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What is the central question to this study? Is there a relationship between a patent foramen ovale and the development of acute mountain sickness and an exaggerated increase in pulmonary pressure in response to 7-10 h of normobaric hypoxia? What is the main finding and its importance? Patent foramen ovale presence did not increase susceptibility to acute mountain sickness or result in an exaggerated increase in pulmonary artery systolic pressure with normobaric hypoxia. This suggests hypobaric hypoxia is integral to the increased susceptibility to acute mountain sickness previously reported in those with patent foramen ovale, and patent foramen ovale presence alone does not contribute to the hypoxic pulmonary pressor response.Acute mountain sickness (AMS) develops following rapid ascent to altitude, but its exact causes remain unknown. A patent foramen ovale (PFO) is a right-to-left intracardiac shunt present in ∼30% of the population that has been shown to increase AMS susceptibility with high altitude hypoxia. Additionally, high altitude pulmonary oedema (HAPE) is a severe type of altitude illness characterized by an exaggerated pulmonary pressure response, and there is a greater prevalence of PFO in those with a history of HAPE. However, whether hypoxia per se is causing the increased incidence of AMS in those with a PFO and whether a PFO is associated with an exaggerated increase in pulmonary pressure in those without a history of HAPE is unknown. Participants (n = 36) matched for biological sex (18 female) and the presence or absence of a PFO (18 PFO+) were exposed to 7-10 h of normobaric hypoxia equivalent to 4755 m. Presence and severity of AMS was determined using the Lake Louise AMS scoring system. Pulmonary artery systolic pressure, cardiac output and total pulmonary resistance were measured using ultrasound. We found no significant association of PFO with incidence or severity of AMS and no association of PFO with arterial oxygen saturation. Additionally, there was no effect of a PFO on pulmonary pressure, cardiac output or total pulmonary resistance. These data suggest that hypobaric hypoxia is necessary for those with a PFO to have increased incidence of AMS and that presence of PFO is not associated with an exaggerated pulmonary pressor response.

Key points The mechanism(s) that regulate hypoxia-induced blood flow through intrapulmonary arteriovenous anastomoses (QIPAVA ) are currently unknown. Our previous work has demonstrated that the mechanism of hypoxia-induced QIPAVA is not simply increased cardiac output, pulmonary artery systolic pressure or sympathetic nervous system activity and, instead, it may be a result of hypoxaemia directly. To determine whether it is reduced arterial PO2 (PaO2) or O2 content (CaO2) that causes hypoxia-induced QIPAVA , individuals were instructed to breathe room air and three levels of hypoxic gas at rest before (control) and after CaO2 was reduced by 10% by lowering the haemoglobin concentration (isovolaemic haemodilution; Low [Hb]). QIPAVA , assessed by transthoracic saline contrast echocardiography, significantly increased as PaO2 decreased and, despite reduced CaO2 (via isovolaemic haemodilution), was similar at iso-PaO2. These data suggest that, with alveolar hypoxia, low PaO2 causes the hypoxia-induced increase in QIPAVA , although where and how this is detected remains unknown. Abstract Alveolar hypoxia causes increased blood flow through intrapulmonary arteriovenous anastomoses (QIPAVA ) in healthy humans at rest. However, it is unknown whether the stimulus regulating hypoxia-induced QIPAVA is decreased arterial PO2 (PaO2) or O2 content (CaO2). CaO2 is known to regulate blood flow in the systemic circulation and it is suggested that IPAVA may be regulated similar to the systemic vasculature. Thus, we hypothesized that reduced CaO2 would be the stimulus for hypoxia-induced QIPAVA . Blood volume (BV) was measured using the optimized carbon monoxide rebreathing method in 10 individuals. Less than 5 days later, subjects breathed room air, as well as 18%, 14% and 12.5% O2 , for 30 min each, in a randomized order, before (CON) and after isovolaemic haemodilution (10% of BV withdrawn and replaced with an equal volume of 5% human serum albumin-saline mixture) to reduce [Hb] (Low [Hb]). PaO2 was measured at the end of each condition and QIPAVA was assessed using transthoracic saline contrast echocardiography. [Hb] was reduced from 14.2 ± 0.8 to 12.8 ± 0.7 g dl(-1) (10 ± 2% reduction) from CON to Low [Hb] conditions. PaO2 was no different between CON and Low [Hb], although CaO2 was 10.4%, 9.2% and 9.8% lower at 18%, 14% and 12.5% O2 , respectively. QIPAVA significantly increased as PaO2 decreased and, despite reduced CaO2, was similar at iso-PaO2. These data suggest that, with alveolar hypoxia, low PaO2 causes the hypoxia-induced increase in QIPAVA . Whether the low PO2 is detected at the carotid body, airway and/or the vasculature remains unknown.

Blood flow through intrapulmonary arteriovenous anastomoses (IPAVAs) has been demonstrated to increase in healthy humans during a variety of conditions; however, whether or not this blood flow represents a source of venous admixture (Q VA /QT) that impairs pulmonary gas exchange efficiency (i.e. increases the alveolar-to-arterial PO2 difference (A-aDO2)) remains controversial and unknown. We hypothesized that blood flow through IPAVAs does provide a source of Q VA /QT. To test this, blood flow through IPAVAs was increased in healthy humans at rest breathing room air and 40% O2: (1) during intravenous adrenaline (epinephrine) infusion at 320 ng kg(-1) min(-1) (320 ADR), and (2) with vagal blockade (2 mg atropine), before and during intravenous adrenaline infusion at 80 ng kg(-1) min(-1) (ATR + 80 ADR). When breathing room air the A-aDO2 increased by 6 ± 2 mmHg during 320 ADR and by 5 ± 2 mmHg during ATR + 80 ADR, and the change in calculated Q VA /QT was +2% in both conditions. When breathing 40% O2, which minimizes contributions from diffusion limitation and alveolar ventilation-to-perfusion inequality, the A-aDO2 increased by 12 ± 7 mmHg during 320 ADR, and by 9 ± 6 mmHg during ATR + 80 ADR, and the change in calculated Q VA /QT was +2% in both conditions. During 320 ADR cardiac output (QT) and pulmonary artery systolic pressure (PASP) were significantly increased; however, during ATR + 80 ADR only QT was significantly increased, yet blood flow through IPAVAs as detected with saline contrast echocardiography was not different between conditions. Accordingly, we suggest that blood flow through IPAVAs provides a source of intrapulmonary shunt, and is mediated primarily by increases in QT rather than PASP.

Adults with a history of very preterm birth (CO) relative to individuals born at term (CONT). Low DLCO may predispose PRET to diffusion limitation during exercise, particularly while breathing hypoxic gas because of a reduced O2 driving gradient and pulmonary capillary transit time. We hypothesized that PRET would have significantly worse pulmonary gas exchange efficiency [i.e., increased alveolar-to-arterial Po2 difference (AaDO2)] during exercise breathing room air or hypoxic gas (FiO2 = 0.12) compared with CONT. To test this hypothesis, we compared the AaDO2 in PRET ( n = 13) with a clinically mild reduction in DLCO (72 ± 7% of predicted) and CONT ( n = 14) with normal DLCO (105 ± 10% of predicted) pre- and during exercise breathing room air and hypoxic gas. Measurements of temperature-corrected arterial blood gases, and direct measure of O2 saturation (SaO2), were made prior to and during exercise at 25, 50, and 75% of peak oxygen consumption (V̇o2peak) while breathing room air and hypoxic gas. In addition to DLCO, pulmonary function and exercise capacity were significantly less in PRET. Despite PRET having low DLCO, no differences were observed in the AaDO2 or SaO2 pre- or during exercise breathing room air or hypoxic gas compared with CONT. Although our findings were unexpected, we conclude that reduced pulmonary function and low DLCO resulting from very preterm birth does not cause a measureable reduction in pulmonary gas exchange efficiency.

Mean pulmonary arterial pressure (Ppa) during exercise is significantly higher in individuals aged ≥50 yr compared with their younger counterparts, but the reasons for this are unknown. Blood flow through intrapulmonary arteriovenous anastomoses (IPAVA) can be detected during exercise or while breathing hypoxic gas mixtures using saline contrast echocardiography in almost all healthy young individuals. It has been previously hypothesized that a lower degree of exercise-induced blood flow through IPAVA is associated with high Ppa during exercise. This association may suggest that individuals who are known to have high Ppa during exercise, such as those ≥50 yr of age, may have lower blood flow through IPAVA, but the presence and degree of exercise-induced blood flow through IPAVA has not been specifically studied in older populations. Using transthoracic saline contrast echocardiography, we investigated the potential effects of age on exercise-induced blood flow through IPAVA in a cross-section of subjects aged 19–72 yr. To verify our findings, we assessed the effects of age on hypoxia-induced blood flow through IPAVA. Age groups were ≤41 yr (younger, n = 16) and ≥50 yr (older, n = 14). Qualitatively measured exercise- and hypoxia-induced blood flow through IPAVA was significantly lower in older individuals compared with younger controls. Older individuals also had significantly higher pulmonary arterial systolic pressure and total pulmonary resistance (TPR) during exercise. Low blood flow through IPAVA was independently associated with high TPR. The reasons for the age-related decrease in blood flow through IPAVA are unknown.

Our purpose was to report the prevalence of healthy, young, asymptomatic humans who demonstrate left heart contrast at rest, breathing room air. We evaluated 176 subjects (18-41 years old) using transthoracic saline contrast echocardiography. Left heart contrast appearing ≤3 cardiac cycles, consistent with a patent foramen ovale (PFO), was detected in 67 (38%) subjects. Left heart contrast appearing >3 cardiac cycles, consistent with the transpulmonary passage of contrast, was detected in 49 (28%) subjects. Of these 49 subjects, 31 were re-evaluated after breathing 100% O2 for 10-15min and 6 (19%) continued to demonstrate the transpulmonary passage of contrast. Additionally, 18 of these 49 subjects were re-evaluated in the upright position and 1 (5%) continued to demonstrate the transpulmonary passage of contrast. These data suggest that ~30% of healthy, young, asymptomatic subjects demonstrate the transpulmonary passage of contrast at rest which is reduced by breathing 100% O2 and assuming an upright body position.

Skeletal muscle vasodilatation persists following a single bout of exercise and can potentially influence glucose uptake by recovering muscle. To investigate whether blood flow is a rate-limiting component in postexercise muscle glucose uptake, we tested the hypothesis that oral ingestion of H(1)- and H(2)-receptor antagonists, known to attenuate the sustained postexercise vasodilatation, would reduce leg glucose uptake after a bout of cycling. Healthy, recreationally active subjects (n = 8) exercised for 1 h at 60% of peak oxygen consumption on each of two days, with (blockade) and without (control) histamine-receptor antagonism. For 2 h of recovery following exercise, arteriovenous glucose differences were assessed from the radial artery and femoral vein, and leg blood flow was measured using Doppler ultrasonography on the common femoral artery. Femoral blood flow following exercise was 65.4 ± 16.4 ml min(-1) lower on the blockade day compared with the control day (P < 0.05). Likewise, glucose delivery was 0.177 ± 0.045 mmol min(-1) lower with blockade (P < 0.05). However, histamine-receptor antagonism produced no consistent effect on leg glucose uptake following exercise, due to high interindividual variability. In conclusion, while oral ingestion of H(1)- and H(2)-receptor antagonists alters postexercise recovery by attenuating vasodilatation, leg glucose uptake is not universally affected in recreationally active individuals.

Sources of venous admixture (QVA/QT) that impair pulmonary gas exchange efficiency, defined by an increased alveolar-arterial PO2 difference (AaDO2), are ventilation-perfusion inequality (VA/Q), diffusion limitation, and shunt. Blood flow through intrapulmonary arteriovenous anastomoses (QIPAVA) increases QVA/QT and the AaDO2. However, it is unclear whether increased cardiac output (QT) or pulmonary artery systolic pressure (PASP) cause the increase in QIPAVA. We hypothesized that an increase in QT alone would increase QIPAVA resulting in an increased AaDO2 at rest breathing room air and 40% O2 to prevent contributions from diffusion and VA/Q. Epinephrine, i.v. at 320 ng/kg/min (EPI), and low dose epinephrine (80 ng/kg/min) combined with 2 mg of atropine (EPI+ATR) were used in healthy human subjects (n=5) to increase QT. When breathing either room air or 40% O2, EPI and EPI+ATR increased QT, (measured by acetylene uptake) from 7.8±1.0 to 13.3±3.4 L/min. Only EPI significantly increased PASP (to 54±14 mmHg...

In their letter (Frise & Dorrington, 2015), Drs Frise and Dorrington have provided a number of critiques on our recent study, entitled ‘Increased cardiac output, not pulmonary artery systolic pressure, increases intrapulmonary shunt in healthy humans breathing room air and 40% O2’ (Elliott et al. 2014). Specifically, they have concerns, ‘that the title and content of [our] manuscript raise two fundamental issues related to fluid mechanics.’ First, it was most appropriate to specify ‘pulmonary artery systolic pressure’ (PASP) in the title because Doppler ultrasound was used to determine pulmonary pressure and we did not want readers to think that we had measured anything but PASP. This technique measures the velocity of retrograde blood flow across the tricuspid valve during systole, and thus the peak blood pressure developed in the pulmonary artery during systole can be calculated using the modified Bernoulli equation. The potential that ‘systolic [pulmonary] pressure’ per se, is the period of the cardiac cycle responsible for increasing intrapulmonary arteriovenous anastomoses (IPAVAs) blood flow () is neither implied from the title, nor discussed in our manuscript. Second, Drs Frise and Dorrington state: ‘cardiac output cannot directly increase an intrapulmonary shunt, since the latter is simply a flow of blood down some tubes.’ In our opinion, this is an oversimplification that ignores the many physiological intricacies of the regulation of pulmonary blood flow. For example, pulmonary blood flow is dependent upon a myriad of factors, including, but not limited to, gravity, architecture of the pulmonary vascular tree, oxygen tension, and may even be determined by precapillary sphincters associated with supernumerary vessels that are still poorly understood. Clearly pressure at the beginning of the tube needs to be greater than the pressure at the end of the tube to facilitate orthograde blood flow. However, in one of our experimental conditions, that combined atropine (ATR) and intravenous (i.v.) adrenaline (ADR) at 80 ng kg−1 min−1 (ATR + 80 ADR), PASP was not statistically increased, and therefore we could not state that there was an increase in pulmonary pressure; had we done so, we would have been lying and likely to be challenged by the reviewers, and rightly so, for over-interpreting or misinterpreting our data. Additionally, when cardiac output () increases, as occurs during low intensity exercise, there is recruitment of under- and/or non-perfused pulmonary blood vessels, which may include IPAVAs. In this way, increases in may be able to recruit IPAVAs without significant increases in pulmonary pressure and subsequently result in a shunt, if blood flow through these pathways does not participate in gas exchange. Several other studies, referenced in our manuscript, demonstrate an increase in right-to-left shunt secondary to increases in . Third, Drs Frise and Dorrington state: ‘It would seem desirable to avoid the use of vasoactive drugs, which might directly alter IPAVA tone independent of an effect on cardiac output.’ Central to this concern is the assumption that ATR and ADR specifically affect the vascular tone of IPAVAs, and do not alter the tone of the rest of the pulmonary vasculature. For example, the observation of increased without significant increases in PASP could be explained independent of any change in the vascular tone of IPAVAs if either ATR caused pulmonary vasodilatation of the conventional pulmonary circulation (not IPAVAs), or the lower dose of ADR provided less of a vasoconstrictor influence on the rest of the conventional pulmonary circulation – possibilities that we detailed in our manuscript. Our data neither imply, nor do we claim, that there was a ‘constant drop in pressure across the tubes [IPAVAs]’ during ATR + 80 ADR. We also addressed this issue by providing references to work where other authors concluded that, ‘…the increase in shunt from pharmacologically increased is probably not due to vasoconstrictor or vasodilator activity of these drugs as the increase in shunt is observed when is increased via mechanical means as well.’ A final statement from Drs Frise and Dorrington was that the complexity of our study ‘…makes it difficult to draw any conclusions about mechanisms determining flow through IPAVA…’ and quoted us as follows: ‘considering the unique experimental conditions used in the present study, it is difficult to extrapolate these findings to their potential physiological relevance.’ The entire quote from our work was: ‘Considering the unique experimental conditions used in the present study, it is difficult to extrapolate these findings to their potential physiological relevance during other conditions known to increase blood flow through IPAVAs, such as exercise.’ Again, we acknowledged the complexities of the regulation of pulmonary blood flow while being careful not to misinterpret or over-interpret our data. We recognize the complexities of quantifying pressure, flow and in humans. As such, we specifically commented in our paper that: ‘Nevertheless, future work in this area will be helpful in clarifying the roles of pressure and flow under other experimental conditions such as hypoxia and exercise.’ This statement very clearly acknowledges that our findings might not be applicable to other conditions. In summary, our manuscript measured PASP and and provides evidence that: (1) is associated with an impairment in pulmonary gas exchange efficiency, i.e. an increase in the alveolar-to-arterial difference (A-aDO2), and calculated volume of venous admixture during unique and tightly controlled experimental conditions that reduce/eliminate the potential contribution of alveolar ventilation-to-perfusion inequality and diffusion limitation to the A-aDO2, and (2) primarily depends on increases in , as it occurred independent of significant increases in PASP. These data provide the impetus to investigate the relative importance of and mean pulmonary arterial pressure or pulmonary vascular resistance with respect to , and we are actively working on this. For more information on this exciting area of physiology, and a description of the various physiological conditions in which is, and is not, detected, we refer the reader to very recent reviews (Duke et al. 2014; Lovering et al. 2015) of the relevant literature to date on this topic.

Skeletal muscle vasodilatation persists following a single bout of exercise and can potentially influence glucose uptake by recovering muscle. To investigate whether blood flow is a rate-limiting component in postexercise muscle glucose uptake, we tested the hypothesis that oral ingestion of H(1)- and H(2)-receptor antagonists, known to attenuate the sustained postexercise vasodilatation, would reduce leg glucose uptake after a bout of cycling. Healthy, recreationally active subjects (n = 8) exercised for 1 h at 60% of peak oxygen consumption on each of two days, with (blockade) and without (control) histamine-receptor antagonism. For 2 h of recovery following exercise, arteriovenous glucose differences were assessed from the radial artery and femoral vein, and leg blood flow was measured using Doppler ultrasonography on the common femoral artery. Femoral blood flow following exercise was 65.4 ± 16.4 ml min(-1) lower on the blockade day compared with the control day (P0.05). Likewise, glucose delivery was 0.177 ± 0.045 mmol min(-1) lower with blockade (P0.05). However, histamine-receptor antagonism produced no consistent effect on leg glucose uptake following exercise, due to high interindividual variability. In conclusion, while oral ingestion of H(1)- and H(2)-receptor antagonists alters postexercise recovery by attenuating vasodilatation, leg glucose uptake is not universally affected in recreationally active individuals.