Autonomic nervous modulation: early treatment for pulmonary artery hypertension

Abstract

Pulmonary artery hypertension (PAH) is a chronic vascular disease defined by the elevation of pulmonary vascular resistance and mean pulmonary artery pressure, which arises due to pulmonary vascular remodelling. Prior research has already established a link between the autonomic nervous system (ANS) and PAH. Therefore, the rebalancing of the ANS offers a promising approach for the treatment of PAH. The process of rebalancing involves two key aspects: inhibiting an overactive sympathetic nervous system and fortifying the impaired parasympathetic nervous system through pharmacological or interventional procedures. However, the understanding of the precise mechanisms involved in neuromodulation, whether achieved through medication or intervention, remains insufficient. This limited understanding hinders our ability to determine the appropriate timing and scope of such treatment. This review aims to integrate the findings from clinical and mechanistic studies on ANS rebalancing as a treatment approach for PAH, with the ultimate goal of identifying a path to enhance the safety and efficacy of neuromodulation therapy and improve the prognosis of PAH.

Introduction

Pulmonary hypertension (PH) is an abnormal condition in the pulmonary circulation caused by a variety of factors. Its primary character is the persistent increase in pulmonary vascular resistance (PVR), ultimately resulting in right heart dysfunction and premature mortality. The definition and classification of PH underwent partial revision during the 6th World Symposium on Pulmonary Hypertension (WSPH) ¹ in 2018. In terms of abnormal haemodynamic features of pulmonary circulation, ² PH is categorized into three primary groups: pre‐capillary pulmonary hypertension (pre‐PH) induced by conditions that impact the pulmonary pre‐capillary arteries; post‐capillary pulmonary hypertension (post‐PH) primarily caused by increased pressure in the pulmonary veins resulting from left heart diseases; and pre‐ and post‐capillary pulmonary hypertension (cpc‐PH), happening when both the pulmonary pre‐ and post‐capillary artery pressures increase simultaneously. Another concept worth noting is the notion of ‘marginal status’, which directs our focus to the initial stage of pulmonary vascular lesions, when a mean pulmonary artery pressure (mPAP) is between 20 and 25 mmHg.

Pulmonary artery hypertension (PAH), the first group of PH clinical classification (Group I), including idiopathic PAH (iPAH), heritable PAH, and drug‐ and toxin‐induced PAH, is regarded as a form of pre‐PH and serves as the focus of this review. ³ The 3 year survival rate of PAH ranges from 48% to 92%, ⁴ , ⁵ revealed by global PAH registries such as COMPERA (NCT01347216), ⁶ REVEAL (NCT00370214), ⁷ and CHINESE ⁸ recently. Therefore, it is essential to closely monitor the global survival rate of individuals with PAH. Currently, the primary approach to treating PAH focuses on targeted medication therapy, such as drugs that target endothelin, nitric oxide, and prostacyclin to primarily mediate vasoconstriction. However, these medications offer limited benefits of enhancing the survival rate among individuals with PAH. Although the 2018 WSPH emphasized the substantial significance of commencing combined drug therapy, the side effects and economic burden of long‐term medication can reduce patient adherence and the associated advantages of combined drug therapy. ¹

Currently, there is a widely embraced perspective that alternations in the structure of blood vessel walls play a role in the development of various PH forms. Remodelled blood vessels display distinctive features, including the development of occlusive lesions, thickening of the intimal and/or medial layers of muscular arteries, increased stiffness in the elastic proximal pulmonary arteries, smooth muscle cell proliferation and migration within the pulmonary arteries, and cellular trans‐differentiation, among other characters. In recent years, studies have expanded their focus to encompass fields like genomics, DNA damage, transcriptomics, epigenetics, disordered metabolism, and inflammatory reactions to explore the mechanisms behind pulmonary vascular remodelling. Additionally, discussions have taken place concerning treatments specifically aimed at addressing vessel remodelling. Autonomic nervous dysfunction has been confirmed in several studies related to PAH. ⁹ , ¹⁰ Furthermore, therapies targeting the autonomic nervous system (ANS) have demonstrated effectiveness in reversing pulmonary artery remodelling in both patients and animal models. ¹¹ Therefore, modulating the activity of autonomic nerves holds promise as a potential avenue for the treatment of PAH. This review scrutinizes research on the mechanisms and current state of vascular remodelling with regard to autonomic system regulation as along with therapies in the initial phase of PAH. The objective is to offer insights and recommendations for future research avenue in the field of PH.

Roles of autonomic nerves in pulmonary artery hypertension

Sympathetic nervous system

Three decades ago, Bristow et al. ¹² made a significant discovery regarding the altered distribution of β‐adrenergic receptors (ARs) in patients with PH and right heart dysfunction. They observed a decrease in the expression of β₁ receptors and an increase in β₂ receptors using radioligand binding techniques. This discovery provided valuable insights into the potential role of ANS in the development of PH and right heart insufficiency. In a study conducted by Velez‐Roa et al., ¹⁰ microneurography was employed to measure the muscle sympathetic nerve activity (MSNA) in patients with PAH and control groups. The findings indicated a notably elevated level of MSNA in PAH patients when compared with the control group. This marked the initial direct validation of increased sympathetic nerve activity in PAH patients. Subsequently, accumulating evidence has consistently demonstrated the crucial role of sympathetic nerve overactivity in the progression of PAH. This has paved the way for the exploration of autonomic system modulation therapies in the treatment of PAH.

Parasympathetic nervous system

Furthermore, da Silva Gonçalves Bós et al. ¹³ and Hemnes and Brittain ¹⁴ conducted a study to assess the effectiveness of oral pyridostigmine (PYR), an acetylcholinesterase inhibitor, in the treatment of PAH and associated right heart failure. The researchers utilized a SuHx rat model and confirmed the baseline parameters at Week 6 and then divided the animals into two groups: the control group (n = 12) and the treatment group (n = 12). Ultrasonic cardiogram and right heart catheterization (RHC) with pressure–volume analyses were performed at the end of the study (4 weeks after grouping) or earlier if signs of right heart failure were observed. Lung tissues were collected for further analysis. The outcome showed that PYR did not impact the expression of cholinergic receptor in the lung tissue. However, it did reduce systemic or perivascular inflammation and attenuate pulmonary artery remodelling, leading to a decrease in right ventricular (RV) afterload and restoration of RV function. In the RV tissue, PYR normalized cholinergic receptor expression, reduced RV remodelling, alleviated inflammation, and ultimately restored RV function. In summary, the study's conclusion highlighted that PYR primarily exerts its influence on the pulmonary vasculature by modulating the status of inflammation rather than directly restoring autonomic function. Nonetheless, it was observed that there was a clear modulation of autonomic nerve function in the right ventricle, as evidenced by the restoration of cholinergic receptor expression.

Adrenoreceptor antagonists

Bogaard et al. ¹⁵ conducted a study to investigate the effects of carvedilol, an α₁/β₁/β₂‐AR blocker, on treating PH with right heart dysfunction in a rat model. The results demonstrated a significant improvement in right heart function and a partial reversal of RV remodelling. Nonetheless, there was no observed effect on the morphology of pulmonary vasculature or the afterload of the right ventricle.

Perros et al. ¹⁶ compared the effects of nebivolol, a β₁‐antagonist and β_2,3‐agonist, and metoprolol, a β₁‐selective beta‐blocker lacking intrinsic sympathomimetic activity, in the treatment of severe PH with right heart failure in a rat model induced by monocrotaline (MCT). The results indicated that, in severe PH rats, nebivolol yielded more significant benefits in comparison with metoprolol, including improvements in cardiac output and PVR. However, there were no significant changes observed in haemodynamic parameters like mPAP or RV systolic pressure. In particular, nebivolol significantly ameliorated RV and pulmonary vascular remodelling when compared with metoprolol. Further examination revealed a lower mPAP induced by nebivolol. Research on bisoprolol, a β₁‐selective beta‐blocker, conducted by de Man and the research team, ¹⁷ showed that bisoprolol delayed the progression of RV fibrosis and the onset of right heart failure without affecting the structure of pulmonary vasculature or the afterload of the right ventricle.

The studies mentioned above suggest that selective β₁‐blockers, such as bisoprolol and metoprolol, do not have a noteworthy impact on the structure of pulmonary vasculature. Bisoprolol, with higher β₁‐AR selectivity, improves the remodelling of the right ventricle. However, nebivolol, a β₁‐antagonist and β_2,3‐agonist, demonstrates a significant capacity to reverse RV and pulmonary vascular remodelling, particularly in the context of pulmonary artery remodelling. It is worth noting that α₁‐AR is extensively distributed throughout the pulmonary circulation and situated on vascular smooth muscle cells. When α₁‐AR is activated (Figure  1 ), the second messenger inositol 1,4,5‐triphosphate produced by cytomembrane coupled G‐protein combines to the endoplasmic reticulum to release stored Ca²⁺, K⁺ channels on the cell membrane that are blocked, leading to membrane depolarization and the entry of Ca²⁺ from extracellular sources through voltage‐dependent Ca²⁺ channels; these two main mechanisms involve the increase of intracellular Ca²⁺ concentration that regulates the vasoconstriction of the pulmonary vasculature. In the normal pulmonary circulation, the equilibrium between vascular relaxation, mediated by β‐AR and vascular contraction, controlled by α‐AR, can be perturbed by pathological factors like hypoxia (Figure  1 ). This disruption, along with increased levels of endothelin‐1 (ET‐1) and platelet‐derived growth factor, further promotes the process of pulmonary artery remodelling. However, β₁‐AR is more sensitive to the heart and plays a crucial role in the treatment of left‐sided systolic heart failure. Hence, it is possible that β₁‐selective blockers may be more effective than modulating the β₂‐AR or α₁‐AR signalling pathways in cases of severe PH accompanied by right heart dysfunction. Further research is imperative to explore the functions of drugs that target different AR subtypes at different stages of PH, especially in the initial stages. This is essential to ascertain the appropriate medications that can potentially decelerate or even halt disease progression and enhance prognosis for PH patients. The related studies were listed in Table 1 .

Figure 1.

Signal transduction pathways of α₁‐adrenergic receptors in smooth muscle cells and pathways leading to pulmonary hypertension. Bcl‐2, B‐cell lymphoma 2; IP3, inositol 1,4,5‐triphosphate; MAP Kinase, mitogen‐activated protein kinase; NFκB, nuclear factor κB; PIP2, phosphatidylinositol 4,5‐biphosphate; PKC, protein kinase C; PLC, phospholipase C.

Table 1.

Researches of beta‐blocker in pulmonary hypertension

Drug	Subtype of blocker	PH model (pre‐clinical study) or PAH subtype (clinical study)	Beta‐blocker effects	Animal (pre‐clinical study) or trial registration (clinical study)	Reference
Carvedilol	α1/β1/β2‐antagonist	SU5416 and hypoxia	Survival rate, RV remodelling, and RV function improved	Rat	Bogaard et al. 15
Nebivolol	β1‐antagonist and β2,3‐agonist	MCT	Cardiac function, pulmonary vascular remodelling, and inflammation improved	Rat	Perros et al. 16
Metoprolol	β1‐antagonist	MCT	Cardiac function, pulmonary vascular remodelling, and inflammation improved	Rat	Perros et al. 16
Bisoprolol	β1‐antagonist	iPAH	6MWT unchanged VO2 peak unchanged LVEF/RVEF increased CI reduced HR reduced	NCT01246037	van Campen et al. 18

6MWT, 6 min walk test; CI, cardiac index; HR, heart rate; iPAH, idiopathic pulmonary artery hypertension; LVEF, left ventricular ejection fraction; MCT, monocrotaline; PAH, pulmonary artery hypertension; PH, pulmonary hypertension; RV, right ventricular; RVEF, right ventricular ejection fraction; VO₂ peak, maximal oxygen uptake.

Non‐pharmacological neuromodulation therapy

Pulmonary artery denervation

Considering the pivotal role of sympathetic nerve overactivity in PH, Professor S. L. Chen has introduced a novel approach to treat PH called pulmonary artery denervation (PADN). PADN is a minimally invasive, catheter‐based therapy that employs endovascular radiofrequency ablation to induce controlled damage to the sympathetic nerve surrounding the pulmonary artery. This procedure effectively mitigates the reactivity of the pulmonary artery baroreceptor. Numerous clinical and animal trials have demonstrated the effectiveness of PADN in treating PH. ¹⁹ , ²⁰ , ²¹ , ²² , ²³ , ²⁴ , ²⁵ These findings have been comprehensively reviewed. ²⁶ , ²⁷ However, the precise mechanisms underlying the effects of PADN remain a topic of ongoing debate. In a study by Zhou et al., ²⁸ a canine model of PAH was established using dehydrogenized monocrotaline (DHMC), and the results indicated that PADN had the capacity to partially alleviate pulmonary vascular remodelling. The canines were randomly divided into two groups: control group (n = 20) and test group (n = 20). The test group was administered DHMC injections. After 8 weeks, the canines in the test group, exhibiting an mPAP exceeding 25 mmHg, were subsequently randomized into either sham or PADN groups. This was followed by a 14 week study aimed at evaluating various haemodynamic parameters, the extent of pulmonary arterial muscularization, medial wall thickness, and messenger ribonucleic acid (mRNA) expression of genes in lung tissues. The results showed that, in comparison with the sham group, the PADN group exhibited a reduction in mPAP (23.5 ± 2.3 vs. 33.7 ± 5.8 mmHg), PVR (3.5 ± 2.3 vs. 7.7 ± 1.7 Wood units), and medial wall thickness (22.3 ± 3.3% vs. 30.4 ± 4.1%). Furthermore, there was a suppression of mRNA expression in genes associated with inflammation, proliferation, and vasoconstriction. In the discussion regarding the mechanism of PADN, Liu et al. ²² proposed that PADN inhibited overactivity of the renin‐angiotensin‐aldosterone system (RAAS) at the local tissue level, thus attenuating the progression of PAH and right heart dysfunction.

Undoubtedly, further exploration of the mechanism is crucial for the selection of suitable patients and the optimal timing of treatment. This is essential for maximizing treatment efficacy and ensuring patient safety.

Pre‐clinical studies have indicated that the sympathetic nerves are primarily distributed around the bifurcation of pulmonary artery. One potential strategy to enhance efficacy and reduce side effects is to precisely locate the target nerves using high‐output burst electric stimulation. ²⁹ , ³⁰ , ³¹ Additionally, the selection of an energy source is also a topic of ongoing discussion. While the majority of catheter‐based PADN studies have utilized radiofrequency ablation, some studies have suggested that the sympathetic nerves are primarily located in the adventitial layer of the pulmonary artery. In this regard, the Therapeutic Intravascular Ultrasound System (TIVUS) offers a percutaneous non‐contact catheter alternative that provides thermal effect up to a depth of 10 mm. This depth corresponds to the anticipated location of the efferent and afferent autonomic nerves in the pulmonary artery adventitia. In the research conducted on PAH patients using TIVUS, researchers observed improvements in PVR and the distance covered in 6 min walk test after a span of 4–6 months. Apart from radiofrequency and ultrasound energy, encouraging results have also been achieved through laser ablation in an ovine model. ³² , ³³ , ³⁴

Renal sympathetic denervation

Extensive researches have been conducted to investigate the role of neurohormonal regulation in the initiation and advancement of PH. It has been found that local alterations in the RAAS contribute to the initiation and advancement of PH. The modulation of the autonomic system via the local RAAS signalling pathway has demonstrated promise as a therapeutic approach for PH. Numerous studies have investigated the activation of RAAS in the pathological progression of PH. The chronic activation has been associated with cell proliferation, migration, pulmonary vasoconstriction, extracellular matrix remodelling, and fibrosis. ³⁵ One study by de Man et al. ³⁶ found elevated levels of angiotensin I (Ang I) and angiotensin II (Ang II) in the blood samples of patients with iPAH.

Renal sympathetic denervation (RSD) is a minimally invasive therapy aimed at reducing sympathetic nerve overactivity and has been studied for its potential in PH treatment. ³⁷ , ³⁸ , ³⁹ , ⁴⁰ Research group of Congxin ³⁹ , ⁴⁰ conducted a study on RSD treatment for PAH in canines. In that study, canines were divided into three groups: ① control group treated by dimethylformamide; ② PAH group induced by DHMC; and ③ PAH + RSD group (RSD was performed immediately after DHMC injection). Baseline data were obtained before injection through RHC; 8 weeks after grouping, the RHC was operated again, and tissues were collected. Results demonstrated the following things: ① serological tests: 8 weeks later, in the PAH group, there was a notable increase in Ang II and ET‐1 levels. However, in the PAH + RSD group, ET‐1 demonstrated a decrease; ② lung tissues: ET‐1 level was increased in both the PAH and PAH + RSD groups when compared with the control group; ③ pulmonary artery tissues: Ang II type 1 receptor level was greater in the PAH group when compared with both the PAH + RSD group and the control group; and ④ the extent of remodelling and fibrosis in both pulmonary artery and right ventricle was more pronounced in the PAH group than in the PAH + RSD and control groups. RSD was identified as a means to regulate sympathetic and RAAS activities, subsequently resulting in enhanced remodelling and a reduction in mPAP. These effects could be attributed to alterations in the Ang II signalling pathway and modulation of the ET‐1 system. Moreover, RSD was employed as a preventive procedure, suggesting the potential of early intervention in modulating sympathetic and RAAS activities to prevent remodelling and fibrosis of both the pulmonary artery and right heart tissues.

In contrast to the Congxin research, da Silva Gonçalves Bos et al. ¹¹ conducted a study on RSD therapy in moderate–severe PH models. They used two well‐established animal models for PH, the MCT and the SuHx model, to assess the effects of RSD on pulmonary vasculature and right heart remodelling. The study confirmed the presence of PH at specific time points through the use of ultrasonic cardiogram. Subsequently, the animals were randomly assigned to undergo either sham operations or RSD procedures. The findings showed a significant delay in the PH process in both animal models, along with improvements in medial wall thickness, occlusion lesions, vascular thickness, and RV stiffness. This indicates that RSD can reverse pulmonary vasculature and right heart remodelling.

Another notable finding from the study by da Silva Gonçalves Bos et al. ¹¹ was the reduced expression of mineralocorticoid receptors (MRs) in both pulmonary artery and RV tissues following RSD surgery. MR signalling is involved in vasoconstriction, proliferation, inflammation, fibrosis, and sympathetic system stimulation. The suppression of pulmonary vascular remodelling noted following RSD may be facilitated through the modulation of the MR signalling pathway. The changes in MR expression suggest the involvement of RAAS activity, including Ang II and aldosterone signalling, in the reversal of remodelling processes.

Vagal nerve stimulation

Vagal nerve stimulation (VNS) is a minimally invasive therapeutic approach that involves the direct electrical excitation of the parasympathetic nerve. Numerous animal experiments have demonstrated the therapeutic benefits of VNS for various cardiovascular diseases. ⁴¹ , ⁴² , ⁴³ , ⁴⁴ Yoshida et al. ⁴⁵ conducted a study to investigate the effects of VNS on the treatment and prevention of PAH. The research was divided into two parts: Protocol 1 encompassed chronic VNS in free‐moving rats, comprising both a prevention group (VNS initiated immediately after SU5416 injection and continued for 5 weeks) and a treatment group (VNS initiated 5 weeks after SU5416 injection and continued for 5 weeks), each compared with a sham‐stimulated (SS) group. Protocol 2 focused on acute VNS in anaesthetized rats with established PAH (5 weeks after SU5416 injection, with 90 min of VNS or SS). The results showed that VNS improved the survival rates of rats with PAH in both the prevention and treatment groups. A pathophysiological analysis revealed that, in the chronic VNS study, autonomic dysfunction, mPAP, right heart insufficiency, and pulmonary artery remodelling exhibited improvement (plasma norepinephrine levels significantly decreased after chronic VNS). In the acute VNS study, only anti‐inflammatory responses were observed. Overall, this study demonstrated significant reductions in severe PAH, mPAP, PVR, and pulmonary vascular and RV remodelling.

Strategies targeting endothelin‐1 signalling in pulmonary hypertension

Maron et al. ⁴⁶ conducted a study on rats with PAH (the MCT and SuHx models). They observed a significant increase of 274% in ET‐1 levels in blood samples and a 183% increase in lung tissue. These findings were consistent with the elevated levels of aldosterone, which showed a 442% increase in blood samples and a 183% increase in lung homogenate. The previous study showed that ET‐1 was a secretagogue of aldosterone ⁴⁷ ; elevated ET‐1 could promote an increase in aldosterone. Abnormal elevated ET‐1 levels were frequently observed in both PAH patients and animal models. ⁴⁸

Based on the crucial role of ET‐1 in PH generation and progression, research on therapeutic vaccines targeting for ET_A‐receptor (ETAR) was carried out. ⁴⁹ MCT rat model was induced; all animals were randomly assigned into one of the following groups: control group, MCT group, MCT + bosentan group, MCT + ETRQβ‐002 (the specific antibodies against epitope ETR‐002 belonging to the second extracellular loop of ETAR, which include the polyclonal and monoclonal antibody) group, MCT + ETRQβ‐002[A1C5] (the monoclonal antibody against ETR‐002) group, and MCT + VLP (virus‐like particle) group. Among these groups, bosentan, the vaccine, and monoclonal antibody were administered immediately after the injection of MCT. The results indicated that the ETRQβ‐002 vaccine, as well as monoclonal antibody, could ameliorate pulmonary artery and RV remodelling in MCT or SuHx rat model by suppressing ET‐1 signalling pathway. This presents a novel therapeutic approach for PAH.

Summary

PH is a rapidly progressing disease with uncertain underlying pathophysiological mechanisms. Despite advancements in the treatment of PAH, the overall prognosis remains unfavourable. Some researchers have proposed that PAH shares similarities with the treatment of cancer. ⁵⁰ , ⁵¹ , ⁵² This indicates that a targeted treatment is needed at particular disease stages. Various treatments targeting different factors should be considered, particularly in the early stages of the disease, which is crucial for improving the prognosis.

The consideration of aetiological and pathophysiological characteristics has led to the exploration of innovative approaches to treating PAH, with ANS modulation being one aspect of these. It plays a crucial role in PAH and right heart failure that balances the dysregulated nervous system, including SNS overactivation and neurohormonal regulation involving the RAAS and endothelin axis. Therefore, ANS modulation holds promise as a therapeutic avenue for PAH. Figure 2 summarizes a schematic diagram of neuromodulation therapy for PAH until now.

Figure 2.

Schematic diagram of neuromodulation therapy for pulmonary artery hypertension. AT1, angiotensin II type 1 receptor; MR, mineralocorticoid receptor; PA, pulmonary artery; PADN, pulmonary artery denervation; PYR, pyridostigmine; RAAS, renin‐angiotensin‐aldosterone system; RSD, renal sympathetic denervation; RV, right ventricular; SNS, sympathetic nervous system; VNS, vagal nerve stimulation. Source: This figure was partly generated using Servier Medical Art with adapted ‘sympathetic nervous system’, ‘pulmonary circulation’, and ‘kidney’, provided by Servier, licensed under a Creative Commons Attribution 3.0 unported license.

Receptors such as α₁‐adrenergic and β₂‐adrenergic, mediating opposing vascular responses, are widely expressed in the pulmonary circulation. On the other hand, β₁‐ARs are primarily expressed in the cardiac tissue and have minimal effects on the pulmonary vessels. Studies suggest that α₁‐antagonists and β₂‐agonists may provide greater advantages in the early stages of PAH. In contrast, patients with severe PAH‐related right heart dysfunction may benefit more from β₁‐selective blockers. The oral acetylcholinesterase inhibitor PYR can increase parasympathetic activity to rebalance autonomic dysfunction, primarily observed in the right ventricle rather than the pulmonary artery in animal models of PAH. This implies its potential for treating right heart failure. Approaches such as PADN, RSD, and VNS have shown promising results in the research of PH treatment. Mechanism studies have demonstrated that these prophylactic and therapeutic effects are associated with local ET‐1 signalling and RAAS alteration.

However, existing cell culture models and animal models only provide limited representation of clinical cases and fail to capture the complexity of the disease's pathophysiology. Therefore, developing more appropriate disease models should be addressed and focused on future researches. In addition, for ANS modulation, both medication (such as beta‐blockers and PYR) and intervention therapy (such as PADN, RDN, and VNS) carry the risk of excessive inhibition of sympathetic activity, which may weaken the body's compensatory ability. Thus, the timing and intensity of the treatment is crucial and should be selected with comprehensive evaluation.

Conflict of interest

None declared.

Xueyuan, L. , Yanping, X. , Jiaoqiong, G. , and Yuehui, Y. (2024) Autonomic nervous modulation: early treatment for pulmonary artery hypertension. ESC Heart Failure, 11: 619–627. 10.1002/ehf2.14616.