Progress in Pediatric Cardiology 43 (2016) 7180

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Progress in Pediatric Cardiology

journal homepage: www.elsevier.com/locate/ppedcard

Review

Right sided heart failure and pulmonary hypertension: New insights into
disease mechanisms and treatment modalities
Diana Drogalis-Kim a,, John Jefferies b, Ivan Wilmot b, Juan Alejos a
a
Mattel Children's Hospital UCLA, Department of Pediatric Cardiology, Los Angeles, CA, USA 90095
b
Cincinnati Children's Hospital Medical Center, Department of Pediatric Cardiology, Los Angeles, CA, USA, 90095

a r t i c l e i n f o a b s t r a c t

Article history: Pulmonary hypertension (PH), a rare chronic progressive disorder, is a well-established cause of right heart fail-
Received 11 February 2016 ure. Given that right heart function is the most important determinant of PH patient longevity Sandoval et al.
Received in revised form 9 May 2016 (1994), D'Alonzo et al. (1991), Benza et al. (2010) [13], right heart pressure overload and failure secondary to
Accepted 12 May 2016
PH is a critical aspect of the disease to review. In this article, we will highlight new research on the mechanisms
Available online 13 May 2016
of PH induced right heart failure, as well as review the latest PH treatments aimed at improving or sustaining
right heart function.
Published by Elsevier Ireland Ltd.

Pulmonary hypertension is a progressive disorder dened as a
sustained resting mean pulmonary artery pressure N25 mmHg during
right heart cardiac catheterization [4]. According to the most recent
classications of PH at the 5th World Symposium of Pulmonary Hyper-
tension held in Nice, France in 2013, there are currently 5 subcategories
under the generalized term of pulmonary hypertension. They were re-
ned during this meeting [5] (Table 1). The rst group, pulmonary arte-
rial hypertension (PAH), is hemodynamically dened as pulmonary
capillary wedge pressure less than or equal to 15 mmHg at end expira-
tion and pulmonary vascular resistance N3 Wood's units [4,6]. In this re-
view, we will mainly focus on PAH as a cause of pressure overload
affecting the right ventricle.
1. Morbidity/Mortality of PH Patients
As previously stated, a consistent nding of large cohort PH studies
continues to demonstrate how well the right heart adapts to afterload
increase is a predictor of PH patient longevity [2,3]. Despite advances
in our understanding of PH, morbidity and mortality of this disease is
still very high. Five-year outcomes from the Registry to Evaluate Early
and Long-term PAH Disease Management (REVEAL) study, noted that
survival of advanced PAH remains poor at 5 years despite treatment ad-
vances. In this study Faber et al. concluded that previously diagnosed
Abbreviations: cGMP, cyclic guanosine monophosphate; PDE5-I, Prosphodiesterase
type 5 inhibitor; PDE5, Prosphodiesterase type 5; 5GMP, 5 Guanosine monophosphate;
cAMP, cyclic adenosine monophosphate; ETRA, Endothelin receptor antagonist; AC,
adenylate cyclase.
No disclaimers or sources of support
Corresponding author at: Mattel Children's Hospital UCLA, Department of Pediatric
Cardiology, 200 UCLA Medical Plaza, Suite 330, Los Angeles, CA 90095, USA.
E-mail address: ddrogalis-kim@mednet.ucla.edu (D. Drogalis-Kim).
PAH patients in New York Heart Association functional classes IIV
had an estimated 5-year survival rate of 88.0%, 75.6%, 57.0%, and
27.2%, respectively, compared with 72.2%, 71.7%, 60.0%, and 43.8% for
newly diagnosed patients [7]. This same registry was also used in a sub-
sequent large cohort study to assess hospitalization rates of newly diag-
nosed PAH patients. Approximately 50% of newly diagnosed PH patients
will require PH related re-hospitalization within 3 years of their initial
hospitalization, and three-year survival estimates for these same PH re-
lated re-hospitalized patients were only 5359% [8]. The French PAH
registry also assesses mortality in their adult cohort and noted a 3-
year survival outcome of 67% (95% CI 6371) [9].
One of the leading causes of PAH patient hospital admissions con-
tinues to be right heart failure. In one study right heart failure admission
rates for PAH patients were as high as 56% with an overall mortality of
14% of those patients [10]. A study from 2011 noted that short-term
mortality in patients with PAH and acute right heart failure (RHF) may
be as high as 40% in patients who require admission to the hospital [11].
2. Pathogenesis of Pulmonary Hypertension on the Pulmonary
Vasculature
Normal pulmonary artery tone is low, but has been demonstrated to
increase in tone in the setting of hypoxia or application of vasoconstric-
tive agents [12]. Pulmonary artery vasodilation occurs during exercise
to allow increase amount of oxygen delivery to the lungs. This tone is
largely dependent on calcium balance in the smooth muscle cell
(SMC). Normally, when oxygen levels are appropriate, calcium is
inhibited from entering the cell secondary to hyperpolarization from
potassium efux. Factors, released from the endothelium, that affect
the potassium channel include nitric oxide (NO), endothelium-derived
hyperpolarizing factor, prostaglandin I2. In a hypoxic environment, po-
tassium efux in the SMC is inhibited, thus allowing calcium inow, and

http://dx.doi.org/10.1016/j.ppedcard.2016.05.002
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72 D. Drogalis-Kim et al. / Progress in Pediatric Cardiology 43 (2016) 7180

Table 1 3. Pathophysiology of Right Ventricular Dysfunction in Pulmonary

Updated classication of pulmonary hypertension: Established at 5th World Symposium Hypertension
of pulmonary hypertension held in Nice, France in 2013.

Group Diagnosis
1 Pulmonary arterial hypertension
1 Pulmonary veno-occlusive disease and/or pulmonary capillary
hemangiomatosis
2 Pulmonary hypertension due to left heart disease
3 Pulmonary hypertension due to lung diseases and/or hypoxia
4 Chronic thromboembolic pulmonary hypertension
5 Pulmonary hypertension with unclear multifactorial mechanisms
inducing pulmonary vasoconstriction [13,14]. NO, endothelin, and pros-
tacyclin pathways have become targets for current PH treatments. Cel-
lular calcium pumps are also activated by protein kinases, which in
turn are regulated by secondary messages, namely cAMP and cGMP.
These have also been targeted as PH therapies.
It is also important to note that the pathogenesis of PAH not only
involves cellular mechanisms, but also genetic and environment
factors as well have been studied. Any or all of these factors may con-
tribute to vasoconstriction, vascular smooth muscle cell and endo-
thelial cell proliferation/brosis, inammation, remodeling and in-
situ thrombosis, leading to progressive disease [15]. PH therapeutic
goals currently are focused on avoiding acute vasoconstriction, and
halting and reversing vascular remodeling. These, as well as new
therapies being introduced into the market, will be discussed further
in this article.
PAH is a progressive disorder that affects both the pulmonary vascu-
lature as well as the heart [6,16]. In animal studies, it has been demon-
strated that right ventricular hypertrophy (RVH) is the rst sign that is
acutely apparent in a right ventricle under pressure overload [17]. Ini-
tially then the right ventricle adapts to the increased afterload by in-
creasing its wall thickness and contractility. In most cases however,
this compensation is insufcient leading to worsening right ventricle
(RV) contractility and chamber dilation in order to allow preload to
compensate to maintain stroke volume. As contractility continues to
worsen, clinical evidence of right heart failure becomes apparent with
diminished cardiac output, elevated lling pressures, and diastolic dys-
function [18,19] (Fig. 1). Tricuspid regurgitation secondary to chamber
enlargement leading to poor coaptation of the tricuspid valve leaets
is known to worsen symptoms as well [20].
Recent PH studies have assessed the heart and pulmonary vascula-
ture as a unit instead of separate entities in order to better determine
disease mechanisms and treatment therapies [21]. These studies dem-
onstrate that right ventricular adaptation to PAH depends on the right
ventricle's innate ability to increase contractility in response to pressure
overload [22,23]. An objective measure in the literature to assess the re-
lationship of ventricular contractility and afterload is a phenomenon
known as ventriculoarterial (VA) coupling. That is, a ratio between ven-
tricular elastance and arterial elastance. It is mainly based on left ven-
tricular research. It assumes that the normal ratio of right ventricular
VA elastance is 1.52.0 when taking into account the amount of RV con-
tractility and oxygen consumption [16,21,22].

Fig. 1. Pathophysiology of Right Ventricular Dysfunction in Pulmonary Hypertension.

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4. Adaptive vs. Maladaptive Remodeling of the Right Ventricle
Though PH remodeling is a continuum, experimental studies often
differentiate ventricular remodeling into adaptive and maladaptive pro-
cesses dependent on geometric and molecular characteristics. Adaptive
remodeling is characterized by high mass to volume ratio (i.e. concen-
tric remodeling), normal to mildly dilated RV size, and preserved systol-
ic and diastolic function and VA coupling. Maladaptive remodeling is
associated with RV enlargement, decreased RV systolic and diastolic
function, low VA coupling, and decreased perfusion. Recent studies
have suggested that RV interventricular dyssynchrony is a marker for
maladaptive remodeling and severe dysfunction [2426] (Figs. 2 and
3). Since action potentials are increased when myocytes are under me-
chanical stress, such as in PAH, this prolongs contraction time. In PAH,
because of this delayed action potential, the RV free wall contraction is
prolonged while the LV is now in its early diastolic phase, thus leading
to dyssynchrony [2728].
Several mechanisms contribute to maladaptive remodeling of the
pressure-overloaded ventricle: increased levels of reactive oxygen spe-
cies, activation of myocardial apoptotic pathways, activation of adrener-
gic and angiotensin pathways [29,30], and nally cardiomyocyte
hibernation and growth arrest with resistance to apoptosis unlike in
pulmonary vasculature with PH [31].
Change in myocardial metabolism is also another well studied
mechanism in RV remodeling. Myocardial metabolism transitions aero-
bic to anaerobic pathways (i.e. from fatty acids oxidation to glycolysis)
in order to minimize oxygen consumption [30]. During end stage PH,
Fig. 2. Adapative vs. Maladaptive pulmonary hypertension remodeling of the right
ventricle (RV). (A) Adaptive Remodeled RV as demonstrated by mild concentric
remodeling, normal to mildly dilated RV size. Systolic/diastolic function would be
preserved. (B) Maladaptive Remodeled RV as demonstrated by RV enlargement and
dilation. This heart also demonstrated decreased RV systolic and diastolic function
which is consistent with maladaption.
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73
this metabolic transition, as well as insufcient adaption of the capillary
network and myocardial ischemia, has also been known to impair vas-
cular endothelial growth factor and this, in turn, increases hypertrophic
response in the RV [31].
5. Future Research Directions in Right Ventricle Remodeling
Mechanisms
The etiology of right ventricular failure in PH patients is complex and
continues to be explored in current literature. Right ventricular failure
depends not only on the severity of pulmonary vascular disease but
also on a variety of other factors including: rate and time of onset of pul-
monary hypertension, PH underlying etiology, neurohormonal activa-
tion, coronary perfusion, myocardial metabolism, and genetic and
epigenetic factors [22,28,29,35].
New mechanisms for RV remodeling currently being explored in-
clude: pluripotent stem cell research and genetic research [3639].
There have been specic loci identied in connection with PH, but fur-
ther larger studies need to be performed to identify loci involved in
right ventricular remodeling [28].
Inammatory responses have also been studied in recent literature
as a disease mechanism for RV failure in the pressure overloaded RV
[4043]. Neutrophils have been seen acutely in the RV myocardium
after an acute afterload increase while macrophages have been noted
later in the remodeling stages of chronic pulmonary hypertension
[44]. Investigations into the role of inammatory markers is still
ongoing.
6. Clinical Symptoms of RHF in PH Patients
Exercise limitation is the earliest symptom of RHF and is a strong
predictor of survival in PAH patients [3,45]. This is related to a decrease
in cardiac output during exercise [46]. Patients with severe PH also have
an elevated incidence of arrhythmias, estimated at 12% with SVT which
can contribute to exercise limitations [34,47].
7. Current Therapies Available to Target the RV in PH
Current therapies approved for PAH target the balance between ex-
cessive vasoconstriction (endothelian-1 (ET-1) pathway) and lack of
vasodilation (prostacyclin and nitric oxide (NO) pathways) in the pul-
monary arterial system [48].
ET-1 is a potent endothelium-derived vasoconstrictor peptide which
is stimulated by a variety of factors including hypoxia, growth factors,
cytokines, shear stress, thrombin and angiotensin II, and acts on ETA
and ETB receptors. These receptors are then blocked, causing elevation
in Gq protein and formation of inositol triphosphate (IP3). Increased
IP3 causes calcium release leading to smooth muscle cell contraction
[49,50].
NO is a gaseous lipophilic free radical that causes vasodilation and
inhibits leukocyte adhesion and platelet aggregation [48,51].
PGI2 is a potent vasodilator, produced as the major active metabolite
of arachidonic acid, that inhibits thrombogenesis [48].
8. New Treatment Strategies
Given the limited currently available treatment options and recog-
nized morbidity and mortality related to pulmonary hypertension,
there is signicant interest in developing new therapies that might fa-
vorably impact the course of this disease. Although limited data exist re-
garding improvements in outcome in patients with class IV PAH and
right-sided heart failure, the use of combination therapies and the de-
velopment of new medications may offer additional treatment options.
In addition, newer strategies regarding earlier diagnosis may lead to ad-
vancements in care. Recent identication of circulating biomarkers in
pulmonary hypertension may offer a unique opportunity to identify
74 D. Drogalis-Kim et al. / Progress in Pediatric Cardiology 43 (2016) 7180

Fig. 3. Mechanism of Action and Targets of Therapy in Pulmonary Hypertension.

patients earlier in the course of the disease as well as help individualize
treatment plans [52]. Given that much of the morbidity and mortality in
this disease is secondary to right ventricular remodeling, the ability to
detect early changes in RV function or metabolism and alter manage-
ment may lead to improved outcomes [53]. This continued evolution
of proteomics in the eld of pulmonary hypertension will offer currently
unrecognized treatment opportunities.
8.1. Combination Therapy
The use of combination therapy is increasingly leveraged in clinical
practice. There are numerous reports regarding the utility of multiple
drugs being used in PH and this is reected in current management ap-
proaches with 52% on patients in North America being on combination
therapy as per the Registry to Evaluate Early and Long-term (REVEAL)
registry [54]. Part of the current debate regarding combination therapy
is whether to add therapies sequentially or whether to start combina-
tion therapy upfront [55]. There are compelling randomized control
trial data that sequential combination therapy can be used successfully.
The Pulmonary Arterial Soluble Guanylate Cyclase-Stimulator Trial 1
(PATENT-1) was a phase 3 double blind study involving 443 symptom-
atic PH subjects that assessed changes in the primary endpoint of 6 min
walk distance with addition of different regimens on Riociguat vs. place-
bo [56]. Importantly, 222 of the subjects enrolled were on background
PH therapy (endothelin receptor antagonists or prostanoids) and this
pre-specied subgroup met the primary endpoint as well as other sec-
ondary endpoints. Similarly, the Study with an Endothelin Receptor An-
tagonist in Pulmonary Hypertension to Improve Clinical Outcome
(SERAPHIN) study randomized 742 patients to placebo vs. varying
doses of macitentan [57]. Of these, 471 patients were on background
therapy of either a PDE5 inhibitor or an oral or inhaled prostanoid.
The primary composite endpoint of morbidity and mortality was met
in the pre-specied subgroup. However, other studies assessing se-
quential combination therapy, such as the FREEDOM-C and FREEDOM
C2 trials assessing the benets of adding oral treprostinil to baseline
therapies, have not met primary endpoints [58,59]. The results of the
Ambrisentan and Tadalal in Patients with Pulmonary Arterial Hyper-
tension (AMBITION) trial convey the potential utility of upfront combi-
nation therapy [60]. This prospective, double blind, event driven study
randomized class II or III PH previously untreated patients to either com-
bination therapy of ambrisentan + tadalal vs. ambrisentan + placebo
vs. tadalal + placebo. The primary end-point was a time to clinical fail-
ure as dened by a composite of death, hospitalization for worsening
PH, disease progression, or unsatisfactory long term clinical response.
The hazard ratio of 0.5 for the primary endpoint in the combination ther-
apy group was signicantly less than the combined ratio for the mono-
therapy groups (CI 0.350.72; p b 0.001). Although the current reported
treatment algorithms tend to use the sequential approach of combination
therapy, emerging reports are shifting the eld to a more proactive, up-
front combination strategy based on data from studies such as the
AMBITION trial [61]. Table 2 outlines major pulmonary arterial hyperten-
sion drug trials.
9. New Medications
9.1. Prostacyclin-receptor Agonists
Oral prostacyclin-receptor agonists are a relatively new treat-
ment option for PAH. These drugs potentially may have a very impor-
tant place in the treatment algorithms for PAH. The benets of
prostacyclin therapy are well documented and use is recommended
in the most recent guideline statement [62,63]. However, drugs such
as epoprostenol are delivered intravenously and there are risks asso-
ciated with therapy which may limit more widespread use in appro-
priate candidates [64,65]. Furthermore, prostacyclins bind broadly to
the 5 types of prostanoid receptors [66]. Oral prostacyclin-receptor
agonists have the advantage of binding selectively to the prostacy-
clin (IP) receptor with the down-stream effects of vasodilation and

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Table 2
Major pulmonary arterial hypertension drug trail results.

Trial Number Entry criteria Permissible use of Use of Endpoints Outcome

of existing therapies combination
subjects therapies

REVEAL [7]
Registry to evaluate early
and long-term PAH
disease management
compared outcomes
between early and
long-term PAH disease
management.
N=2749 Newly and previously
Previously diagnosed patients 3
diagnosed months with WHO
= 2039 group 1 PAH from
Newly 3/2006 to 12/2009 and
diagnosed functional class IIV
= 710
Y Y
Mortality Survival in long-term group was
slightly better than newly
diagnosed at 1 year (90.4% vs.
86.3%) and 5 year (65.4% vs.
61.2%).
Previously diagnosed patient
survival by functional classes I, II,
III, and IV was (88%, 75.6%, 57%,
and 27.2%) compared to newly
diagnosed patients (72.2%, 71.7,
60%, 43.8).
Increased functional class, BNP,
and mean RAP associated with
mortality. Decreased 6MWD
associated with mortality.

French PAH registry [14]

Prospective study N = 46 PAH with mean PAP Y Y ICU mortality Overall ICU mortality of 41.3%
evaluating PAH patients 25 mmHg and PAWP BNP predictor of mortality
requiring catecholamine 15 mmHg from
treatment in the ICU. 11/2005 to 4/2007

PATENT-1 [62]
Phase 3, double-blind
study, using Riociguat
(soluble Guanylate
cyclase stimulator trial)
vs. placebo.
N = 443 PAH with mean PAP Y Y 6 min walk distance (6MWD) 6MWD decreased by mean of 30
25 mmHg with 6MWD 222 patients on Change in PVR m in the 2.5 mgmaximum
150450 m prior ERA or Riociguat group and decreased by
prostanoid a mean of 6 m in the placebo
therapy group.
PVR signicantly decreased in the
Riociguat treated groups
compared to placebo.

SERAPHIN [63]
Study with an endothelin
receptor antagonist in
pulmonary hypertension
to improve clinical
outcome.
Phase 3 multicenter
double-blind placebo
controlled trial using
Macitentan (new dual
ERA).
N = 742 PAP, 12-year-old with Y Y Composite endpoint of time to Event related to PAH or death as
6MWD N50 m and 471 patients on rst event related to worsening of the rst event was signicantly
WHO functional classes prior PDE5 PAH (initiation of IV/SC less in the higher dose 10 mg
IIV from 5/2008 to inhibitor or prostanoids, lung transplantation, macitentan group (HR 0.55 vs.
12/2009. prostanoid or or atrial septostomy) or death 0.70, P b 0.001) when compared
calcium channel from any cause up to end of to the lower dose 3 mg group.
blockers, or treatment. Death due to PAH or
l-arginine therapy hospitalization was reduced in
the higher dose 10 mg
macitentant group (HR 0.50 vs.
0.67, P b 0.001) when compared
to the lower dose 3 mg group.

AMBITION [66]
Ambrisentan and Tadalal
in patients with
pulmonary arterial
hypertension
Double blind, randomized
class II or II PAH previously
treated patients to either.
N = 500 In patients 18 to 75 N Ambrisenten Composite endpoint of time to The combination therapy group
years of age with WHO + tadall vs. clinical failure (death, (ambrisentan + tadalal) had
group 1 PAH and mean ambrisentan hospitalization for worsening PH, superior outcomes when
PAP 25 from 10/2010 + placebo vs. disease progression, or compared to monotherapy (HR
to 7/2014 tadall + unsatisfactory long term clinical 0.5 (CI 0.350.72; pb0.001).
response) Hospitalization for worsening
placebo
PAH was less in the combination
therapy group than monotherapy
group (4% vs 12%, P b 0.001)

Yes, Y; No, N; World Health Organization, WHO; PAP, pulmonary aterial hypertension; PAP, pulmonary arterial pressure; PAWP, pulmonary arterial wedge pressure; 6 min walk distance,
6MWD; endothelin receptor antagonists, ERA; pulmonary vascular resistance, PVR; phosphodiesterase type 5 inhibitor, PDE5 inhibitor; intravenous, IV; subcutaneous, SC.

inhibition of smooth muscle proliferation. Selexipag, an oral selec-
tive IP prostacyclin-receptor agonist, was recently evaluated in the
Prostacyclin (PGI2) Receptor Agonist in Pulmonary Hypertension
(GRIPHON) study [67]. Based on results from a phase 2 trial revealing
a signicant reduction in PVR [68], the GRIPHON study was a double-
blind, placebo-controlled study which recruited 1156 adult subjects
(mean age 48.1 15.37 years) with pulmonary arterial hyperten-
sion. The primary combined endpoint consisted of death from any
cause or a complication related to pulmonary arterial hypertension.
The risk of death from any cause or complication from PAH was
signicantly lower in the selexipag group with a hazard ratio of 0.6
(p b 0.001). However, the discontinuation of therapy secondary to
adverse events including headache, diarrhea, nausea, and jaw pain
was higher in the selexipag group as compared to the placebo
group (14.3% vs. 7%, respectively) (Table 3).
Ralinepag, another investigational oral prostacyclin-receptor ago-
nist, is currently under investigation in an active Phase 2 international
study for adults with pulmonary arterial hypertension. It may become
an additional drug in this space in the future. Additional information
can be found at www.clinicaltrials.gov.

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Table 3
Medications used in treatment of pulmonary hypertension.

Medication Mechanism of action Route FDA Comments

(PO/IV/SC/inhaled) approved

Current
Epoprostenol Prostacyclin receptor agonist stimulates cAMP resulting in IV Y
vasodilation and antiproliferation.
Treprostinil Prostacyclin receptor agonist stimulates cAMP resulting in SC/inhaled Y
vasodilation and antiproliferation.
Iloprost Prostacylin stimulates cAMP resulting in vasodilation and Inhaled Y
antiproliferation.
Bosentan Endothelin-receptor antagonist for ETA and ETB PO Y
Ambrisentan Endothelin-receptor antagonist for ETA PO Y
Sildenal PDE-5 inhibitor PO/IV Y
iNO iNO stimulates cGMP production and vasodilation and Inhaled ODD
antiproliferation.
New
Macitentan Dual ERA Endothelin (ET-1) binds ETA and ETB PO Y
receptors-elevated Gq protein increased IP3 and
intracellular Ca2+ smooth muscle contraction.
Selexipag IP prostacyclin-receptor agonist PO Y GRIPHON [73] trial with decreased all cause death in PAH
patients treated with Selexipag. Side effects of headaches,
diarrhea, nausea, and jaw pain.
Ralinepag IP prostacyclin-receptor agonist PO N
Adrenomedullin Vasodilatory peptide. Acts by autocrine and paracrine IV N Study showing decreased PVR and improved CI in patients
(AM) effects on endothelial cells. receiving AM infusion [96].
Aviptadil Synthetic form of vasoactive intestinal peptite (VIP). Acts IV ODD Study showing improved stroke volume and mixed venous
by anti-proliferative and relaxant effects on smooth oxygenation in patients with PAH [98].
muscle.
Imatinib Tyrosine Kinase inhibitor PO N IMPRES [99] trial with 33% of patients discontinuing
medications related to adverse side effects.
Fasudil Rho-kinase inhibitor (ROCK inhibitor) IV/PO N Improved cardiac index in patients treated with Fasudil, but no
change in 6MWD [102].
Riociguat Soluble guanylate cyclase-stimulator PO Y PATENT-1 [62] study showed improved hemodynamics,
dyspnea, decreased time to clinical worsening, and exercise
capacity in patients treated with Riociguat.
Avoid co-administration with PDE-5 inhibitors.

Oral, PO; Intravenous, IV; subcutaneous, SC; Endothelin A receptor, ETA; Endothelin B receptor, ETB; Endothelin receptor antagonist, ERA; phosphodiesterase type 5 inhibitors, PDE-5 in-
hibitor; inhaled nitric oxide, iNO; Pulmonary vascular resistance, PVR; Cardiac index, CI; 6 min walk distance, 6MWD; Orphan drug designation, ODD.

10. Targeting cAMP/cGMP Pathways
10.1. New Adenyl Cyclase Stimulators
The production of cAMP is largely driven by the enzyme adenylyl cy-
clase. Given that cAMP levels are decreased in PAH, investigation re-
garding the activation of adenylyl cyclase have been pursued as
another possible avenue for medical treatment. Forskolin is a
diterpenoid and can be isolated from the Coleus forskohlii plant
grown in India, Thailand, and Nepal. Forskolin, and the water soluble
form called colforsin, are known to activate adenlylyl cyclase. Although
much of the existing literature for these drugs has been based on other
conditions, there are data to suggest that in animal models these drugs
may have benet. Forskolin has been studied in human pulmonary ar-
tery smooth muscle cells. The addition of forskolin stimulated cAMP
production and inhibited DNA synthesis [69]. These are important nd-
ings as DNA synthesis plays a signicant role in the remodeling seen in
PH. Furthermore, in hypoxic rat models of PH, cAMP mediated pulmo-
nary artery vasodilatory responses were impacted by the use of
colforsin [70]. The role of these drugs in human populations remains
to be dened.
10.2. PDE-1 Inhibitors (IBMX)
Phosphodiesterases (PDEs) are known to play an important role in
the hydrolysis of the cyclic nucleotide secondary messengers, cAMP
and cGMP. Both of these are well described to play important roles in
regulating smooth muscle cell proliferation and vascular tone [71].
There are 11 different recognized PDE families currently and each family
has several subtypes. Phosphodiesterase 1 (PDE1) is known to be up
regulated in animal models of PAH as well as humans with idiopathic
pulmonary arterial hypertension and offers a possible target for therapy
[72]. Sildenal, an approved PDE inhibitor, is known to have inhibitory
effects on PDE1, PDE5, and PDE6 [73]. Preclinical data suggests that
the benecial effects of sildenal may be mediated by both its effects
on PDE1 and PDE5 in combination and not just PDE5 alone [74]. The se-
lective PDE1 inhibitor 8-isobutyl-methylxanthine (8-IBMX) has been
the topic of increasing investigation in this area. The etiology of pulmo-
nary arterial hypertension is multifactorial but one possible contribu-
tion to the phenotype is cold exposure. Exposure to cold has been
shown to result in PAH in animal models [75,76]. Crosswhite and Sun
studied a cold-exposure induced PH model in rats and reported that
8-IBMX signicantly attenuated the development of PH in these rats
as compared to controls [77]. Specically, 8-IBMX was noted to suppress
macrophage inltration and superoxide production suggesting that
these factors contribute to some of the inammation driving PH and
that PDE1 may be a driver of these pathways.
10.3. MRP-4 Inhibitors
Multidrug resistance-associated protein 4 (MRP4, also known as
Abcc4), is a transmembrane protein that is an energy dependent trans-
porter of cyclic nucleotides such as cAMP and cGMP [78]. MRP4 has
been shown to be a regulator of cAMP homeostasis in a variety of cells
including cardiac myocytes [79]. MRP4 has been identied as an impor-
tant regulator in PH. Humans with PAH have overexpression of MRP4 in
the media of arteries, pneumocytes, and endothelial cells when com-
pared to healthy controls [80]. Furthermore, a series of investigations
in mouse models revealed that hypoxia-induced PH can be prevented
in MRP4 knockout mice and that treatment with the MRP4 inhibitor
MK571 can reverse PH in the same hypoxia-induced model with an in-
crease in intracellular cAMP and cGMP [80]. Recent data describing the

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 D. Drogalis-Kim et al. / Progress in Pediatric Cardiology 43 (2016) 7180
inhaled delivery of an AAV-based MRP4 silencing RNA in a
monocrotaline-induced rat model of PH resulted in decreased distal
pulmonary artery remodeling when compared to controls [81]. These
data suggest that the inhibition of MRP4 may be an appealing target
for human investigation.
10.4. Natriuretic Peptides, Adrenomedullin, and Vasoactive Intestinal
Peptide
Natriuretic peptides (Brain Natriuretic Peptide [BNP], Atrial Na-
triuretic Peptide [ANP]) are released in response to myocardial
strain, and increased atrial pressure. Both BNP and ANP levels have
been well reported to be elevated in individuals with PH [82,83].
BNP has been shown to be a valuable biomarker with reports of
correlating with hemodynamic parameters (pulmonary artery pres-
sure, pulmonary vascular resistance), severity of PH, and mortality
[8486]. Given the biologic properties of vasodilation and natriuresis
of natriuretic peptides, systemic infusion of Nesiritide has been pro-
posed as a therapy in PH also.
Adrenomedullin (AM) is a potent vasodilatory peptide. AM gene ex-
pression is promoted by various stimuli including inammation, hypox-
ia, oxidative stress, mechanical stress, and activation of the renin-
angiotensin and sympathetic nervous systems. AM was initially identi-
ed from pheochromocytoma tissue [87]. However, subsequent studies
have identied an association between elevated AM levels and various
disease states including myocardial infarction, heart failure, and PH
[88]. AM has been identied at elevated levels in vascular smooth mus-
cle cells where it acts as an autocrine and or paracrine factor playing a
key role in the regulation of cardiovascular function. AM has been
shown to reduce mean pulmonary artery pressures, and the synthesis
of collagen I, Collagen III, and TGF- in animal models of PH [89]. As
such, AM appears to not only play a role in vasodilation but also in the
regulation of factors involved in pulmonary vascular remodeling and in-
ammation. Nagaya and colleagues evaluated the pulmonary vasodila-
tor response to intrapulmonary and intravenous infusion of AM in
human subjects with PH [90]. In this small study of 15 patients AM infu-
sion was associated with a signicant reduction in pulmonary vascular
resistance, and increase in cardiac index. AM appears to serve a regula-
tory role in the vascular endothelium augmenting blood ow to areas of
inammation and injury, and regulating cardiac function. As such it may
serve as a promising future therapy in the management of PH.
Aviptadil, a fully synthetic form of Vasoactive Intestinal Peptide
(VIP), is the generic name given to VIP by the World Health Organi-
zation in 1997. VIP has several biologic effects including inhibiting
platelet activation, and anti-proliferative and relaxant effects on
smooth muscle. VIP levels are decreased in individuals with PH
[91]. As such it has been studied as a potential PH therapy. In a trial
utilizing a single dose of aerosolized aviptadil in 20 patients with
PH undergoing acute right heart catheterization, study individuals
had improved stroke volume and mixed venous oxygenation. Al-
though the effects of aviptadil were short lived, there were no signif-
icant reported side-effects [92].
10.5. Tyrosine Kinase Inhibitors
Tyrosine kinase inhibition may prove to have an antiproliferative
benet in PH. Imatinib was the rst studied tyrosine kinase inhibitor
in PAH. Although initial reports of improved pulmonary hemodynamics,
reversibility of pulmonary arterial remodeling and survival were prom-
ising, subsequent studies such as the RCT IMPRES led to a third of pa-
tients discontinuing the drug related to serious adverse events [93,94].
Although promising as a therapy in PH management, the side effect pro-
le of several tyrosine kinase inhibitors have limited wide spread use of
this class of medication.
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77
10.6. Rho-kinase Inhibitors
Rho-kinase (ROCK) is involved in many cellular functions including
cell migration, contraction, proliferation and apoptosis [95]. Fasudil is
a ROCK inhibitor that has been studied in humans with PAH. Although
studies using Fasudil in intravenous and inhaled forms have been per-
formed, studies utilizing oral formulations are ongoing. A long-acting
oral formulation of Fasudil was studied in 23 patients with PAH in
Japan [96]. In this randomized control study the 6-minute walk times
showed no difference, but the pulmonary hemodynamics trended to-
wards improvement in the patients treated with Fasudil and showed
improved cardiac indexes also. Additional clinical studies utilizing
Rho-kinase inhibitors are needed.
10.7. Agents Targeting Serotonin Pathway
Serotonin (5-hydroxytryptamine [5-HT]) induced mitogenesis has
been implicated in the pathogenesis of PH. Tryptophan hydroxylase
(TPH) is the enzyme responsible for serotonin synthesis. Its activity is
increased in individuals with PH, and the enzyme expression appears
to be conned to the pulmonary vessel intima by immunostaining
[97]. Interestingly, the serotonin transporter (5-HTT) appears to be
largely conned to the pulmonary vessel media on immunohistochem-
ical analysis [97]. Thus the mitogenic action of 5-HT on pulmonary ar-
tery smooth muscle cells appears to be mediated by the serotonin
transporter (5-HTT) [98,99]. Studies involving blocking the serotonin
transporter using Fluoxetine, and inhibiting serotonin synthesis
with p-chlorophenaylalanine have shown reduction in this growth
mitogenesis [97]. Thus agents targeted at blocking this serotonin path-
way show promise in reducing the pulmonary arteriolar hyperplasia
seen in individuals with PH.
10.8. Agents Targeting Nitric Oxide Pathways
Although older therapies utilizing the nitric oxide pathway as a
treatment for PAH relied upon increasing intra alveolar nitric oxide con-
centration with subsequent increased cGMP resulting in pulmonary va-
sodilation, newer therapies are targeted at increasing cGMP through
soluble guanylate cyclase stimulators (sGC) and preventing cGMP deg-
radation with PDE-5 inhibitors.
Riociguat (Adempas) is a soluble guanylate cyclase (sGC) stimula-
tor, which was recently approved for PAH treatment by the FDA.
Riociguat stimulates the biosynthesis of cGMP by stimulating sCG and
increasing their sensitivity towards low endogenous NO levels [100].
Stimulation of sGC has been shown to reverse right ventricular hyper-
trophy and improve structural vascular remodeling in animal models
[101]. The randomized controlled trial PATENT-1 assessed the efcacy
and safety of Riociguat in symptomatic patients with PAH [56]. The
study involved Riociguat doses up to 2.5 mg three times daily over
12 weeks. Individuals receiving the drug had improvements in hemody-
namics, dyspnea, time to clinical worsening, and exercise capacity. The
most common serious adverse event reported was syncope (placebo
group 4% vs. Rociguat group 1%). Although long-term studies evaluating
this drug are ongoing (i.e. PATENT-2), Rociguat seems to be well toler-
ated with only mild to moderate side effects. Most commonly reported
side effects include headache, ushing, and orthostatic hypotension. Co-
administration of Rociguat with PDE-5 inhibitors is contraindicated sec-
ondary to hypotension and other reported adverse events [61].
10.9. Inhibitors of Endoplasmic Reticulum Stress and Mitochondrial
Suppression
The interplay of the endoplasmic reticulum stress response and mi-
tochondrial suppression have been implicated in the pathophysiology
of PH [102104]. Endothelial cells (EC) expressing the HLA-B35 allele
have been associated with PH [105]. Although proposed mechanisms
78 D. Drogalis-Kim et al. / Progress in Pediatric Cardiology 43 (2016) 7180
for this association are reported through stimulation of the Endothelin-
1 (ET-1) pathway, there are increasing reports of additional complex
metabolic alterations in the pathophysiology of PH. Lenna and col-
leagues report the up-regulation of ET-1 in HLA-B35 endothelial cells,
but also the down regulation of endothelial nitric oxide synthase via en-
doplasmic reticulum stress response [102]. The endoplasmic stress re-
sponse can reduce mitochondrial calcium by causing functional
disruption of the ER-mitochondrion unit [106,107]. Additionally, in-
creasing studies identify the association of suppressed mitochondrial
apoptosis and suppressed signaling that affects several proliferative
downstream extramitochondrial factors in the complex molecular ab-
normalities on PH [103,108]. These mitochondrial effects seen in PH
have been proposed to be analogous to some of the same processes
seen in cancer cells [109]. Given the numerous complex processes iden-
tied in the pathogenesis of PH, regulation of this mitochondrial sup-
pression has been proposed as potential novel common target in PH
management. Paulin and colleagues outline several therapeutic
targets inhibiting the endoplasmic reticulum stress response (i.e. 4-
Phenylbutarate, Salubrinal), and regulating mitochondrial suppression
(i.e. Dichloroacetate, iron supplementation, Trimetazidine) [52].
Dichloroacetate has been reported to show reversal of right ventricular
remodeling via inhibition of mitochondria-dependent apoptosis in ani-
mal models of PH [110]. Sun and colleagues evaluated the effects of
Dichloroacetate on myocardial mitochondria. They noted a signicant
decrease in mean pulmonary artery pressures, pulmonary vascular re-
sistance, reduction in right ventricular hypertrophy, brosis, capillary
rarefaction, apoptosis and restored right ventricular mitochondrial
function in animals treated with Dichloroacetate. Although there is
strong preclinical evidence to support use of inhibitors of endoplasmic
reticulum and mitochondrial suppression in the treatment of PH, addi-
tional clinical study is required.
10.10. Cell Based Therapies
Endothelial dysfunction, injury, and the capacity for repair are pro-
posed mechanisms of PH. Studies utilizing endothelial progenitor cells
(EPC's), which have the capacity for repair, are promising as a therapy
for PH. EPC's have the ability to circulate, proliferate, and differentiate
into mature cells. Several studies utilizing EPC's in animal models of
PH have shown attenuation of pulmonary hypertension [111,112]. A
pilot randomized controlled trial utilizing infusion of EPC's in individ-
uals with PH was conducted by Wang and colleagues [113]. The primary
end point was change in 6-minute walk test, and the secondary end
point was changes in hemodynamic variables measured by right heart
catheterization. Individuals in the EPC infusion group had a signicantly
better 6-minute walk distance, mean pulmonary artery pressure, pul-
monary vascular resistance, and cardiac output [113]. Although the
novel use of EPC's in the treatment of PH show promising results, addi-
tional larger scale human studies are required at this time.
11. Summary
Pulmonary hypertension (PH) is a well-established cause of right
heart failure. Right heart function is the most important determinant
of PH patient longevity.
Despite advances in our understanding of PH, morbidity and mortality
of this disease is still very high.
The mechanism of PH is largely dependent on calcium balance in the
smooth muscle cell (SMC). Nitric oxide (NO), endothelium-derived
hyperpolarizing factor, prostaglandin I2, and cellular calcium pumps
(regulated by secondary messages such as cAMP and cGMP), all of
which affect smooth muscle cell calcium balance, are targets for cur-
rent PH treatments.
Pulmonary hypertension disease mechanism is associated with mal-
adaptive remodeling of the right ventricle.
New mechanisms for RV remodeling currently being explored include
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pluripotent stem cell research and genetic research.
New treatment strategies aimed at improving or sustaining right
heart function and clinical trials testing these pharmacologic treat-
ments are currently ongoing and discussed in depth in this review.
References
[1] Sandoval J, Bauerle O, Palomar A, et al. Survival in primary pulmonary hyperten-
sion. Validation of a prognostic equation. Circulation 1994;89:173344.
[2] D'Alonzo GE, Barst RJ, Ayres SM, et al. Survival in patients with primary pulmonary
hypertension. Results from a national prospective registry. Ann Intern Med 1991;
115:3439.
[3] Benza RL, Miller DP, Gomberg-Maitland M, et al. Predicting survival in pulmonary
arterial hypertension: insights from the registry to evaluate early and long-term
pulmonary arterial hypertension disease management (REVEAL). Circulation
2010;122:16472.
[4] Hoeper MM, Bogaard HJ, Condliffe R, et al. Denitions and diagnosis of pulmonary
hypertension. J Am Coll Cardiol 2013;62:D4250 (25 Suppl).
[5] Simonneau G, Gatzoulis M, Adatia I, et al. Updated clinical classication of pulmo-
nary hypertension. J Am Coll Cardiol 2013;62 (Supplement:D3441).
[6] Farber HW, Loscalzo J. Pulmonary arterial hypertension. N Engl J Med 2004;351:
165565.
[7] Farber HW, Miller D, Poms AD, et al. Five-year outcomes of patients enrolled in the
REVEAL registry. Chest 2015;148:104354.
[8] Burger CD, Long PK, Shah MR, et al. Characterization of rst-time hospitalizations in
patients with newly diagnosed pulmonary arterial hypertension in the REVEAL
registry. Chest 2014;146:126373.
[9] Humbert M, et al. Including French pulmonary arterial hypertension network. Sur-
vival in incident and prevalent cohorts of patients with pulmonary arterial hyper-
tension. Eur Respir J 2010;36:54955.
[10] Campo SC, Mathai J, Pavec L, et al. Outcomes of hospitalisation for right heart failure
in pulmonary arterial hypertension. Eur Respir J 2011;38:35967.
[11] Sztrymf B, Souza R, Bertoletti L, et al. Prognostic factors of acute heart failure in pa-
tients with pulmonary arterial hypertension. Eur Respir J 2010;35:128693.
[12] Mcdaniel SS, Platoshyn O, Wang J, et al. Capacitative ca2+ entry in agonist-induced
pulmonary vasoconstriction. American Journal of Physiology - Lung Cellular and
Molecular Physiology 2001;280:L87080.
[13] Reeve HL, Weir EK, Archer SL, Corneld DN. A maturational shift in pulmonary
K + channels, from Ca 2+ sensitive to voltage dependent. Am J Physiol Lung
Cell Mol Physiol 1998;275:L101925.
[14] Olschewski H, Olschewski A, Rose F, et al. Physiologic basis for the treatment of pul-
monary hypertension. J Lab Clin Med 2001;138:28797.
[15] Clin YP, Acta C. Molecular mechanisms of pulmonary hypertension. Clin Chim Acta
2009;403:916.
[16] Chesler NC, Roldan A, Vanderpool RR, Naeije R. How to measure pulmonary vascu-
lar and right ventricular function. Proceedings of the Annual International Confer-
ence of the IEEE Engineering in Medicine and Biology Society, IEEE, New York, NY;
2009. p. 17780.
[17] Dias CA, Assad RS, Caneo LF, et al. Reversible pulmonary trunk banding. II. An ex-
perimental model for rapid pulmonary ventricular hypertrophy. J Thorac
Cardiovasc Surg 2002;124:9991006.
[18] Chen EP, Craig DM, Bittner HB, Davis RD, Van Trigt P. Pharmacological strategies for
improving diastolic dysfunction in the setting of chronic pulmonary hypertension.
Circulation 1998;97:160612.
[19] Haddad F, Doyle R, Murphy DJ, Hunt SA. Right ventricular function in cardiovascu-
lar disease, part II: pathophysiology, clinical importance, and management of right
ventricular failure. Circulation 2008;117:171731.
[20] Fora PR, Fisher MR, Mathai SC, et al. Tricuspid annular displacement predicts sur-
vival in pulmonary hypertension. Am J Respir Crit Care Med 2006;174:103441.
[21] Champion HC, Michelakis ED, Hassoun PM. Comprehensive invasive and noninva-
sive approach to the right ventricle-pulmonary circulation unit: state of the art and
clinical and research implications. Circulation 2009;120:9921007.
[22] Kuehne T, Yilmaz S, Steendijk P, et al. Magnetic resonance imaging analysis of right
ventricular pressure-volume loops: in vivo validation and clinical application in pa-
tients with pulmonary hypertension. Circulation 2004;110:20106.
[23] Guihaire J, Haddad F, Boulate D, et al. Non-invasive indices of right ventricular func-
tion are markers of ventricular-arterial coupling rather than ventricular contractil-
ity: insights from a porcine model of chronic pressure overload. Eur Heart J
Cardiovasc Imaging 2013;14:11409.
[24] Lumens J, Arts T, Marcus JT, Vonk-Noordegraaf A, Delhaas T. Early-diastolic left ven-
tricular lengthening implies pulmonary hypertension-induced right ventricular de-
compensation. Cardiovasc Res 2012;96:28695.
[25] Handoko ML, de Man FS, Allaart CP, Paulus WJ, Westerhof N, Vonk-Noordegraaf A.
Perspectives on novel therapeutic strategies for right heart failure in pulmonary ar-
terial hypertension: lessons from the left heart. Eur Respir Rev 2010;19:7282.
[26] Marcus JT, Gan CT, Zwanenburg JJ, et al. Interventricular mechanical asynchrony in
pulmonary arterial hypertension: left-to-right delay in peak shortening is related
to right ventricular overload and left ventricular underlling. J Am Coll Cardiol
2008;51:7507.
[27] Helderman F, Mauritz GJ, Andringa KE, Vonk-Noordegraaf A, Marcus JT. Early onset
of retrograde ow in the main pulmonary artery is a characteristic of pulmonary
arterial hypertension. J Magn Reson Imaging 2011;33:13628.
 D. Drogalis-Kim et al. / Progress in Pediatric Cardiology 43 (2016) 7180
[28] Vonk-Noordegraaf A, Haddad F, Chin KM, et al. Right heart adaptation to pulmo-
nary arterial hypertension: physiology and pathobiology. J Am Coll Cardiol 2013;
62(25 Suppl):D2233.
[29] Bogaard HJ, Abe K, Vonk Noordegraaf A, Voelkel NF. The right ventricle under pres-
sure: cellular and molecular mechanisms of right-heart failure in pulmonary hy-
pertension. Chest 2009;135:794804.
[30] Watts JA, Marchick MR, Kline JA. Right ventricular heart failure from pulmonary
embolism: key distinctions from chronic pulmonary hypertension. J Card Fail
2010;16:2509.
[31] Tuder RM, Davis LA, Graham BB. Targeting energetic metabolism: a new frontier in
the pathogenesis and treatment of pulmonary hypertension. Am J Respir Crit Care
Med 2012;185:2606.
[34] Tanaka Y, Takase B, Yao T, Ishihara M. Right ventricular electrical remodeling and
arrhythmogenic substrate in rat pulmonary hypertension. Am J Respir Cell Mol
Biol 2013;49:42636.
[35] Haddad F, Peterson T, Fuh E, et al. Characteristics and outcome after hospitalization
for acute right heart failure in patients with pulmonary arterial hypertension. Circ
Heart Fail 2011;4:6929.
[36] Takemiya K, Hisashi K, Yasukawa H, Tahara N, Kato S, Imaizum T. Mesenchymal
stem cell-based prostacyclin synthase gene therapy for pulmonary hypertension
rats. Basic Res Cardiol 2010;105:40917.
[37] Lee JC, Cha CI, Kim D-S, Choe SY. Therapeutic effects of umbilical cord blood derived
mesenchymal stem cell-conditioned medium on pulmonary arterial hypertension
in rats. J Pathol Transl Med 2015;49:47280.
[38] Lu Long, Ormiston ML, Yang X, et al. Selective enhancement of endothelial
BMPR-II with BMP9 reverses pulmonary arterial hypertension. Nat Med
2015;21:77785
[39] Gouadon E, Moore-Morris T, Smit NW, et al. Concise review: pluripotent stem cell-
derived cardiac cells, a promising cell source for therapy of heart failure: where do
We stand? Stem Cells 2016;34:3443.
[40] Wrigley BJ, Lip GY, Shantsila E. The role of monocytes and inammation in the
pathophysiology of heart failure. Eur J Heart Fail 2011;13:116171.
[41] Belhaj A, Dewachter L, Kerbaul F, Brimioulle S, Dewachter C, Naeije R, et al. Heme
oxygenase-1 and inammation in experimental right ventricular failure on
prolonged Overcirculation-induced pulmonary hypertension. PLoS One 2013;8,
e69470.
[42] Kisarova Y, Safdar Z, Katarzyna C, Entman ML. Animal Model of Pulmonary Arterial
Hypertension is Associated with Inammation in the Heart. Right Ventricle: Struc-
ture and Function C61. American Thoracic Society International Conference Ab-
stracts; 2015(A4858-A4858).
[43] Soon E, Crosby A, Southwood M, et al. Bone morphogenetic protein receptor type ii
deciency and increased inammatory cytokine production. A gateway to pulmo-
nary arterial hypertension. Am J Respir Crit Care Med 2015;192:85972.
[44] Watts JA, Zagorski J, Gellar MA, Stevinson BG, Kline JA. Cardiac inammation con-
tributes to right ventricular dysfunction following experimental pulmonary embo-
lism in rats. J Mol Cell Biol 2006;41:296307.
[45] Humbert M, Sitbon O, Chaouat A, et al. Survival in patients with idiopathic, familial,
and anorexigen-associated pulmonary arterial hypertension in the modern man-
agement era. Circulation 2010;122:15663.
[46] Provencher S, Herve P, Sitbon O, Humbert M, Simonneau G, Chemla D. Changes in
exercise haemodynamics during treatment in pulmonary arterial hypertension.
Eur Respir J 2008;32:3938.
[47] Tongers J, Schwerdtfeger B, Klein G, et al. Incidence and clinical relevance of supra-
ventricular tachyarrhythmias in pulmonary hypertension. Am Heart J 2007;153:
12732.
[48] Montani D, Chaumais MC, Guignabert C, et al. Targeted therapies in pulmonary ar-
terial hypertension. Pharmacol Ther 2014;141:17291.
[49] Lador F, Sekarski N, Beghetti M. Treating pulmonary hypertension in pediatrics. Ex-
pert Opin Pharmacother 2015;16:71126.
[50] Perrin S, Chaumais MC, O'Connell C, et al. New pharmacotherapy options for pul-
monary arterial hypertension. Expert Opin Pharmacother 2015;16:211331.
[51] Mayer B, Hemmens B. Biosynthesis and action of nitric oxide in mammalian cells.
Trends Biochem Sci 1997;22:47781.
[52] Lewis GD, Ngo D, Hemnes AR, et al. Metabolic proling of right ventricular-pulmo-
nary vascular function reveals circulating biomarkers of pulmonary hypertension. J
Am Coll Cardiol 2016;67:17489.
[53] Gupte AA, Cordero-Reyes AM, Youker KA, et al. Differential mitochondrial function
in remodeled right and Nonremodeled left ventricles in pulmonary hypertension. J
Card Fail 2016;22:7381.
[54] Badesch DB, Raskob GE, Elliott CG, et al. Pulmonary arterial hypertension: baseline
characteristics from the REVEAL registry. Chest 2010;137:37687.
[55] Humbert M, Lau EM, Montani D, Jais X, Sitbon O, Simonneau G. Advances in ther-
apeutic interventions for patients with pulmonary arterial hypertension. Circula-
tion 2014;130:2189208.
[56] Ghofrani HA, Galie N, Grimminger F, et al. Riociguat for the treatment of pulmonary
arterial hypertension. N Engl J Med 2013;369:33040.
[57] Pulido T, Adzerikho I, Channick RN, et al. Macitentan and morbidity and mortality
in pulmonary arterial hypertension. N Engl J Med 2013;369:80918.
[58] Tapson VF, Torres F, Kermeen F, et al. Oral treprostinil for the treatment of pulmo-
nary arterial hypertension in patients on background endothelin receptor antago-
nist and/or phosphodiesterase type 5 inhibitor therapy (the FREEDOM-C study):
a randomized controlled trial. Chest 2012;142:138390.
[59] Tapson VF, Jing ZC, Xu KF, et al. Oral treprostinil for the treatment of pulmonary ar-
terial hypertension in patients receiving background endothelin receptor antago-
nist and phosphodiesterase type 5 inhibitor therapy (the FREEDOM-C2 study): a
randomized controlled trial. Chest 2013;144:9528.
Downloaded for Anonymous User (n/a) at Los Angeles County Department of Health Services from ClinicalKey.com by Elsevier on October 21, 2017.
For personal use only. No other uses without permission. Copyright 2017. Elsevier Inc. All rights reserved.
79
[60] Galie N, Barbera JA, Frost AE, et al. Initial use of ambrisentan plus tadalal in pulmo-
nary arterial hypertension. N Engl J Med 2015;373:83444.
[61] Galie N, Corris PA, Frost A, et al. Updated treatment algorithm of pulmonary arterial
hypertension. J Am Coll Cardiol 2013;62:D6072.
[62] Barst RJ, Rubin LJ, Long WA, et al. A comparison of continuous intravenous
epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hy-
pertension. N Engl J Med 1996;334:296301.
[63] Galie N, Humbert M, Vachiery JL, 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). Eur Heart J 2016;37:67119.
[64] McLaughlin VV, Langer A, Tan M, et al. Contemporary trends in the diagnosis and
management of pulmonary arterial hypertension: an initiative to close the care
gap. Chest 2013;143:32432.
[65] Frantz RP, Schilz RJ, Chakinala MM, et al. Hospitalization and survival in patients
using epoprostenol for injection in the PROSPECT observational study. Chest
2015;147:48494.
[66] Whittle BJ, Silverstein AM, Mottola DM, Clapp LH. Binding and activity of the pros-
tacyclin receptor (IP) agonists, treprostinil and iloprost, at human prostanoid re-
ceptors: treprostinil is a potent DP1 and EP2 agonist. Biochem Pharmacol 2012;
84:6875.
[67] Sitbon O, Channick R, Chin KM, et al. Selexipag for the treatment of pulmonary ar-
terial hypertension. N Engl J Med 2015;373:252233.
[68] Simonneau G, Torbicki A, Hoeper MM, et al. Selexipag: an oral, selective prostacy-
clin receptor agonist for the treatment of pulmonary arterial hypertension. Eur
Respir J 2012;40:87480.
[69] Wharton J, Davie N, Upton PD, Yacoub MH, Polak JM, Morrell NW. Prostacyclin an-
alogues differentially inhibit growth of distal and proximal human pulmonary ar-
tery smooth muscle cells. Circulation 2000;102:31306.
[70] Yokochi A, Itoh H, Maruyama J, et al. Colforsin-induced vasodilation in chronic hyp-
oxic pulmonary hypertension in rats. J Anesth 2010;24:43240.
[71] Koyama H, Bornfeldt KE, Fukumoto S, Nishizawa Y. Molecular pathways of cyclic
nucleotide-induced inhibition of arterial smooth muscle cell proliferation. J Cell
Physiol 2001;186:110.
[72] Schermuly RT, Pullamsetti SS, Kwapiszewska G, et al. Phosphodiesterase 1 upregu-
lation in pulmonary arterial hypertension: target for reverse-remodeling therapy.
Circulation 2007;115:23319.
[73] Ballard SA, Gingell CJ, Tang K, Turner LA, Price ME, Naylor AM. Effects of sildenal
on the relaxation of human corpus cavernosum tissue in vitro and on the activities
of cyclic nucleotide phosphodiesterase isozymes. J Urol 1998;159:216471.
[74] Schermuly RT, Inholte C, Ghofrani HA, et al. Lung vasodilatory response to inhaled
iloprost in experimental pulmonary hypertension: amplication by different type
phosphodiesterase inhibitors. Respir Res 2005;6:76.
[75] Watanabe K, Koizumi T, Ruan Z, Kubo K, Sakai A, Shibamoto T. Reduced pulmonary
vascular reactivity after cold exposure to acute hypoxia: a role of nitric oxide (NO).
High Alt Med Biol 2007;8:439.
[76] Li JC, Pan JQ, Huang GQ, et al. Expression of PDGF-beta receptor in broilers with pul-
monary hypertension induced by cold temperature and its association with pulmo-
nary vascular remodeling. Res Vet Sci 2010;88:11621.
[77] Crosswhite P, Sun Z. Inhibition of phosphodiesterase-1 attenuates cold-induced
pulmonary hypertension. Hypertension 2013;61:58592.
[78] Wielinga PR, van der Heijden I, Reid G, Beijnen JH, Wijnholds J, Borst P. Character-
ization of the MRP4- and MRP5-mediated transport of cyclic nucleotides from in-
tact cells. J Biol Chem 2003;278:1766471.
[79] Sassi Y, Abi-Gerges A, Fauconnier J, et al. Regulation of cAMP homeostasis by the ef-
ux protein MRP4 in cardiac myocytes. FASEB J 2012;26:100917.
[80] Hara Y, Sassi Y, Guibert C, et al. Inhibition of MRP4 prevents and reverses pulmo-
nary hypertension in mice. J Clin Invest 2011;121:288897.
[81] Claude C, Mougenot N, Bechaux J, et al. Inhalable delivery of AAV-based MRP4/
ABCC4 silencing RNA prevents monocrotaline-induced pulmonary hypertension.
Mol Ther Methods Clin Dev 2015;2:14065.
[82] Wiedemann R, Ghofrani HA, Weissmann N, et al. Atrial natriuretic peptide in se-
vere primary and nonprimary pulmonary hypertension: response to iloprost inha-
lation. J Am Coll Cardiol 2001;38:11306.
[83] Morice AH, Pepke-Zaba J, Brown MJ, Thomas PS, Higenbottam TW. Atrial natriuret-
ic peptide in primary pulmonary hypertension. Eur Respir J 1990;3:9103.
[84] Nagaya N, Ando M, Oya H, et al. Plasma brain natriuretic peptide as a noninvasive
marker for efcacy of pulmonary thromboendarterectomy. Ann Thorac Surg 2002;
74:1804 [discussion 4].
[85] Williams MH, Handler CE, Akram R, et al. Role of N-terminal brain natriuretic pep-
tide (N-TproBNP) in scleroderma-associated pulmonary arterial hypertension. Eur
Heart J 2006;27:148594.
[86] Leuchte HH, El Nounou M, Tuerpe JC, et al. N-terminal pro-brain natriuretic peptide
and renal insufciency as predictors of mortality in pulmonary hypertension. Chest
2007;131:4029.
[87] Kitamura K, Kangawa K, Kawamoto M, et al. Adrenomedullin: a novel hypotensive
peptide isolated from human pheochromocytoma. Biochem Biophys Res Commun
1993;192:55360.
[88] Ishimitsu T, Ono H, Minami J, Matsuoka H. Pathophysiologic and therapeutic impli-
cations of adrenomedullin in cardiovascular disorders. Pharmacol Ther 2006;111:
90927.
[89] Qi JG, Xing CQ, Ding YG, Du JB. Adrenomedullin alleviates collagen accumulation in
pulmonary arteries of rats with hypoxic pulmonary hypertension. Zhongguo Dang
Dai Er Ke Za Zhi 2012;14:548.
80 D. Drogalis-Kim et al. / Progress in Pediatric Cardiology 43 (2016) 7180
[90] Nagaya N, Miyatake K, Kyotani S, Nishikimi T, Nakanishi N, Kangawa K. Pulmonary
vasodilator response to adrenomedullin in patients with pulmonary hypertension.
Hypertens Res 2003;26(Suppl):S1416.
[91] Petkov V, Mosgoeller W, Ziesche R, et al. Vasoactive intestinal peptide as a new
drug for treatment of primary pulmonary hypertension. J Clin Invest 2003;111:
133946.
[92] Leuchte HH, Baezner C, Baumgartner RA, et al. Inhalation of vasoactive intestinal
peptide in pulmonary hypertension. Eur Respir J 2008;32:128994.
[93] Hoeper MM, Barst RJ, Bourge RC, et al. Imatinib mesylate as add-on therapy for pul-
monary arterial hypertension: results of the randomized IMPRES study. Circulation
2013;127:112838.
[94] Schermuly RT, Dony E, Ghofrani HA, et al. Reversal of experimental pulmonary hy-
pertension by PDGF inhibition. J Clin Invest 2005;115:281121.
[95] Odagiri K, Watanabe H. Effects of the rho-kinase inhibitor, fasudil, on pulmonary
hypertension. Circ J 2015;79:12134 Ofcial Journal of the Japanese Circulation
Society.
[96] Fukumoto Y, Yamada N, Matsubara H, et al. Double-blind, placebo-controlled clin-
ical trial with a rho-kinase inhibitor in pulmonary arterial hypertension. Circ J
2013;77:261925 Ofcial Journal of the Japanese Circulation Society.
[97] Eddahibi S, Guignabert C, Barlier-Mur AM, et al. Cross talk between endothelial and
smooth muscle cells in pulmonary hypertension: critical role for serotonin-induced
smooth muscle hyperplasia. Circulation 2006;113:185764.
[98] Eddahibi S, Fabre V, Boni C, et al. Induction of serotonin transporter by hypoxia in
pulmonary vascular smooth muscle cells. Relationship with the mitogenic action of
serotonin. Circ Res 1999;84:32936.
[99] Davie N, Haleen SJ, Upton PD, et al. ET(A) and ET(B) receptors modulate the prolif-
eration of human pulmonary artery smooth muscle cells. Am J Respir Crit Care Med
2002;165:398405.
[100] O'Callaghan DS, Savale L, Montani D, et al. Treatment of pulmonary arterial hyper-
tension with targeted therapies. Nat Rev Cardiol 2011;8:52638.
[101] Schermuly RT, Stasch JP, Pullamsetti SS, et al. Expression and function of soluble
guanylate cyclase in pulmonary arterial hypertension. Eur Respir J 2008;32:
88191.
[102] Lenna S, Townsend DM, Tan FK, et al. HLA-B35 upregulates endothelin-1 and
downregulates endothelial nitric oxide synthase via endoplasmic reticulum stress
response in endothelial cells. J Immunol 2010;184:465461.
Downloaded for Anonymous User (n/a) at Los Angeles County Department of Health Services from ClinicalKey.com by Elsevier on October 21, 2017.
For personal use only. No other uses without permission. Copyright 2017. Elsevier Inc. All rights reserved.
[103] Paulin R, Michelakis ED. The metabolic theory of pulmonary arterial hypertension.
Circ Res 2014;115:14864.
[104] Dromparis P, Michelakis ED. Mitochondria in vascular health and disease. Annu Rev
Physiol 2013;75:95126.
[105] Santaniello A, Salazar G, Lenna S, et al. HLA-B35 upregulates the production of
endothelin-1 in HLA-transfected cells: a possible pathogenetic role in pulmonary
hypertension. Tissue Antigens 2006;68:23944.
[106] Sutendra G, Dromparis P, Wright P, et al. The role of Nogo and the mitochondria-
endoplasmic reticulum unit in pulmonary hypertension. Sci Transl Med 2011;3:
88ra55.
[107] Nagendran J, Gurtu V, Fu DZ, et al. A dynamic and chamber-specic mitochondrial
remodeling in right ventricular hypertrophy can be therapeutically targeted. J
Thorac Cardiovasc Surg 2008;136:16878 (78 e13).
[108] Patel M, Predescu D, Tandon R, et al. A novel p38 mitogen-activated protein kinase/
elk-1 transcription factor-dependent molecular mechanism underlying abnormal
endothelial cell proliferation in plexogenic pulmonary arterial hypertension. J Biol
Chem 2013;288:2570116.
[109] Sutendra G, Dromparis P, Paulin R, et al. A metabolic remodeling in right ventricu-
lar hypertrophy is associated with decreased angiogenesis and a transition from a
compensated to a decompensated state in pulmonary hypertension. J Mol Med
2013;91:131527.
[110] Sun XQ, Zhang R, Zhang HD, et al. Reversal of right ventricular remodeling by
dichloroacetate is related to inhibition of mitochondria-dependent apoptosis.
Hypertens Res 2016.
[111] Nagaya N, Kangawa K, Kanda M, et al. Hybrid cell-gene therapy for pulmonary hy-
pertension based on phagocytosing action of endothelial progenitor cells. Circula-
tion 2003;108:88995.
[112] Zhao YD, Courtman DW, Deng Y, Kugathasan L, Zhang Q, Stewart DJ. Rescue of
monocrotaline-induced pulmonary arterial hypertension using bone marrow-
derived endothelial-like progenitor cells: efcacy of combined cell and eNOS
gene therapy in established disease. Circ Res 2005;96:44250.
[113] Wang XX, Zhang FR, Shang YP, et al. Transplantation of autologous endothelial pro-
genitor cells may be benecial in patients with idiopathic pulmonary arterial hy-
pertension: a pilot randomized controlled trial. J Am Coll Cardiol 2007;49:156671.