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><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

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

1.2K 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

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.

缺血性心力衰竭在临床前模型的转基因

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

科研

医学

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.

多能干细胞衍生的心肌修复心肌细胞

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

发育生物学

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 ...

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.

药理试验药物的疗效在心包目标交付模型在猪

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.

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 ...

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.

经皮超声心动图引导心肌注射液与大鼠前体细胞的临床研究

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.

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 ...

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 ...

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.

用于评估基因治疗缺血性心脏疗效的大型动物模型

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.

猪模型中经皮栓塞线圈部署的心肌梗死

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