PULMONARY HYPERTENSION

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PULMONARY HYPERTENSION
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INTRODUCTION BRIEF
HISTORY WHAT IS
PH? WHAT
CAUSES PH? SIGNS AND
SYMPTOMS DIAGNOSIS OF PH
TREATMENT OF PH
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INTRODUCTION
In the human body, there are two types of
circulation that enable distribution of blood
throughout the body. The portion that pumps
oxygenated blood from the left side of the heart
via the left ventricle to all parts of the body
is known as the SYSTEMIC CIRCULATION. On the
other hand, the portion that pumps deoxygenated
blood from the right side of the heart via the
right ventricle into the lungs to obtain oxygen
is referred to as the PULMONARY CIRCULATION.
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INTRODUCTION
Millions of people are affected by a condition
known as high blood pressure (hypertension)
whereby the blood travels through the bodys
arteries at a pressure higher than
normal. PULMONARY HYPERTENSION is a far less
common type of high blood pressure that affects
specifically the arteries in the lungs. Pressures
in the lung arteries are normally significantly
lower than the pressures in the systemic
circulation. Pulmonary hypertension occurs when
the pressure in the pulmonary circulation becomes
abnormally elevated. It is a serious condition
that becomes progressively worse and eventually
proves fatal.
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INTRODUCTION
An estimated of 500 1000 new cases are
diagnosed annually. There is an incidence of
about 2-3 per million per year and a prevalence
of 15 per million. This disease can occur in
men, women and children of all ages. However, it
is most common in females between 20 and 40 years
old, with twice as many cases reported in women
then men. The condition is rare in children but
is sometimes seen in infants born with heart
defects. Pulmonary hypertension may be a primary
or secondary cause of hypoxia in neonates.
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H I S T O R Y

• The first reported case 1891
• E. Romberg, German doctor
• published description of a patient who, at
  autopsy, showed
• thickening of the pulmonary artery but no
  heart or lung disease
• In 1951, 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. It was later removed from the market.

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WHAT IS PULMONARY HYPERTENSION?
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Ordinarily, blood vessels in the lungs provide
less resistance to blood flow than blood vessels
in the rest of the body do. Hence, blood pressure
is usually much lower in the lungs. While
pressure in general circulation is about 120/80
mm Hg, in the pulmonary arteries, it is only
around 25/15 mm Hg. Mean (average) pulmonary
artery pressure number between highest and
lowest pressures
Normal
at rest 14 mm Hg
Pulmonary hypertension
at rest 25 mm Hg
during exercise 30 mm Hg
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• Primary Pulmonary Hypertension
• no underlying cause for the high blood pressure
  in lungs
• likely to begin with spasm of the muscle layer
  in pulmonary arteries
• patients are rather sensitive to substances that
  cause blood vessels
• to constrict
• may have an inherited predisposition for the
  disease
• Secondary Pulmonary Hypertension
• results directly from another medical problem
• most probable from diseases that impedes flow of
  blood through
• lungs or that causes periods of low oxygen in
  blood
• eg. Chronic Obstructive Pulmonary Disease,
  scleroderma, sleep
• apnea, pulmonary fibrosis, lung diseases such
  as asbestosis

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Abnormally high BP in pulmonary arteries
Increased pressure damages large and small
pulmonary arteries
Blood vessel walls thicken
Cannot transfer oxygen and carbon dioxide
normally
Levels of oxygen in blood fall
Constriction of pulmonary arteries
Further increase in pressure in pulmonary
circulation
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Pulmonary Hypertension
right side of heart must work harder
push blood through pulmonary arteries to lungs
right ventricle thickens and enlarges
cor pulmonale
Heart Failure
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WHAT CAUSES PULMONARY HYPERTENSION?
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Although the exact cause of primary pulmonary
hypertension is unknown, scientists believe that
most people who develop the disorder are
especially sensitive to substances that cause
blood vessels to constrict. Cocaine and
fenfluramine (fen-phen), which was withdrawn from
the market in 1997, are two of the substances
that may contribute to PH in many people. Other
people with PH have an inherited predisposition
for the disease. In these people, PH is triggered
by another medical condition such as chronic
liver disease (cirrhosis), AIDS, sickle cell
anemia, scleroderma and lupus.
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• Pulmonary hypertension resulting directly from
  another medical problem is called secondary
  pulmonary hypertension. Medical conditions that
  may lead to secondary PH include
• blood clots in the lungs (pulmonary emboli)
• chronic obstructive pulmonary disease such as
  emphysema
• connective tissue disorders, such as scleroderma
• sleep apnea upper airway obstructed during
  sleep
• congenital heart disease
• obesity with reduced ability to breathe
  (Pickwickian syndrome)
• neuromuscular diseases involving respiratory
  muscles
• HIV infection
• lung diseases such as pulmonary fibrosis (causes
  scarring in
• the tissue between the lungs air sacs)

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• Left-sided heart failure
• hearts left ventricle weakens and cannot pump
  out enough blood
• increase in pressure backs up through pulmonary
  veins to
• arteries in lungs
• High Altitude
• above altitude of 8000 feet - may develop PH
• low blood oxygen (hypoxemia)
• constricts small pulmonary arteries
• climb to high elevations without first becoming
  acclimated
• risk of pulmonary edema too air sacs filled
  with fluid instead of
• with air, always associated with PH

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The overall rise in blood pressure in PH is the
end result of a process which begins with changes
in the endothelial cells that line the lungs
arteries. Changes ? causes formation of extra
tissue ? blockage in vessels Scarring (fibrosis)
usually also occurs ? arteries stiff and
narrow These causes increased resistance to
blood flow which raises pressure in the pulmonary
arteries. Less often, PH is caused by extensive
loss of lung tissue from surgery/trauma.
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Injury to endothelial cells leads to
overproduction of endothelin key cause of blood
vessel scarring and spasm to reduced production
of nitric oxide and prostacyclins 2 key body
chemicals which keep blood vessels relaxed and
open.
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The Two-Hit Hypothesis
According to the hypothesis, vascular
abnormalities characteristic of PPH are triggered
by accumulation of genetic and/or environmental
insults in a susceptible individual. A
combination of germline BMPR2 mutation (first
hit) and the ingestion of appetite suppressants
(second hit) were used to generate the clinical
disease.
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A genetic cause of the familial form of primary
PH has been discovered. It is caused by mutations
in a gene called BMPR2, as used in the Two-Hit
Hypothesis. BMPR2 encodes a receptor
(transforming growth factor beta type II
receptor) that sits on the surface of cells and
binds molecules of the TGF-beta
superfamily. Binding triggers conformational
changes ? series of biochemical reactions

?

affect cells behaviour The
mutations block this process. Hence, this
discovery provides means of genetic diagnosis and
a potential target for the therapy with familial
and possibly, sporadic primary pulmonary
hypertension.
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SIGNS AND SYMPTOMS
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Like other forms of high blood pressure
(hypertension), the signs and symptoms of
pulmonary hypertension are subtle in the early
stages of the disease and may not be apparent for
months or even years. As the disease progresses,
these signs become more noticeable. Also, the
symptoms of PH are often hidden by the underlying
condition causing the disease. Symptoms,
however, tend to vary from patient to
patient. The diagnosis of PH are often
overlooked by physicians. It is sufficiently
common and of such high impact that all patients
with scleroderma should be screened for its
presence on a regular basis.
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• shortness of breath (dyspnea)
• Initially, only short of breath when exert
  oneself physically but
• eventually may be short of breath most of the
  time, even when
• at rest.
• fatigue or light-headed upon exertion
• dizziness or fainting spells (syncope)
• swelling (edema) in ankles, legs and eventually
  in
• abdomen (ascites) fluid leak out of veins
  and into tissues
• bluish colour to lips and skin (cyanosis)

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• coughing (sometimes with blood) and wheezing
• distended neck veins
• enlarged liver
• racing pulse or heart palpitations
• angina-like chest pain
• feel weak body tissues not receiving enough
  oxygen
• achy joints (often developed years before
  apparent onset of
• disorder)

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• Signs and Symptoms in
  Children
• The symptoms of PH for children are similar to
  that of an adult, though children are more likely
  to experience tiredness, dizziness and
  breathlessness and for many, fainting is common.
• fail to put on weight like a normal child
• slowed growth
• Children tend to be diagnosed earlier than
  adults, but just like adults, they are often
  misdiagnosed several times before a correct
  diagnosis is made. The commonest misdiagnosis is
  asthma.
• Untreated PH in children worsens quicker than the
  same condition in adults. However, with
  treatment, children appear to have an overall
  better prognosis than adults.

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DIAGNOSIS OF PH
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It is often very difficult to initially diagnose
PH. In fact, there is often a lengthy delay
between the time when patients first visit their
doctor and the time they receive specialist care
at a hospital. Since there is no single test
that will tell the healthcare team if a patient
has PH, it is important to consider all
associated diseases as well as other causes of
breathlessness, such as certain lung and heart
diseases and blood clots. The ruling out of
different diseases that are possible causes of
particular symptoms is called the differential
diagnosis. A definite diagnosis of PH usually
requires passing a tube through a vein in an arm
or a leg into the right side of the heart to
measure the blood pressure in the right ventricle
and the pulmonary artery.
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• For patients with suspected PH, there are several
  initial steps that are commonly taken to confirm
  the diagnosis. These are first discussed between
  the patient and the healthcare team
• history of present illnesses
• past medical history
• family history
• any past or present medications that the patient
  may have taken
• A thorough physical examination will also take
  place. After this, a number of tests may be
  ordered to aid in assessment and diagnosis of PH.

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Chest X-Ray
Based on the symptoms, a doctor may suspect PH in
people who have an underlying lung disorder. A
chest x-ray may show that the pulmonary arteries
are enlarged. This imaging test offers the
physician a picture of the general size, shape
and structure of the heart and lungs. One of the
things the physician will check is whether the
right side of the heart is enlarged.
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Echocardiography (Ultrasonic Cardiography)

• This test uses sound waves to track the structure
  and function of the heart. It can compose images
  of a beating heart on a monitor and detects
• hearts thickness, size and function
• motion pattern and structure of the four heart
  valves
• ? revealing any potential leakage
  (regurgitation)
• thickening of right ventricle, enlarged right
  heart
• reversal of blood through tricuspid valve
• extent of lung damage
• A specific echocardiogram, Doppler ultrasound, is
  sometimes used to determine pulmonary artery
  pressure.
• Exercise echocardiogram determine how well
  heart works under stress

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Electrocardiogram (ECG)

• ECG is a record of the electrical activity
  produced by the heart. Abnormal rhythms
  (arrhythmias) may indicate that the heart or part
  of the heart is undergoing unusual stress.
• Exercise ECG helps evaluation of performance of
  the heart during exercise, for example, walking
  on a treadmill in the examination room.

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Perfusion Lung Scan

• Uses small amounts of radioactive tracers
  (radioisotopes) to study blood flow in the lungs.
  Radioisotopes are attached to radiopharmaceuticals
  which are then injected into a vein the arm. A
  gamma camera takes pictures of blood flow in the
  lungs blood vessels. It is generally used to
  determine whether blood clots may be causing
  symptoms of PH.

Pulmonary Function Tests

• Non-invasive tests to measure how much air your
  lungs can hold and the airflow in and out of your
  lungs. They can also measure the amount of gases
  exchanged across the membrane between the lung
  wall and capillary membrane. During the tests,
  the patient will be asked to blow into a
  spirometer. An abnormality here may be amongst
  the first indication of PH.

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Computerized Tomography (CT)

• Organs can be scanned in two-dimensional
  slices. Split-second computer processing
  creates images as a series of very thin x-ray
  beams pass through the body. A contrast medium is
  used to help visualization. The fast CT machine
  can scan arteries in less than 20 seconds as
  opposed to 20 minutes for a standard CT. Speed is
  important because it allows the dye to be
  visualized while still in the arteries.

Magnetic Resonance Imaging (MRI)

• Uses no x-rays but instead, a computer creates
  tissue slices from data generated by a powerful
  magnetic field and radio waves. Although not yet
  routinely used to diagnose PH, it is showing
  great value in assessing the pulmonary arteries.
  It cannot, however, measure artery pressure.

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• Other screening or
  diagnostic methods
• exercise testing
• ventilation-perfusion (V/O) scanning
• arterial blood gas studies
• central hematocrit count
• serum glucose and calcium levels count
• platelet count
• hyperoxia (100 oxygen) challenge test

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TREATMENT OF PH
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Until recently, nothing much could be done for
people with pulmonary hypertension. Before 1990,
there were very few treatments available for PH
and the survival rate was approximately two to
four years. Since then, a number of exciting new
treatments that are able to slow progression of
the disease and may even reverse some of the
damage to lungs and heart are gradually becoming
available. Some people do well on drugs others
may need a transplant. Some patients might also
require supplemental oxygen delivered through
nasal prongs or a mask if breathing becomes
difficult whereas some need oxygen around the
clock. In severely affected cases, a heart-lung,
single lung of double lung transplantation may be
appropriate.
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PH patients respond differently to different
medicines that are prescribed to dilate or relax
blood vessels and no one drug can be said to be
consistently effective in all patients. Because
individual reactions vary, different drug have to
be tried before chronic or long-term treatment
begins. During the course of disease, the amount
and type of medicine may also have to be changed.
To find out which medicine works best for a
particular patient, the drugs should be evaluated
via cardiac catheterization. This way, they can
see the effect of the medicine on the patients
heart and lungs. They can also adjust the dose to
reduce the side effects such as systemic low BP,
nausea, angina, headache etc that may occur. To
determine whether a drug is improving a patients
condition, both the pulmonary pressure and the
amount of blood being pumped by the heart
(cardiac output) must be evaluated.
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• Calcium Channel Blockers
• blocks entry of calcium into muscle cells of
  heart arteries
• improve ability of heart to pump blood
• relaxes smooth muscle in walls of heart and
  blood vessels
• amlodipine (Norvasc), diltiazem (Cardizem,
  Tiazac),
• nifedipine (Adalat, Procardia), nicardipine
  (Cardene) etc.
• only small number of people with PH respond to
  them
• side effects constipation, nausea, headache,
  rash, edema,
• drowsiness, dizziness, low blood pressure

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Blood Vessel Dilators

• Prostacyclin
• substance that acts like a hormone
  (prostaglandin)
• imitates behaviour of natural prostacyclin
• powerful vasodilator and anti-clotting agent
• prevent blood clots from forming
• given intravenously through catheter
• bridge to help those waiting for transplant
• Epoprostenol (Flolan) - 1st vasodilator approved
  by FDA
• Ilopost - inhaled through nebulizer
• Treprostinil - injected under skin
• side effects - jaw pain, nausea, leg cramps etc
• need comprehensive follow-up care

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Endothelin Receptor Antagonists

• available in pill form
• reverse effect of endothelin (blood vessels
  constriction)
• Bosentan (Tracleer) - may improve stamina of
  people with PH
• not for pregnant women
• need monthly liver monitoring - risk of liver
  complications

Phosphodiesterase Inhibitors

• Revatio contains sildenafil
• same active ingredient used in Viagra
• blocks the enzyme phosphodiesterase
• accentuates actions of nitric oxide
• opens blood vessels in the lungs - dilation
• side effect - vision problems

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Anticoagulant

• warfarin (Coumadin)
• prevent formation of blood clots within
  pulmonary arteries
• risk of bleeding complications prevent normal
  blood coagulation
• periodic blood tests check how well the drug
  is working
• more than 100 drugs can interact with
  anticoagulants

Diuretics

• water pills
• eliminate excess fluid from body
• reduces amount of work heart has to do
• limit fluid buildup in the lungs
• improve exchange of gases in lungs

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Oxygen

• oxygen therapy
• especially for those who live in high altitude
• or have sleep apnea
• continuous use of oxygen through
• nasal prongs/oxygen mask
• relieve shortness of breath

Cardiotonics

• strengthen the contractions of the heart
• heart does not need to beat as often to
  circulate adequate
• blood for body

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Transplants

• surgical interventions considered only in
  extreme cases
• treatment for severe secondary PH if treatment
  of the underlying
• disorder fails
• surgically replace damage organs with healthy
  donated organs
• lung and/or heart transplantation
• most common single-lung transplant, fewer
  complications than
• double-lung or heart-lung transplant
• lung transplant - improvement in structure and
  functioning
• of right ventricle
• major risks rejection of transplanted organ,
  serious infection
• take immunosuppressant drugs for life help
  reduce chance of
• rejection
• survival rate is about 60 per year and 37 per
  5 years

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Lung and heart for transplant
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Other treatment procedures

• Dilation Atrial Septostomy
• experimental procedure
• use in patient with severe PH
• makes a small hole in the heart, slowly
  enlarging it to
• relieve some of the pressure in the hearts
  right side
• shunts blood across the atrial septum and into
  the left side
• of the heart
• similar to balloon atrial septostomy naturally
  occurring
• hole present at birth is enlarged to help
  those with
• congenital heart defects
• Other areas of research for treatment of PH
  includes gene therapy and stem cell research.

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Pregnancy and PH
The consensus of medical opinion is that PH and
pregnancy is very dangerous. The life of the
mother and baby are put at great risk. Pregnancy
can really take its toll on a womans body. For
example, heart rate speeds up and the immune
system does not work quite as well. For a woman
whose body already has to deal with a severe
illness, pregnancy can actually have catastrophic
consequences. The risk of pregnancy-related death
in women with PH is substantial reported to be
as high as 30-50. Some drugs commonly used to
treat PH can be harmful to the developing fetus
(e.g. warfarin). Because of this twofold risk to
both mother and baby, use of some form of birth
control to avoid pregnancy is strongly advised in
women of childbearing age with PH.
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Children and PH
Unfortunately, there is no minimum age for PH
sufferers. Newborn, young children, teenagers and
even in early adulthood, PH may occur.
Untreated PH in children worsens more quickly
than the same condition in adults. Children also
change more quickly than adults and have to be
watched closely. However, with treatment,
children appear to have an overall better
prognosis than adults. Children are responsive
to the same treatments as adults. Treatment for
PH is lifelong. The treatment used has to be
individualized and adjusted according to how the
child is responding.
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Children and PH
A child with PH can still go to school, dance,
play sports or ride a bike. Just like other
children, a child with PH can help themselves by
eating a healthy and balanced diet and have good
rest periods. It is really important to have a
greater degree of caution in allowing other
non-PH doctors prescribe medication for a child
with PH.
It is hard but children with PH should be treated
as normally as possible. The child will be
happier and feel safer if they are treated just
like the rest of the family.
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News From Home
KUALA LUMPUR Siti Salmah Jasni is on a
heart-and-lung support machine and still in
critical condition. A statement issued by the
National Heart Institute (IJN) said Siti Salmah
is awake and able to respond to doctors.Siti
Salmah underwent a six-hour heart and lung
transplant at 12.10am on Friday at IJN. She was
suffering from pulmonary hypertension. The
18-year-old is the first in IJN's history to
receive a combined heart and lung
transplant.The organs were harvested by a
10-member IJN team on Thursday night at the
Sultanah Bahiyah Hospital in Kedah from a woman
donor who became brain dead after a road
accidentIJN thanked the donor's family for
their generosity during their hour of grief.
New Straits Times 2007/11/04
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Recent advances in genetics and newer
understandings in cell biology are providing
fresh insights into the nature of this disease.
New therapies offer an improved quality of life
and increased survival rates in both adults and
children.
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gov/medlineplus/pulmonaryhypertension.html www.pha
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