Ottawa Hospital Research Institute Institute de recherche de l Hopital d Ottawa Update On Current Concepts And Treatment Of Pulmonary Hypertension ACC Rockies March 11-14, 2012 Dr. Duncan J. Stewart, CEO and Scientific Director, Ottawa Hospital Research Institute, VP Research, The Ottawa Hospital, Professor of Medicine, uottawa
Financial Interest Disclosure (over the past 24 months) Company Speaker Advisory Research Northern Therapeutics United Therapeutics Lung Rx
Learning objectives Review the current approach to the work up and management of PAH Provide an update on new concepts in the pathogenesis of pulmonary vascular disease Introduce some of the next generation therapies based on new insight into the mechanisms underlying PAH
Clinical Classification of Pulmonary Hypertension (Dana Point Classification 2008) Group 5 Group 1 PAH Group 1 PVOD and/or PCH Group 2 PH with Unclear Multifactorial Mechanisms PH due to Left Heart Disease Group 4 Chronic Thromboembolic Pulmonary Hypertension (CTEPH) Group 3 PH due to Lung Diseases and/or Hypoxia Simonneau G, et al. J Am Coll of Cardiol. 2009;54:Suppl S43-54.
Hemodynamic Definition of PAH Mean pulmonary arterial pressure of 25 mmhg at rest + Pulmonary capillary wedge pressure of < 15 mmhg + Pulmonary vascular resistance of > 3 mmhg/l/min (Wood units) European Society of Cardiology Guidelines. European Heart Journal. 2004;25:2243-78; Canadian Cardiovascular Society and Canadian Thoracic Society PAH Position Statement. Can J Cardiol. 2005;21:909-14
Group 1: PAH PAH Idiopathic PAH (primary) Heritable PAH (Bmpr2 mutation) Drug- and toxin-induced Persistent PH of newborn Associated with: Connective tissue disease HIV infection Portal hypertension Congenital heart disease Schistosomiasis Chronic hemolytic anemia Fenfluramine Amphetamines Cocaine St. John s wort SSRI Phenylpropanolamine Toxic rapseed oil Group 1 Pulmonary Veno-occlusive Disease and/or Pulmonary Capillary Hemangiomatosis Simonneau G, et al. J Am Coll Cardiol. 2004;43:S5-12. Simonneau G, et al. J Am Coll of Cardiol. 2009;54:Suppl S43-54.
Treatment Algorithm for Symptomatic PAH General Treatment Measures 1 anticoagulant, diuretic, oxygen, digoxin Cardiac catheterization Acute Vasoreactivity Testing No - mpap > 10 mmhg - Final mpap < 40 mmhg - Normal or a high CO Yes No Improvement Deterioration FC II Treatment with PAH-Specific Medications (Chosen Based on Patient Functional Class) FC III FC IV Oral CCB 3 Combination Therapy? lung transplantation Sildenafil [A] Bosentan 4 [A] Sildenafil 4 [A] Epoprostenol [A] Treprostinil [B/C] Careful monitoring of response is necessary Epoprostenol [A] Bosentan 2 [B] Treprostinil [C] Sustained Response? No Yes Continue 1 Should be considered for all PAH patients 2 Limited data for WHO/NYHA Class IV 3 No calcium channel blocker has an indication for PAH approved in Canada Adapted from Badesch DB, et al. Chest. 2007;131(6):1917-28.
American Heart Journal, Volume 153, Issue 6, June 2007, Pages 1037-1047 A meta-analysis of trials of pulmonary hypertension: A clinical condition looking for drugs and research methodology Alejandro Macchia, Roberto Marchioli, RosaMaria Marfisi, Marco Scarano, Giacomo Levantesi, Luigi Tavazzi, Gianni Tognoni survival Prostaglandins Endothelin Receptor Antagonists Posphodiesterase inhibitors
Functional pruning of the lung microvasculature in Pulmonary Hypertension Normal Pulmonary Hypertension How? MR perfusion images courtesy of Evangelos Michelakis, Edmonton, Alberta
Characteristic pathology of PAH SMC hypertrophy Primary or secondary Role of endothelial injury/dysfunction? Intimal hyperplasia Not found in most animal models Likely an important mechanism of occlusive remodeling Plexiform lesions hallmark lesion of PAH
What is the root-cause of PAH? Several distinct processes have been implicated Proliferative Increased vascular cell growth arteriolar obliteration/occlusion Inflammatory Innate and adaptive local tissue damage and recruitment of circulating inflammatory/stem cells Degenerative EC injury/apoptosis loss of functional arterioles (pruning) Not separate or mutually exclusive
The Hypoxia-SU5416 Model of Severe PAH is Dependent on EC Apoptosis Effect of VEGF receptor antagonist (SU5416) Activated caspase 3 PCNA Taraseviciene-Stewart et al. FASEB J. 15:427,2001 Effects of SU5416 reversed by z-asp
Abe at al. Circulation. 2010;121:2747-2754 Sprott Stem Cell Centre Complex vascular lesions up to 14 wks in the rat hypoxia-su5416 model Lung vascular EC apoptosis is a trigger for PAH leading to reactive vascular cell proliferation and inflammation
New insight into the pathogenesis of PAH from the genetics of Familial PAH 6 12% of cases of PPH familial, autosomal dom. PPH gene identified (Nat Gen 26:81,2000) BMPR2 loss-of-function mutations TGF-b receptor superfamily ~60% of familial and 25% of sporadic PAH Bone Morphogenetic Protein Receptor 2
BMPs inhibit growth and induce apoptosis of human PA SMCs Loss of function Zhang S, AmJ Physiol Lung Cell Mol Physiol, 2003
TUNEL Positive Nuclei (%) Circulation Research 2005 Sprott Stem Cell Centre Effect of BMP-2 on TNFa-induced endothelial cell apoptosis (TUNEL) TNF 10.0 8.0 * 6.0 TNF+BMP 4.0 2.0 0.0 TNF TNF+BMP
Circulation Research 2005 Fold-increase in Apoptosis BMPRII gene silencing by sirna Control RNAiFect sirna NS sirna Silencing b c 4 * 3 BMPRII Control sirna Silencing 115kDa Increased susceptibility for EC apoptosis is a key mechanism β-actin by which sirna sirna 40 kda Bmpr2 mutations lead to PAH 2 1 0 NS Silencing
Delivery of early-growth EPCs in the rat monocrotaline (MCT) model Pre-capillary arteriole Pulmonary arteriole 15 minutes 1 week post MCT Zhao et al. Circ Res. 2005; 96(4):442-50
Effect of EPCs on PAH in the monocrotaline (MCT) prevention model of PAH 60 50 40 30 20 10 RVSP (mmhg) * * Control MCT-FB MCT-EPC FMA SMA 0 Con MCT FB EPC Zhao et al. Circ Res. 2005; 96(4):442-50
RVSP (mmhg) Zhao et al. Circ Res. 2005; 96(4):442-50 Sprott Stem Cell Centre Effect of EPCs in the reversal of MCTinduced PAH (RVSP) 80 60 * * ** p<0.01 vs. d21 MCT p<0.001 vs. d21 MCT Day 21 40 ** Day 35 20 0 Control MCT EPCs EPCs/ enos
Cumulative Survival Sprott Stem Cell Centre Survival analysis following cell therapy in the treatment MCT-PAH model 1.0 N = 63 0.9 0.8 MCT-CAC/eNOS 0. 7 0. 6 0.5 MCT-CAC P<0.05 P<0.02 0.4 MCT 0.3 25 27 29 31 33 35 Days post MCT Zhao et al. Circ Res. 2005; 96(4):442-50
Pulmonary Hypertension And Cell Therapy (PHACeT) Trial Safety study I o EP: tolerability of cell transplantation in patients with PAH refractory to all standard therapies Cell delivery enos transfected autologous early growth EPCs Delivery via SG catheter Pacing port (i.e. RV delivery) allows continuous monitoring of PA pressure Dose ranging for enos transfected cells given over 3 days in divided doses
PHACeT Trial Cell Processing Transfection with enos Viability: >98% 2.5 x10 6 henos-tx EPCs/ml
Overlapping, dose escalation protocol Panel 2 Panel 3 10x10 6 20x10 6 Day 3 3x10 6 10x10 6 10x10 6 20x10 6 = 23 million cells = 50 million cells Panel 1 1x10 6 3x10 6 3x10 6 Day 1 Day 2 Day 3 = 7 million cells 3 patients/panel 3 additional pts at highest panel
TPVR (dyne*s*cm-5) Sprott Stem Cell Centre Hemodynamic Data n=7 1600 P=0.05 1400 1200 1000 800 600 400 200 0 1 2 3 Days pre Post 1160 NO-mediated effect of enos transfected cells? 781 ~ 400 dyne*s*cm -5 Pre cell delivery 30 post cell delivery
Inhibition of breakdown of cgmp enhances NO action
TPVR (% change) Sprott Stem Cell Centre TPVR (% change) Hemodynamic Data Interaction with PDEV inhibitor No Sildenafil (n=3) On Sildenafil (n=4) 120 120 100 80 60 40 100 ~20% 80 60 40 pre Post ~40% 20 20 0 1 2 3 0 1 2 3 Days Days
Change 6MW (meters) Change in 6MW (meters) Change 6MW (meters) 70 60 50 40 30 20 10 Six minute walk distance * 100 90 80 70 60 50 40 30 20 10 0 1M 2M 3M 100 90 80 70 60 50 0 30 Consistent 1M with 2M our 3M preclinical data 20supporting the * P<0.01 10 importance enos-enhanced cell therapy 0 in the 1M 2M 3M reversal of established PAH 40
PHACeT-2: proposed trial design Randomized DB controlled Unblinded extension apheresis Placebo (saline) 2:1 randomization elective henos-epcs (150 million cells) 50M 50M 50M 50M 50M 50M -1 0 1 2 3 months 6 7 8 9 12 6MWT Echo, 6MWT Hemodynamics Echocardiography 6MWT (1 o EP) Hemodynamics Echocardiography 6MWT
Summary and Conclusions Lung vascular EC apoptosis is a trigger for PAH leading to reactive vascular cell proliferation and inflammation Increased susceptibility for EC apoptosis is a key mechanism by which Bmpr2 mutations lead to PAH Progenitor cell therapy may hold promise for repair and regeneration of pulmonary microcirculation in PAH Both preclinical and early clinical data support the importance enos-enhanced cell therapy in the reversal of established PAH
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