Haemodynamic effects, safety, and pharmacokinetics of human stresscopin in heart failure with reduced ejection fraction

Mihai Gheorghiade*, Stephen J. Greene, Piotr Ponikowski, Aldo P. Maggioni, Jerzy Korewicki, Cezar MacArie, Marco Metra, Jacek Grzybowski, Serban Ion Bubenek-Turconi, Waldemar Radziszewski, Allan Olson, Orlando F. Bueno, Atalanta Ghosh, Lawrence I. Deckelbaum, Lilian Y. Li, Ayan R. Patel, Andreas Koester, Marvin A. Konstam

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

AimsHuman stresscopin is a corticotropin-releasing factor (CRF) type 2 receptor (CRFR2) selective agonist and a member of the CRF peptide family. Stimulation of CRFR2 improves cardiac output and left ventricular ejection fraction (LVEF) in patients with stable heart failure (HF) with reduced LVEF. We examined the safety, pharmacokinetics, and effects on haemodynamics and serum biomarkers of intravenous human stresscopin acetate (JNJ-39588146) in patients with stable HF with LVEF ≤35% and cardiac index (CI) ≤2.5 L/min/m2.Methods and resultsSixty-two patients with HF and LVEF ≤35% were instrumented with a pulmonary artery catheter and randomly assigned (ratio 3:1) to receive an intravenous infusion of JNJ-39588146 or placebo. The main study was an ascending dose study of three doses (5, 15, and 30 ng/kg/min) of study drug or placebo administered in sequential 1 h intervals (3 h total). Statistically significant increases in CI and reduction in systemic vascular resistance (SVR) were observed with both the 15 ng/kg/min (2 h time point) and 30 ng/kg/min (3 h time point) doses of JNJ-39588146 without significant changes in heart rate (HR) or systolic blood pressure (SBP). No statistically significant reductions in pulmonary capillary wedge pressure (PCWP) were seen with any dose tested in the primary analysis, although a trend towards reduction was seen.ConclusionIn HF patients with reduced LVEF and CI, ascending doses of JNJ-39588146 were associated with progressive increases in CI and reductions in SVR without significant effects on PCWP, HR, or SBP.Trial registration: NCT01120210. All rights reserved.

Original languageEnglish (US)
Pages (from-to)679-689
Number of pages11
JournalEuropean Journal of Heart Failure
Volume15
Issue number6
DOIs
StatePublished - Jun 2013

Keywords

  • Corticotropin-releasing factor type 2 receptor
  • Haemodynamics
  • Heart failure
  • Human stresscopin
  • Pharmacokinetics

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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