Circulation

PERSPECTIVE

The New World Symposium on Pulmonary

Hypertension Guidelines
Should Twenty-One Be the New Twenty-Five?

Those who made the decisions with imperfect knowledge will be judged Nicole F. Ruopp, MD
in hindsight by those with considerably more information at their disposal Harrison W. Farber, MD
and time for reflection.
—Donald Rumsfeld, Known and Unknown: A Memoir

A
dvancements in the diagnosis and treatment of pulmonary arterial hyper-
tension (PAH) over the past 30 years have improved symptoms, functional
status, and survival; however, PAH remains a progressive, deadly disease.
Early diagnosis and aggressive treatment have been shown to improve outcomes,
but no appreciable improvement in time to diagnosis has occurred. Thus, increased
diagnostic sensitivity is desperately needed. In an attempt to do such, and after
re-evaluation of “normal” values of pulmonary artery pressure, the recent World
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Symposium on Pulmonary Hypertension suggested new PAH hemodynamic guide-

lines for diagnosis and intervention. Several aspects of these suggestions are clearly
controversial and may engender unforeseen consequences.
The previously adopted mean pulmonary artery pressure (mPAP) ≥25 mm Hg
was chosen arbitrarily. Although the normal range for mPAP in healthy controls has
been known with reasonable accuracy from the early days of right heart catheter-
ization, specific thresholds for pulmonary hypertension (PH) were not agreed upon
until the 1970s to 1980s, during and after performance of multicenter registries
and early clinical trials.
More recently, the increased mortality risk in patients with mPAP <25 mm Hg
has prompted a reevaluation of these thresholds. The normal range for mPAP is
approximately 14±3.3 mm Hg, resulting in an upper limit of normal of approxi-
mately 20 mm Hg.1 Thus, the newly suggested World Symposium on Pulmonary
Hypertension hemodynamic thresholds include a mPAP >20 mm Hg, a pulmonary
artery wedge pressure ≤15 mmHg, and a pulmonary vascular resistance (PVR) of
≥3 Wood units to define precapillary PH; the isolated reduction in mPAP compared
to previous thresholds is largely aimed at increasing the sensitivity of the diagnostic
criteria. However, with any increase in sensitivity comes the additional risk of in-
creased false positives and lower positive predictive value.
While it is true that a mPAP of 21 to 24 mm Hg is associated with increased The opinions expressed in this article are
mortality in the general population, and, in some studies, with pulmonary vascular not necessarily those of the editors or
of the American Heart Association.
remodeling, an elevation in NT-proBNP (N-terminal pro-b-type natriuretic peptide),
or early changes in right ventricular morphology, it also true that a mPAP of 21 to Key Words: hemodynamics
◼ hypertension, pulmonary ◼ pulomary
24 mm Hg is associated with increasing age, an elevated body mass index, and artery ◼ pulmonary vascular resistance
coexistent left heart and/or lung disease. Currently, it is unknown whether any
© 2019 American Heart Association, Inc.
mortality increase that has been reported is truly independent of such confound-
ers.2,3 Furthermore, while mPAP 21 to 24 mm Hg has been correlated with an https://www.ahajournals.org/journal/circ

1134 October 1, 2019 Circulation. 2019;140:1134–1136. DOI: 10.1161/CIRCULATIONAHA.119.040292

 Ruopp and Farber
abnormal pulmonary vascular response during exercise
and an increased risk of exercise-induced PH, one does
not necessarily predict the other; moreover, the natural
history of patients within this “borderline” hemody-
namic profile remains largely unknown. For example,
although Valerio et al observed that scleroderma pa-
tients with a borderline mPAP were at increased risk of
progression to PH, defined as a mPAP ≥25 mm Hg, only
47% progressed over 3 years.4 Given such observations
in a high-risk population and the paucity of robust data,
how do we rectify early diagnosis with the real pos-
sibility of overdiagnosis? Moreover, do all “borderline”
patients progress, and given the known variability of
day-to-day, hour-to-hour mPAP measurements, is the
21 mm Hg of today really the 19 mm Hg of tomorrow?
In reality, there exist very few data to define the clinical
status and outcomes of this cohort with any degree of
confidence.
From a technical standpoint, although one can dis-
cuss the merits of the current mPAP thresholds in a
data-driven fashion, the current PVR threshold of ≥3
Wood units is also an arbitrary value; in fact, there
are data suggesting that PVR >2 Wood units may
be abnormal.1 Aside from the fact that changing 1
threshold and not the other seems counterintuitive,
there may be an even more important issue. As PVR is
calculated, decreasing the mPAP threshold without a
concomitant PVR change necessarily enriches for only
those patients in whom cardiac output has been im-
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pacted enough to yield the PVR threshold and may
not optimally select for early detection. Prospective
studies in high-risk individuals evaluating the natural
history of multiple different hemodynamic threshold
permutations would be necessary (but not likely or
feasible) to determine the optimal criteria for diagno-
sis. As such, developing better metrics for determining
diagnostic and treatment algorithms in these patients
seems paramount.
Regardless of the aforementioned thresholds, mPAP
and PVR are imperfect markers and only model down-
stream effects after significant pathologic involvement.
Thus, ultimately, increased sensitivity, and therefore ear-
lier diagnosis, may come from more novel and direct
measurements of disease progression.
Even if we assume that the new hemodynamic crite-
ria are appropriate and reliable, and that 100% of pa-
tients with “borderline” PH will progress to mPAP ≥25
mm Hg, appropriate treatment of this cohort and the
outcome of such treatment are completely unknown.
In fact, the World Symposium on Pulmonary Hyper-
tension statement on treatment of these “borderline”
patients may be the most telling indictment of these
suggestions:
“The haemodynamic inclusion criteria in the ma-
jority of the [randomized controlled trials] were as
follows: pulmonary arterial wedge pressure ≤15 mm
Circulation. 2019;140:1134–1136. DOI: 10.1161/CIRCULATIONAHA.119.040292
New PH Guidelines
Hg, mean pulmonary arterial pressure ≥25 mm Hg
FRAME OF REFERENCE
and pulmonary vascular resistance >3 Wood Units (>5
Wood Units in some [randomized controlled trials]). It
is not clear if the efficacy/safety ratio of the PAH drugs
is favourable when used in patients not fulfilling the
above criteria.”5
Although treatment of select high-risk, symptom-
atic “borderline” PH patients has been undertaken
on an individual basis at some expert centers, this ap-
proach has not been adequately studied. And while the
guidelines stop short of a treatment recommendation
in these patients, they also avoid providing guidance
on how these newly diagnosed PAH patients should be
managed, risk-stratified, or followed.
Despite these issues, the weight of clinical experi-
ence leads us to believe that patients with “borderline”
hemodynamics are not “normal,” and may benefit
from closer follow-up and treatment. However, the
decision to do so must balance patient advocacy with
a firm awareness of the evidence base as it currently
stands. Moreover, the economic burden of these thera-
pies is significant. Why would any third party payer ap-
prove such expensive therapies in a cohort of patients
without confirmed benefit?
To develop robust scientific data in these individuals,
they should be enrolled in registries and/or randomized
controlled trials aimed at gaining a greater understand-
ing of their natural clinical course and response to treat-
ment. Is treatment with pulmonary vasodilators safe?
Does it reduce morbidity or alter the risk of mortality?
To that end, current randomized controlled trials should
strongly consider adding an amendment to enroll these
patients, and/or future clinical trials should include a
subgroup of these patients.
In summary, however well intentioned and pro-
vocative the recent hemodynamic threshold altera-
tions might be, without further study there are cur-
rently insufficient data to support a PH diagnosis in
this “borderline” cohort. Moreover, there are no data
to support treatment. Diagnosis and treatment al-
gorithms should focus on early identification of this
cohort with subsequent enrollment in clinical trials
or registries to define their risk profiles and optimal
treatment strategies. It really is the only scientific and
rational approach.
ARTICLE INFORMATION
Correspondence
Harrison W. Farber, MD, Tufts Medical Center Division of Pulmonary, Critical
Care and Sleep Medicine, 800 Washington Street, #257 (Tupper 3), Boston, MA
02111. Email hfarber@tuftsmedicalcenter.org
Affiliations
Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hos-
pital, Boston, MA (N.F.R.). Division of Pulmonary, Critical Care, and Sleep Medi-
cine, Tufts Medical Center, Boston, MA (H.W.F.).
October 1, 2019 1135
 Ruopp and Farber
Disclosures
FRAME OF REFERENCE
Dr Farber is a Consultant/Scientific Advisory Board for Actelion, Bellerophon,
Boehringer-Ingelheim, and Arena/United Therapeutics, and has received Speak-
ers’ Bureau/Honoraria from Actelion and Bayer.
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New PH Guidelines
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Circulation. 2019;140:1134–1136. DOI: 10.1161/CIRCULATIONAHA.119.040292