This work was funded by grants from the National Health and Medical Research Council APP1194139/APP1126276 (JC), National Stem Cell Foundation of Australia and New South Wales Government Office of Health and Medical Research (JC). DS was supported by the Royal Australasian College of Physicians, the Institute of Clinical Pathology and Medical Research, and the Australian Government Research Training Program. TD was supported by the Institute of Clinical Pathology and Medical Research, Penfolds Family Scholarship, National Health and Medical Research Council (APP2002783) and the National Heart Foundation of Australia (104615).

<ol>
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The authors have nothing to disclose.

Transepicardial intramyocardial injection 
This procedure has the benefit of direct cardiac visualization and has been demonstrated to provide greater local retention of therapeutics than systemic administration methods9,10,14. However, thoracotomies are invasive, require considerable technical skill, and present a greater risk of morbidity and mortality than other methods discussed10,15. Knowledge of the critical and precarious stages of the procedure can assist in the mediation of this increased risk.
Great care must be exercised upon manipulating the heart to expose the cardiac apex due to the high risk of arrhythmia and associated hemodynamic compromise. Continuous invasive blood pressure monitoring and electrocardiography allow for rapid identification of hypotension or unstable arrhythmias, facilitating prompt intervention and correction. Transient hypotension can generally be treated with metaraminol boluses. Sustained hypotension may be temporized by reducing inhalant anaesthetic (careful monitoring of anaesthetic depth) and commencing a vasopressor infusion, while concurrently determining the cause of altered hemodynamics. Unstable arrhythmias, such as ventricular tachycardia or ventricular fibrillation, can be treated by electrical cardioversion with or without intravenous antiarrhythmics.
Equally important for animal survival is the successful removal of free gas from the pleural cavity before closing the chest. Failure to do so can culminate in developing a pneumothorax, leaving the animal at great risk of respiratory compromise and death once disconnected from the mechanical ventilator at recovery. Positive airway pressure must be maintained for at least 30 s until bubbling is no longer observed. The silicone tubing is promptly removed upon the cessation of bubbling, and the thorax is then rapidly closed. It is also possible to surgically place a thoracostomy tube at closure, allowing manual air and inflammatory fluid removal over the next 24-72 h. This, however, is difficult to keep clean and intact, especially if animals are housed together. Damage or contamination of the tube can lead to pyothorax, pneumothorax, or sepsis. In our experience, inserting a temporary chest drain is not required if free gas is adequately removed prior to chest closure.
Percutaneous transendocardial intramyocardial injection 
This method of therapeutic administration has the benefit of allowing for local tissue delivery with lower risk due to its less invasive nature compared with a surgical approach10,14. This technique is already used in large animal studies, with both fluoroscopy and electromechanical mapping as a guide in the absence of direct visualization10,16,17.
Given the heart isn&#39;t under direct vision, it is prudent for the proceduralist to use orthogonal fluoroscopic views when selecting an injection site. Furthermore, the injection of diluted iodine contrast before and delivery of the therapeutic is extremely valuable in confirming myocardial contact. Appropriate contact can be confirmed by observing a characteristic &#39;myocardial blush&#39;, which may be one of the only markers of injection success prior to tissue harvest. Due to the risk of chamber perforation, the myocardial wall thickness at the selected injection site is also recommended to be greater than 9 mm14,16.
Jugular venous osmotic minipump 
The osmotic minipump is a popular device commonly employed in small animal studies. There has been increasing interest in using this device in large animal models7,18,19, given its unique advantage of administering a therapeutic agent at a consistent rate over a set time period. A possible limitation of this method is the inability to alter or stop infusion rates of the drug without replacing or removing the pump. This should be considered before trialing therapy in this manner.
This study demonstrated that this method could be performed with a high success rate in swine, with low morbidity and mortality. It must be noted that many vital structures are adjacent to the surgical site, including lymph nodes, the thymus, and the carotid artery. Adherence to the method, and consultation of anatomical texts20, are strongly recommended to prevent inadvertent damage to any of these structures. The most concerning complication of this method is hemorrhagic shock due to inadvertent injury to the jugular vein or a surrounding structure. It is therefore critical that the soft tissue surrounding the jugular vein is carefully removed. Failure to properly complete this step can lead to difficulty in placing the minipump tubing or controlling inadvertent bleeding.
This article has described three methods for the delivery of cardioactive therapeutics. Despite the reported success of each technique, there are inherent limitations to be considered. Invasive procedures (transepicardial injection) allow for increased accuracy of therapeutic delivery; however, they bring a greater risk of potentially fatal complications. Furthermore, invasive delivery has a greater requirement for technical skills to minimize the risk of complications. Similarly, fluoroscopic-guided, transendocardial injection requires a degree of technical skill for catheterization and manipulation of hardware. If this method is performed improperly, injection failure and fatal complications are possible.
The direct injection methods described allow for the one-off administration of a therapeutic into the target tissue. The jugular venous osmotic minipump allows for the systemic administration of a therapeutic over a 7 day period. Comparatively, this method is simpler and associated with less risk, however, it relies on a systemic therapeutic finding its way to the myocardium. Additionally, once the pump is in place, it is impossible to discontinue administration or alter the dose rate without re-anaesthetizing the animal and removing the pump.
All methods described in this article were performed on animals on the day or 2 weeks after myocardial infarction. Therefore, this work cannot report the success of mentioned methods in healthy animals or animals subjected to an alternative cardiac pathology. Finally, the pharmacology and biotechnology of any intended agent are to be carefully considered, as this will be inherently linked to the efficacy of the chosen delivery route. A detailed discussion of this is beyond the scope of this manuscript.
Comprehensive depictions of preclinical methods benefit animal welfare and the wider scientific community. The resultant enhanced reproducibility of procedures and results leads to fewer animal health complications, reduced number of animals required to produce significant results, and greater confidence in experimental outcomes21,22. Three methods of administration of novel therapeutics are described in this article for the treatment of myocardial infarction in a porcine model. By detailing the techniques used and articulating the benefits and risks of each, it is anticipated that researchers will be able to comfortably create consistent and reliable preclinical models that suit their research goals.

Coronary artery disease (CAD) and associated ST-elevation myocardial infarction (STEMI) are the preeminent causes of death worldwide. In the past two decades, great progress has been made in reducing in-hospital mortality of patients presenting with STEMI, through the advent of percutaneous coronary intervention, fibrinolytic therapies, and standardization of treatment algorithms to ensure that reperfusion is achieved in a timely manner1,2,3. Despite this, the morbidity associated with STEMI remains a significant burden, thus creating a great need for developing novel cardioprotective and regenerative therapies2,3. An essential component of therapeutic development is the determination of how a novel therapy is to be administered4. The safety, efficacy, and feasibility of each method need to be matched with the characteristics of the therapy itself.
Physiologically relevant large animal models are critical in assessing these attributes of various therapeutic delivery strategies5. Due to their similarities to humans in cardiovascular physiology, coronary vascular anatomy, and heart weight to body weight ratio, swine is one of the preferred species in the preclinical evaluation of new therapies for myocardial infarction6. We have previously used a porcine STEMI model to demonstrate the reparative capacity of a recombinant protein therapy7, and continue to investigate novel pharmacologic, cellular, and genetic therapies using this model. Here, three techniques of therapeutic administration used in swine models after infarct creation are described: thoracotomy and transepicardial injection, percutaneous transendocardial injection, and jugular venous osmotic minipump implantation. The first two methods enable local tissue delivery, reducing required dosages, off-target effects, and hepatic first-pass metabolism8,9,10. The osmotic minipump allows continuous delivery of a drug with a short half-life, negating reliance on an infusion pump and patent intravenous cannula, both of which are challenging to institute in large animal models.
By describing these techniques, it is hoped that this article can aid translational scientists in investigating novel cardioprotective or regenerative agents following myocardial infarction in large animal models.

<table><tbody><tr><td>&lt;strong&gt;Central line placement&lt;/strong&gt;</td><td></td><td></td><td></td></tr><tr><td>2-0 sutures</td><td>Ethicon</td><td>JJ9220</td><td></td></tr><tr><td>Arrow&#039; Paediatric Two-Lumen Central Venous Catheterisation Set with Blue FlexTip Catheter (contains 18G cook needle and 0.035&quot; J-tip wire)</td><td>Teleflex</td><td>CS-14502</td><td>Central Line</td></tr><tr><td>Green Fluorsence Protein (GFP)</td><td>Abcam</td><td>ab13970</td><td>1:100 dilution ratio</td></tr><tr><td>&lt;strong&gt;Histology antibodies&lt;/strong&gt;</td><td></td><td></td><td></td></tr><tr><td>Ku80</td><td>Cell Signalling Technology</td><td>C48E7</td><td>1:500 dilution ratio</td></tr><tr><td>No. 11 scalpel</td><td>Swann-Morton</td><td>203</td><td></td></tr><tr><td>Sparq&#039; Ultrasound System</td><td>Philips</td><td>MP11742 Medpick</td><td></td></tr><tr><td>Sterile ultrasound probe cover</td><td>Atris</td><td>28041947</td><td></td></tr><tr><td>Swine Jacket with Pocket, size &#039;Medium&#039;</td><td>Lomir Biomedical</td><td>SS J2YJJET</td><td></td></tr><tr><td>&lt;strong&gt;Jugular vein osmotic minipump implantation&lt;/strong&gt;</td><td></td><td></td><td></td></tr><tr><td>Adson Brown Tissue Forceps</td><td>Icon Medical Supplies</td><td>KLINI316012</td><td></td></tr><tr><td>Bellucci Self-Retaining Retractor</td><td>surgicalinstruments.net.au</td><td>group-24.26.02</td><td>Self retaining tissue retractor</td></tr><tr><td>Electrosurgical Pencils with &#039;Edge&#039; Coated Electrodes</td><td>Covidien</td><td>E2450H</td><td>Cautery Pencil</td></tr><tr><td>Metzenbaum Scissors</td><td>Icon Medical Supplies</td><td>ARMO3250</td><td></td></tr><tr><td>No. 22 scalpel blade</td><td>Swann-Morton</td><td>208</td><td></td></tr><tr><td>Nylon Suture&amp;nbsp; (2-0, 3-0)</td><td>Ethicon</td><td>D9635, 663G</td><td></td></tr><tr><td>Osmotic Infusion Minipump</td><td>Alzet</td><td>2ML1, 2ML2, 2ML4</td><td></td></tr><tr><td>Vascular Silicone Ties</td><td>Vecmedical</td><td>95001</td><td></td></tr><tr><td>Vicryl suture (5-0)</td><td>Ethicon</td><td>W9982</td><td></td></tr><tr><td>&lt;strong&gt;Percutaneous transedocardial injection&lt;/strong&gt;</td><td></td><td></td><td></td></tr><tr><td>Artis Zee&#039; C-Arm Fluoroscopy&amp;nbsp;</td><td>Siemens&amp;nbsp;</td><td>IR-19-1994</td><td></td></tr><tr><td>CARTO&#039; 3 System&amp;nbsp;&amp;nbsp;</td><td>Biosense Webster</td><td></td><td>Electrophysiological Mapping Software &amp;amp; System</td></tr><tr><td>Cook Access Needle</td><td>Cook Medical</td><td>G07174</td><td>Cannulation needle</td></tr><tr><td>Fast-Cath&#039; Introducer (6 French, 8 French)</td><td>Abbott</td><td>406204, 406142</td><td>Vascular sheath with introducer and guidewire</td></tr><tr><td>Myostar&#039; Injection Catheter</td><td>Biosense Webster</td><td>121117S, 121119S, 1211120S</td><td>Intramyocardial injection catheter</td></tr><tr><td>No.11 scalpel</td><td>Swann-Morton</td><td>203</td><td></td></tr><tr><td>Omnipaque&#039; Iohexol Contrast</td><td>GE Healthcare</td><td>AUST R 39861&amp;nbsp;</td><td>Iodinated contrast agent</td></tr><tr><td>Sparq&#039; Ultrasound System</td><td>Philips</td><td>MP11742 Medpick</td><td></td></tr><tr><td>&lt;strong&gt;Sedation &amp;amp; general anaesthesia&lt;/strong&gt;</td><td></td><td></td><td></td></tr><tr><td>Compound Sodium Lactate Hartmann&#039;s Solution</td><td>Free flex</td><td>894451</td><td></td></tr><tr><td>Fentanyl 50 mcg/mL</td><td>Pfizer</td><td>AUST R 107027.</td><td>Intravenous anaesthesia and analgesia</td></tr><tr><td>Forthane&#039; Isoflurane</td><td>Abbott</td><td>AUST R 29656&amp;nbsp;</td><td>Inhalant anaesthetic</td></tr><tr><td>GE Aestiva 5 Anaesthesia Machine&amp;nbsp;</td><td>Datex Ohmeda</td><td>17002-9, 17002A9 Avante Health Solutions</td><td>Anaesthetic Machine&amp;nbsp;</td></tr><tr><td>Hypnovel&#039; Midazolam 5 mg/mL</td><td>Roche</td><td>AUST R 13726</td><td>Sedative</td></tr><tr><td>Intravenous cannula</td><td>BD Angiocath</td><td>381137</td><td>20 gauge cannula</td></tr><tr><td>Ketamil&#039; Ketamine 10 mg/mL</td><td>Ilium</td><td>APVMA number: 51188c&amp;nbsp;</td><td>Sedative</td></tr><tr><td>Laryngoscope</td><td>Miller</td><td>VDI-6205</td><td></td></tr><tr><td>Medetomidine 1 mg/mL</td><td>Ilium</td><td>APVMA number 64251; ACVM number A10488&amp;nbsp;</td><td>Sedative</td></tr><tr><td>Metaraminol 10 mg/mL</td><td>Phebra</td><td>AUST R 284784</td><td>Short-acting vasopressor</td></tr><tr><td>Methadone 10 mg/mL</td><td>Ilium</td><td>APVMA number: 63712&amp;nbsp;</td><td>Sedative, Restricted drug</td></tr><tr><td>Onsetron&#039; Ondansetron 2 mg/mL</td><td>Accord Healthcare</td><td>AUST R 205593&amp;nbsp;</td><td>Anti-emetic</td></tr><tr><td>Propofol-Lipuro&#039; Propofol 10 mg/mL</td><td>Braun</td><td>AUST R 142906&amp;nbsp;</td><td>Intravenous anaesthetic</td></tr><tr><td>Pulse Oximeter&amp;nbsp;</td><td>Meditech</td><td>GVPMT-M3S</td><td>Portable pulse oximeter</td></tr><tr><td>Shiley&#039; Cuffed Basic Endotracheal Tube (Size 5.5 &amp;amp; 6.0)</td><td>Medtronic</td><td>86108-, 86109-</td><td></td></tr><tr><td>Shiley&#039; Intubating Stylet, 10 Fr</td><td>Medtronic</td><td>85864</td><td></td></tr><tr><td>Sodium Chloride 0.9%</td><td>Free flex</td><td>FAH1322</td><td></td></tr><tr><td>&lt;strong&gt;Thoracotomy and epicardial Cell Injection&lt;/strong&gt;</td><td></td><td></td><td></td></tr><tr><td>27 G Insulin needle</td><td>Terumo</td><td>51907</td><td></td></tr><tr><td>Adson Brown Tissue Forceps</td><td>Icon Medical Supplies</td><td>KLINI316012</td><td></td></tr><tr><td>CARTO&#039; 3 System&amp;nbsp;&amp;nbsp;</td><td>Biosense Webster</td><td></td><td>Electrophysiological Mapping Software &amp;amp; System</td></tr><tr><td>Cefazolin 1 g Vial</td><td>AFT Pharmaceuticals</td><td>9421900137367 CH2</td><td>Antibiotic Prophylaxis&amp;nbsp;</td></tr><tr><td>Chest drainage tube</td><td>SurgiVet</td><td>SKU-336</td><td></td></tr><tr><td>Cook Access Needle</td><td>Cook Medical</td><td>G07174</td><td>Cannulation needle</td></tr><tr><td>Cooley Sternotomy Retractor Paediatric</td><td>Millennium Surgical</td><td>9-61287</td><td></td></tr><tr><td>Durogesic&#039; 100 mcg/h Fentanyl Patch</td><td>Janssen</td><td>AUST R 112371&amp;nbsp;</td><td>Postoperative analgesia</td></tr><tr><td>Electrosurgical Pencils with &#039;Edge&#039; Coated Electrodes</td><td>Covidien</td><td>E2450H</td><td>Cautery Pencil</td></tr><tr><td>Electrosurgical Pencils with &#039;Edge&#039; Coated Electrodes</td><td>Covidien</td><td>E2450H</td><td>Cautery Pencil</td></tr><tr><td>Fast-Cath&#039; Introducer (6 French, 8 French)</td><td>Abbott</td><td>406204, 406142</td><td>Vascular sheath with introducer and guidewire</td></tr><tr><td>Lignocaine 20 mg/mL</td><td>Pfizer</td><td>AUST R 49296, AUST R 49297, AUST R 49293 and AUST R 49295.</td><td>Local anaesthesia, anti-arrhythmic</td></tr><tr><td>Marcaine&#039; Bupivacaine 0.5%</td><td>Pfizer</td><td>AUST R 48328&amp;nbsp;</td><td>Local anaesthesia.&amp;nbsp;</td></tr><tr><td>Metzenbaum Scissors</td><td>Icon Medical Supplies</td><td>ARMO3250</td><td></td></tr><tr><td>No. 22 scalpel</td><td>Swann-Morton</td><td>208</td><td></td></tr><tr><td>Nylon Suture&amp;nbsp; (2-0, 3-0)</td><td>Ethicon</td><td>D9635, JJ76264</td><td></td></tr><tr><td>Size 1 PDS suture</td><td>Ethicon</td><td>JJ75414</td><td></td></tr><tr><td>Sparq&#039; Ultrasound System</td><td>Philips</td><td>MP11742 Medpick</td><td></td></tr><tr><td>Sterile gauze</td><td>Kerlix</td><td>KE5072</td><td></td></tr><tr><td>Sterile laparotomy sponges</td><td>Propax</td><td>2907950</td><td></td></tr><tr><td>Thermocool Smartouch&#039; Catheter</td><td>Biosense Webster</td><td>D133601, D133602, D133603</td><td>Epicardial Mapping Catheter</td></tr></tbody></table>

delivery of cardioactive therapeutics in a porcine myocardial infarction model

Myocardial infarction is one of the leading causes of death and disability worldwide, and there is an urgent need for novel cardioprotective or regenerative strategies. An essential component of drug development is determining how a novel therapeutic is to be administered. Physiologically relevant large animal models are of critical importance in assessing the feasibility and efficacy of various therapeutic delivery strategies. Due to their similarities to humans in cardiovascular physiology, coronary vascular anatomy, and heart weight to body weight ratio, swine is one of the preferred species in the preclinical evaluation of new therapies for myocardial infarction. The present protocol describes three methods of administering cardioactive therapeutic agents in a porcine model. After percutaneously induced myocardial infarction, female landrace swine received treatment with novel agents through either: (1) thoracotomy and transepicardial injection, (2) catheter-based transendocardial injection, or (3) intravenous infusion via jugular vein osmotic minipump. The procedures employed for each technique are reproducible, resulting in reliable cardioactive drug delivery. These models can be easily adapted to suit individual study designs, and each of these delivery techniques can be used to investigate a variety of possible interventions. Therefore, these methods are a useful tool for translational scientists pursuing novel biological approaches in cardiac repair following myocardial infarction.

Thoracotomy and epicardial cell injection 
Of the 29 animals that underwent thoracotomy and epicardial injection, 26 survived. Histological analysis confirmed the engraftment of human cells delivered by this method in all surviving animals (Figure 1E). One animal experienced fatal arrhythmias during cell injection and could not be resuscitated. Another experienced pulseless electrical activity during closure and prolonged application of positive pressure to the airways and was unable to be recovered. A third animal both vomited and went into respiratory arrest upon extubation. This animal was unable to be resuscitated.
Two animals experienced major complications but were able to be recovered. One animal developed ventricular fibrillation during intramyocardial injection and was able to be resuscitated with internal defibrillation paddles and cardiac massage. The second animal vomited upon extubation and had a brief respiratory arrest but was able to be rapidly re-intubated and recovered well. All of these events occurred during early experiments, with reduced adverse events as team experience with the protocol increased (Table 1).
Jugular vein osmotic minipump implantation 
No reported mortality or major complications were associated with jugular osmotic minipump implantation. Most of the seven animals experienced mild swelling at the surgical site within the first 24 h, which resolved without intervention. ELISA performed on serum on day 3 post-pump implantation demonstrated the efficacy of the pump, achieving a significant blood concentration of platelet-derived growth factor-AB human (PDGF-AB) compared to controls7 (Figure 2E).
Percutaneous transendocardial injection 
A total of 22 animals received endocardial injections. Of these injections, 17 were considered &#39;successful&#39;, determined by fluorescence or ink staining observed in the target tissue at post-mortem (Figure 3B). There were no mortalities associated with this procedure. One animal developed a small volume pericardial effusion from right ventricular perforation. This was self-limiting and did not result in cardiovascular compromise. This same animal did die; however, this was from an unrelated additional procedure after the intramyocardial injection.
<img alt="Figure 1" class="xfigimg" src="/files/ftp_upload/64177/64177fig01.jpg" /> 
Figure 1:&#160;Transepicardial cardiomyocyte injection allows for direct cardiac visualization and achieves a high proportion of viable cells delivered to the myocardium. (A) The cardiac apex is exposed through a moistened gauze sling guided under the base of the heart. (B) An epicardial mapping catheter delineates scar and border zones and annotates injection sites. (C) A 31 G needle is used to transepicardially inject cells into the myocardium. (D) Epicardial voltage map with injection site annotation. Purple: normal voltage, healthy myocardium; Red: abnormal voltage, diseased myocardium; Grey dots: injection sites. Following sacrifice, the heart is collected and formalin-fixed for downstream histological assessment. In (E), engrafted human cells are detected by immunostaining for the human anti-nuclear antibody, Ku80, and an anti-GFP antibody. Scale bar = 200 &#181;m. <a href="https://www.jove.com/files/ftp_upload/64177/64177fig01large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 2" class="xfigimg" src="/files/ftp_upload/64177/64177fig02.jpg" /> 
Figure 2: Jugular vein minipump insertion provides a safe and reliable method of PDGF delivery over a 7 day time period. (A) The right jugular vein is exposed, and soft tissue is cleared away from the vessel. (B) Vascular ties occlude the vessel while a 14 G needle is used to make a puncture, through which the minipump tubing is threaded. (C) The minipump tubing is advanced into the vein, and the minipump body is secured to adjacent soft tissue. (D) The minipump body and tubing prior to implantation. (E) The serum concentration of the recombinant protein delivered via the minipump and the PDGF-AB was measured using ELISA from each animal on day 3 post-implantation. Animals receiving PDGF-AB were demonstrated to have a significantly higher blood concentration of PDGF-AB than control animals, confirming the efficacy of the osmotic minipump administration method. **denotes a statistically significant difference between groups (p = 0.005, Mann-Whitney U test) <a href="https://www.jove.com/files/ftp_upload/64177/64177fig02large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 3" class="xfigimg" src="/files/ftp_upload/64177/64177fig03.jpg" /> 
Figure 3:&#160;Transendocardial intramyocardial injection allows for a minimally-invasive therapeutics administration method. (A) A right anterior oblique fluoroscopic image demonstrating the injection catheter (white arrow) administering contrast material (yellow arrow) into the myocardium. The contrast material injection both precedes and follows therapeutic injection so that needle placement within the myocardium can be confirmed. (B) The injected vector expressed green fluorescent protein (GFP) so that injected material would fluoresce upon tissue collection, thus confirming the success of the injection. <a href="https://www.jove.com/files/ftp_upload/64177/64177fig03large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<table border="1" fo:keep-together.within-page="1" fo:keep-with-next.within-page="always">
	<tbody>
		<tr>
			<td></td>
			<td>Transepicardial Injection (n = 29)</td>
			<td>Transendocardial Injection (n = 22)</td>
			<td>Osmotic Minipump (n = 7)</td>
		</tr>
		<tr>
			<td>Mortality&#160;</td>
			<td>3</td>
			<td>0</td>
			<td>0</td>
		</tr>
		<tr>
			<td>Post-operative vomiting and respiratory arrest</td>
			<td>1</td>
			<td>0</td>
			<td>0</td>
		</tr>
		<tr>
			<td>Ventricular Fibrillation during injection</td>
			<td>1</td>
			<td>0</td>
			<td>0</td>
		</tr>
		<tr>
			<td>Pulseless electrical activity during chest closure</td>
			<td>1</td>
			<td>0</td>
			<td>0</td>
		</tr>
		<tr>
			<td>Morbidity</td>
			<td>0</td>
			<td>1</td>
			<td>0</td>
		</tr>
		<tr>
			<td>Pneumothorax</td>
			<td>0</td>
			<td>0</td>
			<td>0</td>
		</tr>
		<tr>
			<td>Pleural effusion</td>
			<td>0</td>
			<td>0</td>
			<td>0</td>
		</tr>
		<tr>
			<td>Cardiac chamber perforation</td>
			<td>0</td>
			<td>1</td>
			<td>0</td>
		</tr>
		<tr>
			<td>Hemorrhage</td>
			<td>0</td>
			<td>0</td>
			<td>0</td>
		</tr>
	</tbody>
</table>
Table 1:&#160;Complications list.

Watch this Scientific Journal Video about Delivery of Cardioactive Therapeutics in a Porcine Myocardial Infarction Model at JoVE.com

Delivery of Cardioactive Therapeutics in a Porcine Myocardial Infarction Model

The present protocol describes three methods of administering cardioactive therapeutic agents in a porcine model. Female landrace swine received treatment through either: (1) thoracotomy and transepicardial injection, (2) catheter-based transendocardial injection, or (3) intravenous infusion via jugular vein osmotic minipump.

Myocardial infarction is one of the leading causes of death and disability worldwide, and there is an urgent need for novel cardioprotective or ...

delivery-cardioactive-therapeutics-porcine-myocardial-infarction

Research

JoVE Journal

Medicine

1.2K Views.  The University of Sydney. Dit protocol beschrijft drie methoden voor het toedienen van cardioactieve therapeutische middelen in een varkensmodel. Vrouwelijke landrasvarkens werden behandeld door middel van: (1) thoracotomie en transepicardiale injectie, (2) transendocardiale injectie op basis van katheter, of (3) intraveneuze infusie via halsaderosmotische minipomp.

Video: Delivery of Cardioactive Therapeutics in a Porcine Myocardial Infarction Model

Gene Transfer for Ischemic Heart Failure in a Preclinical Model

Various emerging technologies are being developed for patients with heart failure. Well-established preclinical evaluations are necessary to determine their efficacy and safety.
Gene therapy using viral vectors is one of the most promising approaches for treating cardiac diseases. Viral delivery of various different genes by changing the carrier gene has immeasurable therapeutic potential.
In this video, the full process of an animal model of heart failure creation followed by gene transfer is presented using a swine model. First, myocardial infarction is created by occluding the proximal left anterior descending coronary artery. Heart remodeling results in chronic heart failure. Unique to our model is a fairly large scar which truly reflects patients with severe heart failure who require aggressive therapy for positive outcomes. After myocardial infarct creation and development of scar tissue, an intracoronary injection of virus is demonstrated with simultaneous nitroglycerine infusion. Our injection method provides simple and efficient gene transfer with enhanced gene expression. This combination of a myocardial infarct swine model with intracoronary virus delivery has proven to be a consistent and reproducible methodology, which helps not only to test the effect of individual gene, but also compare the efficacy of many genes as therapeutic candidates.

A method of gene transfer for the treatment of ischemic heart failure is described using a swine model of myocardial infarction. Our simple and reproducible method enables us to readily evaluate the efficacy of various gene transfers with a very simple and reproducible way.

Various emerging technologies are being developed for patients with heart failure. Well-established preclinical evaluations are necessary to determine ...

Pluripotent Stem Cell Derived Cardiac Cells for Myocardial Repair

Human induced pluripotent stem cells (hiPSCs) must be fully differentiated into specific cell types before administration, but conventional protocols for differentiating hiPSCs into cardiomyocytes (hiPSC-CMs), endothelial cells (hiPSC-ECs), and smooth muscle cells (SMCs) are often limited by low yield, purity, and/or poor phenotypic stability. Here, we present novel protocols for generating hiPSC-CMs, -ECs, and -SMCs that are substantially more efficient than conventional methods, as well as a method for combining cell injection with a cytokine-containing patch created over the site of administration. The patch improves both the retention of the injected cells, by sealing the needle track to prevent the cells from being squeezed out of the myocardium, and cell survival, by releasing insulin-like growth factor (IGF) over an extended period. In a swine model of myocardial ischemia-reperfusion injury, the rate of engraftment was more than two-fold greater when the cells were administered with the cytokine-containing patch comparing to the cells without patch, and treatment with both the cells and the patch, but not with the cells alone, was associated with significant improvements in cardiac function and infarct size.

We present three novel and more efficient protocols for differentiating human induced pluripotent stem cells into cardiomyocytes, endothelial cells, and smooth muscle cells and a delivery method that improves the engraftment of transplanted cells by combining cell injection with patch-mediated cytokine delivery.

Human induced pluripotent stem cells (hiPSCs) must be fully differentiated into specific cell types before administration, but conventional protocols for ...

Developmental Biology

Myocardial Infarction and Functional Outcome Assessment in Pigs

Introduction of newly discovered cardiovascular therapeutics into first-in-man trials depends on a strictly regulated ethical and legal roadmap. One important prerequisite is a good understanding of all safety and efficacy aspects obtained in a large animal model that validly reflect the human scenario of myocardial infarction (MI). Pigs are widely used in this regard since their cardiac size, hemodynamics, and coronary anatomy are close to that of humans. Here, we present an effective protocol for using the porcine MI model using a closed-chest coronary balloon occlusion of the left anterior descending artery (LAD), followed by reperfusion. This approach is based on 90 min of myocardial ischemia, inducing large left ventricle infarction of the anterior, septal and inferoseptal walls. Furthermore, we present protocols for various measures of outcome that provide a wide range of information on the heart, such as cardiac systolic and diastolic function, hemodynamics, coronary flow velocity, microvascular resistance, and infarct size. This protocol can be easily tailored to meet study specific requirements for the validation of novel cardioregenerative biologics at different stages (i.e. directly after the acute ischemic insult, in the subacute setting or even in the chronic MI once scar formation has been completed). This model therefore provides a useful translational tool to study MI, subsequent adverse remodeling, and the potential of novel cardioregenerative agents.

This protocol describes the porcine myocardial infarction (MI) model using a 90 min closed-chest coronary balloon occlusion of the left anterior descending artery (LAD), followed by reperfusion. Furthermore, the protocol for several outcome parameters, such as cardiac function, hemodynamics, microvascular resistance, and infarct size, are also presented.

Introduction of newly discovered cardiovascular therapeutics into first-in-man trials depends on a strictly regulated ethical and legal roadmap. One ...

Testing the Efficacy of Pharmacological Agents in a Pericardial Target Delivery Model in the Swine

To date, many pharmacological agents used to treat or prevent arrhythmias in open-heart cases create undesired systemic side effects. For example, antiarrhythmic drugs administered intravenously can produce drops in systemic pressure in the already compromised cardiac patient. While performing open-heart procedures, surgeons will often either create a small port or form a pericardial cradle to create suitable fields for operation. This access yields opportunities for target pharmacological delivery (antiarrhythmic or ischemic preconditioning agents) directly to the myocardial tissue without undesired side effects.
We have developed a swine model for testing pharmacological agents for target delivery within the pericardial fluid. While fully anesthetized, each animal was instrumented with a Swan-Ganz catheter as well as left and right ventricle pressure catheters, and pacing leads were placed in the right atrial appendage and the right ventricle. A medial sternotomy was then performed and a pericardial access cradle was created; a plunge pacing lead was placed in the left atrial appendage and a bipolar pacing lead was placed in the left ventricle. Utilizing a programmer and a cardiac mapping system, the refractory period of the atrioventricular node (AVN), atria and ventricles was determined. In addition, atrial fibrillation (AF) induction was produced utilizing a Grass stimulator and time in AF was observed. These measurements were performed prior to treatment, as well as 30 min&#160;and 60 min&#160;after pericardial treatment. Additional time points were added for selected studies. The heart was then cardiopleged and reanimated in a four chamber working mode. Pressure measurements and function were recorded for 1 hr after reanimation. This treatment strategy model allowed us to observe the effects of pharmacological agents that may decrease the incidence of cardiac arrhythmias and/or ischemic damage, during and after open-heart surgery.

We have developed a swine model for the target delivery of pharmacological agents within the pericardial space/fluid. Using this approach, the relative benefits of administered agents on induced atrial fibrillation, relative refractory periods and/or ischemic protection can be investigated.

To date, many pharmacological agents used to treat or prevent arrhythmias in open-heart cases create undesired systemic side effects. For example, ...

Primary Outcome Assessment in a Pig Model of Acute Myocardial Infarction

Mortality after acute myocardial infarction remains substantial and is associated with significant morbidity, like heart failure. Novel therapeutics are therefore required to confine cardiac damage, promote survival and reduce the disease burden of heart failure. Large animal experiments are an essential part in the translational process from experimental to clinical therapies. To optimize clinical translation, robust and representative outcome measures are mandatory. The present manuscript aims to address this need by describing the assessment of three clinically relevant outcome modalities in a pig acute myocardial infarction (AMI) model: infarct size in relation to area at risk (IS/AAR) staining, 3-dimensional transesophageal echocardiography (TEE) and admittance-based pressure-volume (PV) loops. Infarct size is the main determinant driving the transition from AMI to heart failure and can be quantified by IS/AAR staining. Echocardiography is a reliable and robust tool in the assessment of global and regional cardiac function in clinical cardiology. Here, a method for three-dimensional transesophageal echocardiography (3D-TEE) in pigs is provided. Extensive insight into cardiac performance can be obtained by admittance-based pressure-volume (PV) loops, including intrinsic parameters of myocardial function that are pre- and afterload independent. Combined with a clinically feasible experimental study protocol, these outcome measures provide researchers with essential information to determine whether novel therapeutic strategies could yield promising targets for future testing in clinical studies.

Reliable and accurate outcome assessment is the key for translation of preclinical therapies into clinical treatment. The current paper describes how to assess three clinically relevant primary outcome parameters of cardiac performance and damage in a pig acute myocardial infarction model.

Mortality after acute myocardial infarction remains substantial and is associated with significant morbidity, like heart failure. Novel therapeutics are ...

Percutaneous Contrast Echocardiography-guided Intramyocardial Injection and Cell Delivery in a Large Preclinical Model

Cell and gene therapy are exciting and promising strategies for the purpose of cardiac regeneration in the setting of heart failure with reduced ejection fraction (HFrEF). Before they can be considered for use, and implemented in humans, extensive preclinical studies are required in large animal models to evaluate the safety, efficacy, and fate of the injectate (e.g., stem cells) once delivered into the myocardium. Small rodent models offer advantages (e.g., cost effectiveness, amenability for genetic manipulation); however, given inherent limitations of these models, the findings in these rarely translate into the clinic. Conversely, large animal models such as rabbits, have advantages (e.g., similar cardiac electrophysiology compared to humans and other large animals), whilst retaining a good cost-effective balance. Here, we demonstrate how to perform a percutaneous contrast echocardiography-guided intramyocardial injection (IMI) technique, which is minimally invasive, safe, well tolerated, and very effective in the targeted delivery of injectates, including cells, into several locations within the myocardium of a rabbit model. For the implementation of this technique, we also have taken advantage of a widely available clinical echocardiography system. After putting in practice the protocol described here, a researcher with basic ultrasound knowledge will become competent in the performance of this versatile and minimally invasive technique for routine use in experiments, aimed at hypothesis testing of the capabilities of cardiac regenerative therapeutics in the rabbit model. Once competency is achieved, the whole procedure can be performed within 25 min after anaesthetizing the rabbit.

Novel therapeutic strategies in cardiac regenerative medicine require extensive and detailed studies in large preclinical animal models before they can be considered for use in humans. Here, we demonstrate a percutaneous contrast echocardiography-guided intramyocardial injection technique in rabbits, which is valuable for hypothesis testing the efficacy of such novel therapies.

Cell and gene therapy are exciting and promising strategies for the purpose of cardiac regeneration in the setting of heart failure with reduced ejection ...

Improvement of a Closed Chest Porcine Myocardial Infarction Model by Standardization of Tissue and Blood Sampling Procedures

Myocardial ischemia reperfusion (I/R) injury contributes to almost half of the necrotic area after myocardial infarction. To date there is no approved drug to prevent or reduce myocardial I/R injury. The study and understanding of the pathophysiological mechanisms of myocardial I/R injury is essential to develop successful treatments. Large animal experiments are an important step in translational methods. The porcine model of acute myocardial infarction has been established and described by ourselves and others. We aimed to further improve the value of the model by focusing in detail on the sampling techniques for use in future experiments. Furthermore, we emphasize small but important steps that can affect the quality of the final results. To mimic the clinical situation of myocardial I/R injury, a percutaneous coronary intervention (PCI) catheter was inserted into the left anterior descending coronary artery (LAD) of an anesthetized pig. &#176;&#176;&#176;This model mimics acute myocardial infarction and PCI treatment in humans with the possibility of accurately determining the area at risk as well as the necrotic- and viable ischemic tissue. Here the model was used to investigate the effect of a bicyclic peptide inhibitor of FXIIa. The model can also be modified to allow longer reperfusion times to study later effects of myocardial infarction.

Here we demonstrate a protocol to standardize sampling procedures of an established porcine model of acute myocardial infarction in order to increase its translational value in the understanding of the pathophysiology of myocardial ischemia/reperfusion injury and to test novel drug candidates.

Myocardial ischemia reperfusion (I/R) injury contributes to almost half of the necrotic area after myocardial infarction. To date there is no approved ...

Establishing a Swine Model of Post-myocardial Infarction Heart Failure for Stem Cell Treatment

Although advances have been achieved in the treatment of heart failure (HF) following myocardial infarction (MI), HF following MI remains one of the major causes of mortality and morbidity around the world. Cell-based therapies for cardiac repair and improvement of left ventricular function after MI have attracted considerable attention. Accordingly, the safety and efficacy of these cell transplantations should be tested in a preclinical large animal model of HF prior to clinical use. Pigs are widely used for cardiovascular disease research due to their similarity to humans in terms of heart size and coronary anatomy. Therefore, we sought to present an effective protocol for the establishment of a porcine chronic HF model using closed-chest coronary balloon occlusion of the left circumflex artery (LCX), followed by rapid ventricular pacing induced with pacemaker implantation. Eight weeks later, the stem cells were administered by intramyocardial injection in the peri-infarct area. Then the infarct size, cell survival, and left ventricular function (including echocardiography, hemodynamic parameters, and electrophysiology) were evaluated. This study helps establish a stable preclinical large animal HF model for stem cell treatment.

We sought to establish a swine model of heart failure induced by left circumflex artery blockage and rapid pacing to test the effect and safety of intramyocardial administration of stem cells for cell-based therapies.

Although advances have been achieved in the treatment of heart failure (HF) following myocardial infarction (MI), HF following MI remains one of the major ...

Large Animal Model for Evaluating the Efficacy of the Gene Therapy in Ischemic Heart

Coronary artery disease is one of the significant causes of mortality and morbidity worldwide. Despite the progression of current therapeutics, a considerable proportion of coronary artery disease patients remain symptomatic. Gene therapy-mediated therapeutic angiogenesis offers a novel therapeutic method for improving myocardial perfusion and relieving symptoms. Gene therapy with different angiogenic factors has been studied in few clinical trials. Due to the novelty of the method, the progress of myocardial gene therapy is a continuous path from bench to bedside. Therefore, large animal models are needed for evaluating the safety and efficacy. The more the large animal model identifies the original disease and the endpoints used in clinics, the more predictable outcomes are from clinical trials. Here, we introduce a large animal model for evaluating the efficacy of the gene therapy in the ischemic porcine heart. We use clinically relevant imaging methods such as ultrasound imaging and 15H2O-PET. For targeting the gene transfers into the desired area, electroanatomical mapping is used. The aim of this method is: (1) to mimic chronic coronary artery disease, (2) to induce therapeutic angiogenesis at hypoxic areas of the heart, and (3) to evaluate the safety and efficacy of the gene therapy by using relevant endpoints.

Myocardial gene therapy for ischemic heart disease holds great promise for future therapeutics. Here, we introduce a large animal model for evaluating the efficacy of gene therapy in the ischemic heart.

Coronary artery disease is one of the significant causes of mortality and morbidity worldwide. Despite the progression of current therapeutics, a ...

Myocardial Infarction by Percutaneous Embolization Coil Deployment in a Swine Model

Myocardial infarction (MI) is the leading cause of mortality worldwide. Despite the use of evidence-based treatments, including coronary revascularization and cardiovascular drugs, a significant proportion of patients develop pathological left-ventricular remodeling and progressive heart failure following MI. Therefore, new therapeutic options, such as cellular and gene therapies, among others, have been developed to repair and regenerate injured myocardium. In this context, animal models of MI are crucial in exploring the safety and efficacy of these experimental therapies before clinical translation. Large animal models such as swine are preferred over smaller ones due to the high similarity of swine and human hearts in terms of coronary artery anatomy, cardiac kinetics, and the post-MI healing process. Here, we aimed to describe an MI model in pig by permanent coil deployment. Briefly, it comprises a percutaneous selective coronary artery cannulation through retrograde femoral access. Following coronary angiography, the coil is deployed at the target branch under fluoroscopic guidance. Finally, complete occlusion is confirmed by repeated coronary angiography. This approach is feasible, highly reproducible, and emulates the pathogenesis of human non-revascularized MI, avoiding the traditional open-chest surgery and the subsequent postoperative inflammation. Depending on the time of follow-up, the technique is suitable for acute, sub-acute, or chronic MI models.

Myocardial infarction (MI) animal models that emulate the natural process of the disease in humans are crucial to understanding pathophysiological mechanisms and testing the safety and efficacy of new emergent therapies. Here, we describe an MI swine model created by deploying a percutaneous embolization coil.

Myocardial infarction (MI) is the leading cause of mortality worldwide. Despite the use of evidence-based treatments, including coronary revascularization ...

Delivery of Cardioactive Therapeutics in a Porcine Myocardial Infarction Model

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