塞斯Verlaan，乔伊斯维瑟，MEREL Schurink和格雷斯克罗夫特是体谅他们的动物实验出色的技术援助。

所有的体内实验均按照指南编写实验动物资源研究所实验动物的护理和使用进行。实验经当地动物实验委员会。 1，药物治疗，麻醉，静脉通路，并插管<ol><li>药物和麻醉<ol><li>术前用药<ol><li>启动胺碘酮150毫克/千克，手术前10天，防止心律失常。从手术当天继续胺碘酮在100毫克/公斤的剂量，直到第28天。降低剂量至50毫克/公斤的29天，并继续下去，直到研究结束。 </li><li>开始抗血小板治疗，1毫克/千克氯吡格雷从第3天在手术前和4.5毫克/千克乙酰水杨酸术前1天。继续氯吡格雷1毫克/每天每公斤体重和乙酰水杨酸80毫克/天。 </li><li>开始疼痛用药1天之前由手术芬太尼贴剂，25微克/小时〜70公斤猪。继续使用芬太尼贴剂的24小时手术后，以确保有足够的止痛药。此外，每日监测对推定的不适症状（ 即行为，呼吸，步态，流动性等 ），以增加止痛药。 </li><li>快的动物12小时，保持无限饮水。 </li></ol></li><li>麻醉<ol><li>为了防止不必要的压力和不适，通过注射咪达唑仑0.4毫克/千克，氯胺酮10毫克/千克，而阿托品0.014毫克/千克的混合物肌内注射镇静剂的猪在其稳定。 </li><li>由cannulating耳静脉与18G的静脉插管取得静脉通路。诱导麻醉以5毫克/公斤sodiumthiopental静脉内给药，并且得到1000/100毫克的阿莫西林/克拉维酸，以防止感染。手术作为抗生素治疗后，猪会收到1,000 / 100毫克阿莫西林/克拉维酸的一天。 </li><li>通过使用endotrach插管猪EAL管（大小为8.5猪体重〜70千克）。如果需要进行球囊通气12/min的频率和运输猪的手术室。 </li><li>在到来的手术室，立即开始机械正压通气吸入氧浓度0.50，将10毫升/公斤潮气量，并12/min下的频率继续二氧化碳图。 </li><li>通过继续咪达唑仑0.5毫克/公斤/小时，舒芬太尼2.5微克/公斤/小时，泮库溴铵0.1毫克/千克/小时的组合静脉滴注开始平衡麻醉。在整个操作中，连续监测ECG，动脉血压，温度，二氧化碳浓度监测仪来测量麻醉深度。例如，如果一个窦性心动过速存在，检查是否止痛药和/或麻醉是足够的。 </li><li>注入4.3毫克/千克胺碘酮在500毫升venofundin静脉注射6％。 </li><li>由5监测心脏节律导联心电图。 </li><li>剃须和清洁颈部和后LIMB区。 </li><li>插入尿管。 </li></ol></li></ol></li></ol> 2，经胸超声心动图<ol><li>将动物右侧卧位。长白猪，如Dalland猪，只有胸骨旁意见（长，短轴）可以得到。由于胸部的形状，顶视图采集是不可行的。 </li><li>东方并获得二维（B型）胸骨旁长轴切面。确定了LV的尺寸舒张末期和收缩末期在M模式。 </li><li>旋转echo探测顺时针旋转90°，同时保持它的胸骨位置采集了LV短轴浏览在二尖瓣，乳头肌及心尖水平。乳头肌和心尖部短轴视图可能需要的回波探头放置一个或两个肋间隙相对较低，为二尖瓣短轴视图的位置。 </li></ol> 3，手术准备及血管通路<ol><li> Disin通电，以外科手术的区域用碘酒2％，并使用无菌手术布覆盖猪的非无菌部分。 </li><li>使内侧切口在颈部。通过白线，以减少肌肉损伤，并直言不讳地接近颈动脉和旁边的气管颈内静脉。 </li><li>仔细分离颈总动脉和颈内静脉。确保迷走神经是完好的。广场周围两艘船薇乔缝线2-0赢得容器控制。通过使用Seldinger技术cannulating颈内动脉与8F鞘实现动脉进入。固定护套的动脉，确保动脉不完全缝合闭塞。静脉通路可以通过cannulating颈静脉带9F护套也采用Seldinger技术被收购。前固定护套确保静脉结扎。或者，股动脉，也可用于动脉进入。 </li><li>插入s​​heat后立即辖100 IE /公斤肝素HS抑制血栓的形成。 </li><li>对于一个稳定和不断动脉测压，导管插入的后肢之一，通过一个小的切口动脉上方的小动脉之一。动脉被刚下的皮肤上发现，脉动可以通过皮肤表现出来。从它的周围组织分离出动脉。将容器约2薇乔2-0缝线，1近端和远端1。结扎远侧端和插入18G的静脉插管和安全紧密连接的压力。 </li></ol> 4，有创压力容量环分析<ol><li>通过在颈内静脉先前放在鞘插入斯旺-Ganz导管（SG）。 </li><li>心脏输出设备连接到高潮在近端管腔SG的一部分。 </li><li>注入5毫升0.9％盐水进入SG的近侧管腔和测量心输出量;重复此三次，平均指数。 </li><li>通过使用先前校准PV系统测定心输出量。 </li><li> 经颈内动脉入透视引导下左心室插入7F电导导管。 </li><li>选择最大的细分市场目前在LV的体积测量，并执行下呼吸基线扫描。 </li><li>后体积校准完成后，记录10-15下呼吸暂停甘拜下风。 </li><li>除去SG和放置球囊导管在下腔静脉在隔膜的水平透视指导下进行。 </li><li>通过在呼吸暂停充气气球进行预压降低，并记录相应的PV-循环。 </li></ol> 5，冠状动脉内压力和流量测量<ol><li>稀硝酸甘油在100微克/毫升的浓度和稀释腺苷中的30微克/毫升的浓度。 </li><li>在左冠状动脉的开口处放置一个8F导引导管。 </li><li>将合并的压力/流量导线在左冠状动脉阿特的近侧部分年。 </li><li>管理200微克硝酸甘油冠状动脉内的和归一化的远端压力（Pd）等的金属丝计量，其动脉压。 </li><li>将线在中左前降支（LAD）的一部分。 </li><li>开始测量基线的压力和流量。通过施用60微克腺苷冠状动脉内的，与2ml生理盐水冲洗诱发充血和充血测量的压力和流量。等待流量恢复到基线值。重复测量两次。 </li><li>注入另一个200微克冠脉内硝酸甘油，并重复步骤1.6和1.7的左冠状动脉回旋支。 </li></ol> 6，诱导心肌梗死<ol><li>将心腔内除颤导管中使用的静脉鞘右心室。远侧电极应该在脑室的先端，在心房和/或优越腔静脉近端电极。导管连接到除颤器并将其设置为50J. </li><li>来自美联社的第二对角（D2）和劳30°视角测量LAD远端的直径。 </li><li>选择一个血管成形术用球囊。根据从D2在LAD远端（ 图1）的直径的直径。 </li><li>通过导引导管远端在LAD定位导丝。 </li><li>推进球囊导管导丝。从D2将气囊前端。 </li><li>辖30个IE浏览器/公斤肝素。 </li><li>充气气球，直到压力法援署的右侧直径相匹配。 </li><li>检查LAD完全闭塞的血管造影（ 图1）。 </li><li>覆盖无菌工作领域，伤口在颈部，用无菌窗帘布。释放胸部从任何保障，使其可用于胸外按压或经胸除颤。 </li><li>检查气球的压力在未来90分钟内，如果需要恢复的压力。 </li><li>若心室颤动:<ol><li>立即开始胸外按压与100/min的频率。 </li><li>静脉内给药300mg的胺碘酮作为一种快速推注（〜1分钟）。 </li><li>启动心腔内除颤，给予50 J.震荡</li><li>经过5不成功的冲击，重新启动胸外按压。改变心腔内除颤经胸除颤和冲击150 J。万一不成功休克，变更为200 J。 </li><li>如果需要的话，管理150毫克胺碘酮和/或1毫克肾上腺素另一剂量。用3-5分钟，必要时重播肾上腺素的两倍。 </li><li>持续胸外按压，穿插经胸除颤</li></ol></li></ol>完成外科手术（对于长期随访） <ol><li> 90分钟后检查血管造影，如果法援署仍完全闭塞。 </li><li>辖30另一个IE /公斤肝素和放气的气球。检查再灌注损伤。除去瘪气球的GUID从颈动脉鞘ING导管。 </li><li>小心地取出动脉鞘并用吻合钳（ 图1）立刻夹住颈动脉。继续使用针（6-0普理灵）关闭颈动脉。取出钳，检查是否有渗漏。 </li><li>除去内部除颤导管，并从颈内静脉取出护套。鞘进入结扎近端。 </li><li>关闭该颈部的皮下组织和皮肤中使用2-0薇乔两层。 </li></ol> 7，心脏磁共振成像<ol><li>首先将动物的MRI检查表头下连续麻醉仰卧位。 </li><li>放置一个专用的相控阵心脏线圈在动物的胸部。 </li><li>对于形象策划取得球探图像短轴和两腔长轴意见。 </li><li>获得心电门控稳态自由进动短轴（自由进动）电影（从顶点到的LV基地）和两个室使用ř长轴意见。 </li><li>晚期钆增强（LGE）可以使用反转恢复三维涡轮梯度回波技术，双倍剂量静脉推注一个基于钆对比剂后15分钟被收购。 </li><li>随着功能参数验证的软件进行离线分析。评估左心室射血分数（LVEF），左室质量，舒张末期容积，收缩末期容积，每搏量，心输出量，疤痕质量。 </li></ol>研究和梗死面积8。结束<ol><li>在研究结束时，遵循协议1-5和7获得后续计量。 </li><li>使中位30-40厘米的切口从正下方的胸骨上切迹到刚好低于剑突的一个点。提前通过白线向下胸骨。分裂剑突，并使用剪刀科林贝尔向胸骨后从谨慎心包分离。用剪刀直言后继续进一步分离。执行胸骨bŸ 如用锤子和Lebsch刀。骨髓出血是由摩擦骨蜡对骨髓最小化。与胸骨牵开器打开胸腔。 </li><li>进入第三胸膜腔和定位于纵隔的下腔静脉。 </li><li>人道切割深麻醉下的下腔静脉安乐死的动物。除去血液与抽吸装置。放置一个9伏电池上的顶点诱发心室颤动。 </li><li>的心脏切除后，切开右和左心室成从基片5到顶点和培养在1％三苯基四唑鎓氯化物溶解在0.9％盐水在37℃下持续15分钟。接着，洗净切片在0.9％盐水和从两侧拍摄切片。 </li></ol>

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这项工作是由HGG集团BV公司（SK），在"Wijnand M.傍斯蒂廷"（SC，SK）的支持。本研究形成了生物医用材料研究所，由荷兰经济部，农业与创新（SJL，JG）共同资助的项目P1.04 SMARTCARE的一部分。所有作者报告说，他们没有关系，不方便透露。

在LAD冠状动脉内球囊阻断提供了一种可再现的和一致的临床前梗死模型中的猪，可用于研究的安全性和新的心血管疗法的疗效，密切模仿人的情况。 如图5所示 ，提出了缺血/再灌注梗死模型提供了可以进一步针对调查MI和MI后重塑的不同阶段，同时在初始缺血/再灌注损伤是相同的两个平台。 这里列出的描述协议的成功是依赖于心肌缺血作为协议的最关键阶段。气球远端法援署的第二对角支的正确位置是达到足够的梗死面积，同时确保高成活率的关键。在此基础上心肌梗死模型中，约15％的死亡率，观察，而大量的中和前，中隔和阴尸的心尖段或墙壁被梗塞所看到的CMR和TTC染色（ 图2A和2B）。缺血的持续时间可以根据所期望的梗塞大小进行调整。虽然我们在这个协议中使用长白猪，小型猪（ 即哥廷根小型猪）通常需要心肌缺血（ 例如 150分钟闭塞）的持续时间较长。 在临床前和临床研究心肌梗死预后分析往往是基于对左室射血分数。虽然较低的左室射血分数已经牢牢地与增加心血管死亡风险相关，但它仍然依赖于血流动力学参数，如预紧9。可以说，因为平均只有10-15％的LV是梗死，一些理论和实践的局限性都与左室射血分数即左室收缩功能的全球性措施，而不是反映局部改进10。因此，在这个模型中使用结果的建议措施，阐明不同的火花<html> MI和心梗后重塑从而提供调查人员准确地评估新的治疗方法多层次的疗效的手段。 从临床前模型优化翻译到临床实践中，我们选择使用大猪，而不是小型猪。血流动力学测量，用药剂量和手术设备可以很容易地与临床实践中进行交换。相比于小型猪，大猪获得相对多的重量。这可能会导致长期的问题跟进，关于串口结果的可比性。女Dalland长白猪体重约70Kg在6个月的年龄。为了防止在随访期间丰富的体重增加，动物被保存在一个限制饮食。猪收到750克的定制低热量的食物（含:蛋白质15.6％，脂肪2.0％，纤维14.8％，灰分8.8％，钙0.9％，磷0.57％，镁0.29％，钾0.18％），每天两次，并获得约10千克的重量在4周内。 e_content"&gt;麦考尔和他的同事先前已经发表了类似的协议，用于心肌梗死猪11。该协议与他们之间存在着相当大的重叠，强调优先法援署，而不是左回旋支（LCX）或右冠状动脉（RCA ），在我们的经验，存在使用LCX总左心室梗塞大小的程度较轻，而RCA梗死伴随的不需要的传导障碍的机会较高（ 即窦房结功能障碍，AV-节点功能障碍）。之间的一个区别这两个协议涉及使用在本协议中增加了药物的血小板抑制，正如我们所观察到的无复流的基础上血栓形成为90分钟止血闭塞冠状动脉的结果率较高，这是观察与行猪12已知血液高凝状态观察，虽然麦考使用一个单一的，高剂量，推注肝素，提出氏加入议定书依赖于多个低剂量传遍整个手术，以减少血栓并发症肝素的使用。 综上所述，我们提出了一个猪心肌梗死模型，使研究人员能够使人类疾病的一个有效的，可重复的和高于一切实用的大动物模型研究新疗法作为迈向第一在人临床试验的重要一步使用。

A correction was made to <a href="/video/51269">Myocardial Infarction and Functional Outcome Assessment in Pigs</a>. An author's middle initial was omitted at publication.
The author's name was updated from:
Sanne Jansen of Lorkeers
to:
Sanne J. Jansen of Lorkeers

A correction was made to <a href="/video/51269">Myocardial Infarction and Functional Outcome Assessment in Pigs</a>.
The middle initial J. has been added to author Sanne Jansen of Lorkeers.

Erratum: Myocardial Infarction and Functional Outcome Assessment in Pigs

急性心肌梗死（AMI）和它的长期后遗症如慢性心脏衰竭（CHF）深刻地影响患者的预后和生活质量，更遑论强加给我们的现有医疗资源1成本高的限制。瑞士法郎在西方世界的患病率估计为1-2％，其中〜案件的60％是急性心肌梗死的后果是主要原因2。仅在美国，约5.7万患者从瑞士法郎遭受占比约为3000十亿在每年的医疗费用在2008年，在成本每年在2030年上升至97美元十亿预测一式三份1。综合起来，这些数字使了一个有力的论据发展，对于迅速转换，依赖于可重复和可靠的大型动物心肌梗塞模型，准确地模仿人类的​​场景新的cardioregenerative治疗。 猪（ 野猪 ）正越来越多地在cardiovascu使用LAR研究药理和毒理试验3。一个负责这一成功的转化型研究工具的特征之一是其心脏功能和解剖结构与人类心脏4,5相似。例如，猪心脏对体重的比例，心脏大小和冠状动脉解剖分布都证明是非常相似的男人4。此外，心肌细胞代谢，电生理特性和响应于缺血性损伤如急性心肌梗死的报道，显示高水平的与人的情况6,7协议。最终，以满足上述标准，规范的MI协议产生强大而持久的心肌梗死的研究性新药（IND）的测试是必要的。在这里，我们提出这样一个使用的左前降支（LAD），再灌注90分钟闭胸冠状动脉球囊阻断一个标准化的模式，从而创建可重复的心肌中梗死覆盖anteroapical，室间隔和左心室inferoseptal墙壁。

<table><tbody><tr><td>0.9% Saline</td><td>Braun</td><td></td><td></td></tr><tr><td>6-0 Prolene</td><td>Ethicon</td><td></td><td></td></tr><tr><td>Acetylsalicylic acid</td><td>Ratiopharm</td><td></td><td>80 mg</td></tr><tr><td>Adenosine</td><td>Apotheek UMCU</td><td></td><td>3 mg/ml</td></tr><tr><td>AdVantage PV loop system</td><td>Transonic Science</td><td></td><td></td></tr><tr><td>Amiodarone</td><td>Cordarone I.V. (Sanofi)</td><td></td><td></td></tr><tr><td>Amiodaron HCl (PCH)</td><td></td><td></td><td></td></tr><tr><td>Amoxicilline/clavulaanzuur</td><td>Sandoz</td><td></td><td>500/50 mg</td></tr><tr><td>Atropinesulfate</td><td>PCH</td><td></td><td>0.5 mg/ml</td></tr><tr><td>Bone Marrow Wax</td><td>Syneture</td><td></td><td></td></tr><tr><td>Cardiac Defibrillator</td><td>Philips</td><td></td><td></td></tr><tr><td>Clopidogrel</td><td>Apothecon B.V.</td><td></td><td>Clopidrogel 75A</td></tr><tr><td>Contrast agent</td><td>Telebrix</td><td></td><td></td></tr><tr><td>Endotracheal tube</td><td>Covidien</td><td></td><td></td></tr><tr><td>Fentanyl patch</td><td>Durogesic (Janssen-Cilag)</td><td></td><td>25 &amp;#956;g/hr</td></tr><tr><td>Fogarty catheter</td><td>Edwards Life Sciences</td><td></td><td></td></tr><tr><td>Gadolinium</td><td>Gadovist</td><td></td><td></td></tr><tr><td>Guidewire</td><td>Abbott</td><td></td><td></td></tr><tr><td>Heparin</td><td>Leo</td><td></td><td></td></tr><tr><td>I.V. cannula</td><td>Abbocath (Hospira Venisystems)</td><td></td><td></td></tr><tr><td>Iodine</td><td>Jodiumtictuur 2% (Eurovet)</td><td></td><td></td></tr><tr><td>Ketamine</td><td>Narketan 10 V&amp;eacute;toquinol</td><td></td><td></td></tr><tr><td>Midazolam</td><td>Actavis</td><td></td><td>5 mg/ml</td></tr><tr><td>Nitroglycerin</td><td>Pohl Boskamp</td><td></td><td>1 mg/ml</td></tr><tr><td>Pancuronium bromide</td><td></td><td></td><td>2 mg/ml</td></tr><tr><td>Seldinger vascular sheath 8F</td><td>Arrow</td><td></td><td></td></tr><tr><td>Sufentanil&amp;nbsp;</td><td>Sufentanil-Hameln</td><td></td><td>50 &amp;#956;g/ml</td></tr><tr><td>Swann-Ganz catheter</td><td>Criticath ref 680078 (Argon)</td><td></td><td></td></tr><tr><td>Synolux</td><td>Pfizer</td><td></td><td>250 mg</td></tr><tr><td>Tetra-polar catheter</td><td>Transonic Science</td><td></td><td></td></tr><tr><td>Thiopental</td><td>Inresa</td><td></td><td>0.5 g</td></tr><tr><td>Triphenyl-tetrazolium chloride</td><td>Merck</td><td></td><td></td></tr><tr><td>Venofundin</td><td>Braun</td><td></td><td></td></tr><tr><td>Vicryl 2-0</td><td>Ethicon</td><td></td><td></td></tr><tr><td>Volcano ComboMap system</td><td>Volcano</td><td></td><td></td></tr></tbody></table>

myocardial infarction and functional outcome assessment in pigs

介绍新发现的心血管治疗学为先在人的试验依赖于严格规范的道德和法律的路线图。其中一个重要的前提是在一个大的动物模型，有效地反映心肌梗死（MI）的人类场景获得的所有安全性和有效性方面有很好的理解。猪被广泛使用在这方面，因为它们的心脏大小，血流动力学和冠状动脉解剖接近人类的。在这里，我们提出了一个有效的协议使用左前闭胸冠状动脉球囊闭塞降支（LAD），再灌注采用猪心肌梗死模型。这种方法是基于90分钟的心肌缺血，诱发前，室间隔及inferoseptal墙壁的大左心室梗死。此外，我们提出的协议的结果，提供了广泛的对心脏的信息的各种措施，如心脏收缩和舒张功能，hemodynamiCS，冠脉血流速度，微血管抵抗力和梗死面积。这个协议可以很容易地定制，以满足研究的新型cardioregenerative生物在不同阶段的验证（ 即后直接在急性缺血性损伤，在亚急性设置，甚至在慢性心肌梗死后瘢痕形成已经完成）的具体要求。因此，该模型提供了一个有用的翻译工具来研究心肌梗死，随后的不良重塑，以及新颖的cardioregenerative剂的潜力。

死亡率和梗死面积在我们的中心，出32头猪（女Dalland长白，6个月，〜70千克）经受这种MI协议，五（15.6％）认为缺血时死于顽固性室颤。该协议将创建一个覆盖梗死左心室约10-15％，位于前间壁，室间隔及inferoseptal墙（ 图2A）。如果梗死面积的串行无创性评估是必要的，对CMR晚钆增强（LGE）可以用来跟随无生存能力梗死面积随着时间的推移（ 图2B）。 心功能及重塑四周后心肌梗死，全球性和区域性的参数，反映心功能应该比较健康的基线值下降。具体来说，左室射血分数（LVEF），应减少至约〜35-45％四，周后，心肌梗死。除了整体收缩功能，几个参数反映MI后的不良重塑也可以测量，如LV形态和使用CMR和超声心动图（ 图3A和3B）的直径。 MI，作为不良重构的标志增加舒张末期容积（EDV）可以预期四周后（ 图3A和3B）。 冠脉流量和压力等参数血管生成和形成新的毛细血管通常被认为是缺血性心脏疾病8重要的治疗目标。微血管性的评定，可以间接地根据冠脉内压力和流速的综合测量。在正常条件下和最大充血代表压力和流速测量值，如图4所示。后4周MI相比，充血微血管阻力应增加在梗死相关冠状动脉（LAD）对于基线情况8。 <img alt="图1" fo:content-width="5in" fo:src="/files/ftp_upload/51269/51269fig1highres.jpg" src="/files/ftp_upload/51269/51269fig1.jpg" /> 图1心肌梗死模型的基础上LAD球囊闭塞（A）和标准手术设备:1）毛巾夹子; 2）蚊子; 3）解剖钳; 4）圆形容器; 5）持针器（精细与粗糙）; 6）科林贝尔剪刀; 7）解剖剪刀（直线和曲线）; 9）钳（德BAKEY，精细与粗糙）; 10）软管夹; 11）吻合钳; 12）纱布; 13）电铅笔; 14）手术刀持有人; 15）Dreesman（吸）; 16）牵引器; 17）灯座。 （B）左LAD和LCX的前路斜透视视图。 （三）可视化第二对角支后，定位球只是远端对D2的两个不透射线的标记（见插图，黑色箭头）。 Inflate和确保冠脉血流量被成功阻断注射对比剂（见星号）。心内除颤器导线可以在右心室可以看出（见白色箭头）。法援署表示左前降支; LCX表示左回旋支;劳表示左前斜位;美联社表示前后视图; D1表示第一对角支; D2表示第二对角支。 <a href="https://jove.unicartagenaproxy.elogim.com/files/ftp_upload/51269/51269fig1highres.jpg" target="_blank">点击这里查看大图。</a> <img alt="图2" fo:content-width="5in" fo:src="/files/ftp_upload/51269/51269fig2highres.jpg" src="/files/ftp_upload/51269/51269fig2.jpg" /> 心梗后图2。心肌梗死面积（A）童子的90分钟球囊闭塞导致广泛的心肌损伤和瘢痕形成（白色），1个月时通过可视化TTC染色跟进。（B）示意图梗死分布显示，梗死位于前壁，心脏前间壁和inferoseptal段。 （C，D）和短长轴晚期钆增强CMR图像显示的广泛梗死瘢痕（白信号时，看到黑箭头）定位于前，心脏前间壁和inferoseptal段。 LGE-CMR表示后期钆增强心脏磁共振。比例尺表示3厘米。 <a href="https://jove.unicartagenaproxy.elogim.com/files/ftp_upload/51269/51269fig2highres.jpg" target="_blank">点击这里查看大图。</a> <img alt="图3" fo:content-width="4in" src="/files/ftp_upload/51269/51269fig3highres.jpg" width="400" /> 图3:在评价缺血性心肌梗死模型心功能（A）代表CMR电影圈图像舒张末期和收缩末期展示inf文件的功能障碍ARCT疤痕段。 （B）M-2D模式胸骨旁长轴超声心动图的图像，显示左心室扩张（增加LVIDd比值）1个月后，心肌梗死，以及功能障碍（缺乏室间隔增厚）。 EDV表示舒张末容积; ESV表示收缩末期容积; LVIDd比值表示左室内径在舒张和LVIDs表示左室内径在收缩。 <a href="https://jove.unicartagenaproxy.elogim.com/files/ftp_upload/51269/51269fig3highres.jpg" target="_blank">点击这里查看大图。</a> <img alt="图4" fo:content-width="5in" fo:src="/files/ftp_upload/51269/51269fig4highres.jpg" src="/files/ftp_upload/51269/51269fig4.jpg" /> 图4。冠脉内压力和流速导出参数。冠脉内压力和流速录音使用Combowire呈现高RESPONS之前MI（A）参考值e来充血（黑箭头）。 （B）1个月后心肌梗死，梗死相关动脉（LAD）在冠状动脉血流速度（黑色箭头）降低充血反应。其结果是，压力和流速派生的参数（HMR）或血流储备（CFR）进行比较，以基线降低。 BAPV是指基平均峰值速度; pAPV表示峰值平均峰值速度; CFR是指冠状动脉血流储备; HMR表示微血管充血阻力。 <a href="https://jove.unicartagenaproxy.elogim.com/files/ftp_upload/51269/51269fig4highres.jpg" target="_blank">点击这里查看大图。</a> <img alt="图5" fo:content-width="5in" fo:src="/files/ftp_upload/51269/51269fig5highres.jpg" src="/files/ftp_upload/51269/51269fig5.jpg" /> 多个可能的研究设计不同的研究设计如图5所示。概述（一 ）示意图，以验证研究性新药（独立非执行董事）在心肌梗死的使用这个LAD心肌梗死动物模型的各个阶段。依赖于心肌梗死的选择阶段是在调查，分析的功能只可以在处理之前分配，以危险区的基线值和评估来进行。 <a href="https://jove.unicartagenaproxy.elogim.com/files/ftp_upload/51269/51269fig5highres.jpg" target="_blank">点击这里查看大图。</a>

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Myocardial Infarction and Functional Outcome Assessment in Pigs

本协议描述了猪心肌梗死（MI）模型中使用的左前降支（LAD）的90分钟闭胸冠状动脉球囊闭塞，再灌注。此外，该协议对于几个结果的参数，如心脏功能，血液动力学，微血管性和梗塞的大小，也被提出。

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 ...

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27.7K 次观看.  University Medical Center Utrecht. 本协议描述了猪心肌梗死（MI）模型中使用的左前降支（LAD）的90分钟闭胸冠状动脉球囊闭塞，再灌注。此外，该协议对于几个结果的参数，如心脏功能，血液动力学，微血管性和梗塞的大小，也被提出。 

视频: Myocardial Infarction and Functional Outcome Assessment in Pigs

Acute Myocardial Infarction in Rats

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

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

大鼠急性心肌梗死

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

科研

医学

Induction of Myocardial Infarction in Adult Zebrafish Using Cryoinjury

The mammalian heart is incapable of significant regeneration following an acute injury such as myocardial infarction1. By contrast, urodele amphibians and teleost fish retain a remarkable capacity for cardiac regeneration with little or no scarring throughout life2,3. It is not known why only some non-mammalian vertebrates can recreate a complete organ from remnant tissues4,5. To understand the molecular and cellular differences between regenerative responses in different species, we need to use similar approaches for inducing acute injuries.
In mammals, the most frequently used model to study cardiac repair has been acute ischemia after a ligation of the coronary artery or tissue destruction after cryoinjury6,7. The cardiac regeneration in newts and zebrafish has been predominantly studied after a partial resection of the ventricular apex2,3. Recently, several groups have established the cryoinjury technique in adult zebrafish8-10. This method has a great potential because it allows a comparative discussion of the results obtained from the mammalian and non-mammalian species.
Here, we present a method to induce a reproducible disc-shaped infarct of the zebrafish ventricle by cryoinjury. This injury model is based on rapid freezing-thawing tissue, which results in massive cell death of about 20% of cardiomyocytes of the ventricular wall. First, a small incision was made through the chest with iridectomy scissors to access the heart. The ventricular wall was directly frozen by applying for 23-25 seconds a stainless steel cryoprobe precooled in liquid nitrogen. To stop the freezing of the heart, fish water at room temperature was dropped on the tip of the cryoprobe. The procedure is well tolerated by animals, with a survival rate of 95%.
To characterize the regenerative process, the hearts were collected and fixed at different days after cryoinjury. Subsequently, the specimen were embedded for cryosectioning. The slides with sections were processed for histological analysis, in situ hybridization and immunofluorescence. This undertaking enhances our understanding of the factors that are required for the regenerative plasticity in the zebrafish, and provide new insights into the machinery of cardiac regeneration. A conceptual and molecular understanding of heart regeneration in zebrafish will impact both developmental biology and regenerative medicine.

Zebrafish represents a valuable model to study the mechanisms of heart regeneration in vertebrates. Here, we present a protocol for induction of a heart infarct in adult zebrafish using cryoinjury. This method results in massive cell death within 20% of the ventricular wall, similar to that observed in mammalian infarcts.

在成年斑马鱼心肌梗死的感应使用Cryoinjury

The mammalian heart is incapable of significant regeneration following an acute injury such as myocardial infarction1. By contrast, urodele amphibians and ...

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 ...

Histological Quantification of Chronic Myocardial Infarct in Rats

Myocardial infarction is defined as cardiomyocyte death due to prolonged ischemia; an inflammatory response and scar formation (fibrosis) follow the ischemic injury. Following the initial acute phase, chronic remodeling of the left ventricle (LV) modifies the structure and function of the heart. Permanent coronary ligation in small animals has been widely used as a reference model for a chronic model of MI. Thinning of the infarcted wall progressively develops to transmural fibrosis. Histological assessment of infarct size is commonly performed; nevertheless, a standardization of the methods for quantification is missing. Indeed, important methodological aspects, such as the number of sections analyzed and the sampling and quantification methods, are usually not described and therefore preclude comparison across investigations. Too often, quantification is performed on a single section obtained at the level of the papillary muscles. Because novel strategies aimed at reducing infarct expansion and remodeling are under investigation, there is an important need for the standardization of accurate heart sampling protocols. We describe an accurate method to quantify the infarct size using a systematic sampling of harvested rat heart and image analyses of trichromatic stained histological sections obtained from base to apex. We also provide evidence that calculating the expansion index (EI) allowed for infarct size assessment, taking into account changes of the left ventricle throughout the remodeling.

The post-mortem assessment of myocardial infarction (MI) in rodents is based on quantification of the infarct on stained heart sections. We describe an accurate method to quantify the infarct size using systematic sampling of harvested rat hearts from base to apex and image analyses of trichrome-stained histological sections.

大鼠慢性心肌梗塞的组织学定量分析

Myocardial infarction is defined as cardiomyocyte death due to prolonged ischemia; an inflammatory response and scar formation (fibrosis) follow the ...

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 ...

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 ...

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 ...

Transthoracic Echocardiography to Assess Post-Resuscitation Left Ventricular Dysfunction After Acute Myocardial Infarction and Cardiac Arrest in Pigs

One of the main causes of out-of-hospital cardiac arrest is acute myocardial infarction (AMI). After successful resuscitation from cardiac arrest, approximately 70% of patients die before hospital discharge due to post-resuscitation myocardial and cerebral dysfunction. In experimental models, myocardial dysfunction after cardiac arrest, characterized by an impairment in both left ventricular (LV) systolic and diastolic function, has been described as reversible but very little data are available in cardiac arrest models associated with AMI in pigs. Transthoracic echocardiography is the first-line diagnostic test for the assessment of myocardial dysfunction, structural changes and/or AMI extension. In this pig model of ischemic cardiac arrest, echocardiography was done at baseline and 2-4 and 96 hours after resuscitation. In the acute phase, the examinations are done in anesthetized, mechanically ventilated pigs (weight 39.8 &#177; 0.6 kg) and ECG is recorded continuously. Mono- and bi-dimensional, Doppler and tissue Doppler recordings are acquired. Aortic and left atrium diameter, end-systolic and end-diastolic left ventricular wall thicknesses, end-diastolic and end-systolic diameters and shortening fraction (SF) are measured. Apical 2-, 3-, 4-, and 5-chamber views are acquired, LV volumes and ejection fraction are calculated. Segmental wall motion analysis is done to detect the localization and estimate the extent of myocardial infarction. Pulsed Wave Doppler echocardiography is used to record trans-mitral flow velocities from a 4-apical chamber view and trans-aortic flow from a 5-chamber view to calculate LV cardiac output (CO) and stroke volume (SV). Tissue Doppler Imaging (TDI) of LV lateral and septal mitral anulus is recorded (TDI septal and lateral s&#39;, e&#39;, a&#39; velocities). All the recordings and measurements are done according to the recommendations of the American and European Societies of Echocardiography Guidelines.

Transthoracic echocardiography is the first-line diagnostic test for post-resuscitation left ventricular dysfunction and structural changes in a pig model of cardiac arrest.