Pulmonary hypertension: diagnostic method to test the true curative efficacy of a drug

Background : A decrease in resting pulmonary vascular resistance (PVR), caused by vasodilator drugs, does not correspond to an improvement in the perfused capillary surface area in patients with pulmonary hypertension (PH). Intrapulmonary arteriovenous anastomoses (IPAVA) are linked to PVR, but their role within the pulmonary circuit is still unclear. Method : Taking inspiration from the laws regulating electrical circuits with two groups of resistors connected in parallel and from Kirchhoff's first law, after adapting them to fluid dynamics, I developed a law applicable to the pulmonary circuit with open IPAVA and new hemodynamic parameters : RQp (arteriolar equivalent resistance), RQipava (IPAVA equivalent resistance), and PVR (calculated with RQp and RQipava). These parameters were applied to experimental data from subjects in acute hypoxia ( F IO ₂ = 0.125) at rest after receiving placebo and acetazolamide (ACZ), a drug that decreases PVR. Results : ACZ actually caused an increase in arteriolar vasoconstriction (RQp = + 0.20 WU versus placebo). The decrease in PVR (- 0.25 WU versus placebo) was due to the significant decrease in RQipava (-24.05 WU versus placebo). Consequently, blood flow through the pulmonary microcirculation (Qp) decreased with ACZ (-1.08 L/min versus placebo), whereas blood flow through IPAVA (Qipava) increased, and VCO ₂ decreased. Conclusions : This diagnostic method reveals the true mechanism of action of a drug on the pulmonary circuit and offers the possibility of monitoring its therapeutic efficacy. This study also allowed a new definition of the primary endpoint phase 2 studies, which may contribute to the clinical approval of new drugs for PH.