这项工作由中国国家自然科学基金 (81671685) 和上海卫生与计划生育委员会 (201440538 号) 资助。

十五只雄性猎犬 (12 至18月大, 体重约 10.0-12.0 公斤) 被购买并接受实验。所有程序均遵照美国国立卫生研究院出版的《护理和使用实验动物指南》 (85-23 号修订版 1996), 并经复旦大学中山医院动物护理委员会批准。大学.图 1显示了所有协议步骤的示意图工作流。
1. 手术前准备和基线数据收集
<ol><li>剃掉一个后肢的头发, 以便静脉穿刺。用静脉导管 (22 克, 0.9 毫米 x 25 毫米), 通过实验性比格犬小隐静脉的侧支建立静脉通路。通过静脉导管缓慢注射戊巴比妥钠 (30 毫克/千克), 引起麻醉, 这是由于睫毛反射丧失所证实的。在手术中麻醉恢复的情况下, 给予戊巴比妥钠10毫克/千克的剂量。</li>
	<li>用粗绳将四肢固定在操作桌上, 使动物处于仰卧位。</li>
	<li>夹住四肢和胸部的毛发。将肢体铅电极贴在胸壁上六指定位置的肢体四肢和胸铅电极上。记录基线心电图 (ECG)。</li>
	<li>
超声心动图评估
	<ol>
<li>将超声心动图的铅电极粘贴到动物的四肢上。</li>
		<li>进行标准的超声心动图检查。从常规的顶端四室 (A4C) 和顶端两室 (A2C) 视图, 获得 lv 端舒张容积 (左), lv 端收缩容积 (LVESV), 和 lv 弹射分数 (LVEF) 计算使用双辛普森的方法。</li>
		<li>用二维散斑跟踪成像法评价低压纵应变。对 A4C、A2C 和顶端长轴视图 (APLAX) 执行散斑跟踪。</li>
		<li>从上述三顶端的角度, 获得每面墙的基底、中心室和顶端水平的纵应变曲线 (A4C: 隔膜和侧壁;A2C: 前壁和下壁;APLAX: 前隔膜和后壁)。该软件将自动集成这些数据, 以产生一个公牛的眼睛图17段, 包括6段在基底水平 (隔膜, 侧壁, 前壁, 下壁, 前隔膜, 后壁), 6 段在中心室水平 (隔膜, 侧壁, 前壁, 下壁, 前隔膜, 后壁), 4 段在顶端水平 (隔膜, 侧壁, 前壁, 下壁), 和一个顶盖。</li>
		<li>峰值应变时间由 QRS 波开始至应变曲线的最低点的时间间隔, 表明最大纵应变。计算17段的标准差 (PSD), 以评估 LV 机械同步。</li>
		<li>记录 transaortic 多普勒流速在顶端五室视图。测量和平均 aVTI 在3-4 连续节拍。</li>
	</ol>
</li>
	<li>
气管插管与机械通气
	<ol>
<li>轻轻拔出舌头, 保持舌头的延伸, 准备气管插管。将动物定位在 "嗅探" 的位置。</li>
		<li>慢慢地推进喉镜的弯曲的刀片, 直到刀片尖端位于舌头的底部和会厌之间。抬起喉镜向上露出声带。将气管插管插入口腔, 并将导管越过声带。用胶带把管子固定在动物头上。</li>
		<li>听诊两肺, 以确认适当的气管插管放置, 证明了双侧和对称呼吸声音在正压通气期间。</li>
		<li>将气管导管的外端连接至容积式循环呼吸机。使用室内空气启动和维护辅助机械通气。将呼吸频率设置为每分钟8-20 次, 潮汐量为8-15 毫升/千克。根据脉冲氧测量的2设置参数。</li>
	</ol>
</li>
</ol>2. 心外膜 LV 起搏电极植入术
<ol><li>将心脏除颤器/显示器引线连接到与四肢相连的皮肤电极上。用0.3 克左氧氟沙星静脉注射 guttae 对动物进行预用药。</li>
	<li>剃后颈部和胸部的头发, 消毒前胸区和左颈部地区与碘伏和铺消毒片。</li>
	<li>
切口
	<ol>
<li>在右侧压位位置执行肌肉备用开胸手术。经静脉连续输液 (0.01 毫克/千克/小时) 管理芬太尼后, 在第四肋间空间从左胸骨旁线横向切割皮肤。</li>
		<li>在钝性解剖3层胸肌 (胸大, 胸小, 肋), 打开左胸腔在第四肋间空间 (4th和 5th肋骨) 通过尖锐的解剖。将肋骨牵引器放入肋间空间。包不育纱布浸泡在0.9% 氯化钠周围的肺裂片, 以保护肺部和保持一个明确的视野。</li>
		<li>用烙小心切开侧心包。打开心包充分暴露 LV 侧壁与停留缝合 (0 缝合)。</li>
	</ol>
</li>
	<li>
LV 起搏电极植入术
	<ol>
<li>将单极 lv 起搏电极缝合到 lv 侧壁上的心肌上, 用一针4-0 缝合。在缝合上做一个温和的结, 以防止划破心肌组织。</li>
		<li>将起搏导线的端子金属销连接到桥接电缆以测试引线参数。在达到满意的引线参数后, 通过起搏阈值 < 2.0 V 在 0.48 ms 和引线阻抗 < 2000 Ω, 轻微拉电极引线保证牢固的固定。</li>
	</ol>
</li>
	<li>取出留缝线, 仔细检查手术区域, 消除活动出血。</li>
	<li>用 2-0/T 缝线缝合两针的心包。取出填充纱布和肋骨牵引器。</li>
	<li>使用两个 pericostal 缝合 (0 缝合) 近似 4th和 5th肋骨。用 2-0/T 缝线缝合几针肋间筋膜。在最后缝合前通过气管插管, 充分利用辅助气球充气肺部。通过肋确认肺正常扩张。</li>
	<li>将肌肉层重新定位在没有缝合的地方。起搏铅穿透心包、肋间筋膜和肌肉层, 通过手术结之间的间隙先后。</li>
	<li>切开左颈部的皮肤, 解剖皮下的组织, 直到用弯曲钳到达深筋膜。用直钳在胸区的深招牌上建立一个皮下隧道。</li>
	<li>使用直钳将引线的端子销通过隧道拉到左颈部区域。用 2-0/T 缝线将端子销盖上绝缘套筒。将套管周围的铅缝合到筋膜上, 并在颈部左侧嵌入铅。</li>
	<li>用0缝线闭合胸部和颈部切口的皮下组织和皮肤。</li>
	<li>停止麻醉诱导, 当动物正在进行自发性呼吸时, 将气管插管与呼吸机断开。当动物从麻醉中恢复后, 取出气管插管和静脉导管。保持观察动物直到完全恢复。</li>
	<li>术后2周, 每12小时注射肌肉 80万 U 青霉素。</li>
</ol>3. RA 和 RV 起搏电极植入术
<ol><li>植入 RA 和 RV 起搏电极2周后, LV 电极植入, 当动物从开胸恢复。在心脏导管手术室进行手术, 配备透视仪。</li>
	<li>在步骤1.1 诱导麻醉。将四肢固定在手术台上, 并保持仰卧位的动物。用0.3 克左氧氟沙星静脉注射 guttae 对动物进行预用药。</li>
	<li>夹住四肢的毛发。将心电图监测导线与皮肤电极连接, 将皮肤电极粘贴到肢体四肢。打开心电图监控器, 并为程序内监控选择第二主角。</li>
	<li>剃掉颈部的毛发后, 用碘伏消毒左颈部区域, 并将不育的床单下垂。在全过程中静脉注射 (0.01 毫克/千克/小时) 连续输液 (芬太尼)。</li>
	<li>
静脉入路
	<ol>
<li>在颈部左侧的伤口处做一个小的垂直切口。采用钝夹层, 将筋膜分开, 露出左颈外静脉。小心地用蚊子钳把静脉从结缔组织中分离出来。</li>
		<li>用弯曲的钳轻轻地拉起静脉, 在静脉下面通过两 2-0/T 缝线。把远端缝合线系上。</li>
		<li>轻轻抬起远端缝线, 用虹膜剪刀在两条缝线中间切开一个小孔。使用静脉摘出, 插入被动 J 型 RA 铅和主动 RV 铅进入左外颈静脉。</li>
	</ol>
</li>
	<li>
RV 铅植入术
	<ol>
<li>一旦 rv 铅被推进到低右心房或下腔静脉下透视, 退出直接鞘从 RV 铅。在鞘的远端形成 J 形, 再通过 RV 引线插入。</li>
		<li>在弯曲的鞘的帮助下, 引入贯穿三尖瓣和流出道的铅。慢慢地撤回铅和鞘, 允许铅尖下垂向 RV 顶端。</li>
		<li>用直线替换曲线鞘。提前向顶端的铅。</li>
		<li>测试引线参数与鞘撤回约一半。满意的参数包括起搏阈值 < 1.0 V 在0.48 毫秒, R 波振幅 > 5.0 mV, 和铅阻抗 < 2000 Ω。一旦获得可接受的电气参数, 扩展活动螺旋线, 移除鞘, 并重新测量参数。</li>
	</ol>
</li>
	<li>
RA 铅植入术
	<ol>
<li>保持 RA 铅定向向高前心房, 慢慢地撤回直鞘, 允许收缩的预制 J 型铅与其尖端进入附属物。可以观察到具有心房活动的电极的特性来来回运动。</li>
		<li>满意的参数包括起搏阈值 < 1.0V 在0.48 毫秒, P 波振幅 > 2.0 mV, 和铅阻抗 < 2000 Ω。同样, 当获得可接受的参数时, 调整引线松弛并移除鞘。</li>
	</ol>
</li>
	<li>检查两个引线的稳定性后, 拧紧近 venotomy 的缝合线。把两个或三 2-0/T 缝合线围绕缝合袖子的基础深筋膜。在缝合后重新检查两条引线在透视下的电参数和位置。</li>
	<li>使一个脉冲发生器口袋附近的静脉进入和在一个平面上的筋膜层和下方的皮下脂肪。使用弯曲钳, 用钝夹层创建口袋。它应该只是足够大, 以适应发电机和冗余的线索。</li>
	<li>清洁并烘干引线针脚。用绝缘套筒盖住心房引线的端子销, 并将引线缝合到口袋的底部。将心室引线插入起搏器脉冲发生器中, 并将其与远端连接器引脚拧紧, 通过发电机的固定螺钉。</li>
	<li>将发电机放入口袋中, 并将多余的引线卷入设备下。用 2-0/T 缝线将发电机绑在发板上, 通过在发电机头上的栓孔缝合。对整个系统进行透视检查。</li>
	<li>检查止血后, 用 2-0/T 缝线关闭口袋和浅层筋膜。最后用0缝线近似皮肤边缘, 用遥测棒将起搏器编程到蛋模式。</li>
	<li>对于假组的动物, 植入 LV, RV 和 RA 的线索类似的方式, 但没有发电机插入。</li>
</ol>4. LBB 消融术
<ol><li>在 RV 和 RA 铅植入术后立即在透视指导下进行导管消融术。剃去胸部、背部和右腹股沟区域的毛发。使动物处于仰卧位。</li>
	<li>准备一个多通道的电生理记录仪, 用于同时进行表面和心内心电图记录, 过滤器设置为30-400 赫 (双极) 或0.05-500 赫 (单极), 信号放大5000倍。将无绳返回电极连接到背部, 并将标准的12引线电极固定在四肢和胸部。将所有引线连接到电生理记录器, 并以100毫米/秒的扫描速度记录心电图。</li>
	<li>
静脉和动脉方法
	<ol>
<li>在右腹股沟区域进行例行消毒和悬垂后, 通过皮肤垂直切开小切口。采用钝夹层分离筋膜, 识别右股静脉和股动脉。</li>
		<li>轻轻拉上股静脉和放置两个留缝线 (2-0/T 缝合) 的静脉。在远端系上静脉。在股动脉上做同样的动作。</li>
		<li>稍微拾起股静脉, 并在两条缝线之间引入微穿刺针。保持针稳定, 并插入一个灵活的尖端 (软盘 J 形) 导丝通过针。</li>
		<li>当足够的导丝进入静脉时, 取出针并将扩张和鞘组合 (6 法郎) 在导丝到股静脉内。取出导丝和扩张与鞘剩余的导管介绍。用静脉鞘在 venotomy 附近的静脉上系上松散的缝线。</li>
		<li>同样, 插入一个7法郎鞘到股动脉。将100的 U/千克生理盐水稀释肝素送到动脉鞘中, 以防止凝血。</li>
	</ol>
</li>
	<li>
右侧映射他的捆绑潜力
	<ol>
<li>通过静脉鞘推进6法郎导向 quadripolar 导管进入股静脉。通过电缆通过导管输入模块将导管末端连接到多通道电生理记录仪。</li>
		<li>通过导管进入右心房, 并通过三尖瓣, 直到它清楚地在右心室。在右前斜 (饶) 的30°透视视图, 撤回导管横跨三尖瓣孔, 直到心房电位出现并变得更大。轻微的顺时针扭矩有助于保持电极与隔膜接触。当心房和心室电位大小近似相等时, 两者之间出现双相或三相偏转, 代表右侧的束电位。</li>
	</ol>
</li>
	<li>
左束分支电位 (LBP) 映射和烧蚀
	<ol>
<li>通过动脉鞘引入7法郎4毫米的导向消融导管进入股动脉。将消融导管的末端连接到射频发生器和多通道电生理记录仪。</li>
		<li>通过动脉导管 retrogradely 横跨主动脉瓣膜和前进到 LV 在饶的看法。转移导管尖向室隔膜。保持电极与隔膜紧密接触。</li>
		<li>在左前斜 (老挝) 45°透视视图, 慢慢地撤回导管沿隔膜, 直到左侧他的捆绑电位被记录在心房和心室心电图之间, 就在主动脉瓣膜下方。然后慢慢推进导管沿隔膜和操作提示, 以确定一个离散的 LBP, 这是记录在主动脉瓣下, 通常 1-1. 5 厘米低于左侧他的捆绑记录网站。</li>
		<li>当电位-心室心电图间隔比高压间隔短约10毫秒时, 观察 < 1:10 的 A/V 心电图比, 确定了 LBP。通常的 lbp 到最早的心室心电图间隔 (lbp V) 短于20毫秒, 这可能会降低完全 A V 阻滞的风险。</li>
		<li>一旦获得满意的 LBP 位置, 开始导管消融与射频发生器, 提供500赫 unmodulated 正弦波能量 (功率范围 30-40 W)。在电极-组织界面上调整功率以达到60摄氏度的目标温度。如果温度在十五年代内不超过摄氏50摄氏度, 停止能量传递, 调整导管尖端, 然后重新开始。</li>
		<li>在能量应用过程中不断地监测阻抗。在能量传递过程中, 阻抗大于6-8 Ω的下降被认为是良好的组织接触和足够的加热的标志。</li>
		<li>典型 LBBB 的定义是: QRS 持续时间的延长;QRS 阳性在主角 I, II, V5, V6 具缺口 R 波浪和阴性在主角 aVR, V1;和心电图的损失。如果十年代后 QRS 形态学没有变化, 停止能量传递, 调整导管以找到新的 LBP 靶。当一个典型的 LBBB QRS 形态学出现在表面心电图, 继续能量应用 60-90 s 或直到突然上升的阻抗。</li>
		<li>在完全 (3rd度) 房室阻滞或心室颤动 (VF) 的情况下立即停止能量传递。当 VF 发生时, 迅速实施电除颤。</li>
		<li>当 LBBB QRS 形态学达到时, 观察表面心电图稳定期为30分钟。如果正常 QRS 形态学再现, 重复上述消融过程。</li>
	</ol>
</li>
	<li>导管消融术完成后, 取出两个导管。切除静脉和动脉鞘, 并在近端缝合上迅速打结以防止出血。</li>
	<li>经过仔细检查, 以排除主动出血, 关闭筋膜层使用 2-0/T 缝合。最后用0缝线关闭皮肤。</li>
	<li>切断动物的所有电极, 并经常监测动物, 直到完全恢复麻醉。术后1周, 每12小时注射肌肉 80万 U 青霉素。</li>
	<li>LBB 消融不是为假组进行。</li>
</ol>5. 高频感应快速起搏
<ol><li>当动物从手术中恢复后, 再次记录表面心电图, 确认1周后永久 LBBB 存在。然后用遥测棒将起搏器编程到 VVI 模式, 每分钟260次 (bpm)。</li>
	<li>诱导麻醉 (如步骤 1.1) 和程序起搏器到蛋模式后4周快速起搏。</li>
	<li>执行超声心动图评估 LVEF (参照步骤 1.4)。如果 LVEF 低于 35%, 为 CRT 性能准备动物。如果 LVEF 仍然在35% 以上, 提交动物快速 RV 起搏再次通过重新编程起搏器到 VVI 模式在 260 bpm。</li>
	<li>每2周进行一次超声心动图, 直到 LVEF 低于35%。一旦达到 LVEF 目标, 终止快速 RV 起搏, 并准备 CRT 策略。</li>
	<li>假组动物不提交快速起搏。</li>
</ol>6. 心脏再同步治疗的性能
<ol><li>随机将与 HF 的动物分为对照组和 CRT 组。对于 HF 控制组, 让动物再活8周, 无需干预。对于 crt 组, 通过心室起搏启动 crt 性能。</li>
	<li>麻醉诱导后 (如步骤 1.1), 通过将四肢固定在手术台上, 使动物处于仰卧位。用0.3 克左氧氟沙星静脉注射 guttae 对动物进行预用药。剃掉颈部的毛发, 消毒左颈部区域, 并将不育的床单下垂。</li>
	<li>经静脉连续输液 (0.01 毫克/千克/小时) 治疗芬太尼后, 在颈部左侧的前伤口旁做一个小的垂直切口。使用钝解剖, 分开的筋膜, 以隔离脉冲发生器和起搏线索 (包括 RV, LV 和 RA 线索) 没有伤害。</li>
	<li>松开螺钉, 使 RV 引线的端子销脱离发电机头。小心地切开紧固在 LV 和 RA 主角和 uncap 终端别针。在乙醇中浸泡并连续使用干纱布, 清洁所有引线的针脚。</li>
	<li>将 RA、RV 和 LV 插入到 CRT 脉冲发生器的标头中, 并拧紧螺钉。用钝夹层放大口袋, 适合新发电机。把发电机放到口袋里, 用 2-0/T 缝合线把发电机绑在口袋的地板上。</li>
	<li>检查口袋里是否有止血。用 2-0/T 缝线关闭口袋和浅层筋膜。然后用0缝线关闭皮肤。</li>
	<li>将起搏器设置为与房室 (AV) 延迟的 DDD 模式, 其值为70毫秒和室 (), 延迟0毫秒. 检查动物经常, 直到恢复麻醉。注射 80万 U 青霉素肌肉每12小时1周。</li>
	<li>经过8周的 CRT 性能, 再次执行经胸超声心动图对所有组的动物 (如步骤 1.4)。</li>
</ol>7. 祭祀动物和组织学分析
<ol><li>在全身麻醉下, 将动物的四肢固定在手术台上。注射100毫克/千克静脉注射戊巴比妥进行动物牺牲。确保动物死亡的心脏跳动和呼吸运动没有。</li>
	<li>切开左侧宫颈区的皮肤。用尖锐和钝的解剖组合, 释放发电机和引线。松开螺钉, 从发电机上拔下所有引线。</li>
	<li>从皮下组织中逐渐释放出线索, 直到静脉进入点。识别缝合袖子并切开所有的固定缝线。收回房车的主动固定螺旋, 以方便去除。</li>
	<li>从胸骨线到左锁骨中线线, 在第四肋间空间进行横切口。释放 LV 铅从胸筋膜, 沿皮下隧道, 直到左颈部地区, 用一个直钳。</li>
	<li>胸部肌肉钝解剖后, 打开左胸腔。将肋骨牵引器放入肋间空间。完全打开心包。</li>
	<li>切断在心外膜 LV 铅电极上的缝合线。通过切断电极周围的一小块心肌组织, 将电极与心脏分开。</li>
	<li>切开与隔膜一起打开右室。用尖锐的和钝的解剖方法从心肌中分离 RA 和 RV 电极。通常电极提示是由纤维和心肌组织封装。如果需要, 从心脏切开周围的组织。</li>
	<li>通过终端引脚通过一个直鞘到每个引线的尖端。从静脉入口提取 RV 和 RA 引线, 从皮下隧道中取出 LV 铅。如果由于纤维粘连而无法摆脱引线, 则用钝夹层去除导线上的纤维粘连。</li>
	<li>轻轻拉起心脏, 通过靠近主动脉的心脏组织夹住心脏。把心脏放在一个不育的碗里, 用生理盐水冲洗几次。将壁心肌从侧 LV 壁切片进行组织学分析。</li>
	<li>用缓冲的福尔马林固定心肌组织, 然后脱水, 并嵌入石蜡。在切割成5µm 厚的切片后, deparaffinize 的样品和染色与苏木精和伊红 (他) 和马尾三色。</li>
	<li>测量与他染色的纵断面的细胞直径。表达 CVF 的百分比的胶原染色面积除以总组织面积的马尾三色染色部分。为每个节随机选择并计数五个高功率字段 (400x)。拍摄数字照片, 并使用高分辨率的数字图像分析系统进行分析。</li>
</ol>

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作者声明他们没有竞争的财政利益。

扩张型心肌病是充血性心力衰竭的主要病因, 其特点为心室扩张、收缩功能不全、LVEF 减少、舒张期异常 (11)。由于慢性心动过速介导 HF 是公认的临床条件, 快速起搏的心房或心室至少3至4周作为一种常用的动物模型诱发 CHF11。快速起搏后, 血流动力学的变化发生在24小时后, 心脏功能持续恶化长达3至5周。然而, 从起搏诱发的 HF 的恢复是这个模型的戏剧性和独特的...

晚期慢性 HF 是导致各种心血管疾病死亡的主要原因。充血性心力衰竭患者 (CHF) 的一个子集也发展心室传导 discoordination, 加重症状和预后。CRT, 也称为心室起搏, 已被介绍为这些病人的替代治疗20年以上1,2。不幸的是, 大约20-40% 的患者对 CRT 反应不佳。此后, 为了最大限度地提高 CRT 响应3, 已经进行了许多研究。现在人们已经认识到, LBBB 患者比非 LBBB4更能受益于 CRT, 因为 LBBB 模式会导致较大的心脏不同步, 因为间隔和侧壁之间的壁运动自由不对称。.同时, 最近的研究已经开始探索与 CRT5相关的基因表达和分子重塑的变化。伴随着 CRT 诱导的结构反向重构, 细胞和分子恢复到正常水平是非常感兴趣的6。因此, 有必要建立一个独立 LBBB 的 CHF 的最佳模型, 以研究 CRT 的优点。
慢性, 快速心室起搏曾经用来产生 CHF 的犬模型。RV 起搏无疑会产生延迟的 LV 收缩作为 LBBB 收缩模式的模型。然而, 这种类型的功能异步与完整的传导系统可能不会模拟解剖 LBBB, 并没有被认为是一个适当的模型, 研究 CRT 性能, 其本质是协调受损的电激活和心肌收缩。在停止起搏后, 快速恢复 lv 收缩力和部分恢复 lv 尺寸也报告了7。
实验研究通过射频消融诱导慢性 LBBB 建立异步心室收缩8。全球泵功能减少和区域无效机械工作的结合, 可能会导致心力衰竭, 产生心脏低效和心脏重塑在组织, 细胞和分子水平。在 LBBB 的心脏, 工作负荷是最低的隔膜和最高的 LV 侧壁。因此, 心脏重塑最明显的侧壁9。本研究的目的是: (i) 采用快速 RV 起搏与 LBB 消融相结合的方法, 在室和脑室机械异步的情况下, 推进一种稳定、慢性 HF 模型;(ii) 确认 dyssynchronous HF 在我们的模型和 CRT 的好处, 协调收缩的二维散斑跟踪超声心动图和 aVTI;(iii) 初步探讨 CRT 诱发的细胞反向重塑。

<table><tbody><tr><td>Closed iv catheter system (0.9mm&amp;times;25mm)</td><td>Becton Dickinson Medical</td><td>5264442</td><td>Used as venous retention needle</td></tr><tr><td>Sodium pentobarbital</td><td>Sigma-Aldrich Company</td><td>130205</td><td>For anesthesia</td></tr><tr><td>Pet clipper</td><td>Wuhan Shernbao pet supplies Co., Ltd.</td><td>PGC-660</td><td>For hair shaving</td></tr><tr><td>Electrocardiograph</td><td>Shanghai photoelectric medical electronic instrument Co., Ltd.</td><td>ECG-6511</td><td>For electrocardiogram recording</td></tr><tr><td>Echocardiograph</td><td>GE-Vingmed Ultrasound Company</td><td>VIVID E9</td><td>For echocardiographic assessment</td></tr><tr><td>EchoPAC software</td><td>GE healthcare</td><td>Version201</td><td>Offline analysis</td></tr><tr><td>Laryngoscope</td><td>Shanghai Medical Instrument Co., Ltd</td><td></td><td>Orotracheal intubation</td></tr><tr><td>Endotracheal tube</td><td>SIMS Portex Inc, UK</td><td>274093</td><td>Orotracheal intubation</td></tr><tr><td>Volume cycled respirator</td><td>Newport Corporation</td><td>C100</td><td>Artificial ventilation</td></tr><tr><td>HeartStart XL Defibrillator/Monitor</td><td>Philips Medical Systems</td><td>M4735A</td><td>Electrocardiogram monitor during operation</td></tr><tr><td>Benzalkonium Bromide Tincture</td><td>Shanghai Yunjia Pharmaceutical Co., Ltd.</td><td>H31022694</td><td>Used for skin disinfection</td></tr><tr><td>Rib retractor</td><td>Shanghai Medical Instrument Co., Ltd.</td><td></td><td>For thoracotomy</td></tr><tr><td>4-0 suture</td><td>Shanghai Pudong Jinhuan Medical Products Co., LTD.</td><td>24L1005</td><td>Suture of LV epicardial electrode</td></tr><tr><td>2-0/T suture</td><td>Shanghai Pudong Jinhuan Medical Products Co., LTD.</td><td>11M0505</td><td>Suture of pacing leads, fascia, vessels, etc.</td></tr><tr><td>0-suture</td><td>Shanghai Pudong Jinhuan Medical Products Co., LTD.</td><td>11P0501</td><td>Skin suture</td></tr><tr><td>penicillin powder</td><td>North China Pharmaceutical Co., Ltd.</td><td>F6034105</td><td></td></tr><tr><td>DSA X-ray machine</td><td>Philips</td><td>Allura Xper FD10</td><td>X-ray for fluoroscopy</td></tr><tr><td>LV pacing electrode</td><td>Medtronic, Inc.</td><td>LBT 4965</td><td></td></tr><tr><td>RV pacing electrode</td><td>St. Jude Medical</td><td>Tendril 1888</td><td></td></tr><tr><td>RA pacing electrode</td><td>St. Jude Medical</td><td>IsoFlex 1642T</td><td></td></tr><tr><td>Pacemaker pulse generator</td><td>Medtronic, Inc.</td><td>Enpulse E2DR01</td><td>For rapid RV pacing</td></tr><tr><td>CRT pulse generator</td><td>St. Jude Medical</td><td>Anthem PM 3212</td><td>For CRT performance</td></tr><tr><td>Multi-channel electrophysiologic recorder</td><td>GE Medical Systems</td><td>2003232-004</td><td>For surface and intracardiac electrogram</td></tr><tr><td>Catheter input module</td><td>GE Medical Systems</td><td>301-00202-08</td><td>Multiple pole switches for stimulation or recording</td></tr><tr><td>Radiofrequency generator</td><td>Johnson-Johnson Company</td><td>ST-4460</td><td>For RF current delivery</td></tr><tr><td>Cordless return electrode</td><td>Covidien</td><td>E7509</td><td>For current circuit formation</td></tr><tr><td>Cordis 6-Fr sheath</td><td>Johnson-Johnson Company</td><td>504-606X</td><td>Access for mapping catheter</td></tr><tr><td>Cordis 7-Fr sheath</td><td>Johnson-Johnson Company</td><td>504-607X</td><td>Access for mapping and ablation catheter</td></tr><tr><td>6-Fr quadripolar catheter</td><td>Johnson-Johnson Company</td><td>F6QRA005RT</td><td>Mapping catheter</td></tr><tr><td>7-Fr 4mm-tip steerable ablation catheter</td><td>St. Jude Medical</td><td>402823</td><td>Mapping and ablation catheter</td></tr><tr><td>Prucka Cardio-Lab&lt;sup&gt;&amp;reg;&lt;/sup&gt;2000</td><td>GE Medical Systems</td><td>6.9.00.000</td><td>Software package for electrogram recording</td></tr><tr><td>Heparin</td><td>Haitong Pharmaceutical Co., Ltd</td><td>160505</td><td>Anticoagulant during catheter ablation</td></tr><tr><td>Digital image analysis system</td><td>Leica Microsystems</td><td>Qwin V3</td><td>For histologic analysis</td></tr></tbody></table>

benefits of cardiac resynchronization therapy in an asynchronous heart failure model induced by left bundle branch ablation and rapid pacing

现在人们已经认识到, 心力衰竭 (HF) 患者左束支阻滞 (LBBB) 从心脏再同步治疗 (crt) 获得了大量的临床好处, LBBB 已成为 CRT 反应的重要预测因素之一。传统的 tachypacing 诱发 HF 模型有几个主要的局限性, 包括没有稳定的 LBBB 和快速逆转左心室 (LV) 功能障碍停止后起搏。因此, 有必要建立一个具有孤立 LBBB 的慢性 HF 的最佳模型来研究 CRT 的优点。在本研究中, 建立了由左束支 (LBB) 消融和4周快速右心室 (RV) 起搏引起的异步 HF 犬模型。RV 和右心房 (RA) 起搏电极通过颈静脉的方法, 连同心外膜 LV 起搏电极, 被植入的 CRT 性能。本文介绍了射频导管消融、起搏引导植入和快速起搏策略的详细协议。术中还提供心内和表面电图, 以更好地了解 LBB 消融。采用二维散斑跟踪成像和主动脉速度时间积分 (aVTI) 验证了具有 LV 异步和 CRT 优点的慢性稳定 HF 模型。通过协调心室活化和收缩, CRT 制服 lv 机械工作和恢复 lv 泵功能, 其次是逆转的 lv 扩张。此外, 病理学研究显示, 显着恢复的心肌细胞直径和胶原体积分数 (CVF) 后 crt 的表现, 表明组织学和细胞反向重塑诱发的 crt。在本报告中, 我们描述了一种可行的和有效的方法来发展一个慢性异步 HF 模型, 这是适合研究结构和生物逆向重塑后, CRT。

成功的 LBB 消融:
图 2表示导管消融过程中的典型表面和心内心电图。测量的平均 LBP 为18.8 ±2.8 ms, 比基线 h-v 间隔短10毫秒 (28.8 ±2.6 ms, p < 0.01)。在 LBB 消融后, QRS 持续时间从59.2 ±6.8 ms 延长到94.2 ±8.6 ms (p < 0.01)。心电图的丢失证实了成功的 LBB 消融。
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Watch this Scientific Journal Video about Benefits of Cardiac Resynchronization Therapy in an Asynchronous Heart Failure Model Induced by Left Bundle Branch Ablation and Rapid Pacing at JoVE.com

Benefits of Cardiac Resynchronization Therapy in an Asynchronous Heart Failure Model Induced by Left Bundle Branch Ablation and Rapid Pacing

心脏再同步治疗在左束分支消融和快速起搏诱发的异步心力衰竭模型中的益处

采用快速起搏联合左束分支消融法建立慢性心力衰竭 (HF) 模型。应用二维散斑跟踪成像和主动脉速度时间积分验证了该模型的左心室异步性和心脏再同步治疗的益处。

It is now well recognized that heart failure (HF) patients with left bundle branch block (LBBB) derive substantial clinical benefits from cardiac ...

benefits-cardiac-resynchronization-therapy-an-asynchronous-heart

Research

JoVE Journal

Biology

10.4K 次观看.  Zhongshan Hospital, Fudan University. 采用快速起搏联合左束分支消融法建立慢性心力衰竭 (HF) 模型。应用二维散斑跟踪成像和主动脉速度时间积分验证了该模型的左心室异步性和心脏再同步治疗的益处。

视频: Benefits of Cardiac Resynchronization Therapy in an Asynchronous Heart Failure Model Induced by Left Bundle Branch Ablation and Rapid Pacing

Programmed Electrical Stimulation in Mice

Genetically-modified mice have emerged as a preferable animal model to study the molecular mechanisms underlying conduction abnormalities, atrial and ventricular arrhythmias, and sudden cardiac death.1 Intracardiac pacing studies can be performed in mice using a 1.1F octapolar catheter inserted into the jugular vein, and advanced into the right atrium and ventricle. Here, we illustrate the steps involved in performing programmed electrical stimulation in mice. Surface ECG and intracardiac electrograms are recorded simultaneously in the atria, atrioventricular junction, and ventricular myocardium, whereas intracardiac pacing of the atrium is performed using an external stimulator. Thus, programmed electrical stimulation in mice provides unique opportunities to explore molecular mechanisms underlying conduction defects and cardiac arrhythmias.

Programmed electrical stimulation provides the ability to determine conduction properties of the heart, and the possibility to induce and terminate cardiac arrhythmias using various pacing protocols. Using a transvenous catheter, intracardiac electrogram recordings can be obtained in mice following programmed electrical stimulation protocols to identify arrhythmogenic substrates.

程控电刺激小鼠

Genetically-modified mice have emerged as a preferable animal model to study the molecular mechanisms underlying conduction abnormalities, atrial and ...

科研

医学

Simultaneous Electrical and Mechanical Stimulation to Enhance Cells' Cardiomyogenic Potential

Cardiovascular diseases are the leading cause of death in developed countries. Consequently, the demand for effective cardiac cell therapies has motivated researchers in the stem cell and bioengineering fields to develop in vitro high-fidelity human myocardium for both basic research and clinical applications. However, the immature phenotype of cardiac cells is a limitation on obtaining tissues that functionally mimic the adult myocardium, which is mainly characterized by mechanical and electrical signals. Thus, the purpose of this protocol is to prepare and mature the target cell population through electromechanical stimulation, recapitulating physiological parameters. Cardiac tissue engineering is evolving toward more biological approaches, and strategies based on biophysical stimuli, thus, are gaining momentum. The device developed for this purpose is unique and allows individual or simultaneous electrical and mechanical stimulation, carefully characterized and validated. In addition, although the methodology has been optimized for this stimulator and a specific cell population, it can easily be adapted to other devices and cell lines. The results here offer evidence of the increased cardiac commitment of the cell population after electromechanical stimulation. Electromechanically stimulated cells show an increased expression of main cardiac markers, including early, structural, and calcium-regulating genes. This cell conditioning could be useful for further regenerative cell therapy, disease modeling, and high-throughput drug screening.

Here we present a protocol for training a cell population using electrical and mechanical stimuli emulating cardiac physiology. This electromechanical stimulation enhances the cardiomyogenic potential of the treated cells and is a promising strategy for further cell therapy, disease modeling, and drug screening.

同时进行机电刺激增强细胞心肌成功能的潜能

Cardiovascular diseases are the leading cause of death in developed countries. Consequently, the demand for effective cardiac cell therapies has motivated ...

生物工程

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

A stable and reliable model of chronic heart failure is required for many experiments to understand hemodynamics or to test effects of new treatment methods. Here, we present such a model by tachycardia-induced cardiomyopathy, which can be produced by rapid cardiac pacing in swine.
A single pacing lead is introduced transvenously into fully anaesthetized healthy swine, to the apex of the right ventricle, and fixated. Its other end is then tunneled dorsally to the paravertebral region. There, it is connected to an in-house modified heart pacemaker unit that is then implanted in a subcutaneous pocket. 
After 4 - 8 weeks of rapid ventricular pacing at rates of 200 - 240 beats/min, physical examination revealed signs of severe heart failure - tachypnea, spontaneous sinus tachycardia, and fatigue. Echocardiography and X-ray showed dilation of all heart chambers, effusions, and severe systolic dysfunction. These findings correspond well to decompensated dilated cardiomyopathy and are also preserved after the cessation of pacing.
This model of tachycardia-induced cardiomyopathy can be used for studying the pathophysiology of progressive chronic heart failure, especially hemodynamic changes caused by new treatment modalities like mechanical circulatory supports. This methodology is easy to perform and the results are robust and reproducible.

Here, we present a protocol to produce tachycardia-induced cardiomyopathy in swine. This model represents a potent way to study the hemodynamics of progressive chronic heart failure and the effects of applied treatment.

心动过速诱发的心肌病作为猪慢性心力衰竭模型的研究

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

Ablation of Ischemic Ventricular Tachycardia Using a Multipolar Catheter and 3-dimensional Mapping System for High-density Electro-anatomical Reconstruction

Ventricular tachycardia (VT) in patients with ischemic cardiomyopathy mainly results from endocardial scars after myocardial infarction; those scars represent zones of slow conduction that allow the occurrence and maintenance of reentrant circuits. Catheter ablation enables substrate modification of those low voltage areas and thus can help to alter the scar tissue in such a way that arrhythmias cannot appear anymore. Hospitalizations of concerned patients decrease, quality of life and outcome rise. Consequently, VT ablation represents a growing field in electrophysiology, especially for patients with endocardial scars in ischemic heart disease after myocardial infarction. However, ablation of ventricular tachycardia remains one of the most challenging procedures in the electrophysiology lab. Precise scar definition and localization of abnormal potentials are critical for ablation success. The following manuscript describes the use of a multipolar mapping catheter and 3-dimensional (3D) mapping system to create a high density electro-anatomical map of the left ventricle including a precise scar representation as well as mapping of fractionated and late potentials in order to allow a highly accurate substrate modification.

With the following protocol, we provide an approach to Ventricular Tachycardia (VT) ablation using high density mapping with a multipolar catheter and 3D mapping system enhancing the success of the procedure.

采用多极导管三维测图系统进行缺血性室性心动过速的高密度电解剖重建

Ventricular tachycardia (VT) in patients with ischemic cardiomyopathy mainly results from endocardial scars after myocardial infarction; those scars ...

Studying Left Ventricular Reverse Remodeling by Aortic Debanding in Rodents

To better understand the left ventricular (LV) reverse remodeling (RR), we describe a rodent model wherein, after aortic banding-induced LV remodeling, mice undergo RR upon removal of the aortic constriction. In this paper, we describe a step-by-step procedure to perform a minimally invasive surgical aortic debanding in mice. Echocardiography was subsequently used to assess the degree of cardiac hypertrophy and dysfunction during LV remodeling and RR and to determine the best timing for aortic debanding. At the end of the protocol, terminal hemodynamic evaluation of the cardiac function was conducted, and samples were collected for histological studies. We showed that debanding is associated with surgical survival rates of 70-80%. Moreover, two weeks after debanding, the significant reduction of ventricular afterload triggers the regression of ventricular hypertrophy (~20%) and fibrosis (~26%), recovery of diastolic dysfunction as assessed by the normalization of left ventricular filling and end-diastolic pressures (E/e&#39;&#160;and LVEDP). Aortic debanding is a useful experimental model to study LV RR in rodents. The extent of myocardial recovery is variable between subjects, therefore, mimicking the diversity of RR that occurs in the clinical context, such as aortic valve replacement. We conclude that the aortic banding/debanding model represents a valuable tool to unravel novel insights into the mechanisms of RR, namely the regression of cardiac hypertrophy and the recovery of diastolic dysfunction.

Here we describe a step-by-step protocol of surgical aorta debanding in the well-established mice model of aortic-constriction. This procedure not only allows studying the mechanisms underlying the left ventricular reverse remodeling and regression of hypertrophy but also to test novel therapeutic options that might accelerate myocardial recovery.

研究左心室反向改造由主动脉脱体在啮齿动物

To better understand the left ventricular (LV) reverse remodeling (RR), we describe a rodent model wherein, after aortic banding-induced LV remodeling, ...

Advanced Cardiac Rhythm Management by Applying Optogenetic Multi-Site Photostimulation in Murine Hearts

Ventricular tachyarrhythmias are a major cause of mortality and morbidity worldwide. Electrical defibrillation using high-energy electric shocks is currently the only treatment for life-threatening ventricular fibrillation. However, defibrillation may have side-effects, including intolerable pain, tissue damage, and worsening of prognosis, indicating a significant medical need for the development of more gentle cardiac rhythm management strategies. Besides energy-reducing electrical approaches, cardiac optogenetics was introduced as a powerful tool to influence cardiac activity using light-sensitive membrane ion channels and light pulses. In the present study, a robust and valid method for successful photostimulation of Langendorff perfused intact murine hearts will be described based on multi-site pacing applying a 3 x 3 array of micro light-emitting diodes (micro-LED). Simultaneous optical mapping of epicardial membrane voltage waves allows the investigation of the effects of region-specific stimulation and evaluates the newly induced cardiac activity directly on-site. The obtained results show that the efficacy of defibrillation is strongly dependent on the parameters chosen for photostimulation during a cardiac arrhythmia. It will be demonstrated that the illuminated area of the heart plays a crucial role for termination success as well as how the targeted control of cardiac activity during illumination for modifying arrhythmia patterns can be achieved. In summary, this technique provides a possibility to optimize the on-site mechanism manipulation on the way to real-time feedback control of cardiac rhythm and, regarding the region specificity, new approaches in reducing the potential harm to the cardiac system compared to the usage of non-specific electrical shock applications.

This work reports a method for controlling the cardiac rhythm of intact murine hearts of transgenic channelrhodopsin-2 (ChR2) mice using local photostimulation with a micro-LED array and simultaneous optical mapping of epicardial membrane potential.

通过在小鼠心脏中应用光遗传学多位点光刺激进行高级心律管理

Ventricular tachyarrhythmias are a major cause of mortality and morbidity worldwide. Electrical defibrillation using high-energy electric shocks is ...

Transesophageal Atrial Burst Pacing for Atrial Fibrillation Induction in Rats

Animal studies have brought important insights into our understanding regarding atrial fibrillation (AF) pathophysiology and therapeutic management. Reentry, one of the main mechanisms involved in AF pathogenesis, requires a certain mass of myocardial tissue in order to occur. Due to the small size of the atria, rodents have long been considered 'resistant' to AF. Although spontaneous AF has been shown to occur in rats, long-term follow-up (up to 50 weeks) is required for the arrhythmia to occur in those models. The present work describes an experimental protocol of transesophageal atrial burst pacing for rapid and efficient induction of AF in rats. The protocol can be successfully used in rats with healthy or remodeled hearts, in the presence of a wide variety of risk factors, allowing the study of AF pathophysiology, identification of novel therapeutic targets, and evaluation of novel prophylactic and/or therapeutic strategies.

The present work describes an experimental protocol of transesophageal atrial burst pacing for efficient induction of atrial fibrillation (AF) in rats. The protocol can be used in rats with healthy or remodeled hearts, allowing the study of AF pathophysiology, identification of novel therapeutic targets, and evaluation of new therapeutic strategies.

经食管心房爆破起搏在大鼠心房颤动诱导中的应用

Animal studies have brought important insights into our understanding regarding atrial fibrillation (AF) pathophysiology and therapeutic management. ...

A Model of Long-Term Ventricular Fibrillation in Isolated Rat Hearts

Ventricular fibrillation (VF) is a fatal arrhythmia with a high incidence in cardiac patients, but VF arrest under perfusion is a neglected method of intraoperative arrest in the field of cardiac surgery. With recent advances in cardiac surgery, the demand for prolonged VF studies under perfusion has increased. However, the field lacks simple, reliable, and reproducible animal models of chronic ventricular fibrillation. This protocol induces long-term VF through alternating current (AC) electrical stimulation of the epicardium. Different conditions were used to induce VF, including continuous stimulation with a low or high voltage to induce long-term VF and stimulation for 5 min with a low or high voltage to induce spontaneous long-term VF. The success rates of the different conditions, as well as the rates of myocardial injury and recovery of cardiac function, were compared. The results showed that continuous low-voltage stimulation induced long-term VF and that 5 min of low-voltage stimulation induced spontaneous long-term VF with mild myocardial injury and a high rate of recovery of cardiac function. However, the low-voltage, continuously stimulated long-term VF model had a higher success rate. High-voltage stimulation provided a higher rate of VF induction but showed a low defibrillation success rate, poor recovery of cardiac function, and severe myocardial injury. On the basis of these results, continuous low-voltage epicardial AC stimulation is recommended for its high success rate, stability, reliability, reproducibility, low impact on cardiac function, and mild myocardial injury.

This protocol presents a model of long-term ventricular fibrillation in rat hearts induced by continuous stimulation with low-voltage alternating current. This model has a high success rate, is stable, reliable, and reproducible, has a low impact on cardiac function, and causes only mild myocardial injury.

孤立大鼠心脏长期心室颤动模型

Ventricular fibrillation (VF) is a fatal arrhythmia with a high incidence in cardiac patients, but VF arrest under perfusion is a neglected method of ...

<meta charset="utf8"></head><body>优化肺动脉束带以实现一致的右心衰竭诱导

Rat Model of Right-Sided Cardiac Remodeling and Arrhythmia Using Pulmonary Artery Banding

Clinical conditions, including chronic obstructive pulmonary disease or pulmonary arterial hypertension (PAH), can lead to chronic right ventricle pressure overload and progressive right heart failure (RHF). RHF can be identified by right-sided cardiac hypertrophy and dilation associated with abnormal myocardial function affecting the RV and the right atrium (RA). We recently demonstrated that severe RHF is accompanied by an increased risk of atrial inflammation, atrial fibrosis, and atrial fibrillation (AF), the most common type of cardiac arrhythmia (CA). Recent studies have shown that RV and RA inflammation plays an important role in the arrhythmogenesis of CA, including AF. However, the impact of inflammation in the development of CA and AF in RHF is poorly described.
Experimental models of RHF are required to better understand the association between right-sided myocardial inflammation and CA. The rat model of monocrotaline (MCT)-induced pulmonary hypertension (PH) is well-established to provoke RHF. However, MCT triggers severe pneumo-toxicity and pulmonary inflammation. Hence, MCT-induced RHF does not help to distinguish whether the subsequent myocardial inflammation originates from the RHF per se or circulating inflammatory signals secreted by the injured lung.
In this article, a mechanical method involving pulmonary artery trunk banding (PAB) was used to provoke right-sided cardiac arrhythmogenesis. The PAB consists of performing a permanent suture of the pulmonary artery trunk for 3 weeks. Such an approach generates increased right-sided pressure overload. At D21 post-PAB, the suture results in hypertrophied, dilated, and inflamed RV and RA. The PAB-induced RHF is also accompanied by vulnerability to ventricular and atrial arrhythmias, including AF.

<meta charset="utf8"></head><body>使用肺动脉束带法的右侧心脏重塑和心律失常大鼠模型

Right heart failure (RHF) is characterized by right-sided cardiac dilation and hypertrophy, leading to ventricular and atrial malfunction. Cardiopulmonary conditions associated with RHF are accompanied by an increased risk for cardiac arrhythmias. This article describes a standardized model of pulmonary artery banding-induced RHF associated with enhanced ventricular and atrial arrhythmogenesis.