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.

Evaluation of 9 biomarkers for predicting 10-year cardiovascular risk in patients undergoing coronary angiography: findings from the LUdwigshafen RIsk and Cardiovascular Health (LURIC) study.

BACKGROUND Conventional factors do not fully explain the distribution of cardiovascular outcomes. Biomarkers are known to participate in well-established pathways associated with cardiovascular disease, and may therefore provide further information over and above conventional risk factors. This study sought to determine whether individual and/or combined assessment of 9 biomarkers improved discrimination, calibration and reclassification of cardiovascular mortality. METHODS 3267 patients (2283 men), aged 18-95 years, at intermediate-to-high-risk of cardiovascular disease were followed in this prospective cohort study. Conventional risk factors and biomarkers were included based on forward and backward Cox proportional stepwise selection models. RESULTS During 10-years of follow-up, 546 fatal cardiovascular events occurred. Four biomarkers (interleukin-6, neutrophils, von Willebrand factor, and 25-hydroxyvitamin D) were retained during stepwise selection procedures for subsequent analyses. Simultaneous inclusion of these biomarkers significantly improved discrimination as measured by the C-index (0.78, P = 0.0001), and integrated discrimination improvement (0.0219, P<0.0001). Collectively, these biomarkers improved net reclassification for cardiovascular death by 10.6% (P<0.0001) when added to the conventional risk model. CONCLUSIONS In terms of adverse cardiovascular prognosis, a biomarker panel consisting of interleukin-6, neutrophils, von Willebrand factor, and 25-hydroxyvitamin D offered significant incremental value beyond that conveyed by simple conventional risk factors.

Cystatin C is independently associated with total and cardiovascular mortality in individuals undergoing coronary angiography. The Ludwigshafen Risk and Cardiovascular Health (LURIC) study.

AIMS Cystatin C is a well established marker of kidney function. There is evidence that cystatin C concentrations are also associated with mortality. The present analysis prospectively evaluated the associations of cystatin C with all-cause and cardiovascular (CV) mortality in a well-characterized cohort of persons undergoing angiography, but without overt renal insufficiency. METHODS Cystatin C was available in 2998 persons (mean age: 62.7 ± 10.5 years; 30.3% women). Of those 2346 suffered from coronary artery disease (CAD) and 652 (controls) did not. Creatinine (mean ± SD: 83.1 ± 47.8 vs. 74.1 ± 24.7 μmol/L, p = 0.036) but not Cystatin C (mean ± SD: 1.02 ± 0.44 vs. 0.92 ± 0.26 mg/L, p = 0.065) was significantly higher in patients with CAD. After a median follow-up of 9.9 years, in total 898 (30%) deaths occurred, 554 (18.5%) due to CV disease and 326 (10.9%) due to non-CV causes. Multivariable-adjusted Cox analysis (adjusting for eGFR and established cardiovascular risk factors, lipid lowering therapy, angiographic coronary artery disease, and C-reactive protein) revealed that patients in the highest cystatin C quartile were at an increased risk for all-cause (hazard ratio (HR) 1.93, 95% CI 1.50-2.48) and CV mortality (HR 2.05 95% CI 1.48-2.84) compared to those in the lowest quartile. The addition of cystatin C to a model consisting of established cardiovascular risk factors increased the area under the receiver-operating characteristic curve for CV and all-cause mortality, but the difference was statistically not significant. However, reclassification analysis revealed significant improvement by addition of cystatin C for CV and all-cause mortality (p < 0.001), respectively. CONCLUSION The concentration of cystatin C is strongly associated with long-term all-cause and cardiovascular mortality in patients referred to coronary angiography, irrespective of creatinine-based renal function.

High intestinal cholesterol absorption is associated with cardiovascular disease and risk alleles in ABCG8 and ABO: evidence from the LURIC and YFS cohorts and from a meta-analysis.

OBJECTIVES This study sought to determine whether high intestinal cholesterol absorption represents a cardiovascular risk factor and to link ABCG8 and ABO variants to cardiovascular disease (CVD). BACKGROUND Plant sterol-enriched functional foods are widely used for cholesterol lowering. Their regular intake yields a 2-fold increase in circulating plant sterol levels that equally represent markers of cholesterol absorption. Variants in ABCG8 and ABO have been associated with circulating plant sterol levels and CVD, thereby suggesting atherogenic effects of plant sterols or of cholesterol uptake. METHODS The cholestanol-to-cholesterol ratio (CR) was used as an estimate of cholesterol absorption because it is independent of plant sterols. First, we investigated the associations of 6 single nucleotide polymorphisms in ABCG8 and ABO with CR in the LURIC (LUdwisghafen RIsk and Cardiovascular health study) and the YFS (Young Finns Study) cohorts. Second, we conducted a systematic review and meta-analysis to investigate whether CR might be related to CVD. RESULTS In LURIC, the minor alleles of rs4245791 and rs4299376 and the major alleles of rs41360247, rs6576629, and rs4953023 of the ABCG8 gene and the minor allele of rs657152 of the ABO gene were significantly associated with higher CR. Consistent results were obtained for rs4245791, rs4299376, rs6576629, and rs4953023 in YFS. The meta-analysis, including 6 studies and 4,362 individuals, found that CR was significantly increased in individuals with CVD. CONCLUSIONS High cholesterol absorption is associated with risk alleles in ABCG8 and ABO and with CVD. Harm caused by elevated cholesterol absorption rather than by plant sterols may therefore mediate the relationships of ABCG8 and ABO variants with CVD.

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.

Copper, ceruloplasmin, and long-term cardiovascular and total mortality (the Ludwigshafen Risk and Cardiovascular Health Study)

BACKGROUND Copper and its main transport protein ceruloplasmin have been suggested to promote the development of atherosclerosis. Most of the data come from experimental and animal model studies. Copper and mortality have not been simultaneously evaluated in patients undergoing coronary angiography. METHODS AND RESULTS We examined whether serum copper and ceruloplasmin concentrations are associated with angiographic coronary artery disease (CAD) and mortality from all causes and cardiovascular causes in 3253 participants of the Ludwigshafen Risk and Cardiovascular Health Study. Age and sex-adjusted hazard ratios (HR) for death from any cause were 2.23 (95% CI, 1.85-2.68) for copper and 2.63 (95% CI, 2.17-3.20) for ceruloplasmin when we compared the highest with the lowest quartiles. Corresponding hazard ratios (HR) for death from cardiovascular causes were 2.58 (95% CI, 2.05-3.25) and 3.02 (95% CI, 2.36-3.86), respectively. Further adjustments for various risk factors and clinical variables considerably attenuated these associations, which, however, were still statistically significant and the results remained consistent across subgroups. CONCLUSIONS The elevated concentrations of both copper and ceruloplasmin are independently associated with increased risk of mortality from all causes and from cardiovascular causes.

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 size.

Dusty punch cards and an eternal enigma: high-density lipoproteins and atherosclerosis

Epidemiological, clinical, and experimental evidence has accumulated during the last decades suggesting that high-density lipoproteins (HDLs) may protect from atherosclerosis and its clinical consequences. However, more than 55 years after the first description of the link between HDL and heart attacks, many facets of the biochemistry, function, and clinical significance of HDL remain enigmatic. This applies particularly to the completely unexpected results that became available from some recent clinical trials of nicotinic acid and of inhibitors of cholesteryl ester transfer protein (CETP). The concept that raising HDL cholesterol by pharmacological means would decrease the risk of vascular disease has therefore been challenged.

C-reactive protein predicts mortality in patients referred for coronary angiography and symptoms of heart failure with preserved ejection fraction

AIMS Heart failure with preserved ejection fraction (HFpEF) has a different pathophysiological background compared to heart failure with reduced ejection fraction (HFrEF). Tailored risk prediction in this separate heart failure group with a high mortality rate is of major importance. Inflammation may play an important role in the pathogenesis of HFpEF because of its significant contribution to myocardial fibrosis. We therefore aimed to assess the predictive value of C-reactive protein (CRP) in patients with HFpEF. METHODS AND RESULTS Plasma levels of CRP were determined in 459 patients with HFpEF in the LUdwigshafen Risk and Cardiovascular Health (LURIC) study using a high-sensitivity assay. During a median follow-up of 9.7 years 40% of these patients died. CRP predicted all-cause mortality with an adjusted hazard ratio (HR) of 1.20 [95% confidence interval (CI) 1.02-1.40, P = 0.018] and cardiovascular mortality with a HR of 1.32 (95% CI 1.08-1.62, P = 0.005) per increase of one standard deviation. CRP was a significantly stronger mortality predictor in HFpEF patients than in a control group of 522 HFrEF patients (for interaction, P = 0.015). Furthermore, CRP added prognostic value to N-terminal pro B-type natriuretic peptide (Nt-proBNP): the lowest 5-year mortality rate of 6.8% was observed for patients in the lowest tertile of Nt-proBNP as well as CRP. The mortality risk peaked in the group combining the highest values of Nt-proBNP and CRP with a 5-year rate of 36.5%. CONCLUSION It was found that CRP was an independent and strong predictor of mortality in HFpEF. This observation may reflect immunological processes with an adverse impact on the course of HFpEF.

Case innovation and agentive marking: A comparative overview of Central Indo-Aryan

A split-ergative construction had developed during the late MIA period (Bubenik 1998; Peterson 1998) in which subjects of perfective transitive clauses were marked ergative by an oblique form, in contrast with the nominative form for non-ergative subjects. Later in the NIA period, most NIA languages (e.g. Urdu/Hindi) developed a postpositional clitic that was added to the oblique suffix, while others (e.g. Sindhi) continued to mark ergative subjects with a generic oblique suffix. This paper focuses on one exceptional case: the Dehwali language of Gujarat. Dehwali has an ergative marker that is a fusional suffix (i.e. layer I - Masica 1991: 231) and appears to inflect to agree in number and gender with the subject it marks. I will present two possible scenarios as to the origin of the Dehwali ergative marker: that it may be the remnant of an archaic MIA oblique form, or that it may be a more recent innovation as the result of increased contact with neighbouring varieties. Based on theories of grammaticisation, I argue that the former hypothesis is more likely. These theories show that it is not uncommon for oblique case forms (i.e. ablative; genitive) to carry agentive properties.

Von Willebrand Factor Improves Risk Prediction in Addition to N-Terminal Pro-B-type Natriuretic Peptide in Patients Referred to Coronary Angiography and Signs and Symptoms of Heart Failure and Preserved Ejection Fraction.

BACKGROUND Heart failure with preserved ejection fraction (HFpEF) represents a growing health burden associated with substantial mortality and morbidity. Consequently, risk prediction is of highest importance. Endothelial dysfunction has been recently shown to play an important role in the complex pathophysiology of HFpEF. We therefore aimed to assess von Willebrand factor (vWF), a marker of endothelial damage, as potential biomarker for risk assessment in patients with HFpEF. METHODS AND RESULTS Concentrations of vWF were assessed in 457 patients with HFpEF enrolled as part of the LUdwigshafen Risk and Cardiovascular Health (LURIC) study. All-cause mortality was observed in 40% of patients during a median follow-up time of 9.7 years. vWF significantly predicted mortality with a hazard ratio (HR) per increase of 1 SD of 1.45 (95% confidence interval, 1.26-1.68; P<0.001) and remained a significant predictor after adjustment for age, sex, body mass index, N-terminal pro-B-type natriuretic peptide (NT-proBNP), renal function, and frequent HFpEF-related comorbidities (adjusted HR per 1 SD, 1.22; 95% confidence interval, 1.05-1.42; P=0.001). Most notably, vWF showed additional prognostic value beyond that achievable with NT-proBNP indicated by improvements in C-Statistic (vWF×NT-proBNP: 0.65 versus NT-proBNP: 0.63; P for comparison, 0.004) and category-free net reclassification index (37.6%; P<0.001). CONCLUSIONS vWF is an independent predictor of long-term outcome in patients with HFpEF, which is in line with endothelial dysfunction as potential mediator in the pathophysiology of HFpEF. In particular, combined assessment of vWF and NT-proBNP improved risk prediction in this vulnerable group of patients.

Hemoglobin, iron metabolism and angiographic coronary artery disease (The Ludwigshafen Risk and Cardiovascular Health Study).

BACKGROUND Anemia has been shown to be a risk factor for coronary artery disease and mortality. The involvement of body iron stores in the development of CAD remains controversial. So far, studies that examined hemoglobin and parameters of iron metabolism simultaneously do not exist. METHODS AND RESULTS Hemoglobin and iron status were determined in 1480 patients with stable angiographic coronary artery disease (CAD) and in 682 individuals in whom CAD had been ruled out by angiography. The multivariate adjusted odds ratios (OR) for CAD in the lowest quartiles of hemoglobin and iron were 1.62 (95%CI: 1.22-2.16), and 2.05 (95%CI: 1.51-2.78), respectively compared to their highest gender-specific quartiles. The fully adjusted ORs for CAD in the lowest quartiles of transferrin saturation, ferritin (F) and soluble transferrin receptor (sTfR)/log10F index were 1.69 (95%CI: 1.25-2.27), 1.98 (95%CI: 1.48-2.65), and 1.64 (95%CI: 1.23-2.18), respectively compared to their highest gender-specific quartiles. When adjusting in addition for iron and ferritin the OR for CAD in the lowest quartiles of hemoglobin was still 1.40 (95%CI: 1.04-1.90) compared to the highest gender-specific quartiles. Thus, the associations between either iron status or low hemoglobin and CAD appeared independent from each other. The sTfR was only marginally associated with angiographic CAD. CONCLUSIONS Both low hemoglobin and iron depletion are independently associated with angiographic CAD.

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.

Intestinal cholesterol absorption, treatment with atorvastatin, and cardiovascular risk in hemodialysis patients.

BACKGROUND Hemodialysis patients are high absorbers of intestinal cholesterol; they benefit less than other patient groups from statin therapy, which inhibits cholesterol synthesis. OBJECTIVES This study sought to investigate whether the individual cholesterol absorption rate affects atorvastatin's effectiveness to reduce cardiovascular risk in hemodialysis patients. METHODS This post-hoc analysis included 1,030 participants in the German Diabetes and Dialysis Study (4D) who were randomized to either 20 mg of atorvastatin (n = 519) or placebo (n = 511). The primary endpoint was a composite of major cardiovascular events. Secondary endpoints included all-cause mortality and all cardiac events. Tertiles of the cholestanol-to-cholesterol ratio, which is an established biomarker of cholesterol absorption, were used to identify high and low cholesterol absorbers. RESULTS A total of 454 primary endpoints occurred. On multivariate time-to-event analyses, the interaction term between tertiles and treatment with atorvastatin was significantly associated with the risk of reaching the primary endpoint. Stratified analysis by cholestanol-to-cholesterol ratio tertiles confirmed this effect modification: atorvastatin reduced the risk of reaching the primary endpoint in the first tertile (hazard ratio [HR]: 0.72; p = 0.049), but not the second (HR: 0.79; p = 0.225) or third tertiles (HR: 1.21; p = 0.287). Atorvastatin consistently significantly reduced all-cause mortality and the risk of all cardiac events in only the first tertile. CONCLUSIONS Intestinal cholesterol absorption, as reflected by cholestanol-to-cholesterol ratios, predicts the effectiveness of atorvastatin to reduce cardiovascular risk in hemodialysis patients. Those with low cholesterol absorption appear to benefit from treatment with atorvastatin, whereas those with high absorption do not benefit.