Prior myocardial infarction, coronary artery disease extent, diabetes mellitus, and CERT2 score for risk stratification in stable coronary artery disease

Peer reviewe

Low-density lipoprotein particle diameter and mortality: the Ludwigshafen Risk and Cardiovascular Health Study

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 siz

Conodonts from the “Pelmatozoan Limestone” (Upper Ordovician), northern Sevilla, Ossa-Morena Zone (Spain)

27 páginas, 1 figura, 2 tablas, 2 láminas.[EN] Several limestone levels of the “Caliza de Pelmatozoos” were sampled for conodonts in sections of the Cerrón del Hornillo and Valle synclines. The conodont fauna includes: Amorphognathus ordovicicus, A. aff. ordovicicus, Amorphognathus sp., Amorphognathus? sp., Drepanoistodus cf. suberectus, Drepanoistodus? sp., Hamarodus europaeus, Icriodella cf. superba, Istorinus erectus, Panderodus gracilis, Plectodina tenuis?, Sagittodontina robusta, Scabbardella altipes, Scabbardella sp A., Walliserodus amplissimus? y Walliserodus? sp. This association is attributed to the Amorphognathus ordovicus Zone by the presence of the index species, and to the Sagittodontina-Scabbardella Biofacies of the Mediterranean Province of conodonts by the relative abundance of these two taxa. This fauna is close related to coeval associations from several localities of the Iberian Peninsula, except that of the Malaguide Complex, but the presence of Plectodina and Drepanoistodus suggest possible faunal exchange with Anglo-Baltic faunas.[ES] El estudio para conodontos de numerosos niveles de la “Caliza de Pelmatozoos” en secciones de los sinclinales del Cerrón del Hornillo y del Valle ha permitido identificar los taxones: Amorphognathus ordovicicus, A. aff. ordovicicus, Amorphognathus sp., Amorphognathus? sp., Drepanoistodus cf. suberectus, Drepanoistodus? sp., Hamarodus europaeus, Icriodella cf. superba, Istorinus erectus, Panderodus gracilis, Plectodina tenuis?, Sagittodontina robusta, Scabbardella altipes, Scabbardella sp A., Walliserodus amplissimus? y Walliserodus? sp. Esta asociación, que se adscribe a la Provincia Mediterránea de conodontos, es atribuida a la Zona de Amorphognahus ordovicicus, Kralodvoriense, por la presencia del taxón nominal. Dentro de esta provincia ha sido posible identificar la Biofacies de Sagittodontina-Scabbardella por la abundancia relativa de ambos taxones. Si bien existe una gran similitud entre esta fauna y las de edad equivalente reconocidas en el ámbito de dicha provincia, la presencia de Plectodina y Drepanoistodus sugieren que el área de estudio se encontraba emplazada en latitudes más bajas que el resto de la Península Ibérica, exceptuando la del Complejo Maláguide, y que este hecho favoreció el intercambio faunal con las provincias Británica y Báltica de conodontos.Este trabajo es una contribución al proyecto PATRIORSI (CGL2006-07628/BTE) del Ministerio de Ciencia e Innovación, al proyecto IGCP 503 “Ordovician Palaeogeography and Palaeoclimatology” y Grupo UCM 910231.Peer reviewe

Which leukocyte subsets predict cardiovascular mortality? From the LUdwigshafen RIsk and Cardiovascular Health (LURIC) Study

AbstractObjectiveWhite blood cells are known to predict cardiovascular mortality, but form a highly heterogeneous population. It is therefore possible that specific subtypes disproportionally contribute to the prediction of cardiovascular outcomes. Therefore, we compared leukocyte subsets alone and in conjunction with an established inflammatory marker, C-reactive protein, for predicting death due to cardiovascular disease in a high-risk population.MethodsPatients, 3316, (mean [SD] age, 62 [10] years) scheduled for coronary angiography were prospectively followed up. Neutrophil, monocyte and lymphocyte counts were determined. Neutrophil and monocyte subsets were further analysed on the basis of surface expression of CD11b, CD18, CD31, CD40 and CD58. Lymphocytes were further subdivided into CD3, CD4, CD8, and CD19 subsets. The association between each marker and subsequent cardiovascular mortality was assessed using multivariable Cox regression models.ResultsDuring a median follow-up period of 7.8 years, 745 (22.5%) patients died, of which 484 were due to cardiovascular events. After entering conventional risk factors and removing patients with a current infection, neutrophil count (HR [95% CI]=1.90 [1.39, 2.60], P<0.001) and the neutrophil/lymphocyte ratio (HR [95% CI]=1.68 [1.24, 2.27], P=0.003) emerged as independent predictors of cardiovascular mortality. After mutual adjustment, neutrophil count (HR [95% CI]=1.87 [1.35, 2.50], P<0.001) out-performed C-reactive protein (HR [95% CI] 1.32 [0.99, 1.78], P=0.06) as a predictor of cardiovascular mortality.ConclusionsDue to its predictive potential and inexpensive determination, assessment of high neutrophil counts may represent an important marker, possibly improving cardiovascular mortality risk prediction

High genetic risk for depression as an independent risk factor for mortality in patients referred for coronary angiography

BackgroundDifferent observations have suggested that patients with depression have a higher risk for a number of comorbidities and mortality. The underlying causes have not been fully understood yet.AimsThe aim of our study was to investigate the association of a genetic depression risk score (GDRS) with mortality [all-cause and cardiovascular (CV)] and markers of depression (including intake of antidepressants and a history of depression) in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study involving 3,316 patients who had been referred for coronary angiography.Methods and resultsThe GDRS was calculated in 3,061 LURIC participants according to a previously published method and was found to be associated with all-cause (p = 0.016) and CV mortality (p = 0.0023). In Cox regression models adjusted for age, sex, body mass index, LDL-cholesterol, HDL-cholesterol, triglycerides, hypertension, smoking, and diabetes mellitus, the GDRS remained significantly associated with all-cause [1.18 (1.04–1.34, p = 0.013)] and CV [1.31 (1.11–1.55, p = 0.001)] mortality. The GDRS was not associated with the intake of antidepressants or a history of depression. However, this cohort of CV patients had not specifically been assessed for depression, leading to marked underreporting. We were unable to identify any specific biomarkers correlated with the GDRS in LURIC participants.ConclusionA genetic predisposition for depression estimated by a GDRS was independently associated with all-cause and CV mortality in our cohort of patients who had been referred for coronary angiography. No biomarker correlating with the GDRS could be identified

Genome-wide meta-analysis of phytosterols reveals five novel loci and a detrimental effect on coronary atherosclerosis

Phytosterol serum concentrations are under tight genetic control. The relationship between phytosterols and coronary artery disease (CAD) is controversially discussed. We perform a genome-wide meta-analysis of 32 phytosterol traits reflecting resorption, cholesterol synthesis and esterification in six studies with up to 9758 subjects and detect ten independent genome-wide significant SNPs at seven genomic loci. We confirm previously established associations at ABCG5/8 and ABO and demonstrate an extended locus heterogeneity at ABCG5/8 with different functional mechanisms. New loci comprise HMGCR, NPC1L1, PNLIPRP2, SCARB1 and APOE. Based on these results, we perform Mendelian Randomization analyses (MR) revealing a risk-increasing causal relationship of sitosterol serum concentrations and CAD, which is partly mediated by cholesterol. Here we report that phytosterols are polygenic traits. MR add evidence of both, direct and indirect causal effects of sitosterol on CAD

High-density lipoprotein cholesterol, coronary artery disease, and cardiovascular mortality

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 patient

Serum amyloid A: high-density lipoproteins interaction and cardiovascular risk

Aims High-density lipoproteins (HDLs) are considered as anti-atherogenic. Recent experimental findings suggest that their biological properties can be modified in certain clinical conditions by accumulation of serum amyloid A (SAA). The effect of SAA on the association between HDL-cholesterol (HDL-C) and cardiovascular outcome remains unknown. Methods and results We examined the association of SAA and HDL-C with mortality in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study, which included 3310 patients undergoing coronary angiography. To validate our findings, we analysed 1255 participants of the German Diabetes and Dialysis study (4D) and 4027 participants of the Cooperative Health Research in the Region of Augsburg (KORA) S4 study. In LURIC, SAA concentrations predicted all-cause and cardiovascular mortality. In patients with low SAA, higher HDL-C was associated with lower all-cause and cardiovascular mortality. In contrast, in patients with high SAA, higher HDL-C was associated with increased all-cause and cardiovascular mortality, indicating that SAA indeed modifies the beneficial properties of HDL. We complemented these clinical observations by in vitro experiments, in which SAA impaired vascular functions of HDL. We further derived a formula for the simple calculation of the amount of biologically ‘effective' HDL-C based on measured HDL-C and SAA from the LURIC study. In 4D and KORA S4 studies, we found that measured HDL-C was not associated with clinical outcomes, whereas calculated ‘effective' HDL-C significantly predicted better outcome. Conclusion The acute-phase protein SAA modifies the biological effects of HDL-C in several clinical conditions. The concomitant measurement of SAA is a simple, useful, and clinically applicable surrogate for the vascular functionality of HD

Mitochondrial genome-wide analysis of nuclear DNA methylation quantitative trait loci

Mitochondria have a complex communication network with the surrounding cell and can alter nuclear DNA methylation (DNAm). Variation in the mitochondrial DNA (mtDNA) has also been linked to differential DNAm. Genome-wide association studies have identified numerous DNAm quantitative trait loci, but these studies have not examined the mitochondrial genome. Herein, we quantified nuclear DNAm from blood and conducted a mitochondrial genome-wide association study of DNAm, with an additional emphasis on sex- and prediabetes-specific heterogeneity. We used the Young Finns Study (n = 926) with sequenced mtDNA genotypes as a discovery sample and sought replication in the Ludwigshafen Risk and Cardiovascular Health study (n = 2317). We identified numerous significant associations in the discovery phase (P < 10(-9)), but they were not replicated when accounting for multiple testing. In total, 27 associations were nominally replicated with a P < 0.05. The replication analysis presented no evidence of sex- or prediabetes-specific heterogeneity. The 27 associations were included in a joint meta-analysis of the two cohorts, and 19 DNAm sites associated with mtDNA variants, while four other sites showed haplogroup associations. An expression quantitative trait methylation analysis was performed for the identified DNAm sites, pinpointing two statistically significant associations. This study provides evidence of a mitochondrial genetic control of nuclear DNAm with little evidence found for sex- and prediabetes-specific effects. The lack of a comparable mtDNA data set for replication is a limitation in our study and further studies are needed to validate our results.Peer reviewe

Blood pressure and Mortality in the 4D Study

Introduction: Systolic (SBP), diastolic (DBP) and mean arterial pressure (MAP) are risk factors for cardiovascular mortality (CVM). Pulse pressure (PP) is an easily available parameter of vascular stiffness, but its impact on CVM in chronic dialysis patients with diabetes is unclear. Methods: Therefore, we have examined the predictive value of baseline, predialytic PP, SBP, DBP and MAP in the German Diabetes and Dialysis (4D) study, a prospective, randomized, double-blind trial enrolling 1255 patients with type 2 diabetes on hemodialysis in 178 German dialysis centers. Results: Mean age was 66.3 years, mean blood pressure 146/76 mmHg, mean time suffering from diabetes 18.1 years and mean time on maintenance dialysis 8.3 months. Considered as continuous variables, PP, MAP, SBP and DBP could not provide a significant mortality prediction for either cardiovascular or all-cause mortality. After dividing the cohort into corresponding tertiles, we did also not detect any significant mortality prediction for PP, SBP, DBP or MAP, both for all-cause mortality and CVM after adjusting for age and sex. Nevertheless, when comparing the HR plots of the corresponding blood pressure parameters, a pronounced U-curve was seen for PP for both all-cause mortality and CVM, with the trough range being 70-80 mmHg. Discussion: In patients with end-stage renal disease and long-lasting diabetes mellitus predialytic blood pressure parameters at study entry are not predictive for mortality, presumably because there is a very high rate of competing mortality risk factors, resulting in overall very high rates of all-cause and cardiovascular mortality, that may no longer be significantly modulated by blood pressure control