And Treatment Of Pulmonary Hypertension ACC Rockies March 11-14, - - PowerPoint PPT Presentation
Ottawa Hospital Research Institute Institute de recherche de lHopital dOttawa 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 Institute de recherche de l’Hopital d’Ottawa
CEO and Scientific Director, Ottawa Hospital Research Institute, VP Research, The Ottawa Hospital, Professor of Medicine, uOttawa
Company Speaker Advisory Research Northern Therapeutics √ United Therapeutics √ √ Lung Rx √ √
Simonneau G, et al. J Am Coll of Cardiol. 2009;54:Suppl S43-54.
Group 1 PAH Group 2 PH due to Left Heart Disease Group 3 PH due to Lung Diseases and/or Hypoxia Group 4
Chronic Thromboembolic Pulmonary Hypertension (CTEPH)
Group 5 PH with Unclear Multifactorial Mechanisms Group 1’ PVOD and/or PCH
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‘ – 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. Fenfluramine Amphetamines Cocaine
SSRI Phenylpropanolamine Toxic rapseed oil
Adapted from Badesch DB, et al. Chest. 2007;131(6):1917-28.
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
General Treatment Measures1
Combination Therapy? lung transplantation Careful monitoring of response is necessary
FC III
Bosentan4 [A] Sildenafil4 [A] Epoprostenol [A] Treprostinil [B/C]
Treatment with PAH-Specific Medications (Chosen Based on Patient Functional Class)
FC II
Sildenafil [A]
FC IV
Epoprostenol [A] Bosentan2 [B] Treprostinil [C]
Oral CCB3
Yes Sustained Response?
Continue
Yes No No
Acute Vasoreactivity Testing Cardiac catheterization
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
American Heart Journal, Volume 153, Issue 6, June 2007, Pages 1037-1047
Prostaglandins Endothelin Receptor Antagonists Posphodiesterase inhibitors survival
Normal Pulmonary Hypertension
MR perfusion images courtesy of Evangelos Michelakis, Edmonton, Alberta
– Primary or secondary – Role of endothelial injury/dysfunction?
– Not found in most animal models – Likely an important mechanism of
Plexiform lesions – hallmark lesion of PAH
Taraseviciene-Stewart et al. FASEB J. 15:427,2001
Activated caspase 3 PCNA
Abe at al. Circulation. 2010;121:2747-2754
– TGF-b receptor superfamily – ~60% of familial and 25%
Bone Morphogenetic Protein Receptor 2
Zhang S, AmJ Physiol Lung Cell Mol Physiol, 2003 Loss of function
TNF TNF+BMP 0.0 2.0 4.0 6.0 8.0 10.0
TNF
†
TNF+BMP TUNEL Positive Nuclei (%) Circulation Research 2005
b c Control siRNA Silencing siRNA NS RNAiFect
115kDa BMPRII β-actin
Control siRNA Silencing
40 kDa
Fold-increase in Apoptosis siRNA NS siRNA Silencing
1 2 3 4
Circulation Research 2005
1 week post MCT Pre-capillary arteriole
Pulmonary arteriole
15 minutes
Zhao et al. Circ Res. 2005; 96(4):442-50
FMA SMA
Control MCT-FB MCT-EPC Zhao et al. Circ Res. 2005; 96(4):442-50
10 20 30 40 50 60
RVSP (mmHg)
Con MCT FB EPC
MCT EPCs EPCs/ eNOS 20 40 60 80 Control Day 21 Day 35
Zhao et al. Circ Res. 2005; 96(4):442-50
1.0 0.9 0.8 0. 7 0. 6 0.5 0.4 0.3
Cumulative Survival
35 33 31 29 27 25
Days post MCT Zhao et al. Circ Res. 2005; 96(4):442-50
MCT MCT-CAC
P<0.05
MCT-CAC/eNOS
P<0.02
N = 63
– allows continuous monitoring of PA pressure
Transfection with eNOS Viability: >98% 2.5 x106 heNOS-Tx EPCs/ml
3 patients/panel Panel 2 = 23 million cells
3x106 10x106 10x106
Panel 3 = 50 million cells
Day 3 10x106 20x106 20x106
= 7 million cells Panel 1
Day 1 Day 2 1x106 3x106 3x106 Day 3
3 additional pts at highest panel
200 400 600 800 1000 1200 1400 1600 1 2 3 Days TPVR (dyne*s*cm-5)
1160 781 ~↓400 dyne*s*cm-5
Pre cell delivery 30’ post cell delivery
P=0.05
No Sildenafil (n=3)
20 40 60 80 100 120 1 2 3 TPVR (% change)
Days ~20%
On Sildenafil (n=4)
20 40 60 80 100 120 1 2 3
~40% Days
10 20 30 40 50 60 70
1M 2M 3M
Change 6MW (meters)
10 20 30 40 50 60 70 80 90 100
1M 2M 3M
Change 6MW (meters) 10 20 30 40 50 60 70 80 90 100
1M 2M 3M
Change in 6MW (meters)
7 8 9 2
1 6 Hemodynamics Echocardiography 6MWT (1oEP) Echo, 6MWT 3 6MWT 2:1 randomization heNOS-EPCs (150 million cells) apheresis Unblinded extension 12 Randomized DB controlled elective months Hemodynamics Echocardiography 6MWT Placebo (saline) 50M 50M 50M 50M 50M 50M