C-terminal provasopressin (copeptin) as a novel and prognostic marker in acute myocardial infarction: Leicester Acute Myocardial Infarction Peptide (LAMP) study.

BACKGROUND: The role of the vasopressin system after acute myocardial infarction is unclear. Copeptin, the C-terminal part of the vasopressin prohormone, is secreted stoichiometrically with vasopressin. We compared the prognostic value of copeptin and an established marker, N-terminal pro-B-type natriuretic peptide (NTproBNP), after acute myocardial infarction. METHODS AND RESULTS: In this prospective single-hospital study, we recruited 980 consecutive post-acute myocardial infarction patients (718 men, median [range] age 66 [24 to 95] years), with follow-up over 342 (range 0 to 764) days. Plasma copeptin was highest on admission (n=132, P<0.001, day 1 versus days 2 to 5) and reached a plateau at days 3 to 5. In the 980 patients, copeptin (measured at days 3 to 5) was elevated in patients who died (n=101) or were readmitted with heart failure (n=49) compared with survivors (median [range] 18.5 [0.6 to 441.0] versus 6.5 [0.3 to 267.0] pmol/L, P<0.0005). With logistic regression analysis, copeptin (odds ratio, 4.14, P<0.0005) and NTproBNP (odds ratio, 2.26, P<0.003) were significant independent predictors of death or heart failure at 60 days. The area under the receiver operating characteristic curves for copeptin (0.75) and NTproBNP (0.76) were similar. The logistic model with both markers yielded a larger area under the curve (0.84) than for NTproBNP (P<0.013) or copeptin (P<0.003) alone, respectively. Cox modeling predicted death or heart failure with both biomarkers (log copeptin [hazard ratio, 2.33], log NTproBNP [hazard ratio, 2.70]). In patients stratified by NTproBNP (above the median of approximately 900 pmol/L), copeptin above the median (approximately 7 pmol/L) was associated with poorer outcome (P<0.0005). Findings were similar for death and heart failure as individual end points. CONCLUSIONS: The vasopressin system is activated after acute myocardial infarction. Copeptin may predict adverse outcome, especially in those with an elevated NTproBNP (more than approximately 900 pmol/L).

Prognostic value of midregional pro-adrenomedullin in patients with acute myocardial infarction: the LAMP (Leicester Acute Myocardial Infarction Peptide) study.

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 < 0.0001). Using a multivariate binary logistic model, log MR-proADM (odds ratio 4.22) and log NTproBNP (odds ratio 3.20) were significant independent predictors of death or HF (with creatinine, age, gender, and history of AMI). The areas under the receiver-operating characteristic curve for MR-proADM, NTproBNP, and the logistic model with both markers were 0.77, 0.79, and 0.84 respectively. Cox models for the predictors of death or HF showed the same variables (including log MR-proADM, hazard ratio 3.63; log NTproBNP, hazard ratio 2.67). The MR-proADM provided further risk stratification in those patients who had NTproBNP levels above the median (p < 0.0001). Findings were similar for death and HF as individual end points. 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.

Oxygen-regulated protein 150 and prognosis following myocardial infarction.

ORP150 (oxygen-regulated protein 150) is a chaperonin expressed in tissues undergoing hypoxic or endoplasmic reticulum stress. In the present study, we investigated plasma levels of ORP150 in patients with AMI (acute myocardial infarction) and its relationship with prognosis, together with a known risk marker N-BNP (N-terminal pro-B-type natriuretic peptide). Plasma from 396 consecutive patients with AMI was obtained for measurement of ORP150 and N-BNP. Mortality and cardiovascular morbidity (acute coronary syndromes/heart failure) was determined during follow-up. A specific ORP150 assay detected the 150 kDa protein in plasma extracts, including 3 and 7 kDa fragments. During follow-up (median, 455 days), 43 (10.9%) patients died. Both N-BNP and ORP150 levels were higher in those who died compared with the survivors [N-BNP, 724 (14.5-28840) compared with 6167 (154.9-33884) pmol/l (P<0.0005); ORP150, 257 (5.9-870.9) compared with 331 (93.3-831.8) pmol/l (P<0.001); values are medians (range)]. In a Cox regression model for mortality prediction, both N-BNP (odds ratio, 5.06; P<0.001) and ORP150 (odds ratio, 2.39; P<0.01) added prognostic information beyond creatinine and the use of thrombolytics. A Kaplan-Meier survival analysis revealed that ORP150 added prognostic information to N-BNP, especially in those with supra-median N-BNP levels. A simplified dual-marker approach with both markers below and either above or both above their respective medians effectively stratified mortality risk (log rank statistic for trend, 32.7; P<0.00005). ORP150 levels were not predictive of other cardiovascular morbidity (acute coronary syndromes or heart failure). In conclusion, ORP150 and peptide fragments derived from it are secreted following AMI and provide independent prognostic information on mortality. High levels associated with endoplasmic reticulum/hypoxic stress predict a poor outcome.

Is plasma N-BNP a good indicator of the functional reserve of failing hearts? The FRESH-BNP study.

AIMS: Whether plasma N-terminal brain natriuretic peptide (N-BNP) is useful in the diagnosis of heart failure (HF) depends traditionally on whether it is as good as the putative 'gold-standard', left ventricular ejection fraction (LVEF), in indicating cardiac dysfunction. However, since HF is primarily an impairment of function of the cardiac pump, we explored the relationship between N-BNP and direct and indirect indicators of cardiac pump dysfunction. METHODS AND RESULTS: Eighty-six HF patients (mean age 56 years) with a range of LVEF's (mean 36.9+/-15.2%, range 15-66%) and 10 age-matched healthy controls were recruited into the study and had resting N-BNP measured. Cardiopulmonary exercise testing was performed to assess peak oxygen consumption (Vo(2)). A subgroup of 23 subjects underwent further exercise haemodynamic assessment to evaluate peak cardiac power output (CPO). The CHF group had significantly higher N-BNP (median [interquartile range]) levels (299 [705] fmol/ml) than the control group (7 [51] fmol/ml, P<0.005). Significant correlations between N-BNP and peak Vo(2), and N-BNP and peak CPO were observed (R> or =0.5, P<0.005). Although significant correlation was observed between N-BNP and LVEF (R=0.34, P=0.01), the correlations between LVEF and peak Vo(2) or peak CPO (all R<0.3, P>0.3) were not significant. Multivariate analysis identified plasma N-BNP and NYHA class, but not LVEF, as independent predictors of peak Vo(2). CONCLUSIONS: We have found that N-BNP was surprisingly good as a simple indicator of cardiac pump dysfunction. Since heart failure is an inadequacy of function, these results strongly support the notion that N-BNP is a useful blood test in estimating the extent of cardiac pump dysfunction and helpful in establishing positive diagnosis of heart failure.

Comparison of plasma N-brain natriuretic peptide, peak oxygen consumption, and left ventricular ejection fraction for severity of chronic heart failure.

We investigated whether a simple blood test of plasma N-brain natriuretic peptide (N-BNP), compared with echocardiographic left ventricular ejection fraction (LVEF), both measured at rest, correlated well with aerobic exercise capacity (peak oxygen consumption [VO(2)]) in patients with chronic heart failure. Plasma N-BNP was found to significantly correlate with peak VO(2) (p <0.001) and exercise duration (p = 0.001), whereas LVEF showed very poor correlations with peak VO(2) and exercise duration (both p >0.3). The results suggest that N-BNP actually reflects functional cardiac impairment better than LVEF.

N-terminal pro-atrial natriuretic peptide (N-ANP) and N-terminal pro-B-type natriuretic peptide (N-BNP) in the prediction of death and heart failure in unselected patients following acute myocardial infarction.

Elevated plasma natriuretic peptide levels after AMI (acute myocardial infarction) are associated with adverse outcome. The aim of the present study was to examine the relationship of plasma N-ANP (N-terminal pro-atrial natriuretic peptide) and N-BNP (N-terminal pro-B-type natriuretic peptide) with mortality and heart failure following AMI. We studied 403 patients with AMI. Blood was sampled for measurement of N-ANP and N-BNP on a single occasion between 72 and 96 h after symptom onset. Natriuretic peptide levels were related to all-cause mortality and heart failure episodes. During follow up (median, 462 days; range 5-764), 43 (10.7%), 25 (6.2%) and 49 (12.2%) patients suffered death, heart failure hospitalization and outpatient heart failure respectively. Only N-BNP (P < 0.0005), N-ANP (P = 0.005) and previous AMI (P = 0.016) were independently predictive of death. N-BNP, but not N-ANP, predicted 30-day mortality. N-ANP, but not N-BNP, predicted mortality after 30 days. N-BNP was the better predictor of heart failure. N-ANP and N-BNP were above the median in 35 and 38 respectively, of 43 patients who later died. N-ANP, N-BNP, or both were above the median in 41 out of 43 patients. Of 25 patients hospitalized with heart failure, N-ANP and N-BNP was above the median in 20 and 24 respectively, and one or other was elevated in all cases. Above-median N-ANP predicted 36 and N-BNP predicted 41 out of 49 episodes of outpatient heart failure. One or other peptide was above the median in 45 out of 49 patients. Our results indicate that N-BNP predicts 30-day and N-ANP >30-day mortality. We conclude that consideration of both N-ANP and N-BNP identifies a greater number of patients at risk of death or heart failure than either peptide alone.

Plasma urocortin in human systolic heart failure.

Urocortin (UCN), a member of the corticotrophin-releasing factor family, is expressed in heart, brain and gut. UCN has potent cardiostimulatory, cardioprotective, vasodilator and diuretic/natriuretic effects, and cardiac UCN expression is increased in heart failure (HF). In the present study, we investigated plasma levels of UCN in 119 patients with HF and 212 age- and gender-matched controls to clarify its relationship with gender and disease severity. UCN was elevated in HF [normal males, 19.5 (3.9-68.8) pmol/l and HF males, 50.2 (6.9-108.2) pmol/l, P < 0.0005; normal females, 14.2 (3.9-53.5) pmol/l and HF females, 21.8 (3.9-112.5) pmol/l, P < 0.001; values are medians (range)]. The relative increase was greater in males than females ( P < 0.03). UCN fell with increasing age, especially in HF patients ( r(s) = -0.56, P < 0.0005) and with increasing New York Heart Association (NYHA) class ( r(s) = -0.55, P < 0.0005). The fall in UCN levels with increasing NYHA class was reinforced by a significant correlation between UCN and ejection fraction ( r(s) = 0.45, P < 0.0005) in HF patients. Although receiver operating characteristic (ROC) curves for diagnosis of all HF cases yielded an area under the curve (AUC) of 0.76, ROC AUCs for patients with early HF (NYHA class I and II) were better (0.91). ROC AUCs for logistic models incorporating N-terminal probrain natriuretic peptide (N-BNP) and UCN were better than either peptide alone. In conclusion, plasma UCN is elevated in HF, especially in its early stages. Its decline with increasing HF severity may expedite disease progression due to diminished cardioprotective/anti-inflammatory effects. UCN measurement may also complement N-BNP in the diagnosis of early HF.

Pre-discharge, but not admission, levels of NT-proBNP predict adverse prognosis following acute LVF.

BACKGROUND: Circulating natriuretic peptide levels provide prognostic information following acute coronary syndromes and in chronic heart failure. Little evidence exists of their utility following hospitalisation with acute left ventricular failure (LVF). AIMS: To examine the relative prognostic value of admission and pre-discharge plasma N-terminal pro B-type natriuretic peptide (NT-proBNP) following hospitalisation with acute heart failure. METHODS: NT-proBNP was measured at admission in 96 patients hospitalised with acute LVF. In a subset of 34 patients, NT-proBNP was also measured prior to discharge. Multivariate analysis was performed of the clinical and serological predictors of a combined primary endpoint of death or heart failure (hospitalisation or as an outpatient). RESULTS: During follow up (median 350 days, range 2-762), 37 (38.5%) patients died (n=16, 16.7%), or experienced at least 1 heart failure event (n=21, 21.9%). For the entire cohort of 96 patients, only a prior history of heart failure was associated with the primary endpoint (OR 3.5 [1.10-11.08], P=0.034). Admission plasma NT-proBNP was not predictive (OR 1.84 [0.75-4.51], P=0.185). In the 34 patients for whom both admission and pre-discharge NT-proBNP was available, 19 (55.9%) died (n=8, 23.5%) or experienced heart failure (n=11, 32.4%). Only pre-discharge plasma NT-proBNP (OR 15.30 [95% CI: 1.4-168.9], P=0.026) was independently predictive of the composite endpoint. The area under the receiver-operator-characteristic (AUC ROC) curve for pre-discharge NT-proBNP was superior to that for admission NT-proBNP for prediction of death or heart failure (AUC ROC 0.87 cf 0.70), for death (0.79 cf 0.66), LVF hospitalisation (0.78 cf 0.70) or heart failure as an outpatient (0.71 cf 0.61). CONCLUSIONS: Plasma NT-proBNP measured pre-discharge provides useful prognostic information following hospitalisation with acute LVF.

Myotrophin in human heart failure.

OBJECTIVES: The goal of this study was to investigate plasma levels of myotrophin in heart failure (HF) and their relationship to gender and disease severity. BACKGROUND: Myotrophin is a myocardial hypertrophy-inducing factor initially demonstrated in hypertrophied and cardiomyopathic hearts. Recent evidence suggests an interaction with the transcription factor nuclear factor kappa B (NFkappaB), which is activated in HF and modulates myocardial protein expression. It is unknown whether this peptide has an endocrine/paracrine role in man. We hypothesized that it may have a role in HF and would be raised in plasma. METHODS: We developed a competitive binding assay specific for human myotrophin. Myotrophin was measured in plasma extracts of 120 HF patients and 130 age- and gender-matched normal controls. RESULTS: Myotrophin in plasma existed as the full-length 12 kD form with also a 2.7 kD form (possibly a degradation product). Log normalized myotrophin levels were significantly elevated in HF patients (mean +/- SEM [geometric mean, range], 2.402 +/- 0.021 [252, 72 to 933] vs. 2.268 +/- 0.021 [185, 28 to 501] fmol/ml, p < 0.0005). There was no relationship between myotrophin and age or gender in controls. However, males with HF had higher levels of myotrophin than females (p < 0.001). There was an inverse relationship of myotrophin levels with New York Heart Association class in patients with no gender difference in the relationship. CONCLUSIONS: There is evidence of early activation of the myotrophin system in HF, which is more evident in males. This response is attenuated in more severe disease. The contribution of myotrophin to NFkappaB-mediated gene transcription and preservation of cardiac muscle mass remains to be investigated further.

Plasma urotensin in human systolic heart failure.

BACKGROUND: Human urotensin II (UTN) has potent vasoactive and cardiostimulatory effects, acting on the G protein-linked receptor GPR14. Myocardial UTN expression is upregulated in heart failure, and UTN stimulates myocardial expression of the natriuretic peptides. We investigated plasma UTN levels in heart failure (HF; left ventricular systolic dysfunction) in comparison with plasma N-terminal pro-brain natriuretic peptide (N-BNP) levels. METHODS AND RESULTS: N-BNP and UTN were measured in plasma from 126 patients with HF and 220 age- and sex-matched controls. Both peptides were elevated in plasma of HF patients and were correlated (r(s)=0.35, P<0.001). In contrast to N-BNP, there was no relationship of plasma UTN with New York Heart Association (NYHA) class. Although plasma N-BNP showed a positive relationship with age and female sex, there was no such age-dependent change in plasma UTN, and control women had lower levels compared with control men. Receiver operating characteristic curves for the diagnosis of HF had areas of 0.90 and 0.86 for N-BNP and UTN, respectively (P<0.001 for both). Receiver operating characteristic curve area for diagnosis of NYHA class I HF with UTN was better than that with N-BNP. CONCLUSIONS: Plasma UTN is elevated in HF, which suggests a pathophysiological role for this peptide. Plasma UTN may be a useful alternative to N-BNP in the diagnosis of HF, inasmuch as its levels are elevated irrespective of age, sex, or NYHA class.

Augmented expression of cardiotrophin-1 in failing human hearts is accompanied by diminished glycoprotein 130 receptor protein abundance.

BACKGROUND: Cardiotrophin-1 (CT-1), a member of the interleukin-6 superfamily, is a potent inducer of cardiomyocyte hypertrophy that prolongs myocyte survival. Although cardiac CT-1 gene expression is known to be upregulated in some animal models of congestive heart failure, the activation state of the CT-1 system in patients with congestive heart failure is unknown. METHODS AND RESULTS: This study was designed to determine left ventricular expression of CT-1 and its glycoprotein 130 (gp130)/leukemia inhibitory factor receptor complex in human end-stage heart failure due to ischemic and dilated cardiomyopathy. In addition, we investigated the activation state of signal transducer and activator of transcription 3 (STAT3), the downstream effector of gp130 signaling. In the failing left ventricular myocardium, expression levels of CT-1 mRNA and protein were significantly increased by 142% and 68%, respectively, compared with non-failing donor hearts. Immunohistochemistry confirmed the increased expression of CT-1 in cardiac myocytes. Although gp130 gene expression was increased by 91% (P<0.001), gp130 protein abundance was significantly diminished by 34% in the failing myocardium. In contrast, leukemia inhibitory factor receptor and suppressor of cytokine signaling-3 protein concentrations were not changed. In addition, the ratio of activated tyrosine phosphorylated STAT3 to total STAT3 was not significantly altered in failing hearts compared with non-failing controls. CONCLUSIONS: Our data suggest that gp130 receptor downregulation balances enhanced CT-1 expression in human heart failure and thereby inhibits excessive activation of the gp130 signaling pathway.

Non-competitive immunochemiluminometric assay for cardiotrophin-1 detects elevated plasma levels in human heart failure.

Cardiotrophin-1 (CT-1) leads to a specific form of ventricular hypertrophy characterized by sarcomeres added in series, and has been reported to be elevated in heart failure. Previous competitive assays for CT-1 necessitate the extraction of plasma and involve prolonged incubations. We describe the development of a non-competitive assay for CT-1 that can measure plasma levels without the need for extraction. Two antibodies specific for the mid-section (amino acids 105-120) and C-terminal (amino acids 186-199) portions of CT-1 were developed in rabbits. One antibody was immobilized and used as the capture antibody. The other antibody was affinity purified and biotinylated. Unextracted plasma was incubated with these antibodies, and detection was with methylacridinium ester-labelled streptavidin. Plasma was obtained from 40 patients with heart failure and 40 normal control subjects. The non-competitive assay demonstrated a linear increase in chemiluminescence (measured as relative light units) with increasing amounts of full-length recombinant CT-1, with no evidence of a hook effect at high concentrations. The lower limit of detection was 2.9 fmol/ml. Intra-assay coefficients of variation ranged from 3.1% to 4.2% in the 10-40 fmol/well concentration range, and interassay coefficients of variation ranged from 3.5% to 4.5% in the 550-950 fmol/ml range. Measurements of CT-1 levels in patients with heart failure (median 166.5 fmol/ml; range 49.5-2788 fmol/ml) revealed very significantly elevated levels compared with those in normal controls (median 43.5 fmol/ml; range 11.2-258.6 fmol/ml; P<0.0001 by Mann-Whitney test). At a CT-1 concentration of 68 fmol/ml, sensitivity and specificity were 95% and 82.5% respectively. Thus this new non-competitive immunochemiluminometric assay for CT-1 could successfully detect full-length recombinant CT-1 in unextracted plasma, and demonstrated that plasma levels of CT-1 were significantly elevated in patients with heart failure.

Plasma cardiotrophin-1 following acute myocardial infarction: relationship with left ventricular systolic dysfunction.

The glycoprotein 130 (gp 130) signalling pathway is important in the development of heart failure. Cardiotrophin-1 (CT-1), a cytokine acting via the gp 130 pathway, is involved in the process of ventricular remodelling following acute myocardial infarction (AMI) in animals. The aims of the present study were to examine the profile of plasma CT-1 following AMI in humans, and its relationship with echocardiographic parameters of left ventricular (LV) systolic function. Serial measurements of plasma CT-1 levels were made in 60 patients at 14-48 h, 49-72 h, 73-120 h and 121-192 h following AMI and at a later clinic visit. LV function was assessed using a LV wall motion index (WMI) score on admission (WMI-1) and at the clinic visit (WMI-2). Compared with values in control subjects (29.5+/-3.6 fmol/ml), the plasma CT-1 concentration was elevated in AMI patients at 14-48 h (108.1+/-15.1 fmol/ml), 49-72 h (105.2+/-19.7 fmol/ml), 73-120 h (91.2+/-14.9 fmol/ml) and 121-192 h (118.8+/-22.6 fmol/ml), and at the clinic visit (174.9+/-30.9 fmol/ml) (P<0.0001). Levels were higher following anterior compared with inferior AMI. For patients with anterior AMI, CT-1 levels were higher at the clinic visit than at earlier times. WMI-1 correlated with CT-1 at all times prior to hospital discharge (P<0.05). On best subsets analysis, the strongest correlate with WMI-1 was CT-1 level at 49-72 h (R(2)=20%, P<0.05). In conclusion, plasma levels of CT-1 are elevated soon after AMI in humans and rise further in the subsequent weeks in patients after anterior infarction. CT-1 measured soon after AMI is indicative of LV dysfunction, and this cytokine may have a role in the development of ventricular remodelling and heart failure after AMI.