Effect of Urocortins in Patients With Heart Failure

University of Edinburgh22 enrolled

Overview

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 Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

SINGLE

Enrollment

Conditions

Heart Failure Endothelium

Interventions

Urocortin 2, Urocortin 3 and Substance PDRUG

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.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 80 YearsHealthy volunteers:

Medical Language ↔ Plain English

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

Outcomes

Primary Outcomes

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.

Time frame: 3 hours

Secondary Outcomes

Absolute forearm blood flow

Absolute forearm arterial blood flow in response to Ucn2, Ucn3 and Substance P.