Effects of Apelin on the Lung Circulation in Pulmonary Hypertension

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Pulmonary Arterial Hypertension, Heart Failure

Intervention / Treatment
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* Drug: Apelin
* Drug: Saline (Placebo)
* Drug: Saline (Placebo)
* Drug: Apelin


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 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: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Apelin/Saline<br>Apelin infusion then crossover to Saline infusion | Drug: Apelin<br>* 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.<br>Drug: Saline (Placebo)<br>* 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.<br>|
| Experimental: Saline/Apelin<br>Saline infusion then crossover to Apelin infusion | Drug: Saline (Placebo)<br>* 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.<br>Drug: Apelin<br>* 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.<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pulmonary Hypertension, Heart Failure, Apelin, Haemodynamics, pulmonary vascular resistance, cardiac output