Effect of pulmonary artery denervation in postcapillary pulmonary hypertension: results of a randomized controlled translational study

Abstract

The authors thank Gonzalo J. López for the high-quality cardiac magnetic resonance examinations. Tamara Córdoba, Oscar Sanz, Nuria Valladares, Eugenio Fernández and the rest of the staff working in the animal facilities and CNIC ś farm were outstanding in animal care and unconditional collaboration. Laura García, Alberto Barroso and Xavier Navarro provided us with the ablation clamps and catheters and assisted us during the denervation procedures. Paula Garcia-Lunar provided valuable support with tissue sampling when it was most needed. SOURCES OF FUNDING:This work has been partially funded by the grant "Translational research project from the Sociedad Española de Cardiología" (to Dr. García-Álvarez) and by an unrestricted grant from Medtronic. The CNIC is supported by the Ministerio de Ciencia, Innovación y Universidades and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505).IDIBAPS belongs to the CERCA Programme and receives partial funding from the Generalitat de Catalunya.

Neurohormonal Modulation as a Therapeutic Target in Pulmonary Hypertension

“…Thirty years later, Chen et al [78] suggested, for the first time, that percutaneous PA denervation (using a dedicated catheter) could acutely reduce the increase in PA pressure and PVR generated by a balloon occlusion of a pulmonary branch. Since this first publication, PA denervation has been further tested in another seven experimental studies [8][9][10][79][80][81][82], the details of their main characteristics and findings can be found in Table 3. Studies using acute models of PH have reported an acute improvement in PA hemodynamics after the percutaneous PA denervation procedures using radiofrequency [78] or intravascular ultrasound [10].…”

“…Although the study was again positive in terms of PA hemodynamics, RV function, and pulmonary vascular remodeling, the low efficacy and high mortality of the PH model (78 rats were required to have 18 animals with complete follow-up) together with the probable variability of manual dissection of the PA adventitia in a small animal, made the results difficult to interpret. The first negative experimental study in PA denervation was published in 2019 by Garcia-Lunar et al [81] and used a different methodology from prior publications. First, the PH model was a swine model of chronic postcapillary PH (generated by a pulmonary vein banding) and the authors used a surgical approach with application of radiofrequency directly to the external layer of the PA with bipolar clamps for the PA denervation with histological confirmation.…”

“…Nevertheless, there are important gaps of knowledge regarding the mechanism of action and potential benefit of this intervention. For example, how a percutaneous denervation that does not fully interrupt all sympathetic nervous fibers [81] may have a predictable and reproducible effect on pulmonary hemodynamics or if there is a way to avoid injuring parasympathetic nerve fibers during the procedure. Until now, PADN trials have used empirical strategies to guide the denervation procedures, mainly based on fluoroscopic landmarks [11].…”

“…If this were the case, the intervention may lose efficacy over time and re-do procedures may be necessary. Finally, studies with dedicated RV anatomy and function evaluation are needed to elucidate whether there may be a direct and potentially deleterious effect of PA denervation on cardiac remodeling and function [81].…”

Pulmonary artery denervation – the time has come for a multicentre blinded randomised controlled trial

“…Chen et al 9 Zhou et al 14 Garcia-Lunar et al 15 Rothman et al 16 Townsend et al 10 PADN-1 (first-in-man) 17 PADN-1 (phase II) 18 PADN-5 19 Number 12 trials have provided new biological proof of principle for the blood pressure-lowering efficacy of renal denervation. The same rigorous standards as in these trials will have to be adopted by the PADN trials; however, critical differences between the systemic and pulmonary circulation have to be taken into account.…”