2014 - Treatment For Pulmonary Arterial Hypertension-Associated Right Ventricular Dysfunction PDF

ANNALSATS Articles in Press. Published on 31-July-2014 as 10.1513/AnnalsATS.
201312-425FR
Page 1 of 55
Treatment for Pulmonary Arterial Hypertension-Associated
Right Ventricular Dysfunction
Jose Gomez-Arroyo MD, PhD1,2, Julio Sandoval MD2, Marc A. Simon MD, MS3, Erick
Dominguez-Cano MD, MS2, Norbert F. Voelkel MD4 and Harm J. Bogaard MD, PhD5
1
Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, United
States; 2Departamento de Cardioneumologia, Instituto Nacional de Cardiologia Ignacio
Chavez, Mexico City, Mexico; 3Heart and Vascular Institute, University of Pittsburgh
Medical Center, Pittsburgh, Pennsylvania, United States; 4Department of Biochemistry
and Molecular Biology, Virginia Commonwealth University, Richmond, Virginia, United
States; 5Department of Pulmonary Medicine, VU Medical Center, Amsterdam,
Netherlands
Word Count: 6281
Corresponding author:
Harm Jan Bogaard, MD PhD
Associate Professor of Pulmonary Medicine
Department of Pulmonary Medicine
VU University Medical Center
Amsterdam, the Netherlands
hj.bogaard@vumc.nl
Copyright 2014 by the American Thoracic Society

ANNALSATS Articles in Press. Published on 31-July-2014 as 10.1513/AnnalsATS.201312-425FR
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Abstract
Pulmonary arterial hypertension (PAH) includes a heterogeneous group of diseases
characterized by pulmonary vasoconstriction and remodeling of the lung circulation.
Although PAH is a disease of the lungs, patients with PAH frequently die of right heart
failure. Indeed, survival of PAH patients depends on the adaptive response of the right
ventricle to the changes in the lung circulation. PAH specific drugs affect the function of
right ventricle through afterload reduction and perhaps also through direct effects on the
myocardium. Prostacyclins, type 5 phosphodiesterase inhibitors and guanylyl cyclase
stimulators may directly enhance myocardial contractility through increased cyclic
adenosine and guanosine monophosphate availability. While this may initially improve
cardiac performance, the long term effects on myocardial oxygen consumption and
function are unclear. Cardiac effects of endothelin receptor antagonists may be opposite,
as endothelin-1 is known to suppress cardiac contractility. Because PAH is increasingly
considered as a disease with quasi-malignant growth of cells in the pulmonary vascular
wall, therapies are being developed which inhibit hypertrophy and angiogenesis, and
promote apoptosis. The inherent danger of these therapies is a further compromise to
the already ischemic, fibrotic and dysfunctional right ventricle. More recently, the right
heart was identified as a direct treatment target in PAH. The effects of well-established
therapies for left heart failure, such as -adrenergic receptor blockers, inhibitors of the
renin-angiotensin system, exercise training and assist devices are currently investigated
in PAH. Future treatment of PAH patients will likely consist of a multifaceted approach
aiming to reduce the pressure in the lung circulation and improving right heart
adaptation.
Key words: heart failure; pharmacology; pulmonary heart disease; right ventricle

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Introduction
The primary determinant of survival in pulmonary arterial hypertension (PAH) is the
response of the right ventricle (RV) to the functional and structural alterations of the
pulmonary circulation1-3. As reviewed recently4, PAH-associated RV failure is thought to
result from multiple interactions between an increased afterload and a derailed
autocrine, paracrine and neuro-endocrine signaling, ultimately leading to RV-arterial
uncoupling, a loss of cardiomyocytes, metabolic remodeling, mitochondrial dysfunction,
maladaptive changes of the extracellular matrix, myocardial ischemia and inflammation5
The relative importance of these interacting pathological mechanisms is unclear and the
impact of current PAH treatments on the adapting RV are, likewise, obscure. In this
review we sought to recapitulate some of the known effects of standard PAH treatments
on the heart, as well as to explore potentially new additional therapies to directly treat
RV failure. The pharmacological management of acute RV failure (with inotropes or
vasopressors) is not a topic included in this review and we refer the interested reader to
existing reviews on this matter6.
Current PAH-specific pharmacotherapies and their effect on the right ventricle
Guidelines for the treatment of PAH patients recommend oxygen and diuretics as
needed, as well as anticoagulants in patients without contraindications7;8. Calcium
channel blockers are used in patients with significant pulmonary vascular reactivity,
while other symptomatic patients are treated with prostacyclin (PGI2) analogs, endothelin
(ET)-1 receptor antagonists and type 5 phosphodiesterase (PDE5) inhibitors, alone or in
combinations7. It is clear that current pharmacotherapies improve pulmonary

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hemodynamics, cardiac performance and functional class of patients with PAH,
however, whether any of the clinical benefits from the above mentioned groups of drugs
can be explained by direct effects on the RV has not yet been fully investigated.
When it comes to the evaluation of direct RV effects of vasodilator treatment in PAH, two
pathophysiological concepts need to be considered. First, RV contractility is greater than
normal in virtually all PAH patients and therefore RV dysfunction is best explained by an
increase in afterload out of proportion to the increase in RV contractility (RV-arterial
uncoupling, assessed using pressure volume analysis)9. RV-arterial coupling can be
improved by either an increase in contractility or by a decrease in afterload. Even if a
pulmonary vasodilator drug has negative inotropic effects it could still improve RV-
arterial coupling, as long as the decrease in afterload is larger than the decrease in
contractility. Second, while a short term increase in contractility may be beneficial, long-
term effects of enhanced contractility (and an accompanying increase in myocardial
oxygen consumption) may be detrimental. In other words, increasing contractility might
not be the ideal long-term goal of treatment if cardiac cellular homeostasis has not been
similarly restored.
Supportive treatment and calcium channel blockers
Oxygen is thought to lower pulmonary vascular resistance by releasing hypoxic
pulmonary vasoconstriction and decelerating vascular remodeling; a target oxygen
saturation of 90% has been recommended10. There is no evidence for direct effects of
supplemental oxygen on the RV in PAH, while either a protection against ischemia11 or
an increased production of reactive oxygen species and suppression of hypoxia
inducible factor (HIF)-1 expression could be hypothesized.

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The consensus use of anticoagulant therapy is based on indirect evidence12;13, however,
a recent analysis from the Comparative, Prospective Registry of Newly Initiated
Therapies for Pulmonary Hypertension (COMPERA) reported that at least in patients
with idiopathic PAH anticoagulant therapy was associated with a significantly better 3-
year survival when compared to patients who never received anticoagulation13.
Although there is data to suggest that digoxin treatment results in an acute increase in
cardiac output along with a reduction in serum nor-epinephrine levels14, the long-term
benefit of digoxin in PAH remains unclear. Diuretic treatment leads to symptomatic
improvement in the fluid-overloaded patient. The beneficial effect of the aldosterone
antagonist spironolactone in heart failure; however, is also associated with immune
modulation, reversal of maladaptive remodeling and prevention of hypokalemia and
arrhythmia, which are all potentially important but unexplored mechanisms in RV
dysfunction associated with PAH15.
Calcium channel blockers are used by a small group of PAH patients with a positive
vasoreactivity test in whom a survival benefit has been suggested12. The consequences
of potentially negative inotropic effects of calcium channel blockers on RV function in
PAH are unknown, although dihydropyridine-type calcium channel blocker (nifedipine
and amlodipine) are generally considered safe in PAH.
Prostacyclin analogues
For almost twenty years, intravenous administration of epoprostenol (synthetic PGI2) has
been the cornerstone of PAH treatment16. It is generally assumed that the therapeutic
effect of PGI2 in PAH is explained by an induction of pulmonary vasodilatation and
inhibition of vascular remodeling17. However, no evidence exists that chronic

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prostacyclin treatment reverses lung vessel remodeling in PAH18 and there is histological
data to suggest that pulmonary vascular remodeling in PAH progresses despite long-
term PGI2 treatment19. Rich et al reported that long-term prostacyclin treatment might
have an antithrombotic effect but does not prevent or reverse the formation of advanced
vascular lesions20.
It has to be recognized, however, that PGI2 has important direct effects on the heart. In
patients with severe heart failure, PGI2 treatment results in an immediate and substantial
increase in cardiac output and a reduction in cardiac filling pressures21. Recent work
shows that unlike other pulmonary vasodilators, PGI2 analogs improve RV stroke work in
PAH22, which is probably a better reflection of cardiac function than cardiac output.
Although this improvement in cardiac function could be an adaptive response to
systemic vasodilation or the result of pulmonary vasodilation with improved right
ventriculo-arterial coupling21;23, a direct effect on cardiac cells and cell signaling
pathways is another possibility. In an animal model of flow-associated PAH, a PGI2
analog, iloprost, improved RV contractility and capillary-to-myocyte ratio, independently
from a change in RV afterload24. Syed et al recently reported that treatment with iloprost
does not modify the pulmonary artery pressure, but does improve RV contractility and
reduces fibrosis in the sugen (SU5416)/hypoxia rat model of RV failure and severe
PAH25. In addition, PGI2 has been reported to suppress pressure overloadinduced left
ventricular hypertrophy26 and fibrosis27. Both effects are considered to originate from the
action of cells other than cardiomyocytes, however, the exact mechanism remains
undetermined26.
Potentially beneficial direct effects of PGI2 treatment on the heart were the main reason
for initiating large clinical trials with epoprostenol treatment in patients with severe left

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heart failure. Unexpectedly and despite previous positive results, six months of treatment
with epoprostenol was associated with increased mortality28;29. A possible explanation
for this adverse outcome was the increase in cardiac output upon initiation of
epoprostenol therapy21. As such, increases in myocardial contractility and cardiac output
may initially improve exercise capacity, but the accompanying increase in myocardial
oxygen consumption could be detrimental in the long-term. Such a sequence of events
could be related to the results from the Beraprost Study, which is the only randomized
clinical trial with a follow-up time of one year with specific PAH therapy. It was reported
that although exercise capacity improved after 12 weeks of treatment with an oral PGI2
analog, this benefit disappeared after one year30.
Indeed, the effects of prostacyclin analogues on the function of the RV are still poorly
understood. An increase in myocardial contractility may play a different role in PAH
(where improved RV-arterial coupling is desired) when compared to end-stage left heart
disease. In the future it will be important to evaluate whether any potential direct cardiac
effects of prostacyclin treatment depend on exposure time or are just an idiosyncratic
response to therapy, specific for every patient.
Endothelin receptor blockers
In PAH and heart failure, ET-1 serum concentrations are elevated due to increased
production by endothelial cells and cardiomyocytes in response to various stimuli (e.g.
vasoactive hormones, growth factors, shear stress, hypoxia and reactive oxygen
species, ROS)31-34. ET-1 not only increases pulmonary vascular tone, but also regulates
a variety of biological processes in non-vascular tissues. ET-1 augments cardiomyocyte
contractility and plays a role in the development of pressure overload-induced cardiac
hypertrophy31;35. In patients with PAH associated heart failure, the direct effects of ET-1

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signaling on the heart are mixed with indirect effects via stimulation of pulmonary
vasoconstriction and vascular remodeling. ET-1 exerts its effects through two receptor
subtypes, ETA and ETB, the former predominating in the rat myocardium36. Heart failure
in rats leads to an increased ETA receptor density33. ET-1 affects cardiomyocyte survival
and pressure overload induced hypertrophy by interacting with bcl-237, the epidermal
growth factor receptor (EGF-R)38 and mitogen-activated protein kinase (MAPK)
cascades35.
Clinical trials in patients with left sided heart failure with orally administered ET-receptor
antagonists (REACH-1, ENCOR, ENABLE and EARTH were the largest, although the
results have never been fully published) suggest that direct effects of ET-receptor
antagonists on the heart are not favorable39-41. It has been postulated that the inotropic
actions of ET-1 are in fact beneficial in chronic heart failure, providing partial
compensation for a decreased contractility.
Detrimental actions of ET receptor blocker in the RV of patients with PAH have not (yet)
been shown. Experimental studies, however, do suggest that endothelin receptor
blockade worsens the contractility of the pressure overloaded RV in rats42. Whether this
occurs in PAH and would translate into negative effects for individual patients would
depend on the relative magnitudes of decreases in afterload and contractility and the
resultant effect on RV-arterial coupling.
Phosphodiesterase inhibitors
Cyclic guanosine monophosphate (cGMP) is a ubiquitous intracellular secondary
messenger. The natriuretic peptides generate cGMP via activation of the particulate
guanyl cyclase (pGC), whereas nitric oxide (NO) induces the formation of cGMP through

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activation of soluble guanylate cyclase (sGC)43. cGMP is degraded by the action of
phosphodiesterases (PDEs). Some PDE subtypes hydrolyze only cGMP (PDE5, PDE6,
PDE9), whereas others degrade cAMP (PDE3, PDE4, PDE7, PDE8) or both cGMP and
cAMP (PDE1, PDE2)44. cGMP lowers Ca2+ sensitivity and intracellular Ca2+
concentration in pulmonary vascular smooth muscle cells. The resulting vasodilating and
antiproliferative properties of the molecule explain the therapeutic benefit of the PDE5
inhibitors, sildenafil and tadalafil in PAH45;46. More recently, the therapeutic benefit of
increasing cGMP availability with the sGC stimulator Riociguat has been shown in a
randomized clinical trial47. cGMP/protein kinase G (PKG) signaling protects the heart
from apoptosis48;49 and blunts the hypertrophic response to pressure overload and
isoproterenol (an adrenergic agonist)50-52.
Multiple roles for cGMP in cardiac contractility, lusitropy and ion channel responsivity
have been well characterized, however the extent to which natriuretic peptides
predominate over NO to mediate these effects is less clear53. The effect of cGMP on
myocardial contractility depends on its interactions with PDEs and cAMP. Theoretically,
cGMP can decrease contractility by decreasing cAMP concentrations through inhibition
of adenylate cyclase and induction of PDE254;55. In addition, phosphorylation of troponin I
by a cGMP-dependent protein kinase can decrease the sensitivity of the contractile
apparatus to Ca2+ and accelerate myocardial relaxation54. On the other hand, it was
recently shown in PAH patients and in rats with monocrotaline (MCT) induced RV
hypertrophy, that cGMP can in fact increase contractility by increasing cAMP
concentrations56. The authors explained this apparent paradox by cGMP related
inhibition of the cGMP sensitive PDE3. They also showed that, compared with a normal
RV, RV hypertrophy (both in humans and rats) is associated with a considerable

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decrease in PKG activity. At the same time, PDE5 was only expressed in the
hypertrophic RV and not in the normal RV56.
Once again, the long-term effects of PDE5 inhibition and sGC stimulation on RV
adaptation in PAH are unknown. The initial preclinical evidence seemed to justify a
provisional conclusion that these strategies could have positive direct effects on the
heart. PDE5 inhibition prevents and reverses pressure overload induced hypertrophy in
mice, which was associated with enhanced systolic function52. Sildenafil protects against
cardiomyocyte apoptosis48;49, and may decrease myocardial oxygen consumption by
inhibiting adenylate cyclase55 and accelerating myocardial relaxation54.
Despite such positive experimental data, clinical studies of drugs that increase cGMP
availability in patients with heart failure have yielded mixed results. After first positive
results of PDE5 inhibition in patients with non-PAH heart failure with decreased57;58 and
preserved ejection fraction (HFPEF)59, recent randomized clinical trials using sildenafil
and riociguat in these patient categories failed to meet their primary endpoints60;61. A
single dose of sildenafil was shown to improve RV diastolic function in PAH patients62. It
remains to be determined whether this is a direct cardiac effect or whether it was
mediated by a decrease in RV afterload.
New treatment strategies in PAH: good for the lung, bad for the heart?
One hypothesis that has been advanced to explain the pathobiology of severe PAH is
based on the concept of a quasi-malignant nature of endothelial cells in the lung
vasculature. This hypothesis postulates that after an initial injury, pulmonary vascular
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endothelial cells undergo apoptosis, but a group of surviving cells switch their phenotype
and become apoptosis-resistant and hyperproliferative to the point of lumen occlusion. In
other words, the hypothesis reflects a process of wound healing gone awry5. There is
now a search for molecular targets and mechanisms which could potentially drive this
quasi-malignant lung vessel remodeling. However, as the knowledge of the
pathobiology of PAH evolves, future therapeutic strategies face one critical paradox:
While the remodeled lung vasculature in PAH is characterized by angiogenesis,
apoptosis resistance and cell proliferation, the failing RV may suffer from ischemia,
capillary rarefaction and cardiomyocyte apoptosis63. Thus, new treatments designed to
tackle any quasi-malignant feature in the sick-lung circulation could have detrimental
effects in an ischemic, fibrotic and dysfunctional RV.
Experimental models of right ventricular dysfunction
As is the case with many other diseases, potential new compounds for the treatment of
PAH are generally tested first in animals. Several experimental models have been
developed and the interested reader is referred to a recent review on this topic providing
a detailed overview64. Rat models have generally provided superior insights into the
mechanisms of severe pulmonary vascular disease and associated RV failure, as severe
pulmonary hypertension is very difficult to induce in mice65. Pulmonary artery banding,
which creates mechanical stress on the RV without pulmonary vascular disease, has
been useful to explore side effects of drugs on RV adaptation without the interfering
effects from changes in pulmonary vascular resistance63;66.
Tyrosine kinase inhibitors
Platelet derived growth factor (PDGF) has been implicated in the pathobiology of
pulmonary vascular remodeling in PAH67 and treatment with imatinib, an inhibitor of the
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tyrosine kinase domain of the PDGF receptor has been beneficial in isolated cases68-71.
Nonetheless, a phase II trial with PAH patients failed to meet its primary endpoint of
improved exercise capacity after 4 months72 and a randomized clinical trial in selected
PAH patients (PVR 800 dynescm-5; IMPRES study) showed no improvements in
functional class, time to clinical worsening or mortality with imatinib, despite a small
improvement in exercise capacity73. The trial was discontinued because of severe side
effects, in particular subdural hematoma. Another major concern with imatinib treatment
in PAH is the fact that the drug may have detrimental effects on the heart74;75. After
myocardial infarction, PDGF enhances cardiomyocyte survival, modulates inflammatory
responses and activates pro-angiogenic progenitor cells76-78. Because RV capillary
rarefaction and ischemia may play a role in the transition from adaptive hypertrophy to
RV dilatation and failure4;63, imatinib could potentially worsen maladaptive cardiac
remodeling in PAH. Negative direct cardiac effects were not seen in a post-hoc analysis
of echocardiographic parameters in patients treated with imatinib in the IMPRES trial,
however79.
In contrast to PDGF receptor blockers, EGF-R blockers may have beneficial effects on
both pulmonary vascular and RV remodeling. In maladaptive cardiac remodeling,
activation of the type 1 angiotensin receptor (AT1R), the mineralocorticoid receptor and
the type A endothelin receptor (ETA) results in a transactivation of the EGF-R38;80;81.
Moreover, pulmonary hypertension in rats with MCT-induced PAH is ameliorated by
EGF-R blockers82. Interestingly, although not mechanistically tested, the reduced RV
hypertrophy observed in this study, might have not been necessarily the result of a
reduced afterload, but could have also resulted from decreased myocardial fibrosis and
inflammation.
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Paradoxically, tyrosine kinase inhibitors are not only potential treatments for PAH, they
have also been implicated in the development of the disease. First, the vascular
endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor SU5416, in
combination with a hypoxic or allergic challenge, has provided a useful tool to study PAH
in rats83. Second, Dasatinib, a dual Src/Abl kinase inhibitor used in the treatment of
chronic myelogenous leukaemia, was associated with cases of severe PAH, potentially
reversible after dasatinib withdrawal84. Possible dual effects of tyrosine kinase inhibitors
need to be taken in account if this group of drugs is further developed for PAH treatment.
Rho kinase inhibitors and HMG-CoA reductase inhibitors (statins)
Inhibition of Rho kinase (ROCK) has been suggested as a new target for PAH treatment.
Acute administration of ROCK inhibitors has resulted in modest pulmonary vasodilation
in PAH patients85;86 and chronic administration prevented pulmonary vascular
remodeling in experimental pulmonary hypertension87-91. The effects of long-term ROCK
inhibition on the RV in PAH are unknown and based on the available literature, both
beneficial (inhibition of apoptosis, reduction of inflammatory cell influx) or detrimental
effects (contractile depression and excessive reduction of hypertrophy) can be
postulated4. Statins may interfere with ROCK activation through inhibition of isoprenoid
synthesis and subsequent rho geranylgeranylation, which is the proposed mechanism by
which statins reduce cardiac ROS production and hypertrophy after ATII infusion and
pressure overload92. Additional beneficial effects of statins in heart failure consist of
inhibition of ET-1 and renin-angiotensin signaling, stimulation of NO production,
restoration of autonomic imbalance and prevention of matrix metalloproteinase
activation93. Statins have been shown to be effective in reversing pulmonary vascular
remodeling and RV hypertrophy in the SU5416/hypoxia model94, but the results from the
clinical trial evaluating simvastatin in human PAH were disappointing95.
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Control of gene expression by histone acetylation/deacetylation
Histone-dependent packaging of genomic DNA is central mechanism for gene regulation
in eukaryotes. When there is no transcription, DNA is wrapped around histone
octameres in nucleosomes, which are the basic units of chromatin. The highly compact
structure that is formed by interacting nucleosomes limits access of transcriptional
enzymes to genomic DNA, thereby repressing gene expression96. Acetylation of
histones by histone acetylases relaxes the nucleosomal structures, thereby facilitating
gene expression. The opposite effect is established by histone deacytelases (HDACs),
which repress transcription. Inhibitors of HDACs have been shown to reverse pulmonary
artery smooth muscle cell hypertrophy in experimental models of pulmonary
hypertension97.
By repressing the transcription of genes encoding proteins involved in signaling that
leads to cardiac hypertrophy98;99, HDAC inhibitors could be hypothesized to have
positive direct effects on the RV. Surprisingly, RV adaptation to mechanical pressure
overload in the pulmonary artery banding animal model, is seriously hampered by the
HDAC inhibitors trichostatin A and valproic acid66. The opposite effects of HDAC
inhibitors in the two pressure overloaded ventricles is a strong reminder of the fact that
success of a drug in the treatment of left sided heart failure, does not guarantee
beneficial effects in the context of PAH associated RV failure.
RV-targeted therapies: a new concept
Indeed, patients with PAH die of RV failure and the prognostic role of the RV has
recently been revisited. Van de Veerdonk et al. demonstrated that even after decreasing
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the pulmonary vascular resistance with PAH-specific therapy, those patients that remain
with low RV ejection fraction continue to have a poor prognosis3. However, despite its
prognostic importance, the cellular and molecular mechanisms that explain RV failure
are limited and frequently extrapolated from studies of chronic left heart failure.
Nonetheless, there is increasing evidence to support the hypothesis that mechanisms of
RV failure may not be identical to those of the left ventricle. Some therapeutic options to
treat left heart failure have been successfully applied to treat the RV in experimental
PAH, but others have demonstrated contradictory results.
-adrenoreceptor blockers
Similar to patients with left heart failure, PAH is characterized by increased activity of the
sympathetic nervous system (which finding has prognostic significance)100 and down-
regulation of the -adrenergic receptor (AR)101. Counteracting these mechanisms led to
a firm central place of -AR blocker treatment in patients with left heart failure102.
However, direct effects of -AR blockade such as systemic vasodilatation, reduction of
myocardial contractility and decreased heart rate, have prevented the use of this class of
drugs in PAH. In portopulmonary hypertension, -AR blockers have been associated
with worsening hemodynamics and a decreased exercise capacity103.
There are, however, a number of reasons why the careful use of -AR blockers in
selected patients may be considered. The associated reduction of myocardial oxygen
consumption is probably one of the explanations of the benefit of -AR blockers in heart
failure. In addition, leakiness of the Ryanodine receptor (RyR) is reversed by -AR
blockers, thereby restoring Ca2+ handling and preventing calcineurin/nuclear factor of
activated T-cells (NFAT) upregulation104. -AR blockers are effective in preventing
arrhythmias, which is a problem associated with a markedly increased mortality in
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PAH105. Interestingly, in a recent prospective study, So and collaborators reported that
the use of -AR blockers in PAH is not uncommon106 and most importantly, this study
reported no statistical differences in PAH-related hospitalization or all-cause mortality
between patients with or without -AR blocker treatment. However, a properly designed
clinical trial to assess the safety of this class of drugs is warranted.
Experimentally, carvedilol treatment improves exercise tolerance, induces RV
capillarization and improves RV function107;108. In another study in rats with MCT induced
pulmonary hypertension, bisoprolol treatment resulted in an improved RV-arterial
coupling and improved survival109. In comparison to the more selective 1-AR blockers,
carvedilol has a unique mechanism by which it suppresses ventricular arrhythmias
through inhibition of the spontaneous release of calcium from the sarcoplasmic
reticulum110. In addition, carvedilol has intrinsic antioxidant properties 111;112

by which the
drug is capable to prevent ROS-induced cardiomyocyte apoptosis113. Some of the
cardioprotective effects of carvedilol seem to be independent of blockade of the - or -
AR, such as direct transactivation of the EGF-R via beta arrestins stimulation114. and up-
regulation of the expression of the peroxisome proliferator-activated receptor gamma
coactivator 1- (PGC-1), a master regulator of mitochondrial biology and cardiac
metabolism115 Another strategy to restore -AR function without the negative
chronotropic effects of -AR blockade would be to prevent G protein-coupled receptor
kinase-2 (GRK2)-mediated uncoupling of -AR using the small molecule Gallein.116
ACE inhibitors and AT1R antagonists
Although the renin angiotensin system is clearly involved in pressure overload related
cardiac remodeling, the role of ACE inhibitors and AT1R antagonists in PAH has not
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been thoroughly evaluated and its use as a treatment for PAH-associated RV failure
remains controversial. In a small-case series study, four-days of treatment with captopril
reduced mean pulmonary arterial pressure and increased RV ejection fraction in three
out of four patients117. In another study, however, 12-weeks of captopril did not modify
pulmonary hemodynamics or exercise capacity118 Experimentally, both the ACE inhibitor
ramipril and the AT1R blocker losartan improved RV systolic function in rabbits subjected
to pulmonary artery banding. In contrast, no direct effects of ACE inhibitors or AT1R
blockers on RV function or hypertrophy were seen in experimental models of pulmonary
hypertension94;119;120. The improved RV function after pulmonary artery banding with
ACE inhibition seemo be related to a decreased rate of apoptosis but not as a
consequence of reduced hypertrophy121.
Metabolic modulators
Abnormal mitochondrial metabolism has long been implicated in the development of
chronic heart failure and it has been proposed that a switch from aerobic to anaerobic
metabolism could contribute to the development of RV failure122;123. Whereas it has been
demonstrated that RV failure is characterized by increased expression of glycolysis-
related genes107 and increased glycolysis enzymatic rates124, it is unclear whether this
metabolic remodeling is an adaptive or a maladaptive response. We have
demonstrated that along with increased glycolysis, RV failure is characterized by a
downregulated expression of multiple genes required for fatty acids metabolism
supporting a switch in substrate utilization125 The mechanisms responsible for the
downregulation of fatty acid oxidation in the failing RV are not well defined, but reduced
transcriptional activation of genes regulated by the coactivator PGC-1 and its
corresponding nuclear receptor PPAR- appear to be involved125.
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Multiple studies have shown that the rate of fatty acid oxidation is preserved or
increased in physiological/adaptive left ventricular hypertrophy, and that it decreases
during the progression of heart failure126. In a similar fashion, rats with adaptive RV
hypertrophy after pulmonary artery banding have increased rates of fatty acid
oxidation127. However, whether or not decreased impaired fatty acid oxidation
contributes to the development of RV failure has not been mechanistically evaluated.
Metabolic modulators designed block fatty acid oxidation such as trimetazidine or
ranolazine, have been used to prevent cardiac output reduction in rats with pulmonary
artery banding, however, the effects of partial fatty acid oxidation inhibition is modest
when treating established RV dysfunction127.
We have evaluated the effects of etomoxir, a potent fatty acid oxidation blocker in the
SU5416/hypoxia PAH model and report that etomoxir treatment neither worsens nor
improves RV failure (Figure 1). Multiple clinical trials evaluating the role of fatty acid
oxidation blockers in left heart failure have been designed, however, none of these
metabolic modulators have become a standard treatment of heart failure128.
It has also been proposed that not only fatty acid oxidation but also glucose oxidation is
impaired and that it could be restored using a pyruvate dehydrogenase kinase (PDK)
inhibitor: dichloroacetate (DCA)124. In MCT-induced pulmonary hypertension, DCA
decreased the severity of pulmonary hypertension and regressed RV hypertrophy, an
effect which was perhaps partially related to a reduction in afterload. The effects of DCA
therapy were only moderate in pulmonary artery banding -induced RV hypertrophy124. A
clinical trial studying DCA in PAH-associated RV failure is currently underway
(ClinicalTrials.gov Identifier NCT01083524).
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Antioxidants and tetrahydrobiopterin
ROS have been implicated in the pathobiology of chronic left heart dysfunction for a long
time129 but their role in RV failure remains to be investigated in depth. ROS can reduce
myocyte contractility by affecting calcium handling through suppression of L-type Ca2+
channels and SERCA: the Ca2+-ATPase of the sarcoplasmic reticulum130;131. ROS can
be generated from many sources (such as NADPH oxidases). In the heart, mitochondria
are an important source of ROS, as they are generated as byproducts of an incomplete
reduction of oxygen in the electron transport chain. ROS are very unstable, electrophilic
and react with macromolecules, such as proteins and nucleic acids, generating adducts
and altering function132. Interruption of the ATII-rho-NAD(P)H-ROS pathway with the

133
xanthine oxidase inhibitor allopurinol improves myocardial contractility and
ameliorates chronic hypoxic PAH in rats134. Hydralazine inhibits NADPH oxidase, but it is
unclear whether its antioxidant effects can be achieved at concentrations that are
employed clinically53. Another source of ROS in chronic pressure overload comes from
uncoupled nitric oxide synthetase (NOS)3 and is associated with reduced availability of
tetrahydrobiopterin (BH4), a NOS3 reducing cofactor. Supplementing BH4 in a pressure
overload mouse model of NOS3 uncoupling has been shown to be sufficient to reduce
ROS production and prevent maladaptive remodeling in experimental left heart failure135.
Probably, the strongest evidence for the role of ROS in RV dysfunction comes from the
study of hemeoxygenase-1 (HO-1) knock-out mice. HO-1 plays a categorical role in the
hearts response to ROS by inducing the expression of genes that codify for antioxidant
enzymes. Yet, Lee and collaborators demonstrated that mice lacking HO-1 show severe
RV dilatation and infarction after hypoxia-induced pulmonary hypertension136. On the
other hand, we have shown that treatment with protrandim, upregulates HO-1
expression and is associated with less RV dysfunction in experimental pulmonary
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63
hypertension . Importantly, ROS play a dual role in cells. Whereas ROS have a direct
toxic effect, they also serve as signaling mediators to induce an antioxidant response132.
This dual role could potentially complicate the therapeutic potential of antioxidant
treatment for RV failure.
Non-pharmacological RV-targeted therapies
Exercise
It was previously believed that physical exercise had to be avoided by patients with PAH.
After it was shown that exercise training corrected endothelial dysfunction and improved
137
exercise capacity in chronic heart failure , a randomized controlled trial was designed
138
to evaluate the effects of exercise rehabilitation in PAH . An exercise and respiratory
training program of 4 months duration was well tolerated and improved scores of quality
of life and exercise capacity (peak workload and oxygen uptake). The mean difference in
the six-minute walking distance between intervention and control groups (15 patients in
both groups) was 111 meters, which is a considerably larger improvement than
observed in most PAH drug trials. Since systolic PAP at rest and exercise cardiac output
did not change significantly after training, the authors attributed the positive outcome to
138
adaptations in gas exchange and respiratory and peripheral muscle function .
However, hemodynamic data were obtained non-invasively and the increase in peak
oxygen uptake could have been due to an improvement in RV performance.
Experimental data has suggested that exercise could have direct positive effects in the
heart. For instance, exercise induces the expression of PGC-1, which is also
139
associated with increased VEGF expression and reduced capillary rarefaction .
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However, whether PGC-1-induced angiogenesis could explain an improvement in RV
function after exercise training has yet to be determined.
Cardiac resynchronization
Cardiac dyssynchrony is a common problem in left heart failure and even patients with
mild-to-moderate left ventricular systolic dysfunction benefit from cardiac-
resynchronization therapy.140 Indeed, the ResynchronizationDefibrillation for
Ambulatory Heart Failure Trial (RAFT) showed that among patients with NYHA class II
or III heart failure, a wide QRS complex, and left ventricular systolic dysfunction, the
addition of cardiac-resynchronization therapy to an implantable cardioverterdefibrillator
reduced rates of death and hospitalization for heart failure.140
Recently a post follow-up analysis from the Multicenter Automatic Defibrillator
Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT) demonstrated
that in patients with mild heart failure, left ventricular dysfunction, and left bundle-branch
block, early intervention with cardiac-resynchronization therapy with a defibrillator was
associated with a significant long-term survival benefit. However resynchronization
defibrillation did not confer any clinical benefit in patients without left bundle-branch
block141.
Ventricular dyssynchrony is also common in patients with PAH and often easily
recognized by echocardiogram (paradoxical septal movement), however, compared to
the left heart failure, ventricular dyssynchrony in PAH is mostly caused by a difference in
duration of RV contraction rather than a difference in the onset of contraction142. There is
significantly less evidence to support the use of CRT in patients with severe RV failure,
but experimental data has demonstrated that RV pacing improves RV systolic function,
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improves adverse diastolic interaction and resynchronized RV and LV peak pressures143.
A small study evaluating RV pacing in patients with chronic thromboembolic pulmonary
hypertension demonstrated an improvement in diastolic relaxation, LV stroke volume
and RV contractility144, but larger studies evaluating safety and efficacy are warranted.
Atrial septostomy
It has been shown that some PAH patients can benefit from decompressing therapeutic
strategies such as atrial septostomy (AS) or Potts shunt. Atrial septostomy is a
procedure that creates a right-to-left shunt at the inter-atrial septum level with the use of
a balloon-catheter in a step-by-step fashion145. This results in an increase in LV preload
and systemic cardiac output at the expense of a drop in systemic arterial oxygen
saturation (SaO2%). Theoretically, the drop in SaO2% is compensated by the increase
in cardiac output and thus systemic oxygen transport is maintained. Atrial septostomy
may also decompress the RV by reducing its preload146;147.
The results of this intervention are sometimes spectacular with disappearance of
syncope and fluid retention within a matter of days, but not all patients improve after
septostomy and the procedure is not risk free. In a recent review of almost 400
procedures performed worldwide148, there was a 24 hour procedure-related mortality of
about 7% mainly resulting from refractory hypoxemia, and a one-month mortality rate of
5% due to RV failure progression. It is fair to say, however, that in most circumstances
this intervention has been performed in severely ill patients.
There are no current guidelines for the optimal size of the shunt and therefore the
appropriate size should be individualized. Massive right-to-left shunting as a result of an
excessively large shunt may result in inadequate pulmonary blood flow and severe,
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refractory hypoxemia and death the aim is to achieve a fall in SaO2% below 10%. No
studies have evaluated the effect of shunting on the RV at the molecular level. It is
important to underscore the fact that balloon dilation atrial septostomy should only be
performed in centers experienced in both interventional cardiology and pulmonary
hypertension. The creation of a post-tricuspid shunt (Potts anastomosis) instead of an
interatrial shunt might be another (surgical or transcatheter) approach to manage
refractory RV dysfunction in the setting of PAH, particularly in children149.
Mechanical RV support and transplantation
Mechanical support of the failing RV has generally been thought of as a palliative
temporary approach, although as newer technologies develop, there continues to be an
interest in the potential for longer term support. Extracorporeal membrane oxygenation
(ECMO) has been reported as a method to support the RV in patients with PH and
massive pulmonary embolism150;151. It can be implanted quickly, making it advantageous
during emergent situations. Cannulae are implanted surgically, typically in a venoarterial
arrangement, in which venous blood is withdrawn, pumped through an oxygenator and
then returned to the arterial system, bypassing the lungs. Risks include bleeding,
thromboembolism, and vessel injury. ECMO support is only temporary and requires a
plan for removal: i.e. there is a high likelihood of RV recovery, transplant within a short
timeframe is likely and possible, or transition to a more permanent support (such as a
right ventricular assist device; to date unlikely in PH) is an option.
Mechanical circulatory assist devices, or ventricular assist devices (VADs), have been
used in the setting of RV failure after cardiotomy, cardiac transplant, RV infarct, or LV
assist device (LVAD) implantation152-155. They have not been used for the treatment of
PAH-associated RV failure largely owing to the concern of pulmonary hemorrhage due
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to input of high flows into a diseased vasculature, which is a result of the pumps being
designed for support of the LV. This has raised interest in the concept of partial-assist
pumps that could provide enough flow to assist circulation without the risk of pulmonary
hemorrhage. Additional benefits of a partial assist pump would be a smaller device size
that could reduce surgical times and complications. These potential benefits must be
weighed against the risk of thrombosis at lower flows, which has been another limiting
factor in adapting LV pumps to the RV. In addition to thromboembolism, other risks of
mechanical blood pumps to bear in mind are bleeding and infection. For RV support,
blood is typically withdrawn from a cannula surgically placed in the RV and returned from
the pump via a cannula in the pulmonary artery.
Although originally developed for support of the LV, there are two devices approved by
the FDA for support of the RV, the Thoratec PVAD and CentriMag (both manufactured
by Thoratec, Pleasanton, CA, USA). The Thoratec PVAD is a pneumatically driven
pulsatile pump that can be used for long-term support. The CentriMag is a continuous
flow pump used for short-term support (approved for up to 30 days)156. The field of
cardiac mechanical support has progressed to preferentially use continuous-flow (axial
or centrifugal in design) devices as they are smaller and have improved durability. Two
continuous-flow devices have been developed that are placed percutaneously for
temporary support: TandemHeart (CardiacAssist, Inc., Pittsburgh, PA) and Impella
(Abiomed, Danvers, MA)157-159. The Impella has a unique design with its small axial flow
pump being located on the end of the catheter where it sits in the ventricle and its
adaptation for RV support, the Impella RP, recently received approval in Europe with a
trial in the US to start soon160;161.
Lung transplantation
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Lung transplantation should be considered for severe PAH if the RV is not severely
dysfunctional (typically defined as the need for inotropic support), although such cases
represent only 3% of all lung transplants162. Combined heart-lung transplantation can
occasionally be considering in cases of severe PAH with RV failure although less than
100 cases are performed worldwide per year. Median survival after lung transplant is 5
years for PAH, which improves to 10 years for patients that survive the first year after
transplant; similar results are seen for heart-lung transplant163. The limited number of
organs available requires better treatment strategies for RV failure in PAH.
Conclusions
The first decade of the 21st century finds the community of PAH trialists and researchers
in a peculiar situation: The available drugs have some impact on patient survival but do
not alter the remodeled lung circulation. Conversely, effective treatments targeting the
lung vessels could have detrimental effects on the failing RV. Thus, the development of
PAH treatments that both reduce pulmonary vascular resistance and improve RV
function is not straightforward.
There are contrasting priorities within the different cell populations of heart and lungs.
For example, we look for increased contractility in cardiomyocytes but relaxation in
pulmonary vascular smooth muscle cells. On the other hand, we look for apoptosis of
the pulmonary endothelial cells in plexiform lesions, whilst we need to promote
cardiomyocyte and cardiac endothelial cells survival. It is very well possible to define
common goals, however. Mitigating the inflammatory response, preventing ROS/RNS
disequilibrium and reversing extracellular matrix remodeling are likely to be beneficial in
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both the heart and the pulmonary circulation. Aldosterone receptor blockers (and other
inhibitors of the Renin-Angiotensin-Aldosterone system), BH4, statins and EGF-R
blockers could fulfill the task. It may also be possible to specifically target the heart,
without affecting pulmonary vasculature. Specific support of RV function can perhaps be
accomplished directly with carvedilol or metabolic modulators. Other important effects
that ought to be considered for the treatment of RV failure are summarized in Figure 2.
Finally, it is important to remember that PAH is a cardiopulmonary disease. Thus, as
new treatments arise, trialists should not only focus on the lung circulation, but also
consider every potential positive or negative effect that a drug may have on the RV.
Disclosures:
None.
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147. Ciarka, A., J. L. Vachiery, A. Houssiere, M. Gujic, E. Stoupel, S. Velez-Roa, R. Naeije,
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Table 1: Proposed direct cardiac effects of current PAH therapies and their impact
on the right ventricle
Proposed Direct Cardiac Impact on the right

Treatment
Effects ventricle
Angiogenesis
Prostacyclin Analogues Positive effect
Fibrosis
Maladaptive hypertrophy
Endothelin receptor blockers Negative effect
Cardiomyocyte apoptosis
Apoptosis
PDE-5 inhibitors/sGC inducers Myocardial relaxation Positive effect
Contractility
Angiogenesis
Tyrosine kinase inhibitors Mitochondrial Dysfunction Negative effect
Apoptosis
Apoptosis
Positive effect
Inflammation
Rho-kinase inhibitors Contractility
Excessive reduction of Negative effect
hypertrophy
ROS production
Statins Nitric oxide production Positive effect
Inflammation
50

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Table 2: Potential RV-targeted therapies and the direct or indirect effects on the
right ventricle
Drug Proposed effects on RV Evidence for use in
function PAH
Carvedilol, bisoprolol Angiogenesis Only experimental
Heart rate evidence in animal
Fibrosis models
Metabolic modulator
Natriuretic peptides Maladaptive No evidence
hypertrophy
RV Volume-overload
(by diuresis)
Apoptosis
Fibrosis
Metabolic modulator
Systemic vasodilators
Blockers of the Renin-Angiotensin- Remodelling of No evidence
Aldosterone Axis extracellular matrix
Fibrosis
HDAC inhibitors (Trichostatin-A Fibrosis Only experimental
and Valproic acid) Angiogenesis evidence in animal
Cardiomyocyte models
apoptosis
Antioxidants (BH4, protandim) Fibrosis Only experimental
51

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Apoptosis evidence in animal
ROS-induced damage models
Exercise One clinical Trial:
Improved exercise
capacity and increase
six-minute walk distance
52

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Legends to the Figures
Figure 1. A) Inhibition of fatty acid oxidation with etomoxir treatment had no impact in
mean pulmonary artery pressure (MPAP) in comparison to vehicle-treated rats. B)
Paired analysis demonstrated that two-weeks treatment with etomoxir was insufficient to
prevent deterioration in RV function, as assessed by tricuspid annulus plane systolic
excursion (TAPSE). C-E) Echocardiographic analysis demonstrates no difference in RV
diastolic area between controls, vehicle and etomoxir treated rats.
Figure 2. Treatment goals for prevention of a deterioration of RV function. After the
initial hemodynamic changes in the lung circulation (reduced blood flow, increased
resistance and increased pulmonary artery pressure) the RV is capable of adaptation as
long as there is sufficient hypertrophy, adequate capillary density, adequate substrate
utilization and a controlled amount of reactive oxygen species. RV function
decompensation may eventually occur leading to severe RV dysfunction and failure.
Treatment goals should be oriented towards maintenance of contractility with reduced
energy consumption, prevention of metabolic remodeling, prevention of fibrosis,
increased capillarisation (induction of angiogenesis), control of reactive oxygen species,
adequate cell growth and inhibition of cardiomyocyte apoptosis.
53

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190x254mm (96 x 96 DPI)

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ANNALSATS Articles in Press. Published on 31-July-2014 as 10.1513/AnnalsATS.

Treatment for Pulmonary Arterial Hypertension-Associated

Right Ventricular Dysfunction

States; 2Departamento de Cardioneumologia, Instituto Nacional de Cardiologia Ignacio

Medical Center, Pittsburgh, Pennsylvania, United States; 4Department of Biochemistry

and Molecular Biology, Virginia Commonwealth University, Richmond, Virginia, United

States; 5Department of Pulmonary Medicine, VU Medical Center, Amsterdam,

Word Count: 6281

Harm Jan Bogaard, MD PhD

Associate Professor of Pulmonary Medicine

Department of Pulmonary Medicine

VU University Medical Center

Amsterdam, the Netherlands

Copyright 2014 by the American Thoracic Society

Pulmonary arterial hypertension (PAH) includes a heterogeneous group of diseases

characterized by pulmonary vasoconstriction and remodeling of the lung circulation.

myocardium. Prostacyclins, type 5 phosphodiesterase inhibitors and guanylyl cyclase

stimulators may directly enhance myocardial contractility through increased cyclic

as endothelin-1 is known to suppress cardiac contractility. Because PAH is increasingly

considered as a disease with quasi-malignant growth of cells in the pulmonary vascular

promote apoptosis. The inherent danger of these therapies is a further compromise to

Copyright 2014 by the American Thoracic Society

The primary determinant of survival in pulmonary arterial hypertension (PAH) is the

pulmonary circulation1-3. As reviewed recently4, PAH-associated RV failure is thought to

result from multiple interactions between an increased afterload and a derailed

autocrine, paracrine and neuro-endocrine signaling, ultimately leading to RV-arterial

uncoupling, a loss of cardiomyocytes, metabolic remodeling, mitochondrial dysfunction,

maladaptive changes of the extracellular matrix, myocardial ischemia and inflammation5

RV failure. The pharmacological management of acute RV failure (with inotropes or

existing reviews on this matter6.

Current PAH-specific pharmacotherapies and their effect on the right ventricle

needed, as well as anticoagulants in patients without contraindications7;8. Calcium

(ET)-1 receptor antagonists and type 5 phosphodiesterase (PDE5) inhibitors, alone or in

combinations7. It is clear that current pharmacotherapies improve pulmonary

Copyright 2014 by the American Thoracic Society

hemodynamics, cardiac performance and functional class of patients with PAH,

pathophysiological concepts need to be considered. First, RV contractility is greater than

increase in afterload out of proportion to the increase in RV contractility (RV-arterial

uncoupling, assessed using pressure volume analysis)9. RV-arterial coupling can be

improved by either an increase in contractility or by a decrease in afterload. Even if a

term effects of enhanced contractility (and an accompanying increase in myocardial

oxygen consumption) may be detrimental. In other words, increasing contractility might

Supportive treatment and calcium channel blockers

Oxygen is thought to lower pulmonary vascular resistance by releasing hypoxic

pulmonary vasoconstriction and decelerating vascular remodeling; a target oxygen

supplemental oxygen on the RV in PAH, while either a protection against ischemia11 or

an increased production of reactive oxygen species and suppression of hypoxia

inducible factor (HIF)-1 expression could be hypothesized.

Copyright 2014 by the American Thoracic Society

The consensus use of anticoagulant therapy is based on indirect evidence12;13, however,

a recent analysis from the Comparative, Prospective Registry of Newly Initiated

Therapies for Pulmonary Hypertension (COMPERA) reported that at least in patients

year survival when compared to patients who never received anticoagulation13.

benefit of digoxin in PAH remains unclear. Diuretic treatment leads to symptomatic

improvement in the fluid-overloaded patient. The beneficial effect of the aldosterone

antagonist spironolactone in heart failure; however, is also associated with immune

modulation, reversal of maladaptive remodeling and prevention of hypokalemia and

arrhythmia, which are all potentially important but unexplored mechanisms in RV

dysfunction associated with PAH15.

of potentially negative inotropic effects of calcium channel blockers on RV function in

PAH are unknown, although dihydropyridine-type calcium channel blocker (nifedipine

and amlodipine) are generally considered safe in PAH.

effect of PGI2 in PAH is explained by an induction of pulmonary vasodilatation and