Impact of Oxygen Supplementation on Brachial Artery Hemodynamics and Vascular Function During Ascent to 5,050 m.

Vizcardo-Galindo, Gustavo A., Connor A. Howe, Ryan L. Hoiland, Howard H. Carter, Christopher K. Willie, Philip N. Ainslie, and Joshua C. Tremblay. Impact of oxygen supplementation on brachial artery hemodynamics and vascular function during ascent to 5,050 m. High Alt Med Biol. 24:27-36, 2023.-High-altitude trekking alters upper limb hemodynamics and reduces brachial artery vascular function in lowlanders. Whether these changes are reversible with the removal of hypoxia is unknown. We investigated the impact of 20 minutes of oxygen supplementation (O2) on brachial artery hemodynamics, reactive hyperemia (RH; microvascular function), and flow-mediated dilation (FMD; endothelial function). Participants (aged 21-42 years) were examined before and with O2 at 3,440 m (n = 7), 4,371 m (n = 7), and 5,050 m (n = 12) using Duplex ultrasound (days 4, 7, and 10 respectively). At 3,440 m, O2 decreased brachial artery diameter (-5% ± 5%; p = 0.04), baseline blood flow (-44% ± 15%; p < 0.001), oxygen delivery (-39 ± 16; p < 0.001), and peak RH (-8% ± 8%; p = 0.02), but not RH normalized for baseline blood flow. Elevated FMD (p = 0.04) with O2 at 3,440 m was attributed to the reduction in baseline diameter. At 5,050 m, a reduction in brachial artery blood flow (-17% ± 22%; p = 0.03), but not oxygen delivery, diameter, RH, or FMD occurred with O2. These findings suggest that during early trekking at high altitude, O2 causes vasoconstriction in the upper limb along the arterial tree (conduit and resistance arteries). With incremental high-altitude exposure, O2 reduces blood flow without compromising oxygen delivery, RH, or FMD, suggesting a differential impact on vascular function modulated by the duration and severity of high-altitude exposure.

Lifelong exposure to high-altitude hypoxia in humans is associated with improved redox homeostasis and structural-functional adaptations of the neurovascular unit.

High-altitude (HA) hypoxia may alter the structural-functional integrity of the neurovascular unit (NVU). Herein, we compared male lowlanders (n = 9) at sea level (SL) and after 14 days acclimatization to 4300 m (chronic HA) in Cerro de Pasco (CdP), Péru (HA), against sex-, age- and body mass index-matched healthy highlanders (n = 9) native to CdP (lifelong HA). Venous blood was assayed for serum proteins reflecting NVU integrity, in addition to free radicals and nitric oxide (NO). Regional cerebral blood flow (CBF) was examined in conjunction with cerebral substrate delivery, dynamic cerebral autoregulation (dCA), cerebrovascular reactivity to carbon dioxide (CVRCO2 ) and neurovascular coupling (NVC). Psychomotor tests were employed to examine cognitive function. Compared to lowlanders at SL, highlanders exhibited elevated basal plasma and red blood cell NO bioavailability, improved anterior and posterior dCA, elevated anterior CVRCO2 and preserved cerebral substrate delivery, NVC and cognition. In highlanders, S100B, neurofilament light-chain (NF-L) and T-tau were consistently lower and cognition comparable to lowlanders following chronic-HA. These findings highlight novel integrated adaptations towards regulation of the NVU in highlanders that may represent a neuroprotective phenotype underpinning successful adaptation to the lifelong stress of HA hypoxia. KEY POINTS: High-altitude (HA) hypoxia has the potential to alter the structural-functional integrity of the neurovascular unit (NVU) in humans. For the first time, we examined to what extent chronic and lifelong hypoxia impacts multimodal biomarkers reflecting NVU structure and function in lowlanders and native Andean highlanders. Despite lowlanders presenting with a reduction in systemic oxidative-nitrosative stress and maintained cerebral bioenergetics and cerebrovascular function during chronic hypoxia, there was evidence for increased axonal injury and cognitive impairment. Compared to lowlanders at sea level, highlanders exhibited elevated vascular NO bioavailability, improved dynamic regulatory capacity and cerebrovascular reactivity, comparable cerebral substrate delivery and neurovascular coupling, and maintained cognition. Unlike lowlanders following chronic HA, highlanders presented with lower concentrations of S100B, neurofilament light chain and total tau. These findings highlight novel integrated adaptations towards the regulation of the NVU in highlanders that may represent a neuroprotective phenotype underpinning successful adaptation to the lifelong stress of HA hypoxia.

Preserved peak exercise capacity in Andean highlanders with excessive erythrocytosis both before and after isovolumic hemodilution.

In chronic mountain sickness (CMS), increased blood oxygen (O2)-carrying capacity due to excessive erythrocytosis (EE, [Hb] ≥ 21 g/dL) could be offset, especially during exercise by both impaired cardiac output (Q̇t) and O2 diffusion limitation in lungs and muscle. We hypothesized that EE results in reduced peak V̇o2 despite increased blood O2-carrying capacity, and that isovolumic hemodilution (IVHD) improves exercise capacity. In 14 male residents of Cerro de Pasco, Peru (4,340 m), six with and eight without EE, we measured peak cycle-exercise capacity, V̇o2, Q̇t, arterial blood gas parameters, and (resting) blood volume. This was repeated for participants with EE after IVHD, reducing hematocrit by 20% (from 67% to 53%). From these data, we quantified the major O2 transport pathway components (ventilation, pulmonary alveolar-capillary diffusion, Q̇t, and blood-muscle mitochondria diffusion). Participants with EE had similar peak V̇o2, systemic O2 delivery, and O2 extraction as non-EE controls, however, with lower Q̇t and higher arterial [O2]. After IVHD, peak V̇o2 was preserved (but not enhanced), with lower O2 delivery (despite higher Q̇t) balanced by greater O2 extraction. The considerable variance in exercise capacity across the 14 individuals was explained essentially completely by differences in both pulmonary and muscle O2 diffusional conductances and not by any differences in ventilation, [Hb], nor Q̇t. In conclusion, EE does not result in lower peak V̇o2 in Andean males, and IVHD maintains, but does not enhance, exercise capacity.NEW & NOTEWORTHY Male Andean highlanders with and without excessive erythrocytosis (EE) have similar peak V̇o2 at 4,340 m, with higher arterial [O2] in EE and lower cardiac output (Q̇t), thus maintaining similar O2 delivery. Peak V̇o2 in participants with EE was unaffected by isovolumic hemodilution (hematocrit reduced from 67% to 53%), with lower O2 delivery balanced by slightly increased Q̇t and greater O2 extraction. Differences in lung and muscle diffusing capacity, and not hematocrit variation, accounted for essentially all interindividual variance in peak V̇o2.

Cerebral endothelium-dependent function and reactivity to hypercapnia: the role of α1-adrenoreceptors.

We assessed hypercapnic cerebrovascular reactivity (CVR) and endothelium-dependent function [cerebral shear-mediated dilation (cSMD)] in the internal carotid artery (ICA) with and without systemic α1-adrenoreceptor blockade via Prazosin. We hypothesized that CVR would be reduced, whereas cSMD would remain unchanged, after Prazosin administration when compared with placebo. In 15 healthy adults (3 female, 26 ± 4 years), we conducted ICA duplex ultrasound during CVR [target +10 mmHg partial pressure of end-tidal carbon dioxide ([Formula: see text]) above baseline, 5 min] and cSMD (+9 mmHg [Formula: see text] above baseline, 30 s) using dynamic end-tidal forcing with and without α1-adrenergic blockade (Prazosin; 0.05 mg/kg) in a placebo-controlled, double-blind, and randomized design. The CVR in the ICA was not different between placebo and Prazosin (P = 0.578). During CVR, the reactivities of mean arterial pressure and cerebrovascular conductance to hypercapnia were also not different between conditions (P = 0.921 and P = 0.664, respectively). During Prazosin, cSMD was lower (1.1 ± 2.0% vs 3.8 ± 3.0%; P = 0.032); however, these data should be interpreted with caution due to the elevated baseline diameter (+1.3 ± 3.6%; condition: P = 0.0498) and lower shear rate (-14.5 ± 23.0%; condition: P < 0.001). Therefore, lower cSMD post α1-adrenoreceptor blockade might not indicate a reduction in cerebral endothelial function per se, but rather, that α1-adrenoreceptors contribute to resting cerebral vascular restraint at the level of the ICA.NEW & NOTEWORTHY We assessed steady-state hypercapnic cerebrovascular reactivity and cerebral endothelium-dependent function, with and without α1-adrenergic blockade (Prazosin), in a placebo-controlled, double-blind, and randomized study, to assess the contribution of α1-adrenergic receptors to cerebrovascular CO2 regulation. After administration of Prazosin, cerebrovascular reactivity to CO2 was not different compared with placebo despite lower blood flow, whereas cerebral endothelium-dependent function was reduced, likely due to elevated baseline internal carotid arterial diameter. These findings suggest that α1-adrenoreceptor activity does not influence cerebral blood flow regulation to CO2 and cerebral endothelial function.

Brachial artery responses to acute hypercapnia: The roles of shear stress and adrenergic tone.

NEW FINDINGS: What is the central question of this study? What are the contributions of shear stress and adrenergic tone to brachial artery vasodilatation during hypercapnia? What is the main finding and its importance? In healthy young adults, shear-mediated vasodilatation does not occur in the brachial artery during hypercapnia, as elevated α1-adrenergic activity typically maintains vascular tone and offsets distal vasodilatation controlling flow. ABSTRACT: We aimed to assess the shear stress dependency of brachial artery (BA) responses to hypercapnia, and the α1-adrenergic restraint of these responses. We hypothesized that elevated shear stress during hypercapnia would cause BA vasodilatation, but where shear stress was prohibited (via arterial compression), the BA would not vasodilate (study 1); and, in the absence of α1-adrenergic activity, blood flow, shear stress and BA vasodilatation would increase (study 2). In study 1, 14 healthy adults (7/7 male/female, 27 ± 4 years) underwent bilateral BA duplex ultrasound during hypercapnia (partial pressure of end-tidal carbon dioxide, +10.2 ± 0.3 mmHg above baseline, 12 min) via dynamic end-tidal forcing, and shear stress was reduced in one BA using manual compression (compression vs. control arm). Neither diameter nor blood flow was different between baseline and the last minute of hypercapnia (P = 0.423, P = 0.363, respectively) in either arm. The change values from baseline to the last minute, in diameter (%; P = 0.201), flow (ml/min; P = 0.234) and conductance (ml/min/mmHg; P = 0.503) were not different between arms. In study 2, 12 healthy adults (9/3 male/female, 26 ± 4 years) underwent the same design with and without α1-adrenergic receptor blockade (prazosin; 0.05 mg/kg) in a placebo-controlled, double-blind and randomized design. BA flow, conductance and shear rate increased during hypercapnia in the prazosin control arm (interaction, P < 0.001), but in neither arm during placebo. Even in the absence of α1-adrenergic restraint, downstream vasodilatation in the microvasculature during hypercapnia is insufficient to cause shear-mediated vasodilatation in the BA.

Global Research Expedition on Altitude-related Chronic Health 2018 Iron Infusion at High Altitude Reduces Hypoxic Pulmonary Vasoconstriction Equally in Both Lowlanders and Healthy Andean Highlanders.

BACKGROUND: Increasing iron bioavailability attenuates hypoxic pulmonary vasoconstriction in both lowlanders and Sherpas at high altitude. In contrast, the pulmonary vasculature of Andean individuals with chronic mountain sickness (CMS) is resistant to iron administration. Although pulmonary vascular remodeling and hypertension are characteristic features of CMS, the effect of iron administration in healthy Andean individuals, to our knowledge, has not been investigated. If the interplay between iron status and pulmonary vascular tone in healthy Andean individuals remains intact, this could provide valuable clinical insight into the role of iron regulation at high altitude. RESEARCH QUESTION: Is the pulmonary vasculature in healthy Andean individuals responsive to iron infusion? STUDY DESIGN AND METHODS: In a double-blinded, block-randomized design, 24 healthy high-altitude Andean individuals and 22 partially acclimatized lowlanders at 4,300 m (Cerro de Pasco, Peru) received an IV infusion of either 200 mg of iron (III)-hydroxide sucrose or saline. Markers of iron status were collected at baseline and 4 h after infusion. Echocardiography was performed in participants during room air breathing (partial pressure of inspired oxygen [Pio2] of approximately 96 mm Hg) and during exaggerated hypoxia (Pio2 of approximately 73 mm Hg) at baseline and at 2 and 4 h after the infusion. RESULTS: Iron infusion reduced pulmonary artery systolic pressure (PASP) by approximately 2.5 mm Hg in room air (main effect, P < .001) and by approximately 7 mm Hg during exaggerated hypoxia (main effect, P < .001) in both lowlanders and healthy Andean highlanders. There was no change in PASP after the infusion of saline. Iron metrics were comparable between groups, except for serum ferritin, which was 1.8-fold higher at baseline in the Andean individuals than in the lowlanders (95% CI, 74-121 ng/mL vs 37-70 ng/mL, respectively; P = .003). INTERPRETATION: The pulmonary vasculature of healthy Andean individuals and lowlanders remains sensitive to iron infusion, and this response seems to differ from the pathologic characteristics of CMS.

Global REACH 2018: volume regulation in high-altitude Andeans with and without chronic mountain sickness.

The high-altitude maladaptation syndrome known as chronic mountain sickness (CMS) is characterized by polycythemia and is associated with proteinuria despite unaltered glomerular filtration rate. However, it remains unclear if indigenous highlanders with CMS have altered volume regulatory hormones. We assessed NH2-terminal pro-B-type natriuretic peptide (NT pro-BNP), plasma aldosterone concentration, plasma renin activity, kidney function (urinary microalbumin, glomerular filtration rate), blood volume, and estimated pulmonary artery systolic pressure (ePASP) in Andean males without (n = 14; age = 39 ± 11 yr) and with (n = 10; age = 40 ± 12 yr) CMS at 4,330 m (Cerro de Pasco, Peru). Plasma renin activity (non-CMS: 15.8 ± 7.9 ng/mL vs. CMS: 8.7 ± 5.4 ng/mL; P = 0.025) and plasma aldosterone concentration (non-CMS: 77.5 ± 35.5 pg/mL vs. CMS: 54.2 ± 28.9 pg/mL; P = 0.018) were lower in highlanders with CMS compared with non-CMS, whereas NT pro-BNP was not different between groups (non-CMS: 1394.9 ± 214.3 pg/mL vs. CMS: 1451.1 ± 327.8 pg/mL; P = 0.15). Highlanders had similar total blood volume (non-CMS: 90 ± 15 mL·kg-1 vs. CMS: 103 ± 18 mL·kg-1; P = 0.071), but Andeans with CMS had greater total red blood cell volume (non-CMS: 46 ± 10 mL·kg-1 vs. CMS: 66 ± 14 mL·kg-1; P < 0.01) and smaller plasma volume (non-CMS: 43 ± 7 mL·kg-1 vs. CMS: 35 ± 5 mL·kg-1; P = 0.03) compared with non-CMS. There were no differences in ePASP between groups (non-CMS: 32 ± 9 mmHg vs. CMS: 31 ± 8 mmHg; P = 0.6). A negative correlation was found between plasma renin activity and glomerular filtration rate in both groups (group: r = -0.66; P < 0.01; non-CMS: r = -0.60; P = 0.022; CMS: r = -0.63; P = 0.049). A smaller plasma volume in Andeans with CMS may indicate an additional CMS maladaptation to high altitude, causing potentially greater polycythemia and clinical symptoms.

Global Reach 2018: Nitric oxide-mediated cutaneous vasodilation is reduced in chronic, but not acute, hypoxia independently of enzymatic superoxide formation.

We tested the hypotheses that 1) cutaneous microvascular function is impaired by acute normobaric and chronic hypobaric hypoxia and 2) that the superoxide free radical (via NADPH oxidase or xanthine oxidase) contributes to this impairment via nitric oxide (NO) scavenging. Local heating-induced cutaneous hyperemia (39 °C) was measured in the forearm of 11 male lowlanders at sea level (SL) and following 14-18 days at high altitude (HA; 4340 m in Cerro de Pasco, Peru), and compared to 11 highlanders residing permanently at this elevation. Cutaneous vascular conductance (CVC; laser-Doppler flux/mean arterial pressure) was not different during 39 °C [control site: 73 (19) vs. 71 (18)%max; P = 0.68] between normoxia and acute normobaric hypoxia (FIO2 = 0.125; equivalent to HA), respectively. At HA, CVC was reduced during 39 °C in lowlanders compared to SL [control site: 54 (14) vs. 73 (19)%max; P < 0.01] and was lower in Andean highlanders compared to lowlanders at HA [control site: 50 (24) vs. 54 (14)%max; P = 0.02]. The NO contribution to vasodilation during 39 °C (i.e., effect of NO synthase inhibition) was reduced in lowlanders at HA compared to SL [control site: 41 (11) vs 49 (10)%max; P = 0.04] and in Andean highlanders compared to lowlanders at HA [control site: 32 (21) vs. 41 (11)%max; P = 0.01]. Intradermal administration (cutaneous microdialysis) of the superoxide mimetic Tempol, inhibition of xanthine oxidase (via allopurinol), or NADPH oxidase (via apocynin) had no influence on cutaneous endothelium-dependent dilation during any of the conditions (all main effects of drug P > 0.05). These results suggest that time at HA impairs NO-mediated cutaneous vasodilation independent of enzymatic superoxide formation.

Global REACH 2018: dysfunctional extracellular microvesicles in Andean highlander males with excessive erythrocytosis.

High altitude-related excessive erythrocytosis (EE) is associated with increased cardiovascular risk. The experimental aim of this study was to determine the effects of microvesicles isolated from Andean highlanders with EE on endothelial cell inflammation, oxidative stress, apoptosis, and nitric oxide (NO) production. Twenty-six male residents of Cerro de Pasco, Peru (4,340 m), were studied: 12 highlanders without EE (age: 40 ± 4 yr; BMI: 26.4 ± 1.7; Hb: 17.4 ± 0.5 g/dL, Spo2: 86.9 ± 1.0%) and 14 highlanders with EE (43 ± 4 yr; 26.2 ± 0.9; 24.4 ± 0.4 g/dL; 79.7 ± 1.6%). Microvesicles were isolated, enumerated, and collected from plasma by flow cytometry. Human umbilical vein endothelial cells were cultured and treated with microvesicles from highlanders without and with EE. Microvesicles from highlanders with EE induced significantly higher release of interleukin (IL)-6 (89.8 ± 2.7 vs. 77.1 ± 1.9 pg/mL) and IL-8 (62.0 ± 2.7 vs. 53.3 ± 2.2 pg/mL) compared with microvesicles from healthy highlanders. Although intracellular expression of total NF-κB p65 (65.3 ± 6.0 vs. 74.9 ± 7.8.9 AU) was not significantly affected in cells treated with microvesicles from highlanders without versus with EE, microvesicles from highlanders with EE resulted in an ∼25% higher (P < 0.05) expression of p-NF-κB p65 (173.6 ± 14.3 vs. 132.8 ± 12.2 AU). Cell reactive oxygen species production was significantly higher (76.4.7 ± 5.4 vs. 56.7 ± 1.7% of control) and endothelial nitric oxide synthase (p-eNOS) activation (231.3 ± 15.5 vs. 286.6 ± 23.0 AU) and NO production (8.3 ± 0.6 vs. 10.7 ± 0.7 µM/L) were significantly lower in cells treated with microvesicles from highlanders with versus without EE. Cell apoptotic susceptibility was not significantly affected by EE-related microvesicles. Circulating microvesicles from Andean highlanders with EE increased endothelial cell inflammation and oxidative stress and reduced NO production.NEW & NOTEWORTHY In this study, we determined the effects of microvesicles isolated from Andean highlanders with excessive erythrocytosis (EE) on endothelial cell inflammation, oxidative stress, apoptosis, and NO production. Microvesicles from highlanders with EE induced a dysfunctional response from endothelial cells characterized by increased cytokine release and expression of active nuclear factor-κB and reduced nitric oxide production. Andean highlanders with EE exhibit dysfunctional circulating extracellular microvesicles that induce a proinflammatory, proatherogenic endothelial phenotype.

Global REACH 2018: Andean highlanders, chronic mountain sickness and the integrative regulation of resting blood pressure.

NEW FINDINGS: What is the central question of this study? Does chronic mountain sickness (CMS) alter sympathetic neural control and arterial baroreflex regulation of blood pressure in Andean (Quechua) highlanders? What is the main finding and its importance? Compared to healthy Andean highlanders, basal sympathetic vasomotor outflow is lower, baroreflex control of muscle sympathetic nerve activity is similar, supine heart rate is lower and cardiovagal baroreflex gain is greater in mild CMS. Taken together, these findings reflect flexibility in integrative regulation of blood pressure that may be important when blood viscosity and blood volume are elevated in CMS. ABSTRACT: The high-altitude maladaptation syndrome chronic mountain sickness (CMS) is characterized by excessive erythrocytosis and frequently accompanied by accentuated arterial hypoxaemia. Whether altered autonomic cardiovascular regulation is apparent in CMS is unclear. Therefore, during the 2018 Global REACH expedition to Cerro de Pasco, Peru (4383 m), we assessed integrative control of blood pressure (BP) and determined basal sympathetic vasomotor outflow and arterial baroreflex function in eight Andean natives with CMS ([Hb] 22.6 ± 0.9 g·dL-1 ) and seven healthy highlanders ([Hb] 19.3 ± 0.8 g·dL-1 ). R-R interval (RRI, electrocardiogram), beat-by-beat BP (photoplethysmography) and muscle sympathetic nerve activity (MSNA; microneurography) were recorded at rest and during pharmacologically induced changes in BP (modified Oxford test). Although [Hb] and blood viscosity (7.8 ± 0.7 vs. 6.6 ± 0.7 cP; d = 1.7, P = 0.01) were elevated in CMS compared to healthy highlanders, cardiac output, total peripheral resistance and mean BP were similar between groups. The vascular sympathetic baroreflex MSNA set-point (i.e. MSNA burst incidence) and reflex gain (i.e. responsiveness) were also similar between groups (MSNA set-point, d = 0.75, P = 0.16; gain, d = 0.2, P = 0.69). In contrast, in CMS the cardiovagal baroreflex operated around a longer RRI (960 ± 159 vs. 817 ± 50 ms; d = 1.4, P = 0.04) with a greater reflex gain (17.2 ± 6.8 vs. 8.8 ± 2.6 ms·mmHg-1 ; d = 1.8, P = 0.01) versus healthy highlanders. Basal sympathetic vasomotor activity was also lower compared to healthy highlanders (33 ± 11 vs. 45 ± 13 bursts·min-1 ; d = 1.0, P = 0.08). In conclusion, our findings indicate adaptive differences in basal sympathetic vasomotor activity and heart rate compensate for the haemodynamic consequences of excessive erythrocyte volume and contribute to integrative blood pressure regulation in Andean highlanders with mild CMS.

Global Reach 2018: reduced flow-mediated dilation stimulated by sustained increases in shear stress in high-altitude excessive erythrocytosis.

Excessive erythrocytosis [EE; hemoglobin concentration (Hb) ≥ 21 g/dL in adult men] is a maladaptive high-altitude pathology associated with increased cardiovascular risk and reduced reactive hyperemia flow-mediated dilation (FMD); however, whether a similar impairment occurs in response to more commonly encountered sustained increases in shear stress [sustained stimulus (SS)-FMD] over a range of overlapping stimuli is unknown. We characterized SS-FMD in response to handgrip exercise in Andeans with and without EE in Cerro de Pasco, Peru (4,330 m). Andean highlanders with EE (n = 17, Hb = 23.2 ± 1.2 g/dL) and without EE (n = 23, Hb = 18.7 ± 1.9 g/dL) performed 3 min of rhythmic handgrip exercise at 20, 35, and 50% of maximum voluntary contraction (MVC). Duplex ultrasound was used to continuously record blood velocity and diameter in the brachial artery, and blood viscosity was measured to accurately calculate shear stress. Although baseline shear stress did not differ, Andeans with EE had 22% lower shear stress than Andeans without at 50% MVC (P = 0.004). At 35 and 50% MVC, SS-FMD was 2.1 ± 2.0 and 2.8 ± 2.7% in Andeans with EE compared with 4.1 ± 3.4 and 7.5 ± 4.5% in those without (P = 0.048 and P < 0.001). The stimulus-response slope (∆shear stress vs. ∆diameter) was lower in Andeans with EE compared with Andeans without (P = 0.028). This slope was inversely related to Hb in Andeans with EE (r2 = 0.396, P = 0.007). A reduced SS-FMD in response to small muscle mass exercise in Andeans with EE indicates a generalized reduction in endothelial sensitivity to shear stress, which may contribute to increased cardiovascular risk in this population.NEW & NOTEWORTHY High-altitude excessive erythrocytosis (EE; hemoglobin concentration ≥ 21 g/dL) is a maladaptation to chronic hypoxia exposure and is associated with increased cardiovascular risk. We examined flow-mediated dilation (FMD) in response to sustained elevations in shear stress achieved using progressive handgrip exercise [sustained stimulus (SS)-FMD] in Andean highlanders with and without EE at 4,330 m. Andeans with EE demonstrated lower SS-FMD compared with those without. Heightened hemoglobin concentration was related to lower SS-FMD in Andeans with EE.

Global REACH 2018: High Blood Viscosity and Hemoglobin Concentration Contribute to Reduced Flow-Mediated Dilation in High-Altitude Excessive Erythrocytosis

Excessive erythrocytosis (EE; hemoglobin concentration [Hb] ≥21 g/dL in adult males) is associated with increased cardiovascular risk in highlander Andeans. We sought to quantify shear stress and assess endothelial function via flow-mediated dilation (FMD) in male Andeans with and without EE. We hypothesized that FMD would be impaired in Andeans with EE after accounting for shear stress and that FMD would improve after isovolemic hemodilution. Brachial artery shear stress and FMD were assessed in 23 male Andeans without EE (age: 40±15 years [mean±SD]; Hb<21 g/dL) and 19 male Andeans with EE (age: 43±14 years; Hb≥21 g/dL) in Cerro de Pasco, Peru (4330 m). Shear stress was quantified from Duplex ultrasound measures of shear rate and blood viscosity. In a subset of participants (n=8), FMD was performed before and after isovolemic hemodilution with blood volume replaced by an equal volume of human serum albumin. Blood viscosity and Hb were 48% and 23% higher (both P<0.001) and FMD was 28% lower after adjusting for the shear stress stimulus ( P=0.013) in Andeans with EE compared to those without. FMD was inversely correlated with blood viscosity ( r2=0.303; P<0.001) and Hb ( r2=0.230; P=0.001). Isovolemic hemodilution decreased blood viscosity by 30±10% and Hb by 14±5% (both P<0.001) and improved shear stress stimulus-adjusted FMD from 2.7±1.9% to 4.3±1.9% ( P=0.022). Hyperviscosity, high Hb, or both, actively contribute to acutely reversible impairments in FMD in EE, suggesting that this plays a pathogenic role in the increased cardiovascular risk.