Name: a pre-clinical porcine model of orthotopic heart transplantation
Uploaded: 2019-04-27T14:30:00
Description: Watch this Scientific Journal Video about A Pre-Clinical Porcine Model of Orthotopic Heart Transplantation at JoVE.com

The authors have no acknowledgements.

The institutional animal care committee approved all experimental protocols and animals were treated following the &#8220;Guide for the Care and Use of Laboratory Animals&#8221; prepared by the Institute of Laboratory Animal Resources, National Research Council, 1996. Male Yorkshire pigs (40&#8211;50 kg) were used to perform the orthotopic heart transplants (animal size can vary according to the investigators discretion and experimental goals).
1. Donor Procedure
<ol>
	<li>Anesthetic inducti...

<ol>
	<li>Lund, L. H., Edwards, L. B., 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+Registry+of+the+International+Society+for+Heart+and+Lung+Transplantation:+Thirty-third+Adult+Heart+Transplantation+Report-2016;+Focus+Theme:+Primary+Diagnostic+Indications+for+Transplant.">The Registry of the International Society for Heart and Lung Transplantation: Thirty-third Adult Heart Transplantation Report-2016; Focus Theme: Primary Diagnostic Indications for Transplant.</a> The Journal of Heart and Lung Transplantation. 35 (10), 1158-1169 (2016).</li><li>Lund, L. H., Edwards, L. B., 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+Registry+of+the+International+Society+for+Heart+and+Lung+Transplantation_+Thirty-first+Official+Adult+Heart+Transplant+Report-2014;+Focus+Theme_+Retransplantation.">The Registry of the International Society for Heart and Lung Transplantation_ Thirty-first Official Adult Heart Transplant Report-2014; Focus Theme_ Retransplantation.</a> The. Journal of Heart and Lung Transplantation. 33 (10), 996-1008 (2014).</li><li>Cos&#237;o Carmena, M. D. G., G&#243;mez Bueno, M., 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=Primary+graft+failure+after+heart+transplantation:+characteristics+in+a+contemporary+cohort+and+performance+of+the+RADIAL+risk+score.">Primary graft failure after heart transplantation: characteristics in a contemporary cohort and performance of the RADIAL risk score.</a> The Journal of Heart and Lung Transplantation. 32 (12), 1187-1195 (2013).</li><li>Fedak, P. W. M., Rao, V., 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=Combined+endothelial+and+myocardial+protection+by+endothelin+antagonism+enhances+transplant+allograft+preservation.">Combined endothelial and myocardial protection by endothelin antagonism enhances transplant allograft preservation.</a> The Journal of Thoracic and Cardiovascular Surgery. 129 (2), 407-415 (2005).</li><li>Ramzy, D., Rao, V., 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=Cardiac+allograft+preservation+using+donor-shed+blood+supplemented+with+L-arginine.">Cardiac allograft preservation using donor-shed blood supplemented with L-arginine.</a> The Journal of Heart and Lung Transplantation. 24 (10), 1665-1672 (2005).</li><li>Rao, V., Feindel, C. M., Weisel, R. D., Boylen, P., Cohen, G. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Donor+blood+perfusion+improves+myocardial+recovery+after+heart+transplantation.">Donor blood perfusion improves myocardial recovery after heart transplantation.</a> Journal of Heart and Lung Transplantation. 16 (6), 667-673 (1997).</li><li>Wicomb, W. N., Cooper, D. K., Barnard, C. N. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Twenty-four-hour+preservation+of+the+pig+heart+by+a+portable+hypothermic+perfusion+system.">Twenty-four-hour preservation of the pig heart by a portable hypothermic perfusion system.</a> Transplantation. 34 (5), 246-250 (1982).</li><li>Badiwala, M. V., Ramzy, 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=Donor+pretreatment+with+hypertonic+saline+attenuates+primary+allograft+dysfunction:+a+pilot+study+in+a+porcine+model.">Donor pretreatment with hypertonic saline attenuates primary allograft dysfunction: a pilot study in a porcine model.</a> Circulation. 120, 206-214 (2009).</li><li>Ribeiro, R. V. P., Badiwala, M. V., Ramzy, D., Tumiati, L. C., Rao, V. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Recipient+Hypertonic+Saline+Infusion+Prevents+Cardiac+Allograft+Dysfunction.">Recipient Hypertonic Saline Infusion Prevents Cardiac Allograft Dysfunction.</a> The Journal of Thoracic and Cardiovascular Surgery. , (2018).</li><li>Townsend, D. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Measuring+Pressure+Volume+Loops+in+the+Mouse.">Measuring Pressure Volume Loops in the Mouse.</a> Journal of Visualized Experiments. (111), e53810 (2016).</li><li>Ratschiller, T., Deutsch, M. -. A., 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=Heterotopic+Cervical+Heart+Transplantation+in+Mice.">Heterotopic Cervical Heart Transplantation in Mice.</a> Journal of Visualized Experiments. (102), e52907 (2015).</li><li>Fukunaga, N., Bissoondath, V., Rao, V. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Submandibular+Gland-preserving+Technique+for+Heterotopic+Cervical+Heart+Transplantation+in+Mice.">Submandibular Gland-preserving Technique for Heterotopic Cervical Heart Transplantation in Mice.</a> Transplantation. 1, (2018).</li><li>Gong, W. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Mouse+Heterotopic+Abdominal+Heart+Transplant+Model.">Mouse Heterotopic Abdominal Heart Transplant Model.</a> Rodent Transplant Medicine. , 107-118 (2014).</li><li>Robinson, N., Souslian, L., Gallegos, R. P., Rivard, A. L., Dalmasso, A. P., Bianco, R. W. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Animal+Models+for+Cardiac+Research.">Animal Models for Cardiac Research.</a> Handbook of Cardiac Anatomy, Physiology, and Devices. , 469-491 (2015).</li><li>Bianco, R. W., Gallegos, R. P., Rivard, A. L., Voight, J., Dalmasso, A. P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Animal+Models+for+Cardiac+Research.">Animal Models for Cardiac Research.</a> Handbook of Cardiac Anatomy, Physiology, and Devices. , 393-410 (2009).</li></ol>

This manuscript describes a large-animal pre-clinical model of orthotopic heart transplantation. Various small animal models of heterotopic heart transplantation have been successfully used to study the effects of novel treatments to improve organ preservation and decrease ischemia-reperfusion injury11,12,13. Additionally, small animal models permit survival models and long-term follow-up to investigate the development of reject...

Fifty-years following the first successful report, cardiac transplantation remains the gold-standard treatment for eligible patients with advanced heart failure1. Although ischemic times of up to four hours are tolerated adequately, an ischemic time of greater than six hours is associated with inferior outcomes2. Primary graft dysfunction remains the principal cause of early morbidity and mortality following transplantation2,3. The causes of primary graft dysfunction are multifactorial and include the use of marginal organs, recipient pulmonary vascular disease, hyperacute rejection, and ischemia-reperfusion injury sustained at the time of transplantation3.
Multiple studies have investigated novel methods for donor heart preservation to reduce the incidence of primary graft dysfunction4,5,6,7. It is common practice to assess new techniques and treatments in murine models of ischemia-reperfusion injury or heterotopic heart transplantation. Additionally, small animal models permit survival models and long-term follow-up to investigate the development of rejection and cardiac allograft vasculopathy11,12,13. However, most of these strategies fail initial clinical pilot trials or never reach this stage. It is of paramount importance to evaluate new therapies in a clinically relevant large-animal model for efficient and reliable translation of basic studies&#39;&#160;findings.
The porcine heart is often considered the most anatomically similar to the human heart when using large-animal models. As such, it is an ideal platform to perform cardiac surgical research. However, there are several important factors to consider when using a porcine model. First, the tissue is typically described as fragile and friable, especially in the right atrium and the pulmonary artery, being prone to tears14. Additionally, the pig heart is considered sensitive to manipulation and prone to arrhythmias, which is why one should routinely administer an anti-arrythmetic to each animal at the beginning of the experiment. An important anatomical difference between the porcine model and clinical heart transplantation is the left hemiazygous vein in the swine which drains directly into the coronary sinus. This has to be ligated during the recipient procedure to avoid continuous bleeding. Finally, the porcine model is very sensitive to ischemia, but it is still appropriate for acute studies in heart transplantation15.
This manuscript describes a pre-clinical large-animal (porcine) model of orthotopic heart transplantation that has been firmly established and utilized to investigate novel cardioprotective strategies5,6,8,9.

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a pre-clinical porcine model of orthotopic heart transplantation

Fifty-years following the first successful report, cardiac transplantation remains the gold-standard treatment for eligible patients with advanced heart failure. Multiple small-animal models of heart transplantation have been used to study the acute and long-term effects of novel therapies. However, few are tested and demonstrated success in clinical trials. It is of critical importance to evaluate new therapies in a clinically relevant large-animal model for efficient and reliable translation of basic studies&#39;&#160;findings. Here, we describe a pre-clinical large-animal (porcine) model of orthotopic heart transplantation that has been firmly established and previously used to investigate novel cardioprotective strategies. This procedure focuses on acute ischemia-reperfusion injury and is a reliable method to investigate novel interventions which have been tested and validated in smaller experimental models, such as the murine model. We demonstrate its usefulness in assessing cardiac performance during the early post-transplantation period and other potential possibilities enabled by the model.

This pre-clinical model has been used successfully since 19945,6,8,9. Table 1 demonstrates representative results from pressure-volume relationships and echocardiographic parameters taken at baseline, and 3 h post-transplantation in a set of 5 experiments. Although we see a decrease in myocadial contractility following transplantation, this was not statistically significant.</p...

Watch this Scientific Journal Video about A Pre-Clinical Porcine Model of Orthotopic Heart Transplantation at JoVE.com

A Pre-Clinical Porcine Model of Orthotopic Heart Transplantation

Here, we describe a pre-clinical large-animal (porcine) model of orthotopic heart transplantation that has been firmly established and utilized to investigate novel cardioprotective strategies.

Fifty-years following the first successful report, cardiac transplantation remains the gold-standard treatment for eligible patients with advanced heart ...

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