BackgroundCurrent risk prediction models in heart failure (HF) including clinical characteristics and biomarkers only have moderate predictive value. The aim of this study was to use matrix assisted laser desorption ionisation mass spectrometry (MALDI-MS) profiling to determine if a combination of peptides identified with MALDI-MS will better predict clinical outcomes of patients with HF.MethodsA cohort of 100 patients with HF were recruited in the biomarker discovery phase (50 patients who died or had a HF hospital admission vs. 50 patients who did not have an event). The peptide extraction from plasma samples was performed using reversed phase C18. Then samples were analysed using MALDI-MS. A multiple peptide biomarker model was discovered that was able to predict clinical outcomes for patients with HF. Finally, this model was validated in an independent cohort with 100 patients with HF.ResultsAfter normalisation and alignment of all the processed spectra, a total of 11,389 peptides (m/z) were detected using MALDI-MS. A multiple biomarker model was developed from 14 plasma peptides that was able to predict clinical outcomes in HF patients with an area under the receiver operating characteristic curve (AUC) of 1.000 (p=0.0005). This model was validated in an independent cohort with 100 HF patients that yielded an AUC of 0.817 (p=0.0005) in the biomarker validation phase. Addition of this model to the BIOSTAT risk prediction model increased the predictive probability for clinical outcomes of HF from an AUC value of 0.643 to an AUC of 0.823 (p=0.0021). Moreover, using the prediction model of fourteen peptides and the composite model of the multiple biomarker of fourteen peptides with the BIOSTAT risk prediction model achieved a better predictive probability of time-to-event in prediction of clinical events in patients with HF (p=0.0005).ConclusionsThe results obtained in this study suggest that a cluster of plasma peptides using MALDI-MS can reliably predict clinical outcomes in HF that may help enable precision medicine in HF.

Objective— BMS-986120 is a novel first-in-class oral PAR4 (protease-activated receptor 4) antagonist with potent and selective antiplatelet effects. We sought to determine for the first time, the effect of BMS-986120 on human ex vivo thrombus formation. Approach and Results— Forty healthy volunteers completed a phase 1 parallel-group PROBE trial (Prospective Randomized Open-Label Blinded End Point). Ex vivo platelet activation, platelet aggregation, and thrombus formation were measured at 0, 2, and 24 hours after (1) oral BMS-986120 (60 mg) or (2) oral aspirin (600 mg) followed at 18 hours with oral aspirin (600 mg) and oral clopidogrel (600 mg). BMS-986120 demonstrated highly selective and reversible inhibition of PAR4 agonist peptide (100 μM)-stimulated P-selectin expression, platelet-monocyte aggregates, and platelet aggregation ( P <0.001 for all). Compared with pretreatment, total thrombus area (μm 2 /mm) at high shear was reduced by 29.2% (95% confidence interval, 18.3%–38.7%; P <0.001) at 2 hours and by 21.4% (9.3%–32.0%; P =0.002) at 24 hours. Reductions in thrombus formation were driven by a decrease in platelet-rich thrombus deposition: 34.8% (19.3%–47.3%; P <0.001) at 2 hours and 23.3% (5.1%–38.0%; P =0.016) at 24 hours. In contrast to aspirin alone, or in combination with clopidogrel, BMS-986120 had no effect on thrombus formation at low shear ( P =nonsignificant). BMS-986120 administration was not associated with an increase in coagulation times or serious adverse events. Conclusions— BMS-986120 is a highly selective and reversible oral PAR4 antagonist that substantially reduces platelet-rich thrombus formation under conditions of high shear stress. Our results suggest PAR4 antagonism has major potential as a therapeutic antiplatelet strategy. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT02439190.

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.

Introduction: Despite current anti-platelet agents, many individuals continue to experience recurrent ischaemic events. BMS-986120 is a novel anti-platelet agent that antagonises protease-activated...

AimsWe sought to compare the prognostic utility of growth hormone (GH) with NT-proBNP) and the ADHERE score in a large cohort of acute heart failure (HF) patients, subcategorized into HF with reduced EF <50% (HFrEF) and preserved EF 50% (HFpEF).Methods and resultsGH and NTproBNP levels were measured in 537 patients (HFrEFn = 415; HFpEFn = 122) with acute HF recruited into this prospective cohort study. The main outcome measure was death or HF readmission at 1 year. GH levels were higher in both HFrEF [1.26 (0.54-2.62) vs. 0.8 (0.26-1.94) ng/mL, P < 0.001] and HFpEF [1.04 (0.48-2.92) vs. 0.53 (0.18-1.94) ng/mL, P = 0.020] patients with the outcome compared with event-free survivors. GH levels were independently predictive for the outcome at 1 year in the entire cohort [HR 1.47, 95% confidence interval (CI) 1.16-1.86, P = 0.001] and those with HFrEF (HR 1.54, 95% CI 1.19-1.99, P = 0.001) in multivariate Cox hazard analysis. GH improved risk classification as measured by continuous net reclassification improvement (NRI) when added to the ADHERE multivariate logistic model of age, sex, urea, heart rate, and systolic blood pressure, for all patients [NRI 29.6 (12.1-47.1), P = 0.001] and HFrEF NRI 21.7 (1.9-41.6), P = 0.034] patients, as well as in addition to the ADHERE model combined with NT-proBNP for all patients [NRI 25.4 (7.8-43.1), P = 0.005].ConclusionsGH offers incremental prognostic information over the ADHERE score clinical predictors and NT-proBNP for risk stratification of acute HF patients.

We undertook this systematic review to determine the prognostic significance of adrenomedullin (ADM) in patients with heart failure and acute myocardial infarction (AM!). Given the difficulty in measuring mature ADM, its surrogate, tnidregional proadrenomedullin (MRproADM) has been used in most studies. Systematic search of original published studies through MEDLINE and the Cochrane Collaboration databases restricted to reports in English from January 1, 1993, to June 30, 2014, in humans was undertaken. Heterogeneity of studies prohibited a meta-analysis. In patients with heart failure, the area under the curve for prediction of mortality by MRproADM ranged from 0.68 to 0.81 (95% confidence intervals [CI] 0.63 to 0.91) across studies. One nmol/l increase in MRproADM was associated with hazard ratios (HRs) ranging from 1.77 to 2.79 (95% CI 1.29 to 5.95) for death in patients with heart failure. In patients with AMI, the area under the curve for MRproADM predicting MACE ranged from 0.64 to 0.80 (CI 0.51 to 0.87) across studies and death 0.79 to 0.84 (CI 0.73 to 0.90). One nmol/l increase in MRproADM was associated with HR for MACE ranging from 1.78 to 4.10 (CI 1.20 to 10.12), whereas log10 of MRproADM had HRs of 3.63 to 9.75 (CI 1.48 to 26.16) for MACE and 4.86 to 16.68 (CI 4.56 to 60.99) for death across studies in patients with AMI. In conclusion, adrenomedullin is an independent predictor of death in patients with heart failure and of MACE and death in patients who have suffered an AMI. Quantification of this peptide might contribute to improved risk stratification in settings of heart failure and myocardial infarction. 2015 Elsevier Inc. All rights reserved.

Background The differences in concentrations of MMP and its natural inhibitor TIMP in patients with EF <45 and EF >45 during hospitalisation with acute heart failure have yet to be defined. The objectives of this study were to compare the prognostic value of biomarkers of remodelling and fibrosis between these populations. Herein we evaluated the potential difference of circulating MMP (2,3,9) and TIMP (1–4) levels in these two groups of patients hospitalised with AHF Methods A prospective observational study of 400 patients hospitalised with symptomatic acute heart failure was performed. Plasma levels of NT-proBNP, MMP-2, MMP-3, MMP-9, along with inhibitors (TIMP-1 to 4) were measured at admission and at discharge. Patients were divided into two groups (EF <45 and EF >45) based on TTE and the prognostic ability of the remodelling biomarkers was assessed prospectively. The primary end point was composite of all cause mortality and HF related hospitalisation at one year. Results Mean LVEF was 25.6 ± 96 ± 9.1% in group 1 (282 patients) and 63.3 ± 73 ± 7.3% in group 2 (97 patients). High admission NT-proBNP, MMP-2 and low MMP-9 levels were noted in patients with EF <45 as compared to with EF >45 (P < 0P <0.05), the only significant difference between the groups remaining after adjusting for possible confounding variables was NT-proBNP (P = P = 0.001). Inpatients with EF <45 (group 1), above median MMP-3 (p 0.001) as compared to below median MMP-9 (p 0.01) in EF >45 (group 2) were more likely to experience outcome. In addition we noticed those with EF <45 had low sBP, high EDV, ESV and more likely to be prescribed beta blockers and spironolactone at discharge. Conclusions Patients with EF <45 or EF >45 presenting with similar symptoms and functional limitations exhibit differential concentration of MMP-2, MMP-3 and MMP-9 during hospitalisation with acute heart failure. Those with EF <45 exhibits significantly high NT-proBNP levels as compared to patients with EF >45. Higher median MMP-3 levels in group 1 and low median MMP-9 levels in group 2 predicts future combined outcome suggesting heterogeneity and differences in the mechanisms related to their release or clearance. No significant differences were noted in TIMP levels between the two groups.

Purpose Changes in the intercellular matrix have previously been found to be important in left ventricle (LV) remodelling in chronic heart failure (HF). We investigated whether plasma matrix metalloproteinase (MMP) 3 and 9 were associated with adverse clinical outcomes in acute HF. Methods In a prospective cohort study pre-discharge plasma MMP-3 and 9 levels were measured in 400 consecutive patients presenting to hospital with acute HF. LV ejection fraction (LVEF) was assessed by echocardiography. The clinical endpoints were death and death or HF readmission at 1 year. Results By 1 year 103 patients had died and 173 patients had died or been readmitted with HF. MMP-3 was significantly greater in males (p < 0.001), those with hypertension (p < 0.01) and with a past history of chronic HF (p = 0.01) and chronic kidney disease (CKD) (p < 0.001). MMP-3 was significantly correlated with age (p < 0.001) while being inversely correlated with eGFR (p < 0.001) and heart rate (p < 0.008). MMP-3 was significantly greater in patients with a LVEF < 40% compared with those with EF > 40% (p = 0.017). MMP-3 levels were significantly greater in the 108 patients who died compared to those who did not [median = 29.7 [19. to 41.1] vs. 18.9 [11.8 to 30.7] pg/ml, p < 0.001) as well as in those with the combined endpoint compared to those without (26.1 [16.7 to 36.4] vs. 17.9 [11.4 to 31.3] pg/ml, p < 0.001). In Kaplan-Meier analysis, patients with above median MMP-3 levels were significantly more likely to experience the endpoint (p < 0.001) compared to those who did not. Discharge MMP-9 levels were significantly inversely correlated with age (p = 0.003) but had no relationship with LVEF. MMP-9 levels were significantly lower in patients who died (p < 0.007) and in those with the combined outcome of death or HF readmission (p < 0.001). In Kaplan-Meier analysis, patients with below median MMP-9 levels were significantly more likely to experience the endpoint (p = 0.007) compared to those who did not. The AUC of MMP-3 combined with NTproBNP was significantly greater than NTproBNP alone (p = 0.044) for outcome death but not death or HF readmission (p = 0.092) while the AUC of MMP-9 combined with NTproBNP was significantly greater than NTproBNP alone for the combined endpoint (p = 0.027) but not death alone (p = 0.085) Conclusion Increased MMP-3 but decreased MMP-9 levels are associated with worse prognosis after admission with acute HF. MMP-3 added prognostic value to NTproBNP for prediction of death while MMP-9 added prognostic value to NTproBNP for prediction of death or HF readmission at 1 year.

BACKGROUND Pro-substance P (ProSP) is a stable surrogate marker for labile substance P, which has pro-inflammatory effects, increases platelet aggregation and clot strength, and reduces fibrinolysis.OBJECTIVES This study assessed whether ProSP was associated with poor prognosis after acute myocardial infarction (AMI) to identify novel pathophysiological mechanisms.METHODS ProSP was measured in 1,148 AMI patients (825 men, mean age 66.2 +/- 12.8 years). Endpoints were major adverse cardiac events (composite of death, reinfarction, and heart failure [HF] hospitalization), death/reinfarction, and death/HF. GRACE (Global Registry of Acute Coronary Events) scores were compared with ProSP for death and/or reinfarction at 6 months.RESULTS During 2-year follow-up, there were 140 deaths, 112 HF hospitalizations, and 149 re-AMI. ProSP levels were highest on the first 2 days after admission and related to estimated glomerular filtration rate, age, history of diabetes, ischemic heart disease or hypertension, Killip class, left ventricular wall motion index, and sex. Multivariate Cox regression models showed ProSP level was a predictor of major adverse events (hazard ratio [HR]: 1.30; 95% confidence interval [CI]: 1.10 to 1.54; p < 0.002), death and/or AMI (HR: 1.42; 95% CI: 1.20 to 1.68; p < 0.0005), death and/or HF (HR: 1.38; 95% CI: 1.14 to 1.67; p < 0.001). ProSP levels with GRACE scores were independent predictors of 6-month death and/or reinfarction (p < 0.0005 for both). ProSP-adjusted GRACE scores reclassified patients significantly (overall category-free net reclassification improvement of 31.6 (95% CI: 14.3 to 49.0; p < 0.0005) mainly by down-classifying those without endpoints.CONCLUSIONS ProSP levels post-AMI are prognostic for death, recurrent AMI, or HF, and they improve risk prediction of GRACE scores, predominantly by down-classifying risk in those without events. (C) 2014 by the American College of Cardiology Foundation.

Objectives The goal of this research was to assess the prognostic value of proenkephalin (PENK) levels in acute myocardial infarction (AMI) by using N-terminal pro-B-type natriuretic peptide and Global Registry of Acute Coronary Events (GRACE) scores as comparators and to identify levels that might be valuable in clinical decision making.Background PENK is a stable analyte of labile enkephalins. Few biomarkers predict recurrent AMI.Methods We measured PENK in 1,141 patients (820 male subjects; mean age 66.2 +/- 12.8 years) with AMI. Endpoints were major adverse events (composite of death, myocardial infarction [MI], and heart failure [HF] hospitalization) and recurrent MI at 2 years. GRACE scoring was used for comparisons with PENK for the death and/or MI endpoint at 6 months.Results During follow-up, 139 patients died, and there were 112 HF hospitalizations and 149 recurrent AMIs. PENK levels were highest on admission and were related to estimated glomerular filtration rate, left ventricular wall motion index, sex, blood pressure, and age. Multivariable Cox regression models found that the PENK level was a predictor of major adverse events (hazard ratio [HR]: 1.52 [95% confidence interval (Cl): 1.19 to 1.94]), death and/or AMI (HR: 1.76 [95% Cl: 1.34 to 2.30]), and death and/or HF (HR: 1.67 [95% Cl: 1.24 to 2.25]) (all comparisons p < 0.001), as well as recurrent AMI (HR: 1.43 [95% Cl: 1.07 to 1.91]; p < 0.01). PENK levels were independent predictors of 6-month death and/or MI compared with GRACE scores. PENK-adjusted GRACE scores reclassified patients significantly (overall category-free net reclassification improvement [>0] of 21.9 [95% Cl: 4.5 to 39.4]; p < 0.014). PENK levels <48.3 pmo1/1 and >91 pmo1/1 detected low- and high-risk patients, respectively.Conclusions PENK levels reflect cardiorenal status post-AMI and are prognostic for death, recurrent AMI, or HF. Cutoff values define low- and high-risk groups and improve risk prediction of GRACE scores. (1 Am Coll Cardiol 2014;63:280-9) 2014 by the American College of Cardiology Foundation

Background: Soluble ST2 is a marker of cellular stress and injury whose natural ligand is interleukin-33. We investigate, for the first time, the relationship of IL-33 and ST2 with death at 30-days, 1-year and beyond in unselected STEMI patients. We assess the incremental value they offer over GRACE score and NT-proBNP. Secondary endpoints were heart failure readmission and re-infarction.Methods: ST2 and IL-33 were measured in 677 patients 3-5 days after admission. Median follow-up was 587 (134-2818) days during which 101 (15%) patients died.Results: ST2 was higher in those who died when compared to event-free survivors (median [range] 1125 [123-15781] vs. 630 [59-11729] pg/ml, p<0.001) as was IL-33 (75 [5.4-17893] vs. 5.4 [5.4-16466] pg/mL, p=0.006). Multivariate Cox regression analysis reveals that elevated ST2 is associated with increased risk of mortality at 30-days (HR 9.34, p<0.001) and 1-year (HR 3.15, p=0.001). These relationships continued after further adjustment for GRACE-RS and NT-proBNP. Combining ST2 (c-statistic 0.82, p<0.001), GRACERS (0.82, p<0.001) and NT-proBNP (0.84, p<0.001) leads to a significant improvement in the c-statistic for 30-day mortality to 0.90 (p=0.01). IL-33 above 5.4 pg/ml was independently associated with increased mortality at 30-days (HR 4.16, p=0.007) and 1-year (HR 2.29, p=0.008) but, did not add incremental prognostic value over using GRACE-RS and NT-proBNP. The ratio IL-33/ST2 was not associated with events.Conclusions: Elevated ST2 and IL-33 were both associated with increased mortality. ST2 demonstrated incremental value over contemporary risk markers but, IL-33 did not. ST2 has a potential role in risk stratification using a multi-marker approach. (C) 2012 Elsevier Ireland Ltd. All rights reserved.

The uroguanylin system is a newly discovered endocrine/paracrine system that may have a role in the regulation of salt balance, appetite and gut health. The precursor pro-uroguanylin is predominantly synthesized in the gut, although there may be other sites of synthesis, including the kidney tubules. Products from pro-uroguanylin may mediate natriuresis following oral consumption of a salt load through both GC-C (guanylate cyclase C)-dependent and -independent mechanisms, and recent evidence suggests a role in appetite regulation. Local paracrine effects in the gut through GC-C stimulation may have tumour-suppressing actions through the regulation of cell proliferation and metabolism. Although most information on this system has been derived from knockout models, recent human studies have indicated possible roles in heart failure and renal failure. An improved understanding of the nature of its natriuretic, appetite and tumour-suppressing actions may facilitate the discovery of new therapies for heart failure, obesity and cancer prophylaxis.

Background Risk stratification is vital to the optimal management of patients with non ST-elevation myocardial infarction (NSTEMI) however, current tools are not fully discriminatory. Copeptin, the stable 39 amino acid C-terminal portion of pro-vasopressin, is a recognised prognostic marker in ST elevation myocardial infarction (STEMI) that is also useful to exclude MI as levels rise early after onset. Copeptin has not been evaluated in a NSTEMI population to date. Aims We hypothesised that copeptin is an independent predictor of mortality following NSTEMI and, in accordance with AHA criteria for the evaluation of novel biomarkers, assess whether copeptin adds prognostic information to GRACE risk score (GRACE-RS). We use NT-proBNP for comparison. Methods and Results In this prospective observational study plasma copeptin and NT-proBNP was measured in 754 NSTEMI patients (519 men, median age 70±13 years) within 36 h of symptoms. The primary endpoint of all-cause mortality at 6 months was reached by 56 (7.4%) patients. Median copeptin levels were 7.9 range 0.3 to 523.0 pmol/l and were significantly higher in those that reached the primary endpoint than the event free survivors; median (IQR), 32.0 (12.0–88.7) vs 7.2 (4.0–16.7) respectively p<0.001. Both copeptin and NT-proBNP were predictive of the primary endpoint on univariate Cox regression analysis (HR 5.98 p<0.0005 and HR 6.07 p<0.0005 respectively). On adjustment for baseline clinical and biochemical variables copeptin remained predictive (HR 3.03 p=0.009) but NT-proBNP did not (p=0.70). Kaplan-Meier analysis revealed that supra-median levels of copeptin were associated with increased mortality (log rank 28.4 p<0.001). ROC curve c-statistics for GRACE-RS of 0.799 increased to 0.835 when combined with copeptin (0.785), when combined with NT-proBNP (0.730) increased to 0.802. Re-classification analysis shows that copeptin improves accuracy of risk stratification when combined with the GRACE-RS as determined by net reclassification improvement (NRI 13.3% p=0.008) whereas, NT-proBNP does not (NRI −4.9% p=0.21). The relative utilities for logistic regression models using GRACE-RS alone, GRACE-RS + copeptin and GRACE-RS + NTproBNP as covariates are shown in Abstract 11 figure 1. The relevant region was the region to the right of the sample risk for 6 months mortality, 0.074. The relative utility for GRACE-RS + copeptin was consistently more than the relative utility for GRACE-RS + NTproBNP across a range of risks; for example at a risk threshold of 15% the additional utility of adding copeptin to the GRACE-RS was 0.097 compared to 0.009 for NTproBNP. Conclusions High plasma copeptin levels indicate a worse outcome in NSTEMI patients. We have demonstrated that copeptin fulfils AHA criteria by improving risk stratification over established markers GRACE score and NT-proBNP. Copeptin is also useful for rapid rule-out of MI and the current findings further support clinical uptake.

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<0.001] or were readmitted with heart failure [598 (231.6–1803.9) ng/ml, P<0.004] compared with event-free survivors [486.9 (29.3–3118.2) ng/ml]. Using Cox modelling, log10 PR3 [HR (hazard ratio), 3.80] and log10 NT-proBNP (HR, 2.51) were significant independent predictors of death or heart failure. When patients were stratified by plasma NT-proBNP (median, 1023 pmol/l), PR3 gave additional predictive value for death or heart failure, in both the patients in whom NT-proBNP level was above the median (log rank for trend, 12.54; P<0.0004) and those with NT-proBNP level below the median (log rank for trend, 3.83; P<0.05). Neither marker predicted recurrent AMI. In conclusion, this is the first report showing a potential role for the serine protease PR3 in determining mortality and incidence of heart failure following AMI, independent of established conventional risk factors. PR3 may represent a clinically useful marker of prognosis after an AMI as part of a multimarker strategy.

Background Soluble ST2 is a marker of biomechanical strain for which the natural ligand is interleukin 33 (IL-33). They have not been studied together in non-ST-elevation myocardial infarction (NSTEMI). We investigated their relationship with death, heart failure (HF) readmission, and reinfarction combined (termed major adverse cardiac events [MACE]) and, separately, in unselected patients using Global Registry of Acute Coronary Events Risk Scoring (GRACE-RS) and n terminal pro B type natriuretic peptide (NT-proBNP) as benchmark comparators.Methods ST2 and IL-33 were measured in 577 patients 3 to 5 days after admission. Mean follow-up was 532 (150-1059) days, during which 156 patients (27%) reached the primary end point.Results ST2 was higher in those who experienced MACE when compared with event-free survivors (median 782 pg/mL vs 596, P < .001), but there was no difference in IL-33 levels across any end point. Multivariate Cox regression analysis reveals that elevated ST2 is independently associated with increased risk of MACE during the long term (hazard ratio [HR] 2.01, P = .005). This relationship continues on further adjustment for either GRACE risk score or NT-proBNP individually but not on adjustment for both. ST2 also independently predicts reinfarction (HR 2.48, P = .03) and 30-day mortality (HR 4.43, P = .02, c-statistic 0.73, P < .001). Adding ST2 to GRACE or to NT-proBNP did not lead to significant improvements in the c-statistic for MACE for long-term follow-up (P = .27 and P = .57, respectively) or the net reclassification index. Neither IL-33 nor its ratio with ST2 was associated with study end points.Conclusions Elevated ST2 predicts adverse outcome in non-ST-elevation myocardial infarction but does not significantly improve risk stratification for established markers. Interleukin 33 was not related to adverse events. (Am Heart J 2011;161:1163-70.)

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<0.006 and P=0.01 respectively), but were similar in patients with HF (n=106) or MI (n=138). MMP-9 levels were similar across study end points. Using Cox proportional hazards modelling, MMP-2 demonstrated an independent prediction of death [HR (hazard ratio) 6.60, P=0.001], along with NT-proBNP (HR 4.62, P<0.001) and the GRACE score (HR 1.03, P<0.001), but MMP-3, MMP-9 or log10-troponin I did not. For 1 year mortality, the areas under the receiver operating characteristic curves were 0.60 and 0.58 for MMP-2 and MMP-3 respectively, compared with 0.82 for NT-proBNP and 0.84 for the GRACE score (all P<0.001). Kaplan-Meier analysis revealed that MMP-2 levels in the top quartile were associated with higher mortality rates (log rank 12.49, P=0.006). On univariate analysis, MMP-2 and MMP-3 had a weak association with HF readmission, which was lost after adjustment for clinical factors. None of the MMPs tested predicted MI. In conclusion, this is the first single centre study that identifies MMP2 as an independent predictor of all-cause mortality post-ACS (acute coronary syndrome); however, NT-proBNP and the GRACE score are superior for risk stratification in this cohort.

Objective 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.Design Observational cohort study.Setting Teaching hospital coronary care unit.Patients 1725 patients admitted with acute coronary syndrome (56.3% ST elevation ACS; median age 67, range 24-97 years).Measurements 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.Outcome measures The primary end point was the occurrence of MACE (death, recurrent myocardial infarction or hospitalisation with heart failure).Results 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 (p<0.005), strongest for patients with NT-proBNP in the top quartile of observed values (HR=2.768, p<0.001). 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).Conclusions 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.

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<0.0005) higher compared with levels in healthy controls [5.5 (0.4–22.3 μg/l) for proguanylin and 6.3 (2.5–16.9) μg/l for prouroguanylin]. In patients with HF, increased age, a history of hypertension, diabetes and atrial fibrillation, use of diuretics, a higher NYHA (New York Heart Association) class and a lower eGFR (estimated glomerular filtration rate) were significant univariate predictors of proguanylin and prouroguanylin levels. In multivariate analysis, a history of hypertension and low eGFR both had strong independent associations with proguanylin and prouroguanylin levels. Proguanylin and prouroguanylin varied significantly between NYHA class with a trend of increasing plasma concentrations with worsening severity of symptoms. In conclusion, plasma proguanylin and prouroguanylin are elevated in patients with HF. Elevated plasma proguanylin and prouroguanylin levels are associated with hypertension, renal impairment and increasing severity of HF. This novel endocrine system may contribute to the pathophysiology of HF.

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 < 0.001). Admission sAM was particularly associated with early (<30 days) mortality (c-statistic = 0.90, p < 0.001), and when compared with N-terminal pro-B-type natriuretic peptide and GRACE score, it was the only independent predictor of this end point. Admission sAM >1.11 nmol/l identified those at highest risk of death (p < 0.001). Patients with above-median admission sAM may benefit from revascularization. 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.