1. Elazer R Edelman ere@mit.edu
Effects of Orbital Atherectomy Treatment on Drug Absorption in Calcified Peripheral Arteries
Elazer R Edelman

2. Elazer Edelman, MD PhD
I have no relevant financial relationships

3. 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?

4. Drug retention forces Active and nonspecific binding Lovich & Edelman
Biophys J 1996
Active and
nonspecific
binding
animate
Internalization

5. Drug retention = F(ultrastructure)M NI b. NI M A NI M A NI M A d. c.
Tzafriri, et al JCR 2010

6. 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

7. Radiolabeled Paclitaxel in Atheromatous Human Aorta
Tzafriri, et al JCR 2010
This did not examine calcification

8. Arterial transport forces
Solvent Drag = f(Solute: , , , )
Lovich & Edelman
Circ Res 1995
Diffusion
Active and
nonspecific
binding
Radv
Rmed
animate
Rend
Internalization

9. 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

10. Layer dependent diffusive resistance30 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

11. 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

12. Peripheral lesions complex morphology
Motivates the use of cadaveric arteris
Native untreated arteries, no contrast.

13. 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

14. 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

15. 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

16. 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

17. 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

18. 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

19. Conclusions
Atherosclerotic plaques inhibit intravascular drug penetration.
Modification of plaque burden with orbital atherectomy improves drug penetration.

20. Acknowledgments Peter Markham, MS (attending CRT, markham@cbset.org)
James Stanley, DVM, MS
Rami Tzafriri, PhD (attending CRT,
Brett Zani, PhD