Pulmonary Hypertension and its management

Seminar on Pulmonary Hypertension and its management by Mohit Goyal on 21-08-2013

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

2. 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

3. Pulmonary Hypertension and its management

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

5. Genesis of PH :- Increased pulmonary blood flow Increased pulmonary vascular resistance Increased left heart resistance to blood flow Pulmonary Hypertension and its management

6. Right Ventricular Output ᾳ Right Ventricular Systolic Pressure Pulmonary Vascular Resistance Pulmonary Hypertension and its management

7. 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

8. 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

9. 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

10. Heart Diseases Mitral stenosis Increased left atrial pressure Increased pulmonary venous pressure Increased pulmonary arterial pressure Pulmonary Hypertension and its management

11. COLD/ILD Destruction of lung parenchyma Fewer alveolar capillaries Increased pulmonary arterial resistance Increased pulmonary arterial pressure Pulmonary Hypertension and its management

12. Pulmonary thromboembolism Pulmonary emboli Reduced functional cross sectional area Increased pulmonary vascular resistance Increased pulmonary arterial pressure Pulmonary Hypertension and its management

13. Pulmonary Hypertension and its management Pulmonary embolism Chronic thromboembolism

14. 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

15. Underlying mechanisms in Secondary PH S hear 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

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

17. 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

18. 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

19. I nactivating 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

20. 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 . Pulmonary Hypertension and its management

21. 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

22. 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

23. 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

24. 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

25. Pulmonary Hypertension and its management Gross appearance of atheroma formation Marked medial hypertrophy Plexiform lesions in PH due to drugs, HIV

26. Symptoms Exertional dyspnoea Fatigue Angina pectoris Syncope , near syncope Peripheral oedema Pulmonary Hypertension and its management

27. Signs Raised JVP Reduced carotid pulse Increased component of P 2 in S 2 Right Sided S 4 Tricuspid regurgitation Peripheral cyanosis and oedema in late stage Pulmonary Hypertension and its management

28. 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.

29. Investigations Chest Radiography Electrocardiogram Echocardiography Lung function testing Ventilation-perfusion scanning HRCT scanning Pulmonary angiography Cardiac catheterization Exercise testing Pulmonary Hypertension and its management

30. 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

31. Pulmonary Hypertension and its management

32. Electrocardiogram RAD Right Ventricular Enlargement Pulmonary Hypertension and its management

33. Echocardiogram and Continuous W ave Colour Doppler Thickened right ventricle Regurgitant flow across the tricuspid valve Regurgitant flow across the pulmonic valve Pulmonary Hypertension and its management

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35. Pulmonary Hypertension and its management

36. Pulmonary Hypertension and its management Cardiac catheterization

37. Cardiac catheterization Determination of:- Right atrial pressure Right ventricular pressure PAP PCWP Pulmonary blood flow (cardiac output) Vasoreactivity Pulmonary Hypertension and its management

38. Pulmonary Hypertension and its management

39. Other Investigations Lung function testing Ventilation-perfusion scanning HRCT scanning Lung biopsy Pulmonary angiography Exercise testing Pulmonary Hypertension and its management

40. Pulmonary Hypertension and its management 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

41. Pulmonary Hypertension and its management Management options Drug therapy Atrial septostomy Lung transplantation

42. Pulmonary Hypertension and its management Drug options Calcium channel blockers Endothelin receptor antagonists Phosphodiesterase-5 inhibitors Prostacyclin analogues

43. Pulmonary Hypertension and its management

44. 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.

45. 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 H igh 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

46. 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

47. Pulmonary Hypertension and its management P hosphodiesterase-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

48. 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

49. Pulmonary Hypertension and its management Prostacyclin analogues Epoprostenol A pproved as a chronic IV treatment of PAH Improvement in symptoms, exercise tolerance, and survival A dministration 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

50. 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

51. 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

52. Pulmonary Hypertension and its management Lung transplantation Only 1/3 rd 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

53. 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

54. Pulmonary Hypertension and its management 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.