title: Increased Vascular Permeability Measured With an Albumin-Binding Magnetic Resonance Contrast Agent Is a Surrogate Marker of Rupture-Prone Atherosclerotic Plaque.
abstract: BACKGROUND
  Compromised structural integrity of the endothelium and higher microvessel density increase vascular permeability. We investigated whether vascular permeability measured in vivo by magnetic resonance imaging using the albumin-binding contrast agent, gadofosveset, is a surrogate marker of rupture-prone atherosclerotic plaque in a rabbit model.
  
  
  RESULTS
  New Zealand white rabbits (n=10) were rendered atherosclerotic by cholesterol-diet and endothelial denudation. Plaque rupture was triggered with Russell's viper venom and histamine. Animals were imaged pre-triggering, at 3 and 12 weeks, to quantify plaque area, vascular permeability, vasodilation, and stiffness and post-triggering to identify thrombus. Plaques identified on the pretrigger scans were classified as stable or rupture-prone based on the absence or presence of thrombus on the corresponding post-trigger magnetic resonance imaging, respectively. All rabbits had developed atherosclerosis, and 60% had ruptured plaques. Rupture-prone plaques had higher vessel wall relaxation rate (R1; 2.30±0.5 versus 1.86±0.3 s-1; P<0.001), measured 30 minutes after gadofosveset administration, and higher R1/plaque area ratio (0.70±0.06 versus 0.47±0.02, P= 0.01) compared with stable plaque at 12 weeks. Rupture-prone plaques had higher percent change in R1between the 3 and 12 weeks compared with stable plaque (50.80±7.2% versus 14.22±2.2%; P<0.001). Immunohistochemistry revealed increased vessel wall albumin and microvessel density in diseased aortas and especially in ruptured plaque. Electron microscopy showed lack of structural integrity in both luminal and microvascular endothelium in diseased vessels. Functionally, the intrinsic vasodilation of the vessel wall decreased at 12 weeks compared with 3 weeks (18.60±1.0% versus 23.43±0.8%; P<0.001) and in rupture-prone compared with stable lesions (16.40±2.0% versus 21.63±1.2%; P<0.001). Arterial stiffness increased at 12 weeks compared with 3 weeks (5.00±0.1 versus 2.53±0.2 m/s; P<0.001) both in animals with stable and rupture-prone lesions.
  
  
  CONCLUSIONS
  T1 mapping using an albumin-binding contrast agent (gadofosveset) could quantify the changes in vascular permeability associated with atherosclerosis progression and rupture-prone plaques.
authors.affiliation: From the Division of Imaging Science and Biomedical Engineering (A.P., M.E.A., B.L., R.M.B.), Academic Department of Surgery, Cardiovascular Division (A.S., P.S.), BHF Centre of Excellence, Cardiovascular Division (A.S., R.M.B.), and Wellcome Trust and EPSRC Medical Engineering Center (P.S., R.M.B.), King's College London, United Kingdom; and Radiology Department, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile (M.E.A.). alkystis.1.phinikaridou@kcl.ac.uk.
authors.forename: Alkystis
authors.initials: A
authors.lastname: Phinikaridou
authors.affiliation: From the Division of Imaging Science and Biomedical Engineering (A.P., M.E.A., B.L., R.M.B.), Academic Department of Surgery, Cardiovascular Division (A.S., P.S.), BHF Centre of Excellence, Cardiovascular Division (A.S., R.M.B.), and Wellcome Trust and EPSRC Medical Engineering Center (P.S., R.M.B.), King's College London, United Kingdom; and Radiology Department, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile (M.E.A.).
authors.forename: Marcelo E
authors.initials: ME
authors.lastname: Andia
authors.affiliation: From the Division of Imaging Science and Biomedical Engineering (A.P., M.E.A., B.L., R.M.B.), Academic Department of Surgery, Cardiovascular Division (A.S., P.S.), BHF Centre of Excellence, Cardiovascular Division (A.S., R.M.B.), and Wellcome Trust and EPSRC Medical Engineering Center (P.S., R.M.B.), King's College London, United Kingdom; and Radiology Department, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile (M.E.A.).
authors.forename: Begoña
authors.initials: B
authors.lastname: Lavin
authors.affiliation: From the Division of Imaging Science and Biomedical Engineering (A.P., M.E.A., B.L., R.M.B.), Academic Department of Surgery, Cardiovascular Division (A.S., P.S.), BHF Centre of Excellence, Cardiovascular Division (A.S., R.M.B.), and Wellcome Trust and EPSRC Medical Engineering Center (P.S., R.M.B.), King's College London, United Kingdom; and Radiology Department, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile (M.E.A.).
authors.forename: Alberto
authors.initials: A
authors.lastname: Smith
authors.affiliation: From the Division of Imaging Science and Biomedical Engineering (A.P., M.E.A., B.L., R.M.B.), Academic Department of Surgery, Cardiovascular Division (A.S., P.S.), BHF Centre of Excellence, Cardiovascular Division (A.S., R.M.B.), and Wellcome Trust and EPSRC Medical Engineering Center (P.S., R.M.B.), King's College London, United Kingdom; and Radiology Department, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile (M.E.A.).
authors.forename: Prakash
authors.initials: P
authors.lastname: Saha
authors.affiliation: From the Division of Imaging Science and Biomedical Engineering (A.P., M.E.A., B.L., R.M.B.), Academic Department of Surgery, Cardiovascular Division (A.S., P.S.), BHF Centre of Excellence, Cardiovascular Division (A.S., R.M.B.), and Wellcome Trust and EPSRC Medical Engineering Center (P.S., R.M.B.), King's College London, United Kingdom; and Radiology Department, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile (M.E.A.).
authors.forename: René M
authors.initials: RM
authors.lastname: Botnar
mesh_terms: D000818:Animals; D001011:Aorta / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000503:physiopathology; D001018:Aortic Diseases / Q000000981:diagnostic imaging* / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D019540:Area Under Curve; D050197:Atherosclerosis / Q000000981:diagnostic imaging* / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D002199:Capillary Permeability; D002791:Cholesterol, Dietary; D003287:Contrast Media / Q000378:metabolism*; D004195:Disease Models, Animal; D018450:Disease Progression; D004730:Endothelium, Vascular / Q000000981:diagnostic imaging / Q000378:metabolism / Q000503:physiopathology; D005682:Gadolinium / Q000378:metabolism*; D006632:Histamine; D008279:Magnetic Resonance Imaging; D008297:Male; D055806:Microvessels / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000503:physiopathology; D009942:Organometallic Compounds / Q000378:metabolism*; D058226:Plaque, Atherosclerotic; D011237:Predictive Value of Tests; D011485:Protein Binding; D012372:ROC Curve; D011817:Rabbits; D012422:Rupture, Spontaneous; D017840:Daboia; D012709:Serum Albumin / Q000378:metabolism*; D013997:Time Factors; D059289:Vascular Stiffness; D014664:Vasodilation; D014757:Viper Venoms
chemical_list: D002791:Cholesterol, Dietary; D003287:Contrast Media; D009942:Organometallic Compounds; D012709:Serum Albumin; D014757:Viper Venoms; D006632:Histamine; D005682:Gadolinium; C109932:gadofosveset trisodium
keywords: atherosclerosis; capillary permeability; cardiovascular diseases; magnetic resonance imaging; models, animal