Current status of pulmonary artery denervation

Abstract

Pulmonary hypertension is a progressive disease with a poor long-term prognosis and high mortality. Pulmonary artery denervation (PADN) is emerging as a potential novel therapy for this condition. The basis of pursuing a sympathetic denervation strategy has its origins in a body of experimental translation work that has demonstrated that denervation can reduce sympathetic nerve activity in various animal models. This reduction in pulmonary sympathetic nerve activity is associated with a reduction in pathological pulmonary hemodynamics in response to mechanical, pharmacological, and toxicologically induced pulmonary hypertension. The most common method of PADN is catheter-directed thermal ablation. Since 2014, there have been 12 reports on the role of PADN in 490 humans with pulmonary hypertension (311:179; treated: control). Of these, six are case series, three are randomized trials, and three are case reports. Ten studies used percutaneous PADN techniques, and two combined PADN with mitral and/or left atrial surgery. PADN treatment has low mortality and morbidity and is associated with an improved 6-minute walking distance, a reduction in both mean pulmonary artery pressure and pulmonary vascular resistance, and an improvement in cardiac output. These improved outcomes were seen over a median follow-up of 12 months (range 2-46 months). A recent meta-analysis of human trials also supports the effectiveness of PADN in carefully selected patients. Based on the current literature, PADN can be effective in select patients with pulmonary hypertension. Additional randomized clinical trials against best medical therapy are required.

Keywords: narrative review; outcomes; pulmonary denervation; pulmonary hypertension; therapy.

Figure 1

A graphic of the pulmonary arterial tree showing the common locations of baroreceptors and the current PADN treatment sites in the pulmonary trunk, the pulmonary bifurcation, and the pulmonary arteries.

Figure 2

Pathophysiology of pulmonary hypertension. The wall is composed of endothelial cells (EC) and vascular smooth muscle cells (SMC), and these cells sit in an environment of extracellular matrix (ECM). Both types of cells have ion channels for Ca²⁺ and K⁺ and receptors for prostaglandins (thromboxane and prostacyclin) and G-protein agonists (angiotensin, endothelin, serotonin, and catecholamines). In addition, nitric oxide from EC modulates SMCs. Soluble adenyl (sAC) and guanyl cyclases (sGC), and phosphodiesterases (PDE) modulate the ATP and GTP systems. EC and SMC are further influenced by sympathetic nerves in the wall. The combination of activation of EC and SMC, inflammation led by polymorphonucleocytes (PMN) and macrophages (MAC) coupled to progenitor cells, changes in the ECM, surges in or depletion of vasoactive factors and cytokines, altered receptor and ion channel expression, and overactivity of the sympathetic system led to pulmonary hypertension, vessel remodeling, myointimal hyperplasia, and occlusion in the pulmonary vasculature.