Author + information
- Received April 15, 2013
- Revision received July 8, 2013
- Accepted July 15, 2013
- Published online October 1, 2013.
- W. Y. Wandy Chan, MBChB∗,†∗ (, )
- Christopher M. Frampton, PhD∗,
- Ian G. Crozier, MD†,
- Richard W. Troughton, MD, PhD∗,† and
- A. Mark Richards, MD, PhD∗,‡
- ∗Christchurch Heart Institute, University of Otago, Christchurch, New Zealand
- †Cardiology Department, Christchurch Hospital, Christchurch, New Zealand
- ‡Cardiovascular Research Institute, National University Health System, Singapore
- ↵∗Reprint requests and correspondence:
Dr. W. Y. Wandy Chan, Heart Failure and Transplant Unit, Prince Charles Hospital, Rode Road, Chermside QLD 4032, Australia.
Objectives The purpose of this study is to investigate the effects of urocortin-2 as adjunct therapy in acute decompensated heart failure (ADHF).
Background Urocortin-2 produced favorable integrated effects in experimental heart failure but there are no equivalent human data. We describe the first therapeutic study of urocortin-2 infusion in ADHF.
Methods Fifty-three patients with ADHF were randomly assigned to 5 ng/kg/min of urocortin-2 or placebo infusion for 4 h as an adjunct therapy. Changes in vital signs, plasma neurohormonal and renal indices during treatment were compared using repeated-measures analysis of covariance. Ten patients in each arm underwent more detailed invasive hemodynamic evaluation.
Results Urocortin-2 produced greater falls in systolic blood pressure compared to placebo (16 ± 5.8 mm Hg, p < 0.001) with nonsignificant increases in heart rate (5.7 ± 3.8 beats/min, p = 0.07) and increased cardiac output (2.1 ± 0.4 l/min vs. −0.1 ± 0.4 l/min, p < 0.001) associated with a 47% reduction in calculated total peripheral resistance (p = 0.015). Falls in pulmonary artery and pulmonary capillary wedge pressures did not differ significantly between groups. Urocortin-2 reduced urine volume and creatinine clearance during infusion but these returned to above baseline level in the 8 h after infusion. Plasma renin activity rose briefly with urocortin-2 coinciding with reductions in blood pressure (p < 0.001). B-type natriuretic peptide levels fell significantly over 24 h with urocortin-2 (p < 0.01) but not with placebo.
Conclusions Urocortin-2 infusion in ADHF markedly augmented cardiac output without significant reflex tachycardia. Renal indices fell transiently concurrent with urocortin-2-induced reductions in blood pressure. Further investigations are required to uncover the full potential of urocortin-2 in treating ADHF.
Acute decompensated heart failure (ADHF) is a major cause of hospitalization, mortality, and morbidity (1). Conventional treatment for ADHF is frequently limited by compromised hemodynamic status including hypotension (2,3) and renal dysfunction (4). Recent trials of new therapies in ADHF have been largely disappointing (5–8). Hence, there is a need for pharmacotherapy in ADHF that can provide concurrent beneficial effects on hemodynamics—including optimizing filling pressures and cardiac output, and on neurohormonal activation while preserving renal function.
Urocortin-2 is an endogenous vasoactive peptide that belongs to the corticotrophin-releasing factor (CRF) family (9). It has selective affinity for the CRF2 receptor and has predominant effects on the cardiovascular system (9). Urocortin-2 is an arterial vasodilator with positive inotropic and lusitropic properties (10–12); it is protective against ischemia-reperfusion injury and suppresses cardiac sympathetic nerve activity (13,14). Intravenous boluses and constant infusions of urocortin-2 exhibit a powerful combination of beneficial hemodynamic, neurohormonal and renal effects in severe experimental heart failure (15,16). Although consistent hemodynamic effects were seen in stable heart failure patients, renal and neurohormonal effects were minor in comparison with those observed in the pre-clinical studies (12). We hypothesized that treatment with urocortin-2 would be beneficial in ADHF, and we undertook a pilot trial comparing symptomatic, hemodynamic, neurohormonal, and renal responses to a 4-h infusion of urocortin-2 or placebo in addition to standard therapy for ADHF.
The UNICORN (Urocortin-2 in the Treatment of Acute Heart Failure as an Adjunct Over Conventional Therapy) study was a single-center, randomized, double-blind, placebo-controlled trial (Australian New Zealand Clinical Trials Registry number ACTRN12609000508279). The study protocol was approved by the ethics committee of the New Zealand Ministry of Health (Upper South B, Canterbury), and the Standing Committee on Therapeutic Trials. The study was conducted under the oversight of the Data Monitoring Committee of the Health Research Council of New Zealand. Although Neurocrine Biosciences Inc. provided the trial peptide and the initial toxicology information for assessment by the Standing Committee on Therapeutic Trials, they made no other financial or intellectual contribution, and the trial was entirely designed by the investigators and funded by a grant from the Health Research Council. All participants gave signed written informed consent to take part in the trial. All participants were invited to take part in the right heart catheter substudy for more detailed hemodynamic observations with additional consent until 20 right heart catheter studies were completed.
Inclusion criteria were as follows: patients ≥18 years of age were eligible if they were recruited within 36 h of admission for ADHF and less than 24 h from first dose of intravenous loop diuretic agents, had dyspnea at rest or with minimal exertion, with at least 1 clinical sign of heart failure (specifically, either respiratory rate >20/min or pulmonary edema with crackles to at least one-third above lung bases), and at least 1 objective measurement consistent with heart failure (either chest x-ray film showing pulmonary congestion, brain natriuretic peptide [BNP] >115 pmol/l or N-terminal-pro brain natriuretic peptide [NT-proBNP] >120 pmol/l, or left ventricular ejection fraction <40% on echocardiogram).
Exclusion criteria were acute coronary syndrome, systolic blood pressure <100 mm Hg, significant valvular stenosis, restrictive, constrictive or hypertrophic cardiomyopathy or pericardial disease, varying dose of intravenous nitrate or inotropes within 3 h of randomization, severe pulmonary disease affecting assessment of dyspnea, end-stage renal disease, noncardiac disease with a life expectancy <6 months, and body mass index >35 kg/m2.
The study was performed within the coronary care unit at Christchurch Hospital. Patients were randomly allocated in a double-blind 1:1 sequence, from a computer-generated list performed in permuted blocks of 4, to 4-h intravenous infusion of either urocortin-2 (400 μg urocortin-2 and 50 mg mannitol in each vial, dissolved in 2 ml water; 0.6 ml of this solution was made up to 60 ml with normal saline [2 μg/ml]) at 5 ng/kg/min or placebo (each vial contained 50 mg mannitol, infusion prepared in the same manner as urocortin-2) supplied by Neurocrine Biosciences Inc. (San Diego, California), as an adjunct to conventional therapy including intravenous diuretic agents and vasodilators as per the treating physician. If possible, medications that could cause hypotension were withheld from 2 h before commencement of infusion until infusion was completed. The dose of urocortin-2 in this study was equivalent to the low dose (25 μg over 1 h) studied in stable heart failure patients previously reported to produce desirable hemodynamic effects without adverse hormonal activation (12). The randomization sequence ensured balance within the right heart catheter subgroup.
Heart rate, rhythm, and blood pressure were recorded at baseline and every 30 min during infusion followed by hourly recording for 4 h, then at +12 h and +24 h.
Samples for plasma urocortin-1, urocortin-2, atrial natriuretic peptide (ANP), BNP, NT-proBNP, endothelin-1, plasma renin activity (PRA), angiotensin-II, aldosterone, and cortisol were obtained at 0, +1, +2, +4, +6, +12, and +24 h. Venous blood was collected into ethylenediaminetetraacetic acid (EDTA) tubes, except for urocortin-2 (heparin) and angiotensin-II (0.125 M EDTA, 0.05 M o-phenanthroline, 2% ethanol, 0.2% neomycin sulphate, and 0.03 mg/ml enalkiren). Samples were immediately separated (4,000 rpm for 10 min in a refrigerated centrifuge) and stored at −80°C until assayed using previously validated methods (17,18). All samples from the same patient were measured in the same assay to avoid interassay variations. Intra-assay coefficients of variation measured were all <15%, except for BNP (17.1%).
Samples for serial plasma sodium, potassium, and creatinine were obtained at 0, +2, +4, +6, +12, and +24 h.
Patients were requested to void within 15 min before commencement of infusions to standardize urine collection. Urine was collected in 3 phases, at 0 to 4 h, +4 to 12 h, and +12 to 24 h from commencement of infusions for measurement of volume, creatinine, sodium, and potassium. Estimated glomerular filtration rate was calculated using the Modification of Diet in Renal Disease equation (19).
For patients who underwent right heart catheterization, a 7F Swan-Ganz catheter was positioned in the pulmonary artery through the right internal jugular vein using fluoroscopy while the patient was lying supine. Pulmonary capillary wedge pressure (PCWP) was confirmed by typical waveform appearance. Thermodilution cardiac output (20), right atrial pressure, pulmonary artery pressure, and PCWP were obtained after 30 s of quiet respiration at −0.5 h, 0 h, +0.5 h, and +1 h, then hourly until the catheter was removed at +8 h. Cardiac output divided by the mean arterial pressure was used to calculate the calculated total peripheral resistance (cTPR). Each recording was an average of 3 measurements.
The sample size was determined on the basis of the neurohormonal data from a group of patients admitted to our institution who fulfilled the study enrollment criteria. To confirm a 50% relative reduction in the mean values of key neurohormonal indicators using log normalized data with 80% power (2-tailed α = 0.05) a sample size of 25 patients per treatment limb was required. This sample size also offered similar or greater power to detect 10% changes in key hemodynamic variables on the basis of prior successful detection of hemodynamic changes in response to urocortin-2 infusions in human and animal models in group sizes of 8, and to detect a 10% shift in calculated GFR (12,15,18).
The effect of urocortin-2 on hemodynamics, renal function and neurohormones over the 24-h period and in phases relative to the commencement of infusion were examined using repeated measures analysis of covariance, with the randomized treatment as the between-subject factor, time as the within-subject factor, and the relevant baseline level as covariate. The term of most importance in these analyses was the time-by-randomized-treatment interaction, indicating differential responses over time. Where significant interaction effects were identified, these were further explored using paired t tests for changes within groups and independent t tests for differences between study groups at specific times. Non-normally distributed neurohormonal data were log-transformed for analysis and subsequently expressed as geometric means with 95% confidence intervals. Categorical data were tested using chi-square tests. A 2-tailed p value <0.05 was regarded as statistically significant. All data were analyzed using SPSS version 19 (SPSS, Inc. Chicago, Illinois).
From Oct 2009 to Dec 2011, 55 patients were randomized (Fig. 1). Two patients were withdrawn because of vasovagal hypotensive episodes at right heart catheter insertion before the commencement of study drug infusion. Of 53 patients starting and completing trial infusions, 26 received placebo and 27 received urocortin-2 infusions. Demographics and baseline variables were well matched (Table 1).
Urocortin-2 exerted a rapid and pronounced hypotensive effect with clear intergroup differences apparent within 30 min of the start of infusion. The peak effect was noted between +1.5 h and +2.5 h. During infusion period, reductions in systolic and diastolic blood pressures were 16.3 ± 5.5 mm Hg and 12.6 ± 4.1 mm Hg, respectively, greater than time-matched placebo (both p < 0.001) (Fig. 2). Four patients required down-titration of urocortin-2 due to blood pressure falling below our pre-set threshold for ceasing infusion (systolic blood pressure <85 mm Hg); all were asymptomatic. Infusion was restarted at half the previous dose once systolic blood pressure was sustained above 90 mm Hg for at least 20 min. Heart rate tended to increase in the urocortin-2 group (6.6 ± 3.9 beats/min, compared with time-matched control, p = 0.07) with the peak effect at +1 h, earlier than the nadir of arterial pressures (Fig. 2).
Right heart catheterization
Demographics and baseline variables were well matched except a significantly lower cardiac index was noted in the urocortin-2 arm (Table 2). Urocortin-2 induced immediate and marked increases in cardiac output (52 ± 19% more than placebo, p < 0.001) and falls in cTPR (cTPR 40 ± 8.4% more than placebo during the infusion period, p = 0.02) (Fig. 3). The effect was confined to the first 5 h from commencement of urocortin-2 infusion. Peak cardiac output was achieved between +1 and +2 h and fell within the first hour after urocortin-2 infusion was halted. Maximal reduction in cTPR was seen at +2h and increased slowly after cessation, indicating a persistent vasodilatory effect after cessation of infusion. There was a trend to greater and more rapid early falls in PCWP with urocortin-2 than with placebo (p = 0.096) (Fig. 3). In both treatment arms similar falls in pulmonary artery systolic and diastolic pressures were observed.
Plasma creatinine, urine output, measured creatinine clearance, and sodium excretion were all reduced significantly during urocortin-2 infusion compared to placebo. All renal indices rebounded post-infusion (Fig. 4). Although mean estimated GFR was marginally elevated compared to baseline, there was no significant difference between treatment arms at +24 h (urocortin-2 53 ± 2.6 ml/min/1.73 m2 vs. placebo 56 ± 3.3 ml/min/1.73 m2, p = 0.4). Cumulative urine volume and sodium and potassium excretion (2,065 ± 271 ml vs. 2440 ± 202 ml, 181 ± 33 mmol vs. 196 ± 20 mmol, and 56 ± 4 mmol vs. 56 ± 4 mmol, respectively) over the 24-h period were similar in urocortin-2 and placebo groups. Plasma sodium and potassium were unaffected by urocortin-2 infusion.
Twelve patients in the placebo group (46%) and 16 patients in the urocortin-2 group (59%, p = 0.24) who were clinically assessed by a single-blind investigator (W.W.C.) received an extra intravenous dose of furosemide in the 8 h post-infusion period for persistent symptoms and signs of pulmonary congestion. The average dose was significantly higher with placebo (149 ± 30 mg vs. 85 ± 14 mg, p = 0.047). Additional furosemide nonsignificantly increased diuresis or natriuresis with urocortin-2 (Fig. 4).
Peak plasma urocortin-2 concentrations of sevenfold the baseline level were achieved at +2 h and returned to baseline within 2 h after the infusion (Fig. 5). Plasma urocortin-1 levels were unaffected by urocortin-2 (Fig. 5).
Urocortin-2 infusion significantly affected BNP and NT-proBNP over 24 h (p < 0.01) (Fig. 6). There was a nonsignificant increase in NT-proBNP during infusion, but little change was observed for ANP or BNP with urocortin-2. Post-infusion out to +12 h, BNP and NT-proBNP were significantly lower after urocortin-2 than after placebo (BNP 13.5%, p = 0.02; NT-proBNP 16.2%, p = 0.001). The BNP (p = 0.17) and NT-proBNP (p = 0.02) levels continued to diverge from placebo between +12 and +24 h.
During urocortin-2 infusion, PRA rose by 1.1 nmol/l/h to exceed time-matched placebo values by 46.3% (p < 0.001) (Fig. 5). The maximal increment in PRA change coincided with the time of the lowest arterial blood pressure. There were no corresponding acute elevations in angiotensin-II or aldosterone, resulting in a significant reduction in the aldosterone:renin ratio (p < 0.001) with urocortin-2. The PRA, angiotensin-II, and aldosterone all gradually increased similarly in both study arms from +12 to +24 h.
Urocortin-2 infusion attenuated the fall in cortisol compared to placebo during infusion (−17% vs. −39%, p = 0.03) (Fig. 6). Plasma glucose was unaffected (at the end of infusion, glucose +0.6 ± 0.6 mmol/l with urocortin-2, placebo −0.7 ± 0.6 mmol/l; p = 0.08). Although there appeared to be a transient small spike in endothelin-1 during the second half of the urocortin-2 infusion, the change was not significantly different from placebo (Fig. 6).
More flushing was observed with urocortin-2 than with placebo (15 of 27 vs. 6 of 26, respectively; p = 0.016), although the majority were subjectively unaware of the effect. Nonsustained ventricular tachycardia was observed in 1 patient in each study arm during infusion and during 16 h post-infusion in 2 from the urocortin-2 arm and 3 from the placebo arm. All were asymptomatic, and 4 had a prior history of ventricular tachycardia.
This is the first report to provide pilot data on urocortin-2 as a novel adjunct to conventional therapy in ADHF. In this study, administration of urocortin-2 was feasible, symptomatically well tolerated, and was associated with clear hemodynamic effects. Our study confirmed urocortin-2 is a potent vasodilator with a 47% reduction in cTPR associated with substantial falls in arterial pressures that outlasted the period of infusion. Much of the increase in cardiac output is likely to reflect reduced peripheral vascular resistance. Urocortin-2 has known mild positive inotropic effects that may have contributed to increases in cardiac output (21); however, we were not able to directly measure contractility in our study. Urocortin-2 also appeared to have a greater effect on afterload than preload. For the large fall in blood pressure observed, there was little accompanying increase in heart rate. Blunting of baroreflex-mediated tachycardia may be explained by urocortin-2's known cardiac sympathetic nerve suppressant effects (14).
There were mixed neurohormonal effects during urocortin-2 infusion. Notably, no acute elevation of aldosterone accompanied the brief rise in PRA. The pattern of response in plasma natriuretic peptides over 24 h suggests urocortin-2 facilitated cardiac decongestion, with this effect outlasting the period of infusion. The renin activation (albeit brief) and reduced renal indices (albeit reversible) were unexpected and very different from observations in experimental heart failure, where urocortin-2 infusion markedly enhanced diuresis, natriuresis, increased GFR, and clearly suppressed the renin-angiotensin-aldosterone-system (15). The effects on PRA and renal indices in this study were short lived and occurred most likely in response to falls in blood pressure and associated falls in renal perfusion pressure. The chosen hourly urocortin-2 dose in this study was equivalent to the low dose (25 μg/h) studied in stable heart failure patients (12) but administered for the longer duration of 4 h. However, the achieved peak plasma urocortin-2 concentration of 2,830 pg/ml (range 2,542 to 3,512 pg/ml) was twice that observed in an earlier study in patients with stable chronic heart failure at 1,390 pg/ml (range 1,210 to 1,590 pg/ml) at an equivalent dose, and the hemodynamic changes were closer to those previously observed with higher dose (100 μg/h) urocortin-2. A lower dose with less hypotensive effect may avoid the PRA and renal changes seen here.
Urocortin-2 is a unique peptide with a distinct structure and actions through a unique receptor. No study has directly compared the effects of urocortin-2 to those of other vasodilators. Urocortin-2 has a rapid onset of action, is a potent vasodilator, and the magnitude of cardiac output augmentation in proportion to the vasodilation achieved is significant. With respect to the renal effects of urocortin-2, it is notable that renal indices recovered rapidly once systemic pressure rose after completion of the infusion. Advances in vasodilator treatment in ADHF have been minimal over the past decades. Adverse hypotension or renal dysfunction has often been observed during studies of new therapies, even leading to premature study termination despite favorable reduction in intracardiac pressures (22). Renal safety concerns were also raised with nesiritide after a meta-analysis of small randomized trials (23); this concern was not upheld in the subsequent pivotal trial (8). Indeed, hypotension occurred more often with urocortin-2 in this study and is likely to account for the observed worsening in renal function; however, it was in the setting of a higher than expected plasma concentration achieved and greater than anticipated hypotensive effects. It may be premature to rule out any therapeutic potential of urocortin-2 in ADHF without further in-depth study of dose-response relationships, which may reveal doses achieving balanced and beneficial renal, neurohormonal, and hemodynamic effects.
This pilot study was small and heart failure presentations were heterogeneous. Effects on symptoms improvement and outcomes are not reported as the study was not powered to detect changes in these endpoints. Right heart catheterization was performed in only a subgroup and may have limited the power to detect differential effects of urocortin-2 on filling pressures. The infusion was started relatively late (mean 21 h from admission), compared to the continuous conventional heart failure therapy administered to all patients throughout the hospital stay; therefore, some patients might not be as compromised at the time of enrollment, and subsequently, the potential effect of urocortin-2 in ADHF may have been underestimated.
Urocortin-2 administration in the setting of ADHF was feasible and resulted in vasodilation and increased cardiac output. Urocortin-2 produced a sustained fall in B-type natriuretic peptides levels. A transient decline in renal indices reflected pronounced falls in systemic arterial pressure seen with the dose of urocortin-2 used in the current study. The role of urocortin-2 in ADHF, in particular at a lower dose with less blood pressure lowering effect, may warrant further research.
Support for this work was provided through grants from the Health Research Council and the National Heart Foundation of New Zealand. The urocortin-2 peptide was provided by Neurocrine Biosciences Inc. Dr. Crozier is an investigator with Cameron Health and St. Jude Medical; and receives fellowship support from Medtronic. Dr. Troughton has relationships with Roche Diagnostics and St. Jude Medical. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- acute decompensated heart failure
- atrial natriuretic peptide
- brain natriuretic peptide
- corticotrophin-releasing factor
- calculated total peripheral resistance
- glomerular filtration rate
- N-terminal pro-brain natriuretic peptide
- pulmonary capillary wedge pressure
- plasma renin activity
- Received April 15, 2013.
- Revision received July 8, 2013.
- Accepted July 15, 2013.
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