Chinese Medical Journal 2014;127 (19) 3491

DOI: 10.3760/cma.j.issn.0366-6999.20140984
Division of Cardiology, Second Department of Internal Medicine,
Kyorin University School of Medicine, Tokyo, Japan (Satoh T) (Tel:
81-422-47-5511. Fax: 81-422-44-0683. Email: tsatoh@ks.kyorin-u.
ac.jp)
Review article
Current practice for pulmonary hypertension
Toru Satoh
Keywords: pulmonary hypertension; epidemiology; diagnosis; treatment
Objective To investigate the current practice of pulmonary hypertension including current epidemiology, diagnosis and
treatment.
Data sources The review was based on data obtained from the published articles and guidelines.
Study selection Articles with high level of evidence or current best evidence in each issue were selected to be reviewed.
Results Overall prevalence of pulmonary hypertension was 0.3% to 6% with left heart disease occupying the most
proportion, followed by pulmonary disease, pulmonary arterial hypertension and chronic thromboembolic pulmonary
hypertension. In diagnosis, a fow diagram of diagnosis of pulmonary hypertension, differential diagnosis of pulmonary
hypertension and how to determine the severity of pulmonary hypertension are explained including recent development of
magnetic resonance imaging and gene abnormality study on bone morphogenetic protein receptor II. In treatment, newly-
developed pulmonary vasodilators and the way to use them are shown to treat pulmonary hypertension.
Conclusion Safer and more effective treatment algorithm and basic researches and clinical trials are warranted to be
explored.
Chin Med J 2014;127 (19): 3491-3495
P
ulmonary hypertension (PH) is caused by 4 distinct
etiologic diseases. Category 1 is pulmonary arterial
hypertension (PAH), which comprises of idiopathic
PAH and associated PAH like connective tissue disease
(CTD), congenital heart disease, liver disease, human
immunodeficiency virus (HIV) infection, and so on.
Category 2 is left heart disease such as valvular heart
disease, myocardial disease, ischemic heart disease and
et cetera. Category 3 is pulmonary disease or hypoxic
condition and category 4 is chronic thromboembolic
pulmonary hypertension (CTEPH) causing obliteration of
thick pulmonary arteries by organized thrombi or emboli.
PH has been defined as an increase in mean pulmonary
arterial pressure (PAP) 25 mmHg at rest as assessed by
right heart catheterization and the borderline PH is defned
as mean PAP between 21 and 24 mmHg. Because PAP is
distributed continuously in a Gaussian manner, to draw a
line between normal and PH is very diffcult. But to decide
the criteria for PH is necessary in terms of socioeconomic
standpoint, for example in determining an inclusion of
certain patients for special support of medical expenses in
PAH in Japan. It is well recognized that PH is diagnosed
with high specificity when mean PAP is elevated more
than 25 mmHg but with high sensitivity when it is over
21 mmHg. And pulmonary vascular resistance more
than 3 Wood Units is added to these criteria when PAH
is diagnosed under new criteria.
1
The notion exercise-
induced PH was still not acknowledged as a criterion for
PH, or probably the early-phase PH in the 5th international
PH conference in Nice, France in 2013, but the detailed
understanding on normal responses of pulmonary
circulation during exercise was explained very clearly as
a product of the Nice conference.
2
The breakdown of PH
etiologic diseases in a community was recently reported.
3

Overall, at least echocardiography was performed in all the
residents in Armadale and surrounding regions in western
Australia (population: 165 450, male/female=1:1, mean
age: 35 years old) to screen for PH and the exact etiologies
were scrutinized if PH was detected. Estimated systolic
PAP of more than 40 mmHg was suspected of PH. The
minimum indicative prevalence for all forms of PH is
326 cases/100 000 inhabitants of the local population,
with left heart disease-associated PH being the commonest
cause (250 cases/100 000), PAH being 15 cases/100 000
inhabitants, and an additional 144 individuals (15%) with
no identifed cause for their PH. According to this report,
rough estimation of all-cause PH is 0.3%. Another similar
report,
4
though of small scale in the number of patients,
mentioned the overall PH prevalence rate of 6.6%, chiefy
enrolling older residents. Therefore, the prevalence of PH
including all causes in general population is considered to
be 0.3% to 6%. Regarding PAH, the prevalence was about
15/100 000 population according to the Ministry of Welfare
statistics in Japan and this figure is very precise because
medical expenses of the patients with PAH are almost
completely reimbursed and registration for PAH is strictly
checked and rarely missed. It was reported as 10/100 000 in
France.
5
Though the prevalence of PAH was 150/100 000
in the Armadale statistics mentioned above, it may not be
exact because the absolute number of patients with PAH
was small and widened the measurement error. In summary,
the prevalence of PAH is 10 to 15 per 100 000 population.
Diagnosis
Differential diagnosis of PH
Differential diagnosis of PH is very important because it
Chin Med J 2014;127 (19) 3492
leads to decision of treatment and expectation of prognosis
(Figure 1).
1
After taking history and physical examinations,
echocardiograph is needed to be conducted if there is
possibility of PH. With echocardiography, diagnosis of PH
is usually made and the next step is to determine the causes
of PH. In most cases, diagnosis left heart disease (category
2) is also made with echocardiography. The patients then
should take chest X-ray, electrocardiogram, arterial blood
gas analysis, pulmonary function test (PFT) including lung
diffusion capacity using carbon monoxide (DLCO), and
chest CT, to decide whether pulmonary disease is a cause
of PH (category 3). When pulmonary disease is denied, V/
Q scintigraphy is required to diagnose thromboembolic
pulmonary arterial hypertension (CTEPH: category 4). For
therapeutic decision, pulmonary angiography with right
heart catheterization (RHC) is mandatory. In excluding
the diseases in categories 2, 3, 4, diagnosis of pulmonary
arterial hypertension (PAH: category 1) is made. PAH
includes PH due to CTD, congenital heart disease, porto-
pulmonary hypertension, drugs and toxins, HIV infection
and PVOD (pulmonary veno occlusive disease).
Evaluation of PH severity
Right heart catheterization
It is performed through femoral, internal jugular or brachial
vein. It is sometimes very difficult to insert the catheter
via femoral or brachial vein because of their remote
location from the heart. Jugular vein is the best place
for its easier access to the pulmonary artery and early
ambulation after the exam. Hemodynamic values obtained
from the right heart catheterization are the gold standards
to assess the severity of PH and differentiate PH due to
left heart disease from other causes. PH was classified
according to pulmonary arterial wedge pressure (PAWP)
and transpulmonary pressure gradient (TPR) demonstrated
in 2008 at the Dana-Point World PH Conference and a bit
changed to the new classification in 2013 at the Nice PH
World Conference. In the old classifcation, the cause of PH
was diagnosed as left heart disease when PAWP exceeds
15 mmHg. Then they were subdivided into reactive when
TPR is over 12 mmHg and passive when TRP less than 12
mmHg. In the new classification in Nice, PH due to left
heart disease is diagnosed when DPG (diastolic pressure
gradient = diastolic PAPPAWP) is less than 7 mmHg.

Vasoreactivity test: For patients with PAH, vasoreactivity
test during right heart catheterization should also be
performed to find patients with good response to Ca-
channel blockers and good prognosis with the drugs for
at least 5 years thereafter. It has been reported that these
responders comprise of 5 to 10
percent among all PAH patients,
but those responders are very
rare in Japanese patients and it
may be applied to patients in
China.
He modyna mi c va r i a bl e s
including pulmonary arterial
oxygen saturation, mean right
atrial pressure, cardiac output,
pulmonary vascular resistance
and PAP are prognostic and
some studies suggested that the
reduced arterial O
2
saturation,
low systolic blood pressure are
good variables in evaluating
prognosis.
6
Brain natriuretic peptide (BNP)
/uric acid
BNP has long been known as a
maker of left ventricular failure.
However it is also elevated
when PH patients have right
ventricular overload. Right
vent ri cul ar fai l ure usual l y
accompanies a BNP increase.
It, therefore, predicts prognosis
after the patients are treated.
7

Uric acid, one of the major
DNA metabolites, is increased
when venous congestion causes
tissue hypoxia. Uric acid has
Figure 1. Differential diagnosis of pulmonary hypertension (derived from the reference 1).
Chinese Medical Journal 2014;127 (19) 3493
the same hemodynamic abnormality as BNP, is elevated
when patients have right ventricular overload
8
and is more
useful in detecting PH due to CTD than BNP because
BNP increases with inflammation in CTD without right
ventricular overload.
Magnetic resonance imaging (MRI)/3-dimentional
echocardiography
Right ventricular function has long been difficult to
estimate because of its complicated shape different from
the left ventricle of elliptic cone. However, the advent of
MRI provides the accurate information on right ventricular
volume and ejection fraction leading to estimation of
prognosis.
9
Three-dimensional echocardiography also
yielded precise information on the right heart estimation
similar to MRI and is easier to perform.
10
Bone morphogenetic protein receptor II (BMPRII)
abnormality
About 6 percent of patients with IPAH, which was
previously known as primary PH at that time, were
known to be inherited and suffer PH. In 2000 gene
abnormality was reported to be ascribed to BMPRII gene
mutation. It is located on the cell surface membrane,
stimulates Smad system in the cell and leads to production
of transforming growth factor (TGF)-, the cytokine.
11

One of functions of TGF- is to control cell proliferation.
Therefore, when BMPRII is genetically damaged,
pulmonary arteriolar wall thickening, characteristic
structural changes of PAH, ensues. This gene abnormality
has been noted in about 25% of sporadic IPAH patients.
Only 20% of patients with BMPRII gene mutation are
afflicted with clinical IPAH. They are categorized as
hereditary PAH apart from IPAH. There have been many
reports on the relation of this gene abnormality to clinical
phenotypes but no unifed fndings.
Treatment
Principal treatment strategy is determined according to the
classifcation of PH.
PAH
General treatment
Activity such as climbing and running should be limited
and pregnancy prohibited because of high mortality of the
mother with PAH and aggravation of PH when pregnant.
When right heart failure supervenes, diuretics and/or
cardiotonic drugs such as digoxin, dobutamine should
be added. When hypoxia is noted, ambulatory oxygen
inhalation should be instituted. Anticoagulant, Coumadin,
was once thought to be effective in improving prognosis in
patients with PAH but now it is considered harmful to be
administered with contemporary pulmonary vasodilators.
Targeted therapy
There are 3 different kinds of drugs with different
mechanisms of action. The oldest drugs are prostaglandins.
Prostaglandins: The representative drug is epoprostenol,
which is administered via central vein continuously. It is
actually most effective, but needs intensive handling and
is the most expensive. According to the latest treatment
guideline in the western countries, epoprostenol is the
most recommended drug when patients are in the NYHA
functional class IV. One of the other prostaglandins
now orally available is long-acting beraprost developed
in Japan.
12
It is not so strong in its effectiveness but
inexpensive and useful when patients are not so serious.
The trial of a newly-developed prostacyclin receptor
agonist, NS-304, has finished and the drug will soon be
released worldwide.
Endothelin receptor antagonists (ERA): Bosentan was frst
invented with antagonism against both endothelin receptors
A (vasoconstrictive) and B (vasodilatory). Some experts
insisted that this kind of dual antagonism is more effective
in treating PAH. Its effect in improving exercise capacity
has been established.
13
Liver dysfunction, leuko- and
thrombocytopenia and drug interactions are problematic
side effects. Ambrisentan is the sole receptor-A-antagonist,
is exempt from these side effects but occasionally induces
edema and aggravation of interstitial pneumonitis.
14
Phosphodiesterase-5 (PDE-5) inhibitor: Nitrous oxide
(NO) secreted from vascular endothelium increases cyclic
guanosine monophosphate (cGMP), which exerts on
vascular smooth muscle for dilatation of the vessel. Then
breakdown of cGMP is inhibited by PDE-5, abundant
in pulmonary vessels in addition to testis vessels. PDE-
5 inhibitor used in testis is famous for its treatment of
erectile dysfunction. An improvement in exercise capacity,
hemodynamics has been reported.
15,16
Riociguat is newly-
developed drug and guanilate cyclase stimulant. NO
binds to guanilate cyclase and produces cyclic guanosine
monophosphate, a vasodilating metabolite acting on the
vascular smooth muscle cells. Therefore, riociguat mediates
vasodilation through NO. The trial of Riociguat has been
fnished and the drug is available in western countries and
will be available in Japan soon.
17
Tadalafl is a long-acting
PDE-5 inhibitor, developed and released a couple of years
ago, and also useful in improving symptoms and avoiding
clinical worsening.
18
Drug usage
The European guidelines show how to use these pulmonary
vasodilators. When one drug is insufficient to improve
symptoms and/or hemodynamics, then start the combination
therapy. This strategy is called sequential combination
therapy. Recently wave-front combination treatment,
meaning more than one vasodilators are started at once, is
beginning to be used with great effcacy, though side effects
like blood pressure reduction requires attention.
19
Mechanism of pulmonary vasodilators
Originally the mechanism of these drugs was thought
to dilate the pulmonary arterioles. However as the
pathology causing PAH is considered the proliferation
Chin Med J 2014;127 (19) 3494
of the pulmonary arteriolar walls, reverse remodeling of
these thickened vessels has been recently reported as the
mechanism of vasodilators.
20
Novel therapy
Imatinib: Imatinib, one of tyrosine kinase inhibitors
and recently-developed anticancer-agent used for
chronic myelogenous leukemia was also proved to have
antiproliferative effect on the pulmonary arteriolar wall. As
arteriolar wall proliferation has been considered playing
a major role in causing PAH, imatinib was expected to
cure PAH and the trial (IMPRES study) was done. The
results were that imatinib was effective in improving
hemodynamics and 6-minute-walk distance in patients
with PAH refractory to other vasodilators,
21
but could not
be commercialized because of high rates of adverse events
such as thrombopenia and leukopenia. Tyrosine kinase
inhibitors have alsobeen reported to alleviate pulmonary
venoocclusive disease (PVOD).
22
Endothelial progenitor cells (EPCs): Revolutional treatment
using genetic technology such as EPCs was reported to be
effective in patients with IPAH in 6-minute-walk distance
and hemodynamics in China.
23
Further study will be
anticipated in near future.
PH due to left heart disease and pulmonary disease
Basic strategy is to treat the original or causal diseases.
Chronic thromboembolic PH (CTEPH )
Medical treatment
Pulmonary vasodilators are also effective in alleviating
symptoms and prognosis
24
because PH induced by
thromboembolic stenosis and obstruction of pulmonary
arteries with bigger diameters causes secondary arteriolar
lesions, ie, arteriolar vessel wall thickening. The
vasodilators can improve the latter abnormality.
Pulmonary endarterectomy (PEA)
This is a specialized operation in which thickened
endothelia are removed, using extracorporeal circulation
and extra low-temperature cooling, requiring high-
quality technique. It was started in 1970s in USA, now is
performed worldwide and has all been established in South
East Asia.
25,26
Balloon pulmonary angioplasty
It was frst performed intensively in 2001 in USA but was
abandoned because of frequent severe complications. A
renewed light has been casted to this technique in Japan
since late 2000s.
27,28
Techniques and strategies to avoid
fatal complications
29
have contributed to advancing this
catheter-based, less-invasive treatment with its effects
equivalent to that of PEA.
Summary and conclusion
The prevalence of PH is 0.3% to 6.0% according to the
accumulated evidences worldwide, and the left heart
disease accounts for the most proportion of PH, followed
by pulmonary disease, PAH and CTEPH. The classifcation
of PH plays a vital role because prognosis and treatment
responses are different within the groups of patients.
Though the response to therapy is variable depending
on the disease process, the medication, and the route of
drug administration, the effcacy of general treatment and
targeted therapy including 3 kinds of vasodilators were
demonstrated. Although the drug therapy for PH are far
more advanced today than in the past decades, the surgery
still strongly affects CTEPH in terms of symptoms relief
and prognosis improvement. Recent advances in genomics
and biological technologies are helping to pave a new road
toward personalized treatment and further understanding of
the pathogenesis including genomics will help to develop
new strategies for PH. Collaboration across disciplines
and countries are demanded to shift these scientific and
technological advances toward triumph over PH.
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(Received April 28, 2014)
Edited by Guo Lishao