Rofo 2015; 187(2): 92-101
DOI: 10.1055/s-0034-1385451
Review
© Georg Thieme Verlag KG Stuttgart · New York

Molecular Imaging in Cardiovascular Diseases

Molekulare kardiovaskuläre MRT-Bildgebung
R. M. Botnar
1   Imaging Sciences, King’s College London BHF Centre, Division of Imaging Science, Biomedical Research Centre of Guy’s and St. Thomas’ NHS Foundation Trust, London, UK, London
,
H. Ebersberger
2   Heart Center Munich-Bogenhausen, Munich, Germany, Department of Cardiology and Intensive Care Medicine, Munich
,
D. Noerenberg
3   Institute for Radiology, CCM, Charité, Berlin
,
C. H. P. Jansen
1   Imaging Sciences, King’s College London BHF Centre, Division of Imaging Science, Biomedical Research Centre of Guy’s and St. Thomas’ NHS Foundation Trust, London, UK, London
,
A. J. Wiethoff
1   Imaging Sciences, King’s College London BHF Centre, Division of Imaging Science, Biomedical Research Centre of Guy’s and St. Thomas’ NHS Foundation Trust, London, UK, London
,
A. Schuster
1   Imaging Sciences, King’s College London BHF Centre, Division of Imaging Science, Biomedical Research Centre of Guy’s and St. Thomas’ NHS Foundation Trust, London, UK, London
,
M. Kasner
5   Department of Cardiology, CBF, Charité, Berlin
,
T. C. Walter
6   Institute for Radiology, CVK, Charité, Berlin
,
G. Knobloch
3   Institute for Radiology, CCM, Charité, Berlin
,
P. Hoppe
7   Department of Nuclear Medicine, Charité, Berlin
,
G. Diederichs
3   Institute for Radiology, CCM, Charité, Berlin
,
B. Hamm
3   Institute for Radiology, CCM, Charité, Berlin
,
M. R. Makowski
3   Institute for Radiology, CCM, Charité, Berlin
› Author Affiliations
Further Information

Publication History

07 January 2014

08 September 2014

Publication Date:
13 January 2015 (online)

Abstract

Cardiovascular diseases remain the leading cause of morbidity and mortality in industrialized and developing countries. In clinical practice, the in-vivo identification of atherosclerotic lesions, which can lead to complications such as heart attack or stroke, remains difficult. Imaging techniques provide the reference standard for the detection of clinically significant atherosclerotic changes in the coronary and carotid arteries. The assessment of the luminal narrowing is feasible, while the differentiation of stable and potentially unstable or vulnerable atherosclerotic plaques is currently not possible using non-invasive imaging. With high spatial resolution and high soft tissue contrast, magnetic resonance imaging (MRI) is a suitable method for the evaluation of the thin arterial wall. In clinical practice, native MRI of the vessel wall already allows the differentiation and characterization of components of atherosclerotic plaques in the carotid arteries and the aorta. Additional diagnostic information can be gained by the use of non-specific MRI contrast agents. With the development of targeted molecular probes, that highlight specific molecules or cells, pathological processes can be visualized at a molecular level with high spatial resolution. In this review article, the development of pathophysiological changes leading to the development of the arterial wall are introduced and discussed. Additionally, principles of contrast enhanced imaging with non-specific contrast agents and molecular probes will be discussed and latest developments in the field of molecular imaging of the vascular wall will be introduced.

Key Points:

• Molecular magnetic resonance imaging has great potential to improve the in vivo characterization of atherosclerotic plaques.

• Based on the molecular information is feasible to enable a better differentiation of stable and unstable (vulnerable) atherosclerotic plaques.

Citation Format:

• Botnar RM, Ebersberger H, Noerenberg D et al. Molecular imaging in cardiovascular diseases. Fortschr Röntgenstr 2015; 187: 92 – 101

Zusammenfassung

Kardiovaskuläre Erkrankungen sind nach wie vor die häufigste Ursache für Morbidität und Mortalität in den westlichen Industrieländern, aber auch in Entwicklungsländern. Im klinischen Alltag bleibt die In-vivo-Identifizierung von arteriosklerotischen Läsionen, die zu Komplikationen wie Herzinfarkten oder Schlaganfällen führen können, weiterhin schwierig. Bildgebende Verfahren sind gegenwärtig der Referenzstandard für die Detektion klinisch relevanter arteriosklerotischer Veränderungen der Koronararterien und der Karotiden. Dabei bleibt die Beurteilung auf die bildmorphologische Lumeneinengung beschränkt, während eine Differenzierung von stabilen und potenziell instabilen oder vulnerablen arteriosklerotischen Plaques aktuell im Rahmen der nichtinvasiven Bildgebung nicht möglich ist. Mit hoher räumlicher Auflösung und hohem Weichteilkontrast ist die Magnetresonanztomografie (MRT) eine gut geeignete Methode zur Darstellung und Beurteilung der dünnen Arterienwand. In der klinischen Praxis erlaubt die native MRT der Gefäßwand bereits eine Differenzierung sowie Charakterisierung von Komponenten arteriosklerotischer Plaques der Karotiden und der Aorta. Ein Zugewinn an diagnostischer Information kann durch den Einsatz zugelassener unspezifischer MRT-Kontrastmittel erreicht werden. Mit der Entwicklung von zielgerichteten molekularen Sonden, die bestimmte Moleküle oder Zellen markieren, lassen sich pathologische Prozesse auf molekularer Ebene mit hoher räumlicher Auflösung darstellen. In diesem Übersichtsartikel werden zunächst die zur Entwicklung der Arteriosklerose führenden pathophysiologischen Veränderungen der arteriellen Gefäßwand erläutert. Es folgt eine Darstellung der Wirkweise sowie der Eigenschaften unspezifischer Kontrastmittel sowie molekularer Sonden für die MRT-Bildgebung. Zusätzlich werden die neuesten Entwicklungen auf dem Gebiet der molekularen Bildgebung der Gefäßwand erörtert.

Deutscher Artikel/German Article

 
  • References

  • 1 Roger VL, Go AS, Lloyd-Jones DM et al. Heart disease and stroke statistics--2011 update: a report from the American Heart Association. Circulation 2011; 123: e18-e209
  • 2 Ambrose JA, Tannenbaum MA, Alexopoulos D et al. Angiographic progression of coronary artery disease and the development of myocardial infarction. J Am Coll Cardiol 1988; 12: 56-62
  • 3 Burke AP, Kolodgie FD, Farb A et al. Morphological predictors of arterial remodeling in coronary atherosclerosis. Circulation 2002; 105: 297-303
  • 4 Varnava AM, Mills PG, Davies MJ. Relationship between coronary artery remodeling and plaque vulnerability. Circulation 2002; 105: 939-943
  • 5 Glagov S, Weisenberg E, Zarins CK et al. Compensatory enlargement of human atherosclerotic coronary arteries. N Engl J Med 1987; 316: 1371-1375
  • 6 Rentrop KP. Thrombi in acute coronary syndromes: revisited and revised. Circulation 2000; 101: 1619-1626
  • 7 Botnar RM, Stuber M, Kissinger KV et al. Noninvasive coronary vessel wall and plaque imaging with magnetic resonance imaging. Circulation 2000; 102: 2582-2587
  • 8 Fayad ZA, Fuster V, Fallon JT et al. Noninvasive in vivo human coronary artery lumen and wall imaging using black-blood magnetic resonance imaging. Circulation 2000; 102: 506-510
  • 9 Corti R, Fuster V, Fayad ZA et al. Effects of aggressive versus conventional lipid-lowering therapy by simvastatin on human atherosclerotic lesions: a prospective, randomized, double-blind trial with high-resolution magnetic resonance imaging. J Am Coll Cardiol 2005; 46: 106-112
  • 10 Ibrahim T, Makowski MR, Jankauskas A et al. Serial contrast-enhanced cardiac magnetic resonance imaging demonstrates regression of hyperenhancement within the coronary artery wall in patients after acute myocardial infarction. JACC Cardiovasc Imaging 2009; 2: 580-588
  • 11 Gore JC, Yankeelov TE, Peterson TE et al. Molecular imaging without radiopharmaceuticals?. Journal of nuclear medicine: official publication, Society of Nuclear Medicine 2009; 50: 999-1007
  • 12 Sato Y, Hatakeyama K, Marutsuka K et al. Incidence of asymptomatic coronary thrombosis and plaque disruption: comparison of non-cardiac and cardiac deaths among autopsy cases. Thromb Res 2009; 124: 19-23
  • 13 Libby P, Ridker PM, Hansson GrK. Progress and challenges in translating the biology of atherosclerosis. Nature 2011; 473: 317-325
  • 14 Krettek A, Sukhova GK, Libby P. Elastogenesis in human arterial disease: a role for macrophages in disordered elastin synthesis. Arterioscler Thromb Vasc Biol 2003; 23: 582-587
  • 15 Kolodgie FD, Narula J, Yuan C et al. Elimination of neoangiogenesis for plaque stabilization: is there a role for local drug therapy?. Journal of the American College of Cardiology 2007; 49: 2093-2101
  • 16 Kolodgie FD, Gold HK, Burke AP et al. Intraplaque hemorrhage and progression of coronary atheroma. The New England journal of medicine 2003; 349: 2316-2325
  • 17 Narula J, Garg P, Achenbach S et al. Arithmetic of vulnerable plaques for noninvasive imaging. Nature Clinical Practice Cardiovascular Medicine 2008; 5: S2-S10
  • 18 Stone GW, Maehara A, Lansky AJ et al. A prospective natural-history study of coronary atherosclerosis. The New England journal of medicine 2011; 364: 226-235
  • 19 Burke AP, Farb A, Malcom GT et al. Effect of risk factors on the mechanism of acute thrombosis and sudden coronary death in women. Circulation 1998; 97: 2110-2116
  • 20 Johnson RC, Leopold JA, Loscalzo J. Vascular calcification: pathobiological mechanisms and clinical implications. Circ Res 2006; 99: 1044-1059
  • 21 Aikawa E, Nahrendorf M, Figueiredo JL et al. Osteogenesis associates with inflammation in early-stage atherosclerosis evaluated by molecular imaging in vivo. Circulation 2007; 116: 2841-2850
  • 22 Proudfoot D, Skepper JN, Hegyi L et al. Apoptosis regulates human vascular calcification in vitro: evidence for initiation of vascular calcification by apoptotic bodies. Circ Res 2000; 87: 1055-1062
  • 23 Tyson KL, Reynolds JL, McNair R et al. Osteo/chondrocytic transcription factors and their target genes exhibit distinct patterns of expression in human arterial calcification. Arteriosclerosis, thrombosis, and vascular biology 2003; 23: 489-494
  • 24 Virmani R, Ladich ER, Burke AP et al. Histopathology of carotid atherosclerotic disease. Neurosurgery 2006; 59: S219-S227
  • 25 Johnson GA, Benveniste H, Black RD et al. Histology by magnetic resonance microscopy. Magn Reson Q 1993; 9: 1-30
  • 26 Schmitz SA, Coupland SE, Gust R et al. Superparamagnetic iron oxide-enhanced MRI of atherosclerotic plaques in Watanabe hereditable hyperlipidemic rabbits. Invest Radiol 2000; 35: 460-471
  • 27 Caravan P, Ellison JJ, McMurry TJ et al. Gadolinium(III) Chelates as MRI Contrast Agents: Structure, Dynamics, and Applications. Chem Rev 1999; 99: 2293-2352
  • 28 Weinmann HJ, Brasch RC, Press WR et al. Characteristics of gadolinium-DTPA complex: a potential NMR contrast agent. Am J Roentgenol Am J Roentgenol 1984; 142: 619-624
  • 29 Nazarpoor M. Effects of inversion and saturation times on relationships between contrast agent concentrations and signal intensities of T1-weighted magnetic resonance images. Radiol Phys Technol 2010; 3: 120-126
  • 30 Mugler 3rd JP, Brookeman JR. Theoretical analysis of gadopentetate dimeglumine enhancement in T1-weighted imaging of the brain: comparison of two-dimensional spin-echo and three-dimensional gradient-echo sequences. J Magn Reson Imaging 1993; 3: 761-769
  • 31 Kok M, Hak S, Mulder W et al. Cellular compartmentalization of internalized paramagnetic liposomes strongly influences both T 1and T 2relaxivity. Magnetic Resonance in Medicine 2009; 61: 1022-1032
  • 32 Caravan P, Farrar CT, Frullano L et al. Influence of molecular parameters and increasing magnetic field strength on relaxivity of gadolinium- and manganese-based T1 contrast agents. Contrast Media Mol Imaging 2009; 4: 89-100
  • 33 Nivorozhkin AL, Kolodziej AF, Caravan P et al. Enzyme-Activated Gd(3+) Magnetic Resonance Imaging Contrast Agents with a Prominent Receptor-Induced Magnetization Enhancement. Angew Chem Int Ed Engl 2001; 40: 2903-2906
  • 34 Caravan P. Strategies for increasing the sensitivity of gadolinium based MRI contrast agents. Chemical Society Reviews 2006; 35: 512
  • 35 Botnar RM, Buecker A, Wiethoff AJ et al. In vivo magnetic resonance imaging of coronary thrombosis using a fibrin-binding molecular magnetic resonance contrast agent. Circulation 2004; 110: 1463-1466
  • 36 Flacke S, Fischer S, Scott MJ et al. Novel MRI contrast agent for molecular imaging of fibrin: implications for detecting vulnerable plaques. Circulation 2001; 104: 1280-1285
  • 37 Winter PM, Morawski AM, Caruthers SD et al. Molecular imaging of angiogenesis in early-stage atherosclerosis with alpha(v)beta3-integrin-targeted nanoparticles. Circulation 2003; 108: 2270-2274
  • 38 Weissleder R, Elizondo G, Wittenberg J et al. Ultrasmall superparamagnetic iron oxide: characterization of a new class of contrast agents for MR imaging. Radiology 1990; 175: 489-493
  • 39 Farrar CT, Dai G, Novikov M et al. Impact of field strength and iron oxide nanoparticle concentration on the linearity and diagnostic accuracy of off-resonance imaging. NMR Biomed 2008; 21: 453-463
  • 40 Ferrucci JT, Stark DD. Iron oxide-enhanced MR imaging of the liver and spleen: review of the first 5 years. Am J Roentgenol Am J Roentgenol 1990; 155: 943-950
  • 41 Small WC, Nelson RC, Bernardino ME. Dual contrast enhancement of both T1- and T2-weighted sequences using ultrasmall superparamagnetic iron oxide. Magn Reson Imaging 1993; 11: 645-654
  • 42 Makowski MR, Wiethoff AJ, Blume U et al. Assessment of atherosclerotic plaque burden with an elastin-specific magnetic resonance contrast agent. Nat Med 2011; 17: 383-388
  • 43 Makowski MR, Varma G, Wiethoff A et al. Non-Invasive Assessment of Atherosclerotic Plaque Progression in ApoE-/- Mice Using Susceptibility Gradient Mapping. Circ Cardiovasc Imaging 2011; DOI: 10.1161/CIRCIMAGING.110.957209.
  • 44 von Bary C, Makowski M, Preissel A et al. MRI of Coronary Wall Remodeling in a Swine Model of Coronary Injury Using an Elastin-Binding Contrast Agent. Circ Cardiovasc Imaging 2011; 4: 147-155
  • 45 Meding J, Urich M, Licha K et al. Magnetic resonance imaging of atherosclerosis by targeting extracellular matrix deposition with gadofluorine M. Contrast Media Mol Imaging 2007; 2: 120-129
  • 46 Sirol M, Itskovich VV, Mani V et al. Lipid-rich atherosclerotic plaques detected by gadofluorine-enhanced in vivo magnetic resonance imaging. Circulation 2004; 109: 2890-2896
  • 47 Sirol M, Moreno P, Purushothaman K et al. Increased Neovascularization in Advanced Lipid-Rich Atherosclerotic Lesions Detected by Gadofluorine-M-Enhanced MRI: Implications for Plaque Vulnerability. Circulation: Cardiovascular Imaging 2009; 2: 391-396
  • 48 Ronald JA, Chen Y, Belisle AJ et al. Comparison of gadofluorine-M and Gd-DTPA for noninvasive staging of atherosclerotic plaque stability using MRI. Circ Cardiovasc Imaging 2009; 2: 226-234
  • 49 Tavora F, Cresswell N, Li L et al. Immunolocalisation of fibrin in coronary atherosclerosis: implications for necrotic core development. Pathology 2010; 42: 15-22
  • 50 Botnar RM, Perez AS, Witte S et al. In vivo molecular imaging of acute and subacute thrombosis using a fibrin-binding magnetic resonance imaging contrast agent. Circulation 2004; 109: 2023-2029
  • 51 Spuentrup E, Buecker A, Katoh M et al. Molecular Magnetic Resonance Imaging of Coronary Thrombosis and Pulmonary Emboli With a Novel Fibrin-Targeted Contrast Agent. Circulation 2005; 112: 1594-1600
  • 52 Spuentrup E, Botnar RM, Wiethoff A et al. MR imaging of thrombi using EP-2104R, a fibrin specific contrast agent: initial results in patients. European Radiology 2008; 18: 1995-2005
  • 53 Cybulsky MI, Gimbrone Jr MA. Endothelial expression of a mononuclear leukocyte adhesion molecule during atherogenesis. Science 1991; 251: 788-791
  • 54 Nahrendorf M, Jaffer F, Kelly K et al. Noninvasive Vascular Cell Adhesion Molecule-1 Imaging Identifies Inflammatory Activation of Cells in Atherosclerosis. Circulation 2006; 114: 1504-1511
  • 55 Kooi ME, Cappendijk VC, Cleutjens KB et al. Accumulation of ultrasmall superparamagnetic particles of iron oxide in human atherosclerotic plaques can be detected by in vivo magnetic resonance imaging. Circulation 2003; 107: 2453-2458
  • 56 Ruehm SG, Corot C, Vogt P et al. Magnetic resonance imaging of atherosclerotic plaque with ultrasmall superparamagnetic particles of iron oxide in hyperlipidemic rabbits. Circulation 2001; 103: 415-422
  • 57 Schmitz SA, Coupland SE, Gust R et al. Superparamagnetic iron oxide-enhanced MRI of atherosclerotic plaques in Watanabe hereditable hyperlipidemic rabbits. Investigative radiology 2000; 35: 460-471
  • 58 Morishige K, Kacher DF, Libby P et al. High-resolution magnetic resonance imaging enhanced with superparamagnetic nanoparticles measures macrophage burden in atherosclerosis. Circulation 2010; 122: 1707-1715
  • 59 Korosoglou G, Weiss RG, Kedziorek DA et al. Noninvasive detection of macrophage-rich atherosclerotic plaque in hyperlipidemic rabbits using "positive contrast" magnetic resonance imaging. Journal of the American College of Cardiology 2008; 52: 483-491
  • 60 Mani V, Briley-Saebo KC, Itskovich VV et al. Gradient echo acquisition for superparamagnetic particles with positive contrast (GRASP): sequence characterization in membrane and glass superparamagnetic iron oxide phantoms at 1.5T and 3T. Magn Reson Med 2006; 55: 126-135
  • 61 Amirbekian V, Lipinski MJ, Briley-Saebo KC et al. Detecting and assessing macrophages in vivo to evaluate atherosclerosis noninvasively using molecular MRI. Proc Natl Acad Sci U S A 2007; 104: 961-966
  • 62 Frias JC, Ma Y, Williams KJ et al. Properties of a versatile nanoparticle platform contrast agent to image and characterize atherosclerotic plaques by magnetic resonance imaging. Nano Lett 2006; 6: 2220-2224
  • 63 Cormode DP, Briley-Saebo KC, Mulder WJ et al. An ApoA-I mimetic peptide high-density-lipoprotein-based MRI contrast agent for atherosclerotic plaque composition detection. Small 2008; 4: 1437-1444
  • 64 Chen W, Vucic E, Leupold E et al. Incorporation of an apoE-derived lipopeptide in high-density lipoprotein MRI contrast agents for enhanced imaging of macrophages in atherosclerosis. Contrast Media Mol Imaging 2008; 3: 233-242
  • 65 Purushothaman KR, Sanz J, Zias E et al. Atherosclerosis neovascularization and imaging. Curr Mol Med 2006; 6: 549-556
  • 66 Kerwin WS, O'Brien KD, Ferguson MS et al. Inflammation in carotid atherosclerotic plaque: a dynamic contrast-enhanced MR imaging study. Radiology 2006; 241: 459-468