Pulmonary Hypertension

Saurabh Biswas
PGT,Dept. of Chest Medicine,
CNMCH
• Definition
• Classification
• Pathobiology
• Diagnosis
• Treatment
• Primary pulmonary hypertension is a disease in
which there is a persistent elevation of
pulmonary artery pressure without demonstrable
cause.
• mean pulmonary artery pressure greater than 25
mm Hg at rest or a mean pressure in excess of
30 mm Hg during exercise.
• Idiopathic PAH (IPAH), in place of the previously
(and often loosely) used term primary pulmonary
hypertension (PPH).
• Idiopathic pulmonary arterial hypertension
by definition is a diagnosis of exclusion.
• A classification system for pulmonary
hypertensive disorders was developed at a
World Health Organization conference in
1998 and further refined in 2003 at a
World Symposium on pulmonary
hypertension
 Classification of the pulmonary hypertensive
states as adapted at the 2003 World Symposium

Pulmonary artery hypertension PH associated with disorders of the

PPH respiratory system and/orhypoxemia
Sporadic COPD
Familial Interstitial lung disease
Related to: Sleep-disordered breathing
Collagen vascular disease Alveolar hypoventilatory disorders
Congenital systemic to pulmonary Long-term exposure to high altitude
shunts PH due to chronic thrombotic and/or
Portal hypertension embolic disease
HIV infection Thromboembolic obstruction of proximal
Drugs/toxins pulmonary arteries
Persistent PH of the newborn Pulmonary embolism (thrombus, tumor, ova
Pulmonary venous hypertension and/or parasites, foreign material)
Left-sided atrial or ventricular heart PH due to disorders directly affecting the
disease pulmonary vasculature
Left-sided valvular heart disease Schistosomiasis
Fibrosing mediastinitis Sarcoidosis
Adenopathy/tumors Pulmonary capillary hemangiomatosis
Pulmonary veno-occlusive disease
• The pathogenetic mechanisms leading to
pulmonary hypertension have been sorted
into six categories
Pathogenesis of IPAH
pathogenesis of pulmonary arterial
hypertension-increase in resistance and an
impaired cardiac output.
• Imbalance of Vasoactive Mediators-
NO,PGI2 and Vasoactive intestinal
protein (VIP)
serotonin (5-HT), serotonin
transporter (5-HTT), TXA2, Endothelin-1
(ET-1)
• Vasoconstriction, smooth muscle
proliferation, or platelet aggregation
• voltage-gated K+ (Kv) channels- Ca+
+ - vasoconstriction
 Genetic Changes and Altered Cell
Growth
• Two genes involved in the pathogenesis of
both idiopathic and familial pulmonary
arterial hypertension
• Bone morphogenetic protein receptor
II(BMP-RII) and activin receptor kinase-like
1 (ALK1)--receptors of the TGFβ
superfamily.
• The expression of BMP-RII is reduced and
its function is abnormal in IPAH
• angiopoietin1 and its ligand TIE2, VEGF
and its receptor tyrosine kinase receptors
 In Situ Thrombosis

• Local imbalance of pro- and anticoagulant forces

• Activation and altered function of the
endothelium leading to a shift from anti- to
procoagulant activities
• Platelets also promote thrombus formation by
releasing thromboxane metabolites and
serotonin
• Increased PAI,fibrinopeptide A,increased factor
VIII C
 Changes in the Extracellular
Matrix
• Increased ECM degradation
• Elastase,matrix metalloproteiases
• Perivenular inflammatory cell infiltrate
• Increased – IL 1B, Increased IL-6
 Histopathological Changes

• Constrictive lesions of the intima

• Remodeling of the media and adventitia
• Complex lesions affecting the histological
appearance of the entire vessel wall
• Constrictive lesions include medial
hypertrophy involving an increase in the
number and size of smooth muscle cells
• Intimal thickening occurs with or without
associated medial hypertrophy and in
three patterns: concentric laminar,
eccentric, and concentric nonlaminar
• Complex lesions involve the entire vessel
wall-plexiform and dilation lesions.
• Concentric laminar
intimal
thickening is a
distinctive lesion
composed of
onionskin-like layers
of fibroblasts,
myofibroblasts,and
Smooth muscle cells.
• Nonlaminar
intimal
thickening-
concentric
• Nonlaminar
intimal
thickening-
eccentric
• A plexiform lesion (arrow) characterized by small
channels of blood and granulation tissue
• Dilation lesions(arrows)
consist of thin-walled
sinusoidal channels.
Such lesions are found
distal to plexiform
lesions.Site of
bleeding
Diagnosis
Signs and Symptoms
• Pulmonary hypertension is generally
asymptomatic until severe
• By one estimate, an average of 2.5 years
elapse between the development of
symptoms and the diagnosis of IPAH
• Dyspnea on exertion is by far the most
common presenting complaint.
• The mechanism responsible-unclear
• Angina-like or nondescript chest pain is
common in patients with severe pulmonary
hypertension
• Chest pain attributed to right ventricular
overload and myocardial ischemia
• Might also occur if the left main coronary
artery is compressed by an enlarged
pulmonary artery
• Hoarseness, due to paralysis of the left
recurrent laryngeal nerve, may result from
trapping of the nerve between the aorta
and the dilated left pulmonary artery (a
form of Ortner syndrome)
• Hemoptysis-usually due to pulmonary
venous congestion-bleeding from bronchial
veins in MS.
• A large a wave in the jugular venous pulse
• Splitting of the second heart sound with
accentuation of the pulmonic component
• A sharp systolic ejection click over the
region of the pulmonary artery
• Enlargement of the right ventricle- a
palpable cardiac impulse near the left
sternal border and in the hypogastrium
• An important sign of cor pulmonale- a right-
sided (ventricular), diastolic (S3) gallop
• It is accentuated by inspiration
• Right atrial gallop (S4)- suggests an increase in
the filling pressure of the right side of the heart.
• tricuspid insufficiency develops-holosystolic
murmur, best heard in the fourth interspace to the
left of the sternum-prominent v wave-distended
neck veins pulsate with each heartbeat
• right ventricular failure-hepatic engorgement,
edema at the lower extremities
• Hydrothorax and ascites are uncommon
• peripheral cyanosis secondary to a
reduced cardiac output and peripheral
vasoconstriction
• The physical examination should focus on
the presence of additional signs to indicate
a possible cause of pulmonary
hypertension
Investigations
• Pulmonary hypertension is suspected- the
echocardiogram- appropriate first test
• Doppler examination is able to quantify the
tricuspid regurgitant jet
• Right ventricular systolic pressure
(RVSP=4v2+right atrial pressure; where v
=tricuspid jet velocity in meters per second)and is
assumed to equal the pulmonary artery systolic
pressure
• Normal RVSP has been reported as 28+/-5mm
Hg
• Echocardiographic evaluations during exercise
• Diagnostic catheterization confirms the
diagnosis and is useful in guiding therapy
in PAH
• Chest X-ray-Early in the evolution of
pulmonary hypertension- appears normal.
In time, the central pulmonary arteries
become increasingly prominent as the
peripheral vessels become attenuated,
and the cardiac silhouette enlarges
• ECG-evidence of right ventricular
overload, usually in conjunction with right
atrial impairment
 right axis deviation and dominant
R waves over the right precordium consistent

with right ventricular hypertrophy .

• Left heart catheterization and measurement of the
LVEDP - important to exclude left atrial
hypertension
• Direct measurement may be required in the
presence of severe pulmonary hypertension
-adequate estimate of LVEDP cannot be obtained
using a wedged pulmonary artery catheter

• Pulmonary arterial hypertension is present when

there is pulmonary hypertension and an
adequately measured pulmonary capillary wedge
pressure or, if necessary, a directly recorded
LVEDP, is less than 15 mmHg
 MANAGEMENT

• No currently available medical treatment is

curative.
• Lung transplantation remains an option
for some who fail medical therapy
 Exercise and the Avoidance of
Deconditioning

• Regular, steady aerobic exercise should

be encouraged
• Activities that tend to cause
lightheadedness or syncope are to be
avoided- hot showers or baths and
bending over to lift heavy objects
 Oxygen Therapy

• Levels of arterial oxygen saturation below

90 percent require supplemental oxygen
• Air travel- airlines maintain cabin
pressures equivalent to an altitude of
about 8000 feet above sea level-
Supplemental oxygen to avoid arterial
oxygen saturation below 90 percent
• Immunizations against influenza and
pneumococcal pneumonia -preventive
measures in all patients with pulmonary
hypertension and cor pulmonale.
• Anticoagulation-target international
normalized ratio (INR) for warfarin therapy
in patients withPAH is 1.5 to 2.5.
Fluid Management and Diuretics

• Avoid fluid overload -central to the

management of cor pulmonale of any
cause and restriction of sodium intake.
• Diuretics can improve alveolar ventilation
and arterial oxygenation in cor pulmonale.
• In general, the choice of initial therapy
depends upon the functional class and
hemodynamic status of the patient-oral or
iv?
 Acute Vasodilator Testing and
CalciumChannel
Antagonist Therapy
• Diminish vascular tone by preventing an increase
in cytosolic calcium concentration by inhibiting
both the influx of extracellular calcium and the
release of calcium from intracellular stores
• The long term prognosis is good for some IPAH
patients who respond acutely to the
administration of short-acting pulmonary
vasodilators
• Acute vasodilator testing-inhaled NO, infused
adenosine, or epoprostenol administered by
either route-detect suitability of CCB rx
• Decrease in the mPAP of at least 10 mmHg to
less than 40 mmHg, and a cardiac output
increased or unchanged is generally considered
to be a positive response
• Nifedipine or diltiazem-verapamil, which exert
negative inotropic effects, should be avoided
 Endothelin Receptor Antagonists

• Both dual ETA/ETB and relatively ETA-selective

antagonists for oral use
• Bosentan is a dual ETA/ETB antagonist
• Initiated at a dose of 62.5 mg twice daily by
mouth
• If liver function remains normal, the dose is
increased after 1 month to 125 mg twice daily
• Ambrisentan and sitaxsentan are relatively
specific ETA-receptor antagonists
• Both drugs appear to have a lower
incidence of increase in liver enzymes
than bosentan
 Phosphodiesterase Inhibition

• Sildenafil citrate-FDA-approved dosage for

treatment of PAH is 20 mg by mouth three
times daily.
• Side effects-headache, flushing, diarrhea,
and epistaxis; systemic hypotension
 Prostanoid Therapies

• Prostacyclin- powerful vasodilator (both

pulmonary and systemic) as well as an
inhibitor of smooth muscle proliferation
and platelet aggregation
• Epoprostenol, treprostinil, and iloprost by
cont. IV.
• Treprostinil-subcutaneous infusion
• Iloprost-inhalation
• beraprost is rarely used-oral
• Epoprostenol therapy is initiated at 1 to 4
ng/kg/min and progressively increased in
0.5 to 1 ng/kg/min increments
• Steady dosage between 20 and 40
ng/kg/min after several months
• The drug is unstable at room temperature
and must be mixed daily and kept cool
with ice packs
• Treprostinil-longer half-life (3 hours) and stability
at room temperature
• Treprostinil is also available for subcutaneous
administration.
• Iloprost inhalational therapy is initiated with a
dosage of 2.5 μg and, if tolerated, increased to 5
μg with the subsequent dose
• Inhaled iloprost requires multiple repeated
administrations daily (six to nine treatments
lasting approximately 10 minutes each while
awake)
 Lung transplantation

• Failed medical therapy

• Single-lung, double-lung, and heart-lung
transplants
• Outcomes favor a doublelung procedure
• Outcome of patients-poorer than for other
indications(1 yr survival 65% compared to
74%)
Atrial septostomy
• Recurrent syncope/RVF despite maximal medical therapy (at least for 6
months)

• Palliative therapy
• Procedure BBAS – Blade balloon atrial septostomy
BDAS – Balloon dilatation AS

• Only small series / case reports

• Successful AS - significant clinical improvement
beneficial and long lasting hd effects
trend towards increased survival
• Procedure related mortality 16%
• CI – Severe RHF , mRAP>20 mm Hg ,Spo2<80%
 Prognosis of IPAH

• Without effective therapy the prognosis of IPAH

is very poor.
• WorldHealth Organization (WHO)functional
classes III and IV symptoms -median survival of
only 31.5 months as compared with a median
survival of 58.6 months in patients with milder
impairment (class I or II)
• 6-minute walk test
• Enlargement of the right atrium and/or the
presence of a large pericardial effusion-bad
• A relative increase in the isovolumetric
contraction and relaxation times of the RV as
compared to its ejection time-RV dysfunction-
poor
• Increased Endothelin, catecholamines, and atrial
natriuretic peptide in serum-bad
• Increases in serum uric acid, von Willebrand
factor, D-dimer, troponin-T, and brain natriuretic
peptide
• Low serum albumin-bad
• Decreased survival -in association with both
increasing and decreasing mean pulmonary
artery pressures
References:
1)Fishman’s pulmonary diseases
2)Crofton’s respiratory diseases
THANK YOU