Visualization of Atherosclerotic

Vulnerable PlaqueSuper Paramagnetic Iron Oxide As

a Contrast Media for MRI Mitra Rajabi, MD

Mohammed Asif, MD

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Atherosclerosis• Coronary artery disease is the

leading cause of death in the USA and the developed countries.

• The majority of myocardial

infarctions are not caused by atherosclerotic plaques that cause a hemodynamically significant stenosis, but rather by smaller plaques, which called ”vulnerable “plaque.

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Vulnerable Plaque

•Large lipid core

•Thin fibrous cap

•Inflammation

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Ruptured Vulnerable Plaque

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Available/Suggested Techniques for Detection of

Vulnerable Plaques Invasive

Angiography IVUSMRIOCTAngioscopySpectroscopyThermographyElastography

Non-Invasive MRA&MRI EBCT Radioisotope

Imaging

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Intra Vascular Ultra Sound

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Angioscopy

A B C

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Optical Coherence Tomography

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Spectroscopy

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Thermography

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Electron Beam Computed Tomography

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Magnetic Resonance Angiography(MRA)

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Magnetic Resonance Imaging

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Intravascular MRI

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Elastography Femoral artery

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Nuclear Cardiology

• Instrumentations and techniques Planar SPECT PET• Radiopharmaceuticals Thallium201

Technetium99

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Radiotracers for imaging Atherosclerosis• Platelets

• Low density Lipoproteins (LDL)• Lipoprotein(a)• Modified LDL• Monocytes• Fibrinogen• Fibronectin

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….Continue

• Porphyrins• Human IgG• Peptides • Monoclonal antibodies

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A patient with 80% stenosis of the right 1 hour after injection of 99 Te-ox-LDL.

R L

Transaxial section of neck obtained by SPET

Anteroposterior gamma camera image

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Gamma images of an experimental atherosclerotic rabbit injected with negative charge–modified 111In-labeled chimeric Z2D3-73.30 F(ab')2

Immediately 24 hours

48 hours

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SPECT Images: Focal uptake of the right carotid artery absent uptake on the left side. Carotid angiogram showing the stenotic region corresponding to the plaque.

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Endarterectomy specimen With Intense Radioactivity to the Z2D3 Antibody Uptake

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Immunoperoxidase staining of the endarterectomy specimen demonstrates antibody uptake in the region that contains smooth muscle cells. The uptake is represented by the brown peroxide stain. The lipid- and foam cell-rich areas are negative for color reaction

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Cerebral angiography(A), US (B), and platelet imaging (C ,D) in a patient with T.I.A. obvious ulcerated lesions in the right internal carotid artery(Rt) (Large arrows in A and B ) (57% stenosis with a unilateral plaque score of 6.0); carotid bifurcation (small arrows in B&C), pathological, positive platelet accumulation in the right carotid artery. Images in C and D were obtained by means of a dual-tracer method that used (C) In 111-labeled platelets and (D) Tc 99m-labeled human serum albumin

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Other Targeted studies Lipid-conjugated Gd-DTPA was

incorporated into the surfactant layer of biotinylated perfluorocarbon emulsions (Biotinylated antifibrin monoclonal antiobodies and avidin were used to couple the emulsion nanoparticles to fibrin clots. (Flacke et al, ISMRM 2000)

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The need for assessment of functional properties of plaques in particular its macrophage activity is beyond doubt, as these inflammatory cells are considered the major culprit agents promoting plaque rupture

Presence of inflammation has led to find new diagnostic ways based on thermal and or PH detection of vulnerable plaques, and the idea of finding active macrohages by using new contrast media for MR imaging of plaques. MR spectroscopy

MRI Study of Macrophages Activity and

Functional Property of Atherosclerotic Plaques

(SPIO, USPIO)

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SPIO, USPIO• Magnetic resonance imaging

contrast medium with a central core of iron oxide generally coated by a polysaccharide layer

• Shortening MR relaxation time • Phagocyted by and

accumulated in cells with phagocytic activity

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SPIO in Macrophages

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SPIO Injection

A 4-cm metastasis in segment 4

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SPIO /USPIO• MR contrast for detection of cancer

and liver diseases• MR contrast for MR angiographies• MR contrast for detection of

apoptosis(ISMRM)

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Our Previous Study Shows the Iron Particles in The Plaques

No plaque, No Iron

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Comparison of the Number of Iron Particles in ApoE &Normal Mice

0

5

10

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AtheroscleroticAorta

Averagenumber of ironparticles persample

P <0.001

Normal

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Extra Magnification withSPIO

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Normal artery

Stable Plaque

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Vulnerable Plaque

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Stable Plaque

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Inflammation Imaging

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USPIOs Enter the Atherosclerotic Plaque Through

• Macrophages that engulfed them• Fissured or thin cap • Extensive angiogenesis • vasa vasorum leakage • Intra plaque hemorrhage

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Hypotheses• Active macrophages in the inflamed vulnerable

plaques can be visualized following injection of USPIO into the systemic circulation by virtue of a significant change in T1 and T2 relaxation time of the plaque after injection. Also other characteristics of vulnerability such as thin/disrupted cap shoulders, extensive angiogenesis associated with loose vasa vaserum which causes extravasation and leaking of macromolecules… and intra plaque hemorrhage all of them representing vulnerable plaque may contribute to retaining of USPIO inside the plaque.

• These MR imaging findings correlate with

vulnerability of the plaque

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Study Design

P athology evaluationH &E ,P earl's , Im m unosta in ing

S acrif ice& inv itro M R I

M R I w ith and w ithout in travascular coilin 3 th ,5th,7th day

U SP IO in jec tion

M R I w ith &w ithout in travascular M R coil

10 R ab b its

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Under Study•Magnetic resonance

imaging of carotid atherosclerotic plaques with MRI using a dedicated phase array coil (special superficial coil)

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Preliminary studies in Imaging the Aorta in Apo-E mice

• MRI of the thoracic and abdominal aorta of Apo-E mouse with Respiratory gating

• Intravenous injection of 40mol Fe/Kg Feridex to Apo-E mice

• MRI in Days 1,2 ,5 and 10 after injection

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Pre injection MRI

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MRI 5 Days After Injection

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• We have seen Feridex particles are trapped by RES mostly in liver and spleen, some pulmonary macrophages, and also lymphatic nodes.

• 5- We plan to redo the study with other soon to be available contrast media names Combidex, Clariscan, MION, LCIO, AND our own plaque specific USPIO in collaboration with Dr Daniel Chan.

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