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Aims The aim of the study was to examine whether differences in average diameter of low-density lipoprotein (LDL) particles were associated with total and cardiovascular mortality. Methods and results We studied 1643 subjects referred to coronary angiography, who did not receive lipid-lowering drugs. During a median follow-up of 9.9 years, 398 patients died, of these 246 from cardiovascular causes. We calculated average particle diameters of LDL from the composition of LDL obtained by β-quantification. When LDL with intermediate average diameters (16.5–16.8 nm) were used as reference category, the hazard ratios (HRs) adjusted for cardiovascular risk factors for death from any cause were 1.71 (95% CI: 1.31–2.25) and 1.24 (95% CI: 0.95–1.63) in patients with large (>16.8 nm) or small LDL (<16.5 nm), respectively. Adjusted HRs for death from cardiovascular causes were 1.89 (95% CI: 1.32–2.70) and 1.54 (95% CI: 1.06–2.12) in patients with large or small LDL, respectively. Patients with large LDL had higher concentrations of the inflammatory markers interleukin (IL)-6 and C-reactive protein than patients with small or intermediate LDL. Equilibrium density gradient ultracentrifugation revealed characteristic and distinct profiles of LDL particles in persons with large (approximately even distribution of intermediate-density lipoproteins and LDL-1 through LDL-6) intermediate (peak concentration at LDL-4) or small (peak concentration at LDL-6) average LDL particle diameters. Conclusions Calculated LDL particle diameters identify patients with different profiles of LDL subfractions. Both large and small LDL diameters are independently associated with increased risk mortality of all causes and, more so, due to cardiovascular causes compared with LDL of intermediate size. [ABSTRACT FROM PUBLISHER]

Aims The purpose of this study was to identify novel genetic variants influencing circulating asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) levels and to evaluate whether they have a prognostic value on cardiovascular mortality. Methods and results We conducted a genome-wide association study on the methylarginine traits and investigated the predictive value of the new discovered variants on mortality. Our meta-analyses replicated the previously known locus for ADMA levels in DDAH1 (rs997251; P = 1.4 × 10−40), identified two non-synomyous polymorphisms for SDMA levels in AGXT2 (rs37369; P = 1.4 × 10−40 and rs16899974; P = 1.5 × 10−38) and one in SLC25A45 (rs34400381; P = 2.5 × 10−10). We also fine-mapped the AGXT2 locus for further independent association signals. The two non-synonymous AGXT2 variants independently associated with SDMA levels were also significantly related with short-term heart rate variability (HRV) indices in young adults. The major allele (C) of the novel non-synonymous rs16899974 (V498L) variant associated with decreased SDMA levels and an increase in the ratio between the low- and high-frequency spectral components of HRV (P = 0.00047). Furthermore, the SDMA decreasing allele (G) of the non-synomyous SLC25A45 (R285C) variant was associated with a lower resting mean heart rate during the HRV measurements (P = 0.0046), but not with the HRV indices. None of the studied genome-wide significant variants had any major effect on cardiovascular or total mortality in patients referred for coronary angiography. Conclusions AGXT2 has an important role in SDMA metabolism in humans. AGXT2 may additionally have an unanticipated role in the autonomic nervous system regulation of cardiac function. [ABSTRACT FROM PUBLISHER]

Aims High-density lipoprotein (HDL) cholesterol is a strong predictor of cardiovascular mortality. This work aimed to investigate whether the presence of coronary artery disease (CAD) impacts on its predictive value. Methods and results We studied 3141 participants (2191 males, 950 females) of the LUdwigshafen RIsk and Cardiovascular health (LURIC) study. They had a mean ± standard deviation age of 62.6 ± 10.6 years, body mass index of 27.5 ± 4.1 kg/m², and HDL cholesterol of 38.9 ± 10.8 mg/dL. The cohort consisted of 699 people without CAD, 1515 patients with stable CAD, and 927 patients with unstable CAD. The participants were prospectively followed for cardiovascular mortality over a median (inter-quartile range) period of 9.9 (8.7–10.7) years. A total of 590 participants died from cardiovascular diseases. High-density lipoprotein cholesterol by tertiles was inversely related to cardiovascular mortality in the entire cohort (P = 0.009). There was significant interaction between HDL cholesterol and CAD in predicting the outcome (P = 0.007). In stratified analyses, HDL cholesterol was strongly associated with cardiovascular mortality in people without CAD [3rd vs. 1st tertile: HR (95% CI) = 0.37 (0.18–0.74), P = 0.005], but not in patients with stable [3rd vs. 1st tertile: HR (95% CI) = 0.81 (0.61–1.09), P = 0.159] and unstable [3rd vs. 1st tertile: HR (95% CI) = 0.91 (0.59–1.41), P = 0.675] CAD. These results were replicated by analyses in 3413 participants of the AtheroGene cohort and 5738 participants of the ESTHER cohort, and by a meta-analysis comprising all three cohorts. Conclusion The inverse relationship of HDL cholesterol with cardiovascular mortality is weakened in patients with CAD. The usefulness of considering HDL cholesterol for cardiovascular risk stratification seems limited in such patients. [ABSTRACT FROM PUBLISHER]

Aims The genetic polymorphism of apolipoprotein E (APOE) has been suggested to modify the effect of smoking on the development of coronary artery disease (CAD) in apparently healthy persons. The interaction of these factors in persons undergoing coronary angiography is not known. Methods and results We analysed the association between the APOE-genotype, smoking, angiographic CAD, and mortality in 3263 participants of the LUdwigshafen RIsk and Cardiovascular Health study. APOE-genotypes were associated with CAD [ɛ22 or ɛ23: odds ratio (OR) 0.56, 95% confidence interval (CI) 0.43–0.71; ɛ24 or ɛ34 or ɛ44: OR 1.10, 95% CI 0.89–1.37 compared with ɛ33] and moderately with cardiovascular mortality [ɛ22 or ɛ23: hazard ratio (HR) 0.71, 95% CI 0.51–0.99; ɛ33: HR 0.92, 95% CI 0.75–1.14 compared with ɛ24 or ɛ34 or ɛ44]. HRs for total mortality were 1.39 (95% CI 0.39–0.1.67), 2.29 (95% CI 1.85–2.83), 2.07 (95% CI 1.64–2.62), and 2.95 (95% CI 2.10–4.17) in ex-smokers, current smokers, current smokers without, or current smokers with one ɛ4 allele, respectively, compared with never-smokers. Carrying ɛ4 increased mortality in current, but not in ex-smokers (HR 1.66, 95% CI 1.04–2.64 for interaction). These findings applied to cardiovascular mortality, were robust against adjustment for cardiovascular risk factors, and consistent across subgroups. No interaction of smoking and ɛ4 was seen regarding non-cardiovascular mortality. Smokers with ɛ4 had reduced average low-density lipoprotein (LDL) diameters, elevated oxidized LDL, and lipoprotein-associated phospholipase A2. Conclusion In persons undergoing coronary angiography, there is a significant interaction between APOE-genotype and smoking. The presence of the ɛ4 allele in current smokers increases cardiovascular and all-cause mortality. [ABSTRACT FROM PUBLISHER]

Aims Both elevated inflammatory activity and sustained tachycardia reflect unfavourable cardiovascular risk profiles, and there is evidence to suggest the deleterious effects of inflammation are amplified by increased heart rate. The purpose of this study was to assess the interaction between resting heart rate and inflammation in cardiovascular mortality. Methods and results A total of 3267 patients (2283 men), aged 18–95 years, scheduled for coronary angiography, were followed prospectively. By principle component analysis, we developed an overall multi-marker index of inflammation weighting the respective coefficients of five inflammatory markers including: interleukin-6, C-reactive protein, serum amyloid A, neutrophils, and fibrinogen. Cox proportional hazard regression models were employed to evaluate the relationship between inflammation and heart rate with cardiovascular mortality. Across 29 940 person years of follow-up, there were 546 (17%) deaths due to cardiovascular disease (CVD). Significantly, we observed a strong synergistic effect of inflammatory activity and concurrent elevated heart rate. For CVD mortality, patients in the highest quartile of inflammation had an adjusted hazard ratio (95% confidence interval) of 1.84 (1.31–2.57), P < 0.0001 if their resting heart rate was <75 b.p.m. Substantially, patients had a greater adjusted HR of 7.50 (3.21–17.50), P < 0.0001 if their resting heart rate was ≥75 b.p.m. Conclusion The present analyses underline elevated inflammation as a risk factor for cardiovascular mortality. The effects of inflammation appeared to be strongly amplified by a faster resting heart rate. If confirmed by additional studies, this association may prove a useful adjunct for therapeutic approaches to alleviate symptoms and prolong survival. [ABSTRACT FROM PUBLISHER]

Aims Previous risk assessment scores for patients with coronary artery disease (CAD) have focused on primary prevention and patients with acute coronary syndrome. However, especially in stable CAD patients improved long-term risk prediction is crucial to efficiently apply measures of secondary prevention. We aimed to create a clinically applicable mortality prediction score for stable CAD patients based on routinely determined laboratory biomarkers and clinical determinants of secondary prevention. Methods and results We prospectively included 547 patients with stable CAD and a median follow-up of 11.3 years. Independent risk factors were selected using bootstrapping based on Cox regression analysis. Age, left ventricular function, serum cholinesterase, creatinine, heart rate, and HbA1c were selected as significant mortality predictors for the final multivariable model. The Vienna and Ludwigshafen Coronary Artery Disease (VILCAD) risk score based on the aforementioned variables demonstrated an excellent discriminatory power for 10-year survival with a C-statistic of 0.77 (P < 0.001), which was significantly better than an established risk score based on conventional cardiovascular risk factors (C-statistic = 0.61, P < 0.001). Net reclassification confirmed a significant improvement in individual risk prediction by 34.8% (95% confidence interval: 21.7–48.0%) compared with the conventional risk score (P < 0.001). External validation of the risk score in 1275 participants of the Ludwigshafen Risk and Cardiovascular Health study (median follow-up of 9.8 years) achieved similar results (C-statistic = 0.73, P < 0.001). Conclusion The VILCAD score based on a routinely available set of risk factors, measures of cardiac function, and comorbidities outperforms established risk prediction algorithms and might improve the identification of high-risk patients for a more intensive treatment. [ABSTRACT FROM PUBLISHER]

Background. Vitamin D deficiency is found in the majority of patients with chronic kidney disease (CKD) and may contribute to various chronic diseases. Current guidelines suggest correcting reduced 25-hydroxyvitamin D [25(OH)D] concentrations in CKD patients with an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m2. Whether low 25(OH)D levels in these patients are associated with higher mortality is unclear. This issue was addressed in the present work.Methods. We examined 444 patients with eGFR <60 mL/min/1.73m2 from the Ludwigshafen Risk and Cardiovascular Health Study. This prospective cohort study includes Caucasian patients without primary kidney disease who were routinely referred to coronary angiography at baseline (1997–2000).Results. During a median follow-up time of 9.4 years, 227 patients died including 159 deaths from cardiovascular causes. Multivariate adjusted hazard ratios (HRs) (with 95% confidence intervals) in severely vitamin D-deficient [25(OH)D <10 ng/mL] compared to vitamin D-sufficient patients [25(OH)D ≥30 ng/mL] were 3.79 (1.71–8.43) for all-cause and 5.61 (1.89–16.6) for cardiovascular mortality. Adjusted HRs per 10 ng/mL increase in 25(OH)D levels were 0.63 (0.50–0.79) for all-cause and 0.59 (0.45–0.79) for cardiovascular mortality. There was no significant interaction with parathyroid hormone concentrations.Conclusions. Low 25(OH)D levels are associated with increased all-cause and cardiovascular mortality in CKD patients. These findings support suggestions to correct vitamin D deficiency, but whether vitamin D supplementation improves survival remains to be proven in randomized controlled trials. [ABSTRACT FROM AUTHOR]

Aims: Elevated parathyroid hormone (PTH) levels have been associated with increased cardiovascular risk in the general population. We aimed to elucidate whether PTH levels are associated with mortality and fatal cardiovascular events in patients referred for coronary angiography. [ABSTRACT FROM PUBLISHER]