Invited Speaker

Evolution of Prostaglandins in the Treatment of Pulmonary Hypertension
Miguel Angel Gómez Sánchez
Spain


Pulmonary arterial hypertension is a rare fatal disease defined as a sustained elevation of pulmonary arterial pressure to more than 25 mmHg at rest, with a mean pulmonary-capillary wedge pressure and left ventricular end-diastolic pressure of less than 15 mmHg at rest. Histopathology of PAH is founded on structural modifications on the vascular wall of small pulmonary arteries characterized by thickening of all its layers. These changes, named as vascular remodelling, include vascular proliferation, fibrosis, and vessel obstruction. In clinical practice the diagnosis of Pulmonary Hypertension relies on measurements of pulmonary vascular pressure and cardiac output, and calculation of pulmonary vascular resistances. Direct evaluation of pulmonary vascular structure is not routinely performed in pulmonary hypertension since current imaging techniques are limited and since little is known about the relationship between structural changes and functional characteristics of the pulmonary vasculature. Intravascular ultrasound studies in patients with pulmonary hypertension have shown a thicker middle layer, increased wall-thickness ratio and diminished pulsatility than in control patients. Optical Coherence Tomography, a new high resolution imaging modality that has proven its superiority over IVUS for the detection and characterization of coronary atherosclerotic plaque composition, may potentially be a useful technique for the in vivo study of the pulmonary arterial wall. In addition the analysis of the pressure-volume curves of the right ventricle will help to better evaluate the effect of drugs on the intrinsic load independent contractility of this ventricle. This would allow the in vivo study of right ventricular and pulmonary artery remodelling in PAH. The aim of the lecture is to give an historical perspective of the pathophysiological rationale and the clinical application of prostaglandins in the treatment of pulmonary hypertension since the discovery of the beneficial effect of epoprostenol in this setting.

The prostacyclins act through an increase in cyclic AMP, which produces vasodilatation. Prospective randomized trials by Barst and McLaughlin have demonstrated improved exercise tolerance and survival in patients with idiopathic pulmonary hypertension treated with Epoprostenol. Epoprostenol has a very short half life (t½). Therefore, a permanent central venous access is needed for administration and hence a risk of potentially serious complications thereof. Therefore, a more stable PGI2 analogue like Iloprost offers theoretical advantages. By inhalation route, less of the drug reaches systemic circulation thus making it a “pseudoselective pulmonary vasodilator”.

Currently, intravenously prostaglandins are the first line of treatment for patients in advanced New York Heart Association (NYHA). However, in the future, patients with less severe disease (NYHA II, III) may be initially treated with one of the novel prostaglandins. The propensity for serious central venous catheter related infections in case of intravenous epoprostenol led to the development of Trepostinil, a stable prostacyclin analog for subcutaneous infusion. The most common side effect was infusion site pain Oral Beraprost another prostacyclin analogue appears to be beneficial in the treatment of PPH.