Taking vascular health to new heights: the short‐ and long‐term impacts of altitude on cardiovascular function

It has long been established that acute physiological and psychological stressors can directly impact measurements of vascular function, mediated through the sympathetic regulation of vascular tone. Examples of such acute stressors include serial subtraction, cold presser test, handgrip exercise, and both locally and systemically induced hypoxia (Badrov et al. 2013). While the acute manifestations of physiological and psychological stressors are well studied, it remains poorly understood how prolonged, or rather chronic, exposure to any one of these stress stimuli impacts vascular function via potential peripheral or central adaptations. Such information would prove useful in helping to elucidate the impact of sympathetic regulation on vascular function. In exploring the role of stress-induced sympathetic regulation of the vasculature, altitude exposure has previously been employed as a physiological stress stimulus (Ainslie et al. 2012; Dempsey et al. 2013). In a recent issue of The Journal of Physiology, Lewis et al. (2014) investigated the impact of both acute and chronic altitude exposure on measures of vascular structure and function in an attempt to identify underlying vascular adaptions. The specific focus of the present research was to determine if acute altitude-induced hypoxia would stimulate vascular dysfunction in otherwise healthy lowlanders (n = 12) and if those acute changes would dissipate following chronic (∼2 weeks) exposure to high altitude. This population of healthy lowlanders was compared to two samples: native highlanders (n = 12) at high altitude and native lowlanders in a normobaric hypoxia chamber under α1-adrenoreceptor blockade (n = 11). Briefly, results revealed that lowlanders experienced vascular dysfunction following an acute high-altitude hypoxic stimulus, evidenced through reduced brachial artery endothelium-dependent vasodilatation (via flow-mediated dilatation; FMD), reduced endothelium-independent vasodilatation (via glyceryl trinitrate; GTN), and increased arterial stiffness (via pulse wave velocity; PWV). This vascular dysfunction did not dissipate over the course of 2 weeks. The measures of endothelial dysfunction in the lowlanders under high-altitude hypoxic stress are comparative to baseline vascular assessments of native highlanders, indicating that a lifetime of high altitude exposure neither attenuates nor intensifies vascular impairments. The authors proposed that the reported vascular dysfunction may be a result of changes to vascular tone mediated through hypoxia-induced sympathoactiviation. Further investigation of this hypothesis revealed that α1-adrenoreceptor blockade in the normobaric hypoxia chamber was able to reverse the hypoxic-induced reductions in FMD. The authors speculate that the vascular dysfunction seen at high altitude is a result of this α1-adrenoreceptor activation. A strong aspect of the present investigation was the utilization of the gold-standard methods for assessing arterial stiffness (PWV) and endothelial function (FMD). The use of these measurements was further strengthened by the authors’ response to scrutiny regarding the potential bias associated with percentage FMD, as it may fail to consider baseline arterial diameter. In accordance with recently published procedural and assessment guidelines, statistical quantification of FMD occurred using an allometric scaling approach. This method adjusts for the influence of baseline diameter on FMD, which strengthens the analysis, as subject-to-subject variability in resting artery diameters may be impossible to avoid (Atkinson & Batterham, 2013). Logistically, organizing a study of this nature, which focuses around altitude-induced hypoxia is challenging and we think the authors do a good job overcoming potential timing issues. Lewis et al. (2014) employed an extended and progressive altitude climb en route to the desired elevation, which included multiple rest days. During the last stage of ascent (from 4371 m to 5050 m), participants were staggered to facilitate the timing of experimental data acquisition. However, this staggering resulted in a time discrepancy between participants with rest at 4371 m ranging from 1 to 3 days. The authors do not comment on the potential variations resulting from this difference in acclimatization time at the 4371 m altitude. That being said, the potential variations may be minimal given the 2 weeks of prior partial altitude acclimatization. In comparing native highlanders to native lowlanders Lewis et al. (2014) noted differences in baseline measurements at their respective natural altitudes such that highlanders had lower mean arterial blood pressure, higher heart rate (HR), and higher central PWV. However, these differences were abolished once native lowlanders reached high altitude. This observation is consistent with previous researchers who recruited similar highlander and lowlander subgroups from the same geographical location within Nepal and found no statistically significant differences in resting measurements of blood pressure, HR, or PWV at 5050 m (Schneider et al. 2001). Both studies have small samples sizes, a noted constraint for all research consisting of high-altitude research parameters. In our opinion, it would have been interesting for Lewis et al. (2014) to include some additional assessments within the current research design. As it is, native highlanders were only studied for comparative baseline measurements at high altitude. Since the native lowlanders ascended, it would have been very interesting to have had the native highlanders descend over the same time duration. Including a highlander descent would have allowed for observations of the potential changes that accompany descent from altitude and the removal of chronic sympathoactivation, and could also been used to contrast changes occurring during ascent. In addition to the added descent component, it may have also been useful for Lewis et al. (2014) to have included an assessment and/or control on habitual exercise patterns. As the authors note, it is well known that habitual exercise has a marked impact on vascular variables via improved endothelial health. Therefore, limiting this confound would have strengthened the experimental design and the applicability of vascular observations in our opinion. Based on traditional lifestyle habits, the Sherpas from the native highlander cohort are more likely to be active in comparison to their western counterparts from the lowlander cohort. While the authors note unknown physical activity habits as a potential shortcoming, a simple Seven Day Physical Activity Recall interview could have easily been administered to shed some light on the impact of both acute and chronic physical activity levels on the presently selected outcome variables. In addition, this recall interview would have identified any outliers with respect to daily physical activity within the context of the collected subject pool. The authors conclude that ‘high-altitude exposure in lowlanders caused persistent impairment in vascular function, which was mediated partially via oxidative stress and sympathoexcitation.’ The novelty of identifying oxidative stress as a potential mechanism of vascular impairment is a strong aspect of this paper; however, despite observations supporting sympathoexcitation at sea level via α1-adrenoreceptor blockade, quantification of autonomic nervous system (ANS) activation at altitude did not occur given the absence of blood samples and therefore noradrenaline levels. Previous research has found that rapid ascent in unacclimatized healthy subjects results in suppression of ANS activity and a shift of the sympathovagal balance toward increased sympathetic activity (Chen et al. 2008). In our opinion, with the addition of venous blood samples in the present study to quantify ANS activity at altitude, this research could have been strengthened and provided some additional evidence to support the above statement. In closing, the recently published article by Lewis et al. (2014) provides interesting insight into the effects of acute and chronic altitude exposure on vascular function, while identifying α1-adrenoreceptor activation as a possible underlying mechanism responsible for impaired vascular function at altitude. As stated by the authors, the amount of sympathetic activation responsible for inducing these alterations still requires further research and quantification to allow for a better interpretation of the mechanism of action identified in the present study. None to declare. D.C.B. is supported by a Canadian Institutes of Health Research doctoral research award. R.F.B. is supported by an Ontario Graduate Scholarships doctoral research award. The authors would like to thank Nia Lewis and the entire research team for this research. We would also like to acknowledge that unfortunately not all pertinent articles in the field could be included in this review due to space constraints.

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