Effect of Urocortins in Patients With Heart Failure

Study Overview
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Brief Summary
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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.

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

Conditions
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Heart Failure, Endothelium

Intervention / Treatment
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* Drug: Urocortin 2, Urocortin 3 and Substance P


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with heart failure: 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. 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% Age 18-80 years (inclusive) at recruitment Healthy volunteers: Age and sex-matched healthy volunteers Exclusion Criteria: Lack of informed consent Age <18 years and > 80 years Current involvement in a clinical trial Systolic blood pressure >190 mmHg or <90 mmHg, untreated malignant arrhythmias Haemodynamically significant valvular heart disease Severe or significant co-morbidity including bleeding diathesis, renal or hepatic failure History of anaemia Recent infective/inflammatory condition Recent blood donation (prior 3 months) Women of child bearing potential

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Patients with heart failure<br>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<br>* 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.<br>|
| Other: Healthy controls<br>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<br>* 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.<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Urocortin 2, Urocortin 3, Forearm venous occlusion plethysmography, Heart failure, Endothelium, Substance P