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.

Area-based socioeconomic status and mortality: the Ludwigshafen Risk and Cardiovascular Health study.

BACKGROUND: Low individual socioeconomic status (SES) is a known risk factor for morbidity and mortality. A related measure is the area-based SES (abSES), which describes the average SES of a region. The association of measures of abSES with morbidity and mortality is less well studied. METHODS: The Ludwigshafen Risk and Cardiovascular Health study consists of 3316 patients hospitalized for coronary angiography between 1997 and 2000 at a tertiary care centre in Germany. Patients were followed up for a median of 10 years. Two measures of abSES were used: the regional purchasing index (PPI, data obtained from IQVIA GmbH) and the German Index of Socioeconomic Deprivation (GISD, developed by the Robert-Koch Institute). The association of abSES with disease and with mortality was analysed using logistic regression and Cox proportional hazards regression, respectively. RESULTS: Study participants living in regions with higher abSES had lower HbA1c and high-sensitive C-reactive protein. A higher abSES was associated with lower prevalence of active smoking, vitamin D deficiency and diabetes mellitus. We further found significantly increased mortality for participants in the lowest PPI quartile (age- and sex-adjusted hazard ratio (95% CI) of 0.58 (0.38-0.90) as compared to the first quartile), and in the highest GISD tertile (HR of 1.32 (1.13-1.54) as compared to the first tertile). CONCLUSION: Living in an area with a low abSES was associated with a higher burden of diabetes mellitus, a higher percentage of severe vitamin D deficiency, higher systemic inflammation and a significant increase in mortality.

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.

Recurrent tendosynovitis as a rare manifestation of a lipid disorder.

A 33-year-old female had suffered from spontaneously recurrent bursitis and tendosynovitis/enthesitis of the patellar and Achilles tendons for about 10 years. The episodes of immobilization increased. Ultrasound imaging of the swollen and painful tendons showed chronic inflammation with neoangiogenesis within the tendons and hypoechoic lesions. Clinical and laboratory tests did not provide evidence for a rheumatic disease. Low density lipoprotein cholesterol was elevated. Biopsies of skin lesions did not confirm the suspicion of cutaneous xanthomas. Genetic testing for familial hypercholesterolemia was negative. Campesterol and sitosterol were elevated 7- to 12-fold and 20- to 38-fold over the upper limit of normal on two occasions. There was no relevant mutation in ABCG5. In ABCG8, we identified a missense mutation c.1267G>A in exon 9 changing glutamic acid 423 into lysine within the transmembrane domain, and an insertion of adenine (c.1487insA) leading to a frameshift and a premature stop codon (Ile497Aspfs*105). The patient had no clinical evidence of premature atherosclerosis. Therapeutic approaches with nonsteroidal antirheumatic drugs, prednisone, statins, and ezetimibe accompanied by a diet poor in plant sterols led to a relief of symptoms. This case report shows that tendon xanthoma along with tendosynovitis, especially on extensor areas, is suspicious for hypercholesterolemia as the underlying cause. The absence of atherosclerotic plaques in the abdominal aorta and in the carotid arteries on ultrasound may suggest that phytosterolemia is not necessarily accompanied by premature vascular disease.

Lipid-modifying therapy and low-density lipoprotein cholesterol goal attainment in patients with familial hypercholesterolemia in Germany: The CaReHigh Registry.

BACKGROUND AND AIMS: Familial hypercholesterolemia (FH) is amongst the most common genetic disorders encountered in primary care. Yet, only a minority of affected patients is diagnosed and treated. This interim analysis of the CaRe High Registry aims at examining the state of treatment and attainment of lipid goals in German FH patients. METHODS: The CaRe High registry includes FH patients from lipid clinics and private practices. Data have been collected using questionnaires filled in by the recruiting physicians and by interviewing the participating patients. RESULTS: We examined 512 F H patients diagnosed according to clinical criteria. Median age at the time of the first FH diagnosis was 39 (25th and 75th percentile: 27-50) years, median treatment naïve LDL cholesterol (LDL-C) was 239.4 mg/dl (6.19 mmol/l), 25th to 75th percentile 191.8-342.5 mg/dl (4.96-8.86 mmol/l). 27% of the participants did not receive lipid-lowering drugs. Among the patients treated with lipid-lowering drugs, 19% received a PCSK9 inhibitor (PCSK9i) in combination with a statin, 9% were treated with a PCSK9i alone and 3% were treated with a combination of PCSK9i and a non-statin drug. Patients with pre-existing CVD were more likely to be treated with lipid-lowering drugs and more likely to receive a PCSK9i, but LDL-C targets were only achieved by a minority of patients (<20%). Gap to target LDL-C was lowest and the median achieved LDL-C reduction was 1.4 times higher with PCSK9i treatment than with (oral) lipid-lowering therapy without PCSK9i. CONCLUSIONS: The Care High registry has included patients with the typical clinical features of familial hypercholesterolemia. PCSK9i treatment in addition to standard therapy allows attainment of target values in many patients with initially very high LDL-C.

Subclases de Lipoproteínas de Alta Densidad, Enfermedad Coronaria y Mortalidad Cardiovascular / High Density Lipoprotein Subclasses, Coronary Artery Disease, and Cardiovascular Mortality

Antecedentes: La relación inversa entre el colesterol HDL y la mortalidad cardiovascular se debilita en presencia de enfermedad coronaria (EC). El objetivo de este trabajo fue investigar las asociaciones de las concentraciones de partículas de HDL con la mortalidad cardiovascular y el impacto de la EC en estas asociaciones. También se buscó evaluar comparativamente las concentraciones de colesterol HDL y partículas de HDL en la predicción de la mortalidad cardiovascular. Métodos: Las concentraciones totales de HDL y sus sub-clases se midieron mediante espectroscopía de resonancia magnética nuclear en 2.290 participantes del estudio LUdwigshafen RIsk and Cardiovascular Health remitidos para angiografía coronaria. Los participantes fueron seguidos prospectivamente durante una mediana (rango intercuartílico) con una duración de 10,0 (6,1-10,6) años. Resultados: La media de la edad (DE) de los participantes (1.575 hombres, 715 mujeres) fue de 62,9 (10,4) años, índice de masa corporal 27,6 (4,1) kg/m², colesterol-HDL 39 (11) mg/dL [1 (0,29) mmol/L], y la concentración total de partículas de HDL 24,1 (5,8) μmol/L. Cuatroscientos treinta y cuatro de los participantes murieron de enfermedad cardiovascular. En análisis multivariados, los tercilos de las concentraciones totales de partículas de HDL se relacionaron inversamente con la mortalidad cardiovascular (Hazard Ratio para 3° frente a 1° tercilo = 0,55; p<0,001). Esta asociación fue mediada principalmente por las partículas de HDL pequeñas (p<0,001). La adición a los modelos de predicción multivariada de las concentraciones de partículas HDL totales o pequeñas, en lugar de colesterol HDL, mejoró las métricas de rendimiento para predicción de mortalidad cardiovascular. La presencia de EC no tuvo impacto en las asociaciones entre las concentraciones de partículas de HDL y la mortalidad cardiovascular. Conclusiones: La alta concentración de partículas de HDL se encuentra asociada con una disminución de la mortalidad cardiovascular de manera consistente e independiente de la EC. Sin embargo, si esta relación inversa entre la concentración de partículas de HDL y la mortalidad cardiovascular se puede traducir en nuevas estrategias terapéuticas está aún bajo investigación.

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 2,290 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 (1,575 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. 434 persons died from cardiovascular diseases. In multivariate analyses, tertiles of total HDL particle concentrations were inversely related to cardiovascular mortality (HR for 3rd vs. 1st 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.

Familial hypercholesterolemia in primary care in Germany. Diabetes and cardiovascular risk evaluation: Targets and Essential Data for Commitment of Treatment (DETECT) study.

BACKGROUND AND AIMS: Familial hypercholesterolemia (FH) is an inherited disorder of lipoprotein metabolism characterised by impaired removal of low-density lipoproteins (LDL) from the circulation, which leads to an increased risk of cardiovascular disease (CVD). This risk can be significantly lowered by early diagnosis and treatment. In Germany, reliable estimates of the prevalence of FH are lacking. We therefore examined the prevalence rate of FH in Germany in a primary care based cohort. METHOD: We utilized records of 4722 participants in the DETECT study, in whom complete data on blood lipids and medical history were available. Prevalence rates were assessed using the Dutch Lipid Clinics Network (DLCN) and the US-MEDPED criteria. We stratified for gender and age. Group differences were analyzed using Chi2 and ANOVA tests. RESULTS: Using the DLCN (probable or definite FH) and the US.MEDPED criteria yielded prevalence rates of 1:278 and 1:295, respectively. The established diagnostic scores used in this analysis identify different patients. In women below 50 years of age, the LDL-C concentration is lower than in men, leading to the possibility of under-diagnosing FH in this group because women under the age of 50 are less likely to reach a higher DLCN-Score. CONCLUSIONS: FH has a higher than expected prevalence in Germany. Clinical diagnostic algorithms may not be concordant.

Biomarker-Based Risk Model to Predict Cardiovascular Mortality in Patients With Stable Coronary Disease.

BACKGROUND: Currently, there is no generally accepted model to predict outcomes in stable coronary heart disease (CHD). OBJECTIVES: This study evaluated and compared the prognostic value of biomarkers and clinical variables to develop a biomarker-based prediction model in patients with stable CHD. METHODS: In a prospective, randomized trial cohort of 13,164 patients with stable CHD, we analyzed several candidate biomarkers and clinical variables and used multivariable Cox regression to develop a clinical prediction model based on the most important markers. The primary outcome was cardiovascular (CV) death, but model performance was also explored for other key outcomes. It was internally bootstrap validated, and externally validated in 1,547 patients in another study. RESULTS: During a median follow-up of 3.7 years, there were 591 cases of CV death. The 3 most important biomarkers were N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin T (hs-cTnT), and low-density lipoprotein cholesterol, where NT-proBNP and hs-cTnT had greater prognostic value than any other biomarker or clinical variable. The final prediction model included age (A), biomarkers (B) (NT-proBNP, hs-cTnT, and low-density lipoprotein cholesterol), and clinical variables (C) (smoking, diabetes mellitus, and peripheral arterial disease). This "ABC-CHD" model had high discriminatory ability for CV death (c-index 0.81 in derivation cohort, 0.78 in validation cohort), with adequate calibration in both cohorts. CONCLUSIONS: This model provided a robust tool for the prediction of CV death in patients with stable CHD. As it is based on a small number of readily available biomarkers and clinical factors, it can be widely employed to complement clinical assessment and guide management based on CV risk. (The Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy Trial [STABILITY]; NCT00799903).

Neutrophil gelatinase-associated lipocalin levels are U-shaped in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study-Impact for mortality.

INTRODUCTION: Neutrophil gelatinase-associated lipocalin (NGAL) is a glycoprotein released by damaged renal tubular cells and mature neutrophils. It is elevated in kidney injury, but also in patients with coronary artery disease (CAD) and myocardial infarction. We investigated the prognostic value of NGAL for total and cardiovascular mortality in patients undergoing coronary angiography without history of renal insufficiency at inclusion into the study. PARTICIPANTS: The LURIC study is an ongoing prospective cohort study of patients referred for coronary angiography and is designed to evaluate determinants of cardiovascular health. RESULTS: NGAL was determined in plasma of 2997 persons (mean age: 62.7 years; 69.7% men) with a follow up for 10 years. 2358 patients suffered from CAD and 638 did not-these patients served as controls. Stable CAD was found in 1408 and unstable CAD in 950 patients. Death rate from cardiovascular events and all causes was highest in patients within the 4th quartile of NGAL (≥56 ng/ml, p<0.001 vs third quartile), even after adjustment for age and gender. According to multivariable-adjusted Cox analysis adjusting for well-known cardiovascular risk factors, as well as lipid lowering therapy, angiographic CAD, and C-reactive protein we found patients in the highest NGAL quartile being at increased risk for cardiovascular (hazard ratio (HR) 1.33, 95%CI 1.05-1.67, p = 0.016) and all cause mortality (HR 1.29 95%CI 1.07-1.55, p = 0.007) compared to those in the third quartile. The lowest risk was seen in the third quartile of NGAL (41-56 ng/ml) suggesting a U-shaped relationship between NGAL and mortality. Further adjustment for creatinine abrogated the predictive effect of NGAL. However, the 3rd and 4th quartiles of NGAL were significantly associated with higher neutrophil counts, which were associated with CAD, non-ST elevation and ST-elevation myocardial infarction (p<0.05). CONCLUSIONS: Plasma NGAL concentrations are mainly derived from neutrophils and do not predict mortality independent of renal function.

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.

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.

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.

Glycated hemoglobin predicts all-cause, cardiovascular, and cancer mortality in people without a history of diabetes undergoing coronary angiography.

OBJECTIVE: Glycated hemoglobin has been suggested to be superior to fasting glucose for the prediction of vascular disease and death from any cause. The aim of the present work was to analyze and compare the predictive value of glycated hemoglobin and fasting glucose on all-cause and cause-specific mortality in subjects who underwent coronary angiography. RESEARCH DESIGN AND METHODS: We studied 2,686 participants of the Ludwigshafen Risk and Cardiovascular health study without a history of diabetes. The majority of this cohort had coronary artery disease. Glycated hemoglobin was measured at the baseline examination. The mean (± SD) duration of the follow-up for all-cause, cardiovascular, and cancer mortality was 7.54 ± 2.1 years. RESULTS: A total of 508 deaths occurred during the follow-up. Of those, 299 were accounted for by cardiovascular diseases and 79 by cancer. Baseline glycated hemoglobin was predictive of all-cause, cardiovascular, and cancer mortality. The multivariable-adjusted hazard ratios (HR) (95% CI) for glycated hemoglobin values of <5.0, 5.0-5.4, 5.5-5.9, 6.0-6.4, 6.5-7.4, and ≥7.5% for all-cause mortality were 1.36 (0.85-2.18), 1.00 (0.76-1.32), 1.00 (reference), 1.11 (0.88-1.41), 1.39 (1.07-1.82), and 2.15 (1.32-3.53), respectively. Similar J-shaped relationships were found between glycated hemoglobin and cardiovascular and cancer mortality. The associations of glycated hemoglobin with all-cause and cardiovascular mortality remained significant after inclusion of fasting glucose as a covariate. However, fasting glucose was not significantly related to mortality when adjusting for glycated hemoglobin. CONCLUSIONS: Glycated hemoglobin significantly and independently of fasting glucose predicts all-cause and cardiovascular mortality in whites at intermediate to high cardiovascular risk.

Neopterin as a predictor of total and cardiovascular mortality in individuals undergoing angiography in the Ludwigshafen Risk and Cardiovascular Health study.

BACKGROUND: Neopterin is produced upon activation of the cell-mediated immune response, and may be a novel risk marker for adverse outcomes resulting from coronary artery disease. METHODS: We measured neopterin in 1801 study participants with and 511 without angiographic coronary artery disease. Rates of death were determined after a median follow-up of 8.0 years. RESULTS: Estimated glomerular filtration rate and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were the strongest predictors of neopterin. Neopterin was positively related to age and inversely related to LDL cholesterol, HDL cholesterol, and triglycerides. Use of lipid-lowering drugs lowered neopterin. Sex, body mass index, diabetes mellitus, hypertension, smoking status, Friesinger coronary score, and clinical instability at presentation were not associated with neopterin. Unlike C-reactive protein, neopterin was not increased in unstable angina pectoris, non-ST-elevation myocardial infarction, or ST-elevation myocardial infarction. In the third and fourth quartiles of neopterin, unadjusted hazard ratios for death from any cause were 1.94 (95% CI 1.44-2.61) and 3.32 (95% CI 2.53-4.30) compared to individuals in the first quartile, whereas hazard ratios for death from cardiovascular causes were 2.14 (95% CI 1.44-3.18) and 3.84 (95% CI 2.67-5.52), respectively. Neopterin remained predictive of total and cardiovascular mortality after adjusting for sex, age, body mass index, type 2 diabetes, hypertension, smoking status, LDL cholesterol, HDL cholesterol, triglycerides, estimated glomerular filtration rate, NT-proBNP, and clinical status at presentation, but NT-proBNP substantially weakened this association. CONCLUSIONS: Neopterin is an independent predictor of all-cause and cardiovascular mortality in individuals with or without stable coronary artery disease.