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Dear Editor-in-ChiefIn a recent review on the relative effectiveness of different preacclimatization strategies on physiological responses (e.g., end-tidal carbon dioxide [PETCO2], arterial oxygen saturation [SaO2]) and endurance performance of previously nonacclimatized subjects, Fulco et al. (3) provided sets of data highlighting the potential differences in physiological mechanisms of acclimatization and exercise between hypobaric hypoxia (HH) and normobaric hypoxia (NH).The authors are to be commended for the consistency (e.g., investigators’ team, subject characteristics, assessment protocols, target altitude) among dozens of studies (most of them conducted at Pikes Peaks Laboratory, Colorado, 4300 m) within two decades, which enabled a robust comparison of benefits and effectiveness of different HH versus NH preacclimatization strategies.Their conclusions are convincing enough to recommend HH instead of NH for preacclimatization because of the more developed ventilatory acclimatization and lesser decrease in performance when assessed at 4300 m.However, stricto sensus, the review by Fulco et al. (3) did not clarify if the differences observed between HH and NH (4,6) are clinically relevant and lead to a higher severity of acute mountain sickness (AMS) in HH than in NH, a topic highly debated (Millet et al. (4) vs Schommer et al. (7)) where, to date, there is no well-controlled comparative crossover study.To our view, the most striking and novel finding arising from Fulco et al. (3) is the very low (or lack of) transfer of the benefits induced by the NH acclimatization to the HH condition.When transported to 4300 m (HH), subjects who were preacclimatized in NH had a minimal benefit (e.g., no or <1 mm Hg decrease in PETCO2 or AMS prevalence of 50%–64% instead of 80%–100% in nonacclimatized subjects). In addition, the NH preacclimatization did not induce any reduction in the acute performance decrement observed during the first 24 h after arrival at 4300 m. These results highlight a specificity of the HH condition and an (unresolved) indirect influence of the barometric pressure. Moreover, the findings show that the ventilatory acclimatization can be effective in NH, but not in HH, and that the light ventilatory and AMS benefits retained in HH for the NH preacclimatized groups did not translate to performance benefits.These data raise many questions about the mechanisms because they “remain elusive” (3) and cannot be explained by the slight differences in ventilation, fluid balance, and nitric oxide metabolism already described between NH and HH (4,6). In a recent study (2), we confirmed the differences in ventilation (e.g., higher PETCO2) and the impaired nitric oxide bioavailability in HH versus NH but also reported a higher oxidative stress that may be explained by a lower plasma pH.Obviously, disentangling hypoxia and hypobaria is of importance for athletes or mountaineers who use NH to prepare for altitude competitions or expeditions. Moreover, the role of barometric pressure on oxidative and nitrosative stress during exposure to hypoxia might have interesting medical implications, as suggested by recent developments of therapeutic intermittent hypoxic methods (1,8) in several pathologies (e.g., ischemic heart disease, stroke, cancer, chronic lung disease, hypertension). Indeed, oxidative stress pathway has been recognized to regulate the hypoxia-inducible factor 1 (5), known to have a pivotal role in such disease progression/treatment. In conclusion, the review by Fulco et al. (3) suggests further investigations on the differences in mechanisms and therapeutic use of HH versus NH are needed.Grégoire P.