cases) improved net reclassification for GRS1 (13.8%) and GRS2 (12.5%). Net reclassification improvement remained significant for both scores when family history of CHD was added to the baseline model for this male subgroup improving prediction of early onset CHD events.

Conclusions

Genetic risk scores add precision to risk estimates for CHD and improve prediction beyond classic risk factors, particularly for middle aged men.

OBJECTIVE

We examined the association between retinol-binding protein 4 (RBP4), a novel adipokine, and prediabetes (isolated impaired fasting glucose [i-IFG], isolated impaired glucose tolerance [i-IGT], and combined IFG and IGT) in men and women aged 32–81 years.

RESEARCH DESIGN AND METHODS

The analysis was based on 2,614 participants without previously diagnosed diabetes and those with newly diagnosed diabetes of the Cooperative Health Research in the Region of Augsburg (KORA) F4 Study, conducted from 2006 to 2008 in southern Germany. Plasma RBP4 was analyzed by immunonephelometry.

RESULTS

In logistic regression analysis, RBP4 levels in the fourth quartile versus the first quartile were significantly associated with prediabetes (i-IGT, i-IFG, and IFG/IGT; reference normal glucose tolerance) independent of known metabolic risk factors and lifestyle variables (odds ratio 1.63 [95% CI 1.17–2.27] after multivariable adjustment). Stratification by sex showed generally similar results.

CONCLUSIONS

RBP4 levels were associated with prediabetes in individuals from the general population. Prospective studies investigating the impact of RBP4 on the development of glucose intolerance are needed.

Background

Chronic kidney disease (CKD) represents a global public health problem. Few data exist in the elderly. The objective of the current study is to estimate the prevalence of CKD by means of various established and new equations and to identify the main determinants of CKD in elderly.

Methods

The ActiFE Ulm (Activity and Function in the Elderly in Ulm) study is a population-based cohort study in people of 65 years and older. Kidney function was assessed by means of estimated glomerular filtration rate (eGFR) based on two creatinine- (Cr-; MDRD, CKD-EPI) and one cystatin C - (CysC-) based method. The relationship between various potential risk factors and CKD was quantified using unconditional logistic regression.

Results

A total of 1471 subjects were in the final analysis (mean age 75.6 years, SD 6.56). Overall, prevalence of CKD (eGFR < 60 mL/min/1.73 m2) was 34.3% by MDRD, 33.0% by CKD-EPI, and 14.6% by the CysC-based eGFR. All eGFRs showed statistically significant correlations with C-reactive protein, uric acid, as well as with lipid values. In multivariable analysis age was clearly related to prevalence of CKD and the risks were highest with the CysC-based equation. Females had a higher risk for CKD stages 3–5 with MDRD (OR 1.63; 95% CI: 1.23–2.16) whereas the OR was 1.23 (95% CI 0.92–1.65) with the CKD-Epi and OR = 0.89 (95% CI 0.58–1.34) with the CysC-based equation after multivariable adjustment. Although the cystatin C based definition of CKD resulted in a lower prevalence compared to the creatinine based ones, other measures of renal damage such as albuminuria were more prevalent in those defined by CysC-eGFR.

Conclusions

Prevalence of CKD is very variable based on the used estimating equation. More work is needed to evaluate the various estimating equations especially in elderly before we are able to assess the practical consequences of the observed differences.

Background

Plasma levels of high density lipoprotein cholesterol (HDL-C) are known to be heritable, but only a fraction of the heritability is explained. We used a high density genotyping array containing SNPs from HDL-C candidate genes selected on known biology of HDL-C metabolism, mouse genetic studies, and human genetic association studies. SNP selection was based on tagging-SNPs but also included low-frequency nonsynonymous SNPs.

Methods and Results

Association analysis in a cohort containing extremes of HDL-C (case-control, n=1733) provided a discovery phase, with replication in three additional populations for a total meta-analysis in 7,857 individuals. We replicated the majority of loci identified through genome wide association studies and present on the array (including ABCA1, APOA1/C3/A4/A5, APOB, APOE/C1/C2, CETP, CTCF-PRMT8, FADS1/2/3, GALNT2, LCAT, LILRA3, LIPC, LIPG, LPL, LRP4, SCARB1, TRIB1, ZNF664), and provide evidence suggestive of association in several previously unreported candidate gene loci (including ABCG1, GPR109A/B/81, NFKB1, PON1/2/3/4). There was evidence for multiple, independent association signals in five loci, including association with low frequency nonsynonymous variants.

Conclusions

Genetic loci associated with HDL-C are likely to harbor multiple, independent causative variants, frequently with opposite effects on the HDL-C phenotype. Cohorts composed of extreme individuals may be efficiently used in a case-control discovery of quantitative traits.

Background

A recent randomized placebo-controlled trial of the effect of atorvastatin treatment on the progression of newly diagnosed type 1 diabetes suggested a slower decline of residual beta cell function with statin treatment. Aim of this secondary analysis was to identify patient subgroups which differ in the decline of beta cell function during treatment with atorvastatin.

Methodology/Principal Findings

The randomized placebo-controlled Diabetes and Atorvastatin (DIATOR) Trial included 89 patients with newly diagnosed type 1 diabetes and detectable islet autoantibodies (mean age 30 years, 40% females), in 12 centers in Germany. Patients received placebo or 80 mg/d atorvastatin for 18 months. As primary outcome stimulated serum C-peptide levels were determined 90 min after a standardized liquid mixed meal. For this secondary analysis patients were stratified by single baseline characteristics which were considered to possibly be modified by atorvastatin treatment. Subgroups defined by age, sex or by baseline metabolic parameters like body mass index (BMI), total serum cholesterol or fasting C-peptide did not differ in C-peptide outcome after atorvastatin treatment. However, the subgroup defined by high (above median) baseline C-reactive protein (CRP) concentrations exhibited higher stimulated C-peptide secretion after statin treatment (p = 0.044). Individual baseline CRP levels correlated with C-peptide outcome in the statin group (r2 = 0.3079, p<0.004). The subgroup with baseline CRP concentrations above median differed from the corresponding subgroup with lower CRP levels by higher median values of BMI, IL-6, IL-1RA, sICAM-1 and E-selectin.

Conclusions/Significance

Atorvastatin treatment may be effective in slowing the decline of beta cell function in a patient subgroup defined by above median levels of CRP and other inflammation associated immune mediators.

Trial Registration

ClinicalTrials.gov NCT00974740

Background

The chemokine RANTES (regulated on activation, normal T-cell expressed and secreted)/CCL5 is involved in the pathogenesis of cardiovascular disease in mice, whereas less is known in humans. We hypothesised that its relevance for atherosclerosis should be reflected by associations between CCL5 gene variants, RANTES serum concentrations and protein levels in atherosclerotic plaques and risk for coronary events.

Methods and Findings

We conducted a case-cohort study within the population-based MONICA/KORA Augsburg studies. Baseline RANTES serum levels were measured in 363 individuals with incident coronary events and 1,908 non-cases (mean follow-up: 10.2±4.8 years). Cox proportional hazard models adjusting for age, sex, body mass index, metabolic factors and lifestyle factors revealed no significant association between RANTES and incident coronary events (HR [95% CI] for increasing RANTES tertiles 1.0, 1.03 [0.75–1.42] and 1.11 [0.81–1.54]). None of six CCL5 single nucleotide polymorphisms and no common haplotype showed significant associations with coronary events. Also in the CARDIoGRAM study (>22,000 cases, >60,000 controls), none of these CCL5 SNPs was significantly associated with coronary artery disease. In the prospective Athero-Express biobank study, RANTES plaque levels were measured in 606 atherosclerotic lesions from patients who underwent carotid endarterectomy. RANTES content in atherosclerotic plaques was positively associated with macrophage infiltration and inversely associated with plaque calcification. However, there was no significant association between RANTES content in plaques and risk for coronary events (mean follow-up 2.8±0.8 years).

Conclusions

High RANTES plaque levels were associated with an unstable plaque phenotype. However, the absence of associations between (i) RANTES serum levels, (ii) CCL5 genotypes and (iii) RANTES content in carotid plaques and either coronary artery disease or incident coronary events in our cohorts suggests that RANTES may not be a novel coronary risk biomarker. However, the potential relevance of RANTES levels in platelet-poor plasma needs to be investigated in further studies.

Background

Serum type II secretory phospholipase A2 (sPLA2-IIa) has been found to be predictive of adverse outcomes in patients with stable coronary heart disease. Compounds targeting sPLA2-IIa are already under development. This study investigated if an association of sPLA2-IIa with secondary cardiovascular disease (CVD) events may be of causal nature or mainly a matter of confounding by correlated cardiovascular risk markers.

Methodology/Principal Findings

Eight-year follow-up data of a prospective cohort study (KAROLA) of patients who underwent in-patient rehabilitation after an acute cardiovascular event were analysed. Associations of polymorphisms (SNP) in the sPLA2-IIa-coding gene PLA2G2A with serum sPLA2-IIa and secondary fatal or non-fatal CVD events were examined by multiple regression. Hazard ratios (HR) were compared with those expected if the association between sPLA2-IIa and CVD were causal. The strongest determinants of sPLA2-IIa (rs4744 and rs10732279) were associated with an increase of serum concentrations by 81% and 73% per variant allele. HRs (95% confidence intervals) estimating the associations of the SNPs with secondary CVD events were increased, but not statistically significant (1.16 [0.89–1.51] and 1.18 [0.91–1.52] per variant allele, respectively). However, these estimates were very similar to those expected when assuming causality (1.18 and 1.17), based on an association of natural log-transformed sPLA2-IIa concentration with secondary events with HR = 1.33 per unit.

Conclusion

The present findings regarding genetic polymorphisms, determination of serum sPLA2-IIa, and prognosis in CVD patients are consistent with a genuine causal relationship and thus might point to a valid drug target for prevention of secondary CVD events.

Background: Increasing evidence suggests a proatherogenic role for lipoprotein-associated phospholipase A2 (Lp-PLA2). A meta-analysis of published cohorts has shown that Lp-PLA2 is an independent predictor of coronary heart disease events and stroke.

Objective: In this study, we investigated whether the association between air pollution and cardiovascular disease might be partly explained by increased Lp-PLA2 mass in response to exposure.

Methods: A prospective longitudinal study of 200 patients who had had a myocardial infarction was performed in Augsburg, Germany. Up to six repeated clinical examinations were scheduled every 4–6 weeks between May 2003 and March 2004. Supplementary to the multicenter AIRGENE protocol, we assessed repeated plasma Lp-PLA2 concentrations. Air pollution data from a fixed monitoring site representing urban background concentrations were collected. We measured hourly means of particle mass [particulate matter (PM) < 10 µm (PM10) and PM < 2.5 µm (PM2.5) in aerodynamic diameter] and particle number concentrations (PNCs), as well as the gaseous air pollutants carbon monoxide (CO), sulfur dioxide (SO2), ozone (O3), nitric oxide (NO), and nitrogen dioxide (NO2). Data were analyzed using mixed models with random patient effects.

Results: Lp-PLA2 showed a positive association with PM10, PM2.5, and PNCs, as well as with CO, NO2, NO, and SO2 4–5 days before blood withdrawal (lag 4–5). A positive association with O3 was much more immediate (lag 0). However, inverse associations with some pollutants were evident at shorter time lags.

Conclusion: These preliminary findings should be replicated in other study populations because they suggest that the accumulation of acute and subacute effects or the chronic exposure to ambient particulate and gaseous air pollution may result in the promotion of atherosclerosis, mediated, at least in part, by increased levels of Lp-PLA2.

Background

This study compares inflammation-related biomarkers with established cardiometabolic risk factors in the prediction of incident type 2 diabetes and incident coronary events in a prospective case-cohort study within the population-based MONICA/KORA Augsburg cohort.

Methods and Findings

Analyses for type 2 diabetes are based on 436 individuals with and 1410 individuals without incident diabetes. Analyses for coronary events are based on 314 individuals with and 1659 individuals without incident coronary events. Mean follow-up times were almost 11 years. Areas under the receiver-operating characteristic curve (AUC), changes in Akaike's information criterion (ΔAIC), integrated discrimination improvement (IDI) and net reclassification index (NRI) were calculated for different models. A basic model consisting of age, sex and survey predicted type 2 diabetes with an AUC of 0.690. Addition of 13 inflammation-related biomarkers (CRP, IL-6, IL-18, MIF, MCP-1/CCL2, IL-8/CXCL8, IP-10/CXCL10, adiponectin, leptin, RANTES/CCL5, TGF-β1, sE-selectin, sICAM-1; all measured in nonfasting serum) increased the AUC to 0.801, whereas addition of cardiometabolic risk factors (BMI, systolic blood pressure, ratio total/HDL-cholesterol, smoking, alcohol, physical activity, parental diabetes) increased the AUC to 0.803 (ΔAUC [95% CI] 0.111 [0.092–0.149] and 0.113 [0.093–0.149], respectively, compared to the basic model). The combination of all inflammation-related biomarkers and cardiometabolic risk factors yielded a further increase in AUC to 0.847 (ΔAUC [95% CI] 0.044 [0.028–0.066] compared to the cardiometabolic risk model). Corresponding AUCs for incident coronary events were 0.807, 0.825 (ΔAUC [95% CI] 0.018 [0.013–0.038] compared to the basic model), 0.845 (ΔAUC [95% CI] 0.038 [0.028–0.059] compared to the basic model) and 0.851 (ΔAUC [95% CI] 0.006 [0.003–0.021] compared to the cardiometabolic risk model), respectively.

Conclusions

Inclusion of multiple inflammation-related biomarkers into a basic model and into a model including cardiometabolic risk factors significantly improved the prediction of type 2 diabetes and coronary events, although the improvement was less pronounced for the latter endpoint.

P-selectin and intercellular adhesion molecule-1 (ICAM-1) participate in inflammatory processes by promoting adhesion of leukocytes to vascular wall endothelium. Their soluble levels have been associated with adverse cardiovascular events. To identify loci affecting soluble levels of P-selectin (sP-selectin) and ICAM-1 (sICAM-1), we performed a genome-wide association study in a sample of 4115 (sP-selectin) and 9813 (sICAM-1) individuals of European ancestry as a part of The Cohorts for Heart and Aging Research in Genome Epidemiology consortium. The most significant SNP association for sP-selectin was within the SELP gene (rs6136, P = 4.05 × 10−61) and for sICAM-1 levels within the ICAM-1 gene (rs3093030, P = 3.53 × 10−23). Both sP-selectin and sICAM-1 were associated with ABO gene variants (rs579459, P = 1.86 × 10−41 and rs649129, P = 1.22 × 10−15, respectively) and in both cases the observed associations could be accounted for by the A1 allele of the ABO blood group. The absence of an association between ABO blood group and platelet-bound P-selectin levels in an independent subsample (N = 1088) from the ARIC study, suggests that the ABO blood group may influence cleavage of the P-selectin protein from the cell surface or clearance from the circulation, rather than its production and cellular presentation. These results provide new insights into adhesion molecule biology.

Background

There are limited randomized data on statins for primary prevention in older people, and the relative hazard of cardiovascular disease associated with elevated cholesterol weakens with advancing age.

Objective

To assess the efficacy and safety of rosuvastatin in individuals 70 years of age or older.

Design

Secondary analysis of the JUPITER trial, a randomized, double-blind, placebo-controlled trial.

Setting

1315 sites in 26 countries randomized subjects in JUPITER.

Participants

Among the 17802 randomized participants with low-density lipoprotein cholesterol (LDL) levels of less than 130 mg/dL and high-sensitivity C-reactive protein levels of 2.0 mg/L or higher, and without cardiovascular disease, 5695 were 70 years of age or older.

Intervention

Participants were randomly assigned in a 1:1 ratio to receive 20 mg rosuvastatin daily or placebo.

Measurements

The primary end point was the occurrence of a first cardiovascular event (myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina, or death from cardiovascular causes).

Results

The 32% of trial participants aged 70 years or older accrued 49% (N=194) of the 393 confirmed primary end points. The rates of the primary end point in this age group were 1.22 and 1.99 per 100 person-years of follow-up in the rosuvastatin and placebo groups, respectively (hazard ratio 0.61; [95% CI, 0.46 to 0.82]; P<0.001). Corresponding rates of all-cause mortality in this age group were 1.63 and 2.04 (hazard ratio 0.80; [95% CI, 0.62 to 1.04]; P=0.090). While there was no significant heterogeneity in treatment effects by age, absolute reductions in event rates associated with rosuvastatin were greater in older individuals. The relative rate of any serious adverse event among older people in the rosuvastatin group versus placebo was 1.05 (95% CI: 0.93–1.17).

Limitations

Effect estimates from this exploratory analysis with age cutpoint chosen after trial completion should be viewed in the context of the overall trial results.

Conclusion

In apparently healthy older people without hyperlipidemia but with elevated high-sensitivity C-reactive protein, rosuvastatin reduces the incidence of major cardiovascular events.

Primary Funding Source

AstraZeneca

Background

Plasma levels of coagulation factors VII (FVII), VIII (FVIII), and von Willebrand factor (vWF) influence risk of hemorrhage and thrombosis. We conducted genome-wide association studies to identify new loci associated with plasma levels.

Methods and Results

Setting includes 5 community-based studies for discovery comprising 23,608 European-ancestry participants: ARIC, CHS, B58C, FHS, and RS. All had genome-wide single nucleotide polymorphism (SNP) scans and at least 1 phenotype measured: FVII activity/antigen, FVIII activity, and vWF antigen. Each study used its genotype data to impute to HapMap SNPs and independently conducted association analyses of hemostasis measures using an additive genetic model. Study findings were combined by meta-analysis. Replication was conducted in 7,604 participants not in the discovery cohort. For FVII, 305 SNPs exceeded the genome-wide significance threshold of 5.0×10-8 and comprised 5 loci on 5 chromosomes: 2p23 (smallest p-value 6.2×10-24), 4q25 (3.6×10-12), 11q12 (2.0×10-10), 13q34 (9.0×10-259), and 20q11.2 (5.7×10-37). Loci were within or near genes, including 4 new candidate genes and F7 (13q34). For vWF, 400 SNPs exceeded the threshold and marked 8 loci on 6 chromosomes: 6q24 (1.2×10-22), 8p21 (1.3×10-16), 9q34 (<5.0×10-324), 12p13 (1.7×10-32), 12q23 (7.3×10-10), 12q24.3 (3.8×10-11), 14q32 (2.3×10-10) and 19p13.2 (1.3×10-9). All loci were within genes, including 6 new candidate genes, as well as ABO (9q34) and VWF (12p13). For FVIII, 5 loci were identified and overlapped vWF findings. Nine of the 10 new findings replicated.

Conclusions

New genetic associations were discovered outside previously known biologic pathways and may point to novel prevention and treatment targets of hemostasis disorders.

Background

For evaluation of patients with chest pain and suspected acute coronary syndrome (ACS), consensus guidelines recommend use of a cardiac troponin cut-point that corresponds to the 99th percentile of a healthy population. Most conventional troponin methods lack sufficient precision at this very low level.

Methods and results

In a cross-sectional study, 377 patients (mean age 53.7 years, 64.2% male) with chest pain and low-to-intermediate likelihood for ACS were enrolled in the emergency department. Blood was tested using a pre-commercial high sensitivity troponin T assay (hsTnT) and compared to a conventional cardiac troponin T method (cTnT). Patients underwent a 64-slice coronary computed tomography (CT) coronary angiogram at the time of phlebotomy, on average 4 hours from initial presentation. Among patients with acute chest pain, 37 (9.8%) had an ACS. Using the 99th percentile cut-point for a healthy population (13 pg/mL), hsTnT had 62% sensitivity, 89% specificity, 38% positive predictive value, and 96% negative predictive value for ACS. Compared to cTnT, hsTnT detected 27% more ACS cases (P =.001), and an hsTnT above the 99th percentile strongly predicted ACS (odds ratio 9.0, 95% confidence interval 3.9–20.9; P <.001). Independent of ACS diagnosis, CT angiography demonstrated concentrations of hsTnT were determined by numerous factors including the presence and severity of coronary artery disease as well as left ventricular mass, left ventricular ejection fraction, and regional left ventricular dysfunction.

Conclusions

Among low-to-intermediate risk patients with chest pain, hsTnT provides good sensitivity and specificity for ACS. Elevation of hsTnT identifies patients with myocardial injury and significant structural heart disease, irrespective of the diagnosis of ACS.

Background

Recent evidence suggests that the lipid-lowering agent atorvastatin is also a potent immunomodulator. The aim of this study was to investigate the possible effect of atorvastatin on the decline of residual beta cell function in recent-onset type 1 diabetes.

Methods and Findings

The randomised placebo-controlled Diabetes and Atorvastatin (DIATOR) Trial included 89 patients with newly diagnosed type 1 diabetes and islet autoantibodies (mean age 30 years, 40% females), in 12 centres in Germany. Patients received placebo or 80 mg/d atorvastatin for 18 months. As primary outcome stimulated serum C-peptide levels were determined 90 min after a standardized liquid mixed meal. An intent-to-treat analysis was performed. Fasting and stimulated C-peptide levels were not significantly different between groups at 18 months. However, median fasting serum C-peptide levels dropped from baseline to 12 and 18 months in the placebo group (from 0. 34 to 0.23 and 0.20 nmol/l, p<0.001) versus a nonsignificant decline in the atorvastatin group (from 0.34 to 0.27 and 0.30 nmol/l, ns). Median stimulated C-peptide concentrations declined between baseline and 12 months (placebo from 0.89 to 0.71 nmol/l, atorvastatin from 0.88 to 0.73 nmol/l, p<0.01 each) followed by a major loss by month 18 in the placebo group (to 0.48 nmol/l, p = 0.047) but not in the atorvastatin group (to 0.71 nmol/l, ns). Median levels of total cholesterol and C-reactive protein decreased in the atorvastatin group only (p<0.001 and p = 0.04). Metabolic control was similar between groups.

Conclusions

Atorvastatin treatment did not significantly preserve beta cell function although there may have been a slower decline of beta-cell function which merits further study.

Trial Registration

ClinicalTrials.gov NCT00974740

BACKGROUND

Stress myocyte biomarkers are used prognostically in patients with cardiovascular disease. We examined associations between amino-terminal pro–B-type natriuretic peptide (NT-proBNP), midregional pro–A-type natriuretic peptide (MR-proANP), and midregional proadrenomedullin (MR-proADM) concentrations and cardiac chamber volumes in chest pain patients without heart failure by use of computed tomography (CT).

METHODS

At the time of 64-slice CT scan, we acquired plasma and serum samples for these biomarkers from 346 patients [mean (SD) age 53 (12) years, 65% men]. Left atrial volume (LAV) and left ventricular volumes at end-diastole (LVEDV) and end-systole (LVESV) were measured and indexed to body surface area (LAVI, LVEDI, LVESI).

RESULTS

Concentrations of both natriuretic peptides were correlated with LAV and LAVI (r=0.19–0.32, all P ≤ 0.0005) and MR-proADM with LV volumes and indices (r=−0.14 to −0.21, all P ≤ 0.01). NT-proBNP and MR-proANP concentrations were higher in the top quartiles of patients than the lowest quartiles using LAV and LAVI, whereas MR-proADM concentrations were lower in the top quartiles of LV measures. In adjusted analyses, patients had 2- to 4-fold increased risk of LA enlargement for every incremental increase in log10NT-proBNP [LAV odds ratio (OR) 2.4, P = 0.03; LAVI OR 4.0, P = 0.003] and 10- to 13-fold increased risk of LA enlargement for every incremental increase in log10MR-proANP (LAV OR 10.7, P = 0.009; LAVI OR 13.1, P = 0.004).

CONCLUSIONS

In patients without heart failure, both NT-proBNP and MR-proANP concentrations are independently associated with LA enlargement, whereas MR-proADM concentrations are correlated with LV volumes. This may partially explain the well-recognized value of natriuretic peptides for use in risk stratification.

Elevated levels of acute-phase serum amyloid A (A-SAA) cause amyloidosis and are a risk factor for atherosclerosis and its clinical complications, type 2 diabetes, as well as various malignancies. To investigate the genetic basis of A-SAA levels, we conducted the first genome-wide association study on baseline A-SAA concentrations in three population-based studies (KORA, TwinsUK, Sorbs) and one prospective case cohort study (LURIC), including a total of 4,212 participants of European descent, and identified two novel genetic susceptibility regions at 11p15.5-p13 and 1p31. The region at 11p15.5-p13 (rs4150642; p = 3.20×10−111) contains serum amyloid A1 (SAA1) and the adjacent general transcription factor 2 H1 (GTF2H1), Hermansky-Pudlak Syndrome 5 (HPS5), lactate dehydrogenase A (LDHA), and lactate dehydrogenase C (LDHC). This region explains 10.84% of the total variation of A-SAA levels in our data, which makes up 18.37% of the total estimated heritability. The second region encloses the leptin receptor (LEPR) gene at 1p31 (rs12753193; p = 1.22×10−11) and has been found to be associated with CRP and fibrinogen in previous studies. Our findings demonstrate a key role of the 11p15.5-p13 region in the regulation of baseline A-SAA levels and provide confirmative evidence of the importance of the 1p31 region for inflammatory processes and the close interplay between A-SAA, leptin, and other acute-phase proteins.

Author Summary

An elevated level of acute-phase serum amyloid A (A-SAA), a sensitive marker of the acute inflammatory state with high heritability estimates, causes amyloidosis and is a risk factor for atherosclerosis and its clinical complications, type 2 diabetes, as well as various malignancies. This study describes the first genome-wide association study on baseline A-SAA concentrations. In a meta-analysis of four genome-wide scans totalling 4,212 participants of European descent, we identified two novel genetic susceptibility regions on chromosomes 11 and 1 to be associated with baseline A-SAA concentrations. The chromosome 11 region contains the serum amyloid A1 gene and the adjacent genes and explains a high percentage of the total estimated heritability. The chromosome 1 region is a known genetic susceptibility region for inflammation. Taken together, we identified one region, which seems to be of key importance in the regulation of A-SAA levels and represents a novel potential target for the investigation of related clinical entities. In addition, our findings indicate a close interplay between A-SAA and other inflammatory proteins, as well as a larger role of a known genetic susceptibility region for inflammatory processes as it has been assumed in the past.

Aims

On the basis of the JUPITER trial, European health authorities recently approved the use of rosuvastatin to reduce first major cardiovascular events among ‘high' global risk primary prevention patients defined either by Framingham risk score >20% or European systematic coronary risk evaluation (SCORE) ≥5%. However, as these are post hoc analyses, data describing these subgroups have not previously been available to the clinical community.

Methods and results

We randomized 17 802 apparently healthy men aged ≥50 and women ≥60 with low-density lipoprotein cholesterol (LDL-C) <3.4 mmol/L, who were at an increased vascular risk due to elevated levels of C-reactive protein measured with a high-sensitivity (hs) assay to rosuvastatin 20 mg daily or placebo. Patients with high global cardiovascular risk at baseline were identified by 10-year Framingham risk score >20% or SCORE risk ≥5%. During 1.8-year median follow-up (maximum 5 years) of patients with Framingham risk >20%, the rate of myocardial infarction/stroke/cardiovascular death was 9.4 and 18.2 per 1000 person-years in rosuvastatin and placebo-allocated patients, respectively [hazard ratio (HR): 0.50, 95% confidence interval (CI): 0.27–0.93, P = 0.028]. Among patients with SCORE risk ≥5%, the corresponding rates were 6.9 and 12.0 using a model extrapolating risk for age ≥65 years (HR: 0.57, 95% CI: 0.43–0.78, P = 0.0003) and rates were 5.9 and 12.7 when risk for age was capped at 65 years (HR: 0.47, 95% CI: 0.32–0.68, P < 0.0001).

Conclusion

In primary prevention patients with elevated hs C-reactive protein who have high global cardiovascular risk (10-year Framingham risk score >20% or SCORE risk ≥5%), but LDL-C levels not requiring pharmacologic treatment, rosuvastatin 20 mg significantly reduced major cardiovascular events.

ClinicalTrial.gov Identifier: NCT00239681

Dilated cardiomyopathy (DCM) is a structural heart disease with strong genetic background. Monogenic forms of DCM are observed in families with mutations located mostly in genes encoding structural and sarcomeric proteins. However, strong evidence suggests that genetic factors also affect the susceptibility to idiopathic DCM. To identify risk alleles for non-familial forms of DCM, we carried out a case-control association study, genotyping 664 DCM cases and 1,874 population-based healthy controls from Germany using a 50K human cardiovascular disease bead chip covering more than 2,000 genes pre-selected for cardiovascular relevance. After quality control, 30,920 single nucleotide polymorphisms (SNP) were tested for association with the disease by logistic regression adjusted for gender, and results were genomic-control corrected. The analysis revealed a significant association between a SNP in HSPB7 gene (rs1739843, minor allele frequency 39%) and idiopathic DCM (p = 1.06×10−6, OR = 0.67 [95% CI 0.57–0.79] for the minor allele T). Three more SNPs showed p < 2.21×10−5. De novo genotyping of these four SNPs was done in three independent case-control studies of idiopathic DCM. Association between SNP rs1739843 and DCM was significant in all replication samples: Germany (n = 564, n = 981 controls, p = 2.07×10−3, OR = 0.79 [95% CI 0.67–0.92]), France 1 (n = 433 cases, n = 395 controls, p = 3.73×10−3, OR = 0.74 [95% CI 0.60–0.91]), and France 2 (n = 249 cases, n = 380 controls, p = 2.26×10−4, OR = 0.63 [95% CI 0.50–0.81]). The combined analysis of all four studies including a total of n = 1,910 cases and n = 3,630 controls showed highly significant evidence for association between rs1739843 and idiopathic DCM (p = 5.28×10−13, OR = 0.72 [95% CI 0.65–0.78]). None of the other three SNPs showed significant results in the replication stage.

This finding of the HSPB7 gene from a genetic search for idiopathic DCM using a large SNP panel underscores the influence of common polymorphisms on DCM susceptibility.

Author Summary

Dilated cardiomyopathy is a severe disease of the heart muscle and often leads to chronic heart failure, eventually with the consequence of cardiac transplantation. Identification of genetic disease markers in at-risk persons could play an important role in preventive health care. Several mutations in familial forms of the disease are described. Here, we examine the role of common genetic variants on the sporadic form of dilated cardiomyopathy. By screening about 2,000 candidate genes previously related to cardiovascular disease in more than 1,900 cases and 3,600 controls, we show that a polymorphism in the HSPB7 gene (rs1739843) is strongly associated with susceptibility to dilated cardiomyopathy. We also show that the effect on disease risk is present in both German and French cohorts. Therefore, this study is an important step towards revealing insight in the genetic background of the sporadic form of dilated cardiomyopathy.

OBJECTIVE

Subclinical inflammation leads to insulin resistance and β-cell dysfunction. This study aimed to assess whether levels of circulating transforming growth factor-β1 (TGF-β1)—a central, mainly immunosuppressive, and anti-inflammatory cytokine—were associated with incident type 2 diabetes.

RESEARCH DESIGN AND METHODS

We measured serum levels of TGF-β1 from 460 individuals with and 1,474 individuals without incident type 2 diabetes in a prospective case-cohort study within the population-based MONICA (MONItoring of Trends and Determinants in CArdiovascular Disease)/KORA (Cooperative Health Research in the Region of Augsburg) cohort.

RESULTS

Elevated TGF-β1 concentrations were associated with higher, not lower, risk for type 2 diabetes (age-, sex-, and survey-adjusted hazard ratios [95% CI] for increasing TGF-β1 tertiles: 1.0, 1.08 [0.83–1.42], and 1.41 [1.08–1.83]; Pfor trend = 0.012). Adjustment for BMI and metabolic and lifestyle factors had virtually no impact on the effect size.

CONCLUSIONS

Elevated serum concentrations of the cytokine TGF-β1 indicate an increased risk for type 2 diabetes. TGF-β1 may be upregulated to counterbalance metabolic and immunological disturbances preceding type 2 diabetes.

Background

Plasma levels of coagulation factors VII (FVII), VIII (FVIII), and von Willebrand factor (vWF) influence risk of hemorrhage and thrombosis. We conducted genome-wide association studies to identify new loci associated with plasma levels.

Methods and Results

Setting includes 5 community-based studies for discovery comprising 23,608 European-ancestry participants: ARIC, CHS, B58C, FHS, and RS. All had genome-wide single nucleotide polymorphism (SNP) scans and at least 1 phenotype measured: FVII activity/antigen, FVIII activity, and vWF antigen. Each study used its genotype data to impute to HapMap SNPs and independently conducted association analyses of hemostasis measures using an additive genetic model. Study findings were combined by meta-analysis. Replication was conducted in 7,604 participants not in the discovery cohort. For FVII, 305 SNPs exceeded the genome-wide significance threshold of 5.0×10−8 and comprised 5 loci on 5 chromosomes: 2p23 (smallest p-value 6.2×10−24), 4q25 (3.6×10−12), 11q12 (2.0×10−10), 13q34 (9.0×10−259), and 20q11.2 (5.7×10−37). Loci were within or near genes, including 4 new candidate genes and F7 (13q34). For vWF, 400 SNPs exceeded the threshold and marked 8 loci on 6 chromosomes: 6q24 (1.2×10−22), 8p21 (1.3×10−16), 9q34 (<5.0×10−324), 12p13 (1.7×10−32), 12q23 (7.3×10−10), 12q24.3 (3.8×10−11), 14q32 (2.3×10−10) and 19p13.2 (1.3×10−9). All loci were within genes, including 6 new candidate genes, as well as ABO (9q34) and VWF (12p13). For FVIII, 5 loci were identified and overlapped vWF findings. Nine of the 10 new findings replicated.

Conclusions

New genetic associations were discovered outside previously known biologic pathways and may point to novel prevention and treatment targets of hemostasis disorders.