| SERIES

WORLD SYMPOSIUM ON PULMONARY HYPERTENSION

Diagnosis of pulmonary hypertension

Adaani Frost1, David Badesch2, J. Simon R. Gibbs3, Deepa Gopalan4,

Dinesh Khanna5, Alessandra Manes6, Ronald Oudiz7, Toru Satoh8,
Fernando Torres9 and Adam Torbicki10

Number 5 in the series

“Proceedings of the 6th World Symposium on Pulmonary Hypertension”
Edited by N. Galiè, V.V. McLaughlin, L.J. Rubin and G. Simonneau

Affiliations: 1Dept of Medicine, Institute of Academic Medicine, Houston Methodist Hospital, Houston, TX, USA.
2
Divisions of Pulmonary Sciences and Critical Care Medicine, and Cardiology, University of Colorado, Denver,
CO, USA. 3National Heart and Lung Institute, Imperial College of London, London, UK. 4Dept of Radiology,
Imperial College Healthcare NHS Trust and Imperial College London, Hammersmith Hospital, London, UK.
5
University of Michigan Scleroderma Program, Ann Arbor, MI, USA. 6Cardio-Thoracic and Vascular Dept,
Sant’Orsola University Hospital, Bologna, Italy. 7LA Biomedical Research Institute at Harbor-UCLA Medical
Center, Torrance, CA, USA. 8Division of Cardiology, Kyorin University Hospital, Tokyo, Japan. 9University of
Texas Southwestern Medical School, Dallas, TX, USA. 10Dept of Pulmonary Circulation and Cardidology,
Medical Center for Postgraduate Education, ECZ-Otwock, Otwock, Poland.

Correspondence: Adaani Frost, Dept of Medicine, Institute of Academic Medicine, Houston Methodist Hospital,
Suite 1001, 6550 Fannin Street, Houston, TX 77030-2707, USA. E-mail: [email protected]

@ERSpublications
State of the art and research perspectives in the diagnostic procedures of patients with pulmonary
hypertension including a comprehensive diagnostic algorithm http://ow.ly/Ow9730mknM6

Cite this article as: Frost A, Badesch D, Gibbs JSR, et al. Diagnosis of pulmonary hypertension. Eur Respir J
2019; 53: 1801904 [https://doi.org/10.1183/13993003.01904-2018].

ABSTRACT A revised diagnostic algorithm provides guidelines for the diagnosis of patients with
suspected pulmonary hypertension, both prior to and following referral to expert centres, and includes
recommendations for expedited referral of high-risk or complicated patients and patients with
confounding comorbidities. New recommendations for screening high-risk groups are given, and current
diagnostic tools and emerging diagnostic technologies are reviewed.

Received: Oct 05 2018 | Accepted: Oct 09 2018

Copyright ©ERS 2019. This article is open access and distributed under the terms of the Creative Commons Attribution
Non-Commercial Licence 4.0.

https://doi.org/10.1183/13993003.01904-2018 Eur Respir J 2019; 53: 1801904

 WORLD SYMPOSIUM ON PULMONARY HYPERTENSION | A. FROST ET AL.

Introduction
There has been no meaningful decrease in the time from symptom onset to diagnosis of pulmonary
hypertension (PH) in the past 20 years. Therefore, the diagnostic algorithm and guidelines for screening
at-risk groups have been modified, balancing the benefits of earlier diagnosis and disease recognition
against the economic healthcare burden of additional screening and increased referrals to PH centres.

Diagnostic approach in patients with clinical suspicion for PH/pulmonary arterial

hypertension
PH due to parenchymal, cardiac, thromboembolic and other diseases (diagnostic groups 2, 3, 4 and 5,
respectively) is associated with worse outcomes and limited treatment options, resulting in referral of these
patients to PH centres. Guidelines for the diagnosis and management for these subgroups are addressed
separately by the relevant 6th World Symposium on Pulmonary Hypertension (WSPH) Task Force articles
in this issue of the European Respiratory Journal [1–3].

Clinical suspicion of PH
Symptoms
Symptoms of PH are non-specific: exertional dyspnoea, fatigue, weakness, chest pain, light-headedness/
syncope and, less frequently, cough. Progressive right-sided heart failure (oedema, ascites, abdominal
distension) occurs in later or more accelerated disease. Rarely, haemoptysis, Ortner’s syndrome/hoarseness
(unilateral vocal chord paralysis) and arrhythmias may characterise PH.

Physical findings
Physical findings include augmented second heart sound (P2 component), right ventricular lift, jugular
venous distension, hepatojugular reflux, ascites, hepatomegaly and/or splenomegaly, oedema, tricuspid
regurgitant or pulmonary regurgitant murmurs, and S3 gallop.
Diseases associated with PH can be suggested by history and physical exam.

Established diagnostic tools

Electrocardiography
Since the US National Institutes of Health (NIH) registry report on primary PH in 1987 [4], the ECG has
been considered a reliable clue to the presence of PH. ECG features in patients with pulmonary arterial
hypertension (PAH) have been demonstrated to be associated with worse prognosis [5, 6]. The derivative
populations for these conclusions were patients with known PAH, predominantly World Health
Organization Functional Class III and IV. The utility of the ECG as a screening tool in complicated
patients or those early in the course of their disease is uncertain. A normal ECG does not exclude PH.

Blood tests and immunology

Blood tests are not useful for PH diagnosis, but distinguish some forms of PH and indicate end-organ
compromise. Routine biochemistry, haematology and thyroid function tests are required in all patients.
Liver function abnormalities may represent congestion, primary liver disease and/or consequences of
therapy. Thyroid disease is common in PAH, may develop during the disease and should be considered in
cases of abrupt deterioration. Elevations of brain natriuretic peptide (BNP) and N-terminal pro-BNP
(NT-proBNP) are associated with right ventricular overload, and are predictors of worse outcome.
Routine screening for connective tissue disease (CTD), hepatitis and HIV is required. Elevated antinuclear
antibodies (ANAs) occur frequently, although in low titres (1:80). Recommended serological testing for
scleroderma includes ANAs (as ELISA can be associated with false-negative tests, ANA
immunofluorescence is recommended and should be considered positive at ⩾1:160). If there is a high
index of suspicion, consider a panel that consists of anticentromere, antitopoisomerase, anti-RNA
polymerase III, double-stranded DNA, anti-Ro, anti-La and U1-RNP antibodies.
Patients with CTD (associated with thombophilic states) and chronic thromboembolic PH (CTEPH)
should undergo screening for coagulopathies and thrombophilia, including anticardiolipin antibodies,
lupus anticoagulant and anti-β2-glycoprotein antibodies.

Pulmonary function tests and arterial blood gases

Pulmonary function tests are addressed in the PH lung disease Task Force article in this issue of the
European Respiratory Journal [2], and should include total lung capacity and diffusing capacity of the lung
for carbon monoxide (DLCO). In most patients with PAH there is a mild restrictive component. Marked
reduction in DLCO (<60% of predicted) or severe exertional hypoxaemia can indicate pulmonary
veno-occlusive disease/pulmonary capillary haemangiomatosis [7].

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Cardiopulmonary exercise testing

Cardiopulmonary exercise testing (CPET) for diagnostic purposes can be done non-invasively or with
haemodynamic testing [8]. CPET can quantify the degree of relative hypoperfusion of the lung and the
systemic circulation that occurs during exercise in patients with PH [9], and can grade the severity of
exercise limitation and assess responses to therapy [10].
Abnormalities in effort-independent ratio of minute ventilation to carbon dioxide production (V̇ E/V̇ CO2)
and end-tidal carbon dioxide tension (PETCO2) obtained during CPET have been used to estimate the
likelihood of PH (lower peak oxygen uptake (V̇ O2) and/or higher V̇ E/V̇ CO2 signifying an increasing
likelihood of pulmonary vascular disease) [11]. Several investigators have demonstrated the utility of CPET
in defining abnormal exercise responses specific to PAH [12–15]. CPET can be particularly useful in
helping identify the predominant underlying cardiopulmonary pathophysiology [13, 16–19]. A detailed
description of the methodologies used in CPET for PH can be found in SUN et al. [9]. Submaximal
exercise testing to evaluate PAH severity using a simplified gas exchange system has also been
proposed [20].
Accurate utilisation of CPET requires performance by a competent facility and interpretation by a clinician
with expertise in gas exchange in conjunction with the patient’s history, physical and laboratory findings.
CPET is useful for determining the nature of the exercise limitation in patients with unexplained
dyspnoea, but should not be used as the sole screening tool for asymptomatic subjects at risk for
developing PAH; CPET can help evaluate cardiopulmonary limitations and assess pulmonary vascular
involvement in these patients; emerging evidence suggests that CPET may be useful for evaluating
symptomatic patients at high risk for developing PAH [15]. In addition, CPET should be considered after
diagnosis of PAH to quantify the severity of exercise impairment and to estimate prognosis.

Transthoracic echocardiography
The transthoracic echocardiogram (TTE) remains the most important non-invasive screening tool and
right heart catheterisation (RHC) remains mandatory to establish the diagnosis.
The echocardiographic probability of PH was derived from previously published data in normal adults
[21–23], and consolidated by expert opinion using the combination of tricuspid regurgitant velocity, right
ventricular size, interventricular septal function, inferior vena cava diameter fluctuations with respiratory
cycle, systolic right atrial area, pattern of systolic flow velocity and early diastolic pulmonary regurgitant
velocity, and diameter of the pulmonary artery (tables 1 and 2) [24–27].

Ventilation/perfusion lung scanning

Ventilation/perfusion (V/Q) lung scanning is addressed in the CTEPH Task Force article in this issue of
the European Respiratory Journal [3]. A normal V/Q scan remains the preferred diagnostic tool and rules
out CTEPH. Nuclear medicine societies are recommending a transition of V/Q reporting to a binary
interpretation [28, 29].

Chest computed tomography

Chest computed tomography (CT) demonstrating right ventricular dilation, right atrial dilation, enlarged
main pulmonary artery (diameter ⩾29 mm) or a main pulmonary artery/ascending aorta diameter ratio

TABLE 1 Echocardiographic probability of pulmonary hypertension (PH) in symptomatic patients

with a suspicion of PH

Peak tricuspid regurgitation velocity m·s–1 Presence of other Echocardiographic

echocardiographic "PH signs"# probability of PH
≤2.8 or not measurable No Low
≤2.8 or not measurable Yes
Intermediate
2.9–3.4 No
2.9–3.4 Yes
High
>3.4 Not required

#
: see table 2. Reproduced and modified from [24] with permission.

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TABLE 2 Echocardiographic signs suggesting pulmonary hypertension (PH) used to assess the
probability of PH in addition to tricuspid regurgitation velocity measurement in table 1

A: The ventricles B: Pulmonary artery C: Inferior vena cava and

right atrium

Right ventricle/left ventricle Right ventricular outflow Doppler Inferior cava diameter >21 mm
basal diameter ratio >1.0 acceleration time <105 ms and/or with decreased inspiratory
mid-systolic notching collapse (<50% with a sniff
or <20% with quiet inspiration)
Flattening of the interventricular Early diastolic pulmonary Right atrial area (end-systole)
septum (left ventricular regurgitation velocity >2.2 m·s–1 >18 cm2
eccentricity index >1.1 in
systole and/or diastole)

Pulmonary artery
diameter >25 mm

Echocardiographic signs from at least two different categories (A/B/C) from the list should be present to
alter the level of echocardiographic probability of PH. Reproduced and modified from [24] with permission.

⩾1 is suggestive of PH [30]. High-resolution non-contrast examination can identify parenchymal lung

disease and discriminate between PH lung disease and PAH (group 3 versus group 1).

Current state-of-the-art diagnostic algorithm

The modified diagnostic algorithm divides the diagnostic approach into 1) that undertaken outside the PH
expert centre, including recommendations for high-risk/accelerated disease requiring expedited triage to
the expert centre (figure 1), and 2) that focusing on the diagnosis of PH once referred to a PH expert
centre (figure 2).

Practice recommendations (including high-risk population screening

recommendations)
Patients with congenital heart disease (CHD), CTD, HIV and portopulmonary hypertension (POPH) are
at increased risk for PH. As little or no progress has been made in earlier diagnosis, this Task Force
recommends more aggressive assessment and screening of some of these high-risk populations.

Scleroderma (systemic sclerosis) and scleroderma spectrum

The 5th WSPH report, the 2015 European Society of Cardiology (ESC)/European Respiratory Society
(ERS) PH guidelines and the NIH-supported 2013 CTD-PAH guidelines recommend annual screening in
patients with systemic sclerosis (SSc) [24, 31, 32]. All guidelines recommend the DETECT algorithm
(evidence-based detection of PAH in SSc) in patients with SSc spectrum disorders (SSc, mixed CTD or
other CTDs with prominent scleroderma features (e.g. sclerodactyly, nail fold capillary abnormalities and
SSc-specific autoantibodies)) associated with DLCO <60% of predicted and disease duration >3 years. The
current diagnosis Task Force undertook a systematic review of the published literature for screening tools
available for CTD-PAH [33]. The review supports incorporating TTE, DETECT (with preliminary data on
its performance with those with DLCO <80% of predicted) or forced vital capacity (FVC)/DLCO ratio >1.6
and blood markers (such as NT-proBNP) in SSc spectrum disorders. Based on this data and on the
published guidelines, this Task Force recommends the incorporation of DETECT, TTE or FVC/DLCO ratio
with elevated NT-proBNP to screen for SSc spectrum disorders. Although the prevalence of PAH is lower
in those with DLCO ⩾80% of predicted, review of two large cohorts in the USA ([33] and Steve Mathai,
Johns Hopkins, Baltimore, MD, USA; personal communication) suggested that PAH is present in these
patients.

Recommendations
• For patients with SSc and SSc spectrum with uncorrected DLCO <80% of predicted, annual screening
should be considered. The appropriate screening tools include DETECT, the 2015 ESC/ERS
recommendations for TTE or FVC/DLCO ratio >1.6 (assuming none-to-mild interstitial lung disease)
and >2-fold upper limit of normal of NT-proBNP. If any of these screening tests are positive, these
patients should be referred for RHC. For those with uncorrected DLCO ⩾80% of predicted, screening
may be considered with TTE.

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History, symptoms, signs and/or laboratory

tests suggestive of PH

Echocardiographic probability Low

Assess probability of PH
of PH#

Identify high-risk Fast-track referral of Consider other

patients High or intermediate
selected patients causes and/or
follow-up¶

Consider V/Q scan to

screen for CTEPH+

Consider left heart

Diagnose common disease (assess pre-test
causes of PH V/Q scan abnormal
probability) and lung
disease§

No clinically significant
left heart disease or
lung disease

Refer to PH expert
Diagnose rare causes of PH centreƒ

FIGURE 1 Algorithm for the diagnosis of pulmonary hypertension (PH) and its causes: triage of urgent cases
and diagnosis of common conditions (for more details, see the accompanying text). V/Q: ventilation/perfusion;
CTEPH: chronic thromboembolic PH. #: described in the 2015 European Society of Cardiology/European
Respiratory Society PH guidelines [24]; ¶: these include chronic thromboembolic disease without PH, which
should be considered in patients with risk factors and/or previous venous thromboembolism; +: single photon
emission computed tomography or planar V/Q scan is acceptable (interpretation is binary: normal or
abnormal); §: see algorithms for left heart disease and lung disease/hypoxia-related PH [1–3], which provide
details of further management of these patients; ƒ: referral of a patient to be seen in person or for a
teleconsultation.

HIV
Although the incidence of PAH in HIV is low, the large number of HIV-infected individuals worldwide
makes HIV a major contributor to the worldwide incidence of PAH and a significant contributor to HIV-
related death. Prior guidelines did not recommend PAH screening in HIV-infected patients, a conclusion
derived from contemporary RHC-based studies in Europe [34] and the USA [35].
Preliminary data from an ongoing RHC-based study in Atlanta HIV clinics suggests a higher incidence of
PH than previously reported in the USA ( prevalence 2% in this US-based African-American population)
(Marshaleen Henriques-Forsythe, Morehouse School of Medicine, Atlanta, GA, USA and Harrison
W. Farber, Pulmonary Center, Boston University School of Medicine, Boston, MA, USA; personal
communication). Risks for PAH in HIV include sex and i.v. drug use. Males are more frequently infected
with HIV than females, but HIV-infected females are disproportionately diagnosed with PAH (around
2-fold). Intravenous drug use has been associated with HIV-PAH [36] in univariate analysis, although it
dropped out in multivariate analysis; however, a biological rationale for this association has been
demonstrated [37]. Data suggest that cocaine acts synergistically with the HIV-1 Tat (transactivator of
transcription) protein [38] by suppressing bone morphogenetic protein receptor expression on pulmonary
artery smooth muscle cells.
Other studies report an association between HIV-PAH and female sex [39], chronic hepatitis C virus infection
(multivariate OR 3.01, 95% CI 1.2–8.2; p=0.02 [21, 40]) and origin from high-prevalence country [41].
The following higher-risk features are proposed for PAH screening in HIV to enrich the likelihood of
earlier diagnosis of HIV-PAH in asymptomatic patients: female sex, i.v. drug use/cocaine use, hepatitis C
virus infection, origin from high-prevalence country, known Nef (negative regulatory factor) or Tat HIV
proteins and US African-American patients independent of symptoms.

Recommendations
• Screen for PAH in HIV patients with symptoms or with more than one risk factor for HIV-PAH.

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Management at
PH expert centre

CTEPH diagnostic Review or

Any mismatched perform Normal perfusion
algorithm perfusion defect V/Q scan#

Multimodality
diagnostic
assessment

PH not PH not
confirmed confirmed RHC for PH diagnosis
Consider other and haemodynamic
causes¶ characterisation

PH confirmed

CTEPH not confirmed Review by

multidisciplinary PH
team+
Monitor and
reassess
CTEPH confirmed PH classification
PH classified§
not certain

Appropriate Consider trial of

treatment treatmentƒ

FIGURE 2 Algorithm for the diagnosis of pulmonary hypertension (PH) and its causes: role of the PH expert
centre. CTEPH: chronic thromboembolic PH; V/Q: ventilation/perfusion; RHC: right heart catheterisation.
#
: single photon emission computed tomography or planar V/Q scan is acceptable; ¶: these include patients
with chronic thromboembolic disease without PH; +: the composition of the multidisciplinary team may differ
depending on the type of clinical problem; §: according to clinical classification of PH; ƒ: only in expert centres
and only with a reassessment plan in place.

Heritable
Recommendations in the USA for PAH genetic screening are largely ignored, misunderstood or unfunded
[42]. In contrast, genetic screening and counselling offered by French PH referral centres have identified
PAH mutations in 16.9% of presumed sporadic PAH patients, in 89% of patients with a family history
[43] and in asymptomatic first-degree relatives of mutation carriers pre-emptively screened. Recent
longevity data indicates a lifelong risk of developing disease in 14% of male and 42% of female carriers,
prompting our recommendation for annual echocardiography in asymptomatic carriers [44].

Recommendations
• Genetic counselling of all idiopathic, anorexiant and familial PAH patients and first-generation
asymptomatic family members of patients with known genetic mutations.
• Subsequent evaluations for PAH should be offered (e.g. CPET and TTE), in mutation-positive
individuals.
• National databases for genotyping all PAH patients should be advocated by the WSPH. Biobanking of
samples and/or genotyping should be mandated in future interventional studies in PAH patients and
possibly in PH patients.

Other heritable PH
Hereditary haemorrhagic telangiectasia
The French hereditary haemorrhagic telangiectasia (HHT) registry [45] demonstrated the
echocardiographic prevalence of PH in HHT as 4.23%, although this was usually associated with
high-output left heart failure. However, the review indicated that while PAH was rare, it was associated
with much poorer survival.

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Recommendations
• In symptomatic patients and those with heart failure or hepatic arteriovenous malformations, with
HHT or family history of HHT, genetic testing and an echocardiogram should be undertaken. If TTE
positive (tables 1 and 2) or suggestive of PH, RHC should be undertaken to distinguish the aetiology
of PH.

Portopulmonary hypertension
The frequency of PH in patients with liver disease varies with disease severity and duration. By time of
liver transplantation 10.3% of patients had RHC-proven mean pulmonary arterial pressure (mPAP)
>35 mmHg [46]. A retrospective review of the UK National Registry of all incident treatment-naive
patients with POPH suggested a prevalence of 0.85 cases per million population [47]. The prevalence of
POPH in the portal hypertensive population has been previously estimated as 2–6%. Estimated median
survival time was 3.75 years in this patient population, with 1-, 2-, 3- and 5-year survival of 85%, 73%,
60% and 35%, respectively.

Recommendations
• Echocardiographic screening is recommended in all patients with portal hypertension. If a tricuspid
regurgitant jet of >3.4 m·s−1 or right atrial or right ventricular enlargement or dysfunction is found,
then further evaluation with RHC and referral to PH expert centre is recommended.

Congenital heart disease

In CHD, PAH can be identified in four distinct subgroups of patients: 1) Eisenmenger syndrome, 2)
persistent systemic-to-pulmonary shunts, 3) those with small, coincidental defects, and 4) patients who
have undergone defect correction. PAH is present by definition in subgroups 1 and 3. Thus, PAH
screening in the CHD population should be undertaken in subgroup 2 and, importantly, subgroup 4.

Recommendations
• Post-operative PAH screening in subgroup 4 should include clinical and echocardiographic and ECG
screening during follow-up visits 3–6 months after correction and then throughout their planned
long-term cardiological follow-up. Annual screening should be planned for corrected patients who
presented with increased baseline pulmonary vascular resistance or with combinations of other
predisposing factors.

Novel diagnostic modalities

Innovative imaging
V/Q single photon emission CT
V/Q single photon emission CT (SPECT) has higher sensitivity compared with planar imaging and outcome
studies have confirmed a high negative predictive value in excluding pulmonary embolism [48, 49].
Dual-modality techniques with varying combinations of hybrid SPECT/CT pulmonary imaging can
improve the specificity of V/Q SPECT by identifying lung diseases in patients with perfusion
abnormalities. The addition of low-dose CT improves the specificity of V/Q SPECT from 88% to 100%
while maintaining the same high sensitivity of 97% [50]. V/Q SPECT reduces radiation exposure relative to
CT [51–53].
The three-dimensional aspects of V/Q SPECT allow for data objectification and facilitate automated
analysis. The perfusion redistribution index as measured by V/Q SPECT showed perceptible reduction in
the normal gravity-dependent redistribution of lung perfusion in PAH patients compared with the normal
population [54] and hence can be a potential marker of pulmonary vascular disease.
V/Q SPECT and hybrid pulmonary imaging are not universally available.

Dual-energy CT: pulmonary perfusion

Dual-energy CT (DECT) offers visualisation of morphological and perfusion abnormalities in the
pulmonary vasculature. Perfusion alterations were less common but more homogeneous in PAH and were
mainly in the form of patchy defects [55]. In CTEPH, perfusion alterations were more frequent and
heterogeneous with a high level of concordance with V/Q scintigraphy. The utility of DECT in the
diagnosis and prognosis of PH, particularly CTEPH, requires further evaluation.

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Three-dimensional dynamic contrast-enhanced magnetic resonance: lung perfusion

Dynamic contrast-enhanced magnetic resonance estimates of perfusion are based on quantification of
tissue enhancement at serial time-points after injection of gadolinium and the technique has comparable
sensitivity to perfusion scintigraphy for diagnosing CTEPH [56, 57]. Although the lack of ionising
radiation makes this an attractive alternative, limited availability and higher costs preclude this technique
from superseding V/Q scintigraphy.

Functional magnetic resonance imaging: ventilation

The ready availability and ease of inhaled oxygen as a contrast medium makes pulmonary magnetic
resonance imaging (MRI) a promising tool for assessing ventilation. In a small study, oxygen-enhanced
ventilation and contrast-enhanced perfusion MRI was concordant with scintigraphy [58]. Standardisation
of analyses and reproducibility of oxygen-enhanced MRI metrics is needed before routine use in clinical
practice.

Subclinical right ventricular dysfunction

Parametric mapping
A review of the magnetic resonance literature found 21 magnetic resonance metrics indicative of PH [59].
Of these, the ventricular mass index (VMI) was frequently used to assess right ventricular functional and
structural changes compared with RHC. A meta-analysis of VMI revealed a positive likelihood ratio of
4.894, indicating a modest ability to differentiate PH patients from healthy controls.
Late gadolinium enhancement (LGE) at the right ventricular insertion points in PH due to delayed
clearance of gadolinium correlates inversely with right ventricular performance [60]; however, its utility
has been called into question in recent studies as a prognostic indicator in PH [61].
T1 mapping is a non-invasive technique for extracellular volume (ECV) quantification and facilitates early
detection of myocardial involvement that is not detectable by LGE. PH has been shown in a small study to
be independently associated with increased right ventricular ECV even after adjustment for right
ventricular dilatation and dysfunction [62].
Larger studies are required to determine if right ventricular ECV reliably predicts adverse clinical
outcomes, offering the potential for risk stratification, prognostication and therapeutic efficacy assessment.

Right ventricular strain

Cardiac magnetic resonance-based right ventricular strain imaging evaluates regional myocardial function
by measuring the percentage change in myocardial deformation. Cardiac magnetic resonance feature
tracking has shown a significant reduction in right ventricular strain in PH patients with normal right
ventricular ejection fraction, predicting subsequent clinical deterioration [63]. Magnetic resonance strain
indices are similar to echocardiographic indices, but longitudinal and circumferential strain measurements
are more reliable.

Pulmonary artery four-dimensional flow imaging

Time-resolved three-dimensional phase-contrast MRI, also known as four-dimensional flow magnetic
resonance, visualises and quantifies cardiovascular blood flow. The pulmonary artery flow patterns can be
a non-invasive early marker in those at risk for developing PH.
Main pulmonary artery flow vortices are a marker of elevated mPAP. Vortical blood flow in the main
pulmonary artery >14.3% of the cardiac interval corresponds to PH with 97% sensitivity and 96%
specificity [64]. The duration of the vortical flow shows a linear increase with mPAP and can be used to
estimate PAPs [65]. Early onset of retrograde flow in the dorsal aspect of the main pulmonary artery is
another characteristic of PAH [66].
Wall shear stress is reduced in the proximal pulmonary arteries of PAH patients, and may contribute to
pulmonary endothelial cell dysfunction and PAH progression [67]. Wall shear stress can be characterised
by four-dimensional flow magnetic resonance with the ability to discriminate PAH patients from normal
controls [68–70].
These metrics are not available from routine RHC and therefore have potential for non-invasive PH
screening and monitoring. Data extraction is complex and clinical trials are necessary to explore the
benefits of four-dimensional flow magnetic resonance over standard practices.

Intravascular ultrasound and optical coherence tomography in PAH

Intravascular ultrasound and optical coherence tomography (OCT) can demonstrate intimal fibrosis, a
surrogate marker of pulmonary arterial remodelling that correlates negatively with pulmonary arterial

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compliance and is associated with unfavourable clinical outcomes during mid-term follow-up [71]. OCT
has shown development of pulmonary arterial remodelling in patients with borderline PH and the
occurrence of reverse remodelling following effective treatment [72].

Machine learning
Technological advances in cardiac imaging coupled with exceptional computing power and innovative
analytical modelling offer an unprecedented amount of data that can contribute to the search for novel
imaging biomarkers.
A recently published machine learning-based survival model had incremental prognostic power when
compared with conventional parameters to more accurately predict outcomes in PH [73]. Such
computational simulations can illuminate pathophysiological mechanisms of right ventricular failure, risk
stratify different PH groups and identify imaging end-points following therapeutic interventions.

Future biomarkers
Numerous potential biomarkers (e.g. asymmetric dimethylarginine, cystatin C, volatile exhaled gases,
exhaled nitric oxide (NO) fraction (FENO) and NOx derivates) [74] have been associated with endothelial
cell dysfunction, inflammation, epigenetics, cardiac function, oxidative stress, metabolism, extracellular
matrix and exhaled breath condensate [75, 76]; while novel, these have not yet demonstrated sensitivity
and specificity for diagnosis, risk assessment or management of PH.
The future of laboratory biomarkers may hinge on the ability to use “deep phenotyping”, i.e. characteristic
patterns in the genome, transcriptome, proteome and/or metabolome of the patient [77–81]. Currently
metabolomics emerges as a potentially informative area of systems biology. In the future, a metabolomics
fingerprint may inform treatment decisions, while changes may be considered “deep monitoring” of
treatment results. Currently, however, abnormal responses versus normal responses to abnormal stimuli are
indistinguishable and metabolic signatures have only been evaluated in well-defined, homogenous study
populations. New research paradigms are necessary to prove their value for early detection and differential
diagnosis of PAH in real life.

Conflict of interest: A. Frost reports personal fees and non-financial support (travel and lodging for attendance and
participation in the 6th WSPH) from Actelion, Gilead, United Therapeutics and Bayer, honoraria for presentations from
Gilead, and honoraria for participation in an end-point adjudication committee for an FDA-approved study from
United Therapeutics, during the conduct of the study; and personal fees (honoraria and travel and lodging for
presentations at meetings) from Actelion Pharmaceuticals, outside the submitted work. D. Badesch reports grants and
personal fees (as steering committee member and site investigator) from Acceleron, Complexa, Bellerophon and
Liquidia, grants, personal fees and advisory board work from Actelion, is a long-term stock holder of Johnson and
Johnson, grants and personal fees (as advisory board member and site investigator) from Arena, Gilead and United
Therapeutics/Lung LLC, personal fees for consultancy from Respira, grants and personal fees (as site investigator,
advisory board member and consultant) from Bayer, outside the submitted work. J.S.R. Gibbs reports grants and
personal fees from Actelion, GSK, MSD and Pfizer, personal fees from Arena, Bayer, Bellerophon, Complexa and
Acceleron, and grants from United Therapeutics, during the conduct of the study. D. Gopalan has nothing to disclose.
D. Khanna reports personal fees from Actelion, Bayer, Boehringer Ingelheim, Chemomab, Corbus, Covis, Cytori, EMD
Sereno, Genentech/Roche, Gilead, GSK, Sanofi-Aventis and UCB Pharma; grants from Bayer, Boehringer Ingelheim,
Genentech/Roche, Pfizer and Sanofi-Aventis; and has stock options with Eicos Sciences, Inc. He was also supported by
the NIH/NIAMS (K24 AR063120). A. Manes reports grants and personal fees from Actelion, and grants from Bayer and
Pfizer, outside the submitted work. R. Oudiz reports grants and consulting and speaker fees from Actelion, Gilead and
United Therapeutics, grants from Aadi and GSK, consulting fees from Complexa, Acceleron and Medtronic, and grants
and consulting fees from Arena and Reata, outside the submitted work. T. Satoh has nothing to disclose. F. Torres
reports personal fees from Actelion, Bayer, Reata and Arena, and grants from Gilead, United Therapeutics, Medtronic,
Eiger and Bellerophon, during the conduct of the study. A. Torbicki reports personal fees from Actelion, AOP Orphan
Pharmaceutics, Bayer and MSD, and non-financial support from Pfizer, outside the submitted work; and is also a
chairperson of the Foundation for Pulmonary Hypertension, which receives donations from outside parties to support
its activities. The chair receives no financial compensation for this function.

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