Hyperoxia-Induced Modulation of Intrapulmonary Arteriovenous Anastomoses: from Saline Contrast Echocardiography


Intrapulmonary arteriovenous anastomoses (IPAVA) are vascular conduits in the lungs that are bypasses between the arterial and venous systems, which traditionally are not considered to be significant in healthy adults at rest. However, during exercise or hypoxia, these channels can open up and impact pulmonary gas exchange and systemic oxygen delivery. Previous studies have shown that the flow through these anastomoses, and quantified as blood flow through IPAVA, increases during exercise and hypoxia but might be suppressed in hyperoxic conditions, which suggests a potential adaptive response to altered oxygen levels. Better understanding of the IPAVA regulation is essential because it may relate directly to clinical conditions such as exercise intolerance and diseases involving pulmonary shunts, such as pulmonary arteriovenous malformations. It also has implications in patients requiring supplemental oxygen, where the impact on pulmonary blood flow and gas exchange efficiency needs careful consideration. To this end, a new study published in American Journal of Physiology-Regulatory, Integrative and Comparative Physiology and conducted by Assistant professor James Davis from Indiana University School of Medicine alongside Assistant Professor Jonathan Elliott from Oregon Health & Science University, Associate Professor Joseph Duke from Northern Arizona University, Doctor Alberto Cristobal and Professor Andrew Lovering from University of Oregon, the researchers investigated the dynamics of IPAVA during varied oxygenation states in exercise conditions. They focused on the stability of saline contrast microbubbles under different oxygen conditions and how this relates to the presence of a patent foramen ovale (PFO), a common intracardiac shunt.

In their study, the team included 32 participants and split them into three groups based on the presence of a PFO where 16 participants without PFO, 8 with PFO, and 8 who exhibited late-appearing left-sided contrast but without PFO. The inclusion of individuals with and without PFO enriches the study’s applicability to a broader population. They also included both males and females, and exercise loads were adjusted accordingly (males: 250 W, females: 175 W). They participants underwent five 4-minute bouts of constant-load cycle ergometer exercise under different fractions of inspired oxygen (FIO2 levels: 0.21, 0.40, 0.60, 0.80, and 1.00), using a balanced Latin Squares design to control for order effects. Afterward, the researchers used transthoracic saline contrast echocardiography to assess IPAVA flow both at rest and during exercise. The precision in the measurement techniques, including constant-load cycle ergometer challenges calibrated for gender and continuous monitoring, underscores the robustness of the experimental setup. This involved the injection of saline contrast microbubbles and scoring their appearance in the left heart as a measure of shunt activity. Moreover, they developed a bubble scoring system where they scored bubbles from 0 (no microbubbles) to 5 (extensive microbubble presence), with particular attention to changes in scores across different oxygen levels.

The authors found that at lower FIO2 levels (0.21, 0.40, and 0.60), bubble scores were relatively unchanged and indicated active IPAVA flow during exercise.  They observed significant reductions in bubble scores at higher oxygen levels (FIO2 = 0.80 and 1.00), particularly in participants without PFO, which suggests a decrease in IPAVA flow under hyperoxic conditions. To investigate the effects of PFO, participants with PFO showed higher bubble scores at an FIO2 of 1.00 compared to those without PFO, indicating that the presence of PFO might maintain some IPAVA flow even under conditions that would typically reduce it in non-PFO individuals.

The stability of microbubbles, as indicated by their presence across increasing FIO2 levels, suggests that hyperoxia leads to a functional rather than a physical closure of IPAVAs. This is inferred from the consistent decrease in bubble scores without complete disappearance, indicating that while the anastomoses remain patent, their functionality or the stability of the microbubbles is compromised. According to the authors, the decrease in IPAVA flow during hyperoxia might be due to oxygen-induced vasoconstriction or other regulatory mechanisms affecting vascular tone. This mirrors mechanisms observed in systemic circulatory adaptations, like the ductus arteriosus closure after birth.

Overall, the new study by professor James Davis and colleagues demonstrated a clear influence of hyperoxia on IPAVA function during exercise, marked by a reduction in flow that is not necessarily accompanied by physical closure. The presence of a PFO modulates the response, which suggests a complex interaction between intracardiac shunts and pulmonary vascular responses. These authors’ findings enhance our understanding of pulmonary vascular physiology, especially in response to varying oxygen levels, with significant implications for clinical management of oxygen therapy in various diseases. Additionally, future studies could investigate the molecular and cellular mechanisms underlying the oxygen sensitivity of IPAVAs and the impact of chronic exposure to different oxygen levels which could improve chronic lung disease management or adaptations to high altitude.


Davis JT, Elliott JE, Duke JW, Cristobal A, Lovering AT. Hyperoxia-induced stepwise reduction in blood flow through intrapulmonary, but not intracardiac, shunt during exercise. Am J Physiol Regul Integr Comp Physiol. 2023;325(1):R96-R105. doi: 10.1152/ajpregu.00014.2023.

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