Con: Rebuttal

Professor Naeije argues that hypoxic pulmonary vasoconstriction (HPV) limits exercise at high altitude either through impaired arterial oxygenation or by limiting cardiac output due to excessive right ventricular (RV) afterload. He provides a nice overview of the interactions between hypoxia, altitude and exercise with HPV. These interactions are not in dispute. How phosphodiesterase-5 inhibitors (PDE5I) (e.g. sildenafil) or endothelin receptor blockers (ERBs) (e.g. bosentan or sitaxentan) alter arterial oxygen saturation (SaO₂) is less clear and the evidence supporting an ergogenic effect is limited. Studies utilizing non-invasive methods to estimate SaO₂ have found widely variable responses to PDE5I and ERBs with some showing increased SaO₂ while others found no change or even a lower SaO₂. The best current evidence comes from a study by Olfert using indwelling arterial catheters (Olfert et al., 2011). In their study during acute hypoxic exposure and exercise intensities up to ∼90% of maximal, both ERBs (bosentan) and PDE5I (sildenafil) increased SaO₂. Any intervention which raises the SaO₂ is likely to increase VO₂max if all other things are constant. Conversely an intervention that lowers SaO₂ during maximal exercise at altitude, other things being equal, would impair VO₂max.

More importantly what role does HPV play in limiting cardiac output? We contend that HPV does not substantially limit maximal cardiac output and even if it did, this mechanism would have little or no effect on VO₂max. Answering this question requires accurate and precise measurements of cardiac output during maximal exercise at altitude along with VO₂max under two sets of conditions: 1) altering HPV (RV afterload) without changing arterial oxygenation, and 2) altering cardiac output without changing arterial oxygenation. Implementing this experimental design will prove challenging and none of the existing trials achieve these standards or give adequate clues for definitive conclusions.

In his discussion on how pulmonary vasodilator medicines improve cardiac output, Professor Naeije discounts the existing sildenafil studies due to their improvements in SaO₂, leaving his strongest argument from studies of ERBs. Two studies from his group suggest improved VO₂max at altitude though the mechanisms for this effect are unclear. With acute hypoxic exposure bosentan improved maximal work capacity and VO₂max (Faoro et al., 2009) while a second trial using sitaxentan (never approved in the United States and withdrawn from the market in the European Union) found ∼10% improvement in VO₂max after taking the drug one week at 5050m (Naeije et al., 2010). Both studies estimated saturation using pulse oximetry and both found slightly, but not significantly, higher saturations. The findings of Olfert's study showing increased SaO₂ with bosentan by direct arterial blood gas measurement, suggest that a real increase in O₂ saturation in Naeije's ERB studies went undetected by pulse oximetry (Olfert et al., 2011). If true, ERB studies do not provide a method to reliably distinguish afterload effects from O₂ saturation effects on exercise performance.

We wholeheartedly agree with Professor Naeije that more definitive studies using direct measurements of maximal cardiac output and evaluation of RV function during exercise are necessary to support the hypothesis that RV afterload limits cardiac output thereby limiting convectional O₂ transport. In conclusion, the evidence that HPV limits maximal cardiac output remains speculative, at best.