We are grateful for funding from the British Heart Foundation to TK and to the UK Medical Research Council for a postgraduate research studentship to GB.

All components of this study were carried out in accordance with the UK Animals (Scientific Procedures) Act, 1986, and with the approval of the University of Cambridge Ethical Review Panel.
1. Animal Preparation
<ol>
	<li>Induce infarcts with a surgical intervention7,8. For measuring at the acute stage, perform imaging 24 hr after intervention.</li>
	<li>Prepare a thin syringe tubing for drug delivery with a 25 G needle at one extremity and a syringe with a 25 G needle at the othe...

<ol>
	<li>Borst, O., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Methods+employed+for+induction+and+analysis+of+experimental+myocardial+infarction+in+mice.">Methods employed for induction and analysis of experimental myocardial infarction in mice.</a> Cell. Physiol. Biochem. 28, 1-12 (2011).</li><li>Pacher, P., Nagayama, T., Mukhopadhyay, P., B&#225;tkai, S., Kass, D. A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Measurement+of+cardiac+function+using+pressure-volume+conductance+catheter+technique+in+mice+and.">Measurement of cardiac function using pressure-volume conductance catheter technique in mice and.</a> 3, 1422-1434 (2008).</li><li>Larsen, T. S., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+isolated+working+mouse+heart:+methodological+considerations.">The isolated working mouse heart: methodological considerations.</a> Pfl&#252;gers Arch. 437, 979-985 (1999).</li><li>Epstein, F. H. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=MR+in+mouse+models+of+cardiac+disease.">MR in mouse models of cardiac disease.</a> NMR Biomed. 20, 238-255 (2007).</li><li>Schneider, J. E., Wiesmann, F., Lygate, C. A., Neubauer, S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=How+to+perform+an+accurate+assessment+of+cardiac+function+in+mice+using+high-resolution+magnetic+resonance+imaging.">How to perform an accurate assessment of cardiac function in mice using high-resolution magnetic resonance imaging.</a> J. Cardiov. Magn. Reson. 8, 693-701 (2006).</li><li>Buonincontri, G., Methner, C., Krieg, T., Carpenter, T. A., Sawiak, S. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+fast+protocol+for+infarct+quantification+in+mice.">A fast protocol for infarct quantification in mice.</a> J. Magn. Reson. Imaging. , (2013).</li><li>Methner, C., Schmidt, K., Cohen, M. V., Downey, J. M., Krieg, T. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Both+A2a+and+A2b+adenosine+receptors+at+reperfusion+are+necessary+to+reduce+infarct+size+in+mouse+hearts.">Both A2a and A2b adenosine receptors at reperfusion are necessary to reduce infarct size in mouse hearts.</a> Am. J. Physiol. 299, 1262-1264 (2010).</li><li>Methner, C., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Protection+through+postconditioning+or+a+mitochondria-targeted+S-nitrosothiol+is+unaffected+by+cardiomyocyte-selective+ablation+of+protein+kinase.">Protection through postconditioning or a mitochondria-targeted S-nitrosothiol is unaffected by cardiomyocyte-selective ablation of protein kinase.</a> , (2013).</li><li>Heiberg, E., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Design+and+validation+of+Segment--freely+available+software+for+cardiovascular+image+analysis.">Design and validation of Segment--freely available software for cardiovascular image analysis.</a> BMC Med. Imaging. 10, 1 (2010).</li><li>Sawiak, S. J., Wood, N. I., Williams, G. B., Morton, A. J., Carpenter, T. A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Voxel-based+morphometry+in+the+R6/2+transgenic+mouse+reveals+differences+between+genotypes+not+seen+with+manual+2D+morphometry.">Voxel-based morphometry in the R6/2 transgenic mouse reveals differences between genotypes not seen with manual 2D morphometry.</a> Neurobiol. Dis. 33, 20-27 (2009).</li><li>Zaidi, H., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Design+and+performance+evaluation+of+a+whole-body+Ingenuity+TF+PET-MRI+system.">Design and performance evaluation of a whole-body Ingenuity TF PET-MRI system.</a> Phys. Med. Biol. 56, 3091-3106 (2011).</li><li>Thomas, D., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=T1-weighted+cine+FLASH+is+superior+to+IR+imaging+of+post-infarction+myocardial+viability+at+4.7T.">T1-weighted cine FLASH is superior to IR imaging of post-infarction myocardial viability at 4.7T.</a> J. Cardiov. Magn. Reson. 8, 345-352 (2006).</li><li>Protti, A., Sirker, A., Shah, A. M., Botnar, R. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Late+gadolinium+enhancement+of+acute+myocardial+infarction+in+mice+at+7T:+cine-FLASH+versus+inversion+recovery.">Late gadolinium enhancement of acute myocardial infarction in mice at 7T: cine-FLASH versus inversion recovery.</a> J. Magn. Reson. Imaging. 32, 878-886 (2010).</li><li>Bohl, S., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Advanced+methods+for+quantification+of+infarct+size+in+mice+using+three-dimensional+high-field+late+gadolinium+enhancement+MRI.">Advanced methods for quantification of infarct size in mice using three-dimensional high-field late gadolinium enhancement MRI.</a> Am. J. Physiol. 296, 1200-1208 (2009).</li><li>Chapon, C., Herlihy, A. H., Bhakoo, K. K. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Assessment+of+myocardial+infarction+in+mice+by+late+gadolinium+enhancement+MR+imaging+using+an+inversion+recovery+pulse+sequence+at+9.4T.">Assessment of myocardial infarction in mice by late gadolinium enhancement MR imaging using an inversion recovery pulse sequence at 9.4T.</a> J. Cardiov. Magn. Reson. 10, 6 (2008).</li><li>Price, A. N., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Cardiovascular+magnetic+resonance+imaging+in+experimental+models.">Cardiovascular magnetic resonance imaging in experimental models.</a> The open cardiov medicine journal. 4, 278-292 (2010).</li><li>Hiba, B., Richard, N., Thibault, H., Janier, M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Cardiac+and+respiratory+self-gated+cine+MRI+in+the+mouse:+comparison+between+radial+and+rectilinear+techniques+at+7T.">Cardiac and respiratory self-gated cine MRI in the mouse: comparison between radial and rectilinear techniques at 7T.</a> Magn. Reson. Med. 58, 745-753 (2007).</li><li>Buonincontri, G., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=PET/MRI+in+the+infarcted+mouse+heart+with+the+Cambridge+split+magnet.">PET/MRI in the infarcted mouse heart with the Cambridge split magnet.</a> Nucl. Instrum. Methods Phys. Res. A. , (2012).</li><li>B&#252;scher, K., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Isochronous+assessment+of+cardiac+metabolism+and+function+in+mice+using+hybrid+PET/MRI.">Isochronous assessment of cardiac metabolism and function in mice using hybrid PET/MRI.</a> J. Nucl. Med. 51, 1277-1284 (2010).</li><li>Berr, S. S., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Images+in+cardiovascular+medicine.+Serial+multimodality+assessment+of+myocardial+infarction+in+mice+using+magnetic+resonance+imaging+and+micro-positron+emission+tomography+provides+complementary+information+on+the+progression+of+scar+formation.">Images in cardiovascular medicine. Serial multimodality assessment of myocardial infarction in mice using magnetic resonance imaging and micro-positron emission tomography provides complementary information on the progression of scar formation.</a> Circulation. 115, 428-429 (2007).</li><li>Lee, W. W., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=PET/MRI+of+inflammation+in+myocardial+infarction.">PET/MRI of inflammation in myocardial infarction.</a> J. Am. Coll. Cardiol. 59, 153-163 (2012).</li><li>Lucas, A. J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Development+of+a+combined+microPET-MR+system.">Development of a combined microPET-MR system.</a> Technol. Cancer Res. Treat. 5, 337-341 (2006).</li><li>Hawkes, R. C., Fryer, T. D., Siegel, S., Ansorge, R. E., Carpenter, T. A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Preliminary+evaluation+of+a+combined+microPET-MR+system.">Preliminary evaluation of a combined microPET-MR system.</a> Technol. Cancer Res. Treat. 9, 53-60 (2010).</li></ol>

There is nothing to disclose.

PET/MRI is a comprehensive measurement method for the noninvasive and longitudinal evaluation of systolic function, tissue viability and specific metabolic markers in mouse models of myocardial infarction. Here we have described a protocol for performing MRI and PET sequentially, where coregistration is simplified by the transfer of the same bed between systems. This strategy, also adopted by manufacturers of clinical systems11, does not require a combined PET/MRI scanner and can be performed with standard equ...

In order to measure the efficacy of new treatment strategies for myocardial infarction (MI) in preclinical studies, the assessment of the acute stage as well as long-term outcome is required1. Methods such as histopathology, intracardiac catheters2, and ex vivo heart models3 are commonly used for preclinical studies in mice. It is impossible, however, to follow up treatment with ex vivo&#160;or highly invasive methods. Noninvasive measurement techniques as in vivo&#160;magnetic resonance imaging (MRI) and positron emission tomography (PET) allow longitudinal experimental designs for disease staging in single subjects. Cine-MRI is used to derive global functional parameters such as left ventricular mass (LVM), ejection fraction (EF) and cardiac output (CO). In addition, after the injection of a gadolinium contrast agent, due to impaired perfusion and washout in the infarction, tissue viability can be assessed with late gadolinium enhancement (LGE) MRI. Complementarily, PET offers a sensitive measure of radiolabeled molecules in order to assess tissue metabolism. The high accuracy of these techniques permits significant reductions in the number of animals required for testing new drugs targeting MI.
The PET and MRI procedures are involved, and without a carefully designed protocol reproducibility is hard to maintain. Procedures established in the clinic for patients require substantial modification for use in mice, due to their considerably faster heart rate and smaller dimensions of the heart4. There is wide variation between individual subjects, both at baseline and in response to induced injury, so a considerable number of mice are needed to establish treatment efficacy.
In this report, we describe our method for sequential PET/MRI imaging of the mouse heart. Both modalities use intravenous contrast agents, which are delivered through the tail vein. MRI consists of standard assessment with Cine-MRI5&#160;with an optimal protocol for LGE as described in our previous work6. The entire MRI procedure lasts 30 min. We have obtained consistent fittings for the beds of our instruments so it is possible to transfer the animal on a platform with the same monitoring and anesthetic delivery apparatus between the machines. The PET scan lasts 45 min with in situ injection once the scan is started. The final step is to measure the parameters from both MRI and PET images following coregistration.

<table border="0" cellpadding="0" cellspacing="0" width="516">
	<colgroup>
		<col />
		<col />
		<col />
		<col />
	</colgroup>
	<tbody>
		<tr height="34">
			<td height="34" style="height:34px;width:111px;">Material name</td>
			<td style="width:91px;">Company</td>
			<td style="width:136px;">Catalogue number</td>
			<td style="width:179px;">Comments</td>
		</tr>
		<tr height="69">
			<td height="69" style="height:69px;width:111px;">Gadovist</td>
			<td style="width:91px;">Bayer Schering Pharma</td>
			<td style="width:136px;">PL 00010/0535</td>
			<td style="width:179px;"></td>
		</tr>
		<tr height="63">
			<td height="63" style="height:63px;width:111px;">FDG</td>
			<td style="width:91px;">IBA Molecular</td>
			<td style="width:136px;"></td>
			<td style="width:179px;"></td>
		</tr>
		<tr height="20">
			<td height="20" style="height:20px;"></td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr height="20">
			<td height="20" style="height:20px;"></td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">Equipment</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr height="43">
			<td height="43" style="height:43px;width:111px;">Material name</td>
			<td style="width:91px;">Company</td>
			<td style="width:136px;">Catalog number</td>
			<td style="width:179px;">Comments</td>
		</tr>
		<tr height="64">
			<td height="64" style="height:64px;width:111px;">Bruker BioSpec 47/40</td>
			<td style="width:91px;">Bruker</td>
			<td style="width:136px;"></td>
			<td style="width:179px;"></td>
		</tr>
		<tr height="67">
			<td height="67" style="height:67px;width:111px;">Bruker mouse bed</td>
			<td style="width:91px;">Bruker</td>
			<td style="width:136px;"></td>
			<td style="width:179px;">This bed includes tubing for anesthesia delivery and scavenging.</td>
		</tr>
		<tr height="64">
			<td height="64" style="height:64px;width:111px;">12 cm diameter birdcage transmitter</td>
			<td style="width:91px;">Bruker</td>
			<td style="width:136px;">T5346</td>
			<td style="width:179px;"></td>
		</tr>
		<tr height="74">
			<td height="74" style="height:74px;width:111px;">2 cm diameter surface coil receiver</td>
			<td style="width:91px;">Bruker</td>
			<td style="width:136px;">T7027</td>
			<td style="width:179px;"></td>
		</tr>
		<tr height="103">
			<td height="103" style="height:103px;width:111px;">Red Dot Neonatal monitoring electrodes</td>
			<td style="width:91px;">3M</td>
			<td style="width:136px;">P/N: 2330</td>
			<td style="width:179px;"></td>
		</tr>
		<tr height="98">
			<td height="98" style="height:98px;width:111px;">Monitoring equipment</td>
			<td style="width:91px;">SA Systems</td>
			<td style="width:136px;"></td>
			<td style="width:179px;">The monitoring kit includes respiratory pillow and rectal probe for temperature measurements.</td>
		</tr>
		<tr height="64">
			<td height="64" style="height:64px;width:111px;">Anesthesia equipment</td>
			<td style="width:91px;">General Anesthetic Services</td>
			<td style="width:136px;"></td>
			<td style="width:179px;"></td>
		</tr>
		<tr height="64">
			<td height="64" style="height:64px;width:111px;">Induction box</td>
			<td style="width:91px;">Vet Tech Solutions LTD</td>
			<td style="width:136px;"></td>
			<td style="width:179px;"></td>
		</tr>
		<tr height="160">
			<td height="160" style="height:160px;width:111px;">Cambridge split-magnet PET/MRI scanner</td>
			<td style="width:91px;">University of Cambridge</td>
			<td style="width:136px;"></td>
			<td style="width:179px;">A custom built PET/MRI scanner22 was used to perform the PET, its PET performance similar to an F120 micropet scanner23</td>
		</tr>
		<tr height="64">
			<td height="64" style="height:64px;width:111px;">Segment software</td>
			<td style="width:91px;">Medviso, Lund University</td>
			<td style="width:136px;"></td>
			<td style="width:179px;">Freely available</td>
		</tr>
		<tr height="43">
			<td height="43" style="height:43px;width:111px;">SPM-mouse</td>
			<td style="width:91px;">University of Cambridge</td>
			<td style="width:136px;"></td>
			<td style="width:179px;">Freely available</td>
		</tr>
	</tbody>
</table>

mri and pet in mouse models of myocardial infarction

Myocardial infarction is one of the leading causes of death in the Western world. The similarity of the mouse heart to the human heart has made it an ideal model for testing novel therapeutic strategies.
In vivo magnetic resonance imaging (MRI) gives excellent views of the heart noninvasively with clear anatomical detail, which can be used for accurate functional assessment. Contrast agents can provide basic measures of tissue viability but these are nonspecific. Positron emission tomography (PET) is a complementary technique that is highly specific for molecular imaging, but lacks the anatomical detail of MRI. Used together, these techniques offer a sensitive, specific and quantitative tool for the assessment of the heart in disease and recovery following treatment.
In this paper we explain how these methods are carried out in mouse models of acute myocardial infarction. The procedures described here were designed for the assessment of putative protective drug treatments. We used MRI to measure systolic function and infarct size with late gadolinium enhancement, and PET with fluorodeoxyglucose (FDG) to assess metabolic function in the infarcted region. The paper focuses on practical aspects such as slice planning, accurate gating, drug delivery, segmentation of images, and multimodal coregistration. The methods presented here achieve good repeatability and accuracy maintaining a high throughput.

One of the advantages of using MRI is that a longitudinal design can be used in order to stage disease. This is especially important when evaluating novel compounds, as the time course of effect may not be known. Variations in heart volumes due to the disease progression in the same animal are shown in Figure 4. The figure clearly shows the effects of remodeling post myocardial infarction.
Correct slice geometry is crucial for the success of a cardiac MRI experiment. Represent...

Watch this Scientific Journal Video about MRI and PET in Mouse Models of Myocardial Infarction at JoVE.com

MRI and PET in Mouse Models of Myocardial Infarction

We describe how to perform MRI and PET imaging of the mouse heart. The protocol is tailored to assess treatment efficacy in models of myocardial infarction and heart failure.

Myocardial infarction is one of the leading causes of death in the Western world. The similarity of the mouse heart to the human heart has made it an ...

mri-and-pet-in-mouse-models-of-myocardial-infarction

Research

JoVE Journal

Medicine

11.6K visualizações.  Unversity of Cambridge. We describe how to perform MRI and PET imaging of the mouse heart. The protocol is tailored to assess treatment efficacy in models of myocardial infarction and heart failure.