The main findings of this study are as follows: (1) VCP is clearly identifiable during incremental exercise at HA; (2) in conditions of persistent hypoxia, such as that elicited by HA exposure, VCP can be easily estimated by the analysis. In the present study on young healthy individuals, applying standard methods for the identification, VCP could be identified both at SL and HA. Our data are in accordance with the observation of Agostoni et al., who demonstrated that at HA the VCP was clearly identifiable .
Of note, we observed a 30% reduction in -VCP when moving from SL to HA. The lower VCP at HA likely reflected the shortening of the isocapnic buffering period because of the increased hypoxic sensitivity of the carotid chemoreflex . A further influence was presumably the premature development of metabolic acidosis during exercise at HA, as demonstrated by the lower θL likely due both to the reduction in arterial O2 content and impaired convective O2 transport to the exercising muscles .
Importantly, as demonstrated by the Bland-Altman analysis, we were able to demonstrate that the approach is a reliable method for VCP estimation during incremental exercise at HA. The limits of agreement and the coefficient of variation between the and methods for VCP estimation are quite narrow and likely to fall within the between-day intra-subject variability .
The results of the present study are in agreement with a previous work of our group that demonstrated the reliability of the breakpoint for VCP estimation at SL during incremental exercise [10, 11]. At SL, assuming a linear relationship between and HR (at least up to the heavy-intensity domain), the steepening of the slope is more evident above VCP where (1) a steeper increase in relationship is expected  and (2) the HR response could either maintain the same linearity as for more moderate exercise or in some instances (depending on exercise performance and protocol) reduce its rate of increment with respect to work rate . Interestingly, at HA, we observed higher S1 and S2 slopes. These findings are in accordance with previous studies demonstrating that at rest and at any given work rate during exercise is increased at HA because of the greater hypoxic drive [12–26] and also because of the reduction in the rate of increase in HR between rest and peak exercise that is commonly observed at HA [15, 16]. Moreover, compared to SL, we observed an increase in the S2/S1 ratio for at HA. This finding suggests that S2 is influenced both by hypoxic ventilatory drive and possibly by an augmented contribution to from the metabolic acidosis above the VCP . However, our reasoning remains speculative as, for technical reasons, we were unable to measure arterial (or arterialized) [lactate] or pH during the exercise.
Below VCP, an earlier (in the S1 region) but less evident breakpoint in was discernible in some instances (5 out of 12), but only in one out five cases such a breakpoint was coincident with the anaerobic threshold.
We are aware that our study has limitations, particularly with regard to the small sample size and the constrained characteristics of our study population, which prevented the evaluation of factors such as age, sex, and level of fitness, each of which is known to influence the variables of interest. Also, we are aware (1) that the choice of a rapid work rate incremental protocol may have influenced the results utilized, i.e., different results may be observed if a slower work rate increment protocol is used, and (2) of the lack of validation for pulmonary gas exchange measurement at HA. We took precautions to limit errors in the calibration procedures, with all equipment being calibrated before each test and all tests being performed indoors in the Pyramid Laboratory at an ambient temperature of approximately 20°C and the necessary corrections for barometric pressure, humidity, and environmental temperature being applied through the dedicated software. Thus, our investigation should be considered as a pilot study conducted at extreme altitude, with the conclusions only being applicable to healthy untrained young adults.
In conclusion, we were able to demonstrate the reliability of the method for the estimation of VCP at HA in a small group of sea-level residents, an environmental condition associated with different ventilatory and cardiac responses to exercise compared to SL. The attraction of the method is that it is a less expensive method for VCP estimation, compared to those that utilize expired gas measurements, and may therefore be utilized in sports medicine and in extreme conditions such as high altitude.