High adventure shunts old notions of pulmonary vascular control during hypoxic exercise: contrasting views that might just burst your bubble!

In the absence of intracardiac shunt, the entire cardiac output embraces the lungs through the pulmonary vascular system. Branching conduits carry blood from the right cardiac ventricle through to the pulmonary capillary beds, facilitating gas exchange with millions of functional units contemporaneously engaged by rhythmic tidal flow connecting alveoli to external air. Invigorated blood returns through pulmonary veins to the left cardiac atrium. Arteriovenous anastomoses in mammalian lungs can serve as low-resistance short circulatory routes that bypass the business end of gas exchange. Although blood flow through arteriovenous circuits is generally regarded as negligible at rest in healthy humans, it increases during exercise in an intensity-dependent manner (Eldridge et al. 2004) when, amongst other things, cardiac output and pulmonary artery pressure both increase. Intrapulmonary vascular shunt is also increased by the administration of cardiac inotropes. Alveolar bypass by way of exercise-induced recruitment of intrapulmonary arteriovenous conduits could detract from efficient gas exchange, potentially contributing to a widening of alveolar–arterial difference during exercise (Stickland et al. 2007), notwithstanding the possibility that potential deficits could be offset by separate exercise-induced events and lack of evidence of right-to-left physiological shunt during exercise in several studies using assessments of gas exchange. It is also reasoned that intrapulmonary anastomoses could serve to limit excessive gains in pulmonary pressure; a ‘safety valve’, protecting the delicate capillary network of the lung. Mechanical stress is suggested as one plausible mechanism governing patency of the pulmonary portals, with changes in both arterial and venous arms of the circuit relevant to the discussion. Interestingly, blood flow through intrapulmonary anastomoses increases strikingly during normobaric hypoxic exercise, but is minimized during exercise whilst breathing hyperoxic gas, implicating as a pertinent stimulus; a proposition all the more intriguing given the long-standing interest in the potent effects of hypoxia on pulmonary vascular resistance. Indeed, it is established that acute normobaric hypoxaemia in humans is associated with increased blood flow through pulmonary arteriovenous anastomoses independent of both arterial oxygen content (Duke et al. 2016) and pulmonary artery systolic pressure (Tremblay et al. 2015). Breathing 100% oxygen reverses the opening of anastomoses in catecholamine-infused healthy subjects at rest. Curiously, however, anastomotic flow does not increase during rest in lowlanders at high altitude (Foster et al. 2014), despite hypoxaemia and elevated pulmonary pressures, albeit at cardiac outputs equivalent to sea level. Until now, the impact of exercise on intrapulmonary vascular shunt in lowlander lungs at high altitude was unknown. In this issue of Experimental Physiology, Boulet et al. (2017) tackle the tricky task with a spirit of great adventure, performing contrast echocardiography in healthy subjects during recumbent cycle ergometry at the Ev-K2-CNR Pyramid Laboratory in Nepal at 5050 m, after baseline assessments performed at ‘sea level’ (Kelowna, British Columbia, Canada; 344 m). In subjects without a patent foramen ovale, intravenous injection of agitated saline allowed imaging of the density and spatial distribution of microbubbles appearing after circulatory delay in the left cardiac chamber. A standard scoring system was used to estimate the extent of bubble carriage through intrapulmonary arteriovenous anastomoses at rest and during exercise. Subject heart rate, estimated oxygen saturation, cardiac output and pulmonary artery systolic pressure were determined at rest and during incremental workloads to 25, 50 and 75% of peak oxygen consumption at sea level and to 25 and 50% of the sea-level peak oxygen consumption at high altitude. Consistent with previous studies, Boulet et al. (2017) report no apparent flow through lung anastomoses in healthy subjects at sea level during rest, but bubble scores were increased as a function of exercise intensity, confirming the recruitment of arteriovenous shunts. In the same healthy subjects acclimatized for 4–7 days at 5050 m (after a 10–12 day hike to the Pyramid laboratory from Lukla), there was a small increase in bubble score in some subjects at rest. However, no further increase in intrapulmonary vascular shunting was observed during high-altitude exercise achieving cardiac outputs equivalent to levels achieved at sea level, but with substantially elevated pulmonary systolic pressures and pronounced hypoxaemia compared with sea level. Thus, it appears, contrary to expectation, that acclimatization to hypoxia decreases flow through arteriovenous anastomoses during exercise notwithstanding equivalent or greater mechanical stressors at high altitude compared with sea level. The study suggests the likely pivotal role of prolonged hypobaric hypoxic stress in the control of intrapulmonary vascular shunt. The authors draw focus to three factors relevant to the environmental and experimental settings: hypobaria per se, pulmonary vascular remodelling during acclimatization to hypoxia, and bubble stability at high altitude. There is evidence that hypobaria, independent of hypoxia, alters pulmonary vascular resistance. The impact of chronic hypoxia on the pulmonary vasculature is well described. The authors carefully address the important issue of microbubble dissolution, presenting a case to suggest that bubble instability at high altitude is not likely to be a confounder in the interpretation of the findings. A theoretical model is presented, which posits that factors influencing bubble stability are likely to be insufficient in the round to perturb contrast detection in the left ventricle, such that the restraint in the appearance of bubbles during high-altitude exercise can be viewed as indirect evidence of reduced arteriovenous flow; that is, lack of recruitment of intrapulmonary anastomoses during exercise, which differs from the sea-level response. Although the argument is convincing, one cannot but wonder, notwithstanding that cardiac outputs are matched to sea-level exercise, if altered flow dynamics in the high-altitude lung affect bubble stability. Had bubbles appeared in the left ventricle during high-altitude exercise, one could readily postulate increased flow through intrapulmonary anastomoses, but the absence of bubbles opens new avenues of doubt. Clearly, there are no bubbles in the left ventricle, but are intrapulmonary anastomoses patent during hypobaric hypoxic exercise? No amount of observations of absent bubbles confirms with certainty closed anastomoses, as long as the fate of the bubbles is unclear. Readers are left to pick holes or plug gaps in the study's findings! The future challenge will be to provide greater assurance of the method, more so than the observation. Accepting the authors’ conclusions, there is also the ‘hypoxia paradox’ to consider; hypoxia opens and closes intrapulmonary anastomoses. The duration of exposure to hypoxia and/or ambient pressure appear key qualities of the stimulus in this regard. The observation that hyperoxia dramatically reduces flow through arteriovenous shunts might hold some clues. It appears that 100% (not 50%) oxygen is required to prevent blood flow through anastomoses. Therefore, perhaps redox stress, common to experimental hyperoxia and high-altitude hypoxia, serves as a potent regulator of intrapulmonary arteriovenous blood flow? Antioxidant strategies could prove useful in delineating oxygen-dependent regulation of intrapulmonary blood flow during conditions of hypoxic stress. There is also the intriguing possibility that intrapulmonary anastomoses are directly sensitive to alterations in the . But models accounting for altered gas tensions could serve to burst that bubble! The physiological significance of blood flow through intrapulmonary arteriovenous anastomoses remains an issue for debate. The field is a step closer to considerations that control of anatomical anastomoses of the lung is an active phenomenon. Given the complexities of high-altitude physiology, we may be set for a long journey, with no short cuts in finding solutions! We eagerly await the outcomes of future high adventure in the shadows of the holy mountains or the hypobaric chamber. None declared. None.

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