Pulmonary hypertension

PULMONARY
HYPERTENSION
DR. ABHAY MANGE

PULMONARY CIRCULATION
 The pulmonary circulation is the vascular system that
conducts blood from the right to left side of the heart
through the lungs
 Pulmonary arteries are very thin walled and distensible.
 Pulmonary vascular resistance (PVR) is a measure of the
impedance to flow in the pulmonary vasculature
 PVR Depends on pulmonary artery pressure ,left atrial
pressure and the cardiac output
 Normal pulmonary artery pressure=25/8 mmHg
 Normal mean pulmonary artery pressure=15+/-3mmHg

INTRODUCTION
 Pulmonary hypertension (PH) is an abnormal
elevation in pulmonary artery pressure
 It is a feature of advanced disease.
 The pulmonary artery pressure and pulmonary
vascular resistance progressively rises, leading to
right heart failure and death.
 Over the years, improvement in understanding the
pathogenesis has resulted in the development of
targeted approaches to the treatment of PH.
 Survival advantage has also been shown with some
of the pharmacologic agents.

DEFINATIONS
 Pulmonary hypertension (PH) is haemodynamic
and pathophysiological condition defined as
mean pulmonary artery pressure > 25 mmHg at
rest by Right heart Catheterization(RHC).

 Pulmonary arterial hypertension (PAH) is a clinical
condition characterized by the presence of pre-
capillary PH in absence of other causes of pre-
capillary PH such as PH due to lung
diseases, chronic thromboembolic PH, or other
rare diseases

HISTORY
 E. Romberg, German doctor published description of
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.
 Between 1967 and 1973, a 10-fold increase in
unexplained PH 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.

CLASSIFICATION OF
PULMONARY HYPERTENSION

 First version was proposed in 1973 at the first
international conference on PPH by WHO.
 Second and third world meetings on PAH in 1998 and
2003, respectively.
 Fourth World meet on PH held in 2008 in Dana
Point, California,adopted new clinical classification.

GROUP 1. PULMONAY ARTERIAL HYPERTENSION
Key feature: Elevation in PAP with normal PCWP
 Idiopathic (IPAH)
 Heritable ( BMPR2, ALK1, endoglin , Unknown)
 Exposure to drugs or toxins
 Persistent pulmonary hypertension of the newborn
 Associated with (APAH)
 Collagen vascular disease
 Congenital heart diseases
 Portal hypertension
 HIV infection
 Schistosomiasis
 Chronic haemolytic anaemia
GROUP 1’ Pulmonary veno-occlusive disease(PVOD) and
pulmonary capillary haemangiomatosis

GROUP 2. Pulmonary venous
hypertension

Key feature: Elevation in PAP with elevation in PCWP
Includes:
 Systolic dysfunction
 Diastolic dysfunction
 Valvular disease

GROUP 3. PH ASSOCIATED WITH
HYPOXEMIC LUNG DISEASE.

Key feature: chronic hypoxia with mild elevation of
PAP, Includes:
 Chronic obstructive lung disease
 Interstitial lung disease
 Sleep-disordered breathing
 Alveolar hypoventilation disorders
 Chronic exposure to high altitude
 Developmental abnormalities

GROUP 4. PH DUE TO CHRONIC
THROMBOEMBOLIC DISEASE

Key feature: elevation of PA pressure with
documentation of pulmonary arterial obstruction for
>3 months Includes:
 Chronic pulmonary thromboembolism

GROUP 5. WITH UNCLEAR AND/OR
MULTIFACTORIAL MECHANISMS

Key feature: elevation in PAP in association with a systemic disease
where a causal relationship is not clearly understood. Includes:
 Haematological disorders: myeloproliferativedisorder,splenectomy.
 Systemic disorders : sarcoidosis, pulmonary Langerhans cell
histiocytosis, neurofibromatosis, vasculitis
 Metabolic disorders: Glycogen storage disease, Gaucher disease
Thyroid disorders
 Others: Tumoural obstruction, fibrosing mediastinitis
chronic renal failure on dialysis

PATHOLOGY OF PH

 Different pathological features characterize the diverse
clinical PH groups.
Group 1 - PAH
 Affect the distal pulmonary arteries (<500 um of
diameter) in particular, are characterized by
 Medial hypertrophy,
 Eccentric and concentric intimal fibrosis,
 Recanalized thrombi appearing as fibrous webs,
 Plexiform lesions
 Pulmonary veins are classically unaffected.

PATHOLOGY OF PH

Group 1’ : Includes mainly PVOD
 Which involves septal veins and pre-septal venules
with occlusive fibrotic lesions, venous
muscularization, capillary proliferation , pulmonary
oedema, occult alveolar haemorrhage, lymphatic
dilatation and lymph node enlargement.
 Distal pulmonary arteries are affected .

PATHOLOGY OF PH
Group 2 - PH due to left heart disease:
 Characterized by enlarged and thickened pulmonary
veins, pulmonary capillary dilatation, interstitial
oedema,alveolar haemorrhage, and lymphatic vessel
and lymph node enlargement.
 Distal pulmonary arteries may be affected
Group 3 - PH due to lung diseases and/or hypoxia:
 Include medial hypertrophy and intimal obstructive
proliferation of the distal pulmonary arteries.
 A variable degree of destruction of the vascular bed in
emphysematous or fibrotic areas may also be present.

PATHOLOGY OF PH
Group 4 -CTEPH:
 Characterized by organized thrombi tightly attached to
medial layer in pulmonary arteries, replacing the
normal intima.
 These may completely occlude the lumen or form
different grades of stenosis, webs, and bands.
 Collaterals from the systemic circulation can grow.

Group 5-PH - unclear and/or multifactorial
mechanisms:
 Includes conditions with different pathological
pictures
 Aetiology is unclear or multifactorial.

PATHPHYSIOLOGY OF PH
Group 1-The exact processes that initiate the pathological
changes seen in PAH are still unknown
 The increase in PVR is related to vasoconstriction,proliferative and
obstructive remodelling of the pulmonary vessel
wall, inflammation, and thrombosis.
 Excessive vasoconstriction related to abnormal function or
expression of potassium channels in the smooth muscle cells and
endothelial dysfunction.

Group 2- the mechanisms are multiple and include
 Passive backward transmission of the pressure elevation .
 The elevation of PVR is due to an increase in vasomotor tone of
pulmonary arteries and fixed structural obstructive remodelling
 Vasoconstrictive reflexes arising from stretch receptors in the left
atrium and pulmonary veins, and endothelial dysfunction

PATHPHYSIOLOGY OF PH
Group 3- mechanisms include
 Hypoxic vasoconstriction, mechanical stress of
hyperinflated lungs, inflammation and toxic effects of
cigarette smoke.
Group 4 - Non-resolution of acute embolic masses
which later undergo fibrosis leading to mechanical
obstruction of pulmonary arteries
 Pulmonary thromboembolism or in situ thrombosis
may be initiated or aggravated by abnormalities in
either the clotting cascade, endothelial cells, or
platelets,
Group 5- PH with unclear and/or multifactorial
mechanisms

PULMONARY ARTERIAL HYPERTENSION
 PAH refers to a variety of diseases that include
idiopathic PAH.
 PAH Characterized by
 presence of pre-capillary PH in the absence of other
causes of pre-capillary PH.
 Mean PAP >25 mmHg
 PCWP< 15 mmHg .
 CO normal or reduced

MOLECULAR ABNORMALITIES IN PAH
Prostacyclin
 Prostacyclin is a potent vasodilator, inhibits platelet
activation, and has antiproliferative properties
 Prostacyclin synthase is decreased in the pulmonary arteries in
PAH
Endothelin-1
 Endothelin-1 (ET-1) is a potent vasoconstrictor and stimulates
PASMC proliferation.
 Plasma levels of ET-1 are increased in PAH and clearance is
reduced
Nitric Oxide
 Nitric oxide (NO) is a vasodilator and inhibitor of platelet
activation and vascular smooth-muscle cell proliferation.
 Once formed, the effects of NO are largely mediated by cGMP
which is rapidly inactivated by PDE, especially the PDE-5
isoenzymes.

MOLECULAR ABNORMALITIES IN PAH

Serotonin (5-HT) is a vasoconstrictor and promotes PASMC
hypertrophy and hyperplasia.
 Allelic variation in serotonin transporter present in PAH
Vasoactive intestinal peptide (VIP) has a pharmacologic
profile similar to prostacyclins.
 Serum and lung tissue VIP levels are decreased in PAH
patients

GENETICS OF PAH

BONE MORPHOGENETIC PROTEIN RECEPTOR 2 GENE(BMPR2)
 BMPR2 gene encodes a type 2 receptor for bone morphogenetic
proteins, which belong to the TGF-b superfamily involved in the
control of vascular cell proliferation
 mutations are detected in at least 70% of cases PAH occurs in a
familial context.
 Mutations of this gene can also be detected in 11–40% of
apparently sporadic cases.
ACTIVIN RECEPTOR-LIKE KINASE 1 AND ENDOGLIN, have been
identified in PAH

IDIOPATHIC PAH
 IPAH corresponds to sporadic disease,without any
familial history of PAH or known triggering factor.
 Formerly referred to as primary pulmonary
hypertension
 1-2 cases per million
 Females>males (1.7:1)

SIGNS AND SYMPTOMS
OF PH

SYMPTOMS

Easy fatigability, lethargy
Exertional chest discomfort
Syncope with exertion
Cough
Hemoptysis
Hoarseness of voice

SIGNS
 Increased intensity of the pulmonic component of the
second heart sound (P2)
 Systolic ejection murmur from TR S/O Advanced Disease.
 Diastolic murmur of PI in severe PH.
 left parasternal lift or heave
 Prominent ‘a’ wave in jugular venous system.
 Signs of RV failure:
 Jugular venous distension
 Hepatomegaly
 Ascites, and/or peripheral edema

WHO CLASSIFICATION OF FUNCTIONAL STATUS OF
PATIENTS WITH PH
Class Description
I Patients with PH in whom there is no limitation of usual physical activity;
ordinary physical activity does not cause increased dyspnea, fatigue,
chest pain, or presyncope.
II Patients with PH who have mild limitation of physical activity. There is no
discomfort at rest, but normal physical activity causes increased dyspnea,
fatigue, chest pain, or presyncope.
III Patients with PH who have a marked limitation of physical activity. There
is no discomfort at rest, but less than ordinary activity causes increased
dyspnea, fatigue, chest pain, or presyncope.
IV Patients with PH who are unable to perform any physical activity at rest
and who may have signs of right ventricular failure. Dyspnea and/or
fatigues may be present at rest, and symptoms are increased by almost
any physical activity. Chest 2004:126 (Suppl), JACC 2004:43 (Suppl)

NATURAL HISTORY AND SURVIVAL

 Median survival 2.8 years, with 1-, 3-, and 5-year survival
rates of 68%, 48%, and 34%, respectively.
 Functional class remains a strong predictor of survival
 The prognosis in patients with PAH associated with the
scleroderma is worse than for IPAH.
 CHD have a better prognosis than those with IPAH
 Cause of death is usually RV failure, manifest by progressive
hypoxemia, tachycardia, hypotension, and edema

PARAMETERS OF WORSE PROGNOSIS
IN PAH
 Presence of RV failure
 Rapid progression of symptoms
 Syncope
 WHO –FC IV
 6 MWT < 300 m
 Pericardial effusion

ELECTROCARDIOGRAPHY
 ECG has sensitivity(55%) and specificity (70%)
detecting significant PH ,may demonstrate
 Right ventricular hypertrophy or strain
 Right axis deviation
 P pulmonale due to right atrial enlargement.
 Ventricular arrhythmias are rare.
 SVT may be present in advanced stages

Electrocardiogram

Electrocardiogram
demonstrating the
 Right ventricular
hypertrophy with
strain
 Right axis
deviation ,
 Increased P-wave
amplitude in lead
II

CHEST RADIOGRAPH

 In 90% of patients with IPAH the chest radiograph is
abnormal.
 Findings include central pulmonary arterial
dilatation, which contrasts with ‘pruning’ (loss) of the
peripheral blood vessels.
 Right atrium and RV enlargement may be seen

CHEST RADIOGRAPH

 Enlargement of 
the central
pulmonary
arteries with
attenuation of
the peripheral
vessels

 Right ventricular
enlargement and
seen.

ECHOCARDIOGRAPHY
 Is performed to estimate the pulmonary artery systolic
pressure and to assess RV size, thickness, and function.
 In addition, left ventricular systolic and diastolic
function, and valve function, while detecting pericardial
effusions and intracardiac shunts.
 PH may have echocardiographic signs of right ventricular
pressure overload, including paradoxical bulging of the
septum into the left ventricle during systole and hypertrophy
of the right ventricular free wall.
 As the right ventricle fails, there is dilation and
hypokinesis, septal flattening, right atrial dilation, and
tricuspid regurgitation

ECHOCARDIOGRAPHY
 Echocardiography uses Doppler ultrasound to estimate the
pulmonary artery systolic pressure .
 This technique takes advantage of the tricuspid
regurgitation that usually exists.
 The maximum tricuspid regurgitant jet velocity is recorded
and the pulmonary artery systolic pressure (PASP) is then
calculated by Bernoulli’s equation
PAP systolic = 4 x ( tricuspid jet velocity squared)m/s
+ RAP
Theoretically, calculation of mean PAP from PA systolic
pressure is possible
mean PAP =0.61 X PAP systolic + 2 mmHg.
 A systolic PAP greater than 40 mmHg is suggestive of PH.

ECHOCARDIOGRAPHY

A four-chamber
echocardiographic
view of a patient who
has severe PAH.
Note the massively
dilated right ventricle
(RV) and right atrium
(RA) that have
shifted the septa and
narrowed the left
ventricle (LV) and
left atrium (LA).

Representation of echocardiographic findings in
pulmonary hypertension

VENTILATION-PERFUSION 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 .
 Pulmonary angiography is necessary to confirm the
positive V/Q scan and to define the extent of disease.

PULMONARY ANGIOGRAM

Used to measure
circulation in the lungs and
to visualize clots in the
lung on x-rays.

PULMONARY FUNCTION TESTS

 Pulmonary function tests (PFTs) are performed to
identify and characterize underlying lung disease
contributing to PH.
 An obstructive pattern is suggestive of COPD,
 Restrictive disease suggests ILD, neuromuscular
weakness, or chest wall disease.
 In most circumstances, PH should not be attributed
to lung disease if the PFTs are only mildly abnormal.

LABORATORY TESTS
 HIV serology to screen for HIV-associated PH
 Liver function tests to screen for porto-pulmonary
hypertension
 Antinuclear antibody (ANA)
 Thyroid function test
 NT-proBNP is the precursor of BNP in right heart failure .
 Anti-centromere antibodies in scleroderma
 Thrombophilia screening including anti-phospholipid
antibodies, lupus anticoagulant, and anti-cardiolipin
antibodies should be performed in CTEPH

OVERNIGHT OXIMETRY
 Nocturnal oxyhemoglobin desaturation can be
identified by overnight oximetry in patients with
PH —obstructive sleep apnea-hypopnea (OSAH)
coexists .
 Polysomnography is the gold standard diagnostic
test for OSAH.

ULTRASONOGRAPHY
 Useful in portal hypertension

EXERCISE TESTING

 Exercise testing is most commonly performed
using the six minute walk test (6MWT)
 Provide benchmarks for disease
severity, response to therapy, and progression.
 In addition to distance walked, dyspnoea on
exertion and finger O2 saturation are recorded.
 Walking distances , <250 m and O2 desaturation
10% indicate impaired prognosis in PAH.

RIGHT HEART CATHETERIZATION

 Right heart catheterization is necessary to
confirm the diagnosis of PH .
 Accurately determine the severity of the
hemodynamic derangements.
 PH is confirmed if the mean pulmonary artery
pressure is greater than 25 mmHg at rest .
 RHC is required to guide therapy
 An additional benefit of RHC is that the
presence and/or severity of a congenital or
acquired left-to-right shunt.

VASOREACTIVITY TEST
Aim: To detect the residual properties of vasodilatation
of small pulmonary arteries and arterioles .
 It is recommended in patients with group 1 PAH .
 This involves the administration of a short-acting
vasodilator and then measurement of the
hemodynamic response .
 Agents commonly used for vasoreactivity testing
include epoprostenol, adenosine, and inhaled nitric
oxide .
 Epoprostenol is infused at a starting rate of 1 to 2
ng/kg per min and increased by 2 ng/kg per min
every 5 to 10 minutes until a clinically significant fall
in blood pressure, an increase in heart rate, or
adverse symptoms develop .

VASOREACTIVITY TEST

 Test is positive if mPAP 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.
 Patients with a positive vasoreactivity test are
candidates for a trial of CCB therapy.
 Negative vasoreactivity test should be treated
with an alternative agent .

COMPUTERIZED TOMOGRAPHY

 High-resolution CT provides detailed views of the
lung parenchyma and facilitates the diagnosis of
interstitial lung disease and emphysema.
 High-resolution CT may be very helpful where there
is a clinical suspicion of PVOD
 Contrast CT angiography of the PA is helpful in
determining whether there is evidence of surgically
accessible CTEPH.

MAGNETIC RESONANCE IMAGING

 Cardiac MRI may soon supersede this as the gold standard.
 RV mass which is difficult to quantify by other methods can
be accurately done by MRI.
 By MRI, it can be shown that right ventricle has a crescent
shape and left ventricle has a more circular shape.
 When the right ventricle pressure is elevated quite the
opposite happens. This can be well demonstrated by MRI.

LUNG BIOPSY

 Is reserved only in an unusual patient in whom PH is
not thought to be the primary disease.
 In such patients, one always finds abnormalities such
as lung infiltrates or other findings such as
pulmonary hemangiomatosis or pulmonary
venoocclusive disease.

ALGORITHM FOR INVESTIGATION OF SUSPECTED PH

TREATMENT OF PH

 Early identification and treatment PH is generally
suggested because advanced disease may be less
responsive to therapy .
 Treatment begins with a baseline assessment of
disease severity, followed by primary therapy.
 Primary therapy is directed at the underlying cause of
the PH.
 Some patients progress to advanced therapy, which is
therapy directed at the PH itself, rather than the
underlying cause of the PH.
 It includes treatment with prostanoids, endothelin
receptor antagonists, phosphodiesterase 5
inhibitors, or, rarely, certain calcium channel blockers.

BASELINE ASSESSMENT

 The baseline severity assessment is essential because the
response to therapy will be measured as the change from
baseline.
 The functional significance of the PH is determined by
measuring exercise capacity.
 From the exercise capacity, the patient's WHO functional class
can be determined .
 Pulmonary artery systolic pressure and right ventricular
function can be estimated by echocardiography, and then used
to make a presumptive diagnosis of PH.
 Right heart catheterization must be performed to accurately
measure the hemodynamic parameters and confirm that PH
exists.

PRIMARY THERAPY
Primary therapy refers to treatment that is directed at the
underlying cause of the PH.
Group 1 PAH
 There are no effective primary therapies for most types ,
advanced therapy is often needed.
Group 2 PH — Patients with group 2 PH have PH secondary to
left heart diseases.
 Primary t/t of the underlying heart disease.
Group 3 PH — Patients with group 3 PH have PH secondary to
various causes of hypoxemia.
 treatment of the underlying cause of hypoxemia and
correction of the hypoxemia with supplement of oxygen

PRIMARY THERAPY

Group 4 PH — Patients with group 4 PH have PH due to
thromboembolic occlusion .
 Anticoagulation is primary medical therapy for patients .
 Surgical thromboendarterectomy is primary surgical
therapy for selected patients with thromboembolic
obstruction of the proximal pulmonary arteries .
 Perioperative mortality for this procedure is less than 10
percent
Group 5 PH — Group 5 PH is uncommon and includes PH
with unclear multifactorial mechanisms.
 Primary therapy is directed at the underlying cause.

GENERAL MEASURES
 All groups — Several therapies should be considered in all
patients with PH. .
Diuretics —
 Diuretics are used to treat fluid retention due to PH .
 Should be administered with caution to avoid decreased
cardiac output , arrhythmias induced by hypokalemia, and
metabolic alkalosis.
Oxygen therapy —
 Oxygen the cornerstone of therapy in patients with group 3 PH.
 Oxygen is generally administered at 1 to 4 L/min and adjusted
to maintain the oxygen saturation above 90 percent .
 Supplemental oxygen will not significantly improve the oxygen
saturation of patients who have Eisenmenger physiology.

GENERAL MEASURES
Digoxin —
 Improves the right ventricular ejection fraction of patients
with group 3 PH due to COPD and biventricular failure
 helps control the heart rate of patients who have SVT
associated with RV dysfunction .
Anticoagulation —
 increased risk for intrapulmonary thrombosis and
thromboembolism, due to sluggish pulmonary blood
flow, dilated right heart chambers, venous stasis, and a
sedentary lifestyle.
 indicated in patients with IPAH , hereditary PAH , drug-
induced PAH , or group 4 PH.
 The anticoagulant of choice is warfarin.
 Goal of an INR of approximately 2.

GENERAL MEASURES

 It is recommended to avoid pregnancy
 Immunization against influenza and pneumococcal
infection is recommended.
 Psychosocial support should be considered in
patients with PAH.
 Epidural anaesthesia instead of general anaesthesia
should be utilised, if possible, for elective surgery.
 Excessive physical activity that leads to distressing
symptoms is not recommended in patients.

ADVANCED THERAPY

 Advanced therapy is directed at the PH itself, rather
than the underlying cause of the PH.
 It includes treatment with prostanoids, endothelin
receptor antagonists, phosphodiesterase 5
inhibitors, or, rarely, certain calcium channel
blockers.
 Patient selection — Advanced therapy is considered
for patients who have evidence of persistent PH and
a World Health Organization WHO functional class
II, III.

CALCIUM CHANNEL BLOCKERS(CCB)
 Patient who may benefit from CCB therapy can be identified
acute vasodilator response test in PAH.
 The dosages used are quite high; 90–180 mg/day for nifedipine
(up to 240 mg/day) and 240–720 mg/day for diltiazem (up to
900 mg/day). or amlodipine, 20 mg/d
 <20% of patients respond to calcium channel blockers in the
long term.
 Not effective in patients who are not vasoreactive.
 Patients with BMPR2 receptor mutation do not respond .
 Side effects –
constipation, nausea, headache, rash, edema, drowsiness, dizzi
ness, low blood pressure

PROSTACYCLIN

 The main product of arachidonic acid in the vascular
endothelium causes relaxation of smooth muscle
 Also results in inhibition of growth of smooth muscle
cells.
 Intravenous prostacyclin was first introduced in the
early 1980s.
 Successfully used in the treatment of PH resulting
from left to right shunt, portal hypertension and HIV
infection.

EPOPROSTENOL
 Potent vasodilator ,Unstable at acidic pH, not taken orally.
 Very short half life,<6 min requires constant Iv administration
 Initial dose: 1 – 2 ng/kg/min
 Titrating in increments of 1- 2 ng/kg/min, based upon side
effects and tolerance to reach a “plateau” between 20 – 40
ng/kg/min
 Side effects: Flushing, headache, jaw pain with first bite of
food, diarrhea, nausea, erythematous rash and
musculoskeletal pain.
 Chronic IV therapy: Line related infections, catheter associated
venous thrombosis, thrombocytopenia
 Not available in India.

TREPROSTINIL

 Stable prostacyclin analogue.
 Can be given intravenously or subcutaneously and
Inhalation.
 Half life of 3 hours.
 Stable at room temperature
 Initially 1.25 ng/kg/min up to maximum of 22.5
ng/kg/min.
 Side effects: Headache, diarrhea, nausea, rash, jaw
pain, infusion site pain, erythema or induration.

ILOPROST
 Prostacyclin analogue.
 Serum half-life of 20 – 25 mins
 For functional class 3 – 4.
 Administered via nebulized
aerosol.
 Administered 6 – 9 times a
day, each inhalation requires
10 – 15 mins.
 Dose: 2.5 – 5 ug, median
inhaled dose of 30 ug/day.
 Side effects: Cough, headache
and flushing.

BERAPROST

 First chemically stable and orally active prostacyclin
analogue.
 Peak concentration is reached after 30 minutes and
elimination half-life is 35 – 40 minutes after oral
administration.
 Median dose of 80 ug PO daily.

ENDOTHELIN RECEPTOR ANTAGONISTS
 Endothelin-1 is a potent vasoconstrictor and smooth
muscle mitogen.
 High concentrations of endothelin-1 have been
recorded in the lungs of patients with group 1
PAH, including scleroderma and congenital cardiac
shunt lesions .
 Emerged as an initial therapy for group 1 PAH in the
late 1990s.

BOSENTAN

 Nonselective endothelin receptor antagonist,
 improves hemodynamics and exercise capacity in
patients with group 1 PAH.
 Orally active nonpeptide antagonist of both endothelin
receptor subtypes.
 Prevents and even reverses the development of
PH, pulmonary vascular remodelling and right ventricular
hypertrophy.
 Initial dose of 62.5 mg bid for first 4 weeks and followed
by target dose of 125 mg bid.
 Side effects: Hepatotoxicity and teratogenicity.
 Available in India.

SITAXSENTAN
 Selective ETA antagonist
 Has oral bioavailability and a long duration of action (t
1/2, 5-7h) .
 Side effects: ↑ INR and PT .

AMBRISENTAN
 ETA selective antagonist
 Under research

PHOSPHODIESTERASE INHIBITORS
SILDENAFIL
 Orally administered cyclic GMP phosphodiesterase 5 (PDE5)
inhibitors that prolong the vasodilatory effect of NO in
group 1 PAH.
 Approved dose is 20 mg t.i.d., but the durability of effect up
to a up-titration beyond 20 mg t.i.d. (mainly 40–80 mg
t.i.d.) is needed quite frequently.
 Contraindicated with Nitrates and nicorandil.
 Prevent rebound pulmonary vasoconstriction
Tadalafil and vardenafil also appear to improve outcomes in
patients with group 1 PAH.

NITRIC OXIDE
 Inhaled form.
 Acts as direct smooth muscle
relaxant via activation of the
guanylate cyclase system.
 Short therapeutic half life.
 Ameliorates hypoxemia and
lowers PVR by direct pulmonary
vasodilatation.

SURGICAL INTERVENTIONS

Balloon Atrial Septostomy
 Allow R - L shunting to increase systemic output that
 In spite of fall in the systemic arterial oxygen saturation, will
produce an increase in systemic oxygen transport.
 Shunt at the atrial level would allow decompression of the RA and
RV, alleviating s/s of right heart failure.
 Considered after short term failure of maximal medical therapy.
 Severe IPAH has been the main indication other include PAH
associated with surgically corrected CHD, CTD, distal
CTEPH, PVOD, and pulmonary capillary haemangiomatosis.

HEART / LUNG TRANSPLANTATION

 1 year survival of 70%.
 5 year survival of 50%.
 Effective therapy for patients with end stage pulmonary
vascular disease.
Other areas of research for treatment of PH includes
 Gene therapy
 serotonin transporter
 vasoactive intestinal peptide and tyrosine kinase inhibitors.
 Angiogenic factors and stem cells .
 Imatinib

:Treatment algorithm for pulmonary
arterial hypertension

REFERENCES

 European Heart Journal (2009) 30, 2493–
2537doi:10.1093/eur heart/ehp297
 Journal of the American College of Cardiology/Volume 53,
Issue 17, April Â 28,2009.
 Harrison's Principles of Internal Medicine18 th edition .
 http://www.uptodate.com/contents/treatment-of-
pulmonary-hypertension-in-adults
 Indian Heart Journal 6401 (2012) 60–73

SPECIFIC CONDTIONS
ASSOCIATED WITH PH

COLLAGEN TISSUE DISEASES
 Occurs commonly with the CREST syndrome .
 Often have coexistent interstitial pulmonary fibrosis.
 Fall in diffusing capacity precede the development of PH.
 Treatment is identical to that of patients with IPAH but is less
effective.
 The treatment of the PH, not affect the natural history of the
underlying collagen vascular disease.
 Immunosuppressive may result in clinical improvement in patients
with PAH associated with SLE or mixed CTD

CONGENITAL SYSTEMIC TO
PULMONAY SHUNTS
 It is common for large post-tricuspid cardiac shunts
(e.g.VSD, PDA) less common, in pre tricuspid shunts (e.g. ASD).
 3-year survival rate of 77% compared with 35% for untreated
IPAH.
 Prevalence of PAH in adult CHD, 5–10%.
 Secondary erythrocytosis is beneficial for adequate O2
transport and delivery.
 Bosentan is currently approved in Europe for WHO-FC III
Eisenmenger’s syndrome patients.
 Heart–lung or lung transplantation with heart surgery is an
option in special cases

PORTAL HYPERTENSION
 1–2%of patients with liver disease and portal hypertension
develop PAH.
 The pathogenesis may be related to toxic substances derived from
the gastrointestinal tract, due to portosystemic shunts, causing
damage to the lung endothelium.
 Another possibility is high CO state is inducing PAH.
 Epoprostenol,bosentan, and sildenafil may exert beneficial
haemodynamic and clinical effects in patients.
 Anticoagulation is not recommended
 Significant PAH is a contraindication to liver transplantation if
mean PAP is 35 mmHg

LV DIASTOLIC DYSFUCTION

 PH as a result of LV diastolic failure is common but often
unrecognized .
 It can occur with or without LV systolic failure.
 The most common risk factors are hypertensive heart
disease; coronary artery disease; and impaired LV compliance
related to age, diabetes, obesity, and hypoxemia.
 Symptoms of orthopnea and paroxysmal nocturnal dyspnea
are prominent.
 Many patients improve considerably if LV end-diastolic
pressure is lowered.

MITRAL VALVE DISEASE
 Mitral stenosis and mitral regurgitation represent important
causes of PH from reactive pulmonary vasoconstriction
resulting in marked elevations in PAP.
 In patients with MS, corrective surgery predictably results in a
reduction in PAP and PVR.
 Patients with MR, however, may not have as dramatic a
response to surgery because of persistent elevations in LV end-
diastolic pressure.

CHRONIC OBSTRUCTIVE LUNG
DISEASE(COPD)
 COPD associated with mild PH in the advanced stages .
 Incidence of PH in COPD with at least one previous
hospitalization for exacerbation is 20%.
 In advanced COPD, PH is highly prevalent 50% .
 Echocardiography is recommended as a screening .
 Continuous oxygen therapy relieves the pulmonary
vasoconstriction, reverses chronic ischemia and improves survival.
 Long-term oxygen therapy is indicated if the resting arterial Po2
remains <55 mmHg.
 vasodilators can worsen gas exchange and not used.

INTERSTITIAL LUNG DISEASE

 PH in interstitial lung disease that results from parenchymal and
vascular remodelling .
 The prevalence of PH is between 32 and 39%.
 Coexisting hypoxemia occurs frequently and contributes to
morbidity.
 ILD often associated with the collagen vascular diseases.
 Many patients have pulmonary fibrosis of unknown etiology.
 The pulmonary vasodilators approved for PAH have not been
shown to be helpful.

THROMBOEMBOLIC DISEASES

 Most patients treated for acute PTE with IV heparin and oral
warfarin do not develop chronic PH.
 Pulmonary thromboendarterectomy is an established surgical
treatment in patients whose thrombi are accessible .
 Lifelong anticoagulation using warfarin is mandatory
 Target INR 2.0 .

SICKLE CELL DISEASE
 The etiology is multifactorial, including
hemolysis, hypoxemia, thromboembolism, chronic high cardiac
output, and chronic liver disease.
 Intravascular hemolysis leading to NO deficiency is hypothesized
as a major pathogenetic mechanism for PAH in SCD.
 Prevalance 32 and mortality is 40% in 45 month gldwin etal
 Intensification of SCD–specific therapy appears to reduce the
morbidity.

HIV INFECTION
 Pathogenesis of HIV-related PAH remains unclear
 Incidence is estimated at 1 per 200 cases.
 Treatment is less well established in comparison with other forms
of PAH.
 Epoprostenol, inhaled iloprost may improve exercise tolerance,
haemodynamics and symptoms
 3-year survival rate as low as 21% in the most advanced cases
(WHO-FC III/IV)

Pulmonary hypertension

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