国家卫生研究院国家心脏、肺脏和血液研究所的校内研究部为该项目提供了内部资助。我们要感谢 Dr., Dr., nih 兽医资源部和国立卫生研究院心胸外科研究项目的工作人员。

此处描述的程序由国家心脏、肺脏和血液研究所动物护理和使用委员会批准, 并符合公共卫生服务政策中概述的政策对实验室动物的人道关怀和使用, 动物福利法, 以及对实验室动物的关心和使用的指南. 
 注意: 本外科手术的目的是产生一种慢性心肌缺血动物模型, 可用于开发与严重 CAD 患者相关的临床治疗。不能使用 体外 模型来完成此任务. 
 1. 动物 <ol> <li> 使用在12和15公斤之间重的男性约克郡猪. </li> </ol>
 2. 手术前程序 <ol> <li> 预防性抗生素, 使用阿莫西林和克拉维钾 (15 毫克/千克), 每天口服两次, 开始手术前24小时. 
	注: 这种口服抗生素是在手术前开始, 以确保猪会吞下它, 并确保他们不会有过敏反应的药物术. </li>
	<li> 在手术前12小时扣留猪的食物和水. </li>
	<li> 在手术当天, 麻醉用氯胺酮鸡尾酒 (33 毫克/千克), 咪唑安定 (0.5-0.75 毫克/千克), 和溴 (0.01 毫克/千克) 给猪肌肉注射 (IM). </li>
	<li> 将20克静脉注射 (IV) 导管放在耳静脉内, 并用7.0 法郎的气管插管给动物. 
	注意: 根据猪的大小调整 IV 导管和气管插管的大小. </li>
	<li> 将猪的左侧的毛发 (剃须) 从肩部移到肚脐, 从腹中线到椎柱. </li>
	<li> 管理预防性抗生素 (哌拉西林和他唑巴坦: 100 毫克/千克 IV) 和止痛药 (丁丙诺啡持续释放: 0.2 毫克/千克皮下 (SC) 或芬太尼透皮贴剂25-50 和 #181; g/小时) 
	注: 静脉注射抗生素是因为动物在手术前禁食12小时, 在这段时间内没有收到先前提到的口服抗生素. </li>
	<li> 将猪运到手术室, 并将气管插管与装有流传感器的麻醉机连接, 以监测气道气体。机械地用10毫升/千克的潮汐容积作为起始点, 不超过30厘米 H 2 的气道压力, 将呼吸速率设置为每分钟10-20 次呼吸 (bpm), 并根据需要调整以保持最终潮汐 CO 2 (佩科 2 ) 级别介于28和35毫米汞柱之间. 用异氟醚 (1-3%) 或七氟醚 (2-5%) 维持麻醉. </li>
	<li> 将猪放在手术台的右侧。附上所有必要的探头, 以监测体温 (BT), 心电图 (心电图), 脉冲氧 ( 2 ), 等 </li> <li> 准备手术现场通过三交替磨砂与 2% chlorohexidine 和70% 酒精 (适用于圆周运动从中心开始, 向外移动). </li>
	<li> 使用无菌技术对手术部位进行悬垂 21 . </li>
</ol> 3。手术过程 <ol> <li> 通过左开胸切开心脏。
	<ol> <li> 使皮肤切口平行于 4 th 和 5 th 肋间空间, 长度约为 8-9 厘米, 使用的是10手术刀刀片. </li>
		<li> 用一对弯曲的 Metzenbaum 剪刀和棕色 Adson 钳切开背阔肌和锯鮈肌。必要时使用电来维持止血. </li>
		<li> 进入胸腔通过肋间肌肉 4 th 和 5 th 肋骨与 Metzenbaum 剪刀切割沿前方面的 4 th 肋骨。为了减少意外损坏肺部的几率, 在进入胸腔前, 将呼吸机关闭呼气。一旦胸腔被攻破, 将呼吸机重新打开. </li>
		<li> 使用小 Finochietto 牵引器将肋骨分开, 露出心脏. </li>
	</ol> </li> <li> 使用脉钳来抓取和提起心包。用茶煲剪刀在心包内做一个小洞, 使空气进入心包间隙。继续切口与茶煲剪刀在连接的小伙子和漏的动脉. </li>
	<li> 使用钳夹收回左心房附件。使用脉和小直角钳, 解剖漏动脉从周围组织前或近 1 st 和 #160; 钝边缘分支. </li>
	<li> 在解剖漏动脉下放置两个血管循环, 每一个在一端。用小的直角钳夹住一个大小为3.0 毫米的 ameroid, 并提起血管环, 以轻轻引导漏动脉通过开口的括约肌。轻轻地旋转缩进, 使开口朝上。卸下容器回路。请参见 图 1 . 
	注: 充分的动脉解剖是必不可少的, 以防止康祺。为单个动物选择适当大小的缩的。适当大小的缩窄将密切包围该船只, 而不首先压缩该船只。在12和15公斤之间称的国内猪需要 ameroid 蟒蛇大小的 2.5-3.5 毫米。在血管上的 ameroid 的位置取决于所需的缺血面积大小. </li>
	<li> 重新近似的心包和关闭4-0 聚丙烯缝合线. </li>
	<li> 通过在胸腔间隙中插入12根胸管或等效物来重建负胸压, 最后在闭合层之间退出, 通常两个肋间空间在开胸后的部位. 
	注: 在关闭肋骨前观察肺不张。如果有任何 underinflation 的迹象, 重新的肺部手动高达30毫米汞的压力. </li>
	<li> 用1聚丙烯缝合线为肋间层, 0 聚丙烯缝合线的锯和筋膜层, 2-0 聚丙烯缝合皮下层, 和3-0 聚丙烯缝合的 subcuticular 层。装订或缝合皮肤. </li>
	<li> 将三路止回阀塞到胸管的末端, 并用40-60 毫升的注射器将空气排出胸腔, 直到达到负密封。将动物卷到胸骨或另一侧, 以方便去除所有的空气。一旦胸腔保持负压, 取出胸管, 缝合出口部位。如果动物单独术, 切口可以包扎好几天. </li>
</ol> 4。术后 <ol> <li> 关闭后, 沿切口两侧切开0.25% 布比卡因. </li>
	<li> 将动物从呼吸机上断奶, 关闭麻醉。一旦动物自行呼吸并吞咽, 取出气管导管. </li>
	<li> 监测动物, 直到它完全恢复 (清醒和胸骨)。心电图不应出现异常或心律失常, BT 应为 38.7-39.8 和 #176; C、 2 为 95-100%, 呼吸速率应为 32-58 bpm. </li>
	<li> 口服胺碘酮 (每日100毫克) 和硫酸氢氯吡格雷 (每天口服75毫克), 以防止血栓形成和心律失常。继续使用阿莫西林和克拉维钾 (15 毫克/千克) 口服两次, 每天术后10天。术后疼痛控制与丁丙诺啡 SR 和 #160;(持续释放) 0.2 毫克/千克。每三天一平方。和 #160; 卡洛芬 (4.4 毫克/千克) 一次和 #160; 然后 (2.2 毫克/千克) PO 或 IM 出价可以补充丁丙诺啡锶. </li>
	<li> 将所有床上用品和觅食材料保存在动物和 #39 的居住区, 直到切口完全愈合. </li>
</ol>

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作者没有利益冲突的披露。

Ameroid 蟒蛇已被广泛应用于建立慢性心肌缺血、慢性心肌梗死和心力衰竭的动物模型5,6,7,9,10,11,12,13,15,16,17,18,19,22. 虽然这些模型可以通过使用支架, 水力堵, 或固定狭窄堵, ameroid 使用的流行在科学文献允许研究员更准确地比较他们的工作结果与以前 发布的研究5,6,7,9,10,11,12,1315,16,17,18,19,22. 使用 ameroid 括约肌的另一个优点是该过程相对简单, 可以由任何有合理手术技能的人成功执行, 并且不需要专门的仪器。其他上述方法需要更大的技术技能, 在液压封堵器的情况下, 需要强烈的术后监测, 由于外部设备6,13。
使用 ameroid 的主要限制是阻塞率的可变性9,13。一般情况下, 大多数使用 ameroid 的研究发现, 在前两周, 狭窄率最高, 然后逐渐变细直到完全闭塞发生23,24。前体直接测量 ameroid 管腔闭合率的研究证实, 在头两个星期内, 流明直径最大的减小发生在后两周, 并随后减慢25、26。然而, 这些同样的研究也表明, 周围的葡萄糖和蛋白质浓度会影响 ameroid 闭合的速率和完整性, 从而表明在体内条件最有可能导致变异在 ameroid 遮挡率25,26。其他研究人员认为, 由 ameroid 放置程序本身引起的机械性创伤、炎症、纤维化和血栓形成可能导致这种变异性5,6,25.后一种情况很可能是本研究中观察到的过早死亡和心力衰竭的原因。在 ameroid 的两侧进行细致、充分的动脉解剖, 以防止血管康祺, 这一点是不够重要的。
适当地放置 ameroid 的大血管是至关重要的, 以发展的心脏缺血区域, 这是一个巨大的足够治疗, 但不太大, 它导致死亡。在第一个钝边缘分支之前, 把 ameroid 的漏放在约克郡的猪身上是最有效的。据报道, 在其他地方, 这导致缺血面积约25-30% 左右的左心室6。放置 ameroid 任何较低的导致缺血的地区, 这是不足够的具体治疗, 正在研究中。
在手术过程中出现心律失常是罕见的。管理口服胺碘酮术后通过研究结束, 可防止心律失常在2至3周后, 当 ameroid 关闭。此外, 照顾和医务人员应特别警惕, 注意到在这段时间的任何咳嗽, 这可能是肺水肿/心力衰竭的早期迹象。
多年来, ameroid 的设计得到了改进。Ameroids 目前可在许多大小, 允许外科医生选择一个 ameroid, 匹配的直径的船只被遮挡。ameroid 的外圈可用不锈钢、钛或塑料制成。这在评估受影响的心脏使用 MRI 时尤其重要。所有的金属都会导致核磁共振图像上的伪影钛 ameroids 造成的工件比不锈钢的少, 而塑料没有留下任何。MRI 图像显示钛 ameroid 和塑料 ameroid 之间的差异分别显示在图 2和图 3中。在图 2中, 心脏右侧的工件是由包围 ameroid 的钛环引起的。直到最近, 塑料 ameroid 上的密封圈太笨重, 无法在冠状动脉周围放置, 而不康祺血管。本研究中使用的 ameroid (参见材料表) 是一个更简化的版本, 它的外径与金属 ameroids 相同。

冠状动脉疾病 (CAD), 导致心肌缺血, 是导致残疾, 死亡, 和医疗保健费用在世界各地的4 , 并可归因于大约1的每3死亡在美国1,2,3,4,5,6. 虽然经皮穿刺和手术治疗有许多进展, 但由于年龄、健康状况不佳或不理想的解剖, 有多达三分之一的 CAD 患者没有资格获得这些治疗,45,6,7. 为了评估诊断成像或治疗的新方法, 建立一个适当的动物模型是至关重要的。
在开发一种动物模型的疾病, 诱导障碍应密切模仿的解剖和生理特征的障碍在人类8,9。其中最广泛使用的大型动物的心血管研究是猪。猪的心脏是最相似的人的心脏在大小, 解剖学和生理方面3,6。与人的心脏相似, 猪心脏的心肌不拥有广泛的抵押循环6。因此, 猪心不耐受急性冠状动脉闭塞, 但它能耐受渐进性冠状动脉闭塞。如果冠状动脉缓慢闭塞, 可作为慢性心肌缺血、慢性心肌梗死和心力衰竭的模型,5,6,9,10,11,12,13. 慢性心肌缺血可通过支架置入或放置液压封堵器、固定狭窄的堵塞或 ameroid 的缩窄引起。在各种出版物中详细列出的所有这些方法都有其优缺点6,9,13但最常用的方法是 ameroid 放置5, 6、10、11。
ameroid 缩, 包括在不锈钢, 塑料或钛环内包裹的酪蛋白材料。一旦放置在动脉周围 (通常是左前降冠状动脉 (童子) 或左旋冠脉 (漏)), 酪蛋白材料吸收周围的液体, 导致内腔逐渐缩小, 模仿缓慢的狭窄动脉和最终导致完全闭塞9,13,14。这个过程本身或与其他方法一起使用的结果是一个区域的慢性心肌缺血和/或梗塞的心脏左心室是有用的开发和评估新的成像技术8, 10,15, 治疗治疗7,16,17,18和手术程序19,20。

<table><tbody><tr><td>Anesthesia: ketamine</td><td>Putney, INC</td><td></td><td>Dose: 25mg/kg, IM</td></tr><tr><td>Anesthesia: midazolam</td><td>App Pharmaceuticals</td><td></td><td>Dose: 0.75mg/kg, IM</td></tr><tr><td>Anesthesia: isoflurane</td><td>Baxter</td><td></td><td>Dose: 1-3%, INH</td></tr><tr><td>Antibiotics: amoxicillin and clavulanate potassium</td><td>WG Critical Care</td><td></td><td>Dose: 15mg/kg, IV</td></tr><tr><td>Antibiotics: piperacillin and tazobactam</td><td>Fresenius Kabl</td><td></td><td>Dose: 100mg/kg, PO</td></tr><tr><td>Analgesia: buprenorphine (sustained release)</td><td>Zoo Pharm</td><td></td><td>10mg/ml bottle, Dose: 0.2mg/kg SC</td></tr><tr><td>Analgesia: fentanyl patch</td><td>Mylan</td><td></td><td>Dose: 25-50mcg/hr, TD</td></tr><tr><td>Analgesia: bupivicaine 0.25%</td><td>Hospira</td><td></td><td>Give SC at incision site for analgesia</td></tr><tr><td>Alcohol 70%</td><td>Humco</td><td>NDC 0395-4202-28</td><td>for scrubbing surgical site</td></tr><tr><td>Chlorhexidine scrub 2%</td><td>Vet One</td><td>510083</td><td>for scrubbing surgical site</td></tr><tr><td>Datex-Ohmeda Aestiva /5 anesthesia machine</td><td>GE Healthcare Madison WI.</td><td></td><td></td></tr><tr><td>Pediatric anesthesia circuit</td><td>Westmed</td><td>7-8901</td><td>www.westmedinc.com</td></tr><tr><td>Water blanket</td><td>Cincinnati Sub Zero</td><td>Blanketrol 2</td><td></td></tr><tr><td>EKG</td><td>Medtronics- Physiocontrol</td><td>LifePak 20</td><td></td></tr><tr><td>Oxygen saturation monitor</td><td>GE Healthcare Madison WI.</td><td></td><td></td></tr><tr><td>Temperature probe</td><td>GE Healthcare Madison WI.</td><td></td><td></td></tr><tr><td>Electrical cautery unit</td><td>Valley Labs</td><td>Force 2</td><td>Cut-30 Coag-40</td></tr><tr><td>Endotracheal tube</td><td>Hudson RCI</td><td>HUD510312</td><td>Hudson brand - appropriate size for animal</td></tr><tr><td>Intravenous catheter, size 20 gauge</td><td>Santa Cruz Biotechnology, Inc</td><td>SC-360097</td><td>Fluid and drug administration</td></tr><tr><td>Lactated Ringers Solution</td><td>Hospira</td><td>NDC 0409-7953-03</td><td></td></tr><tr><td>Macro IV drip set 15 drops/ml</td><td>Hospira</td><td>12672-28</td><td></td></tr><tr><td>Surgical gowns</td><td>Kimberly Clark</td><td>90142</td><td></td></tr><tr><td>Utility drapes</td><td>Kimberly Clark</td><td>89731</td><td></td></tr><tr><td>Adult laparotomy drape</td><td>Medline</td><td>DYNJP3004</td><td></td></tr><tr><td>Sterile surgical gloves</td><td>Cardinal Health (Allegiance)</td><td>22537-570</td><td>Size 7 - use appropriate size for surgeon</td></tr><tr><td>Needle mat - sterile</td><td>Medline</td><td>NC30MBR</td><td></td></tr><tr><td>Cautery pencil</td><td>Medline</td><td>ESPB 2000</td><td></td></tr><tr><td>Suction tubing</td><td>Medline</td><td>DYND50251</td><td></td></tr><tr><td>Suction tip; Yankauer</td><td>Medline</td><td>DYND50130</td><td></td></tr><tr><td>Suction cannister</td><td>Cardinal Health (Allegiance)</td><td>65651-220</td><td></td></tr><tr><td>Ameroid constrictors sizes 2.5mm -3.5mm</td><td>Research Instruments SW, Inc.</td><td>760-764-9411</td><td>Types: Stainless steel, titanium, or plastic</td></tr><tr><td>3-way stopcock</td><td>Cardinal Health (Allegiance)</td><td>455991</td><td>For chest tube</td></tr><tr><td>Stomach tube - 18 Fr</td><td>Cardinal Health (Allegiance)</td><td>DC4418</td><td>For chest tube</td></tr><tr><td>60cc syringe</td><td>Cardinal Health (Allegiance)</td><td>SY35060LL</td><td>For chest tube</td></tr><tr><td>3cc syringe</td><td>Cardinal Health (Allegiance)</td><td>SY35003LL</td><td>For post-op analgesia injection</td></tr><tr><td>Skin stapler - 35W</td><td>Ethicon&amp;nbsp; Endo-Surgery</td><td>PMW 35</td><td>skin closure</td></tr><tr><td>Scalpel blade - size #10</td><td>Cardinal Health (Allegiance)</td><td>32295-010</td><td></td></tr><tr><td>Mini silicone vessel loops 1 Pak</td><td>Aspen Surgical</td><td>011001PBX</td><td>for elevating circumflex artery to apply ameroid</td></tr><tr><td>1 (polypropylene) taper</td><td>Ethicon</td><td>BB #8425H</td><td>close ribs</td></tr><tr><td>2-0 (polypropylene) taper</td><td>Ethicon</td><td>SH #8523</td><td>close muscle layers</td></tr><tr><td>4-0 (polypropylene) taper</td><td>Ethicon</td><td>BB #8581H</td><td>close pericardium</td></tr><tr><td>20 gauge needle</td><td>Cardinal Health (Allegiance)</td><td>81-200219</td><td>post-op analgesia injection</td></tr><tr><td>antimicrobial drape</td><td>3M</td><td>6640EZ</td><td></td></tr><tr><td>Finochietto rib retractor - infant size</td><td>Codman</td><td>50-8057</td><td></td></tr><tr><td>Potts-Smith scissors</td><td>Roboz</td><td>RS-6043</td><td></td></tr><tr><td>Babcock forceps</td><td>Roboz</td><td>RS-8022</td><td></td></tr><tr><td>Pean hemostatic forceps curved</td><td>Codman</td><td>30-4565</td><td></td></tr><tr><td>scalpel handle #7</td><td>Codman</td><td>11-5534</td><td></td></tr><tr><td>Brown Adson forceps</td><td>Roboz</td><td>RS-5231</td><td></td></tr><tr><td>Debakey forceps</td><td>Roboz</td><td>RS-7562</td><td></td></tr><tr><td>Mayo scissors</td><td>Roboz</td><td>RS-6870SC</td><td></td></tr><tr><td>Metzenbaum dissecting scissors</td><td>Codman</td><td>36-5011</td><td></td></tr><tr><td>Metzenbaum dissecting scissors</td><td>Codman</td><td>36-5016</td><td></td></tr><tr><td>Mayo-Hegar needle holder</td><td>Codman</td><td>36-2017</td><td></td></tr><tr><td>Ryder needle holder</td><td>Codman</td><td>36-3012</td><td></td></tr><tr><td>Kelly hemostatic forceps</td><td>Roboz</td><td>RS-7130</td><td></td></tr><tr><td>Reynolds hemostatic forcep</td><td>Roboz</td><td>RS-7211</td><td></td></tr><tr><td>Weitlander retractor</td><td>Roboz</td><td>RS-8612</td><td></td></tr><tr><td>Yorkshire domestic pigs</td><td></td><td></td><td></td></tr></tbody></table>

a chronic cardiac ischemia model in swine using an ameroid constrictor

心血管疾病仍然是美国死亡率的头号原因。有许多方法来治疗这些疾病, 但不管采用何种方法, 都需要一个体内模型来测试每种治疗。猪是心血管疾病最常用的大型动物模型之一。它的心脏是非常相似的在解剖学和作用对人。ameroid 放置技术在心脏缺血区产生, 在心肌梗死的研究中有许多有用的应用。该模型已用于外科研究, 药物研究, 成像技术和细胞疗法。
有几种方法可诱导心脏缺血区。每一个都有其优缺点, 但 ameroid 的位置仍然是最广泛使用的技术。使用 ameroid 的主要优点是它在现有的研究中的流行程度, 它在各种大小的可用性, 以适应解剖和血管的大小, 以收缩, 手术是一个相对简单的程序, 和术后监测是最小的, 因为没有外部设备可供维护。本文对 ameroid 括约肌放置的适当技术进行了详细的综述。

在分析了在两年的时间内在我们的工厂进行的 ameroid 安置手术的数据后, 我们发现存活率为80%。该程序是对25只在 12-15 公斤重的约克郡猪进行的。在25只猪中, 有20只存活到随访过程中, 2 fibrillated, 在关闭后不久死亡, 2 人因严重心力衰竭和肺水肿而被安乐死, 1 例在随访中有麻醉死亡。尸检发现在手术后24小时内死亡的动物的左心室梗塞区。这是怀疑, 但无法证实, 动脉避免由于存在的 ameroid, 因为 ameroid 的流明仍然开放。从那些因心力衰竭而被安乐死的动物身上得到的 ameroids 检查。18天内腔内完全闭合。
存活的动物在28天的 post-ameroid 位置进行磁共振成像 (MRI), 以测量缺血区的心脏功能和大小。图 2和图 3分别显示了从带有钛包 ameroid 的猪和带有塑料装箱 ameroid 的猪身上获得的 MRI 图像。成像后, 第二次开胸手术, 无论是细胞注射或假手术。动物被跟随了, 只要16星期 post-ameroid 安置。
<img alt="Figure 1" class="xfigimg" src="/files/ftp_upload/56190/56190fig1.jpg"> 
图 1: ameroid 放置过程中的猪心脏图像。(A)猪心脏的图像, 显示童子、漏和钝的边缘动脉 (OM)。(B)在 ameroid 放置前解剖的漏动脉的图像。(C)图像的正确放置 ameroid 周围的漏与开放的 ameroid 面临或远离心脏。<a href="//ecsource.jove.com/files/ftp_upload/56190/56190fig1large.jpg" target="_blank">请单击此处查看此图的较大版本.</a>
<img alt="Figure 2" class="xfigimg" src="/files/ftp_upload/56190/56190fig2.jpg"> 
图 2: 用钛包裹的 ameroid 的猪心脏 MRI 图像.在漏动脉上放置一颗钛包 ameroid 后四周的猪心脏的 MRI 图像。箭头指向由钛创造的工件。<a href="//ecsource.jove.com/files/ftp_upload/56190/56190fig2large.jpg" target="_blank">请单击此处查看此图的较大版本.</a>
<img alt="Figure 3" class="xfigimg" src="/files/ftp_upload/56190/56190fig3.jpg"> 
图 3: 猪心脏的 MRI 图像与塑料包裹的 ameroid.四周后, 在漏动脉上放置一个塑料包裹 ameroid 的猪心脏的 MRI 图像。箭指向 ameroid 的蟒蛇。未观察到工件。<a href="//ecsource.jove.com/files/ftp_upload/56190/56190fig3large.jpg" target="_blank">请单击此处查看此图的较大版本.</a>

Watch this Scientific Journal Video about A Chronic Cardiac Ischemia Model in Swine Using an Ameroid Constrictor at JoVE.com

A Chronic Cardiac Ischemia Model in Swine Using an Ameroid Constrictor

应用 Ameroid 的猪慢性心肌缺血模型

该协议的目的是证明在猪模型中放置一个延迟压缩装置 (ameroid 缩) 在冠状动脉周围。该装置创造了心脏缺血区, 这是有用的研究新的诊断成像技术和新的治疗方法。

Cardiovascular disease remains the number one cause of mortality in the United States. There are numerous approaches to treating these diseases, but ...

a-chronic-cardiac-ischemia-model-in-swine-using-an-ameroid-constrictor

Research

JoVE Journal

Medicine

10.5K 次观看.  National Institutes of Health. 该协议的目的是证明在猪模型中放置一个延迟压缩装置 (ameroid 缩) 在冠状动脉周围。该装置创造了心脏缺血区, 这是有用的研究新的诊断成像技术和新的治疗方法。

视频: A Chronic Cardiac Ischemia Model in Swine Using an Ameroid Constrictor

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 ...

科研

医学

Surgical Placement of Catheters for Long-term Cardiovascular Exercise Testing in Swine

This protocol describes the surgical procedure to chronically instrument swine and the procedure to exercise swine on a motor-driven treadmill. Early cardiopulmonary dysfunction is difficult to diagnose, particularly in animal models, as cardiopulmonary function is often measured invasively, requiring anesthesia. As many anesthetic agents are cardiodepressive, subtle changes in cardiovascular function may be masked. In contrast, chronic instrumentation allows for measurement of cardiopulmonary function in the awake state, so that measurements can be obtained under quiet resting conditions, without the effects of anesthesia and acute surgical trauma. Furthermore, when animals are properly trained, measurements can also be obtained during graded treadmill exercise.
Flow probes are placed around the aorta or pulmonary artery for measurement of cardiac output and around the left anterior descending coronary artery for measurement of coronary blood flow. Fluid-filled catheters are implanted in the aorta, pulmonary artery, left atrium, left ventricle and right ventricle for pressure measurement and blood sampling. In addition, a 20 G&#160;catheter is positioned in the anterior interventricular vein to allow coronary venous blood sampling.
After a week of recovery, swine are placed on a motor-driven treadmill, the catheters are connected to pressure and flow meters, and swine are subjected to a five-stage progressive exercise protocol, with each stage lasting 3 min. Hemodynamic signals are continuously recorded and blood samples are taken during the last 30 sec of each exercise stage.
The major advantage of studying chronically instrumented animals is that it allows serial assessment of cardiopulmonary function, not only at rest but also during physical stress such as exercise. Moreover, cardiopulmonary function can be assessed repeatedly during disease development and during chronic treatment, thereby increasing statistical power and hence limiting the number of animals required for a study.

Here we present a protocol to assess cardiopulmonary function in awake swine, at rest and during graded treadmill exercise. Chronic instrumentation allows for repeated hemodynamic measurements uninfluenced by cardiodepressive anesthetic agents.

导管手术放置了长期的心血管运动试验猪

This protocol describes the surgical procedure to chronically instrument swine and the procedure to exercise swine on a motor-driven treadmill. Early ...

Surgical Swine Model of Chronic Cardiac Ischemia Treated by Off-Pump Coronary Artery Bypass Graft Surgery

Chronic cardiac ischemia that impairs cardiac function, but does not result in infarct, is termed hibernating myocardium (HM). A large clinical subset of coronary artery disease (CAD) patients have HM, which in addition to causing impaired function, puts them at higher risk for arrhythmia and future cardiac events. The standard treatment for this condition is revascularization, but this has been shown to be an imperfect therapy. The majority of pre-clinical cardiac research focuses on infarct models of cardiac ischemia, leaving this subset of chronic ischemia patients largely underserved. To address this gap in research, we have developed a well-characterized and highly reproducible model of hibernating myocardium in swine, as swine are ideal translational models for human heart disease. In addition to creating this unique disease model, we have optimized a clinically relevant treatment model of coronary artery bypass surgery in swine. This allows us to accurately study the effects of bypass surgery on heart disease, as well as investigate additional or alternate therapies. This model surgically induces single vessel stenosis by implanting a constrictor on the left anterior descending (LAD) artery in a young pig. As the pig grows, the constrictor creates a gradual stenosis, resulting in chronic ischemia with impaired regional function, but preserving tissue viability. Following the establishment of the hibernating myocardium phenotype, we perform off-pump coronary artery bypass graft surgery to revascularize the ischemic region, mimicking the gold-standard treatment for patients in the clinic.

This protocol presents a surgical large animal model of chronic, single vessel ischemia that results in regional abnormalities but does not create infarct, known as hibernating myocardium. Following establishment of chronic ischemia, animals are treated with off-pump LIMA-LAD coronary artery bypass graft surgery to revascularize the ischemic tissue.

非体外循环冠状动脉旁路移植术治疗慢性心肌缺血的外科猪模型

Chronic cardiac ischemia that impairs cardiac function, but does not result in infarct, is termed hibernating myocardium (HM). A large clinical subset of ...

Standardized Model of Ventricular Fibrillation and Advanced Cardiac Life Support in Swine

Cardiopulmonary resuscitation after cardiac arrest, independent of its origin, is a regularly encountered medical emergency in hospitals as well as preclinical settings. Prospective randomized trials in human subjects are difficult to design and ethically ambiguous, which results in a lack of evidence-based therapies. The model presented in this report represents one of the most common causes of cardiac arrests, ventricular fibrillation, in a standardized setting in a large animal model. This allows for reproducible observations and various therapeutic interventions under clinically accurate conditions, hence facilitating the generation of better evidence and eventually the potential for improved medical treatment.

Cardiopulmonary resuscitation and defibrillation are the only effective therapeutic options during cardiac arrest caused by ventricular fibrillation. This model presents a standardized regimen to induce, assess, and treat this physiological state in a porcine model, thus providing a clinical approach with various opportunities for data collection and analysis.

猪心室颤动和高级心脏生命支持标准化模型

Cardiopulmonary resuscitation after cardiac arrest, independent of its origin, is a regularly encountered medical emergency in hospitals as well as ...

Novel Percutaneous Approach for Deployment of 3D Printed Coronary Stenosis Implants in Swine Models of Ischemic Heart Disease

Minimally invasive methods for creating models of focal coronary narrowing in large animals are challenging. Rapid prototyping using three-dimensionally (3D) printed coronary implants can be employed to percutaneously create a focal coronary stenosis. However, reliable delivery of the implants can be difficult without the use of ancillary equipment. We describe the use of a mother-and-child coronary guide catheter for stabilization of the implant and for effective delivery of the 3D printed implant to any desired location along the length of the coronary vessel. The focal coronary narrowing was confirmed under coronary cineangiography and the functional significance of the coronary stenosis was assessed using gadolinium-enhanced first-pass cardiac perfusion MRI. We showed that reliable delivery of 3D printed coronary implants in swine models (n = 11) of ischemic heart disease can be achieved through repurposing mother-and-child coronary guide catheters. Our technique simplifies the percutaneous delivery of coronary implants to create closed-chest swine models of focal coronary artery stenosis and can be performed expeditiously, with a low procedural failure rate.

We describe a novel, cost-effective, and efficient technique for percutaneous delivery of three-dimensionally printed coronary implants to create closed-chest swine models of ischemic heart disease. The implants were fixed in place using a mother-and-child extension catheter with high success rate.

在缺血性心脏病的猪模型中部署3D打印冠状动脉狭窄植入物的新颖的皮下方法

Minimally invasive methods for creating models of focal coronary narrowing in large animals are challenging. Rapid prototyping using three-dimensionally ...

An Intact Pericardium Ischemic Rodent Model

This protocol has shown that the pericardium and its contents play an essential anti-fibrotic role in the ischemic rodent model (coronary ligation to induce myocardial injury). The majority of pre-clinical myocardial infarction models require the disruption of pericardial integrity with loss of the homeostatic cellular milieu. However, recently a methodology has been developed by us to induce myocardial infarction, which minimizes pericardial damage and retains the heart&#39;s resident immune cell population. An improved cardiac functional recovery in mice with an intact pericardial space following coronary ligation has been observed. This method provides an opportunity to study inflammatory responses in the pericardial space following myocardial infarction. Further development of the labeling techniques can be combined with this model to understand the fate and function of pericardial immune cells in regulating the inflammatory mechanisms that drive remodeling in the heart, including fibrosis.

This protocol outlines the steps for inducing myocardial infarction in mice while preserving the pericardium and its contents.

完整的心包缺血性啮齿动物模型

This protocol has shown that the pericardium and its contents play an essential anti-fibrotic role in the ischemic rodent model (coronary ligation to ...

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 ...

Swine Models of Aneurysmal Diseases for Training and Research

Large animal models, specifically swine, are widely used to research cardiovascular diseases and therapies, as well as for training purposes. This paper describes two different aneurysmal swine models that may help researchers to study new therapies for aneurysmal diseases. These aneurysmal models are created by surgically adding a pouch of tissue to carotid arteries in swine. When the model is used for research, the pouch must be autologous; for training purposes, a synthetic pouch suffices.
First, the right external jugular vein (EJV) and right common carotid artery (CCA) must be surgically exposed. The EJV is ligated and a vein pouch fashioned from a short segment. This pouch is then sutured to an elliptical arteriotomy performed in the CCA. Animals must be kept heparinized during model creation, and local vasodilators may be used to decrease vasospasms. Once the suture is completed, correct blood flow should be inspected, checking for bleeding from the suture line and vessel patency. Finally, the surgical incision is closed by layers and an angiography performed to image the aneurysmal model.
A simplification of this aneurysmal carotid model that decreases invasiveness and surgical time is the use of a synthetic, rather than venous, pouch. For this purpose, a pouch is tailored in advance with a segment of a polytetrafluoroethylene (PTFE) prosthesis, one end of which is sutured close using polypropylene vascular suture and sterilized prior to surgery. This "sac" is then attached to an arteriotomy performed in the CCA as described. 
Although these models do not reproduce many of the physiopathological events related to aneurysm formation, they are hemodynamically similar to the situation found in the clinical setting. Therefore, they can be used for research or training purposes, allowing physicians to learn and practice different endovascular techniques in animal models that are close to the human system.

Description of two different aneurysmal swine models for neuroradiology training courses and research studies. This study provides evidence of the feasibility of these aneurysm porcine model creations and the reproducible methods that are close to the clinical setting.

Large animal models, specifically swine, are widely used to research cardiovascular diseases and therapies, as well as for training purposes. This paper ...

用于研究压力超负荷诱发的心力衰竭的升主动脉束带

A Minimally Invasive Model of Aortic Stenosis in Swine

Large animal models of heart failure play an essential role in the development of new therapeutic interventions due to their size and physiological similarities to humans. Efforts have been dedicated to creating a model of pressure-overload induced heart failure, and ascending aortic banding while still supra-coronary and not a perfect mimic of aortic stenosis in humans, closely resembling the human condition.
The purpose of this study is to demonstrate a minimally invasive approach to induce left ventricular pressure overload by placing an aortic band, precisely calibrated with percutaneously introduced high-fidelity pressure sensors. This method represents a refinement of the surgical procedure (3Rs), resulting in homogenous trans-stenotic gradients and reduced intragroup variability. Additionally, it enables swift and uneventful animal recovery, leading to minimal mortality rates. Throughout the study, animals were followed for up to 2 months after surgery, employing transthoracic echocardiography and pressure-volume loop analysis. However, longer follow-up periods can be achieved if desired. This large animal model proves valuable for testing new drugs, particularly those targeting hypertrophy and the structural and functional alterations associated with left ventricular pressure overload.

作者聚焦:开发用于可靠且可重复的心血管研究的微创大型动物模型 

This protocol describes a minimally invasive surgical procedure for ascending aortic banding in swine.

猪主动脉瓣狭窄的微创模型

Large animal models of heart failure play an essential role in the development of new therapeutic interventions due to their size and physiological ...