Effect of Urocortins in Patients With Heart Failure

Urocortins 2 & 3-Effects on Forearm Arterial Blood Flow in Patients With Heart Failure

Despite modern advances in treatment, heart failure continues to carry a poor prognosis with high morbidity and mortality rates. Hence, there remains a major interest in the development of novel therapeutic agents for this debilitating condition. Urocortins have recently shot into limelight with their potential role in the pathophysiology and treatment of heart failure.

Recent studies by the investigators group (REC no: 09/S1103/41) have confirmed that Urocortin 2 and 3 are potent arterial vasodilators, the effects of which are reproducible and well tolerated in healthy male volunteers. Previous studies using heart failure models in animals1-7, as well studies in heart failure patients (Urocortin 2), suggest that there is great scope for Urocortins as novel biomarkers and as potential therapeutic agents in heart failure. With this in mind, the investigators wish to study the local vasomotor effects of these peptides in greater detail in patients with heart failure.

Study Overview

• Status: Completed
• Conditions: Heart Failure; Endothelium
• Intervention / Treatment: Drug: Urocortin 2, Urocortin 3 and Substance P

• Study Type: Interventional
• Enrollment (Actual): 22
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United Kingdom
  • Edinburgh, United Kingdom, EH16 4SA
    • Wellcome Trust Clinical Research Facility, Royal Infirmary of Edinburgh

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Patients with heart failure:

1. Patients with stable heart failure (NYHA class II-IV) on maximum tolerated doses of an ACE inhibitor and beta-blocker for at least 3 months.
2. Baseline echocardiographic parameters (echo performed within last 12 months) at recruitment: ejection fraction (EF) <35%, left ventricular end dimension >5.5cm and fractional shortening <20%
3. Age 18-80 years (inclusive) at recruitment

Healthy volunteers:

• Age and sex-matched healthy volunteers

Exclusion Criteria:

1. Lack of informed consent
2. Age <18 years and > 80 years
3. Current involvement in a clinical trial
4. Systolic blood pressure >190 mmHg or <90 mmHg, untreated malignant arrhythmias
5. Haemodynamically significant valvular heart disease
6. Severe or significant co-morbidity including bleeding diathesis, renal or hepatic failure
7. History of anaemia
8. Recent infective/inflammatory condition
9. Recent blood donation (prior 3 months)
10. Women of child bearing potential

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Patients with heart failure; Assessing the response to infusion of intra-arterial Urocortin 2, 3 and Substance P in patients with heart failure	Drug: Urocortin 2, Urocortin 3 and Substance P; After a 20-min infusion of intra-arterial saline, ascending doses of Urocortin 2 (3.6, 12 and 36 pmol/min [15, 50 and 150 ng/min] to achieve estimated end-organ concentrations of 0.6, 2 and 6 µg/L, respectively), Urocortin 3 1200, 3600 and 12000 pmol/min (5, 15 and 50 micrograms/min) [to achieve estimated end-organ concentrations of 199, 600 and 2000 micrograms/L respectively] and substance P (a control endothelium-dependent vasodilator that evokes endogenous t-PA release [2, 4 and 8 pmol/min]) will be administered intra-arterially. Baseline blood samples will be taken at the start of the study for full blood count, cholesterol, glucose, renal function Bilateral venous blood samples will be taken at baseline, immediately before the start of Ucn2/Ucn3 infusion and at the end of each dose of Ucn2/Ucn3 for subsequent measurement of plasma Ucn 2 and 3 concentrations and other hormones.
Other: Healthy controls; Assessing response to intra-arterial infusions of Urocortin 2, 3 and Substance P in age and sex-matched healthy volunteers as controls.	Drug: Urocortin 2, Urocortin 3 and Substance P; After a 20-min infusion of intra-arterial saline, ascending doses of Urocortin 2 (3.6, 12 and 36 pmol/min [15, 50 and 150 ng/min] to achieve estimated end-organ concentrations of 0.6, 2 and 6 µg/L, respectively), Urocortin 3 1200, 3600 and 12000 pmol/min (5, 15 and 50 micrograms/min) [to achieve estimated end-organ concentrations of 199, 600 and 2000 micrograms/L respectively] and substance P (a control endothelium-dependent vasodilator that evokes endogenous t-PA release [2, 4 and 8 pmol/min]) will be administered intra-arterially. Baseline blood samples will be taken at the start of the study for full blood count, cholesterol, glucose, renal function Bilateral venous blood samples will be taken at baseline, immediately before the start of Ucn2/Ucn3 infusion and at the end of each dose of Ucn2/Ucn3 for subsequent measurement of plasma Ucn 2 and 3 concentrations and other hormones.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Forearm blood flow	Difference between forearm blood flow in response to doses of Ucn2, Ucn3 and Substance P between heart failure patients and healthy controls.	3 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Absolute forearm blood flow	Absolute forearm arterial blood flow in response to Ucn2, Ucn3 and Substance P.	3 hours

Collaborators and Investigators

• Sponsor: University of Edinburgh
• Collaborators: NHS Lothian
• Investigators: Principal Investigator: David E Newby, PhD, FRCP, University of Edinburgh

Study record dates

Study Major Dates

• Study Start: May 1, 2012
• Primary Completion (Actual): July 1, 2012
• Study Completion (Actual): July 1, 2012

Study Registration Dates

• First Submitted: May 14, 2012
• First Submitted That Met QC Criteria: May 15, 2012
• First Posted (Estimate): May 16, 2012

Study Record Updates

• Last Update Posted (Estimate): June 25, 2013
• Last Update Submitted That Met QC Criteria: June 24, 2013
• Last Verified: June 1, 2013

More Information

Terms related to this study

• Keywords: Heart failure; Substance P; Endothelium; Urocortin 2; Urocortin 3; Forearm venous occlusion plethysmography
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Substance P; Neurokinin A
• Other Study ID Numbers: UcnHFP2