Name: a surgical model of heart failure with preserved ejection fraction in tibetan minipigs
Uploaded: 2022-02-18T14:30:00
Description: Watch this Scientific Journal Video about A Surgical Model of Heart Failure with Preserved Ejection Fraction in Tibetan Minipigs at JoVE.com

本研究得到了广东省科技计划（2008A08003、2016A020216019、2019A030317014）、广州市科技计划（201804010206）、国家自然科学基金（31672376、81941002）和广东省实验动物重点实验室（2017B030314171）的支持。

所有动物研究均获得广东省实验动物监测所机构动物护理和使用委员会的批准（批准号。IACUC2017009）。所有动物实验均按照《实验动物护理和使用指南》（第 8 版，2011 年，美国国家科学院）进行。这些动物被安置在广东省实验动物监测研究所（许可证号）AAALAC认可的设施中。SYXK （YUE） 2016-0122， 中国）。使用6只雄性藏族迷你猪（假猪组和DAC组各n=3头，体重25-30公斤）开发HFpEF模型。
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<ol>
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本研究利用DAC技术建立了藏小型猪的HFpEF模型。本文介绍了动物和器械的分步制备方案，包括镇静、气管插管、静脉插管、外科手术和术后护理。此外，还介绍了超声心动图B型和M型心脏图像的记录技术。DAC 后，心脏在第 4 周和第 6 周出现左心室肥厚，第 8 周后出现扩张。LVEF 在 12 周期间得以保存。在DAC心脏中观察到纤维化和炎症。 
开胸手术和主动脉收缩的结合已被用于开?...

射血分数保留的心力衰竭 （HFpEF） 占心力衰竭病例的一半以上，并已成为全球公共卫生问题1。临床观察表明 HFpEF 的几个关键特征：（1） 心室舒张功能障碍，伴有收缩刚度增加，（2） 静息时射血分数正常，运动表现受损，以及 （3） 心脏重塑2.提出的机制包括激素失调、全身性微血管炎症、代谢紊乱以及肌节和细胞外基质蛋白的异常3。然而，实验研究表明，射血分数降低的心力衰竭 （HFrEF） 会导致这些改变。临床研究探讨了血管紧张素受体抑制剂和药物治疗 HFpEF中 HFrEF 的治疗效果 4,5。然而，需要独特的HFpEF治疗方法。与了解临床症状相比，HFpEF在病理学、生物化学和分子生物学方面的改变仍然不明确。
已经开发了 HFpEF 的动物模型来探索其机制、诊断标志物和治疗方法。实验动物，包括猪、狗、大鼠和小鼠，可发生HFpEF，并选择高血压、糖尿病和衰老等多种危险因素作为诱导因素6,7。例如，单独使用醋酸脱氧皮质酮或与高脂肪/高糖饮食联合使用可诱导猪的 HFpEF 8,9。心室压力超负荷是另一种用于在大型和小型动物模型中开发 HFpEF的技术 10。此外，近年来，各大洲都采用了特定的EF临界值来定义HFpEF，如欧洲心脏病学会指南、美国心脏病学会基金会/美国心脏协会11、日本循环学会/日本心力衰竭学会12所示。因此，如果采用临床标准，许多先前建立的模型可能适用于 HFpEF 研究。例如，Youselfi等人声称转基因小鼠品系Col4a3-/-是一种有效的HFpEF模型。该菌株出现典型的 HFpEF 心脏症状，例如舒张功能障碍、线粒体功能障碍和心脏重塑13。之前的一项研究使用高能量饮食在老年猴子14 中诱导具有中等 EF 的心脏重塑，其特征是代谢紊乱、纤维化和心肌中肌动球蛋白 MgATP 酶减少。小鼠横主动脉收缩 （TAC） 是模拟高血压诱导的室性心肌病最广泛使用的模型之一。左心室从向心性肥大（EF升高）进展为扩张性重塑（EF降低15.16）。这两个典型阶段之间的过渡表型表明，主动脉收缩技术可用于研究 HFpEF。
猪 HFpEF 模型的病理特征、细胞信号转导和 mRNA 谱之前已发表17。在这里，提出了建立该模型的分步方案以及评估该模型表型的方法。该过程如 图 1 所示。简而言之，手术计划由主要研究者、外科医生、实验室技术人员和动物护理人员共同制定。这些迷你猪接受了健康检查，包括生化测试和超声心动图检查。手术后，进行了抗炎和镇痛手术。超声心动图、组织学检查和生物标志物用于评估表型。

<table border="1" fo:keep-together.within-page="1" fo:keep-with-next.within-page="always">
	<tbody>
		<tr>
			<td>Absorbable surgical suture</td>
			<td>Putong Jinhua Medical Co. Ltd, China</td>
			<td>4-0</td>
			<td></td>
		</tr>
		<tr>
			<td>Aesthesia ventilator station</td>
			<td>Shenzhen Mindray Bio-Medical Electronics Co., Ltd, China</td>
			<td>WATO EX-35vet</td>
			<td></td>
		</tr>
		<tr>
			<td>Aspirator</td>
			<td>Shanghai Baojia Medical Apparatus Co., Ltd, China</td>
			<td>YX930D</td>
			<td></td>
		</tr>
		<tr>
			<td>Benzylpenicillin</td>
			<td>Sichuan Pharmaceutical. INC, China</td>
			<td>H5021738</td>
			<td></td>
		</tr>
		<tr>
			<td>Disposal endotracheal tube with cuff</td>
			<td>Shenzhen Verybio Co., Ltd, China</td>
			<td>20 cm, ID 0.9</td>
			<td></td>
		</tr>
		<tr>
			<td>Disposal transducer</td>
			<td>Guangdong Baihe Medical Technology Co., Ltd, China</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Dissection blade</td>
			<td>Shanghai&#160;Medical&#160;Instruments (Group)&#160;Co., Ltd, China</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Electrocautery</td>
			<td>Shanghai&#160;Hutong Medical Instruments (Group)&#160;Co., Ltd, China</td>
			<td>GD350-B</td>
			<td></td>
		</tr>
		<tr>
			<td>Enzyme-linked immunosorbent assay ELISA kit</td>
			<td>Cusabio Biotech Co., Ltd, China</td>
			<td>CSB-E08594r</td>
			<td></td>
		</tr>
		<tr>
			<td>Eosin</td>
			<td>Sigma-Aldrich Corp.</td>
			<td>E4009</td>
			<td></td>
		</tr>
		<tr>
			<td>Flunixin meglumine</td>
			<td>Shanghai Tongren Pharmaceutical Co., Ltd., China</td>
			<td>Shouyaozi(2012)-090242103</td>
			<td></td>
		</tr>
		<tr>
			<td>Forceps</td>
			<td>Shanghai&#160;Medical&#160;Instruments (Group)&#160;Co., Ltd.,China</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Hematoxylin</td>
			<td>Sigma-Aldrich Corp.</td>
			<td>H3136</td>
			<td></td>
		</tr>
		<tr>
			<td>Isoflurane</td>
			<td>RWD Life Science Co., Ltd, China</td>
			<td>Veteasy for animals</td>
			<td></td>
		</tr>
		<tr>
			<td>Laryngoscope</td>
			<td>Taixing Simeite Medical Apparatus and Instruments Limited Co., Ltd, China</td>
			<td>For adults</td>
			<td></td>
		</tr>
		<tr>
			<td>LED surgical lights</td>
			<td>Mingtai Medical Group, China</td>
			<td>ZF700</td>
			<td></td>
		</tr>
		<tr>
			<td>Microplate reader</td>
			<td>Thermo Fisher Scientific, USA</td>
			<td>Multiskan FC</td>
			<td></td>
		</tr>
		<tr>
			<td>Microscope</td>
			<td>Leica, Germany</td>
			<td>DM2500</td>
			<td></td>
		</tr>
		<tr>
			<td>Mobile restraint unit</td>
			<td>Customized</td>
			<td>N/A</td>
			<td>A mobile restraint unit, made by metal frame and wheels, with a canvas cover</td>
		</tr>
		<tr>
			<td>Oxygen</td>
			<td>Local suppliers, Guangzhou, China</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Paraformaldehyde</td>
			<td>Sigma-Aldrich Corp.</td>
			<td>V900894</td>
			<td></td>
		</tr>
		<tr>
			<td>Patient monitor</td>
			<td>Shenzhen Mindray Bio-Medical Electronics Company, China</td>
			<td>Beneview T5</td>
			<td></td>
		</tr>
		<tr>
			<td>Peripheral Intravenous (IV) Catheter</td>
			<td>Shenzhen Yima Pet Industry Development Co., Ltd., China</td>
			<td>26G X 16 mm</td>
			<td></td>
		</tr>
		<tr>
			<td>Propofol</td>
			<td>Guangdong Jiabo Phamaceutical Co., Ltd.</td>
			<td>H20051842</td>
			<td></td>
		</tr>
		<tr>
			<td>Rib retractor</td>
			<td>Shanghai&#160;Medical&#160;Instruments (Group)&#160;Co., Ltd.,China</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Ruler</td>
			<td>Deli&#160;Manufacturing&#160;Company, China</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Scalpel handles</td>
			<td>Shanghai&#160;Medical&#160;Instruments (Group)&#160;Co., Ltd.,China</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Scissors (g)</td>
			<td>Shanghai&#160;Medical&#160;Instruments (Group)&#160;Co., Ltd.,China</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Suture</td>
			<td>Medtronic-Coviden Corp.</td>
			<td>3-0, 4-0</td>
			<td></td>
		</tr>
		<tr>
			<td>Ultrasonic gel</td>
			<td>Tianjin Xiyuansi Production Institute, China</td>
			<td>TM-100</td>
			<td></td>
		</tr>
		<tr>
			<td>Veterinary monitor</td>
			<td>Shenzhen Mindray Bio-Medical Electronics Company, China</td>
			<td>ePM12M Vet</td>
			<td></td>
		</tr>
		<tr>
			<td>Veterinary ultrasound system</td>
			<td>Esatoe, Italy</td>
			<td>MyLab30</td>
			<td>Equiped with phased array transducer (3-8 Hz)</td>
		</tr>
		<tr>
			<td>Xylazine hydrochloride injection</td>
			<td>Shenda Animal Phamarceutical Co., Ltd., China</td>
			<td>Shouyaozi(2016)-07003</td>
			<td></td>
		</tr>
		<tr>
			<td>Zoletil injection</td>
			<td>Virbac, France</td>
			<td>Zoletil 50</td>
			<td>Tiletamine and zolazepam for injection</td>
		</tr>
	</tbody>
</table>

a surgical model of heart failure with preserved ejection fraction in tibetan minipigs

全球超过一半的心力衰竭 （HF） 病例被归类为射血分数保留心力衰竭 （HFpEF）。大型动物模型在研究HFpEF的基本机制和确定潜在的治疗靶点方面受到限制。本工作详细介绍了藏族小型猪降主动脉收缩（DAC）的外科手术过程，以建立HFpEF的大型动物模型。该模型使用精确控制的降主动脉收缩来诱导左心室的慢性压力超负荷。超声心动图用于评估心脏的形态学和功能变化。DAC应激12周后，室间隔肥厚，但后壁厚度明显减少，伴有左心室扩张。然而，在 12 周期间，模型心脏的左心室射血分数保持在 >50%。此外，DAC模型显示心脏损伤，包括纤维化、炎症和心肌细胞肥大。DAC组的心力衰竭标志物水平显著升高。这种 DAC 诱导的小型猪 HFpEF 是研究这种疾病的分子机制和临床前测试的有力工具。

超声心动图 在第 0、2、4、6、8、10 和 12 周评估心脏结构和功能。胸骨旁短轴视图的 B 模式和 M 模式记录显示在图 4A 中。超声心动图测量包括室间隔厚度（VST）、后壁厚度（PWT）和左心室内部尺寸（LVID）。在观察期间，DAC心脏中舒张末期的VST增加，而舒张末期的PWT增加然后减少，这表明DAC迷你猪的左心室中存在肥厚重塑（图4B，C?...

Watch this Scientific Journal Video about A Surgical Model of Heart Failure with Preserved Ejection Fraction in Tibetan Minipigs at JoVE.com

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

本方案描述了使用降主动脉收缩建立射血分数保留的心力衰竭迷你猪模型的分步程序。还介绍了评估该疾病模型的心脏形态学、组织学和功能的方法。

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 ...

全世界超过一半的心力衰竭病例被归类为射血分数保留的心力衰竭或HFpEF。该视频介绍了对 HFpEF 迷你猪进行建模的分步统计程序以及用于评估心脏功能的超声心动图技术。该模型具有单个诱发过滤器。有主动脉收缩，诱发压力超负荷。因此，该模型有助于研究某种类型的HFpEF。除了手术计划的手术技术外，动物质量控制和术后动物护理也是关键步骤。生化测试和心电图有助于监测动物的健康状况以及其结构和功能的变化。李晓晖，临床心脏外科医生。谭伟江，训练有素的动物外科医生。Xiang Li，一名训练有素的麻醉师。陈爽，训练有素的手术室护士。训练有素的手术室护士陈宏华（Honghua Chen）将演示该程序。在手术前 14 天开始使动物适应设施。准备手术室和设备。约束并将迷你猪置于手术台上的右侧侧卧位置。打开加热系统以保持动物的体温。进行超声心动图检查并采集两毫升血样。以每公斤潮气量 8 毫升和每分钟 30 次呼吸开始通气。使用来自耳静脉的外周静脉导管建立静脉插管。然后将动物连接到兽医监视器。剃掉左胸区域。使用0.7%碘和75%酒精对从肩胛骨到横膈膜的皮肤进行无菌准备。将无菌窗帘放在手术区域。沿第四肋间隙标记一个约 15 厘米长的切口。然后用电烙术做皮肤切口。使用烧灼术和肌肉和结缔组织的钝性解剖相结合打开胸部。使用肋骨牵开器展开肋骨。定位胸降主动脉段并确定收缩部位，并使用两个三 OTT 手术缝合线绕该段两次。设置压力测量单位。为了确定收缩程度，逐渐收紧降主动脉段周围的手术缝合线，以达到所需的收缩程度。让压力读数稳定 20 分钟并永久收紧手术结。使用胸腔引流管排出胸腔内的空气和多余的液体。监测动物是否存在眨眼和肢体运动。断开呼吸机，但离开气管插管并监测是否存在自主呼吸。将动物放在带有帆布盖的移动约束装置中。剃掉动物的左胸。将手指放在胸部的左中央，感受脉搏。将超声波凝胶涂抹在周围区域。将超声系统的相控阵换能器放在第三肋间隙。将换能器向前或向后移动并调整缺口角度。识别心房、心室和主动脉，并记录 B 模式和 M 模式胸骨周长轴图像。接下来，在胸骨旁短轴视图中，识别室间隔、左心室后壁和肌，并记录 B 模式和 M 模式图像。使用超声系统制造商提供的工作站来评估心脏结构和功能。心脏结构和功能评估显示经胸骨短轴的B模式和M模式记录。观察期间，降主动脉收缩心脏室间隔厚度增大，后壁厚度先增大后减小，提示降主动脉收缩小猪左心室肥厚重塑。舒张末期左心室内尺寸在第 4 周和第 6 周下降，然后在第 8 周后逐渐增加，提示心室在扩张前经历了同心性肥大。模型心脏的左心室射血分数在12周内保持在50%以上。与假心脏相比，观察到降主动脉收缩心脏扩大。在相应时间点，降主动脉收缩组在第 4、8 和 12 周的心力衰竭标志物心肌肌钙蛋白 I 显著高于假手术组。心房、室间隔和心室的心肌细胞表现为肥大伴偏墩。子宫内膜瓣膜肌肉层减少，主动脉内皮增生。此外，降主动脉收缩诱导迷你猪心肌广泛纤维化，伴有左心室、右心房和主动脉壁炎症细胞浸润。该模型是研究压力过载诱导的 HFpEF 中的组织损伤、纤维化、炎症和同心功能障碍的有力工具。

Research

JoVE Journal

Medicine

Gene Transfer for Ischemic Heart Failure in a Preclinical Model

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

Surgical Technique for Spinal Cord Delivery of Therapies: Demonstration of Procedure in Gottingen Minipigs

外科技术治疗脊髓交付：在哥廷根小型猪演示程序

This is a  compact visual description of a combination of surgical technique and device  for the  delivery of (gene and cell) therapies into the spinal ...

Transplantation of Pulmonary Valve Using a Mouse Model of Heterotopic Heart Transplantation

肺动脉瓣使用异位心脏移植小鼠模型移植

Tissue engineered heart valves, especially decellularized valves, are starting to gain momentum in clinical use of reconstructive surgery with mixed ...

Permanent Ligation of the Left Anterior Descending Coronary Artery in Mice: A Model of Post-myocardial Infarction Remodelling and Heart Failure

左冠状动脉前降支的小鼠结扎：对心肌梗死后重塑和心衰模型

Heart failure is a syndrome in which the heart fails to pump blood at a rate commensurate with cellular oxygen requirements at rest or during stress. It ...

A Novel Murine Model of Arteriovenous Fistula Failure: The Surgical Procedure in Detail

动静脉内瘘失败的新型小鼠模型：在详细介绍手术过程

The arteriovenous fistula (AVF) still suffers from a high number of failures caused by insufficient remodeling and intimal hyperplasia from which the ...

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

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

Isolation of Atrial Cardiomyocytes from a Rat Model of Metabolic Syndrome-related Heart Failure with Preserved Ejection Fraction

代谢综合征心力衰竭模型大鼠心房心肌细胞的分离与保留射血分数的关系

In this article, we describe an optimized, Langendorff-based procedure for the isolation of single-cell atrial cardiomyocytes (ACMs) from a rat model of ...

Induction and Phenotyping of Acute Right Heart Failure in a Large Animal Model of Chronic Thromboembolic Pulmonary Hypertension

慢性血栓栓塞性肺动脉高压大型动物模型中急性右心衰竭的诱导和表型分析

The development of acute right heart failure (ARHF) in the context of chronic pulmonary hypertension (PH) is associated with poor short-term outcomes. The ...

Integration of Brain Tissue Saturation Monitoring in Cardiopulmonary Exercise Testing in Patients with Heart Failure

心力衰竭患者心肺运动测试中脑组织饱和监测的集成

Cerebral hypo-oxygenation during rest or exercise negatively impacts the exercise capacity of patients with heart failure with reduced ejection fraction ...

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

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 ...