Under pressure: Pulmonary hypertension associated with left heart disease

Abstract

Pulmonary hypertension (PH) associated with left heart disease (PH-LHD) is the most common type of PH, but its natural history is not well understood. PH-LHD is diagnosed by right heart catheterisation with a mean pulmonary arterial pressure ⩾25 mmHg and a pulmonary capillary wedge pressure >15 mmHg. The primary causes of PH-LHD are left ventricular dysfunction of systolic and diastolic origin, and valvular disease. Prognosis is poor and survival rates are low. Limited progress has been made towards specific therapies for PH-LHD, and management focuses on addressing the underlying cause of the disease with supportive therapies, surgery and pharmacological treatments. Clinical trials of therapies for pulmonary arterial hypertension in patients with PH-LHD have thus far been limited and have provided disappointing or conflicting results. Robust, long-term clinical studies in appropriate target populations have the potential to improve the outlook for patients with PH-LHD. Herein, we discuss the knowledge gaps in our understanding of PH-LHD, and describe the current unmet needs and challenges that are faced by clinicians when identifying and managing patients with this disease.

Full text

Under pressure: pulmonary hypertension
associated with left heart disease
Harrison W. Farber
1
and Simon Gibbs
2
Affiliations:
1
Pulmonary Center, Boston University School of Medicine, Boston, MA, USA.
2
National Heart and
Lung Institute, Imperial College London and Hammersmith Hospital, London, UK.
Correspondence: Harrison W. Farber, Pulmonary Center, Boston University School of Medicine, 72 East
Concord Street, R-304, Boston, MA 02118, USA. E-mail: hfarber@bu.edu
ABSTRACT Pulmonary hypertension (PH) associated with left heart disease (PH-LHD) is the most
common type of PH, but its natural history is not well understood. PH-LHD is diagnosed by right heart
catheterisation with a mean pulmonary arterial pressure ⩾25 mmHg and a pulmonary capillary wedge
pressure >15 mmHg. The primary causes of PH-LHD are left ventricular dysfunction of systolic and
diastolic origin, and valvular disease. Prognosis is poor and survival rates are low. Limited progress has
been made towards specific therapies for PH-LHD, and management focuses on addressing the underlying
cause of the disease with supportive therapies, surgery and pharmacological treatments. Clinical trials of
therapies for pulmonary arterial hypertension in patients with PH-LHD have thus far been limited and
have provided disappointing or conflicting results. Robust, long-term clinical studies in appropriate target
populations have the potential to improve the outlook for patients with PH-LHD. Herein, we discuss the
knowledge gaps in our understanding of PH-LHD, and describe the current unmet needs and challenges
that are faced by clinicians when identifying and managing patients with this disease.
@ERSpublications
Pulmonary hypertension due to left heart disease is associated with multiple unmet medical
needs http://ow.ly/TFET8
Case study part 1: initial assessment
A 63-year-old male with hypertension, diabetes mellitus, dyslipidaemia, coronary artery disease and
obstructive sleep apnoea presented to the clinic with worsening dyspnoea upon exertion (World Health
Organization (WHO) functional class IIIb). Echocardiography revealed a normal-sized left ventricle, left
ventricular ejection fraction (LVEF) of 35–40%, delayed left ventricular diastolic relaxation, normal left
atrium, right ventricular dilation with moderately depressed systolic function, mild right atrial enlargement,
flattened interventricular septum, dilated inferior vena cava, and a pulmonary artery systolic pressure of
85 mmHg. Computed tomography pulmonary angiography revealed no pulmonary embolus or parenchymal
lung disease. The patient failed to reach the target heart rate in a treadmill exercise test, but there was no
evidence of myocardial ischaemia. Pulmonary function testing and right heart catheterisation (RHC) were
performed (table 1).
Question 1: Based on these data, what would be your initial assessment of this patient?
This real-life patient case study highlights some of the many factors that can make diagnosing pulmonary
hypertension associated with left heart disease (PH-LHD) challenging. Based on the information
presented, would you diagnose this patient with PH-LHD?
Copyright ©ERS 2015. ERR articles are open access and distributed under the terms of the Creative Commons
Attribution Non-Commercial Licence 4.0.
Received: Aug 21 2015 | Accepted after revision: Oct 14 2015
Conflict of interest: Disclosures can be found alongside the online version of this article at err.ersjournals.com
Provenance: Publication of this peer-reviewed article was sponsored by Actelion Pharmaceuticals Ltd, Allschwil,
Switzerland (principal sponsor, European Respiratory Review issue 138).
Eur Respir Rev 2015; 24: 665–673 | DOI: 10.1183/16000617.0059-2015 665
REVIEW
PULMONARY HYPERTENSION

In this review, we will discuss the challenges that are associated with diagnosing and managing PH-LHD,
before revisiting the case study at the end of this article. The topics that will be presented here might
change your evaluation of this patient’s diagnosis.
Introduction
PH-LHD is a common form of pulmonary hypertension (PH) that is associated with a poor prognosis
and high rate of morbidity and mortality [1, 2]. However, there is still a lack of understanding about its
pathophysiology, epidemiology and treatment [1–14]; as such, there are numerous unmet needs for this
condition (table 2). Multiple disorders are responsible for PH-LHD, including: 1) left ventricular systolic
dysfunction (heart failure with reduced ejection fraction (HFrEF)); 2) left ventricular diastolic dysfunction
(heart failure with preserved ejection fraction (HFpEF)); 3) left-sided valvular disease; and 4) congenital/
acquired left heart inflow/outflow tract obstruction and congenital cardiomyopathies [2, 5]. In many cases
of PH-LHD, there is a degree of overlap in these aetiologies [5].
PH-LHD is characterised by backwards transmission of filling pressures due to impaired left ventricular
diastolic function. A loss of left atrial compliance, exercise-induced mitral regurgitation and diastolic
dysfunction, combined with increased pulsatile load caused by the increased pulmonary artery wedge
pressure (PAWP), can lead to and/or exacerbate the PH [4]. Increases in mean pulmonary arterial pressure
(PAP) in certain individuals may trigger development of PH. In some patients, additional factors, such as
endothelial dysfunction (resulting in decreased nitric oxide availability and increased expression of
endothelin) [15], an altered response to brain natriuretic peptide (BNP) (impacting vascular tone) [16],
and vasoconstriction and/or vascular remodelling [3], can lead to further increases in vascular resistance and,
hence, raised PAP [4]. As such, extensive vascular remodelling can occur in PH-LHD, resulting in decreased
vascular compliance; right ventricle overload and right ventricular failure can then ensue, eventually leading to
death [4]. It is important to remember that the most common cause of right ventricular dysfunction is still
chronic heart failure [17].
There is no consensus regarding the true prevalence of PH-LHD in heart failure; it is estimated that up to
80% of patients with heart failure develop PH, depending on the methodology used to provide the
TABLE 1 Case study: results from pulmonary function testing and right heart catheterisation
Pulmonary function testing
Forced vital capacity 2.96 L (74% pred)
FEV12.31 L (81% pred)
Total lung capacity 5.99 L (98% pred)
DLCO 20.23 mL·min
−1
(79% pred)
Right heart catheterisation
Mean right atrial pressure 7 mmHg
Right ventricular pressure 70/3 mmHg
Pulmonary arterial pressure 72/34 mmHg
Pulmonary artery wedge pressure 13 mmHg
Cardiac output/cardiac index
#
2.3/1.2 L·min·m
−2
Pulmonary vascular resistance 1251 dyn·s·cm
–5
(15.6 Wood units)
Systemic vascular resistance 3614 dyn·s·cm
–5
(45.2 Wood units)
FEV1: forced expiratory volume in 1 s; DLCO: diffusing capacity of the lung for carbon monoxide.
#
: measured by thermodilution.
TABLE 2 Unmet needs for pulmonary hypertension associated with left heart disease (PH-LHD)
A better understanding of the natural history
Information about the disease prevalence
Better definitions of clinical trial study populations and study end-points
Availability of specific therapies
An understanding of the potential interactions of PH-LHD comorbidities and concomitant medications
Improved patient prognosis
666 DOI: 10.1183/16000617.0059-2015
PULMONARY HYPERTENSION | H.W. FARBER AND S. GIBBS

estimates [18–23]. PH is common in patients with HFpEF and can be severe; ∼50% of patients with heart
failure will have HFpEF [18]. Depending on the method of detection, PH has been shown to occur in
⩾60% of patients with systolic dysfunction [6, 24]. In patients undergoing heart transplantation, PH has
been reported as the cause of perioperative death in 44% of cases. Furthermore, the presence of PH could
be considered a contraindication for carrying out transplantation [25].
In this review, we discuss the knowledge gaps in our understanding of PH-LHD and challenges faced by
clinicians in the diagnosis and management of patients with PH-LHD. This review also provides an
overview of how PH-LHD is currently managed in patients, and reflects on a number of potential
strategies that might improve patient outcomes.
Classification and diagnosis of PH-LHD
Differential diagnosis of PH-LHD from other forms of PH can be highly challenging due to
misunderstandings about the determinants of the disease, heterogeneity in the definitions and
terminology, and variations in the different haemodynamic presentations. PH-LHD belongs to group 2 of
the World Symposium on Pulmonary Hypertension PH clinical classification [26]. This group is defined
as post-capillary PH, characterised by a mean PAP of ⩾25 mmHg and PAWP of >15 mmHg (fig. 1) [26,
27]. In contrast, the haemodynamic definition of pre-capillary PH differs from post-capillary PH in that
PAWP is ⩽15 mmHg [27]. Pulmonary arterial hypertension (PAH) (group 1), PH due to pulmonary
disease (group 3), chronic thromboembolic PH (group 4), and PH with unclear and/or multifactorial
mechanisms (group 5) are all types of pre-capillary PH [27]. Thus, group 2 PH is the only current
classification that is characterised purely by post-capillary PH (some of the entities in group 5 can involve
both post- and pre-capillary mechanisms).
Challenges in diagnosis
A major challenge associated with diagnosing PH-LHD is the variation in terminology. PH is a known
result of left-sided heart failure, regardless of the cause [18]. When differentiating HFpEF from HFrEF it is
important to consider that although patients in both subgroups will present with signs and symptoms of
heart failure, HFrEF is associated with a marked reduction in LVEF, whereas HFpEF is associated with a
normal LVEF [18]. Management strategies and outcomes for patients with HFpEF and HFrEF may differ;
however, differentiating between these two states can be challenging [28].
Differentiating between pre- and post-capillary PH, especially in patients with HFpEF, can also be
diagnostically challenging. Misdiagnosis of PH-LHD as PAH could result in patients receiving inappropriate,
or even detrimental, therapies [4]. In addition, a previously elevated but now normalised PAWP (with
persistence of pulmonary vascular disease) can be seen in patients who have received diuretics and/or
undergone the overnight fast associated with catheterisation. This is often the case in patients with HFpEF [4],
leading to confusion between group 2 and group 1 PH patients at the time of catheterisation.
Variations in how to describe the different haemodynamic components is another potential cause of
confusion in PH-LHD. Previous definitions categorised patients as having “passive”or “reactive”(also
mPAP ≥25 mmHg
PH
DPG <7 mmHg
Isolated post-capillary PH
DPG ≥7 mmHg
Post-capillary PH with a
pre-capillary component
PAWP ≤15 mmHg
Cardiac output normal/reduced
Pre-capillary PH
1) PAH
3) Pulmonary disease, hypoxia
4) CTEPH
5) Multifactorial, unclear
PAWP >15 mmHg
Cardiac output normal/reduced
Post-capillary PH
2) Left heart disease
FIGURE 1 Definition of pulmonary hypertension (PH) associated with left heart disease. mPAP: mean
pulmonary arterial pressure; PAWP: pulmonary artery wedge pressure; PAH: pulmonary arterial
hypertension; CTEPH: chronic thromboembolic pulmonary hypertension; DPG: diastolic pressure gradient.
Information from [4, 26, 27].
DOI: 10.1183/16000617.0059-2015 667
PULMONARY HYPERTENSION | H.W. FARBER AND S. GIBBS

termed “out of proportion”) disease [4, 29]. An updated classification for post-capillary haemodynamics
has recently been proposed [4]. This method takes into account the diastolic pressure gradient (DPG)
(defined as the difference between diastolic PAP and mean PAWP), and defines patients with a low DPG
(<7 mmHg) and PAWP >15 mmHg as having isolated post-capillary PH, but patients with DPG ⩾7 mmHg
and PAWP >15 mmHg as having post-capillary PH with a pre-capillary component (fig. 1) [4].
What is the advantage of this new definition?
Defining PH-LHD based on DPG has several advantages in classifying patients, including the fact that
DPG is low in healthy individuals and is relatively simple to calculate. Relying on measurement of the
DPG to distinguish between post-capillary PH with a pre-capillary component enables assessment of a
patient’s status while avoiding assumptions about the haemodynamic components of vasoconstriction and
remodelling [23]. An association between elevated DPG and vascular remodelling, which is associated with
significant pulmonary vascular disease and increased risk of mortality, has been demonstrated by a single
study [30]. However, the prognostic benefit of this measurement might be limited, as factors other than
vascular remodelling can lead to increases in DPG [31]. In a large study of patients with heart failure
undergoing heart transplantation, DPG did not predict post-transplant survival [31]. In the 2015
guidelines for the diagnosis and treatment of PH [27], the joint task force of the European Society of
Cardiology (ESC) and the European Respiratory Society (ERS) recommends that a combination of
pulmonary vascular resistance (PVR) and DPG should be used to define the different types of PH-LHD:
isolated post-capillary pulmonary hypertension (DPG <7 mmHg and/or PVR ⩽3 Wood units) and
combined post-capillary and pre-capillary pulmonary hypertension (DPG ⩾7 mmHg and/or PVR
>3 Wood units). Furthermore, these guidelines state that patients with PH-LHD who have a high DPG
and/or PVR should be referred to an expert PH centre for a complete diagnostic work-up and decisions
about treatment [27].
Diagnostic methods
Several invasive and noninvasive methods can be used for diagnosis of suspected PH-LHD [2]. An
understanding of patient comorbidities and disease risk factors can greatly assist with the differential
diagnosis from other conditions and types of PH. Medical history review can help determine the clinical
course and evaluate risk factors such as orthopnoea and paroxysmal nocturnal dyspnoea [2]. Physical
examination can detect pulmonary oedema and pleural effusions [2], as well as signs of cardiac
enlargement, left-sided S3 or S4 and murmurs consistent with valvular disease [6]. If PH is suspected,
echocardiography can evaluate the patient’s ventricular and valve function [6]. Laboratory tests can rule
out anaemia and renal, thyroid or hepatic dysfunction [6]. The level of BNP and N-terminal pro-brain
natriuretic peptide (NT-proBNP) can also be measured [6]; in patients with acute HFpEF a high level of
NT-proBNP is a risk factor for poor short-term prognosis [32].
Cardiac catheterisation can be used to distinguish pre- and post-capillary PH [23, 33, 34]. As well as
assessing pulmonary haemodynamics, catheterisation can be used to identify coronary artery disease and
valvular disease and to measure left-sided filling pressure, if necessary by direct measurement of left
ventricular pressure [4, 6]. One of the pitfalls of relying on RHC for differentiating PAH from PH-LHD is
that most patients will be in a fasted and diuresed state, which can lead to underestimation of left heart
filling pressure [22]. Administration of ∼500 mL saline to patients undergoing RHC has been shown to
increase PAWP, which could help differentiate patients with PAH from those with occult left ventricular
dysfunction [35]. However, as yet, this technique has not been validated, although it has recently been
recommended [36].
Vasoreactivity testing can be used to assess PH reversibility in cardiac transplant candidates [6]. This can
be carried out at the same time as RHC, and involves the administration of parenteral nitroprusside,
nitroglycerin or inhaled nitric oxide, with close titration, to achieve a positive vasodilator response
(reduction in PVR to <2.5 Wood units) [37]. However, vasoreactivity testing in nontransplant candidates
with PH-LHD has not been investigated and is currently not recommended, as there is currently no
internationally accepted protocol for this procedure [4, 33].
Prognosis
PH-LHD is associated with a poor prognosis, and high risk of morbidity and mortality [3, 29, 38–40]. The
12-month mortality rates for PH-LHD have been estimated to be as high as 32%, with predictors of
mortality including older age, male sex, right ventricular dysfunction, renal disease and lower functional
class [41]. Among patients with advanced heart failure, reduced right ventricular ejection fraction (RVEF)
(using a value of <35% as a surrogate for right ventricular systolic dysfunction) is associated with a high
risk of death or the need for urgent transplantation, whereas patients with preserved RVEF have a
prognosis that is very similar to patients with normal PAP [39]. Furthermore, in a large cohort of patients
668 DOI: 10.1183/16000617.0059-2015
PULMONARY HYPERTENSION | H.W. FARBER AND S. GIBBS

with chronic HFrEF (LVEF ⩽40%), those with pre-capillary PH, as determined by PVR ⩾3 Wood units,
mean PAP ⩾25 mmHg and PAWP ⩾15 mmHg, were found to have a greater risk of death than patients
with PH-LHD (PVR <3 Wood units, mean PAP ⩾25 mmHg and PAWP ⩾15 mmHg) (hazard ratio 1.55,
95% CI 1.11–2.20; p<0.001), suggesting that PH-LHD in HFrEF carries a greater risk of death than when
other types of PH are present [42]. Among patients with PH-LHD who have acute decompensated heart
failure, 6-month survival rates are lower in patients with post-capillary PH with a pre-capillary component
than those with isolated post-capillary PH (48.3% versus 21.8% mortality, respectively) [38].
Prognosis in patients with heart failure can be determined by measuring RVEF [43–46]. In moderate
congestive heart failure, RVEF has been shown to be an independent predictor of survival, with 1-year
survival rates for RVEF <25%, ⩾25% to <35% and ⩾35% of 80%, 90% and 95%, respectively [43].
Moreover, increased PAP (mean PAP >20 mmHg) coupled with low RVEF (<35%) is associated with
lower patient survival than normal PAP plus preserved/low RVEF or high PAP/preserved RVEF [39]. In
patients with PH-LHD due to HFpEF, right ventricular systolic dysfunction is associated with higher
mortality than patients with pulmonary artery systolic pressure >47 mmHg, even after adjustment for age
and pulmonary artery systolic pressure [29].
Management of PH-LHD
Although a treatment algorithm has been developed for group 1 PH (PAH) in the ESC/ERS guidelines, it
does not apply to patients with PH-LHD [27]. Prior to the assessment of patients for PH-LHD, the ESC/
ERS guidelines recommend that treatment of underlying conditions should be optimised and any other
causes of PH should be ruled out [27]. General supportive therapies for PAH include supplemental
oxygen, diuretics, oral anticoagulants and digoxin, and specific drug therapy includes calcium channel
blockers, prostanoids, endothelin receptor agonists, soluble guanylyl cyclase stimulators and
phosphodiesterase type-5 inhibitors [27]. There is currently no similar approved specific therapy for
PH-LHD; furthermore, clinical trial data for these patients are lacking [2–4]. Managing the underlying
cause of PH is an important first step in treating PH-LHD [4]. For example, in the case of left heart
disease due to valve disease, surgical repair or replacement of mitral or aortic valves can improve patient
outcomes [2, 3, 47]. Reducing left heart filling pressures can also be achieved using established treatments
for heart failure [2]. Diuretics are the mainstay of medical treatment for fluid control and relief of
congestion, whereas angiotensin-converting enzyme inhibitors and β-blockers are indicated to improve
outcomes in heart failure associated with HFrEF [23].
Several clinical trials have investigated the use of PAH therapies (e.g. prostanoids, endothelin receptor
antagonists and phosphodiesterase type 5 inhibitors) in patients with suspected PH-LHD [48–60];
however, there is no clinical evidence to support the use of PAH therapies in the clinical management of
patients with PH-LHD [27]. The results of studies that have investigated PAH-specific therapies in
PH-LHD (many of which are summarised in table 3) have generally been negative and some could even
be regarded as harmful. Furthermore, some of the trials that have been carried out have been prospective,
randomised, placebo-controlled studies, while others have been retrospective, open-label studies. Studies of
sildenafil in PH-LHD have been inconsistent; while some have seen improvements in exercise capacity,
haemodynamics and quality of life in patients with systolic and diastolic heart failure [53, 55], others have
found no benefit [59, 62].
There are several limitations to clinical trials for pharmacological agents in PH-LHD. Patients are seldom
stratified by the underlying cause of PH, and haemodynamic evaluation is not carried out systematically
[23]. It has been recommended that patients with post-capillary PH with a pre-capillary component
should represent the target population for clinical trials [4]; however, there are very few current studies
in this patient population. In addition, it has been recommended that trial end-points should assess
safety first, and efficacy can then be based on measurable clinical outcomes [4]. One of the few trials to
address the limitations of previous studies is MELODY-1 [57], an ongoing trial that is evaluating the
safety and tolerability of macitentan, an endothelin receptor antagonist, in patients with post-capillary
PH with a pre-capillary component. The primary (safety) outcome will be the proportion of patients
experiencing significant fluid retention or a worsening of WHO functional class from baseline. The secondary
(efficacy) outcomes will be the change from baseline in cardiopulmonary haemodynamic parameters and
echocardiographic parameters of systolic and diastolic function after 12 weeks of treatment [57].
In conjunction with specific pharmacological strategies for managing PH-LHD, treating patients’
underlying comorbidities is beneficial, e.g. the aggressive control of cardiovascular risk factors [23].
Obesity frequently coexists with PH, and in severe obesity an excess volume load is placed on the left
ventricle, which can eventually lead to heart failure [63]. Haemodynamic improvement has been observed
with bariatric surgery for PH [64], and this could be explored further as a potential therapy for PH-LHD
in patients who have concomitant obesity.
DOI: 10.1183/16000617.0059-2015 669
PULMONARY HYPERTENSION | H.W. FARBER AND S. GIBBS

TABLE 3 Completed and ongoing trials of pulmonary arterial hypertension (PAH)-specific therapies in patients with suspected pulmonary hypertension associated
with left heart disease (PH-LHD)
Drug, year [ref.] Study acronym/
identifier
#
Subjects n Patient characteristics Design Primary end-point Key results
Epoprostenol
1996 [51]
FIRST 471 Severe heart failure,
WHO FC IIIb–IV
1:1 randomisation
Event-driven
Mean dose 4 ng·kg
−1
·min
−1
Survival Early termination (trend to decreased survival
in treated group)
Bosentan 2002
[50]
ENABLE 1613 Severe heart failure,
WHO FC IIIb–IV
1:1 randomisation
18-month duration
125 mg twice daily
Mortality and hospital stays No effect
Early risk of worsening heart failure
necessitating hospitalisation due to fluid
retention with treatment
Bosentan 2005
[49]
REACH-1 370 Severe heart failure,
WHO FC IIIb–IV
1:1:1 randomisation
26-week duration
500 mg twice daily via rapid or slow
infusion
Change in clinical status No effect
Early termination (safety concerns)
Darusentan 2002
[56]
HEAT 179 Chronic heart failure,
WHO FC III
1:1:1:1 randomisation
3-week duration
Doses of 30, 100 and 300 mg daily
Haemodynamics (change in
PAWP/cardiac index)
Increased cardiac index
No change in PAWP
Darusentan 2004
[52]
EARTH 642 Chronic heart failure,
WHO FC II–IV
1:1:1:1:1 randomisation
6-month duration
Doses of 10, 25, 50, 100 and 300 mg
daily
LVESV changes by MRI and
clinical events
No effect
Sildenafil 2007
[53]
NCT00309816 13 Heart failure, WHO FC
III
Nonrandomised, open-label
50 mg single dose
Exercise capacity and
haemodynamics after 60 min
Significant reduction in resting PAP, SVR and
PVR, and increased resting and exercise
cardiac index (p<0.05)
Sildenafil 2007
[55]
NCT00309790 34 Heart failure, WHO FC
II–IV
1:1 randomisation
12-week duration
25–75 mg three times daily
Haemodynamics (change in
peak V′O
2
)
Significantly greater increase in V′O
2
(p=0.02)
Sildenafil 2007
[54]
NCT00407446 46 Chronic heart failure,
WHO FC II–III
1:1 randomisation
6-month duration
50 mg twice daily
Exercise performance, ventilation
efficiency, symptoms
Significant increases at 3 and 6 months
(p<0.01)
Sildenafil 2013
[59]
RELAX 216 Heart failure, WHO FC
II–IV
1:1 randomisation
24-week duration
20 mg three times daily for
12 weeks, then 60 mg three times
daily for 12 weeks
Haemodynamics (change in
peak V′O
2
)
No effect
Riociguat 2013
[48]
LEPHT 201 Heart failure, WHO FC
II–IV
2:1:1:2 randomisation
16-week duration
0.5 mg, 1 mg or 2 mg three times
daily
Change in mPAP No effect
Riociguat 2014
[61]
DILATE-1 39 HFpEF 1:1:1:1 randomisation
0.5 mg, 1 mg or 2 mg single dose
Largest mPAP change from
baseline ⩽6 h after drug
administration
No effect
Tadalafil 2015
[58]
PITCH-HF 23 Heart failure,
NYHA FC II–IV
2:1 randomisation
⩽3-year duration
40 mg daily
Cardiovascular mortality or
hospitalisation due to heart
failure
Trial terminated early
Macitentan 2015
[57]
MELODY-1 Estimated
enrolment=60
CpcPH due to left
ventricular
dysfunction
1:1 randomisation
12-week duration
10 mg once daily
Safety and tolerability Estimated completion quarter 4 2015
WHO FC: World Health Organization functional class; PAWP: pulmonary artery wedge pressure; LVESV: left ventricular end-systolic volume; MRI: magnetic resonance imaging; PAP:
pulmonary arterial pressure; SVR: systolic vascular resistance; PVR: pulmonary vascular resistance; V′O
2
: oxygen uptake; mPAP: mean pulmonary arterial pressure; HFpEF: heart failure
with preserved ejection fraction; NYHA FC: New York Heart Association functional class; CpcPH: post-capillary pulmonary hypertension with a pre-capillary component.
#
: identifier
numbers listed are for the https://clinicaltrials.gov/ registry.
670 DOI: 10.1183/16000617.0059-2015
PULMONARY HYPERTENSION | H.W. FARBER AND S. GIBBS

Case study part 2: follow-up
Based on the patient’s initial assessment, would you have diagnosed him with PH-LHD?
A volume challenge with 500 mL of normal saline during RHC did not result in an increase in PAWP.
Despite his extensive cardiac risk factors and history, it was felt that the PH in this patient was
predominantly group 1 PAH. Because of the severity, intravenous epoprostenol was initiated with slow
titration, to reach a final initial dose of 6 ng·kg
−1
·min
−1
.
Surveillance RHC 1 year later (at an epoprostenol dose of 37 ng·kg
−1
·min
−1
) showed a right atrial pressure
of 1 mmHg, right ventricular pressure of 71/7 mmHg, systolic/diastolic/mean PAP of 75/36/48 mmHg,
PAWP of 12 mmHg, cardiac output/cardiac index of 3.6/2.0 L·min
−1
, PVR of 799 dyn·s·cm
–5
(9.9 Wood
units) and systemic vascular resistance of 2069 dyn·s·cm
–5
(25.9 Wood units). PVR was decreased by 36%,
the PVR/systemic vascular resistance ratio had increased from 0.35 to 0.39, cardiac output had increased
by 67% and the patient was WHO functional class II.
Interestingly, 4 years after his diagnosis, the patient’s 33-year-old daughter was diagnosed with PAH.
Genetic testing in the patient demonstrated a bone morphogenetic protein receptor 2 (BMPR2) mutation.
This same mutation was present in the daughter.
Although many of the patient’s clinical signs and risk factors were suggestive of PH-LHD, the presence of
the BMPR2 mutation also demonstrated the likelihood of heritable PAH. This case, although somewhat
atypical, demonstrates that in real life there can be more than one potential cause of PH and that such a
scenario of multiple potential aetiologies of PH is not uncommon. In addition, it is important to
remember that there is no standard presentation of PH-LHD, and that even cases that appear superficially
to be PH-LHD may not be such. Thus, it is important to consider all aspects of the patient’s condition.
Diagnosing PH-LHD is certainly challenging, with considerable potential for misdiagnosis.
Conclusion
There are multiple unmet needs for patients with PH-LHD. Despite PH being a frequent complication of
left heart disease, data on the true incidence are sparse. The differing methodology of epidemiological
studies make estimation of incidence challenging, and this is compounded by variations in haemodynamic
definitions and terminology, wide variations in disease presentations, and a lack of knowledge surrounding
the aetiology and differing phenotypes of PH-LHD. The case presented here highlights the complexity of
differentiating PH-LHD from other types of PH, and the multiple factors that should be considered before
confirming the diagnosis. Although there is no single pharmacotherapy that is specific for PH-LHD, there
are promising signs that clinical trial designs will be adapted in the future to include patients with the
most appropriate risk–benefit profile, and to select more relevant clinical end-points.
Acknowledgements
The authors would like to thank Kate Bradford from PAREXEL (Uxbridge, UK) for medical writing assistance, funded
by Actelion Pharmaceuticals Ltd (Allschwil, Switzerland).
References
1Oudiz RJ. Pulmonary hypertension associated with left-sided heart disease. Clin Chest Med 2007; 28: 233–241.
2Schmeisser A, Schroetter H, Braun-Dulleaus RC. Management of pulmonary hypertension in left heart disease.
Ther Adv Cardiovasc Dis 2013; 7: 131–151.
3Guazzi M, Borlaug BA. Pulmonary hypertension due to left heart disease. Circulation 2012; 126: 975–990.
4Vachiery JL, Adir Y, Barbera JA, et al. Pulmonary hypertension due to left heart diseases. J Am Coll Cardiol 2013;
62: Suppl., D100–D108.
5Fang JC, DeMarco T, Givertz MM, et al. World Health Organization Pulmonary Hypertension group 2:
pulmonary hypertension due to left heart disease in the adult –a summary statement from the Pulmonary
Hypertension Council of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant
2012; 31: 913–933.
6Barnett CF, De Marco T. Pulmonary hypertension associated with left-sided heart disease. Heart Fail Clin 2012; 8:
447–459.
7Mathier MA. Pulmonary hypertension owing to left heart disease. Clin Chest Med 2013; 34: 683–694.
8Adir Y, Amir O. Pulmonary hypertension associated with left heart disease. Semin Respir Crit Care Med 2013; 34:
665–680.
9Georgiopoulou VV, Kalogeropoulos AP, Borlaug BA, et al. Left ventricular dysfunction with pulmonary
hypertension: Part 1: epidemiology, pathophysiology, and definitions. Circ Heart Fail 2013; 6: 344–354.
10 Guazzi M, Galiè N. Pulmonary hypertension in left heart disease. Eur Respir Rev 2012; 21: 338–346.
11 Haddad F, Kudelko K, Mercier O, et al. Pulmonary hypertension associated with left heart disease: characteristics,
emerging concepts, and treatment strategies. Prog Cardiovasc Dis 2011; 54: 154–167.
12 Corte TJ, McDonagh TA, Wort SJ. Pulmonary hypertension in left heart disease: a review. Int J Cardiol 2012; 156:
253–258.
13 Guazzi M, Arena R. Pulmonary hypertension with left-sided heart disease. Nat Rev Cardiol 2010; 7: 648–659.
14 Gehlbach BK, Geppert E. The pulmonary manifestations of left heart failure. Chest 2004; 125: 669–682.
DOI: 10.1183/16000617.0059-2015 671
PULMONARY HYPERTENSION | H.W. FARBER AND S. GIBBS

15 Moraes DL, Colucci WS, Givertz MM. Secondary pulmonary hypertension in chronic heart failure: the role of the
endothelium in pathophysiology and management. Circulation 2000; 102: 1718–1723.
16 Casserly B, Klinger JR. Brain natriuretic peptide in pulmonary arterial hypertension: biomarker and potential
therapeutic agent. Drug Des Devel Ther 2009; 3: 269–287.
17 Haddad F, Doyle R, Murphy DJ, et al. Right ventricular function in cardiovascular disease, part II:
pathophysiology, clinical importance, and management of right ventricular failure. Circulation 2008; 117:
1717–1731.
18 Lam CS, Roger VL, Rodeheffer RJ, et al. Pulmonary hypertension in heart failure with preserved ejection fraction:
a community-based study. J Am Coll Cardiol 2009; 53: 1119–1126.
19 Bursi F, McNallan SM, Redfield MM, et al. Pulmonary pressures and death in heart failure: a community study.
J Am Coll Cardiol 2012; 59: 222–231.
20 Damy T, Goode KM, Kallvikbacka-Bennett A, et al. Determinants and prognostic value of pulmonary arterial
pressure in patients with chronic heart failure. Eur Heart J 2010; 31: 2280–2290.
21 Leung CC, Moondra V, Catherwood E, et al. Prevalence and risk factors of pulmonary hypertension in patients
with elevated pulmonary venous pressure and preserved ejection fraction. Am J Cardiol 2010; 106: 284–286.
22 Robbins IM, Newman JH, Johnson RF, et al. Association of the metabolic syndrome with pulmonary venous
hypertension. Chest 2009; 136: 31–36.
23 Cheli M, Vachiery JL. Controversies in pulmonary hypertension due to left heart disease. F1000Prime Rep 2015; 7: 07.
24 Kiefer TL, Bashore TM. Pulmonary hypertension related to left-sided cardiac pathology. Pulm Med 2011; 2011:
381787.
25 Costard-Jackle A, Fowler MB. Influence of preoperative pulmonary artery pressure on mortality after heart
transplantation: testing of potential reversibility of pulmonary hypertension with nitroprusside is useful in defining
a high risk group. J Am Coll Cardiol 1992; 19: 48–54.
26 Simonneau G, Gatzoulis MA, Adatia I, et al. Updated clinical classification of pulmonary hypertension. J Am Coll
Cardiol 2013; 62: Suppl., D34–D41.
27 Galiè N, Humbert M, Vachiery JL, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary
hypertension. Eur Respir J 2015; 46: 903–975.
28 Watson CJ, Gupta SK, O’Connell E, et al. MicroRNA signatures differentiate preserved from reduced ejection
fraction heart failure. Eur J Heart Fail 2015; 17: 405–415.
29 Guazzi M. Pulmonary hypertension in heart failure preserved ejection fraction: prevalence, pathophysiology, and
clinical perspectives. Circ Heart Fail 2014; 7: 367–377.
30 Gerges C, Gerges M, Lang MB, et al. Diastolic pulmonary vascular pressure gradient: a predictor of prognosis in
“out-of-proportion”pulmonary hypertension. Chest 2013; 143: 758–766.
31 Tedford RJ, Beaty CA, Mathai SC, et al. Prognostic value of the pre-transplant diastolic pulmonary artery
pressure-to-pulmonary capillary wedge pressure gradient in cardiac transplant recipients with pulmonary
hypertension. J Heart Lung Transplant 2014; 33: 289–297.
32 Wang X, Liu Y, Yuan Y, et al. Short-term prognostic factors in the patients after acute heart failure. Int J Clin Exp
Med 2015; 8: 1515–1520.
33 Hoeper MM, Barbera JA, Channick RN, et al. Diagnosis, assessment, and treatment of non-pulmonary arterial
hypertension pulmonary hypertension. J Am Coll Cardiol 2009; 54: Suppl., S85–S96.
34 Rosenkranz S, Preston IR. Right heart catheterization: best practice and pitfalls in pulmonary hypertension. Eur
Respir Rev 2015; 24: 642–652.
35 Robbins IM, Hemnes AR, Pugh ME, et al. High prevalence of occult pulmonary venous hypertension revealed by
fluid challenge in pulmonary hypertension. Circ Heart Fail 2014; 7: 116–122.
36 Hoeper MM, Bogaard HJ, Condliffe R, et al. Definitions and diagnosis of pulmonary hypertension. J Am Coll
Cardiol 2013; 62: Suppl., D42–D50.
37 Shah RV, Semigran MJ. Pulmonary hypertension secondary to left ventricular systolic dysfunction: contemporary
diagnosis and management. Curr Heart Fail Rep 2008; 5: 226–232.
38 Aronson D, Eitan A, Dragu R, et al. Relationship between reactive pulmonary hypertension and mortality in
patients with acute decompensated heart failure. Circ Heart Fail 2011; 4: 644–650.
39 Ghio S, Gavazzi A, Campana C, et al. Independent and additive prognostic value of right ventricular systolic
function and pulmonary artery pressure in patients with chronic heart failure. J Am Coll Cardiol 2001; 37:
183–188.
40 Tampakakis E, Leary PJ, Selby VN, et al. The diastolic pulmonary gradient does not predict survival in patients
with pulmonary hypertension due to left heart disease. JACC Heart Fail 2015; 3: 9–16.
41 Dzudie A, Kengne AP, Thienemann F, et al. Predictors of hospitalisations for heart failure and mortality in
patients with pulmonary hypertension associated with left heart disease: a systematic review. BMJ Open 2014; 4:
e004843.
42 Miller WL, Grill DE, Borlaug BA. Clinical features, hemodynamics, and outcomes of pulmonary hypertension due
to chronic heart failure with reduced ejection fraction: pulmonary hypertension and heart failure. JACC Heart Fail
2013; 1: 290–299.
43 de Groote P, Millaire A, Foucher-Hossein C, et al. Right ventricular ejection fraction is an independent predictor
of survival in patients with moderate heart failure. J Am Coll Cardiol 1998; 32: 948–954.
44 Di Salvo TG, Mathier M, Semigran MJ, et al. Preserved right ventricular ejection fraction predicts exercise capacity
and survival in advanced heart failure. J Am Coll Cardiol 1995; 25: 1143–1153.
45 Polak JF, Holman BL, Wynne J, et al. Right ventricular ejection fraction: an indicator of increased mortality in
patients with congestive heart failure associated with coronary artery disease. J Am Coll Cardiol 1983; 2: 217–224.
46 Baker BJ, Wilen MM, Boyd CM, et al. Relation of right ventricular ejection fraction to exercise capacity in chronic
left ventricular failure. Am J Cardiol 1984; 54: 596–599.
47 McLaughlin VV, Archer SL, Badesch DB, et al. ACCF/AHA 2009 expert consensus document on pulmonary
hypertension: a report of the American College of Cardiology Foundation Task Force on Expert Consensus
Documents and the American Heart Association developed in collaboration with the American College of Chest
Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association. J Am Coll Cardiol
2009; 53: 1573–1619.
672 DOI: 10.1183/16000617.0059-2015
PULMONARY HYPERTENSION | H.W. FARBER AND S. GIBBS

48 Bonderman D, Ghio S, Felix SB, et al. Riociguat for patients with pulmonary hypertension caused by systolic left
ventricular dysfunction: a phase IIb double-blind, randomized, placebo-controlled, dose-ranging hemodynamic
study. Circulation 2013; 128: 502–511.
49 Packer M, McMurray J, Massie BM, et al. Clinical effects of endothelin receptor antagonism with bosentan in
patients with severe chronic heart failure: results of a pilot study. J Card Fail 2005; 11: 12–20.
50 Kalra PR, Moon JC, Coats AJ. Do results of the ENABLE (Endothelin Antagonist Bosentan for Lowering Cardiac
Events in Heart Failure) study spell the end for non-selective endothelin antagonism in heart failure? Int J Cardiol
2002; 85: 195–197.
51 Califf RM, Adams KF, McKenna WJ, et al. A randomized controlled trial of epoprostenol therapy for severe
congestive heart failure: The Flolan International Randomized Survival Trial (FIRST). Am Heart J 1997; 134:
44–54.
52 Anand I, McMurray J, Cohn JN, et al. Long-term effects of darusentan on left-ventricular remodelling and clinical
outcomes in the EndothelinA Receptor Antagonist Trial in Heart Failure (EARTH): randomised, double-blind,
placebo-controlled trial. Lancet 2004; 364: 347–354.
53 Lewis GD, Lachmann J, Camuso J, et al. Sildenafil improves exercise hemodynamics and oxygen uptake in
patients with systolic heart failure. Circulation 2007; 115: 59–66.
54 Guazzi M, Samaja M, Arena R, et al. Long-term use of sildenafil in the therapeutic management of heart failure.
J Am Coll Cardiol 2007; 50: 2136–2144.
55 Lewis GD, Shah R, Shahzad K, et al. Sildenafil improves exercise capacity and quality of life in patients with
systolic heart failure and secondary pulmonary hypertension. Circulation 2007; 116: 1555–1562.
56 Lüscher TF, Enseleit F, Pacher R, et al. Hemodynamic and neurohumoral effects of selective endothelin A (ET(A))
receptor blockade in chronic heart failure: the Heart Failure ET(A) Receptor Blockade Trial (HEAT). Circulation
2002; 106: 2666–2672.
57 ClinicalTrials.gov. Safety and tolerability of macitentan in subjects with combined pre- and post-capillary
pulmonary hypertension due to left ventricular dysfunction (MELODY-1). https://clinicaltrials.gov/ct2/show/
NCT02070991 Date last accessed: July 21, 2015. Date last updated: September, 2015.
58 ClinicalTrials.gov. Phosphodiesterase type 5 inhibition with tadalafil changes outcomes in heart failure
(PITCH-HF). https://clinicaltrials.gov/ct2/show/NCT01910389 Date last accessed: June 19, 2015. Date last updated:
April, 2015.
59 Redfield MM, Chen HH, Borlaug BA, et al. Effect of phosphodiesterase-5 inhibition on exercise capacity and
clinical status in heart failure with preserved ejection fraction: a randomized clinical trial. JAMA 2013; 309:
1268–1277.
60 Finch KT, Stratton EA, Farber HW. Ranolazine as treatment of pulmonary hypertension associated with heart
failure with preserved ejection fraction. Circulation 2013; 128: A10662.
61 Bonderman D, Pretsch I, Steringer-Mascherbauer R, et al. Acute hemodynamic effects of riociguat in patients with
pulmonary hypertension associated with diastolic heart failure (DILATE-1): a randomized, double-blind,
placebo-controlled, single-dose study. Chest 2014; 146: 1274–1285.
62 Hoendermis ES, Liu LC, Hummel YM, et al. Effects of sildenafil on invasive haemodynamics and exercise capacity
in heart failure patients with preserved ejection fraction and pulmonary hypertension: a randomized controlled
trial. Eur Heart J 2015; 36: 2565–2573.
63 Friedman SE, Andrus BW. Obesity and pulmonary hypertension: a review of pathophysiologic mechanisms.
J Obes 2012; 2012: 505274.
64 Pugh ME, Newman JH, Williams DB, et al. Hemodynamic improvement of pulmonary arterial hypertension after
bariatric surgery: potential role for metabolic regulation. Diabetes Care 2013; 36: e32–e33.
DOI: 10.1183/16000617.0059-2015 673
PULMONARY HYPERTENSION | H.W. FARBER AND S. GIBBS