Plasma proteins associated with cardiovascular death in patients with chronic coronary heart disease: A retrospective study.

BACKGROUND: Circulating biomarkers are associated with the development of coronary heart disease (CHD) and its complications by reflecting pathophysiological pathways and/or organ dysfunction. We explored the associations between 157 cardiovascular (CV) and inflammatory biomarkers and CV death using proximity extension assays (PEA) in patients with chronic CHD. METHODS AND FINDINGS: The derivation cohort consisted of 605 cases with CV death and 2,788 randomly selected non-cases during 3-5 years follow-up included in the STabilization of Atherosclerotic plaque By Initiation of darapLadIb TherapY (STABILITY) trial between 2008 and 2010. The replication cohort consisted of 245 cases and 1,042 non-cases during 12 years follow-up included in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study between 1997 and 2000. Biomarker levels were measured with conventional immunoassays and/or with the OLINK PEA panels CVD I and Inflammation. Associations with CV death were evaluated by Random Survival Forest (RF) and Cox regression analyses. Both cohorts had the same median age (65 years) and 20% smokers, while there were slight differences in male sex (82% and 76%), hypertension (70% and 78%), and diabetes (39% and 30%) in the respective STABILITY and LURIC cohorts. The analyses identified 18 biomarkers with confirmed independent association with CV death by Boruta analyses and statistical significance (all p < 0.0001) by Cox regression when adjusted for clinical characteristics in both cohorts. Most prognostic information was carried by N-terminal prohormone of brain natriuretic peptide (NTproBNP), hazard ratio (HR for 1 standard deviation [SD] increase of the log scale of the distribution of the biomarker in the replication cohort) 2.079 (95% confidence interval [CI] 1.799-2.402), and high-sensitivity troponin T (cTnT-hs) HR 1.715 (95% CI 1.491-1.973). The other proteins with independent associations were growth differentiation factor 15 (GDF-15) HR 1.728 (95% CI 1.527-1.955), transmembrane immunoglobulin and mucin domain protein (TIM-1) HR 1.555 (95% CI 1.362-1.775), renin HR 1.501 (95% CI 1.305-1.727), osteoprotegerin (OPG) HR 1.488 (95% CI 1.297-1.708), soluble suppression of tumorigenesis 2 protein (sST2) HR 1.478 (95% CI 1.307-1.672), cystatin-C (Cys-C) HR 1.370 (95% CI 1.243-1.510), tumor necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAIL-R2) HR 1.205 (95% CI 1.131-1.285), carbohydrate antigen 125 (CA-125) HR 1.347 (95% CI 1.226-1.479), brain natriuretic peptide (BNP) HR 1.399 (95% CI 1.255-1.561), interleukin 6 (IL-6) HR 1.478 (95% CI 1.316-1.659), hepatocyte growth factor (HGF) HR 1.259 (95% CI 1.134-1.396), spondin-1 HR 1.295 (95% CI 1.156-1.450), fibroblast growth factor 23 (FGF-23) HR 1.349 (95% CI 1.237-1.472), chitinase-3 like protein 1 (CHI3L1) HR 1.284 (95% CI 1.129-1.461), tumor necrosis factor receptor 1 (TNF-R1) HR 1.486 (95% CI 1.307-1.689), and adrenomedullin (AM) HR 1.750 (95% CI 1.490-2.056). The study is limited by the differences in design, size, and length of follow-up of the 2 studies and the lack of results from coronary angiograms and follow-up of nonfatal events. CONCLUSIONS: Profiles of levels of multiple plasma proteins might be useful for the identification of different pathophysiological pathways associated with an increased risk of CV death in patients with chronic CHD. TRIAL REGISTRATION: ClinicalTrials.gov NCT00799903.

Iron Metabolism, Hepcidin, and Mortality (the Ludwigshafen Risk and Cardiovascular Health Study).

BACKGROUND: Anemia has been shown to be a risk factor for coronary artery disease (CAD) and mortality, whereas the role of iron metabolism remains controversial. METHODS: We analyzed iron metabolism and its associations with cardiovascular death and total mortality in patients undergoing coronary angiography with a median follow-up of 9.9 years. Hemoglobin and iron status were determined in 1480 patients with stable CAD and in 682 individuals in whom significant CAD had been excluded by angiography. RESULTS: Multivariate-adjusted hazard ratios (HRs) for total mortality in the lowest quartiles of iron, transferrin saturation, ferritin, soluble transferrin receptor (sTfR), and hemoglobin were 1.22 (95% CI, 0.96-1.60), 1.23 (95% CI, 0.97-1.56), 1.27 (95% CI, 1.02-1.58), 1.26 (95% CI, 0.97-1.65), and 0.99 (95% CI, 0.79-1.24), respectively, compared to the second or third quartile, which served as reference (1.00) because of a J-shaped association. The corresponding HRs for total mortality in the highest quartiles were 1.44 (95% CI, 1.10-1.87), 1.37 (95% CI, 1.05-1.77), 1.17 (95% CI, 0.92-1.50), 1.76 (95% CI, 1.39-2.22), and 0.83 (95% CI, 0.63-1.09). HRs for cardiovascular death were similar. For hepcidin, the adjusted HRs for total mortality and cardiovascular deaths were 0.62 (95% CI, 0.49-0.78) and 0.70 (95% CI, 0.52-0.90) in the highest quartile compared to the lowest one. CONCLUSIONS: In stable patients undergoing angiography, serum iron, transferrin saturation, sTfR, and ferritin had J-shaped associations and hemoglobin only a marginal association with cardiovascular and total mortality. Hepcidin was continuously and inversely related to mortality.

NFAT5 and SLC4A10 Loci Associate with Plasma Osmolality.

Disorders of water balance, an excess or deficit of total body water relative to body electrolyte content, are common and ascertained by plasma hypo- or hypernatremia, respectively. We performed a two-stage genome-wide association study meta-analysis on plasma sodium concentration in 45,889 individuals of European descent (stage 1 discovery) and 17,637 additional individuals of European descent (stage 2 replication), and a transethnic meta-analysis of replicated single-nucleotide polymorphisms in 79,506 individuals (63,526 individuals of European descent, 8765 individuals of Asian Indian descent, and 7215 individuals of African descent). In stage 1, we identified eight loci associated with plasma sodium concentration at P<5.0 × 10-6 Of these, rs9980 at NFAT5 replicated in stage 2 meta-analysis (P=3.1 × 10-5), with combined stages 1 and 2 genome-wide significance of P=5.6 × 10-10 Transethnic meta-analysis further supported the association at rs9980 (P=5.9 × 10-12). Additionally, rs16846053 at SLC4A10 showed nominally, but not genome-wide, significant association in combined stages 1 and 2 meta-analysis (P=6.7 × 10-8). NFAT5 encodes a ubiquitously expressed transcription factor that coordinates the intracellular response to hypertonic stress but was not previously implicated in the regulation of systemic water balance. SLC4A10 encodes a sodium bicarbonate transporter with a brain-restricted expression pattern, and variant rs16846053 affects a putative intronic NFAT5 DNA binding motif. The lead variants for NFAT5 and SLC4A10 are cis expression quantitative trait loci in tissues of the central nervous system and relevant to transcriptional regulation. Thus, genetic variation in NFAT5 and SLC4A10 expression and function in the central nervous system may affect the regulation of systemic water balance.

High-Density Lipoprotein Subclasses, Coronary Artery Disease, and Cardiovascular Mortality.

BACKGROUND: The inverse relationship between HDL cholesterol and cardiovascular mortality is weakened in coronary artery disease (CAD). We aimed to investigate the associations of HDL particle concentrations with cardiovascular mortality and the impact of CAD on these associations. We also sought to comparatively evaluate HDL cholesterol and HDL particle concentrations in predicting cardiovascular mortality. METHODS: Total and subclass HDL particle concentrations were measured by nuclear magnetic resonance spectroscopy in 2290 participants of the LUdwigshafen RIsk and Cardiovascular Health study referred for coronary angiography. The participants were prospectively followed over a median (interquartile range) duration of 10.0 (6.1-10.6) years. RESULTS: The mean (SD) age of the participants (1575 males, 715 females) was 62.9 (10.4) years; body mass index, 27.6 (4.1) kg/m2; HDL cholesterol, 39 (11) mg/dL [1 (0.29) mmol/L]; and total HDL particle concentration, 24.1 (5.8) µmol/L. Of the participants, 434 died from cardiovascular diseases. In multivariate analyses, tertiles of total HDL particle concentrations were inversely related to cardiovascular mortality (hazard ratio for third vs first tertile = 0.55, P < 0.001). This association was primarily mediated by small HDL particles (P < 0.001). Adding total or small HDL particle concentrations rather than HDL cholesterol to multivariate prediction models improved performance metrics for cardiovascular mortality. The presence of CAD had no impact on the associations between HDL particle concentrations and cardiovascular mortality. CONCLUSIONS: High HDL particle concentration is consistently and independently of CAD associated with decreased cardiovascular mortality. Whether the inverse relationship between HDL particle concentration and cardiovascular mortality may be translated into novel therapies is under investigation.

Vitamin-D concentrations, cardiovascular risk and events - a review of epidemiological evidence.

Vitamin D has long been established as an elemental factor of bone physiology. Beyond mineral metabolism, the expression of the vitamin D receptor has been identified throughout the cardiovascular (CV) system. Experimental studies showed beneficial effects of vitamin D on heart and vessels, but vitamin D intoxication in animals also led to hypercalcemia and vascular calcification. Our knowledge has been extended by epidemiological studies that showed that 25-hydroxyvitamin D (25(OH)D) levels are inversely associated with an increased CV risk itself, but also with established CV risk factors, such as arterial hypertension, endothelial dysfunction and atherosclerosis. Conversely, randomized controlled trials could not document significant and consistent effects of vitamin D supplementation on CV risk or events. Potential explanations may lie in differences in reference ranges or the possibility that low vitamin D in CV disease is only an epiphenomenon. In the latter case, the key question is why low 25(OH)D levels are such a strong predictor of health. While we wait for new data, the current conclusion is that vitamin D is a strong risk marker for CV risk factors and for CV diseases itself.

Uric Acid and Cardiovascular Events: A Mendelian Randomization Study.

Obesity and diets rich in uric acid-raising components appear to account for the increased prevalence of hyperuricemia in Westernized populations. Prevalence rates of hypertension, diabetes mellitus, CKD, and cardiovascular disease are also increasing. We used Mendelian randomization to examine whether uric acid is an independent and causal cardiovascular risk factor. Serum uric acid was measured in 3315 patients of the Ludwigshafen Risk and Cardiovascular Health Study. We calculated a weighted genetic risk score (GRS) for uric acid concentration based on eight uric acid-regulating single nucleotide polymorphisms. Causal odds ratios and causal hazard ratios (HRs) were calculated using a two-stage regression estimate with the GRS as the instrumental variable to examine associations with cardiometabolic phenotypes (cross-sectional) and mortality (prospectively) by logistic regression and Cox regression, respectively. Our GRS was not consistently associated with any biochemical marker except for uric acid, arguing against pleiotropy. Uric acid was associated with a range of prevalent diseases, including coronary artery disease. Uric acid and the GRS were both associated with cardiovascular death and sudden cardiac death. In a multivariate model adjusted for factors including medication, causal HRs corresponding to each 1-mg/dl increase in genetically predicted uric acid concentration were significant for cardiovascular death (HR, 1.77; 95% confidence interval, 1.12 to 2.81) and sudden cardiac death (HR, 2.41; 95% confidence interval, 1.16 to 5.00). These results suggest that high uric acid is causally related to adverse cardiovascular outcomes, especially sudden cardiac death.

HDL cholesterol, apolipoproteins, and cardiovascular risk in hemodialysis patients.

High concentrations of HDL cholesterol are considered to indicate efficient reverse cholesterol transport and to protect from atherosclerosis. However, HDL has been suggested to be dysfunctional in ESRD. Hence, our main objective was to investigate the effect of HDL cholesterol on outcomes in maintenance hemodialysis patients with diabetes. Moreover, we investigated the associations between the major protein components of HDL (apoA1, apoA2, and apoC3) and end points. We performed an exploratory, post hoc analysis with 1255 participants (677 men and 578 women) of the German Diabetes Dialysis study. The mean age was 66.3 years and the mean body mass index was 28.0 kg/m(2). The primary end point was a composite of cardiac death, myocardial infarction, and stroke. The secondary end point included all-cause mortality. The mean duration of follow-up was 3.9 years. A total of 31.3% of the study participants reached the primary end point and 49.1% died from any cause. HDL cholesterol and apoA1 and apoC3 quartiles were not related to end points. However, there was a trend toward an inverse association between apoA2 and all-cause mortality. The hazard ratio for death from any cause in the fourth quartile compared with the first quartile of apoA2 was 0.63 (95% confidence interval, 0.40 to 0.89). The lack of an association between HDL cholesterol and cardiovascular risk may support the concept of dysfunctional HDL in hemodialysis. The possible beneficial effect of apoA2 on survival requires confirmation in future studies.

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 ß-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.

Low serum tryptophan predicts higher mortality in cardiovascular disease.

BACKGROUND: The essential amino acid tryptophan is required for protein synthesis and formation of the neurotransmitter serotonin and may exert immunoregulatory functions. An accelerated tryptophan breakdown rate is associated with inflammation and immune activation. MATERIALS AND METHODS: Serum concentrations of free tryptophan, neopterin and high-sensitivity C-reactive protein (hsCRP) were measured in 1196 patients with coronary artery disease (CAD) derived from the LUdwigshafen RIsk and Cardiovascular Health (LURIC) study. RESULTS: Tryptophan concentrations did not differ between patients with (mean ± SD: 40.1 ± 9.8 µM) or without (42.3 ± 23.9 µM; not significant, Welch's test) angiographic CAD, but patients with CAD had higher neopterin (9.1 ± 8.2 nM) and hsCRP (9.3 ± 18.5 mg/L) concentrations compared to patients without (neopterin: 7.6 ± 4.7 nM, hsCRP: 5.8 ± 7.6 mg/L; both P < 0.0001). There existed an inverse correlation between serum tryptophan and neopterin (Spearman's rank correlation: rs = -0.273) and hsCRP (rs = -0.163; both P < 0.0001) concentrations. Median observation time was 10.5 years, and 385 patients had died, including 244 patients due to cardiovascular and 132 due to noncardiovascular causes. After adjustments for cardiovascular risk factors and other possible confounders, the hazard ratio (with 95% CI) in the first tryptophan quartile of the study population was 1.51 (1.19-1.90; P = 0.0006) for total mortality, 1.41 (1.05-1.89; P = 0.0224) for cardiovascular and 1.79 (1.20-2.67; P = 0.0042) for noncardiovascular mortalities, respectively, thus indicating a significantly higher risk of death in patients with tryptophan concentrations < 34 µM. CONCLUSIONS: Low serum tryptophan in patients with CAD is associated with immune activation and indicates reduced life expectancy.

Genome-wide association study on dimethylarginines reveals novel AGXT2 variants associated with heart rate variability but not with overall mortality.

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.

Smoking, apolipoprotein E genotypes, and mortality (the Ludwigshafen RIsk and Cardiovascular Health study).

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 [ε22 or ε23: odds ratio (OR) 0.56, 95% confidence interval (CI) 0.43-0.71; ε24 or ε34 or ε44: OR 1.10, 95% CI 0.89-1.37 compared with ε33] and moderately with cardiovascular mortality [ε22 or ε23: hazard ratio (HR) 0.71, 95% CI 0.51-0.99; ε33: HR 0.92, 95% CI 0.75-1.14 compared with ε24 or ε34 or ε44]. 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 ε4 allele, respectively, compared with never-smokers. Carrying ε4 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 ε4 was seen regarding non-cardiovascular mortality. Smokers with ε4 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 ε4 allele in current smokers increases cardiovascular and all-cause mortality.

Evidence of a synergistic association between heart rate, inflammation, and cardiovascular mortality in patients undergoing coronary angiography.

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.

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 patients.

Association of 25-hydroxyvitamin D with type 2 diabetes among patients undergoing coronary angiography: cross-sectional findings from the LUdwigshafen Risk and Cardiovascular Health (LURIC) Study.

OBJECTIVE: Evidence suggests that vitamin D may protect against the onset of diabetes. However, the mechanisms underlying the role of vitamin D on glycaemic status are unclear and warrant further investigation. We sought to determine the relationship between serum 25-hydroxyvitamin D (25[OH]D) and glycaemic status among intermediate-to-high-risk patients scheduled for coronary angiography. METHODS: Participants were 3316 male and female patients (mean ± SD age, 62·7 ± 10·6 years). Four categories were formed according to serum 25[OH]D levels. The association between serum 25[OH]D and diabetes was assessed using multivariable logistic regression. RESULTS: Fasting and 2 h post-load glucose, HbA1c and the HOMA-IR indices diminished with increasing serum 25[OH]D levels (P < 0·001). However, no associations were observed between insulin, pro-insulin or C-peptide and serum 25[OH]D concentrations. The pro-inflammatory markers IL-6 and hs-CRP also decreased considerably with higher vitamin D levels (P < 0·001). After full adjustment, those with optimal serum 25[OH]D levels had a reduced odds for fasting diabetes (OR = 0·63; 95% CI, 0·46-0·86; Ptrend = 0·01), 2 h post-load diabetes (OR = 0·46; 95% CI, 0·29-0·74; Ptrend = 0·004), both fasting/2 h post-load diabetes (OR = 0·61; 95% CI, 0·42-0·87; Ptrend = 0·001) and all of the combined hyperglycaemic states (OR = 0·68; 95% CI, 0·52-0·80; Ptrend = 0·01). CONCLUSIONS: Higher serum 25[OH]D levels were associated with better glycaemic status and lower inflammation. Should these observations be confirmed in future studies, vitamin D supplementation may prove a useful adjunct in attenuating the onset of diabetes.

High-sensitivity cardiac troponin T and N-terminal pro-B-type natriuretic peptide predict mortality in stable coronary artery disease: results from the Ludwigshafen Risk and Cardiovascular Health (LURIC) study.

BACKGROUND: The simultaneous assessment of high-sensitivity cardiac troponin T (hscTnT) and NT-proBNP for predicting death in stable coronary artery disease (CAD) has yet not been examined. We investigated the additional contribution of hscTnT to the risk of mortality prediction of NT-proBNP in patients with stable CAD. METHODS: We studied 1469 patients with stable CAD enrolled in the Ludwigshafen Risk and Cardiovascular Health Study (LURIC). hscTnT and NT-proBNP were measured in baseline samples using immunoassays (Roche Diagnostics, Germany). RESULTS: Thirty-five percent (n=525) of the patients died during a median follow-up of 7 and a half years. In total 59.0% of the non-survivors and 25.2% of the survivors exhibited concentrations of hscTnT≥14 ng/L. Logistic regression analysis identified hscTnT and NT-proBNP as independent risk markers for short-term (1-year follow-up) and long-term (9-years follow-up) mortality. ROC curve analysis determined optimal univariate cut-offs at 14 ng/L and 443 µg/L for hscTnT (AUC 0.725, p<0.0001) and NT-proBNP (AUC 0.742, p<0.0001), respectively. Kaplan-Meier survival analysis based on optimized cut-offs for the simultaneous determination of both biomarkers confirmed the usefulness of additive hscTnT especially in prediction of short-term mortality. The prognostic benefit of the combined assessment of hscTnT and NT-proBNP could be confirmed by a significantly increased reclassification index (NRI) of 24.2%. CONCLUSIONS: The majority of non-survivors exhibited increased hscTnT concentrations above 14 ng/L. The simultaneous determination of NT-proBNP and hscTnT was superior for risk stratification compared to determining either marker alone. Especially the prediction of the clinically important 1-year mortality was significantly improved by addition of hscTnT to NT-proBNP.

Routinely available biomarkers improve prediction of long-term mortality in stable coronary artery disease: the Vienna and Ludwigshafen Coronary Artery Disease (VILCAD) risk score.

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.

The German CaRe high registry for familial hypercholesterolemia - Sex differences, treatment strategies, and target value attainment.

Background and aims: Familial hypercholesterolemia (FH) is among the most common genetic disorders in primary care. However, only 15% or less of patients are diagnosed, and few achieve the goals for low-density lipoprotein cholesterol (LDL-C). In this analysis of the German Cascade Screening and Registry for High Cholesterol (CaRe High), we examined the status of lipid management, treatment strategies, and LDL-C goal attainment according to the ESC/EAS dyslipidemia guidelines. Methods: We evaluated consolidated datasets from 1501 FH patients diagnosed clinically and seen either by lipid specialists or general practitioners and internists. We conducted a questionnaire survey of both the recruiting physicians and patients. Results: Among the 1501 patients, 86% regularly received lipid-lowering drugs. LDL-C goals were achieved by 26% and 10% of patients with atherosclerotic cardiovascular disease (ASCVD) according to the 2016 and 2019 ESC/EAS dyslipidemia guidelines, respectively. High intensity lipid-lowering was administered more often in men than in women, in patients with ASCVD, at higher LDL-C and in patients with a genetic diagnosis of FH. Conclusions: FH is under-treated in Germany compared to guideline recommendations. Male gender, genetic proof of FH, treatment by a specialist, and presence of ASCVD appear to be associated with increased treatment intensity. Achieving the LDL-C goals of the 2019 ESC/EAS dyslipidemia guidelines remains challenging if pre-treatment LDL-C is very high.

Combination of low free testosterone and low vitamin D predicts mortality in older men referred for coronary angiography.

CONTEXT: Low levels of 25-hydroxyvitamin D [25(OH)D] and free testosterone (FT) are both associated with increased mortality. Experimental studies show a complex interplay of vitamin D and androgen metabolism suggesting that a deficiency of both hormones may be associated with a particularly adverse clinical outcome. OBJECTIVE: To evaluate the impact of parallel FT and 25(OH)D deficiency in a large cohort of older men. DESIGN: We measured total testosterone (TT), sex hormone-binding globulin and 25(OH)D levels in 2069 men who were routinely referred for coronary angiography (1997-2000). MAIN OUTCOME MEASURES: Cox proportional hazard ratios (HRs) (with 95% confidence intervals) for mortality from all causes, cardiovascular and noncardiovascular causes according to combined deficiency of FT and 25(OH)D. RESULTS: In multivariate-adjusted analyses, we found an increased risk for all-cause mortality, cardiovascular and noncardiovascular mortality for men in the lowest FT [HR 1·26 (1·03-1·54), 1·24 (0·96-1·60) and 1·39 (1·00-1·93), respectively] and 25(OH)D quartile [HR 1·77 (1·47-2·13), 1·65 (1·29-2·10) and 1·89 (1·38-2·60) respectively] compared with men in higher FT and 25(OH)D quartiles. There was no independent association of TT levels with mortality. Multivariate-adjusted HRs progressively increased with the number of hormones (FT and 25(OH)D) in the lowest quartile [0 vs 2 hormone deficiencies: 2·11 (1·60-2·79) for all cause, 1·77 (1·23-2·55) for cardiovascular and 2·33 (1·45-3·47) for noncardiovascular mortality, respectively]. CONCLUSION: A combined deficiency of FT and 25(OH)D is significantly associated with fatal events in a large cohort of men referred for coronary angiography.

Vitamin D deficiency parallels inflammation and immune activation, the Ludwigshafen Risk and Cardiovascular Health (LURIC) study.

BACKGROUND: Low vitamin D concentrations are detected in patients suffering from various clinical conditions which are characterized also by inflammation and immune activation.We investigated whether vitamin D levels in patients with coronary artery disease (CAD) are related to markers of immune activation. METHODS: Serum concentrations of 25-hydroxyvitamin D[25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH) 2 D] and the immune activation markers neopterin and high sensitivity C-reactive protein (hsCRP) were measured in 2015 patients derived from the LUdwigshafen RIsk and Cardiovascular Health (LURIC) study, a cohort study among patients referred for coronary angiography. RESULTS: Serum concentrations of 25(OH)D and 1,25(OH) 2 D did not differ between patients with CAD [mean } SD:25(OH)D: 17.4 } 9.4 µ g/L; 1,25(OH) 2 D: 34.4 } 13.3 ng/L] and controls [25(OH)D: 18.4 } 11.7 µ g/L; 1,25(OH) 2 D: 35.3 } 12.7ng/L; Welch ' s t-test: p = n.s.] but CAD patients had higher neopterin (8.6 } 7.4 nmol/L) and hsCRP (9.6 } 19.6 mg/L) concentrations compared to controls (neopterin: 7.5 } 4.8 nmol/L;p = 0.0004; hsCRP: 5.4 } 10.0 mg/L; p < 0.0001). There was an inverse correlation between serum 25(OH)D or 1,25(OH) 2 D concentrations and serum neopterin [Spearman ' s rank correlation:25(OH)D: r s = ­ 0.183; 1,25(OH)2D: r s = ­ 0.230] and hsCRP [25(OH)D: r s = ­ 0.142; 1,25(OH) 2 D: r s = ­ 0.130; allp < 0.0001] concentrations. CONCLUSIONS: Our results indicate increased inflammatory processes in patients with low vitamin D status. Further studies should clarify the underlying mechanisms for the observed associations of vitamin D status and inflammatory parameters.

Association of TCF7L2 SNPs with age at onset of type 2 diabetes and proinsulin/insulin ratio but not with glucagon-like peptide 1.

BACKGROUND: Variants in TCF7L2 have been associated with the age at onset of type 2 diabetes in Mexican Americans. However, there is a lack of data on this relationship in Caucasians. Furthermore, risk alleles in TCF7L2 have been suggested to account for decreased conversion of proinsulin to insulin and decreased expression of GLP-1. We investigated the effect of the allelic variants rs1225537 and rs7903146 in TCF7L2 on the age at onset of type 2 diabetes, the plasma concentrations of proinsulin and GLP-1, and the ratio of proinsulin to insulin in a German cohort. METHODS: We studied 3185 participants of the LUdwigshafen RIsk and Cardiovascular health (LURIC) study. Among these, 1021 subjects had type 2 diabetes. Data on age at onset of diabetes were available in 925 subjects. OGTTs were performed in a subgroup not previously known to have diabetes. RESULTS: Carriers of the risk alleles in rs1225537 and rs7901346 had increased risk of type 2 diabetes and elevated HbA(1c) (all p < 0.001). The risk alleles were also associated with early onset of type 2 diabetes, decreased insulin secretion and markedly increased proinsulin and proinsulin to insulin ratio (all p < 0.03). GLP-1 was not significantly related to the TCF7L2 genotype. CONCLUSIONS: Our data demonstrate that TCF7L2 variants are associated with an early age of onset of type 2 diabetes in Caucasians and affects the conversion of proinsulin to insulin. However, TCF7L2 is not consistently associated with fasting GLP-1.