JACC: Heart Failure Vol. 1, No. 5, 2013� 2013 by the American College of Cardiology Foundation ISSN 2213-1779/$36.00Published by Elsevier Inc. http://dx.doi.org/10.1016/j.jchf.2013.07.003

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Urocortin-2 Infusion in Acute DecompensatedHeart Failure

Findings From the UNICORN Study (Urocortin-2 in theTreatment of Acute Heart Failure as an Adjunct OverConventional Therapy)

W. Y. Wandy Chan, MBCHB,*y Christopher M. Frampton, PHD,* Ian G. Crozier, MD,yRichard W. Troughton, MD, PHD,*y A. Mark Richards, MD, PHD*zChristchurch, New Zealand; and Singapore

From the *

Zealand; yCland; and th

Singapore.

Research C

urocortin-2

investigator

support from

and St. Jude

relevant to t

Manuscri

accepted Jul

ded From

Objectives T

Christchurch Heart Insti

ardiology Department, C

e zCardiovascular ResearcSupport for this work w

ouncil and the Nationa

peptide was provided by

with Cameron Health a

Medtronic. Dr. Trough

Medical. All other autho

he contents of this paper

pt received April 15, 20

y 15, 2013.

: http://heartfailure.o

he purpose of this study is to investigate the effects of urocortin-2 as adjunct therapy in acute decompensatedheart failure (ADHF).

Background U

rocortin-2 produced favorable integrated effects in experimental heart failure but there are no equivalent humandata. We describe the first therapeutic study of urocortin-2 infusion in ADHF.

Methods F

ifty-three patients with ADHF were randomly assigned to 5 ng/kg/min of urocortin-2 or placebo infusion for 4 h asan adjunct therapy. Changes in vital signs, plasma neurohormonal and renal indices during treatment werecompared using repeated-measures analysis of covariance. Ten patients in each arm underwent more detailedinvasive hemodynamic evaluation.

Results U

rocortin-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 ¼ 0.07) and increased cardiac output (2.1 � 0.4l/min vs. �0.1 � 0.4 l/min, p < 0.001) associated with a 47% reduction in calculated total peripheral resistance(p ¼ 0.015). Falls in pulmonary artery and pulmonary capillary wedge pressures did not differ significantly betweengroups. Urocortin-2 reduced urine volume and creatinine clearance during infusion but these returned to abovebaseline level in the 8 h after infusion. Plasma renin activity rose briefly with urocortin-2 coinciding with reductions inblood 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 U

rocortin-2 infusion in ADHF markedly augmented cardiac output without significant reflex tachycardia. Renalindices fell transiently concurrent with urocortin-2-induced reductions in blood pressure. Further investigations arerequired to uncover the full potential of urocortin-2 in treating ADHF. (J Am Coll Cardiol HF 2013;1:433–41)ª 2013 by the American College of Cardiology Foundation

Acute decompensated heart failure (ADHF) is a majorcause of hospitalization, mortality, and morbidity (1).Conventional treatment for ADHF is frequently limitedby compromised hemodynamic status including hypo-tension (2,3) and renal dysfunction (4). Recent trials of

tute, University of Otago, Christchurch, New

hristchurch Hospital, Christchurch, New Zea-

h Institute, National University Health System,

as provided through grants from the Health

l Heart Foundation of New Zealand. The

Neurocrine Biosciences Inc. Dr. Crozier is an

nd St. Jude Medical; and receives fellowship

ton has relationships with Roche Diagnostics

rs have reported that they have no relationships

to disclose.

13; revised manuscript received July 8, 2013,

nlinejacc.org/ by Umesh Samal on 10/22/201

new therapies in ADHF have been largely disappointing(5–8). Hence, there is a need for pharmacotherapy inADHF that can provide concurrent beneficial effects on

See page 442

hemodynamicsdincluding optimizing filling pressuresand cardiac output, and on neurohormonal activationwhile preserving renal function.

Urocortin-2 is an endogenous vasoactive peptide thatbelongs to the corticotrophin-releasing factor (CRF) family(9). It has selective affinity for the CRF2 receptor and haspredominant effects on the cardiovascular system (9).Urocortin-2 is an arterial vasodilator with positive inotropicand lusitropic properties (10–12); it is protective against

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Figure 1 Recruitment and

RHC ¼ right heart catheterization.

Abbreviationsand Acronyms

ADHF = acute

decompensated heart failure

ANP = atrial natriuretic

peptide

BNP = brain natriuretic

peptide

CRF = corticotrophin-

releasing factor

cTPR = calculated total

peripheral resistance

GFR = glomerular filtration

rate

NT-proBNP = N-terminal pro-

brain natriuretic peptide

PCWP = pulmonary capillary

wedge pressure

PRA = plasma renin activity

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ischemia-reperfusion injury andsuppresses cardiac sympatheticnerve activity (13,14). Intrave-nous boluses and constant infu-sions of urocortin-2 exhibita powerful combination of be-neficial hemodynamic, neuro-hormonal and renal effects insevere experimental heart failure(15,16). Although consistenthemodynamic effects were seenin stable heart failure patients,renal and neurohormonal effectswere minor in comparison withthose observed in the pre-clinicalstudies (12). We hypothesizedthat treatment with urocortin-2would be beneficial in ADHF,and we undertook a pilot trialcomparing symptomatic, hemo-

dynamic, neurohormonal, and renal responses to a 4-hinfusion of urocortin-2 or placebo in addition to standardtherapy for ADHF.

Methods

The UNICORN (Urocortin-2 in the Treatment of AcuteHeart Failure as an Adjunct Over Conventional Therapy)study was a single-center, randomized, double-blind, placebo-controlled trial (Australian New Zealand Clinical Trials

Treatment Allocation Flow Diagram

nlinejacc.org/ by Umesh Samal on 10/22/201

Registry number ACTRN12609000508279). The studyprotocol was approved by the ethics committee of the NewZealand Ministry of Health (Upper South B, Canterbury),and the Standing Committee on Therapeutic Trials. Thestudy was conducted under the oversight of the Data Moni-toring Committee of the Health Research Council of NewZealand. Although Neurocrine Biosciences Inc. provided thetrial peptide and the initial toxicology information forassessment by the Standing Committee on TherapeuticTrials, they made no other financial or intellectual contribu-tion, and the trial was entirely designed by the investigatorsand funded by a grant from the Health Research Council. Allparticipants gave signed written informed consent to take partin the trial. All participants were invited to take part in theright heart catheter substudy for more detailed hemodynamicobservations with additional consent until 20 right heartcatheter studies were completed.

Patient eligibility. Inclusion criteria were as follows:patients �18 years of age were eligible if they wererecruited within 36 h of admission for ADHF and lessthan 24 h from first dose of intravenous loop diureticagents, had dyspnea at rest or with minimal exertion, withat least 1 clinical sign of heart failure (specifically, eitherrespiratory rate >20/min or pulmonary edema with cracklesto at least one-third above lung bases), and at least 1objective measurement consistent with heart failure (eitherchest x-ray film showing pulmonary congestion, brainnatriuretic peptide [BNP] >115 pmol/l or N-terminal-probrain natriuretic peptide [NT-proBNP] >120 pmol/l, orleft ventricular ejection fraction <40% on echocardiogram).

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Table 1Basic Demographics and Characteristics ofParticipants

Placebo(n ¼ 26)

Urocortin-2(n ¼ 27) p Value

Age, yrs 68 � 12 63 � 12 0.20

Male 16 22 0.11

Ethnicity 0.09

Caucasian 25 22

Non-Caucasian 1 5

BMI, kg/m2 25 � 4 27 � 4 0.24

LVEF, % 42 � 19 34 � 17 0.11

Etiology 0.92

Ischemic 38% 37%

Nonischemic 62% 63%

History

CAD 52% 42% 0.49

Prior MI 41% 35% 0.65

Prior PCI 8% 26% 0.08

Prior CABG 31% 30% 0.93

Hypertension 64% 56% 0.54

Atrial fibrillation 50% 52% 0.90

Diabetes mellitus 27% 33% 0.61

Hyperlipidemia 52% 73% 0.20

CVA 15% 12% 0.69

Smoking 69% 70% 0.93

COPD 28% 37% 0.49

Furosemide prior 24 h, mg 195 � 73 200 � 115 0.97

Baseline drug use

ACEI/ARB 73% 63% 0.43

BB 50% 52% 0.89

MRA 15% 30% 0.22

Presentation to start of infusion, h 21 � 9 22 � 8 0.68

Baseline measurements

Systolic BP, mm Hg 131 � 31 123 � 20 0.25

Heart rate, beats/min 83 � 17 79 � 15 0.41

Plasma creatinine, mmol/l 109 � 33 116 � 35 0.46

Estimated GFR, ml/min 58 � 17 58 � 15 1.0

BNP, pmol/l 130 � 112 105 � 103 0.42

Values are mean � SD, n, or %.ACEI ¼ angiotensin-converting enzyme inhibitor; ARB ¼ angiotensin-II receptor blocker; BB ¼

beta-blocker; BMI ¼ body-mass index; BNP ¼ brain natriuretic peptide; BP ¼ blood pressure;CABG ¼ coronary artery bypass graft surgery; CAD ¼ coronary artery disease; COPD ¼ chronicobstructive pulmonary disease; CVA ¼ cerebrovascular accident; GFR ¼ glomerular filtration rate;LVEF ¼ left ventricular ejection fraction; MI ¼ myocardial infarction; PCI ¼ percutaneous coronaryintervention; MRA ¼ mineralocorticoid receptor antagonist.

Figure 2 Hemodynamic Responses

Mean � SEM of hemodynamic effects during and after 4-h infusions (shaded in

gray) of placebo (open circles) or urocortin-2 (Ucn2) (solid circles). *p < 0.05,

**p < 0.01, and yp < 0.001 indicate significant time-by-treatment interaction in

the specific time phase.

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Exclusion criteria were acute coronary syndrome, systolicblood pressure <100 mm Hg, significant valvular stenosis,restrictive, constrictive or hypertrophic cardiomyopathy orpericardial disease, varying dose of intravenous nitrate orinotropes within 3 h of randomization, severe pulmonarydisease affecting assessment of dyspnea, end-stage renaldisease, noncardiac disease with a life expectancy<6 months,and body mass index >35 kg/m2.Protocol. The study was performed within the coronarycare unit at Christchurch Hospital. Patients were randomlyallocated in a double-blind 1:1 sequence, from a computer-generated list performed in permuted blocks of 4, to 4-hintravenous infusion of either urocortin-2 (400 mgurocortin-2 and 50 mg mannitol in each vial, dissolved in

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2 ml water; 0.6 ml of this solution was made up to 60 mlwith normal saline [2 mg/ml]) at 5 ng/kg/min or placebo(each vial contained 50 mg mannitol, infusion prepared inthe same manner as urocortin-2) supplied by NeurocrineBiosciences Inc. (San Diego, California), as an adjunct toconventional therapy including intravenous diuretic agentsand vasodilators as per the treating physician. If possible,medications that could cause hypotension were withheldfrom 2 h before commencement of infusion until infusionwas completed. The dose of urocortin-2 in this studywas equivalent to the low dose (25 mg over 1 h) studied instable heart failure patients previously reported to produce

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Table 2Basic Demographics and Characteristics of RightHeart Catheter Substudy Participants

Placebo(n ¼ 10)

Urocortin-2(n ¼ 10) p Value

Age, yrs 63 � 14 61 � 13 0.75

Male 7 10 0.21

Ethnicity 1.0

Caucasian 9 9

Non-Caucasian 1 1

BMI, kg/m2 26 � 5 27 � 4 0.82

LVEF, % 41 � 19 35 � 19 0.46

Etiology 1.0

Ischemic 40% 30%

Nonischemic 60% 70%

History

CAD 50% 30% 0.65

Prior MI 33% 20% 0.63

Prior PCI 0% 20% 0.47

Prior CABG 20% 10% 1.0

Hypertension 60% 50% 1.0

Atrial fibrillation 30% 50% 0.65

Diabetes mellitus 30% 30% 1.0

Hyperlipidemia 20% 40% 0.30

CVA 10% 10% 1.0

Smoking 70% 70% 1.0

COPD 20% 30% 1.0

Furosemide prior 24 h, mg 270 � 518 14 � 38 0.14

Baseline drug use

ACEI/ARB 50% 30% 0.65

BB 30% 40% 1.0

MRA 10% 30% 1.0

Presentation to start of infusion, h 27 � 8 24 � 8 0.47

Baseline measurements

Systolic BP, mm Hg 133 � 30 118 � 18 0.19

Heart rate, beats/min 83 � 17 85 � 16 0.78

Plasma creatinine, mmol/l 121 � 44 111 � 22 0.54

Estimated GFR, ml/min 56 � 22 62 � 15 0.53

BNP, pmol/l 158 � 151 101 � 73 0.35

RAP, mm Hg 7 � 6 8 � 5 0.61

Mean PAP, mm Hg 32 � 11 34 � 8 0.57

PCWP, mm Hg 22 � 9 26 � 7 0.39

Cardiac output, l/min 4.9 � 1.8 3.7 � 0.8 0.08

Cardiac index, l/min/m2 2.6 � 0.9 1.8 � 0.4 0.03

Values are mean � SD, n, or %.PAP ¼ pulmonary artery pressure; PCWP ¼ pulmonary capillary wedge pressure; RAP ¼ right

atrial pressure; other abbreviations as in Table 1.

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desirable hemodynamic effects without adverse hormonalactivation (12). The randomization sequence ensuredbalance within the right heart catheter subgroup.

Heart rate, rhythm, and blood pressure were recorded atbaseline and every 30 min during infusion followed byhourly recording for 4 h, then at þ12 h and þ24 h.

Samples for plasma urocortin-1, urocortin-2, atrial nat-riuretic peptide (ANP), BNP, NT-proBNP, endothelin-1,plasma renin activity (PRA), angiotensin-II, aldosterone,and cortisol were obtained at 0, þ1, þ2, þ4, þ6, þ12,and þ24 h. Venous blood was collected into ethyl-enediaminetetraacetic acid (EDTA) tubes, except for

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urocortin-2 (heparin) and angiotensin-II (0.125 M EDTA,0.05 M o-phenanthroline, 2% ethanol, 0.2% neomycinsulphate, and 0.03 mg/ml enalkiren). Samples were imme-diately separated (4,000 rpm for 10 min in a refrigeratedcentrifuge) and stored at �80�C until assayed using previ-ously validated methods (17,18). All samples from the samepatient were measured in the same assay to avoid interassayvariations. Intra-assay coefficients of variation measuredwere all <15%, except for BNP (17.1%).

Samples for serial plasma sodium, potassium, and creati-nine were obtained at 0, þ2, þ4, þ6, þ12, and þ24 h.

Patients were requested to void within 15 min be-fore commencement of infusions to standardize urine col-lection. Urine was collected in 3 phases, at 0 to 4 h, þ4 to12 h, and þ12 to 24 h from commencement of infu-sions for measurement of volume, creatinine, sodium, andpotassium. Estimated glomerular filtration rate was calcu-lated using the Modification of Diet in Renal Diseaseequation (19).

For patients who underwent right heart catheterization,a 7F Swan-Ganz catheter was positioned in the pulmonaryartery through the right internal jugular vein using fluoros-copy while the patient was lying supine. Pulmonary capillarywedge pressure (PCWP) was confirmed by typical waveformappearance. Thermodilution cardiac output (20), right atrialpressure, pulmonary artery pressure, and PCWP wereobtained after 30 s of quiet respiration at �0.5 h, 0 h, þ0.5h, and þ1 h, then hourly until the catheter was removedat þ8 h. Cardiac output divided by the mean arterial pres-sure was used to calculate the calculated total peripheralresistance (cTPR). Each recording was an average of3 measurements.Statistical analysis. The sample size was determined on thebasis of the neurohormonal data from a group of patientsadmitted to our institution who fulfilled the study enroll-ment criteria. To confirm a 50% relative reduction in themean values of key neurohormonal indicators using lognormalized data with 80% power (2-tailed a ¼ 0.05)a sample size of 25 patients per treatment limb was required.This sample size also offered similar or greater power todetect 10% changes in key hemodynamic variables on thebasis of prior successful detection of hemodynamic changesin response to urocortin-2 infusions in human and animalmodels in group sizes of 8, and to detect a 10% shift incalculated GFR (12,15,18).

The effect of urocortin-2 on hemodynamics, renal func-tion and neurohormones over the 24-h period and in phasesrelative to the commencement of infusion were examinedusing repeated measures analysis of covariance, with therandomized treatment as the between-subject factor, time asthe within-subject factor, and the relevant baseline levelas covariate. The term of most importance in these analyseswas the time-by-randomized-treatment interaction, indi-cating differential responses over time. Where significantinteraction effects were identified, these were furtherexplored using paired t tests for changes within groups

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Figure 3Pulmonary Pressures, Cardiac Output, and CalculatedTotal Peripheral Resistance Responses

Right heart catheter parameters (mean � SEM) during and after 4-h infusions

(shaded in gray) of placebo (open circles) or urocortin-2 (solid circles). *p < 0.05

and yp< 0.001 indicate significant time-by-treatment interaction in the specific time

phase. cTPR ¼ calculated total peripheral resistance; PAP ¼ pulmonary artery

pressure; PCWP ¼ pulmonary capillary wedge pressure; RA ¼ right atrial.

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and independent t tests for differences between studygroups at specific times. Non-normally distributed neuro-hormonal data were log-transformed for analysis andsubsequently 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 asstatistically significant. All data were analyzed using SPSSversion 19 (SPSS, Inc. Chicago, Illinois).

Results

From Oct 2009 to Dec 2011, 55 patients were randomized(Fig. 1). Two patients were withdrawn because of vasovagalhypotensive episodes at right heart catheter insertion beforethe commencement of study drug infusion. Of 53 patientsstarting and completing trial infusions, 26 received placeboand 27 received urocortin-2 infusions. Demographics andbaseline variables were well matched (Table 1).Hemodynamics. Urocortin-2 exerted a rapid and pro-nounced hypotensive effect with clear intergroup differencesapparent within 30 min of the start of infusion. The peakeffect was noted between þ1.5 h and þ2.5 h. Duringinfusion period, reductions in systolic and diastolic bloodpressures were 16.3 � 5.5 mm Hg and 12.6 � 4.1 mm Hg,respectively, greater than time-matched placebo (bothp < 0.001) (Fig. 2). Four patients required down-titrationof 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 restartedat half the previous dose once systolic blood pressure wassustained above 90 mm Hg for at least 20 min. Heart ratetended to increase in the urocortin-2 group (6.6 � 3.9 beats/min, compared with time-matched control, p ¼ 0.07) withthe peak effect at þ1 h, earlier than the nadir of arterialpressures (Fig. 2).Right heart catheterization. Demographics and baselinevariables were well matched except a significantly lowercardiac index was noted in the urocortin-2 arm (Table 2).Urocortin-2 induced immediate and marked increases incardiac output (52 � 19% more than placebo, p < 0.001)and falls in cTPR (cTPR 40 � 8.4% more than placeboduring the infusion period, p ¼ 0.02) (Fig. 3). The effectwas confined to the first 5 h from commencement ofurocortin-2 infusion. Peak cardiac output was achievedbetween þ1 and þ2 h and fell within the first hour afterurocortin-2 infusion was halted. Maximal reduction incTPR was seen at þ2h and increased slowly after cessation,indicating a persistent vasodilatory effect after cessation ofinfusion. There was a trend to greater and more rapid earlyfalls in PCWP with urocortin-2 than with placebo(p ¼ 0.096) (Fig. 3). In both treatment arms similar falls inpulmonary artery systolic and diastolic pressures wereobserved.Renal function. Plasma creatinine, urine output, measuredcreatinine clearance, and sodium excretion were all reducedsignificantly during urocortin-2 infusion compared to placebo.

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Figure 4 Renal Responses

(Left panels) Mean � SEM of renal responses during and after 4-h infusions of placebo (open bars) or urocortin-2 (Ucn2) (solid bars). CrCL ¼ creatinine clearance. (Right

panels) Renal responses to placebo without additional furosemide (Fru�) (open bars) and with additional furosemide (Fruþ) (light gray bars), and Ucn2 Fru� (solid bars) and

Ucn2 Fruþ (dark gray bars) in þ4 h to þ12 h.

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All renal indices rebounded post-infusion (Fig. 4). Althoughmean estimated GFR was marginally elevated compared tobaseline, there was no significant difference between treatmentarms at þ24 h (urocortin-2 53 � 2.6 ml/min/1.73 m2 vs.placebo 56� 3.3 ml/min/1.73 m2, p¼ 0.4). Cumulative urinevolume and sodium and potassium excretion (2,065� 271 mlvs. 2440 � 202 ml, 181 � 33 mmol vs. 196 � 20 mmol, and56 � 4 mmol vs. 56 � 4 mmol, respectively) over the 24-hperiod were similar in urocortin-2 and placebo groups.Plasma sodium and potassium were unaffected by urocortin-2infusion.

Twelve patients in the placebo group (46%) and 16patients in the urocortin-2 group (59%, p ¼ 0.24) who

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were clinically assessed by a single-blind investigator(W.W.C.) received an extra intravenous dose of furosemidein the 8 h post-infusion period for persistent symptoms andsigns of pulmonary congestion. The average dose wassignificantly higher with placebo (149 � 30 mg vs. 85 � 14mg, p ¼ 0.047). Additional furosemide nonsignificantlyincreased diuresis or natriuresis with urocortin-2 (Fig. 4).Neurohormones. Peak plasma urocortin-2 concentrations ofsevenfold the baseline level were achieved atþ2 h and returnedto baseline within 2 h after the infusion (Fig. 5). Plasmaurocortin-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

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Figure 5Responses of Ucn-2, PRA, AngII, Aldosterone, andUcn-1

Mean � 95% confidence interval of plasma aldosterone, angiotensin-II (AngII),

plasma renin activity (PRA), urocortin-2 (Ucn2), and urocortin-1 (Ucn1) during and

after 4-h infusions (shaded in gray) of placebo (open circles) or Ucn2 (solid

circles). yp < 0.001 indicates significant time-by-treatment interaction in the

specific time phase.

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a nonsignificant increase in NT-proBNP during infusion, butlittle change was observed for ANP or BNP with urocortin-2.Post-infusion out to þ12 h, BNP and NT-proBNP weresignificantly lower after urocortin-2 than after placebo (BNP13.5%, p ¼ 0.02; NT-proBNP 16.2%, p ¼ 0.001). The BNP(p ¼ 0.17) and NT-proBNP (p ¼ 0.02) levels continued todiverge from placebo between þ12 and þ24 h.

During urocortin-2 infusion, PRA rose by 1.1 nmol/l/h toexceed time-matched placebo values by 46.3% (p < 0.001)(Fig. 5). The maximal increment in PRA change coincidedwith the time of the lowest arterial blood pressure. Therewere no corresponding acute elevations in angiotensin-II oraldosterone, resulting in a significant reduction in thealdosterone:renin ratio (p < 0.001) with urocortin-2. ThePRA, angiotensin-II, and aldosterone all gradually increasedsimilarly in both study arms from þ12 to þ24 h.

Urocortin-2 infusion attenuated the fall in cortisolcompared to placebo during infusion (�17% vs. �39%,p¼ 0.03) (Fig. 6). Plasma glucose was unaffected (at the endof infusion, glucose þ0.6 � 0.6 mmol/l with urocortin-2,placebo �0.7 � 0.6 mmol/l; p ¼ 0.08). Although thereappeared to be a transient small spike in endothelin-1 duringthe second half of the urocortin-2 infusion, the change wasnot significantly different from placebo (Fig. 6).Adverse events. More flushing was observed withurocortin-2 than with placebo (15 of 27 vs. 6 of 26,respectively; p ¼ 0.016), although the majority weresubjectively unaware of the effect. Nonsustained ventriculartachycardia was observed in 1 patient in each study armduring infusion and during 16 h post-infusion in 2 from theurocortin-2 arm and 3 from the placebo arm. All wereasymptomatic, and 4 had a prior history of ventriculartachycardia.

Discussion

This is the first report to provide pilot data on urocortin-2 asa novel adjunct to conventional therapy in ADHF. In thisstudy, administration of urocortin-2 was feasible, symp-tomatically well tolerated, and was associated with clearhemodynamic effects. Our study confirmed urocortin-2 isa potent vasodilator with a 47% reduction in cTPR associ-ated with substantial falls in arterial pressures that outlastedthe period of infusion. Much of the increase in cardiacoutput is likely to reflect reduced peripheral vascular resis-tance. Urocortin-2 has known mild positive inotropic effectsthat may have contributed to increases in cardiac output(21); however, we were not able to directly measurecontractility in our study. Urocortin-2 also appeared to havea greater effect on afterload than preload. For the large fall inblood pressure observed, there was little accompanyingincrease in heart rate. Blunting of baroreflex-mediatedtachycardia may be explained by urocortin-2’s knowncardiac sympathetic nerve suppressant effects (14).

There were mixed neurohormonal effects duringurocortin-2 infusion. Notably, no acute elevation of

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Figure 6 Responses of Natriuretic Peptides, ET-1, and Cortisol

Mean � 95% confidence interval of atrial natriuretic peptide (ANP), brain natri-

uretic peptide (BNP), cortisol, endothelin-1 (ET-1), and N-terminal pro-brain natri-

uretic peptide (NT-proBNP) during and after 4-h infusions (shaded in gray) of

placebo (open circles) or urocortin (Ucn2) (solid circles). *p < 0.05 and **p <

0.01 indicate significant time-by-treatment interaction in the specific time phase.

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aldosterone accompanied the brief rise in PRA. The patternof response in plasma natriuretic peptides over 24 h suggestsurocortin-2 facilitated cardiac decongestion, with this effectoutlasting the period of infusion. The renin activation (albeitbrief) and reduced renal indices (albeit reversible) wereunexpected and very different from observations in experi-mental heart failure, where urocortin-2 infusion markedlyenhanced diuresis, natriuresis, increased GFR, and clearlysuppressed the renin-angiotensin-aldosterone-system (15).The effects on PRA and renal indices in this study wereshort lived and occurred most likely in response to falls inblood pressure and associated falls in renal perfusion pres-sure. The chosen hourly urocortin-2 dose in this studywas equivalent to the low dose (25 mg/h) studied in stableheart failure patients (12) but administered for the longerduration of 4 h. However, the achieved peak plasmaurocortin-2 concentration of 2,830 pg/ml (range 2,542 to3,512 pg/ml) was twice that observed in an earlier study inpatients with stable chronic heart failure at 1,390 pg/ml(range 1,210 to 1,590 pg/ml) at an equivalent dose, and thehemodynamic changes were closer to those previouslyobserved with higher dose (100 mg/h) urocortin-2. A lowerdose with less hypotensive effect may avoid the PRA andrenal changes seen here.

Urocortin-2 is a unique peptide with a distinct structureand actions through a unique receptor. No study has directlycompared the effects of urocortin-2 to those of other vaso-dilators. Urocortin-2 has a rapid onset of action, is a potentvasodilator, and the magnitude of cardiac output augmen-tation in proportion to the vasodilation achieved is signifi-cant. With respect to the renal effects of urocortin-2, it isnotable that renal indices recovered rapidly once systemicpressure rose after completion of the infusion. Advances invasodilator treatment in ADHF have been minimal over thepast decades. Adverse hypotension or renal dysfunction hasoften been observed during studies of new therapies, evenleading to premature study termination despite favorablereduction in intracardiac pressures (22). Renal safetyconcerns were also raised with nesiritide after a meta-analysis of small randomized trials (23); this concern wasnot upheld in the subsequent pivotal trial (8). Indeed,hypotension occurred more often with urocortin-2 in thisstudy and is likely to account for the observed worsening inrenal function; however, it was in the setting of a higher thanexpected plasma concentration achieved and greater thananticipated hypotensive effects. It may be premature to ruleout any therapeutic potential of urocortin-2 in ADHFwithout further in-depth study of dose-response relation-ships, which may reveal doses achieving balanced andbeneficial renal, neurohormonal, and hemodynamic effects.Study limitations. This pilot study was small and heartfailure presentations were heterogeneous. Effects on symp-toms improvement and outcomes are not reported as thestudy was not powered to detect changes in these endpoints.Right heart catheterization was performed in only a sub-group and may have limited the power to detect differential

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JACC: Heart Failure Vol. 1, No. 5, 2013 Chan et al.October 2013:433–41 Urocortin-2 Infusion in Acute Heart Failure

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effects of urocortin-2 on filling pressures. The infusion wasstarted relatively late (mean 21 h from admission), comparedto the continuous conventional heart failure therapyadministered to all patients throughout the hospital stay;therefore, some patients might not be as compromised at thetime of enrollment, and subsequently, the potential effect ofurocortin-2 in ADHF may have been underestimated.

Conclusions

Urocortin-2 administration in the setting of ADHF wasfeasible and resulted in vasodilation and increased cardiacoutput. Urocortin-2 produced a sustained fall in B-typenatriuretic peptides levels. A transient decline in renalindices reflected pronounced falls in systemic arterial pres-sure seen with the dose of urocortin-2 used in the currentstudy. The role of urocortin-2 in ADHF, in particular ata lower dose with less blood pressure lowering effect, maywarrant further research.

Reprint requests and correspondence: Dr. W. Y. Wandy Chan,Heart Failure and Transplant Unit, Prince Charles Hospital, RodeRoad, Chermside QLD 4032, Australia. E-mail: wandy_chan@health.qld.gov.au.

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Key Words: acute heart failure - double-blind method - hormone -

randomized controlled trial - urocortin-2.

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