Pulmonary Hypertension Murali Chakinala, M.D. Washington University School of Medicine
Pulmonary Circulation Alveolar Capillary relationship
Pulmonary Circulation High flow, low resistance PVR ~1/15 of SVR due to large cross-sectional area High capacitance Accommodate CO Arterioles offer very little resistance Systemic arterioles supply 75% total peripheral resistance
Determinants of PA Pressure and Flow vascular tone tissue pressure Pcap P PA FLOW P LA P PA = LA + (CO X PVR) Courtesy J. Newman
Systemic versus Pulmonary Circulation Systemic Circulation 120/80, mean 93 25/8, mean 14 Systemic Pulmonary Arteries Arteries Pulmonary Circulation Mean 30 RA Mean 2-5 LA Mean 5 Mean 12 Body Lung Systemic Veins RV 25 / 2- LV 120 / 5-10 Pulmonary Veins 5
Netter FH. Atlas of Human Anatomy
What is Pulmonary Hypertension?? High pressures in the blood vessels responsible for transporting blood from the right-side of the heart to the lungs Impairs the constant flow of blood from the heart to the lungs (Circulatory disorder) Limits the use of oxygen that is breathed into the lungs (Respiratory insufficiency)
Definition of Pulmonary HTN Mean Pulmonary Artery Pressure 25 mm Hg (rest) pre-capillary hypertension Pulmonary Vascular Resistance 3 Woods Units (240 dynes/sec/cm 5 ) Trans-pulmonary gradient 12 mm Hg
Classification of Pulmonary HTN 2008 Dana Point Pulmonary arterial hypertension (PAH) Idiopathic Heritable Drug & Toxin Associated Pulmonary veno-occlusive Disease and/or capillary hemanigiomatosis Pulmonary hypertension owing to lung diseases and/or hypoxia Chronic obstructive pulmonary disease Interstitial lung diseases Other pulmonary diseases with mixed obstructive & restrictive pattern Sleep-disordered breathing Alveolar hypoventilation disorders Pulmonary hypertension owing to left heart disease Systolic dysfunction Diastolic dysfunction Valvular disease Simonneau G. JACC. 2009; 54: S43-54 Chronic thromboembolic pulmonary HTN Pulmonary hypertension with unclear multifactorial mechanisms Hematologic disorders: splenectomy Systemic disorders: sarcoid, Langerhans cell Metabolic disorders: glycogen storage Others: fibrosing mediastinitis, dialysis
Determinants of PA Pressure and Flow vascular tone tissue pressure Pcap P PA Raises vasoconstriction obstruction obliteration flow Compression Lowers vasodilation recruitment FLOW P PA = LA + (CO X PVR) Courtesy J. Newman P LA Raises LVEDP LA venous obstruction blood volume Lowers afterload reduction
French Registry: Kaplan-Meier Survival Estimates in Combined PAH Population vs NIH-predicted 100 Observed 80 Survival (%) 60 40 Predicted (NIH Registry) 20 0 0 12 24 36 No. at risk: Time (mo) All patients 56 69 98 113 120 127 133 Humbert M et al. Circulation. 2010;122:156-163.
BMPR-II Signaling System TGF-β superfamily BMPR-II located on PASMC & Endothelial cells cell inhibition cell differentiation Activate MAPK pathways cell proliferation 25% Sporadic IPAH 75% FPAH 8% Anorexigen-induced 6% CHD PVOD cases Newman JH, et al. NEJM. 2001; 345(5): 319-24
Archer SL. Circulation. 2010; 121: 2045
Vasoactive Substances and the Pulmonary Circulation Constricts HYPOXIA Alpha catecholamine H1 Histamine Serotonin Thromboxanes Leukotrienes Angiotensin Endothelin A (low ph augments) Dilates OXYGEN Beta agonists H2 Histamine Prostacyclins Nitric Oxide (NO) Acetylcholine (NO)
Mediators Thromboxane A 2 Endothelin-1 11-Dehydro-thromboxane B 2 (pg/mg of creatinine) 10,000 8000 6000 4000 2000 0 P<0.05 Normal Controls (n=14) Patients Patients With With Primary PH Due PH to Other (n=20) Causes (n=8) Patients With CVD- Induced PH (n=6) iret-1 (pg/ml) 20 15 10 5 0 NS P<0.001 Normal CAD IPAH Christman BW, et al. NEJM. 1992;327:70-75. Stewart DJ, et al. Ann Intern Med. 1991;114:464-69
Mediators 800 Prostacyclin Nitric Oxide metabolites 2,3-Dinor-6-keto-PGF 1α (pg/mg of creatinine) 600 400 200 0 Normal Controls (n=9) P<0.05 Patients With Primary PH (n=10) Patients With PH Due to Other Causes (n=5) Patients With CVD- Induced PH (n=2) 50 40 30 20 10 0 Controls P<0.01 PAH Christman BW, et al. NEJM. 1992;327:70-75. Cella G, et al. Chest. 2001;120:1226-30.
Blood Vessel Imbalances NORMAL PULMONARY HYPERTENSION Thromboxane A 2 Endothelin-1 Angiotensin II Serotonin Prostacyclin Nitric oxide ANP / BNP Adrenomedullin Thromboxane A 2 Endothelin-1 Angiotensin II Serotonin Prostacyclin Nitric oxide ANP / BNP Adrenomedullin
Homeostatic Imbalances Vasoconstriction Vasodilation Prothrombotic Antithrombotic Proliferation Apoptosis
Panvasculoapthy Archer SL. Circulation. 2010; 121: 2045
Pathology of PAH WHO Group I: Characterized by progressive growth and vasoconstriction of small pulmonary arteries Gaine S. JAMA. 2000;284:3160-3168.
Integrative Pathogenesis Genetic Predisposition Other Risk Factors Altered Pathways and Mediators Proliferation Thrombosis Vasoconstriction Vascular Remodeling
Vascular Remodeling Normal PAH high flow low resistance low flow high resistance Adapted from Gaine S. JAMA 2002
As PAH Progresses Cardiac Output Declines Pre-symptomatic/ Compensated Symptomatic/ Decompensating Declining/ Decompensated CO Symptom Threshold PAP PVR Right Heart Dysfunction Time
Does this patient have PAH?? YES NO Treat with PAH specific therapies Optimize underlying condition
Right Heart Catheterization
PAH Treatment Goals Reverse remodeling >> CURE Improve QOL Prolong survival Prevent hospitalization Delay clinical worsening Lessen symptoms Improve exercise capacity
Treatment Pathways Endothelin pathway Endothelin cells Pre-proendothelin Proendothelin Nitric oxide pathway Vessel lumen Prostacyclin pathway Arachidonic acid Prostaglandin I 2 Endothelin receptor A Endothelin receptor antagonist s Endothelin 1 Endothelin receptor B Vasodilation and proliferation L-arginine L-citrulline Phosphodiesterase type 5 Nitric oxide cgmp + Exogenous nitric oxide Vasodilation and antiproliferation Prostacyclin (prostaglandin I 2 ) camp + Vasodilation and antiproliferation Prostacyclin derivatives Smooth muscle cells Phosphodiesteras e type 5 inhibitor Humbert M. N Engl J Med 2004;351:1425-36
PAH Specific Therapies Therapeutic Class Drug Route of Administration Functional Class Indication Phosphodiesterase 5 - Inhibitors Sildenafil Tadalafil PO II IV II - IV Endothelin Receptor Antagonists Bosentan Ambrisentan PO II IV II - III Iloprost IH III - IV Prostanoid Treprostinil SC*, IV, IH II - IV Epoprostenol IV III - IV *SC Treprostinil only approved for functional class II patients IH treprostinil only approved for FC III patients
Prostacyclin Analogues: Intravenous, Subcutaneous, or Inhaled Treprostinil (Remodulin ) Epoprostenol (Flolan or Veletri ) Treprostinil (Remodulin ) Treprostinil (Tyvaso )
Flolan (Epoprostenol) Continues infusion (24/7) Potent vasodilator Anti platelet agent Anti proliferative agent Reduces symptoms Prolongs lives
Epoprostenol - Hemodynamics L/min/m 2 6.0 4.0 2.0 0.0 Cardiac index * * * Baseline Period 1 Period 2 Period 3 mm Hg 100 90 80 70 60 50 40 30 20 10 0 Mean pulmonary pressure Baseline Period 1 Period 2 Period 3 McLaughlin VV. Circulation 2002;106:1477-82
Epoprostenol Long Term Sitbon O. J Am Coll Cardiol. 2002;40:780-788 1482 McLaughlin VV. Circulation. 2002;106:1477-
Treprostinil IV: 6MWD (TRUST) Mean 6MWD (m) 400 350 300 250 200 150 100 50 Placebo (n=14) Treprostinil IV (n=30) * 100 90 80 70 60 50 40 30 20 10 Mean dose (ng/kg/min) 0 Baseline Week 1 Week 4 Week 8 Week 12 0 *p=0.022. 6MWD values are mean+se. Hiremath J et al. J Heart Lung Transplant. 2010;29:137-149.
Implantable Pump: Prostanoid Delivery