Autonomic nervous system involvement in pulmonary arterial hypertension
Vaillancourt et al. Respiratory Research
Autonomic nervous system involvement in pulmonary arterial hypertension
Mylène Vaillancourt 0
Pamela Chia 0
0 Equal contributors Department of Anesthesiology and Perioperative Medicine, Division of Molecular Medicine, David Geffen School of Medicine, University of California Los Angeles (UCLA) , Los Angeles, CA BH 520A CHS , USA
Pulmonary arterial hypertension (PAH) is a chronic pulmonary vascular disease characterized by increased pulmonary vascular resistance (PVR) leading to right ventricular (RV) failure. Autonomic nervous system involvement in the pathogenesis of PAH has been demonstrated several years ago, however the extent of this involvement is not fully understood. PAH is associated with increased sympathetic nervous system (SNS) activation, decreased heart rate variability, and presence of cardiac arrhythmias. There is also evidence for increased renin-angiotensin-aldosterone system (RAAS) activation in PAH patients associated with clinical worsening. Reduction of neurohormonal activation could be an effective therapeutic strategy for PAH. Although therapies targeting adrenergic receptors or RAAS signaling pathways have been shown to reverse cardiac remodeling and improve outcomes in experimental pulmonary hypertension (PH)-models, the effectiveness and safety of such treatments in clinical settings have been uncertain. Recently, novel direct methods such as cervical ganglion block, pulmonary artery denervation (PADN), and renal denervation have been employed to attenuate SNS activation in PAH. In this review, we intend to summarize the multiple aspects of autonomic nervous system involvement in PAH and overview the different pharmacological and invasive strategies used to target autonomic nervous system for the treatment of PAH.
Pulmonary arterial hypertension; Autonomic nervous system; Right ventricle; Sympathetic nervous system; Renin angiotensin aldosterone system
Overview of the autonomic regulation of heart and lungs
The autonomic nervous system
The autonomic nervous system is composed of
sympathetic and parasympathetic divisions and is often divided
by neural and endocrine regulatory components. The
sympathetic nervous system (SNS) originates from the
thoracolumbar region of the spinal cord (Fig. 1). Short
preganglionic fibers from the T1-L2 segments synapse on
paravertebral or prevertebral ganglia, enabling long
postganglionic fibers to innervate target organs such as the
heart and lungs. On the other hand, the parasympathetic
nervous system originates from cranial nerves III, VII, IX,
and X and the sacral nerves S2-S4. In general,
parasympathetics cause vasodilation of blood vessels including the
pulmonary vasculature, and sympathetics cause
] (Table 1).
Autonomic innervation of the pulmonary vasculature
The pulmonary vasculature is innervated by sympathetic,
parasympathetic, and sensory nerve fibers. Increased
vascular resistance is mediated by α-adrenoreceptors upon
sympathetic nerve stimulation [
]. Noradrenergic fibers
are activated by baroreceptors in the pulmonary artery [
and proximal airway segments [
respond to decreased arterial PO2 levels to increase
sympathetic nerve stimulation by the sympathetic chain neurons
]. Parasympathetic activation via vagal stimulation
results in cholinergic-mediated relaxation of pulmonary
arteries . Many other factors (i.e. non-adrenergic and
non-cholinergic mediators, peptides, trophic factors,
differential release of transmitters by high or low frequencies)
are implicated in sympathetic and parasympathetic
regulation of lung vasculature, though their functions have not
entirely been elucidated [
] (Table 1).
Autonomic innervation of the heart
The heart is also innervated by both parasympathetic and
sympathetic fibers (Fig. 1). The parasympathetic fibers are
responsible for decreasing chronotropy, dromotropy, and
inotropy via cholinergic action on cardiac M2 receptors.
The SNS acts on β1 adrenergic receptors to increase
chronotropy, dromotropy, and inotropy of the heart [
Interestingly, β-adrenergic stimulation has been shown to
have a significantly greater positive inotropic effect on left
ventricular (LV) contractility than on right ventricular
(RV) contractility [
]. On the contrary, adrenergic
stimulation of alpha 1 receptors result in increased inotropy in
the LV but decreased inotropy in the RV [
] (Table 1).
Patients with PAH often have normal systemic blood
pressures and lung volumes. However, they may suffer
from hypoxia, hypercarbia, acidosis, and, in later stages,
RV hypertrophy and failure. Neural pathways controlling
the heart and lungs are described in detail within current
scientific literature [
Autonomic nervous system and RAAS involvement in
PAH is a clinical syndrome characterized by pathologic
pulmonary 1) vasoconstriction, 2) vascular remodelling,
and 3) thrombosis. Progressive sequelae include
increased pulmonary vascular resistance (PVR), RV
hypertrophy and dysfunction, and ultimately death. The
extent of involvement of the autonomic nervous system
in the pathogenesis of PAH is not fully understood. It is
postulated that the patients with PAH often have a low
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cardiac output and may compensate for that by
upregulation of neurohormonal systems such as SNS and
reninangiotensin-aldosterone system (RAAS) [
] (Fig. 1).
Inflammatory and RAAS molecules are specifically
upregulated in PAH and are implicated in the development of the
disease through their effects on the brain [
There is an increasing body of evidence linking
autonomic nervous system involvement in the pathogenesis
of PAH. Here we review the available literature on SNS
activation, heart rate variability, baroreflex sensitivity
and arrhythmias, and RAAS dysregulation in PAH. We
also summarize the therapeutic strategies for modulating
the autonomic nervous system and RAAS in PAH.
Sympathetic nervous system activation in PAH
Over the last 30 years, accumulating evidence has
supported the involvement of the autonomic nervous
system in PAH, strengthening the hypothesis for the role
of SNS activation in PAH development.
Microneurography was used to compare the muscle sympathetic nerve
activity (MSNA) between patients with PAH and healthy
controls and showed increased sympathetic nerve traffic
in PAH patients [
]. MSNA was also directly correlated
with heart rate, presence of pericardial effusion, oxygen
saturation, New-York Heart Association class, 6-min
walk distance (6-MWD), and pulmonary arterial
acceleration time and was associated with clinical deterioration
]. Administration of hyperoxia decreased MSNA
frequency and burst amplitude, suggesting that
peripheral chemoreceptors contribute in part to increased
Increased SNS activity in PAH was also assessed by
neurohormonal activation, despite conflicting results between
studies. In a small clinical study comprising 32 patients
with PAH, plasma norepinephrine concentration was
strongly correlated to PVR and was associated with poor
estimated 5-year survival [
]. Some other studies have
shown an increase in plasma norepinephrine
concentration in PAH patients compared to healthy controls,
although these norepinephrine levels did not exceed normal
values and were not correlated with any hemodynamic
]. To determine the involvement of
catecholamine pathway in PAH, many groups have directed
their research towards catecholamine receptors.
Bristow and colleagues [
] were the first to describe
local changes in β-adrenergic receptors in the failing RV
myocardium of PAH patients. Since then, the impact of
βadrenergic receptor signaling in PAH development has
been extensively studied using different α/β-adrenergic
receptor agonists/antagonists. Ishikawa and colleagues [
showed that administration of arotinolol, a pure
α/β-adrenergic receptor antagonist, prevents monocrotaline
(MCT)induced PH development by keeping cardiopulmonary
pressures below pathological threshold and decreasing RV/
body weight ratio in treated rats. Treatment with the
nonselective adrenergic receptor antagonist carvedilol was also
reported to reverse established RV failure in two different
rat models of PH (Sugen/hypoxia and MCT-induced PH)
and improved survival in MCT rats [
improvement in RV function was associated with reduced RV
hypertrophy, dilation, and fibrosis, as well as an improved
capillary density of the myocardium . Interestingly,
carvedilol also decreased pro-fibrotic signaling and
extracellular matrix remodelling in right and left ventricles of treated
rats via transforming growth factor-β1, connective tissue
growth factor, SMAD2/3, p38, and metalloproteinases 2
and 3 pathways. Drake and colleagues [
] performed an
extensive microarray gene expression analysis on the RV of
Sugen/hypoxia PH rats either treated with carvedilol for
4 weeks or untreated. Within the top canonical pathways
revealed in this analysis, one was involved in cardiac
hypertrophy by protein synthesis and included regulation of
eukaryotic initiation factor 4 and 5 and p70S6k signaling,
all of which were downregulated with carvedilol. Ceramide
signaling and glucocorticoid receptor signaling pathways,
considered injurious for the heart, were also two of the top
five canonical pathways and were downregulated in
carvedilol-treated rats. Other canonical pathways included
the peroxisome proliferator-activator receptor signaling,
peroxisome proliferator-activator receptor/retinoid X
receptor-activation, and nuclear respiratory factor
2mediated oxidative stress response. These pathways are
involved in metabolism, mitochondrial function, and
oxidative stress response and are critical for adequate heart
function. All these findings highlight the role of adrenergic
receptors in RV failure and suggest that the use of
βblockers could be beneficial for PAH patients. In the clinical
settings, carvedilol showed encouraging results by
improving RV ejection fraction in chronic heart failure [
did not lead to any notable adverse event or deterioration
] (Table 2). In a recent 6-month double-blind,
randomized, controlled trial, patients treated with carvedilol
had an improved heart rate recovery after exercising
compared to those who received placebo . This is important
since heart rate recovery after exercise is not only a
predictor of increased risk of death but also of clinical
worsening in PAH. RV function was also assessed by an improved
glycolytic rate related to carvedilol treatment. [
trials are still ongoing to confirm the therapeutic benefit
and safety of carvedilol in PAH patients (ClinicalTrials.gov
Identifier: NCT02120339 and NCT02507011).
De Man and colleagues [
] investigated the use of
bisoprolol, a cardioselective β-adrenergic receptor
blocker, in the progession of RV failure in MCT-induced
PH model. They showed that RV failure progression was
significantly delayed in bisoprolol treated rats with an
improvement in RV contractility and filling, a partially
recovered cardiac output, and decreased RV interstitial
6-MWD 6-min walk distance, APAH associated pulmonary arterial hypertension, BNP brain natriuretic peptide, CPET cardiopulmonary exercise testing, HPAH
heritable pulmonary arterial hypertension, HR heart rate, iPAH idiopathic pulmonary arterial hypertension, NT-proBNP N-terminal pro-brain natriuretic peptide, PA
pulmonary artery, PAH pulmonary arterial hypertension, PAP pulmonary arterial pressure, PAWP pulmonary artery wedge pressure, PETCO2 end-tidal carbon dioxide
tension, PH pulmonary hypertension, PVR pulmonary vascular resistance, RV right ventricle, RVEF right ventricular ejection fraction, RVSP right ventricular systolic
pressure, TAPSE tricuspid annular plane systolic excursion, TPG transpulmonary pressure gradient, VCO2 volume of carbon dioxide production, VE pulmonary
ventilation, WHO class World Health Organization Class
fibrosis and myocardial inflammation. Bisoprolol restored
β-adrenergic receptor signaling assessed by increased
phosphorylation of its downstream targets, myosin binding
protein C and troponin I. In contrast, decreased
phosphorylation of these proteins in PAH cardiomyocytes leads to
an increase in sarcomere Ca2+ sensitivity, thus impairing
RV relaxation and contributing to RV stiffness [
However, these beneficial effects were not confirmed in an
explorative study involving 18 PAH patients (Table 2) [
In this randomized, placebo-controlled, crossover study,
bisoprolol did not improve patients’ conditions. Despite a
trend to increase RV ejection fraction, patients had a
significant decrease in cardiac index and a near significant
drop in 6-MWD, demonstrating no real benefit of
bisoprolol in PAH (Table 2).
Finally, Perros and colleagues [
] compared the effects
of nebivolol, a third generation β-adrenergic receptor
blocker, to the first generation β1-adrenergic receptor
blocker metoprolol in MCT-induced PH rats. Nebivolol is
a β1-adrenergic receptor antagonist and β2,3-adrenergic
receptor agonist and has vasodilator properties in addition
to its adrenergic-modulating characteristics. Daily
administration of nebivolol for one week in established PH
improved cardiopulmonary hemodynamics and partially
reversed RV hypertrophy and pulmonary vascular
remodeling with a greater effect than metropolol. In vitro nebivolol,
but not metropolol, significantly decreased human
pulmonary endothelial cell proliferation as well as the
production of pro-inflammatory cytokines such as interleukin-6
and monocyte chemoattractant protein-1, epidermal and
fibroblast growth factors, and the vasoconstrictor
endothelin-1. Furthermore, human smooth muscle cell
proliferation was decreased when cells were cultured in the
endothelial cell + nebivolol-conditioned media [
clinical trial is currently recruiting patients to assess the
therapeutic potential and safety of nebivolol in clinical
managment of the PAH patients (ClinicalTrials.gov
Despite encouraging results of adrenoreceptor
blockade in experimental PH, the use of β-blockers in clinical
PAH is still largely debated due to the poor beneficial
results as well as safety concerns revealed in clinical trials
] (Table 2). Although β-blockers partially reverse
RV structural and molecular remodeling [
seem beneficial and well-tolerated at low or escalating
25, 26, 29, 31–34
], their negative inotropic and
chronotropic effects may actually impair RV function in
severe heart failure. Thus, the choice based on the
specificity of the β-blocker used to target one or the other
βreceptor sub-type may be of importance. The divergent
results found in clinical studies may also be the
consequence of several limiting factors, such as study design,
cohort size, diversity in pulmonary hypertension etiology
within cohorts, and variability in pre-existing
comorbidities and treatments taken by patients.
Heart rate variability and baroreflex sensitivity in PAH
Heart failure is associated with abnormalities in autonomic
nervous system control, including decreased heart rate
variability and blunted baroreflex sensitivity [
], which were
predictors of cardiovascular mortality among
postmyocardial infarction patients [
]. Considering the
evidence of an altered autonomic control in PAH, these two
parameters were investigated in different PAH cohorts. In a
small cohort of 9 PAH patients, heart rate variability was
assessed by a time-domain method and was found to be
significantly decreased compared to the control group (n =
20) . In a larger cohort, Wensel and colleagues [
used a frequency-domain method to show a reduction of
total power of heart rate variability in PAH patients (n =
42) compared to healthy subjects (n = 41) but without any
significant difference between low/high frequency power
ratio. Baroreflex sensitivity was also reduced in PAH
patients, determined by the controlled breath method and the
α-index of low frequency. Both heart rate variability and
baroreflex sensitivity parameters were correlated with
decreased peak oxygen uptake during exercise, demonstrating
the impact of cardiac autonomous modulation in exercise
]. In a cohort of 47 children with severe PAH,
heart rate variability was correlated with 6-MWD and was
predictive of transplantation and/or mortality [
bivariate analysis, standard deviation of mean values for the
beat-to-beat interval over 5 min predicted outcome
independently of functional status, syncope, RV function, and
haemodynamic parameters [
]. More recently, Yi and
] also confirmed that time-domain heart rate
variability parameters, as well as frequency-domain indices,
were significantly decreased in PAH patients (n = 26)
compared to the controls (n = 51). Furthermore, heart rate
variability parameters correlated to mean pulmonary
arterial pressure (PAP) in patients [
]. Further studies in
larger patient cohorts are needed to confirm if the heart
rate variability and baroreflex sensitivity changes seen in
PAH are indeed associated with a decrease in the vagal tone
and whether they carry prognostic significance.
Cardiac arrhythmias in PAH
In experimental PH, our group and others have described
spontaneous ventricular fibrillation events and have
extensively investigated their mechanisms [
]. Benoist and
] showed in isolated hearts that the
monophasic action potential duration at 25, 50 and 90%
repolarization was significantly prolonged in hearts from
MCTinduced PH rats compared to controls for both RV and LV.
Futhermore, RV monophasic action potential duration at
90% repolarization strongly correlated with cardiac
hypertrophy. These changes in the action potential duration were
associated with decreased K+ and L-type Ca2+ channel
expressions as well as an increase in T-type Ca2+ channels in
the RV of MCT rats [
]. In a subsequent study, the same
group monitored MCT rats using electrocardiograms and
showed an increased QT interval in RV failure from day 15
post-MCT injection consistent with the prolonged action
potential duration [
]. Alternans of both T-wave amplitude
and QT interval were also observed in animals with heart
failure. In isolated hearts, alternans occurred in four out of
six failing hearts and were always discordant. Action
potential duration alternans have been associated with
dysfunctional Ca2+ homeostasis, resulting in increased intracellular
Ca2+ concentration and contractile alternans. Ca2+ transient
alternans were confirmed in isolated myocytes from failing
RVs and were shown to be provoked by dysregulation of
sarcoplasmic Ca2+ uptake, load, and release. Consistent
with this, failing RVs of MCT rats showed a reduced
SERCA2a activity, an increased sarcoplasmic reticulum Ca2+
release fraction, and an increased Ca2+ spark leak. [
In MCT rats, our group [
] showed that the onset of
ventricular fibrillation was preceded by early afterdepolarizations,
triggering an activity which caused a non-sustained
ventricular tachycardia which then degenerated to ventricular
fibrillation. PH-induced RV failure was associated with RV
epicardial and endocardial fibrosis, which is known to
promote early afterdepolarizations by cardiomyocytes and cause
ventricular fibrillation. In addition to fibrosis, we proposed
that a selective downregulation of Kv1.5, KCNE2, and
SERCA2a in failing RV may lead to reduction of RV myocyte
repolarization reserve, which could also facilitate the formation
of early afterdepolarizations [
]. These episodes of
ventricular fibrillation were detected between days 23 and 32 after
MCT injection, corresponding to a period of expected
sudden death in these animals. We also showed a 10-day
window between the drop of RV ejection fraction (from ~72% at
day 14 to ~38% at day 21) and the beginning of this sudden
death period, suggesting that mortality during this critical
period may be caused by early afterdepolarizations-mediated
triggered activity in the RV [
In clinical PAH, cardiac arrhythmias are common in
patients and are associated with worsening prognosis.
Cardiac arrhythmias include supraventricular
arrhythmias (SVA), which are the most common with a
reported incidence between 11 and 30% [
the ventricular arrhythmias, which were reported to
be relatively rare in PAH [
]. The most common
SVAs seen in PAH patients are atrial fibrillation,
flutter, and tachycardia [
49, 51, 53
]. In a 6-year
retrospective single-center analysis including 231 PAH
patients, 31 SVA episodes were detected in 27
patients (cumulative incidence 11.7%, annual risk 2.8%
per patient) [
]. In most episodes (n = 26), onset of
supraventricular tachycardia resulted in clinical
deterioration and/or RV failure. Furthermore, mortality was
significantly higher in patients with persistent atrial
fibrillation compared with the patients in whom sinus
rhythm was restored. In a 5-year prospective study
including 239 patients, at least one episode of atrial
flutter or atrial fibrillation was detected in 20% of the
]. Compared to patients who did not
develop SVA, patients who developed atrial flutter and
fibrillation had significantly higher baseline values for
right atrial pressure, mean PAP, PVR, lower baseline
values for cardiac output, and mixed venous oxygen
saturation. Futhermore, the estimated 1, 2, 3, and
5 year survival rates after diagnosis of PH in patients
with permanent atrial fibrillation were 80, 66, 22, and
22%, respectively [
]. Presence of SVA in PAH
patients is also associated with deterioration of the RV
function, assessed by an increase in B-type natriuretic
peptide, atrial and ventricular diameter, mean atrial
pressure, and PVR, as well as a reduction of the
cardiac index [
]. The estimated survival rate is lower
in patients who develope SVA, and is significantly
worse in patients with permanent SVA compared to
transient or without SVA [
]. A good
understanding of cardiac arrhythmias and other autonomic
nervous system dysregulations is important not only
because they are determinants of the outcome for the
patients, but they also determine the clinical
management of PAH in these patients [
Renin-angiotensin-aldosterone-system dysregulation in PAH
Chronic activation of the RAAS in PAH patients is well
described. As extensively reviewed by Maron and Leopold,
RAAS activation promotes pulmonary vasoconstriction, cell
proliferation, migration, extracellular matrix remodeling
and fibrosis resulting in pulmonary vascular remodeling in
experimental PH (Fig. 2) [
Renin, angiotensin I, and angiotensin II
In PAH patients, circulating renin activity as well as
plasma angiotensin I and II are significantly up-regulated
and associated with disease worsening, suggesting a role
for systemic RAAS activation in PAH progression [
Futhermore, plasma renin and angiotensin II were
strongly associated with an increased risk of death or lung
transplant, making them potentially reliable biomarkers
for clinical prognosis . To determine whether local
RAAS activation was also involved in PAH, de Man et al.
] investigated angiotensin II signaling pathway in
human PAH lung tissues. They found a two-fold increase of
angiotensin II receptor AT1, but not AT2, in the
pulmonary vasculature of PAH patients along with an increase in
activity of its downstream targets Src and ERK. This is an
important finding given that AT1 signaling is involved in
vasoconstriction, oxidative stress, inflammation, and
proliferation, while AT2 signaling leads to vasodilation and is
vasculoprotective (Fig. 2) [
]. Exposing pulmonary
endothelial cells to angiotensin I revealed a significatly
increased angiotensin II production by cells isolated from
PAH patients compared to control, which was abolished
with the angiotensin-converting enzyme (ACE) inhibitor
]. This high angiotensin II production by
endothelial cells induces smooth muscle cell proliferation,
resulting in pulmonary vascular medial hypertrophy and
obliteration. In vivo, pharmacological AT1 receptor
antagonism using losartan significantly delayed disease
progression in MCT-induced PH rats by reducing RV afterload,
restoring ventricular–arterial coupling, and improving RV
diastolic function. Furthermore, losartan significantly
reduced pulmonary vascular remodeling in treated-rats but
without any change in RV hypertrophy [
these results are inconsistent with previous studies in
MCT rats using the same AT1 antagonist, in which
researchers did not find any prophylactic effect of losartan
against the development of PAH [
independent groups also tested losartan in a pressure-overload right
heart failure model. Borgdorff and colleagues  treated
pulmonary artery banded (PAB)-rats with combined
losartan + eplerenone treatment until RV failure criteria were
met or for a maximum of 11 weeks. Combined losartan +
eplerenone treatment did not prevent adverse RV
remodeling or clinical RV failure. Interestingly, treated PAB rats
did have a significant decrease in LV peak and aortic
pressures, highlighting inherent differences between right and
left ventricles and their significance in research for
therapies in the context of PAH [
]. PAB model was also used
to compare the preventive effect of losartan and bisoprolol
on development of RV hypertrophy and dysfunction [
After 6 weeks of treatment with either losartan or
bisoprolol, rats did not show any signs of improvement in RV
hypertrophy, dysfunction, fibrosis or capillary density.
Furthermore, neither losartan nor bisoprolol reversed gene
expression levels of cardiac hypertrophy and dysfunction
biomarkers.This study is additional evidence of how the
RV differs substantially from the LV when responding to
inhibition of the increased neurohormonal activation
occurring in heart failure.
In the clinical setting, 33 PH patients from different
etiologies were followed after 8 week- treatment of
losartan (Table 2) [
]. A modest but significant decrease in
mean PAP and increase in RV ejection fraction were
observed in subjects taking losartan compared to their
baseline. They also found an improvement in 6-MWD
and in several cardiopulmonary exercise testing
parameters. However, the duration of treatment was relatively
brief, and the study was lacking a control group.
Furthermore, since the cohort was comprised of subjects
from different PH classification groups, further studies
are needed to assess the real potential of losartan in
Another method to counter the vasoconstrictive and
proliferative ACE/angiotensin II/AT1 receptor axis in PAH
was demonstrated by activating the vasoprotective ACE2/
Angiotensin-(1–7)/Mas axis of the RAAS. Ferreira and
] administered the compound XNT, a
synthetic activator of ACE2, in MCT-induced PH rats during
the 28 days of the protocol. XNT significantly decreased
RV pressure and hypertrophy in treated rats. This
improvment was abolished when XNT was co-administrered
with A779, a Mas antagonist, supporting the hypothesis
that beneficial effects of ACE2 activation would be
mediated by an increase in Ang-(1–7) levels to shift the balance
from the ACE/angiotensin II/AT1 receptor axis toward
the ACE2/Angiotensin-(1–7)/Mas axis of the RAAS.
MCT treatment alone caused significant increases in renin
and angiotensinogen mRNA as well as in the AT1
receptor and ACE mRNA levels, all of which were reversed
with XNT treatment. ACE2 activation also significantly
attenuated the mRNA levels of the inflammatory mediators
tumor necrosis factor-α, interleukin-1, interleukin-6,
monocyte chemoattractant protein-1, as well as nuclear
factor-kappa B p50 and p65 [
]. Similar results were
found when MCT rats were treated with compound C21,
an AT2 receptor agonist, suggesting an endogenous
protective role of AT2 receptors in PH [
either AT2 receptor or Mas blockade prevented the
protective effect of the C21, suggesting a connection
between both receptors. The same group showed that daily
oral administration of 500 mg of bioencapsulated ACE2
or angiotensin-(1–7) prevents and rescues MCT-induced
PH, with a greater effect when both therapies were
]. ACE2 and angiotensin-(1–7) improved RV
function, and decreased pulmonary vascular wall thickness
and inflammatory markers as well as autophagy assessed
by the reduction of LC3B-II protein level. Li and
] demonstrated the prevention of PH using the
pharmacological compound resorcinolnaphthalein, an
ACE2 activator, in a severe PH model. Briefly, they
injected a single dose of MCT (40 mg/kg) 1 week after
performing pneumonectomy in rats. At the time of MCT
injection, they implanted osmotic minipumps containing
either resorcinolnaphthalein or the vehicle for 21 days of
infusion. ACE2 activation decreased mean PAP and
subsequent RV hypertrophy without any effect on systemic
pressure. This change in mean PAP was at least in part
due to a partial restoration of acetylcholine-induced
pulmonary vasorelaxation. Resorcinolnaphthalein also
decreased the neointimal formation in small pulmonary
arteries, from 95% in MCT + pneumonectomy group to
29% in treated rats. In accordance with the findings of
Ferreira and colleagues [
], beneficial effects of ACE2
activation in PAH seem to be at least partly mediated through
angiotensin-(1–7)/Mas axis, since improvements of mean
PAP, RV hypertrophy, pulmonary vasorelaxation, and
neointimal formation were all abolished by the Mas
antagonist A779 [
]. Finally, the role of ACE2/angiotensin (1–7)/
mas axis in autonomic nervous system modulation was
demonstrated using diminazene aceturate, a putative
angiotensin 1–7 converting enzyme activator [
Diminazene treatment resulted in significant improvement in
power spectrum parameters, such as normalized high and
low frequency components in treated rats compared to
MCT alone, thus reversing the imbalance in the
autonomic nervous system modulation seen in PH. Clinical
trials are now in progress to assess mechanism, safety, and
efficacy of ACE-2 treatment for PAH patients
(ClinicalTrials.gov Identifier: NCT01884051 and NCT03177603).
Another key player of RAAS is the steroid hormone
aldosterone. Maron and colleagues [
] found an increase
of aldosterone levels in plasma and lung tissues of
MCT- and Sugen/hypoxia-induced PH animals. Elevated
aldosterone levels were mediated by endothelin-1 via
peroxisome proliferator-activated receptor gamma
coactivator-1α/steroidogenesis factor-1, and increased
oxidative stress in pulmonary artery endothelial cells,
leading to an inhibition of nitric oxide production. Both
in preventive and rescue protocols, spironolactone, a
mineralocorticoid receptor antagonist, improved RV
hypertrophy, PAP, PVR, and pulmonary artery
remodeling along with decreased reactive oxygen species
generation and restoration of nitric oxide production [
The therapeutic effect of spironolactone was further
confirmed in a chronic hypoxia-induced PH mouse
]. Furthermore, the latest study demonstrated
that mineralocorticoid receptor, once activated by
aldosterone, induces transcriptional activity and proliferation
in pulmonary arterial smooth muscle cells, which was
prevented by spironolactone [
In a clinical study, Maron and colleagues [
hyperaldosteronism in a small cohort of PAH patients..
Among controls (n = 5) and treatment-naïve PAH patients
(n = 6), aldosterone levels also positively correlated with
PVR and transpulmonary gradient and inversely
correlated with cardiac output. Maron and colleagues [
analyzed the data from patients in whom spironolactone
use was reported during ARIES-1 and -2 studies, which
were randomized, double-blind, placebo-controlled trials
assessing the effect of the endothelin receptor antagonist
ambrisentan for 12 weeks on clinical outcomes in PAH
(Table 2). Compared to patients treated with ambrisentan
alone (n = 57), patients in whom spironolactone therapy
was reported during the trial (n = 10) had a trend toward
further improvement in 6-MWD, a 1.7 fold increase in
B-type natriuretic peptide plasma levels, as well as
improvement in World Health Organization functional
classification. However, a recent and larger study showed no
association between B-type natriuretic peptide levels,
6-MWD, Borg dyspnea score, RV systolic pressure, cardiac
output, or cardiac index [
]. Aldosterone levels were also
not associated with mortality. This discrepancy highlights
the need for further investigations on larger cohorts to
define the usefulness of aldosterone antagonism in PAH.
Clinical trials are actually ongoing to define the effect,
safety and tolerability of the use of aldosterone antagonists
in PAH (ClinicalTrials.gov Identifier: NCT01468571,
Invasive strategies for modulating the autonomic nervous system in PAH
Sympathetic ganglion block for the attenuation of
The activation of the SNS in PAH is well recognized, and,
as seen previously, different methodologies have been
considered to decrease this activation and improve PAH. Na
and colleagues [
] investigated the therapeutic potential
of a sympathetic ganglion block (SGB) in experimental
PH (Fig. 1). Briefly, two weeks after MCT injection in rats,
they administered daily injections of either saline or
ropivacaine, a local anesthetic, into the left superior cervical
ganglion for 14 days. Compared to MCT rats treated with
saline, SGB significantly decreased RV pressures, RV
hypertrophy, and pulmonary arterial wall thickness. This
improvement was associated with a switch in endothelial
nitric oxide synthase and arginase activity in rats injected
with ropivacaine compared to those injected with saline,
resulting in an increase in lung cGMP and plasma nitrite
]. Finally, SGB decreased pulmonary oxidative
stress, assessed by a restoration of superoxide dismutase
activity and decreased malondialdehyde and nitrotyrosine
levels in the lung tissues. These findings support SGB as a
potential novel therapeutic approach to treat PAH.
this technique in PAH (ClinicalTrials.gov Identifier:
NCT02516722, NCT02220335 and NCT02525926).
Pulmonary artery denervation for the treatment of PAH
Baroreceptors and sympathetic nerve fibers are localized
in or near the bifurcation area of the main pulmonary
artery. Chen and colleagues [
] first tested pulmonary
artery denervation (PADN) in baloon-occlusion-induced
PAH by occluding the left pulmonary interlobar artery in
10 Mongolian dogs. Five minutes after the occlusion, the
mean absolute hemodynamic changes reached their peak
with mean PAP Δ16.6 mmHg, RVSP Δ14.1 mmHg, and
PVR Δ1.144 dynes/s/cm5 compared to baseline. These
changes at five minutes were completely abolished with
the PADN treatment compared to baseline. Recently, the
nerve distribution around the pulmonary artery has been
investigated in a swine model to determine the effect of
radiofrequency PADN on acute PH induced by
vasoconstriction using thromboxane A2 agonist [
]. Mean PAP
was significantly decreased following thromboxane A2
agonist injection in swine treated with PADN (n = 4)
compared to the sham group (n = 4). This change correlated
with the number of histological denervation lesions in
pulmonary arteries. Furthermore, they demonstrated that
the depth of histological changes induced by
radiofrequency energy delivery varied with anatomic location and
wall thickness, indicating that the location is critical to
Chen and colleagues [
] tested for the first time the
safety and efficacy of PADN intervention in patients with
PAH (PADN-1 study). At 3 months follow-up, patients
who underwent PADN procedure (n = 13) showed
significant reduction of mean PAP and PVR and significant
improvement of 6-MWD, World Health Organization class,
and N-terminal brain natriuretic peptide level compared
to control group (n = 8). A few years later, a phase II of
this study was performed in a cohort of 66 patients with
mixed PH ethiologies who all underwent PADN treatment
]. Compared to baseline, the 6 months follow-up
confirmed an improvement of parameters cited above. None
of the parameters changed between the 6 months and
1 year follow-up, confirming the maintenance of benefical
effects (Table 2). These clinical studies are the
demonstration of a promising new strategy for treatment of PAH.
However, these results should be interpreted carefully
since either there was no control group, or whenever there
was one, that group did not undergo the catheter insertion
(sham) procedure. Furthermore, PADN procedure should
be tested in combination with current pharmacological
therapies used in PAH. In summary, further clinical trials
testing PADN in addition to current therapies, including a
control (sham) group, are needed to assess the
effectiveness and safety of PADN strategy in the treatment of
PAH. Clinical trials are ongoing to assess the efficacy of
Catheter-based renal denervation as a treatment of PAH
Catheter based renal denervation is an intervention that
reduces activation of the SNS and the RAAS (Fig. 1) by
destroying sympathetic nerve fibers of the renal
periarterial nerve plexus via small bursts of radiofrequency
energy along the lengh of the nerve. Qingyan and
] reported the first preclinical results of
this strategy in a proof-of-concept study that evaluated
the efficacy of catheter renal denervation as a treatment
for PAH in a canine MCT experimental model. Renal
denervation improved cardiopulmonary hemodynamics,
attenuated pulmonary vascular remodeling, and
decreased myocardial fibrosis in experimental PH. At the
molecular level, renal denervation reduced angiotensin
II type-1, but not type 2, receptor expression in the
pulmonary arterial tissue [
]. However, these beneficial
effects should be analyzed cautiously, since this study lack
of control-stimulation (sham) group. This is particularly
important since a large, prospective, single-blind,
randomized, sham-controlled trial reported a significant
decrease of the systolic blood pressure in the sham group
(n = 171) as well as in systemic hypertensive patients
(n = 364) [
]. Very recently, a group responded to this
important issue by performing renal denervation 24 h
and 2 weeks after MCT injection in rats, with control
groups undergoing a sham renal denervation surgery
]. After a 35 days follow-up, they confirmed the
beneficial effects of this procedure on the lung and cardiac
histopathology. Interestingly, the sooner the surgery was
performed during the development of the disease, the
better were the results. These exciting results support a
potential benefit of catheter-based renal denervation for
the treatment of PAH patients.
Although PAH is generally associated with increased
sympathetic nervous system activation, the precise role of
autonomic nervous system involvement in the
pathogenesis of PAH is still not fully understood. Pharmacologic
adrenergic blockade, reduction of neurohormonal
activation, and novel direct methods to attenuate sympathetic
nervous system activation such as renal denervation and
pulmonary artery denervation may be beneficial in PAH.
Further studies are needed to determine the extent of
involvement of the autonomic nervous system in PAH and
to assess the effectiveness and safety of targeting the
autonomic nervous system and RAAS for the treatment of
6-MWD: 6-Minutes walk distance; ACE: Angiotensin-converting enzyme;
LV: Left ventricle; MCT: Monocrotaline; MSNA: Muscle sympathetic nerve
activity; PAB: Pulmonary artery banding; PADN: Pulmonary artery
denervation; PAH: Pulmonary arterial hypertension; PAP: Pulmonary arterial
pressure; PH: Pulmonary hypertension; PVR: Pulmonary vascular resistance;
RAAS: Renin-angiotensin-aldosterone system; RVs: Right ventricle;
SGB: Sympathetic ganglion block; SNS: Sympathetic nervous system;
SVA: Supraventricular arrythmias
Foundation for Anesthesia Education and Research (FAER) Mentored
Research Training Grant (MRTG) (SU).
Availability of data and materials
Not applicable (review article).
MV: Conception, design, writing and revising the manuscript, preparation of
the figure, preparation of the table. PC: Conception, design, writing and
revising the manuscript. SS: Writing and revising the manuscript, preparation
of the figure. JN: Writing and revising the manuscript, preparation of the
table. NH: Conception, design, writing and revising the manuscript. GR:
Preparation of the figure, writing and revising the manuscript. ME:
Conception, design, writing and revising the manuscript. AM: Conception,
design, writing and revising the manuscript. SU: participated in the
conception and design of the study, drafting of the manuscript, modifying
the figure, overall supervision of the project and revising it critically for
important intellectual content. All authors read and approved the final
Ethics approval and consent to participate
Consent for publication
The authors declare that they have no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
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