Pulmonary Hypertension in 2012
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1 Pulmonary Hypertension in 2012 Evan Brittain, MD December 7, 2012 Kingston, Jamaica VanderbiltHeart.com
2 Disclosures None VanderbiltHeart.com
3 Outline Definition and Classification of PH Hemodynamics of PH PH due to Left Heart Disease Clinical Characteristics Diagnosis Management Chronic Thromboembolic PH (CTEPH) Pulmonary Arterial Hypertension (PAH) VanderbiltHeart.com
4 Vascular Pressure in Systemic and Pulmonary Circulations (mmhg) 120/80, mean 93 25/8, mean 14 Systemic Circulation Arteries Arteries Body Mean 30 Right Atrium Mean 2-5 Left Atrium Mean 5 Pulmonary Circulation Mean 12 Lung Veins Right Ventricle 25/2-5 Left Ventricle 120/5-10 Veins
5 Hemodynamic Definition of PH/PAH PH Mean PAP 25 mm Hg PAH Mean PAP 25 mm Hg plus PCWP/LVEDP 15 mm Hg Badesch D et al. J Am Coll Cardiol. 2009;54:S55-S66. McLaughlin VV et al. J Am Coll Cardiol. 2009;53:
6 Importance of Hemodynamics Post-capillary Pulmonary venous hypertension Elevated PCWP, normal PVR, VC RA RV PA PV PC Pre-capillary PAH PH with respiratory disease CTEPH Normal PCWP, elevated PVR, LA LV Ao Other: high CO V = IR P = CO x R
7 1. PAH Clinical Classification of Pulmonary Idiopathic PAH Heritable Drug- and toxin-induced Persistent PH of newborn Associated with: CTD HIV infection portal hypertension CHD schistosomiasis chronic hemolytic anemia Hypertension (Dana Point) 3. PH Owing to Lung Diseases and/or Hypoxia COPD 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 4. Chronic Thromboembolic PH 1. PVOD and/or PCH 2. PH Owing to Left Heart Disease Systolic dysfunction Diastolic dysfunction Valvular disease 5. PH With Unclear Multifactorial Mechanisms Hematologic disorders Systemic disorders Metabolic disorders Others Simonneau G et al. J Am Coll Cardiol. 2009;54;S43-S54.
8 Clinical Classification of Pulmonary Hypertension (Dana Point) 1. PAH Idiopathic PAH Heritable Drug- and toxin-induced Persistent PH of newborn Associated with: CTD HIV infection portal hypertension CHD schistosomiasis chronic hemolytic anemia 1. Pulmonary veno-occlusive disease 2. PH Owing to Left Heart Disease Systolic dysfunction Diastolic dysfunction Valvular disease 3. PH Owing to Lung Diseases and/or Hypoxia COPD ILD Other pulmonary diseases with mixed restrictive and obstructive pattern Sleep-disordered breathing Alveolar hypoventilation disorders Chronic exposure to high altitude Developmental abnormalities 4. CTEPH 5. PH With Unclear Multifactorial Mechanisms Hematologic disorders Systemic disorders Metabolic disorders Others Simonneau G et al. J Am Coll Cardiol. 2009;54;S43-S54.
9 Outcomes in Pulmonary Hypertension PASP estimates predict death in patients with and without CV disease Circulation. 2012;126: VanderbiltHeart.com
10 Is It Left Heart Disease? Symptoms Dyspnea Orthopnea History Diabetes HTN Obesity CAD Metabolic syndrome
11 Percentage of PAH and PVH Patients With Each of the 4 Factors of the Metabolic Syndrome * * PAH PVH Percent of patients * ** 20 0 OR 95% CI HTN 13.7 ( ) Obesity 7.1 ( ) DM 5.7 ( ) HL 4.2 ( ) *p 0.005; **p= Robbins IM et al. Chest. 2009;136:31-36.
12 Is It Left Heart Disease? Symptoms PND orthopnea History diabetes HTN obesity CAD metabolic syndrome ECG Echo atrial fibrillation absence of RAD LAE LVH normal RA, RV abnormal diastolic filling
13 Is It Left Heart Disease? Symptoms PND orthopnea History diabetes HTN obesity CAD metabolic syndrome ECG Echo atrial fibrillation absence of RAD LAE LVH normal RA, RV abnormal diastolic filling ~ 1/3 of patients with diastolic dysfunction will have normal echo
14 PH due to Left Heart Disease: Diagnosis and Management Suspected PH signs/symptoms/ecg/cxr) VanderbiltHeart.com
15 PH due to Left Heart Disease: Diagnosis and Management Suspected PH signs/symptoms/ecg/cxr) Doppler Echo - PASP - RV size/function - LV/Valves - Exercise/Agitated saline VanderbiltHeart.com
16 Copyright American College of Chest Physicians. All rights reserved. From: Inaccuracy of Doppler Echocardiographic Estimates of Pulmonary Artery Pressures in Patients With Pulmonary Hypertension: Implications for Clinical Practice CHEST. 2011;139(5): doi: /chest
17 PH due to Left Heart Disease: Diagnostic Strategies Suspected PH signs/symptoms/ecg/cxr) Doppler Echo - PASP - RV size/function - LV/Valves - Exercise/Agitated saline No clear cause of PH/RV Dysfunction Additional Diagnostic Testing No PH/RV Dysfunction Invasive hemodynamics: mpap, PCWP, PVR, CO Etiologic Evaluation: - PFT - V/Q scan - Polysomnography - Labs (HIV, ANA, liver function) Look for other causes Clear cause of PH - LH disease - Valve disease Treat suspected Cause of PH Persistent Symptoms VanderbiltHeart.com
18 PH Due to Left Heart Disease Management Treat underlying cause Hypertension Volume overload Valve Disease VanderbiltHeart.com
19 Vasodilator Therapy in PH Avoid prostacyclins and endothelin receptor antagonists in PH due to LH disease VanderbiltHeart.com
20 Role of PDE5 Inhibition in Left Heart PH Systolic HF: sildenafil improves exercise capacity and quality of life Diastolic HF: reduced pulmonary resistance and improved RV function Ongoing trials Guazzi et al. Circulation. 2011;124: VanderbiltHeart.com
21 Importance of RV Function Echocardiographic RV function in PH Am J Respir Crit Care Med Vol 174. pp , 2006 Effect of PH and RV function on survival in HF patients no PH, nl RVEF PH, nl RVEF no PH, RVEF PH, RVEF J Am Coll Cardiol Jan;37(1):183-8.
22 Cumulative incidence of CTEPH Incidence of CTEPH Approximately 3% to 4% after acute PE USA: 600,000 cases of acute PE each year VQ scan identifies old PE better than CTA Years Pengo V et al. N Engl J Med. 2004;350: Tapson VF, Humbert M. Proc Am Thorac Soc. 2006;3:
23 CTEPH : A Curable Form of PH Not to Be Missed
24 Right Ventricular Recovery Patient with Chronic Thromboembolic PH 6 months after pulmonary endarterectomy
25 1. PAH Clinical Classification of Pulmonary Idiopathic PAH Heritable Drug- and toxin-induced Persistent PH of newborn Associated with: CTD HIV infection portal hypertension CHD schistosomiasis chronic hemolytic anemia Hypertension (Dana Point) 3. PH Owing to Lung Diseases and/or Hypoxia COPD ILD Other pulmonary diseases with mixed restrictive and obstructive pattern Sleep-disordered breathing Alveolar hypoventilation disorders Chronic exposure to high altitude Developmental abnormalities 4. CTEPH 1. PVOD and/or PCH 2. PH Owing to Left Heart Disease Systolic dysfunction Diastolic dysfunction Valvular disease 5. PH With Unclear Multifactorial Mechanisms Hematologic disorders Systemic disorders Metabolic disorders Others Simonneau G et al. J Am Coll Cardiol. 2009;54;S43-S54.
26 Survival in PAH Percent survival Portopulmonary CTD HIV Congenital heart disease Years IPAH McLaughlin VV et al. Chest. 2004;126:78S-92S.
27 PAH: Hemodynamic and Clinical Course Adventitia Media Intima NORMAL CO PAP PVR NYHA I Adapted from Gaine S. JAMA. 2000;284: Time
28 PAH: Hemodynamic and Clinical Course Adventitia Media Intima Smooth Muscle Hypertrophy Early Intimal Thickening NORMAL REVERSIBLE DISEASE CO PAP PVR NYHA I II III Adapted from Gaine S. JAMA. 2000;284: Time
29 PAH: Hemodynamic and Clinical Course Adventitia Media Intima Smooth Muscle Hypertrophy Early Intimal Thickening Plexiform Lesions Smooth Muscle Hypertrophy Adventitial, Intimal Proliferation Thrombosis NORMAL REVERSIBLE DISEASE IRREVERSIBLE DISEASE CO PAP PVR NYHA I II III IV Adapted from Gaine S. JAMA. 2000;284: Time
30 Chronic Adjuvant Therapies in PAH Oxygen Use to prevent hypoxic vasoconstriction Consider exercise, sleep, altitude Aim for target saturation 90% May not correct hypoxia with shunt Diuretics Most patients need Hypotension not a contraindication Anticoagulation Recommended in IPAH Retrospective data only; need to balance unproven benefits with known risks INR McLaughlin VV et al. J Am Coll Cardiol. 2009;53:
31 Mechanisms of Action of Therapies for PH Endothelin Pathway Pre-proendothelin Proendothelin Endothelial cells Nitric Oxide Pathway Endothelial cells Prostacyclin Pathway Arachidonic acid Prostaglandin I 2 Endothelin receptor A Endothelinreceptor antagonists Endothelin-1 Smooth muscle cells Endothelin receptor B Vasoconstriction and proliferation L-arginine Phosphodiesterase type 5 Nitric Oxide cgmp L-citrulline Phosphodiesterase type 5 inhibitor Exogenous nitric oxide Vasodilation and antiproliferation Prostacyclin (prostaglandin I 2 ) camp Vasodilation and antiproliferation Smooth muscle cells Prostacyclin derivatives Humbert M et al. N Engl J Med. 2004;351:
32 Survival (%) Survival Among Patients With IPAH: Epoprostenol vs Conventional Therapy Epoprostenol (n=41) p=0.003* Conventional therapy (n=40) Week *Two-sided, by log-rank test. Barst RJ et al for the PPH Study Group. N Engl J Med. 1996;334:
33 Survival in IPAH Long-term CCB Responders Long-term CCB responders ( 6% of IPAH patients) Cumulative survival Long-term CCB failure Vasodilator Response p= Fall in mpap 10 mm Hg, and 2. mpap (absolute) <40 mm Hg 0.0 Subjects at risk, n Years Sitbon O et al. Circulation. 2005;111: Long-term CCB responders Long-term CCB failure
34 Adapted ACCP Evidence-Based Clinical Practice Guidelines Pulmonary arterial hypertension Anticoagulants, diuretics, O 2 Vasoreactivity test + Calcium Channel Blocker FC I-II Bosentan Sildenafil Prostanoid Epoprostenol IV FC III-IV Prostanoid Epoprostenol IV Bosentan Sildenafil No improvement Atrial septostomy Lung transplant Adapted with permission from Badesch DB et al. Chest. 2007;131:
35 Comparison of Medical Treatments for PAH Cost $ (annual) Route Frequency Ease of Use Side effects Long-term Data Epoprostenol ~80,000 IV Continuous Yes Treprostinil >150,000 SQ, IV, Inhaled Continuous 4x per day Yes Iloprost 60-70,000 Inhaled 6-9x per day Yes Sildenafil Tadalafil Bosentan Ambrisentan ~20,000 Oral TID QD ~60,000 Oral BID QD Yes Yes Yes
36 Thank you for your attention VanderbiltHeart.com
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