ABSTRACT
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.
Subject(s)
Altitude Sickness , Humans , Male , Carbon Dioxide , Altitude , Hypoxia , Acclimatization/physiology , Oxidation-Reduction , Nitric Oxide , HomeostasisABSTRACT
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.
Subject(s)
Brachial Artery , Hypercapnia , Young Adult , Humans , Female , Male , Brachial Artery/physiology , Adrenergic Agents , Regional Blood Flow/physiology , Vasodilation/physiology , Prazosin , Blood Flow Velocity/physiologyABSTRACT
RATIONALE: Chronic exposure to hypoxia is associated with elevated sympathetic nervous activity and reduced vascular function in lowlanders, and Andean highlanders suffering from excessive erythrocytosis (EE); however, the mechanistic link between chronically elevated sympathetic nervous activity and hypoxia-induced vascular dysfunction has not been determined. OBJECTIVE: To determine the impact of heightened sympathetic nervous activity on resistance artery endothelial-dependent dilation (EDD), and endothelial-independent dilation, in lowlanders and Andean highlanders with and without EE. METHODS AND RESULTS: We tested healthy lowlanders (n=9) at sea level (344 m) and following 14 to 21 days at high altitude (4300 m), and permanent Andean highlanders with (n=6) and without (n=9) EE at high altitude. Vascular function was assessed using intraarterial infusions (3 progressive doses) of acetylcholine (ACh; EDD) and sodium nitroprusside (endothelial-independent dilation) before and after local α+ß adrenergic receptor blockade (phentolamine and propranolol). Intraarterial blood pressure, heart rate, and simultaneous brachial artery diameter and blood velocity were recorded at rest and during drug infusion. Changes in forearm vascular conductance were calculated. The main findings were (1) chronic hypoxia reduced EDD in lowlanders (changes in forearm vascular conductance from sea level: ACh1: -52.7±19.6%, ACh2: -25.4±38.7%, ACh3: -35.1±34.7%, all P≤0.02); and in Andeans with EE compared with non-EE (changes in forearm vascular conductance at ACh3: -36.4%, P=0.007). Adrenergic blockade fully restored EDD in lowlanders at high altitude, and normalized EDD between EE and non-EE Andeans. (2) Chronic hypoxia had no effect on endothelial-independent dilation in lowlanders, and no differences were detected between EE and non-EE Andeans; however, EID was increased in the non-EE Andeans after adrenergic blockade (P=0.012), but this effect was not observed in the EE Andeans. CONCLUSIONS: These data indicate that chronic hypoxia reduces EDD via heightened α-adrenergic signaling in lowlanders and in Andeans with EE. These vascular mechanisms have important implications for understanding the physiological consequences of acute and chronic high altitude adaptation.
Subject(s)
Adaptation, Physiological , Altitude Sickness/metabolism , Polycythemia/metabolism , Receptors, Adrenergic/metabolism , Vasodilation , Acetylcholine/metabolism , Acetylcholine/pharmacology , Adrenergic Agents/pharmacology , Adult , Altitude , Altitude Sickness/blood , Altitude Sickness/physiopathology , Blood Pressure , Blood Vessels/drug effects , Blood Vessels/metabolism , Blood Vessels/physiopathology , Heart Rate , Humans , Male , Nitroprusside/pharmacology , Phentolamine/pharmacology , Polycythemia/etiology , Polycythemia/physiopathology , Propranolol/pharmacology , Signal Transduction , Sympathetic Nervous System/drug effects , Sympathetic Nervous System/metabolism , Sympathetic Nervous System/physiopathology , Vasodilator Agents/pharmacologyABSTRACT
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 â¼25% 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.
Subject(s)
Acclimatization , Altitude , Cell-Derived Microparticles/metabolism , Human Umbilical Vein Endothelial Cells/metabolism , Polycythemia/blood , Adult , Apoptosis , Case-Control Studies , Cell-Derived Microparticles/pathology , Cells, Cultured , Human Umbilical Vein Endothelial Cells/pathology , Humans , Inflammation Mediators/metabolism , Interleukin-6/metabolism , Interleukin-8/metabolism , Male , Nitric Oxide/metabolism , Nitric Oxide Synthase Type III/metabolism , Oxidative Stress , Peru , Phenotype , Polycythemia/pathology , Polycythemia/physiopathology , Reactive Oxygen Species/metabolism , Transcription Factor RelA/metabolismABSTRACT
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.
Subject(s)
Acclimatization , Altitude Sickness/physiopathology , Altitude , Blood Volume , Polycythemia/physiopathology , Adult , Albuminuria/etiology , Albuminuria/physiopathology , Aldosterone/blood , Altitude Sickness/blood , Altitude Sickness/diagnosis , Altitude Sickness/etiology , Arterial Pressure , Biomarkers/blood , Chronic Disease , Glomerular Filtration Rate , Humans , Kidney/physiopathology , Male , Middle Aged , Natriuretic Peptide, Brain/blood , Peptide Fragments/blood , Polycythemia/blood , Polycythemia/diagnosis , Polycythemia/etiology , Pulmonary Artery/physiopathology , Renin/bloodABSTRACT
NEW FINDINGS: What is the central question of this study? What is the effect of sub-maximal aerobic exercise training on signs and symptoms of chronic mountain sickness (CMS) in Andean highlanders? What is the main finding and its importance? Aerobic exercise training (ET) effectively reduces haematocrit, ameliorates symptoms and improves aerobic capacity in CMS patients, suggesting that a regular aerobic ET programme might be used as a low-cost non-invasive/non-pharmacological management strategy of this syndrome. ABSTRACT: Excessive erythrocytosis is the hallmark sign of chronic mountain sickness (CMS), a debilitating syndrome associated with neurological symptoms and increased cardiovascular risk. We have shown that unlike sedentary residents at the same altitude, trained individuals maintain haematocrit within sea-level range, and thus we hypothesise that aerobic exercise training (ET) might reduce excessive haematocrit and ameliorate CMS signs and symptoms. Eight highlander men (38 ± 12 years) with CMS (haematocrit: 70.6 ± 1.9%, CMS score: 8.8 ± 1.4) from Cerro de Pasco, Peru (4340 m) participated in the study. Baseline assessment included haematocrit, CMS score, pulse oximetry, maximal cardiopulmonary exercise testing and in-office plus 24 h ambulatory blood pressure (BP) monitoring. Blood samples were collected to assess cardiometabolic, erythropoietic, and haemolysis markers. ET consisted of pedalling exercise in a cycloergometer at 60% of VÌO2peak for 1 h/day, 4 days/week for 8 weeks, and participants were assessed at weeks 4 and 8. Haematocrit and CMS score decreased significantly by week 8 (to 65.6 ± 6.6%, and 3.5 ± 0.8, respectively, P < 0.05), while VÌO2peak and maximum workload increased with ET (33.8 ± 2.4 vs. 37.2 ± 2.0 ml/min/kg, P < 0.05; and 172.5 ± 9.4 vs. 210.0 ± 27.8 W, P < 0.01; respectively). Except for an increase in high-density lipoprotein cholesterol, other blood markers and BP showed no differences. Our results suggest that reduction of haematocrit and CMS symptoms results mainly from haemodilution due to plasma volume expansion rather than to haemolysis. In conclusion, we show that ET can effectively reduce haematocrit, ameliorate symptoms and improve aerobic capacity in CMS patients, suggesting that regular aerobic exercise might be used as a low-cost non-invasive and non-pharmacological management strategy.
Subject(s)
Altitude Sickness , Altitude , Blood Pressure Monitoring, Ambulatory , Chronic Disease , Exercise , Hematocrit , Humans , MaleABSTRACT
NEW FINDINGS: What is the central question of this study? Are coagulation and fibrinolytic factors disrupted in Andean highlanders with excessive erythrocytosis? What is the main finding and its importance? Excessive erythrocytosis is not associated with prothombotic disruptions in coagulation or the fibrinolytic system in Andean highlanders. Impairments in coagulation and fibrinolysis may not contribute to the increased vascular risk associated with excessive erythrocytosis. ABSTRACT: Increased coagulation and reduced fibrinolysis are central factors underlying thrombotic risk and events. High altitude-induced excessive erythrocytosis (EE) is prevalent in Andean highlanders, contributing to increased cardiovascular risk. Disruption in the coagulation-fibrinolytic axis resulting in uncontrolled fibrin deposition might underlie the increased thrombotic risk associated with high-altitude EE. The experimental aim of this study was to determine whether EE is associated with a prothrombotic blood coagulation and fibrinolytic profile in Andean highlanders. Plasma coagulation factors (von Willebrand factor and factors VII, VIII and X), fibrinolytic factors [tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1)] and D-dimer levels were determined in 26 male residents of Cerro de Pasco, Peru (4340 m a.s.l.): 12 without EE (age, 40 ± 13 years; haemoglobin, 17.4 ± 1.9 g/dl) and 14 with EE (age, 43 ± 15 years; haemoglobin, 24.4 ± 1.6 g/dl). There were no significant differences in von Willebrand factor (40.5 ± 24.8 vs. 45.5 ± 22.4%), factor VII (77.0 ± 14.5 vs. 72.5 ± 8.9%), factor VIII (55.6 ± 19.8 vs. 60.7 ± 26.8%) and factor X (73.9 ± 8.3 vs. 67.3 ± 10.9%) between the Andean highlanders without or with EE. The t-PA antigen (8.5 ± 3.6 vs. 9.6 ± 5.4 ng/ml), t-PA activity (5.5 ± 2.4 vs. 5.8 ± 1.6 IU/ml), PAI antigen (45.0 ± 33.8 vs. 40.5 ± 15.8 ng/ml), PAI-1 activity (0.24 ± 0.09 vs. 0.25 ± 0.11 IU/ml) and the molar concentration ratio of active t-PA to active PAI-1 (1:0.051 ± 0.034 vs. 1:0.046 ± 0.021 mmol/l) were also similar between the groups, as were D-dimer levels (235.0 ± 126.4 vs. 268.4 ± 173.7 ng/ml). Collectively, the results of the present study indicate that EE is not associated with a hypercoagulable, hypofibrinolytic state in Andean highlanders.
Subject(s)
Blood Coagulation , Fibrinolysis , Polycythemia , Adult , Altitude , Heart , Hemoglobins , Humans , Male , Middle Aged , South AmericaABSTRACT
NEW FINDINGS: What is the central question of this study? Herein, a methodological overview of our research team's (Global REACH) latest high altitude research expedition to Peru is provided. What is the main finding and its importance? The experimental objectives, expedition organization, measurements and key cohort data are discussed. The select data presented in this manuscript demonstrate the haematological differences between lowlanders and Andeans with and without excessive erythrocytosis. The data also demonstrate that exercise capacity was similar between study groups at high altitude. The forthcoming findings from our research expedition will contribute to our understanding of lowlander and indigenous highlander high altitude adaptation. ABSTRACT: In 2016, the international research team Global Research Expedition on Altitude Related Chronic Health (Global REACH) was established and executed a high altitude research expedition to Nepal. The team consists of â¼45 students, principal investigators and physicians with the common objective of conducting experiments focused on high altitude adaptation in lowlanders and in highlanders with lifelong exposure to high altitude. In 2018, Global REACH travelled to Peru, where we performed a series of experiments in the Andean highlanders. The experimental objectives, organization and characteristics, and key cohort data from Global REACH's latest research expedition are outlined herein. Fifteen major studies are described that aimed to elucidate the physiological differences in high altitude acclimatization between lowlanders (n = 30) and Andean-born highlanders with (n = 22) and without (n = 45) excessive erythrocytosis. After baseline testing in Kelowna, BC, Canada (344 m), Global REACH travelled to Lima, Peru (â¼80 m) and then ascended by automobile to Cerro de Pasco, Peru (â¼4300 m), where experiments were conducted over 25 days. The core studies focused on elucidating the mechanism(s) governing cerebral and peripheral vascular function, cardiopulmonary regulation, exercise performance and autonomic control. Despite encountering serious logistical challenges, each of the proposed studies was completed at both sea level and high altitude, amounting to â¼780 study sessions and >3000 h of experimental testing. Participant demographics and data relating to acid-base balance and exercise capacity are presented. The collective findings will contribute to our understanding of how lowlanders and Andean highlanders have adapted under high altitude stress.
Subject(s)
Adaptation, Physiological/physiology , Altitude Sickness/physiopathology , Heart/physiopathology , Hypoxia/physiopathology , Adult , Altitude , Chronic Disease , Cohort Studies , Expeditions , Humans , Male , PeruABSTRACT
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.
Subject(s)
Altitude Sickness/physiopathology , Arterial Pressure/physiology , Blood Pressure/physiology , Blood Volume/physiology , Sympathetic Nervous System/physiopathology , Adult , Baroreflex/physiology , Chronic Disease , Hemodynamics/physiology , Humans , Hypoxia/physiopathology , Male , Middle Aged , Muscle, Skeletal/physiology , Musculoskeletal Physiological Phenomena , Young AdultABSTRACT
High-altitude (>2,500 m) exposure results in increased muscle sympathetic nervous activity (MSNA) in acclimatizing lowlanders. However, little is known about how altitude affects MSNA in indigenous high-altitude populations. Additionally, the relationship between MSNA and blood pressure regulation (i.e., neurovascular transduction) at high-altitude is unclear. We sought to determine 1) how high-altitude effects neurocardiovascular transduction and 2) whether differences exist in neurocardiovascular transduction between low- and high-altitude populations. Measurements of MSNA (microneurography), mean arterial blood pressure (MAP; finger photoplethysmography), and heart rate (electrocardiogram) were collected in 1) lowlanders (n = 14) at low (344 m) and high altitude (5,050 m), 2) Sherpa highlanders (n = 8; 5,050 m), and 3) Andean (with and without excessive erythrocytosis) highlanders (n = 15; 4,300 m). Cardiovascular responses to MSNA burst sequences (i.e., singlet, couplet, triplet, and quadruplet) were quantified using custom software (coded in MATLAB, v.2015b). Slopes were generated for each individual based on peak responses and normalized total MSNA. High altitude reduced neurocardiovascular transduction in lowlanders (MAP slope: high altitude, 0.0075 ± 0.0060 vs. low altitude, 0.0134 ± 0.080; P = 0.03). Transduction was elevated in Sherpa (MAP slope, 0.012 ± 0.007) compared with Andeans (0.003 ± 0.002, P = 0.001). MAP transduction was not statistically different between acclimatizing lowlanders and Sherpa (MAP slope, P = 0.08) or Andeans (MAP slope, P = 0.07). When resting MSNA is accounted for (ANCOVA), transduction was inversely related to basal MSNA (bursts/minute) independent of population (RRI, r = 0.578 P < 0.001; MAP, r = -0.627, P < 0.0001). Our results demonstrate that transduction is blunted in individuals with higher basal MSNA, suggesting that blunted neurocardiovascular transduction is a physiological adaptation to elevated MSNA rather than an effect or adaptation specific to chronic hypoxic exposure.NEW & NOTEWORTHY This study has identified that sympathetically mediated blood pressure regulation is reduced following ascent to high-altitude. Additionally, we show that high altitude Andean natives have reduced blood pressure responsiveness to sympathetic nervous activity (SNA) compared with Nepalese Sherpa. However, basal sympathetic activity is inversely related to the magnitude of SNA-mediated fluctuations in blood pressure regardless of population or condition. These data set a foundation to explore more precise mechanisms of blood pressure control under conditions of persistent sympathetic activation and hypoxia.
Subject(s)
Acclimatization , Altitude , Arterial Pressure , Cardiovascular System/innervation , Heart Rate , Muscle, Skeletal/innervation , Sympathetic Nervous System/physiology , Adult , Female , Homeostasis , Humans , Male , Middle Aged , Nepal , Peru , Time FactorsABSTRACT
Excessive erythrocytosis (EE) is the main sign of chronic mountain sickness (CMS), a maladaptive clinical syndrome prevalent in Andean and other high-altitude populations worldwide. The pathophysiological mechanism of EE is still controversial, as physiological variability of systemic respiratory, cardiovascular, and hormonal responses to chronic hypoxemia complicates the identification of underlying causes. Induced pluripotent stem cells derived from CMS highlanders showed increased expression of genes relevant to the regulation of erythropoiesis, angiogenesis, cardiovascular, and steroid-hormone function that appear to explain the exaggerated erythropoietic response. However, the cellular response to hypoxia in native CMS cells is yet unknown. This study had three related aims: to determine the hypoxic proliferation of native erythroid progenitor burst-forming unit-erythroid (BFU-E) cells derived from CMS and non-CMS peripheral blood mononuclear cells; to examine their sentrin-specific protease 1 (SENP1), GATA-binding factor 1 (GATA1), erythropoietin (EPO), and EPO receptor (EPOR) expression; and to investigate the functional upstream role of SENP1 in native progenitor differentiation into erythroid precursors. Native CMS BFU-E colonies showed increased proliferation under hypoxic conditions compared with non-CMS cells, together with an upregulated expression of SENP1, GATA1, EPOR; and no difference in EPO expression. Knock-down of the SENP1 gene abolished the augmented proliferative response. Thus, we demonstrate that native CMS progenitor cells produce a larger proportion of erythroid precursors under hypoxia and that SENP1 is essential for proliferation. Our findings suggest a significant intrinsic component for developing EE in CMS highlanders at the cellular and gene expression level that could be further enhanced by systemic factors such as alterations in respiratory control, or differential hormonal patterns.
Subject(s)
Altitude Sickness/epidemiology , Altitude , Erythroid Precursor Cells/metabolism , Oxygen/metabolism , Oxygen/pharmacology , Chronic Disease , Erythropoietin/blood , Gene Expression Regulation/drug effects , Genetic Predisposition to Disease , Homeostasis , Humans , Hypoxia , Iron/metabolism , Leukocytes, Mononuclear , TranscriptomeABSTRACT
NEW FINDINGS: What is the central question of this study? What is the impact of oxygen on the circulatory responses to an isocapnic cold pressor test (CPT) in lowlanders and Andean highlanders? What is the main finding and its importance? Overall, the circulatory responses to an isocapnic CPT were largely unaltered with acute normobaric hypoxia and chronic hypobaric hypoxia exposure in lowlanders. However, the relationship between mean arterial pressure and common carotid artery diameter was dampened in hypoxic conditions. Furthermore, there were no differences in the circulatory responses to the CPT between lowlanders and Andean highlanders with lifelong exposure to high altitude. ABSTRACT: The impact of oxygen on the circulatory responses to a cold pressor test (CPT) in lowlanders and Andean highlanders remains unknown. Our hypotheses were as follows: (i) in lowlanders, acute normobaric and hypobaric hypoxia would attenuate the common carotid artery (CCA) diameter response to the CPT compared with normobaric normoxia; (ii) Andean highlanders would exhibit a greater CCA diameter response compared with lowlanders; and (iii) a positive relationship between CCA diameter and blood pressure in response to the CPT would be present in both lowlanders and highlanders. Healthy lowlanders (n = 13) and Andean highlanders (n = 8) were recruited and conducted an isocapnic CPT, which consisted of a 3 min foot immersion into water at 0-1°C. Blood pressure (finger photoplethysmography) and CCA diameter and blood flow (Duplex ultrasound) were recorded continuously. The CPT was conducted in lowlanders at sea level in isocapnic normoxic and hypoxic conditions and after 10 days of acclimatization to 4300 m (Cerro de Pasco, Peru) in hypoxic and hyperoxic conditions. Andean highlanders were tested at rest at high altitude. The main findings were as follows: (i) in lowlanders, normobaric but not hypobaric hypoxia elevated CCA reactivity to the CPT; (ii) no differences in response to the CPT were observed between lowlanders and highlanders; and (iii) although hypobaric hypoxaemia reduced the relationship between CCA diameter and blood pressure compared with normobaric normoxia (P = 0.132), hypobaric hyperoxia improved this relationship (P = 0.012), and no relationship was observed in Andean highlanders (P = 0.261). These data demonstrate that the circulatory responses to a CPT were modified by oxygen in lowlanders, but were unaltered with lifelong hypoxic exposure.
Subject(s)
Altitude Sickness/physiopathology , Arterial Pressure/physiology , Carotid Arteries/physiology , Hypoxia/physiopathology , Adult , Altitude , Altitude Sickness/metabolism , Carotid Arteries/metabolism , Cold Temperature , Female , Hemodynamics/physiology , Humans , Hypoxia/metabolism , Male , Oxygen/metabolismABSTRACT
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.
Subject(s)
Acclimatization , Altitude Sickness/physiopathology , Altitude , Brachial Artery/physiopathology , Polycythemia/physiopathology , Vasodilation , Adult , Altitude Sickness/blood , Altitude Sickness/diagnostic imaging , Biomarkers/blood , Blood Flow Velocity , Blood Viscosity , Brachial Artery/diagnostic imaging , Case-Control Studies , Hand Strength , Hemoglobins/metabolism , Humans , Male , Middle Aged , Muscle Contraction , Peru , Polycythemia/blood , Polycythemia/diagnosis , Regional Blood Flow , Stress, Mechanical , Time Factors , Ultrasonography, Doppler, DuplexABSTRACT
Hypoxia-inducible factor pathway genes are linked to adaptation in both human and nonhuman highland species. EPAS1, a notable target of hypoxia adaptation, is associated with relatively lower hemoglobin concentration in Tibetans. We provide evidence for an association between an adaptive EPAS1 variant (rs570553380) and the same phenotype of relatively low hematocrit in Andean highlanders. This Andean-specific missense variant is present at a modest frequency in Andeans and absent in other human populations and vertebrate species except the coelacanth. CRISPR-base-edited human cells with this variant exhibit shifts in hypoxia-regulated gene expression, while metabolomic analyses reveal both genotype and phenotype associations and validation in a lowland population. Although this genocopy of relatively lower hematocrit in Andean highlanders parallels well-replicated findings in Tibetans, it likely involves distinct pathway responses based on a protein-coding versus noncoding variants, respectively. These findings illuminate how unique variants at EPAS1 contribute to the same phenotype in Tibetans and a subset of Andean highlanders despite distinct evolutionary trajectories.
Subject(s)
Adaptation, Physiological , Altitude , Hematocrit , South American People , Humans , Adaptation, Physiological/genetics , Adaptation, Physiological/physiology , East Asian People , Hypoxia/genetics , Hypoxia/metabolism , Mutation, Missense/genetics , South American People/geneticsABSTRACT
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.
Subject(s)
Brachial Artery , Oxygen , Humans , Brachial Artery/physiology , Hemodynamics , Upper Extremity , Oxygen Inhalation Therapy , Vasodilation/physiology , Endothelium, Vascular/physiology , Blood Flow Velocity/physiologyABSTRACT
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 (QÌt) and O2 diffusion limitation in lungs and muscle. We hypothesized that EE results in reduced peak VÌo2 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, VÌo2, QÌt, 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, QÌt, and blood-muscle mitochondria diffusion). Participants with EE had similar peak VÌo2, systemic O2 delivery, and O2 extraction as non-EE controls, however, with lower QÌt and higher arterial [O2]. After IVHD, peak VÌo2 was preserved (but not enhanced), with lower O2 delivery (despite higher QÌt) 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 QÌt. In conclusion, EE does not result in lower peak VÌo2 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 VÌo2 at 4,340 m, with higher arterial [O2] in EE and lower cardiac output (QÌt), thus maintaining similar O2 delivery. Peak VÌo2 in participants with EE was unaffected by isovolumic hemodilution (hematocrit reduced from 67% to 53%), with lower O2 delivery balanced by slightly increased QÌt and greater O2 extraction. Differences in lung and muscle diffusing capacity, and not hematocrit variation, accounted for essentially all interindividual variance in peak VÌo2.
Subject(s)
Altitude Sickness , Polycythemia , Humans , Male , Altitude , Exercise Tolerance , Hemodilution , Oxygen/metabolism , Oxygen ConsumptionABSTRACT
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.
Subject(s)
Carotid Artery, Internal , Hypercapnia , Adult , Female , Humans , Adrenergic Agents , Blood Flow Velocity/physiology , Carbon Dioxide , Carotid Artery, Internal/physiology , Cerebrovascular Circulation/physiology , Prazosin/pharmacology , Receptors, Adrenergic, alpha-1 , Male , Young AdultABSTRACT
STUDY OBJECTIVES: Chronic mountain sickness (CMS) is commonly observed among Andean and other highland populations. Sleep-disordered breathing (SDB) is highly prevalent at high altitude, and SDB and nocturnal hypoxemia have been observed in CMS. Phlebotomy is commonly performed to treat CMS, but it is unknown whether reducing hematocrit improves SDB. We hypothesized that isovolemic hemodilution (IVHD) in CMS would reduce SBD severity and improve sleep efficiency. METHODS: Six participants with CMS and 8 without CMS, all residents of Cerro de Pasco, Peru (altitude 4340 m), completed baseline nocturnal sleep studies. CMS participants then underwent IVHD, and nocturnal sleep studies were repeated 24-48 hours after IVHD. We analyzed sleep apnea severity, nocturnal oxygenation, and sleep quality in those with CMS relative to those without CMS, and the effects of IVHD in CMS participants. RESULTS: Participants with CMS did not have altered sleep architecture, sleep apnea severity, or nocturnal oxygenation relative to non-CMS participants. However, IVHD in CMS increased apnea-hypopnea index (40.9 ± 6.9 events/h to 61.5 ± 7.7 events/h, P = .009). IVHD increased oxyhemoglobin desaturation index (P = .008) and the percentage of sleep time spent with oxyhemoglobin saturation at or below 80% (P = .012). There was no effect of IVHD on sleep efficiency, arousal index, or sleep staging. CONCLUSIONS: In this cohort, CMS was not associated with worsened SDB or changes in sleep architecture. IVHD, a putative therapeutic option for participants with CMS, appears to worsen nocturnal oxygenation and SDB within 48 hours post-IVHD. CITATION: Sanchez-Azofra A, Villafuerte FC, DeYoung PN, et al. Isovolemic hemodilution in chronic mountain sickness acutely worsens nocturnal oxygenation and sleep apnea severity. J Clin Sleep Med. 2022;18(10):2423-2432.
Subject(s)
Altitude Sickness , Sleep Apnea Syndromes , Altitude , Altitude Sickness/complications , Altitude Sickness/therapy , Chronic Disease , Hemodilution , Humans , Oxyhemoglobins , Sleep Apnea Syndromes/complications , Sleep Apnea Syndromes/therapyABSTRACT
High-altitude exposure results in a hyperventilatory-induced respiratory alkalosis followed by renal compensation (bicarbonaturia) to return arterial blood pH (pHa) toward sea-level values. However, acid-base balance has not been comprehensively examined in both lowlanders and indigenous populations-where the latter are thought to be fully adapted to high altitude. The purpose of this investigation was to compare acid-base balance between acclimatizing lowlanders and Andean and Sherpa highlanders at various altitudes (â¼3,800, â¼4,300, and â¼5,000 m). We compiled data collected across five independent high-altitude expeditions and report the following novel findings: 1) at 3,800 m, Andeans (n = 7) had elevated pHa compared with Sherpas (n = 12; P < 0.01), but not to lowlanders (n = 16; 9 days acclimatized; P = 0.09); 2) at 4,300 m, lowlanders (n = 16; 21 days acclimatized) had elevated pHa compared with Andeans (n = 32) and Sherpas (n = 11; both P < 0.01), and Andeans had elevated pHa compared with Sherpas (P = 0.01); and 3) at 5,000 m, lowlanders (n = 16; 14 days acclimatized) had higher pHa compared with both Andeans (n = 66) and Sherpas (n = 18; P < 0.01, and P = 0.03, respectively), and Andean and Sherpa highlanders had similar blood pHa (P = 0.65). These novel data characterize acid-base balance acclimatization and adaptation to various altitudes in lowlanders and indigenous highlanders.NEW & NOTEWORTHY Lowlander, Andean, and Sherpa arterial blood data were combined across five independent high-altitude expeditions in the United States, Nepal, and Peru to assess acid-base status at â¼3,800, â¼4,300, and â¼5,000 m. The main finding was that Andean and Sherpa highlander populations have more acidic arterial blood, due to elevated arterial carbon dioxide and similar arterial bicarbonate compared with acclimatizing lowlanders at altitudes ≥4,300 m.
Subject(s)
Altitude Sickness , Expeditions , Acclimatization , Acid-Base Equilibrium , Altitude , HumansABSTRACT
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.