From adaptation to maladaptation: regulatory reserve and ventilatory control responses to high altitude

Altitude exposure can promote beneficial physiological adaptations but may also lead to altitude-related illnesses. Despite decades of research, the mechanisms explaining why some individuals acclimatize successfully whereas others do not remain incompletely understood. Traditional models of altitude acclimatization focus on the steps of the oxygen cascade but only partially account for the marked interindividual variability observed in acclimatization. In this perspective, the concept of regulatory reserve, defined as the capacity of integrated physiological control systems to maintain homeostasis during environmental hypoxia is proposed. Successful acclimatization would not only depend on the functional reserves of organs at each step of the oxygen cascade, but also on the coordinated regulation of respiratory, cardiovascular, cerebrovascular, autonomic, and diffusive processes. Conversely, altitude-related illnesses may arise when this regulatory reserve becomes insufficient, exhausted, or dysregulated. Examples from ventilatory control and pulmonary diffusion are used to highlight how adaptive responses can become maladaptive when this regulatory reserve fails. The discussion focuses on how dynamic physiological markers, including breathing variability, loop gain, heart rate variability, baroreflex sensitivity, and diffusion reserve may improve the prediction of altitude acclimatization. In addition, a systems physiology approach in which acclimatization is viewed as an emergent property of interacting control networks is outlined. Such concepts may provide new insights into altitude acclimatization, maladaptation, and the prediction of human responses to altitude.