Hormonal adaptation to acute and chronic hypoxia : the role of brain natriuretic peptide and stress hormones in the diagnosis and etiology of altitude illness

Abstract

Data was collected in two main phases; 1. A field study undertaken in the Cordillera Real Region of Bolivia. 2. Laboratory investigation of terrestrial, hypobaric and normobaric hypoxia. Phase 1 The aim of phase one of the studies was to investigate the endocrine changes (specifically brain natriuretic peptide (BNP), arginine vasopressin (AVP), cortisol, catecholamine and copeptin) with ascent to high altitude. These changes were investigated during a “real world” trekking expedition to Bolivia. Other potential markers for AMS namely high-sensitivity C reactive protein (hs-CRP), high-sensitivity cardiac troponin T (hs-cTnT) and neutrophil gelatinase associated lipocalin (NGAL) were also studied. The overarching hypothesis was that Acute Mountain Sickness (AMS) would be associated with fluid retention and elevated BNP and that changes in other hormones involved in fluid balance such as AVP, copeptin and cortisol may also reflect AMS. The hypotheses investigated included;  That BNP would rise with high altitude (HA) illness and be associated with both AMS and a high pulmonary artery systolic pressure (PASP).  That copeptin would accurately reflect changes in AVP at altitude and therefore have utility in future field studies as a surrogate for AVP.  That AMS would be associated with either elevated copeptin/AVP or with failure to suppress the copeptin/AVP response to exercise.  Inflammation and/or rises in PASP occur with the development of high altitude illness and would lead to a detectable rise in hs-cTnT, NGAL or hs-CRP.  The dynamic changes in stress hormones associated with exercise are key in the pathogenesis of altitude illness.  The physiological stress of HA would lead to a rise in cortisol. This would contribute to fluid retention and be linked to the development of AMS.  There would be no difference between total body water (TBW) measured by single or multifrequency bioimpedance analysis. v Methods: This was an observational study with data collection at sea-level and then subsequently over a 10 day ascent from 3800m to 5129m. Daily physiological data was collected with more detailed investigation performed at 3833m, 4450m and 5129m. At these altitudes, data was collected post exercise (after the ascent) and at rest (the following day). Venous blood samples were collected for hormonal assays. BNP and NGAL were analysed in situ using point of care testing technology. Assessment of TBW was performed using bioimpedance devices and pulmonary artery systolic pressure (PASP) was estimated using transthoracic echocardiography. Results and implications: 50 subjects were recruited to the study, 48 of whom were studied at 3833m and 4450m with 47 subjects studied at 5129m. Results presented as mean (range, SD) unless otherwise stated. Significant findings were: Oxygen saturations fell with ascent to altitude to a nadir of 79% (SD 4.4., range 68-88) at 5129m. Fluid balance showed no significant change with altitude or relation to AMS. Plasma osmolality did not change with ascent. AVP and copeptin did not increase until extreme altitude (5129m) and both increased by a greater degree in those recording higher levels of perceived exertion. This was despite no change in osmolality which suggests a non-osmotic stimulus to their secretion. Cortisol secretion increased at 5129m and may support the possibility that the rise in copeptin and AVP was related to physiological stress at extreme altitude. Plasma normetanephrine increased with increasing altitude reaching a maximum of 1423.72 (786.0, 355–4159 pmol/L) at 5129m. Thirst proved difficult to quantify and the visual analogue scale used showed no correlation with total body water, osmolality or AVP. BNP (and NT-proBNP) increased with increasing severity of AMS as assessed by Lake Louise Score (LLS). vi BNP (and NT-proBNP) were higher in those with a high PASP. Hs-cTnT showed an increase with PASP and but no association with AMS. Hs-CRP showed an increase with altitude but no association with AMS. NGAL showed no association with change in altitude. A consistent finding was an evident separation between subjects recording a low Borg score and those recording a Borg rating consistent with “hard work”. Subjects recording a Borg score > 15 (“hard work”) had higher cortisol, AVP, copeptin and an increased LLS. This led to investigation of an additional hypothesis that a higher rating of perceived exertion will lead to an increase in reported AMS symptoms. This was found to be the case with significantly lower SpO2 at rest, higher heart rates and higher LLS in those reporting a Borg RPE > 15.