Prognostic Value of Elevated Serum Ceruloplasmin Levels in Patients With Heart Failure

Background: Ceruloplasmin (Cp) is a copper-binding acute-phase protein that is increased in inflammatory states and deficient in Wilson\u27s disease. Recent studies demonstrate that increased levels of Cp are associated with increased risk of developing heart failure. Our objective was to test the hypothesis that serum Cp provides incremental and independent prediction of survival in stable patients with heart failure. Methods and Results: We measured serum Cp levels in 890 patients with stable heart failure undergoing elective cardiac evaluation that included coronary angiography. We examined the role of Cp levels in predicting survival over 5 years of follow-up. Mean Cp level was 26.6 ± 6.9 mg/dL and demonstrated relatively weak correlation with B-type natriuretic peptide (BNP; r = 0.187; P \u3c .001). Increased Cp levels were associated with increased 5-year all-cause mortality (quartile [Q] 4 vs Q1 hazard ratio [HR] 1.9, 95% confidence interval [CI] 1.4–2.8; P \u3c .001). When controlled for coronary disease traditional risk factors, creatinine clearance, dialysis, body mass index, medications, history of myocardial infarction, BNP, left ventricular ejection fraction (LVEF), heart rate, QRS duration, left bundle branch blockage, and implantable cardioverter-defibrillator placement, higher Cp remained an independent predictor of increased mortality (Q4 vs Q1 HR 1.7, 95% CI 1.1–2.6; P \u3c .05). Model quality was improved with addition of Cp to the aforementioned covariables (net reclassification improvement of 9.3%; P \u3c .001). Conclusions: Ceruloplasmin is an independent predictor of all-cause mortality in patients with heart failure. Measurement of Cp may help to identify patients at heightened mortality risk

Prognostic Value of Estimating Functional Capacity with The Use of The Duke Activity Status Index in Stable Patients with Chronic Heart Failure

BACKGROUND: Over the years, several methods have been developed to reliably quantify functional capacity in patients with heart failure. Few studies have investigated the prognostic value of these assessment tools beyond cardiorenal prognostic biomarkers in stable patients with chronic heart failure. METHODS AND RESULTS: We administered the Duke Activity Status Index (DASI) questionnaire, a self-assessment tool comprising 12 questions for estimating functional capacity, to 1,700 stable nonacute coronary syndrome patients with history of heart failure who underwent elective diagnostic coronary angiography with 5-year follow-up of all-cause mortality. In a subset of patients (n = 800), B-type natriuretic peptide (BNP) was measured. In our study cohort, the median DASI score was 26.2 (interquartile range [IQR] 15.5-42.7). Low DASI score provided independent prediction of a 3.3-fold increase in 5-year mortality risk (quartile 1 vs quartile 4: hazard ratio [HR] 3.33, 95% confidence interval [CI] 2.57-4.36; P \u3c .0001). After adjusting for traditional risk factors, BNP, and estimated glomerular filtration rate, low DASI score still conferred a 2.6-fold increase in mortality risk (HR 2.57, 95% CI 1.64-4.15; P \u3c .0001). CONCLUSIONS: A simple self-assessment tool of functional capacity provides independent and incremental prognostic value for mortality prediction in stable patients with chronic heart failure beyond cardiorenal biomarkers

Trimethylamine N-Oxide and Mortality Risk in Patients With Peripheral Artery Disease

Background: Production of the proatherogenic metabolite, trimethylamine N-oxide (TMAO), from dietary nutrients by intestinal microbiota enhances atherosclerosis development in animal models and is associated with atherosclerotic coronary artery disease in humans. The utility of studying plasma levels of TMAO to risk stratify in patients with peripheral artery disease (PAD) has not been reported. Methods and Results: We examined the relationship between fasting plasma TMAO and all-cause mortality (5-year), stratified by subtypes of PAD and presence of coronary artery disease in 935 patients with PAD who underwent elective angiography for cardiac evaluation at a tertiary care hospital. Median plasma TMAO was 4.8 μmol/L (interquartile range, 2.9–8.0 μmol/L). Elevated TMAO levels were associated with 2.7-fold increased mortality risk (fourth versus first quartiles, hazard ratio 2.86, 95% CI 1.82–3.97, P\u3c0.001). Following adjustments for traditional risk factors, inflammatory biomarkers, and history of coronary artery disease, the highest TMAO quartile remained predictive of 5-year mortality (adjusted hazard ratio 2.06, 95% CI 1.36–3.11, P\u3c0.001). Similar prognostic value for elevated TMAO was seen for subjects with carotid artery, non–carotid artery, or lower extremity PAD. TMAO provided incremental prognostic value for all-cause mortality (net reclassification index, 40.22%; P\u3c0.001) and improvement in area under receiver operator characteristic curve (65.7% versus 69.4%; P=0.013). Conclusions: TMAO, a pro-atherogenic metabolite formed by gut microbes, predicts long-term adverse event risk and incremental prognostic value in patients with PAD. These findings point to the potential for TMAO to help improve selection of high-risk PAD patients with or without significant coronary artery disease, who likely need more aggressive and specific dietary and pharmacologic therapy

Schur Polynomials and the Yang-Baxter equation

We show that within the six-vertex model there is a parametrized Yang-Baxter equation with nonabelian parameter group GL(2)xGL(1) at the center of the disordered regime. As an application we rederive deformations of the Weyl character formule of Tokuyama and of Hamel and King.Comment: Revised introduction; slightly changed reference

Diminished Antioxidant Activity of High-Density Lipoprotein–Associated Proteins in Chronic Kidney Disease

Background:Decreased serum arylesterase activity, catalyzed by the high-density lipoprotein–associated paraoxonase (PON)-1, is associated with increased oxidant stress and atherosclerosis risk. We sought to determine the prognostic value of serum PON-1 activity, as monitored by PON or arylesterase activities, in subjects with chronic kidney disease (CKD), particularly in relation to established cardiac biomarkers.Methods and Results: Serum arylesterase and PON activities were measured in sequential subjects with CKD (n=630; estimated glomerular filtration rate [eGFR] \u3c60 mL/min per 1.73 m2) and an age- and sex-matched control group of non-CKD subjects (n=315) presenting for cardiac evaluations and prospectively followed for incident (3-year) major adverse cardiac events (composite of death, nonfatal myocardial infarction, and stroke). Serum arylesterase activity in CKD subjects was lower compared with that in non-CKD control subjects [median (interquartile range) 94 (77 to 112) versus 103 (85 to 121) μmol(L·min) per mL, P\u3c0.001]; similarly, PON activity in CKD subjects was lower compared with that in non-CKD control subjects [median (interquartile range) 474 (275 to 936) versus 586 (301 to 1118) nmol(L·min) per mL, P\u3c0.001]. Lower serum arylesterase (hazard ratio 1.8, 95% CI 1.26 to 2.57, P\u3c0.01) was a predictor of poorer outcomes. After adjusting for traditional risk factors and medication use, lower serum arylesterase (hazard ratio 1.55, 95% CI 1.08 to 2.23, P\u3c0.05) still conferred an increased risk of major adverse cardiac events at 3 years. Conclusions: In patients with CKD, decreased serum arylesterase activity, a measure of diminished antioxidant properties of PON-1, predicts higher risk of incident long-term adverse cardiovascular events (heart attack, stroke, or death) in multivariable models adjusting for established clinical and biochemical risk factors

Nitrated Fibrinogen is A Biomarker of Oxidative Stress in Venous Thromboembolism

The pathogenesis of venous thromboembolism (VTE) is linked to inflammation and oxidant production, although specific markers for these pathways with pathological relevance to VTE have not been explored. The coagulant protein fibrinogen is posttranslationally modified by nitric oxide-derived oxidants to nitrated fibrinogen in both acute and chronic inflammatory states. Therefore, nitrated fibrinogen may serve as a marker of inflammation and oxidative stress in VTE. To test this hypothesis we enrolled subjects (n=251) presenting with suspected VTE at the University of Pennsylvania Hospital emergency department, 50 (19.9%) of whom were positive by imaging or 90-day follow-up. Mean nitrated fibrinogen was elevated in VTE-positive (62.7 nM, 95% CI 56.6–68.8) compared to VTE-negative patients (54.2 nM, 95% CI 51.4–57.1; P\u3c0.01). Patients in the highest quartile of nitrated fibrinogen had an increased risk of VTE compared with patients in the lowest quartile (OR 3.30; 95% CI 1.25–8.68; P\u3c0.05). This risk persisted after univariate adjustment for age, active cancer, and recent surgery, but not after multivariate adjustment. Mean fibrinogen levels measured either by the Clauss assay or by ELISA were not different between VTE-negative and VTE-positive patients. These data indicate that nitrated fibrinogen is an oxidative risk marker in VTE, providing a novel mechanistic link between oxidant production, inflammation, and VTE

Plasma Ceruloplasmin, A Regulator of Nitric Oxide Activity, and Incident Cardiovascular Risk in Patients With CKD

Background and objectives: Increased serum levels of the acute-phase reactant ceruloplasmin predict adverse clinical outcomes in the setting of acute coronary syndromes and heart failure, but their role in patients with CKD is unclear. This study investigated the relationship of ceruloplasmin with clinical outcomes in CKD, especially with regard to traditional cardiac biomarkers. Design, setting, participants, & measurements: Serum ceruloplasmin levels in consecutive study participants with CKD (n=654; estimated GFR\u3c60 ml/min per 1.73 m2) as well as a control group of non-CKD participants matched for age and sex (n=250) were measured. Study participants were enrolled during 2001–2006 from a population of patients presenting for elective diagnostic coronary angiography and prospectively followed for 3 years (median follow-up=1095 days) to determine incident major adverse cardiac events (defined as a composite of death, nonfatal myocardial infarction, and stroke). Results: Serum ceruloplasmin levels in CKD patients were elevated versus controls (median [interquartile range]; 25.5 [21.8–29.6] versus 22.7 [19.7–26.5] mg/dl; P\u3c0.001) and associated with increased risk of future major adverse cardiac events (hazard ratio, 1.35; 95% confidence interval, 1.0 to 1.82; P=0.04). After adjusting for traditional risk factors, higher serum ceruloplasmin was still associated with higher risk of major adverse cardiac events at 3 years (hazard ratio, 1.61; 95% confidence interval, 1.15 to 2.25; P=0.01). Conclusion: In CKD patients, increased serum ceruloplasmin, a regulator of nitric oxide activity, is associated with increased risk of long-term adverse cardiovascular events, even after multivariable model adjustment for traditional clinical and biologic risk factors

Prognostic Value of Estimated Functional Capacity Incremental to Cardiac Biomarkers in Stable Cardiac Patients

Background: Few studies have investigated functional capacity self-assessment tools in either prediction of future major adverse cardiac outcomes beyond all-cause mortality or direct comparisons with clinically available biomarkers. Methods and Results: We estimated functional capacity using the Duke Activity Status Index (DASI) questionnaire in 8987 sequential stable patients without acute coronary syndrome who were undergoing elective diagnostic coronary angiography with 3-year follow-up of major adverse cardiac events (death, nonfatal myocardial infarction, or stroke). A low DASI score provided independent prediction of a 4.8-fold increase in future risk of incident major adverse cardiac events at 3 years (quartiles 1 versus 4 hazard ratio [95% CI] 4.76 [4.03 to 5.61], P\u3c0.001), and a 3.8-fold increased risk after adjusting for traditional risk factors (3.77 [3.15 to 4.51], P\u3c0.001). The prognostic value of the DASI score was evident in both primary and secondary prevention cohorts, with and without heart failure, as well as high and low C-reactive protein and B-type natriuretic peptide levels. The DASI score reclassified 15% of patients (P\u3c0.001) beyond traditional risk factors in predicting future MACE. Conclusion: A simple self-assessment tool of functional capacity in stable patients undergoing elective diagnostic cardiac evaluation provides independent and incremental prognostic value for prediction of both significant coronary angiographic disease and long-term adverse clinical events

Prognostic Value of Elevated Levels of Intestinal Microbe-Generated Metabolite Trimethylamine-N-Oxide in Patients With Heart Failure: Refining the Gut Hypothesis

Background: Altered intestinal function is prevalent in patients with heart failure (HF), but its role in adverse outcomes is unclear. Objectives: This study investigated the potential pathophysiological contributions of intestinal microbiota in HF. Methods: We examined the relationship between fasting plasma trimethylamine-N-oxide (TMAO) and all-cause mortality over a 5-year follow-up in 720 patients with stable HF. Results:The median TMAO level was 5.0 μM, which was higher than in subjects without HF (3.5 μM; p \u3c 0.001). There was modest but significant correlation between TMAO concentrations and B-type natriuretic peptide (BNP) levels (r = 0.23; p \u3c 0.001). Higher plasma TMAO levels were associated with a 3.4-fold increased mortality risk. Following adjustments for traditional risk factors and BNP levels, elevated TMAO levels remained predictive of 5-year mortality risk (hazard ratio [HR]: 2.2; 95% CI: 1.42 to 3.43; p \u3c 0.001), as well as following the addition of estimated glomerular filtration rate to the model (HR: 1.75; 95% CI: 1.07 to 2.86; p \u3c 0.001). Conclusions: High TMAO levels were observed in patients with HF, and elevated TMAO levels portended higher long-term mortality risk independent of traditional risk factors and cardiorenal indexes

Prognostic Value of Estimated Functional Capacity Incremental to Cardiac Biomarkers in Stable Cardiac Patients

Background: Few studies have investigated functional capacity self-assessment tools in either prediction of future major adverse cardiac outcomes beyond all-cause mortality or direct comparisons with clinically available biomarkers. Methods and Results: We estimated functional capacity using the Duke Activity Status Index (DASI) questionnaire in 8987 sequential stable patients without acute coronary syndrome who were undergoing elective diagnostic coronary angiography with 3-year follow-up of major adverse cardiac events (death, nonfatal myocardial infarction, or stroke). A low DASI score provided independent prediction of a 4.8-fold increase in future risk of incident major adverse cardiac events at 3 years (quartiles 1 versus 4 hazard ratio [95% CI] 4.76 [4.03 to 5.61], P\u3c0.001), and a 3.8-fold increased risk after adjusting for traditional risk factors (3.77 [3.15 to 4.51], P\u3c0.001). The prognostic value of the DASI score was evident in both primary and secondary prevention cohorts, with and without heart failure, as well as high and low C-reactive protein and B-type natriuretic peptide levels. The DASI score reclassified 15% of patients (P\u3c0.001) beyond traditional risk factors in predicting future MACE. Conclusion: A simple self-assessment tool of functional capacity in stable patients undergoing elective diagnostic cardiac evaluation provides independent and incremental prognostic value for prediction of both significant coronary angiographic disease and long-term adverse clinical events