High altitude vascular dysfunction: can we 'C' our way to a remedy?

Abstract

Acute and chronic high altitude hypoxaemia evoke a variety of adaptive and maladaptive cardiovascular changes, including increased cardiac output, mild hypertension and vascular dysfunction, which may set the stage for stroke, myocardial injury and thrombosis. Sympathetic nervous system (SNS) activation acting directly on vascular smooth muscle and the vascular endothelium is thought to underlie the development of vascular dysfunction, but exactly how is not fully understood. The dysfunction is not at the smooth muscle level, but at the endothelium, and may involve increased oxidative stress as found in cardiovascular diseases at low altitude (Frei, 1999). Earlier work by Lewis et al. (2014) found an association of impaired vascular function and increased oxidative stress in both short term visitors and long term residents at high altitude (Lewis et al. 2014). In this issue of The Journal of Physiology, Stone et al. (2022) present convincing evidence supporting oxidative stress as a basis for the peripheral vascular dysfunction developing when healthy individuals ascend to high altitude. This vascular dysfunction resides at the endothelial cell, as studied by changes in flow-mediated dilatation (FMD). FMD is dependent on the vascular endothelium since the response to infused vasodilators acting directly on vascular smooth muscle, such as sodium nitroprusside (SNP), is not affected. In contrast, when drugs acting on the endothelium are administered, such as the vasodilator acetylcholine that generates nitric oxide (NO) formation, increases in stimulated blood flow are diminished when vascular dysfunction is present. A further finding supporting the role of the endothelium is that when α-adrenergic blockers are co-infused, even their effect to partially reverse vascular dysfunction is not altered when SNP is given. Stone and colleagues directly focused on oxidative stress, i.e. the formation of oxygen radicals with hypoxia. The various forms of oxygen radicals have myriad effects on cell signalling and vasoactive mediator balance. Importantly, NO is an endothelial cell-derived vasodilator that can be rapidly oxidized to non-vasodilating compounds by reactive oxygen species (ROS). To test the hypothesis that ROS generation underlies high altitude vascular dysfunction, as it does in many cardiovascular diseases (Frei, 1999), they took healthy people to 4300 m in the Peruvian Andean city of Cerro de Pasco and studied them over 3 weeks. They compared measurements of blood flow changes by the strain gauge venous occlusion plethysmography technique (which incorporates both macroand microvascular responses) at near sea level (344 m, Kelowna, British Columbia) and then, after flying to Lima and driving for 4–6 h, at Cerro de Pasco. Between 4 and 6 days after arrival, the subjects were restudied, at which time the average increase in blood pressure was 7%. The basic protocol involved placement of an antecubital arterial catheter for infusions of various amounts of acetylcholine to induce endothelial cell-mediated hyperaemia, SNP for direct vascular smooth muscle relaxation, and the well-known antioxidant vitamin C to provide ROS scavenging. By infusing vitamin C locally and briefly, they likely avoided systemic delivery to the central nervous system and thus SNS effects, but this cannot be ruled out in the absence of concomitant adrenergic blockade experiments and measurement of vitamin C plasma concentrations. In support of their hypothesis, they found a significant hypoxia-mediated ROS contribution to vascular endothelial cell dysfunction at high altitude. By 4–6 days at 4300 m, there was development of decreased hyperaemia mediated by acetylcholine, but not by SNP, and this was abrogated by local intra-arterial vitamin C infusion in five of the 10 subjects, with little change in three, and a paradoxical fall in two, suggesting a considerable bidirectional range of responses (Figure 3 in Stone et al. 2022). Part of this heterogeneity may be related to the subject’s degree of hypoxaemia, because they found a large effect on the degree of individual arterial oxygen desaturation and forearm blood flow increase to acetylcholine, with those most desaturated demonstrating the least increase with acetylcholine and conversely the greatest effect of vitamin C to induce more blood flow. In Figure 4 of Stone et al. (2022), it would have been interesting to have each subject identified for how vitamin C altered their FMD with acetylcholine. The authors show impaired vascular endothelial cell-mediated hyperaemia by hypoxia after 4–6 days, which is evident even with acute hypoxaemia of half an hour and sustained in subjects studied after 3 weeks in other work by this group. Questions left unanswered include the influences of ventilation differences between subjects and the impact of arterial PCO2 , because acid–base status has important effects on SNS activity (Swenson, 2016), and perhaps differences in haematocrit, since red cells also scavenge nitric oxide. Effects of hypocapnia and hypercapnia on vascular endothelial dysfunction have not been studied. Travel and unfamiliar environments wreak havoc with sleep, and it is well known that sleep disruption and deficiency also elevate ROS production and could be a cause of vascular dysfunction as shown by members of this group. Experiments using inhibitors of endothelial NO synthase would help further elucidate the role of endothelial NO generation versus that of prostaglandins and other vasoactive mediators that are elaborated by the endothelium. I have listed a long menu of other experiments that ought to be performed, but for the meantime, Stone et al. have provided new data that may pave the way to better treatment of vascular dysfunction both in the systemic and pulmonary circulations at high altitude. Finally, it may be premature to advise vitamin C for improving vascular health at high altitude. First, can one achieve systemic circulating levels of vitamin C by oral ingestion that duplicate the effects of the concentrations attained locally with the intra-arterial infusion? If it requires