Pulmonary Artery Denervation for the Treatment of PAH

While the development of therapies targeting the endothelin, nitric oxide, and prostacyclin pathways have led to significant improvements in clinical outcomes for patients with pulmonary arterial hypertension (PAH), a significant number of patients exhibit a limited response to these agents and may be considered for lung or heart-lung transplantation. For patients awaiting transplantation and those who are ineligible for transplantation, there is a pressing need for nonpharmacologic interventions to alleviate symptoms and improve quality of life.¹

As PAH progresses, the sympathetic nervous system is activated and the renal-angiotensin-aldosterone system is upregulated to compensate for the elevation in pulmonary vasculature resistance and the increased right ventricle afterload.² Although autonomic dysregulation is not believed to represent a primary mechanism in the pathogenesis of PAH, sympathetic nervous system activation was shown to predict clinical deterioration.³

In the absence of drugs modulating sympathetic nervous system activation, a viable alternative consists of interventional options that block the sympathetic nerve supply to pulmonary arteries.¹ One technique showing promise in emerging studies is pulmonary artery denervation (PADN), which has been found to reduce the sympathetic activity of the pulmonary circulation.

Studies in animal models of acute and chronic pulmonary hypertension (PH) indicate beneficial effects of surgical and chemical PADN, including reduced muscularization of the pulmonary arteries, improvements in pulmonary hemodynamics, reduced right ventricle (RV) mass and improved RV function, upregulation of β-adrenoceptor expression, and downregulation of α-adrenoceptor expression.¹

In humans, PADN with catheter-based radiofrequency ablation or high-energy endovascular ultrasound has been found to be safe and efficacious. In a 2015 phase II clinical trial, in which 66 patients with PH (39 with PAH, 18 with PH secondary to left heart disease, and 9 with chronic thromboembolic PH) were treated for 12 months with endovascular radiofrequency ablation, 6-minute walk distance (6MWD) was found to be improved (94 m increase), mean pulmonary arterial pressure (mPAP) was reduced from 41 to 36 mmHg, and RV function enhanced (tricuspid excursion index decreased from 0.63 to 0.39). The majority of patients (71%) experienced chest pain during the procedure.⁴

Preliminary results from an ongoing open-label phase I safety study (TROPHY1) in which 14 patients with PAH on combination therapy were enrolled, PADN using high-frequency intravascular ultrasound was not associated with serious adverse events such as arterial perforation, aneurysm, dissection, or death. Analyses of secondary efficacy endpoints indicate a small but statistically significant change in pulmonary vascular resistance (9.4 vs 8 WU, P <.01) accompanied by a reduction in mPAP (52.7 mmHg to 44.5 mmHg, P =.01), but no significant change in 6MWD.⁵

In a prospective randomized sham-controlled trial (PADN-5), researchers examined the effects of PADN in patients with pre- and post-capillary PH secondary to left-sided heart failure. Participants were randomly assigned to receive PADN (n=48) or sildenafil plus sham PADN (n=50) in addition to standard therapy for heart failure. Six months after PADN, 6MWD (the primary endpoint) increased by 83m in the PADN group and 15m in the sildenafil group (least square mean difference, 66 m; 95% CI, 38.2-98.8 m; P <.001). In addition, pulmonary vascular resistance (secondary endpoint) was found to be lower in the PADN vs sildenafil group (4.2 ± 1.5 WU vs 6.1 ± 2.9 WU, respectively; P =.001). A post-hoc analysis indicated that clinical worsening was less frequent in patients treated with PADN vs sildenafil (16.7% vs 40%, respectively; P =.014). There were 2 cases of pulmonary embolism (the main safety endpoint) and 7 all-cause deaths by the end of the study.⁶

These results suggest a role for PADN in the treatment of patients with PAH, but there are many remaining questions regarding the “short and long-term efficacy of PADN, its mechanism of action and appropriate patient selection and timing,” the review authors concluded.¹ These points “need to be appropriately addressed in large rigorously designed multi-national randomized controlled trials investigating robust efficacy end-points, before PADN can be recommended for routine clinical use.”

Among other specific areas of focus, the authors recommend that future research explore the anatomy and physiology of the autonomic system during the PADN procedure, as well as its impact on the hemodynamics of the left and right heart.

References

1. Constantine A, Dimopoulos K. Pulmonary artery denervation for pulmonary arterial hypertension. Trends Cardiovasc Med. 2020;S1050-1738(20)30059-1. doi:10.1016/j.tcm.2020.04.00
2. Le T, Makar C, Morway P, Hoftman N, Umar S. Pulmonary artery denervation: a novel treatment modality for pulmonary hypertension. J Thorac Dis. 2019;11(4):1094-1096. doi:10.21037/jtd.2019.02.93
3. Ciarka A, Doan V, Velez-Roa S, Naeije R, van de Borne P. Prognostic significance of sympathetic nervous system activation in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2010;181(11):1269-1275. doi:10.1164/rccm.200912-1856OC
4. Chen SL, Zhang H, Xie DJ, et al. Hemodynamic, functional, and clinical responses to pulmonary artery denervation in patients with pulmonary arterial hypertension of different causes: phase II results from the Pulmonary Artery Denervation-1 study. Circ Cardiovasc Interv. 2015;8(11):e002837. doi:10.1161/CIRCINTERVENTIONS.115.002837
5. Rothman AMK, Vachiery JL, Howard L, Lang I, Avriel A, Jonas M, et al. Pulmonary artery denervation for the treatment of pulmonary arterial hypertension: preliminary results of the TROPHY 1 Study. Eur Heart J. 2018;39(Suppl_1). doi:10.1093/eurheartj/ehy564.P567
6. Zhang H, Zhang J, Chen M, et al. Pulmonary artery denervation significantly increases 6-min walk distance for patients with combined pre- and post-capillary pulmonary hypertension associated with left heart failure: the PADN-5 Study. JACC Cardiovasc Interv. 2019;12(3):274-284. doi:10.1016/j.jcin.2018.09.021