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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.

For studying the possibility of using catheter denervation of the pulmonary artery for the treatment of pulmonary hypertension, large animals, such as pigs, are more suitable, because the diameter of the pulmonary artery in this case allows manipulation of the ablation catheter. The study of the perivascular adipose tissue of the trunk and bifurcation of the pulmonary artery in humans and pigs revealed differences in the density and diameter of nerve fibers, but their depth did not differ. Immunohistochemical analysis with different markers of the autonomic nervous system receptors revealed similar receptor profile in human and pigs, though the expression of all studied markers in pigs was less pronounced than in humans. These findings attest to similarity of the innervation of the pulmonary arteries in humans and pigs under normal conditions.

Transcatheter pulmonary artery denervation (PADN) has been developed for the correction of pulmonary hypertension. We investigated pulmonary artery stimulation mapping and its role in PADN procedures. Artery stimulation was performed in 17 Landrace pigs. Low-frequency stimulation defined areas of ventricular and atrial capture. High-frequency stimulation evoked the following responses: sinus rhythm slowing and/or atrial rhythm acceleration in 59% of animals, phrenic nerve capture in 100%, and laryngeal recurrent nerve capture in 23%. The sites with evoked heart rate responses were marked by discrete radiofrequency ablations (RFA). An autopsy showed nerves in the adventitia and perivascular fat under the RFA sites, and the lack of muscarinic-1, tyrosine hydroxylase, and dopamine-5 receptors' expression. During PADN, areas adjacent to the course of phrenic and recurrent laryngeal nerves should be avoided. RFA at points with heart rate responses leads to the non-reproducibility of evoked reactions and the disappearance of neural markers' expression. Graphical abstract.

Objective. We aimed to assess the effects of renal denervation (RDN) on systemic and pulmonary hemodynamics in a swine model of thromboxane A2- (TXA2-) induced pulmonary arterial hypertension (PAH). Methods. The study protocol comprised two PAH inductions with a target mean pulmonary artery pressure (PAP) of 40 mmHg at baseline and following either the RDN or sham procedure. Ten Landrace pigs underwent the first PAH induction; then, nine animals were randomly allocated in 1 : 1 ratio to RDN or sham procedure; the second PAH induction was performed in eight animals (one animal died of pulmonary embolism during the first PAH induction, and one animal died after RDN). In the RDN group, ablation was performed in all available renal arteries, and balloon inflation within artery branches was performed in controls. An autopsy study of the renal arteries was performed. Results. At baseline, the target mean PAP was achieved in all animals with 25.0 [20.1; 25.2] mcg of TXA2. The second PAH induction required the same mean TXA2 dose and infusion time. There was no statistically significant difference in the mean PAP at second PAH induction between the groups ( 39.0 ± 5.3 vs. 39.75 ± 0.5 mmHg, P > 0.05 ). In the RDN group, the second PAH induction resulted in a numerical but insignificant trend toward a decrease in the mean systemic blood pressure and systemic vascular resistance, when compared with the baseline induction ( 74 ± 18.7 vs. 90.25 ± 28.1 mmHg and 1995.3 ± 494.3 vs. 2433.7 ± 1176.7 d y n ∗ sec ∗ c m − 5 , P > 0.05 , respectively). No difference in hemodynamic parameters was noted in the sham group between the first and second PAH induction. Autopsy demonstrated artery damage in both groups, but RDN resulted in more severe lesions. Conclusions. According to our results, RDN does not result in significant acute pulmonary or systemic hemodynamic changes in the TXA2-induced PAH model. The potential chronic effects of RDN on PAH require further research.

Introduction Pulmonary hemodynamics improvement after pulmonary artery denervation (PADN) was demonstrated in PAH. Questions arise regarding PADN perioperative effectiveness and the accuracy of the target nerves damage. The aim of the study was to evaluate whether PADN decreases pulmonary artery pressure (PAP) in acute thromboxane A2 (U46619)–induced PAH, and damages PA perivascular nerve fibers. Materials and methods 10 male Landrace swine (34.7±5.1 kg). In 6 swine acute reversible target mean PAP of 40 mm Hg was induced with synthetic thromboxane A2 infusion (U46619). Control group: 4 swine with PADN. Hemodynamics was assessed throughout the study, PAH modeling was done before and 20 min after PADN (radiofrequency energy, 40 Watts), followed by pathology and immunohistochemical studies. Results The mean number of RF applications was 17.5±3.6. Pulmonary embolism (PE) was observed after PADN in 3 swine with U46619 infusion, which were excluded. There was no differences in mPAP, PVR and U46619 dosage after PADN in PAH model (12.3±3.5 vs 12.1±1 mm Hg, p=0.2; 150.4±48.7 vs 129.2±64.1 dynes s cm–5; p=0.2; 24.9±3.3 vs 22.4±4.1 mcg; p=0.18; respectively). Similar hemodynamic results were observed in the control group after PADN (mPAP; p=0.3; PVR; p=0.58). S100 expression was evident in the majority of RFA PA species and in some species loss in tyrosine hydroxylase and M1 acetylcholine receptors expression was detected with no hemodynamic correlation. Conclusions PADN using an electrophysiological catheter with unipolar energy does not lead to an acute PA perivascular nerve fibers destruction and detectable mPAP changes in U46619-induced PAH. Delayed nerve damage might be attributable to PADN effects observed in previous studies. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Grant from the Ministry of Science and Higher Education of the Russian Federation (agreement #075-15-2020-800).

Background: Pulmonary artery denervation (PADN) is an evolving interventional procedure capable to reduce pulmonary artery (PA) pressure. We aimed to compare PA nerve distribution in different specimens and assess the feasibility of an ovine model for a denervation procedure and evaluate the acute changes induced by laser energy. Methods: The experiment was divided into two phases: (1) the analysis of PA nerve distribution in sheep, pigs, and humans using histological and immunochemical methods, (2) fiberoptic PADN in sheep and postmortem laser lesion characteristics. Results: PA nerve density and distribution in sheep differ from humans, although pigs and sheep share similar characteristics, nerve fibers are observed in the media layer, adventitia, and perivascular tissue in sheep. Necrosis of the intima and focal hemorrhages within the media, adventitia, and perivascular adipose tissue were evidenced post laser PADN. Among the identified lesions, 40% reached adventitia and could be classified as effective for PADN. The use of 20 W ablation energy was safer and 30 W-ablation led to collateral organ damage. Conclusions: An ovine model is suitable for PADN procedures, however, nerve distribution in the PA bifurcation and main branches differ from human PA innervation. Laser ablation can be safely used for PADN procedures.

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

OnBehalf EHRA-ESC EORP AFA LT registry Introduction Despite the effectiveness of atrial fibrillation (AF) catheter ablation (CA), antiarrhythmic therapy (AAT) remains an important part of the complex treatment. Purpose To analyze AAT dynamics in Russian patients undergoing AF ablation, and to reveal potential factors associated with ongoing AAT in patients without arrhythmia recurrence. Methods The ESC-EHRA AF ablation registry was conducted in 2012-2016 in EHRA countries. The current analysis included 476 patients (57.1 male; 57.1 ± 8.7 years) who underwent AF ablation in 13 Russian clinics. AAT before, during and at 12-month follow-up (12-FU) was assessed. At baseline, paroxysmal AF was present in 320 (67.2%) patients, persistent AF - in 94 (19.7%), long-standing persistent AF- in 53 (11,1%), in 9 (1.9%) AF type was unknown. Hypertension (H) was present in 355 (74.6%) patients; congestive heart failure (CHF) (NYHA≥2) in 184 (38.7%) patients; coronary artery disease (CAD) in 132 (27.7%) patients. The CA was the first in 396 (83.2%) cases, redo ablation was performed in 80 (16.8%) cases. AF recurrences were registered according to local clinical practice. Any atrial tachyarrhythmia >30s was considered as a recurrence. Results A three-month FU (3-FU) visit was performed in 476 (100%) patients, 12-FU - in 390 (81.9%). Prior to PV isolation 439 (92.2%) patients received AAT, while after ablation there was an increase in the number of patients on AAT - 459 (96.4%). The highest number of patients on AAT was detected at 3-FU - 463 (97.3%). During 12 months at least one episode of arrhythmia recurrence was documented in 203 (52.1%) patients, and 370 (94.8%) patients were on AAT at the 12-month visit. After the 12-month visit 307 (78.7%) patients continued to receive AAT, and in 187 (47.9%) of them there was no arrhythmia recurrence after the index ablation. Five (2.7%) of these patients continued a Ic class AAT drug, 35 (18.7%) patients - class III, 129 (69.0%) patients - β-blockers (BB) and 18 (9.6%) patients - calcium channel blockers (CCB). All 187 patients had co-morbidities (75.4% - H; 41.7% - CHF (NYHA≥2; 31.6% - CAD). There were no statistically significant predictors of AAT use in patients without arrhythmia reccurence. According to the univariant regression analysis, the use of AAT III class (mainly-sotalol) at 12 months had a small but statistically significant negative association with left atrial size enlargement (OR = 0.917; 0.860-0.997); class III AAT was negatevely associated with BB therapy (OR = 0.057; 0.016-0.198); CCB therapy was associated with an older age (OR = 1.073; 1.053-1.151). Conclusions About one-half of patients without apparent arrhythmia recurrence following AF ablation do receive AAT. There were no clinical or procedure-related factors associated with AAT after effective AF ablation. Paradoxically, patients with a smaller left atrial size and without arrhythmia recurrence had more chances to receive class III AAT, what requires further analysis.

Objectives. We sought to assess acute changes in systemic and pulmonary hemodynamics and microscopic artery lesions following extended renal artery denervation (RDN). Background. RDN has been proposed to reduce sympathetic nervous system hyperactivation. Although the effects of RDN on systemic circulation and overall sympathetic activity have been studied, data on the impact of RDN on pulmonary hemodynamics is lacking. Methods. The study comprised 13 normotensive Landrace pigs. After randomization, 7 animals were allocated to the group of bilateral RDN and 6 animals to the group of a sham procedure (SHAM). Hemodynamic measures, cannulation, and balloon-based occlusion of the renal arteries were performed in both groups. In the RDN group, radiofrequency ablation was performed in all available arteries and their segments. An autopsy study of the renal arteries was carried out in both groups. Results. The analysis was performed on 12 pigs (6 in either group) since pulmonary thromboembolism occurred in one case. A statistically significant drop in the mean diastolic pulmonary artery pressure (PAP) was detected in the RDN group when compared with the SHAM group (change by 13.0 ± 4.4 and 10.0 ± 3.0 mmHg , correspondingly; P = 0.04 ). In 5 out of 6 pigs in the RDN group, a significant decrease in systemic systolic blood pressure was found, when compared with baseline ( 98.8 ± 17.8 vs. 90.2 ± 12.6 mmHg , P = 0.04 ), and a lower mean pulmonary vascular resistance (PVR) ( 291.0 ± 77.4 vs. 228.5 ± 63.8 dyn ∗ sec ∗ c m − 5 , P = 0.03 ) after ablation was found. Artery dissections were found in both groups, with prevalence in animals after RDN. Conclusions. Extensive RDN leads to a rapid and significant decrease in PAP. In the majority of cases, RDN is associated with an acute lowering of systolic blood pressure and PVR. Extended RDN is associated with artery wall lesions and thrombus formation underdiagnosed by angiography.