Biomarkers In Chronic Heart Failure Research Articles

Neutrophil Gelatinase-Associated Lipocalin in chronic heart failure

Event Abstract Back to Event Neutrophil Gelatinase-Associated Lipocalin in chronic heart failure Nilgun Isiksacan1*, Murat Koser1, Mehmet Erturk2, Ibrahim Faruk Akturk2, Serkan Yazan2, Mehmet Rifat Yildirim2, Vesile Ornek Diker1 and Ihsan Bakir3 1 Istanbul Mehmet Akif Ersoy Cardiovascular Training and Research Hospital, Central Laboratory, Turkey 2 Istanbul Mehmet Akif Ersoy Cardiovascular Training and Research Hospital, Cardiology, Turkey 3 Istanbul Mehmet Akif Ersoy Cardiovascular Training and Research Hospital, Cardiovascular Surgery, Turkey Introduction Chronic heart failure (CHF) is a progressive and complicated clinical syndrome, it is mostly accompanied by chronic renal disease. Glomerular filtration rate (GFR) is decreased in 30 to 50 % of patients with CHF. NGAL, neutrophil gelatinase-associated lipocalin, which is expressed mainly from neutrophils as a response to bacterial infections in innate immunity, is a new marker for renal function. The aim of this study is to evaluate the renal functions of the patients with CHF and determining the clinic importance of NGAL parameter as a biomarker in CHF. Material and Method Hundred patients (mean age: 67 ± 12 years) from cardiology outpatient clinic diagnosed as CHF enrolled to this study. Creatinine, CRP, BUN and NGAL levels were measured from venous blood samples in 2 hours after collection. According to CRP results, a possible bacterial infection is excluded. All the cases received written inform on the study including Ethics Committee Approval before the study was initiated. Spearman Correlation Analysis is performed. Results Patients with high CRP levels were excluded and NGAL levels did not correlate with normal CRP results(r=0.093, p=0.364). A weak correlation but a statistically significance was observed between NGAL and BUN levels (r=0.293, p=0.03). Also a correlation and a highly statistically significance was found between NGAL and creatinine (r=0.520, p<0.001). Conclusion In this study NGAL performance was found significantly better than BUN. A good correlation between NGAL and creatinine indicates that NGAL may be a candidate biomarker for renal functions in patients with CHF. References 1- Cystatin C and neutrophil gelatinase-associated lipocalin: biomarkers for acute kidney injury after congenital heart surgery. Seitza S, Rauh M, Gloeckler M, Cesnjevard R, Dittricha S, Kocha AME. Swiss Med Wkly. 2013;143:w13744. 2- Neutrophil Gelatinase-Associated Lipocalin (NGAL) predicts renal injury in acute decompensated cardiac failure: a prospective observational study. Macdonald S, Arendts G, Nagree Y, Xu XF. BMC Cardiovascular Disorders 2012, 12:8. Keywords: NGAL, CHF, Neutrophil, Renal functions, Creatinine Conference: 15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013. Presentation Type: Abstract Topic: Translational immunology and immune intervention Citation: Isiksacan N, Koser M, Erturk M, Akturk I, Yazan S, Yildirim M, Ornek Diker V and Bakir I (2013). Neutrophil Gelatinase-Associated Lipocalin in chronic heart failure. Front. Immunol. Conference Abstract: 15th International Congress of Immunology (ICI). doi: 10.3389/conf.fimmu.2013.02.00108 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 11 Mar 2013; Published Online: 22 Aug 2013. * Correspondence: Dr. Nilgun Isiksacan, Istanbul Mehmet Akif Ersoy Cardiovascular Training and Research Hospital, Central Laboratory, Istanbul, Turkey, nisiksacan@gmail.com Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Nilgun Isiksacan Murat Koser Mehmet Erturk Ibrahim Faruk Akturk Serkan Yazan Mehmet Rifat Yildirim Vesile Ornek Diker Ihsan Bakir Google Nilgun Isiksacan Murat Koser Mehmet Erturk Ibrahim Faruk Akturk Serkan Yazan Mehmet Rifat Yildirim Vesile Ornek Diker Ihsan Bakir Google Scholar Nilgun Isiksacan Murat Koser Mehmet Erturk Ibrahim Faruk Akturk Serkan Yazan Mehmet Rifat Yildirim Vesile Ornek Diker Ihsan Bakir PubMed Nilgun Isiksacan Murat Koser Mehmet Erturk Ibrahim Faruk Akturk Serkan Yazan Mehmet Rifat Yildirim Vesile Ornek Diker Ihsan Bakir Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Concomitant renal and hepatic dysfunctions in chronic heart failure: Clinical implications and prognostic significance

BackgroundThe cardio-renal syndrome is common and eGFR is an established biomarker in chronic heart failure (CHF). Recent findings also indicate a predictive role of liver function abnormalities such as GGT in CHF. We aimed to jointly investigate the characteristics and importance of renal and hepatic failure in CHF. MethodsClinical and laboratory parameters of 1290 ambulatory patients (NYHA class I 25%, II 47%, III/IV 27%; median LV-EF 29%) were evaluated. Hemodynamics was available in 253 patients. The endpoint was defined as death from any cause or heart transplantation. ResultseGFR <60mL/min and GGT elevations were highly prevalent (25% and 44%, respectively; 12.8% for both). Renal and hepatic dysfunctions were correlated with disease severity and independently associated with adverse outcome in univariate (p<0.001) and multivariate analyses (p=0.012 and p<0.001, respectively). Signs of congestion and elevated CVP but not CI were independent predictors of changes in eGFR and GGT. In patients with concurrent impairment of both organs estimated five-year event rate was 46% as compared to 25% in patients with eGFR and GGT in the normal ranges (HR 3.12, 95% CI 2.33–4.18; p<0.001). ConclusionsImpairment of renal and hepatic function is related to functional status and a poor prognosis in patients with mild to moderate heart failure. Concurrent involvement of both organs indicates disease progression and further elevates the hazard for adverse outcomes. Moreover, our data suggest that venous congestion rather than forward failure accounts for the development of renal and hepatic dysfunctions in these patients.

Novel biomarkers in chronic heart failure

Understanding of chronic heart failure (HF) has progressed from a syndrome of disordered hemodynamics caused by alterations in the structure of the heart to one that involves intertwined molecular pathways in disarray. Accordingly, the assessment and treatment of patients with chronic HF has shifted from a focus on hemodynamics to modification of maladaptive molecular processes. Accumulating evidence shows that molecular biomarkers of disease could provide a unique window into the pathophysiology of chronic HF, potentially improving our ability to predict adverse outcomes, provide novel drug targets, and even help gauge therapeutic efficacy. The more 'traditional' biomarkers such as cardiac troponin, natriuretic peptides, and C-reactive protein have been studied in large cohorts of patients with chronic HF and have relatively established clinical applications. In this Review, we summarize the properties, clinical data, and potential applications of some emerging biomarkers that could uniquely indicate the level of biomechanical stretch, inflammation, ventricular remodeling, myocardial injury, and renal dysfunction that occurs in chronic HF. We will also discuss the potential role for these biomarkers within a multimarker-based strategy that could, in the future, lead to better care for these patients.

N-terminal pro-brain natriuretic peptide could be a marker of subclinical atherosclerosis in patients with type 2 diabetes

N-terminal pro-brain natriuretic peptide (NT-proBNP), which is a useful biomarker of chronic heart failure, has been shown to be a strong predictor of cardiovascular mortality. The aim of this study was to evaluate the relationships between NT-proBNP and markers of subclinical atherosclerosis in patients with type 2 diabetes. Relationships of NT-proBNP to pulse wave velocity (PWV) or ankle-brachial index (ABI) as well as to various parameters, including body mass index, blood pressure, serum lipid concentration, serum uric acid concentration, and glycemic control (hemoglobin A1c), age, hemoglobin, serum creatinine concentration, severity of diabetic nephropathy or retinopathy, current treatment of diabetes, cardiothoracic ratio on chest radiograph, presence of left ventricular hypertrophy and/or ST-T changes evaluated by electrocardiograph, smoking status and presence of cardiovascular disease were investigated in 323 consecutive patients with type 2 diabetes. Log (NT-proBNP) correlated positively with PWV (r = 0.283, p < 0.0001) and correlated negatively with ABI (r = -0.144, p = 0.0094). Multiple regression analysis demonstrated that age (β = 0.200, p = 0.0033), systolic blood pressure (β = 0.246, p < 0.0001), total cholesterol (β = -0.135, p = 0.0326), uric acid (β = 0.133, p = 0.0462), creatinine (β = -0.184, p = 0.0122), smoking status (β = -0.129, p = 0.0499) and log (NT-proBNP) (β = 0.177, p = 0.0149) were independently correlated with PWV and that systolic blood pressure (β = -0.145, p = 0.0310), log triglyceride (β = -0.151, p = 0.0397) and log (NT-proBNP) (β = -0.207, p = 0.0094) were independently correlated with ABI. In conclusion, NT-proBNP could be a marker of subclinical atherosclerosis in patients with type 2 diabetes.

B-008 N-TERMINAL PRO-BRAIN NATRIURETIC PEPTIDE COULD BE A MARKER OF SUBCLINICAL ATHEROSCLEROSIS IN PATIENTS WITH TYPE 2 DIABETES

Background Cardiovascular disease (CVD) is the primary cause of mortality and morbidity in patients with type 2 diabetes. N-terminal pro-brain natriuretic peptide (NT-proBNP), which is a useful biomarker of chronic heart failure, has been shown to be a strong predictor of cardiovascular mortality. Furthermore, alterations in vascular structure and function are also recognized increasingly as significant independent predictors of adverse cardiovascularoutcomes. In this study, we investigated the relationships between NT-proBNP and markers of subclinical atherosclerosis in patients with type 2 diabetes. Methods Relationships of NT-proBNP to pulse wave velocity (PWV) or ankle-brachial index (ABI) as wellas to major metabolic risk parameters, including body mass index, blood pressure, serum lipid concentration, serum uric acid concentration,and glycemic control (hemoglobinA1c), age, hemoglobin, serum creatinine concentration, severity of diabetic nephropathy orretinopathy, current treatment of diabetes, smoking status, and presence of CVD were investigated in 323 consecutive patients with type 2 diabetes. Results Log (NT-proBNP) correlated positively with PWV (r = 0.283, p < 0.0001) and correlated negatively with ABI (r = −0.144, p = 0.0094). Multiple regression analysis demonstrated that age (β = 0.267, p < 0.0001), systolic blood pressure (β = 0.249, p < 0.0001), uric acid (β = 0.121, p = 0.0383), creatinine (β = −0.139, p = 0.0239) and log (NT-proBNP) (β = 0.173, p = 0.0043) were independent determinants of PWV and that log triglyceride (β = −0.130, p = 0.0390) andlog (NT-proBNP) (β = −0.153 p = 0.0256) were independent determinants of ABI. Conclusions NT-proBNP was associated with PWV and ABI in patients with type 2 diabetes. NT-proBNP could be a marker of subclinical atherosclerosis in patients with type 2 diabetes.

Modified Troponin I as a Candidate Marker for Chronic Heart Failure

1. Zhang J, Guy MJ, Norman HS, Chen YC, Xu Q, Dong X, Guner H, Wang S, Kohmoto T, Young KH, Moss RL, Ge Y. Top-down quantitative proteomics identified phosphorylation of cardiac troponin I as a candidate biomarker for chronic heart failure. J Proteome Res. 2011;10:4043–4065. ### Study Hypothesis Despite the high incidence and mortality associated with chronic heart failure (CHF), few biomarkers for its diagnosis are approved for clinical practice. Therefore, new markers and diagnostic options are the object of intense research. In this study, Zhang et al address this need by testing their hypothesis that the levels of modified cardiac troponin I (cTnI) correlate with the development of HF. Intriguingly, quantification of cTnI is well established in clinical practice for the assessment and diagnosis of myocardial infarction. Consequently, the team precisely quantified 2 well-established posttranslational modifications (PTMs) of cTnI (ie, phosphorylation and truncation) in tissue specimens from healthy and gradations of diseased hearts. The study eloquently demonstrated a correlation between the levels of phosphorylated cTnI and the degree of deterioration in cardiac function. ### How Was the Hypothesis Tested? Modified forms of cTnI were assessed in the study. Notably, PTMs are emerging as new determinants of phenotypic complexity, potentially making them more descriptive of a specific biological condition, including disease, than aggregate protein levels. In fact, the fast-paced development of technological platforms that separate, measure, and characterize several thousands of proteins …

Plasma NT-proBNP level as a biomarker of left ventricular diastolic dysfunction and renal dysfunction in essential hypertensive patients

Objective: Recent studies showed that NT-proBNP was not only a biomarker of chronic heart failure but of renal failure. Little was known if NT-proBNP could detect the left ventricular (LV) diastolic dysfunction or renal dysfunction. The purpose of this study was to evaluate NT-proBNP as a biomarker of LV diastolic dysfunction and renal dysfunction in essential hypertensive patients. Methods: In 204 patients (mean age 55±14, men 59%) with essential hypertension, we measured LV diastolic function by echocardiography to detect the ratio of early diastolic transmitral E wave velocities to tissue Doppler mitral annulus early diastolic Ea wave velocities (E/Ea). We defined left ventricular diastolic dysfunction as LVEF>50% and E/Ea>15. The evaluation of renal function was estimated by GFR with the scintigraphic determination of the technetium-99m. We defined GFR<60 mL/min as renal dysfunction. Results: In univariate analysis, NT-proBNP was correlated with age, 24 h mean heart rate and 24 h mean systolic blood pressure (the correlation coefficients were 0.43, −0.36 and 0.19 respectively, P<0.05), and it was also correlated with E/Ea, LAVI, LVMI, 24 h urinary protein and GFR (the correlation coefficients were 0.544, 0.38, 0.36, 0.79 and -0.446 respectively, P<0.001). NT-proBNP was significantly correlated with age, 24 h mean heart rate, LVMI, GFR and E/Ea in multivariate analysis. NT-proBNP increased in patients with LV diastolic dysfunction, and the similar results were found in LV hypertrophy patients and in patients with left atrial enlargement. NT-proBNP was increased in renal dysfunction patients, and similar results were found in patients with proteinuria. With the NT-proBNP cut-off value of 108 pg/mL, the ROC area (0.936, sensitivity: 95%, specificity: 86%) was highest for detecting LV diastolic dysfunction with concomitant renal dysfunction. Conclusions: NT-proBNP is a promising biomarker for detecting LV diastolic dysfunction and renal dysfunction in essential hypertensive patients.

Plasma calprotectin levels reflect disease severity in patients with chronic heart failure

Low-grade inflammation has been associated with cardiovascular disease (CVD) and chronic heart failure (CHF). The aim of the present study was to investigate the potential usefulness of the inflammatory protein calprotectin as a biomarker in CHF. Plasma calprotectin was measured in 193 CHF patients with left ventricular function <45% and in 100 healthy controls at baseline. Patients with CHF were followed for a median period of 2.6 years according to mortality. The levels of plasma calprotectin were significantly increased in the CHF patients compared to the control group (P < 0.01), primarily due to elevated levels in the patients with New York Heart Association (NYHA) class III and IV. Furthermore, plasma calprotectin was a superior biomarker of high NYHA classes than other parameters reflecting CHF severity, OR 2.2 (1.1-4.3) (P = 0.019). After the follow-up period, 46 patients had died. Plasma calprotectin levels did not predict mortality in CHF patients. Plasma calprotectin is increased in CHF patients, indicating that inflammatory activity is upregulated in CHF and may be associated with the severity of CHF.

Top-Down Quantitative Proteomics Identified Phosphorylation of Cardiac Troponin I as a Candidate Biomarker for Chronic Heart Failure

The rapid increase in the prevalence of chronic heart failure (CHF) worldwide underscores an urgent need to identify biomarkers for the early detection of CHF. Post-translational modifications (PTMs) are associated with many critical signaling events during disease progression and thus offer a plethora of candidate biomarkers. We have employed a top-down quantitative proteomics methodology for comprehensive assessment of PTMs in whole proteins extracted from normal and diseased tissues. We systematically analyzed 36 clinical human heart tissue samples and identified phosphorylation of cardiac troponin I (cTnI) as a candidate biomarker for CHF. The relative percentages of the total phosphorylated cTnI forms over the entire cTnI populations (%P(total)) were 56.4 ± 3.5%, 36.9 ± 1.6%, 6.1 ± 2.4%, and 1.0 ± 0.6% for postmortem hearts with normal cardiac function (n = 7), early stage of mild hypertrophy (n = 5), severe hypertrophy/dilation (n = 4), and end-stage CHF (n = 6), respectively. In fresh transplant samples, the %P(total) of cTnI from nonfailing donor (n = 4), and end-stage failing hearts (n = 10) were 49.5 ± 5.9% and 18.8 ± 2.9%, respectively. Top-down MS with electron capture dissociation unequivocally localized the altered phosphorylation sites to Ser22/23 and determined the order of phosphorylation/dephosphorylation. This study represents the first clinical application of top-down MS-based quantitative proteomics for biomarker discovery from tissues, highlighting the potential of PTMs as disease biomarkers.

The Vascular Marker Soluble Fms-Like Tyrosine Kinase 1 Is Associated With Disease Severity and Adverse Outcomes in Chronic Heart Failure

We sought to evaluate placental growth factor (PlGF) and soluble Fms-like tyrosine kinase 1 (sFlt-1) as clinical biomarkers in chronic heart failure (HF). Vascular remodeling is a crucial compensatory mechanism in chronic HF. The angiogenic ligand PlGF and its target receptor fms-like tyrosine kinase 1 modulate vascular growth and function, but their relevance in human HF is undefined. We measured plasma PlGF and sFlt-1 in 1,403 patients from the Penn Heart Failure Study, a multicenter cohort of chronic systolic HF. Subjects were followed for death, cardiac transplantation, or ventricular assist device placement over a median follow-up of 2 years. The sFlt-1 was independently associated with measures of HF severity, including New York Heart Association functional class (p < 0.01) and B-type natriuretic peptide (p < 0.01). Patients in the 4th quartile of sFlt-1 (>379 pg/ml) had a 6.17-fold increased risk of adverse outcomes (p < 0.01). This association was robust, even after adjustment for the Seattle Failure Model (hazard ratio: 2.54, 95% confidence interval [CI]: 1.76 to 2.27, p < 0.01) and clinical confounders including HF etiology (hazard ratio: 1.67, 95% CI: 1.06 to 2.63, p = 0.03). Combined assessment of sFlt-1 and B-type natriuretic peptide exhibited high predictive accuracy at 1 year (area under the receiver-operator characteristic curve: 0.791, 95% CI: 0.752 to 0.831) that was greater than either marker alone (p < 0.01 and p = 0.03, respectively). In contrast, PlGF was not an independent marker of disease severity or outcomes. Our findings support a role for sFlt-1 in the biology of human HF. With additional study, circulating sFlt-1 might emerge as a clinically useful biomarker to assess the influence of vascular remodeling on clinical outcomes.

E0613 Plasma microRNA-361-5p as a biomarker of chronic heart failure

AimsRecent studies have showed important roles for microRNAs in multiple cardiovascular diseases, including AMI, hypertension, HF, and so on. However, the signature of plasma miRNA expression in chronic heart failure...

Cytokines and Matrix Metalloproteinases as Potential Biomarkers in Chronic Heart Failure

Heart failure (HF) is accompanied by the upregulation of bioactive signaling molecules, known as cytokines, and a family of downstream proteases, matrix metalloproteinases (MMPs). It is now apparent that these molecules contribute to adverse myocardial remodeling during HF. Elevated levels of cytokines and MMPs exist in the myocardium and can subsequently spill over into the systemic circulation. The purpose of this article is to examine clinical studies of HF that have quantified levels of different types of cytokines, MMPs and endogenous tissue inhibitors of MMPs in relation to this disease process. HF is a complex syndrome that can develop from various etiologies and can be characterized into two distinct phenotypes: systolic and diastolic. This article will present recent clinical studies that have identified significant differences between the cytokine and MMP circulating profile of systolic and diastolic HF patients. In general, elevated levels of cytokines and MMPs exist in systolic HF patients when compared with diastolic HF patients, whereas diastolic HF patients have elevated levels of cytokines and MMPs when compared with controls. Therefore, future studies distinguishing between HF phenotypes may provide more consistent results in determining possible analytes to be used as biomarkers. Furthermore, this article will emphasize why standardization of analytical techniques and establishment of referent cytokine and MMP levels are necessary if these analytes are to be used as biomarkers for the diagnosis, prognosis and evaluation of treatment in the context of HF.

Gene expression profiles in peripheral blood mononuclear cells of chronic heart failure patients

The present study was aimed at identifying chronic heart failure (CHF) biomarkers from peripheral blood mononuclear cells (PBMCs) in patients with ischemic (ICM) and nonischemic dilated (NIDCM) cardiomyopathy. PBMC gene expression profiling was performed by Affymetrix in two patient groups, 1) ICM (n = 12) and 2) NIDCM (n = 12) New York Heart Association (NYHA) III/IV CHF patients, vs. 3) age- and sex-matched control subjects (n = 12). Extracted RNAs were then pooled and hybridized to a total of 11 microarrays. Gene ontology (GO) analysis separated gene profiling into functional classes. Prediction analysis of microarrays (PAM) and significance analysis of microarrays (SAM) were utilized in order to identify a molecular signature. Candidate markers were validated by quantitative real-time polymerase chain reaction. We identified a gene expression profiling that distinguished between CHF patients and control subjects. Interestingly, among the set of genes constituting the signature, chemokine receptor (CCR2, CX(3)CR1) and early growth response (EGR1, 2, 3) family members were found to be upregulated in CHF patients vs. control subjects and to be part of a gene network. Such findings were strengthened by the analysis of an additional 26 CHF patients (n = 14 ICM and n = 12 NIDCM), which yielded similar results. The present study represents the first large-scale gene expression analysis of CHF patient PBMCs that identified a molecular signature of CHF and putative biomarkers of CHF, i.e., chemokine receptor and EGR family members. Furthermore, EGR1 expression levels can discriminate between ICM and NIDCM CHF patients.

Adrenomedullin and endothelin-1 are related to inflammation in chronic heart failure

Adrenomedullin (ADM) and endothelin-1 (ET-1) are novel promising peptide biomarkers in chronic heart failure (CHF). According to recent studies among their pleiotropic effect they play roles in the regulation of inflammation. The aim of the study was to measure the above mentioned two vasoactive peptides in parallel in a well characterized population of patients with CHF, and study their associations with inflammatory markers. A total of 186 patients (138 male, 48 female) with <45% left ventricular ejection fraction (LVEF), and without acute inflammatory disease, were enrolled. Plasma midregional-proADM (MR-proADM) and C-terminal-proET-1 (CT-proET-1) were determined by a novel sandwich immunoluminometric assay. Increased MR-proADM and CT-proET-1 plasma levels were measured in patients with severe CHF (NYHA III-IV) as compared to the group of NYHA I-II (p<0.0001). MR-proADM and CT-proET-1 levels showed significant negative correlation with serum albumin and prealbumin levels (p<or=0.0001), while positive correlations were found with levels of CRP, TNF-alpha, soluble TNF receptors and IL-6 (p<or=0.0001). In multiple linear regression models after adjustments for several potential confounders (disease severity [LV-EF, NYHA classes, NT-proBNP], ion and water homeostasis [sodium and presence of peripheral oedema], renal function [serum creatine]) the relationship between ADM and albumin, CRP, soluble TNF receptors and between ET-1 and CRP, TNF receptors and IL-6 remained significant. Vasoregulation and inflammation may be connected in heart failure patients independently of the disease severity. The observed link may contribute to the understanding of the complex pathomechanism in CHF.

Role of oxidative and nitrosative stress biomarkers in chronic heart failure

In this review, we present recent insights on chronic heart failure (CHF) and the potential role of tumor necrosis factor (TNF)-alpha, interleukins, myeloperoxidase (MPO), and nitrosative stress in the progression of this disease process. Reactive oxygen species (ROS) are produced as a consequence of aerobic metabolism. Under physiologic conditions, their unfavourable effect in causing oxidative damage is counteracted by antioxidants. An imbalance in favour of oxidants leads to oxidative stress, and contributes to myocyte apoptosis, direct negative inotropic effects, and reduced bioavailability of nitric oxide (NO). Together, these effects lead to impaired vasodilatation of the coronary, pulmonary and peripheral vascular beds. In patients with moderate to severe forms of CHF, TNF-alpha leads to the formation of nitrotyrosine and consumption of nitric oxide by virtue of activation of myeloperoxidase. Further studies are required to better elucidate the complex interaction of oxidative stress, endothelial dysfunction and inflammatory activation in CHF. Such insights would likely lead to development of better strategies for the assessment of the disease severity by monitoring of new bio-humoral indices and better treatment approaches.

Comparison of matrix metalloproteinase 9 and brain natriuretic peptide as clinical biomarkers in chronic heart failure

Matrix metalloproteinase 9 (MMP-9) may serve as a biomarker of ventricular remodeling in selected populations, but few studies have assessed its performance in clinical practice. We tested MMP-9 as a biomarker of remodeling and predictor of outcomes in a systolic heart failure cohort derived from clinical practice and compared its performance to brain natriuretic peptide (BNP). Plasma MMP-9 and BNP levels were measured in 395 outpatients with systolic heart failure who participated in the Penn Heart Failure Study. We tested for (1) cross-sectional associations between biomarker levels, left ventricular end-diastolic dimension index (LVEDDI), and ejection fraction (EF), and (2) associations between baseline biomarker levels and risk of subsequent cardiac hospitalization or death over 3 years of follow-up. Matrix metalloproteinase 9 had no significant correlation with LVEDDI (rho = 0.04, P = not significant) or EF (rho = -0.06, P = not significant), whereas BNP showed highly significant correlations (LVEDDI: rho = -0.27, P < .0001; EF: rho = -0.35, P < .0001). In multivariate linear regression models, MMP-9 again showed no significant associations with LVEDDI (P = .6) or EF (P = .14), whereas BNP showed strong independent associations (LVEDDI: P < .001; EF: P = .002). Kaplan-Meier analyses showed no difference in hospital-free survival by baseline MMP-9 tertile (P = .7), whereas higher BNP tertile predicted worse survival (P < .0001). In multivariate Cox models, baseline MMP-9 level did not predict risk of adverse outcome (hazard ratio for log increase 0.98, P = .9), whereas BNP was a significant independent predictor (hazard ratio for log increase 1.15, P = .02). Compared to BNP, MMP-9 is a poor clinical biomarker of remodeling and outcome in patients with systolic heart failure derived from clinical practice.

Annexin A5 and the failing heart; lost or found in translation?

Heart failure is the number one reason for hospital admission in patients above 65 years of age. It is predicted that the number of heart failure patients will almost double in the next 20 years. Ischaemic and hypertensive heart disease are the major causes of this disabling disease. Approximately 22% of women and 46% of men who have had a myocardial infarction will develop heart failure within 6 years.1 Still, hypertension is a chief cause of cardiac failure: diastolic dysfunction accounts for >50% of all heart failure patients.2 In the world we live in, an increasing number of people become at risk of developing hypertension heart disease due to the epidemic proportions of obesity and the concomitant development of diabetes. The obesity epidemic is not restricted to countries in the developed world, but is also starting to conquer some developing countries such as India and China.2 Efficient and rapid identification of patients who are susceptible to develop chronic heart failure (CHF) is going to be of imminent importance. In clinical practice, a combination of clinical exam, serum biomarkers, and imaging technology will provide the tools to establish the diagnosis of heart failure. Advances in serum biomarker diagnostics include the use of N-terminal pro-B type natriuretic peptide (NT-proBNP) as a marker of the failing left ventricle.3 The release of NT-proBNP is triggered by stretch of myocardial cells and, therefore, is a direct reflection of myocardial cell stress. Novel studies on serum biomarkers in CHF comprise the detection of galectin-3, which reflects the activation of macrophages in the failing heart.4 This could provide incremental … *Corresponding author. Tel: +31 43 3882949; fax: +31 43 3871055. E-mail address : s.heymans{at}cardio.unimaas.nl

Does NT‐proBNP Remain a Sensitive Biomarker for Chronic Heart Failure after Administration of a Beta‐blocker?

Beta-blockers exert complex effects on plasma N-terminal-pro-B-type natriuretic peptide (NT-proBNP) level. We aimed to investigate whether NT-proBNP was still able to mirror the severity of chronic heart failure and predict the prognosis of the disease after administration of a beta-blocker. Forty-four patients with chronic congestive heart failure were enrolled in the study to randomly receive carvedilol or bisoprolol in addition to background therapy. These patients underwent clinical measurement and blood sampling for NT-proBNP measurement at baseline and 3 or 7 months after the addition of the beta-blocker. The patients were followed-up for 3 years in order to register the occurrence of all-cause death. NT-proBNP level showed a positive correlation with the severity of heart failure as evaluated by New York Heart Association (NYHA) classification both before and after administration of either beta-blocker. The relationship between NT-proBNP and NYHA class was not weakened with the duration of therapy. Furthermore, NT-proBNP was the only independent predictor of all-cause mortality both before and after administration of either beta-blocker. Left ventricular ejection fraction (LVEF), left ventricular end diastolic diameter (LVEDD), age, NYHA class and treatment group were not independently predictive of mortality in this study. The ability of NT-proBNP to reflect the severity and to predict the endpoint in chronic heart failure is not undermined after administration of a beta-blocker, suggesting that NT-proBNP remains a sensitive biomarker for chronic heart failure both before and after administration of a beta-blocker.

Prognostic Utility of Growth Differentiation Factor-15 in Patients With Chronic Heart Failure

We explored the prognostic utility of growth differentiation factor (GDF)-15 in patients with chronic heart failure (CHF). Growth differentiation factor-15 is a stress-responsive member of the transforming growth factor-beta cytokine superfamily. It has recently been observed that patients with CHF have increased circulating levels of GDF-15. The relations of GDF-15 to other biomarkers and to mortality in CHF have never been studied. Circulating levels of GDF-15 were determined by immunoradiometric assay in 455 patients with CHF with a median left ventricular ejection fraction (LVEF) of 32% (interquartile range 25% to 39%). The median GDF-15 level was 1,949 ng/l (interquartile range 1,194 to 3,577); 74.9% of the patients presented with GDF-15 levels >1,200 ng/l, the upper limit of normal in healthy elderly individuals. The GDF-15 levels were closely related to New York Heart Association (NYHA) functional class and to amino-terminal pro-B-type natriuretic peptide (NT-proBNP). The risk of death during follow-up increased with increasing quartiles of GDF-15. Mortality rates at 48 months were 10.0%, 9.4%, 33.4%, and 56.2% in the respective quartiles (p < 0.001). After adjustment for clinical variables and established biomarkers of adverse prognosis, including NT-proBNP, renal dysfunction, anemia, and hyperuricemia, GDF-15 remained an independent predictor of mortality (adjusted hazard ratio for 1 U in the Ln scale 2.26; 95% confidence interval 1.52 to 3.37; p < 0.001). Growth differentiation factor 15 provided prognostic information in clinically relevant patient subgroups (defined according to age, body mass index, heart failure etiology, concomitant medical therapy, renal function, and the levels of hemoglobin and uric acid) and added prognostic information to NYHA functional class, LVEF, and NT-proBNP. Growth differentiation factor 15 is a new biomarker of the risk of death in patients with CHF that provides prognostic information beyond established clinical and biochemical markers.

Multimarker Approach to Risk Stratification Among Patients with Advanced Chronic Heart Failure

Cardiac troponin I (cTnI), N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity C-reactive protein (hsCRP) each predict adverse cardiac events in chronic heart failure (CHF). However, little is known about the utility of these novel biomarkers of CHF in combination. : We hypothesized that simultaneous assessment of the three biomarkers would enable clinicians to stratify risk more effectively among patients with advanced CHF. Measurements of the biomarkers were performed on 152 patients with symptomatic advanced CHF. Major adverse cardiac events during a median follow-up period of 186 days were determined. Univariate and multivariate analysis revealed that elevations of each biomarker were significant predictors of clinical outcome independently of clinical variables. When patients were categorized on the basis of the number of elevated biomarkers, patients with one, two and three elevated biomarkers respectively had a 2.7-(p = 0.125), 8.6- (p < 0.0001) and 23.4-(p < 0.0001) fold increase in the risk of adverse events. Simultaneous measurement of cTnI, hsCRP, and NT-proBNP could provide complementary information and a simple multimarker strategy that categorizes the patients with advanced CHF based on the number of elevated biomarkers, allowing rapid risk stratification in these patients.