Pulmonary Hypertension and its management
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Transcript of 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
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
Pulmonary Hypertension and its management
Genesis of PH:-
Increased pulmonary blood flow
Increased pulmonary vascular resistance
Increased left heart resistance to blood flow
Pulmonary Hypertension and its management
Right Ventricular Output ᾳ Right Ventricular Systolic Pressure
Pulmonary Vascular Resistance
Pulmonary Hypertension and its management
Adaptability of Right Ventricle to increased vascular resistance depends upon:-
Age of the patient
Rapidity of development of Pulmonary Hypertension
Pulmonary Hypertension and its management
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
Pulmonary Hypertension and its management
Connective tissue diseases e.g. Systemic sclerosis
Intimal fibrosis, Medial hypertrophy
Reduced functional cross sectional area
Increased pulmonary vascular resistance
Increased pulmonary arterial pressure
Pulmonary Hypertension and its management
Heart Diseases
Mitral stenosis
Increased left atrial pressure
Increased pulmonary venous pressure
Increased pulmonary arterial pressure
Pulmonary Hypertension and its management
COLD/ILD
Destruction of lung parenchyma
Fewer alveolar capillaries
Increased pulmonary arterial resistance
Increased pulmonary arterial pressure
Pulmonary Hypertension and its management
Pulmonary thromboembolism
Pulmonary emboli
Reduced functional cross sectional area
Increased pulmonary vascular resistance
Increased pulmonary arterial pressure
Pulmonary Hypertension and its management
Pulmonary Hypertension and its management
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.
Pulmonary Hypertension and its management
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
Pulmonary Hypertension and its management
Idiopathic Pulmonary Hypertension
Uncommon form encountered sporadically in patients whom all known causes of Pulmonary hypertension are excluded.
Pulmonary Hypertension and its management
Familial Pulmonary Hypertension
Least common form having autosomal dominant inheritance with incomplete penetrance, consequently only 10-20% family members developing overt disease.
Pulmonary Hypertension and its management
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.
Pulmonary Hypertension and its management
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.
Pulmonary Hypertension and its management
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.
Pulmonary Hypertension and its management
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.
Pulmonary Hypertension and its management
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.
Pulmonary Hypertension and its management
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
Pulmonary Hypertension and its management
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
Pulmonary Hypertension and its management
Pulmonary Hypertension and its management
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
Pulmonary Hypertension and its management
Signs
Raised JVP
Reduced carotid pulse
Increased component of P2 in S2
Right Sided S4
Tricuspid regurgitation
Peripheral cyanosis and oedema in late stage
Pulmonary Hypertension and its management
Pulmonary Hypertension and its management
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
Pulmonary Hypertension and its management
Chest Radiograph
Enlargement of pulmonary trunk
Pruning of peripheral pulmonary arterial tree
Right ventricular enlargement
Findings corresponding to condition leading to PH
Pulmonary Hypertension and its management
Pulmonary Hypertension and its management
Electrocardiogram
RAD
Right Ventricular Enlargement
Pulmonary Hypertension and its management
Echocardiogram and Continuous Wave Colour Doppler
Thickened right ventricle
Regurgitant flow across the tricuspid valve
Regurgitant flow across the pulmonic valve
Pulmonary Hypertension and its management
Pulmonary Hypertension and its management
Pulmonary Hypertension and its management
Pulmonary Hypertension and its management
Cardiac catheterization
Cardiac catheterization
Determination of:-
Right atrial pressure
Right ventricular pressure
PAP
PCWP
Pulmonary blood flow (cardiac output)
Vasoreactivity
Pulmonary Hypertension and its management
Pulmonary Hypertension and its management
Other Investigations
Lung function testing
Ventilation-perfusion scanning
HRCT scanning
Lung biopsy
Pulmonary angiography
Exercise testing
Pulmonary Hypertension and its management
Pulmonary Hypertension and its management
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
Pulmonary Hypertension and its management
Management options
Drug therapy
Atrial septostomy
Lung transplantation
Pulmonary Hypertension and its management
Drug options
Calcium channel blockers
Endothelin receptor antagonists
Phosphodiesterase-5 inhibitors
Prostacyclin analogues
Pulmonary Hypertension and its management
Pulmonary Hypertension and its management
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.
Pulmonary Hypertension and its management
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
Pulmonary Hypertension and its management
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
Pulmonary Hypertension and its management
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
Pulmonary Hypertension and its management
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
Pulmonary Hypertension and its management
Prostacyclin analogues
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
Pulmonary Hypertension and its management
Prostacyclin analogues
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
Pulmonary Hypertension and its management
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
Pulmonary Hypertension and its management
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
Pulmonary Hypertension and its management
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
Pulmonary Hypertension and its management
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.