Insight into the Physiologic Impact of Right-to-Left Intrapulmonary and Intracardiac Shunt in Healthy Humans

Large diameter intrapulmonary arteriovenous anastomoses (IPAVA) have been known to exist in humans for >60 years, and the prevalence of patent foramen ovale (PFO) is ~35-40% in the general population. However, respiratory physiologists have largely ignored the presence of a PFO and only recently begun to appreciate IPAVA. Reasons some remain critical of IPAVA to be physiologically relevant is due to the relatively undefined role for blood flow through IPAVA to contribute to pulmonary gas exchange efficiency and the unknown and mechanism(s) regulating blood flow through IPAVA. In Chapter IV the role for blood flow through IPAVA to contribute to pulmonary gas exchange efficiency (A-aDO2) was investigated using an experimental paradigm minimizing contributions from alveolar ventilation-to-perfusion inequality and diffusion limitation to the A-aDO2. The increase in blood flow through IPAVA corresponded to an increase in the A-aDO2 and an increase in total venous admixture of ~2% of the cardiac output. Bronchial shunt was estimated to be ~1%, which suggests blood flow through IPAVA and Thebesian blood flow constitute the remaining ~1% of the cardiac output during intravenous infusion of epinephrine. We originally proposed to quantify blood flow through IPAVA during the conditions in Chapter IV using radiolabeled macroaggregated albumin; however, ongoing studies demonstrated the need to validate this technique when breathing hyperoxia. In Chapter V the effect of sildenafil, nifedipine, and acetazolamide on blood flow through IPAVA during exercise breathing room air and 100% O2 was investigated, and no effect was observed. These pharmacologic interventions act through mechanisms with the potential to prevent or reduce the hyperoxia-mediated reduction in blood flow through IPAVA. Nifedipine and acetazolamide may prevent or limit pulmonary vascular smooth muscle contraction, while sildenafil may augment relaxation of pulmonary vascular smooth muscle. Lastly, in Chapter VI it was demonstrated that after acclimatization to hypobaric hypoxia in healthy humans, blood flow through IPAVA was reduced, and subjects with a PFO have impaired pulmonary gas exchange efficiency and a reduced degree of ventilatory acclimatization. This dissertation includes previously unpublished co-authored material