‫ﺑﺴﻢ اﷲ اﻟﺮﺣﻤﻦ اﻟﺮﺣﻴﻢ‬

PULMONARY
HYPERTENSION
DEFINITION:

Pulmonary hypertension (PH) is defined as

a mean pulmonary artery pressure greater
than 25 mmHg at rest or 30 mmHg with
exercise, as measured by right heart
catheterization
(WHO) classified PH into five groups:

1. Pulmonary arterial hypertension (PAH)

2. Pulmonary hypertension with left heart disease
3. Pulmonary hypertension associated with lung
diseases and/or hypoxaemia
4. Pulmonary hypertension because of chronic
thrombotic and/or embolic disease
5. Miscellaneous
1. Pulmonary arterial hypertension (PAH):
1. Idiopathic (IPAH
2. Familial (FPAH)
3. Associated (APAH)
• Collagen vascular disease
• Congenital systemic-to-pulmonary shunts
• Portal hypertension
• HIV infection
• Drugs and toxins
• Other (thyroid disorders, glycogen storage disease, Gaucher
disease, hereditary haemorrhagic
telangiectasia,haemoglobinopathies, myeloproliferative
disorders, splenectomy)
4. Associated with significant venous or capillary involvement
• Pulmonary veno-occlusive disease
• Pulmonary capillary haemangiomatosis
5. Persistent pulmonary hypertension of the newborn
hemodynamic parameters characterize PAH:

1. Mean pulmonary artery pressure (mPAP) >25

mmHg at rest or >30 mmHg with exercise
2. Pulmonary capillary wedge pressure (PCWP)
<15 mmHg
3. Pulmonary vascular resistance (PVR) >120
dynes/sec/cm5
4. Transpulmonary gradient >10 mmHg,
defined as the difference between mPAP and
PCWP
2. Pulmonary hypertension with left heart
disease:

• Left-sided atrial or ventricular heart disease

• Left-sided valvular heart disease
3. Pulmonary hypertension associated with
lung diseases and/or hypoxaemia:

• Chronic obstructive pulmonary disease

• Interstitial lung disease
• Sleep-disordered breathing
• Alveolar hypoventilation disorders
• Chronic exposure to high altitude
• Developmental abnormalities
4. Pulmonary hypertension because of
chronic thrombotic and/or embolic disease:

• Thromboembolic obstruction of proximal

pulmonary arteries
• Thromboembolic obstruction of distal
pulmonary arteries
• Non-thrombotic pulmonary embolism (tumour,
parasites, foreign material)
5. Miscellaneous:

• Sarcoidosis
• histiocytosis X
• lymphangiomyomatosis
• compression of pulmonary vessels
(adenopathy, tumour, fibrosing mediastinitis)
PATHOPHYSIOLOGIC MECHANISMS:
• Hemodynamic variables that contribute to
pulmonary arterial pressure can be identified
using a variation of Ohm's Law:
• Change in pressure = flow x resistance
• Ppa - Ppv = Q x PVR
• Ppa = (Q x PVR) + Ppv
• Ppa is mean pulmonary arterial pressure
• Ppv is mean pulmonary venous pressure
• Q is right-sided cardiac output
• PVR is pulmonary vascular resistance.
• Mean pulmonary venous pressure can be
estimated by the pulmonary capillary wedge
pressure (PCWP), which is measured by right
heart catheterization. Thus,
Ppa = (Q x PVR) + PCWP
• From this equation, it is apparent that mean
pulmonary arterial pressure is determined by:
1. Right-sided cardiac output
2. Pulmonary vascular resistance
3. Mean pulmonary venous pressure
Disease processes associated with an
elevated CO include:

1. congenital systemic to pulmonary shunts

2. hyperthyroid state
3. Arterialvenous fistula
4. portopulmonary hypertension (POPH)
Disease processes associated with an
elevated PVR include:
1. idiopathic PAH
2. Familial PAH
3. portopulmonary hypertension (POPH)
4. Collagen vascular disease
5. HIV infection
6. drug and/or toxin exposure
7. lung disease and/or hypoxaemia
8. Chronic thrombotic and/or embolic disease
9. extrinsic compression of pulmonary vessels
10.pulmonary venoocclusive disease (PVOD)
11.pulmonary capillary haemangiomatosis (PCH)
Disease processes associated with an
elevated Mean pulmonary venous pressure
(Ppv) :

1. left-sided atrial or ventricular disease

2. left-sided valvular disease.
• Regardless of the cause, a predictable
sequence of events occurs. The initial insult
causes mild PH. The elevated pressure
induces additional damage to the pulmonary
vasculature, which narrows the pulmonary
vascular bed. The right ventricle
hypertrophies in order to overcome the
increased resistance. Eventually, the right
ventricle dilates. By this time, patients may
have severe symptoms, including symptoms
at rest.
• Injured endothelial cells release factors that are
known to contribute to PAH. Inhibition of these
factors form the basis of some of the advanced
therapies for PH.
• Plasma levels of endothelin, a vasoconstrictor and
stimulant of vascular smooth muscle cell
proliferation, are elevated in patients with PAH.
• Plasma thromboxane B2 levels are also elevated
in patients with PAH. Thromboxane B2 causes
platelet activation and constriction of pulmonary
arterioles.
COPD and PH:
• Chronic obstructive pulmonary disease (COPD)
induces PH by increasing pulmonary vascular
resistance through two mechanisms:
1. hypoxia-induced vasoconstriction
2. obliteration of the vascular bed
• Chronic bronchitis is more frequently
associated with early chronic hypoxemia and
severe PH
• emphysema is associated with destruction of
the pulmonary vasculature and slower
progression of PH
• Pulmonary hypoxic vasoconstriction is a normal
regulatory mechanism designed to limit blood
flow to hypoxic alveoli and preserve ventilation-
perfusion matching. Its effect on pulmonary
vascular pressure depends on the duration of
the hypoxia. Short-term hypoxia causes
immediate precapillary arteriole vasoconstriction,
which is mediated by mitochondrial signaling in
smooth muscle cells and can be fully reversed
with oxygen therapy.
• Mechanisms by which chronic hypoxia induce
vasoconstriction include:
1. The endogenous vasodilator, nitric oxide, decreases due to
diminished endothelial nitric oxide synthase (eNOS)
production.
2. Production of the voltage-gated potassium channel's alpha
subunit or activity of the full transmembrane protein
decrease, causing the resting membrane potential to
change. As a result, intracellular free calcium increases and
pulmonary artery smooth muscles contract (ie,
vasoconstriction). Cytosolic phospholipase
3. A2 (cPLA2) activity increases, which releases arachidonic
acid from phospholipid membranes. Arachidonic acid can
then be metabolized by cyclooxygenases and lipoxygenases
into a number of different vasoactive eicosanoids, including
prostaglandins, thromboxanes, and leukotrienes. Expression
of endothelin increases.
• Pathologic changes are consistent with the
clinical observation that hypoxic vasoconstriction
is initially reversible, but eventually becomes
irreversible due to vascular remodeling.
• Specifically, initial changes include distal
neomuscularization of the arterioles, intimal
thickening, and medial hypertrophy. Abnormal
collagen matrix is deposited within the adventitia
later.
• The varying degree to which each individual's
disease is reversible may explain, in part, why
the progression to severe PH and cor pulmonale
is unpredictable in patients with COPD.
 MOLECULAR MECHANISMS:
1. Bone morphogenetic protein receptor-
II(BMPR2):
• (BMPR2) may play an important role in the
pathogenesis of IPAH
• up to 25 % of patients with IPAH having
abnormal BMPR2 structure or function.
• The BMPR2 pathway induces apoptosis in some
types of cells and it has been hypothesized that
abnormal pathway activity may permit excess
endothelial cell growth and proliferation in
response to a variety of injuries.
2. Herpesvirus-8 — Human herpesvirus-8
HHV-8:

• also called Kaposi's sarcoma associated

herpesvirus
• HHV-8 genes and proteins were detected
in 10 of 16 patients with IPAH
• the role of HHV-8 in the pathogenesis of
IPAH remains speculative, and may vary
according to environmental factors.
3.Potassium channel dysfunction:

• Some data suggest that IPAH may result

from functional impairment of the
voltage-gated potassium channel
(Kv) in pulmonary artery smooth muscle
cells.
• Such impairment could lead sequentially
to a change in resting membrane
potential, elevation of the intracytoplasmic
free calcium concentration, and an
increase in pulmonary vascular tone
CLINICAL MANIFESTATIONS:

• Complaint:
• exertional dyspnea, lethargy, fatigue
which are due to an inability to increase
cardiac output with exercise
• exertional chest pain (ie, angina), exertional
syncope, and peripheral edema
which are due to right ventricular failure
• anorexia and abdominal pain in the right
upper quadrant
Passive hepatic congestion
• Less common symptoms
cough, hemoptysis
hoarseness (ie, Ortner's syndrome)
due to compression of the left
recurrent laryngeal nerve by a dilated
main pulmonary artery.
Physical examination:
1. accentuation of the pulmonic component of
the second heart sound (P2)
2. Pulmonary ejection sounds, such as a systolic
ejection click and midsystolic ejection murmur
3. diastolic pulmonic regurgitation murmur
4. prominent A wave in the jugular venous pulse
5. right ventricular fourth heart sound (S4) which
is augmented by inspiration
6. left parasternal heave or a downward subxiphoid
thrust
• Right ventricular failure results in systemic venous
hypertension leading to a variety of findings such
as:
7. elevated jugular venous pressure
8. right ventricular third heart sound
9. high-pitched tricuspid regurgitant murmur
accompanied by a prominent V wave in the jugular
venous pulse if tricuspid regurgitation is present
10. hepatomegaly, a pulsatile liver, peripheral
edema, and ascites
 Functional assessment of patients with
pulmonary arterial hypertension:

• Class I
• Patients with PH limitation of physical activity.
• Ordinary physical activity does not cause undue
dyspnoea or fatigue, chest pain or near syncope
• Class II
• Patients with PH resulting in slight limitation of
physical activity. They are comfortable at rest.
• Ordinary physical activity causes undue dyspnoea or
fatigue, chest pain or near syncope
• Class III:
• Patients with PH resulting in marked limitation of
physical activity. They are comfortable at rest.
• Less than ordinary activity causes undue
dyspnoea or fatigue, chest pain or near syncope
• Class IV:
• Patients with PH with inability to carry out any
physical activity without symptoms.
• These patients manifest signs of right heart
failure.
• Dyspnoea and/or fatigue may even be present
at rest.
• Discomfort is increased by any physical activity
DIAGNOSTIC TESTS:

1. Chest radiograph:
• The characteristic chest radiograph shows
enlargement of the central pulmonary arteries
with attenuation of the peripheral vessels,
resulting in oligemic lung fields.
• Right ventricular enlargement (diminished
retrosternal space) and right atrial dilatation
(prominent right heart border) may also be seen.
• Occasionally, the underlying cause of the PH is
apparent on the chest radiograph (eg, interstitial
lung disease).
 Electrocardiography:
• The electrocardiogram (ECG) may demonstrate
signs of right ventricular hypertrophy or strain.
• findings suggestive of chronic right ventricular
overload may exist, including:
- right axis deviation
- R wave/S wave ratio greater than one in lead V1
- incomplete or complete right bundle branch block
- increased P wave amplitude in lead II (P
pulmonale) due to right atrial enlargement.
- Most ECG signs are specific but not sensitive for
the detection of right ventricular disease
 Echocardiography:
• Echocardiography is performed to estimate
the pulmonary artery systolic pressure and to
assess right ventricular size, thickness, and
function.
• In addition, echocardiography can evaluate
right atrial size, left ventricular systolic and
diastolic function, and valve function, while
detecting pericardial effusions and
intracardiac shunts.
Pulmonary function tests:

• Pulmonary function tests (PFTs) are

performed to identify and characterize
underlying lung disease that may be
contributing to PH. An obstructive pattern
is suggestive of COPD, while restrictive
disease suggests interstitial lung disease,
neuromuscular weakness, or chest wall
disease.
Overnight oximetry:

• Nocturnal oxyhemoglobin desaturation can

be identified by overnight oximetery. It is
common in patients with PH and may
prompt supplemental oxygen therapy
during sleep
 V/Q scan:
• Ventilation-perfusion (V/Q) scanning is used to
evaluate patients for thromboembolic disease.
• A normal V/Q scan accurately excludes chronic
thromboembolic disease with a sensitivity of 90 to
100 percent and a specificity of 94 to 100 percent.
• When the V/Q scan suggests that chronic
thromboembolic disease exists, pulmonary
angiography is necessary to confirm the positive
V/Q scan and to define the extent of disease.
• V/Q scans are an important part of the diagnostic
evaluation because PH due to chronic
thromboembolic disease is potentially reversible
with surgery.
 Laboratory tests:

• HIV serology to screen for HIV-associated PH

• Liver function tests to screen for
portopulmonary hypertension
• Antinuclear antibody (ANA), rheumatoid factor
(RF), and antineutrophil cytoplasmic antibody
(ANCA) titers to screen for PH due to the
connective tissue diseases
N-terminal pro-brain natriuretic
peptide (NT-proBNP):
• (NT-proBNP) is the precursor of brain
natriuretic peptide (BNP).
• Both peptides are released from the
myocardial tissue of the right and left
ventricle when stretched.
• Increasing evidence suggests that NT-proBNP
and BNP are helpful in diagnosing heart
failure. It has been hypothesized that
measurement of either peptide may also be
helpful in the diagnosis of PH, since right
heart failure often complicates PH.
Exercise testing:

• Exercise testing is most commonly performed

using the six minute walk test (6MWT) or
cardiopulmonary exercise testing.
• Exercise testing screens for alternative causes of
the patient's symptoms. In addition, the exercise
capacity is used to: Determine the patient's New
York Heart Association (NYHA) or WHO functional
class, which guides therapy . Establish a baseline
from which the response to therapy can be
measured.
Right heart catheterization:

• Right heart catheterization is necessary to

confirm the diagnosis of PH and accurately
determine the severity of the
hemodynamic derangements.
• PH is confirmed if the mean pulmonary
artery pressure is greater than 25 mmHg
at rest or 30 mmHg with exercise
 Treatment of pulmonary hypertension:

• Primary therapy
refers to therapy directed at the underlying
cause of the PH.
• Advanced therapy
refers to the administration of agents with
complex mechanisms of action which promote
vasodilation and impact vascular growth and
remodeling.
therapies should be considered in all
patients with PH, regardless of the etiology:

Diuretics:
• Diuresis will diminish hepatic congestion
and peripheral edema. However, it should
be performed with caution to avoid
decreased cardiac output (due to
decreased right and/or left ventricular
preload), arrhythmias induced by
hypokalemia, and metabolic alkalosis
(which can depress ventilation).
 Oxygen therapy:
• Continuous oxygen administration remains
the cornerstone of therapy in patients with
group 3 PH.
It is inferred that oxygen may benefit
other groups of patients with PH plus
resting, exercise-induced, or nocturnal
hypoxemia. However, long-term data do
not exist.
 Anticoagulation:
• Patients with PH are at increased risk for
intrapulmonary thrombosis and thromboembolism,
due to sluggish pulmonary blood flow, dilated right
heart chambers, venous stasis, and a sedentary
lifestyle. Even a small thrombus can produce
hemodynamic deterioration in a patient with a
compromised pulmonary vascular bed that is
unable to dilate or recruit unused vasculature.
• The anticoagulant of choice is warfarin, with a
therapeutic goal of an International Normalized
Ratio (INR) of approximately two.
 Digoxin:
• Digoxin therapy has been shown to have the
following beneficial effects and drawbacks:
• In patients with group 3 PH due to COPD and
biventricular failure:
• digoxin improves left ventricular ejection
fraction.
• However, patients with COPD may be more
sensitive than most patients to digitalis toxicity
and require close monitoring.
• In patients with supraventricular tachycardias
associated with right ventricular dysfunction,
digoxin helps control the heart rate.
• However, verapamil is preferred for multifocal
atrial tachycardia unless there is concurrent left
ventricular failure.
• Most pharmacologic agents used to treat
PH promote vasodilation and are
antiproliferative. These include:
1. prostanoids (eg, epoprostenol, treprostinil,
and iloprost)
2. endothelin receptor antagonists (eg,
bosentan)
3. phosphodiesterase-5 (PDE5) inhibitors (eg,
sildenafil)
4. Calcium channel blockers (CCBs, primarily
nifedipine)
General approach:
• Patients with PH should undergo an invasive
hemodynamic assessment and an acute vasoreactivity
test prior to the initiation of advanced therapy.
• Patients with a positive vasoreactivity test can be given a
trial of oral CCB therapy.
• In contrast, patients with a negative vasoreactivity test
require advanced therapy with a prostanoid, endothelin
receptor antagonist, or PDE5 inhibitor.
• Combination advanced therapy may be appropriate in truly
refractory cases, although data are limited.
• Lastly, some patients will be refractory to all medical
interventions. In these cases, lung transplantation or
creation of a right to left shunt by atrial septostomy may
be considered.
Vasoreactivity test:

• The test involves administration of a

short-acting vasodilator, then measuring
the hemodynamic response with a right
heart catheter.
• Agents commonly used for vasoreactivity
testing include epoprostenol, adenosine,
and inhaled nitric oxide.
• An acute vasoreactivity test is considered
positive if mean pulmonary artery pressure
decreases at least 10 mmHg and to a value
less than 40 mmHg, with an increased or
unchanged cardiac output, and a minimally
reduced or unchanged systemic blood
pressure.
ADVANCED THERAPY:

DRUG ROUTE DOSE RANGE HALF-LIFE

Epoprostenol IV 1 to 20 ng/kg/min 3-5 min
Treprostinil SC 0.625 to 1.25 4-5 hr
ng/kg/min
Iloprost inhaed 2.5 to 5 mcg, 6-9 1-2 hr
times/day
Bosentan oral 62.5 to 125 mg, 5 hr
2 times/day
Sildenafil oral 20 mg, 3 4 hr
times/day
 DRUG ROUTE DOSE HALF-LIFE
RANGE
Adenosine IV 50 to 200 5-10 sec
μg/kg/min
Nitric oxide Inhaled 5 to 80 ppm 15-30 sec

Nifedipine Oral 30 to 240 2-5 hr

mg/day
Diltiazem Oral 120 to 900 2-4.5 hr
mg/day
Thank you