Left ventricular trabeculation in Hominidae: divergence of the human cardiac phenotype.

Although the gross morphology of the heart is conserved across mammals, subtle interspecific variations exist in the cardiac phenotype, which may reflect evolutionary divergence among closely-related species. Here, we compare the left ventricle (LV) across all extant members of the Hominidae taxon, using 2D echocardiography, to gain insight into the evolution of the human heart. We present compelling evidence that the human LV has diverged away from a more trabeculated phenotype present in all other great apes, towards a ventricular wall with proportionally greater compact myocardium, which was corroborated by post-mortem chimpanzee (Pan troglodytes) hearts. Speckle-tracking echocardiographic analyses identified a negative curvilinear relationship between the degree of trabeculation and LV systolic twist, revealing lower rotational mechanics in the trabeculated non-human great ape LV. This divergent evolution of the human heart may have facilitated the augmentation of cardiac output to support the metabolic and thermoregulatory demands of the human ecological niche.

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, characterized 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 with pre-PHV youths (P ≤ 0.001), males compared with females (P ≤ 0.001), and trained compared with untrained youths (3.26 ± 0.51 vs. 3.11 ± 0.42 mm; 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 with 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.NEW & NOTEWORTHY We report preliminary evidence of the "youth athlete's artery," characterized by training-related arterial remodeling and elevated endothelium-dependent arterial function in children and adolescents. However, training-related adaptations in brachial artery diameter and flow-mediated dilation (FMD) were associated with cardiorespiratory fitness in adolescents, but not in children. Our findings indicate that endothelium-dependent arterial function is modifiable with chronic exercise training during childhood, but the association between FMD and elevated cardiorespiratory fitness is only apparent during later stages of adolescence.

The influence of maturation and sex on intracranial blood velocities during exercise in children.

Cerebral blood velocity (CBv) increases in response to moderate exercise in humans, but the magnitude of change is smaller in children compared with postpubertal adolescents and adults. Whether sex differences exist in the anterior or posterior CBv response to exercise across pubertal development remains to be determined. We assessed middle cerebral artery (MCAv) and posterior cerebral artery (PCAv) blood velocity via transcranial Doppler in 38 prepubertal (18 males) and 48 postpubertal (23 males) with cerebrovascular and cardiorespiratory measures compared at baseline and ventilatory threshold. At baseline, MCAv was higher in both sexes pre- versus postpuberty. Females demonstrated a greater MCAv (P < 0.001) than their male counterparts (prepubertal females; 78 ± 11 cm·s-1 vs. prepubertal males; 72 ± 8 cm·s-1, and postpubertal females; 68 ± 10 cm·s-1 vs. postpubertal males; 62 ± 7 cm·s-1). During exercise, MCAv remained higher in postpubertal females versus males (81 ± 15 cm·s-1 vs. 73 ± 11 cm·s-1), but there were no differences in prepuberty. The relative increase in PCAv was greater in post- versus prepubertal females (51 ± 9 cm·s-1 vs. 45 ± 11 cm·s-1; P = 0.032) but was similar in males and females. Our findings suggest that biological sex alters anterior cerebral blood velocities at rest in both pre- and postpubertal youth, but the response to submaximal exercise is only influenced by sex postpuberty.NEW & NOTEWORTHY Cerebral blood velocity (CBv) in the anterior circulation was higher in females compared with males irrespective of maturational stage, but not in the posterior circulation. In response to exercise, females demonstrated a greater CBv compared with males, especially post-peak height velocity (post-PHV) where the CBv response to exercise was more pronounced. Our findings suggest that both CBv at rest and in response to acute submaximal exercise are altered by biological sex in a maturity-dependent manner.

Adaptation of Left Ventricular Twist Mechanics in Exercise-Trained Children Is Only Evident after the Adolescent Growth Spurt.

BACKGROUND: The extent of structural cardiac remodeling in response to endurance training is maturity dependent. In adults, this structural adaptation is often associated with the adaptation of left ventricular (LV) twist mechanics. For example, an increase in LV twist often follows an expansion in end-diastolic volume, whereas a reduction in twist may follow a thickening of the LV walls. While structural cardiac remodeling has been shown to be more prominent post-peak height velocity (PHV), it remains to be determined how this maturation-dependent structural remodeling influences LV twist. Therefore, we aimed to (1) compare LV twist mechanics between trained and untrained children pre- and post-PHV and (2) investigate how LV structural variables relate to LV twist mechanics pre- and post-PHV. METHODS: Left ventricular function and morphology were assessed (echocardiography) in endurance-trained and untrained boys (n = 38 and n = 28, respectively) and girls (n = 39 and n = 34, respectively). Participants were categorized as either pre- or post-PHV using maturity offset to estimate somatic maturation. RESULTS: Pre-PHV, there were no differences in LV twist or torsion between trained and untrained boys (twist: P = .630; torsion: P = .382) or girls (twist: P = .502; torsion: P = .316), and LV twist mechanics were not related with any LV structural variables (P > .05). Post-PHV, LV twist was lower in trained versus untrained boys (P = .004), with torsion lower in trained groups, irrespective of sex (boys: P < .001; girls: P = .017). Moreover, LV torsion was inversely related to LV mass (boys: r = -0.55, P = .001; girls: r = -0.46, P = .003) and end-diastolic volume (boys: r = -0.64, P < .001; girls: r = -0.36, P = .025) in both sexes. CONCLUSIONS: A difference in LV twist mechanics between endurance-trained and untrained cohorts is only apparent post-PHV, where structural and functional remodeling were related.

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.

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.

Aortic stiffness contributes to greater pressor responses during static hand grip exercise in healthy young and middle-aged normotensive men.

Central arterial stiffness can influence exercise blood pressure (BP) by increasing the rise in arterial pressure per unit increase in aortic inflow. Whether central arterial stiffness influences the pressor response to isometric handgrip exercise (HG) and post-exercise muscle ischemia (PEMI), two common laboratory tests to study sympathetic control of BP, is unknown. We studied 46 healthy non-hypertensive males (23 young and 23 middle-aged) during HG (which increases in cardiac output [Q̇c]) and isolated metaboreflex activation PEMI (no change or decreases in Q̇c). Aortic stiffness (aortic pulse wave velocity [aPWV]; applanation tonometry via SphygmoCor) was measured during supine rest and was correlated to the pressor responses to HG and PEMI. BP (photoplethysmography) and muscle sympathetic nerve activity (MSNA) were continuously recorded at rest, during HG to fatigue (35 % maximal voluntary contraction) and 2-min of PEMI. aPWV was higher in middle-aged compared to young males (7.1 ± 0.9 vs 5.4 ± 0.7 m/s, P < 0.001). Middle-aged males also exhibited greater increases in systolic pressure (∆30 ± 11 vs 10 ± 8 mmHg) and MSNA (∆2313 ± 2006 vs 1387 ± 1482 %/min) compared to young males during HG (both, P < 0.03); with no difference in the Q̇c response (P = 0.090). Responses to PEMI were not different between groups. Sympathetic transduction during these stressors (MSNA-diastolic pressure slope) was not different between groups (P > 0.341). Middle-aged males displayed a greater increase in SBP per unit change of Q̇c during HG (∆SBP/∆Q̇c; 21 ± 18 vs 6 ± 10 mmHg/L/min, P = 0.004), with a strong and moderate relationship between the change in systolic (r = 0.53, P < 0.001) and diastolic pressure (r = 0.34, P = 0.023) and resting aPWV, respectively; with no correlation during PEMI. Central arterial stiffness can modulate pressor responses during stimuli associated with increases in cardiac output and sympathoexcitation in healthy males.

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.

The influence of training status and parasympathetic blockade on the cardiac rate, rhythm, and functional response to autonomic stress.

Apnea (breath-holding) elicits co-activation of sympathetic and parasympathetic nervous systems, affecting cardiac control. In situations of autonomic co-activation (e.g., cold water immersion), cardiac arrhythmias are observed during apnea. Chronic endurance training reduces resting heart rate in part via elevation in parasympathetic tone, and has been identified as a risk factor for development of arrhythmias. However, few studies have investigated autonomic control of the heart in trained athletes during stress. Therefore, we determined whether heightened vagal tone resulting from endurance training promotes a higher incidence of arrhythmia during apnea. We assessed the heart rate, rhythm (ECG lead II), and cardiac inotropic (speckle-tracking echocardiography) response to apnea in 10 endurance trained and 7 untrained participants. Participants performed an apnea at rest and following sympathetic activation using post-exercise circulatory occlusion (PECO). All apneas were performed prior to control (CON) and following vagal block using glycopyrrolate (GLY). Trained participants had lower heart rates at rest (p = 0.03) and during apneas (p = 0.009) under CON. At rest, 3 trained participants exhibited instances of junctional rhythm and 4 trained participants developed ectopy during CON apneas, whereas 3 untrained participants developed ectopic beats only with concurrent sympathetic activation (PECO). Following GLY, no arrhythmias were noted in either group. Vagal block also revealed increased cardiac chronotropy (heart rate) and inotropy (strain rate) during apnea, demonstrating a greater sympathetic influence in the absence of parasympathetic drive. Our results highlight that endurance athletes may be more susceptible to ectopy via elevated vagal tone, whereas untrained participants may only develop ectopy through autonomic conflict.

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.

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.

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.

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: 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 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: 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.

Right Ventricular Function and Region-Specific Adaptation in Athletes Engaged in High-Dynamic Sports: A Meta-Analysis.

BACKGROUND: Structural remodeling of the right ventricle (RV) is widely documented in athletes. However, functional adaptation, including RV pressure generation and systolic free-wall longitudinal mechanics, remains equivocal. This meta-analysis compared RV pressure and function in athletes and controls. METHODS: A systematic review of online databases was conducted up to June 4, 2020. Meta-analyses were performed on RV systolic pressures, at rest and during exercise, tricuspid annular plane systolic displacement, myocardial velocity (S'), and global and regional longitudinal strain. Bias was assessed using Egger regression for asymmetry. Data were analyzed using random-effects models with weighted mean difference and 95% CI. RESULTS: Fifty-three studies were eligible for inclusion. RV systolic pressure was obtained from 21 studies at rest (n=1043:1651; controls:athletes) and 8 studies during exercise (n=240:495) and was significantly greater in athletes at rest (weighted mean difference, 2.9 mmHg [CI, 1.3-4.5 mmHg]; P=0.0005) and during exercise (11.0 [6.5-15.6 mm Hg]; P<0.0001) versus controls. Resting tricuspid annular plane systolic displacement (P<0.0001) and S' (P=0.001) were greater in athletes. In contrast, athletes had similar RV free-wall longitudinal strain (17 studies; n=450:605), compared with controls but showed greater longitudinal apical strain (16 studies; n=455:669; 0.9%, 0.1%-1.8%; P=0.03) and lower basal strain (-2.5% [-1.4 to -3.5%]; P<0.0001). CONCLUSIONS: Functional RV adaptation, characterized by increased tricuspid annular displacement and velocity and a greater base-to-apex strain gradient, is a normal feature of the athlete's heart, together with a slightly elevated RV systolic pressure. These findings contribute to our understanding of RV in athletes and highlight the importance of considering RV function in combination with structure in the clinical interpretation of the athlete's heart.