Pulmonary Artery Denervation (PADN)

Definition

Pulmonary artery denervation (PADN) is a transcatheter procedure that applies radiofrequency energy to the pulmonary arterial wall from within the lumen in order to ablate its sympathetic nerve supply, reducing pulmonary vascular sympathetic tone. The rationale is that sympathetic overactivation — a hallmark of both heart failure and pulmonary hypertension — drives pulmonary-artery vasoconstriction and remodelling, right ventricular–pulmonary-artery uncoupling, and progressive right ventricular dysfunction; interrupting that signalling is proposed to lower pulmonary vascular resistance and right ventricular afterload. It has been studied in WHO group 1 pulmonary arterial hypertension and, most recently and most substantially, in WHO group 2 pulmonary hypertension due to left heart disease — a category with no other therapy directed at its pulmonary vascular component.

Key Concepts

Procedure and Device

As specified in the PADN-HF-PH protocol (sources/padn-hf-ph-nejm-2026, rating: high):

• A pigtail-like catheter with 10 distal electrodes, sized to 1.1–1.2× the diameter of the main pulmonary artery
• Nonselective pulmonary angiography in anteroposterior and 20° left anterior oblique projections, both with 20° cranial angulation
• Ablation at three sites — the distal main pulmonary artery and the left pulmonary-artery bifurcation
• Radiofrequency energy for 150 seconds per site under temperature control (50 °C), with effective ablation defined as ≥120 seconds
• Weight-adjusted unfractionated heparin (bolus 70–100 IU/kg) to maintain ACT >250 s
• Intracardiac pressures measured before randomization, after angiography, and 10 minutes after the procedure
• Dual antiplatelet therapy (aspirin plus clopidogrel) recommended afterwards unless oral anticoagulation was required
• Median procedural time 101 minutes (IQR 86–120); median ablation time 7.1 minutes (7.0–7.7); only 1.5% of patients needed additional analgesia

Mechanistic Rationale

• Sympathetic nervous system activation is a hallmark of heart failure and contributes to its progression; plasma noradrenaline is an established prognostic marker in chronic heart failure
• Increased pulmonary vascular sympathetic activity contributes to pulmonary-artery vasoconstriction and remodelling, RV–PA uncoupling, and progressive right ventricular dysfunction — see concepts/RV-PA-Coupling
• Experimental work shows bidirectional interaction between pulmonary vascular sympathetic signalling and systemic neurohumoral activation, suggesting interruption could influence both pulmonary and cardiac function
• The proposed downstream effect of denervation is reduced pulmonary vascular resistance and RV afterload, improved left ventricular filling and ventricular interaction, and therefore lower left-sided filling pressures

Acute Haemodynamic Effect

• In PADN-HF-PH, at 10 minutes after the procedure, mean pulmonary-artery pressure fell by ≥1% in 87.9% of patients and by ≥10% in 53.4%; pulmonary vascular resistance and pulmonary-artery wedge pressure also fell acutely and cardiac output rose (sources/padn-hf-ph-nejm-2026, rating: high)
• Intracardiac pressures were unchanged at 10 minutes in the medical-therapy group, though the two arms were not assessed under identical conditions — the intervention arm had a procedure and the control arm did not, so this is not a blinded comparison

Evidence History

Efficacy — PADN-HF-PH Primary Result

• Primary composite (death, heart/lung transplantation, HF hospitalisation, outpatient worsening requiring IV diuresis, or ≥10%/>30 m decline in 6-minute walk distance): 2-year Kaplan–Meier 25.7% vs 51.5%; HR 0.49 (95% CI 0.30–0.82); P=0.006 (sources/padn-hf-ph-nejm-2026, rating: high)
• Excluding the 6-minute walk distance component: 20.8% vs 40.3%; HR 0.48 (0.27–0.86) — the effect is not an artefact of the walk test
• Recurrent events: 36.3 vs 56.3 per 100 patient-years; HR 0.59 (0.39–0.89)
• Restricted mean time free from clinical worsening: 19.6 vs 16.7 months; difference 87.6 days (95% CI 26–150)
• Oral diuretic intensification: 27.1% vs 41.8%; HR 0.48 (0.30–0.78) — and the benefit occurred despite less loop diuretic use in the denervation arm

Safety

• Access-site haematomas in 2 patients (denervation) versus 1 (medical therapy); no other procedural complications — no perforation, arrhythmia, acute pulmonary oedema or thrombus (sources/padn-hf-ph-nejm-2026, rating: high)
• Adverse events during follow-up occurred with similar frequency in both groups
• The procedural safety profile is a genuine strength of this evidence base and is not in dispute

Contradictions / Open Questions

• No sham control — and the field has been here before. PADN-HF-PH was open-label, and the authors state that "placebo effects and ascertainment bias cannot be ruled out." This matters acutely because the same procedural-denervation concept failed exactly this test once already: renal denervation produced positive unblinded trials that were followed by a neutral sham-controlled trial (SYMPLICITY HTN-3), and the field's requirement for sham control dates from that episode — see concepts/Renal-Denervation. A large-scale confirmatory international sham-controlled trial in CpcPH secondary to left heart failure has already begun (NCT07214376), and it is the trial that will settle whether PADN's effect is real and how large it is. Until then the direction is credible and the magnitude is not established. (sources/padn-hf-ph-nejm-2026, rating: high)
• The stated target population and the strongest subgroup signal diverge, and the trial does not address it. The rationale rests on CpcPH — the phenotype with pulmonary vascular remodelling and the worst outcomes. But the larger effect appeared in IpcPH (HR 0.31, 0.12–0.79) than in CpcPH (HR 0.71, 0.39–1.28), and in LVEF >40% (HR 0.37, 0.18–0.77) than LVEF ≤40% (HR 0.76, 0.37–1.55). In IpcPH, PVR is ≤2 Wood units by definition, so a pulmonary-vascular mechanism is least plausible in precisely the group showing the biggest benefit — which invites the suspicion that unblinded endpoint assessment, not denervation, is doing the work. (sources/padn-hf-ph-nejm-2026, rating: high)
• The composite is positive while its hard components are null. Death from any cause: HR 0.83 (0.19–1.74). Cardiovascular death: 3 vs 3 events. Heart-failure hospitalisation: HR 0.56 but the CI crosses 1 (0.30–1.04). The composite is carried by the softer, unblinded components — the 6-minute walk distance and outpatient diuretic intensification. Whether PADN changes outcomes patients would notice as survival or hospitalisation is therefore unproven. (sources/padn-hf-ph-nejm-2026, rating: high)
• The mechanism is asserted rather than demonstrated in this trial. Improved RV–PA coupling and sustained reduction in pulmonary vascular resistance are inferred from serial echocardiography and natriuretic peptides, because no follow-up right heart catheterisation was performed. The haemodynamic claim rests on prior, smaller studies. (sources/padn-hf-ph-nejm-2026, rating: high)
• The acute haemodynamic "response" is not a controlled comparison. Pressures were remeasured 10 minutes after the procedure in the intervention arm, and after 10 minutes of no procedure in the control arm. Patients and assessors were unblinded, so an acute fall in mPAP in 87.9% of denervated patients is not by itself evidence of a specific denervation effect — sedation, contrast, heparin and expectation all differ between arms. (sources/padn-hf-ph-nejm-2026, rating: high)
• Durability is unknown. Whether denervation is permanent, whether sympathetic re-innervation occurs, and whether a single procedure's effect on pulmonary vascular remodelling persists beyond the ~11-month median follow-up are all open. The trial's own authors note that longer follow-up is needed to determine whether midterm improvements translate into sustained reductions in mortality and hospitalisation. (sources/padn-hf-ph-nejm-2026, rating: high)
• How PADN would relate to drug therapy in group 2 PH is unaddressed. No drug has been shown to help the pulmonary vascular component of group 2 PH — riociguat failed in HFpEF-associated PH in the haemoDYNAMIC trial and PDE5 inhibitors are not indicated. PADN would therefore enter an empty therapeutic space if confirmed, but there is no evidence on sequencing, repeat procedures, or combination with any future pharmacotherapy. (sources/padn-hf-ph-nejm-2026, rating: high)

Connections

• Related to concepts/Pulmonary-Hypertension — group 2 PH (due to left heart disease) is the target indication; IpcPH vs CpcPH is the phenotype split the trial randomised against
• Related to concepts/Renal-Denervation — the closest procedural analogue and the cautionary precedent on sham control
• Related to concepts/RV-PA-Coupling — the proposed mechanism runs through sympathetic-driven RV–PA uncoupling
• Related to entities/Heart-Failure — GDMT was the comparator arm; the population was symptomatic despite contemporary maximal therapy
• Related to entities/HFpEF — 53% of the trial had preserved LVEF, and the LVEF >40% subgroup carried the larger effect
• Related to entities/HFrEF — 31.5–40.3% of the trial had reduced LVEF
• Related to concepts/Left-Cardiac-Sympathetic-Denervation — a different denervation modality (cardiac sympathetic, for arrhythmia) sharing the rationale of interrupting autonomic overactivity

Sources

• sources/padn-hf-ph-nejm-2026