这项工作由国家健康与医学研究委员会APP1194139/APP1126276（JC），澳大利亚国家干细胞基金会和新南威尔士州政府健康与医学研究办公室（JC）资助。唐氏综合征得到了澳大利亚皇家内科医学院、临床病理学和医学研究所以及澳大利亚政府研究培训计划的支持。TD得到了临床病理学和医学研究所、奔富家庭奖学金、国家健康与医学研究委员会（APP2002783）和澳大利亚国家心脏基金会（104615）的支持。

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作者没有什么可透露的。

经心外膜心内肌注射 该手术具有直接心脏可视化的优点，并且已被证明比全身给药方法提供更大的局部治疗保留 9,10,14。然而，开胸手术是侵入性的，需要相当多的技术技能，并且比所讨论的其他方法具有更大的发病率和死亡风险10,15。了解手术的关键和不稳定阶段有助于调解这种增加的风险。
由于心律失常和相关血流动力学损害的高风险，在操作心脏以暴露心尖时必须格外小心。持续有创血压监测和心电图可以快速识别低血压或不稳定的心律失常，便于及时干预和纠正。一过性低血压通常可以用间羟胺推注治疗。持续性低血压可以通过减少吸入麻醉剂（仔细监测麻醉深度）和开始输注血管加压药来暂时缓解，同时确定血流动力学改变的原因。不稳定型心律失常，如室性心动过速或心室颤动，可通过心脏电复律联合或不联合静脉抗心律失常药进行治疗。
对于动物的生存同样重要的是，在关闭胸部之前，成功地从胸膜腔中清除游离气体。如果不这样做，最终会导致气胸，一旦在恢复时与机械呼吸机断开连接，动物就会面临呼吸功能受损和死亡的巨大风险。气道正压通气必须保持至少 30 秒，直到不再观察到气泡。在冒泡停止后立即取出硅胶管，然后迅速关闭胸部。也可以在闭合时通过手术放置胸腔引流管，允许在接下来的 24-72 小时内手动清除空气和炎症性液体。然而，这很难保持清洁和完好无损，特别是如果动物被关在一起。导管损坏或污染可导致脓胸、气胸或脓毒症。根据我们的经验，如果在胸腔闭合前充分清除游离气体，则不需要插入临时胸腔引流管。
经皮经心内膜心内注射 与手术方法相比，这种治疗给药方法的优点是允许局部组织递送，风险较低，因为它的侵入性较小10,14。该技术已经用于大型动物研究，在没有直接可视化的情况下，透视和机电映射作为指导10,16,17。
鉴于心脏没有直接视野，手术医师在选择注射部位时应谨慎使用正交透视视图。此外，在治疗之前注射稀释的碘造影剂和递送治疗剂对于确认心肌接触极为有价值。适当的接触可以通过观察特征性的“心肌腮红”来确认，这可能是组织收获前注射成功的唯一标志之一。由于腔室穿孔的风险，所选注射部位的心肌壁厚度也建议大于 9 mm14,16。
颈静脉渗透压微型泵 渗透微型泵是小动物研究中常用的一种常用设备。人们对在大型动物模型中使用该装置的兴趣越来越大 7,18,19，因为它具有在设定时间段内以一致速率施用治疗剂的独特优势。这种方法的一个可能的局限性是无法在不更换或移除泵的情况下改变或停止药物的输注速率。在以这种方式尝试治疗之前，应考虑这一点。
本研究表明，该方法可以在猪中以高成功率进行，发病率和死亡率低。必须注意的是，许多重要结构都与手术部位相邻，包括淋巴结、胸腺和颈动脉。强烈建议遵守该方法并查阅解剖学文本20，以防止对任何这些结构的无意损坏。这种方法最令人担忧的并发症是由于颈静脉或周围结构的意外损伤而导致的失血性休克。因此，小心切除颈静脉周围的软组织至关重要。未能正确完成此步骤可能会导致难以放置微型泵管或控制意外出血。
本文介绍了三种提供心脏活性治疗的方法。尽管据报道每种技术都取得了成功，但仍有固有的局限性需要考虑。侵入性操作（经心外膜注射）可提高治疗递送的准确性;然而，它们带来了更大的潜在致命并发症的风险。此外，侵入性分娩对技术技能的要求更高，以最大限度地降低并发症的风险。同样，透视引导下经心内膜注射需要一定程度的导管插入术和硬件操作技术技能。如果这种方法执行不当，可能会导致注射失败和致命的并发症。
所描述的直接注射方法允许将治疗剂一次性施用到靶组织中。颈静脉渗透压微型泵允许在 7 天内全身给药治疗。相比之下，这种方法更简单，风险更小，但是，它依赖于全身治疗找到进入心肌的途径。此外，一旦泵就位，如果不重新麻醉动物并移除泵，就不可能停止给药或改变剂量率。
本文中描述的所有方法均在心肌梗死后一天或2周内在动物身上进行。因此，这项工作不能报告上述方法在健康动物或遭受替代心脏病理学的动物中的成功。最后，应仔细考虑任何预期药物的药理学和生物技术，因为这将与所选给药途径的疗效有内在的联系。对此的详细讨论超出了本手稿的范围。
对临床前方法的全面描述有利于动物福利和更广泛的科学界。由此增强的程序和结果的可重复性导致更少的动物健康并发症，减少产生显着结果所需的动物数量，并提高实验结果的信心21,22。本文描述了三种用于治疗猪模型心肌梗死的新疗法的给药方法。通过详细说明所使用的技术并阐明每种技术的益处和风险，预计研究人员将能够轻松创建适合其研究目标的一致且可靠的临床前模型。

冠状动脉疾病 （CAD） 和相关的 ST 段抬高型心肌梗死 （STEMI） 是全球死亡的主要原因。在过去的二十年中，通过经皮冠状动脉介入治疗、纤溶疗法和治疗流程的标准化，在降低 STEMI 患者的院内死亡率方面取得了巨大进展，以确保及时实现再灌注 1,2,3.尽管如此，与 STEMI 相关的发病率仍然是一个沉重的负担，因此迫切需要开发新的心脏保护和再生疗法 2,3。治疗开发的一个重要组成部分是确定如何实施新疗法4.每种方法的安全性、有效性和可行性都需要与治疗本身的特点相匹配。
生理相关的大型动物模型对于评估各种治疗递送策略的这些属性至关重要5.由于猪在心血管生理学、冠状动脉血管解剖学和心脏重量与体重比方面与人类相似，因此是心肌梗死新疗法临床前评估的首选物种之一6。我们之前曾使用猪 STEMI 模型来证明重组蛋白疗法的修复能力7，并继续使用该模型研究新的药物、细胞和基因疗法。在这里，描述了梗死产生后猪模型中使用的三种治疗给药技术：开胸术和经心外膜注射、经皮经心内膜注射和颈静脉渗透压微型泵植入术。前两种方法可实现局部组织递送，减少所需剂量、脱靶效应和肝脏首过代谢 8,9,10。渗透微型泵允许以较短的半衰期连续输送药物，从而消除了对输液泵和专利静脉插管的依赖，这两者都很难在大型动物模型中实现。
通过描述这些技术，希望本文可以帮助转化科学家在大型动物模型中研究心肌梗死后的新型心脏保护剂或再生剂。

<table border="1" fo:keep-together.within-page="1" fo:keep-with-next.within-page="always">
	<tbody>
		<tr>
			<td>Central line placement</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&#39; Paediatric Two-Lumen Central Venous Catheterisation Set with Blue FlexTip Catheter (contains 18G cook needle and 0.035&#34; 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>Histology antibodies</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&#39; 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 &#39;Medium&#39;</td>
			<td>Lomir Biomedical</td>
			<td>SS J2YJJET</td>
			<td></td>
		</tr>
		<tr>
			<td>Jugular vein osmotic minipump implantation</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 &#39;Edge&#39; 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&#160; (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>Percutaneous transedocardial injection</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Artis Zee&#39; C-Arm Fluoroscopy&#160;</td>
			<td>Siemens&#160;</td>
			<td>IR-19-1994</td>
			<td></td>
		</tr>
		<tr>
			<td>CARTO&#39; 3 System&#160;&#160;</td>
			<td>Biosense Webster</td>
			<td></td>
			<td>Electrophysiological Mapping Software &#38; 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&#39; 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&#39; 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&#39; Iohexol Contrast</td>
			<td>GE Healthcare</td>
			<td>AUST R 39861&#160;</td>
			<td>Iodinated contrast agent</td>
		</tr>
		<tr>
			<td>Sparq&#39; Ultrasound System</td>
			<td>Philips</td>
			<td>MP11742 Medpick</td>
			<td></td>
		</tr>
		<tr>
			<td>Sedation &#38; general anaesthesia</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Compound Sodium Lactate Hartmann&#39;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&#39; Isoflurane</td>
			<td>Abbott</td>
			<td>AUST R 29656&#160;</td>
			<td>Inhalant anaesthetic</td>
		</tr>
		<tr>
			<td>GE Aestiva 5 Anaesthesia Machine&#160;</td>
			<td>Datex Ohmeda</td>
			<td>17002-9, 17002A9 Avante Health Solutions</td>
			<td>Anaesthetic Machine&#160;</td>
		</tr>
		<tr>
			<td>Hypnovel&#39; 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&#39; Ketamine 10 mg/mL</td>
			<td>Ilium</td>
			<td>APVMA number: 51188c&#160;</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&#160;</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&#160;</td>
			<td>Sedative, Restricted drug</td>
		</tr>
		<tr>
			<td>Onsetron&#39; Ondansetron 2 mg/mL</td>
			<td>Accord Healthcare</td>
			<td>AUST R 205593&#160;</td>
			<td>Anti-emetic</td>
		</tr>
		<tr>
			<td>Propofol-Lipuro&#39; Propofol 10 mg/mL</td>
			<td>Braun</td>
			<td>AUST R 142906&#160;</td>
			<td>Intravenous anaesthetic</td>
		</tr>
		<tr>
			<td>Pulse Oximeter&#160;</td>
			<td>Meditech</td>
			<td>GVPMT-M3S</td>
			<td>Portable pulse oximeter</td>
		</tr>
		<tr>
			<td>Shiley&#39; Cuffed Basic Endotracheal Tube (Size 5.5 &#38; 6.0)</td>
			<td>Medtronic</td>
			<td>86108-, 86109-</td>
			<td></td>
		</tr>
		<tr>
			<td>Shiley&#39; 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>Thoracotomy and epicardial Cell Injection</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&#39; 3 System&#160;&#160;</td>
			<td>Biosense Webster</td>
			<td></td>
			<td>Electrophysiological Mapping Software &#38; System</td>
		</tr>
		<tr>
			<td>Cefazolin 1 g Vial</td>
			<td>AFT Pharmaceuticals</td>
			<td>9421900137367 CH2</td>
			<td>Antibiotic Prophylaxis&#160;</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&#39; 100 mcg/h Fentanyl Patch</td>
			<td>Janssen</td>
			<td>AUST R 112371&#160;</td>
			<td>Postoperative analgesia</td>
		</tr>
		<tr>
			<td>Electrosurgical Pencils with &#39;Edge&#39; Coated Electrodes</td>
			<td>Covidien</td>
			<td>E2450H</td>
			<td>Cautery Pencil</td>
		</tr>
		<tr>
			<td>Electrosurgical Pencils with &#39;Edge&#39; Coated Electrodes</td>
			<td>Covidien</td>
			<td>E2450H</td>
			<td>Cautery Pencil</td>
		</tr>
		<tr>
			<td>Fast-Cath&#39; 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&#39; Bupivacaine 0.5%</td>
			<td>Pfizer</td>
			<td>AUST R 48328&#160;</td>
			<td>Local anaesthesia.&#160;</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&#160; (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&#39; 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&#39; 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

心肌梗死是全球死亡和残疾的主要原因之一，迫切需要新的心脏保护或再生策略。药物开发的一个重要组成部分是确定如何管理一种新型疗法。生理相关的大型动物模型对于评估各种治疗策略的可行性和有效性至关重要。由于猪在心血管生理学、冠状动脉血管解剖学和心脏重量与体重比方面与人类相似，因此是心肌梗死新疗法临床前评估的首选物种之一。本方案描述了在猪模型中施用心脏活性治疗剂的三种方法。经皮诱导心肌梗死后，雌性地方白猪通过以下任一方式接受新型药物治疗：（1）开胸和经心外膜注射，（2）基于导管的经心内膜注射，或（3） 通过 颈静脉渗透微型泵静脉输注。每种技术采用的程序都是可重复的，从而产生可靠的心脏活性药物递送。这些模型可以很容易地适应个人的研究设计，并且这些交付技术中的每一种都可用于研究各种可能的干预措施。因此，这些方法对于在心肌梗死后心脏修复中寻求新的生物学方法的转化科学家来说是一个有用的工具。

开胸手术和心外膜细胞注射 在接受开胸手术和心外膜注射的 29 只动物中，有 26 只幸存下来。组织学分析证实了通过这种方法在所有幸存动物中递送的人类细胞的植入（图1E）。一只动物在细胞注射过程中经历了致命的心律失常，无法复苏。另一名患者在闭合期间经历了无脉电活动，并长时间对气道施加正压，无法恢复。第三只动物在拔管时呕吐并呼吸停止。这只动物无法复苏。
两只动物经历了严重的并发症，但能够康复。一只动物在心肌注射过程中出现心室颤动，能够通过内部除颤拨片和心脏按摩进行复苏。第二只动物在拔管时呕吐，并有短暂的呼吸停止，但能够迅速重新插管并恢复良好。所有这些事件都发生在早期实验期间，随着团队使用方案经验的增加，不良事件减少（表1）。
颈静脉渗透压微型泵植入术 没有报告的死亡或主要并发症与颈静脉渗透压小泵植入术相关。7只动物中的大多数在前24小时内手术部位出现轻度肿胀，无需干预即可消退。在泵植入后第 3 天对血清进行的 ELISA 证明了泵的功效，与对照组相比，实现了血小板衍生生长因子-AB 人 （PDGF-AB） 的显着血药浓度7 （图 2E）。
经皮经心内膜注射 共有22只动物接受了心内膜注射。在这些注射中，有17次被认为是“成功的”，这是通过死后在目标组织中观察到的荧光或墨水染色来确定的（图3B）。没有与该手术相关的死亡。一只动物因右心室穿孔而出现少量心包积液。这是自限性的，不会导致心血管损害。这只动物确实死了;然而，这是来自心肌内注射后不相关的附加程序。
<img alt="Figure 1" class="xfigimg" src="/files/ftp_upload/64177/64177fig01.jpg"> 图 1：经心外膜心肌细胞注射可实现直接心脏可视化，并实现高比例的活细胞输送到心肌。 （A） 心脏顶点通过在心脏底部下方引导的湿纱布吊带暴露。（B） 心外膜标测导管划定疤痕和边界区域，并注释注射部位。（C） 使用 31 G 针头经心外膜将细胞注射到心肌中。（D） 带有注射部位注释的心外膜电压图。紫色：电压正常，心肌健康;红色：电压异常，心肌病变;灰点：注射部位。处死后，收集心脏并用福尔马林固定，用于下游组织学评估。在（E）中，通过对人抗核抗体Ku80和抗GFP抗体进行免疫染色来检测移植的人细胞。比例尺 = 200 μm. <a href="https://www.jove.com/files/ftp_upload/64177/64177fig01large.jpg" target="_blank">请点击这里查看此图的较大版本.</a>
<img alt="Figure 2" class="xfigimg" src="/files/ftp_upload/64177/64177fig02.jpg"> 图 2：颈静脉微型泵置入提供了一种安全可靠的 PDGF 方法，可在 7 天内 输送。 （A） 暴露右颈静脉，软组织从血管中清除。（B） 血管系带闭塞血管，同时使用 14 G 针头进行穿刺，微型泵管穿过该穿刺。（C） 将微型泵管推进到静脉中，并将微型泵体固定在相邻的软组织上。（D） 植入前的微型泵体和管道。（E） 在植入后第 3 天使用 ELISA 测量每只动物通过微型泵和 PDGF-AB 递送 的重组蛋白的血清浓度。接受PDGF-AB的动物被证明具有明显高于对照动物的PDGF-AB血液浓度，证实了渗透性微型泵给药方法的有效性。**表示组间差异有统计学意义 （p = 0.005， Mann-Whitney U 检验） <a href="https://www.jove.com/files/ftp_upload/64177/64177fig02large.jpg" target="_blank">请点击这里查看此图的较大版本.</a>
<img alt="Figure 3" class="xfigimg" src="/files/ftp_upload/64177/64177fig03.jpg"> 图 3：经心内膜心肌内注射允许采用微创治疗给药方法。 （A） 右前斜透视图像显示注射导管（白色箭头）将造影剂（黄色箭头）注入心肌。造影剂注射在治疗性注射之前和之后，因此可以确认针头在心肌内的位置。（B）注射的载体表达绿色荧光蛋白（GFP），使注射的材料在组织收集时发出荧光，从而确认注射成功。 <a href="https://www.jove.com/files/ftp_upload/64177/64177fig03large.jpg" target="_blank">请点击这里查看此图的较大版本.</a>
<table border="1" fo:keep-together.within-page="1" fo:keep-with-next.within-page="always"><tbody><tr><td></td>
			<td>经外膜注射 （n = 29）</td>
			<td>经心内膜注射 （n = 22）</td>
			<td>渗透压微型泵 （n = 7）</td>
		</tr><tr><td>死亡率</td>
			<td>3</td>
			<td>0</td>
			<td>0</td>
		</tr><tr><td>术后呕吐和呼吸停止</td>
			<td>1</td>
			<td>0</td>
			<td>0</td>
		</tr><tr><td>注射期间的心室颤动</td>
			<td>1</td>
			<td>0</td>
			<td>0</td>
		</tr><tr><td>胸部闭合期间的无脉电活动</td>
			<td>1</td>
			<td>0</td>
			<td>0</td>
		</tr><tr><td>发病率</td>
			<td>0</td>
			<td>1</td>
			<td>0</td>
		</tr><tr><td>气胸</td>
			<td>0</td>
			<td>0</td>
			<td>0</td>
		</tr><tr><td>胸腔积液</td>
			<td>0</td>
			<td>0</td>
			<td>0</td>
		</tr><tr><td>心腔穿孔</td>
			<td>0</td>
			<td>1</td>
			<td>0</td>
		</tr><tr><td>出血</td>
			<td>0</td>
			<td>0</td>
			<td>0</td>
		</tr></tbody></table>表 1：并发症列表。

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

本方案描述了在猪模型中施用心脏活性治疗剂的三种方法。雌性地方白猪通过以下任一方式接受治疗：（1）开胸术和经心外膜注射，（2）基于导管的经心内膜注射，或（3） 通过 颈静脉渗透微型泵静脉输注。

猪心肌梗死模型中心脏活性疗法的递送

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

1.1K 次观看.  The University of Sydney. 本方案描述了在猪模型中施用心脏活性治疗剂的三种方法。雌性地方白猪通过以下任一方式接受治疗：（1）开胸术和经心外膜注射，（2）基于导管的经心内膜注射，或（3） 通过 颈静脉渗透微型泵静脉输注。

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

Acute Myocardial Infarction in Rats

With heart failure leading the cause of death in the USA (Hunt), biomedical research is fundamental to advance medical treatments for cardiovascular diseases. Animal models that mimic human cardiac disease, such as myocardial infarction (MI) and ischemia-reperfusion (IR) that induces heart failure as well as pressure-overload (transverse aortic constriction) that induces cardiac hypertrophy and heart failure (Goldman and Tarnavski), are useful models to study cardiovascular disease. In particular, myocardial ischemia (MI) is a leading cause for cardiovascular morbidity and mortality despite controlling certain risk factors such as arteriosclerosis and treatments via surgical intervention (Thygesen). Furthermore, an acute loss of the myocardium following myocardial ischemia (MI) results in increased loading conditions that induces ventricular remodeling of the infarcted border zone and the remote non-infarcted myocardium. Myocyte apoptosis, necrosis and the resultant increased hemodynamic load activate multiple biochemical intracellular signaling that initiates LV dilatation, hypertrophy, ventricular shape distortion, and collagen scar formation. This pathological remodeling and failure to normalize the increased wall stresses results in progressive dilatation, recruitment of the border zone myocardium into the scar, and eventually deterioration in myocardial contractile function (i.e. heart failure). The progression of LV dysfunction and heart failure in rats is similar to that observed in patients who sustain a large myocardial infarction, survive and subsequently develops heart failure (Goldman). The acute myocardial infarction (AMI) model in rats has been used to mimic human cardiovascular disease; specifically used to study cardiac signaling mechanisms associated with heart failure as well as to assess the contribution of therapeutic strategies for the treatment of heart failure. The method described in this report is the rat model of acute myocardial infarction (AMI). This model is also referred to as an acute ischemic cardiomyopathy or ischemia followed by reperfusion (IR); which is induced by an acute 30-minute period of ischemia by ligation of the left anterior descending artery (LAD) followed by reperfusion of the tissue by releasing the LAD ligation (Vasilyev and McConnell). This protocol will focus on assessment of the infarct size and the area-at-risk (AAR) by Evan's blue dye and triphenyl tetrazolium chloride (TTC) following 4-hours of reperfusion; additional comments toward the evaluation of cardiac function and remodeling by modifying the duration of reperfusion, is also presented. Overall, this AMI rat animal model is useful for studying the consequence of a myocardial infarction on cardiac pathophysiological and physiological function.

The rat model of acute myocardial infarction (AMI) is useful to study the consequence of a MI on cardiac pathophysiological and physiological function.

大鼠急性心肌梗死

With heart failure leading the cause of death in the USA (Hunt), biomedical research is fundamental to advance medical treatments for cardiovascular ...

科研

医学

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.

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.

MRI和PET心肌梗死小鼠模型

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 ...

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.

心肌梗死和功能预后评估的猪

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

A Hydrogel Construct and Fibrin-based Glue Approach to Deliver Therapeutics in a Murine Myocardial Infarction Model.

The murine MI model is widely recognized in the field of cardiovascular disease, and has consistently been used as a first step to test the efficacy of treatments in vivo1. The traditional, established protocol has been further fine-tuned to minimize the damage to the animal. Notably, the pectoral muscle layers are teased away rather than simply cut, and the thoracotomy is approached intercostally as opposed to breaking the ribs in a sternotomy, preserving the integrity of the ribcage. With these changes, the overall stress on the animal is decreased. 
Stem cell therapies aimed to alleviate the damage caused by MIs have shown promise over the years for their pro-angiogenic and anti-apoptotic benefits. Current approaches of delivering cells to the heart surface typically involve the injection of the cells either near the damaged site, within a coronary artery, or into the peripheral blood stream2-4. While the cells have proven to home to the damaged myocardium, functionality is limited by their poor engraftment at the site of injury, resulting in diffusion into the blood stream5. This manuscript highlights a procedure that overcomes this obstacle with the use of a cell-encapsulated hydrogel patch. The patch is fabricated prior to the surgical procedure and is placed on the injured myocardium immediately following the occlusion of the left coronary artery. To adhere the patch in place, biocompatible external fibrin glue is placed directly on top of the patch, allowing for it to dry to both the patch and the heart surface. This approach provides a novel adhesion method for the application of a delicate cell-encapsulating therapeutic construct.

This protocol aims to alleviate the limitation of poor cell engraftment for stem cell treatment of myocardial infarctions through the use of a hydrogel system and a fibrin-based glue. With this approach, cell-to-tissue contact post-infarction can be maintained, increasing the therapeutic potential of beneficial agents at the site of injury.

水凝胶构造和纤维蛋白基胶方法来提供治疗的小鼠心肌梗死模型。

The murine MI model is widely recognized in the field of cardiovascular disease, and has consistently been used as a first step to test the efficacy of ...

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.

急性心肌梗死的猪模型主要成果评估

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

Myocardial Infarction in Neonatal Mice, A Model of Cardiac Regeneration

Myocardial infarction induced by coronary artery ligation has been used in many animal models as a tool to study the mechanisms of cardiac repair and regeneration, and to define new targets for therapeutics. For decades, models of complete heart regeneration existed in amphibians and fish, but a mammalian counterpart was not available. The recent discovery of a postnatal window during which mice possess regenerative capabilities has led to the establishment of a mammalian model of cardiac regeneration. A surgical model of mammalian cardiac regeneration in the neonatal mouse is presented herein. Briefly, postnatal day 1 (P1) mice are anesthetized by isoflurane and placed on an ice pad to induce hypothermia. After the chest is opened, and the left anterior descending coronary artery (LAD) is visualized, a suture is placed around the LAD to inflict myocardial ischemia in the left ventricle. The surgical procedure takes 10-15 min. Visualizing the coronary artery is crucial for accurate suture placement and reproducibility. Myocardial infarction and cardiac dysfunction are confirmed by triphenyl-tetrazolium chloride (TTC) staining and echocardiography, respectively. Complete regeneration 21 days post myocardial infarction is verified by histology. This protocol can be used to as a tool to elucidate mechanisms of mammalian cardiac regeneration after myocardial infarction.

This protocol describes a highly reproducible model of cardiac regeneration by surgical induction of myocardial infarction in the left ventricle of postnatal day 1 mice. The method involves induction of hypothermic anesthesia and ligation of the left anterior descending coronary artery.

心肌梗死新生小鼠，心肌再生的模型

Myocardial infarction induced by coronary artery ligation has been used in many animal models as a tool to study the mechanisms of cardiac repair and ...

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.

组织和采血程序标准化改善闭合性胸猪心肌梗死模型的研究

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

A Cryoinjury Model to Study Myocardial Infarction in the Mouse

The use of animal models is essential for developing new therapeutic strategies for acute coronary syndrome and its complications. In this article, we demonstrate a murine cryoinjury infarct model that generates precise infarct sizes with high reproducibility and replicability. In brief, after intubation and sternotomy of the animal, the heart is lifted from the thorax. The probe of a handheld liquid nitrogen delivery system is applied onto the myocardial wall to induce cryoinjury. Impaired ventricular function and electrical conduction can be monitored with echocardiography or optical mapping. Transmural myocardial remodeling of the infarcted area is characterized by collagen deposition and loss of cardiomyocytes. Compared to other models (e.g., LAD-ligation), this model utilizes a handheld liquid nitrogen delivery system to generate more uniform infarct sizes.

This article demonstrates a model to study cardiac remodeling after myocardial cryoinjury in mice.

研究小鼠心肌梗死的低温损伤模型

The use of animal models is essential for developing new therapeutic strategies for acute coronary syndrome and its complications. In this article, we ...

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.

建立干细胞治疗心肌梗塞心力衰竭的猪模型

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

Intramyocardial Transplantation of MSC-Loading Injectable Hydrogels after Myocardial Infarction in a Murine Model

One of the major issues facing current cardiac stem cell therapies for preventing postinfarct heart failure is the low retention and survival rates of transplanted cells within the injured myocardium, limiting their therapeutic efficacy. Recently, the use of scaffolding biomaterials has gained attention for improving and maximizing stem cell therapy. The objective of this protocol is to introduce a simple and straightforward technique to transplant bone marrow-derived mesenchymal stem cells (MSCs) using injectable hydroxyphenyl propionic acid (GH) hydrogels; the hydrogels are favorable as a cell delivery platform for cardiac tissue engineering applications due to their ability to be cross-linked in situ and high biocompatibility. We present a simple method to fabricate MSC-loading GH hydrogels (MSC/hydrogels) and evaluate their survival and proliferation in three-dimensional (3D) in vitro culture. In addition, we demonstrate a technique for intramyocardial transplantation of MSC/hydrogels in mice, describing a surgical procedure to induce myocardial infarction (MI) via left anterior descending (LAD) coronary artery ligation and subsequent MSC/hydrogels transplantation.

Stem cell-based therapy has emerged as an efficient strategy to repair injured cardiac tissues after myocardial infarction. We provide an optimal in vivo application for stem cell transplantation using gelatin hydrogels that are able to be enzymatically cross-linked.

Murine 模型心肌梗塞后 MSC 加载注射水凝胶的心内移植

One of the major issues facing current cardiac stem cell therapies for preventing postinfarct heart failure is the low retention and survival rates of ...