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 (∼2 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 (NO2-) 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 (∼19%, P ≤ 0.04), attributable to a narrower CIMT and wider lumen. Although both LOOH and NO2- 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 O2 fraction (F IO 2) = 0.11; 6 h), a sustained reduction in FMD was evident within 1 h of hypoxic exposure when compared to normoxic baseline (5.7 ± 1.6 vs. 8.0 ±1.3%; P < 0.01); this decline in FMD was largely reversed following α1-adrenoreceptor blockade. In conclusion, high-altitude exposure in lowlanders caused persistent impairment in vascular function, which was mediated partially via oxidative stress and sympathoexcitation. Although a lifetime of high-altitude exposure neither intensifies nor attenuates the impairments seen with short-term exposure, chronic high-altitude exposure appears to be associated with arterial remodelling.
Highlights
Ambient hypoxia associated with high altitude is a potent activator of the sympathetic nervous system (Saito et al, 1988; Marshall, 1994; Duplain et al, 1999; Xie et al, 2001; Hansen & Sander, 2003), which causes vascular dysfunction (Hijmering et al, 2002)
Carotid Intima-Medial Thickness (CIMT), common carotid artery (CCA) pulse pressure, CCA distensibilty, CCA wall: lumen ratio, and β-stiffness were unaltered with high-altitude exposure (Table 1; Figure 3)
Given that glyceryl trinitrate (GTN)-dilation and flow-mediated dilatation (FMD) were each reduced by ~14% with acute exposure to 5050 m, these findings indicate that alterations in vascular smooth muscle function and/or structure contributed to the decline in FMD at high altitude
Summary
Ambient hypoxia associated with high altitude is a potent activator of the sympathetic nervous system (Saito et al, 1988; Marshall, 1994; Duplain et al, 1999; Xie et al, 2001; Hansen & Sander, 2003), which causes vascular dysfunction (Hijmering et al, 2002). Information describing alterations in vascular function during either acute or prolonged exposure to high altitude is sparse and often confounded by pathology (i.e. acute / chronic mountain stickiness, metabolic syndrome) and methodological issues. Acute exposure to high altitude (3,450 m and 4,770 m) has been reported to impair endothelial function (Rhodes et al, 2011). Frick et al (2006) assessed endothelial-dependent FMD following acute (1 day) and prolonged (3 week) exposure to a moderate altitude (1,700 m) in individuals with the metabolic syndrome. Methodological issues existed which cloud interpretation of those data, including: lack of a control group; uncertain non standardisation of cuff placement during the FMD assessment, and lack of continuous monitoring of artery diameter and blood flow during reactive hyperaemia (Thijssen et al, 2011). 1700 m is a relatively weak hypoxic stimulus relative to altitudes that are readily accessed or lived in by many, the potential negative effect of highaltitude exposure on vascular function and structure in lowlanders, especially in a non-diseased population has not been adequately established
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