FLOW-MEDIATED DILATION IS MODIFIED BY EXERCISE TRAINING STATUS DURING CHILDHOOD AND ADOLESCENCE: PRELIMINARY EVIDENCE OF THE YOUTH ATHLETE'S ARTERY.

Chronic exercise training is associated with an 'athlete's artery' phenotype in young adults and an attenuated age-related decline in endothelium-dependent arterial function. Adolescence is associated with an influx of sex-specific hormones that may exert divergent effects on endothelial function, but whether training adaptations interact with biological maturation to produce a 'youth athlete's artery' has not been explored. We investigated the influence of exercise training-status on endothelium-dependent arterial function during childhood and adolescence. Brachial artery flow mediated dilation (FMD) was assessed in n=102 exercise-trained (males: n=25, females: n=29) and untrained (males: n=23, females: n=25) youths, characterised as pre- (males: n=25, females: n=26) or post- (males: n=23, females: n=28) predicted age at peak height velocity (PHV). Baseline brachial artery diameter was larger in post- compared to pre-PHV youths (P≤0.001), males compared to females (P≤0.001), and trained compared to untrained youths (3.26 ± 0.51mm vs 3.11 ± 0.42mm; P=0.041). Brachial FMD was similar in pre- and post-PHV youths (P=0.298), and males and females (P=0.946). However, exercise trained youths demonstrated higher FMD when compared to untrained counterparts (5.3 ± 3.3% vs 3.0 ± 2.6%; P≤0.001). Furthermore, brachial artery diameter (r2=0.142; P=0.007 vs r2=0.004; P=0.652) and FMD (r2=0.138; P=0.008 vs r2=0.003; P=0.706) were positively associated with cardiorespiratory fitness in post-, but not pre-PHV youths, respectively. Collectively, our data indicate that exercise training is associated with brachial artery remodeling and enhanced endothelial function during youth. However, arterial remodeling and endothelium-dependent function are only associated with elevated cardiorespiratory fitness during later stages of adolescence.

Mueller maneuver attenuates left atrial phasic volumes and myocardial strain in healthy younger adults.

The left atrium (LA) is a key, but incompletely understood, modulator of left ventricular (LV) filling. Inspiratory negative intrathoracic pressure swings alter cardiac loading conditions, which may impact LA function. We studied acute effects of static inspiratory efforts on LA chamber function, LA myocardial strain, and LV diastolic filling. We included healthy adults (10 males/9 females, 24 ± 4 yr) and used Mueller maneuvers to reduce intrathoracic pressure to -30 cmH2O for 15 s. Over six repeated trials, we used echocardiography to acquire LA- and LV-focused two-dimensional (2-D) images, and mitral Doppler inflow and annular tissue velocity spectra. Images were analyzed for LA and LV chamber volumes, tissue relaxation velocities, transmitral filling velocities, and speckle tracking-derived LA longitudinal strain. Repeated measures were made at baseline, early Mueller, late Mueller, then early release, and late release. In the late Mueller compared with baseline, LV stroke volume decreased by -10 ± 4 mL (P < 0.05) and then returned to baseline upon release; this occurred with a -11 ± 9 mL (P < 0.05) end-diastolic volume reduction. Early diastolic LV filling was attenuated, reflected by decreased tissue relaxation velocity (-2 ± 2 cm/s, P < 0.05), E-wave filling velocity (-13 ± 14 cm/s, P < 0.05), and LA passive emptying volume (-5 ± 5 mL, P < 0.05), each returning to baseline with release. LA maximal volume decreased (-5 ± 5 mL, P < 0.05) during the Mueller maneuver, but increased relative to baseline following release (+4 ± 5 mL, P < 0.05), whereas LA peak positive longitudinal strain decreased (-6 ± 6%, P < 0.05) and then returned to baseline. Attenuated LA and in turn, LV filling may contribute to acute stroke volume reductions experienced during forceful inspiratory efforts.NEW & NOTEWORTHY In healthy younger adults, the Mueller maneuver transiently reduces left atrial filling and passive emptying during the reservoir and conduit phases, respectively. Corresponding reductions are seen in left atrial reservoir and conduit phase longitudinal myocardial strain and strain rate. However, left atrial pump phase active function and mechanics are largely preserved compared with baseline. Rapid changes in LA chamber volumes and myocardial strain with recurrent forceful inspiratory efforts and relaxation may reflect acute LA stress.

Neurovascular coupling and cerebrovascular hemodynamics are modified by exercise training status at different stages of maturation during youth.

Neurovascular coupling (NVC) is mediated via nitric oxide signaling, which is independently influenced by sex hormones and exercise training. Whether exercise training differentially modifies NVC pre- versus postpuberty, where levels of circulating sex hormones will differ greatly within and between sexes, remains to be determined. Therefore, we investigated the influence of exercise training status on resting intracranial hemodynamics and NVC at different stages of maturation. Posterior and middle cerebral artery velocities (PCAv and MCAv) and pulsatility index (PCAPI and MCAPI) were assessed via transcranial Doppler ultrasound at rest and during visual NVC stimuli. N = 121 exercise-trained (males, n = 32; females, n = 32) and untrained (males, n = 28; females, n = 29) participants were characterized as pre (males, n = 33; females, n = 29)- or post (males, n = 27; females, n = 32)-peak height velocity (PHV). Exercise-trained youth demonstrated higher resting MCAv (P = 0.010). Maturity and training status did not affect the ΔPCAv and ΔMCAv during NVC. However, pre-PHV untrained males (19.4 ± 13.5 vs. 6.8 ± 6.0%; P ≤ 0.001) and females (19.3 ± 10.8 vs. 6.4 ± 7.1%; P ≤ 0.001) had a higher ΔPCAPI during NVC than post-PHV untrained counterparts, whereas the ΔPCAPI was similar in pre- and post-PHV trained youth. Pre-PHV untrained males (19.4 ± 13.5 vs. 7.9 ± 6.0%; P ≤ 0.001) and females (19.3 ± 10.8 vs. 11.1 ± 7.3%; P = 0.016) also had a larger ΔPCAPI than their pre-PHV trained counterparts during NVC, but the ΔPCAPI was similar in trained and untrained post-PHV youth. Collectively, our data indicate that exercise training elevates regional cerebral blood velocities during youth, but training-mediated adaptations in NVC are only attainable during early stages of adolescence. Therefore, childhood provides a unique opportunity for exercise-mediated adaptations in NVC.NEW & NOTEWORTHY We report that the change in cerebral blood velocity during a neurovascular coupling task (NVC) is similar in pre- and postpubertal youth, regardless of exercise-training status. However, prepubertal untrained youth demonstrated a greater increase in cerebral blood pulsatility during the NVC task when compared with their trained counterparts. Our findings highlight that childhood represents a unique opportunity for exercise-mediated adaptations in cerebrovascular hemodynamics during NVC, which may confer long-term benefits in cerebrovascular function.

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.

Cerebral blood flow and cerebrovascular reactivity are modified by maturational stage and exercise training status during youth.

NEW FINDINGS: What is the central question of this study? Gonadal hormones modulate cerebrovascular function while insulin-like growth factor 1 (IGF-1) facilitates exercise-mediated cerebral angiogenesis; puberty is a critical period of neurodevelopment alongside elevated gonadal hormone and IGF-1 activity: but whether exercise training across puberty enhances cerebrovascular function is unkown. What is the main finding and its importance? Cerebral blood flow is elevated in endurance trained adolescent males when compared to untrained counterparts. However, cerebrovascular reactivity to hypercapnia is faster in trained vs. untrained children, but not adolescents. Exercise-induced improvements in cerebrovascular function are attainable as early as the first decade of life. ABSTRACT: Global cerebral blood flow (gCBF) and cerebrovascular reactivity to hypercapnia ( CV R C O 2 ${\mathrm{CV}}{{\mathrm{R}}_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ ) are modulated by gonadal hormone activity, while insulin-like growth factor 1 facilitates exercise-mediated cerebral angiogenesis in adults. Whether critical periods of heightened hormonal and neural development during puberty represent an opportunity to further enhance gCBF and CV R C O 2 ${\mathrm{CV}}{{\mathrm{R}}_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ is currently unknown. Therefore, we used duplex ultrasound to assess gCBF and CV R C O 2 ${\mathrm{CV}}{{\mathrm{R}}_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ in n = 128 adolescents characterised as endurance-exercise trained (males: n = 30, females: n = 36) or untrained (males: n = 29, females: n = 33). Participants were further categorised as pre- (males: n = 35, females: n = 33) or post- (males: n = 24, females: n = 36) peak height velocity (PHV) to determine pubertal or 'maturity' status. Three-factor ANOVA was used to identify main and interaction effects of maturity status, biological sex and training status on gCBF and CV R C O 2 ${\mathrm{CV}}{{\mathrm{R}}_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ . Data are reported as group means (SD). Pre-PHV youth demonstrated elevated gCBF and slower CV R C O 2 ${\mathrm{CV}}{{\mathrm{R}}_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ mean response times than post-PHV counterparts (both: P ≤ 0.001). gCBF was only elevated in post-PHV trained males when compared to untrained counterparts (634 (43) vs. 578 (46) ml min-1 ; P = 0.007). However, CV R C O 2 ${\mathrm{CV}}{{\mathrm{R}}_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ mean response time was faster in pre- (72 (20) vs. 95 (29) s; P ≤ 0.001), but not post-PHV (P = 0.721) trained youth when compared to untrained counterparts. Cardiorespiratory fitness was associated with gCBF in post-PHV youth (r2  = 0.19; P ≤ 0.001) and CV R C O 2 ${\mathrm{CV}}{{\mathrm{R}}_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ mean response time in pre-PHV youth (r2  = 0.13; P = 0.014). Higher cardiorespiratory fitness during adolescence can elevate gCBF while exercise training during childhood primes the development of cerebrovascular function, highlighting the importance of exercise training during the early stages of life in shaping the cerebrovascular phenotype.

The influence of maturation on exercise-induced cardiac remodelling and haematological adaptation.

Cardiovascular and haematological adaptations to endurance training facilitate greater maximal oxygen consumption ( V̇O2max${\dot{V}_{{{\rm{O}}_{\rm{2}}}{\rm{max}}}}$ ), and such adaptations may be augmented following puberty. Therefore, we compared left ventricular (LV) morphology (echocardiography), blood volume, haemoglobin (Hb) mass (CO rebreathing) and V̇O2max${\dot{V}_{{{\rm{O}}_{\rm{2}}}{\rm{max}}}}$ in endurance-trained and untrained boys (n = 42, age = 9.0-17.1 years, V̇O2max${\dot{V}_{{{\rm{O}}_{\rm{2}}}{\rm{max}}}}$  = 61.6 ± 7.2 ml/kg/min, and n = 31, age = 8.0-17.7 years, V̇O2max${\dot{V}_{{{\rm{O}}_{\rm{2}}}{\rm{max}}}}$  = 46.5 ± 6.1 ml/kg/min, respectively) and girls (n = 45, age = 8.2-17.0 years, V̇O2max${\dot{V}_{{{\rm{O}}_{\rm{2}}}{\rm{max}}}}$  = 51.4 ± 5.7 ml/kg/min, and n = 36, age = 8.0-17.6 years, V̇O2max${\dot{V}_{{{\rm{O}}_{\rm{2}}}{\rm{max}}}}$  = 39.8 ± 5.7 ml/kg/min, respectively). Pubertal stage was estimated via maturity offset, with participants classified as pre- or post-peak height velocity (PHV). Pre-PHV, only a larger LV end-diastolic volume/lean body mass (EDV/LBM) for trained boys (+0.28 ml/kg LBM, P = 0.007) and a higher Hb mass/LBM for trained girls (+1.65 g/kg LBM, P = 0.007) were evident compared to untrained controls. Post-PHV, LV mass/LBM (boys: +0.50 g/kg LBM, P = 0.0003; girls: +0.35 g/kg LBM, P = 0.003), EDV/LBM (boys: +0.35 ml/kg LBM, P < 0.0001; girls: +0.31 ml/kg LBM, P = 0.0004), blood volume/LBM (boys: +12.47 ml/kg LBM, P = 0.004; girls: +13.48 ml/kg LBM, P = 0.0002.) and Hb mass/LBM (boys: +1.29 g/kg LBM, P = 0.015; girls: +1.47 g/kg LBM, P = 0.002) were all greater in trained versus untrained groups. Pre-PHV, EDV (R2adj  = 0.224, P = 0.001) in boys, and Hb mass and interventricular septal thickness (R2adj  = 0.317, P = 0.002) in girls partially accounted for the variance in V̇O2max${\dot{V}_{{{\rm{O}}_{\rm{2}}}{\rm{max}}}}$ . Post-PHV, stronger predictive models were evident via the inclusion of LV wall thickness and EDV in boys (R2adj  = 0.608, P < 0.0001), and posterior wall thickness and Hb mass in girls (R2adj  = 0.490, P < 0.0001). In conclusion, cardiovascular adaptation to exercise training is more pronounced post-PHV, with evidence for a greater role of central components for oxygen delivery. KEY POINTS: It has long been hypothesised that cardiovascular adaptation to endurance training is augmented following puberty. We investigated whether differences in cardiac and haematological variables exist, and to what extent, between endurance-trained versus untrained, pre- and post-peak height velocity (PHV) children, and how these central factors relate to maximal oxygen consumption. Using echocardiography to quantify left ventricular (LV) morphology and carbon monoxide rebreathing to determine blood volume and haemoglobin mass, we identified that training-related differences in LV morphology are evident in pre-PHV children, with haematological differences also observed between pre-PHV girls. However, the breadth and magnitude of cardiovascular remodelling was more pronounced post-PHV. Cardiac and haematological measures provide significant predictive models for maximal oxygen consumption ( V̇O2max${\dot{V}_{{{\rm{O}}_{\rm{2}}}{\rm{max}}}}$ ) in children that are much stronger post-PHV, suggesting that other important determinants within the oxygen transport chain could account for the majority of variance in V̇O2max${\dot{V}_{{{\rm{O}}_{\rm{2}}}{\rm{max}}}}$ before puberty.

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.

Evidence of region-specific right ventricular functional adaptation in endurance-trained men in response to an acute volume infusion.

NEW FINDINGS: What is the central question of this study? Endurance athletes demonstrate altered regional right ventricular (RV) wall mechanics, characterized by lower basal deformation, in comparison to non-athletic control subjects at rest. We hypothesized that regional adaptations at the RV base reflect an enhanced functional reserve capacity in response to haemodynamic volume loading. What is the main finding and its importance? Free wall RV longitudinal strain is elevated in response to acute volume loading in both endurance athletes and control subjects. However, the RV basal segment longitudinal strain response to acute volume infusion is greater in endurance athletes. Our findings suggest that training-induced cardiac remodelling might involve region-specific adaptation in the RV functional response to volume manipulation. ABSTRACT: Eccentric remodelling of the right ventricle (RV) in response to increased blood volume and repetitive haemodynamic load during endurance exercise is well established. Structural remodelling is accompanied by decreased deformation at the base of the RV free wall, which might reflect an enhanced functional reserve capacity in response to haemodynamic perturbation. Therefore, in this study we examined the impact of acute blood volume expansion on RV wall mechanics in 16 young endurance-trained men (aged 24 ± 3 years) and 13 non-athletic male control subjects (aged 27 ± 5 years). Conventional echocardiographic parameters and the longitudinal strain and strain rate were quantified at the basal and apical levels of the RV free wall. Measurements were obtained at rest and after 7 ml/kg i.v. Gelofusine infusion, with and without a passive leg raise. After infusion, blood volume increased by 12 ± 4 and 14 ± 5% in endurance-trained individuals versus control subjects, respectively (P = 0.264). Both endurance-trained individuals (8 ± 10%) and control subjects (7 ± 9%) experienced an increase in free wall strain from baseline, which was also similar following leg raise (7 ± 10 and 6 ± 10%, respectively; P = 0.464). However, infusion evoked a greater increase in basal longitudinal strain in endurance-trained versus control subjects (16 ± 14 vs. 6 ± 11%; P = 0.048), which persisted after leg raise (16 ± 18 vs. 3 ± 11%; P = 0.032). Apical longitudinal strain and RV free wall strain rates were not different between groups and remained unchanged after infusion across all segments. Endurance training results in a greater contribution of longitudinal myocardial deformation at the base of the RV in response to a haemodynamic volume challenge, which might reflect a greater region-specific functional reserve capacity.

Aortic haemodynamics: the effects of habitual endurance exercise, age and muscle sympathetic vasomotor outflow in healthy men.

PURPOSE: We determined the effect of habitual endurance exercise and age on aortic pulse wave velocity (aPWV), augmentation pressure (AP) and systolic blood pressure (aSBP), with statistical adjustments of aPWV and AP for heart rate and aortic mean arterial pressure, when appropriate. Furthermore, we assessed whether muscle sympathetic nerve activity (MSNA) correlates with AP in young and middle-aged men. METHODS: Aortic PWV, AP, aortic blood pressure (applanation tonometry; SphygmoCor) and MSNA (peroneal microneurography) were recorded in 46 normotensive men who were either young or middle-aged and endurance-trained runners or recreationally active nonrunners (10 nonrunners and 13 runners within each age-group). Between-group differences and relationships between variables were assessed via ANOVA/ANCOVA and Pearson product-moment correlation coefficients, respectively. RESULTS: Adjusted aPWV and adjusted AP were similar between runners and nonrunners in both age groups (all, P > 0.05), but higher with age (all, P < 0.001), with a greater effect size for the age-related difference in AP in runners (Hedges' g, 3.6 vs 2.6). aSBP was lower in young (P = 0.009; g = 2.6), but not middle-aged (P = 0.341; g = 1.1), runners compared to nonrunners. MSNA burst frequency did not correlate with AP in either age group (young: r = 0.00, P = 0.994; middle-aged: r = - 0.11, P = 0.604). CONCLUSION: There is an age-dependent effect of habitual exercise on aortic haemodynamics, with lower aSBP in young runners compared to nonrunners only. Statistical adjustment of aPWV and AP markedly influenced the outcomes of this study, highlighting the importance of performing these analyses. Further, peripheral sympathetic vasomotor outflow and AP were not correlated in young or middle-aged normotensive men.

The overlooked significance of plasma volume for successful adaptation to high altitude in Sherpa and Andean natives.

In contrast to Andean natives, high-altitude Tibetans present with a lower hemoglobin concentration that correlates with reproductive success and exercise capacity. Decades of physiological and genomic research have assumed that the lower hemoglobin concentration in Himalayan natives results from a blunted erythropoietic response to hypoxia (i.e., no increase in total hemoglobin mass). In contrast, herein we test the hypothesis that the lower hemoglobin concentration is the result of greater plasma volume, rather than an absence of increased hemoglobin production. We assessed hemoglobin mass, plasma volume and blood volume in lowlanders at sea level, lowlanders acclimatized to high altitude, Himalayan Sherpa, and Andean Quechua, and explored the functional relevance of volumetric hematological measures to exercise capacity. Hemoglobin mass was highest in Andeans, but also was elevated in Sherpa compared with lowlanders. Sherpa demonstrated a larger plasma volume than Andeans, resulting in a comparable total blood volume at a lower hemoglobin concentration. Hemoglobin mass was positively related to exercise capacity in lowlanders at sea level and in Sherpa at high altitude, but not in Andean natives. Collectively, our findings demonstrate a unique adaptation in Sherpa that reorientates attention away from hemoglobin concentration and toward a paradigm where hemoglobin mass and plasma volume may represent phenotypes with adaptive significance at high altitude.

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.

The influence of hemoconcentration on hypoxic pulmonary vasoconstriction in acute, prolonged, and lifelong hypoxemia.

Hemoconcentration can influence hypoxic pulmonary vasoconstriction (HPV) via increased frictional force and vasoactive signaling from erythrocytes, but whether the balance of these mechanism is modified by the duration of hypoxia remains to be determined. We performed three sequential studies: 1) at sea level, in normoxia and isocapnic hypoxia with and without isovolumic hemodilution (n = 10, aged 29 ± 7 yr); 2) at altitude (6 ± 2 days acclimatization at 5,050 m), before and during hypervolumic hemodilution (n = 11, aged 27 ± 5 yr) with room air and additional hypoxia [fraction of inspired oxygen ([Formula: see text])= 0.15]; and 3) at altitude (4,340 m) in Andean high-altitude natives with excessive erythrocytosis (EE; n = 6, aged 39 ± 17 yr), before and during isovolumic hemodilution with room air and hyperoxia (end-tidal Po2 = 100 mmHg). At sea level, hemodilution mildly increased pulmonary artery systolic pressure (PASP; +1.6 ± 1.5 mmHg, P = 0.01) and pulmonary vascular resistance (PVR; +0.7 ± 0.8 wu, P = 0.04). In contrast, after acclimation to 5,050 m, hemodilution did not significantly alter PASP (22.7 ± 5.2 vs. 24.5 ± 5.2 mmHg, P = 0.14) or PVR (2.2 ± 0.9 vs. 2.3 ± 1.2 wu, P = 0.77), although both remained sensitive to additional acute hypoxia. In Andeans with EE at 4,340 m, hemodilution lowered PVR in room air (2.9 ± 0.9 vs. 2.3 ± 0.8 wu, P = 0.03), but PASP remained unchanged (31.3 ± 6.7 vs. 30.9 ± 6.9 mmHg, P = 0.80) due to an increase in cardiac output. Collectively, our series of studies reveal that HPV is modified by the duration of exposure and the prevailing hematocrit level. In application, these findings emphasize the importance of accounting for hematocrit and duration of exposure when interpreting the pulmonary vascular responses to hypoxemia.NEW & NOTEWORTHY Red blood cell concentration influences the pulmonary vasculature via direct frictional force and vasoactive signaling, but whether the magnitude of the response is modified with duration of exposure is not known. By assessing the pulmonary vascular response to hemodilution in acute normobaric and prolonged hypobaric hypoxia in lowlanders and lifelong hypobaric hypoxemia in Andean natives, we demonstrated that a reduction in red cell concentration augments the vasoconstrictive effects of hypoxia in lowlanders. In high-altitude natives, hemodilution lowered pulmonary vascular resistance, but a compensatory increase in cardiac output following hemodilution rendered PASP unchanged.

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.

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.

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.

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.

The influence of barosensory vessel mechanics on the vascular sympathetic baroreflex: insights into aging and blood pressure homeostasis.

Changes in the arterial baroreflex arc contribute to elevated sympathetic outflow and altered reflex control of blood pressure with human aging. Using ultrasound and sympathetic microneurography (muscle sympathetic nerve activity, MSNA) we investigated the relationships between aortic and carotid artery wall tension (indices of baroreceptor activation) and the vascular sympathetic baroreflex operating point (OP; MSNA burst incidence) in healthy, normotensive young (n = 27, 23 ± 3 yr) and middle-aged men (n = 22, 55 ± 4 yr). In young men, the OP was positively related to the magnitude and rate of unloading and time spent unloaded in the aortic artery (r = 0.56, 0.65, and 0.51, P = 0.02, 0.003, and 0.03), but not related to the magnitude or rate of unloading or time spent unloaded in the carotid artery (r = -0.32, -0.07, and 0.06, P = 0.25, 0.81, and 0.85). In contrast, in middle-aged men, the OP was not related to either the magnitude or rate of unloading or time spent unloaded in the aortic (r = 0.22, 0.21, and 0.27, P = 0.41, 0.43, and 0.31) or carotid artery (r = 0.06, 0.28, and -0.01; P = 0.48, 0.25, and 0.98). In conclusion, in young men, aortic unloading mechanics may play a role in determining the vascular sympathetic baroreflex OP. In contrast, in middle-aged men, barosensory vessel unloading mechanics do not appear to determine the vascular sympathetic baroreflex OP and, therefore, do not contribute to age-related arterial baroreflex resetting and increased resting MSNA.NEW & NOTEWORTHY We assessed the influence of barosensory vessel mechanics (magnitude and rate of unloading and time spent unloaded) as a surrogate for baroreceptor unloading. In young men, aortic unloading mechanics are important in regulating the operating point of the vascular sympathetic baroreflex, whereas in middle-aged men, these arterial mechanics do not influence this operating point. The age-related increase in resting muscle sympathetic nerve activity does not appear to be driven by altered baroreceptor input from stiffer barosensory vessels.

Stimulus-specific functional remodeling of the left ventricle in endurance and resistance-trained men.

Left ventricular (LV) structural remodeling following athletic training has been evidenced through training-specific changes in wall thickness and geometry. Whether the LV response to changes in hemodynamic load also adapts in a training-specific manner is unknown. Using echocardiography, we examined LV responses of endurance-trained (n = 15), resistance-trained (n = 14), and nonathletic men (n = 13) to 1) 20, 40, and 60% one repetition-maximum (1RM), leg-press exercise and 2) intravascular Gelofusine infusion (7 mL/kg) with passive leg raise. While resting heart rate was lower in endurance-trained participants versus controls (P = 0.001), blood pressure was similar between groups. Endurance-trained individuals had lower wall thickness but greater LV mass relative to body surface area versus controls, with no difference between resistance-trained individuals and controls. Leg press evoked a similar increase in blood pressure; however, resistance-trained participants preserved stroke volume (SV; -3 ± 8%) versus controls at 60% 1RM (-15 ± 7%, P = 0.001). While the maintenance of SV was related to the change in longitudinal strain across all groups (R = 0.537; P = 0.007), time-to-peak strain was maintained in resistance-trained but delayed in endurance-trained individuals (1 vs. 12% delay; P = 0.021). Volume infusion caused a similar increase in end-diastolic volume (EDV) and SV across groups, but leg raise further increased EDV only in endurance-trained individuals (5 ± 5 to 8 ± 5%; P = 0.018). Correlation analysis revealed a relationship between SV and longitudinal strain following infusion and leg raise (R = 0.334, P = 0.054); however, we observed no between-group differences in longitudinal myocardial mechanics. In conclusion, resistance-trained individuals better maintained SV during pressure loading, whereas endurance-trained individuals demonstrated greater EDV reserve during volume loading. These data provide novel evidence of training-specific LV functional remodeling.NEW & NOTEWORTHY Training-specific functional remodeling of the LV in response to different loading conditions has been recently suggested, but not experimentally tested in the same group of individuals. Our data provide novel evidence of a dichotomous, training-specific LV adaptive response to hemodynamic pressure or volume loading.

The influence of habitual endurance exercise on carotid artery strain and strain rate in young and middle-aged men.

NEW FINDINGS: What is the central question of this study? Carotid artery peak circumferential strain (PCS) and strain rate attenuate with age, but appear to be modulated by cardiorespiratory fitness status in young males. However, the relationship between habitual endurance exercise (running) and these parameters has not been studied in young and middle-aged men. What is the main finding and its importance? Young and middle-aged runners exhibited elevated PCS and systolic strain rate (S-SR) compared with non-runners, but habitual running did not influence diastolic strain rate (D-SR). Habitual exercise is associated with comparable improvements in carotid strain parameters in young and middle-aged men, but the age-related decline in PCS and S-SR might be more amenable to habitual endurance exercise than D-SR. ABSTRACT: Central arterial stiffness is an independent predictor of cardiovascular risk that can be modified by exercise training. However, conventional local measures of carotid artery stiffness display conflicting responses to habitual endurance exercise in young and older adults. Two-dimensional (2D)-Strain imaging of the common carotid artery (CCA) quantifies circumferential deformation (strain) of the arterial wall across the cardiac cycle, which is more sensitive at detecting age-related alterations in CCA stiffness than conventional methods. Therefore, the study was designed to examine the relationship between habitual endurance exercise (running) and CCA 2D-Strain parameters in young and middle-aged men. Short-axis ultrasound images of the CCA were obtained from 13 young non-runners [23 years of age (95% confidence interval: 21, 26 years of age)], 19 young runners [24 (22, 26) years of age], 13 middle-aged non-runners [54 (52, 56) years of age] and 19 middle-aged runners [56 (54, 58) years of age]. Images were analysed for peak circumferential strain (PCS; magnitude of deformation) and systolic and diastolic strain rates (S-SR and D-SR; deformation velocity), and group differences were examined via two-way ANOVA. PCS, S-SR and D-SR were attenuated in middle-aged men compared with young men (all P ≤ 0.001). PCS and S-SR were elevated in young and middle-aged runners when compared with non-runners (P = 0.002 and P = 0.009, respectively), but no age × training status interaction was observed. In contrast, there was no influence of habitual running on D-SR. Habitual exercise is associated with comparable improvements in CCA 2D-Strain parameters in young and middle-aged men, but the age-related decline in PCS and S-SR might be more amenable to habitual endurance exercise than D-SR.