Hipertension Pulmonar

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 65, NO.
18, 2015
2015 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION ISSN 0735-1097/$36.00
PUBLISHED BY ELSEVIER INC. http://dx.doi.org/10.1016/j.jacc.2015.03.540
THE PRESENT AND FUTURE
STATE-OF-THE-ART REVIEW
Management of
Pulmonary Arterial Hypertension
Vallerie V. McLaughlin, MD,* Sanjiv J. Shah, MD,y Rogerio Souza, MD,z Marc Humbert, MD, PHDx
ABSTRACT
Pulmonary hypertension (PH) is common and may result from a number of disorders, including left heart disease, lung disease,
and chronic thromboembolic disease. Pulmonary arterial hypertension (PAH) is an uncommon disease characterized by pro-
gressive remodeling of the distal pulmonary arteries, resulting in elevated pulmonary vascular resistance and, eventually, in
right ventricular failure. Over the past decades, knowledge of the basic pathobiology of PAH and its natural history, prognostic
indicators, and therapeutic options has exploded. A thorough evaluation of a patient is critical to correctly characterize the PH.
Cardiac studies, including echocardiography and right heart catheterization, are key elements in the assessment. Given the
multitude of treatment options currently available for PAH, assessment of risk and response to therapy is critical in long-term
management. This review also underscores unique situations, including perioperative management, intensive care unit
management, and pregnancy, and highlights the importance of collaborative care of the PAH patient through a multidisci-
plinary approach. (J Am Coll Cardiol 2015;65:197697) 2015 by the American College of Cardiology Foundation.
P ulmonary hypertension (PH) denes a group

of clinical conditions presenting with ab-
normal elevation in the pulmonary circulation
pressure (1,2). The normal mean pulmonary artery
salient features of PH and pulmonary arterial hyper-
tension (PAH).
CLASSIFICATION
pressure (mPAP) at rest is 14 3.3 mm Hg, and the up-
per limit of normal is 20.6 mm Hg (3); nevertheless, The recognition of subgroups of patients sharing
PH is dened as an increase of mPAP $25 mm Hg at specic features has led to the most recent classi-
rest, as assessed by right heart catheterization (4). cation of PH (Table 1) (5). The current classication
Over the past 2 decades, advances in the understand- groups patients with similar pathological ndings,
ing of basic mechanisms, clinical characteristics, and hemodynamic proles, and management strategies.
treatment options have substantially changed our GROUP 1: PAH. PAH is dened by the presence of a
approach to this disease. This paper will review pre-capillary pattern in the invasive hemodynamic
From the *University of Michigan Hospital and Health Systems, Ann Arbor, Michigan; yFeinberg Cardiovascular Research Insti-
tute, Northwestern University Feinberg School of Medicine, Chicago, Illinois; zPulmonary Department, Heart Institute, University
of Sao Paulo Medical School, Sao Paulo, Brazil; and the xUniversity of Paris-Sud, Le Kremlin-Bictre, France; AP-HP, Service de
Pneumologie, DHU Thorax Innovation, Hpital Bictre, Le Kremlin-Bictre, France; and INSERM U999, LabEx LERMIT, Centre
Chirurgical Marie Lannelongue, Le Plessis Robinson, France. Dr. McLaughlin has been a consultant for Actelion Bayer, Gilead, and
United Therapeutics; has received research funding for clinical trials to the University of Michigan from Actelion, Bayer, Gilead,
and the National Institutes of Health (R24 HL123767); and has a relationship with United Therapeutics. Dr. Shah has received
research grant support from the National Institutes of Health (R01 HL107577) and Actelion Pharmaceuticals; has received generous
funding from Jo Anne and Stephen A. Schiller in support of pulmonary hypertension research; has received consulting fees from
the American Board of Internal Medicine, Novartis, Bayer, DC Devices, AstraZeneca, and Alnylam Pharmaceuticals; and has
received speaker fees from the Pulmonary Hypertension Association and the American Society of Echocardiography. Dr. Souza has
received lecture fees from Actelion, Bayer, GlaxoSmithKline, and Bristol-Myers Squibb; and has received advisory board fees from
Actelion and Bayer. Dr. Humbert has served as a consultant for Actelion, Bayer, GlaxoSmithKline, and Pzer.
Listen to this manuscripts audio summary by JACC Editor-in-Chief Dr. Valentin Fuster.
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Manuscript received March 10, 2015; accepted March 23, 2015.

JACC VOL. 65, NO. 18, 2015 McLaughlin et al. 1977
MAY 12, 2015:197697 Management of Pulmonary Arterial Hypertension
without mutations. Up to 80% of familial ABBREVIATIONS

T A B L E 1 Updated Classication of PH*
cases of PAH have been linked to germline AND ACRONYMS
1. Pulmonary arterial hypertension
1.1 Idiopathic PAH
mutations in the gene coding for the bone
CHD = congenital heart disease
1.2 Heritable PAH morphogenetic protein receptor type II
1.2.1 BMPR2 CTD = connective
1.2.2 ALK-1, ENG, SMAD9, CAV1, KCNK3
(BMPR2), a member of the transforming
tissue disease
1.2.3 Unknown growth factor (TGF)-b signaling family (6).
1.3 Drug and toxin induced IPAH = idiopathic pulmonary
1.4 Associated with:
BMPR2 mutations have also been detected in hypertension
1.4.1 Connective tissue disease around 20% of apparently idiopathic cases mPAP = mean pulmonary
1.4.2 HIV infection
1.4.3 Portal hypertension
without a family history of PAH (7). Other artery pressure
1.4.4 Congenital heart diseases mutations in genes from the TGF- b family are PAH = pulmonary arterial
1.4.5 Schistosomiasis
1 0 . Pulmonary veno-occlusive disease and/or pulmonary
also known to be associated with particular hypertension
capillary hemangiomatosis PAH presentations, such as comorbid hered- PCWP = pulmonary capillary
10 0 . Persistent PH of the newborn wedge pressure
itary hemorrhagic telangiectasia (ACVRL1,
2. PH due to left heart disease PH = pulmonary hypertension
2.1 Left ventricular systolic dysfunction Endoglin) (8).
2.2 Left ventricular diastolic dysfunction Recently, mutations in the novel PAH- PVR = pulmonary vascular
2.3 Valvular disease resistance
2.4 Congenital/acquired left heart inow/outow tract associated genes Caveolin 1 and KCNK3 have
obstruction and congenital cardiomyopathies RV = right ventricle/ventricular
been described. Caveolin 1 (9) and KCNK3 (10)
3. PH due to lung diseases and/or hypoxia are not closely related to the TGF-b family, thereby
3.1 Chronic obstructive pulmonary disease
3.2 Interstitial lung disease providing new and different insights in terms of po-
3.3 Other pulmonary diseases with mixed restrictive and tential pathophysiological mechanisms and thera-
obstructive pattern
3.4 Sleep-disordered breathing peutic targets.
3.5 Alveolar hypoventilation disorders D r u g - a n d t o x i n - i n d u c e d P A H . A signicant num-
3.6 Chronic exposure to high altitude
3.7 Developmental lung diseases ber of substances have been described as poten-
4. Chronic thromboembolic PH tially associated with the development of PAH.
5. PH with unclear multifactorial mechanisms Aminorex and fenuramine derivatives are clear
5.1 Hematologic disorders: chronic hemolytic anemia, myelo-
proliferative disorders, splenectomy examples where a robust association between drug
5.2 Systemic disorders: sarcoidosis, pulmonary histiocytosis, exposure and PAH has been demonstrated through
lymphangioleiomyomatosis
5.3 Metabolic disorders: glycogen storage disease, Gaucher the analysis of outbreaks of PAH in the 1960s and
disease, thyroid disorders 1990s (11,12). More recently, benuorex, a benzoate
5.4 Others: tumoral obstruction, brosing mediastinitis,
chronic renal failure, segmental PH ester that shares structural and pharmacologic char-
acteristics with dexfenuramine and fenuramine,
*5th World Symposium on Pulmonary Hypertension, Nice, France, February 27 to
March 1, 2013. Changes since the last symposium are in bold.
has also been associated with the development of
BMPR 2 bone morphogenetic protein receptor type 2; CAV1 caveolin-1; PAH (13). Among other classes of drugs that may be
ENG endoglin; HIV human immunodeciency virus; PAH pulmonary
arterial hypertension; PH pulmonary hypertension.
linked to the development of PAH, dasatinib, a tyro-
sine kinase inhibitor, gained particular attention after
a case series of drug-induced PAH was reported in
chronic myelogenous leukemia patients (14). Type I
evaluation, characterized by an mPAP $25 mm Hg interferons have also been linked to an increased risk
with normal pulmonary artery occlusion pressure of developing PAH (15).
(i.e., pulmonary capillary wedge pressure [PCWP] PAH associated with connective tissue diseases. One
#15 mm Hg) and pulmonary vascular resistance (PVR) of the most important forms of PAH is connective
above 3 Wood units, in the absence of pulmonary tissue disease (CTD)-associated PAH. CTD-associated
parenchymal or thromboembolic disease. As shown in PAH accounts for 15% to 25% of all PAH cases in
Table 1, PAH may occur in isolation or in association worldwide registries, with systemic sclerosis and
with several clinical conditions. systemic lupus erythematosus as the leading causes
I d i o p a t h i c a n d h e r i t a b l e P A H . Although idiopathic (16,17). These patients have a particularly poor prog-
pulmonary arterial hypertension (IPAH) might repre- nosis, with an estimated 30% 1-year mortality,
sent the most studied form of PAH, it corresponds to a compared to 15% in IPAH. It was recently suggested
rare presentation in which no family history of PAH or that implementation of a systematic screening pro-
associated risk factor is present. Therefore, IPAH is gram to allow earlier diagnosis and intervention
only diagnosed after extensive investigation ruling might result in better long-term outcomes for this
out alternative diagnoses (4). subgroup of PAH patients (18,19). Cases of reversible
Heritable forms of PAH include those with identi- PAH have been reported in PAH patients with sys-
ed gene mutations and familial cases with or temic lupus erythematosus and mixed CTD.
1978 McLaughlin et al. JACC VOL. 65, NO. 18, 2015
Management of Pulmonary Arterial Hypertension MAY 12, 2015:197697
PAH associated with human immunodeciency (PVOD) and pulmonary capillary hemangiomatosis,
v i r u s . Patients with human immunodeciency virus rare variants within the same spectrum of disease,
(HIV) are at increased risk of developing PAH. The share some similarities with PAH, although with re-
prevalence of PAH in this group is estimated to markable differences in presentation, mainly with
be 0.5% (20,21), with clinical and hemodynamic pre- respect to chest computed tomography ndings,
sentation very similar to IPAH. Prognosis of HIV- causal homozygous EIF2AK4 mutations in heritable
associated PAH has improved in recent years; in the cases, and clinical course (28,29). These entities
REVEAL (Registry to Evaluate Early And Long-term remain closer to the PAH spectrum of disease than to
PAH Disease Management) registry, the survival of any other PH group and, thus, are classied as 10 . Due
HIV-associated PAH was 93% at 1 year and 75% at 3 to numerous differences with all other forms of PAH,
years (22). Cases of reversible PAH have been re- persistent PH of the newborn has also been with-
ported in HIV patients treated with PAH drugs and drawn from the PAH group and is classied as 1 00 (5).
highly-active antiretroviral drugs (22).
GROUP 2: PH DUE TO LEFT HEART DISEASE. This
P A H a s s o c i a t e d w i t h p o r t a l h y p e r t e n s i o n . About group encompasses the most frequent form of PH. In
6% of patients with portal hypertension develop PAH, these patients, PH is a consequence of the elevated
independent of the severity of the liver disease, lling pressures of the left heart chambers trans-
although the long-term prognosis of these patients is mitted backward to the pulmonary circulation. In this
related to the severity of both the liver and pulmo- setting, PVR is usually normal, as is the gradient be-
nary vascular disease. Portopulmonary hypertension tween the mPAP and the PCWP (transpulmonary
represents an important problem for liver trans- gradient; <12 mm Hg) and the gradient between the
plantation programs because its presence is related to diastolic pulmonary artery pressure and the PCWP
increased mortality during and after the procedure, (diastolic pressure gradient; <5 to 7 mm Hg). Never-
particularly if the mPAP is >35 mm Hg. The prognosis theless, in a subgroup of patients, a pre-capillary
in portopulmonary hypertension is worse than in component might also be present, characterizing a
IPAH; recently reported data suggest a 3-year survival mixed hemodynamic pattern (combined pre- and
of 40% (23). post-capillary PH) (30). Further studies are necessary
PAH associated with congenital heart diseases. to assess the potential benets and risks of PAH-
Due to the improvement in the management of specic therapy in this group.
congenital heart diseases (CHDs), more children with GROUP 3: PH DUE TO LUNG DISEASES AND/OR
CHD survive to adulthood. Because about 10% of HYPOXIA. This group comprises patients with par-
adults with CHD develop PAH (24), CHD-associated enchymal lung diseases or other causes of hypoxia
PAH is a signicant subgroup in PH referral centers. (e.g., obstructive sleep apnea) in whom the presence
P A H a s s o c i a t e d w i t h s c h i s t o s o m i a s i s . PH repre- of PH is considered directly related to these under-
sents one of the most severe complications of chronic lying diseases. Thus, all forms of ventilatory distur-
schistosomiasis (Sch), an infectious disease caused by bances are considered: obstructive, restrictive, and
parasitic trematode worms. A PH screening program the combination of both patterns. In particular, the
identied a 4.6% prevalence of PAH among patients presence of a mixed pattern (obstructive and restric-
diagnosed with hepatosplenic schistosomiasis man- tive), as in the coexistence of pulmonary brosis and
soni (25), highlighting the relevance of this form of emphysema, results in an increased prevalence of PH.
PAH, considering the worldwide distribution of the Thus far, no signicant benet from the use of tar-
infection. A recent registry demonstrated that Sch- geted PAH therapies has been demonstrated in this
PAH might be responsible for about 20% of all group.
newly-diagnosed PAH cases in endemic countries. GROUP 4: CHRONIC THROMBOEMBOLIC PULMONARY
The clinical and histopathological similarities be- HYPERTENSION. Up to 4% of all patients with acute
tween Sch-PAH and IPAH have been recently pulmonary embolism may ultimately develop chronic
described (26), although Sch-PAH apparently has a thromboembolic pulmonary hypertension (CTEPH),
more benign clinical course with a 3-year mortality of which is considered a curable form of PH when per-
about 15% (26). A recent case series also suggested forming a pulmonary endarterectomy is possible.
that these patients might have a benecial response Operability depends on several factors, including
to PAH targeted therapies (27). the pattern of vascular obstruction, hemodynamic
Pulmonary veno-occlusive disease, pulmonary severity, and experience of the referral center, among
capillary hemangiomatosis, and persistent PH others. More recently, PAH-specic medical therapy
o f t h e n e w b o r n . Pulmonary veno-occlusive disease and balloon pulmonary angioplasty have been used
for patients who were not candidates for surgery or been highlighted by cases of heritable PAH due to
who remained with residual PH after surgery with germline mutations of BMPR2, ACVRL1, and Endoglin
benecial results. (37). The products of these genes are involved in the
GROUP 5: PH WITH UNCLEAR OR MULTIFACTORIAL regulation of growth, differentiation, and apoptosis
MECHANISMS. Included in this group are numerous of pulmonary artery endothelial and smooth muscle
forms of PH in which multiple pathophysiological cells. Idiopathic and heritable PAH affect twice as
mechanisms might be implicated in the elevation in many females as males, emphasizing the likely role
pulmonary vascular pressures. Given the heteroge- of additional factors in the pathobiological mecha-
neity of this group, further research is necessary to nisms leading to PAH, including sexual hormones and
better establish appropriate diagnostic criteria and pregnancy (37).
management strategies for each specic subform.
NATURAL HISTORY OF PAH,
PATHOLOGY AND PATHOBIOLOGY OF PAH LESSONS FROM REGISTRIES
In PAH, pulmonary vascular lesions predominantly Until the end of the last century, PAH was a true
affect the small pulmonary arteries (diameter <500 mm). orphan disease, that is, a condition affecting a few
A wide array of changes can all occur in PAH, individuals and overlooked by the medical and
ranging from medial hypertrophy, intimal prolifer- pharmaceutical world. Although rare, a number of
ative and brotic changes (concentric, eccentric), important recent ndings have signicantly im-
adventitial thickening with moderate perivascular proved our understanding of PAH. In 1973, the World
inammatory inltrates (which may be more pro- Health Organization sponsored the rst international
nounced and organized in tertiary lymphoid tissue), conference on a condition that was then named
complex lesions (plexiform, dilated lesions), and primary PH (currently idiopathic, heritable, and
thrombotic lesions (3133). In contrast to PVOD, drug-induced PAH) in Geneva, Switzerland. The
pulmonary veins are less affected in PAH (31). marked increase in the incidence of the disease in
Figure 1 highlights some key pathobiological abnor- patients who had used an anorectic pill (aminorex
malities in PAH. fumarate) explained, at least in part, the medical
Vasoconstriction/vasodilation imbalance, throm- worlds interest in this devastating condition. The
bosis, cell proliferation, and remodeling of the experts attending this conference recommended
pulmonary arterial walls contribute to PAH pathobi- collection of patient information into registry data-
ology (32,33). Several cell types play a role in the bases to enable characterization of the disease in
disease, including endothelial cells, smooth muscle terms of demographics, clinical presentations, and
cells, pericytes, myobroblasts, inammatory cells outcomes. In 1981, the National Heart, Lung, and
(macrophages, dendritic cells, mast cells, T and B Blood Institute of the National Institutes of Health
lymphocytes), and platelets (3235). Pulmonary (NIH) launched the rst national registry of patients
vasoconstriction has long been regarded as an early with so-called primary PH. By the time the reg-
event, and excessive pulmonary vasoconstriction has istry closed in 1987, only 187 patients (mean age
been related to abnormal function or expression of 36 15 years) had been recruited from 32 centers (38).
potassium-channels and to endothelial dysfunction These patients were described and followed for up
characterized by reduced production of vasodilators to 5 years, leading to major advances in the under-
(nitric oxide and prostacyclin) and overproduction of standing of the natural history of the disease, which
vasoconstrictors (endothelin-1) (32). These factors had a poor prognosis with a median survival of 2.8
will increase pulmonary vascular tone and favor years following diagnosis. More recently, several
remodeling, and therefore represent logical pharma- registries have described the characteristics and sur-
cological targets. Other mediators are also believed to vival of PAH patients in the modern management era.
play an important role in subsets of PAH patients, In the early 2000s, the French registry described
including proinammatory cytokines (interleukin-1 consecutive adult patients from 17 expert centers.
and -6, tumor necrosis factor a ), chemokines, sero- Within a year, 674 patients (age 50 15 years) were
tonin, angiopoietins, bone morphogenetic proteins entered in this registry (16). The estimates of preva-
(BMPs), growth factors, and members of the TGF-b lence and incidence of PAH were 15.0 cases/million
superfamily (3236). Proteolysis of the extracellular and 2.4 cases/million per year, respectively. Idio-
matrix and autoimmunity are also likely to contribute pathic, familial, and anorexigen-induced PAH ac-
to disease pathobiology. The key role of the TGF- b counted for around one-half of the cases (39.2%,
superfamily in pulmonary vascular remodeling has 3.9%, and 9.5%, respectively); the other one-half
F I G U R E 1 Pathobiology of PAH
(A) Pulmonary vasoconstriction has long been regarded as an early event, and excessive pulmonary vasoconstriction has been related to abnormal function or expression
of potassium-channels and to endothelial dysfunction characterized by reduced production of vasodilators (nitric oxide and prostacyclin), along with overproduction of
vasoconstrictors (endothelin-1). Recently, a novel channelopathy due to KCNK3 mutation has been identied in heritable cases of pulmonary arterial hypertension (PAH),
which may also favor vasoconstriction. (B) Pulmonary vascular remodeling and inammation: proinammatory cytokines (interleukin-1 and -6, tumor necrosis factor a),
chemokines, serotonin, angiopoietins, bone morphogenetic proteins (BMPs), growth factors, and members of the transforming growth factor (TGF)b superfamily, but
also proteolysis of the extracellular matrix and autoimmunity, are key triggers in smooth muscle cells, endothelial cells, broblasts and pericytes proliferation and
migration. Proteolysis of the extracellular matrix and autoimmunity (as evidenced here by perivascular lymphoid neogenesis) are also likely to initiate or perpetuate
arterial remodeling. (C) Endothelial dysfunction, proliferation, and resistance to apoptosis, triggered by aberrant production of angiogenic growth factors (FGF2, PDGF,
VEGF), and genetic abnormalities in TGF-b signaling (BMPR2, ACVRL1/ALK1, endoglin, SMADs), and in endothelial scaffolding protein (Caveolin-1), may favor aberrant
angiogenesis (and subsequent increased vascular resistance) in PAH that is best exemplied by plexiform lesions. (D) Thrombotic arteriopathy, a highly prevalent
pathological pattern of PAH, is an important pathophysiological feature of the disorder. Indeed, endothelial dysfunction leads to local thrombosis in PAH. Prepared from
original drawings courtesy of Frdric Perros, PhD, Inserm UMR_S 999, Universit Paris-Sud, Hpital Marie Lannelongue Le Plessis Robinson, France.
corresponded to patients with well-characterized symptom onset (mainly dyspnea on exercise) and
comorbidities (diagnosis of CTD, CHD, portal hyper- PAH diagnosis was 27 months, similar to that
tension, or HIV infection was made in 15.3%, 11.3%, observed in the NIH Registry, emphasizing the need
10.4%, and 6.2% of the population, respectively). for better PAH awareness and diagnostic strategy.
Most patients had advanced functional impairment at Patients were then followed for 3 years and survival
the time of diagnosis, with 75% of patients in New rates were analyzed. For incident (newly diagnosed)
York Heart Association (NYHA) functional class III idiopathic, familial, and anorexigen-induced PAH,
or IV and a reduced 6-min walk distance (6MWD) of estimated survival at 1, 2, and 3 years was 85.7% (95%
329 109 m. Severe hemodynamic impairment was condence interval [CI]: 76.5% to 94.9%), 69.6% (95%
present, with an mPAP of 55 15 mm Hg, cardiac CI: 57.6% to 81.6%), and 54.9% (95% CI: 41.8% to
index of 2.5 0.8 l/min/m 2, and PVR index of 20.5 68.0%), respectively (39). This registry demonstrated
10.2 Wood unit index, respectively. Delay between that PAH was still detected late in the course of the
disease in the modern management era, with a ma- risk factors, such as portal hypertension, CTD, CHD,
jority of patients displaying severe functional and HIV, exposure to drugs/toxins known to induce PAH
hemodynamic compromise. (e.g., anorexigens), and a family history of PAH (4,17).
An important objective of registries is to identify Physical examination ndings sometimes observed in
patient characteristics that predict outcome. The NIH PH and right ventricular (RV) dysfunction include: an
Registry was the rst to develop a prognostic equa- elevated jugular venous pressure with prominent A
tion. Use of this equation in the current treatment era waves (due to increased RV stiffness) and V waves
has limitations, as it provides information only on (due to tricuspid regurgitation [TR]); Kussmauls sign
the natural history of untreated idiopathic/heritable (increased jugular venous pressure with inspiration,
PAH. More recent registries have identied predictors due to a noncompliant RV or signicant TR); an RV
of outcome that show similarities between studies, lift; a loud P2; right-sided S3 and/or S4 ; murmur of TR;
including disease etiology, patient sex, functional and signs of right heart failure (e.g., hepatomegaly,
impairment, and factors reective of right heart ascites, and peripheral edema) (2).
function. In the French registry, individual survival Electrocardiographic signs of PH include RV hy-
analysis identied the following factors as signi- pertrophy with strain pattern (increased R-wave
cantly and positively associated with survival: female amplitude with ST-segment depression and T-wave
sex; NYHA functional class I/II; greater 6MWD; lower inversion in the precordial leads) and right atrial
right atrial pressure; and higher cardiac output. enlargement (increased P-wave amplitude in leads II
Multivariable analysis showed that female sex and and V1 ). The right atrium is often quite enlarged in
having a greater 6MWD and higher cardiac output severe PAH and can mimic left atrial enlargement in
were jointly signicantly associated with improved lead V 1 (terminal negative deection of the P-wave >1
survival. Both the French and U.S. REVEAL equations small box), despite the presence of a small and
have shown strong predictive power when cross- underlled left atrium. On chest radiography, loss of
validated in matched patients from the U.S. REVEAL the retrosternal space on the lateral view (a sign of RV
and French registries, respectively (39,40). enlargement), enlarged central pulmonary arteries,
and peripheral pruning can occur in PAH (1,2).
DIAGNOSTIC EVALUATION OF THE PATIENT
WITH SUSPECTED PH ECHOCARDIOGRAPHY. Comprehensive echocardi-
ography, with Doppler and tissue Doppler imaging,
The diagnosis of PAH, especially in those without is essential for screening and initial noninvasive
apparent risk factors, requires a high index of suspi- assessment of PH (41). Besides evaluating for possible
cion because typical presenting symptoms such as PH, the echocardiogram can evaluate for the cause of
dyspnea, exercise intolerance, and fatigue are non- PH (e.g., left heart disease lesions, agitated saline
specic (1,2,4). In contrast, signs of PH, such as bubble study to evaluate for shunt lesions). Although
elevated pulmonary artery systolic pressure (PASP) clinicians are often focused on the PASP when eval-
and enlarged pulmonary arteries, are often encoun- uating patients with PH, it is just as critical to eval-
tered on imaging tests, such as Doppler echocardiog- uate the right heart on echocardiography because of
raphy and chest computed tomography, respectively. the pitfalls of echocardiographic PASP assessment,
In these patients, PAH, which is much more rare than which have been reviewed previously (41). Table 2
other causes of PH (such as left heart disease and displays a checklist of items to remember when
chronic lung disease), is unlikely. Thus, clinicians evaluating the echocardiogram in a patient with
must be able to both recognize clues regarding the known or suspected PH.
presence of PAH (to avoid missing the diagnosis of INVASIVE HEMODYNAMIC TESTING. Cardiac cathe-
this rare disease) and correctly determine the etiology terization is an essential step in the diagnosis of PH,
and type of PH when found incidentally on routine particularly PAH, and should be performed prior to
testing (to avoid incorrect and potentially harmful the initiation of PAH-specic therapy (1,2,4). When
treatment). performed at experienced centers, the risk of major
Although the history and physical examination are complications from right heart catheterization is low
not always denitive, much information can be (42). Nevertheless, invasive hemodynamic testing
gathered from this initial step. Clues in the clinical requires careful technique to avoid potential pitfalls.
history that increase the likelihood of PH include: Standard good clinical practices, such as ensuring
exertional lightheadedness or syncope; symptoms of proper zeroing of pressure transducers, measuring
right heart failure, such as leg swelling, abdominal pressures (particularly PCWP) at end-expiration, and
distension, and anorexia; and the presence of PAH being cognizant of artifacts in the hemodynamic
T A B L E 2 Checklist for the Echocardiographic Evaluation of PH
Completed? Action Item Notes
Record estimated PASP Underestimated when Doppler beam alignment is poor or when TR jet is minimal
Overestimated in patients with signicant anemia or in some cases of agitated saline-enhanced TR jet on
continuous wave Doppler (due to feathering)
Assumes absence of pulmonic stenosis
Echocardiographic PASP does not equal mean PA pressure (denition of PH per guidelines is on the basis of
invasive hemodynamics: mean PA pressure $25 mm Hg)
Evaluate RV size and function Signs of RV enlargement (apical 4-chamber view): RV shares apex with LV; RV bigger than LV; RV basal diameter
>4.2 cm
RV hypertrophy (subcostal view): RV end-diastolic wall thickness >5 mm
RV systolic dysfunction: RV fractional area change <35%; TAPSE <1.6 cm; RV tissue Doppler s0 velocity <10 cm/s
at base of the RV free wall (tricuspid annulus)
Septal attening: in systole RV pressure overload and in diastole RV volume overload
Evaluate for signs of elevated PVR RVOT notching on pulse-wave Doppler prole is a sign of elevated PVR
Peak TR velocity (m/s)/RVOT VTI (cm) <0.18: unlikely PVR is elevated
Estimate volume status Use size and collapsibility of IVC (during sniff maneuver) to determine RA pressure
Hepatic vein ow: systolic ow reversal can be a sign of severe TR, RV overload, and/or increased RV stiffness
Signs of RA overload/enlargement: RA area >18 cm 2 ; interatrial septum bows from right to left
Evaluate severity of TR Features suggestive of severe TR include dense TR jet on continuous-wave Doppler, V-wave cutoff sign; and
systolic ow reversal on hepatic vein pulse-wave Doppler imaging
Evaluate for pericardial effusion In patients with PAH, the presence of a pericardial effusion poor prognostic sign
Evaluate for causes of PH (left heart Left heart disease: look for overt LV systolic dysfunction, grade 2 or worse diastolic dysfunction, severe aortic or
disease, shunt lesions) mitral valvular disease, and less common abnormalities of the left heart (e.g., hypertrophic cardiomyopathy, cor
triatriatum)
Shunt lesions: perform agitated saline bubble study
Differentiate PAH from PVH Signs favoring PVH: LA enlargement (LA size >RA size); interatrial septum bows from left to right; E/A ratio >1.2;
E/e0 (lateral) > 11; lateral e0 <8 cm/s;
In patients with signicantly elevated PASP at rest: grade 1 diastolic dysfunction pattern (E/A ratio <0.8) favors
PAH diagnosis because of underlled LA and decreased LV compliance due to RV/LV interaction (extrinsic
compression of LV by RV).
See also Figure 1
IVC inferior vena cava; LA left atrial/atrium; LV left ventricular/ventricle; PA pulmonary artery; PAH pulmonary arterial hypertension PASP pulmonary artery systolic pressure; PH pulmonary
hypertension; PVH pulmonary vascular hypertension; PVR pulmonary vascular resistance; RA right atrial/atrium; RV right ventricular/ventricle; RVOT right ventricular outow tract; TAPSE
tricuspid annular plane systolic excursion; TR tricuspid regurgitation; VTI velocity-time integral.
tracings (e.g., overshoot in the pressure tracing due to response to pulmonary vasodilator testing should
an air bubble in the catheter, whip artifact due to include all of the following: 1) decrease in mPAP
catheter movement) are essential for making the to #40 mm Hg; 2) decrease of at least 10 mm Hg in
correct diagnosis in patients with suspected or known mPAP; and 3) unchanged or increased cardiac output
PH. In addition, because PCWP is so important for (43). It is important to note that a lack of acute pul-
differentiating PAH from pulmonary venous hyper- monary vasodilator response does not signify a
tension (PVH), special care should be taken to ensure nonresponder to PAH therapies. Most PAH patients
that the PCWP measurement is accurate, including will not have a positive response to a pulmonary
uoroscopic conrmation that the pulmonary artery vasodilator challenge; however, many of these pa-
(PA) catheter is in the PCWP position, and that PCWP tients will respond to long-term selective PAH-specic
hemodynamic waveforms are appropriate. If the ac- therapy (see later section Therapy for PAH). Pulmo-
curacy is in doubt, or if the PCWP value does not t nary vasodilator challenge with agents such as iNO,
with the rest of the clinical picture, left ventricular adenosine, and prostacyclins should not be per-
(LV) end-diastolic pressure should be measured. formed in patients with evidence of signicant PVH
(e.g., PCWP >18 to 20 mm Hg). Furthermore, although
DYNAMIC TESTING DURING INVASIVE HEMODYNAMIC pulmonary vasodilator testing has been used com-
STUDIES. Acute pulmonary vasodilator testing is monly in patients with associated-PAH such as HIV,
indicated in PAH patients with idiopathic, heritable, CTD, CHD, and portopulmonary hypertension, there
or anorexigen-induced PAH. A variety of pulmonary is less rigorous data supporting its use in these pa-
vasodilators can be used, with inhaled nitric oxide tients. There is no data supporting the use of vasodi-
(iNO) used most commonly (43). Pulmonary vasodilator testing or calcium-channel blockers in patients
lator testing helps to determine who is most likely to with PH other than PAH.
respond to calcium-channel blocker therapy and Exercise testing can be very helpful in the assess-
also provides prognostic information. A positive ment of patients with suspected or known PH because
most symptoms occur with exertion. Although the noninvasively the type of PH because invasive he-
diagnosis of exercise-PH is no longer recognized in modynamic testing can sometimes be avoided if it is
guidelines statements, exercise can help evaluate for clear that the etiology of PH is left heart disease. In
PVH. Given the ability to accurately document the some patients, such as those with heart failure with
exercise load, we prefer to use a supine or upright reduced LV ejection fraction or severe aortic or mitral
ergometer (instead of arm exercises) for exercise he- valve disease, the diagnosis of PVH (Group 2) is usu-
modynamic testing. In patients with PVH due to heart ally straightforward. However, many patients who
failure with preserved left ventricular ejection frac- are evaluated for PH have a normal LV ejection frac-
tion (HFpEF), low-level exercise (25 W on a supine tion and no severe valvular lesions. In these patients,
ergometer) typically results in signicant elevations differentiating PAH from PVH hypertension can be
in PCWP (e.g., >20 to 25 mm Hg), and mPAP and challenging. Furthermore, some patients with PVH
PCWP will rise in parallel with exercise-induced in- may have superimposed PAH (the so-called combined
creases in cardiac output (44). In patients with PAH, pre- and post-capillary PH), which adds additional
there will be minimal rise in the PCWP during exer- diagnostic complexities.
cise, whereas mPAP will rise, and the rise will be The clinical history can be helpful in differ-
much steeper than the rise in PCWP. entiating PAH from PVH. Thenappan et al. (45)
Volume challenge during invasive hemodynamic demonstrated that advanced age, the presence of
testing can also be helpful in the diagnosis and man- comorbidities such as systemic hypertension and
agement of PH. Typically, 10 ml/kg of warmed saline coronary artery disease, the absence of right atrial
can be infused intravenously over 10 min in patients if enlargement, higher aortic systolic pressure, higher
there is still a suspicion of PAH or PVH, but the base- mean right atrial pressure, and higher cardiac output
line hemodynamic data is insufcient for the diag- were the best variables to help differentiate
nosis. Fluid challenge can be safely administered if PH-HFpEF (due to PVH) from PAH.
the patient being evaluated has a resting right atrial Figure 2 displays helpful criteria on echocardiog-
pressure <10 mm Hg and mPAP <25 mm Hg, and may raphy and invasive hemodynamic testing for the dif-
be particularly helpful if cardiac output is low-normal ferentiation of PAH versus PVH and for the diagnosis
or decreased (e.g., cardiac index <2.5 to 3.0 l/min/m2 ). of combined pre- and post-capillary PH, such as that
In these patients, signs of PAH include a rise in which occurs in patients with HFpEF with super-
mPAP $25 mm Hg while PCWP remains #15 mm Hg. imposed precapillary PH. In a study of 44 patients
Additional evidence suggestive of the diagnosis after with PH, Willens et al. (46) compared patients with
uid challenge are: 1) a reduction or no rise in cardiac PAH (n 24) to those with PVH (n 20) and found
output; and 2) rise in RA pressure greater than the rise that the E/A and lateral E/e 0 ratios were the 2 most
in PCWP. Passive leg raise alone can also serve as a helpful echocardiographic parameters in differenti-
volume challenge. If PCWP rises signicantly (to >20 ating between types of PH: lateral E/e 0 >9.2 had a
mm Hg) with passive leg raise, it is likely that the sensitivity of 95% and specicity of 96%; E/A ratio
patient has PVH (44). Alternatively, if PCWP changes >1.7 had a sensitivity of 75% and specicity of 91%.
little, but RA pressure increases to >15 mm Hg and Crawley et al. (47) used cardiac magnetic resonance
mPAP rises to >25 mm Hg with minimal change in (CMR) in a similar study (n 37 with IPAH, n 21 with
cardiac output, PAH may be present. PH-HFpEF, and n 23 without PH) and found that left
It is important to note that there is insufcient atrial volume was the best parameter for differenti-
controlled data to provide rm guidelines on invasive ating PAH from PVH.
hemodynamic pressure cutoffs for post-exercise or Invasive hemodynamic testing is the gold stan-
-volume challenge diagnosis of PAH. Thus, the dard for differentiating PAH from PVH. In patients
aforementioned post-exercise and -uid challenge with invasively-documented PH (mPAP $25 mm Hg),
hemodynamic criteria for the presence of possible PH consensus statements recommend the use of a
PAH are rough estimates. Clinicians must integrate partition value of PCWP #15 mm Hg (for diagnosis of
the clinical information, echocardiographic ndings, PAH) versus PCWP >15 mm Hg for diagnosis of PVH
and invasive hemodynamic data (pre- and post- (1,2,4). However, the diagnosis of PVH with super-
challenge) to make an accurate diagnosis. imposed precapillary PH can be challenging. Some
patients with PVH, particularly those with HFpEF,
DIFFERENTIATION OF PAH FROM PVH. In clinical will have a high PA systolic pressure that drives
practice, differentiating PAH from PVH can be chal- mPAP elevation and can result in elevated trans-
lenging. Given the very high prevalence of left heart pulmonary gradient (mPAP-PCWP) and PVR. Because
disease, it is important to try to determine these patients do not necessarily have superimposed
F I G U R E 2 PAH Versus PVH: Echocardiographic and Invasive Hemodynamic Differentiation
Parameter PAH PVH

May be
Lateral E/e = 20
RV size Enlarged
Lateral E/e = 5
enlarged
E/A = 1.4
E/A = 0.5
LA size Small Large

Normal
RA/LA size ratio Increased
(LA > RA size)
Interatrial Bows from Bows from
septum right to left left to right
RVOT notching Common Rare
E/A ratio << 1 >1
Lateral e Normal Decreased
Lateral E/e <8 > 10
Aortic pressure Normal/Low Normal/High
PCWP 15 mmHg > 15 mmHg
PADP-PCWP > 7 mmHg < 5 mmHg
PULMONARY PULMONARY
ARTERIAL VENOUS
HYPERTENSION HYPERTENSION
mPAP = 60 mmHg, PCWP = 10 mmHg, CO = 4 L/min mPAP = 60 mmHg, PCWP = 24 mmHg, CO = 4 L/min mPAP = 48 mmHg, PCWP = 38 mmHg, CO = 4 L/min
PADP-PCWP = 28 mmHg, PVR = 12.5 WU PADP-PCWP = 12 mmHg, PVR = 9 WU PADP-PCWP = 0 mmHg, PVR = 2.5 WU
P res s u re (m m Hg )
Pressure (mm Hg)
Pressure (mm Hg)

PA
PA
PA
PCWP PCWP
PCWP
Pre-capillary PH Combined pre- and post-capillary PH Post-capillary PH
(Left) Prototypical echocardiographic and invasive hemodynamic ndings from a patient with PAH. The RA and RV are severely enlarged, and the LV and LA are small and
underlled. The interatrial septum bows from right to left. On mitral inow, E/A ratio <1 because of underlling of the LA and decreased compliance of the LV due to
extrinsic compression from the enlarged RV. The lateral e0 velocity and lateral E/e0 ratio are normal (<8) suggesting normal LV relaxation and lling pressures. There is
notching in the RV outow tract prole on pulse-wave Doppler imaging due to increased PA stiffness. PCWP is normal and the PADP-PCWP gradient is severely increased.
(Right) Prototypical echocardiographic and invasive hemodynamic ndings from a patient with PVH. The LA is enlarged and the interatrial septum bows from left to
right. On mitral inow, E/A ratio >1, lateral e0 velocity is reduced, and lateral E/e0 ratio is increased, suggestive of grade 2 diastolic dysfunction with impaired LV
relaxation and elevated LV lling pressures. There is no notching in the RV outow tract prole. PCWP is elevated, and there is no gradient between the PADP and PCWP.
Note that although the RV in the right panel is not enlarged, RV enlargement and dysfunction can be present in patients with isolated PVH. (Upper middle) Parameters
helpful for differentiating PAH from PVH on echocardiography and invasive hemodynamic testing. (Lower middle) Invasive hemodynamic ndings in a patient with
combined pre- and post-capillary PH (elevated PCWP and PADP-PCWP gradient). It should be noted that the most challenging patients are in this middle zone (combined
pre- and post-capillary PH), with echocardiographic ndings that lie in the middle of the prototypical examples of PAH and PVH shown here. In these patients, careful
evaluation of the echocardiogram and invasive hemodynamics will be necessary for an accurate diagnosis. E/A ratio of early to late (atrial) mitral inow velocities; E/
e0 ratio of early mitral inow velocity to early diastolic mitral annular tissue velocity; CO cardiac output; LA left atrial; mPAP mean pulmonary arterial pressure;
PADP pulmonary artery diastolic pressure; PAH pulmonary arterial hypertension; PCWP pulmonary capillary wedge pressure; PH pulmonary hypertension;
PVH pulmonary venous hypertension; PVR pulmonary vascular resistance; RA right atrial; RV right ventricular; RVOT right ventricular outow tract.
precapillary PH, an elevated PADP-PCWP gradient superimposed precapillary PH) (30), as shown in
(i.e., diastolic pulmonary gradient) >5 to 7 mm Hg Figure 2.
has been advocated as the best way to diagnose true DIAGNOSTIC EVALUATION OF THE RV. The RV plays
combined pre- and post-capillary PH (i.e., PVH with a central role in the diagnosis and management of PH.
F I G U R E 3 Echocardiographic and CMR Evaluation of the RV in Pulmonary Hypertension
A ES ED D
FAC = 17%
B
E
TAPSE
RV
LV
C
F
RV S
(A) Right ventricular (RV) fractional area change; (B) tricuspid annular plane systolic excursion (TAPSE); (C) RV tissue Doppler longitudinal (s0 )
velocity; (D) RV global longitudinal strain on speckle-tracking echocardiography; (E) late gadolinium enhancement of the RV insertion points on
cardiac magnetic resonance (CMR); and (F) D-sign of the left ventricle (LV) due to RV overload during peak inspiration on CMR. The central
image in the gure displays the supercial muscle layer of the RV (dissection by Damian Sanchez-Quintana, University of Extremadura, Spain
[modied with permission from Ho SY, Nihoyannopoulos P. Anatomy, echocardiography, and normal right ventricular dimensions. Heart
2006;92 Suppl 1:i2-13]). CMR images courtesy of Benjamin Freed, MD, Northwestern University Feinberg School of Medicine. Ao aorta;
FAC fractional area change; ED end-diastole; ES end-systole; PT pulmonary trunk.
In recent years, there has been increased focus on whether the RV is enlarged or dysfunctional.
evaluation of RV structure and function in the setting RV systolic function can be evaluated using
of PH, using echocardiography and CMR as the 2 pri- 2-dimensional images (e.g., RV fractional area chance
mary clinical imaging modalities. Table 2 lists use- in the apical 4-chamber view) (Figure 3A); M-mode
ful echocardiographic parameters for determining (e.g., tricuspid annular plane systolic excursion
[TAPSE]) (Figure 3B); and tissue Doppler imaging and overnight polysomnography are helpful in clas-
(e.g., RV basal free wall systolic [s 0 ] velocity at the sifying PH (13).
level of the tricuspid annulus) (Figure 3C) (41).
THERAPY FOR PAH
These techniques are easy to apply during routine
clinical echocardiography; however, RV fractional
GENERAL MEASURES. Basic counseling and disease
area chance can be challenging to calculate when RV
state education are important components in the care
images are suboptimal, and it is insensitive in cases of
of PAH patients. Low-level graded aerobic exercise,
subtle RV dysfunction; TAPSE and RV tissue Doppler
such as walking, is recommended. The benets of
velocity are more sensitive indicators of RV dys-
intensive pulmonary rehabilitation have been dem-
function, but can be affected by M-mode or Doppler
onstrated (48). Patients are advised against heavy
beam misalignment, respectively, or by tethering to
physical exertion and isometric exercise, as this may
the LV (i.e., if LV systolic function is hyperdynamic,
evoke exertional syncope. Oxygen supplementation
as is often the case in PAH, TAPSE and RV velocity can
to keep saturation above 90% at rest and with
be falsely elevated; alternatively, in patients with
exertion, sleep, or altitude is advisable. A sodium-
severe LV systolic dysfunction, these measures can
restricted diet is advised and is particularly im-
be falsely low). Speckle-tracking echocardiography
portant to manage volume status in those with RV
(Figure 3D) allows for rapid assessment of RV
failure. Routine immunizations, such as those against
myocardial deformation (i.e., RV free wall strain) and
inuenza and pneumococcal pneumonia, are advised.
is not as angle-dependent.
CMR has the advantage of being a tomographic BACKGROUND THERAPY. Despite a paucity of data,
technique that can provide 3-dimensional views of diuretic and anticoagulant agents are often appro-
the RV without being affected by acoustic window priate therapies in PAH patients. Anticoagulant
quality. Thus, CMR provides the most accurate agents have been studied in 4 uncontrolled observa-
noninvasive measurement of RV volumes, mass, and tional series: 2 prospective and 2 retrospective, pri-
ejection fraction. Gadolinium contrast injection dur- marily in IPAH patients (4952). Improved survival
ing CMR can be used to evaluate for focal RV brosis; was observed in all 4 studies. Most guidelines rec-
patients with PAH often exhibit late gadolinium ommend warfarin anticoagulation titrated to an in-
enhancement at the RV insertion points (Figure 3E). ternational normalized ratio of 1.5 to 2.5 in patients
CMR cine images during inspiration can be very with IPAH. One prospective registry also assessed
helpful in understanding the ability of the RV to patients with associated forms of PAH and found no
handle volume overload. During inspiration, as in- benet of anticoagulation in such patients (52).
trathoracic pressure drops, blood is drawn into the Diuretic agents are indicated to manage RV volume
right heart from the systemic veins, lling the RA and overload. Occasionally, intravenous (IV) diuretic
RV. Interventricular septal attening (D sign) agents are required. Serum electrolytes and renal
(Figure 3F) at peak inspiration is indicative of a function should be followed closely. There are few
vulnerable or dysfunctional RV (in the absence of data pertaining to digoxin, although it is sometimes
an alternate etiology of septal attening, such as used in patients with right heart failure and low car-
constrictive pericarditis). In the future, novel imaging diac output and in those with atrial arrhythmias.
techniques for the evaluation of diffuse RV brosis, CALCIUM-CHANNEL BLOCKERS. Calcium-channel blockers
RV metabolism, and RV perfusion will likely be pos- can be a very effective treatment for those few patients
sible and should further enhance our ability to un- with an acute response to vasodilator testing as outlined
derstand RV pathophysiology in the setting of PH. in the previous text. Patients who meet criteria for a
positive vasodilator response can be treated with a
FURTHER TESTING FOR PATIENTS WITH PAH. In the calcium-channel blocker, but should be followed
evaluation of patients with PH, if the diagnosis of closely for both safety and efcacy of therapy. If a pa-
PVH has been established, the focus becomes left tient meeting the denition of an acute response does
heart disease, with further diagnostic measures de- not improve to functional class I or II on calcium-
pending on the type of left heart lesion resulting in channel blockers, an alternative PAH-specic therapy
elevated left atrial pressure. Alternatively, if the should be prescribed. Very few patients (<7%) with IPAH
initial diagnostic evaluation reveals pre-capillary PH, do well over the long-term on calcium-channel blockers
further testing, including laboratory testing for HIV, (43). Long-acting nifedipine, diltiazem, and amlodipine
liver disease, and CTD; pulmonary function testing; are the most commonly-used agents. Due to its potential
arterial blood gas analysis; ventilation-perfusion for negative inotropic effects, verapamil should be
scanning of the lung; chest computed tomography; avoided.
PROSTACYCLINS. Prostacyclin synthase expression common side effects included headache, diarrhea,
is reduced in endothelial cells from PAH patients, rash, and nausea. On the basis of bioequivalence data,
resulting in inadequate production of prostaglandin I2 treprostinil is FDA-approved for a continuous IV de-
(i.e., prostacyclin), a vasodilator with antiproliferative livery. Treprostinil has been approved for intermit-
effects (53). Administering prostanoids has been a tent inhaled use. In a multicenter, randomized,
mainstay of PAH therapy for nearly 2 decades. There placebo-controlled study of 235 PAH patients who
are currently multiple prostanoids commercially were still symptomatic despite oral bosentan or sil-
available: epoprostenol (continuous IV), treprostinil denal therapy, the addition of inhaled treprostinil
(continuous subcutaneous, continuous IV, intermit- resulted in an improvement in the primary endpoint
tent inhaled, and oral) and iloprost (intermittent of 6MWD (59). Common side effects included cough,
inhaled). Prostanoids are complex therapies and are headache, nausea, dizziness, and ushing.
best administered by a center with expertise in the Treprostinil diethanolamine is a salt form of tre-
complicated delivery systems and chronic manage- prostinil designed to release the drug in a sustained-
ment of side effects and dosing. release osmotic tablet for twice daily dosing. Oral
Epoprostenol was the rst therapy approved by the treprostinil has been studied as monotherapy in 349
FDA for IPAH. Randomized controlled clinical trials in PAH patients over 12 weeks (60). An improvement of
IPAH demonstrated improvements in exercise toler- 23 m (p 0.0125) in the primary endpoint of 6MWD
ance, as measured by the 6MWD, hemodynamics, was observed. There were no improvements in the
quality of life, and survival over a 12-week period secondary endpoints of time to clinical worsening or
(54). Long-term observational series have also sug- functional class. The most common adverse events
gested improved survival on IV epoprostenol (55,56). were headache, nausea, diarrhea, and jaw pain. Oral
IV epoprostenol has also been evaluated in PAH treprostinil has also been studied in 2 randomized
related to the scleroderma spectrum of diseases, with controlled trials as add-on therapy to endothelin re-
improvements in 6MWD and hemodynamics demon- ceptor antagonists and/or phosphodiesterase type 5
strated by a 12-week randomized controlled clinical (PDE-5) inhibitors (61,62). The primary endpoint of
trial in this population (57). Observational series have 6MWD was not improved in either trial. The FDA
also reported favorable effects of IV epoprostenol in approved oral treprostinil in December 2013 to
patients with additional forms of associated PAH. improve exercise capacity, noting that the drug did
Epoprostenol must be delivered by continuous IV not offer additional benet when added to other
infusion. Each patient must learn the techniques of vasodilator therapy in 2 16-week double blind,
sterile preparation of the medication, operation of placebo-controlled trials.
the ambulatory infusion pump, and care of the central A 12-week multicenter, randomized, placebo-controlled
venous catheter. More recently, a thermostable for- trial in 207 patients of iloprost, an inhaled prostanoid,
mulation of epoprostenol, which does not require ice demonstrated an improvement in a novel composite
packs and can be mixed less frequently, has been endpoint that included an improvement by at least 1 level
approved. Intravenous epoprostenol is commonly of functional class, improvement in 6MWD by at least
started in the hospital at a dose of 2 ng/kg/min and 10%, and the absence of clinical deterioration (63). Inhaled
up-titrated, depending on symptoms of PAH and side iloprost has also been studied in combination with
effects of the therapy. Although dosing is highly bosentan in a multicenter, randomized, placebo-
individualized, the optimal dose for most adult pa- controlled trial. After 12 weeks, there were improvements
tients tends to be in the range of 25 to 40 ng/kg/min. in functional class and time to clinical worsening. The
Common side effects include jaw pain, ushing, combination appeared to be safe. Common side effects of
nausea, diarrhea, skin rash, and musculoskeletal inhaled iloprost include cough, headache, ushing, and
pain. Infections and infusion interruptions can be jaw pain.
life-threatening. ORAL PAH-SPECIFIC THERAPIES. E n d o t h e l i n p a t h w a y .
Treprostinil is a prostanoid currently approved as a Increased tissue expression and increased plasma levels
continuous subcutaneous infusion, continuous IV of endothelin-1, a potent vasoconstrictor and stimulator
infusion, or an intermittent inhaled treatment. Tre- of cell proliferation, have been described in PAH, high-
prostinil was rst studied as a subcutaneous infusion lighting the potential of targeting this pathway in the
in a placebo-controlled, multicenter randomized trial treatment of PAH. Endothelin receptor antagonists act by
of 470 patients over 12 weeks (58). There was a dose- selectively blocking endothelin-A receptors or by dual
related improvement in 6MWD of 16 m. Adverse ef- blockage of endothelin-A and -B receptors; furthermore,
fects included pain and erythema at the site of the they constituted the rst class of drugs orally administered
subcutaneous infusion in 85% of patients. Other in PAH (6466).
Bosentan, a nonselective endothelin-A and -B liver function tests were similar in the placebo and
receptor antagonist has been studied in multiple macitentan groups. Macitentan was FDA-approved to
placebo-controlled trials in PAH. The BREATHE-1 delay disease progression, including death, initiation
study, a multicenter, randomized, placebo-controlled of prostanoid therapy, or clinical worsening in
trial of 213 functional class III and IV PAH patients PAH. Unlike bosentan, monthly liver function test
demonstrated an improvement in 6MWD and the monitoring is not required, although physicians are
composite endpoint of time to clinical worsening encouraged to monitor as clinically indicated.
over 16 weeks (67). More recently, bosentan has N i t r i c o x i d e p a t h w a y . Nitric oxide (NO) is a potent
been evaluated in functional class II patients in a vasodilator of the pulmonary circulation, acting
6-month multicenter, randomized, placebo-controlled through the increase in cyclic guanosine mono-
trial (68). This study demonstrated an improvement phosphate (cGMP), and cleared mainly as a result of
in PVR and time to clinical worsening. The degradation by PDE-5. Reduction in the expression of
improvement in 6MWD was not statistically signi- NO synthase has been described as a mechanism
cant. Bosentan has been studied specically in pa- associated with the pathogenesis of PH (73).
tients with congenital systemic to pulmonary shunts Currently, there are 2 therapeutic classes of drugs
and Eisenmenger physiology (69). In this population, interacting in the NO pathway, aiming to increase
improvements in PVR, mPAP, and 6MWD were the direct action of cGMP: PDE-5 inhibitors, which
noted, and bosentan did not worsen oxygen satura- decrease cGMP degradation, and soluble guanylate
tion. Bosentan is currently widely used in patients cyclase stimulators, which increase cGMP production.
with PAH. Close follow-up of both efcacy and Phosphodiesterase type 5 inhibitors. Sildenal has
safety is encouraged. The FDA requires liver func- been studied in a 12-week multicenter, randomized,
tion to be checked on a monthly basis, and an placebo-controlled trial and was found to improve
algorithm for managing elevated liver function tests 6MWD and hemodynamics, but not the secondary
is available in the package insert. Other side effects endpoint of time to clinical worsening (74). The
include headache, anemia, and edema. improvement was not dose-related, and sildenal
Ambrisentan, a selective endothelin-A receptor is currently approved at a dose of 20 mg 3 times a
antagonist, has been studied in 2 phase III multi- day. More recently, tadalal was studied in a 16-
center, randomized, placebo-controlled trials in 394 week multicenter, randomized, placebo-controlled
PAH patients and demonstrated an improvement trial and demonstrated an improvement in the
in 6MWD and time to clinical worsening (70). The FDA primary endpoint of 6MWD (75). The highest dose
no longer requires monthly liver function test moni- studied (40 mg) also resulted in an improvement
toring in patients on ambrisentan, although many in the secondary endpoint of time to clinical
experts continue to check liver function periodically. worsening. Tadalal is approved at a dose of 40 mg
Other side effects of ambrisentan include uid once daily. The most common side effects of
retention, nasal congestion, ushing, and anemia. the PDE-5 inhibitors include headache, ushing,
Macitentan, a nonselective endothelin-A and -B dyspepsia, myalgias, and epistaxis.
receptor antagonist, has increased tissue penetration Soluble guanylate cyclase stimulators. Riociguat is a
and more sustained receptor blockade compared with rst-in-class soluble guanylate cyclase stimulator.
bosentan (71). It has been studied in a phase III long- It directly stimulates soluble guanylate cyclase
term morbidity and mortality trial (n 742) in which independent of nitric oxide, and increases the
the primary endpoint was the time from initiation of sensitivity of soluble guanylate cyclase to nitric oxide
treatment to the rst occurrence of a composite (76,77). A randomized controlled trial of 261 patients
endpoint of death, atrial septostomy, lung trans- with either inoperable CTEPH or persistent PH
plantation, initiation of treatment with parenteral after pulmonary endarterectomy demonstrated an
prostanoids, or worsening PAH (72). Patients were improvement in the primary endpoint of 6MWD
randomized to either placebo or macitentan 3 or 10 and the secondary endpoints of PVR, N-terminal pro
mg daily. There were 30% and 45% risk reductions in B-type natriuretic peptide (BNP), and functional class
the primary endpoint with the 3- and 10-mg doses, with riociguat (78). A randomized controlled trial
respectively. Both patients on PAH-specic therapy of 443 PAH patients (44% previously treated with
(such as PDE5 inhibitors) and treatment-nave endothelin receptor antagonists and 6% with
patients had improvements in the primary and nonparenteral prostanoids) also demonstrated an
secondary outcome measures. The most frequent improvement in the primary endpoint of 6MWD as
adverse events were headache, nasopharyngitis, and well as multiple secondary endpoints including PVR,
anemia. The incidence of edema and elevation of N-terminal proBNP, functional class, and time to
clinical worsening with riociguat (79). The most considered in PAH patients in the setting of persistent
common adverse events included syncope, headache, RV failure despite optimal medical management.
dyspepsia, peripheral edema, and hypotension. Bridge therapy should be discussed and initiated
Cases of hemoptysis have also been reported. earlier in the course of RV failure, before the occur-
Concomitant use of riociguat and PDE-5 inhibitors rence of secondary organ injury. Parameters known to
is contraindicated due to hypotension. The FDA be associated with high mortality in PAH patients
approved riociguat to improve exercise capacity, requiring inotropic support include systemic hypo-
functional class, and delay in clinical worsening in tension, elevated creatinine, hyponatremia, high
group 1 PAH and to improve exercise capacity and BNP levels, and increasing inotrope requirements.
functional class in patients with persistent PH after Because of life-threatening RV failure, extracorporeal
surgical pulmonary endarterectomy, or for those life support should support the heart without
with inoperable CTEPH. It must be emphasized compromising oxygenation. Both the pulmonary ar-
that patients with surgically-accessible CTEPH are teryleft atrium Novalung (Xenios AG, Heilbronn,
best treated with surgery, and should not receive Germany) and venoarterial extracorporeal membrane
riociguat instead of pulmonary endarterectomy. oxygenator have been used to bridge PAH patients for
LUNG TRANSPLANTATION AND BRIDGE TO several weeks until transplant (80,82). One must bear
TRANSPLANTATION WITH EXTRACORPOREAL LIFE in mind that extracorporeal life support complica-
SUPPORT. Despite recent advances in medical ther- tions can be serious (e.g., infection at the cannulation
apy, lung and heart-lung transplantation remains an site, hemorrhage, renal failure, neurologic complica-
essential treatment option for PAH patients in the tions, vascular access site injury, thromboembolic
modern management era (8083). It is widely recog- complications), emphasizing the need for these pro-
nized that transplant referral should occur before the cedures to be performed in well-selected patients
patient develops severe RV failure and that eligible treated in experienced centers (80,82). Of note, lung
patients should be counseled about lung transplant transplantation is a life-saving procedure in severe
early in their diagnosis (83). Due to limited organ PAH with survival rates after 1, 5, 10, and 15 years of
availability and high mortality rates while awaiting 70%, 50%, 39% and 26% (heart-lung transplantation)
transplantation, eligible patients who are in NYHA and 79%, 52%, 43%, and 30% (double-lung trans-
functional class III or IV symptoms with other clinical, plantation), respectively (81).
and/or hemodynamic predictors of poor prognosis on
ATRIAL SEPTOSTOMY. Balloon atrial septostomy
best standard of care including a parenteral prosta-
(articial creation of a right-to-left shunt to decom-
cyclin have to be considered for lung transplantation.
press the right heart) can be performed percutane-
The same applies for eligible patients initially pre-
ously with careful graded balloon dilation. This
senting with end-stage PAH in NYHA functional class
approach has been proposed by some experienced
IV. Bilateral sequential lung transplantation is the
centers to improve peripheral oxygen delivery, de-
most common procedure. However, practice may
spite a fall in systemic arterial saturation due to a
vary from center to center, and heart-lung trans-
compensatory rise in cardiac output. Balloon atrial
plantation may be required for some patients in the
septostomy has a high periprocedural mortality in
context of complex Eisenmenger physiology and is
patients with markedly elevated right atrial pressure
also preferred by some centers in the setting of re-
and should only be considered as a palliative therapy
fractory RV failure. Although some patients with
or bridge to transplantation in centers with experi-
PVOD may respond to low-dose PAH therapy, many
ence in this procedure (84).
will have no response or will deteriorate with such
therapy. Thus, PVOD patients should be managed APPROACH TO THERAPY. The optimal therapeutic
with lung transplant teams to offer a timely listing of approach must be individualized for every patient,
lung transplant candidates. taking into account many factors including the
It is important to identify patients with persistent severity of illness, route of administration of therapy,
evidence of RV failure in the presence of maximal side effect prole, comorbid illnesses, treatment
medical treatment before they develop irreversible goals, and clinician experience and preference. Some
end-organ injury. If appropriate, these patients of the factors that place patients at highest risk are
should be considered for bridging to lung trans- listed in Table 3. Aggressive upfront triple combina-
plantation (8083). Indeed, circulatory support may tion therapy may be considered in the most seriously
allow stabilization of patients, with improvement in ill patients upon presentation (85). Emerging evi-
organ function and increased probability of survival. dence favoring upfront dual oral combination therapy
Extracorporeal life support should thus be with tadalal and ambrisentan in treatment-nave
March 15, 2015, at the ACC. 15 in San Diego,

T A B L E 3 High Risk Factors
California (90).
Syncope Yes
The importance of growth factors in pulmonary
NYHA/WHO class IV
vascular remodeling suggests that receptor tyrosine
6MWD <300 m
CPET Peak oxygen uptake <12 ml/kg/min
kinase inhibition could be an interesting anti-
Echocardiographic ndings Pericardial effusion proliferative approach in PAH. The IMPRES (Imatinib
TAPSE <1.5 cm in Pulmonary Arterial Hypertension, a Randomized,
Hemodynamics RAP >15 mm Hg Efcacy Study) study showed that imatinib therapy
Cardiac index #2 l/min/m2 could improve cardiac output with a modest reduc-
CMR RVEF <35%
tion in mPAP in a patient population with advanced
CMR cardiac magnetic resonance; CPET cardiopulmonary exercise testing;

disease despite therapy with at least 2 PAH drugs (91).
NYHA New York Heart Association; RAP right atrial pressure; RVEF right However, the unfavorable risk-benet prole of
ventricular ejection fraction; TAPSE tricuspid annular plane systolic excursion;
WHO World Health Organization; 6MWD 6-min walking distance. imatinib has resulted in cessation of its further ther-
apeutic development in PAH, and its off-label use in
PAH is not encouraged. Targeting growth factors,
however, remains an attractive strategy in PAH, but a
patients has recently been presented. The most better understanding of this treatment approach will
common treatment strategy currently employed is be required to facilitate the development of new
goal-oriented sequential combination therapy. Al- drugs that could block proliferative pathways without
though the primarily observational studies described severe side effects.
previously do not allow for denitive conclusions, Serotonin causes pulmonary artery vasoconstric-
reasonable goals of therapy include (86): tion and pulmonary artery smooth muscle cell pro-
Modied NYHA functional class (World Health Or- liferation. Terguride, a 5HT-2 receptor antagonist,
ganization functional class): I or II was not efcacious in either hemodynamics or exer-
Echocardiography/CMR: normal or near-normal RV cise capacity in a phase II trial. De novo synthesis of
size and function serotonin from tryptophan is catalyzed by tryptophan
Hemodynamics: normal indexes of RV function hydroxylase-1 (TPH-1) and overexpression of the
(right atrial pressure <8 mm Hg and cardiac index TPH-1 gene has been found in remodeled arteries of
>2.5 to 3.0 l/min/m 2) PAH patients. Moreover, hypoxic PH is attenuated in
6MWD >380 to 440 m TPH-1 knockout mice. Thus, inhibition of TPH-1 is
Cardiopulmonary exercise testing: peak oxygen a potential target against the serotonin system in
uptake >15 ml/min/kg and ventilatory equivalents PAH (83,92).
for CO 2 <45 l/min Rho-kinase is the downstream effector of the small
BNP level: normal (determined by local labora- GTPase, RhoA, and mediates a range of cellular
tory cutoff values) functions such as cell migration and smooth muscle
contraction. Fasudil is a potent Rho-kinase inhibitor,
Over the years, many treatment approaches have and acute IV administration has led to a 17% reduc-
been published, including those put forth at the 5th tion in PVR in a small observation study of 9 PAH
World Symposium on PH and by the American College patients. A long-acting oral formulation of fasudil was
of Chest Physicians (87,88). Our proposed treatment recently tested in a pilot randomized controlled trial
algorithm is depicted in the Central Illustration. in Japan involving 23 PAH patients over 12 weeks. No
signicant differences in pulmonary hemodynamics
FUTURE DIRECTIONS and 6MWD were seen between the 2 groups at the end
of the study. Pulmonary edema and pleural effusions
Oral selexipag is a pulmonary vasodilator that acts occurred in 1 patient treated with fasudil, resulting in
on the human prostaglandin I2 (IP) receptor. The ef- death, and a causal relationship with the drug could
cacy of selexipag has been tested in multicenter, not be excluded (93).
randomized controlled trials, including a recently- A link between inammation and PAH patho-
completed large, phase III, double-blind, placebo- genesis is supported by several clinical and pre-
controlled, event-driven, morbidity and mortality clinical observations. Anti-inammatory therapies
trial that enrolled 1,156 PAH patients. In that study, have been explored predominantly in CTD-associated
selexipag signicantly decreased the risk of a PAH, and small case series have reported clinical
morbidity/mortality event versus placebo by 43% response to immunosuppression using a combination
(p < 0.0001) (89). Results of this trial were presented of cyclophosphamide with glucocorticoids. However,
CENTRAL I LLU ST RAT ION Treatment Algorithm for PAH
Patient with suspected pulmonary hypertension (PH)
Diagnostic evaluation to identify pulmonary arterial hypertension (PAH) patients: Echocardiography (to evaluate cardiac causes of PH),
PFT, V/Q scan, CT scan, invasive hemodynamic testing (careful cardiac catheterization), and laboratory testing (ANA, LFTs, HIV)
DIAGNOSIS
Vasoreactivity challenge for idiopathic, heritable, and anorexigen-induced PAH patients in functional class I, II, or III
to help determine which patients are more likely to be long-term responders to calcium-channel-blockers (CCBs)
Does IPAH patient have a positive response to acute pulmonary vasodilator testing?
(Decrease in mean pulmonary arterial pressure [mPAP] to 40 mm Hg; Decrease in mPAP by 10 mm Hg; and Unchanged or increased cardiac output)
Y N
Prescribe calcium-channel blockers (CCBs)
Does patient improve to functional class I or II

with sustained hemodynamics benefits?
Y N
Continue with CCBs Is the patient of higher risk?

with careful monitoring
Y N
TREATMENT
* Initial combination of
ambrisentan and tadalafil is Pulmonary arterial specific therapy: Pulmonary arterial specific therapy:
superior than ambrisentan or Epoprostenol Endothelin receptor antagonist (ERA)
tadalafil alone (in functional Upfront Combination therapy* Consider Phosphodiesterase type 5 inhibitor (PDE5i)
class II and III PAH patients) Endothelin receptor antagonist (ERA) clinical Soluble guanylate cyclase stimulator (sGC)
Highest-risk patients are trials in
Phosphodiesterase type 5 inhibitor (PDE5i) Prostanoids (treprostinil, iloprost)
underrepresented in appropriate
Soluble guanylate cyclase stimulator (sGC) patients Epoprostenol
randomized controlled trials;
Prostanoids (treprostinil, iloprost) Upfront Combination therapy*
Expert opinion favors upfront
combination of 2 to 3 drugs, Consider referral to lung transplant
including epoprostenol
If inadequate response (according to predefined treatment goals), sequential combination therapy:

ERA +/- PDE5i or sGC +/- prostanoids or epoprostenol. Consider clinical trials and/or referral for lung transplant
If inadequate response, consider referral to lung transplant or balloon atrial septostomy (BAS)
McLaughlin, V.V. et al. J Am Coll Cardiol. 2015; 65(18):197697.
ANA antinuclear antibody; BAS balloon atrial septostomy; CCB calcium-channel blockers; CT computed tomography; ERA endothelin receptor antagonist;
HIV human immunodeciency virus; IPAH idiopathic pulmonary hypertension; LFT liver function test; mPAP mean pulmonary arterial pressure; PAH pul-
monary arterial hypertension; PDE5i phosphodiesterase type 5 inhibitor; PFT pulmonary function tests; PH pulmonary hypertension; sGC soluble guanylate
cyclase stimulator; V/Q ventilation perfusion scan.
benecial effects are restricted to PAH that is associ- extreme caution is advocated due to reported symp-
ated with systemic lupus erythematosus and mixed tom worsening with b-blocker administration.
connective tissue disorders (CTD), but not in Pulmonary artery denervation has recently been
scleroderma, the most common CTD associated with proposed for PAH in an attempt to abolish sympa-
PAH (94). A phase II study investigating B-cell thetic nerve supply to the pulmonary circulation. In
depletion with rituximab (monoclonal antibody a rst-in-human single-center proof-of-mechanism
against CD20) in scleroderma-associated PAH is under- study, 13 patients underwent this procedure with
way (NCT01086540) (95). a dedicated radiofrequency ablation catheter. This
Mitochondrial abnormalities with a metabolic investigational approach resulted in signicant im-
switch favoring cytosolic glycolysis, rather than provement of mPAP and 6MWD, but requires further
normal mitochondrial aerobic metabolism, have been conrmation (102).
demonstrated in PAH. Such metabolic abnormalities Potts shunt is a surgical method of RV decom-
can be partially corrected by the agent dichlor- pression via the creation of an anastomosis between
oacetate, which has been shown to reverse PH in the descending aorta and left pulmonary artery. In
animal models (96). A phase I open-label trial is case of suprasystemic PH, an advantage of Potts
currently investigating dichloroacetate in PAH shunt over atrial septostomy is the sparing of the
(NCT01083524) (97). cerebral and coronary circulation from deoxygenated
The leading cause of heritable PAH is germline blood (103). Recently, an investigational small case
mutations in BMPR2. Moreover, the nding that series of adults with NYHA functional class IV PAH
BMPR2 function is also reduced in IPAH has led to demonstrated the feasibility of creating a Potts shunt
major interest in restoring BMPR2 function in PAH via an interventional percutaneous approach (104).
patients. Interestingly, gene transfer of BMPR2 using
adenovirus vector has been shown to improve PH SPECIAL SITUATIONS INCLUDING
induced by hypoxia and monocrotaline in rats. Using PERIOPERATIVE CARE, PREGNANCY,
a transcriptional high-throughput luciferase reporter AND ICU CARE
assay, the calcineurin inhibitor FK506 (tacrolimus)
was recently found to be a candidate compound that PERI-OPERATIVE CARE. Patients with signicant PAH
can up-regulate BMPR2 signaling. Low-dose FK506 are at high risk for general anesthesia. Perioperative
also reverses both hypoxic and monocrotaline forms risk was studied in an international prospective 3-year
of experimental PH (98). questionnaire-based survey among 11 PH centers
Endothelial progenitor cells are bone marrow (105). Major complications occurred in about 6% of
derived progenitor cells involved in vascular ho- patients, and overall perioperative mortality was
meostasis, which can circulate, proliferate, and about 3.5%. The factors that increased complications
differentiate into mature endothelial cells at sites of and mortality were more advanced disease, man-
vascular injury. A study of autologous transplantation ifested by a higher right atrial pressure and a lower
of ex vivo cultured endothelial progenitor cells 6MWD. The need for emergency surgery and the use
has showed interesting short-term results in 31 PAH of perioperative vasopressors also increased risk.
patients (99). Since this initial proof-of-concept PAH can be considered a xed obstructive cardio-
study, no further human trials in adults have been pulmonary lesion with intraoperative physiology
published. similar to severe aortic or mitral stenosis. During in-
As observed in congestive heart failure, PAH is duction of anesthesia, systemic vasodilation is com-
associated with neurohormonal activation, as evi- mon, and systemic blood pressure can decrease.
denced by increased sympathetic nerve trafc and Systemic hypotension can exacerbate RV ischemia by
up-regulation of the renin-angiotensin-aldosterone decreasing the right coronary artery perfusion pres-
system. Interestingly, plasma levels of renin and sure during systole, resulting in decreased cardiac
angiotensin I and II are increased in PAH and have been output due to worsening RV function. The reduction
associated with worse prognosis (100). In addition, in pulmonary blood ow results in more underlling
b-blockers, acetylcholinesterase (ACE) inhibitors, of the LA and LV, worsening the systemic hypo-
angiotensin-II receptor blockers, and aldosterone an- tension. Furthermore, as the LV becomes more
tagonists have produced benecial hemodynamic ef- underlled and the RV becomes more overloaded,
fects in experimental PH (101). In clinical practice, increased interventricular septal attening ensues,
aldosterone antagonists are already widely used in the further decreasing the ability of the LV to ll. These
treatment of RV failure. In contrast, there is limited abnormalities can quickly result in acute decompen-
data to support the use of b -blockers in PAH, and sation and potential death in a patient with PAH.
Given the risk of general anesthesia in a patient should be discussed. If the patient desires to keep the
with PAH, the following strategies can help to ensure pregnancy, the following steps should be followed to
the best outcome perioperatively: 1) if possible, try to try to ensure the best possible outcome for the
avoid general anesthesia (e.g., use a nerve block); mother and child: 1) referral to a PAH specialist and
2) evaluate and treat for decompensated right heart high-risk obstetrician (with close collaboration be-
failure; 3) in patients with severe PAH (e.g., those tween the PAH and obstetrics teams); 2) discontinue
with functional class III or IV symptoms, or on IV or endothelin receptor antagonists immediately (cate-
subcutaneous prostacyclins), perform pre-operative gory X) in patients who are taking them; 3) maintain
right heart catheterization and optimize hemody- patients on anticoagulation (low molecular-weight
namics prior to elective surgery; and 4) in the oper- heparin), oxygen, and diuretic agents; 4) continue
ating room, have available PA catheter monitoring, PDE5 inhibitors and prostacyclins (category B), and
transesophageal echocardiography, and inhaled nitric in patients with signicant PAH who are not yet
oxide. All PAH patients should continue vasodilator on prostacyclin therapy, initiation of such ther-
medications perioperatively, and a PAH specialist apy should be considered; 5) close follow-up with
should be involved in perioperative management, monthly visits and echocardiograms to screen for and
especially in high-risk PAH patients who are on treat RV decompensation and right heart failure; and
advanced prostanoid therapies. 6) perform elective, planned delivery with Caesarean
PREGNANCY. Despite the advent of multiple classes section and spinal-epidural anesthesia (at 34 weeks
of medications for PAH patients, pregnancy is con- of gestation, if possible) (1,107).
traindicated in these patients. Although there is not INTENSIVE CARE UNIT MANAGEMENT. With ad-
much controlled data on pregnancy in PAH, a sys- vances in pharmacological therapy for PAH, many
temic review of case reports demonstrated a very patients can now survive with good functional status.
high 30% to 56% mortality in PAH during pregnancy However, the RV remains vulnerable in these pa-
or in the early post-partum period (106). Bonnin et al. tients, and they can quickly spiral downward in the
(107) found a maternal mortality rate of 36% in a se- setting of stressors, such as infection, medication,
ries of 15 consecutive PAH patients who became and/or dietary noncompliance, and become critically
pregnant in the modern era of PAH treatment. A more ill. Unfortunately, there is scant evidence for the
contemporary description is of 26 pregnancies in PAH appropriate management of PAH patients in the
patients at 13 PAH centers (108). There were 3 deaths intensive care unit, and expert consensus is the pri-
(12%), and 1 patient developed refractory right heart mary basis of treatment guidelines (80).
failure and underwent heart-lung transplantation Management of the RV is central to successfully
post-partum. There were 2 spontaneous and 6 in- treating PAH patients who are critically ill. Often,
duced abortions. Overall, 62% of the pregnancies clinicians have a knee-jerk reaction to give uids to
resulted in a healthy baby without maternal compli- patients with sepsis or hypotension, a management
cations. These women had well-controlled PAH strategy that can have dire consequences in the
(mean PVR 500 352 dynes/s/cm 5). One-half were setting of PAH. For example, in a patient with PAH
long-term calcium-channel blocker responders. who is septic or has a severe infection, systemic
Several normal physiological changes in pregnancy vasodilation occurs. As outlined earlier in describing
can be deleterious to the patient with PAH, particu- the hemodynamic reaction to general anesthesia, the
larly the increase in blood volume and requirement RV can become more ischemic due to decreased RV
for increased cardiac output, along with systemic perfusion, resulting in further exacerbation of sys-
vasodilation. As with other types of xed obstructive temic hypotension due to decreased cardiac output.
lesions (such as aortic and mitral stenosis), pregnancy The RV enlarges and compresses the LV, further
is poorly tolerated in patients with PAH. Further- decreasing LV lling. In this setting, administration
more, certain pulmonary vasodilators, such as the of IV uids will only compound the problem as RV
endothelin receptor antagonists, are contraindicated diastolic pressure rises (further impeding right coro-
in pregnancy because of teratogenicity. Thus, all fe- nary blood ow), and interventricular septal at-
male patients with PH, particularly PAH, should avoid tening will worsen.
pregnancy, and contraception should be used in It is also important to note that acute-on-chronic
sexually-active patients (1). RV failure in PAH is physiologically different than
Despite warnings and contraceptive measures to acute RV failure (e.g., RV myocardial infarction).
avoid pregnancy, some women with PAH will get Most PAH patients are not pre-loaddependent in
pregnant. In these patients, termination of pregnancy the setting of RV failure, and even small boluses of IV
uid can be very harmful. Finally, renal venous

F I G U R E 4 Collaborative Care
congestion often occurs in patients with PAH who are
critically ill with RV failure. RA pressure (and there- Primary care
fore central venous pressure) is high in decom- EMS Rheumatology
pensated PAH, resulting in increased renal venous
Rehabilitation
pressure, and systemic hypotension decreases renal programs Pulmonary
Local
perfusion. These hemodynamic changes decrease Care
Cardiology Local hospital
renal blood ow and result in increased uid
retention.
Screening high risk populations
Given these hemodynamic abnormalities, we Awareness and early diagnosis
advocate the following steps for the management of Diagnostic evaluation
critically ill PAH patients: 1) consider invasive he- Cardiac catheterization and vasodilator testing
modynamic monitoring (e.g., pulmonary artery cath- Acute issues
eter) for diagnostic purposes to determine the PAH specific therapies dose titration
hemodynamic abnormality and lling pressures pre- Fluid Management
sent; 2) increase systemic blood pressure with drugs Side effects
such as dobutamine and/or phenylephrine to achieve ICU management
a systolic blood pressure >90 mm Hg; 3) optimize Clinical trials
central venous pressure to 8 to 10 mm Hg (use IV Transplantation
diuretic agents, ultraltration, or continuous veno- Hospice/palliative care
venous hemoltration if necessary); 4) transfuse
Patient
packed red blood cells to maintain hemoglobin support groups
>10 g/dl; 5) continue pulmonary vasodilator drugs Cardiology Rheumatology
that the patient was taking previously as an outpa- Research Surgeons PEA
tient; and 6) consider prescribing iNO (typical dose coordinators PH & Transplant
20 ppm), especially if the patient is on a ventilator, Social work Care Mental health
remembering to wean off slowly to avoid rebound specialists
elevations in PA pressure. If these measures fail, Pulmonary Dieticians

Nurse Hospice/
adding an inotropic agent to increase RV contractility
clinicians palliative care
can be considered. In addition, the use of short-term,
percutaneous, partial ventricular support devices,
Opportunities for collaboration between local providers and
such as a Tandem Heart (CardiacAssist, Inc., Pitts-
pulmonary hypertension (PH) centers in the care of patients
burgh, Pennsylvania) (inow cannula in the RA and with PH. EMS emergency medical services; PEA pulmonary
outow cannula in the PA) or RV Impella catheter endarterectomy.
(Abiomed, Danvers, Massachusetts) have been des-
cribed in the setting of RV failure (109,110). In severe
cases, where there is a clear reversible cause of RV
decompensation, extracorporeal life support (e.g., and timely diagnosis in instances where local exper-
venoarterial extracorporeal membrane oxygenator) tise is not available.
can be administered and can be life-saving; bilateral Given the complexities of the diagnosis and the
lung transplantation should also be considered in cost and side effect prole of the therapies, referral to
these cases (80). a PH center to conrm the diagnosis and comanage
the patient should be considered. A recent series
COLLABORATIVE CARE OF THE PAH PATIENT. describing new referrals to 3 PH specialty centers
Management of the PAH patient requires a multidis- demonstrated that patients are referred late, with
ciplinary approach and collaboration between local functional class 3 and 4 symptoms, more than one-
care and the PH specialty center (Figure 4). Given the half of the time; the diagnosis is often incorrect
delay from symptom onset to diagnosis, greater (nearly one-half of patients receive a different diag-
awareness in the community is required to achieve nosis after evaluation at the referral center); and
earlier diagnosis. Some community settings may be PAH-specic therapy is commonly started inappro-
equipped to perform a thorough diagnostic evalua- priately (111). In fact, 30% of patients received PAH-
tion, including a right heart catheterization with specic therapies before referral, and 57% of the
vasodilator testing, whereas others may not. An open time the use of PAH-specic therapy was not in
dialogue with a PH center will help facilitate a correct accordance with PH guidelines.
The PH center often can provide specialized care CONCLUSIONS

that is not available in the community. PH nurse cli-
nicians are critical in the management of PAH pa- Over recent decades, many advances have led to a
tients. They provide vital education regarding the better understanding of and treatment for PAH. It is
disease and its therapies, and maintain an active role critical that the appropriate diagnosis be made in
in case management to titrate medications, monitor a timely fashion. Differentiating PAH from PVH
side effects, and recognize complications. Access to is important and requires a thorough evaluation.
clinical research trials and advanced treatment op- Numerous therapies are available to treat PAH, and
tions, such as parenteral prostacyclins and lung or an aggressive approach targeting multiple pathways
heart-lung transplantation, are important aspects of may lead to better outcomes. The health of the RV is
care available at PH centers. the key determinant of prognosis; despite advances
Collaboration is key, and it is incumbent upon the in the treatment of PAH, management of RV failure
PH center to maintain an open dialogue with local remains suboptimal for many patients. Fortunately,
health care providers. The primary care physician or this remains an area of active research with oppor-
local cardiologist or pulmonologist must be kept up to tunities for translational discoveries that have the
date on the patients status and therapies, as they potential to improve patient care.
may be the rst physician to encounter a complica-
tion of PAH therapy (e.g., a line infection), to recog- REPRINT REQUESTS AND CORRESPONDENCE: Dr.
nize disease progression (e.g., uid retention and Vallerie V. McLaughlin, Pulmonary Hypertension
right heart failure), or to diagnose a new problem Program, University of Michigan Hospital and Health
(e.g., pneumonia). As many patients live far from the Systems, Cardiovascular Center, 1500 East Medical
PH center, comanagement of such issues is in the Center Drive, Room 2392, Ann Arbor, Michigan 48109-
patients best interest. 5853. E-mail: vmclaugh@med.umich.edu.
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Hipertension Pulmonar

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JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 65, NO.

2015 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION ISSN 0735-1097/$36.00

PUBLISHED BY ELSEVIER INC. http://dx.doi.org/10.1016/j.jacc.2015.03.540

THE PRESENT AND FUTURE

P ulmonary hypertension (PH) denes a group

Manuscript received March 10, 2015; accepted March 23, 2015.

without mutations. Up to 80% of familial ABBREVIATIONS

Management of Pulmonary Arterial Hypertension MAY 12, 2015:197697

Management of Pulmonary Arterial Hypertension MAY 12, 2015:197697

Management of Pulmonary Arterial Hypertension MAY 12, 2015:197697

T A B L E 2 Checklist for the Echocardiographic Evaluation of PH

Completed? Action Item Notes

Management of Pulmonary Arterial Hypertension MAY 12, 2015:197697

F I G U R E 2 PAH Versus PVH: Echocardiographic and Invasive Hemodynamic Differentiation

Parameter PAH PVH

LA size Small Large

Pressure (mm Hg)

Pressure (mm Hg)

Pre-capillary PH Combined pre- and post-capillary PH Post-capillary PH

F I G U R E 3 Echocardiographic and CMR Evaluation of the RV in Pulmonary Hypertension

Management of Pulmonary Arterial Hypertension MAY 12, 2015:197697

Management of Pulmonary Arterial Hypertension MAY 12, 2015:197697

Management of Pulmonary Arterial Hypertension MAY 12, 2015:197697

March 15, 2015, at the ACC. 15 in San Diego,

CMR cardiac magnetic resonance; CPET cardiopulmonary exercise testing;

CENTRAL I LLU ST RAT ION Treatment Algorithm for PAH

Patient with suspected pulmonary hypertension (PH)

Prescribe calcium-channel blockers (CCBs)

Does patient improve to functional class I or II

Continue with CCBs Is the patient of higher risk?

If inadequate response (according to predefined treatment goals), sequential combination therapy:

McLaughlin, V.V. et al. J Am Coll Cardiol. 2015; 65(18):197697.

Management of Pulmonary Arterial Hypertension MAY 12, 2015:197697

Management of Pulmonary Arterial Hypertension MAY 12, 2015:197697

uid can be very harmful. Finally, renal venous

elevations in PA pressure. If these measures fail, Pulmonary Dieticians

The PH center often can provide specialized care CONCLUSIONS

Management of Pulmonary Arterial Hypertension MAY 12, 2015:197697

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