Pulmonary Hypertension and its management

Pulmonary Hypertension
and its management
Presented by: Mohit Goyal
Under the guidance of: Dr. V. K. Goyal Sir

Pulmonary hypertension (PH) is an abnormal elevation
in pulmonary artery pressure, as a result of left heart
failure, pulmonary parenchymal or vascular
disease, thromboembolism, or a combination of these
factors.
Pulmonary Hypertension and its management

Salient features of Pulmonary circulation:-
 It is a low resistance circuit
 Pulmonary BP is about 1/8th of systemic blood pressure
 PH occurs when Pulmonary BP reaches 1/4th of systemic levels

Genesis of PH:-
 Increased pulmonary blood flow
 Increased pulmonary vascular resistance
 Increased left heart resistance to blood flow

Right Ventricular Output ᾳ Right Ventricular Systolic Pressure
Pulmonary Vascular Resistance

Adaptability of Right Ventricle to increased vascular resistance
depends upon:-
 Age of the patient
 Rapidity of development of Pulmonary Hypertension

Conditions leading to PH (Secondary PH):-
 Those with elevated PAP and normal PCWP
E.g. Idiopathic, Familial, in Collagen disorders, in L to R shunts,
drugs, toxins, persistent PH of newborn
 Those with elevated PAP and PCWP
E.g. Left side valve disease, Pulmonary venoocclusion
 Those associated with chronic hypoxia
E.g. COLD, ILD, Sleep apnoea
 Elevated PAP with Pulmonary arterial obstruction > 3 months
E.g. Pulmonary embolism, Chronic thromboembolism

Connective tissue diseases e.g. Systemic sclerosis
Intimal fibrosis, Medial hypertrophy
Reduced functional cross sectional area
Increased pulmonary vascular resistance
Increased pulmonary arterial pressure

Heart Diseases
Mitral stenosis
Increased left atrial pressure
Increased pulmonary venous pressure

COLD/ILD
Destruction of lung parenchyma
Fewer alveolar capillaries
Increased pulmonary arterial resistance

Pulmonary thromboembolism
Pulmonary emboli
Reduced functional cross sectional area
Increased pulmonary vascular resistance

Pulmonary embolism Chronic thromboembolism

Miscellaneous substances found to cause PH
 Crotolaria spectabilis – tropical leguminous plant
 Aminorex – Appetite depressant
 Adulterated olive oil
 Fenfluramine, Phentermine – anti-obesity drugs
They are postulated to act through effects on serotonin
transporter expression or activity.

Underlying mechanisms in Secondary PH
 Shear and mechanical injury in left to right shunts
 Biochemical injury by fibrin in thromboembolism
 Pulmonary vasoconstriction by decreased
prostacyclin, decreased nitric oxide and increased
endothelin
 Promotion of platelet activation and adhesion by
decreased prostacyclin and nitric oxide

Idiopathic Pulmonary Hypertension
Uncommon form encountered sporadically in patients whom
all known causes of Pulmonary hypertension are excluded.

Familial Pulmonary Hypertension
Least common form having autosomal dominant inheritance
with incomplete penetrance, consequently only 10-20% family
members developing overt disease.

BMPR2 is a cell surface protein belonging to the TGF-β
receptor superfamily, which binds a variety of
cytokines, including TGF-β, bone morphogenetic protein
(BMP), activin, and inhibin.
Apart from its role in bone growth, BMP-BMPR2 signalling is
now known to be important for
embryogenesis, apoptosis, and cell proliferation and
differentiation.

Inactivating germline mutations in the BMPR2 gene are found
in 50% of the familial cases of pulmonary arterial
hypertension and 25% of sporadic cases.
In many families, even without mutations in the coding
regions of the BMPR2 gene, linkage to the BMPR2 locus on
chromosome 2q33 can be established, thus indicating that
other possible lesions such as gene rearrangements, large
deletions, or insertions could be involved.

Unanswered questions
Topics of researches
First, how does loss of a single allele of the BMPR2 gene lead
to complete loss of signalling?
 Either the mutation might act as a dominant negative or
 A secondary loss of the normal allele might occur in the
vascular wall via e.g. microsatellite instability, thus leading
to a homozygous loss of BMPR2.

Why the phenotypic disease occurs only in 10% to 20% of
individuals with BMPR2 mutations?
 Existence of modifier genes like endothelin, prostacyclin
synthetase, and angiotensin converting enzymes.
 Environmental triggers which affect vascular tone.

Thus, a two-hit model has been proposed whereby a genetically
susceptible individual with a BMPR2 mutation requires additional
genetic or environmental insults to develop the disease.

Vasospastic component in PH
Some individuals with PH have a vasospastic component; in
such patients, pulmonary vascular resistance can be rapidly
decreased with vasodilators. Exact mechanism is not known.
“It appears that even in cases with very advanced primary
pulmonary hypertension there is a vasospastic component
which can be influenced by vasodilators e.g. Phentolamine.”
Heinrich U, Angehrn W, Steinbrunn W. (1983). Therapy of primary pulmonary hypertension with
phentolamine, 113(4):145-8. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/6828847

Morphology
 All forms of PH have some common pathologic features
 Medial hypertrophy of muscular and elastic arteries
 Atheromas of pulmonary artery and its major branches
 Right ventricular hypertrophy
 Pulmonary embolism - organizing or recanalized
 Coexistence of diffuse pulmonary fibrosis, or severe emphysema and
chronic bronchitis, points to chronic hypoxia as the initiating event

Gross appearance of
atheroma formation
Marked medial
hypertrophy
Plexiform lesions in
PH due to drugs, HIV

Symptoms
 Exertional dyspnoea
 Fatigue
 Angina pectoris
 Syncope, near syncope
 Peripheral oedema

Signs
 Raised JVP
 Reduced carotid pulse
 Increased component of P2 in S2
 Right Sided S4
 Tricuspid regurgitation
 Peripheral cyanosis and oedema in late stage

Class NYHA WHO
1/I No symptoms with ordinary
physical activity.
Patients with PH but without resulting limitation of
physical activity. Ordinary physical activity does not
cause undue dyspnoea or fatigue, chest pain, or near
syncope.
2/II Symptoms with ordinary
activity. Slight limitation of
activity.
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.
3/III Symptoms with less than
ordinary activity. Marked
limitation of activity.
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.
4/IV Symptoms with any activity
or even at rest.
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.

Investigations
 Chest Radiography
 Electrocardiogram
 Echocardiography
 Lung function testing
 Ventilation-perfusion scanning
 HRCT scanning
 Pulmonary angiography
 Cardiac catheterization
 Exercise testing

Chest Radiograph
 Enlargement of pulmonary trunk
 Pruning of peripheral pulmonary arterial tree
 Right ventricular enlargement
 Findings corresponding to condition leading to PH

Electrocardiogram
 RAD
 Right Ventricular Enlargement

Echocardiogram and Continuous Wave Colour Doppler
 Thickened right ventricle
 Regurgitant flow across the tricuspid valve
 Regurgitant flow across the pulmonic valve

Cardiac catheterization

Cardiac catheterization
Determination of:-
 Right atrial pressure
 Right ventricular pressure
 PAP
 PCWP
 Pulmonary blood flow (cardiac output)
 Vasoreactivity

Other Investigations
 Lung function testing
 Ventilation-perfusion scanning
 HRCT scanning
 Lung biopsy
 Pulmonary angiography
 Exercise testing

Echocardiogram
Dilated RV
PFT
Obstructive Restrictive
Left heart disease
Valvular heart disease
Congenital anomaly
Cardiac Catheterization
COLD HRCT
Normal or enlarged
pulmonary arteries
ILD Pulmonary
thromboembolism
Lab tests: CBC, ANA, HIV, TSH, LFTs
Exercise testing, Catheterization, Vasodilator testing

Management options
 Drug therapy
 Atrial septostomy
 Lung transplantation

Drug options
 Calcium channel blockers
 Endothelin receptor antagonists
 Phosphodiesterase-5 inhibitors
 Prostacyclin analogues

Principles of drug treatment
 Patients should undergo cardiac catheterization before initiating therapy.
 Obtain baseline assessments of the disease to know whether treatments are effective.
 Test Vasoreactivity.
 Reactive patients should be treated with calcium channel blockers.
 Nonreactive patients should be offered other therapies.
 Reassess at 8 weeks; patients who don’t respond are unlikely to respond with longer exposure.
 Ineffective treatments should be substituted rather than new added.
 Patients who fail all treatments should be considered for lung transplantation.
 Only the addition of sildenafil to epoprostenol has been shown to be efficacious.

Calcium channel blockers
 Indicated in patients who respond to vasodilators during catheterization
 Mean PAP<40 mm of Hg and fall > or = 10 mm of Hg
 High doses required e.g. nifedipine 240 mg/d, or amlodipine, 20 mg/d
 Dramatic reductions in PAP, resistance associated with improved symptoms
 Regression of RV hypertrophy
 Improved survival now documented to exceed 20 years
 However <20% patients respond to calcium channel blockers in the long term
 Not approved for the treatment of PAH by the U.S. FDA

Endothelin receptor antagonists
 Bosentan and ambrisentan are approved treatments of PAH
 Both improved exercise tolerance in RCTs
 Bosentan initiated at 62.5 mg BD for first month and increased to 125 mg BD
 Ambrisentan initiated as 5 mg OD and can be increased to 10 mg daily
 Liver function be monitored monthly throughout the duration of use
 Contraindicated in patients on cyclosporine or glyburide concurrently

Phosphodiesterase-5 inhibitors
 Approved for the treatment of PAH
 Phosphodiesterase-5 is responsible for the hydrolysis of cyclic GMP
 Sildenafil and tadalafil improve exercise tolerance
 Effective dose for sildenafil is 20–80 mg TID
 The effective dose for tadalafil is 40 mg OD
 The most common side effect is headache
 Neither drug should be given to patients who are taking nitrovasodilators

Prostacyclin analogues
Iloprost
 Approved via inhalation for PAH
 Improves a composite measure of symptoms and exercise tolerance by 10%
 Given at either 2.5 or 5 µg per inhalation treatment via a dedicated nebulizer
 Most common side effects are flushing and cough
 Very short half-life of <30 min
 Recommended to be administered as often as every 2 h

Epoprostenol
 Approved as a chronic IV treatment of PAH
 Improvement in symptoms, exercise tolerance, and survival
 Administration requires placement of a permanent central venous catheter
 Infusion done through an ambulatory infusion pump system
 Cause vasodilation and platelet inhibition
 Also inhibition of vascular smooth muscle growth and inotropic effects
 Side effects include flushing, jaw pain, and diarrhoea
 Doses of epoprostenol range from 25 to 40 ng/kg per min

Treprostinil
 Analogue of epoprostenol, approved for PAH
 May be given intravenously, subcutaneously, or via inhalation
 Clinical trials have demonstrated an improvement in symptoms with exercise
 Local pain at the infusion site with subcutaneous administration
 Doses of treprostinil range from 75 to 150 ng/kg per min

Atrial Septostomy
 Blade-balloon atrial septostomy is performed
 In patients with severe refractory RV pressure and volume overload
 Decompresses overloaded right heart
 Improves systemic output of the underfilled left ventricle
 Increased venous admixture
 Worsening hypoxaemia is expected over time

Lung transplantation
 Only 1/3rd patients of primary PH are responsive to oral vasodilators
 Indicated in patients on IV prostacyclin, who continue to manifest right heart failure
 Handicapped by shortage of lung donors
 Single/double lung transplantation has largely replaced heart-lung transplantation
 Median survival after transplantation is 3 years
 Rejection phenomena e.g. Bronchiolitis obliterans are limiting factors
 Recurrence not reported after transplantation

What we can do…
 High index of suspicion
 Electrocardiography, Radiography, Echocardiography, Lung
function testing, HRCT, Angiography, Exercise testing
 Easily available – CCBs, Sildenafil
 Educate suitable candidates about catheterization

THANK YOU
HAVE A GOOD DAY
Bibliography
 Rich, S., 2012. Pulmonary Hypertension. In: D. Longo, A. Fauci, D. Kasper, S. Hauser, J. Jameson, J.
Loscalzo, ed. 2012 Harrison’s Principles of Internal Medicine. USA: McGraw-Hill. pp.2076-2082.
 Rubin, L.J., 2001. Pulmonary Hypertension. In: R.A. O’Rourke, V. Fuster, R.W. Alexander, R. Roberts, S.B.
King III, H.J.J. Wellens, eds. 2001. Hurst's The Heart : Manual of Cardiology. USA: McGraw-Hill. Ch.19.
 Husain, A.N., 2010. The Lung. In: V. Kumar, A.K. Abbas, N. Fausto, J.C. Aster, eds. 2010. Robbins and
Cotran Pathologic Basis of Disease. USA: Saunders. Ch.15.

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