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JAMES L. ANGTUACO, M.D., DPPS,DPSPC, FPCC

JAMES L. ANGTUACO, M.D., DPPS,DPSPC, FPCC. U.P. College of Medicine Intarmed Class 1992 Pediatric Residency, UP-PGH 1993-95 Fellowship, Pediatric Cardiology, UP-PGH 1996-99 Fellowship, Pediatric Cardiology, New Children’s Hospital of Westmead, Sydney Australia, 1999-2000 Positions:

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JAMES L. ANGTUACO, M.D., DPPS,DPSPC, FPCC

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  1. JAMES L. ANGTUACO, M.D., DPPS,DPSPC, FPCC U.P. College of Medicine Intarmed Class 1992 Pediatric Residency, UP-PGH 1993-95 Fellowship, Pediatric Cardiology, UP-PGH 1996-99 Fellowship, Pediatric Cardiology, New Children’s Hospital of Westmead, Sydney Australia, 1999-2000 Positions: Chair, CME Programs, Chinese General Hospital, 2010-present Head, OPD Section of Pediatric Cardiology, SLMC 2009-present Member, Committee on Research Philippine Pediatric Society, 2012- Chair, Research Committee, Chinese General Hospital, 2004 – 2010 Member, Residency Training Committee, Chinese General Hospital, 2004-present Faculty, San Beda College of Medicine (2006-present) Vice President RF/ RHD Foundation of the Philippines (2012- ) Affiliations: Metropolitan Medical Center Chinese General Hospital St. Luke’s Medical Center Manila Adventist Medical Center Our Lady of Lourdes Hospital Manila Doctor’s Hospital

  2. Pulmonary Hypertension:Guidelines in the Diagnosis and Treatment James L. Angtuaco, M.D., DPPS, DPSPC, FPCCPediatric Cardiologist

  3. DISCLAIMER

  4. OBJECTIVES: • To discuss the definition of Pulmonary arterial hypertension • To discuss the different pathology / pathobiology of Pulmonary arterial hypertension • To describe the classifications of Pulmonary arterial hypertension • To discuss the clinical presentations of Pulmonary arterial hypertension • To discuss the different diagnostic modalities for Pulmonary arterial hypertension • To discuss the different treatment modalities for Pulmonary arterial hypertension

  5. Pulmonary Hypertension • Definition: • increase in mean pulmonary arterial pressure > 25 mmHg at rest as assessed by right heart catheterization • normal mean pulmonary arterial pressure is 14+3 mmHg. with an upper limit of ~20 mmHg. • gray zone : 21-24 mmHg.

  6. CLINICAL CLASSIFICATION OF PULMONARY ARTERIAL HYPERTENSION(The Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology and the European Respiratory Society, endorsed by the International Society of Heart & Lung Transplantation 2009)European Heart Journal 2009 • GROUP 1: PULMONARY ARTERIAL HYPERTENSION • idiopathic • Heritable • BMPR2 (bone morphogenesis protein receptor 2 gene) • ALK1 (activin receptor like kinase type 1 gene), endoglin (with or without hereditary hemorrhagic telangiectasia) • Unknown • Drugs and toxins induced (weight loss drugs)

  7. CLINICAL CLASSIFICATION OF PULMONARY ARTERIAL HYPERTENSION(The Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology and the European Respiratory Society, endorsed by the International Society of Heart & Lung Transplantation 2009)European Heart Journal 2009 • GROUP 1: PULMONARY ARTERIAL HYPERTENSION • associated with: • connective tissue disease • HIV infection • portal hypertension • Congenital Heart Disease • Schistosomiasis • Chronic hemolytic anemia • Persistent pulmonary hypertension of the newborn

  8. CLINICAL CLASSIFICATION OF PULMONARY ARTERIAL HYPERTENSION(The Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology and the European Respiratory Society, endorsed by the International Society of Heart & Lung Transplantation 2009)European Heart Journal 2009 • GROUP 1’ : PULMONARY VENO-OCCLUSIVE DISEASE WITH PULMONARY CAPILLARY HEMANGIOMATOSIS

  9. CLINICAL CLASSIFICATION OF PULMONARY ARTERIAL HYPERTENSION(The Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology and the European Respiratory Society, endorsed by the International Society of Heart & Lung Transplantation 2009)European Heart Journal 2009 • GROUP 2: PULMONARY HYPERTENSION DUE TO LEFT HEART DISEASE • systolic dysfunction • diastolic dysfunction • valvular disease

  10. CLINICAL CLASSIFICATION OF PULMONARY ARTERIAL HYPERTENSION(The Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology and the European Respiratory Society, endorsed by the International Society of Heart & Lung Transplantation 2009)European Heart Journal 2009 • GROUP 3: PULMONARY HYPERTENSION DUE TO LUNG DISEASE AND/ OR HYPOXIA • chronic obstructive pulmonary disease • interstitial lung disease • other pulmonary diseases with mixed restrictive and obstructive pattern • sleep-disordered breathing • alveolar hypoventilation disorders • chronic exposure to high altitude • developmental abnormalities

  11. CLINICAL CLASSIFICATION OF PULMONARY ARTERIAL HYPERTENSION(The Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology and the European Respiratory Society, endorsed by the International Society of Heart & Lung Transplantation 2009)European Heart Journal 2009 • GROUP 4: CHRONIC THROMBOEMBOLIC PULMONARY HYPERTENSION (CTEPH)

  12. CLINICAL CLASSIFICATION OF PULMONARY ARTERIAL HYPERTENSION(The Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology and the European Respiratory Society, endorsed by the International Society of Heart & Lung Transplantation 2009)European Heart Journal 2009 • GROUP 5 : PULMONARY HYPERTENSION WITH UNCLEAR AND/OR MULTIFACTORIAL MECHANISMS • hematologic disorders : myeloproliferative disorders, splenectomy • systemic disorders : sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis, neurofibromatosis, vasculitis • metabolic disorders: glycogen storage disease: Gaucher disease, thyroid disorders • others: tumoural obstruction, fibrosing mediastinitis, chronic renal failure on dialysis

  13. PATHOLOGY OF PULMONARY HYPERTENSION • Group 1: PAH • affects the distal pulmonary arteries (<500 um in diameter) • medial hypertrophy • intimal proliferation and fibrotic changes (concentric and eccentric) • adventitial thickening with moderate perivascular inflammatory infiltrates • plexiform dilated lesions • thrombotic lesions • PULMONARY VEINS ARE CLASSICALLY UNAFFECTED Pietra GG et. al. JACC 2004 Tuder RM et. al. JACC 2009

  14. PATHOLOGY OF PULMONARY HYPERTENSION • Group 1’: Pulmonary Veno-Occlusive Disease • involves septal veins and pre-septal venules • occlusive fibrotic lesions • venous muscularization • frequent capillary proliferation (patchy) • pulmonary edema • occult alveolar hemorrhage • lymphatic dilatation / lymph node enlargement • distal pulmonary arteries have medial hypertrophy, intimal fibrosis Pietra GG et. al. JACC 2004 Tuder RM et. al. JACC 2009

  15. PATHOLOGY OF PULMONARY HYPERTENSION • Group 2: Left Heart Disease • enlarged, thickened pulmonary veins • pulmonary capillary dilatation • interstitial edema • alveolar hemorrhage • lymphatic vessel and lymph node enlargement • distal pulmonary artery may have medial hypertrophy and intimal fibrosis Pietra GG et. al. JACC 2004 Tuder RM et. al. JACC 2009

  16. PATHOLOGY OF PULMONARY HYPERTENSION • Group 3: PAH due to lung disease • medial hypertrophy and intimal obstructive proliferationof the distal pulmonary arteries • variable degree of destruction of the vascular bed in emphysematous or fibrotic areas Pietra GG et. al. JACC 2004 Tuder RM et. al. JACC 2009

  17. PATHOLOGY OF PULMONARY HYPERTENSION • Group 4: CTEPH • organized thrombi attached to the medial layer of the elastic pulmonary arteries • may cause complete occlusion, stenosis, formation of webs or bands • collateral vessels from bronchial, costal, diaphragmatic or coronary arteries may develop to reperfuse the distal segments Pietra GG et. al. JACC 2004 Tuder RM et. al. JACC 2009

  18. PATHOLOGY OF PULMONARY HYPERTENSION • Group 5: Idiopathic • unclear pathology Pietra GG et. al. JACC 2004 Tuder RM et. al. JACC 2009

  19. PATHOBIOLOGY OF PULMONARY HYPERTENSION • Group 1: PAH • vasoconstriction, proliferative, and obstructive remodelling of pulmonary vessel wall • inflammation and thrombosis • abnormal function or expression of potassium channels in smooth muscle cells • endothelial dysfunction • impaired production of vasodilator and anti-proliferative agents (e.g. NO and prostacyclin) • overexpression of vasoconstrictor & proliferative substances (e.g.. thromboxane A2and endothelin-1) Humbert M. et. al. JACC 2004 Hassoun PM et. al. JACC 2009 Morrell N. et. al JACC 2009

  20. PATHOBIOLOGY OF PULMONARY HYPERTENSION • Group 1: PAH • elevated vascular tone • promote vascular remodelling by proliferative changes (includes endothelial, smooth muscle cells, and fibroblasts) • increased production of extracellular matrix including: collagen, elastin, fibronectin, and tenascin • prothrombotic activity Humbert M. et. al. JACC 2004 Hassoun PM et. al. JACC 2009 Morrell N. et. al JACC 2009

  21. PATHOBIOLOGY OF PULMONARY HYPERTENSION • Group 2: PAH due to left heart disease • vasoconstrictive reflexes from stretch receptors in the left atrium and pulmonary veins • endothelial dysfunction of pulmonary arteries  favour vasoconstriction and proliferation of vessel wall cells Humbert M. et. al. JACC 2004 Hassoun PM et. al. JACC 2009 Morrell N. et. al JACC 2009

  22. PATHOBIOLOGY OF PULMONARY HYPERTENSION • Group 3: PAH due to lung disease • hypoxic vasoconstriction • mechanical stress of hyperinflated lungs • loss of capillaries • inflammation and toxic effects of cigarette smoke • endothelin derived vasoconstrictor – vasodilator imbalance Humbert M. et. al. JACC 2004 Hassoun PM et. al. JACC 2009 Morrell N. et. al JACC 2009

  23. PATHOBIOLOGY OF PULMONARY HYPERTENSION • Group 4: CTEPH • abnormalities in the clotting cascade, endothelial cells, and platelets • shear, stress, pressure, inflammation, and release of cytokines and vasculotropic substances Humbert M. et. al. JACC 2004 Hassoun PM et. al. JACC 2009 Morrell N. et. al JACC 2009

  24. PATHOBIOLOGY OF PULMONARY HYPERTENSION • Group 5: • unknown Humbert M. et. al. JACC 2004 Hassoun PM et. al. JACC 2009 Morrell N. et. al JACC 2009

  25. DIAGNOSIS • CLINICAL PRESENTATION • NON-SPECIFIC SYMPTOMS: • breathlessness • fatigue • weakness • angina • syncope • abdominal distension • symptoms at rest only in very advanced cases Rich S et. al Ann Intern Med 1987

  26. DIAGNOSIS • CLINICAL PRESENTATION • SIGNS: • left parasternal lift • accentuated P2 • holosystolic murmur of tricuspid regurgitation • diastolic murmur of pulmonary regurgitation Rich S et. al Ann Intern Med 1987

  27. DIAGNOSIS • CLINICAL PRESENTATION • SIGNS in more advanced cases: • S3 gallop • jugular vein distension • hepatomegaly • peripheral edema • ascites • cool extremities Gaine SP et al. Lancet 1998

  28. DIAGNOSIS • CLINICAL PRESENTATION • ASSOCIATED SIGNS: • telangiectasia, digital ulceration, sclerodactyly (SCLERODERMA) • inspiratory crackles (INTERSTITIAL LUNG DISEASE) • spider nevi, testicular atrophy, palmar erythema (CHRONIC LIVER DISEASE) • clubbing (IPAH, CHD, PVOD) Rich S et. al Ann Intern Med 1987

  29. DIAGNOSIS • ELECTROCARDIOGRAM: • suggestive or supportive evidence • RV hypertrophy (87%) and strain • Right axis deviation (79%) • RA dilatation • atrial flutter and atrial fibrillation (ADVANCED STAGES) • absence does NOT rule out disease • insufficient sensitivity (55%) and specificity (70%) Rich S et. al Ann Intern Med 1987

  30. DIAGNOSIS • CHEST RADIOGRAPH: • central pulmonary arterial dilatation • pruning (loss of) distal pulmonary vessels • RA and RV enlargement (ADVANCED STAGES) • can be used to exclude moderate to severe lung diseases or pulmonary venous hypertension due to left heart disease • cannot assess the degree of PAH Rich S et. al Ann Intern Med 1987

  31. DIAGNOSIS • PULMONARY FUNCTION TESTS and ABG • decreased lung diffusion capacity of carbon monoxide (40-80% of predicted) • mild to moderate reduction of lung volume • may indicate interstitial lung disease if coupled with above • arterial oxygen tension is normal or slightly lower at rest • arterial carbon dioxide tension is decreased • irreversible airflow obstruction • increased residual volumes • overnight oximetry or polysomnography is with OSA

  32. DIAGNOSIS • ECHOCARDIOGRAPHY • transthoracic echocardiography • estimation of PAP: • peak pressure gradient of TR = 4x(TR velocity)2 • PAP = PG TR jet + estimated RA Pressure • RA Pressure is estimated at 5-10 mmHg. • mPAP = 0.61 x PA systolic pressure + 2 mmHg • may use contrast echocardiography if difficult to assess TR • few studies have been done to find an accurate correlation between these and RHC Fisher MR et. al. Am J. RespCrit Care 2009

  33. DIAGNOSIS • ECHOCARDIOGRAPHY • other findings: • increased velocity of pulmonary valve regurgitation • short acceleration time of RV ejection into the PA • increased dimension of right heart chambers • abnormal shape and function of the interventricular septum • increased RV wall thickness • dilated main PA Murkejee D et al. Rheumatology 2004

  34. VENTILATION-PERFUSION SCAN • useful for potentially treatable CTEPH • higher sensitivity than CT • normal or low-probability VQ scan • excludes CTEPH (sensitivity 90-100% / specificity 94-100%) Tunariu N. et. al. J Nucl Med 2007

  35. HIGH-RESOLUTION CT, CONTRAST-ENHANCED CT, AND PULMONARY ANGIOGRAPHY • detailed view of lung parenchyma  interstitial lung disease and emphysema • suspected PVOD: interstitial edema with diffuse central central ground-glass opacification and thickening of interlobular septa; lymphadenopathy and pleural effusion Resten A et. al. Am J Roentgenol 2004

  36. HIGH-RESOLUTION CT, CONTRAST-ENHANCED CT, AND PULMONARY ANGIOGRAPHY • contrast CT angiography of the PA • to check for evidence of surgically accessible CTEPH • complete obstruction, bands and webs, and intimal irregularities (similar to digital subtraction angiography) • traditional pulmonary angiography • required to identify patients who may benefit from pulmonary endarterectomy • evaluation for vasculitis or pulmonary AVMs Dartevelle P et. al. Eur Respir J 2004

  37. CARDIAC MRI • image RV size, morphology and function • non-invasive assessment of blood flow : including • stroke volume • cardiac output • distensibility of PA • RV mass • decreased stroke volume, increased RV end-diastolic volume* and decreased LV end-diastolic volume (predictors of poor prognosis) * most appropriate marker Torbicki A et. al. Eur Heart J 2007

  38. BLOOD TESTS AND IMMUNOLOGY • serologic test to identify CTD, HIV and hepatitis • limited scleroderma • anti-centromere antibodies, dsDNA, anti-Ro, U3-RNP, B23, Th/To, U1-RNP • diffuse scleroderma • U3-RNP • SLE • anti-cardiolipin antibodies • Thrombophilia in CTEPH • anti-phospholipid antibodies, lupus anticoagulant, anti-cardiolipin antibodies Rich S et. al. JACC 1986 Chu JW et. al. Chest 2002

  39. ABDOMINAL ULTRASOUND • liver cirrhosis and / or portal hypertension Albrecht T. et. al. Lancet 1999

  40. RIGHT HEART CATHETERIZATION • REQUIRED to diagnose PAH • assess severity of hemodynamic impairment • test for vasoreactivity of the pulmonary circulation • PAP (systolic, diastolic, mean), right atrial pressure, PWP, and RV Pressure • Cardiac output

  41. RIGHT HEART CATHETERIZATION • REQUIRED to diagnose PAH • to identify who may benefit from long-term therapy with CCBs. • acute vasodilator challenge with short-acting, safe, and easy to administer drugs with no or limited systemic effects • nitric oxide • intravenous epoprostenol • intravenous adenosine (risky for systemic vasodilator effect) Galie N et. al Am J. Cardiol 1995

  42. RIGHT HEART CATHETERIZATION • REQUIRED to diagnose PAH • positive acute response: • reduction mean PAP > 10 mmHg. to reach an absolute value of mean PAP < 40 mmHg. ; with • an increased or unchanged Cardiac Output • long-term responders to CCBs Sitbon O et. al Circ 2005

  43. exertional dyspnea syncope angina progressive limitation of exercise capacity

  44. Bone Morrphogenetic Protein Receptor 2, Activin receptor –Like Kinase type 1, Endoglin Family History

  45. TREATMENT • GENERAL MEASURES: • degree of social isolation • encourage patients and family members to join patient support groups  positive effect on coping, confidence, outlook

  46. TREATMENT • GENERAL MEASURES: • PHYSICAL ACTIVITY and SUPERVISED REHABILITATION: • active within symptom limits (mild breathlessness is acceptable; avoid severe breathlessness, exertional dizziness, or chest pain) • training program to improve exercise performance • avoid excessive physical activities • when physically deconditioned supervised exercise rehabilitation Mereles D. et. al. Circulation 2006

  47. TREATMENT • GENERAL MEASURES: • PREGNANCY, BIRTH CONTROL, AND POST-MENOPAUSAL HORMONAL THERAPY • pregnancy : 30-50% mortality in patients with PAH • barrier method: unpredictable but safe • progesterone only preparations e.g. medroxyprogesterone acetate and etonogestrel are effective • NOTE: endothelin receptor antagonist bosentan reduces efficacy of contraceptives • Mirena coil is effective but can cause Vasovagal reaction The Task Force on the Management of Cardiovascular Disease During Pregnancy Eur Heart J 2003 Beclard E. et. al Eur Heart J 2009

  48. TREATMENT • GENERAL MEASURES: • TRAVEL • may need in –flight O2 if WHO-FC III/IV and arterial blood O2 <60 mmHg. • 2L / min. sufficient • avoid going to altitudes above 1500-2000 m without supplemental O2 • travel with a written information about the PAH

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