Effect of sildenafil on hypoxia-induced changes in pulmonary circulation and right ventricular function
Introduction
Alveolar hypoxia is a physiological cause of pulmonary vasoconstriction (Motley et al., 1947). This phenomenon is crucial for matching pulmonary perfusion and ventilation. Hypoxic pulmonary vasoconstriction is a frequent cause of pulmonary hypertension in patients with advanced lung disease and permanent residents at high altitude, respectively, leading to right heart failure and early death (Ghofrani et al., 2006, Maggiorini and Leon-Velarde, 2003, Weitzenblum and Chaouat, 2004). Several studies in pulmonary hypertension have been shown that prognosis in this disease is depending on right heart function, and preservation of right ventricular performance is a main therapeutic goal (D’Alonzo et al., 1991, Galie et al., 2004).
Hypoxia induced pulmonary vasoconstriction leads to an increase in pulmonary artery pressure (PAP) and pulmonary vascular resistance also in healthy men. This effect can be observed already after an exposure to hypoxia for 2 h (Dorrington et al., 1997), however is more pronounced in hypoxia exposure over several days or weeks (Richalet et al., 2005). So far it is unclear, if this reaction leads to subsequent changes in right ventricular function in healthy individuals.
The phosphodiesterase V inhibitor sildenafil is an established therapy for pulmonary arterial hypertension of different origin is also known to influence hypoxia-induced pulmonary hypertension in healthy individuals (Zhao et al., 2001, Galie et al., 2005, Ghofrani et al., 2003). Besides a pulmonary vasodilative activity, sildenafil may also have a direct cardiac effect with increase in inotropy of the right ventricle (Nagendran et al., 2007). Previous studies including own investigations showed that sildenafil can reduce the increase in PAP during acute and chronic hypoxia exposure in healthy individuals; however the effect of right ventricular function has not been studied (Richalet et al., 2005, Ghofrani et al., 2004).
Systolic PAP and right-sided cardiac function can be reliably investigated non-invasively by echocardiography. Several parameters for assessment of pulmonary circulation and right ventricular function are currently used in patients with cardiopulmonary disease (Galie et al., 2003, Tei et al., 1996, Forfia et al., 2006). In healthy individuals echocardiographic assessment of pulmonary circulation has been also used as a non-invasive test for disposition for the development of high-altitude pulmonary oedema (HAPE) (Grunig et al., 2000a, Vachiery et al., 1995, Dorrington and Talbot, 2004) and as screening test for predisposition to pulmonary vascular disease (Grunig et al., 2000b, Reichenberger et al., 2005, Reichenberger et al., 2006).
The current study investigated the consequences of acute and prolonged hypoxia on the resting pulmonary circulation and right ventricular function using Doppler echocardiography both at sea level and at high altitude. The acute effects of sildenafil were evaluated in a randomised, double-blinded, placebo controlled, cross-over study.
Section snippets
Methods
We examined 14 healthy Swiss and German members of a Mount Everest expedition (12 men, 2 women, mean age 37, 23–55 years). History, clinical examination, and laboratory study excluded any cardiac, pulmonary, or other organ disorders including high-altitude pulmonary or cerebral oedema.
All echocardiographic examinations were performed by one operator (FR), who was blinded concerning the study medication, using a portable Doppler echocardiography device (ACUSON Cypress, Siemens Medical Inc.,
Initial assessment at low altitude
At baseline, none of the participants exhibited signs of cardiopulmonary disease. Electrocardiogram and pulmonary function tests were within normal limits (forced expiratory volume in 1 s FEV1 3.8(0.5) l = 99(9)% predicted, vital capacity VC 4.7(0.7) l = 101(8)% predicted).
Standard echocardiogram excluded significant left- or right-sided cardiac or valvular changes. In all participants, a minimal insignificant tricuspid regurgitation could be detected. Right ventricular parameters under normoxic
Discussion
This study provides a longitudinal investigation of pulmonary circulation throughout prolonged hypoxia. While the previously published Mt. Everest Sildenafil trial concentrated on the effects of hypoxia on exercise capacity and sPAP (Ghofrani et al., 2004), the present data focus on hypoxia induced changes in pulmonary artery pressure and right ventricular function at rest.
Our study shows that acute hypoxia challenge as well as chronic hypoxia exposure leads to a significant increase in sPAP
Acknowledgements
Funded by the German Research Foundation (Sonderforschungsbereich 547) and in part by an unrestricted independent research grant from Pfizer GmbH, Karlsruhe, Germany.
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