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Pre-clinical functional Magnetic Resonance Imaging part II:

The heart
Nadja M. Mener 1 , Frank G. Zllner ,1 , Raf Kalayciyan, Lothar R. Schad
Computer Assisted Clinical Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
Received 19 November 2013; accepted 17 June 2014

One third of all deaths worldwide in 2008 were caused by
cardiovascular diseases (CVD), and the incidence of CVD
related deaths rises ever more. Thus, improved imaging
techniques and modalities are needed for the evaluation of
cardiac morphology and function.
Cardiac magnetic resonance imaging (CMRI) is a minimally invasive technique that is increasingly important
due to its high spatial and temporal resolution, its high
soft tissue contrast and its ability of functional and quantitative imaging. It is widely accepted as the gold standard
of cardiac functional analysis.
In the short period of small animal MRI, remarkable
progress has been achieved concerning new, fast imaging
schemes as well as purpose-built equipment. Dedicated
small animal scanners allow for tapping the full potential
of recently developed animal models of cardiac disease.
In this paper, we review state-of-the-art cardiac magnetic
resonance imaging techniques and applications in small
animals at ultra-high elds (UHF).

Keywords: Small animal, cardiac disease, MRI,

ultra-high field, functional imaging

Prklinische funktionelle
Magnetresonanztomographie Teil 2: Herz
Ein Drittel aller Todesflle weltweit wurden 2008
durch kardiovaskulre Krankheiten verursacht, und deren
Inzidenz huft sich mehr und mehr. Daher werden verbesserte Bildgebungstechniken und Modalitten
fr die Auswertung kardialer Morphologie und Funktion bentigt. Die kardiale Magnetresonanztomographie
(MRT) ist eine minimal-invasive Technik, die aufgrund
ihrer hohen rtlichen und zeitlichen Ausung, ihres hohen
Weichteilkontrastes und ihrer Fhigkeit zur funktionellen
und quantitativen Bildgebung immer wichtiger wird. Sie
hat sich zu einem Goldstandard fr die funktionelle Untersuchung von Herzkrankheiten entwickelt.
In der kurzen Zeitspanne der Kleintier-MRT wurden
bemerkenswerte Fortschritte erzielt hinsichtlich neuer,
schneller Bildgebungstechniken und speziell angefertigter
Hardware. Dedizierte Kleintierscanner ermglichen es,
das Potenzial neu entwickelter Tiermodelle kardialer
Krankheiten voll auszuschpfen.
In diesem Review werden State-of-the-Art-MRT-Techniken
und Anwendungen zur Untersuchung des Herzens an
Kleintieren bei Ultrahochfeld vorgestellt.
Schlsselwrter: Kleintier, Herzkrankheiten, MRT,
Ultrahochfeld, funktionelle Bildgebung

Corresponding author. Frank G. Zllner, Computer Assisted Clinical Medicine, Medical Faculty Mannheim, Heidelberg University, Theodor-Kutzer-Ufer

1-3, 68167 Mannheim, Germany. Tel.: +49(0)6213835117; fax: +49(0)6213835123.

E-mail: (F.G. Zllner).
both authors contributed equally.

Z. Med. Phys. 24 (2014) 307322


N.M. Mener et al. / Z. Med. Phys. 24 (2014) 307322

Main Challenges in Small Animal Cardiac


Cardiovascular disease is the leading cause of death
in the world [1]. The main causes of this disease
are hypertension and atherosclerosis. Further risk factors
for cardiovascular disease are manifold and arise from
age, gender, high serum cholesterol levels, tobacco smoking, excessive alcohol consumption, sugar consumption,
family history, obesity, lack of physical activity, psychosocial factors, diabetes mellitus, and even air pollution [2,3].
Though cardiovascular disease is attributed to the older population, the antecedents of cardiovascular disease, notably
atherosclerosis, begin in early life [4,5]. Therefore, noninvasive tools to assess or prevent cardiovascular disease are
Cardiac magnetic resonance imaging (CMRI) is such a
modality that fulfills the requirements of spatial and temporal
resolution and is seen as the gold standard of functional cardiac imaging [6]. CMRI in animals started in the mid-1980s
with large animals such as dogs and basic applications like
myocardial mass determination [7]. Other animal models and
techniques were explored thereafter.
CMRI in mice has not been performed until the late
1990s, but as it is technically and economically favorable
and as transgenic (TG) and knockout mice allow investigating the role of individual genes in tasks like myocardial
infarction (MI) remodeling [810], it has become a field
of intense research. Various different MR imaging techniques have been developed [1113], amongst them cine
imaging techniques for structural and functional information
or contrast-enhancement techniques for infarct delineation
[14]. In this paper, we review state-of-the-art CMRI techniques and applications at ultra-high fields (UHF). In contrast,
the first part of this review focuses on pre-clinical kidney
imaging [15].

The cardiovascular systems of large mammals like sheep,

dogs and pigs are comparable to those of humans, but there are
differences in position, size, and shape of the heart [16]. The
conditions in rodents and rabbits are similar, too [17], although
their hearts are obviously far smaller and beat faster (mouse:
400-600 bpm; rat: 320-370 bpm; rabbit: 150-250 bpm) than
the human heart (60-100 bpm). Strong and fast movements
of the heart and the in- and outflowing blood afford a high
temporal resolution and turn CMRI in small animals into a
challenging task. Small dimensions are yet another challenge,
especially in the mouse, where the thickness of the left ventricular (LV) wall (1.5-1.8 mm) and right ventricular (RV) wall
(0.5-0.6 mm) [17] demand for high spatial resolution in the
sub-millimeter range. Image resolutions currently achievable
by CMRI are summarized in Table 1.
High field strengths bring along the advantages of high
spectral resolution and signal-to-noise-ratio (SNR). Although
there have been successful image acquisitions at 17.6 T
[18,19], a range of 7-11.7 T seems to be the best compromise for murine CMRI to avoid high-field related problems
such as susceptibility artifacts [12]. Furthermore, strong and
fast switching gradients are needed to achieve short acquisition windows and prevent motion artifacts. The coils used
for small animal MR can be classified as mid-range coils, as
the product of the frequency and the coil diameter is in the
range 230 MHz-m [20]. Most of them are linear volume
coils, birdcage coils or surface coils. Volume coil excitation and surface coil reception are preferable [21]. The usage
of cryogenically cooled coils (see Fig. 1) brings along the

Table 1
Examples of achievable spatial resolution in small animal cardiac MRI of different functional cardiac MRI techniques at various field
strengths and MR systems.


Resolution [m3 ]

Animal Model


Cine gradient echo

11.7 T animal scanner

9.4 T animal scanner
9.4 T animal scanner + cryogenic
surface coil
7 T animal scanner
1.5 T whole body scanner
17.6 T animal scanner
9.4 T animal scanner
7 T animal scanner
9.4 T animal scanner
7 T animal scanner
3 T whole body scanner
9.4 T animal scanner
4.7 T whole body scanner
1.5 T whole body scanner

117 117 480

150 150 1000
43 138 300


Subgang et al. [133]

Sosnovik et al. [134]
Wagenhaus et al. [22]

156 195 1000

352 440 2000
1000 1000 1000
625 625 2000
1000 1000 3500
500 800 1500
200 200 1000
200 200 1500
150 150 1000
234 234 1000
625 313 2000


Protti et al. [52]

Voelkl et al. [135]
Neuberger et al. [99]
Maguire et al. [100]
Jansen et al. [101]
Van Nierop et al. [94]
Antkowiak et al. [91]
Makowski et al. [88]
Sosnovik et al. [134]
Gilson et al. [58], Zhou et al. [59]
Hyacinthe et al. [136]

Sodium CSI



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similar to small animal kidney imaging at whole body clinical

scanners, see [15]. The feasibility of most CMRI techniques
like cine imaging, relaxometry, tagging, or LGE was reported
[2527]. Nevertheless, one should keep in mind that resolutions reached with clinical scanners are lower than those
achieved with small animal scanners. For cardiac imaging in
mice, clinical scanners yield image resolutions in the range
of 0.2 mm [28] while dedicated animal scanners reach resolutions up to 0.042 mm [22]. This probably limits the application
of clinical scanners in cases where a high spatial resolution
is required, e.g. wall thickness and wall thickening investigations.
Animal Handling

Figure 1. Image of a cryogenic coil used at our institution for small

animal images. The CryoProbe (Bruker Biospin, Ettlingen, Germany) is a cryogenic transceive quadrature RF surface coil, cooled
down to approximately 30 K, which minimizes electronic noise and
results in very high SNR. It contains a temperature control and heating system for the surface because it is in close contact with the
murine body.

advantage of minimal electronic noise and therefore, gains of

3 to 5 in terms of SNR can be achieved compared to conventional room temperature RF coils [22]. An example of a
mouse heart cross sectional image recorded with a room temperature (RT) coil and a cryogenically cooled coil is shown in
Figure 2. The spatial resolution that can be reached so far with
the help of cryogenic cooling is 43 138 300 m3 [22], but
angiography and vessel wall imaging are still the domain of
computed tomography (CT) [23,24].
Inhomogeneities of the magnetic field generated by the
main magnet are corrected with so-called shim coils. Shimming is of great importance for applications at UHF, where the
field is less homogeneous. At pre-clinical scanners, shimming
is performed manually, whereas clinical scanners normally
have automatic shim routines. Clinical scanners are designed
to image humans, but are also practical for the investigation
of large animals such as sheep, pigs, and dogs. Small animal CMRI can also be performed on clinical scanners using
dedicated small animal receive coils and gating equipment

For animal handling, similar principles hold as in the case

of kidney imaging described in part I of this review [15].
The type and the concentration of anesthesia affect hemodynamics and consequently the imaging results. Isoflurane
seems to be the best choice because of minimal cardiac depression [29,30], hence mice and rats are commonly anesthetized
with inhalational isoflurane (concentration of 1.5%), but also
an intravenous injection of an anesthetic such as pentobarital sodium is possible. Rabbit anesthesia is administered via
gas inhalation [31] or intravenous, subcutaneous, intramuscular, or intrahepatic injection [32], depending on the duration
and type of investigation. In dogs, pigs and sheep, anesthesia
normally is induced by injection of an anesthetic drug and
maintained by inhalation of isoflurane.
Vital functions are usually monitored with the help of two
or more ECG leads for cardiac function, a pressure balloon
for breathing and a rectal probe for temperature control (cf.
Figure 3). An eye ointment is applied in order to protect the
eyes from drying-out. The body temperature is maintained via
a warming pad.
The positioning of a mouse or rat can be either horizontal
or vertical, depending on the magnets orientation. The vertical position typically found at high field spectrometers is
more unnatural, but it maintains quasi-physiological conditions [33].
Gating Strategies
For CRMI, synchronization of the acquisition with the cardiac cycle is necessary. Most frequently, electrocardiogram
(ECG) triggering is used to that purpose. It can be performed
prospectively or retrospectively [34]. At UHF and with fast
switching gradients, interferences between the ECG and the
magnetic fields disturb the gating signal. Therefore, alternative ways of gating have been established as well. Self-gating
techniques [35], pulse oximetry gating [36] and respiratory
triggering, which can be combined with cardiac triggering
[37], have proven to be reliable gating methods. Acoustic cardiac triggering [38] or gating with an MR-stethoscope [39]
are alternative ways of gating.


N.M. Mener et al. / Z. Med. Phys. 24 (2014) 307322

Figure 2. Comparison between high resolution (69 115 800 m3) images of a four chamber view acquired with the birdcage resonator
in conjunction with a four channel mouse receive only cardiac surface coil array at room temperature (a) and the CryoProbe (b). Reproduced
from [18].

Imaging in small rodents is often performed without respiratory compensation, as it does not strongly affect image
quality [4042], but with higher field strength it becomes more
and more necessary [43]. Schneider et al. demonstrated that
respiratory gating seems to be more prone to such artifacts in
the vertical position than in the horizontal position at UHF

Figure 3. Example of the animal preparation. For imaging with a

surface coil (see Fig. 1), the mouse is positioned in supine position
on a purpose-built cradle. It is anesthetized and commonly equipped
with a respiration sensor and two ECG electrodes, both secured with
adhesive tape. A rectal probe serves as temperature control.

Functional MRI Techniques

For the investigation of cardiac structure and function, the
most frequently used method is a T1-weighted cine gradient echo (GRE) technique. Example images acquired using
a cine imaging technique and cryogenic cooled surface coils
are given in Figure 4. The myocardial mass was one of the
first parameters that have been investigated, requiring a complete coverage of the heart with cine images [42,44,45]. Other
parameters of interest which help to assess myocardial function are the LV size, mass, shape [46], wall thickness, wall
thickening [47,48], epicardial and endocardial contours and
the ejection fraction (EF) [49], but also the RV is getting more
and more interest as higher resolutions are reached [50]. In
order to investigate myocardial viability, stress cine-MRI of
cardiac function can be performed. To that purpose, dobutamine is given with an intravenous or an intra-peritoneal bolus
injection [51], which mimics the effects of exercise on the
The advantage of Prottis multi-slice cine FLASH [52]
is that a simultaneous determination of myocardial function
and infarct size is possible. Price et al. [53] and Buonicontri
et al. [54] recently used another protocol, sampling multiple slices in each repetition period and being able to reach
larger flip angles, which provide higher signal intensities.
Another method to discriminate between infarct tissue and
healthy myocardium without using contrast agents (CAs) is

N.M. Mener et al. / Z. Med. Phys. 24 (2014) 307322


Figure 4. Example images of the standard cardiac views obtained in a healthy mouse. End-diastole (left column) and end-systole (right
column) shown in the standard cardiac views: The short axis view (SAX, a), the 4 chamber view (4CV, b) and the two chamber view
(2CV, c). The images were acquired with a cine-FLASH sequence (TE/TR = 2.0 ms / 8.5 ms; flip angle = 40 ). The high resolution
(68.7 68.7 800 m3 ) for the SAX and 4CV (retrospectively pulse oximetry triggered) and (97.7 97.7 800 m3 ) for the 2CV (retrospectively ECG triggered), allows a detailed delineation of very small structures such as the right ventricular wall. Such a high resolution
and SNR are possible using the CryoProbe (Bruker Biospin, Ettlingen, Germany) and a small animal scanner (BioSpec 94/20 USR, Bruker
BioSpin, Ettlingen, Germany) operating at a ultra-high field of 9.4 T.


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T1-weighted imaging using long spin-locking pulses [55]. It

can be also useful to identify edema, scar tissue, myocarditis
and ventricular fibrosis [56].
In the fast beating hearts of small animals, ultra-fast acquisition methods such as echo planar imaging (EPI) are of great
advantage, too.
Tagging techniques are useful for the quantification of
intramyocardial function [57]. To have a closer look at strain
and velocity, strain imaging is performed. Spatially selective
saturation pulses are used to tag the heart and follow its movement. The so-called DENSE (Displacement encoding with
stimulated echoes) [58] and the SPAMM (SPAtial Modulation of Magnetization) technique [59,60] have been conducted
with success in both rodents and larger animals. An example
for tagging is given in Figure 5.

Phase-contrast MRI for Motion Mapping

Phase-contrast MRI or tissue phase mapping (TPM) is
another method to characterize regional cardiac function,
especially transmural wall motion (see Fig. 6). Streif et al. used
bipolar gradient pulses to cause a known dependency between
voxel velocity and spin phase and could thus follow the motion
of the murine myocardium at 7 T [61]. DallArmellina et al.
performed TPM at a 9.4 T animal scanner with a 2D multiframe GRE sequence [62]. In pigs, phase-contrast MRI was
used for assessing cardiac output and LV function [63].
The qualitative application of MR imaging is based on
signal intensity changes, which are an indirect measure of concentration and are dependent on MR hardware and sequences,
as well as on cardiac and respiratory rates. In contrast to
that, mapping of the relaxation times allows myocardial

Figure 5. Tagging of a mouse heart. Short-axis and long-axis tagged murine myocardium at end-diastole (a,c) and end-systole (b,d). Tagging
was generated with a SPAMM sequence which was applied after the R-wave trigger signal, followed by cine images covering the whole
cardiac cycle. Tag lines were traced in postprocessing in order to follow cardiac motion in 3D. Reproduced with permission from [131].

N.M. Mener et al. / Z. Med. Phys. 24 (2014) 307322


Figure 6. Velocity maps generated with phase-contrast (PC) MRI in a rat heart. They show long axis views of 4 moments after the R-wave
in the cardiac cycle, from end-diastole to early systole. The velocity vectors indicate in-plane flow of the blood and the cardiac wall. The
sequence applied was a gradient-echo cine pulse sequence with pulsed field gradients. Reproduced with permission from [132].

signal quantification on a standardized scale (msec). Quantitative values of T1 and T2 are used to detect and characterize
cardiac pathology including edema, fibrosis or ischemia [64].
This is performed with or without the help of CAs. For

the investigation of MI, relaxation times can be used as

a measure of how much tissue has been damaged: acute
stage, subacute stage, or chronic stage can be distinguished


N.M. Mener et al. / Z. Med. Phys. 24 (2014) 307322

Figure 7. T1 map (left) s and corresponding end-diastolic morphology (right) in short axis. Imaging was performed using an ECG-triggered
RF spoiled 3D cine FLASH sequence, five different flip angle (2 , 5 , 8 , 11 , and 14 ), and a cryogenic surface coil. Spatial resolution was
0.15 0.15 1.0 mm3 .

T1 mapping

T2* mapping

Maps of the relaxation time T1 are commonly generated

in combination with gadolinium (Gd) based contrast agents.
In chronic infarcts, collagen deposition leads to a prolonged
CA retention and therefore to a higher concentration of CA
in the infarct region compared to remote myocardium [66].
The common methods all include the Look-Locker sequence.
Combined with a saturation recovery preparation (SRLL)
[67], it has been successfully applied to the mouse by Naresh
et al. [68]. The SRLL method was combined with a modified model-based compressed sensing (CS) method to offer
a less time-consuming T1 mapping method in the murine
heart [69]. Another approach, allowing 3D T1 mapping in
the mouse heart, is the variable flip angle (VFA) technique,
developed by Coolen et al. [70]. Yet another method is using a
SNAPSHOTFLASH IR (SNAP-IR) sequence, developed by
Deichmann et al. [71], and realized in the mouse by Bohl et al.
[72] and Schneider et al. [73]. An example of 3D T1 mapping
of the murine heart at ultra-high field using a cryogenic cooled
surface coil is given in Figure 7.

Even more additional information on the myocardium can

be found by T2* mapping. A difference in T2* values between
the acute and the chronic phase of MI in mice has been found
by Aguor et al. with a multi-GRE sequence [79]. The time
course of infarct healing was followed by Ghugre et al. by
assessing T2 and T2* values in a porcine model of myocardial
infarction [80]. However, T2* mapping is difficult near the
liver and lung, where shimming is challenging.

T2 mapping
Although T2 maps can bring additional information for
fibrosis quantification [74] or edema detection [75], as well
as they are used for the quantification of targeted iron-oxide
based MR contrast agents, they have received not as much
attention as T1 mapping in the myocardium. Bohl et al. and
Bun et al. performed T2 mapping in the murine heart by using
a SE sequence with several echoes [74,76]. In contrast to that,
Coolen et al. utilized a FISP sequence with a MLEV weighted
T2 preparation [77]. To detect short T2 species such as collagen, an ultra-short TE method (UTE) has been used at 9.4 T
[78]. UTE sequences are special as they utilize gradient ramp
sampling, which means that data acquisition already happens
during gradient ramp up and allows for short echo times.

Diffusion Tensor Imaging

A new emerging proton MR technique for the heart is diffusion tensor imaging (DTI). It determines the anisotropic
diffusion of water in the myocardium and thus, can help to
reconstruct myocardial fiber bundle orientations. DTI on exvivo mouse hearts were performed by Strijkers et al. [81] and
on ex-vivo porcine hearts by Wu et al. [82]. Huang et al.
managed to perform DTI in the mouse heart in-vivo with a
3D diffusion-encoded SE EPI [83,84]. Other directions of
research are to derive 3D models of the heart and superimposing functional information [85] or to investigate the impact on
surgery procedures on morphology and function of the heart
Perfusion MRI
To measure the perfusion by MRI there are two methods:
arterial spin labeling (ASL) and dynamic contrast enhanced
(DCE-) MRI. Briefly, the first technique uses magnetically
labeled blood as intrinsic tracer, whereas the second method
uses an exogenous tracer, mainly gadolinium based. The basic
principles of the two methods are already outlined in the
first part of this review [15], therefore, here only the specific
aspects of cardiac perfusion imaging are presented.
The design of the pulse sequence for a first pass myocardial perfusion measurement is critical as it determines the

N.M. Mener et al. / Z. Med. Phys. 24 (2014) 307322

achievable spatial and temporal resolution and therefore,

the SNR. Three aspects for cardiac first-pass DCE-MRI are
important: strong T1 enhancement, spatial coverage of the
relevant heart segments, and adequate spatial resolution. Saturation recovery (SR) has become a de facto standard perfusion
imaging technique [87]. Compared to inversion recovery,
SR is less sensitive to heart rate variations and allows to
acquire more slices. Furthermore, a magnetization history
is avoided.
Makowski et al. [88] combined a SR sequence with a kt PCA approach for cardiac perfusion MRI of mice at 3T.
The k-t PCA allows for high undersampling along the time
domain [89,90] and therefore allows for high acceleration of
the acquisition. Thereby, one slice could be acquired during
each R-R interval with a slice thickness of 1.5 mm and spatial
resolution 0.2 0.2 mm2 .
At dedicated small animal scanners, Antkowiak et al. [91]
used also a SR sequence, however, with a spiral readout trajectory for cardiac imaging of mice at 7T. Ten slices with
spatial resolution of 0.2 0.2 1.0 mm3 were acquired in an
interleaved manner. Data acquisition was placed near the end
of the cardiac cycle and temporal resolution was 39 msec per
image, approximately 1/3 of the R-R interval.
Naresh et al. [92] recently proposed a dual contrast SR
approach. In this approach, phase encoding and time domain
undersampling was used to acquire first-pass gadoliniumenhanced images. Two slices were acquired within a cardiac
cycle, one to obtain the AIF (acceleration factor of 7)
and the other to obtain the tissue function (acceleration
factor 4). Images were reconstructed using a compressed
sensing approach that also reduces motion. Image resolutions were the same as for the study of Antkowiak et al.
An ECG triggered SR fast imaging in steady state (FISP)
sequence was used in a study by Coolen et al. [93] and van
Nierop et al. [94]. Measurements were performed at a 9.4 T
scanner obtaining an in plane resolution of 0.5 0.8 mm2 with
a slice thickness of 1.5 mm. The acquisition was segmented
into three segments, each acquired within 15 msec. In total,
images were acquired for 2 min.
X-Nuclei Imaging
Another promising field of research is the usage of Xkernels instead of 1 H nuclei for imaging. Sodium or potassium
MRI for example could bring valuable additional information on tissue viability and therefore, on the reversibility of
injured myocardium. Research of sodium or potassium MRI
was mainly limited to NMR spectroscopy in the past [95,96].
However, with increased available dedicated high field scanners and specifically developed coils [97], sodium imaging
became possible. In the human application, sodium and potassium MRI was shown using a standard 1.5 T whole body
scanner [98]. Initial results of sodium MRI of small animals was presented by Neuberger et al. [99]. An example


of sodium MRI of the mouse heart is given in Figure 8.

Maguire et al. showed a quantification approach of sodium
imaging in the infarcted mouse heart at 9.4 T [100], while
Jansen et al. realized sodium MRI in the rat heart at 7 T using
a chemical shift imaging (CSI) sequence and cine imaging
Imaging with 13 C nuclei has been restricted by a low sensitivity as the polarization at thermal equilibrium is low. This
problem was solved by Ardenkjaer et al. by hyperpolarization enhancement via dynamic nuclear polarization (CNP)
[102]. The most important example of a DNP hyperpolarized
molecule is [1-13C]pyruvate [41], which enables to visualize normal and abnormal metabolism in real time [103] and
therefore, helps to visualize not only the results, but also the
cause of many diseases like ischaemic heart disease, cardiac
hypertrophy and heart failure. Golman et al. monitored the
[1-13C]pyruvate metabolism in pig cardiac muscle cells during an ischemic episode [104,105]. Meanwhile, a lot of MR
spectroscopy experiments have been performed successfully
in rats [106,107], of which Dodd et al. recently performed the
translation from rat to mouse [108].

Infarct Characterization
By contrast-enhanced MRI a detailed visualization of the
processes that occur in the infarcted and remote tissue, both
on the molecular and cellular level [109,110] is possible.
Many different types of contrast agents have been developed, involving targeted agents that bind on dying cells, show
inflammation, or bind to collagen, and non-targeted agents
such as manganese and gadolinium [64]. Non-targeted agents
can be used for infarct delineation and characterization in socalled late-Gadolinium-enhancement (LGE) (see Fig. 9) or
manganese-enhanced MRI (MEMRI) experiments.
Skardal et al. found out that LGE overenhances infarct
size compared to MEMRI, but has the advantage of showing a decrease in signal when the infarction develops from
the acute to the chronic stage, which is not the case for
MEMRI [111]. LGE CMR is accepted as the gold standard
for measuring infarct size [14,112], but there is still a discussion about the best sequence for delayed-enhancement
acquisition. The IR FLASH method has been successfully
adapted for small animals at 9.4 T [72,113] and yields good
results as it nulls the signal of remote myocardium. However, Protti et al. [52] compared this method with a cine-MRI
sequence without preparation and could not find a clear difference in performance at UHF. Other techniques like DTI
to tract fibers and to investigate the remodeling after MI
were presented by Strijkers et al. [81]. Examples of fiber
tracts from several short axes view seven days after MI
are presented in Figure 10. Data was acquired on ex-vivo


N.M. Mener et al. / Z. Med. Phys. 24 (2014) 307322

Figure 8. Short and long axis views from a mouse heart. (a) and (b) are short and long axis views from the proton CINE datasets. (c) and
(d) are corresponding slices from the 3D density-weighted sodium dataset. The left and right ventricle, the septum, and some parts of the
left ventricular free wall are distinguishable, as are the papillary muscles in (c). Data acquisition parameters for the sodium images: 256
complex time-domain data points, a spectral width of 11 kHz, the acquisition time 23ms, echo time 720 s, 2ms gradient spoiling and a
repetition time of 26ms. An exponential filter of 10 Hz was used in the spectroscopic direction, and zero-filling by a factor of two in each
spatial dimension of the data set. A sum-of-squares reconstruction was performed on the 32 spectral data points around the highest peak.
Reproduced with permission from [66].

Myocardial Perfusion
Myocardial perfusion is an indicator for the function of
organs and for many diseases, such as ventricular dysfunction
and hypertrophy [114]. Reduced myocardial perfusion itself
can also cause cardiac pathologies [93]. It can be assessed
by different methods, as explained above. ASL has been performed in mice at 7 T [115117] and also at 9.4 T [118].
Abeykoon et al. propose an alternative approach (SI-method),
making only use of the signal intensity (SI) of slice-select and
non-select inversion recovery (IR) images [119].
The second MRI technique, contrast-enhanced first-pass
perfusion, has first been established in human application, but
is likewise an emerging technique in mice. Using a time-series
of T1-w images, it detects the first-pass of a CA bolus through

the mouse heart. In regions with lower perfusion, the signal

enhancement after CA injection is not as strong as in healthy
myocardium where perfusion is normal [93]. Several groups
successfully implemented such first-pass perfusion measurements in mice at UHF [9294,120].
In dogs, the approach by Fieno et al. was to determine
myocardial perfusion with a T2-prepared SSFP sequence
based on the blood oxygen level-dependent effect (BOLD)
Ischemia/Reperfusion and Permanent Occlusion
MI detection and diagnosis can be best tested and improved
via experimental MI. To that purpose, an infarction is induced

N.M. Mener et al. / Z. Med. Phys. 24 (2014) 307322


Figure 9. IR-GRE multi-slice LGE images of rat and mouse. Example images of late gadolinium enhancement in an acute reperfused rat MI
model using the inversion recovery sequence described. 12 contiguous slices are shown (a), from just above mid-ventricle down through to
apex, highlighting the infarcted region. LGE images from a mouse (b) 2 days following permanent occlusion of LAD, an additional separately
acquired slice taken in the long axis 4-chamber view is shown to illustrate extent of infarction (arrows). Reproduced with permission from

Figure 10. Ex-vivo DTI of mouse heart. (A) Long-axis slices of a heart 7 days after myocardial infarction. (B) Three short-axis slices near
the apex, at the equator, and near the base, as indicated by the red lines in the long-axis slices. The position of the long-axis slices is indicated
by the numbers 1 and 2 and red lines in the upper-right image. (C) Corresponding short-axis slices, color-coded by the direction of the
principal eigenvector. Blue indicates myocardial fibers running in-plane, and red represents fibers out-of-plane. Reproduced with permission
from [57].


N.M. Mener et al. / Z. Med. Phys. 24 (2014) 307322

Table 2
Overview of some important functional cardiac MRI techniques and their possible application in cardiac MRI.



Tissue Property

LV structure
Infarct size
Myocardial fiber orientation
Infarct stage
Ejection fraction
Wall motion
Myocardial perfusion
Myocardial viability


LGE (T1)






13C hyperpol.






by occlusion of an artery. The location and duration of

the interruption of blood supply determine the size of MI
and the possibility of remodeling. For that reason one can
distinguish between ischemia/reperfusion (IR) experiments
[57,122], where the left anterior descending coronary artery
is ligated temporarily, and permanent occlusion (PO) experiments [72]. In TG and knockout mice, such experiments are
performed in the hope of finding the role of individual genes
in LV remodeling [40,123]. For the translation to patients it
has to be considered that the coronary anatomy in the mouse
is different and thus the location and size of the infarct are not
directly comparable. Also, remodeling in mice is accelerated
compared to humans.

In the short period of pre-clinical cardiac MRI, remarkable
progress has been achieved concerning purpose-built equipment as well as new, fast imaging schemes. These advances
probably allow for assessing basic principles and mechanisms
of disease progression for a range of CVD. Table 2 summarizes
techniques and applications reviewed in this work. However,
further improvements in terms of hardware and sequences
are desirable in order to achieve better temporal and spatial
resolution. Including animal preparation, planning views and
high-resolution cine images, which have to be averaged many
times and are prolonged severely by cardiac gating, the total
duration of experiments can be up to several hours. Shorter
total acquisition times will be necessary for being able to
include different techniques like cine, relaxometry and perfusion imaging into one single measurement procedure to have
a comprehensive basis for a later diagnosis. Approaches that
might overcome these limitations are parallel imaging techniques using multiple receiver coils and new reconstruction
Recently, the portfolio of MRI techniques to investigate
the heart was extended by introducing emerging techniques
like diffusion or X-nuclei MRI. Using the increase in SNR
at higher field strength but also, compared to whole body

scanners, the superior gradient system, such techniques benefit if applied at dedicated ultra-high field scanners.
However, despite the many advantages that come along with
pre-clinical research in animal models, direct translation to
the human application has to be treated with caution, as there
are important differences in the morphology of the cardiovascular systems and in genetics. Most imaging techniques
described in this review are also available and well established in human cardiac MR imaging [124,125]. This includes
also new emerging techniques like sodium MRI [1,126130].
Although a direct translation might be difficult, at least the
same functional parameters can be determined.
In conclusion, important insights into the mechanisms of
cardiac function and disease can be gained via pre-clinical
imaging. This might help to understand cardiac diseases and
might lead to new diagnostic tests reducing the risk of cardiac
disease but also, can help in developing new treatments for
cardiac disease.

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