PULMONARY HYPERTENSION

Phosphodiesterase type 5 and high altitude pulmonary hypertension

A A Aldashev¹, B K Kojonazarov¹, T A Amatov², T M Sooronbaev², M M Mirrakhimov², N W Morrell³, J Wharton⁴, M R Wilkins⁴

¹ Institute of Molecular Biology and Medicine, Bishkek, Kyrgyzstan
² National Center of Cardiology and Internal Medicine, Bishkek, Kyrgyzstan
³ Addenbrooke’s Hospital, Cambridge, UK
⁴ Experimental Medicine & Toxicology, Imperial College London, Hammersmith Hospital, London W12 0NN, UK

Correspondence to:
Correspondence to:
Professor M R Wilkins
Experimental Medicine and Toxicology, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK; m.wilkins{at}imperial.ac.uk

Background: This study explored phosphodiesterase type 5 (PDE5) inhibition as a strategy for treating high altitude pulmonary arterial hypertension (HAPH).

Methods: 689 subjects (313 men) of mean (SD) age 44 (0.6) years living above 2500 m were screened for HAPH by medical examination and electrocardiography, and 188 (27%) met the criteria for right ventricular hypertrophy. 44 underwent cardiac catheterisation and 29 (66%) had a resting mean pulmonary artery pressure (PAP) above 25 mm Hg. 22 patients with a raised mean PAP were randomised to receive sildenafil (25 or 100 mg) or matching placebo taken 8 hourly for 12 weeks.

Results: At 3 months, patients on sildenafil 25 mg 8 hourly (n = 9) had a significantly (p = 0.018) lower mean PAP (–6.9 mm Hg) at the end of the dosing interval than those on placebo (n = 8) (95% CI –12.4 to –1.3). The treatment effect for sildenafil 100 mg 8 hourly (n = 5) compared with placebo was –6.4 mm Hg (95% CI –12.9 to 0.1). Both doses improved 6 minute walk distance, the lower dose by 45.4 m (95% CI 11.5 to 79.4; p = 0.011) and the higher dose by 40.0 m (95% CI 0.2 to 79.8; p = 0.049). Sildenafil was well tolerated. Necroscopic lung specimens from three subjects with HAPH showed abundant PDE5 in the muscular coat of remodelled pulmonary arterioles.

Conclusions: PDE5 is an attractive drug target for the treatment of HAPH and a larger study of the long term effects of PDE5 inhibition in HAPH is warranted.

Abbreviations: CO, cardiac output; HAPH, high altitude pulmonary hypertension; 6MW, 6 minute walk test; NO, nitric oxide; PAP, pulmonary artery pressure; PDE5, phosphodiesterase type 5; PVR, pulmonary vascular resistance; RVH, right ventricle hypertrophy

Keywords: phosphodiesterase inhibition; hypoxia induced pulmonary hypertension; altitude

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