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U46619, a synthetic analogue of thromboxane A2 was used for modeling acute stable and reversible pulmonary arterial hypertension. Administration of U46619 in high doses led to vascular collapse and inhibition of cardiac function. The doses of U46619 were empirically selected that allow attaining the target level of pulmonary hypertension without systemic hemodynamic disturbances. The possibility of attaining the target level of pulmonary hypertension and reversibility of changes after termination of U46619 infusion make this model attractive for evaluation of the efficiency of different therapeutic methods of treatment of pulmonary hypertension in large animals.

Introduction Pulmonary artery denervation (PAD) has been recently shown to decrease pulmonary artery (PA) pressure. However, there is a lack of data related to target sites for ablation. Purpose To determine the optimal PA ablation sites based on response to high-frequency stimulation mapping and anatomical areas where radiofrequency ablation (RFA) should be avoided due to the risk of severe collateral damage. Methods A total of 17 Landrace swines were included into the study. PA angiography, hemodynamic measurements by right heart-sided catheterization and electrophysiological mapping (EM) using low (cycle length 330 ms) and high-frequency (33Hz) stimulation (HFS). Stimulation was performed at PA bifurcation and proximal parts of the main PA branches with a 5-mm distance between points; catheter manipulation was performed under fluoroscopic guidance in multiple projections. Points with evoked reactions were tagged on a 3-dimentional PA model in each case. In order to confirm reproducibility of reactions, HFS was performed at least twice at each point with a response. PA models obtained from all animals were combined in one for the final analysis. RFA using an open-irrigated catheter (40 Watts; 40 s; irrigation 30 ml/min) were performed at sites with evoked reactions. Repeated HFS was performed at ablation sites. After the procedure all animals were euthanized and underwent an autopsy study. Results Low-frequency stimulation (LFS) allowed to define areas of ventricular capture (VC) where HFS was avoided due to ventricular fibrillation induction risk. During HFS the following evoked responses were documented: sinus bradycardia, sinus rhythm (SR) acceleration, phrenic nerve capture (PNC), and laryngeal recurrent nerve capture. HFS captured left and right phrenic nerves in all animals at PA trunk, and its course was tagged (Figure 1). Laryngeal recurrent nerve capture was found in 4 (23%) of animals. Atrial capture was found in all cases while LFS at the anterior aspects of both PAs even at low output, and this precluded evaluation of neural autonomic reactions in these areas. Evoked bradycardia and SR acceleration were both found during HFS in 10 (59%) of cases each. Following RFA application evoked reactions were non-reproducible in all cases. RFA was applied in areas where no PNC or VC points were observed. An autopsy study confirmed the presence of RF-induced lesions of the PA wall. Conclusions There are two important findings of our study. First, stimulation-guided PA mapping is feasible and reveals several specific responses to HFS. Ablation at points with responses leads to non-reproducibility of the evoked reactions, confirming that transcatheter RFA may be an adequate approach for PA denervation. Second, previously proposed circular PA ablation might be associated with phrenic and laryngeal recurrent nerve damage. Stimulation-guided PA denervation can be proposed as a safer procedure, and should be evaluated in clinical settings. Figure 1. PA schematic representation Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Russian Foundation for Basic Research

Introduction Survival in PAH is strongly associated with adaptation of the RV to pressure overload. Purpose To investigate acute hemodynamic reactions during infusion of the stable thromboxane A2 (TXA2) analogue U46619 in a porcine model. Materials and methods The study comprised 9 male Landrace pigs (32.7±3.8 kg) under GA. After heparinization, PAH was induced by continuous and stepwise increasing infusion of U46619 (10 mg/ml; Tocris, USA) according to a pre-specified protocol. The target mPAP was 40 mmHg. Hemodynamics was assessed, cardiac output (CO) was calculated using the Fick equation before and during U46619 infusion. Results U46619 infusion at a previously published rate 0.1, 0.2 μg kg–1 min–1 in pig 1 resulted in rapid hemodynamic deterioration. Two-time reduced U46619 dose infusione resulted in a target mPAP but severe mBP drop in 1, 3, 4 pigs and required cathecholamine support. The U46619 dosage was reduced up to ¼ (0.025, 0.05, 0.075, 0.1, 0.12, 0.15, 0.175 μg kg–1 min–1). In animals on 1/4 dosage U46619 infusion, heart rate (HR), mBP, mPAP, RAP and PVR reliably increased and BP was stable (Table 1). There was a positive correlation between the mPAP and heart rate (HR) on U46619 infusion (r=0.66; t=2.38; p=0.048) and between CO and mBP (r=0.66; t=2.36; p=0.04). Low CO was associated with high PVR (r=−0.98; t=−14.3; p Conclusions High dose U46619 infusion was associated with acute RV decompensation due to pressure overload accompanied with systemic BP drop and low CO. Lower dosages of U46619 infusion were characterized by stable target mean PAP. HR acceleration and mean systemic BP are of compensation mechanisms for cardiac output maintenance in PAH. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): RFBR grant 18-315-20050

U46619, a synthetic analogue of thromboxane A2 was used for modeling acute stable and reversible pulmonary arterial hypertension. Administration of U46619 in high doses led to vascular collapse and inhibition of cardiac function. The doses of U46619 were empirically selected that allow attaining the target level of pulmonary hypertension without systemic hemodynamic disturbances. The possibility of attaining the target level of pulmonary hypertension and reversibility of changes after termination of U46619 infusion make this model attractive for evaluation of the efficiency of different therapeutic methods of treatment of pulmonary hypertension in large animals.