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1
MR Contrast Agents for
Vulnerable Plaque Imaging
Philip Graham, PhD
EPIX Medical, Inc.
Cambridge, MA 02142
2
MS-325: Vascular Contrast
Agent
• Albumin binding
•Extends plasma
t1/2
•4-10X increase
in signal
•Slows ECS
uptake
• Pha...
3
Vessel Wall Enhancement with
MS-325
Courtesy of: T. Grist (University of Wisconsin, Madison, WI)
4
Jeffrey H. Maki1,2
, Gregory J. Wilson1
,
Randall B. Lauffer3
, Robert M. Weisskoff3
,
Chun Yuan2
1 - Puget Sound VAHCS,...
5
Vessel Wall Enhancement
with MS-325
• Atherosclerosis = inflammation
• Leaky capillaries supplying vessel
wall
– Increas...
6
Arterial Phase Equilibrium Phase MS-325
Source Images - Left External Iliac Artery
Artery
Vein
7
0
0.5
1
1.5
2
2.5
3
Adj to Plaque No Plaque
Wall Thickness (mm) Related to Plaque
Results
Adj to Plaque No Plaque
P < 0....
8
Results
• Strong wall enhancement with MS-325 because of
increased capillary volume and binding to
extravasated albumin
...
9
Pharmacological trigger
histamine = vasoconstrictor -> increases mechanical force on fibrous cap -> plaque
disruption
Ru...
10
baseline
MS-325
MS-325 improves Plaque Visualization
plaque
contrast uptake no uptake
wall
plaque
thrombus
MS-325
Post-...
11
Direct Clot Detection with Fibrin-
Targeted Contrast Agent
• Fibrin targeting lead discovered in a collaboration with
D...
12
To be annotated, final copy will be printed high definition
Post Gd-BSA (angiography)
Pre contrast
1 minute post EP-187...
13
Pre contrast
10min
1.5h
1h
Post EP-1873 (fibrin agent)
aorta
thrombus
thrombus
thrombus
Botnar RM, Perez AP, Johnstone ...
14
Pre contrast
10min
1.5h
1h
Post EP-1873 (fibrin agent)
Botnar RM, Perez AP, Manning WJ, Johnstone MT
15
Pre contrast 10min 1.5h
Post EP-1873 (fibrin agent)
aorta
thrombus thrombus
Botnar RM, Perez AP, Manning WJ, Johnstone ...
16
Summary
• Prototype clot-enhancing agents for MRI
– High binding affinity and selectivity to human fibrin
– Rapid Enhan...
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Pbg vp mar02_final

  1. 1. 1 MR Contrast Agents for Vulnerable Plaque Imaging Philip Graham, PhD EPIX Medical, Inc. Cambridge, MA 02142
  2. 2. 2 MS-325: Vascular Contrast Agent • Albumin binding •Extends plasma t1/2 •4-10X increase in signal •Slows ECS uptake • Phase III angiography trials ongoing • Hypothesis: MS- 325, an albumin- targeted Gd contrast agent, highlights inflamed vessel wall and facilitates plaque Equilibrium Phase MS-325Arterial Phase
  3. 3. 3 Vessel Wall Enhancement with MS-325 Courtesy of: T. Grist (University of Wisconsin, Madison, WI)
  4. 4. 4 Jeffrey H. Maki1,2 , Gregory J. Wilson1 , Randall B. Lauffer3 , Robert M. Weisskoff3 , Chun Yuan2 1 - Puget Sound VAHCS, Seattle, WA 2 - University of Washington, Seattle, WA 3 - EPIX Medical, Cambridge, MA Vessel Wall Enhancement with MS-325 MRI Facilitates Plaque Detection and Characterization
  5. 5. 5 Vessel Wall Enhancement with MS-325 • Atherosclerosis = inflammation • Leaky capillaries supplying vessel wall – Increased albumin conc. in wall • Consistent enhancement of wall in patients with MS-325 • Implications for stenosis identification and quantitation (and plaque burden) • Enhancement may correlate with risk of rupture Aorta Right Iliac Artery Vessel Wall Vessel Wall Courtesy of: Dr. J Maki (UW/Puget S VA)
  6. 6. 6 Arterial Phase Equilibrium Phase MS-325 Source Images - Left External Iliac Artery Artery Vein
  7. 7. 7 0 0.5 1 1.5 2 2.5 3 Adj to Plaque No Plaque Wall Thickness (mm) Related to Plaque Results Adj to Plaque No Plaque P < 0.01
  8. 8. 8 Results • Strong wall enhancement with MS-325 because of increased capillary volume and binding to extravasated albumin • Low signal between wall and lumen represents atherosclerotic plaque. • Prolonged enhancement of wall and lumen allows high resolution detection of plaque burden • Potentially straightforward method of plaque visualization and quantification • ? Follow statin therapy
  9. 9. 9 Pharmacological trigger histamine = vasoconstrictor -> increases mechanical force on fibrous cap -> plaque disruption Russells viper venom -> triggers blood clotting cascade fresh thrombus lipid core? thin fibrous cap? fresh thrombus vasoconstriction pre-trigger post-trigger disrupted plaque T2w Visualization of Plaque Rupture in Rabbit Model Johnstone MT, Botnar RM, Perez AS, Stewart R, Quist W, Hamilton J, Manning WJ. In Vivo Magnetic Resonance Imaging of Experimental Thrombosis in a Rabbit Model. Arterioscler Thromb Vasc Biol. 2001 Sep;21(9):1556-60. Courtesy: Johnstone, Botnar, Manning: BIDMC
  10. 10. 10 baseline MS-325 MS-325 improves Plaque Visualization plaque contrast uptake no uptake wall plaque thrombus MS-325 Post-trigger Courtesy: Johnstone, Botnar, Manning: BIDMC
  11. 11. 11 Direct Clot Detection with Fibrin- Targeted Contrast Agent • Fibrin targeting lead discovered in a collaboration with Dyax • MR contrast agents EP-1242 and EP-1873 resulted from extensive modifications by EPIX of the original leads • Elimination profile similar to Magnevist® EP-1242 Enhanced Carotid Clot in Guinea Pig In collaboration with Z. Fayad, Ph.D., Mt. Sinai, New York
  12. 12. 12 To be annotated, final copy will be printed high definition Post Gd-BSA (angiography) Pre contrast 1 minute post EP-1873 36 minute post EP-1873 Jugular thrombus Rabbit Carotid thrombus Jugular thrombus Carotid thrombus In collaboration with E. Kent Yucel, Lee Zhou (?) Brigham & Women’s, Boston
  13. 13. 13 Pre contrast 10min 1.5h 1h Post EP-1873 (fibrin agent) aorta thrombus thrombus thrombus Botnar RM, Perez AP, Johnstone MT, Manning WJ
  14. 14. 14 Pre contrast 10min 1.5h 1h Post EP-1873 (fibrin agent) Botnar RM, Perez AP, Manning WJ, Johnstone MT
  15. 15. 15 Pre contrast 10min 1.5h Post EP-1873 (fibrin agent) aorta thrombus thrombus Botnar RM, Perez AP, Manning WJ, Johnstone MT
  16. 16. 16 Summary • Prototype clot-enhancing agents for MRI – High binding affinity and selectivity to human fibrin – Rapid Enhancement of arterial and venous clots – Good in vivo clot uptake and enhancement – No effects on clotting cascade • Thrombotic consequences of plaque rupture directly visible on standard MR scans – Potential for assessing thromboembolic risk in a variety of vascular beds – Follow clot resolution after treatment administration?

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