Hemorheological, cardiorespiratory, and cerebrovascular effects of pentoxifylline following acclimatization to 3,800 m.

Pentoxifylline is a nonselective phosphodiesterase inhibitor used for the treatment of peripheral artery disease. Pentoxifylline acts through cyclic adenosine monophosphate, thereby enhancing red blood cell deformability, causing vasodilation and decreasing inflammation, and potentially stimulating ventilation. We conducted a double-blind, placebo-controlled, crossover, counter-balanced study to test the hypothesis that pentoxifylline could lower blood viscosity, enhance cerebral blood flow, and decrease pulmonary artery pressure in lowlanders following 11-14 days at 3,800 m. Participants (6 males/10 females; age, 27 ± 4 yr old) received either a placebo or 400 mg of pentoxifylline orally the night before and again 2 h before testing. We assessed arterial blood gases, venous hemorheology (blood viscosity, red blood cell deformability, and aggregation), and inflammation (TNF-α) in room air (end-tidal oxygen partial pressure, ∼52 mmHg). Global cerebral blood flow (gCBF), ventilation, and pulmonary artery systolic pressure (PASP) were measured in room air and again after 8-10 min of isocapnic hypoxia (end-tidal oxygen partial pressure, 40 mmHg). Pentoxifylline did not alter arterial blood gases, TNF-α, or hemorheology compared with placebo. Pentoxifylline did not affect gCBF or ventilation during room air or isocapnic hypoxia compared with placebo. However, in females, PASP was reduced with pentoxifylline during room air (placebo, 19 ± 3; pentoxifylline, 16 ± 3 mmHg; P = 0.021) and isocapnic hypoxia (placebo, 22 ± 5; pentoxifylline, 20 ± 4 mmHg; P = 0.029), but not in males. Acute pentoxifylline administration in lowlanders at 3,800 m had no impact on arterial blood gases, hemorheology, inflammation, gCBF, or ventilation. Unexpectedly, however, pentoxifylline reduced PASP in female participants, indicating a potential effect of sex on the pulmonary vascular responses to pentoxifylline.NEW & NOTEWORTHY We conducted a double-blind, placebo-controlled study on the rheological, cardiorespiratory and cerebrovascular effects of acute pentoxifylline in healthy lowlanders after 11-14 days at 3,800 m. Although red blood cell deformability was reduced and blood viscosity increased compared with low altitude, acute pentoxifylline administration had no impact on arterial blood gases, hemorheology, inflammation, cerebral blood flow, or ventilation. Pentoxifylline decreased pulmonary artery systolic pressure in female, but not male, participants.

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.

Duration at high altitude influences the onset of arrhythmogenesis during apnea.

PURPOSE: Autonomic control of the heart is balanced by sympathetic and parasympathetic inputs. Excitation of both sympathetic and parasympathetic systems occurs concurrently during certain perturbations such as hypoxia, which stimulate carotid chemoreflex to drive ventilation. It is well established that the chemoreflex becomes sensitized throughout hypoxic exposure; however, whether progressive sensitization alters cardiac autonomic activity remains unknown. We sought to determine the duration of hypoxic exposure at high altitude necessary to unmask cardiac arrhythmias during instances of voluntary apnea. METHODS: Measurements of steady-state chemoreflex drive (SS-CD), continuous electrocardiogram (ECG) and SpO2 (pulse oximetry) were collected in 22 participants on 1 day at low altitude (1045 m) and over eight consecutive days at high-altitude (3800 m). SS-CD was quantified as ventilation (L/min) over stimulus index (PETCO2/SpO2). RESULTS: Bradycardia during apnea was greater at high altitude compared to low altitude for all days (p < 0.001). Cardiac arrhythmias occurred during apnea each day but became most prevalent (> 50%) following Day 5 at high altitude. Changes in saturation during apnea and apnea duration did not affect the magnitude of bradycardia during apnea (ANCOVA; saturation, p = 0.15 and apnea duration, p = 0.988). Interestingly, the magnitude of bradycardia was correlated with the incidence of arrhythmia per day (r = 0.8; p = 0.004). CONCLUSION: Our findings suggest that persistent hypoxia gradually increases vagal tone with time, indicated by augmented bradycardia during apnea and progressively increased the incidence of arrhythmia at high altitude.

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: 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.

Sympathetic neurovascular transduction following acute hypoxia.

PURPOSE: Following an acute exposure to hypoxia, sympathetic nerve activity remains elevated. However, this elevated sympathetic nerve activity does not elicit a parallel increase in vascular resistance suggesting a blunted sympathetic signaling [i.e. blunted sympathetic neurovascular transduction (sNVT)]. Therefore, we sought to quantify spontaneous sympathetic bursts and related changes in total peripheral resistance following hypoxic exposure. We hypothesized that following hypoxia sNVT would be blunted. METHODS: Nine healthy participants (n = 6 men; mean age 25 ± 2 years) were recruited. We collected data on muscle sympathetic nerve activity (MSNA) using microneurography and beat-by-beat total peripheral resistance (TPR) via finger photoplethysmography at baseline, during acute hypoxia and during two periods of recovery (recovery period 1, 0-10 min post hypoxia; recovery period 2, 10-20 min post hypoxia). MSNA burst sequences (i.e. singlets, doublets, triplets and quads+) were identified and coupled to changes in TPR over 15 cardiac cycles as an index of sNVT for burst sequences. A sNVT slope for each participant was calculated from the slope of the relationship between TPR plotted against normalized burst amplitude. RESULTS: The sNVT slope was blunted during hypoxia [Δ 0.0044 ± 0.0014 (mmHg/L/min)/(a.u.)], but unchanged following termination of hypoxia [recovery 1, Δ 0.031 ± 0.0019 (mmHg/L/min)/(a.u.); recovery 2, Δ 0.0038 ± 0.0014 (mmHg/L/min)/(a.u.) compared to baseline (Δ 0.038 ± 0.0015 (L/min/mmHg)/(a.u.)] (main effect of group p = 0.012). CONCLUSIONS: Contrary to our hypothesis, we have demonstrated that systemic sNVT is unchanged following hypoxia in young healthy adults.

Blunted sympathetic neurovascular transduction is associated to the severity of obstructive sleep apnea.

PURPOSE: Obstructive sleep apnea (OSA) is a common disorder (~ 4%) that augments sympathetic nerve activity (SNA) and elevates blood pressure. The relationship between sympathetic vasomotor outflow and vascular responsiveness, termed sympathetic neurovascular transduction (sNVT), has been sparsely characterized in patients with OSA. Therefore, we sought to quantify spontaneous sympathetic bursts and related changes in diastolic pressure. METHODS: Twelve participants with variable severities of OSA were recruited. We collected muscle sympathetic nerve activity (MSNA) (microneurography) and beat-by-beat diastolic pressure (finger photoplethysmography) during normoxia (FiO2 = 0.21) and hyperoxia (FiO2 = 1.0) to decrease MSNA burst frequency. MSNA burst sequences (i.e. singlets, doublets, triplets and quadruplets) were identified and coupled to changes in diastolic pressure over 15 cardiac cycles as an index of sNVT. sNVT slope for each individual was calculated from the slope of the relationship between peak responses in outcome plotted against normalized burst amplitude. RESULTS: sNVT slope was unchanged during hyperoxia compared to normoxia (normoxia 0.0024 ± 0.0011 Δ mmHg total activity [a.u.]-1 vs. hyperoxia 0.0029 ± 0.00098 Δ mmHg total activity [a.u.]-1; p = 0.14). sNVT slope was inversely associated with burst frequency during hyperoxia (r = -0.58; p = 0.04), but not normoxia (r = -0.11; p = 0.71). sNVT slope was inversely associated with the apnea-hypopnea index (AHI) (r = -0.62; p = 0.030), but not after age was considered. CONCLUSIONS: We have demonstrated that the prevailing MSNA frequency is unmatched to the level of sNVT, and this can be altered by acute hyperoxia.

Global REACH 2018: renal oxygen delivery is maintained during early acclimatization to 4,330 m.

Early acclimatization to high altitude is characterized by various respiratory, hematological, and cardiovascular adaptations that serve to restore oxygen delivery to tissue. However, less is understood about renal function and the role of renal oxygen delivery (RDO2) during high altitude acclimatization. We hypothesized that 1) RDO2 would be reduced after 12 h of high altitude exposure (high altitude day 1) but restored to sea level values after 1 wk (high altitude day 7) and 2) RDO2 would be associated with renal reactivity, an index of acid-base compensation at high altitude. Twenty-four healthy lowlander participants were tested at sea level (344 m, Kelowna, BC, Canada) and on day 1 and day 7 at high altitude (4,330 m, Cerro de Pasco, Peru). Cardiac output, renal blood flow, and arterial and venous blood sampling for renin-angiotensin-aldosterone system hormones and NH2-terminal pro-B-type natriuretic peptides were collected at each time point. Renal reactivity was calculated as follows: (Δarterial bicarbonate)/(Δarterial Pco2) between sea level and high altitude day 1 and sea level and high altitude day 7. The main findings were that 1) RDO2 was initially decreased at high altitude compared with sea level (ΔRDO2: -22 ± 17%, P < 0.001) but was restored to sea level values on high altitude day 7 (ΔRDO2: -6 ± 14%, P = 0.36). The observed improvements in RDO2 resulted from both changes in renal blood flow (Δ from high altitude day 1: +12 ± 11%, P = 0.008) and arterial oxygen content (Δ from high altitude day 1: +44.8 ± 17.7%, P = 0.006) and 2) renal reactivity was positively correlated with RDO2 on high altitude day 7 (r = 0.70, P < 0.001) but not high altitude day 1 (r = 0.26, P = 0.29). These findings characterize the temporal responses of renal function during early high altitude acclimatization and the influence of RDO2 in the regulation of acid-base balance.

Highs and lows of sympathetic neurocardiovascular transduction: influence of altitude acclimatization and adaptation.

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.

Global REACH 2018: The carotid artery diameter response to the cold pressor test is governed by arterial blood pressure during normoxic but not hypoxic conditions in healthy lowlanders and Andean highlanders.

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.

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.

Global REACH 2018: Characterizing Acid-Base Balance Over 21 Days at 4,300 m in Lowlanders.

Steele, Andrew R., Philip N. Ainslie, Rachel Stone, Kaitlyn Tymko, Courtney Tymko, Connor A. Howe, David MacLeod, James D. Anholm, Christopher Gasho, and Michael M. Tymko. Global REACH 2018: characterizing acid-base balance over 21 days at 4,300 m in lowlanders. High Alt Med Biol. 23:185-191, 2022. Introduction: High altitude exposure results in hyperventilatory-induced respiratory alkalosis, followed by metabolic compensation to return arterial blood pH (pHa) toward sea level values. However, previous work has limited sample sizes, short-term exposure, and pharmacological confounders (e.g., acetazolamide). The purpose of this investigation was to characterize acid-base balance after rapid ascent to high altitude (i.e., 4,300 m) in lowlanders. We hypothesized that despite rapid bicarbonate ([HCO3-]) excretion during early acclimatization, partial respiratory alkalosis would still be apparent as reflected in elevations in pHa compared with sea level after 21 days of acclimatization to 4,300 m. Methods: In 16 (3 female) healthy volunteers not taking any medications, radial artery blood samples were collected and analyzed at sea level (150 m; Lima, Peru), and on days 1, 3, 7, 14, and 21 after rapid automobile (∼8 hours) ascent to high altitude (4,300 m; Cerro de Pasco, Peru). Results and Discussion: Although reductions in [HCO3-] occurred by day 3 (p < 0.01), they remained stable thereafter and were insufficient to fully normalize pHa back to sea level values over the subsequent 21 days (p < 0.01). These data indicate that only partial compensation for respiratory alkalosis persists throughout 21 days at 4,300 m.

The sympathetic muscle metaboreflex is not different in the third trimester in normotensive pregnant women.

Isometric handgrip (IHG) is used to assess sympathetic nervous system responses to exercise and may be useful at predicting hypertension in both pregnant and nonpregnant populations. We previously observed altered sympathetic nervous system control of blood pressure in late pregnancy. Therefore, we measured muscle sympathetic nerve activity (MSNA) and blood pressure during muscle metaboreflex activation (IHG) in normotensive pregnant women in the third trimester compared with in healthy nonpregnant women. Further, 19 pregnant (32 ± 3 wk gestation) and 14 nonpregnant women were matched for age, non/prepregnant body mass index (BMI), and parity. MSNA (microneurography), heart rate (ECG), and arterial blood pressure (Finometer) were continuously recorded during 10 min of rest, and then during 2 min of IHG at 30% of maximal voluntary contraction, and 2 min of postexercise circulatory occlusion (PECO). Baseline sympathetic nerve activity (SNA) was elevated in pregnant (41 ± 11 bursts/min) compared with nonpregnant women (27 ± 9 bursts/min; P = 0.005); however, the sympathetic baroreflex gain and neurovascular transduction were not different between groups (P = 0.62 and P = 0.32, respectively). During IHG and PECO, there were no significant differences in the pressor responses (ΔMAP) between groups, (P = 0.25, main effect of group) nor was the sympathetic response different between groups (interaction effect: P = 0.16, 0.25, and 0.27 for burst frequency, burst incidence, and total SNA, respectively). These data suggest that pregnant women who have maintained sympathetic baroreflex and neurovascular transduction also have similar sympathetic and pressor responses during exercise.NEW & NOTEWORTHY We compared sympathetic nervous system activation by muscle metaboreflex between pregnant women in the third trimester and nonpregnant women. We show that the sympathetic nerve activity and associated pressor responses to isometric handgrip and post-exercise circulatory occlusion are not different between third-trimester pregnant and nonpregnant women. These data suggest that unlike other reflexes (e.g., cold pressor test or head-up tilt), metaboreflex control is maintained in pregnant women.

Assessing static and dynamic sympathetic transduction using microneurography.

The relationship between sympathetic nerve activity and the vasculature has been of great interest due to its potential role in various cardiovascular-related diseases. This relationship, termed "sympathetic transduction," has been quantified using several different laboratory and analytical techniques. The most common method is to assess the association between relative changes in muscle sympathetic nerve activity, measured via microneurography, and physiological outcomes (e.g., blood pressure, total peripheral resistance, blood flow, etc.) in response to a sympathetic stressor (e.g., exercise, cold stress, orthostatic stress). This approach, however, comes with its own caveats. For instance, elevations in blood pressure and heart rate during a sympathetic stressor can have an independent impact on muscle sympathetic nerve activity. Another assessment of sympathetic transduction was developed by Wallin and Nerhed in 1982, where alterations in blood pressure and heart rate were assessed immediately following bursts of muscle sympathetic nerve activity at rest. This approach has since been characterized and further innovated by others, including the breakdown of consecutive burst sequences (e.g., singlet, doublet, triplet, and quadruplet), and burst height (quartile analysis) on specific vascular outcomes (e.g., blood pressure, blood flow, vascular resistance). The purpose of this review is to provide an overview of the literature that has assessed sympathetic transduction using microneurography and various sympathetic stressors (static sympathetic transduction) and using the same or similar approach established by Wallin and Nerhed at rest (dynamic neurovascular transduction). Herein, we discuss the overlapping literature between these two methodologies and highlight the key physiological questions that remain.

Short-term hypoxia does not promote arrhythmia during voluntary apnea.

The presence of bradycardic arrhythmias during volitional apnea at altitude may be caused by chemoreflex activation/sensitization. We investigated whether bradyarrhythmic episodes became prevalent in apnea following short-term hypoxia exposure. Electrocardiograms (ECG; lead II) were collected from 22 low-altitude residents (F = 12; age=25 ± 5 years) at 671 m. Participants were exposed to normobaric hypoxia (SpO2 ~79 ± 3%) over a 5-h period. ECG rhythms were assessed during both free-breathing and maximal volitional end-expiratory and end-inspiratory apnea at baseline during normoxia and hypoxia exposure (20 min [AHX]; 5 h [HX5]). Free-breathing HR became elevated at AHX (78 ± 10 bpm; p < 0.0001) and HX5 (80 ± 12 bpm; p < 0.0001) compared to normoxia (68 ± 10 bpm), whereas apnea caused significant bradycardia at AHX (nadir end-expiratory -17 ± 14 bpm; p < 0.001) and HX5 (nadir end-expiratory -19 ± 15 bpm; p < 0.001), but not during normoxia (nadir end-expiratory -4 ± 13 bpm), with no difference in bradycardia responses between apneas at AHX and HX5. Conduction abnormalities were noted in five participants during normoxia (Premature Ventricular Contraction, Sinus Pause, Junctional Rhythm, Atrial Foci), which remained unchanged during apnea at AHX and HX5 (Premature Ventricular Contraction, Premature Atrial Contraction, Sinus Pause). End-inspiratory apneas were overall longer across conditions (normoxia p < 0.05; AHX p < 0.01; HX5 p < 0.001), with comparable HR responses to end-expiratory and fewer occurrences of arrhythmia. While short-term hypoxia is sufficient to elicit bradycardia during apnea, the occurrence of arrhythmias in response to apnea was not affected. These findings indicate that previously observed bradyarrhythmic events in untrained individuals at altitude only become prevalent following chronic hypoxia specificlly.

Cold air exercise screening for exercise induced bronchoconstriction in cold weather athletes.

Exercise Induced Bronchoconstriction (EIB) prevalence in cold weather athletes is high. Currently, no standardized cold air exercise provocation test exists. Thus we aimed to determine EIB prevalence using a Cold Air Test (CAT; 5 km outdoor running; -15 °C) compared to the most common EIB screen the Eucapnic Voluntary Hyperpnea (EVH) test in cold weather athletes. Sixteen (9 male; 20-35 years old) cold weather athletes completed EVH 72 h before CAT. Spirometry, Fractional Expired Nitric Oxide (FENO), respiratory symptoms were measured and atopy status was determined. Five and 7 participants were EIB + on the EVH and CAT, respectively. Level of agreement was 50% between tests. FEV1 recovery was significantly prolonged and Peak Expiratory Flow was decreased after CAT compared to EVH. Predictive characteristics of EIB + included FENO >12 ppb, FEV1/FVC ratio (<0.75) and BMI < 20. EVH does not always reflect EIB triggered by cold weather exercise. More research is required to understand the best EIB screens for cold weather athletes.

Global REACH: Assessment of Brady-Arrhythmias in Andeans and Lowlanders During Apnea at 4330 m.

Background: Ascent to altitude increases the prevalence of arrhythmogenesis in low-altitude dwelling populations (Lowlanders). High altitude populations (i.e., Nepalese Sherpa) may have arrhythmias resistant adaptations that prevent arrhythmogenesis at altitude, though this has not been documented in other High altitude groups, including those diagnosed with chronic mountain sickness (CMS). We investigated whether healthy (CMS-) and CMS afflicted (CMS +) Andeans exhibit cardiac arrhythmias under acute apneic stress at altitude. Methods and Results: Electrocardiograms (lead II) were collected in CMS- (N = 9), CMS + (N = 8), and Lowlanders (N = 13) following several days at 4330 m (Cerro de Pasco, Peru). ECG rhythm and HR were assessed at both rest and during maximal volitional apnea. Both CMS- and CMS + had similar basal HR (69 ± 8 beats/min vs. 62 ± 11 beats/min), while basal HR was higher in Lowlanders (77 ± 18 beats/min; P < 0.05 versus CMS +). Apnea elicited significant bradycardia (nadir -32 ± 15 beats/min; P < 0.01) and the development of arrhythmias in 8/13 Lowlanders (junctional rhythm, 3° atrio-ventricular block, sinus pause). HR was preserved was prior to volitional breakpoint in both CMS- (nadir -6 ± 1 beat/min) and CMS + (1 ± 12 beats/min), with 2/17 Andeans developing arrhythmias (1 CMS+ and 1 CMS-; both Premature atrial contraction) prior to breakpoint. Conclusion: Andeans showed an absence of arrhythmias and preserved HR response to volitional apnea at altitude, demonstrating that potential cardio-resistant adaptations to arrhythmogenesis exist across permanent HA populations. Acclimatized Lowlanders have further demonstrated an increased prevalence of arrhythmias at altitude.