Molecular Imaging of Thrombus
2012; Lippincott Williams & Wilkins; Volume: 125; Issue: 25 Linguagem: Inglês
10.1161/circulationaha.112.112672
ISSN1524-4539
Autores Tópico(s)Cerebrovascular and Carotid Artery Diseases
ResumoHomeCirculationVol. 125, No. 25Molecular Imaging of Thrombus Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBMolecular Imaging of ThrombusTechnology in Evolution Jonathan R. Lindner, MD Jonathan R. LindnerJonathan R. Lindner From the Division of Cardiovascular Medicine, Oregon Health and Science University, Portland, OR. Originally published30 May 2012https://doi.org/10.1161/CIRCULATIONAHA.112.112672Circulation. 2012;125:3057–3059Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2012: Previous Version 1 For some time, scientists with expertise in medical imaging, cell biology, and chemical engineering have teamed together with the goal of producing targeted contrast agents for molecular imaging in cardiovascular disease. The goal of these efforts is to bring about techniques for noninvasively detecting and quantifying specific molecular processes that play a role in the pathophysiology of cardiovascular disease. Although there has been a tendency in the scientific literature to focus on how molecular imaging has been achieved, it is equally important to review why.Article see p 3117In the clinical setting, molecular imaging is likely to enhance and expand the diagnostic capabilities of current imaging applications. Nowhere has this been more successful than in cancer imaging, where targeted contrast agents can detect otherwise nonapparent primary or metastatic disease or be used to select appropriate therapies based on tumor or tumor microvascular phenotype.1 There are several areas of focus where molecular imaging could play an important role for early diagnosis and to guide patient management in cardiovascular disease. Imaging the cellular or molecular profile in atherosclerotic disease could yield important information on susceptibility for acute atherothrombotic complications.2 In the future, it could also potentially be used to determine appropriateness for emerging therapies such as new drugs that interrupt the inflammatory response, which will likely be expensive and have adverse effects. Recent myocardial ischemia can be detected by molecular imaging of either a reduction in myocyte fatty acid utilization or postischemic inflammatory activation of the microvascular endothelium.3,4 This approach could be used for rapid diagnosis in patients with chest pain of unclear origin and allow spatial assessment of the postischemic region even hours after resolution. Large-scale clinical trials with imaging of labeled branched-chain fatty acids have already been completed showing that the technique can accelerate the diagnosis of acute coronary syndrome.3 Molecular imaging of sympathetic nerve activity could potentially be used to evaluate risk for life-threatening ventricular arrhythmia or adverse outcomes in patients with heart failure.5 In the research setting, molecular imaging is already being used in preclinical and clinical investigation as a toolkit to elucidate pathophysiology, or for rapid read-out of the efficacy of new therapies in animal models of disease or patients. Probably the best example of the latter is the use of fluorodeoxyglucose positron emission tomography (FDG-PET) in large vessels as an indirect marker of plaque inflammatory burden.6The likelihood that any given molecular imaging strategy will be translated into clinical practice relies largely on 4 considerations: (1) choosing the right molecular target; (2) being able to target the molecule effectively; (3) choosing the most appropriate imaging methodology (eg, radionuclide imaging techniques, MRI, ultrasound, etc.); and (4) demonstrating incremental value to existing technology. It is in this context that one should examine the study by Wang et al7 in this issue of Circulation, which describes ultrasound imaging of thrombus with microbubble contrast agents targeted to platelets.Molecular imaging with ultrasound has generally involved conjugation of ligands to the surface of lipid-shelled microbubbles (mean diameter 2–3 μm) or other acoustically active nanoparticles at a site density of several hundred to several thousand per μm2 surface area. Taking a lesson from nature, the ligands are usually projected away from the microbubble surface by polymeric molecular spacers to optimize steric conditions. For clot imaging, the use of an ultrasound-based approach is quite reasonable because microbubbles are pure intravascular tracers and have full access to the components of thrombus. Moreover, ultrasound molecular imaging has practical advantages in terms of speed (5- to 15-minute protocols), portability, and cost. An important practical limitation is that imaging of thrombus in large coronary vessels is not feasible from a noninvasive approach with currently existing ultrasound technology.The notion that microbubbles can be targeted to thrombus is not new and was first reported almost 15 years ago.8,9 With respect to choosing the right target, thrombus formation or platelet-endothelial interactions have been imaged with microbubbles or other echogenic particulate compounds in animal models of disease including the platelet adhesion molecules αIIbβ3 integrin and GPIbα fibrin/fibrinogen, tissue factor, and von Willebrand factor.9–12 While the description by Wang et al7 of a contrast agent targeted to αIIbβ3 integrin to detect the platelet component in acute thrombus formation is not new, the strategy of using an antibody against a ligand-induced binding site (LIBS) on αIIbβ3 is novel and potentially important. Many of the previous attempts to target αIIbβ3 with microbubbles have used arginine-glycine-aspartate-containing peptides or similar peptides as targeting ligands. Although this provides a simple and low cost approach, the targeting efficacy of microbubbles bearing these peptides has been somewhat limited probably because of competitive inhibition from plasma components such as fibrinogen under high shear conditions, and their potential to bind to other integrins such as αvβ3 and α5β1. Antibodies against active site αIIbβ3 that bind irrespective of activation state, such as abcixamab, have been used successfully to image human thrombus in vivo.10 The use of LIBS antibodies is potentially advantageous because they bind to sites exposed only on integrin activation, thereby selectively attaching to activated platelets and reducing attachment to quiescent circulating platelets.13 Moreover, unlike nonactivation-specific antibodies and arginine-glycine-aspartate peptides, LIBS antibodies are less likely to trigger ligation-dependent platelet activation through outside-in signaling.13The study by Wang et al7 demonstrates that microbubbles bearing LIBS antibodies attach to platelets or microthrombi and enhance thrombi on ultrasound imaging of the murine carotid artery treated with FeCl. There are a few key steps that are needed in determining the impact of this technological advance. Most importantly, there now needs to be a direct comparison of microbubbles bearing LIBS antibodies with those targeted by either arginine-glycine-aspartate peptides or nonactivation-specific antibodies with regard to both microbubble binding efficiency and thrombus enhancement. Also, examining the influence of plasma on microbubble attachment to platelets in the flow chamber in this study would have been helpful for establishing the degree to which plasma proteins such as fibrinogen inhibit attachment of the LIBS microbubbles under physiological shear conditions.It is worth noting that the peak signal enhancement that was achieved during in vivo imaging with LIBS microbubbles was quite low (40% enhancement), substantially lower than that previously described for contrast ultrasound molecular imaging of the aorta in murine models of atherosclerotic disease where >10-fold enhancement has been achieved.14 It is unlikely that poor targeting efficiency was the primary reason. Instead, low enhancement was likely a result of imaging methodology. High-frequency (40 MHz), single-pulse, fundamental (similar send and receive frequency) imaging may be ideal for defining thrombus in the murine carotid artery, however it is poorly suited to detecting microbubble signal. Instead, low to intermediate frequencies with multi-pulse imaging algorithms that are specifically designed to detect microbubble nonlinear signals are likely to increase signal relative to tissue signal for this agent like it has for most other microbubble agents.15As with any new molecular imaging technology that is developed and shown to be feasible, a critical question is whether targeted imaging of thrombus provides any unique or incremental value to what is already available to the researcher or clinician. The study by Wang et al7 was designed to test feasibility rather than to show incremental value to noncontrast or nontargeted contrast imaging. In other words, we do not know whether contrast ultrasound with LIBS microbubbles improves the detection of small thrombi or provides greater accuracy for sizing thrombus over time. Although the authors state that thrombus imaging can be used to evaluate thrombolytic efficacy, one can certainly imagine other scenarios where molecular imaging of the platelet component of thrombus could have a positive impact. Targeted imaging may provide a unique opportunity to detect or study microvascular thrombus as a mechanism of no-flow in acute coronary syndromes. In large vessels, it could potentially detect microthrombi in stable patients or nonculprit vessels, which have been correlated with heightened risk for plaque progression.16 In stroke or atrial fibrillation, it could be used to optimize anticoagulant therapy on a per-patient basis. Platelet interaction with the intact endothelium, which is partially mediated by dysregulation of von Willebrand factor, appears to contribute to the inflammatory status of atherosclerotic lesions, yet only recently has this process been imaged noninvasively.11 It should also be noted that applications may extend into the therapeutic realm where microbubbles have been shown to enhance coronary sono thrombolysis, the dissolution of clots using ultrasound energy.17There are many more potential cardiovascular or noncardiovascular applications for ultrasound molecular imaging of thrombus that one can imagine if such technology were available. Borrowing some concepts from evolutionary biology, the introduction of new technology in medicine is gradual and requires adaptive radiation, the diversification of form to best suit a niche. Diversification is precisely what the study by Wang et al7 provides; a new approach to thrombus imaging technology that may prove to be important for clinical application of molecular imaging in cardiovascular disease.Sources of FundingDr Lindner is supported by grants R01-DK-063508, R01-HL-078610, and RC1-HL-100659 and R01-HL111969 from the National Institutes of Health, and a grant (#2011101) from the Doris Duke Charitable Foundation.DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to Jonathan R. Lindner, MD, Cardiovascular Division, UHN-62, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd., Portland, OR 97239. E-mail [email protected]eduReferences1. Kircher MF, Hricak H, Larson SM. Molecular imaging for personalized cancer care. Mol Oncol. 2012; 6:182–195.CrossrefMedlineGoogle Scholar2. Choudhury RP, Fisher EA. Molecular imaging in atherosclerosis, thrombosis, and vascular inflammation. Arterioscler Thromb Vasc Biol. 2009; 29:983–991.LinkGoogle Scholar3. Kontos MC, Dilsizian V, Weiland F, DePuey G, Mahmarian JJ, Iskandrian AE, Bateman TM, Heller GV, Ananthasubramaniam K, Li Y, Goldman JL, Armor T, Kacena KA, LaFrance ND, Garcia EV, Babich JW, Udelson JE. Iodofiltic acid I 123 (BMIPP) fatty acid imaging improves initial diagnosis in emergency department patients with suspected acute coronary syndromes: a multicenter trial. J Am Coll Cardiol. 2010; 56:290–299.CrossrefMedlineGoogle Scholar4. Kaufmann BA, Lewis C, Xie A, Mirza-Mohd A, Lindner JR. Detection of recent myocardial ischaemia by molecular imaging of P-selectin with targeted contrast echocardiography. Eur Heart J. 2007; 28:2011–2017.CrossrefMedlineGoogle Scholar5. Caldwell JH, Link JM, Levy WC, Poole JE, Stratton JR. Evidence for pre- to postsynaptic mismatch of the cardiac sympathetic nervous system in ischemic congestive heart failure. J Nucl Med. 2008; 49:234–241.CrossrefMedlineGoogle Scholar6. Fayad ZA, Mani V, Woodward M, Kallend D, Abt M, Burgess T, Fuster V, Ballantyne CM, Stein EA, Tardif JC, Rudd JH, Farkouh ME, Tawakol A. Safety and efficacy of dalcetrapib on atherosclerotic disease using novel non-invasive multimodality imaging (dal-PLAQUE): a randomised clinical trial. Lancet. 2011; 378:1547–1559.CrossrefMedlineGoogle Scholar7. Wang X, Hagemeyer CE, Hohmann JD, Leitner E, Armstrong PC, Jia F, Olschewski M, Needles A, Peter K, Ahrens I. Novel single-chain antibody-targeted microbubbles for molecular ultrasound imaging of thrombosis: validation of a unique noninvasive method for rapid and sensitive detection of thrombi and monitoring of success or failure of thrombolysis in mice. Circulation. 2012; 125:3117–3126.LinkGoogle Scholar8. Unger EC, McCreery TP, Sweitzer RH, Shen D, Wu G. In vitro studies of a new thrombus-specific ultrasound contrast agent. Am J Cardiol. 1998; 81:58G–61G.CrossrefMedlineGoogle Scholar9. Lanza GM, Wallace KD, Scott MJ, Cacheris WP, Abendschein DR, Christy DH, Sharkey AM, Miller JG, Gaffney PJ, Wickline SA. A novel site-targeted ultrasonic contrast agent with broad biomedical application. Circulation. 1996; 94:3334–3340.LinkGoogle Scholar10. Alonso A, Della Martina A, Stroick M, Fatar M, Griebe M, Pochon S, Schneider M, Hennerici M, Allemann E, Meairs S. Molecular imaging of human thrombus with novel abciximab immunobubbles and ultrasound. Stroke. 2007; 38:1508–1514.LinkGoogle Scholar11. McCarty OJ, Conley RB, Shentu W, Tormoen GW, Zha D, Xie A, Qi Y, Zhao Y, Carr C, Belcik T, Keene DR, de Groot PG, Lindner JR. Molecular imaging of activated von Willebrand factor to detect high-risk atherosclerotic phenotype. J Am Coll Cardiol Cardiovasc Imaging. 2010; 3:947–955.CrossrefMedlineGoogle Scholar12. Hamilton AJ, Huang SL, Warnick D, Rabbat M, Kane B, Nagaraj A, Klegerman M, McPherson DD. Intravascular ultrasound molecular imaging of atheroma components in vivo. J Am Coll Cardiol. 2004; 43:453–460.CrossrefMedlineGoogle Scholar13. Schwarz M, Meade G, Stoll P, Ylanne J, Bassler N, Chen YC, Hagemeyer CE, Ahrens I, Moran N, Kenny D, Fitzgerald D, Bode C, Peter K. Conformation-specific blockade of the integrin GPIIb/IIIa: a novel antiplatelet strategy that selectively targets activated platelets. Circ Res. 2006; 99:25–33.LinkGoogle Scholar14. Kaufmann BA, Carr CL, Belcik JT, Xie A, Yue Q, Chadderdon S, Caplan ES, Khangura J, Bullens S, Bunting S, Lindner JR. Molecular imaging of the initial inflammatory response in atherosclerosis: implications for early detection of disease. Arterioscler Thromb Vasc Biol. 2010; 30:54–59.LinkGoogle Scholar15. Kaufmann BA, Wei K, Lindner JR. Contrast echocardiography. Curr Probl Cardiol. 2007; 32:51–96.CrossrefMedlineGoogle Scholar16. Takano M, Inami S, Ishibashi F, Okamatsu K, Seimiya K, Ohba T, Sakai S, Mizuno K. Angioscopic follow-up study of coronary ruptured plaques in nonculprit lesions. J Am Coll Cardiol. 2005; 45:652–658.CrossrefMedlineGoogle Scholar17. Xie F, Lof J, Matsunaga T, Zutshi R, Porter TR. Diagnostic ultrasound combined with glycoprotein IIb/IIIa-targeted microbubbles improves microvascular recovery after acute coronary thrombotic occlusions. Circulation. 2009; 119:1378–1385.LinkGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited ByIzquierdo-Garcia D, Diyabalanage H, Ramsay I, Rotile N, Mauskapf A, Choi J, Witzel T, Humblet V, Jaffer F, Brownell A, Tawakol A, Catana C, Conrad M, Caravan P and Ay I (2021) Imaging High-Risk Atherothrombosis Using a Novel Fibrin-Binding Positron Emission Tomography Probe, Stroke, 53:2, (595-604), Online publication date: 1-Feb-2022. Ezeani M, Hagemeyer C, Lal S and Niego B (2022) Molecular imaging of atrial myopathy: Towards early AF detection and non-invasive disease management, Trends in Cardiovascular Medicine, 10.1016/j.tcm.2020.12.002, 32:1, (20-31), Online publication date: 1-Jan-2022. Kosareva A, Abou-Elkacem L, Chowdhury S, Lindner J and Kaufmann B (2020) Seeing the Invisible—Ultrasound Molecular Imaging, Ultrasound in Medicine & Biology, 10.1016/j.ultrasmedbio.2019.11.007, 46:3, (479-497), Online publication date: 1-Mar-2020. Brown E and Lindner J (2019) Ultrasound Molecular Imaging: Principles and Applications in Cardiovascular Medicine, Current Cardiology Reports, 10.1007/s11886-019-1117-9, 21:5, Online publication date: 1-May-2019. Wang S, Hossack J and Klibanov A (2018) Targeting of microbubbles: contrast agents for ultrasound molecular imaging, Journal of Drug Targeting, 10.1080/1061186X.2017.1419362, 26:5-6, (420-434), Online publication date: 28-May-2018. Ta H, Arndt N, Wu Y, Lim H, Landeen S, Zhang R, Kamato D, Little P, Whittaker A and Xu Z (2018) Activatable magnetic resonance nanosensor as a potential imaging agent for detecting and discriminating thrombosis, Nanoscale, 10.1039/C8NR05095C, 10:31, (15103-15115) Blasi F, Oliveira B, Rietz T, Rotile N, Naha P, Cormode D, Izquierdo-Garcia D, Catana C and Caravan P (2015) Multisite Thrombus Imaging and Fibrin Content Estimation With a Single Whole-Body PET Scan in Rats, Arteriosclerosis, Thrombosis, and Vascular Biology, 35:10, (2114-2121), Online publication date: 1-Oct-2015. Blasi F, Oliveira B, Rietz T, Rotile N, Day H, Naha P, Cormode D, Izquierdo-Garcia D, Catana C and Caravan P (2015) Radiation Dosimetry of the Fibrin-Binding Probe 64 Cu-FBP8 and Its Feasibility for PET Imaging of Deep Vein Thrombosis and Pulmonary Embolism in Rats , Journal of Nuclear Medicine, 10.2967/jnumed.115.157982, 56:7, (1088-1093), Online publication date: 1-Jul-2015. Ay I, Blasi F, Rietz T, Rotile N, Kura S, Brownell A, Day H, Oliveira B, Looby R and Caravan P (2014) In Vivo Molecular Imaging of Thrombosis and Thrombolysis Using a Fibrin-Binding Positron Emission Tomographic Probe, Circulation: Cardiovascular Imaging, 7:4, (697-705), Online publication date: 1-Jul-2014. Lindner J and Sinusas A (2013) Molecular imaging in cardiovascular disease: Which methods, which diseases?, Journal of Nuclear Cardiology, 10.1007/s12350-013-9785-0, 20:6, (990-1001), Online publication date: 1-Dec-2013. Ciesienski K, Yang Y, Ay I, Chonde D, Loving G, Rietz T, Catana C and Caravan P (2013) Fibrin-Targeted PET Probes for the Detection of Thrombi, Molecular Pharmaceutics, 10.1021/mp300610s, 10:3, (1100-1110), Online publication date: 4-Mar-2013. Nallamothu B and Luscher T (2012) Moving from impact to influence: measurement and the changing role of medical journals, European Heart Journal, 10.1093/eurheartj/ehs308, 33:23, (2892-2896), Online publication date: 1-Dec-2012. June 26, 2012Vol 125, Issue 25 Advertisement Article InformationMetrics © 2012 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.112.112672PMID: 22647974 Originally publishedMay 30, 2012 Keywordsmolecular imagingthrombosisEditorialsblood plateletsechocardiographyPDF download Advertisement SubjectsImagingPlateletsThrombosis
Referência(s)