Cardiac Uses of Phosphodiesterase-5 Inhibitors

Bryan G. Schwartz, MD; Laurence A. Levine, MD; Gary Comstock, MD; Vera J. Stecher, PhD; Robert A. Kloner, MD, PhD

Disclosures

J Am Coll Cardiol. 2012;59(1):9-15. 

In This Article

High-altitude Pulmonary Edema and High-altitude Pulmonary Hypertension

High altitudes can cause pulmonary disease acutely (high-altitude pulmonary edema [HAPE]) and chronically (high-altitude pulmonary hypertension [HAPH]). Upon ascent to altitudes >2,500 m, the lungs respond to hypoxia by reducing NO availability, which precipitates pulmonary artery vasoconstriction and increased pulmonary artery pressure. Depending upon altitude and ascent rate, 0.1% to 4% of climbers develop HAPE consisting of pulmonary edema and restricted gas exchange.[31,32] In populations living at ≥3,200 m, HAPH occurs in 5% to 18%.[33] At high altitudes, sustained hypoxia can lead to pulmonary endothelial dysfunction, muscularization, and deposition of connective tissue in the pulmonary arteries and PAH leading to right ventricular hypertrophy and potentially culminating in right heart failure and premature death. The PDE5Is seem ideally suited to prevent and treat HAPE and HAPH, because PDE5Is increase NO availability, improve endothelial function, and reduce pulmonary arterial resistance and pressure ( Table 2 ).

In fact, in climbers with a history of HAPE, prophylactic tadalafil significantly and markedly reduced the incidence of HAPE compared with placebo in 2 separate studies.[34,35] In 10 healthy volunteers, sildenafil almost abolished the 56% increase in pulmonary arterial pressure induced by breathing 11% oxygen for 30 min.[36] Sildenafil was investigated in 10 trained male cyclists studied at sea-level and at simulated high altitude (breathing 12.8% oxygen).[37] At sea-level, sildenafil did not affect any hemodynamic or performance parameters. In contrast, while breathing 12.8% oxygen sildenafil increased stroke volume, cardiac output, and arterial oxygen saturation during set-work-rate exercise, and sildenafil lowered 6-km time-trial time by 15%.[37] Sildenafil was investigated in 14 healthy volunteers assessed at rest and during maximal exercise capacity while breathing 10% oxygen both at low altitude and at high altitude (Mount Everest base camp).[38] At low altitude, sildenafil increased oxygen saturation during exercise, reduced systolic pulmonary arterial pressure during rest and exercise, and increased maximum workload.[38] At high altitude, sildenafil had no effect on oxygen saturation at rest but did reduce pulmonary arterial pressure during rest and exercise and increased maximum workload and cardiac output. Thus, sildenafil and tadalafil seem to reduce pulmonary arterial pressure, increase maximum workload, and reduce the incidence of HAPE, during exercise while breathing air with reduced oxygen content and during ascent to high altitude.

To investigate sildenafil as a therapy for HAPH, 689 subjects living >2,500 m were screened by examination and electrocardiogram, revealing 188 subjects (27%) with right ventricular hypertrophy, of which 44 underwent cardiac catheterization.[39] Twenty-nine of 44 subjects (66%) had resting mean pulmonary arterial pressure >25 mm Hg. Twenty-two of these patients with HAPH were then randomized to placebo or sildenafil. Sildenafil reduced pulmonary arterial pressure and improved 6-min walk distance, after 12 weeks of therapy.[39] Moreover, sildenafil reduced right ventricular systolic pressure, reduced right ventricular hypertrophy, and inhibited pulmonary vascular remodeling, in mice given placebo or sildenafil for 3 weeks during exposure to 10% oxygen.[36] In cultured human pulmonary artery smooth muscle cells exposed to platelet-derived growth factor, sildenafil reduced smooth muscle cell proliferation and DNA synthesis through pathways involving cGMP, protein kinase G, cAMP (sildenafil increased cAMP through cGMP inhibition of phosphodiesterase type 3), and protein kinase A.[40] In conclusion, initial evidence suggests that PDE5Is might prevent and improve HAPE and HAPH.

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