Name: tachycardia-induced cardiomyopathy as a chronic heart failure model in swine
Uploaded: 2018-02-17T15:00:00.000+00:00
Duration: 10 min 8 s
Description: Watch this Scientific Journal Video about Tachycardia-Induced Cardiomyopathy As a Chronic Heart Failure Model in Swine at JoVE.com

这项工作得到了查尔斯大学研究资助 GA 英国538216号和 ga 英国1114213号的支持。

这项实验性议定书是由查尔斯大学第一医学院的机构动物专家委员会审查和批准的, 并在大学生理学系的实验实验室进行, 第一院医学, 查尔斯大学在布拉格捷克共和国根据246/1992 号法令, 关于保护动物免受虐待。根据2011《国家科学院出版社出版的第八版实验动物护理指南》, 对所有动物进行了治疗和照顾。所有的程序都是按照标准的兽医惯例进行的, 在每项研究完成后, 动物被牺牲, 尸检执行。由于解剖学的原因, 本实验包括五只健康的杂交雌性猪 (Sus 鲷家蝇), 其年龄可达6个月。他们的平均体重是 66, 20 公斤的数据收集当天。
1. 全身麻醉
<ol><li>禁食1天后, 通过肌肉注射咪达唑仑 (0.3 毫克/千克) 和盐酸氯胺酮 (15-20 毫克/千克) 对臀区域进行麻醉。</li>
	<li>将外周套管插入边缘耳静脉, 用于静脉用药。</li>
	<li>静脉 boluses 丙泊酚 (2 毫克/千克) 和吗啡 (0.1-0.2 毫克/千克)。</li>
	<li>通过面膜向动物提供氧气, 并提前气管插管, 并带一个直径 6.5-7.5 毫米的袖口气管导管。</li>
	<li>采用异丙酚 (6-12 毫克/千克/小时), 继续全身静脉麻醉, 咪达唑仑 (0.1-0.2 毫克/千克/小时), 吗啡 (0.1-0.2 毫克/千克/小时), 根据个别反应调整剂量-抑制自发性呼吸, 角膜反射, 和motoric 反应。用药膏保护动物的眼睛, 防止干燥。</li>
	<li>通过闭环自动装置设置为自适应支持通风操作机械通气, 以维持目标潮汐 CO2的 38-42 mmHg 和充足的血红蛋白饱和度 95-99%。监测所有重要功能, 特别是心率和体温。</li>
	<li>将其腿轻轻地固定在仰卧位的操作表上, 将动物附着在一起。</li>
	<li>采用耳静脉插管法 (静脉注射1克头孢唑啉) 治疗广谱抗生素。</li>
</ol>2. 心室铅植入术
<ol><li>用剃刀在 (1) 胸锁乳突肌上方的颈静脉区, (2) 在动物颈部的后侧一侧旁区域, 定位外科部位并正确剃须皮肤。</li>
	<li>采用超声血管探针, 可视化颈外静脉, 并标记其在皮肤上的位置。定位颈动脉并预防其损伤。</li>
	<li>经广泛的皮肤消毒使用聚维酮碘, 覆盖与无菌手术悬垂与孔在明显的颈动脉区域。</li>
	<li>准备所有必要的工具, 为起搏器植入和保持他们不育。在整个过程中保持一个不育的环境是至关重要的。</li>
	<li>切开皮肤平行于颈外静脉, 形成浅皮下袋, 软组织不超过10毫米深。不要暴露任何大型船只。</li>
	<li>从预制袋的底部, 使用标准的 Seldinger 技术, 将鞘插入颈外静脉。首先, 插入一个软尖端导丝通过12G 穿刺针, 然后在导丝介绍一个7法国塑料撕裂介绍人鞘与扩张。</li>
	<li>在透视指导下, 引入一个58厘米起搏铅通过这个鞘和位置它的尖端到右心室的顶端。然后, 去掉鞘并将电极的主动尖端紧盯着它的螺旋状的心肌。</li>
	<li>测试起搏参数-心室心电图和阻抗的导感信号必须稳定, 起搏阈值应低于 1 V 的振幅和0.4 毫秒的脉宽。</li>
	<li>在起搏导线上拉一个橡胶套管, 并用两条不可吸收的缝线编织线缝合, 将两个固定在颈动脉皮下袋的底。重要的是, 考虑到动物未来可能的生长, 必须插入足够长的起搏铅。</li>
</ol>3. 皮下铅隧道
<ol><li>把动物放在它的一侧, 对以前剃过的皮肤区域进行消毒, 然后用一个空洞的无菌的手术悬垂盖住。确保颈静脉皮袋和铅保持不育。</li>
	<li>切开的皮肤侧向骨干和形成一个深, 宽敞, 皮下口袋。使用枯燥的准备, 并停止任何可能的出血。</li>
	<li>从无菌输液器中取一个软橡胶延伸管, 并切断两端。使用隧道工具, 预制一个直接皮下隧道连接颈动脉和背部皮下口袋与这个延长管。</li>
	<li>将管的游离端连接到心室引线上, 将其拉到其 IS-1 连接器上, 并通过拔管背将引导穿过预制的隧道插入背部皮下口袋。这可能是有用的, 以确保连接与丝绸领带。</li>
	<li>移除隧道工具和延伸管, 从背部皮下口袋露出心室铅。</li>
</ol>4. 起搏器植入术
<ol><li>用 "Y" 连接部分建立植入式双腔心脏起搏器装置。"Y" 连接允许两个起搏器输出的收敛连接与单个起搏引线 (图 1和图 2) 连接在一起。此设置稍后将提供一系列的起搏频率。</li>
	<li>连接起搏引线后, 将所有 IS-1 连接螺钉固定在起搏器头单元和 "Y" 引线连接上。</li>
	<li>隐藏整个起搏系统在深背口袋。必须有足够的空间来舒适地容纳起搏器单元和任何多余的铅。</li>
	<li>检查最后的起搏参数。确保心脏心室起搏是可能的两个起搏器输出。</li>
	<li>冲洗与聚维酮碘和关闭两个皮下口袋。使用可吸收的编织线缝合纤维组织层和不可吸收的缝合为皮肤适应。</li>
</ol>5. 术后护理
<ol><li>仔细观察动物, 直到它恢复足够的意识。</li>
	<li>继续在广泛的静脉抗生素治疗方案, 直到伤口愈合-头孢唑啉1克每12小时管理镇痛药在适当的剂量, 例如,吗啡0.2 毫克/千克每 6-12 h 3 天通过皮下注射。如有必要, 进行剂量调整, 以充分预防疼痛。</li>
	<li>在室温下, 将动物放在舒适、平静的设施中。允许自由进入水和适当的营养。</li>
	<li>定期用无菌磨砂包扎伤口, 以保持清洁愈合。</li>
	<li>在手术后提供休息, 保持起搏器受原生心律抑制至少3天。</li>
	<li>清除不可吸收的皮肤缝合时, 完全愈合, 大约 10-14 天后的程序。</li>
</ol>6. 起搏协议
<ol><li>在适当的休息期后启动起搏协议。最初, 通过将双腔起搏器设置为模式 D00, 100 节拍/分钟, 并同时调整 AV 延迟为300毫秒 (与速度间隔完全匹配, 请参阅表 1), 将节奏心室心率提高到200次/分钟。选择两个输出中的单极起搏。</li>
	<li>在2周 (图 3) 之后, 将节奏心率逐步提高到220次/分钟, 1 周后240次跳动/分钟。保持连续起搏在这个频率, 除非它不是血流动力学容忍。如果 HF 进展得太快, 在再增加一周之后, 降低心跳速度。</li>
	<li>每日使用心脏跳动、心电图和起搏器审讯的听诊来验证心率和恒定的起搏参数, 包括电池寿命。</li>
</ol>7. 心力衰竭的诱导和监测
<ol><li>确保由专业兽医定期护理, 并监测动物的一般健康状况。临床观察增加本机心脏和呼吸率, 评估周围脉搏氧, 减少自发的体力活动或食欲提供有关 HF 进展的信息。</li>
	<li>利用无线经皮起搏器审讯的优势, 如果可能的话, 持续心电图记录-频繁的非持续性心室心动 (VT) 是严重 HF 进展的标志。</li>
	<li>使用超声心动图评估, 以揭示结构和功能的心脏变化。注意找到一个最佳的图像窗口根据猪的解剖和心脏扩张-对于一个典型的4室视图, 将传感器放置在右侧的剑突和角度, 以指向颈部或左肩。对于短轴视图, 请使用肋间窗口。在几周后, 在原生心律和房室 regurgitations 中降低心室射血分数是值得注意的。 注意: 高速率心室起搏耐受存在显著的个体差异。因此, 经常监测和个别适应调整的起搏协议是必要的。</li>
</ol><img alt="Figure 1" class="xfigimg" src="/files/ftp_upload/57030/57030fig1.jpg"> 图 1: 心脏起搏单元示意图.双腔起搏器 (1), 一个 "Y" 形适配器 (2) 传导 convergently 两个起搏器输出一起到一个单一的起搏铅 (3)。铅的尖端被固定在 RV 腔 (4) 的顶端部分。此设置提供了一系列高起搏频率。<a href="//ecsource.jove.com/files/ftp_upload/57030/57030fig1large.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/57030/57030fig2.jpg"> 图 2: 心脏起搏单元.X 射线 (A) 和摄影 (B) 的双腔起搏器 (1), 一个 "Y" 形适配器 (2) 和心室起搏铅 (3)。<a href="//ecsource.jove.com/files/ftp_upload/57030/57030fig2large.jpg" target="_blank">请单击此处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>期望 HR</td>
			<td>设置起搏器率</td>
			<td>速度与速度间隔</td>
		</tr>
<tr>
<td>节拍/分钟</td>
			<td>节拍/分钟</td>
			<td>女士</td>
		</tr>
<tr>
<td></td>
			<td></td>
			<td></td>
		</tr>
<tr>
<td>200</td>
			<td>100</td>
			<td>300</td>
		</tr>
<tr>
<td>220</td>
			<td>110</td>
			<td>270</td>
		</tr>
<tr>
<td>240</td>
			<td>120</td>
			<td>250</td>
		</tr>
<tr>
<td>250</td>
			<td>125</td>
			<td>240</td>
		</tr>
</tbody></table>表 1: 起搏器参数.为了允许高心率的心脏起搏与植入室内改良双腔起搏器单元, 该表显示预期的节奏心率 (HR) 和匹配速度的速度间隔值。起搏器必须设置为 D00 操作模式, 速度为所需 HR 的一半, 而 AV 延迟设置为相应的速度, 以毫秒为单位的速度间隔。
<img alt="Figure 3" class="xfigimg" src="/files/ftp_upload/57030/57030fig3.jpg"> 图 3: 起搏协议.TIC 诱导的进步阶段在休息的时期以后开始3天。然后, 起搏器设置为 D00 模式, 其起搏频率为所需的节奏频率的 50%, 而 AV 延迟设置为与速度间隔的匹配速度 (见表 1)。多亏了 "Y" 形适配器, 两个起搏器输出都进行一个单一的起搏引线。bpm = 节拍/分钟。<a href="//ecsource.jove.com/files/ftp_upload/57030/57030fig3large.jpg" target="_blank">请单击此处查看此图的较大版本.</a>

作者没有什么可透露的。

慢性 HF 是严重的健康问题, 对发病率和死亡率有很大的贡献。HF 在人类中的发病机制和进展是复杂的, 因此适当的动物模型对于研究其潜在的机制和测试旨在干预本病严重疾病进展的新疗法是至关重要的。为了研究其发病机理, 大型动物模型被用于实验测试。
一般来说, 慢性 HF 的外科模型密切模仿这种疾病。与急性 hf 模型相比, 慢性 hf 模型可以更深入地了解病理生理学, 但代?...

新的心力衰竭治疗方法 (HF) 的多样性, 特别是在全球范围内使用的机械循环支持和体外膜氧合 (ECMO) 在临床实践中, 反映在前体实验试验。主要关注的是血液动力学的变化所造成的检查治疗方式, 即系统性血压1, 心肌收缩力, 压力和体积变化的心脏室和心脏工作2,3,动脉血流在全身和外周动脉, 以及代谢补偿4 -区域组织饱和度, 肺灌注和血气分析。其他研究是针对循环支持的长期影响5, 伴随炎症, 或发生溶血。所有这些类型的研究需要一个稳定的 biomodel 充血性 HF。
对于急性 HF2、6、7、8的实验模型, 大多数已发表的左心室 (LV) 表现和机械循环支持的血流动力学实验进行了研究。,9,10, 甚至在完全完整的心脏上。另一方面, 在临床实践中, 机械循环支持经常被应用于一种在以前存在慢性心脏病的基础上发展的循环失代偿状态。在这种情况下, 适应机制得到充分发展, 并可发挥重要作用, 不一致的结果观察, 根据 "尖锐或慢性" 的潜在心脏病11。因此, 一个稳定的慢性 HF 模型可以为病理生理机制和血流动力学提供新的见解。虽然有理由使用慢性 HF 模型是稀缺的-时间消耗准备, 心律不稳, 伦理问题和死亡率-他们的优势是明确的, 因为他们提供长期神经体液激活的存在,全身适应, 心肌细胞功能改变, 心肌和瓣膜结构改变12,13。
一般而言, 用于血流动力学研究的动物模型的可用性和多样性是广泛的, 为许多特定需求提供了选择。对于这些实验, 主要是猪, 犬, 绵羊, 或小鼠模型, 正在选择和提供一个良好的模拟预期的人体反应14。此外, 单器官实验的形式越来越频繁15。为了可靠地模仿 HF 的病理生理学, 循环正在被人为地恶化。对心脏的损伤可能是由各种方法造成的, 往往是由缺血、心律失常、压力超负荷或 cardiotoxic 作用引起的, 这些都导致了模型的血流动力学恶化。为了产生一个真正的慢性 HF 模型, 必须为发展整个生物体的长期适应提供时间。心动过速诱发的心肌病 (TIC) 是一种可靠稳定的模型, 可以通过实验动物快速心脏起搏产生。
结果表明, 在易感性的心脏, 长期持续不断的失常可能导致收缩功能障碍和扩张与减少的心脏输出。被称为 TIC 的条件首先在 1913年16中被描述, 在 1962年17的实验中被广泛使用, 现在已经是公认的紊乱。它的起源可能存在于各种类型的心律失常-室性和心室心动过速可导致收缩功能的渐进性恶化, 心室扩张, 以及包括腹水, 肿鼓, 嗜睡等症状的渐进性临床征象, 最终心脏失代偿导致晚期 HF, 如果不治疗, 死亡。
通过在动物模型中引入高速率心脏起搏, 观察了循环抑制的相似效应。在猪模型中, 心房或心室心率超过200次/分钟, 足以诱发末期 HF 在 3-5 周 (渐进期) 与 TIC 的特点, 虽然个体差异确实存在18, 19. 这些发现与失代偿性心肌病有很好的对应, 重要的是, 在停止起搏 (慢性相位)19,20,21,22,23。
猪、犬或绵羊 TIC 模型反复准备研究 HF14的病理生理学, 因为对 LV 的改变模仿扩张型心肌病24的特点。血流动力学特征有很好的描述-心室终末期舒张压增高, 心输出量降低, 系统性血管阻力增加, 心室扩张。相比之下, 墙体肥大没有被一致观察, 甚至壁薄也被一些研究人员描述为25,26。随着心室尺寸的发展, 房室瓣膜的返流发展为26。
在这份出版物中, 我们提出了一个协议, 以产生 TIC 长期快速心脏起搏在猪。本 biomodel 是研究失代偿性扩张型心肌病、慢性心力衰竭患者血流动力学及应用治疗效果的有力手段。

<table><tbody><tr><td>&lt;strong&gt;Medication&lt;/strong&gt;</td><td></td><td></td><td></td></tr><tr><td>midazolam</td><td>Roche</td><td>Dormicum</td><td>anesthetic</td></tr><tr><td>ketamine hydrochloride</td><td>Richter Gedeon</td><td>Calypsol</td><td>anesthetic</td></tr><tr><td>propofol</td><td>B.Braun</td><td>Propofol</td><td>anesthetic</td></tr><tr><td>cefazolin</td><td>Medochemie</td><td>Azepo</td><td>antibiotic</td></tr><tr><td>Silver Aluminium Aerosol</td><td>Henry Schein</td><td>9003273</td><td>tincture</td></tr><tr><td>povidone iodine</td><td>Egis Praha</td><td>Betadine</td><td>disinfection</td></tr><tr><td>morphine</td><td>Biotika Bohemia</td><td>Morphin 1% inj</td><td>analgetic</td></tr><tr><td>&lt;strong&gt;Tools&lt;/strong&gt;</td><td></td><td></td><td></td></tr><tr><td>Metzenbaum scissors, lancet with #22 blade, DeBakey forceps, needle driver</td><td>basic surgical equipment</td><td></td><td></td></tr><tr><td>cauterizer</td><td></td><td></td><td></td></tr><tr><td>2-0 Vicryl</td><td>Ethicon</td><td>V323H</td><td>absorbable braided suture</td></tr><tr><td>2-0 Perma-Hand Silk</td><td>Ethicon</td><td>A185H</td><td>silk tie suture</td></tr><tr><td>2-0 Prolene</td><td>Ethicon</td><td>8433H</td><td>non-absorbable suture</td></tr><tr><td>&lt;strong&gt;Diagnostic devices&lt;/strong&gt;</td><td></td><td></td><td></td></tr><tr><td>ESP C-arm</td><td>GE Healthcare</td><td>ESP</td><td>X-ray fluoro C-arm</td></tr><tr><td>Acuson x300</td><td>Siemens Healthcare</td><td></td><td>ultrasound system</td></tr><tr><td>Acuson P5-1</td><td>Siemens Healthcare</td><td></td><td>echocardiographic probe</td></tr><tr><td>Acuson VF10-5</td><td>Siemens Healthcare</td><td></td><td>sonographic vascular probe</td></tr><tr><td>3PSB, 4PSB and 6PSB</td><td>Transonic Systems</td><td></td><td>perivascular flow probes</td></tr><tr><td>TS420</td><td>Transonic Systems</td><td></td><td>perivascular flow module</td></tr><tr><td>TruWave&amp;nbsp;</td><td>Edwards Lifesciences</td><td>T001660A</td><td>fluid-filled pressure transducer</td></tr><tr><td>7.0F VSL Pigtail</td><td>Transonic Systems</td><td></td><td>pressure sensor catheter</td></tr><tr><td>INVOS 5100C Cerebral/Somatic Oximeter</td><td>Somanetics/Medtronic</td><td></td><td>near infrared spectroscopy</td></tr><tr><td>CCO Combo Catheter</td><td>Edwards Lifesciences</td><td>744F75</td><td>Swan-Ganz pulmonary artery catheter</td></tr><tr><td>Vigillace II</td><td>Edwards Lifesciences</td><td>VIG2E</td><td>cardiac output monitor</td></tr><tr><td>7.0F VSL Pigtail</td><td>Transonic Systems</td><td></td><td>pressure-volume catheter</td></tr><tr><td>ADV500</td><td>Transonic Systems</td><td></td><td>pressure-volume system</td></tr><tr><td>LabChart and PowerLab</td><td>ADInstruments</td><td></td><td>data acquisition and analysis system</td></tr><tr><td>Prism 6</td><td>GraphPad</td><td></td><td>statistical analysis software</td></tr><tr><td>&lt;strong&gt;Pacing devices&lt;/strong&gt;</td><td></td><td></td><td></td></tr><tr><td>ICS 3000</td><td>Biotronic</td><td>349528</td><td>pacemaker programmer</td></tr><tr><td>ERA 3000</td><td>Biotronic</td><td>128828</td><td>external pacemaker</td></tr><tr><td>Effecta DR</td><td>Biotronic</td><td>371199</td><td>dual-chamber pacemaker</td></tr><tr><td>Tendril STS</td><td>St. Jude Medical</td><td>2088TC/58</td><td>ventricular pacing lead</td></tr><tr><td>Lead permanent adapter</td><td>Osypka</td><td>Article 53422</td><td>convergent &quot;Y&quot; connecting part</td></tr><tr><td>Lead permanent adapter</td><td>Osypka</td><td>Article 53904</td><td>convergent &quot;Y&quot; connecting part</td></tr><tr><td>Tear-Away Introducer 7F</td><td>B.Braun</td><td>5210593</td><td>tear away introducer sheath&amp;nbsp;</td></tr><tr><td>Split Cath Tunneler</td><td>medComp</td><td>AST-L</td><td>tunneling tool</td></tr><tr><td>infusion line</td><td>MPH Medical Devices</td><td>2200045</td><td>connecting line</td></tr></tbody></table>

tachycardia-induced cardiomyopathy as a chronic heart failure model in swine

许多实验都需要一种稳定可靠的慢性心力衰竭模型来了解血流动力学或检测新治疗方法的效果。在此, 我们提出了这样一个模型的心动过速诱发心肌病, 可以产生的快速心脏起搏在猪。
一个单一的起搏铅被引入 transvenously 完全麻醉健康的猪, 到右心室的顶端, 并固定。它的另一端然后隧道背到旁地区。在那里, 它连接到一个内部的改良心脏起搏器单元, 然后植入皮下袋。
经过 4-8 周的快速心室起搏率为 200-240 节拍/分钟, 体格检查显示严重心力衰竭的迹象-呼吸急促, 自发性窦性心动过速, 和疲劳。超声心动图和 X 线显示所有心脏室、积液和严重收缩功能障碍的扩张。这些发现与失代偿性扩张型心肌病有很好的对应, 在停止起搏后也保留下来。
这种模型的心动过速诱发心肌病可用于研究进展性慢性心力衰竭的病理生理学, 尤其是血液动力学的变化所造成的新的治疗方式, 如机械循环支持。这种方法很容易执行, 结果是健壮和重现性的。

测试模型:在失代偿性慢性 HF 症状出现后, 麻醉和人工通气再次按照上述原则进行, 但由于心脏输出量降低27, 剂量调整。由于麻醉药可能 cardiodepressive 的影响, 需要对重要功能进行仔细的密集监测。
动物被附着在仰卧位, 所有侵入的方法开始。采用标准经皮腔内鞘, 对股静脉、动脉和颈静脉进行穿?...

Watch this Scientific Journal Video about Tachycardia-Induced Cardiomyopathy As a Chronic Heart Failure Model in Swine at JoVE.com

Tachycardia-Induced Cardiomyopathy As a Chronic Heart Failure Model in Swine

心动过速诱发的心肌病作为猪慢性心力衰竭模型的研究

本文提出了一种在猪中产生心动过速诱发心肌病的方案。该模型是研究进展性慢性心力衰竭的血流动力学和应用治疗效果的有效方法。

A stable and reliable model of chronic heart failure is required for many experiments to understand hemodynamics or to test effects of new treatment ...

tachycardia-induced-cardiomyopathy-as-chronic-heart-failure-model

Research

JoVE Journal

Medicine

13.4K 次观看.  Charles University. 本文提出了一种在猪中产生心动过速诱发心肌病的方案。该模型是研究进展性慢性心力衰竭的血流动力学和应用治疗效果的有效方法。

视频: Tachycardia-Induced Cardiomyopathy As a Chronic Heart Failure Model in Swine

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 ...

A Chronic Cardiac Ischemia Model in Swine Using an Ameroid Constrictor

Cardiovascular disease remains the number one cause of mortality in the United States. There are numerous approaches to treating these diseases, but regardless of the approach, an in vivo model is needed to test each treatment. The pig is one of the most used large animal models for cardiovascular disease. Its heart is very similar in anatomy and function to that of a human. The ameroid placement technique creates an ischemic area of the heart, which has many useful applications in studying myocardial infarction. This model has been used for surgical research, pharmaceutical studies, imaging techniques, and cell therapies.
There are several ways of inducing an ischemic area in the heart. Each has its advantages and disadvantages, but the placement of an ameroid constrictor remains the most widely used technique. The main advantages to using the ameroid are its prevalence in existing research, its availability in various sizes to accommodate the anatomy and size of the vessel to be constricted, the surgery is a relatively simple procedure, and the post-operative monitoring is minimal, since there are no external devices to maintain. This paper provides a detailed overview of the proper technique for the placement of the ameroid constrictor.

The purpose of this protocol is to demonstrate the placement of a delayed constricting device (an ameroid constrictor) around a coronary artery in a swine model. This device creates an ischemic area of the heart that is useful for studying new diagnostic imaging techniques and new methods of treatment.

应用 Ameroid 的猪慢性心肌缺血模型

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

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 ...

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 ...

Post-Myocardial Infarction Heart Failure in Closed-chest Coronary Occlusion/Reperfusion Model in G&#246;ttingen Minipigs and Landrace Pigs

The development of heart failure is the most powerful predictor of long-term mortality in patients surviving acute myocardial infarction (MI). There is an unmet clinical need for prevention and therapy of post-myocardial infarction heart failure (post-MI HF). Clinically relevant pig models of post-MI HF are prerequisites for final proof-of-concept studies before entering into clinical trials in drug and medical device development.
Here we aimed to characterize a closed-chest porcine model of post-MI HF in adult G&#246;ttingen minipigs with long-term follow-up including serial cardiac magnetic resonance imaging (CMRI) and to compare it with the commonly used Landrace pig model.
MI was induced by intraluminal balloon occlusion of the left anterior descending coronary artery for 120 min in G&#246;ttingen minipigs and for 90 min in Landrace pigs, followed by reperfusion. CMRI was performed to assess cardiac morphology and function at baseline in both breeds and at 3 and 6 months in G&#246;ttingen minipigs and at 2 months in Landrace pigs, respectively.
Scar sizes were comparable in the two breeds, but MI resulted in a significant decrease of left ventricular ejection fraction (LVEF) only in G&#246;ttingen minipigs, while Landrace pigs did not show a reduction of LVEF. Right ventricular (RV) ejection fraction increased in both breeds despite the negligible RV scar sizes. In contrast to the significant increase of left ventricular end-diastolic (LVED) mass in Landrace pigs at 2 months, G&#246;ttingen minipigs showed a slight increase in LVED mass only at 6 months.
In summary, this is the first characterization of post-MI HF in G&#246;ttingen minipigs in comparison to Landrace pigs, showing that the G&#246;ttingen minipig model reflects post-MI HF parameters comparable to the human pathology. We conclude that the G&#246;ttingen minipig model is superior to the Landrace pig model to study the development of post-MI HF.

The overall goal of the current study is to present the techniques of induction of myocardial infarction (MI) and post-myocardial infarction heart failure (post-MI HF) in closed-chest, adult G&#246;ttingen minipigs and the characterization of post-MI HF model in G&#246;ttingen minipigs as compared to Landrace pigs.

封闭胸冠状动脉闭塞/输液模型中的心肌梗塞后心力衰竭

The development of heart failure is the most powerful predictor of long-term mortality in patients surviving acute myocardial infarction (MI). There is an ...

Sterile Pericarditis in Aachener Minipigs As a Model for Atrial Myopathy and Atrial Fibrillation

Atrial fibrillation (AF) is the most common arrhythmia caused by structural remodeling of the atria, also called atrial myopathy. Current therapies only target the electrical abnormalities and not the underlying atrial myopathy. For the development of novel therapies, a reproducible large animal model of atrial myopathy is necessary. This paper presents a model of sterile pericarditis-induced atrial myopathy in Aachener minipigs. Sterile pericarditis was induced by spraying sterile talcum and leaving a layer of sterile gauze over the atrial epicardial surface. This led to inflammation and fibrosis, two crucial components of the pathophysiology of atrial myopathy, making the atria susceptible to the induction of AF. Two pacemaker electrodes were positioned epicardially on each atrium and connected to two pacemakers from different manufacturers. This strategy allowed for repeated non-invasive atrial programmed stimulation to determine the inducibility of AF at specified time points after surgery. Different protocols to test AF inducibility were used. The advantages of this model are its clinical relevance, with AF inducibility and the rapid induction of inflammation and fibrosis-both present in atrial myopathy-and its reproducibility. The model will be useful in the development of novel therapies targeting atrial myopathy and AF.

We describe a sterile pericarditis model in minipigs to study atrial myopathy and atrial fibrillation (AF). We present surgical and anesthetic techniques, strategies for vascular access, and a protocol to study the inducibility of AF.

Aachener Minipigs的无菌性心包炎作为心房肌病和心房颤动的模型

Atrial fibrillation (AF) is the most common arrhythmia caused by structural remodeling of the atria, also called atrial myopathy. Current therapies only ...

A Surgical Model of Heart Failure with Preserved Ejection Fraction in Tibetan Minipigs

More than half of heart failure (HF) cases are classified as heart failure with preserved ejection fraction (HFpEF) worldwide. Large animal models are limited for investigating the fundamental mechanisms of HFpEF and identifying potential therapeutic targets. This work provides a detailed description of the surgical procedure of descending aortic constriction (DAC) in Tibetan minipigs to establish a large animal model of HFpEF. This model used a precisely controlled constriction of the descending aorta to induce chronic pressure overload in the left ventricle. Echocardiography was used to evaluate the morphological and functional changes in the heart. After 12 weeks of DAC stress, the ventricular septum was hypertrophic, but the thickness of the posterior wall was significantly reduced, accompanied by dilation of the left ventricle. However, the LV ejection fraction of the model hearts was maintained at &gt;50% during the 12-week period. Furthermore, the DAC model displayed cardiac damage, including fibrosis, inflammation, and cardiomyocyte hypertrophy. Heart failure marker levels were significantly elevated in the DAC group. This DAC-induced HFpEF in minipigs is a powerful tool for investigating molecular mechanisms of this disease and for preclinical testing.

The present protocol describes a step-by-step procedure to establish a minipig model of heart failure with preserved ejection fraction using descending aortic constriction. The methods for evaluating cardiac morphology, histology, and function of this disease model are also presented.

藏族小型猪射血分数保留的心力衰竭手术模型

More than half of heart failure (HF) cases are classified as heart failure with preserved ejection fraction (HFpEF) worldwide. Large animal models are ...

Translational Rabbit Model of Chronic Cardiac Pacing

Animal models of cardiac pacing are beneficial for testing novel devices, studying the pathophysiology of artificially paced heart rhythms, and studying arrhythmia-induced cardiomyopathies and subsequent heart failure. Currently, only a few such models are available, and they mostly require extensive resources. We report a new experimental cardiac pacing model in small mammals with the potential to study arrhythmia-induced heart failure.
In six New Zealand white rabbits (mean weight: 3.5 kg) under general inhalational anesthesia the jugular region was dissected and a single pacing lead was inserted via the right external jugular vein. Using fluoroscopic guidance, the lead was further advanced to the right ventricular apex, where it was stabilized using passive fixation. A cardiac pacemaker was then connected and buried in a subcutaneous pocket.
The pacemaker implantation was successful with good healing; the rabbit anatomy is favorable for the lead placement. During 6 months of follow-up with intermittent pacing, the mean sensed myocardial potential was 6.3 mV (min: 2.8 mV, max: 12 mV), and the mean lead impedance measured was 744 &#937; (min: 370 &#937;, max: 1014 &#937;). The pacing threshold was initially 0.8 V &#177; 0.2 V and stayed stable during the follow-up.
This present study is the first to present successful transvenous cardiac pacing in a small-mammal model. Despite the size and tissue fragility, human-size instrumentation with adjustments can safely be used for chronic cardiac pacing, and thus, this innovative model is suitable for studying the development of arrhythmia-induced cardiomyopathy and consequent heart failure pathophysiology.

We present a minimally invasive leporine model of long-term cardiac pacing that can be utilized for artificial pacing and heart failure development in preclinical studies.

慢性心脏起搏的平移兔模型

Animal models of cardiac pacing are beneficial for testing novel devices, studying the pathophysiology of artificially paced heart rhythms, and studying ...

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 ...