Effects of Apelin on the Lung Circulation in Pulmonary Hypertension

Investigating the Acute Pulmonary Vascular Haemodynamic Effects of Apelin in Pulmonary Hypertension

The purpose of this study is to determine the effects of Apelin on the lung circulation. The investigators hypothesise that Apelin will relax the lung blood vessels and improve the pumping ability of the heart.

Study Overview

• Status: Unknown
• Conditions: Heart Failure; Pulmonary Arterial Hypertension
• Intervention / Treatment: Drug: Apelin; Drug: Saline (Placebo)

Detailed Description

Apelin is an endogenous peptide with physiological actions in the cardiovascular system and is abundantly expressed in the pulmonary vasculature. Pre-clinical models and preliminary clinical data indicate that Apelin deficiency may mediate or contribute to the pathogenesis of pulmonary hypertension and heart failure. Apelin causes peripheral vasodilatation and increased cardiac contractility. The investigators will determine the effects of Apelin on the pulmonary circulation in 3 groups; healthy control, people with pulmonary arterial hypertension and people with pulmonary hypertension due to heart failure. Each subject will receive both Apelin infusion and saline placebo infusion in a crossover design. The infusions will be given in a random order which the subject and the investigator will be blinded to. The investigators hypothesise that Apelin will have more marked pulmonary haemodynamic effects than that observed in the systemic circulation. Moreover, the investigators propose that Apelin will have a marked vasodilatory effect on the human pulmonary vasculature and reduce pulmonary vascular resistance in patients with pulmonary arterial hypertension or pulmonary hypertension due to left heart disease.

• Study Type: Interventional
• Enrollment (Anticipated): 63
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United Kingdom
  • Edinburgh, United Kingdom, EH16 4SA
    • Recruiting
    • Royal Infirmary Edinburgh
    • Contact: David E Newby, BM, PhD, DM; Phone Number: +44 (0)131 242 6515; Email: d.e.newby@ed.ac.uk
    • Principal Investigator: David E Newby, BM, Phd, DM
    • Sub-Investigator: Colin Stirrat, MB ChB
  • Glasgow, United Kingdom, G81 4HX
    • Recruiting
    • Golden Jubilee National Hospital
    • Contact: Andrew J Peacock, BSc MPhil MD; Phone Number: +44 (0)141 951 5497; Email: apeacock@udcf.gla.ac.uk
    • Contact: Lauren Brash, MB ChB; Phone Number: +44 (0)7738 569980; Email: laurenbrash@nhs.net
    • Sub-Investigator: Lauren Brash, MBChB
    • Sub-Investigator: Martin K Johnson, MBChB, MD
    • Sub-Investigator: David J Welsh, BSc, PhD
  • London, United Kingdom, W12 0HS
    • Recruiting
    • Hammersmith Hospital
    • Contact: Luke SG Howard, MA, MB BChir; Phone Number: +44 (0)20 83831317; Email: l.howard@imperial.ac.uk
    • Contact: Gareth Barnes, MB ChB; Phone Number: +44 (0)20 83831317; Email: g.barnes@imperial.ac.uk
    • Principal Investigator: Luke SG Howard, MA, MB BChir
    • Sub-Investigator: Gareth Barnes, MBChB
    • Sub-Investigator: Martin R Wilkins, MD, FRCP
    • Sub-Investigator: Simon J Gibbs, MD, MB Bhir

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

PULMONARY ARTERIAL HYPERTENSION

Inclusion Criteria:

• Pulmonary Arterial Hypertension which is Idiopathic, Heritable, associated with connective tissue disease or associated with drugs/toxins
• mean pulmonary artery pressure >/= 25mmHg
• pulmonary capillary wedge pressure < 15 mmHg
• normal/reduced cardiac output
• stable
• WHO functional class II - IV

Exclusion Criteria:

• significant left ventricular dysfunction
• chronic lung disease (FEV1 < 60% or abnormal CT)
• chronic thromboembolic pulmonary hypertension

HEART FAILURE

Inclusion Criteria:

• stable on treatment for 3 months prior to study
• NYHA grade II - IV
• ejection fraction <35%, left ventricular end-diastolic diameter > 5.5 cm and/or shortening fraction < 20%
• Tricuspid regurgitant velocity >/= 3.0 m/s

HEALTHY VOLUNTEERS

Inclusion Criteria:

• mean pulmonary artery pressure < 25 mmHg
• tricuspid regurgitant velocity < 2.5 m/s

Exclusion Criteria:

• obstructive coronary artery disease

ALL SUBJECTS

Exclusion Criteria:

• bleeding diathesis
• women of childbearing potential without pregnancy test
• systolic blood pressure > 190 mmHg or < 100 mmHg
• malignant arrhythmias
• renal or hepatic failure
• haemodynamically significant valvular heart disease
• severe or significant co-morbidity
• pacemaker
• already taking part in another trial
• lack of informed consent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Apelin/Saline; Apelin infusion then crossover to Saline infusion	Drug: Apelin; During right heart catheterisation, Apelin will be infused at 30, 100 and 300 nanomol/min for 5 minutes. Apelin will then be infused at 300 nanomol/min for a further 15 minutes while the subject exercises using a supine ergometer.; Drug: Saline (Placebo); During right heart catheterisation, saline will be infused for 15 minutes while the subject rest and for a further 15 minutes while the subject exercises using a supine ergometer.
EXPERIMENTAL: Saline/Apelin; Saline infusion then crossover to Apelin infusion	Drug: Apelin; During right heart catheterisation, Apelin will be infused at 30, 100 and 300 nanomol/min for 5 minutes. Apelin will then be infused at 300 nanomol/min for a further 15 minutes while the subject exercises using a supine ergometer.; Drug: Saline (Placebo); During right heart catheterisation, saline will be infused for 15 minutes while the subject rest and for a further 15 minutes while the subject exercises using a supine ergometer.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in pulmonary vascular resistance	We will measure the change in pulmonary vascular resistance after infusion of Apelin during right heart catheterisation	5,10,15 and 30 minutes after start of infusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in systemic vascular resistance	We will measure the change in systemic vascular resistance during infusion of Apelin	5,10,15 and 30 minutes after start of infusion
Change in Cardiac Output	We will measure the change in cardiac output after infusion of Apelin during right heart catheterisation.	5,10,15 and 30 minutes after start of infusion

Collaborators and Investigators

• Sponsor: Golden Jubilee National Hospital
• Collaborators: NHS Lothian; Imperial College Healthcare NHS Trust
• Investigators: Principal Investigator: Andrew J Peacock, BSc MPhil MD, National Health Service: Golden Jubilee National Hospital

Publications and helpful links

General Publications

• Brash L, Barnes GD, Brewis MJ, Church AC, Gibbs SJ, Howard LSGE, Jayasekera G, Johnson MK, McGlinchey N, Onorato J, Simpson J, Stirrat C, Thomson S, Watson G, Wilkins MR, Xu C, Welsh DJ, Newby DE, Peacock AJ. Short-Term Hemodynamic Effects of Apelin in Patients With Pulmonary Arterial Hypertension. JACC Basic Transl Sci. 2018 Mar 28;3(2):176-186. doi: 10.1016/j.jacbts.2018.01.013. eCollection 2018 Apr.

Study record dates

Study Major Dates

• Study Start: January 1, 2012
• Primary Completion (ANTICIPATED): January 1, 2014
• Study Completion (ANTICIPATED): January 1, 2014

Study Registration Dates

• First Submitted: October 20, 2011
• First Submitted That Met QC Criteria: October 20, 2011
• First Posted (ESTIMATE): October 21, 2011

Study Record Updates

• Last Update Posted (ESTIMATE): July 15, 2013
• Last Update Submitted That Met QC Criteria: July 12, 2013
• Last Verified: July 1, 2013

More Information

Terms related to this study

• Keywords: Heart Failure; Pulmonary Hypertension; cardiac output; Apelin; Haemodynamics; pulmonary vascular resistance
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Heart Failure; Hypertension; Pulmonary Arterial Hypertension; Hypertension, Pulmonary
• Other Study ID Numbers: 11/CARD/04