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Published byCalvin Jacob Cole Modified over 6 years ago
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Elazer R Edelman ere@mit.edu
Effects of Orbital Atherectomy Treatment on Drug Absorption in Calcified Peripheral Arteries Elazer R Edelman
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Elazer Edelman, MD PhD I have no relevant financial relationships
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Driving Question Is lack of response due to DCB apposition or to the drug barrier effects of plaque? If so, does the plaque barrier have to be physically removed, risking dissection, or is more atraumatic preparation sufficient?
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Drug retention forces Active and nonspecific binding Lovich & Edelman
Biophys J 1996 Active and nonspecific binding animate Internalization
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Drug retention = F(ultrastructure)
M NI b. NI M A NI M A NI M A d. c. Tzafriri, et al JCR 2010
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Rx = - 10.1*[LIPID] + 148.4 r2 = 0.842 DRUG CONTENT LIPID CONTENT 7
7.5 8 8.5 9 9.5 10 LIPID CONTENT 45 50 55 60 65 70 75 80 DRUG CONTENT 80 75 Tzafriri, et al JCR 2010 70 65 60 55 This did not examine calcification 50 45
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Radiolabeled Paclitaxel in Atheromatous Human Aorta
Tzafriri, et al JCR 2010 This did not examine calcification
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Arterial transport forces
Solvent Drag = f(Solute: , , , ) Lovich & Edelman Circ Res 1995 Diffusion Active and nonspecific binding Radv Rmed animate Rend Internalization
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Layer dependent drug binding
Available Space Binding Site Density Binding Affinity B K T Nondenuded Media 0.61± ±1.7 (µM) 6.8±2.5 (µM) Denuded Media 0.70± ±1.1 (µM) 5.0±2.1 (µM) Adventitia 0.87± ±1.3 (nM) 8.1±5.7 (nM) hepari Lovich & Edelman Biophys J 1996
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Layer dependent diffusive resistance
30 R med l D Media 25 20 Rat Abdominal Aorta R adv l D 15 Diffusive Resistance (s/µm) Adventitia 10 5 Endothelium R end heparin 50 100 150 200 Medial or Adventitial Thickness (µm) Lovich & Edelman Circ Res 1995
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Cadaveric study design
5 fresh human lower limbs with calcified arteries, CT imaged Calcified arteries were divided into approximately equal segments (QVA) Proximal or distal segment of each artery treated using the DIAMONDBACK 360® OAS (CSI, MN) 3 legs/7 arteries (10 UT vs 9 OAS) => 14C PTX 2 legs/6 arteries (6 UT vs 6 OAS) => FITC-PTX Intraluminally infused artery segments (3cm) with 14C PTX or FITC-PTX drug solution for Motivates the use of cadaveric arteris
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Peripheral lesions complex morphology
Motivates the use of cadaveric arteris Native untreated arteries, no contrast.
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Orbital Atherectomy Mechanism of Action
Differential Sanding for Intimal Calcium Plaque provides resistance and allows grit to “sand” away intimal calcium Elastic healthy tissue “gives” minimizing the affect of the diamond coated surface on the healthy tissue Centrifugal Force for Medial Calcium While orbiting an eccentric crown delivers a localized mechanical pulsatile force These pulsatile forces disrupt calcification to change lesion compliance
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Impact of treatment of human atherosclerotic plaque on paclitaxel absorption
Untreated OAS Treated Fluoro PTX Fluoro PTX 14C-PTX 14C-PTX Drug signature M NI flip
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Superficial concentrated drug signature
Untreated arteries: superficial drug concentration; limited penetration Lumen FEMORAL ARTERIES Penetration depth = µm M NI Superficial concentrated drug signature Lumen Relative diffusion coefficient: % of healthy pig SFA
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OAS treated arteries: diffuse drug concentration, deeper penetration
FEMORAL ARTERIES Penetration depth = µm M NI Deeper diffuse drug signature Lumen Lumen Relative diffusion coefficient: % of healthy pig SFA
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30-fold faster diffusion in OAS treated arteries reduction D barrier
Untreated OAS Treated Penetration depth = µm Relative Deff = % M NI A Lumen Penetration depth = µm Relative Deff = % M NI A Lumen Treated
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Driving Question Is lack of response due to DCB apposition, to the
drug barrier effects of plaque, or both? Plaque impedes paclitaxel absorption If so, does the plaque barrier have to be physically removed, risking dissection? Atraumatic OAS pretreatment allowed paclitaxel to diffuse deeper and distribute more diffusely in diseased human arteries
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Conclusions Atherosclerotic plaques inhibit intravascular drug penetration. Modification of plaque burden with orbital atherectomy improves drug penetration.
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Acknowledgments Peter Markham, MS (attending CRT, markham@cbset.org)
James Stanley, DVM, MS Rami Tzafriri, PhD (attending CRT, Brett Zani, PhD
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