Russell J. O'brien

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 (rs=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.

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

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).

Diagnosis of heart failure using urinary natriuretic peptides.

In the present study, we assessed the use of urinary natriuretic peptides [N-terminal proatrial natriuretic peptide (N-ANP) and N-terminal pro-brain natriuretic peptide (N-BNP) and C-type natriuretic peptide (CNP)] in the diagnosis of heart failure. Thirty-four consecutive hospitalized heart failure patients (median age, 75.5 years; 14 female) were compared with 82 age- and gender-matched echocardiographically normal controls. All subjects provided plasma and urine specimens. Plasma was assayed for N-BNP, and urine was assayed for N-ANP, N-BNP and CNP. The diagnostic efficiency of peptides was assessed using receiver operating characteristic (ROC) curve analysis. All three urinary natriuretic peptides were significantly elevated in heart failure patients ( P <0.001). Urine N-BNP was correlated with plasma N-BNP ( r (s)=0.53, P <0.0005). Areas under the ROC curves for urinary N-ANP, N-BNP and CNP were 0.86, 0.93 and 0.70 and for plasma N-BNP was 0.96. Correcting urinary peptide levels using urine creatinine produced ROC areas of 0.89, 0.93 and 0.76 respectively. A urine N-BNP level cut-off point of 11.6 fmol/ml had a sensitivity and specificity for heart failure detection of 97% and 78% respectively, with positive and negative predictive values of 64.7 and 98%. In conclusion, although all three natriuretic peptides were elevated in urine in heart failure, urinary N-BNP had diagnostic accuracy comparable with plasma N-BNP. Use of urinary N-BNP for heart failure diagnosis may be suitable for high-throughput screening, especially in subjects reluctant to provide blood samples.

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.

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.

Elevated circulating cardiotrophin-1 in heart failure: relationship with parameters of left ventricular systolic dysfunction

Cardiotrophin-1 (CT-1) is a cytokine that has been implicated as a factor involved in myocardial remodelling. The objective of the present study was to establish the relationship between circulating levels of CT-1 and measures of left ventricular size and systolic function in patients with heart failure. We recruited 15 normal subjects [six male; median age 60 years (range 30-79 years)] and 15 patients [11 male; median age 66 years (range 43-84 years)] with a clinical diagnosis of heart failure and echocardiographic left ventricular systolic dysfunction (LVSD). Echocardiographic variables (left ventricular wall motion index, end-diastolic and -systolic volumes, stroke volume, fractional shortening) and plasma CT-1 levels were determined. In patients with LVSD [median wall motion index 0.6 (range 0.3-1.4)], CT-1 was elevated [median 110.4 fmol/ml (range 33-516 fmol/ml)] compared with controls [wall motion index 2 in all cases; median CT-1 level 34.2 fmol/ml (range 6.9-54.1 fmol/ml); P<0.0001]. Log CT-1 was correlated with log wall motion index (r=-0.76, P<0.0001), log left ventricular end-systolic volume (r=0.54, P<0.05), stroke volume (r=-0.60, P=0.007) and log fractional shortening (r=-0.70, P=0.001). In a multivariate model of the predictors of log wall motion index, the only significant predictor was log CT-1 (R(2)=56%, P=0.006). This is the first assessment of the relationship between plasma CT-1 levels and the degree of LVSD in humans, and demonstrates that CT-1 is elevated in heart failure in relation to the severity of LVSD.

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.

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

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.

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.

Non-competitive immunochemiluminometric assay for cardiotrophin-I 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 anity 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 eect at high concentrations. The lower limit of detection was 2.9 fmol/ml. Intra-assay coecients of variation ranged from 3.1% to 4.2% in the 10‐40 fmol/well concentration range, and interassay coecients 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.