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

<p>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 (NO<sub style="margin: 0px; padding: 0px; border: 0px; outline: 0px; font-size: 0.8em; white-space: nowrap; line-height: 0.7em; font-family: Arial, 'Lucida Grande', Geneva, Verdana, Helvetica, 'Lucida Sans Unicode', sans-serif; background-image: initial; background-attachment: initial; background-size: initial; background-origin: initial; background-clip: initial; background-position: initial; background-repeat: initial;">2</sub><sup style="margin: 0px; padding: 0px; border: 0px; outline: 0px; font-size: 0.8em; line-height: 0.7em; white-space: nowrap; font-family: Arial, 'Lucida Grande', Geneva, Verdana, Helvetica, 'Lucida Sans Unicode', sans-serif; background-image: initial; background-attachment: initial; background-size: initial; background-origin: initial; background-clip: initial; background-position: initial; background-repeat: initial;">–</sup>) 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 <em style="margin: 0px; padding: 0px; border: 0px; outline: 0px; vertical-align: baseline; font-family: Arial, 'Lucida Grande', Geneva, Verdana, Helvetica, 'Lucida Sans Unicode', sans-serif; line-height: 18px; background-image: initial; background-attachment: initial; background-size: initial; background-origin: initial; background-clip: initial; background-position: initial; background-repeat: initial;">vs</em>. 6.8 ± 0.4%; <em style="margin: 0px; padding: 0px; border: 0px; outline: 0px; vertical-align: baseline; font-family: Arial, 'Lucida Grande', Geneva, Verdana, Helvetica, 'Lucida Sans Unicode', sans-serif; line-height: 18px; background-image: initial; background-attachment: initial; background-size: initial; background-origin: initial; background-clip: initial; background-position: initial; background-repeat: initial;">P</em> = 0.004) and GTN-induced dilatation (16.6 ± 0.9 <em style="margin: 0px; padding: 0px; border: 0px; outline: 0px; vertical-align: baseline; font-family: Arial, 'Lucida Grande', Geneva, Verdana, Helvetica, 'Lucida Sans Unicode', sans-serif; line-height: 18px; background-image: initial; background-attachment: initial; background-size: initial; background-origin: initial; background-clip: initial; background-position: initial; background-repeat: initial;">vs</em>. 14.5 ± 0.8%; <em style="margin: 0px; padding: 0px; border: 0px; outline: 0px; vertical-align: baseline; font-family: Arial, 'Lucida Grande', Geneva, Verdana, Helvetica, 'Lucida Sans Unicode', sans-serif; line-height: 18px; background-image: initial; background-attachment: initial; background-size: initial; background-origin: initial; background-clip: initial; background-position: initial; background-repeat: initial;">P</em> = 0.006), and raised central PWV (6.0 ± 0.2<em style="margin: 0px; padding: 0px; border: 0px; outline: 0px; vertical-align: baseline; font-family: Arial, 'Lucida Grande', Geneva, Verdana, Helvetica, 'Lucida Sans Unicode', sans-serif; line-height: 18px; background-image: initial; background-attachment: initial; background-size: initial; background-origin: initial; background-clip: initial; background-position: initial; background-repeat: initial;">vs</em>. 6.6 ± 0.3 m s<sup style="margin: 0px; padding: 0px; border: 0px; outline: 0px; font-size: 0.8em; line-height: 0.7em; white-space: nowrap; font-family: Arial, 'Lucida Grande', Geneva, Verdana, Helvetica, 'Lucida Sans Unicode', sans-serif; background-image: initial; background-attachment: initial; background-size: initial; background-origin: initial; background-clip: initial; background-position: initial; background-repeat: initial;">−1</sup>; <em style="margin: 0px; padding: 0px; border: 0px; outline: 0px; vertical-align: baseline; font-family: Arial, 'Lucida Grande', Geneva, Verdana, Helvetica, 'Lucida Sans Unicode', sans-serif; line-height: 18px; background-image: initial; background-attachment: initial; background-size: initial; background-origin: initial; background-clip: initial; background-position: initial; background-repeat: initial;">P</em> = 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%, <em style="margin: 0px; padding: 0px; border: 0px; outline: 0px; vertical-align: baseline; font-family: Arial, 'Lucida Grande', Geneva, Verdana, Helvetica, 'Lucida Sans Unicode', sans-serif; line-height: 18px; background-image: initial; background-attachment: initial; background-size: initial; background-origin: initial; background-clip: initial; background-position: initial; background-repeat: initial;">P</em> ≤ 0.04), attributable to a narrower CIMT and wider lumen. Although both LOOH and NO<sub style="margin: 0px; padding: 0px; border: 0px; outline: 0px; font-size: 0.8em; white-space: nowrap; line-height: 0.7em; font-family: Arial, 'Lucida Grande', Geneva, Verdana, Helvetica, 'Lucida Sans Unicode', sans-serif; background-image: initial; background-attachment: initial; background-size: initial; background-origin: initial; background-clip: initial; background-position: initial; background-repeat: initial;">2</sub><sup style="margin: 0px; padding: 0px; border: 0px; outline: 0px; font-size: 0.8em; line-height: 0.7em; white-space: nowrap; font-family: Arial, 'Lucida Grande', Geneva, Verdana, Helvetica, 'Lucida Sans Unicode', sans-serif; background-image: initial; background-attachment: initial; background-size: initial; background-origin: initial; background-clip: initial; background-position: initial; background-repeat: initial;">–</sup> increased with high altitude in lowlanders, only LOOH correlated with the reduction in GTN-induced dilatation evident during acute (<em style="margin: 0px; padding: 0px; border: 0px; outline: 0px; vertical-align: baseline; font-family: Arial, 'Lucida Grande', Geneva, Verdana, Helvetica, 'Lucida Sans Unicode', sans-serif; line-height: 18px; background-image: initial; background-attachment: initial; background-size: initial; background-origin: initial; background-clip: initial; background-position: initial; background-repeat: initial;">n</em> = 11, <em style="margin: 0px; padding: 0px; border: 0px; outline: 0px; vertical-align: baseline; font-family: Arial, 'Lucida Grande', Geneva, Verdana, Helvetica, 'Lucida Sans Unicode', sans-serif; line-height: 18px; background-image: initial; background-attachment: initial; background-size: initial; background-origin: initial; background-clip: initial; background-position: initial; background-repeat: initial;">r</em> = −0.53) and chronic (<em style="margin: 0px; padding: 0px; border: 0px; outline: 0px; vertical-align: baseline; font-family: Arial, 'Lucida Grande', Geneva, Verdana, Helvetica, 'Lucida Sans Unicode', sans-serif; line-height: 18px; background-image: initial; background-attachment: initial; background-size: initial; background-origin: initial; background-clip: initial; background-position: initial; background-repeat: initial;">n</em> = 7, <em style="margin: 0px; padding: 0px; border: 0px; outline: 0px; vertical-align: baseline; font-family: Arial, 'Lucida Grande', Geneva, Verdana, Helvetica, 'Lucida Sans Unicode', sans-serif; line-height: 18px; background-image: initial; background-attachment: initial; background-size: initial; background-origin: initial; background-clip: initial; background-position: initial; background-repeat: initial;">r</em> = −0.69; <em style="margin: 0px; padding: 0px; border: 0px; outline: 0px; vertical-align: baseline; font-family: Arial, 'Lucida Grande', Geneva, Verdana, Helvetica, 'Lucida Sans Unicode', sans-serif; line-height: 18px; background-image: initial; background-attachment: initial; background-size: initial; background-origin: initial; background-clip: initial; background-position: initial; background-repeat: initial;">P</em> ≤ 0.01) exposure to 5050 m. In a follow-up, placebo-controlled experiment (<em style="margin: 0px; padding: 0px; border: 0px; outline: 0px; vertical-align: baseline; font-family: Arial, 'Lucida Grande', Geneva, Verdana, Helvetica, 'Lucida Sans Unicode', sans-serif; line-height: 18px; background-image: initial; background-attachment: initial; background-size: initial; background-origin: initial; background-clip: initial; background-position: initial; background-repeat: initial;">n</em> = 11 healthy lowlanders) conducted in a normobaric hypoxic chamber (inspired O<sub style="margin: 0px; padding: 0px; border: 0px; outline: 0px; font-size: 0.8em; white-space: nowrap; line-height: 0.7em; font-family: Arial, 'Lucida Grande', Geneva, Verdana, Helvetica, 'Lucida Sans Unicode', sans-serif; background-image: initial; background-attachment: initial; background-size: initial; background-origin: initial; background-clip: initial; background-position: initial; background-repeat: initial;">2</sub> fraction () = 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 <em style="margin: 0px; padding: 0px; border: 0px; outline: 0px; vertical-align: baseline; font-family: Arial, 'Lucida Grande', Geneva, Verdana, Helvetica, 'Lucida Sans Unicode', sans-serif; line-height: 18px; background-image: initial; background-attachment: initial; background-size: initial; background-origin: initial; background-clip: initial; background-position: initial; background-repeat: initial;">vs</em>. 8.0 ±1.3%; <em style="margin: 0px; padding: 0px; border: 0px; outline: 0px; vertical-align: baseline; font-family: Arial, 'Lucida Grande', Geneva, Verdana, Helvetica, 'Lucida Sans Unicode', sans-serif; line-height: 18px; background-image: initial; background-attachment: initial; background-size: initial; background-origin: initial; background-clip: initial; background-position: initial; background-repeat: initial;">P</em> < 0.01); this decline in FMD was largely reversed following α<sub style="margin: 0px; padding: 0px; border: 0px; outline: 0px; font-size: 0.8em; white-space: nowrap; line-height: 0.7em; font-family: Arial, 'Lucida Grande', Geneva, Verdana, Helvetica, 'Lucida Sans Unicode', sans-serif; background-image: initial; background-attachment: initial; background-size: initial; background-origin: initial; background-clip: initial; background-position: initial; background-repeat: initial;">1</sub>-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.</p>