PAR4 (Protease-Activated Receptor 4) Antagonism With BMS-986120 Inhibits Human Ex Vivo Thrombus Formation.

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 (µm2/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.

Prognostic value of human mature adrenomedullin in patients with acute myocardial infarction.

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.

New Evidence Supporting the Use of Mineralocorticoid Receptor Blockers in Drug-Resistant Hypertension.

Treatment resistant hypertension (TRH), defined as a blood pressure above goal despite treatment with optimally tolerated doses of 3 antihypertensive agents of different classes, ideally including a diuretic, remains a significant problem and its management an area of uncertainty for physicians. One hypothesis is that resistant hypertension is due to abnormal sodium retention, mediated by aldosterone breakthrough occurring despite blockade of the renin-angiotensin-aldosterone system with angiotensin converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB). Thus, there has been renewed interest in the use of mineralocorticoid receptor blockers (MRB) to treat this condition. This article critically evaluates new evidence supporting the use of MRB in TRH published in the last 3 years. We conclude that there is now sufficient evidence to recommend MRB, in particular spironolactone, as the first choice medication to treat this condition, and for its inclusion in future guidelines.

Plasma growth hormone is a strong predictor of risk at 1 year in acute heart failure.

AIMS: We 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 RESULTS: GH and NTproBNP levels were measured in 537 patients (HFrEF n = 415; HFpEF n = 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]. CONCLUSIONS: GH offers incremental prognostic information over the ADHERE score clinical predictors and NT-proBNP for risk stratification of acute HF patients.

Disproportionate effect on child admissions of the change in Medicines and Healthcare Products Regulatory Agency guidance for management of paracetamol poisoning: an analysis of hospital admissions for paracetamol overdose in England and Scotland.

OBJECTIVE: The aim of the present study was to assess the effects of the changes in the management of paracetamol overdose recommended by the UK Commission for Human Medicines on rates of hospital admission. METHODS: An interrupted time series analysis was carried out on data for hospital admissions for paracetamol poisoning for England between January 2010 and June 2014, and for Scotland between January 2010 and Sept. 2014. The main outcome measure was admissions to hospital with paracetamol poisoning (T39.1), as defined by first position coding in children and adults. RESULTS: The time series analysis (Jan 2010 to June 2014) showed that admission rates for paracetamol poisoning were steady from 2010 to the date of change (September 2012), with an estimated 269 [95% confidence interval (CI) 252.5, 285.5] child (0-14 years) and 3541 (95% CI 3454, 3628) adult admissions per month. In September 2013, 12 months after the change, there were an estimated additional 116 [37.3% (95% CI 17.2-67.4)] child and 426 [12.5% (95% CI 4.5-19.6)] adult admissions. Thus, in the year before the change (September 2011 to August 2012) there were 45,181 (3500 child and 41,681 adult) admissions, and in the year after (September 2012 to August 2013) there were 50,198 (4779 child and 45,419 adult) admissions. The overall proportion of child admissions was significantly greater after the change (Chi-square 32.486, P < 0.001), emphasizing the disproportionate effect in children. CONCLUSIONS: Changes to the management guidelines for paracetamol poisoning in September 2012 were rapidly implemented but have particularly increased paediatric hospital admissions for paracetamol poisoning. This impact in children, who are at low risk of mortality from paracetamol toxicity, appears excessive.

Prognostic significance of adrenomedullin in patients with heart failure and with myocardial infarction.

We undertook this systematic review to determine the prognostic significance of adrenomedullin (ADM) in patients with heart failure and acute myocardial infarction (AMI). Given the difficulty in measuring mature ADM, its surrogate, midregional 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.

Pro-substance p for evaluation of risk in acute myocardial infarction.

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.

Proenkephalin and prognosis after acute myocardial infarction.

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 (CI): 1.19 to 1.94]), death and/or AMI (HR: 1.76 [95% CI: 1.34 to 2.30]), and death and/or HF (HR: 1.67 [95% CI: 1.24 to 2.25]) (all comparisons p < 0.001), as well as recurrent AMI (HR: 1.43 [95% CI: 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% CI: 4.5 to 39.4]; p < 0.014). PENK levels <48.3 pmol/l and >91 pmol/l 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.

Pre-discharge risk stratification in unselected STEMI: is there a role for ST2 or its natural ligand IL-33 when compared with contemporary risk markers?

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), GRACE-RS (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.

The uroguanylin system and human disease.

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.

Interleukin 33 and ST2 in non-ST-elevation myocardial infarction: comparison with Global Registry of Acute Coronary Events Risk Scoring and NT-proBNP.

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.

C-terminal provasopressin (copeptin) as a prognostic marker after acute non-ST elevation myocardial infarction: Leicester Acute Myocardial Infarction Peptide II (LAMP II) study.

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 < 0.0005} in univariate analysis and remained a significant predictor in multivariate analysis [HR, 3.03 (05% CI, 1.32-6.98); P = 0.009]. There were no significant differences between the area under ROC (receiver operating characteristic) curves of copeptin, NT-proBNP and the GRACE score. Copeptin improved accuracy of risk classification when used in combination with the GRACE score as determined by net reclassification improvement, whereas NT-proBNP did not. The relative utility of the GRACE score was increased more by copeptin than by NT-proBNP over a wide range of risks. Plasma copeptin is elevated after NSTEMI, and higher levels are associated with worse outcomes. Copeptin used in conjunction with the GRACE score improves risk stratification enabling more accurate identification of high-risk individuals.

Proteinase 3 and prognosis of patients with acute myocardial infarction.

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.

Usefulness of plasma tissue inhibitors of metalloproteinases as markers of prognosis after acute myocardial infarction.

Alterations in the balance of matrix metalloproteinase to tissue inhibitor of metalloproteinase (TIMP) are seen after acute myocardial infarction (AMI) and are associated with adverse left ventricular remodeling and prognosis in this setting. We aimed to investigate the association between TIMP levels and the occurrence of major adverse cardiac events (MACEs) after AMI. We measured plasma TIMP-1, -2, and -4 levels in 1,313 patients presenting with AMI. Subjects were followed over a median period of 520 days for the occurrence of MACEs. Clinical risk was assessed using the Global Registry of Acute Coronary Events (GRACE) score. All TIMP levels correlated with patient age and inversely with estimated glomerular filtration rate (all p values <0.001). Levels were higher in women versus men (p <0.001) and in subjects with a history of diabetes (TIMP-1, p <0.001; TIMP-2, p = 0.002; TIMP-4, p <0.001) or hypertension (TIMP-1, p = 0.031; TIMP-2, p <0.001; TIMP-4, p <0.001). TIMP-1 and TIMP-4 were higher in subjects with previous MI or angina (p <0.001). TIMP levels increased incrementally with quartiles of GRACE score (p <0.001). All TIMPs showed univariate association with the occurrence of MACEs (p <0.001). Areas under the receiver operator characteristic curve for prediction of MACE at 1 year were 0.61 for TIMP-1, 0.57 for TIMP-2, and 0.64 for TIMP-4. Combination of TIMPs with GRACE risk score revealed a greater area under the curve than GRACE score alone (0.72 vs 0.69, p = 0.0015). On multivariable Cox proportional hazards analysis, GRACE score (p <0.001) and plasma TIMPs (log TIMP-1, p = 0.017; log TIMP-2, p <0.001; log TIMP-4, p = 0.011) independently predicted MACEs. Using Kaplan-Meier analysis, the risk of MACEs increased incrementally with the number of TIMPs above their respective median (p <0.001 for all comparisons, log-rank test). In conclusion, higher plasma TIMP-1, -2, and -4 after AMI are associated with MACEs and provide additional prognostic information to that obtained from GRACE clinical risk scores alone.

Prognostic value of mid-regional pro-adrenomedullin levels taken on admission and discharge in non-ST-elevation myocardial infarction: the LAMP (Leicester Acute Myocardial Infarction Peptide) II study.

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.

Identification of potential outcome benefit from ACE inhibition after acute coronary syndrome: a biomarker approach using N-terminal proBNP.

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.

Activation of a novel natriuretic endocrine system in humans with heart failure.

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) microg/l] and prouroguanylin [8.3 (1.7-53.0 microg/l)] were both significantly (P<0.0005) higher compared with levels in healthy controls [5.5 (0.4-22.3 microg/l) for proguanylin and 6.3 (2.5-16.9) microg/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.

Matrix metalloproteinase-2 predicts mortality in patients with acute coronary syndrome.

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.

N-terminal pro-B-type natriuretic peptide complements the GRACE risk score in predicting early and late mortality following acute coronary syndrome.

The GRACE (Global Registry of Acute Coronary Events) risk score has been shown to offer predictive power with regard to death and AMI (acute myocardial infarction) in patients with ACS (acute coronary syndromes). NT-proBNP (N-terminal pro-B-type natriuretic peptide) has also been found to be useful in predicting mortality following ACS. In the present study, we sought to investigate the use of the GRACE score and NT-proBNP levels at predicting risk of early and late deaths following ACS. We studied 1033 patients (740 men, mean age 66.5+/-12.7 years) with AMI. Blood was drawn once within 24 h following the onset of chest pain. The plasma concentration of NT-proBNP was determined using an in-house non-competitive immunoassay. Patients were GRACE risk scored. The 30-day mortality was 3.7% and the 6-month mortality was 7.8%, and all were related to higher GRACE risk scores (P=0.001 for trend). Higher NT-proBNP levels were also related to increased mortality (P<0.0001). In a Cox proportional hazards model, independent predictors of 30-day and 6-month mortality included NT-proBNP levels and the GRACE risk score. The receiver-operating curve for the GRACE risk score was complemented by NT-proBNP levels for prediction of 30-day mortality [AUC (area under the curve), 0.85] and 6-month mortality (AUC, 0.81). NT-proBNP gives complementary information to the GRACE risk score for predicting early and late mortality. The inclusion of the NT-proBNP blood test is useful in risk-stratifying patients after ACS.