European Heart Journal – Cardiovascular Imaging (2015) 16, 606–608 doi:10.1093/ehjci/jev037

EDITORIAL

Cellular imaging: a bright future for 19F-CMR Juerg Schwitter* Division of Cardiology and Cardiac MR Center, University Hospital Lausanne, Rue du Bugnon 46, Lausanne CH-1011, Switzerland Online publish-ahead-of-print 2 March 2015

The PFC family—a field of research In their study, Boenner et al. used a particular PFC, perfluoro-octyl bromide (PFOB) with a biological half-life of 3–8 days,8 which is ideal to monitor cells over hours to days following injection. Interestingly, this compound is also considered safe, as it passed already Phase III clinical trials in the field of surgery, as this compound can facilitate oxygen transport in blood. It was therefore tested as a plasma expander by administration of large volumes of PFOB to patients.9 It is also possible to follow migration of different cell types by 19 F-MRI simultaneously by using various PFCs which differ in their resonance frequency spectrum.10 Another research activity is

exploring the effect of shortening the relaxation time of PFC by introducing gadolinium into the PFC, thereby increasing the signal of the PFCs.11 In the present study by Boenner et al., the PFOB was injected intravenously and the source of the 19F signal in the heart was the macrophage population which had incorporated the circulating PFOB. Other PFCs are designed for labelling various cell types in vitro. Once labelled in vitro, these specific cell types can be injected into the body and their fate is trackable by 19F-MRI in vivo. Currently, a first clinical study in patients is underway, where dendritic cells designed for colorectal cancer treatment are 19F-labeled ex vivo, are injected intradermally, and then tracked successfully in vivo by 19 F-MRI.12 Another field of PFC research is exploring the SPIT technique (sterol-based post insertion technique), a promising platform that allows to attach different ligands (peptides, antibodies, etc.) to PFC nanoemulsions for in vivo 19F-MRI. During thrombus formation, a2-antiplasmin cross-links with fibrin. To visualize this process, the SPIT technique was used to generate a2-antiplasmin-labelled PFC nanoemulsions (a2AP-PFC). In an animal model of deep vein thrombosis and pulmonary embolism, these targeted PFC emulsions were successful in detecting thrombi in vivo.13

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F-MR imaging of PFCs

While the PFOB features a favourable safety profile and a biological half-life to monitor cells over several days, its resonance spectrum is composed of several peaks which is challenging from a MR imaging perspective. To solve this problem, the authors of the current paper developed an elegant MR pulse sequence, which can handle the multi-peak spectrum of PFOB, and thus, they present in their paper a major step forward in the 19F-MRI development. Nevertheless, many MR pulse and reconstruction options are still to explore. For example, the so-called compressed sensing technique allows for acceleration of acquisition if sparsity in the data set is identifiable. This technique was successfully applied in patients for highly accurate LV volume and function analysis.14 This compressed sensing approach appears ideally suited for the reconstruction of 19F data as typically signals are sparsely represented in k-space as demonstrated by Ahrens et al., who accelerated 19F-MRI by a factor up to 8.15 As the simultaneous tracking of various cell types appears desirable, Bauer et al. presented a multi-spectral 19F technique. Such novel 19F-MR pulse sequences can probe PFCs with different resonance peaks

* Corresponding author. Tel: +41 79 327 5543. E-mail: [email protected] Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2015. For permissions please email: [email protected].

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In the study entitled ‘Monocyte Imaging after Myocardial Infarction with 19F-fluorine MRI at 3T—A Pilot Study in explanted porcine hearts’ of this issue of the journal, Boenner and colleagues present several key innovations in the field of 19F-CMR.1 With their approach, they were able to specifically visualize and quantify macrophage infiltrations in the ischaemia-reperfused myocardium on a clinical 3T MR system. While the conventional 1H-proton-based CMR is well known as a most powerful tool for tissue characterization, the 19F-fluorine technique can boost CMR to the next level, i.e. to that of cellular tissue characterization.2 Conventional CMR can identify tissue characteristics such as scar vs. normal viable myocardium, necrosis, oedema, ischaemia, iron overload, intramyocardial haemorrhage, microvascular obstruction, and others.3 – 5 However, the understanding of disease processes and the prediction of prognosis may be facilitated by characterizing the cellular composition of the tissue.6,7 19F-CMR can visualize 19F-containing molecules, which are incorporated into specific cell types, i.e. it can detect and track 19F-labeled cells non-invasively in the intact body (Figure 1). As 19F-fluorine is not present in the human body, 19F-MRI can detect this label with an excellent contrast-to-noise (CNR), as this technique lacks any background signal. If the magnetic resonance (MR) scanner is acquiring the 19F signal at its specific resonance frequency, it can detect 19F-containing molecules [so-called perfluorocarbons (PFC)] similar to nuclear medicine techniques. Unlike nuclear tracers, however, the signal emanating from the 19F-PFC is not decaying over time, and consequently, this technique can monitor 19F signals of migrating cells over hours up to days without radiation.

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Figure 1 To take full advantage of the 19F-MRI technique, further development of PFCs, of labeling strategies, and of 19F-MRI pulse sequences is needed.

Transition of the 19F technique into clinical applications Finally, Boenner and co-workers addressed another important aspect of the 19F technique. Up to now, most studies utilizing this 19 F technique were performed on high-field MR scanners (of 9T and higher) using small animal models. This current study is one of the first to demonstrate the feasibility to achieve a cellular characterization of the myocardium by the 19F technique on a clinical 3T MR scanner. In their study, they convincingly confirmed their 19F-MRI results with immunohistological and flow cytometry data. As no radiation is involved in this type of cell tracking, there appears a bright future for this technique to successfully be translated into clinical routine.

Perspectives In summary, the study of Boenner and colleagues convincingly demonstrates the potential of the PFOB for cellular characterization, when combined with a novel MR pulse sequence scheme and by translating this approach onto a 3T clinical MR machine. Hopefully, the presented findings will further accelerate the transition of this technique from high-field small animal experiments to clinical studies in patients. Once available in patients this 19F-MRI technique could represent a powerful tool to localize the site of inflammation

and to quantify and monitor the response to treatment, e.g. in myocarditis but also in the setting of fever of unknown origin and in other inflammatory diseases. This tool may also allow to studying autoimmune diseases in more detail and could be of great value in the design and monitoring of immunotherapies in cancer patients. Finally, the concept of targeted PFC emulsions could substantially enhance our armamentarium to detect thrombi or other specific targets in the human body. As this technique is radiation free and can monitor cells over hours and days, there is a bright future for this technique to improve diagnosis and to monitor treatment responses in patients.

References 1. Bo¨nner F, Merx MW, Klingel K, Begovatz P, Flo¨gel U, Sager M et al. Monocyte imaging after myocardial infarction with 19F-MRI at 3T – a pilot study in explanted porcine hearts. Eur Heart J Cardiovasc Imaging 2015;16:612 –20. 2. Ahrens ET, Flores R, Xu H, Morel PA. In vivo imaging platform for tracking immunotherapeutic cells. Nat Biotech 2005;23:983–7. 3. McMurray JJV, Adamopoulos S, Anker SD, Auricchio A, Bo¨hm M, Dickstein K et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J 2012;33:1787 – 847. 4. Schwitter J, Arai A. Imaging: assessment of cardiac ischaemia and viability: role of cardiovascular magnetic resonance. Eur Heart J 2011;32:799 –809. 5. Schwitter J. CMR-Update, 2nd ed. Lausanne, Switzerland. www.herz-mri.ch; 2012 (4 February 2015, date last accessed). 6. Temme S, Bo¨nner F, Schrader J, Flo¨gel U. 19F magnetic resonance imaging of endogenous macrophages in inflammation. WILEs Nanomed Nanobiotechnol 2012;4:329–43. 7. Schwitter J. Extending the frontiers of cardiac magnetic resonance. Circulation 2008; 118:109–12. 8. Jacoby C, Temme S, Mayenfels F, Benoit N, Krafft M, Schubert R. Probing different perfluorocarbons for in vivo inflammation imaging by F MRI: image reconstruction, biological half-lives and sensitivity. NMR Biomed 2013;27:261 –71. 9. Spahn D, Waschke K, Standl T, Motsch J, Van Huynegem L, Welte M et al. Use of perflubron emulsion to decrease allogeneic blood transfusion in high-blood-loss noncardiac surgery: results of a European phase 3 study. Anesthesiology 2002;97: 1338 –49.

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that allow to track various cell types simultaneously and noninvasively in the body. At this point, it should be mentioned that the 19F signal obtained by 19F-MRI is fully quantitative as the 19F signal correlates linearly with the number of 19F-fluorine atoms in the imaged tissue volume.16,17

608 10. Partlow KC, Chen J, Brant JA, Neubauer AM, Meyerrose TE, Creer MH et al. 19F magnetic resonance imaging for stem/progenitor cell tracking with multiple unique perfluorocarbon nanobeacons. FASEB J 2007;21:1647 –54. 11. de Vries A, Moonen R, Yildirim M, Langereis S, Lamerichs R, Pikkemaat JA et al. Relaxometric studies of gadolinium-functionalized perfluorocarbon nanoparticles for MR imaging. Contrast Media Mol Imaging 2014;9:83–91. 12. Ahrens ET, Helfer BM, O’Hanlon CF, Schirda C. Clinical cell therapy imaging using a perfluorocarbon tracer and fluorine-19MRI. Magn Reson Med 2014;72:1696 – 701. 13. Temme S, Grapentin C, Quast C, Jacoby C, Grandoch M, Ding Z et al. Non-invasive imaging of early venous thrombosis by 19F-MRI using targeted perfluorocarbon nanoemulsions. ISMRM, Annual Scientific Meeting, Milano, Italy, 2014.

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14. Vincenti G, Monney P, Chaptinel J, Rutz T, Coppo S, Zenge MO et al. A novel compressed sensing single-breathhold multi-slice magnetic resonance approach for fast quantification of left ventricular function, volumes, and mass. J Am Coll Cardiol Cardiovasc Imaging 2014;7:882 – 92. 15. Zhong J, Mills PH, Hitchens TK, Ahrens ET. Accelerated fluorine-19 MRI cell tracking using compressed sensing. Magn Reson Med 2013;69:1683 –90. 16. Srinivas M, Turner MS, Janjic JM, Morel PA, Laidlaw DH, Ahrens ET. In vivo cytometry of antigen-specific T cells using 19F MRI. Magn Reson Med 2009;62:747 –53. 17. van Heeswijk RB, De Blois J, Kania G, Gonzales C, Blyszczuk P, Stuber M et al. Selective in vivo visualization of immune-cell infiltration in a mouse model of autoimmune myocarditis by fluorine-19 Cardiac Magentic Resonance. Circ Cardiovasc Imaging 2013;6:277 –84.

IMAGE FOCUS

doi:10.1093/ehjci/jev015 Online publish-ahead-of-print 5 March 2015

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Flow collision in early aortic ejection: an additional source of kinetic energy loss in patients with mitral prosthetic valves Daniel Rodrı´guez Mun˜oz*, Jose´ Luis Moya Mur, Cristina Lozano Granero, Covadonga Ferna´ndez-golfı´n, and Jose´ Luis Zamorano Go´mez Department of Cardiology, Ramo´n y Cajal University Hospital, Ctra. de Colmenar, Km 9100, Madrid 28031, Spain

* Corresponding author. Tel: +34 91 336 85 15; Fax: +3491 336 85 15, Email: [email protected]

Supplementary data are available at European Heart Journal – Cardiovascular Imaging online. Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2015. For permissions please email: [email protected].

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Echocardiographic left ventricular (LV) flow analysis was performed with vector flow mapping (VFM) in a 48-year-old asymptomatic patient with prior mitral valve replacement by bi-leaflet prosthesis in 2013. Streamlines in Panel A show the consequence of trans-prosthetic mitral inflow directed towards the septum: the development of a dominant posterior vortex showing counter-clockwise (CCW) rotation (see Supplementary data online, Video S1). This flow distribution results in abrupt changes in flow direction towards the LV outflow tract at the initial phase of aortic ejection (Panel B). Panels C and D show an increase in energy loss in the sub-mitral region due to flow collision before its redirection towards the outflow tract, as indicated by the superimposed flow vectors kinetic energy variations. Panels E and F show the predominant anterior vortex redirecting flow towards the outflow tract in healthy subjects. Panels G and H show the low energy-dissipation ejection in normal subjects. LV inflow generates rotational flow that organizes in vortices, with a dominant, clockwiserotating, anterior component—as seen in apical long-axis view—in normal subjects. This vortex contributes to cardiac function through kinetic energy storage and a smooth redirection of flow towards the outflow tract. Patients with mitral prosthetic valves often show changes in inflow resulting in vortex rotation reversal, which has been reported to increase energy loss during diastole. In these images, we show additional kinetic energy loss during early systole due the absence of clockwise flow redirection, which causes flow collision against the mitral prosthesis and mitral-aortic junction before ejection.

Cellular imaging: a bright future for 19F-CMR.

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