Pulmonary Hypertension

Pulmonary Hypertension Timothy M. Fernandes, M.D. Senior Ta T lk, February 2009

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Objectives 1. Review the WHO classification system for the five types of pulmonary hypertension. 2. Provide an overview of the pathophysiology of pulmonary arterial hypertension (PAH). 3. Examine the clinical presentation of PAH and understand the diagnostic approach to PAH. 4. Review the fundamentals of right heart catheterizations including normal pressures and definitions of pulmonary hypertension. 5. Review the evidence-based algorithm for the pharmacologic management of PAH.

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Epidemiology of PH  IPAH is a rare disease with an prevalence of about 15 million worldwide – Adult females are almost three times as likely to present with IPAH than adult males  Other forms of PAH are far more common. – In scleroderma uo to 60% of all patients – In rheumatoid arthritis up to 21% – In systemic lupus erythematosus 4 to 14% – In portal hypertension between 2 to 5% – In HIV about 0.5% – In sickle cell disease ranging from 20 to 40%  Diet pills such as Fen-Phen produced an annual incidence of 25-50 per million per year.  Up to 4% of people who suffer a pulmonary embolism go on to develop chronic thromboembolic disease including pulmonary hypertension.  Only about 1.1% of patients with COPD develop pulmonary hypertension with no other disease to explain the high pressure.  Pickwickian syndrome (obesity-hypoventilation syndrome) is very commonly associated with right heart failure due to pulmonary hypertension

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Epidemiology of PH 40% 39% 35% 30% 25% 20% 15% 15% 11% 10% 10% 9.50% 6% 5% 4% 0% Idiopathic Connective Congenital Portal HTN Appetite HIV Familial Tissues Heart Disease Suppressant Disease – Humbert et al. 173 (9): 1023. (2006)

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WHO Classifications of Pulmonary Hypertension 1. Pulmonary Arterial Hypertension2. Pulmonary Venous Hypertension3. PH Secondary to Chronic Hypoxia4. Chronic Thrombo-Embolic Pulmonary Hypertension (CTEPH) 5. Miscellaneous (usually extrinsic compression of pulmonary arteries) * A favorite PIMP question for every Cherniak attending!

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WHO Classifications of Pulmonary Hypertension 1. Pulmonary Arterial Hypertension – Col agen Vascular Disease– Congenital Heart Disease (LR Shunt)– HIV– Anorexigens (i.e. Fen-Phen)– Porto-pulmonary HTN– Familial Idiopathic PAH * A favorite PIMP question for every Cherniak attending!

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PAH results from pulmonary vascular endothelial cell dysfunction and smooth muscle cell proliferation…

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…which leads to remodeling of the pulmonary vasculature… Rich S , Primary pulmonary hypertension. Prog Cardiovasc Dis 1989 ( 31 ) p 205 – 238.

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…resulting in elevated PA pressures, increased PVR and eventual right-sided heart failure. Channick R. Atlas of Heart Diseases: Cardiopulmonary Diseases and Cardiac Tumors. Edited by Eugene Braunwald (series editor), Samuel Z. Goldhaber. ©1995 Current Medicine Group LLC.

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Pathophysiology of PAH Gaine S , Pulmonary hypertension. JAMA 2000 ( 284 ) p 3160 – 3168.

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Clinical Symptoms of Pulmonary Hypertension (PH)  Most commonly present with dyspnea on exertion, lethargy and fatigue  Concerning symptoms include chest pain and syncope  Advanced PH may present with symptoms of Right Heart Failure  Less common symptoms of PH include cough, hemoptysis, and hoarseness

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Physical Exam Findings in PH  Increased intensity of the pulmonic component of the second heart sound  Splitting of the second heart sound widens as the right ventricle fails or if right bundle branch block develops

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CXR in PH Large central Pulmonary arteries Right Ventricular Hypertrophy Rapid attenuation of pulmonary vessels Clear Lung Fields

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ECG in PH  Right axis deviation An R wave/S wave ratio greater than one in lead V1  Incomplete or complete right bundle branch block  Increased P wave amplitude in lead II (P pulmonale) due to right atrial enlargement

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Diagnostic Work-up of PAH 1. TTE 2. W/U other causes 3. RHC Barst, RJ, McGoon, M, Torbicki, A, et al. Diagnosis and differential assessment of pulmonary arterial hypertension. J Am Col Cardiol 2004; 43:40S.

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Basics of Right Heart Catheterization  Rule of 6’s – RA <6– RV <30/6– PA <30/12– PCWP <12  Pulmonary Vascular Resistance Cardiac Output by the Fick Equation

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Basics of Right Heart Catheterization  Right Atrial Tracing – Normal: <6 Points to Remember: RA ~ CVP; measure in ‘valley of vented patients’

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Basics of Right Heart Catheterization  RV Tracing – Normal: <30/6

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Basics of Right Heart Catheterization  Pulmonary Artery Tracing – Normal: <30/12– Mean PAP: ~12-26 — Check PA saturation

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Basics of Right Heart Catheterization  PCWP Tracing – Normal: <12

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Hemodynamic Definitions of PAH  Mean PAP pressure – At rest: >25mmHg– With exercise: >30mmHg  Wedge Pressure: <15mmHg Pulmonary Vascular Resistance: > 240 dynes-cm-sec-5

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Vasoreactivity Testing During RHC  Inhaled Nitric Oxide (NO) is a preferential pulmonary arterial vasodilator  Positive if: – Mean PAP decreases at least 10 mmHg and to a value less than 40 mmHg – Associated increased or unchanged cardiac output– Minimal y reduced or unchanged systemic blood pressure  Only patients with Positive Vasoreactivity are given treatment trials with Calcium Channel Blockers!

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Why Treat PAH?  The natural history of PPH, from the National Institutes of Health Registry. Median survival was 2.9 years, with 5-year survival less than 40% D’Alonzo GG , Barst RJ , Ayres SM , et al. Survival in patients with primary pulmonary hypertension: results from a national prospective registry. Ann Intern Med 1991 ( 115 ) p 343 ~ 349

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Who do we treat for PAH?  Treatment is based on functional status New York Heart Association Functional Classification Class 1: No symptoms with ordinary physical activity. Class 2: Symptoms with ordinary activity. Slight limitation of activity. Class 3: Symptoms with less than ordinary activity. Marked limitation of activity. Class 4: Symptoms with any activity or even at rest.

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Treatment Algorithm for PAH Badesch, et al. Chest 2007;131;1917-1928

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How do we treat PAH?

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Endothelin Antagonists  Bosentan = Tracleer® Ambrisentan & Staxsentan Endothelin is a potent vasoconstrictor  S/E: hepatotoxicity, peripheral edema Rubin LJ, Badesch, DB, Barst, RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002; 346:896.

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PDE-5 Inhibitors  Sildenafil = Viagra = Revatio  Increases cGMP which has vasodilatory and antiproliferative effects  Treatment results in: – Increase in 6-minute walk – Decreased brain naturetic peptide (BNP) – Decreased PVR Michelakis ED , Tymchak W , Noga M , et al. Long-term treatment with oral sildenafil is safe and improves functional capacity and hemodynamics in patients with pulmonary arterial hypertension. Circulation 2003 ( 108 ) p 2066 ~ 2069

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Prostanoids  Improved survival versus historical controls  Improved functional capacity Ann Intern Med. 1994 Sep 15;121(6):409-15.

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Prostanoids  Epoprostenol  Flolan ® – Continuous IV infusion – Half-life only 6 minutes – S/E: flushing (58%), headache (49%), nausea/vomiting (32%), hypotension (16%), anxiety/nervousness/agitation (11%), jaw/chest pain (11%)  Treprostinil  Remodulin ® – Continuous IV/SQ infusion – Half-life of 4-5 hours – S/E: Infusion site pain (SubQ 85%, may improve after several months of therapy); infusion site reaction (SubQ 83%), Headache (27%), Diarrhea (25%), nausea (22%), Jaw pain (13%), Hypotension (11%)  Iloprost  Ventavis® – Inhaled 6-9 times per day – Theoretical advantage of preferential y acting in lungs only

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Adjunctive Therapies for PAH  Treatment of Underlying Cause of PAH  Diuretics: Symptomatic relief of peripheral edema and RV failure  Digoxin: Improved LV function in biventricular heart failure  Supplemental Oxygen Exercise Anticoagulation

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Anticoagulation and PAH Evidence for anticoagulation is based on old data and is stronger for IPAH then other forms of PAH. Rich S , Kaufman E , Levy PS , The effect of high doses of calcium-channel blockers on survival in primary pulmonary hypertension. N Engl J Med 1992 ( 327 ) p 76-81.

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Failure of Medical Therapy: Consider Atrial Septostomy  Improved left-sided filling  Decreased right- sided pressures  May serve as bridge to transplant  Potential for refractory hypoxemia

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Failure of Medical Therapy: Indications for Lung Transplant  New York Heart Association (NYHA) functional class III or IV  Mean right atrial pressure >10 mmHg  Mean pulmonary arterial pressure >50 mmHg  Cardiac index <2.5 L/min per m2  Failure to improve functional y despite medical therapy  Rapidly progressive disease

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Failure of Medical Therapy: Lung Transplant  Pulmonary arterial hypertension (PAH) accounts for less than 5 percent of al lung transplants  PAH patients receiving transplant have high 30-day mortality In a large lung transplant registry, there is a trend towards a survival benefit from BLT, but it does not achieve statistical significance  Right ventricular dysfunction recovers quickly with the rapid reduction in pulmonary vascular resistance after lung transplantation, making heart transplantation unnecessary J Heart Lung Transplant. 2007 Aug;26(8):782-95.

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MKSAP Question #1 A 49-year-old woman is evaluated for dyspnea. She was a competitive long-distance runner until 1 year ago, when she developed dyspnea during exercise, which has worsened over the past year. She now becomes dyspneic when she walks down her level driveway. Two months ago, dizziness began to accompany dyspnea on exertion. Her symptoms are minimal at rest, although she has noticed that rising from a chair rapidly has caused near syncope. She has no nocturnal dyspnea, and her husband confirms that she has no sleep disturbances. On physical examination, she appears comfortable sitting on the examination table, appears fit, and has a normal weight for her height. The temperature is 37.0 °C (98.5 °F), blood pressure 100/70 mm Hg, heart rate 96/min, and respiration rate 18/min. The lungs are clear to auscultation and percussion. The hemidiaphragms distend normal y during inhalation. Cardiac examination discloses a soft holosystolic murmur at the left sternal border and a fixed split S2. The rest of the physical examination, including neuromuscular, is normal. Walking 20 meters in the clinic hal way produces severe dyspnea, but no change in her lung examination.

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Compl p ete e bl b ood c o c unt i s no n rmal, , as a re rout u ine e ch c em e istry t ests and d tests f or HIV HI and a ntinuc u l c ear a r ntibodies, and d t he e ryt ry hro h cyt y e e sed e iment n ation ra te. Ch est ra di d ogra g ph p s hows n o pa p ren re ch c ym y al l un u g g opa p ci c ties, s a ltho h ugh g t he h h ea e rt b orde rd r i r s e nl n arge rg d. d El E ect c roca c rdiogra g ph p y sho h ws tal R w ave v s i n n V1 a 1 nd d V2 V . P ul u monary f un u ction tes e ts re v re eal a total l un u g g ca c pacity o f f 82% o f pre p di d ct c ed, d fun u ct c ional re sidua u l c a c pa p ci c ty 85% o f p red re icted e , and d res re idu d al v olum u e o f f 8 5% o f p re p di d cted e . M aximum u inspiratory a nd d expiratory p res re sures re are re n ormal. T he h d iffus u ing n c a c pa p ci c ty fo f r c r a c rbo rb n n mo m no n xide d i s 60 % % of f pre p di d ct c ed. d Ech c oca c rdi rd ogra g m s hows a g rossly y e nlarged e a nd d hy h pe p rtrophi h ed e ri gh g t ve v ntricl c e, wi w th a re lativel e y y s mal lleft v en e tricl c e. e T he h p ul u monic v alve v is no n rmal. I nj n ec e tion o f f co c nt n rast di d sc s loses s no n e vi v de d nc n e e of ri gh g t t o l ef e t shu h nt. W hi h ch c o f f t he h f ol o l wing g i s t he m ost a ppro p pria ri te n ex e t st s ep e i n n the e eva v luation of f t hi h s pa p tient n ? A) ) Lun u g g bi b ops p y B) B Ve V ntilation/ n perf e us u ion s can C) C) Righ g t h He art Ca C thet e eri e za z tion D) D T herapeu e tic t rial o f f ca c lcium c ha h nne n l bl b ock c ade e E) ) Coronary artery ry angi g ogra g ph p y

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Diagnostic Work-up of PAH 1. TTE 2. W/U other causes 3. RHC Barst, RJ, McGoon, M, Torbicki, A, et al. Diagnosis and differential assessment of pulmonary arterial hypertension. J Am Col Cardiol 2004; 43:40S.

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MKSAP Question #2 A 56-year-old woman with a 5-month history of dyspnea on exertion is admitted to the intensive care unit with dyspnea and dizziness. For the past several days, she has fainted when rising to a standing position or bending over. On physical examination, the temperature is 37.0 °C (98.6 °F), blood pressure 85/40 mm Hg, heart rate 128/min, and respiration rate 24/min. The lungs are clear on auscultation. Cardiac examination reveals a fixed split S2 and a loud P2 component. Chest radiograph shows clear lung fields, a massively enlarged right ventricle, and “pruned” pulmonary arteries. A ventilation/perfusion scan shows no large regional defects, but a “moth-eaten” appearance of scattered perfusion inhomogeneity.

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Which of the fol owing would be the most appropriate initial therapy for this patient? A) Epoprosenol B) Sildenafil C) Bosentan D)Nifedipine E) Digoxin New York Heart Association functional classification Class 1: No symptoms with ordinary physical activity. Class 2: Symptoms with ordinary activity. Slight limitation of activity. Class 3: Symptoms with less than ordinary activity. Marked limitation of activity. Class 4: Symptoms with any activity or even at rest.

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Treatment Algorithm for PAH Badesch, et al. Chest 2007;131;1917-1928

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References  Archer Sl, Michelakis ED. An evidence-based approach to the management of pulmonary arterial hypertension. Curr Opin Cardiol 2006 (21): 385-392.  Badesch, et al. Medical Therapy for Pulmonary Hypertension. Chest 2007;131;1917-1928  Farber HW, Loscalzo J. Mechanisms of Disease: Pulmonary Arterial Hypertension.N Engl J Med. 2004 Oct 14;351(16):1655-65.  Gaine S. Pulmonary Hypertension. JAMA. 2000; 2843160-3168. Newman JH et al. Narrative Review: The Enigma of Pulmonary Arterial Hypertension: new Insights from Genetic Studies. Ann Intern Med. 2008; 148:278-283.  Rubin, LJ. Pulmonary Arterial Hypertension. Proc AM Thoracic Soc. 2006 (3): 111-115.

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