Lifelong high‐altitude hypoxia induces arterial baroreflex adaptations: new insights and future directions

The arterial baroreflex control of blood pressure (BP) represents a fundamental negative feedback mechanism to maintain BP homeostasis. Unencapsulated, mechanically sensitive, free nerve endings located in the carotid sinus bifurcation and aortic arch relay afferent signals to the cardiovascular control areas in the brainstem regarding beat-to-beat oscillations in arterial BP. These afferent inputs elicit reflex changes in efferent parasympathetic and sympathetic activity to the heart and blood vessels modulating heart rate (cardiac baroreflex) and peripheral vasoconstrictor outflow (sympathetic baroreflex) in order to regulate arterial BP at rest and during cardiovascular stressors such as acute hypoxia (Fadel, 2008). Notably, high-altitude (HA) hypoxia elicits a robust increase in sympathetic outflow, which is significantly larger when compared with acute hypoxic exposure to a similar level. However, at present, the impact of long-term exposure to HA hypoxia on arterial baroreflex control of arterial BP remains poorly understood. In a recent issue of The Journal of Physiology, Simpson et al. (2019) eloquently filled this important information gap by studying Lowlanders and native Highlanders (Sherpas) at low altitude (LA) and HA. The authors sought to characterize the possible adaptations on arterial baroreflex control of BP elicited by lifelong HA exposure in Highlanders and the impact of acclimatization at HA in Lowlanders. To this end, 14 Lowlanders (two women) and nine male Highlanders (Sherpas, living at > 3440 m) were studied on two separate occasions: pre-expedition, LA test (344 m for Lowlanders and 1400 m for Highlanders) and following gradual ascent to 5050 m. Importantly, LA measurements of Sherpas was conducted > 4 days after descent from their resident altitude and the HA measures were conducted 10–14 and 10–20 days above 2860 m for Sherpas and Lowlanders, respectively. Muscle sympathetic nerve activity (MSNA) was directly recorded, from the peroneal nerve, via microneurography. Cardiac and sympathetic baroreflex control of BP were assessed by bolus injection of the vasoactive drugs sodium nitroprusside and phenylephrine to lower and raise BP, respectively (i.e. modified Oxford test). In addition, to assess the possible contribution of peripheral chemoreflex, the modified Oxford test was also performed during acute hypoxia (breathing 11% oxygen) at LA and during acute hyperoxia (breathing 100% oxygen) at LA and HA. The main findings were as follows: (1) despite similar resting BP, Sherpas have a higher MSNA burst frequency at HA than Lowlanders at LA, but it was lower when compared to Lowlanders following ascent to HA; (2) the sensitivity (i.e. gain) of sympathetic baroreflex control of BP is preserved in Lowlanders at HA and is similar to that of Sherpa counterparts, although the operating point was reset upward; (3) Lowlanders at HA presented a decrease in cardiac baroreflex sensitivity compared to at LA, but it was similar to Highlanders at HA; and (4) manipulation of peripheral chemoreceptor drive at HA had minimal effect on arterial baroreflex control of BP in both Lowlanders and Highlanders. Collectively, these findings demonstrated for the first time that upward baroreflex resetting permits chronic activation of resting MSNA in Lowlanders following 10–20 days at HA and lifelong HA hypoxia probably induces beneficial arterial baroreflex adaptations in native Sherpas. Overall, the study by Simpson and colleagues is well designed and uses challenging methodologies in an attempt to address an important question. However, like any comprehensive, mechanistically driven, hypothesis-based, human physiology study, certain issues should be taken into account in interpreting the study's findings. For example, 55% of native Highlanders were regular cigarette smokers and the Lowlander counterparts were non-smokers, which could directly influence the study results. In addition, it is well accepted that cardiovascular control is markedly different between men and women and the lack of female participants (only two Lowlanders) suggest that the findings should be restricted to males. Moreover, the participants were ∼30 years old and apparently healthy, limiting extrapolation of the results to other populations such as the elderly and/or those with disease, who are more susceptible to adverse cardiovascular events during sustained activation of the sympathetic nervous system. With this in mind, future investigations designed to examine the possible effects of sex, ageing and disease will advance our knowledge of the impact of HA exposure on arterial baroreflex control of BP. It is also important to consider the possibility of hysteresis in arterial baroreflex control. Baroreflex sensitivity is greater during falling compared to rising BP in healthy young subjects and basal sympathetic outflow play an important role in the gain of the baroreflex to decreasing and increasing BP (Hart et al. 2011). In fact, individuals with high sympathetic drive at rest respond better to rising than falling BP, whereas individuals with low resting sympathetic drive respond better to falling than rising BP (Hart et al. 2011). Accordingly, because HA exposure induces robust sympathoexcitation, it would be interesting to gain further insight into how baroreflex function operates for upward and downward BP responses. Although the authors did not perform this separate analysis, it is necessary to draw attention to the observation that the same drug dosage used during the modified Oxford test in Lowlanders at LA and HA evoked different BP responses. Indeed, while the same amount of sodium nitroprusside evoked similar falls in arterial BP (LA: 15 ± 6 mmHg vs. HA: 15 ± 6 mmHg; P = 0.78), the same dosage of phenylephrine elicited a significantly smaller increase in BP at HA (LA: 19 ± 9 mmHg vs. HA: 11 ± 3 mmHg; P = 0.02). Thereby, the total BP changes during the modified Oxford test were significantly different between conditions (LA: 35 ± 11 mmHg vs. HA: 26 ± 8 mmHg; P = 0.02). The authors speculated that these differences could be attributable to a reduction in α-adrenergic receptor sensitivity at HA; this hypothesis needs to be directly tested in future studies. Whether differences in BP responses during the modified Oxford test or the possible occurrence of hysteresis could influence the study findings remain to be determined. Interestingly, cardiac baroreflex sensitivity was similar between Sherpas and Lowlanders at HA, but lower than for Lowlanders at LA. Additionally, heart rate was significantly increased (LA: 54 ± 10 bpm vs. HA: 64 ± 13 bpm; P < 0.01) following 10–20 days of acclimatization at 5050 m in Lowlanders, whereas arterial BP remained unchanged. These findings raise the possibility that chronic HA hypoxia induces differential adaptations of cardiac and sympathetic baroreflex control of BP. The underlying mechanisms for this discrepancy remain unclear but some relevant aspects warrant discussion. Hypovolaemia and pulmonary vasoconstriction-mediated impairment in left ventricular function at HA could play a role in the reduced cardiac baroreflex sensitivity. For example, patients with hypertension and preserved left ventricular function present lower cardiac baroreflex sensitivity when compared to normotensive subjects, although this impairment is significantly greater in those patients with left ventricular dysfunction (Grassi et al. 2009). Interestingly, plasma volume expansion and pulmonary vasodilatation restore resting left ventricular function at HA (Stembridge et al. 2019), which could improve cardiac baroreflex sensitivity, but this possibility should be addressed in future studies. Additionally, in contrast to baroreflex control of MSNA, cardiac baroreflex sensitivity is closely related to vagal activity, and increases in resting heart rate at HA are proposed to be mediated by cardiac vagal withdrawal with minimal or no effect of sympathetic activity (Siebenmann et al. 2017). Furthermore, as the authors mentioned, erythropoietin production, systemic inflammation and oxidative stress could also explain the study findings. Another important observation by Simpson and colleagues is that manipulation of peripheral chemoreflex at HA had no effect on arterial baroreflex control of BP in Lowlanders and Highlanders. The authors suggest that mechanisms other than peripheral chemoreflex activation contribute to vascular sympathetic baroreflex resetting and sympathoexcitation at HA. Therefore, future studies are necessary to determine the precise physiological mechanisms by which chronic HA hypoxia promotes differential baroreflex adaptations in native Highlanders and/or acclimatized Lowlanders. In closing, Simpson and colleagues should be commended for their challenging approach which provides an important step forward to our understanding of the effects of chronic HA hypoxia on arterial baroreflex control of BP in humans. They revealed that lifelong HA hypoxia could induce beneficial arterial baroreflex adaptation in native Highlanders. We now await future investigations in different populations (e.g. women, elderly and diseased patients) taking into account the possible occurrence of hysteresis to better clarify the impact of chronic HA hypoxia on arterial baroreflex control of arterial BP in humans. None declared. This work was supported by the Coordination for the Improvement of Higher Education Personnel (CAPES; Finance Code 001). I gratefully thank Dr Lauro C. Vianna for insightful comments on and discussion of the manuscript. Additionally, I would like to apologize for not citing all relevant articles due to reference limitations.