Beyond PVR: A New Hemodynamic Law Integrating Intrapulmonary Arteriovenous Anastomoses and Gas Exchange

The evaluation of drug efficacy in pulmonary hypertension (PH) relies on decreased pulmonary vascular resistance (PVR). However, PVR may provide a misleading interpretation of pulmonary hemodynamics if the role of intrapulmonary arteriovenous anastomoses (IPAVA) is neglected. We coupled the hemodynamic/metabolic data to develop a new hemodynamic law. The pulmonary circuit, with open IPAVA, was modelled like an electrical circuit with two resistances in parallel: arteriolar resistance (R\(\dot{\text{Q}}\) _p ) and IPAVA resistance (R\(\dot{\text{Q}}\) _IPAVA ). This model was applied to healthy subjects under acetazolamide (ACZ) and placebo during acute hypoxia ( F IO ₂  = 0.125) at rest and during exercise in normoxia. Under resting hypoxia, ACZ decreased PVR (-0.25 WU vs. placebo), but there was a contemporary drastic decrease in R\(\dot{\text{Q}}\) _IPAVA (-24.05 WU), which masked a reduction in effective capillary flow (\(\dot{\text{Q}}\)p = -1.08 L/min) and \(\dot{\text{V}}\text{C}{\text{O}}_{2}\). During heavy exercise in normoxia/placebo, the blood flow through IPAVA (\(\dot{\text{Q}}\) _IPAVA ) was 2.4% of cardiac output (\(\dot{\text{Q}}\) _T ), whereas ACZ increased \(\dot{\text{Q}}\) _IPAVA to ~ 15% of \(\dot{\text{Q}}\) _T , reducing \(\dot{\text{Q}}\)p by ~ 11% and \(\dot{\text{V}}\text{C}{\text{O}}_{2}\) by ~ 9%. Crucially, the gas exchange extraction efficiency (\(\text{ϵ}\) = \(\dot{\text{V}}\text{C}{\text{O}}_{2}\)/\(\dot{\text{Q}}\)p) remained stable (\(\text{ϵ}\): 0.199 placebo vs. 0.205 ACZ), indicating that the \(\dot{\text{V}}\text{C}{\text{O}}_{2}\) impairment was mechanistically driven solely by flow redistribution rather than by carbonic anhydrase inhibition. These results suggest that therapeutic efficacy based solely on PVR may be a “hemodynamic illusion” with potential iatrogenic risks for the patient. A new paradigm coupling hemodynamic/metabolic parameters (Lavoisier's mass law) is needed to enable precision medicine, more accurate pharmacovigilance and the development of new therapeutic targets for pulmonary vascular diseases.