Our aim was to quantify the end-tidal-to-arterial gas gradients for O2 (PET-PaO2) and CO2 (Pa-PETCO2) during a CO2 reactivity test to determine their influence on the cerebrovascular (CVR) and ventilatory (HCVR) response in subjects with (PFO+, n = 8) and without (PFO-, n = 7) a patent foramen ovale (PFO). We hypothesized that 1) the Pa-PETCO2 would be greater in hypoxia compared with normoxia, 2) the Pa-PETCO2 would be similar, whereas the PET-PaO2 gradient would be greater in those with a PFO, 3) the HCVR and CVR would be underestimated when plotted against PETCO2 compared with PaCO2, and 4) previously derived prediction algorithms will accurately target PaCO2. PETCO2 was controlled by dynamic end-tidal forcing in steady-state steps of -8, -4, 0, +4, and +8 mmHg from baseline in normoxia and hypoxia. Minute ventilation (V̇E), internal carotid artery blood flow (Q̇ICA), middle cerebral artery blood velocity (MCAv), and temperature corrected end-tidal and arterial blood gases were measured throughout experimentation. HCVR and CVR were calculated using linear regression analysis by indexing V̇E and relative changes in Q̇ICA, and MCAv against PETCO2, predicted PaCO2, and measured PaCO2. The Pa-PETCO2 was similar between hypoxia and normoxia and PFO+ and PFO-. The PET-PaO2 was greater in PFO+ by 2.1 mmHg during normoxia (P = 0.003). HCVR and CVR plotted against PETCO2 underestimated HCVR and CVR indexed against PaCO2 in normoxia and hypoxia. Our PaCO2 prediction equation modestly improved estimates of HCVR and CVR. In summary, care must be taken when indexing reactivity measures to PETCO2 compared with PaCO2.

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.

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Key points The effect of combined inspiratory and expiratory muscle training on resting and reflexive cardiac function, as well as exercise capacity, in individuals with cervical spinal cord injury (SCI) is presently unknown. Six weeks of combined inspiratory and expiratory muscle training enhances both inspiratory and expiratory muscle strength in highly‐trained athletes with cervical SCI with no significant effect on lung function. There was a significant decrease in left‐ventricular filling and stroke volume at rest in response to 45° head‐up tilt, which is irreversible by respiratory muscle training. Combined inspiratory and expiratory muscle training increased peak aerobic work rate and reduced end‐expiratory lung volumes during exercise, which may have implications for left‐ventricular filling during exercise. Abstract To investigate the pulmonary, cardiovascular and exercise responses to combined inspiratory and expiratory respiratory muscle training (RMT) in athletes with tetraplegia, six wheelchair rugby athletes (five males and one female, aged 33 ± 5 years) completed 6 weeks of pressure threshold RMT, 2 sessions day–1 on 5 days week–1. Resting pulmonary and cardiac function, exercise capacity, exercising lung volumes and field‐based exercise performance were assessed at pre‐RMT, post‐RMT and after a 6‐week no RMT period. RMT enhanced maximal inspiratory (pre‐ vs. post‐RMT: −76 ± 15 to −106 ± 23 cmH2O, P = 0.002) and expiratory (59 ± 26 to 73 ± 32 cmH2O, P = 0.007) mouth pressures, as well as peak expiratory flow (6.74 ± 1.51 vs. 7.32 ± 1.60 L/s, P < 0.04). Compared to pre‐RMT, peak work rate was higher at post‐RMT (60 ± 23 to 68 ± 22 W, P = 0.003), whereas exercising end‐expiratory lung volumes were reduced (P < 0.017). Peak oxygen uptake increased in all athletes at post‐RMT (1.24 ± 0.40 vs. 1.40 ± 0.50 l min−1, P = 0.12). After 6 weeks of no RMT all indices returned towards baseline, with peak work rate (P = 0.037), peak oxygen uptake (P = 0.041) and end‐expiratory lung volume (P < 0.034) being significantly lower at follow‐up than at post‐RMT. There was a significant decrease in left‐ventricular end‐diastolic volume and stroke volume in response to 45° head‐up tilt (P = 0.030 and 0.021, respectively); however, all cardiac indices in both supine and tilted positions were unchanged by RMT. Our findings demonstrate the efficacy of RMT with respect to enhancing respiratory muscle strength, lowering exercising lung volumes and increasing exercise capacity. Although the precise mechanisms by which RMT may enhance exercise capacity remain unclear, our data suggest that it is probably not the result of a direct cardiac adaptation associated with RMT.

ObjectiveConduct a meta-analysis to determine the impact of traumatic spinal cord injury (SCI) on echocardiographic measurements of left ventricular (LV) structure and function.MethodsMEDLINE and Embase were used for primary searches of studies reporting LV echocardiographic data in individuals with SCI. Of 378 unique citations, 36 relevant full-text articles were retrieved, and data from 27 studies were extracted for meta-analyses. Literature searches, article screening and data extraction were completed by two independent reviewers and compared for agreement. Primary analyses compared echocardiographic indices between individuals with SCI and able-bodied individuals, using a random effects model.ResultsData are reported as pooled effect estimates (95% CI). Data from 22 articles (474 participants) were included in the primary meta-analysis. Compared with able-bodied individuals, individuals with SCI had reductions to LV stroke volume of 11.8 mL (95% CI −17.8 to −5.9, p<0.001), end-diastolic volume of 19.6 mL (95% CI −27.2 to −11.9, p<0.001) and LV massindex of −7.7 g/m2 (95% CI −11.6 to −3.8, p<0.001), but ejection fraction was not different between the groups (95% CI −2.6% to 0.6%, p=0.236). Individuals with SCI also had altered indices of diastolic function, specifically a lowered ratio of early-to-late filling velocities (p=0.039), and augmented ratio of early diastolic flow-to-tissue velocities (p=0.021).ConclusionsIndividuals with SCI have smaller LV volumes and mass, and altered systolic and diastolic function. While this meta-analysis demonstrates important alterations to echocardiographic measures of cardiac structure and function at rest, future work should consider the impacts of SCI on the heart’s capacity or ‘reserve’ to respond to physiological challenges.PROSPERO registration numberCRD42017072333.

22 Background-Compared to males, females have smaller left ventricular (LV) 23dimensions and volumes, higher ejection fractions (EF), and higher LV longitudinal and 24 circumferential strain. LV twist mechanics determine ventricular function, and are 25 preload-dependent. Therefore, the sex differences in LV structure and myocardial 26 function may result in different mechanics when preload is altered. This study 27 investigated sex differences in LV mechanics during acute challenges to preload. 28Methods and Results-Using conventional and speckle-tracking echocardiography, LV 29 structure and function were assessed in 20 males (24  6.2 yr) and 20 females (23  3.1 30 yr) at baseline and during progressive levels of lower body negative pressure (LBNP). 31Fourteen participants (8 males, 6 females) were also assessed following a rapid infusion 32 of saline. LV end-diastolic volume, end-systolic volume, stroke volume (SV) and EF 33 were reduced in both groups during LBNP (p<0.001). While males had greater absolute 34 volumes (p<0.001) there were no sex differences in allometrically scaled volumes at any 35 stage. Sex differences were not detected at baseline in basal rotation, apical rotation, or 36 twist. Apical rotation and twist increased in both groups (p<0.001) with LBNP. At -60 37 mmHg, females had greater apical rotation (p=0.009), twist (p=0.008) and torsion 38 (p=0.002), and faster untwisting velocity (p=0.02) than males. There were no differences 39 in mechanics following saline infusion. 40 Conclusions-Females have larger LV twist and a faster untwisting velocity than males 41during large reductions to preload, supporting that females have a greater reliance on LV 42 twist mechanics to maintain SV during severe reductions to preload. 43 44 3 New & Noteworthy 45This is the first study to demonstrate sex differences in left ventricular twist mechanics 46 during acute preload challenges. Our data demonstrate that females utilize larger left 47 ventricular twist and faster untwisting velocity than males to maintain mean arterial 48 pressure during severe reductions to preload. 49 50

Chronic obstructive pulmonary disease (COPD) is associated with dynamic lung hyperinflation (DH), increased pulmonary vascular resistance (PVR), and large increases in negative intrathoracic pressure (nITP). The individual and interactive effect of these stressors on left ventricular (LV) filling, emptying, and geometry and the role of direct ventricular interaction (DVI) in mediating these interactions have not been fully elucidated. Twenty healthy subjects were exposed to the following stressors alone and in combination: 1) inspiratory resistive loading of -20 cmHO (nITP), 2) expiratory resistive loading to cause dynamic hyperinflation (DH), and 3) normobaric-hypoxia to increase PVR (hPVR). LV volumes and geometry were assessed using triplane echocardiography. LV stroke volume (LVSV) was reduced during nITP by 7 ± 7% (mean ± SD; P < 0.001) through a 4 ± 5% reduction in LV end-diastolic volume (LVEDV) (P = 0.002), while DH reduced LVSV by 12 ± 13% (P = 0.001) due to a 9 ± 10% reduction in LVEDV (P < 0.001). The combination of nITP and DH (nITP+DH) caused larger reductions in LVSV (16 ± 16%, P < 0.001) and LVEDV (12 ± 10%, P < 0.001) than nITP alone (P < 0.05). The addition of hPVR to nITP+DH did not further reduce LV volumes. Significant septal flattening (indicating DVI) occurred in all conditions, with a significantly greater leftward septal shift occurring with nITP+DH than either condition alone (P < 0.05). In summary, the interaction of nITP and DH reduces LV filling through DVI. However, DH may be more detrimental to LV hemodynamics than nITP, likely due to mediastinal constraint of the heart amplifying DVI.

Key points Iron acts as a cofactor in the stabilization of the hypoxic‐inducible factor family, and plays an influential role in the modulation of hypoxic pulmonary vasoconstriction. It is uncertain whether iron regulation is altered in lowlanders during either (1) ascent to high altitude, or (2) following partial acclimatization, when compared to high‐altitude adapted Sherpa. During ascent to 5050 m, the rise in pulmonary artery systolic pressure (PASP) was blunted in Sherpa, compared to lowlanders; however, upon arrival to 5050 m, PASP levels were comparable in both groups, but the reduction in iron bioavailability was more prevalent in lowlanders compared to Sherpa. Following partial acclimatization to 5050 m, there were differential influences of iron status manipulation (via iron infusion or chelation) at rest and during exercise between lowlanders and Sherpa on the pulmonary vasculature. Abstract To examine the adaptational role of iron bioavailability on the pulmonary vascular responses to acute and chronic hypobaric hypoxia, the haematological and cardiopulmonary profile of lowlanders and Sherpa were determined during: (1) a 9‐day ascent to 5050 m (20 lowlanders; 12 Sherpa), and (2) following partial acclimatization (11 ± 4 days) to 5050 m (18 lowlanders; 20 Sherpa), where both groups received an i.v. infusion of either iron (iron (iii)‐hydroxide sucrose) or an iron chelator (desferrioxamine). During ascent, there were reductions in iron status in both lowlanders and Sherpa; however, Sherpa appeared to demonstrate a more efficient capacity to mobilize stored iron, compared to lowlanders, when expressed as a Δhepcidin per unit change in either body iron or the soluble transferrin receptor index, between 3400–5050 m (P = 0.016 and P = 0.029, respectively). The rise in pulmonary artery systolic pressure (PASP) was blunted in Sherpa, compared to lowlanders during ascent; however, PASP was comparable in both groups upon arrival to 5050 m. Following partial acclimatization, despite Sherpa demonstrating a blunted hypoxic ventilatory response and greater resting hypoxaemia, they had similar hypoxic pulmonary vasoconstriction when compared to lowlanders at rest. Iron‐infusion attenuated PASP in both groups at rest (P = 0.005), while chelation did not exaggerate PASP in either group at rest or during exaggerated hypoxaemia (PnormalIO2 = 67 mmHg). During exercise at 25% peak wattage, PASP was only consistently elevated in Sherpa, which persisted following both iron infusion or chelation. These findings provide new evidence on the complex interplay of iron regulation on pulmonary vascular regulation during acclimatization and adaptation to high altitude.