Name: echocardiographic approaches and protocols for comprehensive phenotypic characterization of valvular heart disease in mice
Uploaded: 2017-02-14T12:30:00.000+00:00
Duration: 12 min 12 s
Description: Watch this Scientific Journal Video about Echocardiographic Approaches and Protocols for Comprehensive Phenotypic Characterization of Valvular Heart Disease in Mice at JoVE.com

This work was supported by NIH grants HL111121 (JDM) and TR000954 (JDM).

1.准备材料和设备（表1和图1） <ol><li>打开超声机上。输入动物ID，日期和时间（串行成像实验）及其他相关信息。 </li><li>使用高频超声换能器，40兆赫成像小鼠小于约20 g或小鼠大于约20 g以上30兆赫。 </li><li>该平台连接到心电图（ECG）监测成像心电门控的某些方式。 注:重要的是，这也允许对心脏心率（HR），它可以用作麻醉的适当深度的多个索引中的一个的瞬时计算。 </li><li>预加热平台至37℃。 注:所有市售的超声设备有一个控制面板，提供图像采集控制和研究管理控制为B型，M型和多普勒超声心动图。一种心测量工具嵌入在机器的自动测量和心脏瓣膜和常见功能超声心动图参数计算。 </li></ol> 2.准备鼠标麻醉的成像和感应<ol><li>轻轻拿起它的尾巴鼠标，并在其颈背牢牢占据动物。 </li><li>引导动物的鼻子到鼻锥。开始在1％异氟烷麻醉流动。确保动物在3-5敞口之气镇静。 </li><li>快速，准确地躺在平台上的动物仰卧位，确保前肢和后肢足趴在平台上的心电图传感器。 </li><li>轻轻地用固定在四肢胶带动物，轻轻敷胶纸以稳定鼻锥装置中的头，并应用胶带以稳定尾巴。这两个后脚和前脚应平放，确保生理成像系统稳定和清晰的ECG信号采集。 </li><li>检查人力资源。这种使用IMA做更改平台心电图功能，或者与外部ECG设备。确保基础心率是700 BPM 600之间。确保HR不低于450 BPM在任何情况下。 注:在实验过程中，人力资源可能会降低略微由于麻醉，但应高于在大多数情况下500 BPM。 </li><li>调节由相应小增量（〜0.1％的增量每隔15秒，直到达到麻醉的稳定状态）的麻醉流动。 注:麻醉的稳定状态，是指上述的心脏参数被保持（参见步骤2.5）和动物没有公开响应从各种成像窗口探针的放置对刺激的条件。重要的是，这是不麻醉的手术平面，这导致显着的心脏抑制小鼠。在长时间成像会议，建议兽医软膏眼睛防止干燥的应用。 </li><li>检查使用直肠温度计体温。<html>保持36.5℃，38℃之间的温度。 注意:在一个适当的环境受控室和在加热的平台，体温（直肠测量）保持在整个过程中恒定，因此，是不随时间影响心血管血液动力学一个混杂因素。 </li><li>剃掉使用电剪设计用于与细发用从胸口发。擦拭胸部用湿纸巾。动物准备成像。 注意:虽然也可以执行化学去除的毛发，避免使用这样的化合物，因为它们可以通过在长期实验时间引起显著皮肤刺激。此外，适当的应用程序和去除这种化学基脱毛产品可以通过2-3分钟（〜10-20％）延长麻醉曝光的持续时间。从麻醉诱导皮肤准备完成的总时间应小于3分钟。 </li></ol>_title"&gt; 3。按照基本原则和准则获取心脏超声图像注意:有在获取图像使用了三个超声模式:B型/ 2-D，M型和多普勒（光谱的脉冲波的多普勒和彩色血流多普勒成像）。有用于获取心脏和心脏瓣膜的图像两个基本传感器的位置:胸骨旁和心尖窗口（ 图2）。 <ol><li>从每个换能器的位置，通过手动旋转和调角传感器获得相对其长轴和短轴的心脏的多个断层图像。 注:旋转指枢转或扭转从胸壁的固定位置的传感器，而角是指换能器的一侧到另一侧的运动从胸壁的固定点。所有超声换能器具有一个凹槽（凹口），外部肋条，或按钮形式的图像索引标记。 </li><li>确保超声SIG纳尔是通过相应地调整换能器的位置在垂直于靶结构。 </li><li>通过超声波束平行于流动所发送的对准优化彩色流动和峰值速度信号。超声波束和流之间的角度应小于60°。 </li><li>优化使用控制面板控制图像质量。只有审讯的区域应填补的图像显示。 注:在传感器和平台位置精确调整几乎总是必要的，以获得清晰的图像。即使在最佳条件下，呼吸运动，胸壁解剖（ 例如小间距肋骨），和变化内部解剖（包括内在的和疾病引起的）可以限制声窗，使图像采集非常具有挑战性。 </li><li>当测量M型和2-D / B模式左心室尺寸，放置在测量卡尺在最连续回波线。 </li><li>调整彩色多普勒部门的通过调整扇区控制，这是在面板上发现D采样体积询问的面积。 注:在多普勒研究中的颜色编码方案表示的速度和血液流动的方向性。是红色多普勒信号指示朝向传感器层的血流。这是蓝色的多普勒信号表明层流从传感器路程。 A"马赛克"的彩色图案表示动荡或者非层血流量（这通常发生在瓣膜狭窄或瓣膜返流）的地区。 </li><li>记录最少两个5秒条（或100帧）的实时B-模式/ 2D从离线分析每个成像窗口呼应。 注:市售的回声机器具有图像获取的设置，捕捉帧或电影圈尺寸的预先设定的次数。图像获取的设置可以被修改，使得较长的电影循环可以获取。高品质的图像采集需要丰富的经验和实验。 Investigators必须找到探头的位置和角度的平台的正确组合，从许多意见和隔声窗获取图像。 </li></ol> 4.主动脉瓣的评估（AV）功能注意:主动脉瓣膜功能的评估包括所述阀的定性评价（ 例如，感知尖厚度，增加的回声由于瓣膜钙化，以及存在或不存在使用彩色多普勒返流喷射）和阀功能的定量测量（ 例如，峰值瓣速度和尖点的间隔距离）。 <ol><li>开始图像通过选择B模式图像采集的主动脉瓣。 </li><li>与牢固地固定在平台和背离研究者远离头部上的动物，倾斜表15-20°到左边。这将促进心脏和向左，更贴近胸壁。在一个应用上的超声波换能器凝胶慷慨金额或直接nimal的胸部。 </li><li> parasternally传感器，约90°与心脏的长轴垂直，与转换向后指向（ 图2）的图像索引标记的位置。而在2D / B模式，直到AV映入眼帘的滑动传感器头侧。这是在主动脉瓣的"短轴"图。 注:正常主动脉瓣具有三个薄尖即在心脏收缩期打开广泛和舒张期间充分关闭，以便不存在的血液返流回到左心室。尖点非常薄，移动非常迅速，而且可以经常有挑战性的可视化。 </li><li>换能器旋转，直至尾侧图像索引标记点旋转。观察主动脉根部，主动脉瓣，左心室流出道，二尖瓣，左心房，并在图像显示器上的右心室流出道的一部分。 注:这是AV的"胸骨旁长轴"的说法。超声检查应确定有贯穿在B模式图像中的心脏周期，这将允许为随后M-模式成像和分析（见下文）可见2主动脉瓣尖。 </li><li>评价这种观点主动脉根部。小心来回扫使得主动脉根部图像包含主动脉根的最大尺寸。测量使用具有嵌入在设备中的测量工具关联的电子卡尺主动脉的最大前 - 后尺寸。 </li><li>定位在长轴主动脉瓣。使得仅在主动脉瓣是在图像显示上通过在控制面板调节图像宽度按钮缩小图像宽度。审讯的M型线在那里相交的主动脉瓣的提示，以准确评估主动脉瓣尖分离位置。 </li><li>在主动脉瓣的M模式显示，测量使用与测量电相关联的电子卡尺尖间隔距离（盒状外观的收缩）嵌在机键相工具。 注:M型成像的最大优点是非常高的时间分辨率，这对于主动脉瓣膜功能的评价是至关重要的。而在AV的M型图像可以在短期和长轴视图被收购，胸骨旁长轴观一般优选的，因为成象平面允许声谱仪来容易地识别的尖端的方向和位置收缩期尖。 </li><li>尽管仍然在主动脉瓣的胸骨旁长轴观，按控制面板上的彩色多普勒控制键。应用颜色多普勒到主动脉瓣的区域。 注意:从左心室通过主动脉瓣收缩期间正常流量是朝向换能器，因而被编码的红色。 </li><li>记录主动脉瓣关闭不全的存在或不存在。 注:主动脉瓣关闭不全是舒张期间发生并且被引导从transduc远的异常流量ER;因此，它被编码为蓝色。 </li><li>按脉冲多普勒控制键。使用位于控制面板轨迹球，将脉冲波的样品体积在近端升主动脉，只是主动脉瓣以上，确保超声波束和血流之间的角度小于60°倾斜的平台和/或换能器。如果可能的话，获得从胸骨上切迹窗口跨主动脉瓣的峰值速度。 </li><li>测量从光谱显示使用具有嵌入在所述机器（ 图3C和3F）测量工具关联的电子卡尺峰值速度。 注:马赛克色彩代表高流速是可能包含非层流模式。 </li></ol> 5.评估二尖瓣（MV）功能注意:二尖瓣功能的评价包括阀的定性评价（ 例如，每可察觉风口浪尖的厚度，回声增强，由于瓣膜钙化，有无彩色多普勒）反流喷气机和瓣膜功能的定量措施。 <ol><li>放置换能器在B模式心尖的位置。使得其朝向鼠标（ 图2C）的头部倾斜的换能器的位置。观察图像显示右心室（RV），左心室（LV），右心房（RA）和左心房（LA）。手动倾斜平台稍稍使动物处于"头下"位置，因为它通到低压形象化二尖瓣。 注:心尖四腔心切面是整个二尖瓣和三尖瓣，以及二尖瓣环的组织速度检查血速度的最佳视图。这也是评估RV及室间隔运动和大小美景。 </li><li>从心尖四腔视图，通过降低图像宽度带来二尖瓣聚焦。观察到二尖瓣瓣叶出现两个薄，移动细丝打开和每个心动周期中关闭。 注:"正常"小鼠的二尖瓣小叶可以是困难的，如果成像是在生理HR（ 即 &gt; 450 BPM）进行可视化。 </li><li>将M型光标跨二尖瓣评估小叶的厚度。 注:前小叶在收缩最好显现时，它是在垂直于超声波束（ 图4）。 </li><li>使用心尖四腔心切面，舒张期通过二尖瓣应用彩色多普勒成像从左心房流。观察二尖瓣关闭不全。 注:流量朝向换能器，因而被编码的红色。反流将被编码的蓝色和收缩（ 图5）的过程中发生。 </li><li>使用心尖长轴视图，切换到脉冲波模式。移动多普勒取样容积的提示二尖瓣瓣叶。注意二尖瓣血流频谱显示的两个峰。如果传单没有充分显现，用彩色多普勒有鲜红或镶嵌彩色图案识别区，并放置在该点的样品体积。 注:二尖瓣血流频谱显示在慢小时（&lt;450 BPM）两个峰。在正常小时（&gt; 450 BPM），早发的（E）和晚期填充（A）流融合。跨二尖瓣血流的频谱多普勒显示左室舒张功能用于评估（见步骤7.5）。 </li></ol> 6.右心瓣膜功能评价注:三尖瓣和肺动脉瓣组成右路心脏瓣膜。三尖瓣可容易地显现在心尖长轴视图，而肺动脉瓣可以在两个胸骨旁长期和短轴视图来可视化。 <ol><li>从心尖长轴观，倾斜或点传感器尖端ü唱摇摆运动，使得右心室是在图像显示的中心。这样只有右心室是在图象显示可见降低图像宽度。 </li><li>在同一图像平面，可视化的三尖瓣瓣叶，这似乎右心房和右心室，而开放和关闭在每个心动周期的过程之间的薄，移动细丝。 </li><li>在三尖瓣区应用彩色多普勒。注意三尖瓣关闭不全。 注:舒张期间发生正常流动，朝向换能器，因而被编码的红色。发生异常返流收缩期间，是针对从换能器远离，因此，被编码的蓝色。该反流束的峰值速度来估计右心室收缩压。 </li><li>移动换能器到胸骨旁短轴位置在主动脉瓣的级别。上面的主动脉瓣是右心室OUTF低道，肺瓣，近端主肺动脉，右和左肺动脉（ 图6）。 </li><li>换能器顺时针改性胸骨旁长轴位置转动。然后倾斜传感器稍微向上以获得肺动脉瓣的短轴图。 </li><li>在此视图中，应用M型成像来评估肺瓣尖（ 图7）的分离距离。 </li><li>应用颜色多普勒在肺动脉瓣的区域，以评估瓣膜反流（舒张期间一个马赛克图案，高速喷射）和狭窄（心脏收缩期间一个马赛克图案，高速喷射）。 </li><li>按脉冲波控制键，然后将样品体积只是肺动脉瓣后。 注:流的频谱多普勒显示的分析被用于估计肺动脉压（ 图8）。 </li></ol> 7.心脏功能评价例如，射血分数，区域壁运动异常，和壁的感知厚度的视觉估计）和左心室的定量测量功能（ 例如，射血分数，左室质量，左室舒张功能，心肌性能指标）。 <ol><li>获得在2D / B模式的LV短轴视图，在乳头肌水平胸骨旁短轴位置换能器。移动所述转换器的上下，从基部到顶点扫描的LV。请遵守室壁运动异常。 </li><li>从左心室的胸骨旁短轴观，按M模式按钮，位于控制面板。使用跟踪球，定位M型光标在左心室腔的中心在乳头肌和obtai的水平N个M模式的图像。 </li><li>测量舒张末期，其中前壁和后壁之间的距离是最大的，并在结束收缩，其中两个前壁和后壁的内运动是最大（ 图9）的左心室腔尺寸。 </li><li>在测量结束舒张和收缩末期的前后壁的厚度。 注意:当乳头肌是确保正确的成像面的重要地标，注意不要将其包含在任何测量。 </li><li>移动换能器的顶端的窗口。请参阅步骤5.1。评估使用跨二尖瓣血流脉冲多普勒在心尖长轴观的左室舒张功能。 </li><li>发生在二尖瓣瓣叶尖端的样本量。测量从脉冲波的多普勒速度的跨二尖瓣频谱显示峰值二尖瓣流入速度。 </li><li> LV INFL之间的样本容量位置流和外流。注意二尖瓣和主动脉瓣关闭和开启的信号。测量容舒张时间，等容收缩时间，和左心室射血时间（ 图10）。 </li><li>在心尖长轴视图下进行二尖瓣环组织多普勒成像（TDI）。按TDI控制键和放置样品体积在二尖瓣环的内侧面。确保样本量不会对二尖瓣瓣叶染指。保持0.21毫米和0.27毫米的多普勒取样容积大小。测量二尖瓣环（ 图11）的舒张早期速度（E&#39;）。 </li></ol> 8.最后的步骤<ol><li>查看获得的图像。确定该获得所有必需的图像。 </li><li>从鼠标的胸部取出多余的超声凝胶，轻轻地取下胶带固定到位的动物。关闭麻醉。 </li><li>放置动物上的吸收性纸巾（未寝具，其可以被吸入或能阻断恢复期间的气道）。观察动物的胸骨斜卧直至达到。如果麻醉适当的管理，恢复应在30秒到60秒发生。 </li></ol>

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The authors have nothing to disclose.

麻醉诱导 适当的麻醉诱导和维持是在心脏瓣膜小鼠变化的准确评估和心脏功能的关键。由于麻醉的快速诱导异氟醚和以下深度麻醉这一麻醉药的相对较长的洗出时间引起的，我们不使用一个独立的腔麻醉诱导。相反，如在详细说明以上，动物被直接引导至麻醉锥，其允许在相对较低的浓度的麻醉剂的麻醉的快速和受控诱导。 小鼠大多数菌株在小于1.5％的异氟醚保持充分镇静。对心功能的异氟醚的累积效应应密切监测，但是，在麻醉药的浓度降低小，可能需要一段时间。往复，在麻醉剂的浓度小增量也可以是网元EDED。仔细监控任何运动动物（提示麻醉深度不足），以及增加或减少人力资源;这允许麻醉深度的快速和积极的管理。 相反给人类，异氟烷引起在HR小鼠的降低。虽然左心室功能最初可能在麻醉药过多的管理时间得以保留，在人力资源的减少几乎无处不在随后左心室扩张继发于心肌收缩的抑制。因此，射血分数下降，跨瓣（主动脉瓣和二尖瓣）的峰值流速下降，主动脉瓣关闭早发生，并且组织多普勒速度下降。因此，当务之急是要持续监测动物的生理状态，以确保人力资源仍远高于450的BPM。对于谁是不是在成像小鼠有经验的个人，包括一个专门的超声医师的做法，建议专门监测麻醉深度第二个调查。 AV功能分析 在临床上，超声心动图指引的美国社会推荐13左室流出道内径的采集和使用脉冲波多谱勒左室流出道速度。 AVA =（CSA 流出道点¯xVTI LVOT）/ VTI AV:峰值跨主动脉瓣流速shuld使用专用的连续波多谱勒计算使用连续性方程主动脉瓣区进行测量。在不存在这些多普勒数据的，建议的解剖（几何）剖如通过二维或三维测量的主动脉瓣口的面积。尽管换能器具有高空间和时间分辨率，主动脉瓣尖不能始终如一地划定短轴图。因此，该AV孔口区域不能准确地跟踪。 Furthermore，或许更重要的是，当前可用的高频小动物专用超声没有配备专用的连续波多普勒能力。因此，对于具有连续性方程使用一个"真"的峰值瓣速度的识别是极具挑战性（并不会被临床认可）。同样地，其它市售的超声波探针可以不必记录非常高的速度的能力，并因此不限于较低的速度。鉴于这些主要限制，使用在小动物朝着高分辨率成像齿轮系统临床成像方案不能完全捕获。 MV功能分析 通常，小鼠对二尖瓣脱垂的发展非常有抗性。在各地迅速HR的设置二尖瓣反流束的可视化是非常具有挑战性。此外，在人的超声心动图，该anteri或和后二尖瓣叶都看得清清楚楚，并脱垂或枷单张容易赞赏。然而，在小鼠中，二尖瓣小叶不能良好划定成前部和后部，并找到一个连枷或脱垂小叶是极具挑战性，因为非钙化，薄组织回声水平低。因此，使用彩色多普勒的展现一个返流是评估在小鼠中二尖瓣功能的最有用的方法。孤立的二尖瓣关闭不全的诊断只应在仔细评估左心功能，主动脉瓣功能，二尖瓣功能进行。 到目前为止，有二尖瓣狭窄的没有强大的小鼠模型。增加二尖瓣回声密度可以建议钙化，但是本土化无论是前或后叶是困难的。在临床上，二尖瓣狭窄的诊断与制约厚，钙化传单的设置是由ED的议案。单张厚度的测定可以通过M模式（ 图4）来完成。使用多普勒，峰值E速度通常增加，并与在压力一半时间prolongations相关联。因此，夺回这些功能将在二尖瓣狭窄的新颖模式的评价是至关重要的。虽然超声心动图美国社会的建议，二尖瓣口面积的估计是利用压力一半时间（MV面积= 220 /压力半时间）完成的，这样的计算还没有在小鼠13验证。 三尖瓣和肺动脉瓣膜功能分析 三尖瓣被评定为单张流动性，瓣膜狭窄和瓣膜返流。通常情况下，这些数据被定性和以二进制方式（即存在或不存在的功能障碍）表示。三尖瓣返流的峰值速度被用来estimatË右心室收缩压。此外，三尖瓣关闭不全是不正常的，不受应力小鼠少见。 肺动脉瓣功能可以通过2D / B模式，M模式，以及彩色血流成像（ 图6和7）来评估。这些方式用于评估肺动脉瓣厚度（ 例如，可见性或回声与2D），测量肺动脉瓣口开口（尖点的间隔距离），并评估肺动脉瓣流动和接合（2D和彩色多普勒）。肺动脉瓣反流可与彩色多普勒容易理解，如上面所述。肺动脉瓣反流的严重程度可以通过舒张期间通过肺动脉瓣高峰逆行血流量（与脉冲多普勒测量）进行评估。 心功能的分析 在短期和长轴视图左心室2D / B模式成像提供一个相<html>心脏功能的UAL评估。虽然这种成像方式使得左心室功能的粗评估，M型成像提供显著高时空分辨率，相比于2D / B模式成像时，使其成为一个卓越的技术。这是很重要的，考虑到一个事实，即正常小鼠可具有的HR范围从450-700的BPM。我们维持高于450 BPM的HR，这样的数据是非麻醉心脏生理和血流动力学的亲密代表。如果人力资源允许由于落过度麻醉和/或过度镇静，左心室扩张，减少在心脏收缩的估计，和戏剧性的改变在跨瓣血液速度和瓣膜功能的其他定性表征（ 例如，改变在二尖瓣反流继发于左心室扩张，在高峰期主动脉瓣血流速度降低，并在二尖瓣血液流入速度降低）经常观察。 帐篷"&gt;在没有节段性室壁运动异常，射血分数（EF）和短轴缩短率（FS）是左室收缩功能的高重现性的措施。使用M型成像，获得和使用的最大舒张和收缩尺寸计算EF，FS和LV质量14,15。 所有这些测量可与超声波机相关联的软件包自动计算。而可使用"标准"临床超声系统来执行心脏和瓣膜功能的评价，分辨率相对较低的水平（ 例如，12-15兆赫探针）可以使心脏和瓣膜功能的准确的评估在小鼠中具有挑战性。 舒张功能是评估左心室的功能的一个组成部分。在临床研究中，心脏舒张功能衰竭被认为是高correlated与发病率和死亡率。舒张功能是通过脉冲多普勒超声心动图和组织多普勒成像评估。在E / A比值（早期快速充盈波，E之间的比率，和已故的填充波由于心房收缩，A）和E减速时间都在小鼠舒张功能因的融合不是有用的参数E和A峰继发于非常高的HR出现在适当的麻醉小鼠。 为了评估左室舒张功能，峰值二尖瓣流入速度，等容舒张时间（IVRT），等容收缩时间（IVCT），左室射血时间，和二尖瓣环组织，该速度（E&#39;）被利用。这些多普勒参数容易获得，可测量和可重复性。组织多普勒成像测量二尖瓣环的舒张早期速度（E&#39;）是左心室心肌松弛的可靠指标峰英里之间的比率二尖瓣流入速度及初二尖瓣环组织速度已在临床研究中被证实与肺毛细血管楔压16到良好的相关性。 左心室整体功能可以使用心肌性能指标，也被称为Tei指数进行评估。这既包括收缩压和舒张压的时间间隔，以便收缩和舒张左心室功能为一体的综合措施。收缩功能不全延长预喷射时间（IVCT），并缩短左室射血时间（ET）。在舒张功能或心肌松弛异常可导致IVRT的显著延长。左心室心肌的性能指数（MPI）可以计算为MPI = IVCT +等容舒张/ LVET 17。在这种情况下，在MPI减少与心脏功能的改善相关，而更高的MPI值是暗示的心脏功能障碍。 <p类="jove_step"&gt; 新兴技术评估小鼠心肌和瓣膜功能:未来的方向 组织多普勒 组织多普勒可使用E，E评估舒张功能&#39;，和E / E&#39;的变量，但这种方法目前并未得到广泛应用。这样，在各种啮齿动物菌株的变异性和测量的再现尚未严格由多个研究小组进行测试。然而，使用E / E&#39;及其与临床环境左心房压力的，潜在的早期检测的小鼠的心脏功能障碍的相关性，与应用到疾病机制的很可能使评估心脏后果了这样的一个组成部分心脏瓣膜病的转化研究。 应变率成像 小动物模型已经被证明是一个非常宝贵的牛逼OOL理解机制，心脏功能基本病理生理改变。虽然二维和多普勒超声心动图提供心脏形态，功能和血流动力学体内的全面和非侵入性的评估，他们缺乏敏感性检测应对慢性压力或容量过载（两种最常见的应激诱导的心肌功能的早期变化由心脏瓣膜病）。 作为这些限制的结果，是在心脏功能 - 例如临床使用的指数作为心肌应变和应变率具有更精确地检测在固有心肌收缩性的早期或亚临床的变化的潜在的应用越来越大的兴趣。应变和应变率成像已经成功应用在啮齿类动物的研究对心脏衰竭18及高血压心脏疾病19，心脏dysynchrony逆转的进展和心功能不全20，和心脏的少年小鼠21的纵向功能。建议在应变速率成像被认为是一种补充的成像技术对心脏功能的透彻二维和组织多普勒衍生的措施。为了保证调查人员的心肌应变和应变率测量的基本原则有基本的了解，随后的章节旨在提供基本原则和应变计算和应变率成像的基本限制。 应变和应变率是从相对于原始长度的心肌纤维的长度的改变得到的（在心脏病学，舒张末期长度和收缩末期长度之间的差被用于该计算）。在心肌纤维长度变化的精确测量由心肌纤维束的螺旋结构复杂化，导致多向整个收缩人应变变形（ 例如，应变在径向，纵向和圆周轴）。在小鼠中最近的研究表明，组织多普勒derived-和斑点跟踪衍生的应变和应变率变形参数密切相关的内在心肌功能22。这两种技术需要添加专门的分析软件来研究的成像系统，其允许在相对自动生成感兴趣的变量的（参见图12中的例子）23。 虽然应变成像有希望，获得高品质的2D图像的斑点跟踪分析是很有挑战性的。另外，手动跟踪应变测量的心内膜和心外膜边界是困难和麻烦的。实践的显著量和可重复性的稳健评估和内部调查测量的一致性（包括图像实施利用应变测量来评估心功能时的质量，一致性成像平面，并且离线分析）是至关重要的。因此，应变和应变率分析，应该通过完全失明，培训的调查人员进行，以确保高质量和可重复的数据。 心电门控高分辨率超声波成像 组织多普勒成像和应变率成像允许在一个完整的心脏周期的心肌变形的测量，但由于它们的时间分辨率（5毫秒充其量），它们仍然有限到心脏24的全局运动。为了实现高帧速率的超声成像的基础上，使用ECG门控的数据采集的另一种方法最近已经提出了心脏和血管的应用程序。心血管组织的ECG门控机械和机电波成像是基于使用超声以高帧成像的组织率，每次s提高到8000帧（fps），通过同步对心电信号24的2D图像采集。这清楚地超过〜1000帧（在生理条件下提供了更高的分辨率，其中心脏速率是〜500-650 BPM在小鼠），并且在心室功能评价这种成像方法的体内可行性的2D / B模式帧速率有在麻醉动物被证明（提供小动物模型25的心脏室壁运动异常优越的检测）。 压力引起的心功能 而运动试验经常用于评估心脏反应在临床设置，以增加有机体应力，在啮齿类动物的需要清醒镇静和/或麻醉使心功能的直接运动后的评价非常具有挑战性。因此，药理学应激试验可能是临床上-relevant平行评估心脏瓣膜疾病（重度主动脉瓣狭窄，中度至重度二尖瓣狭窄和严重原发性二尖瓣关闭不全）的心脏后果。这将是研究的一个特别重要的新兴领域，因为强调压力测试的作用，以澄清症状状态，评估瓣膜异常的动元件，以及揭露亚临床的心肌功能障碍是可能在休息26错过最近的临床准则。 正如前面章节所指出的，小鼠对后负荷引起的心功能不全非常耐磨。因此，多巴酚丁胺负荷超声心动图可以是检测左心室早期下降在小鼠心脏瓣膜病的不同程度，可能无法显而易见一个非常有用的工具。即使有严重钙化性主动脉瓣狭窄的小鼠能有保存较为完好的收缩功能，并有可能为申请提供了一个有益的平台多巴酚丁胺超声心动图的ication来预测这些动物的时间（通常是非常迅速的）心脏衰竭的发病。到今天为止，我们不知道调查的小鼠使用多巴酚丁胺超声心动图的心脏瓣膜疾病的任何程度的研究。 三维超声心动图 在临床上，3D心脏成像是一个特别强大的工具，使舒张和收缩卷，每搏输出量和心输出量的精确测量。三维超声心动图已成为瓣膜狭窄的严重程度由精密阀面积测量的方式评估一个新的临床标准，它允许在二尖瓣病变个别段脱垂的准确识别和量化。 高频换能器的研究超声系统允许采集心脏门控图像和为后续离线reconstruc使用定制软件包3D图像化。虽然可以使用这种硬件和软件的组合，以获得左心室的3D图像，这通常在麻醉下的相对较深的水平（这降低了人力资源和减少呼吸工件）进行的，使得变化的生理意义外推在心脏功能困难。 至于利用三维成像来评估小鼠心脏瓣膜的功能，这是正常的生理条件下给出的体积小，相对较低的回声，以及心脏瓣膜的高速一个非常具有挑战性的命题。直到图像采集和处理技术的进步允许心脏瓣膜在这种条件下的清晰明辨，我们的经验是，3D成像是有限的效用在心脏瓣膜功能的小鼠准确和全面的表征。 总的来说，高科技在小动物成像nological的进步使这一个非常激动人心的时刻洞察潜在的心脏瓣膜疾病及其心脏后果病理生理机制。我们牢牢断言两个心脏瓣膜功能和心脏功能的全面的评估是对理解小鼠心脏瓣膜功能的基因，药理学，或机械操作的影响是至关重要的。我们希望这个手稿不仅将作为研究者追求研究心脏瓣膜病的发病有用的资源，同时也将刺激有关的最佳方法来评估我们的研究社区内这种研究瓣膜和心脏功能的讨论。

衰老与心血管钙化1逐步增加有关。血液动力学显著主动脉瓣狭窄影响了人口的65 2岁以上的3％，而患者甚至中度主动脉瓣狭窄（3-4米/秒峰值速度）小于40％，5年无事件生存率3。目前，有减缓主动脉瓣钙化的进展没有有效的治疗，和手术主动脉瓣置换为先进主动脉瓣狭窄4唯一可用的治疗方法。 旨在获得有助于启动和主动脉瓣钙化进展的机制有更深的了解研究是在走向药理和非手术方法来管理主动脉瓣狭窄5,6的关键的第一步。遗传学LY-改造的小鼠都起到了我们的开发有助于各种疾病，现在即将旨在了解主动脉瓣狭窄6，7，8的生物学机理研究的最前沿机制的理解了重大作用。不像其他心血管疾病如动脉粥样硬化和心脏衰竭，其中用于评估血管和心室功能标准协议是行之有效的，存在与小鼠心脏瓣膜功能的体内表型相关的独特的挑战的大部分。虽然最近的评论已提供了有关的优点和缺点，以众多的成像和用于评估在啮齿类动物中9，10，11阀功能侵入性的方式充分的讨论，到今天为止，我们不知道它提供了一个COMPRE出版物的hensive，一步一步在小鼠表型心脏瓣膜功能的协议。 本手稿的目的是描述该方法和协议，以表型心脏瓣膜功能的小鼠。所有的方法和程序，已通过梅奥诊所的机构动物护理和使用委员会。该协议的主要内容包括麻醉深度，心功能的评价，和心脏瓣膜功能的评价。我们希望这份报告不仅有利于引导有兴趣在心脏瓣膜病领域追求研究调查，但也将启动相关协议标准化，以确保在这一快速增长的领域数据的重现性和有效性的国家和国际对话。重要的是，采用高分辨率超声系统成功成像需要的超声（和术语在超声常用）的原理的工作知识，基本的原理与的理解心脏生理学，并用超声显著经验的莱斯以允许在啮齿类动物心脏功能的准确时间效率的评估。

<table><tbody><tr><td>High resolution ultrasound machine</td><td>VisualSonics, Fujifilm</td><td>Vevo 2100&amp;nbsp;</td><td></td></tr><tr><td>Isoflurane diffuser (capable of delivering 1 % to 1.5 % isoflurane mixed with 1 L/min 100% O&lt;sub&gt;2&lt;/sub&gt;</td><td>VisualSonics, Fujifilm</td><td>N/A</td><td></td></tr><tr><td>Transducers for small mice (550D) or larger mice (400)</td><td>MicroScan, VisualSonics, Fujifilm</td><td>MS 550D, MS 400</td><td></td></tr><tr><td>Animal platform</td><td>VisualSonics, Fujifilm</td><td>11503</td><td></td></tr><tr><td>Advanced physiological monitoring unit</td><td>VisualSonics, Fujifilm</td><td>N/A</td><td></td></tr><tr><td>Isoflurane</td><td>Terrell</td><td>NDC 66794-019-10</td><td></td></tr><tr><td>Nose cone and tubing connected to isoflurane diffuser and 100% O&lt;sub&gt;2&lt;/sub&gt;</td><td>Custom Engineered in-house</td><td>--</td><td></td></tr><tr><td>Hair razor</td><td>Andis Super AGR+ vet pack clipper</td><td>AD65340</td><td></td></tr><tr><td>Ultrasound gel</td><td>Parker Laboratories</td><td>REF 01-08</td><td></td></tr><tr><td>Electrode gel&amp;nbsp;</td><td>Parker Laboratories</td><td>REF 15-25</td><td></td></tr><tr><td>Adhesive tapes</td><td>Fisher Laboratories</td><td>1590120B</td><td></td></tr><tr><td>Paper towels</td><td></td><td></td><td></td></tr></tbody></table>

echocardiographic approaches and protocols for comprehensive phenotypic characterization of valvular heart disease in mice

The aim of this manuscript and accompanying video is to provide an overview of the methods and approaches used for imaging heart valve function in rodents, with detailed descriptions of the appropriate methods for anesthesia, the echocardiographic windows used, the imaging planes and probe orientations for image acquisition, the methods for data analysis, and the limitations of emerging technologies for the evaluation of cardiac and valvular function. Importantly, we also highlight several future areas of research in cardiac and heart valve imaging that may be leveraged to gain insights into the pathogenesis of valve disease in preclinical animal models. We propose that using a systematic approach to evaluating cardiac and heart valve function in mice can result in more robust and reproducible data, as well as facilitate the discovery of previously underappreciated phenotypes in genetically-altered and/or physiologically-stressed mice.

该例行从动物心脏超声成像获得的图像的示例包括在本手稿。传感器安置在动物的胸部一个例证是提供给读者的，其中传感器被定位为，从而获得图像清晰的认识。也包括在超声实验室的建立的照片强调适当的设备，特别是超声换能器中使用和麻醉的方法的重要性。的2D / B模式，M模式，并且正常和异常阀，左，右心室，和主动脉根部的颜色和多普勒显示器被适当标记。虽然不是常规进行应变率成像的例子也包括在内。 二尖瓣关闭不全的特点是在个高，一般非层血流速度（镶嵌着色）通过阀门ystole（ 图5）。从左心室这种马赛克彩色多普勒模式的横跨的MV左心房，之后在心电图跟踪QRS复合发生的存在，允许MR的明确诊断。当这种情况发生在无主动脉瓣关闭不全和/或左心功能不全的，这可以被定性为孤立的二尖瓣脱垂。如果有左心室显著扩张（由于实验诱导的心脏衰竭或麻醉的过度深度），这可以被表征为缺血性二尖瓣反流（或返流继发于心脏功能障碍）。的脉冲波的频谱多普勒显示可用于确认血流返流的存在和定时。 一个正常的主动脉瓣有打开，每个心动周期中充分密三薄，柔韧性尖。主动脉瓣尖分离是在2D引导测在长轴视图主动脉瓣的M型。电子卡尺用于从右侧主动脉尖向左主动脉尖的前缘（ 图3）的前缘测量。在正常小鼠的主动脉瓣尖点的间隔距离为0.9至1.3毫米。彩色多普勒示出在心脏收缩期间通过阀门并进入主动脉根部的层流。紊流可以在增加的流动，条件可以理解，例如在主动脉瓣关闭不全，或增加的压力，如在主动脉瓣狭窄。这表现为在流出道的马赛克的着色。即使是少量的主动脉瓣关闭不全，可导致峰值跨瓣流速对高动力心脏功能显著增加，增加左室前负荷。在正常小鼠中的范围的峰主动脉速度为0.90米/秒至1.50米/秒。 &gt; 5米的峰值主动脉瓣流速/ s已被记录在与严重主动脉瓣狭窄的小鼠。 12（ 图8）的索引。肺动脉加速时间是从收缩期肺动脉流向峰值流速的发生的时间间隔。右心室射血时间是正确的心室射血发作在其中有收缩期肺动脉收缩期血流停止点之间的时间间隔。的缩短的肺动脉加速时间与肺动脉加速时间为右心室射血时间的比率的降低的结合表明的肺动脉高压的存在下（其可使用肺动脉或右心室压力的侵入性或直接的措施来确认） 。 <img alt="图1" src="/files/ftp_upload/54110/54110fig1.jpg" /> 图1:动物Çardiac超声实验室。实验室装备有小动物专用超声机以高频率（30兆赫和40兆赫）换能器（MS 400和MS 550D），异氟烷扩散，动物平台，温度和心脏监测仪，1％至1.5％的异氟烷用1升/分钟100％ 的 O 2，鼻锥和连接到异氟烷扩散和100％ 的 O 2，发剃刀，超声凝胶，电极凝胶，胶带，和纸巾管混合。 <a href="https://ecsource-jove-com.bdigitaluss.remotexs.co/files/ftp_upload/54110/54110fig1large.jpg" target="_blank">请点击此处查看该图的放大版本。</a> <img alt="图2" src="/files/ftp_upload/54110/54110fig2.jpg" /> 图2:基本传感器位置。 （ 一 ）胸骨旁窗口。换能器头被定位在左胸骨旁边界，与尾部定向换能器的图像索引标记。神父嗡这个位置，可以得到左心室，主动脉瓣和主动脉根部和肺动脉瓣的短轴视图的长轴视图。 （B）从胸骨旁窗口中，换能器头逆时针旋转时，与向后定向的凹口。从这个位置，可以得到的左心室和主动脉瓣和肺动脉瓣的长轴观的短轴图。 （C）心尖窗口。该传感器头位于心脏的顶点。从这个位置，可以得到的左，右心室和二尖瓣和三尖瓣长轴视图。 <a href="https://ecsource-jove-com.bdigitaluss.remotexs.co/files/ftp_upload/54110/54110fig2large.jpg" target="_blank">请点击此处查看该图的放大版本。</a> <img alt="图3" src="/files/ftp_upload/54110/54110fig3.jpg" /> 图3:在规范主动脉瓣功能的评价人与鼠与主动脉瓣钙化疾病的老鼠主动脉瓣功能。在长轴观正常的主动脉瓣（A）2D图像。注意，主动脉瓣心脏收缩期间打开良好。 （B）M型图像描绘了正常的主动脉瓣功能（盒状外观）。需要注意的是风口浪尖上，间隔距离在1.12毫米测量。跨越正常主动脉瓣峰值速度（C）频谱多普勒显示在1.3米/秒被meaured。从低密度脂蛋白受体的长轴观钙化主动脉瓣（D）2D图像缺陷（低密度脂蛋白受体- / - ）和载脂蛋白B100只（载脂蛋白B 100/100）鼠标与西方的饮食喂养。在尖增厚，并回声增强，这在收缩导致限制开放。 （E）的M模式图像描绘同一狭窄的主动脉瓣示出0.7mm的尖角分离距离的测量。 （F &lt;/ STRONG&gt;）横跨狭窄的主动脉瓣峰值流速的频谱多普勒显示为4.6米/秒meaured。 <a href="https://ecsource-jove-com.bdigitaluss.remotexs.co/files/ftp_upload/54110/54110fig3large.jpg" target="_blank">请点击此处查看该图的放大版本。</a> <img alt="图4" src="/files/ftp_upload/54110/54110fig4.jpg" /> 图4:正常二尖瓣M型。从心尖窗口，获得二尖瓣长轴视图。审讯的M型线跨二尖瓣瓣应用。虽然二尖瓣厚度理论上可以使用电子卡尺进行测量，这样可以给薄，差的回声是非常具有挑战性的，并快速移动的正常二尖瓣的小叶。箭头指向收缩期二尖瓣小叶的M型。 <a href="https://ecsource-jove-com.bdigitaluss.remotexs.co/files/ftp_upload/54110/54110fig4large.jpg" target="_blank">请cli来</a>这里完蛋查看此图的放大版本。 <img alt="图5" src="/files/ftp_upload/54110/54110fig5.jpg" /> 图5:采用彩色多普勒超声二尖瓣返流的证据。从胸骨旁窗口，获得二尖瓣的变形长轴视图。彩色多普勒询问表示在心脏收缩期间在二尖瓣的镶嵌彩色喷墨（由箭头突出显示）。 <a href="https://ecsource-jove-com.bdigitaluss.remotexs.co/files/ftp_upload/54110/54110fig5large.jpg" target="_blank">请点击此处查看该图的放大版本。</a> <img alt="图6" src="/files/ftp_upload/54110/54110fig6.jpg" /> 图6:主肺动脉的长轴观及其主要分支。主肺动脉的长轴视图（MPA）和右（RPA）和左（LPA）的分支可以从paraste得到<html> RNAL窗口。右室流出道（RVOT），肺动脉瓣（PV）和主动脉（AO）的部分看到。 <a href="https://ecsource-jove-com.bdigitaluss.remotexs.co/files/ftp_upload/54110/54110fig6large.jpg" target="_blank">请点击此处查看该图的放大版本。</a> <img alt="图7" src="/files/ftp_upload/54110/54110fig7.jpg" /> 图7:M型图像描绘了一个普通肺动脉瓣。从胸骨旁窗口，可以得到肺动脉瓣的短期和长轴视图。审讯的M型线穿过肺动脉瓣应用。肺动脉瓣尖分离（箭头）的距离可以从这个观点来测量。 <a href="https://ecsource-jove-com.bdigitaluss.remotexs.co/files/ftp_upload/54110/54110fig7large.jpg" target="_blank">请点击此处查看该图的放大版本。</a> 10fig8.jpg"/&gt; 图8:就会流过肺动脉瓣的脉冲波的多普勒审讯。肺动脉加速时间（PAAT）是从收缩期肺动脉流向峰值流速的发生的时间间隔。右心室射血时间（RVET）是在其中有流的停止点右心室射血的发作之间的间隔。 <a href="https://ecsource-jove-com.bdigitaluss.remotexs.co/files/ftp_upload/54110/54110fig8large.jpg" target="_blank">请点击此处查看该图的放大版本。</a> <img alt="图9" src="/files/ftp_upload/54110/54110fig9.jpg" /> 图9:M型图片说明:左心室的短轴观。从胸骨旁窗口，通过逆时针转动的换能器头得到的左心室的短轴视图使得图像索引标记点向后或背。在M-模询问电子线路设置在乳头肌水平横跨左心室施加。左室舒张末期内径（LVEDD），左室收缩末期尺寸（LVESD）和前壁（AW）和后壁（PW），厚度可以很容易地测量。要小心，不要包含任何测量乳头肌（*）。 <a href="https://ecsource-jove-com.bdigitaluss.remotexs.co/files/ftp_upload/54110/54110fig9large.jpg" target="_blank">请点击此处查看该图的放大版本。</a> <img alt="图10" src="/files/ftp_upload/54110/54110fig10.jpg" /> 图10:彩色多普勒评价与二尖瓣血流的脉冲多普勒频谱显示。 （A）图像显示在心尖长轴观二尖瓣血流的彩色多普勒评价。需要注意的是二维彩色多普勒图像可以是克重要工具uiding收购脉冲多普勒描记的适当样品体积位置（图B表示）。 （ 二 ）采用脉冲多普勒二尖瓣流入的频谱显示。进行跨二尖瓣血流量（在心尖长轴视图）的脉冲多普勒评估，以评估左室舒张功能。样本量是放置在二尖瓣瓣叶的提示。等容舒张时间（IVRT），等容收缩时间（IVCT），左室射血时间（LVET），和峰值二尖瓣血流速度（E）都可以从脉冲波的多普勒速度的跨二尖瓣频谱显示的。 <a href="https://ecsource-jove-com.bdigitaluss.remotexs.co/files/ftp_upload/54110/54110fig10large.jpg" target="_blank">请点击此处查看该图的放大版本。</a> <img alt="图11" src="/files/ftp_upload/54110/54110fig11.jpg" /> 网络连接古尔11:室间隔二尖瓣环组织多普勒成像。从心尖窗口，获得二尖瓣长轴视图。组织多普勒样品体积被定位在二尖瓣环的隔区。峰值二尖瓣流入速度（在图10B的变量E）和峰二尖瓣环组织速度（例如之间的比率&#39;，由白色箭头表示）被用来评估左心室舒张功能（通常称为E / E&#39;）。 <a href="https://ecsource-jove-com.bdigitaluss.remotexs.co/files/ftp_upload/54110/54110fig11large.jpg" target="_blank">请点击此处查看该图的放大版本。</a> <img alt="图12" src="/files/ftp_upload/54110/54110fig12.jpg" /> 图12:左室心肌的应变及应变率的评估。有可用的专门分析软件包市售，应变和应变率变量可以作为在固有心肌收缩性的早期或亚临床的变化的措施得到的。上面所示的实施例描绘了在小鼠中通常获得成像平面径向应变和应变率。请注意，这些成像平面（与应变描记的后续形状）可从人类的图像，这是在心尖长轴或四腔视图频繁采集不同。 <a href="https://ecsource-jove-com.bdigitaluss.remotexs.co/files/ftp_upload/54110/54110fig12large.jpg" target="_blank">请点击此处查看该图的放大版本。</a>

Watch this Scientific Journal Video about Echocardiographic Approaches and Protocols for Comprehensive Phenotypic Characterization of Valvular Heart Disease in Mice at JoVE.com

Echocardiographic Approaches and Protocols for Comprehensive Phenotypic Characterization of Valvular Heart Disease in Mice

This protocol provides a detailed description of the echocardiographic approach for comprehensive phenotyping of heart and heart valve function in mice.

超声心动图方法和协议心脏瓣膜疾病的综合表型特征小鼠

The aim of this manuscript and accompanying video is to provide an overview of the methods and approaches used for imaging heart valve function in ...

echocardiographic-approaches-protocols-for-comprehensive-phenotypic

Universidad San Sebastian

Research

JoVE Journal

Medicine

15.9K 次观看.  Mayo Clinic. This protocol provides a detailed description of the echocardiographic approach for comprehensive phenotyping of heart and heart valve function in mice. 

视频: Echocardiographic Approaches and Protocols for Comprehensive Phenotypic Characterization of Valvular Heart Disease in Mice

Transthoracic Echocardiography in Mice

In recent years, murine models have become the primary avenue for studying the molecular mechanisms of cardiac dysfunction resulting from changes in gene expression. Transgenic and gene targeting methods can be used to generate mice with altered cardiac size and function,1-3 and as a result, in vivo techniques are needed to evaluate their cardiac phenotype. Transthoracic echocardiography, pulse wave Doppler (PWD), and tissue Doppler imaging (TDI) can be used to provide dimensional measurements of the mouse heart and to quantify the degree of cardiac systolic and diastolic performance. Two-dimensional imaging is used to detect abnormal anatomy or movements of the left ventricle, whereas M-mode echo is used for quantification of cardiac dimensions and contractility.4,5 In addition, PWD is used to quantify localized velocity of turbulent flow,6 whereas TDI is used to measure the velocity of myocardial motion.7 Thus, transthoracic echocardiography offers a comprehensive method for the noninvasive evaluation of cardiac function in mice.

Transthoracic echocardiography offers a noninvasive method for the evaluation of cardiac function in mice. A combination of ultrasound and Doppler imaging modalities can be used to obtain dimensional measurements of the heart and intracardiac blood flow, which together provide an assessment of cardiac systolic and diastolic performance.

经胸超声心动图在小鼠

In recent years, murine models have become the primary avenue for studying the molecular mechanisms of cardiac dysfunction resulting from changes in gene ...

科研

医学

Murine Echocardiography and Ultrasound Imaging

Rodent models of cardiac pathophysiology represent a valuable research tool to investigate mechanism of disease as well as test new therapeutics.1 Echocardiography provides a powerful, non-invasive tool to serially assess cardiac morphometry and function in a living animal.2 However, using this technique on mice poses unique challenges owing to the small size and rapid heart rate of these animals.3 Until recently, few ultrasound systems were capable of performing quality echocardiography on mice, and those generally lacked the image resolution and frame rate necessary to obtain truly quantitative measurements. Newly released systems such as the VisualSonics Vevo2100 provide new tools for researchers to carefully and non-invasively investigate cardiac function in mice. This system generates high resolution images and provides analysis capabilities similar to those used with human patients. Although color Doppler has been available for over 30 years in humans, this valuable technology has only recently been possible in rodent ultrasound.4,5 Color Doppler has broad applications for echocardiography, including the ability to quickly assess flow directionality in vessels and through valves, and to rapidly identify valve regurgitation. Strain analysis is a critical advance that is utilized to quantitatively measure regional myocardial function.6 This technique has the potential to detect changes in pathology, or resolution of pathology, earlier than conventional techniques. Coupled with the addition of three-dimensional image reconstruction, volumetric assessment of whole-organs is possible, including visualization and assessment of cardiac and vascular structures. Murine-compatible contrast imaging can also allow for volumetric measurements and tissue perfusion assessment.

This video demonstrates use of a rail-mounted high-frequency ultrasound probe to perform echocardiography on an anesthetized mouse. The methods describe both conventional two-dimensional and M-mode measurements of cardiac function in addition to newer, more powerful tools such as color Doppler, strain analysis, as well as general and targeted contrast imaging.

小鼠超声心动图和超声成像

Rodent models of cardiac pathophysiology represent a valuable research tool to investigate mechanism of disease as well as test new therapeutics.1  ...

Echocardiographic Assessment of the Right Heart in Mice

Transgenic and toxic models of pulmonary arterial hypertension (PAH) are widely used to study the pathophysiology of PAH and to investigate potential therapies. Given the expense and time involved in creating animal models of disease, it is critical that researchers have tools to accurately assess phenotypic expression of disease. Right ventricular dysfunction is the major manifestation of pulmonary hypertension. Echocardiography is the mainstay of the noninvasive assessment of right ventricular function in rodent models and has the advantage of clear translation to humans in whom the same tool is used. Published echocardiography protocols in murine models of PAH are lacking.
In this article, we describe a protocol for assessing RV and pulmonary vascular function in a mouse model of PAH with a dominant negative BMPRII mutation; however, this protocol is applicable to any diseases affecting the pulmonary vasculature or right heart. We provide a detailed description of animal preparation, image acquisition and hemodynamic calculation of stroke volume, cardiac output and an estimate of pulmonary artery pressure.

This article provides a protocol for the echocardiographic assessment of right ventricular size and pulmonary hypertension in mice. Applications include phenotype determination and serial assessment in transgenic and toxin-induced mouse models of cardiomyopathy and pulmonary vascular disease.

右心小鼠的超声心动图评价

Transgenic and toxic models of pulmonary arterial hypertension (PAH) are widely used to study the pathophysiology of PAH and to investigate potential ...

A Pipeline to Characterize Structural Heart Defects in the Fetal Mouse

Congenital heart diseases (CHDs) are major causes of infant death in the United States. In the 1980s and earlier, most patients with moderate or severe CHD died before adulthood, with the maximum mortality during the first week of life. Remarkable advances in surgical techniques, diagnostic approaches, and medical management have led to marked improvements in outcomes. To address the critical research needs of understanding congenital heart defects, murine models have provided an ideal research platform, as they have very similar heart anatomy to humans and short gestation rates. The combination of genetic engineering with high-throughput phenotyping tools has allowed for the replication and diagnosis of structural heart defects to further elucidate the molecular pathways behind CHDs. The use of noninvasive fetal echocardiography to screen the cardiac phenotypes in mouse models coupled with the high fidelity of Episcopic fluorescence image capture (EFIC) using Episcopic confocal microscopy (ECM) histopathology with three-dimensional (3D) reconstructions enables a detailed view into the anatomy of various congenital heart defects. This protocol outlines a complete workflow of these methods to obtain an accurate diagnosis of murine congenital heart defects. Applying this phenotyping protocol to model organisms will allow for accurate CHD diagnosis, yielding insights into the mechanisms of CHD. Identifying the underlying mechanisms of CHD provide opportunities for potential therapies and interventions.

This article details murine congenital heart disease (CHD) diagnostic methods using fetal echocardiography, necropsy, and Episcopic fluorescence image capture (EFIC) using Episcopic confocal microscopy (ECM) followed by three-dimensional (3D) reconstruction.

表征胎儿小鼠结构性心脏缺陷的管道

Congenital heart diseases (CHDs) are major causes of infant death in the United States. In the 1980s and earlier, most patients with moderate or severe ...

发育生物学

Assessment of Cardiac Morphological and Functional Changes in Mouse Model of Transverse Aortic Constriction by Echocardiographic Imaging

Transverse aortic constriction (TAC) in mice has been used as a valuable model to study mechanisms of cardiac hypertrophy and heart failure1. A reliable noninvasive method is essential to assess real-time cardiac morphological and functional changes in animal models of heart disease. Transthoracic echocardiography represents an important tool for noninvasive assessment of cardiac structure and function2. Here we used a high-resolution ultrasound imaging system to monitor myocardial remodeling and heart failure progression over time in a mouse model of TAC. B-mode, M-mode, and Doppler imaging were used to precisely assess cardiac hypertrophy, ventricular dilatation, and functional deterioration in mice following TAC. Color and pulse wave (PW) Doppler imaging was used to noninvasively measure pressure gradient across the aortic constriction created by TAC and to assess transmitral blood flow in mice. Thus transthoracic echocardiographic imaging provides comprehensive noninvasive measurements of cardiac dimensions and function in mouse models of heart disease.

The goal of this protocol is to noninvasively assess cardiac structural and functional changes in a mouse model of heart disease created by transverse aortic constriction, using B- and M-mode echocardiography and color/pulse wave Doppler imaging.

在横向主动脉缩窄的小鼠模型和心脏形态学评估功能改变通过超声心动图成像

Transverse aortic constriction (TAC) in mice has been used as a valuable model to study mechanisms of cardiac hypertrophy and heart failure1. A reliable ...

Murine Echocardiography of Left Atrium, Aorta, and Pulmonary Artery

The present methodology teaches the investigator how to measure and use the LAV as a surrogate of chronic elevations in Left Ventricular diastolic pressure through echocardiography, as well as to obtain measurements of the Aorta and PA diameter in mice.
Mice older than 10 d of age can be analyzed using the present technique. The technique is composed of 3 main steps: set-up, image acquisition, and image analysis. The set-up step consists of getting the mouse anesthetized with 1% isoflurane, shaving it, and taping it in a supine position to a heated EKG board where the image acquisition will take place. The image acquisition step consists of learning to identify the cardiac structures and obtaining all the required images with its correspondent probe and axis in order to be able to calculate volumes and diameters. The image analysis step consists of measuring the previously acquired images with the aid of computer software.
Advantages of the proposed technique include a fast (15 min) procedure that would allow the researcher to evaluate interventions in a non-invasive, non-terminal approach and therefore follow the same mouse over time; each mouse can be used as its own control. This fact plus having the same operator perform all the acquisition and analysis for the entire experiment minimizes the limitation of operator-dependency. The present methodology is useful for mouse researchers in cardiovascular and pulmonary medicine.

The following protocol describes the methodology for the acquisition and analysis of echocardiographic images used to obtain the Left Atrial Volume (LAV), Aorta (Ao) diameter, and Pulmonary Artery (PA) diameter in mice. This technique is a non-invasive, non-terminal procedure that allows assessment of the cardiopulmonary function.

左心房，主动脉和肺动脉的超声心动图小鼠

The present methodology teaches the investigator how to measure and use the LAV as a surrogate of chronic elevations in Left Ventricular diastolic ...

Echocardiographic and Histological Examination of Cardiac Morphology in the Mouse

An increasing number of genetically modified mouse models has become available in recent years. Moreover, the number of pharmacological studies performed in mice is high. Phenotypic characterization of these mouse models also requires the examination of cardiac function and morphology. Echocardiography and magnetic resonance imaging (MRI) are commonly used approaches to characterize cardiac function and morphology in mice. Echocardiographic and MRI equipment specialized for use in small rodents is&#160;expensive and requires a dedicated space. This protocol describes cardiac measurements in mice using a clinical echocardiographic system with a 15 MHz human vascular probe. Measurements are performed on anesthetized adult mice. At least three image sequences are recorded and analyzed for each animal in M-mode in the parasternal short-axis view. Afterwards, cardiac histological examination is performed, and cardiomyocyte diameters are determined on hematoxylin-eosin- or wheat germ agglutinin (WGA)-stained paraffin sections. Vessel density is determined morphometrically after Pecam-1 immunostaining. The protocol has been applied successfully to pharmacological studies and different genetic animal models under baseline conditions, as well as after experimental myocardial infarction by the permanent ligation of the left anterior descending coronary artery (LAD). In our experience, echocardiographic investigation is limited to anesthetized animals and is feasible in adult mice weighing at least 25 g.

Echocardiographic examination is frequently used in mice. Expensive high-resolution ultrasound devices have been developed for this purpose. This protocol describes an affordable echocardiographic procedure combined with histological morphometric analyses to determine cardiac morphology.

超声心动图与小鼠心脏形态学的组织学检查

An increasing number of genetically modified mouse models has become available in recent years. Moreover, the number of pharmacological studies performed ...

Echocardiographic Measurement of Right Ventricular Diastolic Parameters in Mouse

Diastolic dysfunction is a prominent feature of right ventricular (RV) remodeling associated with conditions of pressure overload. However, the RV diastolic function is rarely quantified in experimental studies. This might be due to technical difficulties in the visualization of the RV in the apical four-chamber view in rodents. Here we describe two positions facilitating the visualization of the apical four-chamber view in mice to assess the RV diastolic function.
The apical four-chamber view is enabled by tilting the mouse fixation platform to the left and caudally (LeCa) or to the right and cranially (RiCr). Both positions provide images of comparable quality. The results of the RV diastolic function obtained from two positions are not significantly different. Both positions are comparably easy to perform. This protocol can be incorporated into published protocols and enables detailed investigations of the RV function.

Here we describe and compare two positions for obtaining the apical four-chamber view in mice. These positions enable the quantification of the right ventricular function, provide comparable results, and can be used interchangeably.

小鼠右心室舒张参数的超声心电图测量

Diastolic dysfunction is a prominent feature of right ventricular (RV) remodeling associated with conditions of pressure overload. However, the RV ...

Revealing Subtle Changes in Cardiac Function using Transthoracic Dobutamine Stress Echocardiography in Mice

Left ventricular (LV) dysfunction paves the final pathway for a multitude of cardiac disorders. With the non-invasive high-frequency transthoracic dobutamine stress echocardiography in humans, a reductionist investigation approach to unmask subtle changes in cardiac function has become possible. Here, we provide a protocol for using this technique in mice to facilitate expanded analysis of LV architecture and function in physiology and pathology enabling the observation of alterations in models of cardiac disease hidden in unstressed hearts. This investigation can be performed in one and the same animal and allows both, basal and pharmacologically stress-induced measurements. We outline detailed criteria for appropriate anesthesia, imaging-based LV analysis, consideration of intra- and interobserver variability, and obtaining positive inotrope response that can be attained in mice after intraperitoneal injection of dobutamine under near physiological conditions. To recapitulate the characteristics of human physiology and disease in small animal models, we highlight critical pitfalls in evaluation, e.g., a pronounced Bowditch effect in mice. To further meet translational objectives, we compare stress-induced effects in humans and mice. When used in translational studies, attention must be paid to physiological differences between mice and human. Experimental rigor dictates that some parameters assessed in patients can only be used with caution due to restrictions in spatial and temporal resolution in mouse models.

Left ventricular dysfunction constitutes the final common pathway for a host of cardiac disorders. We here provide a detailed protocol of transthoracic dobutamine stress echocardiography approach for comprehensive evaluation of the left ventricular function of mouse models of cardiac disease as well as cardiac phenotyping.

Left ventricular (LV) dysfunction paves the final pathway for a multitude of cardiac disorders. With the non-invasive high-frequency transthoracic ...

Echocardiographic Characterization of Left Ventricular Structure, Function, and Coronary Flow in Neonate Mice

Echocardiography is a non-invasive procedure that enables the evaluation of structural and functional parameters in animal models of cardiovascular disease and is used to assess the impact of potential treatments in preclinical studies. Echocardiographic studies are usually conducted in young adult mice (i.e., 4-6 weeks of age). The evaluation of early neonatal cardiovascular function is not usually performed because of the small size of the mouse pups and the associated technical difficulties. One of the most important challenges is that the short length of the pups&#39; limbs prevents them from reaching the electrodes in the echocardiography platform. Body temperature is the other challenge, as pups are very susceptible to changes in temperature. Therefore, it is important to establish a practical guide for performing echocardiographic studies in small mouse pups to help researchers detect early pathological changes and study the progression of cardiovascular disease over time. The current work describes a protocol for performing echocardiography in mouse pups at the early age of 7 days old. The echocardiographic characterization of cardiac morphology, function, and coronary flow in neonatal mice is also described.

The present protocol describes the echocardiographic assessment of left ventricular morphology, function, and coronary blood flow in 7-day old neonate mice.

新生小鼠左心室结构、功能和冠状动脉血流的超声心动图表征

Echocardiography is a non-invasive procedure that enables the evaluation of structural and functional parameters in animal models of cardiovascular ...