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Pulmonary artery denervation for pulmonary arterial
hypertension
Andrew Constantine MBBS MA & Konstantinos Dimopoulos MD MSc PhD FESC
From the Adult Congenital Heart Centre and National Centre for Pulmonary Hypertension,
Royal Brompton Hospital, London, UK & the National Heart and Lung Institute, Imperial
College London, UK.
Correspondance to:
Professor Konstantinos Dimopoulos
Adult Congenital Heart Centre
Royal Brompton and Harefield NHS Foundation Trust
Sydney Street, London SW3 6NP, UK
Tel +44 2073 528121
E- mail: [email protected]
Manuscript word count:
3481 words (5529 including references)
Conflicts of interest:
Dr Constantine has received a personal educational grant from Actelion Pharmaceuticals (a
Janssen Pharmaceutical company). Professor Dimopoulos has received nonfinancial support
from Actelion Pharmaceuticals; and has been a consultant to and received grants and personal
fees from Actelion Pharmaceuticals, Pfizer, GlaxoSmithKline, and Bayer/MSD.
Abstract
Pulmonary arterial hypertension remains a progressive, life-limiting disease despite optimal
medical therapy. Pulmonary artery denervation has arisen as a novel intervention in the
treatment of pulmonary arterial hypertension, and other forms of pulmonary hypertension,
with the aim of reducing the sympathetic activity of the pulmonary circulation. Pre-clinical
studies and initial clinical trials have demonstrated that the technique can be performed safely
with some positive effects on clinical, haemodynamic and echocardiographic markers of
disease. The scope of the technique in current practice remains limited given the absence of
well-designed, large-scale, international randomised controlled clinical trials. This review
provides an overview of this exciting new treatment modality, including pathophysiology,
technical innovations and recent trial results.
Key words
Pulmonary artery denervation; pulmonary hypertension; pulmonary arterial hypertension
Abbreviations
6MWD – 6-minute walk distance
6-OHDA – 6-hydroxydopamine
BMPR-II, bone morphogenetic protein receptor type 2
BNP – Brain natriuretic peptide
Ca2+, calcium ion
CHD – congenital heart disease
CMR – cardiac magnetic resonance imaging
CTEPH – chronic thromboembolic pulmonary hypertension
DHMCT – dehydrogenized monocrotaline
EM – electron microscopic
IV – intravenous
mPAP – mean pulmonary arterial pressure
PA – pulmonary artery/arterial
PAH – pulmonary arterial hypertension
PADN – pulmonary artery denervation
PCWP – pulmonary capillary wedge pressure
PE – pulmonary embolism
PH – pulmonary hypertension
PVR – pulmonary vascular resistance
RAAS – renin-angiotensin-aldosterone-system
RHC – right heart catheterisation
RV – right ventricle/ventricular
SAE – severe adverse event
SNA – sympathetic nervous system activation
TGF-β – transforming growth factor beta
TxA2 – thromboxane A2
TPG – transpulmonary gradient
WHO – World Health Organisation
WU – Wood Unit(s)
Introduction
Pulmonary arterial hypertension (PAH) is characterised haemodynamically by the presence
of pre-capillary pulmonary hypertension (PH), with a mean pulmonary arterial pressure
(mPAP) of ≥25 mmHg, a pulmonary artery wedge pressure of ≤15 mmHg, and a pulmonary
vascular resistance (PVR) of >3 Wood units (WU) (1), although a mPAP of 21-24 mmHg is
abnormal and a cut off of >20 mmHg has recently been proposed for the haemodynamic
definition of PH (2). PAH is a clinical diagnosis consisting of various underlying clinical
entities, including idiopathic, heritable, drug or toxin-induced or associated with underlying
systemic disease. This latter group is formed mainly of patients with connective tissue disease
or congenital heart disease (CHD). Endothelial dysfunction with inappropriate
vasoconstriction, pulmonary vascular remodelling and in-situ thrombosis has been identified
as major pathophysiological mechanisms in all types of PAH. As disease develops and
progresses, the cross-sectional area of the distal pulmonary vessels is reduced, causing a rise
in PVR and pulmonary arterial (PA) pressure, which impact on right ventricular function.
Without therapy, the progressive increase in afterload and strain on the right ventricle (RV) is
associated with significant morbidity and mortality.
Several pharmacological therapies have been developed for PAH, focusing on the endothelin,
nitric oxide and prostacyclin pathways (3,4). These therapies have improved clinical
outcomes, and are nowadays often used in combination to maximise benefit (5). However,
many patients can have an inadequate response to treatment and fail to reach therapeutic
targets despite optimal medical therapy. In others, the disease may progress after an initial
positive response and a period of stability on PAH therapies. While appropriate candidates
with PAH failing medical therapy should be assessed for lung or heart-lung transplantation
(6,7), novel treatment strategies are needed to prolong longevity and improve quality of life
prior to transplantation, given the limited availability of donor organs. Moreover, there are
many patients not suitable for transplantation, who rely on treatment escalation and novel
therapeutic options for prolonging their life and limiting their symptoms. Developments in
our understanding of the cellular and molecular mechanisms of disease in PAH, beyond the
vasomotor pathways that are the targets of current vasodilator therapy, have highlighted the
role of emerging pathways amenable to therapeutic intervention (Figure 1) (8). Non-
pharmacological techniques are already in use for the treatment of pulmonary hypertension
(PH). Exercise-based rehabilitation programmes are safe and effective in PH, and can result
in clinically relevant improvements in exercise capacity (9). Invasive treatment strategies
include percutaneous or surgical creation of pulmonary-to-systemic shunts aimed at
offloading the RV and enhancing cardiac output (atrial septostomy, or a Potts shunt between
the descending aorta and left PA) (10–12), and balloon pulmonary angioplasty for patients
with CTEPH (13,14). Various forms of endovascular autonomic system modification have
been proposed in animal models of PH, including sympathetic ganglion blockade and
catheter-based renal denervation (15–18). In recent years, the autonomic function of the
pulmonary vasculature has attracted further attention and most recently this has culminated in
numerous human trials of PA denervation (PADN) (19–25). This treatment has the potential
to add considerably to the management of PH, where novel therapies are in short supply. This
review follows the evolution of the technique, from the initial experiments in animal models
to the latest multi-centre trials. We assess the state of the evidence supporting the adoption of
PADN in clinical practice and review the unanswered questions in this young field.
Autonomic dysregulation in pulmonary hypertension
The pulmonary vasculature receives a rich autonomic nerve supply, with sympathetic
(predominantly), parasympathetic and sensory nerve fibres (26). The anatomy of the
innervation of the lungs and pulmonary vasculature is well documented. Over the past half a
century, our understanding of the role of the autonomic nervous system in health has
increased significantly, with elucidation of central and local reflexes and their interaction
with humoral and local vasoactive mechanisms of control. The role of the nervous system in
disease states, however, is not well understood.
The sympathetic nerve supply to the pulmonary vessels arises from neuronal cell bodies in
the middle and inferior cervical ganglia and the first 5 thoracic ganglia (27). The post-
ganglionic fibres of these nerves meet parasympathetic nerve fibres to form the anterior and
posterior plexi at the carina. From here, nerve fibres enter the lungs forming a peribronchial
plexus, which innervates the bronchial tree, and a periarterial plexus, which runs in the
adventitial layer and innervates the pulmonary vasculature. Although the density and extent
of the sympathetic nerve supply varies significantly between species (for example, adrenergic
nerve fibres are absent in the intrapulmonary arteries of the rat) (28) in humans the
periarterial plexus extends to small PAs of <100µm diameter (29). As in other medium-to-
large vessels, β2-adrenoceptors predominate (30) with evidence of co-existing β1- (31) and α-
adrenoceptors. In the parasympathetic system, descending pre-ganglionic nerves arise from
the brainstem and pass as the pulmonary branches of the vagus nerve to the pulmonary plexus
at the lung roots, where they congregate with postganglionic sympathetic fibres. The
parasympathetic fibres either synapse with the cells of the ganglion or continue in the walls
of the bronchial and arterial trees to the target organs, where they synapse with post-
ganglionic neurons. Of note, the adipose and connective tissues surrounding the pulmonary
trunk are also richly innervated with sympathetic nerve fibres (32). These sympathetic nerve
fibres are in close proximity to the cardiac autonomic supply and the right phrenic nerve,
especially in PAH patients with passive PA dilatation. Thus, any therapy that targets the
sympathetic supply to the lungs is at risk of adversely affecting the nerve supply to adjacent
structures.
In health, pulmonary vascular tone is carefully regulated by a complex network of neural and
humoral factors, which interact with the haemodynamic loads imposed by the systemic
circulation. This results in optimal ventilation-perfusion matching in the pulmonary
circulation, both at rest and during exertion, aimed at maintaining normoxia and oxygen
delivery to peripheral tissues (26). Central and local reflex mechanisms, mediated by
autonomic efferents, are partly responsible for this tight regulation of pulmonary vascular
tone. For example, stimulation of chemoreceptors in the carotid or aortic bodies has a
variable effect on PVR depending on experimental conditions (33,34). It has also been shown
that distension of the large PAs produces vasoconstriction of the distal PAs, mediated by a
local pulmonary reflex involving baroreceptors in the PA bifurcation and along the branch
PAs, with afferent fibres in the adventitia of the large vessels and effector fibres in the muscle
layer (35).
The role of these mechanisms in disease states, including interactions with local mediators,
such as nitric oxide, endothelin and thromboxane, and humoral mechanisms remains unclear.
Indeed, there is overwhelming evidence that autonomic dysregulation is not the major
pathophysiological driver of PAH; rather endothelial dysfunction, excessive proliferation of
PA smooth muscle and a resultant vasoconstriction are the major disease mechanisms. As
pulmonary vascular disease progresses, however, the elevation in PVR and the increased
afterload on the RV lead to an initial compensatory sympathetic nervous system activation
(SNA) and an increase in renin-angiotensin-aldosterone-system (RAAS) activity. As in left
ventricular failure, chronic activation of these systems may be detrimental over a longer
timeframe (36). Chemoreflex mediated SNA (37), reduced heart rate variability (38,39), and
increased cardiac SNA (40), all markers of chronic sympathetic activation, have been
reported in PAH. Increased circulating plasma noradrenaline levels are a variable finding,
having been reported by some investigators (40,41), but not others (37,41,42). SNA is
associated with clinical deterioration in PAH (43), and atrial septostomy (44) was able to
reduce SNA in these patients. Preclinical studies of β-adrenergic receptor blockade in two rat
models of PH (45,46) have provided evidence of attenuated RV remodelling and
improvement in RV function. In a clinical study of beta-blockade in idiopathic PAH,
however, bisoprolol reduced heart rate along with cardiac index and 6-minute walk distance
(6MWD) (47). The possibility of negative inotropy and chronotropy associated with these
agents in patients with already reduced and relatively fixed stroke volumes is a concern (48).
The international PH guidelines do not recommend beta-blockade for PAH unless this is
required by co-morbid conditions e.g. coronary artery disease (1).
RAAS activation in PAH has been a more recent subject of research. Clinical studies have
demonstrated increased plasma levels of renin and angiotensin I and II, along with signs of
local upregulation of angiotensin I receptor expression and signalling in PA smooth muscle
cells in PAH patients (49). Pharmacological modulation of the RAAS, by angiotensin
antagonism, and mineralocorticoid receptor antagonism, has been trialled successfully in
several animal models of PAH. These interventions have led to reduced muscularisation of
small PAs, RV afterload reduction and improved RV ventricular-arterial coupling (50–52).
However, these have not translated into benefit in human trials and the use of angiotensin-
converting enzyme inhibitors and angiotensin-2 receptor antagonists is not recommended in
patients with PAH unless required by comorbidities (1).
Pulmonary artery denervation in animal models of PH
While SNA cannot be targeted pharmacologically in humans, interventional options focusing
on interrupting the sympathetic nerve supply to the PAs may provide a feasible alternative. In
1980, Juratsch et al. (53) performed experiments on a canine model of acute PH, produced by
balloon distension of the main PA. Surgical or chemical denervation of the PA significantly
reduced acute elevations in mPAP produced in this model. This formed the basis of
intervention to disrupt the autonomic nerve supply to the lung.
More recently, percutaneous PADN has been demonstrated in a canine model of acute PH
(54) and animal models of chronic PH. These studies have demonstrated that the innervation
of the pulmonary vasculature stems from large nerve bundles densely packed in the adventitia
of vessels around the PA bifurcation, as described above. It is therefore theoretically possible
to achieve PADN using high-frequency alternating current applied to these sites. These
studies also provided histological evidence of the effects of PADN on nerve endings,
associated with significant improvements in pulmonary haemodynamics, reduced
muscularisation of the PAs and lower RV mass (55,56). In a porcine model of PH secondary
to left heart disease induced by aortic banding, surgical and chemical PADN were associated
with reduced muscularisation of pulmonary arterioles, haemodynamic improvements and
changes in the concentration of adrenoceptors within pulmonary tissue compared to controls
(57).
Some investigators have questioned the ability of percutaneous PADN, as opposed to a
surgical approach, to achieve sufficient denervation (32,58). In an elegant translational study
comparing surgical and percutaneous PADN, Garcia-Lunar et al. (58) reported that PADN by
radiofrequency ablation produced incomplete denervation, with only focal damage to
adventitial nerve fibres. By contrast, surgical PADN was associated with histological
evidence of widespread fibrotic nerve fibres with absent nerve axons in the PA adventitia. It
is obvious that adequate denervation will depend on numerous parameters including the
distribution and depth of the sympathetic nerves in individual patients, the thickness of the
PA wall and the energy that is delivered to these structures.
Pulmonary artery denervation techniques
Multiple techniques for PADN have been described. Surgical PADN via left lateral
thoracotomy, using surgical bipolar radiofrequency clamps applied to the PA bifurcation and
proximal left and right PA branches has been described in pigs (58). Although this process
has been shown to produce more complete denervation than a transcatheter approach,
exposing PAH patients, especially those who have not responded adequately to medical
therapy, to a general anaesthetic and thoracic surgery is a risky and unattractive strategy.
Human studies have, therefore, mainly employed 2 different catheter-based approaches:
radiofrequency ablation (19) and high-energy endovascular ultrasound (Figure 2) (20). In
both, the catheter is positioned in the main PA via a peripheral vein, and energy is applied to
the nerve fibres in the adventitia of the PA wall. PADN trials to date have utilised empirical
strategies for denervation, based on anatomical (fluoroscopic) landmarks. More recently, it
has been suggested that targeted PADN, aimed at areas of autonomic nerve activity, may
improve the efficacy of PADN, while reducing the risks associated with extensive ablation of
the pulmonary trunk (59). In atrial fibrillation ablation, combined computed tomography
nuclear imaging with cardiac cadmium-zinc-telluride cameras (e.g. D-SPECT) have been
used to map ganglionated plexi within the heart, allowing directed denervation of these
structures; this could be applied to PADN. An alternative technique to determine ablation
sites has recently been described in a case study of PADN (21): autonomic nervous responses
were induced by high-output burst electrical stimulation and the anatomical site was mapped
onto a pre-procedural 3-dimensional computed tomography image. Sites where stimulation
induced bradycardia (suggestive of autonomic supply modification) were targeted, whereas
those inducing cough or diaphragmatic twitching were avoided. Mapping of the autonomic
activity around the PAs and the response to PADN may also provide further valuable
information on the mechanisms of action of this technique and the role of the autonomic
nervous system in PAH.
Clinical trials of pulmonary artery denervation
There is preliminary evidence of safety and efficacy of PADN in humans, including patients
with pre-capillary PH (PAH) , combined pre- and post-capillary PH and a handful of patients
with PH secondary to left heart disease and CTEPH (19–25).
In 2013, Chen et al. presented the first-in-man experience with PADN. The PADN-1 study
recruited 13 patients with idiopathic PAH not responding adequately to medical therapy (19).
Eight patients who refused the procedure formed the “control” arm. This was then extended
into a phase II clinical trial reported in 2015 (22), which included 66 patients with PH of
various aetiologies (39 patients with PAH, 18 patients with PH secondary to left heart
disease, and 9 patients with CTEPH) and no control arm. PADN was undertaken by
endovascular radio-frequency ablation. Chest pain was common during the procedure,
reported by 71% of the study participants. At 12 months of follow-up, the authors reported
remarkable improvements in clinical, echocardiographic and haemodynamic variables, with a
94m increase in 6MWD, a reduction in mPAP from 41 to 36mmHg and a favourable change
in RV function (Tei index decreased from 0.63 to 0.39). This preliminary finding needs to be
replicated in larger clinical trials. This study raised some questions regarding the trial
population and design. Many patients in the phase II study were on background medication
that do not represent the current standards of care; 89% of those with PH secondary to left
heart disease were on a prostacyclin analogue. Patients undergoing PADN were withdrawn
from medical PAH therapy, while the vast majority of patients continued on long-term
oxygen therapy. In an accompanying editorial, Galiè and Manes (60) suggest that the
continuation of oxygen therapy may have blunted the hypoxic vasoconstrictive reflex that is
important in maintaining pulmonary ventilation/perfusion matching, and hence may have
influenced the results.
The preliminary results of a phase I multi-national safety study (TROPHY1) were recently
reported (61). A total of 14 patients from 5 study centres in Europe and Israel were enrolled
in this open-label study. PADN was performed in PAH patients who were receiving
combination therapy, using high-frequency, intravascular ultrasound at and around the PA
bifurcation. At 4 months there were no procedure-related serious adverse events (defined as
PA arterial perforation, aneurysm, dissection, stenosis and thrombus formation, haemoptysis,
or death). The investigators also studied secondary efficacy endpoints. An acute change in
pulmonary haemodynamics was not observed following PADN as opposed to previous trials.
At follow-up catheterisation, a very small but statistically significant change in PVR (9.4 vs.
8WU, p<0.01) was accompanied by a fall in mPAP (52.7mmHg to 44.5mmHg, p=0.01)
without significant changes in 6MWD. Since this was a non-randomised study consisting of
only 14 patients, larger, controlled trials are needed to fully appreciate the safety and efficacy
of this procedure. The lack of an acute effect followed by significant longer-term effects,
however, raises questions about the mechanisms underlying PADN using this procedure.
PADN was also recently tested in patients with combined pre- and post-capillary PH in the
PADN-5 study (23). In this single-country multi-centre trial, patients presenting with new-
onset heart failure were randomised to PADN (n = 48) or sham denervation plus sildenafil
therapy (n = 50). Exercise capacity improved markedly in the intervention arm, with the
6MWD increasing by 83m compared to 15m in the sildenafil arm (p<0.001). There was a
concomitant fall in PVR (6.4±3.2 to 4.2±1.5WU, p<0.001) and PA wedge pressure (22.2±6.6
to 16.1±6.2mmHg, p=0.01) in the PADN arm. The results of this ground-breaking trial
should be interpreted keeping in mind various aspects of the study design. Patients were
recruited following an acute hospital contact and uptitration of new heart failure medication
took place during the study period. The use of sildenafil for patients with post-capillary PH is
not standard practice and only acts to detract from the purity of the control group. The role
that pulmonary vasoconstriction plays in combined pre- and post-capillary PH and the effect
of PADN on PA wedge pressure in this population again raise intriguing questions
concerning the mechanism of action of PADN.
These pioneering trials have been successful in demonstrating the safety and feasibility of
this procedure, with positive, yet not conclusive, signals of efficacy. These studies raise as
many questions as they answer, which need to be appropriately addressed in large rigorously
designed multi-national randomised controlled trials investigating robust efficacy end-points,
before PADN can be recommended for routine clinical use.
Unanswered questions and future research challenges
Many novel therapies for PAH have proven efficacious in animal models and small clinical
trials, but not in human studies and have not, thus, entered clinical practice. PADN has shown
promise as a new treatment modality, but carefully designed trials are necessary to further
elucidate the technique’s mechanisms of action, long-term safety and efficacy, and its role in
the current management strategy for PAH and other types of PH. Even if PADN does reverse
sympathetic-dependent vasoconstriction, how can it positively influence the severe, fixed,
obstructive lesions that are typically observed on lung histology in PAH? PADN may have
effects beyond regulating vasomotor response, but these remain to be elucidated.
Evidence to date suggests that PADN does not only act via vasoconstriction of the pulmonary
vasculature. The cardiac autonomic nerves and parasympathetic supply to the lungs are
located close to sympathetic nerves at the level of the main PAs, especially in patients with
PA dilatation, commonly encountered in PAH. This raises the question of whether PADN
modified cardiac autonomic innervation and haemodynamics apart from its effect on the
pulmonary vasculature. The change in heart rate following PADN is not routinely reported,
but negative chronotropy following PADN has been described in some patients (22);
parasympathetic denervation may provide an alternative explanation for the benefit of the
procedure on pulmonary vascular remodelling and RV function (62), although this finding is
not consistent. Furthermore, the significant reduction in PA wedge pressure reported in the
PADN-5 study is also difficult to explain through the effect of PADN on pulmonary
haemodynamics. Differences between species and models of pulmonary hypertension mean
that caution is required when extrapolating the effects of PADN from animal models to
human subjects. The effects of PADN on left and right heart haemodynamics, combined with
methods to study the anatomy and physiology of the autonomic system during PADN, should
be a focus of future studies and may allow refinement of current techniques.
The longevity of PADN using different techniques also remains unknown. In other scenarios,
such as following heart or lung transplantation or arterial switch procedure for transposition
of the great arteries, there is often complete and immediate external cardiac or pulmonary
denervation. Following heart transplantation, for example, parasympathetic vagal neurons
and post-ganglionic sympathetic nerve fibres are transected as they pass from the stellate
ganglion to the myocardium. There is evidence of variable degrees of delayed re-innervation,
occurring in 40-70% of recipients in the late post-transplant period (> 1-year post-transplant)
assessed using Iodine-123 metaiodobenzylguanidine imaging and immunohistochemistry.
Reinnervation can have an impact on functional variables such as exercise tolerance (63,64).
To examine whether delayed reinnervation occurs following PADN, longer term follow-up
data is needed; to date, only one study has shown a sustained effect at 12 months (22).
Future clinical trials of PADN should be adequately powered multi-centre multi-national
ventures based in specialist PH centres. Strict inclusion and exclusion criteria need to be
applied, recruiting patients with similar pathophysiology (e.g. idiopathic PAH only), stable
on combination PAH therapy to avoid bias from rapidly deteriorating disease or escalation of
other concomitant treatments. The control arm should be carefully selected and should only
differ from the active arm in terms of the PADN procedure itself, preferably using sham
procedures. All patients in the trial should be receiving standard treatment as per international
guidelines, to make the results interpretable and applicable worldwide.
Conclusions
PADN has generated some excitement in the PH community, with early positive signs in
non-randomised studies. However, questions remain on the short and long-term efficacy of
PADN, its mechanism of action and appropriate patient selection and timing. There is still a
long way to go before PADN can become part of routine clinical care.
References
1. Galiè N, Humbert M, Vachiery J-L, Gibbs S, Lang I, Torbicki A, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS)Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). European Respiratory Journal. 2015 Oct;46(4):903–75.
2. Simonneau G, Montani D, Celermajer DS, Denton CP, Gatzoulis MA, Krowka M, et al. Haemodynamic definitions and updated clinical classification of pulmonary hypertension. European Respiratory Journal [Internet]. 2018 Jan 1 [cited 2019 Nov 19]; Available from: https://erj.ersjournals.com/content/early/2018/10/11/13993003.01913-2018
3. Humbert M, Lau EMT, Montani D, Jaïs X, Sitbon O, Simonneau G. Advances in therapeutic interventions for patients with pulmonary arterial hypertension. Circulation. 2014 Dec 9;130(24):2189–208.
4. McLaughlin VV, Shah SJ, Souza R, Humbert M. Management of Pulmonary Arterial Hypertension. Journal of the American College of Cardiology. 2015 May 12;65(18):1976–97.
5. Bai Y, Sun L, Hu S, Wei Y. Combination therapy in pulmonary arterial hypertension: a meta-analysis. Cardiology. 2011;120(3):157–65.
6. Fadel E, Mercier O, Mussot S, Leroy-Ladurie F, Cerrina J, Chapelier A, et al. Long-term outcome of double-lung and heart-lung transplantation for pulmonary hypertension: a comparative retrospective study of 219 patients. Eur J Cardiothorac Surg. 2010 Sep;38(3):277–84.
7. Granton J, Mercier O, De Perrot M. Management of severe pulmonary arterial hypertension. Semin Respir Crit Care Med. 2013 Oct;34(5):700–13.
8. Schermuly RT, Ghofrani HA, Wilkins MR, Grimminger F. Mechanisms of disease: pulmonary arterial hypertension. Nature Reviews Cardiology. 2011 Aug;8(8):443–55.
9. Morris NR, Kermeen FD, Holland AE. Exercise-based rehabilitation programmes for pulmonary hypertension. Cochrane Database Syst Rev. 2017 19;1:CD011285.
10. Kerstein D, Levy PS, Hsu DT, Hordof AJ, Gersony WM, Barst RJ. Blade balloon atrial septostomy in patients with severe primary pulmonary hypertension. Circulation. 1995 Apr 1;91(7):2028–35.
11. Blanc J, Vouhé P, Bonnet D. Potts shunt in patients with pulmonary hypertension. N Engl J Med. 2004 Feb 5;350(6):623.
12. Law MA, Grifka RG, Mullins CE, Nihill MR. Atrial septostomy improves survival in select patients with pulmonary hypertension. Am Heart J. 2007 May;153(5):779–84.
13. Feinstein JA, Goldhaber SZ, Lock JE, Ferndandes SM, Landzberg MJ. Balloon pulmonary angioplasty for treatment of chronic thromboembolic pulmonary hypertension. Circulation. 2001 Jan 2;103(1):10–3.
14. Sugimura K, Fukumoto Y, Satoh K, Nochioka K, Miura Y, Aoki T, et al. Percutaneous transluminal pulmonary angioplasty markedly improves pulmonary hemodynamics and long-term prognosis in patients with chronic thromboembolic pulmonary hypertension. Circ J. 2012;76(2):485–8.
15. Na Sungwon, Kim Ok Soo, Ryoo Sungwoo, Kweon Tae Dong, Choi Yong Seon, Shim Hyo Sup, et al. Cervical Ganglion Block Attenuates the Progression of Pulmonary Hypertension via Nitric Oxide and Arginase Pathways. Hypertension. 2014 Feb 1;63(2):309–15.
16. Qingyan Z, Xuejun J, Yanhong T, Zixuan D, Xiaozhan W, Xule W, et al. Beneficial Effects of Renal Denervation on Pulmonary Vascular Remodeling in Experimental Pulmonary Artery Hypertension. Rev Esp Cardiol (Engl Ed). 2015 Jul;68(7):562–70.
17. Hu W, Yu S-B, Chen L, Guo R-Q, Zhao Q-Y. Renal sympathetic denervation prevents the development of pulmonary arterial hypertension and cardiac dysfunction in dogs. Kaohsiung J Med Sci. 2015 Aug;31(8):405–12.
18. Liu Q, Song J, Lu D, Geng J, Jiang Z, Wang K, et al. Effects of renal denervation on monocrotaline induced pulmonary remodeling. Oncotarget. 2017 Feb 7;8(29):46846–55.
19. Chen S-L, Zhang F-F, Xu J, Xie D-J, Zhou L, Nguyen T, et al. Pulmonary Artery Denervation to Treat Pulmonary Arterial Hypertension: The Single-Center, Prospective, First-in-Man PADN-1 Study (First-in-Man Pulmonary Artery Denervation for Treatment of Pulmonary Artery Hypertension). Journal of the American College of Cardiology. 2013 Sep 17;62(12):1092–100.
20. Rothman A. Therapeutic intravascular ultrasound pulmonary artery denervation for the treatment of pulmonary arterial hypertension (TROPHY1): a multicentre, international, open-label trial. EuroPCR 2019; 2019 May 22.
21. Fujisawa T, Kataoka M, Kawakami T, Isobe S, Nakajima K, Kunitomi A, et al. Pulmonary Artery Denervation by Determining Targeted Ablation Sites for Treatment of Pulmonary Arterial Hypertension. Circ Cardiovasc Interv. 2017;10(10).
22. Chen S-L, Zhang H, Xie D-J, Zhang J, Zhou L, Rothman AMK, 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 Nov;8(11):e002837.
23. Zhang H, Zhang J, Chen M, Xie D-J, Kan J, Yu W, 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 Feb 11;12(3):274–84.
24. Kiuchi MG, Andrea BR, da Silva GR, Coelho SBP, Paz LMR, Chen S, et al. Pulmonary artery ablation to treat pulmonary arterial hypertension: a case report. Journal of Medical Case Reports. 2015 Dec 16;9(1):284.
25. Zhang H, Zhang J, Xie D-J, Jiang X, Zhang F-F, Chen S-L. Pulmonary artery denervation for treatment of a patient with pulmonary hypertension secondary to left heart disease. Pulm Circ. 2016 Jun;6(2):240–3.
26. Barnes PJ, Liu SF. Regulation of pulmonary vascular tone. Pharmacol Rev. 1995 Mar;47(1):87–131.
27. Richardson JB. Nerve supply to the lungs. Am Rev Respir Dis. 1979 May;119(5):785–802.
28. Bradley DE, McNary WF, el-Bermani AW. The distribution of acetylcholinesterase and catecholamine containg nerves in the rat lung. Anat Rec. 1970 Jun;167(2):205–7.
29. Kai Y. Study on the distribution of symatheic nerves in the lung using the Falck-Hillarp’s fluorescent method. Bull Chest Dis Res Inst Kyoto Univ. 1969 Mar;2(2):225-245 passim.
30. Carstairs JR, Nimmo AJ, Barnes PJ. Autoradiographic visualization of beta-adrenoceptor subtypes in human lung. Am Rev Respir Dis. 1985 Sep;132(3):541–7.
31. Boe J, Simonsson BG. Adrenergic receptors and sympathetic agents in isolated human pulmonary arteries. Eur J Respir Dis. 1980 Aug;61(4):195–202.
32. Huang Yuan, Liu Yi-Wei, Pan Hai-Zhou, Zhang Xiao-Ling, Li Jun, Xiang Li, et al. Transthoracic Pulmonary Artery Denervation for Pulmonary Arterial Hypertension. Arteriosclerosis, Thrombosis, and Vascular Biology. 2019 Apr 1;39(4):704–18.
33. Aviado DM, Ling JS, Schmidt CF. Effects of anoxia on pulmonary circulation: reflex pulmonary vasoconstriction. Am J Physiol. 1957 May;189(2):253–62.
34. Fitzgerald RS, Dehghani GA, Sham JS, Shirahata M, Mitzner WA. Peripheral chemoreceptor modulation of the pulmonary vasculature in the cat. J Appl Physiol. 1992 Jul;73(1):20–9.
35. Osorio J, Russek M. Reflex changes on the pulmonary and systemic pressures elicited by stimulation of baroreceptors in the pulmonary artery. Circ Res. 1962 Apr;10:664–7.
36. de Man FS, Handoko ML, Guignabert C, Bogaard HJ, Vonk-Noordegraaf A. Neurohormonal Axis in Patients with Pulmonary Arterial Hypertension. Am J Respir Crit Care Med. 2013 Jan 1;187(1):14–9.
37. Velez-Roa S, Ciarka A, Najem B, Vachiery J-L, Naeije R, van de Borne P. Increased sympathetic nerve activity in pulmonary artery hypertension. Circulation. 2004 Sep 7;110(10):1308–12.
38. McGowan CL, Swiston JS, Notarius CF, Mak S, Morris BL, Picton PE, et al. Discordance between microneurographic and heart-rate spectral indices of sympathetic activity in pulmonary arterial hypertension. Heart. 2009 May;95(9):754–8.
39. Wensel R, Jilek C, Dörr M, Francis DP, Stadler H, Lange T, et al. Impaired cardiac autonomic control relates to disease severity in pulmonary hypertension. Eur Respir J. 2009 Oct;34(4):895–901.
40. Mak S, Witte KK, Al-Hesayen A, Granton JJ, Parker JD. Cardiac sympathetic activation in patients with pulmonary arterial hypertension. Am J Physiol Regul Integr Comp Physiol. 2012 May 15;302(10):R1153-1157.
41. Nootens M, Kaufmann E, Rector T, Toher C, Judd D, Francis GS, et al. Neurohormonal activation in patients with right ventricular failure from pulmonary hypertension: Relation to hemodynamic variables and endothelin levels. Journal of the American College of Cardiology. 1995 Dec 1;26(7):1581–5.
42. Richards AM, Ikram H, Crozier IG, Nicholls MG, Jans S. Ambulatory pulmonary arterial pressure in primary pulmonary hypertension: variability, relation to systemic arterial pressure, and plasma catecholamines. Br Heart J. 1990 Feb;63(2):103–8.
43. 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 Jun 1;181(11):1269–75.
44. Ciarka A, Vachièry J-L, Houssière A, Gujic M, Stoupel E, Velez-Roa S, et al. Atrial Septostomy Decreases Sympathetic Overactivity in Pulmonary Arterial Hypertension. Chest. 2007 Jun 1;131(6):1831–7.
45. Bogaard HJ, Natarajan R, Mizuno S, Abbate A, Chang PJ, Chau VQ, et al. Adrenergic receptor blockade reverses right heart remodeling and dysfunction in pulmonary hypertensive rats. Am J Respir Crit Care Med. 2010 Sep 1;182(5):652–60.
46. de Man FS, Handoko ML, van Ballegoij JJM, Schalij I, Bogaards SJP, Postmus PE, et al. Bisoprolol delays progression towards right heart failure in experimental pulmonary hypertension. Circ Heart Fail. 2012 Jan;5(1):97–105.
47. van Campen JSJA, de Boer K, van de Veerdonk MC, van der Bruggen CEE, Allaart CP, Raijmakers PG, et al. Bisoprolol in idiopathic pulmonary arterial hypertension: an explorative study. Eur Respir J. 2016;48(3):787–96.
48. Peacock A, Ross K. Pulmonary hypertension: a contraindication to the use of {beta}-adrenoceptor blocking agents. Thorax. 2010 May;65(5):454–5.
49. de Man FS, Tu L, Handoko ML, Rain S, Ruiter G, François C, et al. Dysregulated renin-angiotensin-aldosterone system contributes to pulmonary arterial hypertension. Am J Respir Crit Care Med. 2012 Oct 15;186(8):780–9.
50. Rouleau JL, Kapuku G, Pelletier S, Gosselin H, Adam A, Gagnon C, et al. Cardioprotective effects of ramipril and losartan in right ventricular pressure overload in the rabbit: importance of kinins and influence on angiotensin II type 1 receptor signaling pathway. Circulation. 2001 Aug 21;104(8):939–44.
51. Okada M, Harada T, Kikuzuki R, Yamawaki H, Hara Y. Effects of telmisartan on right ventricular remodeling induced by monocrotaline in rats. J Pharmacol Sci. 2009 Oct;111(2):193–200.
52. Maron BA, Zhang Y-Y, White K, Chan SY, Handy DE, Mahoney CE, et al. Aldosterone inactivates the endothelin-B receptor via a cysteinyl thiol redox switch to decrease pulmonary endothelial nitric oxide levels and modulate pulmonary arterial hypertension. Circulation. 2012 Aug 21;126(8):963–74.
53. Juratsch CE, Jengo JA, Castagna J, Laks MM. Experimental Pulmonary Hypertension Produced by Surgical and Chemical Denervation of the Pulmonary Vasculature. Chest. 1980 Apr 1;77(4):525–30.
54. Chen S-L, Zhang Y-J, Zhou L, Xie D-J, Zhang F-F, Jia H-B, et al. Percutaneous pulmonary artery denervation completely abolishes experimental pulmonary arterial hypertension in vivo. EuroIntervention. 2013 Jun 22;9(2):269–76.
55. Zhou L, Zhang J, Jiang X-M, Xie D-J, Wang J-S, Li L, et al. Pulmonary Artery Denervation Attenuates Pulmonary Arterial Remodeling in Dogs With Pulmonary Arterial Hypertension Induced by Dehydrogenized Monocrotaline. JACC Cardiovasc Interv. 2015 Dec 28;8(15):2013–23.
56. Rothman AMK, Arnold ND, Chang W, Watson O, Swift AJ, Condliffe R, et al. Pulmonary artery denervation reduces pulmonary artery pressure and induces histological changes in an acute porcine model of pulmonary hypertension. Circ Cardiovasc Interv. 2015 Nov;8(11):e002569.
57. Zhang H, Yu W, Zhang J, Xie D, Gu Y, Ye P, et al. Pulmonary artery denervation improves hemodynamics and cardiac function in pulmonary hypertension secondary to heart failure. Pulm Circ. 2019 Jun;9(2):2045894018816297.
58. Garcia-Lunar I, Pereda D, Santiago E, Solanes N, Nuche J, Ascaso M, et al. Effect of pulmonary artery denervation in postcapillary pulmonary hypertension: results of a randomized controlled translational study. Basic Res Cardiol. 2019 11;114(2):5.
59. Dimopoulos K, Ernst S, McCabe C, Kempny A. Pulmonary Artery Denervation: A New, Long-Awaited Interventional Treatment for Combined Pre- and Post-Capillary Pulmonary Hypertension? JACC Cardiovasc Interv. 2019 Feb 11;12(3):285–8.
60. Galiè N, Manes A. New Treatment Strategies for Pulmonary Arterial Hypertension: Hopes or Hypes?∗. Journal of the American College of Cardiology. 2013 Sep 17;62(12):1101–2.
61. 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 [Internet]. 2018 Aug 1 [cited 2019 Nov 26];39(suppl_1). Available from: https://academic.oup.com/eurheartj/article/39/suppl_1/ehy564.P567/5081677
62. Kuebler WM, Friedberg MK. Letter by Kuebler and Friedberg Regarding Article, ‘Pulmonary Artery Denervation by Determining Targeted Ablation Sites for Treatment of Pulmonary Arterial Hypertension’. Circ Cardiovasc Interv. 2018;11(2):e006148.
63. Parry DS, Foulsham L, Jenkins G, Wharton J, Marron K, Banner N, et al. Incidence and functional significance of sympathetic reinnervation after cardiac transplantation. Transplant Proc. 1997 Mar;29(1–2):569–70.
64. Buendia-Fuentes F, Almenar L, Ruiz C, Vercher JL, Sánchez-Lázaro I, Martínez-Dolz L, et al. Sympathetic Reinnervation 1 Year After Heart Transplantation, Assessed Using Iodine-123 Metaiodobenzylguanidine Imaging. Transplantation Proceedings. 2011 Jul 1;43(6):2247–8.
Figure legends
Figure 1: Known and emerging pathways involved in the pathogenesis of PAH (left), with
associated putative therapeutic targets (right). Current evidence-based therapies target
dysregulation of vascular tone through modulation of vasoactive mediators, promoting
vasodilatation. Abbreviations: BMPR-II, bone morphogenetic protein receptor type 2; Ca2+,
calcium ion; PVR, pulmonary vascular resistance; RAAS, renin-aldosterone-angiotensin
system; TGF-β, transforming growth factor beta.
Figure 2: Schematic of the mode of action of two available PADN catheters. Catheter cross-
sections are shown in black within the pulmonary artery, along with the fluoroscopic
appearance of the catheter tips (insets). In ‘A’, the circular tip of a dedicated 7.5F temperature
sensing and ablation catheter is displayed. Radiofrequency ablation is performed sequentially,
through each of the 10 pre-mounted electrodes, resulting in a circumferential energy
distribution (grey arrows). In ‘B’, a 6F multidirectional intra-vascular ultrasound catheter is
shown. This system (TIVUS, Cardiosonic) uses high-frequency, high-intensity
multidirectional ultrasound to thermally damage the target tissue (golden arrows) and does
not require contact with the vessel wall.
Figure 1
Figure 2
Table 1
Summary of selected pre-clinical and clinical studies of pulmonary artery denervation.
Reference Study type PH model Treatment n (PADN/control)
Mean age
Follow-up
Major inclusion criteria Endpoints Key findings
Pre-clinical
Juratsch et al. 1980 (53)
Prospective case series
Canine, balloon inflation in main PA
Surgical denervation or chemical denervation using IV 6-OHDA
13 / - - 24 hours - PAP, PVR Surgical and chemical PADN reduced or abolished the elevation in PAP produced by balloon distension of main PA. Effects of balloon distension not affected by cervical vagotomy.
Chen et al. 2013 (54)
Prospective case series
Canine, left pulmonary distal basal trunk or interlobar artery occlusion
Percutaneous PADN (7.5F catheter with circular tip, 10 electrodes, fluoroscopy-guided RF ablation)
20 / - - Acute - Invasive haemodynamic measurements
Occlusion of the left pulmonary interlobar artery induced a rise in PA and right ventricular pressure.PADN abolished the PAP response to balloon occlusion.
Rothman et al. 2015 (56)
Prospective non-randomized, sham-controlled trial
Porcine, TxA2 challenge pre- and post-PADN
Percutaneous PADN (6Fr spiral catheter, 1 electrode, fluoroscopy-guided RF ablation)
5 / 3 - Acute - Invasive haemodynamic measurements, changes in microscopy and histological staining
PADN reduced the mPAP and PVR response to the TxA2 challenge.PADN induced acute microscopic and histological changes (intimal disruption and thrombus, reduced medial thickness, altered adventitial architecture, reduced expression of nerve-associated S100 protein)
Zhou et al. 2015 (55)
Prospective randomized, sham-controlled trial
Canine, intra-atrial N-dimethylacetamide or DHMCT
Percutaneous PADN (7Fr catheter, fluoroscopy-guided RF ablation)
10 / 10(SN
substudy20 / 15)
- 14 weeks - Group A: Haemodynamic measurements, PA remodelling Group B: SN injury, SN conduction velocity, EM measurements
PADN reduced mPAP and right atrial pressure, increased cardiac output, and was associated with less RV hypertrophy.PADN induced SN demyelination, axon loss and slowing of SN conduction velocity. PADN was associated with reduced muscularisation of small PAs and
attenuated upregulation of growth factors, induced by DHMCT
Zhang et al. 2018 (57)
Prospective randomized, sham-controlled trial
Rat model, supracoronary aortic banding
Surgical (longitudinal damage to vessel nerves) and chemical (10% phenol applied to nerve surface) PADN
6 / 7 - 4 weeks; 6 months
- Haemodynamic and echocardiographic indices, histological staining
Surgical and chemical PADN improved PA haemodynamics, RV functional indices, and markers of PA relaxation compared to sham.PADN upregulated -adrenoceptor and downregulated -adrenoceptor expression.
Huang et al. 2019 (32)
Prospective randomized, sham-controlled trial
Rat model, IV monocrotaline
Surgical PADN 10/10 - 2 weeks post-
PADN
- Invasive haemodynamics, histological staining, plasma neurohormone, cytokine and neurohormone receptor levels, exercise tolerance
PADN group had lower mPAP, less PA and RV remodelling, and improved RV function.PADN attenuated overactivation of the SN system and reduced expression of neurohormone receptor levels
Garcia-Lunar et al. 2019 (58)
Prospective randomized, sham-controlled trial
Porcine model, pulmonary vein banding
Surgical and percutaneous PADN
6 / 6 (6 healthy subjects
underwent percutaneous
PADN)
- Up to 3 months
- Haemodynamic measurements, CMR, histological staining, plasma neurohormone levels
Surgical PADN did not improve mPAP or PVR compared to sham procedure at any follow-up. PADN was not associated with any benefit in RV anatomy or function.Percutaneous PADN produced focal damage to adventitial fibres compared to the transmural PA lesion produced by surgical PADN
Clinical
Chen et al. 2013 (19)
Non-randomised, non-blinded controlled phase I trial
- Percutaneous PADN (see pre-clinical study by Chen et al. 2013)
13 / 8 40 years 3 months Idiopathic PAH without optimal response to current medical therapy (defined as reduction in mPAP <5mmHg, increment of 6MWD<50m)
1º: ∆mPAP and 6MWD2º: Adverse clinical events
Greater fall in mPAP (PADN:55±5 to 36±5mmHg vs. control:53±5 to 50±5mmHg, p<0.001) and increase in 6MWD (PADN: 324±21 to 491±38m vs. control: 358±30 to 364±38m, p<0.01) in PADN vs. control group.Chest pain during procedure in all. No procedure-related SAEs
Chen et al. 2015 (22)
Open-label phase II trial
- Percutaneous PADN (see Chen et al.
66 / - 52 years 1 year PH at RHC (WHO group 1, 59%; group 2, 27%;
Change in haemodynamic,
Improvements in 6MWT, WHO functional class, BNP,
2013) group 4, 14%). CTEPH included after surgical management
functional and clinical markers; PAH-related clinical events
echocardiographic and RHC measurements.Chest pain during procedure in 71%. Temporary sinus bradycardia in 1 patient. No procedure-related SAEs
Zhang et al. 2019 (23)
Randomised, sham-controlled trial
- Percutaneous PADN (see Chen et al. 2013)
48 / 50 63 years 6 months Combined pre- and post-capillary PH (mPAP≥25mmHg, PCWP>15mmHg, PVR>3WU)
1º: ∆6MWD2º: ∆PVR, occurrence of PE, clinical worsening
Greater increase in 6MWD in PADN than control group (PADN:351±106 to 435±108m, control:344±86 to 359±93m, p<0.001)Greater average reduction in PVR (HR 4.7 95%CI 2.1-10.9, p<0.001) and lower rate of clinical worsening in PADN than control group (HR 2.7, 95%CI 1.2-6.1, p=0.02)
Case reports and conference abstracts were not included in this table. Abbreviations: 6MWD – 6-minute walk distance; 6-OHDA – 6-
hydroxydopamine; BNP – Brain natriuretic peptide; CMR – cardiac magnetic resonance imaging; CTEPH – chronic thrombo-embolic
pulmonary hypertension; DHMCT – dehydrogenized monocrotaline; EM – electron microscopic; IPAH – idiopathic pulmonary arterial
hypertension; IV – intravenous; (m)PAP – (mean) pulmonary artery pressure; PA – pulmonary artery; PADN – pulmonary artery denervation;
PCWP – pulmonary capillary wedge pressure; PE – pulmonary embolism; PH – pulmonary hypertension; PVR – pulmonary vascular
resistance; RHC – right heart catheterisation; SAE – severe adverse event; SN – sympathetic nerve; TxA2 – thromboxane A2; TPG –
transpulmonary gradient; WHO – World Health Organisation.