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 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





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 questionsTopics 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



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 diseaseValvular heart diseaseCongenital 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



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 DAYBibliography

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.

pulmonary hypertension and its management

Health & Medicine

pulmonary hypertension

pulmonary venoocclusion

pulmonary arterial resistance

pulmonary venous pressure

pulmonary artery pressure

pulmonary arterial obstruction

pulmonary blood flow

ph secondary ph