Conduit artery structure and function in lowlanders and native highlanders: relationships with oxidative stress and role of sympathoexcitation

Abstract

Key pointsr Information describing alterations in vascular function during either acute or prolonged normobaric or hypobaric hypoxia is sparse and often confounded by pathology and methodological limitations.r We show that high altitude exposure in lowlanders is associated with impairments in both endothelial and smooth muscle function, and with increased central arterial stiffness; furthermore, in all of these respects, lowlanders' vasculature becomes comparable to that of natives born and raised at altitude.r Changes in endothelial function occur very rapidly in normobaric hypoxia, and partly under the influence of sympathetic nerve activity.r Thus, a lifetime of high-altitude exposure neither attenuates nor intensifies the impairments in vascular function observed with short-term exposure in lowlanders; such impairment and altered structure likely translate into an elevated cardiovascular risk.Abstract Research detailing the normal vascular adaptions to high altitude is minimal and often confounded by pathology (e.g. chronic mountain sickness) and methodological issues. We examined vascular function and structure in: (1) healthy lowlanders during acute hypoxia and prolonged (ß2 weeks) exposure to high altitude, and (2) high-altitude natives at 5050 m (highlanders). In 12 healthy lowlanders (aged 32 ± 7 years) and 12 highlanders (Sherpa; 33 ± 14 years) we assessed brachial endothelium-dependent flow-mediated dilatation (FMD), endothelium-independent dilatation (via glyceryl trinitrate; GTN), common carotid intima-media thickness (CIMT) and diameter (ultrasound), and arterial stiffness via pulse wave velocity (PWV; applanation tonometry). Cephalic venous biomarkers of free radical-mediated lipid peroxidation (lipid hydroperoxides, LOOH), nitrite (NO 2 -) and lipid soluble antioxidants were also obtained at rest. In lowlanders, measurements were performed at sea level (334 m) and between days 3-4 (acute high altitude) and 12-14 (chronic high altitude) following arrival to 5050 m. Highlanders were assessed once at 5050 m. Compared with sea level, acute high altitude reduced lowlanders' FMD (7.9 ± 0.4 vs. 6.8 ± 0.4%; P = 0.004) and GTN-induced dilatation (16.6 ± 0.9 vs. 14.5 ± 0.8%; P = 0.006), and raised central PWV (6.0 ± 0.2 vs. 6.6 ± 0.3 m s −1 ; P = 0.001). These changes persisted at days 12-14, and after allometrically scaling FMD to adjust for altered baseline diameter. Compared to lowlanders at sea level and high altitude, highlanders had a lower carotid wall:lumen ratio (ß19%, P ࣘ 0.04), attributable to a narrower CIMT and wider lumen. Although both LOOH and NO 2 -increased with high altitude in lowlanders, only LOOH correlated with the reduction in GTN-induced dilatation evident during acute (n = 11, r = −0.53) and chronic (n = 7, r = −0.69; P ࣘ 0.01) exposure to 5050 m. In a follow-up, placebo-controlled experiment (n = 11 healthy lowlanders) conducted in a normobaric hypoxic chamber (inspired O 2 fraction (F IO 2 ) = 0.11; 6 h), a sustained reduction in FMD was evident within 1 h of hypoxic exposure wh...

Independent at heart: persistent association of altitude with ischaemic heart disease mortality after consideration of climate, topography and built environment

“…The myocardium of mountaineers has an increased oxygen extraction, an improved mitochondrial energy efficiency and a preference to metabolise glucose over free fatty acids 31 32. Relative hypoxaemia also stimulates myocardial angiogenesis and arterial and ventricular remodelling and enhances the contractile functional reserve of the myocardium 28 29 33. Most likely, these adaptations already occur at moderate altitudes 27 34.…”

Reduced blood flow through intrapulmonary arteriovenous anastomoses during exercise in lowlanders acclimatizing to high altitude

“…This study was part of a larger research expedition conducted in April-June 2012 Lewis et al 2014;Smirl et al 2014;Smith et al 2014;Willie et al 2014Willie et al , 2015Stembridge et al 2015). All participants provided written informed consent before participation in this study.…”

End tidal-to-arterial CO2and O2gas gradients at low- and high-altitude during dynamic end-tidal forcing

“…All participants provided written informed consent before participation in this study. This study was part of a larger research expedition conducted in April-June in 2012 (14,23). As such, participants took part in a number of studies conducted in Kelowna, BC and during 3 wk at the Ev-K2 CNR Pyramid Laboratory located near Mt.…”

“…All participants took acetazolamide (125 mg, 3ϫ day) during the trek to HA to minimize the risk of acute mountain sickness but medication was discontinued 24 h before ascending from Pheriche (4,300 m) to the Pyramid lab, which was at least 5 days before experimentation. The 8-to 10-day ascent profile to 5,050 m has been described in detail elsewhere (14,23,48).…”