作者要感谢皇后大学动物设施个人的帮助和合作。作者要感谢TMED硕士候选人Austin Read的帮助。
这项研究部分得到了美国国立卫生研究院 （NIH） 资助 NIH 1R01HL113003-01A1 （S.L.A.）、NIH 2R01HL071115-06A1 （SLA）、加拿大创新基金会和女王心肺科 （QCPU） 229252 和 33012 （SLA）、加拿大线粒体动力学和转化医学 950-229252 （SLA） 一级加拿大研究主席、加拿大卫生研究院 （CIHR） 基金会资助 CIHR FDN 143261， William J. Henderson 基金会 （S.L.A.）、加拿大血管网络学者奖 （F.P.） 和加拿大肺动脉高压协会 （F.P.） 的帕罗亚家庭奖学金

所有实验均按照女王大学生物安全和伦理准则（ROMEO/TRAQ#6016826）进行。所遵循的程序是按照机构准则执行的。这是一个终端程序。由于左右导管插入术的侵入性，应在数据采集后立即对动物实施安乐死。 安乐死应根据该机构的动物研究指南进行。
1. 实验准备和设置
<ol><li>在开始实验前30分钟，将导管放入含有生理盐水/肝素的10mL注射器中（图1A）。</li>
	<li>30 分钟后，根据制造商的建议校准导管（例如，基线和采集系统）。采集系统显示高校准值和低校准值，用于在开始实验之前校准采集系统。输出这些值并确保它们匹配。<ol><li>使用“压力平衡控制”、“粗略 +/-”或“精细 +/-”按钮将基线压力值设置为零。</li>
		<li>对高信号和低信号执行两点校准。<ol><li>在控制台上，按“导管菜单”中的“系统设置”。</li>
			<li>按“系统设置菜单”中的“发送校准信号”发送低信号。确保压力、体积、相位和幅度分别为 0 mm Hg、0 μL、0° 和 0 μs。</li>
			<li>按“Enter”发送高信号。确保压力、体积、相位和幅度分别为 100 mm Hg、150 μL、20° 和 5,000 μs。</li>
			<li>按“Enter”返回“系统设置菜单”。</li>
			<li>按“6”返回“导管菜单”。然后按“获取数据”。</li>
		</ol></li>
	</ol></li>
	<li>将 30 G 针弯曲至约 90°（图 1B、C）。这根弯曲的针将用于刺穿颈动脉和颈动脉血管。</li>
</ol>2.麻醉和体温控制
<ol><li>将小鼠（28g，本协议中的C57BL / 6）放入含有麻醉气体（即氧气100%，异氟烷3-4%用于诱导）的麻醉室中。</li>
	<li>当动物被麻醉时，对爪子或尾巴捏合没有反应，将小鼠仰卧在设定在37°C的加热垫上。</li>
	<li>通过鼻锥将鼠标连接到呼吸器，鼻锥提供 100% 氧气和 2% 异氟醚的混合物。要自动计算推荐的通气设置，请使用触摸屏将动物的体重输入呼吸机的专有软件。计算使用以下公式： 潮气量 = 6.2 x 动物质量1.01 （kg）， 呼吸速率 = 53.5 x 动物质量 - 0.26 （kg）。</li>
	<li>打开从麻醉室到鼻锥的麻醉管路。</li>
	<li>将温度反馈探头插入直肠，将垫探头插入垫和鼠标背面之间，将所需体温设置为 37 °C–37.5 °C。 在监视器屏幕上控制动物的温度（图2A，B）。</li>
	<li>使用手术胶带将小鼠的前爪和一只远端爪子粘在加热毯上，让一只后爪自由地监测麻醉深度。</li>
</ol>3. 手术部位访问
<ol><li>从手骨到舌骨水平进行 2 cm H 形腹侧颈椎中线切口。<ol><li>将皮肤反射到远离底层肌肉的地方。如果需要，可以切除这些肌肉以获得更好的可视化效果。</li>
		<li>轻轻地将下颌下腺移到一边。</li>
		<li>使用钝解剖方法解剖颈部软组织，并用镊子暴露胸锁乳突肌和胸骨舌骨肌。</li>
		<li>将筋膜从中间分开，覆盖成对的胸骨舌骨。让成对的胸骨舌骨横向缩回以暴露气管。注意不要损伤颈动脉和迷走神经，它们沿着气管运行。</li>
	</ol></li>
	<li>将镊子放在气管下方以抬高气管。然后，将 4.0 手术丝线穿过气管下方，并在缝合线中间打一个潜在的结，稍后将其收紧以固定气管插管（图 3A）。</li>
	<li>用剪刀在喉部水平以下的气管软骨环之间做一个小切口。插入气管插管（图3B）。</li>
	<li>将气管切开插管连接到呼吸器，然后开始用 100% 氧气和 2% 异氟烷通气。拧紧气管周围的结以固定气管插管，并将呼吸器管固定在手术台上。确保气管没有阻塞或塌陷（图3C）。</li>
</ol>4.右颈动脉和右颈动脉隔离
<ol><li>右颈动脉隔离<ol><li>使用钝性夹层，将胸骨舌骨肌外侧移位，以暴露和隔离右颈动脉。</li>
		<li>使用镊子钝性解剖将颈动脉与迷走神经隔离。</li>
		<li>在颈动脉下方通过三根手术缝合线 （4.0），不包括迷走神经。</li>
	</ol></li>
	<li>颈右静脉隔离<ol><li>将下颌下腺和腮腺向外侧移位，以观察右颈静脉。用镊子钝性解剖并暴露右颈静脉。小心地解剖静脉并去除周围的筋膜。</li>
		<li>将镊子穿过颈静脉下方。</li>
		<li>将一根手术缝合线穿过颈静脉下方，然后将其绑在静脉的颅侧。使用止血夹沿头部方向轻轻牵引该缝合线。</li>
		<li>在颈静脉下方再缝两根缝合线。使用止血钳沿尾部方向轻轻拉动最远端的缝合线。在中间缝合线打一个松散的潜在结。</li>
		<li>在预期的静脉切开部位将几滴温热的生理生理盐水滴在血管上。</li>
	</ol></li>
</ol>5. 右心室和左心室导管插入术的外科手术
<ol><li>右心室导管插入术（图 4 A-D）。<ol><li>使用立体显微镜，识别颈静脉。</li>
		<li>轻轻地对静脉施加卓越的牵引力。通过在颅缝线和中间缝合线之间插入 30 G 弯曲针进行静脉切开术。将针头相对于静脉以 140° 角插入，以确保其以同轴方式进入。</li>
		<li>插入时，通过移动针头来扩张静脉切开术。将导管尖端插入针头下方的静脉切开术中。然后轻轻系好中间缝合线，固定导管。 注意：要格外小心，不要将缝合线绑得太紧，因为用力过大会损坏导管。</li>
		<li>松开尾部缝合线，将导管推进到右心室，在连续监护仪上检测经典的右心室压力波形。</li>
		<li>稳定右心室压。确保导管在右心室中的正确定位，以产生最佳的 PV 回路。<ol><li>稳定反映血液和肌肉的幅度，以产生压力大小环（即 Y 轴压力、X 轴大小）。如果需要，轻轻旋转导管轴，使导管沿右心室轴线达到最佳位置。 注意： 反映肌肉的最大相位值应低于 7°。</li>
		</ol></li>
		<li>当压力大小环路信号最佳时，在采集过程中按控制台上的“Enter”键以执行基线扫描。确保监护仪屏幕上报告的心率（以每分钟心跳次数 （bpm） 为单位）在生理范围内（即 400-600 bpm）。</li>
		<li>生成 PV 回路。将“Magnitude”更改为“Volume”作为X轴的参数，并将压力保留为Y轴。当 PV 环路信号最优时，记录 30 秒。</li>
		<li>停止录制。拉回导管并用纱布轻轻擦拭。将导管放入肝素/氯化钠溶液中，并系扎尾部缝合线以止颈静脉出血。</li>
	</ol></li>
	<li>左心室导管插入术（图5 A-D）。<ol><li>轻轻地抬高右颈动脉，该右颈动脉先前通过在动脉下方滑动弯曲的镊子被隔离 （5A）。</li>
		<li>绑上先前的缝合线，从而闭塞动脉。然后，使用止血钳轻轻施加颅骨定向牵引。</li>
		<li>使用止血夹沿尾部方向拉动最远端的缝合线。在中间缝合线上打一个松散的电位结。</li>
		<li>在预期的动脉切开术部位的血管上滴几滴温热的生理盐水。使用立体定位显微镜聚焦于尾部和中缝合线之间的颅骨部分。</li>
		<li>轻轻地对动脉施加超强的牵引力。进行动脉切开术，在颅缝线和中间缝合线之间插入一根 30 G 的弯曲针。将针头相对于动脉 140° 插入，以确保其以同轴方式进入。</li>
		<li>将导管尖端插入动脉切开术，然后拧紧中间缝合线以固定导管。同时，松开远端缝合线，将导管推进主动脉以开始记录。确保压力通道显示典型的主动脉轨迹。</li>
		<li>将导管逆行穿过主动脉瓣进入左心室。从主动脉舒张压突然明显下降可以明显看出进入左心室。</li>
		<li>稳定左心室压。确保导管在左心室中的正确定位，以产生最佳的 PV 环。<ol><li>稳定反映血液和肌肉的幅度，以产生压力大小环（即 Y 轴压力、X 轴大小）。如果需要，轻轻旋转导管轴，以达到导管沿左心室轴线的最佳位置。 注意： 反映肌肉的最大相位值应低于 7°。</li>
		</ol></li>
		<li>停止录制。拉回导管并将其放入肝素/氯化钠溶液中。然后绑上尾部缝合线。</li>
		<li>用酶清洁剂（例如内嘈杂剂）清洁导管。 注意：手术后，根据该机构的动物研究指南对动物实施安乐死。 </li>
	</ol></li>
</ol>6. 数据分析
<ol><li>根据既定建议执行光伏回路分析。<ol><li>选择最佳压力-体积迹线（理想情况下是完整、稳定的 30 秒记录）。在软件上，单击“高级”，单击“循环”，然后单击“离线计算”。</li>
		<li>选择体积作为体积通道，选择压力作为压力通道。</li>
		<li>为了获得一致的结果，至少需要 20 个循环。</li>
	</ol></li>
</ol>

<ol>
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心脏功能评估是临床前心血管和肺血管研究的关键步骤。在这项工作中，我们提出了一种用于小鼠心脏功能的封闭式胸部双心室评估方案。通过这种方法，可以在同一只小鼠中生成右心室和左心室PV环。这种方法可以对心脏功能进行可靠而完整的评估，从而可以测量收缩压和舒张功能，以及每搏输出量和心输出量。与通常用于啮齿动物导管插入术的开胸方法不同，这种闭胸技术可产生更稳定的生理学和更具生理学相关性的数据。虽然在技术上更具挑战性，并且依赖于操作员的技能才能将导管成功定位在右心室和左心室中，但闭合式胸部入路限制了与开胸手术相关的创伤和出血，并减少了与肺部暴露于大气压力相关的剧烈压力变化。闭合式胸部方法还可以更好地模拟患者进行的心导管插入术，这增强了在临床前研究中使用该技术的相关性。
外科手术是协议的关键步骤。即使使用手术显微镜将导管插入颈静脉或颈动脉（推荐使用），该手术也需要实践和技术技能。通过轻柔、钝的解剖方法仔细解剖脱离周围筋膜的血管将增加插管的成功率，同时将出血风险降至最低。为了尽量减少失血，按顺序插管颈动脉至关重要：1）将导管尖端引入颈动脉;2）轻轻地将缝合线系在包含导管的动脉部分周围;3） 松开固定缝合线，允许导管移动，同时保持轻柔的向上牵引，以尽量减少出血;4）将导管推进至主动脉。通过实时波形监测确定将导管定位在心室中是该协议中最具挑战性的部分。所有导管的电极都应在心室腔内，任何电极都不应接触心室壁。导管的任何不当定位都会导致不规则的 PV 环路，并会对数据采集产生不利影响或妨碍数据采集。识别心室内所有电极所产生的特征压力-体积波形，可以确信适当的导管位置。在切换到 PV 模式和容量采集之前，获得稳定的心室压力波形和稳定的压力大小环路至关重要。正确的心脏生理学和解剖学知识对于该手术的成功至关重要。从心房、三尖瓣区域和右心室在线读取 PV 迹线，将显示导管的进展并有助于实现正确的定位。了解小鼠的正常心率 （400-600 bpm） 以及预期的波形和压力（例如，右心室收缩压 18-25 mm Hg、舒张压 <5 mm Hg;左心室收缩压 60-120 mm Hg40、舒张压 <8 mmHg）至关重要，以便操作员评估观察到的数据的真实性。
数据的质量和可重复性将取决于手术的速度和失血或出血。从麻醉到完成数据采集的过程平均需要 ~30-40 分钟/只小鼠。从插入导管到数据采集的右心导管插入术需要 5-10 分钟，左心导管插入术从插入导管到数据采集还需要 10-15 分钟。在~75%的病例中获得了出版质量的数据。心导管插入术的步骤顺序应在动物之间保持恒定。在该过程中，首先对小鼠进行插管，然后进行右心室导管插入术，最后进行左心室导管插入术。决定按此顺序进行是基于左心导管插入术与右心导管插入术的难度和出血风险更大。可以观察到非特异性的50 Hz噪声记录伪影。使用FIR滤波器，可以在软件上降低该噪声，该滤波器截止频率为50 Hz，截止频率低为0。对于音量通道，创建一个新的通道/过滤器/FIR 过滤器。在数据采集过程中，还可以应用50 Hz的陷波滤波器，以消除电源噪声并消除任何射频干扰。
导管插入术完成得越快，数据质量就越好。根据以往的经验，建议在15分钟内获取数据。导管插入时间的增加增加了动物的生理压力，并增加了由于腔内存在导管而导致心律失常的风险。这些力会降低每搏输出量，并损害波形的再现性和可解释性。此外，导管的尖端很锋利，可能会损坏或刺穿心室。这对右心室尤为重要，右心室的厚度是左 心室厚度的 ~ 1/3。
有创气管切开术和正压机械通气导致小鼠稳定和受控的呼吸，并减少PV环采集的变异性。然而，呼气末正压 （PEEP） 与正常通气形成鲜明对比，正常通气是一种负压现象。正压通气和PEEP共同降低心输出量并降低右心压。因此，虽然需要获取稳定的数据，但机械通气以及麻醉的心脏抑制作用会影响 PV 回路，应被视为一种限制。在短暂记录 PV 回路期间暂时停止机械通气用于消除这种潜在的伪影来源。请注意，通风效率可以通过二氧化碳的二氧化碳监测来确认。
闭胸入路所需的技术技能可能是该技术的局限性。同样，在心室中获得导管的正确、稳定定位也具有挑战性。成功的几率随着操作者的经验以及小鼠的大小和重量而增加。低于20g的小鼠的导尿术极具挑战性。右心室独特的腔室几何形状可能会影响容积测量，应予以考虑。使用的麻醉剂、心率、体温和动物品系可能会影响血流动力学参数，应仔细报告和监测。
总之，在该方案中，右心室和左心室导管插入术在同一只小鼠中进行。根据科学家的具体目标，可以使用双心室手术的相关部分独立进行左心室或右心室导管插入术。然而，所提出的方法是全面评估心脏功能的最佳方法。

根据世界卫生组织 （WHO） 的数据，心脏病是全球男性和女性死亡的主要原因 1,2,3。许多研究侧重于诊断和改善受损的心脏功能4.对于这些应用，高质量和可重复的心脏功能评估至关重要。需要高保真度和可重复的导管数据来评估病因学和治疗反应。例如，心功能评估对于评估药物和其他治疗在心肌梗死临床前模型中的疗效至关重要5.虽然许多心血管研究侧重于左心室功能，但右心室功能也是肺血管疾病患者功能能力和预后的关键决定因素6,7。在晚期心力衰竭患者中，右侧和左侧充盈压持续升高可预测死亡、心血管住院和心脏移植的综合风险8。在主动脉瓣和二尖瓣联合疾病中，术前心肌功能（反映在心脏指数和左心室射血分数等参数中）是长期生存的主要预测指标9。右心室功能是肺动脉高压发病率和死亡率的主要预测因子10,11。因此，右心室功能评估是使用肺动脉高压模型进行综合临床前研究的必要组成部分12,13,14。
左心室和右心室功能通常独立研究。然而，由于左心室和右心室的功能密切相关，因此理想的方法是通过单次测试获得收缩和舒张功能的双心室评估15。例如，右心室与左心室共享室间隔中的斜纤维，左心室构成左心室和右心室收缩功能之间的机械联系之一16,17。这种现象称为收缩期心室相互作用，允许左心室收缩以增强右心室收缩。舒张期的心室相互作用也很重要。在舒张期，一个心室的容积会影响对侧心室的容积，从而改变舒张顺应性和前负荷18,19。在病理条件下，一个心室功能下降或容量负荷受损，可直接或间接损害另一个心室20的功能。由于收缩期心室相互作用，左心室功能的整体下降可能会降低右心室的收缩功能15。在由于左心室收缩功能和舒张末期压力升高引起的心力衰竭患者中，肺动脉压力升高，间接增加右心室后负荷21,22。相反，在重度肺动脉高压患者中，右心室压增高和容量超负荷会对左心产生机械性压迫。左心室的这种D形扁平是由室间隔左移引起的，减少了左心室容积，损害了收缩和舒张功能23,24,25,26,27。因此，在人类疾病临床前模型中，左心室和右心室的评估对于评估整体心脏功能至关重要。
心脏功能也可以通过无创超声心动图、磁共振成像（MRI）和有创导管插入术来评估28,29,30。超声心动图是心血管研究中最常用的成像方式，因为它相对便宜且易于使用31。然而，超声心动图存在一些技术局限性，包括间接测量充盈压力和量化舒张功能的能力有限。此外，超声心动图获得的数据质量在很大程度上取决于操作人员。心脏 MRI 是临床前成像武器库中相对较新的补充，在双心室功能定量评估方面具有巨大潜力。心脏 MRI 的定量是准确的，因为它不像超声心动图32 那样对心室形状做出几何假设。然而，MRI成像平台价格昂贵，而且很少可用。此外，MRI 数据的处理需要物理学家或同等科学家的熟练支持，这在许多临床前实验室中是缺乏的33。同样，在临床前研究中使用显微计算机断层扫描 （MicroCT） 可提供可无创获得的定量高分辨率三维 （3D） 解剖数据，从而允许纵向研究34。然而，MicroCT成像需要注射造影剂，这通常很昂贵。MicroCT成像平台与MRI一样，价格昂贵，并且还需要熟练的技术人员。
相比之下，导管插入术是一种侵入性技术，包括在右心室和/或左心室中引入导管以测量压力和/或体积。进行心导管插入术所需的工具不像超声心动图、CT 或 MRI 那么昂贵。然而，需要对导管插入术和小动物麻醉有相当的技术熟练程度。导管插入术可以直接准确地评估心脏功能28。在该方案中，准入 PV 导管用于评估心脏功能。该技术基于血液和心肌独特的电导特性，可以同时记录心腔内的压力和体积，并实时生成PV环路5,35。简而言之，导管由激发电极和记录电极组成。激励电极在右心室或左心室内产生电场。内部记录电极测量电压变化，这与电阻的变化成正比。推导心室容积基于欧姆定律（电压 = 电流 x 电阻），从中计算电导（即电阻的倒数）。在这种情况下，测得的电导值是血液电导率和肌肉电导率的组合。在电场中，血液是纯电阻性的，而肌肉同时具有电容性和电阻性。肌肉的电容特性会导致测量信号出现时间延迟。跟踪这种延迟，称为“相位”角，报告心脏组织在心脏收缩时侵入野外。该测量值在收缩期最大，在舒张期最低。该特性允许将电导的肌肉成分与血液的电导成分分离，并允许收缩压和舒张压的绝对近似值。压力-容积环提供了一系列血流动力学参数，这些参数不容易通过其他方法测量，例如使用充满液体的导管测量心脏压力的简单逆行导管插入术。压力-容积环测量心室压力，但也提供有关收缩力、弹性、功率、能量和效率的数据。此外，PV 回路提供可靠的定量测量36。因此，通过导管插入术产生的 PV 环评估心脏功能已成为临床前研究的金标准37。此外，临床前技术与人类疾病相关，其中心导管插入术很常见，尽管使用充满液体的导管。然而，啮齿动物的心导管插入术需要无可挑剔的麻醉和出色的技术来防止过度失血、通气不足或体温变化。
在人类患者中，心导管插入术以封闭的胸部结构进行，通过右心室的颈静脉或锁骨下静脉以及左心室的桡动脉或股动脉实现血管通路。由于小鼠体型小，闭胸入路通常具有挑战性。因此，在小鼠中进行的研究通常采用开胸方法。该技术包括打开胸部，从而暴露心脏，并通过穿刺左心室和/或右心室顶点38 促进导管插入。虽然这种方法在技术上不那么具有挑战性且相当可重复，但其主要局限性包括出血和心尖插入导管的其他并发症，以及由于将胸腔打开至大气压而导致心内压显着下降。通气啮齿动物打开胸腔会导致左心室收缩压降低 5-10 毫米汞柱，右心室压力降低 2-5 毫米汞柱39。因此，开发了一种封闭式胸部方法，该方法对心脏的创伤较小，并产生更多生理相关的测量值，这些测量值更容易转化为心脏功能的临床评估。

<table border="0" cellpadding="0" cellspacing="0" style="width:664px;" width="663">
	<colgroup>
		<col />
		<col />
		<col />
		<col />
	</colgroup>
	<tbody>
		<tr height="42">
			<td height="42" style="height:42px;width:215px;">ADVantage Pressure-Volume System (ADV500)</td>
			<td style="width:121px;">Transonic</td>
			<td style="width:161px;">FY097B</td>
			<td style="width:167px;"></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:215px;">Endozime AW triple plus</td>
			<td style="width:121px;">Ruhof</td>
			<td style="width:161px;">34521</td>
			<td style="width:167px;"></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:215px;">Fiber optic dual Gooseneck</td>
			<td style="width:121px;">Volpi Intralux</td>
			<td style="width:161px;"># 6000-1</td>
			<td style="width:167px;"></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:215px;">Forceps</td>
			<td style="width:121px;">F.S.T</td>
			<td style="width:161px;">11052-10</td>
			<td style="width:167px;"></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:215px;">Forceps</td>
			<td style="width:121px;">F.S.T</td>
			<td style="width:161px;">11251-20</td>
			<td style="width:167px;"></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:215px;">Gauze sponges</td>
			<td style="width:121px;">Dermacea</td>
			<td style="width:161px;">441400</td>
			<td style="width:167px;"></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:215px;">Hemostatic clamp</td>
			<td style="width:121px;">F.S.T</td>
			<td style="width:161px;">13003-10</td>
			<td style="width:167px;"></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:215px;">Hemostatic clamp</td>
			<td style="width:121px;">F.S.T</td>
			<td style="width:161px;">13018-14</td>
			<td style="width:167px;"></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:215px;">Heparin sodium</td>
			<td style="width:121px;">Sandoz</td>
			<td style="width:161px;">023-3086</td>
			<td style="width:167px;">100 U/L</td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:215px;">High-fidelity admittance catheter</td>
			<td style="width:121px;">Scisence; Transonic</td>
			<td style="width:161px;">FTH-1212B-3518</td>
			<td style="width:167px;"></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:215px;">Isofluorane</td>
			<td style="width:121px;">Baxter</td>
			<td style="width:161px;">CA2L9108</td>
			<td style="width:167px;"></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:215px;">labScribe v4 software</td>
			<td style="width:121px;">iworx</td>
			<td style="width:161px;">LS-30PVL</td>
			<td style="width:167px;"></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:215px;">Needle (30 gauge)</td>
			<td style="width:121px;">BD</td>
			<td style="width:161px;">305106</td>
			<td style="width:167px;"></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:215px;">sodium chloride injection</td>
			<td style="width:121px;">Baxter</td>
			<td style="width:161px;">JB1309M</td>
			<td style="width:167px;">0.9%(wt/vol)</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:215px;">Stereo microscope</td>
			<td style="width:121px;">Cole-Parmer</td>
			<td style="width:161px;">OF-48920-10</td>
			<td style="width:167px;"></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:215px;">Surgical suture</td>
			<td style="width:121px;">SERAFLEX</td>
			<td style="width:161px;">ID158000</td>
			<td style="width:167px;">black braided silk, 4.0</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:215px;">Surgical tape</td>
			<td style="width:121px;">3M, Transpore</td>
			<td style="width:161px;">SN770</td>
			<td style="width:167px;"></td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:215px;">Tabletop Single Animal Anesthesia Systems</td>
			<td style="width:121px;">Harvard apparatus</td>
			<td style="width:161px;">72-6468</td>
			<td style="width:167px;"></td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:215px;">Tracheotomy canula 1.45 mm diameter</td>
			<td style="width:121px;">Harvard apparatus</td>
			<td style="width:161px;">72-1410</td>
			<td style="width:167px;"></td>
		</tr>
		<tr height="63">
			<td height="63" style="height:63px;width:215px;">Ventilator, far infrared warming pad for mice and rats PhysioSuite</td>
			<td style="width:121px;">Kent scientific corporation</td>
			<td style="width:161px;"># PS-02</td>
			<td style="width:167px;"></td>
		</tr>
	</tbody>
</table>

biventricular assessment of cardiac function and pressure-volume loops by closed-chest catheterization in mice

心脏功能评估对于进行心血管和肺血管临床前研究至关重要。在评估收缩期和舒张期心脏功能时，通过记录心导管插入术期间的压力和容量而产生的压力-容积环（PV 环）至关重要。左心和右心功能密切相关，体现在心室的相互依赖性上。因此，记录同一只动物的双心室功能对于获得完整的心脏功能评估很重要。在该方案中，在小鼠中采用与患者导管插入术一致的方式的封闭式胸腔心导管插入术。虽然具有挑战性，但闭胸策略是一种更具生理学的方法，因为打开胸部会导致前负荷和后负荷发生重大变化，从而产生伪影，最明显的是全身血压下降。虽然高分辨率超声心动图用于评估啮齿动物，但心导管插入术是无价的，尤其是在评估双心室舒张压时。
这里描述的是在同一只动物中执行侵入性、封闭式胸部、顺序左心室和右心室压力容积 （PV） 环的程序。PV 环使用带有鼠标压力-容积导管和压力-容积系统采集的导纳技术进行采集。描述了该过程，从进入右颈静脉和右颈动脉所需的颈部清扫术开始，到导管的插入和定位，最后是数据采集。然后，讨论了确保获得高质量光伏回路所需的标准。最后，简要描述了左心室和右心室PV环路的分析以及可用于量化收缩期和舒张期心室功能的不同血流动力学参数。

在导管插入前30分钟，将导管置于含有肝素化盐水溶液的10mL注射器中（图1A）。将30G针弯曲~90°（图1B，C），并制备直径为1.45mm的气管切开插管（图1C）。
维持生理体温至关重要。鼠标被贴上胶带，并通过鼻锥连接到呼吸器。反馈探头放置在鼠标垫和鼠标背面之间。插入直肠探针以监测动物的体温（图2A）。监测体温（37.1°C）和垫子（40.7°C）温度（图2B）。
插管过程关键步骤的照片如图3A-C所示。成功且畅通无阻的插管导致呼吸频率正常，峰值压力稳定（图2B）。
右心导管插入术的关键步骤的图片，从颈静脉的隔离（图4A-C）到将导管插入颈静脉如图4D所示。图 5 显示了左心导管插入术的关键步骤，包括右颈动脉隔离（图 5 A、B）和导管插入（图 5 C、D）
将导管引入颈静脉并进入右心室。然后稳定右心室压，验证正确定位。所有导管的电极（6 mm 长轴长）都需要在右心室腔内，并且不与心室壁接触。 如图6A 所示的导管的最佳定位产生了最佳的PV环路（即三角形、规则形）。 如图6B 所示的不正确定位（即与心室壁接触）将导致有缺陷的PV环路（即塌陷和不规则的环路）。
将导管引入颈动脉，进入主动脉，然后逆行穿过主动脉瓣进入左心室。左心室压稳定，右心室定位得到验证。所有导管的电极（6 mm 长轴长）应位于左心室腔内，不与心室壁接触。 如图6C 所示的导管的最佳定位产生了最佳的PV环路（即矩形、规则形）。 如图 6D 所示的不当定位（即与心室壁接触）导致有缺陷的 PV 环（即塌陷、非矩形和不规则环）。
左右PV环产生的代表性血流动力学显示心率为410 bpm，心输出量为9,107 μL/min，每搏输出量为24.5 μL。 具体右心室参数显示右心室收缩压为 21.9 mm Hg，右心室舒张末期压力为 1.049 mm Hg，射血分数为 56.1%，dp/dt 最大值为 1,469 mm Hg/s， dp/dt max 为 -1,504 mm Hg/s，舒张末期容积为 38.4 μL，每搏功为 0.068 mJ，压力容积面积为 0.089 mJ，肺动脉弹性系数 （Ea） 为 0.83 mm Hg/μL，Tau 因子为 12.8 ms。具体左心室参数显示左心室收缩压为 77.1 mm Hg，左心室舒张末期压力为 2.33 mm Hg，射血分数为 59.1%，dp/dt max 为 4,695 mm Hg/s，dp/dt max 为 -3,553 mm Hg/s，舒张末期容积为 36.9 μL，每搏功为 0.14 mJ，压力容积面积为 0.22 mJ， 动脉弹性系数 （Ea） 为 5.37 mm Hg/μL，Tau 因子为 15.1 ms（表 1）。
<table border="1" fo:keep-together.within-page="1"><tbody><tr><td>血流动力学参数</td>
			<td></td>
		</tr><tr><td>人力资源 （BPM）</td>
			<td>410.6 ± 23.3</td>
		</tr><tr><td>一氧化碳 （μL/min）</td>
			<td>9107 ± 1016</td>
		</tr><tr><td>SV （微升）</td>
			<td>24.5 ± 2.3</td>
		</tr><tr><td>RV功能</td>
			<td></td>
		</tr><tr><td>RVSP （毫米汞柱）</td>
			<td>21.9 ± 2.15</td>
		</tr><tr><td>RVEDP （毫米汞柱）</td>
			<td>1.042 ± 0.12</td>
		</tr><tr><td>EF （%）</td>
			<td>56.1 ± 4.4</td>
		</tr><tr><td>dP/dt 最大值 （mmHg/s）</td>
			<td>1469 ± 170</td>
		</tr><tr><td>dP/dt 最大值 （- mmHg/s）</td>
			<td>1504 ± 215</td>
		</tr><tr><td>EDV （微升）</td>
			<td>38.4 ± 3.7</td>
		</tr><tr><td>SW （兆焦耳）</td>
			<td>0.068 ± 0.008</td>
		</tr><tr><td>PVA（兆焦耳）</td>
			<td>0.084 ± 0.009</td>
		</tr><tr><td>驿 （mmHg/μL）</td>
			<td>0.83 ± 0.09</td>
		</tr><tr><td>Tau 因子 （ms）</td>
			<td>12.8 ± 0.8</td>
		</tr><tr><td>LV 函数</td>
			<td></td>
		</tr><tr><td>LVSP （毫米汞柱）</td>
			<td>77.1 ± 2.4</td>
		</tr><tr><td>低密度电平 （mmHg）</td>
			<td>2.33 ± 0.17</td>
		</tr><tr><td>EF （%）</td>
			<td>59.1 ± 3.6</td>
		</tr><tr><td>dP/dt 最大值 （mmHg/s）</td>
			<td>4695 ± 355</td>
		</tr><tr><td>dP/dt 最大值 （- mmHg/s）</td>
			<td>3553 ± 373</td>
		</tr><tr><td>EDV （微升）</td>
			<td>36.9 ± 4.8</td>
		</tr><tr><td>SW （兆焦耳）</td>
			<td>0.14 ± 0.013</td>
		</tr><tr><td>PVA（兆焦耳）</td>
			<td>0.22 ± 0.03</td>
		</tr><tr><td>驿 （mmHg/μL）</td>
			<td>5.37 ± 0.9</td>
		</tr><tr><td>Tau 因子 （ms）</td>
			<td>15.07 ± 1.7</td>
		</tr><tr><td colspan="2">CO， 心输出量;Ea， 动脉弹性;EDV，舒张末期容积;心率，心率;LVEDP，左心室舒张末期容积;LVSP，左心室收缩压;PVA， 压力容积面积;RVEDP，右心室舒张末期压;RVSP，右心室收缩压;SV， 每搏输出量;SW， 行程功;Tau 因子，Tau Mirsky。N = 6只小鼠。数值± SEM 表示</td>
		</tr></tbody></table>表1：血流动力学参数表。 在六只小鼠中测量的左心室和右心室血流动力学参数。
<img alt="Figure 1" class="xfigimg" src="/files/ftp_upload/61088/61088fig1.jpg"> 图1：实验准备和设置。 （A） 10 mL 生理盐水/肝素注射器中的导管，（B）、（C） 30 G 针头弯曲至约 90°，（D） 气管切开插管，直径 1.45 mm。 <a href="https://www.jove.com/files/ftp_upload/61088/61088fig1large.jpg" target="_blank">请点击这里查看此图的较大版本.</a>
<img alt="Figure 2" class="xfigimg" src="/files/ftp_upload/61088/61088fig2.jpg"> 图2：麻醉、 体温控制 。 （A） 用胶带粘住三只爪子的鼠标，通过鼻锥连接到呼吸器，插入反馈和直肠探头。请注意，加热垫位于手术毯下方。（B） 温度监测器控制显示身体（直肠）和垫（反馈）温度和通气参数：呼吸频率（设定 RR）、平均潮气量 （Meas TV）、峰值压力 （PeakPress） 和分钟通气量 （MinVol）。 <a href="https://www.jove.com/files/ftp_upload/61088/61088fig2large.jpg" target="_blank">请点击这里查看此图的较大版本.</a>
<img alt="Figure 3" class="xfigimg" src="/files/ftp_upload/61088/61088fig3.jpg"> 图 3：插管程序。 （A） 皮肤被拉开并切开。下颌下腺被轻轻地移到一边。将胸锁乳突肌和胸舌骨肌拉开，然后使用轻柔、钝的夹层将镊子穿过气管下方。（B） 将手术丝 （4.0） 穿过气管下方，并在气管的两个软骨环之间向前做一个小切口。插入并结扎气管切开术。（C）将气管切开插管与呼吸机连接，缝合线绑在导管周围。 <a href="https://www.jove.com/files/ftp_upload/61088/61088fig3large.jpg" target="_blank">请点击这里查看此图的较大版本.</a>
<img alt="Figure 4" class="xfigimg" src="/files/ftp_upload/61088/61088fig4v2.jpg"> 图 4：右心室导管插入术。 （A）、（B）、（C）隔离右颈静脉，然后将一条手术缝合线穿过下方并绑在静脉的颅侧。使用止血钳在头部方向上对该缝合线施加轻柔的牵引力。另外两条缝合线从颈静脉下方的远端穿过。使用止血钳沿尾部方向轻轻拉动最远端的缝合线。在中间缝合线处打了一个松散的潜在结。（D）将导管插入颈静脉，将中间缝合线绑在导管上。（C）和（D）中的图像通过体视显微镜放大。 <a href="https://www.jove.com/files/ftp_upload/61088/61088fig4v2large.jpg" target="_blank">请点击这里查看此图的较大版本.</a>
<img alt="Figure 5" class="xfigimg" src="/files/ftp_upload/61088/61088fig5.jpg"> 图 5：左心室导管插入术。 （A）、（B）分离右颈动脉，然后将一根手术缝合线穿过颈静脉下方并绑在静脉的颅侧。使用止血钳在头部方向上对该缝合线施加轻柔的牵引力。在颈动脉下方又穿了两条缝合线。使用止血钳沿尾部方向轻轻拉动最远端的缝合线。在中间缝合线中打了一个松散的潜在结。（C）将导管尖端插入颈动脉，然后将中间缝合线绑在导管上以固定。（D） 导管沿着颈动脉向主动脉逆行。（B）、（C）、（D）中的图像通过体视显微镜放大。 <a href="https://www.jove.com/files/ftp_upload/61088/61088fig5large.jpg" target="_blank">请点击这里查看此图的较大版本.</a>
<img alt="Figure 6" class="xfigimg" src="/files/ftp_upload/61088/61088fig6.jpg"> 图 6：导管定位和由此产生的 PV 回路的示意图。 （A） 右心室中的最佳导管定位。导管的尖端位于心室的中间，与心室壁隔离。由于导管在右心室中的最佳定位（即稳定，三角形）而产生的代表性 PV 环。（B） 右心室导管定位不当。导管的尖端与心室壁接触。由于右心室导管定位不理想（即塌陷、不规则）导致的代表性 PV 环路噪声。（C） 左心室中的最佳导管定位。导管的尖端位于心室的中间，与心室壁隔离。由于导管在左心室中的最佳定位（即稳定、矩形）而产生的代表性 PV 环。（D） 左心室导管定位不当。导管的尖端与心室壁接触。由于左心室导管定位不理想（即塌陷、不规则）导致的代表性 PV 环。应用50 Hz FIR噪声滤波器生成PV环路。 <a href="https://www.jove.com/files/ftp_upload/61088/61088fig6large.jpg" target="_blank">请点击这里查看此图的较大版本.</a>

Watch this Scientific Journal Video about Biventricular Assessment of Cardiac Function and Pressure-Volume Loops by Closed-Chest Catheterization in Mice at JoVE.com

Biventricular Assessment of Cardiac Function and Pressure-Volume Loops by Closed-Chest Catheterization in Mice

这里介绍的是一种评估小鼠双心室心脏功能的方案，通过使用封闭式胸导管插入术从同一动物的右心室和左心室产生压力 - 容积（PV）环。重点是手术和数据采集的技术方面。

小鼠闭胸导管插入术对心功能和压力-容积环的双心室评估

Assessment of cardiac function is essential to conduct cardiovascular and pulmonary-vascular preclinical research. Pressure-volume loops (PV loops) ...

biventricular-assessment-cardiac-function-pressure-volume-loops

Research

JoVE Journal

Medicine

4.0K 次观看.  Queen's University. 这里介绍的是一种评估小鼠双心室心脏功能的方案，通过使用封闭式胸导管插入术从同一动物的右心室和左心室产生压力 - 容积（PV）环。重点是手术和数据采集的技术方面。

视频: Biventricular Assessment of Cardiac Function and Pressure-Volume Loops by Closed-Chest Catheterization in Mice

A Murine Closed-chest Model of Myocardial Ischemia and Reperfusion

Surgical trauma by thoracotomy in open-chest models of coronary ligation induces an immune response which modifies different mechanisms involved in ischemia and reperfusion. Immune response includes cytokine expression and release or secretion of endogenous ligands of innate immune receptors. Activation of innate immunity can potentially modulate infarct size. We have modified an existing murine closed-chest model using hanging weights which could be useful for studying myocardial pre- and postconditioning and the role of innate immunity in myocardial ischemia and reperfusion. This model allows animals to recover from surgical trauma before onset of myocardial ischemia.
Volatile anesthetics have been intensely studied and their preconditioning effect for the ischemic heart is well known. However, this protective effect precludes its use in open chest models of coronary artery ligation. Thus, another advantage could be the use of the well controllable volatile anesthetics for instrumentation in a chronic closed-chest model, since their preconditioning effect lasts up to 72 hours. Chronic heart diseases with intermittent ischemia and multiple hit models are other possible applications of this model.
For the chronic closed-chest model, intubated and ventilated mice undergo a lateral blunt thoracotomy via the 4th intercostal space. Following identification of the left anterior descending a ligature is passed underneath the vessel and both suture ends are threaded through an occluder. Then, both suture ends are passed through the chest wall, knotted to form a loop and left in the subcutaneous tissue. After chest closure and recovery for 5 days, mice are anesthetized again, chest skin is reopened and hanging weights are hooked up to the loop under ECG control.
At the end of the ischemia/reperfusion protocol, hearts can be stained with TTC for infarct size assessment or undergo perfusion fixation to allow morphometric studies in addition to histology and immunohistochemistry.

Surgical trauma induces an inflammatory response. Cytokines and endogenous ligands are known to modulate myocardial infarct size following ischemia and reperfusion. We present a modified closed-chest model of murine ischemia and reperfusion using hanging weights to minimize effects of thoracotomy.

闭胸鼠心肌缺血再灌注模型

Surgical trauma by thoracotomy in open-chest models of coronary ligation induces an immune response which modifies different mechanisms involved in ...

科研

医学

Cardiac Stress Test Induced by Dobutamine and Monitored by Cardiac Catheterization in Mice

Dobutamine is a &beta;-adrenergic agonist with an affinity higher for receptor expressed in the heart (&beta;1) than for receptors expressed in the arteries (&beta;2). When systemically administered, it increases cardiac demand. Thus, dobutamine unmasks abnormal rhythm or ischemic areas potentially at risk of infarction. 
Monitoring of heart function during a cardiac stress test can be performed by either ecocardiography or cardiac catheterization. The latter is an invasive but more accurate and informative technique that the former.
Cardiac stress test induced by dobutamine and monitored by cardiac catheterization accomplished as described here allows, in a single experiment, the measurement of the following hemodynamic parameters: heart rate (HR), systolic pressure, diastolic pressure, end-diastolic pressure, maximal positive pressure development (dP/dtmax) and maximal negative pressure development (dP/dtmin), at baseline conditions and under increasing doses of dobutamine.
As expected, in normal mice we observed a dobutamine dose-related increase in HR, dP/dtmax and dP/dtmin. Moreover, at the highest dose tested (12 ng/g/min) the cardiac decompensation of high fat diet-induced obese mice was unmasked.

We describe the protocol to perform a cardiac stress test induced by dobutamine and monitored by cardiac catheterization in normal mice. Also we show its application to unmask subclinical cardiac disease in high fat diet-induced obese mice.

多巴酚丁胺诱导的心脏压力测试和监控通过在小鼠心脏导管插入术

Dobutamine is a &beta;-adrenergic agonist with an affinity higher for receptor expressed in the heart (&beta;1) than for receptors expressed in the ...

Assessment of Right Ventricular Structure and Function in Mouse Model of Pulmonary Artery Constriction by Transthoracic Echocardiography

Emerging clinical data support the notion that RV dysfunction is critical to the pathogenesis of cardiovascular disease and heart failure1-3. Moreover, the RV is significantly affected in pulmonary diseases such as pulmonary artery hypertension (PAH). In addition, the RV is remarkably sensitive to cardiac pathologies, including left ventricular (LV) dysfunction, valvular disease or RV infarction4. To understand the role of RV in the pathogenesis of cardiac diseases, a reliable and noninvasive method to access the RV structurally and functionally is essential.
A noninvasive trans-thoracic echocardiography (TTE) based methodology was established and validated for monitoring dynamic changes in RV structure and function in adult mice. To impose RV stress, we employed a surgical model of pulmonary artery constriction (PAC) and measured the RV response over a 7-day period using a high-frequency ultrasound microimaging system. Sham operated mice were used as controls. Images were acquired in lightly anesthetized mice at baseline (before surgery), day 0 (immediately post-surgery), day 3, and day 7 (post-surgery). Data was analyzed offline using software.
Several acoustic windows (B, M, and Color Doppler modes), which can be consistently obtained in mice, allowed for reliable and reproducible measurement of RV structure (including RV wall thickness, end-diastolic&#160;and end-systolic dimensions), and function (fractional area change, fractional shortening, PA peak velocity, and peak pressure gradient) in normal mice and following PAC.
Using this method, the pressure-gradient resulting from PAC was accurately measured in real-time using Color Doppler mode and was comparable to direct pressure measurements performed with a Millar high-fidelity microtip catheter. Taken together, these data demonstrate that RV measurements obtained from various complimentary views using echocardiography are reliable, reproducible and can provide insights regarding RV structure and function. This method will enable a better understanding of the role of RV cardiac dysfunction.

Right ventricle (RV) dysfunction is critical to the pathogenesis of cardiovascular disease, yet limited methodologies are available for its evaluation. Recent advances in ultrasound imaging provide a noninvasive and accurate option for longitudinal RV study. Herein, we detail a step-by-step echocardiographic method using a murine model of RV pressure overload.

右心室结构和功能的肺动脉缩窄经胸超声小鼠模型的评估

Emerging clinical data support the notion that RV dysfunction is critical to the pathogenesis of cardiovascular disease and heart failure1-3. Moreover, ...

A Rat Model of Ventricular Fibrillation and Resuscitation by Conventional Closed-chest Technique

A rat model of electrically-induced ventricular fibrillation followed by cardiac resuscitation using a closed chest technique that incorporates the basic components of cardiopulmonary resuscitation in humans is herein described. The model was developed in 1988 and has been used in approximately 70 peer-reviewed publications examining a myriad of resuscitation aspects including its physiology and pathophysiology, determinants of resuscitability, pharmacologic interventions, and even the effects of cell therapies. The model featured in this presentation includes: (1) vascular catheterization to measure aortic and right atrial pressures, to measure cardiac output by thermodilution, and to electrically induce ventricular fibrillation; and (2) tracheal intubation for positive pressure ventilation with oxygen enriched gas and assessment of the end-tidal CO2. A typical sequence of intervention entails: (1) electrical induction of ventricular fibrillation, (2) chest compression using a mechanical piston device concomitantly with positive pressure ventilation delivering oxygen-enriched gas, (3) electrical shocks to terminate ventricular fibrillation and reestablish cardiac activity, (4) assessment of post-resuscitation hemodynamic and metabolic function, and (5) assessment of survival and recovery of organ function. A robust inventory of measurements is available that includes &#8211; but is not limited to &#8211; hemodynamic, metabolic, and tissue measurements. The model has been highly effective in developing new resuscitation concepts and examining novel therapeutic interventions before their testing in larger and translationally more relevant animal models of cardiac arrest and resuscitation.

This article describes a rat model of electrically-induced ventricular fibrillation and resuscitation by chest compression, ventilation, and delivery of electrical shocks that simulates an episode of sudden cardiac arrest and conventional cardiopulmonary resuscitation. The model enables gathering insights on the pathophysiology of cardiac arrest and exploration of new resuscitation strategies.

室颤由传统的封闭胸技术大鼠模型和复苏

A rat model of electrically-induced ventricular fibrillation followed by cardiac resuscitation using a closed chest technique that incorporates the basic ...

Cardiac Catheterization in Mice to Measure the Pressure Volume Relationship: Investigating the Bowditch Effect

Animal models that mimic human cardiac disorders have been created to test potential therapeutic strategies. A key component to evaluating these strategies is to examine their effects on heart function. There are several techniques to measure in vivo cardiac mechanics (e.g., echocardiography, pressure/volume relations, etc.). Compared to echocardiography, real-time left ventricular (LV) pressure/volume analysis via catheterization is more precise and insightful in assessing LV function. Additionally, LV pressure/volume analysis provides the ability to instantaneously record changes during manipulations of contractility (e.g., &#946;-adrenergic stimulation) and pathological insults (e.g., ischemia/reperfusion injury). In addition to the maximum (+dP/dt) and minimum (-dP/dt) rate of pressure change in the LV, an accurate assessment of LV function via several load-independent indexes (e.g., end systolic pressure volume relationship and preload recruitable stroke work) can be attained. Heart rate has a significant effect on LV contractility such that an increase in the heart rate is the primary mechanism to increase cardiac output (i.e., Bowditch effect). Thus, when comparing hemodynamics between experimental groups, it is necessary to have similar heart rates. Furthermore, a hallmark of many cardiomyopathy models is a decrease in contractile reserve (i.e., decreased Bowditch effect). Consequently, vital information can be obtained by determining the effects of increasing heart rate on contractility. Our and others data has demonstrated that the neuronal nitric oxide synthase (NOS1) knockout mouse has decreased contractility. Here we describe the procedure of measuring LV pressure/volume with increasing heart rates using the NOS1 knockout mouse model.

This article describes the measurement of murine left ventricular function via pressure/volume analysis at different heart rates.

心导​​管在小鼠测量压力体积的关系：调查的影响鲍迪奇

Animal models that mimic human cardiac disorders have been created to test potential therapeutic strategies. A key component to evaluating these ...

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 ...

A Closed-chest Model to Induce Transverse Aortic Constriction in Mice

Research on cardiac hypertrophy and heart failure is frequently based on pressure overload mouse models induced by TAC. The standard procedure is to perform a partial thoracotomy to visualize the transverse aortic arch. However, the surgical trauma caused by the thoracotomy in open-chest models changes the respiratory physiology as the ribs are dissected and left unattached after chest closure. To prevent this, we established a minimally invasive, closed chest approach via lateral thoracotomy. Herein we approach the aortic arch via the 2nd intercostal space without entering the chest cavities, leaving the mouse with a less traumatic injury to recover from. We perform this operation using standard laboratory settings for open chest TAC procedures with equal survival rates. Apart from maintaining physiological breathing patterns due to the closed chest approach, the mice seem to benefit by showing rapid recovery, as the less invasive technique appears to facilitate a fast healing process and to reduce immune response after trauma.

Here, we present a protocol of Transverse Aortic constriction (TAC) via a lateral thoracotomy. This technique is a minimally invasive, closed chest surgical procedure aiming to simulate pressure overload and heart failure in mice utilizing standard TAC laboratory settings.

诱导小鼠横向主动脉狭窄的闭合胸模型

Research on cardiac hypertrophy and heart failure is frequently based on pressure overload mouse models induced by TAC. The standard procedure is to ...

Real-time Pressure-volume Analysis of Acute Myocardial Infarction in Mice

Acute myocardial infarction can lead to acute heart failure and cardiogenic shock. The evaluation of hemodynamics is critical for the evaluation of any potential therapeutic approach directed against acute left ventricular (LV) dysfunction. Current imaging modalities (e.g., echocardiography and magnetic resonance imaging) have several limitations since data on LV pressure cannot directly be measured. LV catheterization in mice undergoing coronary artery occlusion could serve as a novel method for a real-time evaluation of LV function.
At the beginning of the procedure, mice were anesthetized followed by endotracheal intubation. For LV catheterization, the right carotid artery was exposed via middle-neck incision. The catheter was introduced and placed into the LV cavity. Left thoracotomy was conducted and the left main coronary artery (LCA) was ligated. To induce reperfusion, the suture was released after 45 min. Pressure-volume data was recorded at all times.
Ligation of the LCA caused a decrease in LV systolic function as evidenced by a 30% reduction in stroke volume, LV ejection fraction (EF), and cardiac output. Maximum dP/dt as a parameter for LV contractility was also significantly reduced and diastolic function was severely impaired (minimum dP/dt -40%). Reperfusion over a period of 20 min did not lead to a complete recovery of LV function.
Real-time pressure-volume analysis served as a valid procedure for monitoring cardiac function during acute myocardial infarction in mice. Maintaining stable anesthesia and a standardized surgical approach was crucial to ensure valid results. As the early phase of acute myocardial infarction is critical for morbidity and mortality, the delineated method could be beneficial for preclinical evaluation of new strategies for cardioprotection.

Acute myocardial infarction in mice induces acute but incompletely characterized changes in left ventricular (LV) function. LV catheterization in mice undergoing coronary artery occlusion serves as a novel method for a real-time evaluation of LV function.

小鼠急性心肌梗死的实时压力容积分析

Acute myocardial infarction can lead to acute heart failure and cardiogenic shock. The evaluation of hemodynamics is critical for the evaluation of any ...

Assessment of Respiratory Function in Conscious Mice by Double-chamber Plethysmography

Air volume changes created by a conscious subject breathing spontaneously within a body box are at the basis of plethysmography, a technique used to non-invasively assess some features of the respiratory function in humans as well as in laboratory animals. The present article focuses on the application of the double-chamber plethysmography (DCP) in small animals. It provides background information on the methodology as well as a detailed step-by-step procedure to successfully assess respiratory function in conscious, spontaneously breathing animals in a non-invasive manner. The DCP can be used to monitor the respiratory function of multiple animals in parallel, as well as to identify changes induced by aerosolized substances over a chosen time period and in a repeated manner. Experiments on control and allergic mice are used herein to demonstrate the utility of the technique, explain the associated outcome parameters, as well as to discuss the related advantages and shortcomings. Overall, the DCP provides valid and theoretically sound readouts that can be trusted to evaluate the respiratory function of conscious small animals both at baseline and after challenges with aerosolized substances.

The objective of the present article is to provide a detailed description of the recommended procedures to evaluate respiratory function in conscious mice by double-chamber plethysmography.

双室 Plethysmography 对清醒小鼠呼吸功能的评价

Air volume changes created by a conscious subject breathing spontaneously within a body box are at the basis of plethysmography, a technique used to ...

Echocardiographic Assessment of Cardiac Anatomy and Function in Adult Rats

The use of experimental animal models has become crucial in cardiovascular science. Most studies using rodent models are focused on two-dimensional imaging to study the cardiac anatomy of the left ventricle and M-mode echo to assess its dimensions. However, this could limit a comprehensive study. Herein, we describe a protocol that allows an assessment of the heart chamber size, left ventricular function (systolic and diastolic) and valvular function. A conventional medical ultrasound machine was used in this protocol and different echo views were obtained through left parasternal, apical and suprasternal windows. In the left parasternal window, the long and short axis were acquired to analyze left chamber dimensions, right ventricle and pulmonary artery dimensions, and mitral, pulmonary and aortic valve function. The apical window allows the measurement of heart chamber dimensions and evaluation of systolic and diastolic parameters. It also allows Doppler assessment with detection and quantification of heart valve disturbances (regurgitation or stenosis). Different segments and walls of the left ventricle are visualized throughout all views. Finally, the ascending aorta, aortic arch, and descending aorta can be imaged through the suprasternal window. A combination of ultrasound imaging, Doppler flow and tissue Doppler assessment have been obtained to study cardiac morphology and function. This represents an important contribution to improve the assessment of cardiac function in adult rats with impact for research using these animal models.

A non-invasive protocol for transthoracic echocardiography assessment of cardiac anatomy and function for adult rats is presented in the current study. The heart valves, all four cardiac chambers and the ascending aorta, aortic arch and descending aorta are studied in detail.

成人大鼠心脏解剖与功能的超声心动图评估

The use of experimental animal models has become crucial in cardiovascular science. Most studies using rodent models are focused on two-dimensional ...