+Model

ACVD-991; No. of Pages 12 ARTICLE IN PRESS

Archives of Cardiovascular Disease (2017) xxx, xxxxxx

Available online at

ScienceDirect
www.sciencedirect.com

REVIEW

Pulmonary hypertension due to left heart

disease
Lhypertension pulmonaire lie aux maladies du cur gauche

Emmanuelle Berthelot a,, Minh Tam Bailly a,b,

Safwane El Hatimi a,b, Ingrid Robard a, Hatem Rezgui a,
Amir Bouchachi a, David Montani b,c,d,
Olivier Sitbon b,c,d, Denis Chemla b,e,
Patrick Assayag a,b

a
AP-HP, Service de Cardiologie, Hpital Bictre, Le Kremlin-Bictre, France
b
Univ. Paris-Sud, Facult de Mdecine, Universit Paris-Saclay, Le Kremlin Bictre, France
c
AP-HP, Service de Pneumologie, Centre de Rfrence de lHypertension Pulmonaire Svre,
Hpital Bictre, Le Kremlin Bictre, France
d
INSERM UMR S 999, Hpital Marie Lannelongue, Le Plessis Robinson, France
e
AP-HP, Service de Physiologie, Unit INSERM U 999, Hpital Bictre, Le Kremlin-Bictre,
France

Received 24 January 2017; accepted 24 January 2017

KEYWORDS Summary Pulmonary hypertension due to left heart disease, also known as group 2 pulmonary
Pulmonary hypertension according to the European Society of Cardiology/European Respiratory Society
hypertension; classication, is the most common cause of pulmonary hypertension. In patients with left heart
Left heart disease; disease, the development of pulmonary hypertension favours right heart dysfunction, which
Pathophysiology; has a major impact on disease severity and outcome. Over the past few years, this condition
Management has been considered more frequently. However, epidemiological studies of group 2 pulmonary

Abbreviations: CMR, cardiac magnetic resonance; CO, cardiac output; ERS, European Respiratory Society; ESC, European Society of
Cardiology; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; HRCT, high-resolution
computed tomography; LA, left atrial; LHD, left heart disease; LV, left ventricular; mPAP, mean pulmonary artery pressure; PAP, pulmonary
artery pressure; PAWP, pulmonary artery wedge pressure; PFT, pulmonary functional test; PH, pulmonary hypertension; PH-LHD, pulmonary
hypertension due to left heart disease; PVR, pulmonary vascular resistance; RHC, right heart catheterization; RV, right ventricular; TAPSE,
tricuspid annular plane systolic excursion; WU, Wood units.
Corresponding author at: Service de Cardiologie, CHU de Bictre, 78 rue du Gnral Leclerc, 94275 Le Kremlin-Bictre, France.

E-mail address: Emmanuelle.berthelot@aphp.fr (E. Berthelot).

http://dx.doi.org/10.1016/j.acvd.2017.01.010
1875-2136/ 2017 Published by Elsevier Masson SAS.

Please cite this article in press as: Berthelot E, et al. Pulmonary hypertension due to left heart disease. Arch Cardiovasc
Dis (2017), http://dx.doi.org/10.1016/j.acvd.2017.01.010
+Model
ACVD-991; No. of Pages 12 ARTICLE IN PRESS
2 E. Berthelot et al.

hypertension are less exhaustive than studies of other causes of pulmonary hypertension. In
group 2 patients, pulmonary hypertension may be caused by an isolated increase in left-sided
lling pressures or by a combination of this condition with increased pulmonary vascular resis-
tance, with an abnormally high pressure gradient between arteries and pulmonary veins. A
better understanding of the conditions underlying pulmonary hypertension is of key importance
to establish a comprehensive diagnosis, leading to an adapted treatment to reduce heart failure
morbidity and mortality. In this review, epidemiology, mechanisms and diagnostic approaches
are reviewed; then, treatment options and future approaches are considered.
2017 Published by Elsevier Masson SAS.

MOTS CLS Rsum Lhypertension pulmonaire lie aux maladies du cur gauche, aussi classe comme
Hypertension hypertension pulmonaire du groupe 2 de la classication de lESC/ERS 2015, est la cause la plus
pulmonaire ; frquente dhypertension pulmonaire. Chez les patients avec une maladie cardiaque gauche
Cardiopathie avance, le dveloppement dune hypertension pulmonaire favorise la dysfonction cardiaque
gauche ; droite qui marque un tournant pjoratif dans lvolution de la maladie. Cette hypertension pul-
Physiopathologie ; monaire est principalement cause par une augmentation des pressions de remplissage gauches,
Prise en charge lie une augmentation de la volmie ou dautres mcanismes. Dans certains cas volus, il
existe en plus une augmentation des rsistances vasculaires pulmonaires, le gradient de pres-
sion entre les artres et les veines pulmonaires devenant anormalement lev. En cardiologie,
la dcouverte dune hypertension pulmonaire doit conduire un bilan tiologique bien codi.
Une meilleure comprhension des conditions sous-jacentes est dune importance capitale pour
tablir un diagnostic complet, conduisant un traitement adapt pour rduire lvolution vers
linsufsance cardiaque et la mortalit. Dans cette revue, lpidmiologie, les mcanismes et
approches diagnostiques sont exposs ; ensuite, les options thrapeutiques et les perspectives
sont discutes.
2017 Publie par Elsevier Masson SAS.

Denitions and classication
The recent European Society of Cardiology/European Respi-
ratory Society (ESC/ERS) guidelines have dened pulmonary
hypertension (PH) as the elevation of mean pulmonary artery
pressure (mPAP) 25 mmHg at rest, as assessed by right
heart catheterization (RHC) [1]. Normal pulmonary artery
wedge pressure (PAWP) is 15 mmHg. Postcapillary PH is thus
dened by mPAP 25 mmHg at rest and PAWP > 15 mmHg.
On the other hand, precapillary PH is dened by
mPAP 25 mmHg, PAWP 15 mmHg [1,2]. In some condi-
tions, chronic elevation of the left-sided lling pressure
may cause excess vasoconstriction, with or without vascular
remodelling, thus leading to elevated pulmonary vascular
resistance (PVR) > 3 WU. This condition has been described
as reactive, out-of-proportion or mixed PH, lead- criminate precapillary PH from group 2 PH. Differentiating
ing to a disproportionate increase in pulmonary artery
pressure (PAP) [3,4]. For a long time, a transpulmonary
pressure gradient > 12 mmHg (i.e. the difference between
mPAP and PAWP) has been used to describe this feature, but
this gradient may be inuenced by volume load and cardiac
function, and does not prognosticate outcome in PH [5]. The
recent ESC/ERS guidelines favour measuring the diastolic
pressure gradient (i.e. the difference between diastolic PAP
and PAWP), which may be less dependent upon stroke vol-
ume and loading conditions [1,6]. In healthy subjects, this
gradient is <5 mmHg [7]. Postcapillary PH is thus further clas-
sied as isolated postcapillary PH if the diastolic pulmonary
gradient is <7 mmHg and/or the PVR is 3 WU, or as com-
bined post- and precapillary PH, if the diastolic pulmonary
gradient is 7 mmHg and/or the PVR is >3 WU [1,4] (Table 1).
The updated classication [8] categorizes four types of
PH associated with left heart disease (LHD), according to
their origin: PH due to heart failure with reduced ejection
fraction (HFrEF); PH due to heart failure with preserved
ejection fraction (HFpEF); PH due to left-sided valvular
heart disease; and PH due to congenital/acquired left heart
inow/outow tract obstruction and congenital cardiomy-
opathies (Fig. 1).
In the setting of mPAP 25 mmHg at rest, measuring
the precise value of PAWP is of major importance to dis-
group 1 from group 2 patients may be difcult, and an
exercise or a saline loading test may be used to unmask
venous PH. A recent study has shown that exercise testing is
more sensitive than saline loading to detect haemodynamic
changes indicative of HFpEF [9]. Combining mPAP > 30 mmHg
and PVR > 3 mmHg*min per L is superior to mPAP > 30 mmHg
alone for dening a pathological haemodynamic response
of the pulmonary circulation during exercise [10]. How-
ever, in exercising patients, there are no reliable data that
dene which level of exercise-induced changes in mPAP has

Please cite this article in press as: Berthelot E, et al. Pulmonary hypertension due to left heart disease. Arch Cardiovasc
Dis (2017), http://dx.doi.org/10.1016/j.acvd.2017.01.010
+Model
ACVD-991; No. of Pages 12 ARTICLE IN PRESS
Pulmonary hypertension due to left heart disease 3

Table 1 Nomenclature and haemodynamic classication of pulmonary hypertension.

PH group from Currently Old used Haemodynamic classication
classication recommended terminology
terminology mPAP PAWP DPG PVR
(mmHg) (mmHg) (mmHg) (WU)
Group 1, 3, 4, Precapillary PH 25 15
5
Group 2 Isolated Pulmonary 25 >15 <7 3
postcapillary PH venous
(Ipc-PH) hypertension
(PVH); passive PH
Combined pre Mixed PH; 25 >15 7 >3
and out-of-proportion
post-capillary PH PH
(Cpc-PH)
DPG: diastolic pulmonary vascular pressure gradient; mPAP: mean pulmonary artery pressure; PAWP: pulmonary artery wedge pressure;
PH: pulmonary hypertension; PVR: pulmonary vascular resistance; TPG: transpulmonary gradient; WU: Wood units.

prognostic implications; thus, a disease entity PH on exer-
cise currently cannot be dened and should not be used
[2,7].
Epidemiology and prognosis
Knowing the prevalence of PH in the population of patients
with heart failure is not easy [11,12]. The progression of
heart failure is frequently associated with PH and right ven-
tricular (RV) dysfunction, which is associated with a poor
prognosis [911].
The prevalence of PH and RV failure in LHD varies depend-
ing on the population studied, the method used to diagnose
PH (echocardiography or RHC) and the haemodynamic crite-
ria used to dene PH. Moreover, day-to-day variation in PAP
may be observed in group 2 patients, depending on volume
load.
In ambulatory outpatients with HFrEF, PH was found in
73% of patients referred for RHC [13]. In patients with acute
decompensated heart failure, PH was diagnosed in 2575%
of patients [14,15]. PH seems to occur even more frequently
in HFpEF. In three studies of patients with HFpEF, PH was
present in 36%, 52% and 83% [1618]. While PH was most
commonly described with mitral stenosis in the past, cardio-
logists are now increasingly facing the discovery of PH, given
the increasing prevalence of HFpEF related to population
ageing and co-morbidities. In parallel, cardiologists aware-
ness of the measurement of pulmonary pressure has grown,
and screening campaigns in pharmacovigilance of medicinal
products (e.g. benuorex or some cancer drugs) have been
developed.
Regarding the haemodynamic characteristics of PH in
HFrEF, a study of 320 patients found that PVR was normal
(<1.5 WU) in 28%, mildly elevated (1.52.49 WU) in 36%,
moderately elevated (2.53.49 WU) in 17% and severely ele-
vated (>3.5 WU) in 19% [19]. When comparing HFrEF and
HFpEF, baseline stroke volume and cardiac output (CO) are
higher in HFpEF than in HFrEF, while mPAP, PAWP and PVR
are similar [2022].

Figure 1. Causes of pulmonary hypertension due to left heart disease (PH-LHD). The fourth common etiology of PH is PH due to congeni-
tal/acquired left heart inow/outow tract obstruction and congenital cardiomyopathies (not shown). HFpEF: heart failure with preserved
ejection fraction; HFrEF: heart failure with reduced ejection fraction.

Please cite this article in press as: Berthelot E, et al. Pulmonary hypertension due to left heart disease. Arch Cardiovasc
Dis (2017), http://dx.doi.org/10.1016/j.acvd.2017.01.010
+Model
ACVD-991; No. of Pages 12 ARTICLE IN PRESS
4 E. Berthelot et al.
Figure 2. Pulmonary hypertension (PH), right ventricular (RV)
function and clinical outcome in acute decompensated heart fail-
ure.
Adapted from [14].
Prognostic signicance of PH
Whereas the prevalence of PH varies greatly, depending
on the study, all cohorts of patients show that PH is asso-
ciated with increased mortality [13,15,23] (Fig. 2). In a
recent retrospective analysis of 21,727 veterans undergo-
ing RHC, a continuum of risk according to mPAP level was
documented, and the 2124 mmHg mPAP range was asso-
ciated with increased mortality and hospitalization [24]. In
both HFrEF and HFpEF, PH seems to be a reliable prognos-
tic marker [1618]. However, it is difcult to argue that
PH is an independent marker of poor prognosis, because
mPAP integrates several components (e.g. blood volume sta-
tus, left ventricular [LV] compliance, mitral valve function),
and is also inuenced by remodelling and loss of compli-
ance of the left atrium, pulmonary vascular remodelling and
renal function all factors known to affect prognosis [25].
Finally, PH prognosis is more linked to RV function than to
the level of PAP [26]. In the late stages of heart failure,
mPAP may decrease because of RV dysfunction, and carries
an adverse short-term prognosis [27]. RV dysfunction is com-
mon, is associated with evidence of more advanced heart
failure and is predictive of poorer outcome [28].
As far as the question of the prognostic value of the
diastolic gradient is concerned, studies are not unanimous
[21,22,29], and these points deserve further investigation.
Physiopathology
Pulmonary circulation is a low-pressure, low-resistance and
high-compliance circulation. Left atrial (LA) pressure is esti-
mated by PAWP. Under physiological conditions, mean PAP is
dened as follows: mPAP = PAWP + PVR * CO; and thus PVR is
dened as PVR = (mPAP PAWP)/CO.
In healthy subjects, any increase in CO (effort, stress),
is accompanied by an only moderate increase in pulmonary
pressure, resulting from a decrease in PVR [7]. This adapta-
tion of PVR is partly caused by dilatation of the pulmonary
Please cite this article in press as: Berthelot E, et al. Pulmonary hypertension due to left heart disease. Arch Cardiovasc
Dis (2017), http://dx.doi.org/10.1016/j.acvd.2017.01.010
vascular bed. Endothelial production of nitric oxide is
involved in the ow-dependent vasodilation [30]. In the
upright position, another mechanism is the large capac-
ity of recruiting blood vessels not perfused at rest [31].
All these mechanisms contribute to optimize the ventila-
tion/perfusion ratio on exercise.
The rst event in the development of PH due to LHD (PH-
LHD) is the increase in left heart lling pressures, leading
to pulmonary venous hypertension [32]. Functional mitral
regurgitation, LV remodelling, increased LV stiffness and LV
dysfunction will result in chronic elevation of LA pressure;
this contributes to increase LA size, and reduce LA compli-
ance and contractility. Systolic and diastolic LA functions are
altered, and the left atrium cannot play its role as a buffer
reservoir before the pulmonary circuit. The elevation of the
left lling pressure is transmitted to PAP in a nearly 1:1
proportion, thus leading to increased pulmonary pressure,
especially during exercise [33,34]. Variation in congestive
state also induces mPAP variation.
At the pulmonary capillary level, endothelial dysfunc-
tion is characterized by decreased production of nitric
oxide, overproduction of endothelin-1, activation of the
reninangiotensinaldosterone system and neurogenic acti-
vation; this leads to pulmonary artery vasoconstriction
and PVR elevation. Next, elevated PAP leads to vascular
damage, with pathological remodelling of the pulmonary
arterioles, such as thickening of the alveolar-capillary mem-
brane, medial hypertrophy and neointimal proliferation
[35], whereas plexiform lesions that are pathognomonic
of pulmonary arterial hypertension are not found [36].
Finally, RV is highly sensitive to slight increases in after-
load, i.e. to increased PVR (steady afterload), and to PA
stiffening (pulsatile load) [37]; this progressively leads to
decreased RV stroke volume. The adaptation of RV to
increased afterload varies over time and depending upon
patients phenotypes. First, the remodelling is character-
ized by RV hypertrophy, to normalize RV wall stress (Laplace
law, and thus RV myocardial oxygen demand). Then, dilata-
tion, spherization and functional tricuspid regurgitation may
be observed. These changes mark a pejorative milestone
in the evolution of the disease. Chronic pressure elevation
in the superior and inferior vena cava progressively leads
to congestion, including impairment of renal function (car-
diorenal syndrome) [38], and of hepatic, splanchnic and gut
function.
It is noteworthy that some patients will develop severe
PH and RV dysfunction whereas others will not. The factors
underlying this susceptibility are unknown, but genetic and
environmental contexts, co-morbidities and the period since
the beginning of LHD are potential contributing factors [12].
Studies are currently in progress to better understand this
point.
Assessment and diagnostic approach
The diagnosis of PH in LHD is not always easy because of the
non-specicity of symptoms and the difculty in interpreting
test results. Symptoms such as orthopnoea and paroxys-
mal nocturnal dyspnoea are common with left-sided heart
failure, and the key symptom of PH is also exertional dysp-
noea. A thorough examination is required before any other
+Model
ACVD-991; No. of Pages 12 ARTICLE IN PRESS
Pulmonary hypertension due to left heart disease 5

Table 2 Assessment of pulmonary hypertension due to left heart disease.

Suggestive of left heart disease Suggestive of other aetiology
History Known LV disease (CAD, valvular disease,
cardiomyopathy, etc.); older age; hypertension;
diabetes; BMI > 30; history of pulmonary oedema
Physical examination Left-sided gallop; left-sided murmurs; rales Cyanosis; ne rales; productive cough;
telangiectasia; Raynaud phenomenon;
sclerodactyly; splenomegaly; spider
angiomata; palmar erythema; etc.
Electrocardiogram LV hypertrophy; atrial brillation; LA RA enlargement; RV hypertrophy; right
enlargement; Q waves bundle branch block; S1Q3 pattern
Echocardiogram LV systolic dysfunction; LV diastolic dysfunction;
LA enlargement; LV hypertrophy
Chest X-ray/HRCT Pulmonary congestion; Kerley B lines; pleural Parenchymal lung disease; chronic
effusion; enlargement of left heart chambers thrombo-embolism
PFT/DLCO Normal spirometry; normal DLCO Normal/obstructive spirometry;
decreased DLCO
V/Q scan Normal To diagnose chronic thromboembolic PH
RHC Resting mPAP 25 mmHg; PAWP > 15 mmHg at rest; Resting mPAP 25 mmHg;
abrupt increase in PAWP by >2025 mmHg PAWP 15 mmHg at rest; exercise PAWP
following exercise, volume loading or pulmonary and LVEDP < 2025 mmHg
specic vasodilator testing
BMI: body mass index; DLCO: diffusing capacity of the lung for carbon monoxide; HRCT: high-resolution computed tomography; LA:
left atrial; LV: left ventricular; LVEDP: LV end-diastolic pressure; mPAP: mean pulmonary artery pressure; PA: pulmonary artery; PAWP:
pulmonary artery wedge pressure; PCO2 : partial pressure of carbon dioxide; PFT: pulmonary function test; PH: pulmonary hypertension;
RA: right atrial; RHC: right heart catheterization; RV: right ventricular; V/Q: ventilation/perfusion.

assessment, to identify an evocative context for LHD (his-
tory of heart failure, coronary artery disease, valvular heart
disease, congenital heart disease). Factors associated with
HFpEF must be ascertained: advanced age; female sex;
diabetes; metabolic syndrome; hypertension; atrial bril-
lation; and sleep-disorder breathing [17,3944]. A recent
classication of the wide HFpEF phenotypic has been pro-
posed, to better understand HFpEF spectrum, including
the cases developing PH [43]. In PH due to LHD, electro-
cardiogram ndings usually show LA enlargement and LV
hypertrophy [45], and atrial brillation is far more fre-
quent than in pulmonary arterial (precapillary) hypertension
[46,47]. Natriuretic peptides may be elevated in any cause
of PH, and B-type natriuretic peptide concentrations are
lower in patients with HFpEF than in patients with HFrEF
[48]. In patients admitted with decompensated heart fail-
ure, there is a signicant correlation between percentage
change in wedge pressure from baseline per hour, and per-
centage change in B-type natriuretic peptide concentration
from baseline per hour, suggesting that rapid testing of B-
type natriuretic peptide may be an effective way to improve
in-hospital management [49].
A comparison of features evocative of LHD and other
aetiologies is presented in Table 2.
Right heart imaging in PH
Echocardiography
Echocardiography is the key examination for PH screening
because of its ease of access; it estimates pulmonary
pressures, documents the effects of PH on the heart and
searches for an LHD explaining PH.
Although RHC is the gold-standard technique for assessing
PH, echocardiography allows an estimation of RV systolic
pressure. In the absence of pulmonary valve stenosis, RV
systolic pressure reects pulmonary artery systolic pressure.
The careful denition of peak tricuspid regurgitation jet by
Doppler permits the calculation of RV systolic pressure with
reasonably good accuracy [5054]. However, the peak tri-
cuspid regurgitation jet is only interpretable in 6070% of
cases [50]. Other markers of chronic RV systolic pressure ele-
vation must be searched for, including rapid deceleration of
the RV outow velocity, dilatation and hypertrophy of the
right ventricle, right atrium enlargement, pulmonary artery
enlargement, attening of the interventricular septum,
abnormal eccentricity index and major tricuspid regurgita-
tion [55]. The systolic deceleration or notching of the
RV outow tract Doppler ow velocity envelope relates to
elevated PVR [56]. These anomalies are indicators of the
severity of the PH (Table 3). Indices focusing on RV function,
such as tricuspid annular plane systolic excursion (TAPSE),
S wave by tissue Doppler and RV fractional area change (RV
fractional area change), are also prognostic markers used in
both HFrEF and HFpEF [5759]. These markers are useful
for the follow-up of patients [60]. Last, new predictors of
outcome have been described, including the intersting asso-
ciation of TAPSE ,tricuspid regurgitation gradient, and high
estimated right atrial pressure [27].
Echocardiography is a helpful tool for detecting the cause
of PH; it allows the analysis of ejection fraction, LV mass,
LA size, left lling pressures and heart valvular disease. The

Please cite this article in press as: Berthelot E, et al. Pulmonary hypertension due to left heart disease. Arch Cardiovasc
Dis (2017), http://dx.doi.org/10.1016/j.acvd.2017.01.010
+Model
ACVD-991; No. of Pages 12 ARTICLE IN PRESS
6 E. Berthelot et al.

Table 3 Distinguishing pulmonary hypertension due to left heart disease using echocardiography.
Echocardiography variables Echocardiography nding Likelihood of
PH-LHD PAH
Ejection fraction <50% +
Left atrial size LAV index > 28 mL/m2 +
LV wall thickening; LV mass >11 mm; LV mass index > 80 g/m2 +
Transmitral Doppler Grade II/III diastolic dysfunction +
Mitral regurgitation Severity > mild +
Right ventricular size RV to LV area > 1; RV end-diastolic area > 27 cm2 +
Interventricular septum Systolic attening; lateral septal TDI disparity +
Interatrial septum Bowing into LA +
RVOT Doppler envelope Notching +
LAV: left atrial volume; LV: ventricular; PAH: pulmonary arterial hypertension; PH-LHD: pulmonary hypertension due to left heart
disease; RVOT: right ventricular outow tract; TDI: tissue Doppler imaging.

presence of reduced LV ejection fraction or signicant valvu-
lar disease (especially mitral) is highly evocative of PH due
to LHD. In the context of HFpEF and no valvular disease,
an increased number of studies strengthens the value of
increased LA size and LV hypertrophy as an important argu-
ment in favour of the venous origin of the PH [41,44,61,62].
Among patients with HFpEF, PH was found to be more preva-
lent in those who had mitral regurgitation [63]. The study of
LV diastolic function may help to diagnose HFpEF [62,64,65].
Tissue Doppler diastolic mitral annular velocity e corre-
lates with LV relaxation, and the E/e ratio is related to
invasive LV end-diastolic pressure. However, some studies
have questioned the reliability of the E/e ratio for assessing
the origin of PH [6668]. It is worth noting that in sev-
eral studies comparing the aetiology of PH, the systolic
PAP value did not discriminate precapillary and venous PH,
with similar tricuspid regurgitation maximum velocity values
being observed in these different groups [41,44,45,61,62].
It remains unclear why, in the setting of heart failure, some
patients will develop severe PH and RV dysfunction whereas
others will not [12]. It is also unclear why some patients
with same PAP level will develop RV dilatation and others
will not.
Recent studies suggest that an exercise-induced increase
in PAP may be associated with dyspnoea-fatigue symptoma-
tology. However, exercise echocardiography has been poorly
used to explore PH in LHD, and denition criteria for PH at
exercise are not established. Vascular resistance and mPAP
were found to be more elevated at exercise in patients with
hypertension than in normal subjects [69]. Looking to a prog-
nostic value in HFpEF, the maximum velocity of tricuspid
regurgitation at exercise was independently associated with
heart failure hospitalization or death after adjustment for
baseline clinical and biological characteristics [70]. Look-
ing to a new index exploring the length-force relationship,
TAPSE versus pulmonary artery systolic pressure at exercise
appears useful in advanced stages of heart failure to dene
different levels of risk [71].
Cardiac magnetic resonance imaging
Cardiac magnetic resonance (CMR) imaging is accurate and
reproducible for measuring ventricular volumes and mass,
and it provides important information about the structure
of the left and right ventricles.
A direct assessment of mPAP is not available, but CMR
has been used in the diagnosis and prognostic assessment of
precapillary PH. The most frequently studied variables are
representative of PH consequences: RV mass, volume and
function (RV ejection fraction, RV fractional area change,
TAPSE); right atrial enlargement; mean PA ow velocity;
PA diameter; and PA compliance (i.e. the variation in the
pulmonary artery diameter between diastole and systole)
[7275]. Quantication of LV septal-to-free wall curvature
ratio measured by CMR [76], pulmonary artery distensibility
and the study of delayed contrast gadolinium enhancement
CMR [77] can identify precapillary PH with high positive pre-
dictive value. These variables have been poorly studied in
LHD.
In the setting of heart failure, LA volume index and RV
systolic dysfunction assessed by CMR are independently asso-
ciated with mortality and clinical status, and provide useful
tools for risk stratication [7880].
Although CMR is a reliable and reproducible evaluation
technique, this is counterbalanced by the high cost, limited
accessibility, postprocessing and lengthy analysis, and the
need to maintain prolonged apnoea, which may be difcult
in patients with PH.
The place of right heart catheterization
RHC remains the gold standard for the diagnosis of PH [2].
In LHD, after careful physical and echographical exami-
nations, RHC may be useful to discriminate group 1 and
group 2 patients in difcult cases and to optimize medical
management, and it is necessary for patients considered for
transplantation or mechanical circulatory support. The mea-
surement of RA, RV and PA pressures is reliable if performed
carefully (Fig. 3). Errors in the measurement of PAWP may
be caused by improper transducer position, false zeroing,
waveform dampening, an incompletely wedged catheter or
respiratory artefacts. The levels of PAP and PAWP must be
interpreted in the light of the loading condition and CO.
These variables may be a source of error of 46 mmHg in
PAWP measurement, which can lead to misclassication of

Please cite this article in press as: Berthelot E, et al. Pulmonary hypertension due to left heart disease. Arch Cardiovasc
Dis (2017), http://dx.doi.org/10.1016/j.acvd.2017.01.010
+Model
ACVD-991; No. of Pages 12 ARTICLE IN PRESS
Pulmonary hypertension due to left heart disease 7

Figure 3. Results of right heart catheterization. Adapted from PCIpedia.org. PAP: pulmonary artery pressure; PAWP: pulmonary artery
wedge pressure.

PH-HFpEF and precapillary PH [8183]. Mitral regurgitation
causes a large V wave that increases PAP and may con-
tribute to PH.
Thus, the role of RHC is, rst, to conrm the presence
of PH when mPAP 25 mmHg; second, to characterize the
type of PH with PAWP measurement (isolated postcapillary
PH, combined PH or precapillary PH); then, to complete the
haemodynamic exploration with right atrial pressure, CO,
mixed venous oxygen saturation, calculation of diastolic gra-
dient and PVR. It is worth noting that the measurement of
right atrial pressure, cardiac index, PVR and pulmonary arte-
rial compliance (the ratio of pulmonary stroke volume over
pulmonary artery pulse pressure) is of prognostic importance
in heart failure whereas the pronostic value of TPG and DPG
remain contraversial. [84].
In the setting of clinical suspicion of PH, if resting RHC
is not fully sufcient to ascertain the diagnosis, exercise
or volume loading might be considered [85,86]. Andersen
et al. found that exercise elicits a greater pulmonary cap-
illary wedge pressure elevation compared with saline in
HFpEF, suggesting that exercise testing is more sensitive
than saline loading for detecting haemodynamic derange-
ments indicative of HFpEF [9]. These ndings suggest the
addition of an exercise test into the algorithm for evalua-
tion of patients with suspected HFpEF. In HFrEF, vasodilator
or inotropic testing may demonstrate reversibility, and the
assessment of this reversibility is essential for inscrip-
tion on the transplantation list and might predict outcome
after transplantation [87,88] although in a large recent
retrospective study neither DPG, TPG nor increased PVR
showed any pronostic value on post-transplant survival in
patients with PH [29]. In HFrEF, even after thorough decon-
gestion and under continuous afterload reduction, PH is
completely reversible in a minority of patients. [89].
Management
To date, there is no specic treatment for PH that has proved
benecial in terms of morbidity and mortality in LHD. The
treatment of PH remains exclusively targeted to treatment
of the cause of LHD, curing signicant organic valvular dis-
ease and checking that treatment of HFrEF is optimal as
recommended [90], with a sufcient dose of diuretic to cor-
rect signs of uid retention and blood volume.
Optimizing medical treatments and devices to
lower lling pressure
In the management of patients with heart failure, lowering
lling pressure is an essential goal. Attention must be paid to
optimization of volemic status and medical therapy as rec-
ommended in guidelines, with achievement of target doses
and interventional treatment [90]. In less than a quarter
of the cases, decongestive therapy and afterload reduction
can lead to signicant decreases in or even normalization
of PAWP in patients with HFrEF [89]. The results from the
CHAMPION study suggest that implantation of a permanent
pulmonary artery sensor device leads to targeted treatment
changes, particularly in diuretics and vasodilators doses, and
is more effective in reducing heart failure hospitalizations

Please cite this article in press as: Berthelot E, et al. Pulmonary hypertension due to left heart disease. Arch Cardiovasc
Dis (2017), http://dx.doi.org/10.1016/j.acvd.2017.01.010
+Model
ACVD-991; No. of Pages 12 ARTICLE IN PRESS
8 E. Berthelot et al.
than the classical management of patients clinically, relying
on signs or symptoms alone [91].
Mitral regurgitation is common in heart failure, and is a
potential cause of worsening of PH. Functional mitral regur-
gitation plays a major role in the early phase of chronic
heart failure, suggesting that this should be the focus of
strategies attempting to reduce it [92]. The treatment of
functional mitral regurgitation (MitraClip [Abbott Vascular
Inc., Santa Clara, CA, USA] and mitral valve repair) sig-
nicantly reduced mitral regurgitation, improved clinical
symptoms and decreased LV dimensions at 12 months in
a high-surgical-risk cohort [93,94]. The implantable unidi-
rectional interatrial shunt is of potential value in regulating
LA pressure and lowering PH. Results of current studies are
promising [95]. Finally, in late-stage heart failure it is impor-
tant not to miss the opportunity for an LV assist device or
heart transplantation.
Specic PAH therapy in PH-LHD
Controlling endothelial vascular tone and permeability is a
potentially interesting target for PH treatment, especially in
HFpEF, for which there is no efcient therapy. Since about
10 years, several molecules have been tested in the treat-
ment of PH-LHD, with inconclusive results. In the rst study,
epoprostenol injection was associated with haemodynamic
improvement, but without clinical benets, and there was
even an increased trend towards death [96], leading to pre-
mature interruption of the trial. Endothelin receptor antag-
onists were initially developed for the treatment of left
heart failure: bosentan (REACH and ENABLE studies [97,98])
and darusentan (HEAT and EARTH studies [99,100]). These
studies showed a lack of efciency at best, and an increase
in deleterious clinical events at worst. More recently, several
studies have focused on other pharmacological therapies,
such as phosphodiesterase type 5 inhibitors, (especially sil-
denal with about 13 studies completed or in progress),
soluble guanylate cyclase stimulators (riociguat, vericiguat)
and another endothelin receptor antagonist (macitentan).
These studies have included different populations, with sta-
ble or decompensated heart failure, or reduced or preserved
ejection fraction [101104], and patients with or without
PH, regardless of any associated precapillary component.
Several single-centre haemodynamic studies have shown a
slight improvement in haemodynamics with sildenal. Only
one multicentre study with sildenal (the RELAX study) has
tested the molecule in a double-blind versus placebo trial in
patients with HFpEF [105,106]. Unlike previous single-centre
studies, this study showed no improvement in functional
class.
All these studies will help to dene the value of a specic
treatment targeting PH related to LV failure particularly in
the patient sub-population with a combined pre and post-
capillary PH.
Finally, from a physiopathological point of view, vascular
remodelling, which is the consequence of chronic elevation
of LA pressure, is aimed at preserving haematosis at the
alveolar level in heart failure. The vasodilatation induced
by the treatment is somehow lifting the last defence against
high blood pressure and congestion, and, logically, may lead
to pulmonary oedema.
Please cite this article in press as: Berthelot E, et al. Pulmonary hypertension due to left heart disease. Arch Cardiovasc
Dis (2017), http://dx.doi.org/10.1016/j.acvd.2017.01.010
Perspectives
In PH due to LHD, many questions remain to be answered.
The haemodynamic denition of postcapillary PH requires
further clarication. Particularly, the precapillary compo-
nent of combined PH needs to be better characterized.
Which hemodynamical parameter best characterizes vascu-
lar remodeling? Is there a prognostic value of this parameter?
Is it a therapeutic target? Evolution over time and depend-
ence on the volume status of the pulmonary gradient are
little explored [107].
The role of stress testing and uid challenge during RHC
in the diagnosis of PH due to LHD needs to be claried, as
well as the thresholds for normal/abnormal PWAP responses
following stress. The factors affecting the various patterns
of RV adaptation in PH are still poorly determined.
The identication of a specic treatment for PH in LHD
is still pending. Studies should be performed after vol-
ume optimization and therapeutic optimization (studies are
ongoing).
Conclusions
In patients with LHD, PH is a frequent consequence of
chronic elevation of LV lling pressure caused by left
myocardial or valvular disease. In the elderly (aged > 65
years), HFpEF is the leading cause of PH, particularly in the
presence of cardiovascular risk factors, such as hyperten-
sion, diabetes, atrial brillation and obesity.
PH and RV dysfunction are related to a worse prognosis in
LHD, mediated by multiple organ dysfunction. The level of
PH and RV dysfunction varies among patients, depending on
volume load, and may sometimes appear disproportionate
relative to the left lling pressures.
Studies are needed to better understand the physiology
of PH in LHD. There are no solid data allowing consideration
of a specic treatment targeting PH in patients with LHD.
Observational studies and ongoing clinical trials should bring
important answers in the coming months.
Source of funding
None.
Disclosure of interest
The authors declare that they have no competing interest.
Drs. Montani and Sitbon reports grants and personal fees
from Actelion, grants and personal fees from Bayer, personal
fees from GSK, personal fees from Pzer.
References
[1] Galie N, Humbert M, Vachiery JL, et al. 2015 ESC/ERS
Guidelines for the diagnosis and treatment of pulmonary
hypertension: The Joint Task Force for the Diagnosis and
Treatment of Pulmonary Hypertension of the European
Society of Cardiology (ESC) and the European Respiratory
Society (ERS): Endorsed by: Association for European Paedi-
atric and Congenital Cardiology (AEPC). International Society
+Model
ACVD-991; No. of Pages 12 ARTICLE IN PRESS
Pulmonary hypertension due to left heart disease
for Heart and Lung Transplantation (ISHLT). Eur Heart J
2016;37:67119.
[2] Hoeper MM, Bogaard HJ, Condliffe R, et al. Denitions
and diagnosis of pulmonary hypertension. J Am Coll Cardiol
2013;62:D4250.
[3] Fang JC, DeMarco T, Givertz MM, et al. World Health
Organization Pulmonary Hypertension group 2: pulmonary
hypertension due to left heart disease in the adulta sum-
mary statement from the Pulmonary Hypertension Council of
the International Society for Heart and Lung Transplantation.
J Heart Lung Transplant 2012;31:91333.
[4] Vachiery JL, Adir Y, Barbera JA, et al. Pulmonary hypertension
due to left heart diseases. J Am Coll Cardiol 2013;62:D1008.
[5] Naeije R, Vachiery JL, Yerly P, Vanderpool R. The transpul-
monary pressure gradient for the diagnosis of pulmonary
vascular disease. Eur Respir J 2013;41:21723.
[6] Gerges C, Gerges M, Lang IM. Characterization of pulmonary
hypertension in heart failure using the diastolic pressure gra-
dient: the conundrum of high and low diastolic pulmonary
gradient. JACC Heart Fail 2015;3:4245.
[7] Kovacs G, Berghold A, Scheidl S, Olschewski H. Pulmonary
arterial pressure during rest and exercise in healthy subjects:
a systematic review. Eur Respir J 2009;34:88894.
[8] Simonneau G, Gatzoulis MA, Adatia I, et al. Updated clinical
classication of pulmonary hypertension. J Am Coll Cardiol
2013;62:D3441.
[9] Andersen MJ, Olson TP, Melenovsky V, Kane GC, Borlaug BA.
Differential hemodynamic effects of exercise and volume
expansion in people with and without heart failure. Circ Heart
Fail 2015;8:418.
[10] Herve P, Lau EM, Sitbon O, et al. Criteria for diagnosis of exer-
cise pulmonary hypertension. Eur Respir J 2015;46:72837.
[11] Guazzi M, Borlaug BA. Pulmonary hypertension due to left
heart disease. Circulation 2012;126:97590.
[12] Rosenkranz S, Gibbs JS, Wachter R, De Marco T, Vonk-
Noordegraaf A, Vachiery JL. Left ventricular heart failure and
pulmonary hypertension. Eur Heart J 2016;37:94254.
[13] Miller WL, Grill DE, Borlaug BA. Clinical features, hemody-
namics, and outcomes of pulmonary hypertension due to
chronic heart failure with reduced ejection fraction: pul-
monary hypertension and heart failure. JACC Heart Fail
2013;1:2909.
[14] Aronson D, Darawsha W, Atamna A, et al. Pulmonary hyperten-
sion, right ventricular function, and clinical outcome in acute
decompensated heart failure. J Card Fail 2013;19:66571.
[15] Khush KK, Tasissa G, Butler J, McGlothlin D, De Marco T,
Investigators E. Effect of pulmonary hypertension on clinical
outcomes in advanced heart failure: analysis of the Evalua-
tion Study of Congestive Heart Failure and Pulmonary Artery
Catheterization Effectiveness (ESCAPE) database. Am Heart J
2009;157:102634.
[16] Lam CS, Roger VL, Rodeheffer RJ, Borlaug BA, Enders FT,
Redeld MM. Pulmonary hypertension in heart failure with
preserved ejection fraction: a community-based study. J Am
Coll Cardiol 2009;53:111926.
[17] Leung CC, Moondra V, Catherwood E, Andrus BW. Prevalence
and risk factors of pulmonary hypertension in patients with
elevated pulmonary venous pressure and preserved ejection
fraction. Am J Cardiol 2010;106:2846.
[18] Shah AM, Shah SJ, Anand IS, et al. Cardiac structure and func-
tion in heart failure with preserved ejection fraction: baseline
ndings from the echocardiographic study of the Treatment of
Preserved Cardiac Function Heart Failure with an Aldosterone
Antagonist trial. Circ Heart Fail 2014;7:10415.
[19] Butler J, Chomsky DB, Wilson JR. Pulmonary hypertension and
exercise intolerance in patients with heart failure. J Am Coll
Cardiol 1999;34:18026.
Please cite this article in press as: Berthelot E, et al. Pulmonary hypertension due to left heart disease. Arch Cardiovasc
Dis (2017), http://dx.doi.org/10.1016/j.acvd.2017.01.010
9
[20] Schwartzenberg S, Redeld MM, From AM, Sorajja P, Nishimura
RA, Borlaug BA. Effects of vasodilation in heart failure with
preserved or reduced ejection fraction implications of dis-
tinct pathophysiologies on response to therapy. J Am Coll
Cardiol 2012;59:44251.
[21] Gerges C, Gerges M, Lang MB, et al. Diastolic pul-
monary vascular pressure gradient: a predictor of prognosis
in out-of-proportion pulmonary hypertension. Chest
2013;143:75866.
[22] Tampakakis E, Leary PJ, Selby VN, et al. The diastolic pul-
monary gradient does not predict survival in patients with
pulmonary hypertension due to left heart disease. JACC Heart
Fail 2015;3:916.
[23] Aronson D, Eitan A, Dragu R, Burger AJ. Relationship between
reactive pulmonary hypertension and mortality in patients
with acute decompensated heart failure. Circ Heart Fail
2011;4:64450.
[24] Maron BA, Hess E, Maddox TM, et al. Association of borderline
pulmonary hypertension with mortality and hospitalization in
a large patient cohort: insights from the veterans affairs clin-
ical assessment, reporting, and tracking program. Circulation
2016;133:12408.
[25] Burke MA, Katz DH, Beussink L, et al. Prognostic importance
of pathophysiologic markers in patients with heart failure
and preserved ejection fraction. Circ Heart Fail 2014;7:
28899.
[26] Ghio S, Temporelli PL, Klersy C, et al. Prognostic relevance
of a non-invasive evaluation of right ventricular function and
pulmonary artery pressure in patients with chronic heart fail-
ure. Eur J Heart Fail 2013;15:40814.
[27] Frea S, Pidello S, Bovolo V, et al. Prognostic incremental
role of right ventricular function in acute decompensa-
tion of advanced chronic heart failure. Eur J Heart Fail
2016;18:56472.
[28] Mohammed SF, Hussain I, AbouEzzeddine OF, et al.
Right ventricular function in heart failure with preserved
ejection fraction: a community-based study. Circulation
2014;130:231020.
[29] 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;33:28997.
[30] Breitling S, Ravindran K, Goldenberg NM, Kuebler WM. The
pathophysiology of pulmonary hypertension in left heart dis-
ease. Am J Physiol Lung Cell Mol Physiol 2015;309:L92441.
[31] Naeije R. Physiology of the pulmonary circulation and the
right heart. Curr Hypertens Rep 2013;15:62331.
[32] West JB, Mathieu-Costello O. Vulnerability of pulmonary
capillaries in heart disease. Circulation 1995;92:62231.
[33] Melenovsky V, Hwang SJ, Redeld MM, Zakeri R, Lin G, Borlaug
BA. Left atrial remodeling and function in advanced heart fail-
ure with preserved or reduced ejection fraction. Circ Heart
Fail 2015;8:295303.
[34] Rossi A, Gheorghiade M, Triposkiadis F, Solomon SD, Pieske B,
Butler J. Left atrium in heart failure with preserved ejection
fraction: structure, function, and signicance. Circ Heart Fail
2014;7:10429.
[35] Delgado JF, Conde E, Sanchez V, et al. Pulmonary vascular
remodeling in pulmonary hypertension due to chronic heart
failure. Eur J Heart Fail 2005;7:10116.
[36] Chen Y, Guo H, Xu D, et al. Left ventricular failure produces
profound lung remodeling and pulmonary hypertension in
mice: heart failure causes severe lung disease. Hypertension
2012;59:11708.
[37] Stevens GR, Garcia-Alvarez A, Sahni S, Garcia MJ, Fuster
V, Sanz J. RV dysfunction in pulmonary hypertension is
+Model
ACVD-991; No. of Pages 12 ARTICLE IN PRESS
10
independently related to pulmonary artery stiffness. JACC
Cardiovasc Imaging 2012;5:37887.
[38] Mullens W, Abrahams Z, Francis GS, et al. Importance
of venous congestion for worsening of renal function in
advanced decompensated heart failure. J Am Coll Cardiol
2009;53:58996.
[39] Berthelot E, Montani D, Algalarrondo V, Dreyfuss C, Rifai R,
Benmalek A, et al. A clinical and echocardiographic score to
identify pulmonary hypertension due to HFpEF. J Card Fail
2017;23(1):2935.
[40] Lam CS, Borlaug BA, Kane GC, Enders FT, Rodeheffer RJ,
Redeld MM. Age-associated increases in pulmonary artery
systolic pressure in the general population. Circulation
2009;119:266370.
[41] Richter SE, Roberts KE, Preston IR, Hill NS. A simple
derived prediction score for the identication of an elevated
pulmonary artery wedge pressure using precatheterization
clinical data in patients referred to a pulmonary hypertension
center. Chest 2016;149:12618.
[42] Robbins IM, Newman JH, Johnson RF, et al. Association of the
metabolic syndrome with pulmonary venous hypertension.
Chest 2009;136:316.
[43] Shah SJ, Katz DH, Deo RC. Phenotypic spectrum of heart
failure with preserved ejection fraction. Heart Fail Clin
2014;10:40718.
[44] Thenappan T, Shah SJ, Gomberg-Maitland M, et al. Clinical
characteristics of pulmonary hypertension in patients with
heart failure and preserved ejection fraction. Circ Heart Fail
2011;4:25765.
[45] Jacobs W, Konings TC, Heymans MW, et al. Noninvasive
identication of left-sided heart failure in a population sus-
pected of pulmonary arterial hypertension. Eur Respir J
2015;46:42230.
[46] Ruiz-Cano MJ, Gonzalez-Mansilla A, Escribano P, et al. Clini-
cal implications of supraventricular arrhythmias in patients
with severe pulmonary arterial hypertension. Int J Cardiol
2011;146:1056.
[47] Tongers J, Schwerdtfeger B, Klein G, et al. Incidence and
clinical relevance of supraventricular tachyarrhythmias in
pulmonary hypertension. Am Heart J 2007;153:12732.
[48] van Veldhuisen DJ, Linssen GC, Jaarsma T, et al. B-type natri-
uretic peptide and prognosis in heart failure patients with
preserved and reduced ejection fraction. J Am Coll Cardiol
2013;61:1498506.
[49] Kazanegra R, Cheng V, Garcia A, et al. A rapid test for B-type
natriuretic peptide correlates with falling wedge pressures
in patients treated for decompensated heart failure: a pilot
study. J Card Fail 2001;7:219.
[50] Amsallem M, Sternbach JM, Adigopula S, et al. Addressing
the controversy of estimating pulmonary arterial pres-
sure by echocardiography. J Am Soc Echocardiogr 2016;29:
93102.
[51] Brennan JM, Blair JE, Goonewardena S, et al. Reappraisal
of the use of inferior vena cava for estimating right atrial
pressure. J Am Soc Echocardiogr 2007;20:85761.
[52] Janda S, Shahidi N, Gin K, Swiston J. Diagnostic accuracy of
echocardiography for pulmonary hypertension: a systematic
review and meta-analysis. Heart 2011;97:61222.
[53] Latte S, Pillois X, Reant P, et al. Estimation of pulmonary
pressures and diagnosis of pulmonary hypertension by Doppler
echocardiography: a retrospective comparison of routine
echocardiography and invasive hemodynamics. J Am Soc
Echocardiogr 2013;26:45763.
[54] Rich JD, Shah SJ, Swamy RS, Kamp A, Rich S. Inaccuracy
of Doppler echocardiographic estimates of pulmonary artery
pressures in patients with pulmonary hypertension: implica-
tions for clinical practice. Chest 2011;139:98893.
Please cite this article in press as: Berthelot E, et al. Pulmonary hypertension due to left heart disease. Arch Cardiovasc
Dis (2017), http://dx.doi.org/10.1016/j.acvd.2017.01.010
E. Berthelot et al.
[55] Bossone E, Ferrara F, Grunig E. Echocardiography in pul-
monary hypertension. Curr Opin Cardiol 2015;30:57486.
[56] Arkles JS, Opotowsky AR, Ojeda J, et al. Shape of the right
ventricular Doppler envelope predicts hemodynamics and
right heart function in pulmonary hypertension. Am J Respir
Crit Care Med 2011;183:26876.
[57] Damy T, Kallvikbacka-Bennett A, Goode K, et al. Preva-
lence of, associations with, and prognostic value of tricuspid
annular plane systolic excursion (TAPSE) among out-patients
referred for the evaluation of heart failure. J Card Fail
2012;18:21625.
[58] Damy T, Viallet C, Lairez O, et al. Comparison of four right
ventricular systolic echocardiographic parameters to predict
adverse outcomes in chronic heart failure. Eur J Heart Fail
2009;11:81824.
[59] Meluzin J, Spinarova L, Hude P, et al. Prognostic importance of
various echocardiographic right ventricular functional param-
eters in patients with symptomatic heart failure. J Am Soc
Echocardiogr 2005;18:43544.
[60] Selton-Suty C, Juilliere Y. Non-invasive investigations of
the right heart: how and why? Arch Cardiovasc Dis
2009;102:21932.
[61] DAlto M, Romeo E, Argiento P, et al. Echocardiographic pre-
diction of pre- versus postcapillary pulmonary hypertension.
J Am Soc Echocardiogr 2015;28:10815.
[62] Opotowsky AR, Ojeda J, Rogers F, et al. A simple echocar-
diographic prediction rule for hemodynamics in pulmonary
hypertension. Circ Cardiovasc Imaging 2012;5:76575.
[63] Marechaux S, Neicu DV, Braun S, et al. Functional mitral regur-
gitation: a link to pulmonary hypertension in heart failure
with preserved ejection fraction. J Card Fail 2011;17:80612.
[64] Nagueh SF, Appleton CP, Gillebert TC, et al. Recommenda-
tions for the evaluation of left ventricular diastolic function
by echocardiography. Eur J Echocardiogr 2009;10:16593.
[65] Paulus WJ, Tschope C, Sanderson JE, et al. How to diagnose
diastolic heart failure: a consensus statement on the diagnosis
of heart failure with normal left ventricular ejection fraction
by the Heart Failure and Echocardiography Associations of the
European Society of Cardiology. Eur Heart J 2007;28:253950.
[66] Bhella PS, Pacini EL, Prasad A, et al. Echocardiographic
indices do not reliably track changes in left-sided lling
pressure in healthy subjects or patients with heart failure
with preserved ejection fraction. Circ Cardiovasc Imaging
2011;4:4829.
[67] Mullens W, Borowski AG, Curtin RJ, Thomas JD, Tang WH. Tis-
sue Doppler imaging in the estimation of intracardiac lling
pressure in decompensated patients with advanced systolic
heart failure. Circulation 2009;119:6270.
[68] Willens HJ, Chirinos JA, Gomez-Marin O, et al. Noninvasive
differentiation of pulmonary arterial and venous hypertension
using conventional and Doppler tissue imaging echocardiog-
raphy. J Am Soc Echocardiogr 2008;21:7159.
[69] Vriz O, Argiento P, DAlto M, et al. Increased pulmonary vascu-
lar resistance in early stage systemic hypertension: a resting
and exercise stress echocardiography study. Can J Cardiol
2015;31:53743.
[70] Donal E, Lund LH, Oger E, et al. Value of exercise echocar-
diography in heart failure with preserved ejection fraction: a
substudy from the KaRen study. Eur Heart J Cardiovasc Imag-
ing 2016;17:10613.
[71] Guazzi M, Villani S, Generati G, et al. Right ventricular
contractile reserve and pulmonary circulation uncoupling dur-
ing exercise challenge in heart failure: pathophysiology and
clinical phenotypes. JACC Heart Fail 2016;4:62535.
[72] Gan CT, Lankhaar JW, Westerhof N, et al. Noninvasively
assessed pulmonary artery stiffness predicts mortality in pul-
monary arterial hypertension. Chest 2007;132:190612.
+Model
ACVD-991; No. of Pages 12 ARTICLE IN PRESS
Pulmonary hypertension due to left heart disease
[73] Peacock AJ, Crawley S, McLure L, et al. Changes in right
ventricular function measured by cardiac magnetic res-
onance imaging in patients receiving pulmonary arterial
hypertension-targeted therapy: the EURO-MR study. Circ Car-
diovasc Imaging 2014;7:10714.
[74] van de Veerdonk MC, Kind T, Marcus JT, et al. Progressive
right ventricular dysfunction in patients with pulmonary arte-
rial hypertension responding to therapy. J Am Coll Cardiol
2011;58:25119.
[75] van Wolferen SA, Marcus JT, Boonstra A, et al. Prognos-
tic value of right ventricular mass, volume, and function
in idiopathic pulmonary arterial hypertension. Eur Heart J
2007;28:12507.
[76] Dellegrottaglie S, Sanz J, Poon M, et al. Pulmonary
hypertension: accuracy of detection with left ventricular
septal-to-free wall curvature ratio measured at cardiac MR.
Radiology 2007;243:639.
[77] Blyth KG, Groenning BA, Martin TN, et al. Contrast enhanced-
cardiovascular magnetic resonance imaging in patients with
pulmonary hypertension. Eur Heart J 2005;26:19939.
[78] Aschauer S, Kammerlander AA, Zotter-Tufaro C, et al. The
right heart in heart failure with preserved ejection fraction:
insights from cardiac magnetic resonance imaging and inva-
sive haemodynamics. Eur J Heart Fail 2016;18:7180.
[79] Gulati A, Ismail TF, Jabbour A, et al. The prevalence
and prognostic signicance of right ventricular systolic dys-
function in nonischemic dilated cardiomyopathy. Circulation
2013;128:162333.
[80] Gulati A, Ismail TF, Jabbour A, et al. Clinical utility and
prognostic value of left atrial volume assessment by car-
diovascular magnetic resonance in non-ischaemic dilated
cardiomyopathy. Eur J Heart Fail 2013;15:66070.
[81] Kovacs G, Avian A, Pienn M, Naeije R, Olschewski H. Read-
ing pulmonary vascular pressure tracings. How to handle the
problems of zero leveling and respiratory swings. Am J Respir
Crit Care Med 2014;190:2527.
[82] LeVarge BL, Pomerantsev E, Channick RN. Reliance on
end-expiratory wedge pressure leads to misclassication of
pulmonary hypertension. Eur Respir J 2014;44:42534.
[83] Ryan JJ, Rich JD, Thiruvoipati T, Swamy R, Kim GH, Rich
S. Current practice for determining pulmonary capillary
wedge pressure predisposes to serious errors in the classi-
cation of patients with pulmonary hypertension. Am Heart J
2012;163:58994.
[84] Al-Naamani N, Preston IR, Paulus JK, Hill NS, Roberts KE.
Pulmonary arterial capacitance is an important predictor of
mortality in heart failure with a preserved ejection fraction.
JACC Heart Fail 2015;3:46774.
[85] Fujimoto N, Borlaug BA, Lewis GD, et al. Hemodynamic
responses to rapid saline loading: the impact of age, sex, and
heart failure. Circulation 2013;127:5562.
[86] Robbins IM, Hemnes AR, Pugh ME, et al. High preva-
lence of occult pulmonary venous hypertension revealed by
uid challenge in pulmonary hypertension. Circ Heart Fail
2014;7:11622.
[87] Costard-Jackle A, Fowler MB. Inuence of preoperative
pulmonary artery pressure on mortality after heart trans-
plantation: testing of potential reversibility of pulmonary
hypertension with nitroprusside is useful in dening a high
risk group. J Am Coll Cardiol 1992;19:4854.
[88] Givertz MM, Hare JM, Loh E, Gauthier DF, Colucci WS. Effect
of bolus milrinone on hemodynamic variables and pulmonary
vascular resistance in patients with severe left ventricular
dysfunction: a rapid test for reversibility of pulmonary hyper-
tension. J Am Coll Cardiol 1996;28:177580.
[89] Verbrugge FH, Dupont M, Bertrand PB, et al. Pulmonary vas-
cular response to exercise in symptomatic heart failure with
Please cite this article in press as: Berthelot E, et al. Pulmonary hypertension due to left heart disease. Arch Cardiovasc
Dis (2017), http://dx.doi.org/10.1016/j.acvd.2017.01.010
11
reduced ejection fraction and pulmonary hypertension. Eur J
Heart Fail 2015;17:3208.
[90] Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines
for the diagnosis and treatment of acute and chronic heart
failure: The Task Force for the diagnosis and treatment of
acute and chronic heart failure of the European Society of
Cardiology (ESC). Developed with the special contribution of
the Heart Failure Association (HFA) of the ESC. Eur Heart J
2016;37:2129200.
[91] Costanzo MR, Stevenson LW, Adamson PB, et al. Inter-
ventions linked to decreased heart failure hospitalizations
during ambulatory pulmonary artery pressure monitoring.
JACC Heart Fail 2016;4:33344.
[92] Bursi F, Barbieri A, Grigioni F, et al. Prognostic implications
of functional mitral regurgitation according to the severity
of the underlying chronic heart failure: a long-term outcome
study. Eur J Heart Fail 2010;12:3828.
[93] Glower DD, Kar S, Trento A, et al. Percutaneous mitral valve
repair for mitral regurgitation in high-risk patients: results of
the EVEREST II study. J Am Coll Cardiol 2014;64:17281.
[94] Rogers JH, Thomas M, Morice MC, et al. Treatment of heart
failure with associated functional mitral regurgitation using
the ARTO system: initial results of the rst-in-human MAVERIC
trial (Mitral Valve Repair Clinical Trial). JACC Cardiovasc
Interv 2015;8:1095104.
[95] Del Trigo M, Bergeron S, Bernier M, et al. Unidirectional left-
to-right interatrial shunting for treatment of patients with
heart failure with reduced ejection fraction: a safety and
proof-of-principle cohort study. Lancet 2016;387:12907.
[96] Califf RM, Adams KF, McKenna WJ, et al. A randomized con-
trolled trial of epoprostenol therapy for severe congestive
heart failure: The Flolan International Randomized Survival
Trial (FIRST). Am Heart J 1997;134:4454.
[97] 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;85:1957.
[98] 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;11:1220.
[99] Anand I, McMurray J, Cohn JN, et al. Long-term effects
of darusentan on left-ventricular remodelling and clinical
outcomes in the Endothelin. A Receptor Antagonist Trial in
Heart Failure (EARTH): randomised, double-blind, placebo-
controlled trial. Lancet 2004;364:34754.
[100] Luscher 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;106:266672.
[101] Guazzi M, Vicenzi M, Arena R, Guazzi MD. Pulmonary hyper-
tension in heart failure with preserved ejection fraction: a
target of phosphodiesterase-5 inhibition in a 1-year study.
Circulation 2011;124:16474.
[102] Hoendermis ES, Liu LC, Hummel YM, et al. Effects of sil-
denal 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;36:256573.
[103] Lewis GD, Shah R, Shahzad K, et al. Sildenal improves exer-
cise capacity and quality of life in patients with systolic heart
failure and secondary pulmonary hypertension. Circulation
2007;116:155562.
[104] Wu X, Yang T, Zhou Q, Li S, Huang L. Additional use of
a phosphodiesterase 5 inhibitor in patients with pulmonary
+Model
ACVD-991; No. of Pages 12 ARTICLE IN PRESS
12
hypertension secondary to chronic systolic heart failure: a
meta-analysis. Eur J Heart Fail 2014;16:44453.
[105] Redeld 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:
126877.
Please cite this article in press as: Berthelot E, et al. Pulmonary hypertension due to left heart disease. Arch Cardiovasc
Dis (2017), http://dx.doi.org/10.1016/j.acvd.2017.01.010
E. Berthelot et al.
[106] Bonderman D, Ghio S, Felix SB, et al. Riociguat for patients
with pulmonary hypertension caused by systolic left ven-
tricular dysfunction: a phase IIb double-blind, randomized,
placebo-controlled, dose-ranging hemodynamic study. Circu-
lation 2013;128:50211.
[107] Gerges M, Gerges C, Lang IM. How to dene pulmonary hyper-
tension due to left heart disease. Eur Respir J 2016;48:5535.