Mechanisms underpinning sympathoexcitation in hypoxia.

Sympathoexcitation is a hallmark of hypoxic exposure, occurring acutely, as well as persisting in acclimatised lowland populations and with generational exposure in highland native populations of the Andean and Tibetan plateaus. The mechanisms mediating altitude sympathoexcitation are multifactorial, involving alterations in both peripheral autonomic reflexes and central neural pathways, and are dependent on the duration of exposure. Initially, hypoxia-induced sympathoexcitation appears to be an adaptive response, primarily mediated by regulatory reflex mechanisms concerned with preserving systemic and cerebral tissue O2 delivery and maintaining arterial blood pressure. However, as exposure continues, sympathoexcitation is further augmented above that observed with acute exposure, despite acclimatisation processes that restore arterial oxygen content ( C a O 2 ${C_{{\mathrm{a}}{{\mathrm{O}}_{\mathrm{2}}}}}$ ). Under these conditions, sympathoexcitation may become maladaptive, giving rise to reduced vascular reactivity and mildly elevated blood pressure. Importantly, current evidence indicates the peripheral chemoreflex does not play a significant role in the augmentation of sympathoexcitation during altitude acclimatisation, although methodological limitations may underestimate its true contribution. Instead, processes that provide no obvious survival benefit in hypoxia appear to contribute, including elevated pulmonary arterial pressure. Nocturnal periodic breathing is also a potential mechanism contributing to altitude sympathoexcitation, although experimental studies are required. Despite recent advancements within the field, several areas remain unexplored, including the mechanisms responsible for the apparent normalisation of muscle sympathetic nerve activity during intermediate hypoxic exposures, the mechanisms accounting for persistent sympathoexcitation following descent from altitude and consideration of whether there are sex-based differences in sympathetic regulation at altitude.

Right ventricular performance during acute hypoxic exercise.

Acute hypoxia increases pulmonary arterial (PA) pressures, though its effect on right ventricular (RV) function is controversial. The objective of this study was to characterize exertional RV performance during acute hypoxia. Ten healthy participants (34 ± 10 years, 7 males) completed three visits: visits 1 and 2 included non-invasive normoxic (fraction of inspired oxygen ( F i O 2 ${F_{{\mathrm{i}}{{\mathrm{O}}_{\mathrm{2}}}}}$ ) = 0.21) and isobaric hypoxic ( F i O 2 ${F_{{\mathrm{i}}{{\mathrm{O}}_{\mathrm{2}}}}}$  = 0.12) cardiopulmonary exercise testing (CPET) to determine normoxic/hypoxic maximal oxygen uptake ( V ̇ O 2 max ${\dot V_{{{\mathrm{O}}_{\mathrm{2}}}{\mathrm{max}}}}$ ). Visit 3 involved invasive haemodynamic assessments where participants were randomized 1:1 to either Swan-Ganz or conductance catheterization to quantify RV performance via pressure-volume analysis. Arterial oxygen saturation was determined by blood gas analysis from radial arterial catheterization. During visit 3, participants completed invasive submaximal CPET testing at 50% normoxic V ̇ O 2 max ${\dot V_{{{\mathrm{O}}_{\mathrm{2}}}{\mathrm{max}}}}$ and again at 50% hypoxic V ̇ O 2 max ${\dot V_{{{\mathrm{O}}_{\mathrm{2}}}{\mathrm{max}}}}$ ( F i O 2 ${F_{{\mathrm{i}}{{\mathrm{O}}_{\mathrm{2}}}}}$  = 0.12). Median (interquartile range) values for non-invasive V ̇ O 2 max ${\dot V_{{{\mathrm{O}}_{\mathrm{2}}}{\mathrm{max}}}}$ values during normoxic and hypoxic testing were 2.98 (2.43, 3.66) l/min and 1.84 (1.62, 2.25) l/min, respectively (P < 0.0001). Mean PA pressure increased significantly when transitioning from rest to submaximal exercise during normoxic and hypoxic conditions (P = 0.0014). Metrics of RV contractility including preload recruitable stroke work, dP/dtmax , and end-systolic pressure increased significantly during the transition from rest to exercise under normoxic and hypoxic conditions. Ventricular-arterial coupling was maintained during normoxic exercise at 50% V ̇ O 2 max ${\dot V_{{{\mathrm{O}}_{\mathrm{2}}}{\mathrm{max}}}}$ . During submaximal exercise at 50% of hypoxic V ̇ O 2 max ${\dot V_{{{\mathrm{O}}_{\mathrm{2}}}{\mathrm{max}}}}$ , ventricular-arterial coupling declined but remained within normal limits. In conclusion, resting and exertional RV functions are preserved in response to acute exposure to hypoxia at an F i O 2 ${F_{{\mathrm{i}}{{\mathrm{O}}_{\mathrm{2}}}}}$  = 0.12 and the associated increase in PA pressures. KEY POINTS: The healthy right ventricle augments contractility, lusitropy and energetics during periods of increased metabolic demand (e.g. exercise) in acute hypoxic conditions. During submaximal exercise, ventricular-arterial coupling decreases but remains within normal limits, ensuring that cardiac output and systemic perfusion are maintained. These data describe right ventricular physiological responses during submaximal exercise under conditions of acute hypoxia, such as occurs during exposure to high altitude and/or acute hypoxic respiratory failure.

The interactive effects of posture and biological sex on the control of muscle sympathetic nerve activity during rhythmic handgrip exercise.

Body posture and biological sex exhibit independent effects on the sympathetic neural responses to dynamic exercise. However, the neural mechanisms (e.g., baroreflex) by which posture impacts sympathetic outflow during rhythmic muscular contractions and whether biological sex affects posture-mediated changes in efferent sympathetic nerve traffic during exercise remains unknown. Thus, we tested the hypotheses that increases in muscle sympathetic nerve activity (MSNA) would be greater during upright compared to supine rhythmic handgrip (RHG) exercise, and that females would demonstrate smaller increases in MSNA during upright RHG exercise than males. Twenty young (30 [6] years; mean [SD]) individuals (9 males, 11 females) underwent 6-minutes of supine and upright (head-up tilt 45°) RHG exercise at 40% maximal voluntary contraction with continuous measurements of MSNA (microneurography), blood pressure (photoplethysmography) and heart rate (electrocardiogram). In the pooled group, absolute MSNA burst frequency (P<0.001), amplitude (P=0.009), and total MSNA (P<0.001) were higher during upright compared to supine RHG exercise. However, body posture did not impact the peak change in MSNA during RHG exercise (range: P=0.063-0.495). Spontaneous sympathetic baroreflex gain decreased from rest to RHG exercise (P=0.006) and was not impacted by posture (P=0.347). During upright RHG exercise, males demonstrated larger increases in MSNA burst amplitude (P=0.002) and total MSNA (P=0.001) compared to females, that coincided with greater reductions in sympathetic baroreflex gain (P=0.004). Collectively, these data indicate that acute attenuation of baroreflex-mediated sympathoinhibition permits increases in MSNA during RHG exercise, and that males exhibit a greater reserve for efferent sympathetic neural recruitment during orthostasis than females.

Adrenergic control of skeletal muscle blood flow during chronic hypoxia in healthy males.

Sympathetic transduction is reduced following chronic high-altitude (HA) exposure; however, vascular α-adrenergic signaling, the primary mechanism mediating sympathetic vasoconstriction at sea level (SL), has not been examined at HA. In nine male lowlanders, we measured forearm blood flow (Doppler ultrasound) and calculated changes in vascular conductance (ΔFVC) during 1) incremental intra-arterial infusion of phenylephrine to assess α1-adrenergic receptor responsiveness and 2) combined intra-arterial infusion of ß-adrenergic and α-adrenergic antagonists propranolol and phentolamine (α-ß-blockade) to assess adrenergic vascular restraint at rest and during exercise-induced sympathoexcitation (cycling; 60% peak power). Experiments were performed near SL (344 m) and after 3 wk at HA (4,383 m). HA abolished the vasoconstrictor response to low-dose phenylephrine (ΔFVC: SL: -34 ± 15%, vs. HA; +3 ± 18%; P < 0.0001) and markedly attenuated the response to medium (ΔFVC: SL: -45 ± 18% vs. HA: -28 ± 11%; P = 0.009) and high (ΔFVC: SL: -47 ± 20%, vs. HA: -35 ± 20%; P = 0.041) doses. Blockade of ß-adrenergic receptors alone had no effect on resting FVC (P = 0.500) and combined α-ß-blockade induced a similar vasodilatory response at SL and HA (P = 0.580). Forearm vasoconstriction during cycling was not different at SL and HA (P = 0.999). Interestingly, cycling-induced forearm vasoconstriction was attenuated by α-ß-blockade at SL (ΔFVC: Control: -27 ± 128 vs. α-ß-blockade: +19 ± 23%; P = 0.0004), but unaffected at HA (ΔFVC: Control: -20 ± 22 vs. α-ß-blockade: -23 ± 11%; P = 0.999). Our results indicate that in healthy males, altitude acclimatization attenuates α1-adrenergic receptor responsiveness; however, resting α-adrenergic restraint remains intact, due to concurrent resting sympathoexcitation. Furthermore, forearm vasoconstrictor responses to cycling are preserved, although the contribution of adrenergic receptors is diminished, indicating a reliance on alternative vasoconstrictor mechanisms.

Exertional Cardiac and Pulmonary Vascular Hemodynamics in Patients With Heart Failure With Reduced Ejection Fraction.

BACKGROUND: Exertional dyspnea is a cardinal manifestation of heart failure with reduced ejection fraction (HFrEF), but quantitative data regarding exertional hemodynamics are lacking. OBJECTIVES: We sought to characterize exertional cardiopulmonary hemodynamics in patients with HFrEF. METHODS: We studied 35 patients with HFrEF (59 ± 12 years old, 30 males) who completed invasive cardiopulmonary exercise testing. Data were collected at rest, at submaximal exercise and at peak effort on upright cycle ergometry. Cardiovascular and pulmonary vascular hemodynamics were recorded. Fick cardiac output (Qc) was determined. Hemodynamic predictors of peak oxygen uptake (VO2) were identified. RESULTS: Left ventricular ejection fraction and cardiac index were 23% ± 8% and 2.9 ± 1.1 L/min/m2, respectively. Peak VO2 was 11.8 ± 3.3 mL/kg/min, and the ventilatory efficiency slope was 53 ± 13. Right atrial pressure increased from rest to peak exercise (4 ± 5 vs 7 ± 6 mmHg,). Mean pulmonary arterial pressure increased from rest to peak exercise (27 ± 13 vs 38 ± 14 mmHg). Pulmonary artery pulsatility index increased from rest to peak exercise, while pulmonary arterial capacitance and pulmonary vascular resistance declined. CONCLUSIONS: Patients with HFrEF suffer from marked increases in filling pressures during exercise. These findings provide new insight into cardiopulmonary abnormalities contributing to impairments in exercise capacity in this population. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT03078972.

Control of blood pressure in the cold: differentiation of skin and skeletal muscle vascular resistance.

NEW FINDINGS: What is the central question of this study? Why does blood pressure increases during cold air exposure? Specifically, what is the contribution of skin and skeletal muscle vascular resistance during whole body versus isolated face cooling? What is the main finding and its importance? Whole-body cooling caused an increase in blood pressure through an increase in skeletal muscle and cutaneous vascular resistance. However, isolated mild face cooling caused an increase in blood pressure predominately via an increase in cutaneous vasoconstriction. ABSTRACT: The primary aim of this investigation was to determine the individual contribution of the cutaneous and skeletal muscle circulations to the cold-induced pressor response. To address this, we examined local vascular resistances in the cutaneous and skeletal muscle of the arm and leg. Thirty-four healthy individuals underwent three different protocols, whereby cold air to clamp skin temperature (27°C) was passed over (1) the whole-body, (2) the whole-body, but with the forearm pre-cooled to clamp cutaneous vascular resistance, and (3) the face. Cold exposure applied to the whole body or isolated to the face increased mean arterial pressure (all, P < 0.001) and total peripheral resistance (all, P < 0.047) compared to thermal neutral baseline. Whole-body cooling increased femoral (P < 0.005) and brachial artery resistance (P < 0.003) compared to thermoneutral baseline. Moreover, when the forearm was pre-cooled to remove the contribution of cutaneous resistance (P = 0.991), there was a further increase in lower arm vasoconstriction (P = 0.036) when whole-body cooling was superimposed. Face cooling also caused a reflex increase in lower arm cutaneous (P = 0.009) and brachial resistance (P = 0.050), yet there was no change in femoral resistance (P = 0.815) despite a reflex increase in leg cutaneous resistance (P = 0.010). Cold stress causes an increase in blood pressure through a change in total peripheral resistance that is largely due to cutaneous vasoconstriction with face cooling, but there is additional vasoconstriction in the skeletal muscle vasculature with whole-body cooling.

The impact of leg position on muscle blood flow and oxygenation during low-intensity rhythmic plantarflexion exercise.

PURPOSE: Resistance training (RT) is an effective countermeasure to combat physical deconditioning whereby localized hypoxia within the limb increases metabolic stress eliciting muscle adaptation. The current study sought to examine the influence of gravity on muscle oxygenation (SmO2) alongside vascular hemodynamic responses. METHODS: In twelve young healthy adults, an ischemic occlusion test and seven minutes of low-intensity rhythmic plantarflexion exercise were used alongside superficial femoral blood flow and calf near-infrared spectroscopy to assess the microvascular vasodilator response, conduit artery flow-mediated dilation, exercise-induced hyperemia, and SmO2 with the leg positioned above or below the heart in a randomized order. RESULTS: The microvascular vasodilator response, assessed by peak blood flow (798 ± 231 mL/min vs. 1348 ± 290 mL/min; p < 0.001) and reperfusion slope 10 s of SmO2 after cuff deflation (0.75 ± 0.45%.s-1 vs.2.40 ± 0.94%.s-1; p < 0.001), was attenuated with the leg above the heart. This caused a blunted dilatation of the superficial femoral artery (3.0 ± 2.4% vs. 5.2 ± 2.1%; p = 0.008). Meanwhile, blood flow area under the curve was comparable (above the heart: 445 ± 147 mL vs. below the heart: 474 ± 118 mL; p = 0.55) in both leg positions. During rhythmic exercise, the increase in femoral blood flow was lower in the leg up position (above the heart: 201 ± 94% vs. below the heart: 292 ± 114%; p = 0.001) and contributed to a lower SmO2 (above the heart: 41 ± 18% vs. below the heart 67 ± 5%; p < 0.001). CONCLUSION: Positioning the leg above the heart results in attenuated peak vascular dilator response and exercise-induced hyperemia that coincided with a lower SmO2 during low-intensity plantarflexion exercise.

Global REACH 2018: increased adrenergic restraint of blood flow preserves coupling of oxygen delivery and demand during exercise at high-altitude.

Chronic exposure to hypoxia (high-altitude, HA; >4000 m) attenuates the vasodilatory response to exercise and is associated with a persistent increase in basal sympathetic nerve activity (SNA). The mechanism(s) responsible for the reduced vasodilatation and exercise hyperaemia at HA remains unknown. We hypothesized that heightened adrenergic signalling restrains skeletal muscle blood flow during handgrip exercise in lowlanders acclimatizing to HA. We tested nine adult males (n = 9) at sea-level (SL; 344 m) and following 21-28 days at HA (∼4300 m). Forearm blood flow (FBF; duplex ultrasonography), mean arterial pressure (MAP; brachial artery catheter), forearm vascular conductance (FVC; FBF/MAP), and arterial and venous blood sampling (O2 delivery ( DO2${D}_{{{\rm{O}}}_{\rm{2}}}$ ) and uptake ( V̇O2${\dot{V}}_{{{\rm{O}}}_{\rm{2}}}$ )) were measured at rest and during graded rhythmic handgrip exercise (5%, 15% and 25% of maximum voluntary isometric contraction; MVC) before and after local α- and ß-adrenergic blockade (intra-arterial phentolamine and propranolol). HA reduced ΔFBF (25% MVC: SL: 138.3 ± 47.6 vs. HA: 113.4 ± 37.1 ml min-1 ; P = 0.022) and Δ V̇O2${\dot{V}}_{{{\rm{O}}}_{\rm{2}}}$ (25% MVC: SL: 20.3 ± 7.5 vs. HA: 14.3 ± 6.2 ml min-1 ; P = 0.014) during exercise. Local adrenoreceptor blockade at HA restored FBF during exercise (25% MVC: SLα-ß blockade : 164.1 ± 71.7 vs. HAα-ß blockade : 185.4 ± 66.6 ml min-1 ; P = 0.947) but resulted in an exaggerated relationship between DO2${D}_{{{\rm{O}}}_{\rm{2}}}$ and V̇O2${\dot{V}}_{{{\rm{O}}}_{\rm{2}}}$ ( DO2${D}_{{{\rm{O}}}_{\rm{2}}}$ / V̇O2${\dot{V}}_{{{\rm{O}}}_{\rm{2}}}$ slope: SL: 1.32; HA: slope: 1.86; P = 0.037). These results indicate that tonic adrenergic signalling restrains exercise hyperaemia in lowlanders acclimatizing to HA. The increase in adrenergic restraint is necessary to match oxygen delivery to demand and prevent over perfusion of contracting muscle at HA. KEY POINTS: In exercising skeletal muscle, local vasodilatory signalling and sympathetic vasoconstriction integrate to match oxygen delivery to demand and maintain arterial blood pressure. Exposure to chronic hypoxia (altitude, >4000 m) causes a persistent increase in sympathetic nervous system activity that is associated with impaired functional capacity and diminished vasodilatation during exercise. In healthy male lowlanders exposed to chronic hypoxia (21-28 days; ∼4300 m), local adrenoreceptor blockade (combined α- and ß-adrenergic blockade) restored skeletal muscle blood flow during handgrip exercise. However, removal of tonic adrenergic restraint at high altitude caused an excessive rise in blood flow and subsequently oxygen delivery for any given metabolic demand. This investigation is the first to identify greater adrenergic restraint of blood flow during acclimatization to high altitude and provides evidence of a functional role for this adaptive response in regulating oxygen delivery and demand.

Global Reach 2018: sympathetic neural and hemodynamic responses to submaximal exercise in Andeans with and without chronic mountain sickness.

Andeans with chronic mountain sickness (CMS) and polycythemia have similar maximal oxygen uptakes to healthy Andeans. Therefore, this study aimed to explore potential adaptations in convective oxygen transport, with a specific focus on sympathetically mediated vasoconstriction of nonactive skeletal muscle. In Andeans with (CMS+, n = 7) and without (CMS-, n = 9) CMS, we measured components of convective oxygen delivery, hemodynamic (arterial blood pressure via intra-arterial catheter), and autonomic responses [muscle sympathetic nerve activity (MSNA)] at rest and during steady-state submaximal cycling exercise [30% and 60% peak power output (PPO) for 5 min each]. Cycling caused similar increases in heart rate, cardiac output, and oxygen delivery at both workloads between both Andean groups. However, at 60% PPO, CMS+ had a blunted reduction in Δtotal peripheral resistance (CMS-, -10.7 ± 3.8 vs. CMS+, -4.9 ± 4.1 mmHg·L-1·min-1; P = 0.012; d = 1.5) that coincided with a greater Δforearm vasoconstriction (CMS-, -0.2 ± 0.6 vs. CMS+, 1.5 ± 1.3 mmHg·mL-1·min-1; P = 0.008; d = 1.7) and a rise in Δdiastolic blood pressure (CMS-, 14.2 ± 7.2 vs. CMS+, 21.6 ± 4.2 mmHg; P = 0.023; d = 1.2) compared with CMS-. Interestingly, although MSNA burst frequency did not change at 30% or 60% of PPO in either group, at 60% Δburst incidence was attenuated in CMS+ (P = 0.028; d = 1.4). These findings indicate that in Andeans with polycythemia, light intensity exercise elicited similar cardiovascular and autonomic responses compared with CMS-. Furthermore, convective oxygen delivery is maintained during moderate-intensity exercise despite higher peripheral resistance. In addition, the elevated peripheral resistance during exercise was not mediated by greater sympathetic neural outflow, thus other neural and/or nonneural factors are perhaps involved.NEW & NOTEWORTHY During submaximal exercise, convective oxygen transport is maintained in Andeans suffering from polycythemia. Light intensity exercise elicited similar cardiovascular and autonomic responses compared with healthy Andeans. However, during moderate-intensity exercise, we observed a blunted reduction in total peripheral resistance, which cannot be ascribed to an exaggerated increase in muscle sympathetic nerve activity, indicating possible contributions from other neural and/or nonneural mechanisms.

Global Reach 2018 Heightened α-Adrenergic Signaling Impairs Endothelial Function During Chronic Exposure to Hypobaric Hypoxia.

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.

Impact of Mechanical Circulatory Support on Exercise Capacity in Patients With Advanced Heart Failure.

Approximately 6 million individuals have heart failure in the United States alone and 15 million in Europe. Left ventricular assist devices (LVAD) improve survival in these patients, but functional capacity may not fully improve. This article examines the hypothesis that patients supported by LVAD experience persistent reductions in functional capacity and explores mechanisms accounting for abnormalities in exercise tolerance.

Power profiling and the power-duration relationship in cycling: a narrative review.

Emerging trends in technological innovations, data analysis and practical applications have facilitated the measurement of cycling power output in the field, leading to improvements in training prescription, performance testing and race analysis. This review aimed to critically reflect on power profiling strategies in association with the power-duration relationship in cycling, to provide an updated view for applied researchers and practitioners. The authors elaborate on measuring power output followed by an outline of the methodological approaches to power profiling. Moreover, the deriving a power-duration relationship section presents existing concepts of power-duration models alongside exercise intensity domains. Combining laboratory and field testing discusses how traditional laboratory and field testing can be combined to inform and individualize the power profiling approach. Deriving the parameters of power-duration modelling suggests how these measures can be obtained from laboratory and field testing, including criteria for ensuring a high ecological validity (e.g. rider specialization, race demands). It is recommended that field testing should always be conducted in accordance with pre-established guidelines from the existing literature (e.g. set number of prediction trials, inter-trial recovery, road gradient and data analysis). It is also recommended to avoid single effort prediction trials, such as functional threshold power. Power-duration parameter estimates can be derived from the 2 parameter linear or non-linear critical power model: P(t) = W'/t + CP (W'-work capacity above CP; t-time). Structured field testing should be included to obtain an accurate fingerprint of a cyclist's power profile.

Global REACH 2018: the adaptive phenotype to life with chronic mountain sickness and polycythaemia.

KEY POINTS: Humans suffering from polycythaemia undergo multiple circulatory adaptations including changes in blood rheology and structural and functional vascular adaptations to maintain normal blood pressure and vascular shear stresses, despite high blood viscosity. During exercise, several circulatory adaptations are observed, especially involving adrenergic and non-adrenergic mechanisms within non-active and active skeletal muscle to maintain exercise capacity, which is not observed in animal models. Despite profound circulatory stress, i.e. polycythaemia, several adaptations can occur to maintain exercise capacity, therefore making early identification of the disease difficult without overt symptomology. Pharmacological treatment of the background heightened sympathetic activity may impair the adaptive sympathetic response needed to match local oxygen delivery to active skeletal muscle oxygen demand and therefore inadvertently impair exercise capacity. ABSTRACT: Excessive haematocrit and blood viscosity can increase blood pressure, cardiac work and reduce aerobic capacity. However, past clinical investigations have demonstrated that certain human high-altitude populations suffering from excessive erythrocytosis, Andeans with chronic mountain sickness, appear to have phenotypically adapted to life with polycythaemia, as their exercise capacity is comparable to healthy Andeans and even with sea-level inhabitants residing at high altitude. By studying this unique population, which has adapted through natural selection, this study aimed to describe how humans can adapt to life with polycythaemia. Experimental studies included Andeans with (n = 19) and without (n = 17) chronic mountain sickness, documenting exercise capacity and characterizing the transport of oxygen through blood rheology, including haemoglobin mass, blood and plasma volume and blood viscosity, cardiac output, blood pressure and changes in total and local vascular resistances through pharmacological dissection of α-adrenergic signalling pathways within non-active and active skeletal muscle. At rest, Andeans with chronic mountain sickness had a substantial plasma volume contraction, which alongside a higher red blood cell volume, caused an increase in blood viscosity yet similar total blood volume. Moreover, both morphological and functional alterations in the periphery normalized vascular shear stress and blood pressure despite high sympathetic nerve activity. During exercise, blood pressure, cardiac work and global oxygen delivery increased similar to healthy Andeans but were sustained by modifications in both non-active and active skeletal muscle vascular function. These findings highlight widespread physiological adaptations that can occur in response to polycythaemia, which allow the maintenance of exercise capacity.

Integrative crosstalk between hypoxia and the cold: Old data and new opportunities.

NEW FINDINGS: What is the topic of this review? The aim was to examine the influence of hypoxia on thermoregulatory and cardiovascular control in the cold. What advances does it highlight? Exposure to hypoxia seems to alter both thermoregulatory and cardiovascular control, but these conclusions are based on limited data, and this review highlights the need for future research in this area. ABSTRACT: Cold stress and hypoxia have been the subject of research for decades; however, humans often encounter these stressors together, such as in the alpine environment. Therefore, this review summarizes previous data with respect to the influence of hypoxia on thermoregulatory and cardiovascular control in the cold and presents new ideas for the future. Altogether, little to no evidence is available on the integrative and adaptive mechanisms by which the human body regulates heat conservation, oxygen delivery and maintenance of blood pressure.

Bilateral regional extracranial blood flow regulation to hypoxia and unilateral duplex ultrasound measurement error.

NEW FINDINGS: What is the central question of this study? Is blood flow regulation to hypoxia different between the internal carotid arteries (ICAs) and vertebral arteries (VAs), and what is the measurement error in unilateral extracranial artery assessments compared to bilateral? What is the main finding and its importance? ICA and VA blood flow regulation to hypoxia is comparable when factoring for vessel type and vessel side. Compared to bilateral assessment, vessels assessed unilaterally had individual measurement errors of up to 37%. Assessing the vessel with the larger resting blood flow, not the left or right vessel, reduces unilateral measurement error. ABSTRACT: Whether blood flow regulation to hypoxia is similar between left and right internal carotid arteries (ICAs) and vertebral arteries (VAs) is unclear. Extracranial blood flow is regularly calculated by doubling a unilateral assessment; however, lateral artery differences may lead to measurement error. This study aimed to determine extracranial blood flow regulation to hypoxia when factoring for vessel type (ICAs or VAs) and vessel side (left or right) effects, and to investigate unilateral assessment measurement error compared to bilateral assessment. In a repeated-measures crossover design, extracranial arteries of 44 participants were assessed bilaterally by duplex ultrasound during 90 min of normoxic and poikilocapnic hypoxic (12.0% fraction of inspired oxygen) conditions. Linear mixed model analyses revealed no Condition × Vessel Type × Vessel Side interaction for blood flow, vessel diameter and flow velocity (all P > 0.05) indicating left and right ICA and VA blood flow regulation to hypoxia was similar. Bilateral hypoxic reactivity was comparable (ICAs, 1.4 (1.0) vs. VAs, 1.7 (1.1) Δ%·Δ SpO2-1 ; P = 0.12). Compared to bilateral assessment, unilateral mean measurement error of the relative blood flow response to hypoxia was up to 5%, but individual errors reached 37% and were greatest in ICAs and VAs with the smaller resting blood flow due to a ratio-scaling problem. In conclusion, left and right ICA and VA regulation to hypoxia is comparable when factoring for vessel type and vessel side. Assessing the ICA and VA vessels with the larger resting blood flow, not the left or right vessel, reduces unilateral measurement error.

The 2018 Global Research Expedition on Altitude Related Chronic Health (Global REACH) to Cerro de Pasco, Peru: an Experimental Overview.

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 ∼45 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 (∼80 m) and then ascended by automobile to Cerro de Pasco, Peru (∼4300 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 ∼780 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.

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.

New insights into resting and exertional right ventricular performance in the healthy heart through real-time pressure-volume analysis.

KEY POINTS: Despite growing interest in right ventricular form and function in diseased states, there is a paucity of data regarding characteristics of right ventricular function - namely contractile and lusitropic reserve, as well as ventricular-arterial coupling, in the healthy heart during rest, as well as submaximal and peak exercise. Pressure-volume analysis of the right ventricle, during invasive cardiopulmonary exercise testing, demonstrates that that the right heart has enormous contractile reserve, with a three- or fourfold increase in all metrics of contractility, as well as myocardial energy production and utilization. The healthy right ventricle also demonstrates marked augmentation in lusitropy, indicating that diastolic filling of the right heart is not passive. Rather, the right ventricle actively contributes to venous return during exercise, along with the muscle pump. Ventricular-arterial coupling is preserved during submaximal and peak exercise in the healthy heart. ABSTRACT: Knowledge of right ventricular (RV) function has lagged behind that of the left ventricle and historically, the RV has even been referred to as a 'passive conduit' of lesser importance than its left-sided counterpart. Pressure-volume (PV) analysis is the gold standard metric of assessing ventricular performance. We recruited nine healthy sedentary individuals free of any cardiopulmonary disease (42 ± 12 years, 78 ± 11 kg), who completed invasive cardiopulmonary exercise testing during upright ergometry, while using conductance catheters inserted into the RV to generate real-time PV loops. Data were obtained at rest, two submaximal levels of exercise below ventilatory threshold, to simulate real-world scenarios/activities of daily living, and maximal effort. Breath-by-breath oxygen uptake was determined by indirect calorimetry. During submaximal and peak exercise, there were significant increases in all metrics of systolic function by three- to fourfold, including cardiac output, preload recruitable stroke work, and maximum rate of pressure change in the ventricle (dP/dtmax ), as well as energy utilization as determined by stroke work and pressure-volume area. Similarly, the RV demonstrated a significant, threefold increase in lusitropic reserve throughout exercise. Ventricular-arterial coupling, defined by the quotient of end-systolic elastance and effective arterial elastance, was preserved throughout all stages of exercise. Maximal pressures increased significantly during exercise, while end-diastolic volumes were essentially unchanged. Overall, these findings demonstrate that the healthy RV is not merely a passive conduit, but actively participates in cardiopulmonary performance during exercise by accessing an enormous amount of contractile and lusitropic reserve, ensuring that VA coupling is preserved throughout all stages of exercise.

Evidence for a physiological role of pulmonary arterial baroreceptors in sympathetic neural activation in healthy humans.

KEY POINTS: In an anaesthetised animal model, independent stimulation of baroreceptors in the pulmonary artery elicits reflex sympathoexcitation. In humans, pulmonary arterial pressure is positively related to basal muscle sympathetic nerve activity (MSNA) under conditions where elevated pulmonary pressure is evident (e.g. high altitude); however, a causal link is not established. Using a novel experimental approach, we demonstrate that reducing pulmonary arterial pressure lowers basal MSNA in healthy humans. This response is distinct from the negative feedback reflex mediated by aortic and carotid sinus baroreceptors when systemic arterial pressure is lowered. Afferent input from pulmonary arterial baroreceptors may contribute to sympathetic neural activation in healthy lowland natives exposed to high altitude. ABSTRACT: In animal models, distension of baroreceptors located in the pulmonary artery induces a reflex increase in sympathetic outflow; however, this has not been examined in humans. Therefore, we investigated whether reductions in pulmonary arterial pressure influenced sympathetic outflow and baroreflex control of muscle sympathetic nerve activity (MSNA). Healthy lowlanders (n = 13; 5 females) were studied 4-8 days following arrival at high altitude (4383 m; Cerro de Pasco, Peru), a setting that increases both pulmonary arterial pressure and sympathetic outflow. MSNA (microneurography) and blood pressure (BP; photoplethysmography) were measured continuously during ambient air breathing (Amb) and a 6 min inhalation of the vasodilator nitric oxide (iNO; 40 ppm in 21% O2 ), to selectively lower pulmonary arterial pressure. A modified Oxford test was performed under both conditions. Pulmonary artery systolic pressure (PASP) was determined using Doppler echocardiography. iNO reduced PASP (24 ± 3 vs. 32 ± 5 mmHg; P < 0.001) compared to Amb, with a similar reduction in MSNA total activity (1369 ± 576 to 994 ± 474 a.u min-1 ; P = 0.01). iNO also reduced the MSNA operating point (burst incidence; 39 ± 16 to 33 ± 17 bursts·100 Hb-1 ; P = 0.01) and diastolic operating pressure (82 ± 8 to 80 ± 8 mmHg; P < 0.001) compared to Amb, without changing heart rate (P = 0.6) or vascular-sympathetic baroreflex gain (P = 0.85). In conclusion, unloading of pulmonary arterial baroreceptors reduced basal sympathetic outflow to the skeletal muscle vasculature and reset vascular-sympathetic baroreflex control of MSNA downward and leftward in healthy humans at high altitude. These data suggest the existence of a lesser-known reflex input involved in sympathetic activation in humans.

Mechanisms of sympathetic restraint in human skeletal muscle during exercise: role of α-adrenergic and nonadrenergic mechanisms.

Sympathetic vasoconstriction is mediated by α-adrenergic receptors under resting conditions. During exercise, increased sympathetic nerve activity (SNA) is directed to inactive and active skeletal muscle; however, it is unclear what mechanism(s) are responsible for vasoconstriction during large muscle mass exercise in humans. The aim of this study was to determine the contribution of α-adrenergic receptors to sympathetic restraint of inactive skeletal muscle and active skeletal muscle during cycle exercise in healthy humans. In ten male participants (18-35 yr), mean arterial pressure (intra-arterial catheter) and forearm vascular resistance (FVR) and conductance (FVC) were assessed during cycle exercise (60% total peak workload) alone and during combined cycle exercise + handgrip exercise (HGE) before and after intra-arterial blockade of α- and ß-adrenoreceptors via phentolamine and propranolol, respectively. Cycle exercise caused vasoconstriction in the inactive forearm that was attenuated ~80% with adrenoreceptor blockade (%ΔFVR, +81.7 ± 84.6 vs. +9.7 ± 30.7%; P = 0.05). When HGE was performed during cycle exercise, the vasodilatory response to HGE was restrained by ~40% (ΔFVC HGE, +139.3 ± 67.0 vs. cycle exercise: +81.9 ± 66.3 ml·min-1·100 mmHg-1; P = 0.03); however, the restraint of active skeletal muscle blood flow was not due to α-adrenergic signaling. These findings highlight that α-adrenergic receptors are the primary, but not the exclusive mechanism by which sympathetic vasoconstriction occurs in inactive and active skeletal muscle during exercise. Metabolic activity or higher sympathetic firing frequencies may alter the contribution of α-adrenergic receptors to sympathetic vasoconstriction. Finally, nonadrenergic vasoconstrictor mechanisms may be important for understanding the regulation of blood flow during exercise.NEW & NOTEWORTHY Sympathetic restraint of vascular conductance to inactive skeletal muscle is critical to maintain blood pressure during moderate- to high-intensity whole body exercise. This investigation shows that cycle exercise-induced restraint of inactive skeletal muscle vascular conductance occurs primarily because of activation of α-adrenergic receptors. Furthermore, exercise-induced vasoconstriction restrains the subsequent vasodilatory response to hand-grip exercise; however, the restraint of active skeletal muscle vasodilation was in part due to nonadrenergic mechanisms. We conclude that α-adrenergic receptors are the primary but not exclusive mechanism by which sympathetic vasoconstriction restrains blood flow in humans during whole body exercise and that metabolic activity modulates the contribution of α-adrenergic receptors.