Circulation. 2008;118:109-112
doi: 10.1161/CIRCULATIONAHA.108.790139
(Circulation. 2008;118:109-112.)
© 2008 American Heart Association, Inc.
Extending the Frontiers of Cardiac Magnetic Resonance
Juerg Schwitter, MD, FESC
From the Cardiac MR Center, University Hospital Zurich and Children’s University Hospital, Zurich, Switzerland.
Correspondence to Juerg Schwitter, MD, FESC, University Hospital Zurich, Cardiology Clinics, Raemistrasse 100, CH-8091 Zurich, Switzerland. E-mail juerg.schwitter{at}usz.ch
Key Words: Editorials • contrast media • imaging • magnetic resonance imaging • metabolism • spectroscopy
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Introduction
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Inflammation is a common reaction in biological systems, which
develops, for example, to defend the body against infectious
agents, to repair tissue, and to respond to ischemic insults.
It can also be a disease process in itself, as in autoimmune
diseases. Flögel et al
1 describe a novel, elegant, and
noninvasive approach to inflammatory mechanisms at a cellular
level. The noninvasive nature of their strategy is of paramount
importance. In particular, it allows for a series of repetitive
measurements to be obtained from the same animal and thus yields
information on the evolution of the inflammatory process without
destruction of the system under investigation. This is almost
impossible to achieve with invasive techniques.
Article p 140
Flögel et al elegantly exploit a primary mode of action of inflammatory cells (ie, phagocytosis of potentially harmful agents), which in this case happens to be a magnetic resonance (MR)–active contrast medium. Another remarkable aspect of their work is the use of the naturally occurring stable fluorine isotope 19F as the MR-active nucleus for imaging. Why is this unique? This 19F-MR imaging strategy takes advantage of the fact that after administration of 19F-containing compounds, any signal detected in the body via MR imaging (MRI) is emanating from the injected contrast medium (ie, an extraordinary contrast-to-noise ratio [CNR] is present, because no background signal from the body is detected by 19F-MR imaging). If the MR scanner is thereafter tuned to the 1H resonance frequency, conventional MRI occurs, and all morphological and functional information on the organ can be acquired. Because this imaging is performed in the same location and with the same equipment, registration is ideal; this allows "fusion imaging" to be used to combine specific signals of inflammatory cells (19F imaging) with organ function and anatomy (conventional 1H imaging).
The performance of the authors’ imaging approach is impressive. In addition to an excellent CNR, the signals are received from voxels as small as 0.5x0.5x2 mm3, and the 19F-containing contrast medium consisting of nanoparticles loaded with perfluorocarbons is biologically inert. Moreover, in the study, these perfluorocarbons were monitored in the body for up to 6 days and were detected not only in the ischemic territories undergoing repair but also in the postoperative sutures and in the liver, where the signals persisted for several months. Considering these features and the high sensitivity of this technique in detecting populations as small as a few hundred macrophages, this approach is a promising candidate for future research. It will likely provide new insight into inflammatory processes in the cardiovascular system and may also be applicable in clinical situations.
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Translation of Animal Multinuclei MRI to Humans: General Considerations
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An average perfluorocarbon loading per cell of <1 pmol was
detectable by the presented
19F-MRI technique in vitro using
a 9.4-T system. Because the MR detection system adds noise to
any signal from the body, the signal-to-noise ratio (SNR) is
a crucial characteristic of imaging-system performance. As shown
in
Figure 1, SNR, spatial resolution, and time for signal acquisition
are inversely related. Rapid imaging typically occurs with lower
SNR, reduced spatial resolution (large voxel volume), or both.
In other words, the SNR is directly proportional to voxel size
and the square root of the acquisition time and is inversely
proportional to the square root of the receiver bandwidth. Thus,
the required spatial resolution and the available imaging acquisition
time dictate the SNR, which relates to the sensitivity to detect
excited
19F and
1H nuclei. Because noise is added from the volume
of the receiver coil, noise increases substantially when small-animal
imaging techniques are applied to humans. As indicated by
Figure 1,
a sufficiently high concentration of
19F isotope must be brought
into the target voxel to generate adequate signal. Although
19F-MRI in mice detects concentrations of
0.2 µmol per
voxel of 0.5
x0.5
x2 mm
3 at 9.4 T, in humans at 3 T and employing
a voxel size of 5
x5
x5 mm
3 in a head coil,
4 mmol would be detected
with the same SNR of 20 after the same acquisition duration
of 20 minutes. The
19F technique with excellent CNR can measure
slow processes, which do not require high temporal resolution,
and hence it allows for long acquisition times and thereby increases
SNR. Accordingly, this
19F technique represents a powerful application
of MR at one end of the MRI spectrum, where slow processes are
to be probed (see
Figure 2).
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Figure 2. The MRI spectrum is illustrated, exploiting various nuclei (19F, 1H, 13C) as signal sources. The 1H nucleus refers to conventional MRI, where the protons in the tissue, primarily water, generate the signal. Gadolinium-based contrast media facilitate the relaxation of the protons, thereby increasing SNR for a given MR pulse sequence. Unlike 1H, the 19F and 13C techniques yield "uncontaminated" signals, because no background signal from the body is received, which generates specific information with extraordinary CNR. All 3 approaches can be combined, thereby opening the spectrum of possible targets in a single examination. Such a multiparametric MRI strategy will deliver quantitative biological information localized in space and time to describe complex biological systems. Moreover, its noninvasive nature and its lack of radiation will allow for serial examinations to track biological processes over time. *Calculated for a field strength of 3 Tesla, a voxel size of 5x5x5 mm3, with a head coil to obtain an SNR of 20. Effective concentration is quantity per voxel. Imaging time for 19F is 20 minutes, for 13C it is 400 ms.
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On the other end of the spectrum, another nucleus, 13C, is present, which allows for very fast MRI of specific processes with high temporal and spatial resolution (Figure 2). For fast processes, long signal acquisition is not feasible. The 13C techniques exploit the hyperpolarization of these 13C compounds, which yield SNRs that are up to 10 000 times higher than can be obtained with conventional 1H MRI.2 Although 19F nuclei in perfluorocarbons remain in the body for weeks and allow (in principle) for very long acquisition times, 13C-labeled compounds "lose" their hyperpolarized state with short half-lives (for [13C]pyruvate, 25 seconds), and imaging can only be performed for 1 to 2 minutes. This means that the sensitivity of the measurements obtained using 13C cannot be increased by increasing the signal acquisition time, and the technique is ideal to study short-lived processes with extremely high sensitivity. Assuming 5% polarization of 13C at the time of imaging in the target voxel of 5x5x5 mm3 in a 3-T scanner using a head coil and measuring for 400 milliseconds (!), 100 µmol of the 13C compound per voxel would be detected. In a recent canine study performed with hyperpolarized [13C]pyurvate in a 3-T scanner, an estimated 5 µmol of [13C]pyruvate was detected per voxel of 5x5x5 mm3 (assuming a homogeneous distribution of the injected [13C]pyruvate in the body 30 seconds after administration).3 Accordingly, this hyperpolarized 13C approach allows for near-real-time noninvasive metabolic imaging at resolutions in the millimeter dimension.4 Not only is the initial SNR enormous as generated by the hyperpolarization, it also allows monitoring of the metabolic fate of, eg, injected [13C]pyruvate metabolized into [13C]lactate, [13C]alanine, and others by means of the serially acquired spectra. This unique feature was recently exploited to invasively monitor pH in tumor tissue.5 As for 19F imaging, this hyperpolarized 13C imaging yields excellent CNRs, as any signal detected in the body is uniquely emanating from the compound injected and its metabolic products. In pig experiments, this technique was used to probe the citric acid cycle in mitochondria after subjecting the animals to short episodes of ischemia.6 In this setting, a "metabolic memory" was identified, which is a potentially adaptive mechanism to preserve function in the postischemic period.6 During congestive heart failure, metabolic adaptations occur that can initiate a vicious cycle (eg, those that occur during diabetic congestive heart failure).7,8 This 13C technique "fused" with conventional 1H cardiac MRI could yield unique information in congestive heart failure on cardiac energetics, metabolic alterations, myocardial function and perfusion, as well as viability.
In conventional 1H imaging, where no hyperpolarization is applied, only 4 to 5 spins out of 1 million (0.0005%) are contributing to the MR signal at the thermal equilibrium at 1.5 T (fully relaxed state), for which the abundance of water (80 mol/L concentration) in biological tissue is compensating. In addition, conventional gadolinium-based contrast media can facilitate recovery of magnetization after excitation, thereby allowing for faster relaxation (ie, faster imaging). Gadolinium chelates coupled to specific targeting molecules are used for molecular imaging, which is covered in detail elsewhere,9 whereas this editorial focuses on cardiac magnetic resonance exploiting nuclei other than 1H. Unfortunately, in 1H imaging, the magnetization cannot be increased beyond full relaxation by any contrast medium, and hence, an additional increase in signal (and thus an increase in sensitivity for 1H nuclei) can only be achieved by prolongation of signal acquisition. As a consequence, spatially restricted processes of a certain duration that require a minimum temporal and/or spatial resolution of imaging10 inherently limit the amount of available signal in 1H imaging.11 Here, 13C imaging can extend the capability of MR through hyperpolarization (20% to 30% of spins at injection deliver signal!).12 At this end of the spectrum, involving fast processes in the micromolar concentration range, 13C imaging can be used. At the opposite end of the spectrum, the 19F imaging is complementary, allowing for excellent CNR with high sensitivity for long-lasting processes such as inflammation, cell migration, differentiation, and others. All of this highly specific information of 19F and 13C imaging can be combined with conventional 1H imaging to yield information on such matters as tissue and organ morphology, function, perfusion,13,14 viability,15 flows,16 endothelial function,17–19 targeted imaging,20 and cell tracking21 (see Figure 2). Fusion of these different modalities (ie, a multiparametric MRI approach) will have a major impact in research and perhaps in clinical cardiology as well.
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Multiparametric MRI: Future Perspectives
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Our knowledge of the human genome has increased rapidly in recent
years, and many signaling pathways involved in disease evolution
and progression are now under intensive investigation. However,
it is also frequently recognized that well-defined genotypes
cannot always unambiguously predict specific phenotypes. In
most cases, the complex interplay of a variety of genes and
a large number of signaling molecules and metabolic reactions
determine the development of a disease state. How can we identify
key signals in such complex systems and differentiate them from
less-important "bystanders," which would only become relevant
in some rare (ie, experimental) conditions? It appears highly
desirable to develop a research tool that would allow us to
monitor and quantify biological processes and to localize them
in space and time to understand the complex interactions and
to isolate key processes, which would become the target for
interventions. Noninvasive imaging is this tool, as it describes
and quantifies biological processes, and it localizes them within
cells, tissues, and organs. By adding
19F and
13C imaging to
conventional
1H imaging, we expect an extraordinary improvement
in our capabilities to investigate complex biological systems
by extending the spectrum into specific imaging of long-lasting
and short-lived processes with a sensitivity and specificity
never before obtained.
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Acknowledgments
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The author’s discussions with S. Petersson, PhD, employee
of GE Healthcare, and his calculations of
19F- and
13C-imaging
sensitivities are highly appreciated.
Disclosures
Dr Schwitter is a consultant for the MR-IMPACT program and for research activities on cardiovascular applications of hyperpolarized 13C compounds sponsored by GE Healthcare.
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Footnotes
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The opinions expressed in this article are not necessarily those
of the editors or of the American Heart Association.
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Introduction
Translation of Animal...