Endothelin-1 Plasma Levels and Acute Mountain Sickness

In their recent publication in this journal, Boos et al. (2016) report about venous endothelin-1 (ET-1) plasma levels and acute mountain sickness (AMS) in a group of 48 trekkers. The prevalence of AMS, defined as a Lake Louise score (LLS) ≥3 points in presence of headache, was 27.1%, 8.7%, and 37.8% at 3833, 4450, and 5129 m, respectively. A possible explanation for this untypically low altitude-specific prevalence and for the unexpected finding that the prevalence of AMS at 4450 m was lower than at 3833 m might be that there were no constraints on the subject's medications. Unfortunately, no information about a potential drug intake that may have affected AMS or ET-1 is provided, and without this information data interpretation is considerably limited.

The authors observed a negative correlation between the oxygen saturation measured by pulse oximetry (SpO₂) and the LLS, and between SpO₂ and ET-1, respectively. These findings are to be expected because hypoxia is the main causative factor for AMS and also is a potent trigger for ET-1 production and release in humans (Kourembanas et al., 1991). These hypoxia-induced effects may explain the weak (r=0.29) but significant correlation between the ET-1 plasma levels and AMS. Based on their multivariate analysis, the authors identified SpO₂ and ET-1 as significant predictors of both AMS and its severity. However, as already outlined, SpO₂ and ET-1 are associated with each other (the authors themselves present an estimated correlation of r=−0.36). Therefore, the statement that ET-1 is an independent predictor of both AMS and its severity cannot be deducted from the present results. Here, it would be interesting to quantify the additional variance explained by ET-1. We would assume that the variance explained by ET-1 is much smaller than that explained by SpO₂. The finding that ET-1 plasma levels were about the same at 3833 and 4450 m but the prevalence of AMS was different argues against a pathogenic role of ET-1 in AMS.

Also other studies addressed the role of ET-1 in AMS. Modesti et al. (2006) investigated the effect of the endothelin antagonist bosentan after rapid, active ascent (<24 hours) from 1130 to 4559 m. In that study, bosentan reduced the degree of high-altitude-induced pulmonary hypertension but did not affect the incidence and/or severity of AMS at any of the four days spent at 4559 m. This finding is in line with another field study that did not find an association between arterial and central venous ET-1 plasma levels, respectively, and the incidence and severity of AMS after rapid, active ascent to 4559 m (Berger et al., 2009). Thus, previous studies do not support a pathophysiologic role of ET-1 in AMS, and the results of the present study do not do so either.