Primary, or unexplained, pulmonary hypertension (PPH) is a
rare lung disorder in which the blood pressure in the
pulmonary artery rises far above normal levels for no
apparent reason. The pulmonary artery is the blood vessel
carrying oxygen-poor blood from the right ventricle, one of
the pumping chambers of the heart, to the lungs. In the
lungs, the blood picks up oxygen and then flows to the left
side of the heart, where it is pumped by the left ventricle
to the rest of the body through the aorta.
Hypertension is the medical term for an abnormally high
blood pressure. Normal mean pulmonary-artery pressure is
approximately 14 mmHg at rest. In the PPH patient, the mean
blood pressure in the pulmonary artery is greater than 25
mmHg at rest and 30 mmHg during exercise. This abnormally
high pressure (pulmonary hypertension) is associated with
changes in the small blood vessels in the lungs, resulting
in an increased resistance to blood flowing through the
This increased resistance, in turn, places a strain on the
right ventricle, which now has to work harder than usual
against the resistance to move adequate amounts of blood
through the lungs.
The true incidence of PPH is unknown. The first reported
case occurred in 1891, when E. Romberg, a German doctor,
published a description of a patient who, at autopsy, showed
thickening of the pulmonary artery but no heart or lung
disease that might have caused the condition. In 1951,
when 39 cases were reported by Dr. D.T. Dresdale in the
United States, the illness received its name.
Between 1967 and 1973, a 10-fold increase in unexplained
pulmonary hypertension was reported in central Europe. The
rise was subsequently traced to aminorex fumarate, an
amphetamine-like drug introduced in Europe in 1965 to
control appetite. Only about 1 in 1,000 people who took the
drug developed PPH. When they stopped taking the drug, some
improved considerably; in others, the disease kept getting
worse. Once aminorex was removed from the market, the
incidence of PPH went down to normal levels.
More recently, in the United States and France, several
cases of PPH have been associated with the appetite
suppressants, fenfluramine and dexfenfluramine.
In the United States it has been estimated that 300 new
cases of PPH are diagnosed each year; the greatest number
are reported in women between the ages of 21 and 40.
Indeed, at one time the disease was thought to occur among
young women almost exclusively; we now know, however, that
men and women in all age ranges, from very young children to
elderly people, can develop PPH. Apparently it also affects
people of all racial and ethnic origins equally.
There may be one or more causes of PPH; however, all remain
unknown. The low incidence makes learning more about the
disease extremely difficult. Studies of PPH also have been
difficult because a good animal model of the disease has not
Researchers think that in most people who develop PPH the
blood vessels are particularly sensitive to certain internal
or external factors and constrict, or narrow, when exposed
to these factors. For example, people with Raynaud's
disease seem more likely than others to develop PPH;
Raynaud's disease is a condition in which the fingers and
toes turn blue when cold because the blood vessels in the
fingers and toes are particularly sensitive to cold. Diet
suppressants, cocaine, HIV, and pregnancy are some of the
factors that are thought to trigger constriction, or
narrowing, in the pulmonary artery.
In about 6 to 10 percent of cases, PPH is familial; that is,
it is inherited from other family members. The familial
form of PPH is similar to the more common form of the
disease, sometimes referred to as "sporadic" PPH.
COURSE OF THE DISEASE
Researchers believe that one of the ways PPH starts is with
injury to the layer of cells (the endothelial cells) that
line the small blood vessels of the lungs. This injury,
which occurs for unknown reasons, may bring about changes in
the way the endothelial cells interact with smooth muscle
cells in the vessel wall. As a result, the smooth muscle
contracts more than normal and thereby narrows the vessel.
The process eventually results in the development of extra
amounts of tissue in the walls of the pulmonary arteries.
The amount of muscle increases in some arteries, and muscle
appears in the walls of arteries that normally have no
muscle. With time, scarring, or fibrosis, of the arteries
takes place, and they become stiff as well as thickened.
Some vessels may become completely blocked. There is also a
tendency for blood clots to form within the smaller
In response to the extra demands placed on it by PPH, the
heart muscle gets bigger, and the right ventricle expands in
size. Overworked and enlarged, the right ventricle gradually
becomes weak and loses its ability to pump enough blood to
the lungs. Eventually, the right side of the heart may fail
completely, resulting in death.
In general, researchers find there is no correlation between
the time PPH is thought to have started, the age at which it
is diagnosed, and the severity of symptoms. In some
patients, especially children, the disease progresses fairly
The first symptom is frequently tiredness, with many
patients thinking they tire easily because they are simply
out of shape. Difficulty in breathing (dyspnea), dizziness,
and even fainting spells (syncope) are also typical early
symptoms. Swelling in the ankles or legs (edema), bluish
lips and skin (cyanosis), and chest pain (angina) are among
other symptoms of the disease.
Patients with PPH may also complain of a racing pulse; many
feel they have trouble getting enough air. Palpitations, a
strong throbbing sensation brought on by the increased rate
of the heartbeat, can also cause discomfort.
Some people with PPH do not seek medical advice until they
can no longer go about their daily routine. The more severe
the symptoms, the more advanced the disease. In these more
advanced stages, the patient is able to perform only minimal
activity and has symptoms even when resting. The disease
may worsen to the point where the patient is completely
PPH is rarely picked up in a routine medical examination.
Even in its later stages, the signs of the disease can be
confused with other conditions affecting the heart and
lungs. Thus, much time can pass between the time the
symptoms of PPH appear and a definite diagnosis is made.
PPH remains a diagnosis of exclusion. This means that it is
diagnosed only after the doctor finds pulmonary hypertension
and excludes or cannot find other reasons for the
hypertension, such as a chronic obstructive pulmonary
disease (chronic bronchitis and emphysema), blood clots in
the lung (pulmonary thromboemboli), or some forms of
congenital heart disease.
The first tests for PPH help the doctor determine how well
the heart and lungs are performing. If the results of these
tests do not give the doctor enough information, the doctor
must perform a cardiac catheterization. The procedure,
discussed below, is the way the doctor can make certain that
the patient's problems are due to PPH and not to some other
The electrocardiogram (ECG) is a record of the electrical
activity produced by the heart. An abnormal ECG may
indicate that the heart is undergoing unusual stress.
In addition to the usual ECG performed while the patient is
at rest, the doctor may order an exercise ECG. This ECG
helps the doctor evaluate the performance of the heart
during exercise, for example, walking a treadmill in the
In an echocardiogram, the doctor uses sound waves to map the
structure of the heart by placing a slim device that looks
like a microphone on the patient's chest. The instrument
sends sound waves into the heart, which then are reflected
back to form a moving image of the beating heart's structure
on a TV screen. A record is made on paper or videotape. The
moving pictures show how well the heart is functioning. The
still pictures permit the doctor to measure the size of the
heart and the thickness of the heart muscle; in the patient
with severe pulmonary hypertension, the still pictures will
show that the right heart is enlarged, while the left heart
is either normal or reduced in size. Echocardiograms are
helpful in excluding some other causes of pulmonary
hypertension and can be useful in monitoring the response to
Pulmonary Function Tests
A variety of tests called pulmonary function tests (PFTs)
evaluate lung function. In these procedures, the patient,
with a nose clip in place, breathes in and out through a
mouthpiece. The patient's breathing displaces the air held
in a container suspended in water. As the container rises
and falls in response to the patient's breathing, the
movements produce a record, or spirogram, that helps the
doctor measure lung volume (how much air the lungs hold) and
the air flow in and out of the lungs. Some devices measure
air flow electronically.
A mild restriction in air movement is commonly seen in
patients with PPH. This restriction is thought to be due,
in part, to the increased stiffness of the lungs resulting
from both the changes in the structure and the high blood
pressure in the pulmonary arteries.
Perfusion Lung Scan
A perfusion lung scan shows the pattern of blood flow in the
lungs; it can also tell the doctor whether a patient has
large blood clots in the lungs. In the perfusion scan, the
doctor injects a radioactive substance into a vein.
Immediately after the injection, the chest is scanned for
radioactivity. Areas in the lung where blood clots are
blocking the flow of blood will show up as blank or clear
Two patterns of pulmonary perfusion are seen in patients
with PPH. One is a normal pattern of blood distribution;
the other shows a scattering of patchy abnormalities in
A major reason for doing a perfusion scan is to distinguish
patients with PPH from those whose pulmonary hypertension is
due to blood clots in the lungs.
Right-Heart Cardiac Catheterization
In right-heart cardiac catheterization, the doctor places a
thin, flexible tube, or catheter, through an arm, leg, or
neck vein in the patient, and then threads the catheter into
the right ventricle and pulmonary artery. Most important in
terms of PPH is the ability of the doctor to get a precise
measure of the blood pressure in the right side of the heart
and the pulmonary artery with this procedure. It is the
only way to get this measure, and must be performed in the
hospital by a specialist.
During catheterization, the doctor can also evaluate the
right heart's pumping ability; this is done by measuring the
amount of blood pumped out of the right side of the heart
with each heartbeat.
Once PPH is diagnosed, most doctors will classify the
disease according to the functional classification system
developed by the New York Heart Association. It is based on
patient reports of how much activity they can comfortably
Class 1--Patients with no symptoms of any kind, and for whom
ordinary physical activity does not cause fatigue,
palpitation, dyspnea, or anginal pain.
Class 2--Patients who are comfortable at rest but have
symptoms with ordinary physical activity.
Class 3--Patients who are comfortable at rest but have
symptoms with less-than-ordinary effort.
Class 4--Patients who have symptoms at rest.
Some patients do well by taking medicines that make the work
of the right ventricle easier. Anticoagulants, for example,
can decrease the tendency of the blood to clot, thereby
permitting blood to flow more freely. Diuretics decrease the
amount of fluid in the body, further reducing the amount of
work the heart has to do.
Until recently, nothing more could be done for people who
have PPH. However, today doctors can choose from a variety
of drugs that help lower blood pressure in the lungs and
improve the performance of the heart in many patients.
Some patients also require supplemental oxygen delivered
through nasal prongs or a mask if breathing becomes
difficult; some need oxygen around the clock. In severely
affected cases, a heart-lung, single lung, or double lung
transplantation may be appropriate.
Doctors now know that PPH patients respond differently to
the different medicines that dilate, or relax, blood vessels
and that no one drug is consistently effective in all
patients. Because individual reactions vary, different
drugs have to be tried before chronic or long-term treatment
begins. During the course of the disease, the amount and
type of medicine may also have to be changed.
To find out which medicine works best for a particular
patient, doctors evaluate the drugs during cardiac
catheterization. This way they can see the effect of the
medicine on the patient's heart and lungs. They can also
adjust the dose to reduce the side effects that may occur--
for example, systemic low blood pressure (hypotension);
nausea; angina; headaches; or flushing.
To determine whether a drug is improving a patient's condition,
both the pulmonary pressure and the amount of blood being pumped
by the heart (the cardiac output) must be evaluated. A decrease
in pulmonary pressure alone, for example, does not necessarily
mean that the patient is recovering; cardiac output must either
increase or remain unchanged. The most desirable response is
a decrease in pressure and an increase in cardiac output. Once
the patient has reached a stable condition, he or she can go home,
returning every few weeks or months to the doctor for followup.
At present, approximately one-quarter to one-half of
patients can be treated with calcium channel blocking drugs
given by mouth. By relaxing the smooth muscle in the walls
of the heart and blood vessels, these calcium channel
blockers improve the ability of the heart to pump blood.
A vasodilator, prostacyclin, is helping some severely ill
patients who are unresponsive to treatment with calcium
channel blockers. The drug, which has been studied in
clinical trials, imitates the natural prostacyclin that the
body produces on its own to dilate blood vessels.
Prostacyclin also seems to help prevent blood clots from
Prostacyclin is administered intravenously by a portable,
battery-operated pump. The pump is worn attached to a belt
around the waist or carried in a small shoulder pack. The
medication is then slowly and continuously pumped into the
body through a permanent catheter placed in a vein in the
Protstacyclin seems to improve pulmonary hypertension and
permit more physical activity. It is sometimes used as a
bridge to help those patients waiting for a transplant,
while in other cases it is used for long-term treatment.
The first heart-lung transplant was performed in this
country in 1981. Many of these operations were performed
for patients with PPH. The survival rate is the same as for
other patients with heart-lung transplants, about 60 percent
for 1 year, and 37 percent for 5 years.
The single lung transplant is the most common method of
transplant used in cases of PPH. This procedure, in which
one lung--either the left or right--is replaced, was first
performed in 1983 in patients with pulmonary fibrosis.
Double lung transplants are also done to treat PPH.
There are fewer complications with the single lung
transplant than with the heart-lung transplant, and the
survival rate is on the order of 70 percent for 1
year. A surprising finding is the remarkable ability of the
right ventricle to heal itself. In patients with lung
transplants, both the structure and function of the right
ventricle markedly improve. Complications of transplantation
include rejection by the body of the transplanted organ, and
infection. Patients take medications for life to reduce
their body's immune system's ability to reject "foreign"
THE PRIMARY PULMONARY HYPERTENSION PATIENT REGISTRY
In 1981, the National Heart, Lung, and Blood Institute
(NHLBI) established the first PPH-patient registry in the
world. The registry followed 194 people with PPH over a
period of at least 1 year and, in some cases, for as long as
7.5 years. Much of what we know about the illness today
stems from this study.
At the time the patients enrolled in the registry, 75
percent were in functional classes 3 or 4. They had an
average mean pulmonary artery pressure three times the
normal, an abnormally high pressure in the right side of the
heart, and a reduced cardiac output. In making the
diagnosis of PPH, investigators found no complications
arising from cardiac catheterization.
The study findings show that pulmonary artery pressure in
patients who had symptoms for less than 1 year was similar
to that in patients who had symptoms for more than 3 years.
Researchers also found that patients whose only symptom was
difficulty in breathing upon exercise already had very high
pulmonary artery pressure. This suggests that the pulmonary
artery pressure rises to high levels early in the course of
No correlations could be found between the cause of PPH and
cigarette smoking, occupation, place of residence,
pregnancy, use of appetite suppressants, or use of
prescription drugs, including oral contraceptives. This
study was designed to serve only as a registry, so it was
not possible to evaluate the effectiveness of treatment.
Because we still do not understand the cause or have a cure
for PPH, NHLBI remains committed to supporting basic and
clinical studies of this illness. Basic research studies
are focusing on the possible involvement of immunologic and
genetic factors in the cause and progression of PPH, looking
at agents that cause narrowing of the pulmonary blood
vessels, and identifying factors that cause growth of smooth
muscle and formation of scar tissue in the vessel walls.
Most important is finding a reliable way to diagnose PPH
early in the course of the disease that does not require
LIVING WITH PRIMARY PULMONARY HYPERTENSION
With the cause of primary pulmonary hypertension still
unknown, there is at present no known way to prevent or cure
this disease. However, many patients report that by changing
some parts of their lifestyle, they can go about many of
their daily tasks. For example, they do relaxation
exercises, try to reduce stress, and adopt a positive mental
People with PPH go to school, work at home or outside the
home part-time or full-time, and raise their children.
Indeed, many patients with PPH do not look sick, and some
feel perfectly well much of the time as long as they do not
strain themselves physically.
Walking is good exercise for many patients. Some patients
with advanced PPH carry portable oxygen when they go out;
patients who find walking too exhausting may use a
wheelchair or motorized scooter. Others stay busy with
activities that are not of a physical nature.
For the patient who lives at a high altitude, a move to a
lower altitude--where the air is not so thin, and thus the
amount of oxygen is higher--can be helpful. Medical care is
important, preferably by a doctor who is a pulmonary
vascular specialist. These specialists are usually located
at major research centers.
PPH patients can also help themselves by following the same
sensible health measures that everyone should observe.
These include eating a healthy diet, not smoking, and
getting plenty of rest. Pregnancy is not advised because it
puts an extra load on the heart. Oral contraceptives are
not recommended, and other methods of birth control should
Most doctors and patients agree that it is important for
both patient and family to be as informed as possible about
PPH. In this way everyone can understand the illness and
apply that information to what is happening. In addition to
family and close friends, support groups can help the PPH