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Pre-eclampsia is a pregnancy-specific disorder characterised by hypertension and proteinuria, which in severe cases results in multi-system disturbances. The maternal syndrome is associated with a pro-inflammatory state, consisting of leukocyte activation, which is thought to contribute to the widespread endothelial dysfunction. We previously showed increased activation of NADPH oxidase in pre-eclampsia, in both neutrophils and B-lymphoblast cell lines (B-LCLs). In this study, the mechanism by which NADPH oxidase activity is increased in pre-eclampsia was further investigated. NADPH oxidase activity was found to be increased in phorbol-12-myristate-13-acetate (PMA) stimulated B-LCLs isolated from women with pre-eclampsia. This correlated with an increase in protein kinase C (PKC) substrate phosphorylation, p47-phox phosphorylation (a regulatory component of NADPH oxidase) and p47-phox directed-kinase activity. Using ion exchange and hydroxyapatite chromatography we identified a major peak of PMA regulated p47-phox kinase activity. Chromatography fractions were probed for PKC isoforms. We found the major peak of p47-phox kinase activity could not be separated from the elution profile of PKC epsilon. Using a peptide inhibitor of PKC epsilon, PMA-induced reactive oxygen species (ROS) production could be reduced to that of a normal B-LCL. These data suggest a pro-inflammatory role for PKC epsilon in the pathogenesis of pre-eclampsia.

Proenkephalin A (PENK) and its receptors are widely distributed. Enkephalins are cardiodepressive and difficult to measure directly. PENK is a stable surrogate analyte of labile enkephalins that is correlated inversely with renal function. Cardiorenal syndrome is common in acute heart failure (HF) and portends poor prognosis.This study assessed the prognostic value of PENK in acute HF, by identifying levels that may be useful in clinical decisions, and evaluated its utility for predicting cardiorenal syndrome.This multicenter study measured PENK in 1,908 patients with acute HF (1,186 male; mean age 75.66 ± 11.74 years). The primary endpoint was 1-year all-cause mortality; secondary endpoints were in-hospital mortality, all-cause mortality or HF rehospitalization within 1 year, and in-hospital worsening renal function, defined as a rise in plasma creatinine ≥26.5 μmol/l or 50% higher than the admission value within 5 days of presentation.During 1-year follow-up, 518 patients died. Measures of renal function were the major determinants of PENK levels. PENK independently predicted worsening renal function (odds ratio: 1.58; 95% confidence interval [CI]: 1.24 to 2.00; p 0.0005) with a model receiver-operating characteristic area of 0.69. PENK was associated with the degree of worsening renal function. Multivariable Cox regression models showed that PENK level was an independent predictor of 1-year mortality (p 0.0005) and 1-year death and/or HF (hazard ratio: 1.27; 95% CI: 1.10 to 1.45; p = 0.001). PENK levels independently predicted outcomes at 3 or 6 months and were independent predictors of in-hospital mortality, predominantly down-classifying risk in survivors when added to clinical scores; levels 133.3 pmol/l and211.3 pmol/l detected low-risk and high-risk patients, respectively.PENK levels reflect cardiorenal status in acute HF and are prognostic for worsening renal function and in-hospital mortality as well as mortality during follow-up.

BACKGROUND B-type natriuretic peptide (BNP) molecular forms 5-32, 4-32, and 3-32 are known to be present in the circulation of heart failure (HF) patients. This study investigated the prognostic role of circulating BNP molecular forms on risk prediction for patients with acute HF. METHODS BNP molecular forms were measured in plasma using an immunocapture MALDI-TOF–mass spectrometry (MS) method. Associations of molecular BNP forms with adverse outcome of all-cause mortality (death) and a composite of all-cause mortality and rehospitalization due to HF (death/HF) at 6 months and 1 year were investigated. RESULTS BNP molecular forms 5-32, 4-32, and 3-32 were detected in 838 out of 904 patient samples. BNP molecular forms were all able to independently predict death and death/HF at 6 months and 1 year. BNP 5-32 was the superior form with strongest predictive qualities for death at 6 months [adjusted hazard ratio (HR) 1.31, P = 0.005] and 1 year (adjusted HR 1.29, P = 0.002) and death/HF at 1 year (adjusted HR 1.18, P = 0.011). BNP 5-32, 4-32, and 3-32 showed decreased survival rates across increasing tertiles of circulating concentrations (P ≤ 0.004). BNP molecular forms showed prognostic ability comparable with conventional BNP measurements across all end points (P = 0.002–0.032 vs P = 0.014–0.039, respectively) and reduced associations with renal dysfunction (blood urea; Spearman correlation rs = 0.187–0.246 vs rs = 0.369, respectively). CONCLUSIONS BNP molecular forms, notably BNP 5-32, showed association with poor prognosis at 6 months and 1 year in patients with acute HF. This is the first study reporting the prognostic ability of molecular BNP forms in HF patients and demonstrated comparable qualities to conventional BNP measurements.

1. Na+/H+ antiport activity was measured in peripheral blood polymorphonuclear and mononuclear cells of 12 healthy subjects by using an intracellular pH clamp technique to determine the external Na+-dependent H+ efflux rate in cells loaded with a pH-sensitive fluorescent dye, bis(carboxyethyl)carboxyfluorescein. The change in external Na+ concentrations for all pH measurements was similar in both cell types. 2. A significant difference between the two types of cells was found, the polymorphonuclear leucocytes having a higher Na+/H+ antiport activity than the lymphocytes. Cellular intrinsic buffering capacity measured in the absence of HCO−3 was also higher in the polymorphonuclear cells than in the lymphocytes. 3. These differences may be associated with a difference in the role of the Na+/H+ exchanger in these two types of cells, although in vivo the presence of HCO−3/Cl− exchangers may also contribute to intracellular pH homoeostasis.

Serum mid-regional pro-atrial natriuretic peptide (MR-proANP) and pro-adrenomedullin (MR-proADM) are novel biomarkers for acute heart failure (AHF). Like other AFH biomarkers, the performance of these tests are affected by the presence of clinical variables such as renal failure and obesity. In a substudy of the Biomarkers from Acute Heart Failure Study, we show that diabetes did not influence the performance of these markers with regards to AHF diagnosis or 90-day all cause death. However, in patients without AHF, increased MR-proADM alone was associated with the presence of diabetes.

Urotensin-II (U-II) is the peptide agonist for the U-II receptor (UT). Putative UT antagonists, urantide and UFP-803, have been found to have variable efficacy in a range of assays. We have used siRNA-mediated RNA interference to probe the efficacy of these ligands compared to U-II. Knockdown of human UT occurs in the same cellular background with the same coupling machinery allowing relative efficacy to be probed. CHO cells stably expressing 1,110 fmol/mg protein of human UT (CHOhUT) were transfected with s194454, s194455 (UT-targeting), or a negative control siRNA using siPORT amine transfection reagent. After 48 h, silencing was assessed using quantitative PCR in a duplex assay format. Functional consequences of silencing were assessed by measuring [Ca2+]i in Fura-2 loaded cells using the NOVOstar plate reader. Silencing with s194455 was greater than that with s194454 (93.5 ± 2.8% and 73.0 ± 2.5% knockdown of UT mRNA respectively at 10−7 M, p = 0.006). Both s194455 and s194454 knocked down UT mRNA expression with equal potency (EC50 1.38 and 0.45 nM). The negative control did not affect UT mRNA expression. U-II (10−6 M) increased [Ca2+]i 630 ± 69, 402 ± 49 and 190 ± 14nM, urantide (10−6 M) increased [Ca2+]i 408 ± 55, 191 ± 40, and 131 ± 10 nM and UFP-803 (10−6 M) increased [Ca2+]i 134 ± 23, 83 ± 11 and 53 ± 3nM for negative control siRNA, s194454 and s194455, respectively. We have demonstrated silencing of UT mRNA and a reduction of absolute efficacy of three UT ligands. However, we were unable to resolve any changes in relative efficacy for urantide and UFP-803. This is likely to result from a high starting expression and retention of a receptor/coupling reserve.

Aims Biomarkers have proven their ability in the evaluation of cardiopulmonary diseases. We investigated the utility of concentrations of the biomarker procalcitonin (PCT) alone and with clinical variables for the diagnosis of pneumonia in patients presenting to emergency departments (EDs) with a chief complaint of shortness of breath. Methods and results The BACH trial was a prospective, international, study of 1641 patients presenting to EDs with dyspnoea. Blood samples were analysed for PCT and other biomarkers. Relevant clinical data were also captured. Patient outcomes were assessed at 90 days. The diagnosis of pneumonia was made using strictly validated guidelines. A model using PCT was more accurate [area under the curve (AUC) 72.3%] than any other individual clinical variable for the diagnosis of pneumonia in all patients, in those with obstructive lung disease, and in those with acute heart failure (AHF). Combining physician estimates of the probability of pneumonia with PCT values increased the accuracy to >86% for the diagnosis of pneumonia in all patients. Patients with a diagnosis of AHF and an elevated PCT concentration (>0.21 ng/mL) had a worse outcome if not treated with antibiotics (P = 0.046), while patients with low PCT values (

Aims Midregional pro atrial natriuretic peptide (MR-proANP) is useful for diagnosing acute heart failure (HF) in patients presenting to the Emergency Department with dyspnoea. Optimal interpretation of MR-proANP requires understanding of how various demographic variables influence its levels and performance as a diagnostic marker. We sought to determine how age, race, sex, and body mass index (BMI) affect the levels and interpretation of MR-proANP for the diagnosis of acute HF. Methods and results The Biomarkers in Acute Heart Failure (BACH) study was an international 15-centre study of 1641 patients presenting to the Emergency Department with acute dyspnoea. Of these, 1352 had complete information on age, race, sex, and BMI. MR-proANP levels increased with age and were higher in men and in patients with lower BMI. MR-proANP performed better as a diagnostic marker in younger individuals and in blacks compared with whites. Despite this, MR-proANP at the recommended cut-off point of 120 pmol/L was >90 % sensitive in ruling out the diagnosis of acute HF in all subgroups of patients except white subjects

In reply: Response to letter to the editor ‘Predictive Value of NT-proBNP in Patients with Acute Myocardial Infarction’; Regarding Article ‘Trimethylamine N-oxide and Risk Stratification after Acute Myocardial Infarction"

Background— In patients with heart failure (HF), increased arginine vasopressin concentrations are associated with more severe disease, making arginine vasopressin an attractive target for therapy. However, AVP is difficult to measure due to its in vitro instability and rapid clearance. Copeptin, the C-terminal segment of preprovasopressin, is a stable and reliable surrogate biomarker for serum arginine vasopressin concentrations. Methods and Results— The Biomarkers in Acute Heart Failure (BACH) trial was a 15-center, diagnostic and prognostic study of 1641 patients with acute dyspnea; 557 patients with acute HF were included in this analysis. Copeptin and other biomarker measurements were performed by a core laboratory at the University of Maryland. Patients were followed for up to 90 days after initial evaluation for the primary end point of all-cause mortality, HF-related readmissions, and HF-related emergency department visits. Patients with copeptin concentrations in the highest quartile had increased 90-day mortality ( P P r =0.047). Conclusions— This study showed significantly increased 90-day mortality, readmissions, and emergency department visits in patients with elevated copeptin, especially in those with hyponatremia. Copeptin was highly prognostic for 90-day adverse events in patients with acute HF, adding prognostic value to clinical predictors, ser um sodium, and natriuretic peptides. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00537628.

Few tools exist that provide objective accurate prediction of short-term mortality risk in patients presenting with acute heart failure (AHF). The purpose was to describe the accuracy of several biomarkers for predicting short-term death rates in patients diagnosed with AHF in the emergency department (ED).

Objectives The aim of this study was to determine the prognostic utility of midregion proadrenomedullin (MR-proADM) in all patients, cardiac and noncardiac, presenting with acute shortness of breath. Background The recently published BACH (Biomarkers in Acute Heart Failure) study demonstrated that MR-proADM had superior accuracy for predicting 90-day mortality compared with B-type natriuretic peptide (area under the curve: 0.674 vs. 0.606, respectively, p Methods The BACH trial was a prospective, 15-center, international study of 1,641 patients presenting to the emergency department with dyspnea. Using this dataset, the prognostic accuracy of MR-proADM was evaluated in all patients enrolled for predicting 90-day mortality with respect to other biomarkers, the added value in addition to clinical variables, as well as the added value of additional measurements during hospital admission. Results Compared with B-type natriuretic peptide or troponin, MR-proADM was superior for predicting 90-day all-cause mortality in patients presenting with acute dyspnea (c index = 0.755, p 3.28), and it was also superior to all other biomarkers. MR-proADM added significantly to the best clinical model (bootstrap-corrected c index increase: 0.775 to 0.807; adjusted standardized hazard ratio: 2.59; 95% confidence interval: 1.91 to 3.50; p Conclusions MR-proADM identifies patients with high 90-day mortality and adds prognostic value to natriuretic peptides in patients presenting with acute shortness of breath. Serial measurement of this biomarker may also prove useful for monitoring, although further studies will be required. (Biomarkers in Acute Heart Failure [BACH]; NCT00537628 )

Aims Implantable cardioverter defibrillator (ICD) therapy improves survival in patients at high sudden cardiac death (SCD) risk. However, some patient groups fulfilling indications for ICD therapy may not gain significant benefit: patients whose absolute risk of SCD is low and patients whose risk of death even with an ICD is high. The value of biomarkers in identifying patients’ potential for survival benefit from ICD therapy is unknown. We performed a pilot study to investigate this. Methods and results Five established cardiovascular biomarkers were measured in patients with ICDs on the background of left ventricular dysfunction: N-terminal pro-brain natriuretic peptide [NT-proBNP], soluble ST2 [sST2], growth differentiation factor-15, C-reactive protein, and interleukin-6. The endpoints were all-cause mortality and survival with appropriate ICD therapy. One hundred and fifty-six patients were enrolled (age 69 years [Q1–Q3 62–77], 85% male, 76% ischaemic aetiology). During a follow-up of 15 ± 3 months, 12 patients died and 43 survived with appropriate ICD therapy. In a Cox proportional hazards model, the strongest predictors of death were Log sST2 ( P < 0.001), serum creatinine ( P < 0.001), and Log NT-proBNP ( P = 0.002). The strongest predictor of survival with appropriate ICD therapy was Log NT-proBNP ( P = 0.01). Conclusion The biomarkers NT-proBNP and sST2 are promising biomarkers for identifying patients with little potential to gain significant survival benefit from ICD therapy. However, their incremental benefit, in addition to currently available clinical risk prediction models, remains unclear. These results demand a confirmatory prospective cohort study, designed and powered to derive and validate prediction algorithms incorporating these markers.

Copeptin, the 39-amino-acid C-terminal portion of provasopressin, has been shown to be an independent predictor for adverse events following STEMI (ST elevation myocardial infarction). We hypothesized that plasma copeptin was an independent predictor for adverse outcomes following acute NSTEMI (non-STEMI) and evaluated whether copeptin added prognostic information to the GRACE (Global Registry of Acute Coronary Events) score compared with NT-proBNP (N-terminal pro-B-type natriuretic peptide). Plasma copeptin and NT-proBNP were measured in 754 consecutive patients admitted to the hospital with chest pain and diagnosed as having NSTEMI in this prospective observational study. The end point was all-cause mortality at 6 months. Upper median levels of copeptin were strongly associated with all-cause mortality at 6 months. Copeptin was a significant predictor of time to mortality {HR (hazard ratio), 5.98 [95% CI (confidence interval, 3.75–9.53]; P

Background: MRproADM and MRproANP can be used as diagnostic and prognostic markers in heart failure.Aim: The objective was to identify confounding factors for the interpretation of plasma MRproADM and MRproANP concentrations.Methods: A total of 518 healthy volunteers with a mean age of 60.84 ± 7.41 years were analyzed. We evaluated the influence of demographic factors, renal function and echocardiographic indices on the candidate peptides.Results: Multivariate analysis revealed that age (P

A multimarker approach may be useful for risk stratification in AMI (acute myocardial infarction) patients, particularly utilizing pathways that are pathophysiologically distinct. Our aim was to assess the prognostic value of PR3 (proteinase 3) in patients post-AMI. We compared the prognostic value of PR3, an inflammatory marker, with an established marker NT-proBNP (N-terminal pro-B-type natriuretic peptide) post-AMI. We recruited 900 consecutive post-AMI patients (700 men; age, 64.6±12.4 years) in a prospective study with follow-up over 347 (0–764) days. Plasma PR3 was significantly higher in patients who died [666.2 (226.8–4035.5) ng/ml; P

Objectives The purpose of this study was to assess the prognostic value of admission and discharge mid-regional pro-adrenomedullin (sAM) levels in non–ST-elevation myocardial infarction (MI) and identify values to aid clinical decision making. N-terminal pro–B-type natriuretic peptide and GRACE (Global Registry of Acute Coronary Events) score were used as comparators. Background sAM is a stable precursor of adrenomedullin. Methods We measured plasma sAM on admission and discharge in 745 non–ST-elevation MI patients (514 men, median age 70.0 ± 12.7 years). The primary end point was a composite of death, heart failure, hospitalization, and recurrent acute MI over mean follow-up of 760 days (range 150 to 2,837 days), with each event assessed individually as secondary end points. Results During follow-up, 120 (16.1%) patients died, and there were 65 (8.7%) hospitalizations for heart failure and 77 (10.3%) recurrent acute MIs. Both admission and discharge levels were increased (median 0.81 nmol/l [range 0.06 to 5.75 nmol/l] and 0.76 nmol/l [range 0.25 to 6.95 nmol/l], respectively) compared with established normal ranges. Multivariate adjusted Cox regression models revealed that both were associated with the primary end point (hazard ratio: 9.75 on admission and 7.54 on discharge; both p 1.11 nmol/l identified those at highest risk of death (p Conclusions sAM level is prognostic for death or heart failure. Admission levels are a strong predictor of early mortality and, when >1.11 nmol/l, complements the GRACE score to improve risk stratification.

To consider whether patients most likely to benefit from ACE inhibition in routine practice after acute coronary syndrome (ACS) may be identified from plasma natriuretic peptide concentrations.Observational cohort study.Teaching hospital coronary care unit.1725 patients admitted with acute coronary syndrome (56.3% ST elevation ACS; median age 67, range 24-97 years).Using Cox proportional hazards analysis, we assessed the adjusted predictive value for major adverse cardiac events (MACE) of prescription of an ACE inhibitor, of plasma N-terminal pro B-type natriuretic peptide (NT-proBNP) and for interaction between these factors. To adjust for demographic differences between patients prescribed or not prescribed an ACE inhibitor, a factor correcting for likelihood of ACE inhibitor prescription (propensity score) was included in the analysis.The primary end point was the occurrence of MACE (death, recurrent myocardial infarction or hospitalisation with heart failure).During the index admission ACE inhibitor was prescribed for 1267/1725 (73.4%) patients. During follow-up (median 528 days, range 0-3873 days), 534/1725 patients experienced MACE. After covariable adjustment, NT-proBNP showed linear association with risk of MACE (p0.005), strongest for patients with NT-proBNP in the top quartile of observed values (HR=2.768, p0.001). Only for patients with NT-proBNP in the top quartile was prescription of ACE inhibitor associated with reduction in risk of MACE (HR=0.532, p=0.003). This association was maintained after correction for propensity scores (HR=0.599, p=0.003).Prognostic benefit from ACE inhibition was seen only in patients with the most marked elevation of plasma NT-proBNP. Plasma NT-proBNP may be a useful indicator of the appropriateness of individual prescription of ACE inhibitor treatment across the spectrum of ACS.

Valvular heart disease, particularly aortic stenosis and mitral regurgitation, accounts for a large proportion of cardiology practice, and their prevalence is predicted to increase. Management of the asymptomatic patient remains controversial. Biomarkers have been shown to have utility in the management of cardiovascular disease such as heart failure and acute coronary syndromes. In this state-of-the-art review, we examine the current evidence relating to natriuretic peptides as potential biomarkers in aortic stenosis and mitral regurgitation. The natriuretic peptides correlate with measures of disease severity and symptomatic status and also can be used to predict outcome. This review shows that natriuretic peptides have much promise as biomarkers in common valvular heart disease, but the impact of their measurement on clinical practice and outcomes needs to be further assessed in prospective studies before routine clinical use becomes a reality.

Objectives Our purpose was to assess the diagnostic utility of mid-regional pro–atrial natriuretic peptide (MR-proANP) for the diagnosis of acute heart failure (AHF) and the prognostic value of mid-regional pro-adrenomedullin (MR-proADM) in patients with AHF. Background There are some caveats and limitations to natriuretic peptide testing in the acute dyspneic patient. Methods The BACH (Biomarkers in Acute Heart Failure) trial was a prospective, 15-center, international study of 1,641 patients presenting to the emergency department with dyspnea. A noninferiority test of MR-proANP versus B-type natriuretic peptide (BNP) for diagnosis of AHF and a superiority test of MR-proADM versus BNP for 90-day survival were conducted. Other end points were exploratory. Results MR-proANP (≥120 pmol/l) proved noninferior to BNP (≥100 pg/ml) for the diagnosis of AHF (accuracy difference 0.9%). In tests of secondary diagnostic objectives, MR-proANP levels added to the utility of BNP levels in patients with intermediate BNP values and with obesity but not in renal insufficiency, the elderly, or patients with edema. Using cut-off values from receiver-operating characteristic analysis, the accuracy to predict 90-day survival of heart failure patients was 73% (95% confidence interval: 70% to 77%) for MR-proADM and 62% (95% confidence interval: 58% to 66%) for BNP (difference p Conclusions MR-proANP is as useful as BNP for AHF diagnosis in dyspneic patients and may provide additional clinical utility when BNP is difficult to interpret. MR-proADM identifies patients with high 90-day mortality risk and adds prognostic value to BNP. (Biomarkers in Acute Heart Failure [BACH]; NCT00537628)

The diagnosis of diabetes and admission blood glucose concentration are associated with adverse outcome after acute coronary syndromes. We compared the relative association with survival after ST elevation AMI (acute myocardial infarction) of admission blood glucose concentration and of diabetes diagnosis. We carried out a retrospective cohort study in 4702 consecutive patients with STEMI (ST elevation AMI) occurring from 1 April 1993 to 31 December 2005, assessed for mortality at 30 days and 1 year. Patients were classified according to antecedent diabetes and by blood glucose concentration at admission (quartile 1, 80% in quartile 3 and by >150% in quartile 4, compared with glucose quartile 1. Antecedent diabetes was associated with an increase in mortality [unadjusted odds ratio (OR) 1.52 (95% CI 1.24, 1.86)]. On multivariable analysis (excluding glucose quartile), this reduced to 1.24 (0.98, 1.58) and changed to a small, statistically non-significant reduction in risk when glucose quartile was added to the analysis [adjusted OR 0.87 (0.67, 1.13)]. Inclusion of antecedent diabetes in multivariable models did not add to the predictive value for mortality of glucose quartile (P=0.368). Similar relationships were observed for 1 year mortality. In patients with STEMI, blood glucose concentration shows graded association with risk of 30-day and 1-year mortality and is of greater prognostic relevance than antecedent diabetes diagnosis. Moderate elevation of blood glucose, below levels previously considered to be clinically relevant, is associated with adverse impact on survival.

Proguanylin and prouroguanylin are the inactive precursors of guanylin and uroguanylin, natriuretic peptides involved in the regulation of sodium balance. Urinary uroguanylin levels have been found previously to be elevated in patients with HF (heart failure). The aim of the present study was to investigate whether plasma proguanylin and prouroguanylin levels are increased in patients with HF and to evaluate their relationship with cardiac and renal function. In this prospective observational study, we recruited 243 patients with HF (151 men) and 72 healthy controls. In patients with HF, plasma levels of proguanylin [median, 7.2 (range, 0.9–79.0) μg/l] and prouroguanylin [8.3 (1.7–53.0 μg/l)] were both significantly (P

The aim of the present study was to investigate the predictive value of MMP (matrix metalloproteinase)-2, MMP-3 and MMP-9 levels in patients with acute coronary syndrome for death, readmission with HF (heart failure) or recurrent MI (myocardial infarction) and to compare them with established markers, NT-proBNP (N-terminal pro-B-type natriuretic peptide) and the GRACE (Global Registry of Acute Coronary Events) score. A single blood test was taken 4 days after admission in 1024 consecutive patients with acute MI with end points observed over 519 (134–1059) days [value is median (range)]. MMP-2 and MMP-3 were increased in patients who died (n=111) compared with survivors (P

Von Willebrand factor (VWF) and tissue plasminogen activator (t-PA) predict adverse cardiovascular outcome following acute myocardial infarction (AMI) and are weakly associated with pre-discharge left ventricular ejection fraction (LVEF). We examined the relationships between VWF, t-PA antigen, matrix metalloproteinase (MMP)-2,-3, and -9, and B-type natriuretic peptide (BNP), and their predictive effect on serial change in LV volumes in a cohort of patients admitted with AMI. Plasma VWF, t-PA antigen, MMP-2,-3,-9, and BNP were measured at a mean 46 h after AMI in 100 patients (mean age 58.9 ± 12 years, 77% male) with depressed LVEF. Cardiac magnetic resonance (CMR) imaging was then performed. Biomarker measurement and CMR were repeated at 12 and 24 weeks. Plasma concentrations of VWF, BNP and MMP-9 were elevated while t-PA antigen concentration was at the upper limits of normal; over 24 weeks VWF, t-PA antigen, MMP-9 and BNP decreased significantly. Baseline VWF correlated with BNP (r = 0.35, P < 0.001) and MMP-3 (r = 0.24, P = 0.019) as did t-PA antigen (r = 0.27, P = 0.007 for BNP; r = 0.40, P < 0.001 for MMP-3). t-PA antigen, VWF, MMP-3 and BNP were univariate predictors of LV end-systolic volume at 24 weeks; tPA antigen and BNP remained significant independent predictors on multivariate analysis. t-PA antigen and VWF are related to medium-term LV volumes after AMI, and to MMP-3. This novel link between the coagulation-fibrinolysis system and matrix turnover merits further study in understanding the pathophysiology of adverse ventricular remodeling after AMI.

Objective: To develop and validate a prognostic risk index of cardiovascular mortality after cardiac resynchronisation therapy (CRT). Design: Prospective cohort study. Setting: District general hospital. Patients: 148 patients with heart failure (mean age 66.7 (SD 10.4) years), New York Heart Association class III or IV, LVEF

Aims Our aim was to assess the long-term prognostic value of growth differentiation factor-15 (GDF-15) in patients post-acute myocardial infarction (AMI). Growth differentiation factor-15 is a member of the transforming growth factor β family. Growth differentiation factor-15 is expressed in the myocardium and upregulated due to ‘stress’ and has been shown to have antiapoptotic actions. Its role in the cardiovascular system however is not well defined. We were interested to see if GDF-15 could provide long-term prognostic value in post-AMI patients. We compared GDF-15 with N-terminal pro-B-type natriuretic peptide (NT-proBNP). Methods and results We recruited 1142 consecutive post-AMI patients [820 men, median (range) age 67 (24–97) years] in a prospective study with a follow-up period of 505 (range 1–2837) days. Growth differentiation factor-15 levels increased with increasing Killip class ( P < 0.001) and were correlated with NT-proBNP ( r = 0.47, P < 0.001). Using a multivariable Cox proportional hazards model, log GDF-15 (HR 1.77), log NT-proBNP (HR 2.06), age (HR 1.03) Killip class above 1, (HR 1.62), use of beta-blockers (HR 0.54) and past history of MI (HR 1.44) were significant independent predictors of death or heart failure (HF). Predictors of death were log NT-proBNP, log GDF-15, age, eGFR, past history of MI, use of beta-blockers, and use of ACE inhibitors or angiotensin receptor blockers. The C-statistic for GDF-15 for predicting death or HF at 1 year was 0.73 (95% CI: 0.70–0.76, P < 0.001) and was 0.76 (95% CI: 0.70–0.80, P < 0.001) for NT-proBNP. Combining these markers yielded an AUC of 0.81 (95% CI: 0.77–0.85), which exceeded that of GDF-15 ( P < 0.001) and NT-proBNP ( P = 0.004) alone. The Kaplan–Meier analysis revealed that those patients with above median GDF-15 and NT-proBNP had the highest event rate for death and HF (log rank 50.22, P < 0.001). Conclusion Growth differentiation factor-15 is a new marker for predicting death and HF in post-AMI patients. GDF-15 provides prognostic information over and above clinical factors and the established biomarker NT-proBNP. Combined levels of GDF-15 with NT-proBNP can identify a high-risk group of patients.

The present study sought to identify confounding factors for the interpretation of copeptin levels in healthy individuals. The natriuretic peptides are recognized as diagnostic and prognostic tools in HF (heart failure). Interpretation of BNP (brain natriuretic peptide) and NTproBNP (N-terminal pro-BNP) levels is multifaceted as their secretion is influenced by many variables. A newly identified glycopeptide called copeptin is comparable with the natriuretic peptides in the diagnosis and prognosis of HF and as a prognostic biomarker after AMI (acute myocardial infarction). Copeptin, derived from the C-terminal portion of the precursor to AVP (arginine vasopressin), is secreted stoichiometrically with vasopressin, hence it can be used as a surrogate marker of the AVP system. In the present study, 706 healthy volunteers were recruited from a local HF screening study. Participants with a history of cardiovascular disease and those with echocardiographic abnormalities were excluded from the study. Copeptin and NTproBNP levels were assayed using in-house immunoluminometric assays. Median copeptin levels were significantly higher in the male volunteers compared with the females [median (range): 4.3 (0.4–44.3) compared with 3.2 (1.0–14.8) pmol/l; P

This is the author's final draft of the version published as Journal of the American College of Cardiology, 2008,51 (19), pp.1857-1864 and can also be accessed via http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T18-4SFJTJ8-5&_user=123215&_coverDate=05%2F13%2F2008&_rdoc=5&_fmt=high&_orig=browse&_srch=doc-info(%23toc%234884%232008%23999489980%23688824%23FLA%23display%23Volume)&_cdi=4884&_sort=d&_docanchor=&_ct=17&_acct=C000010181&_version=1&_urlVersion=0&_userid=123215&md5=a9611cbedb45d00179ea14501182bde8

Introduction: Changes to cardiac matrix are central to ventricular remodelling after acute MI and matrix metalloproteinase expression is implicated in this process. We investigated the temporal profile of MMP-3 and its relationship to LV dysfunction and prognosis following AMI. Methods: We studied 382 patients with AMI. Plasma MMP-3 was measured at 0–12, 12–24 h and for subsequent 24 h periods during admission. LV function (LVEF) was assessed by echocardiography pre-discharge and at a median of 148 days and clinical endpoints at a median of 313 days. Results: MMP-3 peaked prior to discharge thus pre-discharge levels were used in analyses. MMP-3 was associated with patient age (p

The TIMI risk score is a well-validated scoring system used to predict mortality in patients following an ST-segment elevation myocardial infarction (STEMI). N-terminal pro-B-type natriuretic peptide (NTproBNP) has also been found to be useful in predicting mortality following STEMI.To investigate the utility of the TIMI score and NTproBNP levels at predicting risk of death in patients with acute myocardial infarction (AMI).473 patients (352 men, mean (SD) age 63.7 (12.3) years) with AMI were studied. Blood was drawn within 24 hours after the onset of chest pain and the plasma concentration of NTproBNP was determined using an in-house non-competitive immunoassay. Patients' TIMI risk score was measured and patients stratified into low- (0 to 2), intermediate- (3-7) and high-risk (8) groups.Mortality was 8.9% and was related to higher TIMI risk scores (p = 0.029 for trend). Higher NTproBNP levels were also related to increased mortality (median (range) fmol/ml, survivors 700.2 (0.3-11485.3) vs dead 5781.3 (1.4-10835.9), p0.001). In a multivariate binary logistic regression model, independent predictors of mortality were NTproBNP levels in the first 24 hours (odds ratio (OR) = 4.21, 95% CI 1.96 to 9.07, p0.001) together with drug treatments. The receiver operating curve for NTproBNP in the first 24 hours yielded an area under the curve (AUC) of 0.79 (95% CI 0.70 to 0.88), p0.001, for TIMI risk score the AUC was 0.67 (95% CI 0.58 to 0.76), p = 0.001.In the first 24 hours following an AMI, NTproBNP is better than the TIMI risk score at predicting mortality. A simple NTproBNP blood test is more easily applicable and is more accurate than a clinical risk score.

Adrenomedullin (ADM) correlates with adverse cardiovascular outcomes in patients with acute myocardial infarction (AMI) and in patients with heart failure. Measurement of human mature ADM (mADM) has been difficult, and recent studies have used its surrogate - the mid-regional pro-ADM (MRproADM). Our objective was to determine whether mADM measured by a novel sandwich immunoassay, using the anti-C-terminal and an anti-mid-regional monoclonal antibody, was prognostic of 30-day, 90-day, 1-year, and 2-year major adverse cardiovascular events (MACEs) in 1111 consecutive patients who have suffered an AMI. We also compared it with the effect of MRproADM in the same patient population. A total of 311 (27.0%) patients experienced the primary endpoint at 2 years follow-up. The median (inter-quartile range) of mADM was significantly higher in patients who experienced a 2-year MACE [60.90 (44.00-86.97)] pg/ml, compared to event-free survivors [49.59 (36.20-68.15)] pg/ml (P < 0.001). mADM, taken as 1 SD of the continuous variable, was predictive of MACEs in multivariate analysis, with hazard ratios [95% confidence intervals (CIs)] at 90 days [1.28 (1.01-1.62)], 1 year [1.31 (1.08-1.59)], and 2 years [1.42 (1.07-1.64)]. It was also independently predictive of death at 1-year [1.52 (1.12-2.05)] and 2-year [1.42 (1.07-1.89)] follow-up. mADM was a better predictor of these outcomes than MRproADM, apart from death at 90 days, and combined death and heart failure hospitalization at 1 and 2 years, respectively. Human mADM can be reliably measured and predicts MACE events at medium-term follow-up, and confirms the paradigm of risk stratification using MRproADM - a surrogate for the active hormone. The relationship between mADM and MACE appears to be a continuum.

Background Altered activity of the matrix metalloproteinases (MMP-2 and -9), has been implicated in the left ventricular (LV) remodeling process occurring after myocardial infarction (MI). In the acute phase, a relation between plasma MMP-9 levels and parameters of LV dysfunction has been demonstrated. The relationship in long-term survivors has not been investigated. We studied the relationships of these biochemical markers, and N-terminal pro-B-type natriuretic peptide (N-BNP), with measures of long-term LV remodeling. Methods and Results Plasma levels of N-BNP, MMP-2, and MMP-9 were measured at randomization, 1 month, 1 year, and >4 years after complicated AMI. Contrast-enhanced cardiac magnetic resonance (CMR) was performed at 4.4 (±0.4) years in 52 clinically stable long-term survivors of the index AMI. We assessed the relationships of plasma N-BNP, MMP-2, and MMP-9 with myocardial scarring, and measures of long-term LV remodeling. Compared with a reference population, N-BNP and MMP-9 levels were increased at all time points from the acute phase until >4 years after MI. Plasma N-BNP and MMP-9 correlated only in the subacute phase (randomization, mean 3.3 days after MI) days after acute MI ( r = 0.38, P = .006). At CMR assessment ≥4 years, log MMP-9 level was inversely related to LV ejection fraction ( P = .002) and nonscarred myocardial mass ( P = .008). This relationship was independent of MMP-2. Log N-BNP was related to end diastolic volume index ( P = .0002). There was no correlation between log MMP-9 and LV volumes. Conclusion There is a time-dependent relationship between plasma N-BNP and MMP-9 levels, these peptides correlating only in the acute phase after MI. In long-term follow-up, plasma MMP-9 and N-BNP levels were related to different parameters of LV remodeling. These findings suggest that in long-term survivors of complicated MI, different mechanisms modulate plasma levels of MMP-9 and N-BNP.

Background Endothelin-1 is elevated in heart failure (HF) and after acute myocardial infarction (AMI) and gives prognostic information on mortality. Another part of its precursor, C-terminal pro–endothelin-1 (CT-proET-1), is more stable in circulation and ex vivo. We investigated the cardiovascular prognostic value post-AMI of CT-proET-1 and compared it to N-terminal pro–B-type natriuretic peptide (NTproBNP), a marker of death and HF. Methods We measured plasma CT-proET-1 and NTproBNP in 983 consecutive post-AMI patients (721 men, mean age 65.0 ± [SD] 12.2 years), 3 to 5 days after chest pain onset. Results There were 101 deaths and 49 readmissions with HF during follow-up (median 343, range 0-764 days). C-terminal pro–endothelin-1 was raised in patients with death or HF compared to survivors (median [range] [pmol/L], 119.0 [14.0-671.0] vs 73.0 [4.6-431.0], P Conclusion The endothelin system is known to be activated post AMI. C-terminal pro–endothelin-1 is a powerful predictor of adverse outcome, along with NTproBNP. CT-proET-1 may represent a clinically useful marker of prognosis after AMI.

The pacing model of heart failure produces heterogeneous changes in wall stress and myocyte diameter. The purpose of this study was to measure regional changes in cardiotrophin-1 (CT-1), a cytokine thought to play a role in LV remodeling, and regional changes in LV strain as measured with magnetic resonance imaging.Dilated cardiomyopathy was induced in nine mongrel dogs over 4 wk by rapid pacing using a right ventricular epicardial lead. Baseline CT-1 was measured from an apical myocardial biopsy, and regional CT-1 was measured from anterior, lateral, inferior, and septal walls after the induction of heart failure and in six control dogs. Tissue tagged images were divided into similar regions and minimal principal strain (MPS), ejection fraction, and ventricular volumes were compared after induction of heart failure.After induction of heart failure, LV ejection fraction and end-diastolic volume differed significantly from baseline (P0.01 and P = 0.02, respectively). Additionally, regional CT-1 and MPS were significantly different (P0.01 for both). Cardiotrophin-1 increased significantly in the inferior and septal walls (both P0.01) but not in the anterior or lateral walls (both P = NS). Minimum principal strain decreased significantly in the inferior and septal walls (both P0.01) but not in the anterior or lateral walls (both P = NS).The pacing model of heart failure produces heterogeneous changes in regional CT-1 and wall motion as measured by MPS. The greatest regional changes are closest to the pacemaker site: the inferior and septal walls. These differences in regional CT-1 may account for previously noted myocyte hypertrophy and preserved ventricular function in these regions.

UII is elevated in patients with heart failure; however its role in acute myocardial infarction (AMI) is unknown. We sought to compare levels of UII in patients with AMI to controls. We also compared UII to N terminal pro B type natriuretic peptide (NT-BNP) to evaluate whether levels of UII can be used to predict the risk of adverse clinical outcome (ACO).129 patients were studied with serial blood measurements and echocardiogram during their index admission. Plasma concentration of median UII was significantly elevated in AMI compared to controls (median 1.40 vs. 0.42 fmol/ml p0.012). Over the median follow up of 102 days (range 0-189) there were 14 deaths and 14 readmissions with AMI or heart failure. Using a Cox proportional hazards model the only independent predictors of ACO were UII (OR 0.29, p=0.046) and NT-BNP (OR 4.78, p=0.012) between 73 and 96 h. The Kaplan-Meier survival curve revealed a significantly better clinical outcome in patients with UII above the median compared with UII below the median.UII levels are raised in AMI and is an independent predictor of ACO. Patients with a poor outcome mount a lower UII response suggesting a possible cardioprotective role for this peptide.

Objectives This study sought to assess the prognostic impact of midregional pro-adrenomedullin (MR-proADM) after an acute myocardial infarction (AMI). Background Adrenomedullin (ADM) is elevated in heart failure (HF) and after AMI. Another part of its precursor, MR-proADM, is more stable in circulation and ex vivo. We investigated the cardiovascular prognostic value after AMI of MR-proADM and compared it with N-terminal pro-B-type natriuretic peptide (NTproBNP), a marker of death and HF. Methods We measured plasma MR-proADM and NTproBNP in 983 consecutive post-AMI patients (721 men, mean age 65.0 ± 12.2 years), 3 to 5 days after chest pain onset. Results There were 101 deaths and 49 readmissions with HF during follow-up (median 342, range 0 to 764 days). The MR-proADM was increased in patients with death or HF compared with survivors (median 1.19 nmol/l, range 0.09 to 5.39 nmol/l, vs. 0.71 nmol/l, range 0.25 to 6.66 nmol/l, p Conclusions The ADM system is activated after AMI. The MR-proADM is a powerful predictor of adverse outcome, especially in those with an elevated NTproBNP. The MR-proADM may represent a clinically useful marker of prognosis after AMI.

Myotrophin is a 12 kDa protein initially isolated from hypertrophied hearts of spontaneously hypertensive rats and acts by modulating NF-κB (nuclear factor κB) activity. We have reported previously the presence of myotrophin in patients with human systolic heart failure; however, its role as a predictor of MACE (major adverse cardiac events) in patients with ACS (acute coronary syndrome) is unclear. In the present study, we sought to investigate this and compared myotrophin with NTproBNP (N-terminal pro-B-type natriuretic peptide), a marker of MACE. We studied 356 patients with ACS {276 men; mean age, 63.0±12.8 years; 80.6% STEMI [ST segment elevation MI (myocardial infarction)]; and 19.4% NSTEMI (non-STEMI)}. Blood measurement was made at 25–48 h after the onset of chest pain. The plasma concentration of myotrophin and NTproBNP was determined using in-house non-competitive immunoassays. Patients were followed-up for the combined end point of death, MI or need for urgent revascularization. Over the median follow-up period of 355 (range 0–645) days, there were 28 deaths, 27 non-fatal MIs and 73 patients required urgent revascularization. Myotrophin was raised in patients with MACE compared with survivors [510.7 (116.0–7445.6) fmol/ml compared with 371.5 (51.8–6990.4) fmol/ml respectively; P=0.001; values are medians (range)]. Using a Cox proportional hazards model, myotrophin {HR (hazard ratio), 1.64 [95% CI (confidence interval), 0.97–2.76]; P=0.05} and Killip class above 1 [HR, 1.52 (95% CI, 0.93–2.42); P=0.10] were the only independent predictors of MACE. A Kaplan–Meier survival curve revealed a significantly better clinical outcome in patients with myotrophin below the median compared with those with myotrophin above the median (log rank, 7.63; P=0.006). In conclusion, after an ACS, levels of myotrophin are more informative at predicting MACE than NTproBNP and may be useful to risk stratify patients.

Context: Excess growth hormone (GH) is associated with early mortality.Objectives: We assessed the association of GH with prognosis after acute myocardial infarction (AMI), and the effects of secondary prevention therapies.Methods: GH was measured using a high-sensitivity assay in 953 AMI patients (687 males, mean age 66.1 ± 12.8 years).Results: During 2 years follow-up, there were 281 major adverse cardiac events (MACE). Patients with MACE had higher GH levels (median [range], 0.91 [0.04–26.28] μg/L) compared to event-free survivors (0.59 [0.02–21.6], p

Heart failure is a complex clinical syndrome that occurs at the end stage of heart disease. Despite advances in therapy for heart failure, improvement of clinical outcomes remains a challenge for physicians. The identification of treatment response early in the course of disease would be useful to improve management of these patients. The aim of this study was to identify novel biomarkers in plasma that could predict treatment response in patients with heart failure.Patients with heart failure who met inclusion and exclusion criteria according to the guidelines of the European Society of Cardiology were recruited. Uptitration of angiotensin-converting enzyme inhibitors and β blockers was performed over 6 months. Patients were followed up for clinical events within the next 24 months. Plasma proteins in patients who responded to standard treatment (responders) were compared with patients who died or were re-admitted for heart failure (non-responders). Plasma samples were depleted of 14 high abundance proteins with a multiple affinity removal system column (MARS). Then plasma samples were analysed on two-dimensional liquid chromatography coupled to a tandem mass spectrometry (2D LC-ESI-MS/MS) in high definition mode (HDMS(E)) to identify and quantify the different expression of proteins in plasma. Finally, ELISA was used to verify candidate biomarkers.Participants were 100 patients with heart failure matched for sex and age (50 responders [25 women], 50 non-responders [25 women], mean age 76·6 years [SD 8·1]). Of the non-responders, 18 died and 32 were re-admitted to hospital. 2D LC-ESI-MS/MS showed that the expression of neurotrimin (NTM) was highly upregulated, by 26·5 times (p0·0001), in the responder group compared with the non-responder group. ELISA in the verification phase showed that the concentrations of NTM in plasma were significantly higher in the responders and lower in the non-responders (mean 4·73 log10 relative light units [SD 0·07] vs 4·70 [0·08], p=0·036). When ANOVA with Bonferroni post-hoc comparisons was used in three outcome subgroups (responders, patients re-admitted to hospital, and deaths), NTM concentrations were significantly different between death and the other groups (higher in responder vs death group, p0·0001; higher in re-admission vs death group, p=0·001).Our findings suggest that NTM as a novel biomarker in heart failure will not only add information to understand the pathophysiological mechanisms of heart failure better, but also might provide a more accurate prediction of treatment response to guide medical therapy. In addition, a novel therapeutic target could be identified for design of drugs to improve outcomes. Futher work is required in larger populations to confirm this biomarker.European Union's Seventh Framework Programme (BIOSTAT-CHF), John and Lucille van Geest Foundation.

Trimethylamine N-oxide (TMAO) has attracted interest as circulating levels have reported prognostic value in patients with cardiovascular conditions, such as heart failure. With continual advances in accurate mass measurements, robust methods that can employ the capabilities of time of flight mass spectrometers would offer additional utility in the analysis of complex clinical samples. A Waters Acquity UPLC was coupled to a Waters Synapt G2-S high-resolution mass spectrometer. TMAO was measured in plasma by stable-isotope dilution-hydrophilic interaction liquid chromatography-time of flight mass spectrometry with multiple reaction monitoring (LC-ToF-MRM). Two transitions were monitored: m/z 76.1 to 58.066/59.073 and m/z 85.1 to 66.116/68.130. The method was assessed for linearity, lower limits of detection and quantitation, and reproducibility. A selected cohort of patients with systolic heart failure (SHF; n = 43) and healthy controls (n = 42) were measured to verify the assay is suitable for the analysis of clinical samples. Quantitative analysis of TMAO using LC-ToF-MRM enabled linearity to be established between 0.1 and 75 μmol/L, with a lower limit of detection of 0.05 μmol/L. Relative standard deviations reported an inter-day variation of ≤20.8 % and an intra-day variation of ≤11.4 % with an intra-study quality control variation of 2.7 %. Run times were 2.5 min. Clinical application of the method reported that TMAO in SHF was elevated compared to that of healthy controls (p

Inflammation plays a critical role in acute myocardial infarction (MI). One such inflammatory marker is myeloperoxidase (MPO). Its role as a predictor of death or MI in patients with ST segment elevation myocardial infarction (STEMI) is unclear.To investigate the role of MPO as a predictor of death or MI in patients with STEMI and to compare it with N-terminal pro-B-type natriuretic peptide (NT-BNP).384 post STEMI patients were studied. Patients were followed up for the combined end point of death or readmission with non-fatal MI.There were 40 deaths and 37 readmissions with MI. Median MPO was raised in patients experiencing death or MI than in survivors (median (range), 50.6 (15.3-124.1) ng/ml vs 33.5 (6.6-400.2) ng/ml, p = 0.001). Using a Cox proportional hazards model, log median MPO (HR 6.91, 95% CI 1.79 to 26.73, p = 0.005) and log median NT-BNP (HR 4.21, 95% CI 1.53 to 11.58, p = 0.005) independently predicted death or non-fatal MI. MPO had predictive power in both below and above median NT-BNP levels (log rank 5.60, p = 0.020 and log rank 5.12, p = 0.024, respectively). The receiver-operating curve for median NT-BNP yielded an area under the curve (AUC) of 0.72 (95% CI 0.65 to 0.79, p0.001); for median MPO, the AUC was 0.62 (95% CI 0.55 to 0.69, p = 0.001). The logistic model combining the two markers yielded an AUC of 0.76 (95% CI 0.69 to 0.82, p0.001).MPO and NT-BNP may be useful tools for risk stratification of all acute coronary syndromes, including patients with STEMI at higher risk.

We have developed a technique for analysing blood plasma using MALDI-MS with subsequent data analysis to identify significant and specific differences between heart failure (HF) patients and healthy individuals. A training dataset comprising 100 HF patients and 100 healthy individuals was used to search for biomarkers (m/z range 1000-10,000). EWP cartridges when used in tandem with microcon centrifugal filters were found to give the best results. A data management chain including event binning, background subtraction and feature extraction was developed to reduce the data, and statistical analysis was used to map feature intensities on to a common scale. Various mathematical approaches including a simple cumulative score, support vector machines (SVM) and genetic algorithms (GAs) were then used to combine the results from individual features and provide a robust classification algorithm. The SVM gave the most promising results (accuracy 95%, receiver operating characteristic (ROC) score of 0.997 using 18 selected features). Finally, a test dataset comprising a further 32 HF patients and 20 controls was used to verify that the 18 putative biomarkers and classification algorithms gave reliable predictions (accuracy 88.5%, ROC score 0.998).

N-terminal pro-B-type natriuretic peptide (N-BNP) is elevated in left ventricular systolic dysfunction (LVSD) and may be cost-effective for screening in the community but is relatively nonspecific. We sought to improve specificity using inflammatory markers such as C-reactive protein (CRP) and myeloperoxidase (MPO), which have been implicated in cardiovascular disease.A total of 1360 subjects (45-80 years) were invited in this prospective screening study for undiagnosed LVSD (defined as wall motion score1.8 [ejection fractionor = 40%]), and 1331 had analyzable echocardiographic scans and plasma specimens. Peptides were measured using immunoluminometric assays.Twenty-eight patients with LVSD had elevated plasma N-BNP, CRP, and MPO levels compared with healthy subjects (P.0005). Receiver operating characteristic curve areas for N-BNP, CRP, and MPO were 0.839, 0.824, and 0.909, respectively. All tests had high negative predictive values (99%). Specificity was maximized to 88.4% in a logistic model with all 3 markers (all independent predictors, accounting for 44.8% of the variance). This reduced the number of cases to scan to detect 1 case of LVSD from 29.7 (using N-BNP alone) to 6.6. Using plasma MPO (at 33.9 ng/mL) or urinary N-BNP (at 10.7 fmol/mL) as initial screening tests, combinations of plasma N-BNP, MPO, and CRP can achieve specificities up to a maximum of 94.3%. Costs were minimized by using urinary N-BNP as the initial screening test, followed by plasma biomarkers.Plasma CRP and MPO increased the specificity of N-BNP in LVSD screening. Screening is optimized by urinary N-BNP as an initial test, followed by plasma CRP, N-BNP, and MPO.

Background Few studies have compared the relative prognostic value of different natriuretic peptides after acute myocardial infarction (AMI). None has described peptide levels beyond the early post-AMI period. This study describes temporal profiles of 4 natriuretic peptides to 2 years after AMI and relationship with outcome. Methods and Results We assessed profiles of N-terminal proANP (N-ANP), B-type natriuretic peptide (BNP), N-terminal proBNP (N-BNP), and C-type natriuretic peptide (CNP) (study entry, 1 month, 1 year, and 2 years) in 236 patients with AMI complicated by clinical or radiologic evidence of heart failure. We assessed the prognostic value for baseline levels of each peptide for death or reinfarction. We observed distinct natriuretic peptide profiles. BNP and N-BNP levels were highest at baseline and fell thereafter. N-ANP levels increased from baseline to 30 days and fell thereafter. During follow-up (mean 938 days), 34 patients died and a further 25 suffered nonfatal AMI. Baseline natriuretic peptide levels did not have independent predictive power for outcome. N-BNP levels fell from baseline to 30 days in patients surviving to the end of follow-up ( P = .005) but were similar at both times ( P = .76) for those dying after 30 days. Age ( P P = .026) had independent predictive value for death after 30 days. Conclusion N-ANP, BNP, N-BNP, and CNP show distinct plasma profiles after AMI. Failure of plasma N-BNP to fall in the 30 days after AMI indicates adverse prognosis.

The extent of exercise intolerance in patients with chronic heart failure (CHF) is dependent on and representative of the severity of heart failure. However, few primary care physicians have direct access to facilities for formal exercise testing. We have therefore explored whether information readily obtainable in the community can reliably predict the functional capacity of patients.Ninety-six subjects with a wide range of cardiac function (10 healthy controls and 86 CHF patients with NYHA classes I-IV, LVEF 36.9+/-15.2%) were recruited into the study and had resting plasma N-BNP and cardiopulmonary exercise testing to measure peak oxygen consumption (VO2). Significantly higher N-BNP levels were found in the CHF group (299.3 [704.8] fmol/ml, median [IQR]) compared with the healthy control group (7.2 [51.2] fmol/ml), p0.0001. There were significant correlations between peak VO2 and N-BNP levels (R=0.64, P0.001), peak VO2 and NYHA class (R=0.76, P=0.001), but no significant correlation was seen between peak VO2 and LVEF (R=0.0788, P=0.33). Multivariate analysis identified plasma N-BNP (P0.0001) and NYHA class (P0.0001) as significant independent predictors of peak VO2. Logistic modelling with NYHA class and log N-BNP to predict peak VO220 ml/kg/min showed that the area under the curve of receiver-operating-characteristic (ROC) curve was 0.906 (95% CI 0.844-0.968). A nomogram based on the data has been constructed to allow clinicians to estimate the likelihood of peak VO2 to be20 ml/kg/min for given values of plasma N-BNP and NYHA class.By combining information from a simple objective blood test (N-BNP) and a simple scoring of functional status (NYHA), a clinician can deduce the aerobic exercise capacity and indirectly the extent of cardiac dysfunction of patients with CHF.

Phosphodiesterase type 5 (PDE5) inhibition has been proposed for the treatment for pulmonary arterial hypertension (PAH).This study compared adding sildenafil, a PDE5 inhibitor, to conventional treatment with the current practice of adding bosentan, an endothelin receptor antagonist.Twenty-six patients with PAH, idiopathic or associated with connective tissue disease, World Health Organization (WHO) functional class III, were randomized in a double-blind fashion to receive sildenafil (50 mg twice daily for 4 weeks, then 50 mg three times daily) or bosentan (62.5 mg twice daily for 4 weeks, then 125 mg twice daily) over 16 weeks.Changes in right ventricular (RV) mass (using cardiovascular magnetic resonance), 6-minute walk distance, cardiac function, brain natriuretic peptide, and Borg dyspnea index.When analyzed by intention to treat, there were no significant differences between the two treatment groups. One patient on sildenafil died suddenly. Patients on sildenafil who completed the protocol showed significant changes from baseline, namely, reductions in RV mass (-8.8 g; 95% confidence interval [CI], -2, -16; n = 13, p = 0.015) and plasma brain natriuretic peptide levels (-19.4 fmol x ml(-1); 95% CI, -5, -34; p = 0.014) and improvements in 6-minute walk distance (114 m; 95% CI, 67, 160; p = 0.0002), cardiac index (0.3 L x min(-1) x m(-2); 95% CI, 0.1, 0.4; p = 0.008), and systolic left ventricular eccentricity index (-0.2; 95% CI, -0.02, -0.37; p = 0.031). Bosentan improved 6-minute walk distance (59 m; 95% CI, 29, 89; n = 12, p = 0.001) and cardiac index (0.3; 95% CI, 0.1, 0.4; p = 0.008).Sildenafil added to conventional treatment reduces RV mass and improves cardiac function and exercise capacity in patients with PAH, WHO functional class III. Safety monitoring is important until more experience is obtained.

ObjectivesWe sought to compare urinary and plasma N-terminal pro-brain natriuretic peptide (N-BNP) in left ventricular systolic dysfunction (LVSD) diagnosis.BackgroundPlasma N-BNP is elevated in LVSD. Renal tubule cells produce BNP. We tested the incremental value of urinary N-BNP in LVSD diagnosis.MethodsIn this prospective, community-screening study of undiagnosed LVSD, 1,360 subjects (45 to 80 years of age) were invited, and 1,308 had analyzable echocardiographic scans and urine and plasma specimens. The criterion standard for LVSD was defined as a wall motion score over 1.8 (ejection fraction ≤40%).ResultsTwenty-eight patients with LVSD had elevated urinary and plasma N-BNP levels compared with normal subjects (p < 0.0005). Receiver-operating characteristic (ROC) areas under the curve (AUCs) for urinary and plasma N-BNP were 0.831 and 0.840, respectively. Both tests had high negative predictive values (>99%) for excluding LVSD. Urinary N-BNP was more specific (67.2%) than plasma N-BNP (41%). The plasma/urinary N-BNP product yielded a higher ROC-AUC (0.923) and specificity (78%), reducing the number of cases to scan to detect one case of LVSD to 11.4 (compared with 16.6 [urinary N-BNP] and 29.0 [plasma N-BNP]). Sequential application of tests (urinary N-BNP, then plasma N-BNP in the urine-“positive” cases) achieved similar reductions in the number of cases to scan (10.8), while limiting the number of N-BNP tests to be performed. Urinary N-BNP performed poorly in detection of other cardiac abnormalities with preserved systolic function. It was less costly to test urinary N-BNP in the whole population as compared with other strategies, including scanning high-risk cases with N-BNP testing in the remainder.ConclusionsUrinary N-BNP used together with plasma N-BNP could reduce the echocardiographic burden in screening programs.

The recently discovered peptide urocortin-I, which is present in animal and human blood, is elevated in subjects with heart failure. In an experimental animal heart-failure model, urocortin-I had a sustained and beneficial effect on haemodynamic, endocrine and renal parameters. Urocortins (UCN) I, II and III have also been shown to prevent cell death when administered to primary cardiac myocyte cultures before or even after ischemic injury. This raises the possibility of using the urocortin family of peptides or urocortin-like agonists in the therapy of heart failure and as cardioprotective agents.

In the present study, we assessed the use of urinary natriuretic peptides [N-terminal proatrial natriuretic peptide (N-ANP) and N-terminal pro-brain natriuretic peptide (N-BNP) and C-type natriuretic peptide (CNP)] in the diagnosis of heart failure. Thirty-four consecutive hospitalized heart failure patients (median age, 75.5 years; 14 female) were compared with 82 age- and gender-matched echocardiographically normal controls. All subjects provided plasma and urine specimens. Plasma was assayed for N-BNP, and urine was assayed for N-ANP, N-BNP and CNP. The diagnostic efficiency of peptides was assessed using receiver operating characteristic (ROC) curve analysis. All three urinary natriuretic peptides were significantly elevated in heart failure patients (P