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.

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.

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