Primary Pulmonary Hypertension Report
National Heart, Lung, and Blood Institute
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 mm Hg at rest. In the PPH patient, the mean blood pressure in
the pulmonary artery is greater than 25 mm Hg at rest and 30 mm Hg 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 vessels.
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.
INCIDENCE OF PRIMARY
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.
CAUSES OF PRIMARY PULMONARY
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 been available.
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
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.
PHOTOS OF PRIMARY PULMONARY
pulmonary artery with typically thin muscular wall.
|Some of the changes
that can occur in primary pulmonary hypertension:
|Wall of small
pulmonary artery thickens.
scarred, tissue appears on inner wall of small pulmonary
|Bands of scarred
tissue build up on inner wall of small pulmonary artery,
substantially narrowing the blood vessel.
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
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.
SYMPTOMS OF PRIMARY
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 rapidly.
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
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
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
DIAGNOSIS OF PRIMARY
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 doctor's office.
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 treatment.
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
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 areas.
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 blood flow.
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.
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
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
of Functional of Pulmonary Hypertension
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 undertake.
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
PRIMARY PULMONARY HYPERTENSION
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
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 forming.
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 neck.
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
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, but are less common than the single lung transplant for treatment
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
THE PRIMARY PULMONARY
HYPERTENSION PATIENT REGISTRY 1981-1988
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 the disease.
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 cardiac catheterization.
LIVING WITH PRIMARY PULMONARY
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 attitude.
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 be
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 patient.
- Angina: Chest pain that originates in the
Aorta: Blood vessel that delivers oxygen-rich
blood from the left ventricle to the body; it is the largest blood vessel in
Atrium: One of the two receiving chambers of
the heart. The right atrium receives oxygen-poor blood from the body. The
left atrium receives oxygen-rich blood from the lungs. The plural of atrium
Blood pressure: The pressure of blood against
the walls of a blood vessel or heart chamber. Unless there is reference to
another location, such as the pulmonary artery or one of the heart chambers,
it refers to the pressure in the systemic arteries, as measured, for
example, in the forearm.
Cardiac output: Total amount of blood being
pumped by the heart over a particular period of time.
Catheter: Thin, flexible medical tube; one use
is to insert it into a blood vessel to measure blood pressure.
Clinical trials: Medical studies of patients
that evaluate the effectiveness of treatment.
Constrict: Tighten; narrow.
Cyanosis: A bluish color in the skin because
of insufficient oxygen.
Diastolic pressure: The lowest pressure to
which blood pressure falls between contractions of the ventricles.
Dilate: Relax; expand.
Dyspnea: A sensation of difficulty in
Edema: Swelling due to the buildup of fluid.
Endothelial cells: The delicate lining, only
one cell thick, of the organs of circulation.
Fibrosis: Process by which inflamed tissue
Heartbeat: One complete contraction of the
Hyperreactive: Describes a situation in which
a body tissue is especially likely to have an exaggerated reaction to a
Hypertension: Abnormally high blood pressure.
- Hypotension: Abnormally low blood pressure.
- Lung volume: The amount of air the lungs hold.
- Mean blood pressure: The average blood
pressure, taking account of the rise and fall that occurs with each
heartbeat. It is often estimated by multiplying the diastolic pressure by
two, adding the systolic pressure, and then dividing this sum by three.
- Palpitation: The sensation of rapid
- Perfusion: Flow.
- Pulmonary artery: Blood vessel delivering
oxygen-poor blood from the right ventricle to the lungs.
- Pulmonary hypertension: Abnormally high blood
pressure in the arteries of the lungs.
- Smooth muscle: Muscle that performs automatic
tasks, such as constricting blood vessels.
- Spirogram: A record of the amounts of air
being moved in and out of the lungs.
- Syncope: Fainting; temporary loss of
- Systemic: Relating to a process that affects
the body generally; in this instance, the way in which blood is supplied
through the aorta to all body organs except the lungs.
- Systolic pressure: The highest pressure to
which blood pressure rises with the contraction of the ventricles.
- Vasodilator: An agent that widens blood
Ventricle: One of the two pumping chambers of
the heart. The right ventricle receives oxygen-poor blood from the right
atrium and pumps it to the lungs through the pulmonary artery. The left
ventricle receives oxygen-rich blood from the left atrium and pumps it to
the body through the aorta.
U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
Public Health Service
National Institutes of Health
National Heart, Lung, and Blood Institute
NIH Publication No. 96-3291
Originally printed 1992
Revised November 1996