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MR Contrast Agents for Vulnerable Plaque Imaging
Philip Graham, PhDEPIX Medical, Inc.
Cambridge, MA 02142
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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 detection
Equilibrium Phase MS-325Arterial Phase
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Vessel Wall Enhancement with MS-325
Courtesy of: T. Grist (University of Wisconsin, Madison, WI)
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Jeffrey H. Maki1,2, Gregory J. Wilson1, Randall B. Lauffer3, Robert M. Weisskoff3,
Chun Yuan2
1 - Puget Sound VAHCS, Seattle, WA2 - University of Washington, Seattle, WA
3 - EPIX Medical, Cambridge, MA
Vessel Wall Enhancement with MS-325 MRI Facilitates Plaque Detection and
Characterization
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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 IliacArtery
VesselWall
VesselWall
Courtesy of: Dr. J Maki (UW/Puget S VA)
6Arterial Phase Equilibrium Phase MS-325
Source Images - Left External Iliac Artery
Artery
Vein
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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
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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
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Pharmacological triggerhistamine = vasoconstrictor -> increases mechanical force on fibrous cap -> plaque disruptionRussells viper venom -> triggers blood clotting cascade
fresh thrombus
lipid core?
thin fibrous cap?
fresh thrombusvasoconstriction
pre-trigger
post-trigger disrupted plaque
T2w
Visualization of Plaque Rupture in Rabbit ModelJohnstone MT, Botnar RM, Perez AS, Stewart R, Quist W, Hamilton J, ManningWJ. In Vivo Magnetic Resonance Imaging of Experimental Thrombosis in aRabbit Model. Arterioscler Thromb Vasc Biol. 2001 Sep;21(9):1556-60.
Courtesy: Johnstone, Botnar, Manning: BIDMC
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baseline
MS-325
MS-325 improves Plaque Visualization
plaque
contrast uptake no uptake
wall
plaque
thrombusMS-325Post-trigger
Courtesy: Johnstone, Botnar, Manning: BIDMC
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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 PigIn collaboration with Z. Fayad, Ph.D., Mt. Sinai, New York
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To be annotated, final copy will be printed high definitionPost Gd-BSA (angiography)
Pre contrast1 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
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Pre contrast
10min
1.5h
1h
Post EP-1873 (fibrin agent)
aorta
thrombus
thrombus
thrombus
Botnar RM, Perez AP, Johnstone MT, Manning WJ
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Pre contrast
10min
1.5h
1h
Post EP-1873 (fibrin agent)
Botnar RM, Perez AP, Manning WJ, Johnstone MT
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Pre contrast 10min 1.5h
Post EP-1873 (fibrin agent)
aorta
thrombus thrombus
Botnar RM, Perez AP, Manning WJ, Johnstone MT
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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?