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特点, 伴随着激素激活逆转, 表明这种肌病的可逆性质。据记载, LVEF 在起搏终止后1至2周内明显恢复, 几乎所有血流动力学变量在快速起搏后4周返回正常水平12。因此, 在这一具有吸引力的模型中, 预防心脏功能恢复对起搏的作用具有重要意义。
LBBB 可能导致延迟的 lv 活化和相应的延迟 lv 收缩。鼻中隔和 LV 游离壁的异步收缩进行了不成比例的净心肌工作, 这两个地区的工作都白费了。虽然单纯的 LBBB 产生低等级肌病, HF 和 LBBB 之间的协同作用可能会随着时间的推移产生实质性的功能和临床下降, 这可以通过 CRT 改善。RV 起搏诱发的功能 LBBB 是暂时性的, 与解剖 LBBB 存在的情况截然不同。在本研究中, 通过导管消融建立永久性 LBBB, 并在随后的实验中证实其存在。犬有一个相对较长, 更左侧定向穿透束他和普通的左束, 这可能说明 LBB 消融成功率高。LBP 位于他的捆绑和浦肯野潜能之间。正确鉴别 LBP 和保证 a: V 心电图比 < 1:10 有利于成功的 LBB 消融和避免完整的 a-V 块13。常见的左束分为前部和后束在近1/3 沿肌室间隔。如果消融导管位于束枝的远端, 则可能会消融前或后束。然而, 这些簇束的消融不能明显延长 QRS 期。根据先前的研究, LBB 消融后 QRS 持续时间可能增加40-50 毫秒13。在本研究中, QRS 延长平均35毫秒, 这可能是由于不同的动物种类。在心内心电图, 成功消融的平均 LBP 间隔测量约16-19 毫秒, 通常10毫秒短于 H V 间隔, 既不太接近也不离他的捆绑太远。此外, 在成功消融14后, LBP 通常会消失。
先前的一项研究报告说, 快速起搏至少3到4周产生可靠和可重复的 HF 模型11。在 tachypacing 的必要时期, 不同动物之间可能存在一些差异。因此, 超声心动图是每2周进行快速起搏。在 tachypacing 2 周后, 所有的动物都没有显示出 LVEF < 35%, 这表明3到4周的快速起搏是必不可少的。4周后, 一旦 LVEF 低于 35%, 快速起搏被终止。这样的策略有助于统一 HF 的基线严重性。此外, 由于 RV 顶端 (RVA) 起搏一直被证明诱导 LV 不同步和 HF 15, 我们选择 RVA 而不是 RA 快速起搏.因此, 快速起搏诱发 hf 与叠加 LBBB 诱导不同步在我们的研究有助于建立一个稳定和慢性 dyssynchronous 的模式。更重要的是, 在对照组8周的观察中, LV 收缩功能障碍几乎无法恢复。这种动物模型偏爱研究 CRT 的好处而不是自我恢复。
为建立 HF 模型, 我们首先通过左胸切口植入 LV 心外膜铅。从开胸术2周后, 我们通过颈静脉方法植入 RV 和 RA 引线, 然后 LBB 消融。虽然有限的左开胸术, 肌肉保留和肋骨保存策略是极好的微创方法暴露的 LV 侧壁, 手术创伤和术后感染仍然与高死亡率相关。因此, LV 铅植入术前执行其他程序。只有那些存活2周后的手术被提交到 LBB 消融和快速起搏。总的来说, 这是一个经济策略。
超声心动图数据显示, 我们的 CHF 模型存在显著的收缩功能障碍, 心室容积增加, 异步指数增高。CRT 改善了心功能, 减少了异步指数。斑点跟踪应变分析是一种新的评价心肌变形的方法。它已被证明与 crt 后的远期结果有显著关联, 并对 crt 的常规选择标准具有附加的预后价值。在三种不同的心肌变形模式中, 包括径向应变、周向应变和纵应变, 目前仍在争论中, 有冲突的数据, 其中一个用于 LV 不同步指数可以最好地预测 CRT 响应 16 ,17。然而, 据报道, 全球纵向应变一致表现出良好的重现性, 而重复性适中的周向应变和较差的径向方向18。因此, 在本研究中, 我们采用了顶部三面纵应变分析作为 LV 异步指数的计算 PSD。一个更高的 PSD 表示了更严厉的异步。aVTI 已被广泛用于 CRT 患者的 AV 和模型延迟优化。aVTI 中的更改可以作为笔划卷的变更的代理, 因为它与 LV 流出道 VTI19直接成正比。因此, 我们评估 aVTI 评估的血流动力学的好处从 CRT。一个更高的 aVTI 建议更好的 LV 收缩性能。
心肌纤维化以间质胶原和细胞外基质沉积为特征, 是终末期 CHF 的标志。最近的研究表明, CRT 后 LV 反向重塑独立与弥漫性间质心肌纤维化, 这是评估与心肌 T1 映射心脏磁共振 (CMR)20。此外, CRT 诱导的 LV 反向重塑也与降低血浆水平的亲纤维细胞因子, 如转化生长因子 (TGF) β1和骨桥蛋白 (OPN)21,22。在本研究中, 组织学分析显示, 在快速起搏停止后8周心肌细胞直径降低, 心肌纤维化增加, 这表明我们的 HF 模型中有组织学和蜂窝重构。然而, 随着结构的逆向重塑, CRT 恢复了心肌细胞的构型, 并减轻了胶原沉积。这种组织学反向重塑产生了更有益的影响, 超越 CRT 本身。
最近推荐的 CRT 植入包括持续性 HF 症状, 左心室收缩功能与 LVEF ≤35%, LBBB qrs 形态学, 并扩大 QRS 持续时间4。我们的实验模型是一种切实可行的、可重现的、稳定的 HF 模型, 满足了几乎所有这些标准。值得注意的是, 我们的工作建立了犬模型的非缺血性扩张型心肌病, 它可能不适用于其他条件, 如心脏瓣膜疾病, 先天性心脏病, 缺血性 HF,等。特别是冠状动脉结扎术或微栓塞是常见的缺血性 HF, 有较高的心脏猝死风险。然而, 由于缺血性 HF 心肌瘢痕负担的差异, 客观评价 CRT 的疗效并不容易。相比之下, 我们的实验模型相对均匀, 是研究 CRT 性能的合适模型, 包括电行为、超声心动图评估、生物和分子修饰。

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。
通过超声心动图量化慢性 Dyssynchronous CHF 模型和 CRT 的好处:
基线超声心动图参数显示假, HF 控制和 CRT 组之间没有显著差异。正如在我们以前的数据10中所发表的那样, 一个明显恶化的心功能的特点是增加的左和 LVESV, 并减少 LVEF 可以观察到 HF 控制组在实验结束 (图 3)。CRT 改善心功能与减少左和 LVESV, 并增加 LVEF。对于散斑跟踪分析, 同时获得了包括 A4C、A2C 和 APLAX 在内的三平面顶端纵向视图。在跟踪每个顶部视图后, 得到了各平面六段的纵应变曲线。然后计算了该方法和 PSD。因此, HF 控制组与假组相比, 增加了异步指数 (PSD) (51.6 ±5.9 ms vs 32.6 ±2.3 毫秒、 p < 0.01);当 CRT 校正 LV 异步时, 如显着较低的 PSD (44.0 ±4.6 ms vs 51.6 ±5.9 毫秒, p < 0.05) 所展示的。此外, HF 控制动物的 aVTI 明显低于假组 (8.09 ±1.19 厘米vs 14.53 ±2.38 厘米, p < 0.01), 在 CRT 组 (10.92 ±1.31 厘米vs 8.09 ±1.19 厘米, p 中显著增加)。< 0.05) (图 3和图 4)。
CRT 诱发的组织学和细胞反向重塑:
从左心室侧壁切除的心肌组织进行组织学分析。与假组相比, HF 控制组 (4.77 ±0.86 µm vs 7.68 ±1.25 µm、 p < 0.01) 的心肌细胞直径明显降低, 可能对 LV 扩张负责。马尾松三色染色显示, 与假组相比, HF 对照组 CVF 显著增加 (12.56 ±2.10% vs 1.88 ±0.23%, p < 0.01). 然而, 8 周的 CRT 性能导致心肌细胞直径的显著恢复 (6.26 ±0.93 µm vs 4.77 ±0.86 µm, p < 0.01) 和 CVF (6.28 ±1.61% vs. 12.56 ±2.10%, p < 0.01) 与 HF 控制相比组, 指示 CRT 调用的生物反向重构 (图 5)。
<img alt="Figure 1" class="xfigimg" src="/files/ftp_upload/56439/56439fig1.jpg"> 图 1:所有协议步骤的示意图工作流.<a href="//cloudflare-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/56439/56439fig1large.jpg" target="_blank">请单击此处查看此图的较大版本.</a>
<img alt="Figure 2" class="xfigimg" src="/files/ftp_upload/56439/56439fig2.jpg"> 图 2: 12-在 (A) 和后 (B) 导管消融术前记录的铅心电图和心内心电图。(A) 在成功消融地点的典型表面和心内心电图。右端他的束电位是用 quadripolar 导管的远端电极映射而成的, 它的 h-v 间隔为28毫秒. 用17毫秒的 lbp-v 间隔的消融导管对 lbp 进行了映射. lbp 间隔为11毫秒, 短于 H v 区间。(B) 成功消融后典型的 LBBB 形态学。LBB 消融后 QRS 持续时间从63毫秒延长至95毫秒, 这在铅 I、aVF、V6、带缺口 R 波的阳性和 V1 中呈阴性。在消融后, LBP 消失, 右侧他的捆绑潜能仍然存在。<a href="//cloudflare-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/56439/56439fig2large.jpg" target="_blank">请单击此处查看此图的较大版本.</a>
<img alt="Figure 3" class="xfigimg" src="/files/ftp_upload/56439/56439fig3.jpg"> 图 3:条形图表示为左、LVESV、LVEF、PSD 和 aVTI 在三个实验组 (每一个) 的基线和实验结束时的平均值.用单向方差分析法比较实验组之间的值。与假组比较, *p < 0.05, **p < 0.01;与 HF 控制组相比, #p < 0.05, #p < 0.01。<a href="//cloudflare-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/56439/56439fig3large.jpg" target="_blank">请单击此处查看此图的较大版本.</a>
<img alt="Figure 4" class="xfigimg" src="/files/ftp_upload/56439/56439fig4.jpg"> 图 4:斑点跟踪应变成像和主动脉速度时间积分测量.(A) 利用3标准顶端视图的斑点跟踪成像进行二维纵向应变分析。A1 显示了使用 GE 生动 E9 4VD 传感器获得的三平面顶端纵向视图。图像进行了仔细的调整, 以确保顶部四室视图 (A4C), 两个房间视图 (A2C) 和长轴视图 (APLAX) 同时显示。A2 显示了由 APLAX 视图中的跟踪算法创建的六段纵应变曲线的示例。自动定义基底后壁、中后壁、顶后壁、基底前间隔、中前间隔和顶端前间隔段。A3 以 QRS 波开始计算各段的峰值纵应变时间为参考, 当所有节段时间-应变曲线都是从三顶端的角度构造的。HF 控制组可明显提高其弥散性, 并将其作为标准偏差。CRT 的性能显著降低了各段之间的差异。(B) 评估主动脉速度时间积分平均从连续3节拍。B1、B2 和 B3 分别代表了假组、HF 对照组和 CRT 组的典型图像。<a href="//cloudflare-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/56439/56439fig4large.jpg" target="_blank">请单击此处查看此图的较大版本.</a>
<img alt="Figure 5" class="xfigimg" src="/files/ftp_upload/56439/56439fig5.jpg"> 图 5:he 染色 (400X) 和马尾松三色染色 (400X) 的典型照片。从纵切切片测量心肌纤维的直径, 并根据总组织面积除以纤维化面积的百分比来评价胶原体积分数 (CVF)。刻度条 = 50 µm.<a href="//cloudflare-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/56439/56439fig5large.jpg" target="_blank">请单击此处查看此图的较大版本.</a>

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

Nanyang Technological University

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

Testing the Efficacy of Pharmacological Agents in a Pericardial Target Delivery Model in the Swine

To date, many pharmacological agents used to treat or prevent arrhythmias in open-heart cases create undesired systemic side effects. For example, antiarrhythmic drugs administered intravenously can produce drops in systemic pressure in the already compromised cardiac patient. While performing open-heart procedures, surgeons will often either create a small port or form a pericardial cradle to create suitable fields for operation. This access yields opportunities for target pharmacological delivery (antiarrhythmic or ischemic preconditioning agents) directly to the myocardial tissue without undesired side effects.
We have developed a swine model for testing pharmacological agents for target delivery within the pericardial fluid. While fully anesthetized, each animal was instrumented with a Swan-Ganz catheter as well as left and right ventricle pressure catheters, and pacing leads were placed in the right atrial appendage and the right ventricle. A medial sternotomy was then performed and a pericardial access cradle was created; a plunge pacing lead was placed in the left atrial appendage and a bipolar pacing lead was placed in the left ventricle. Utilizing a programmer and a cardiac mapping system, the refractory period of the atrioventricular node (AVN), atria and ventricles was determined. In addition, atrial fibrillation (AF) induction was produced utilizing a Grass stimulator and time in AF was observed. These measurements were performed prior to treatment, as well as 30 min&#160;and 60 min&#160;after pericardial treatment. Additional time points were added for selected studies. The heart was then cardiopleged and reanimated in a four chamber working mode. Pressure measurements and function were recorded for 1 hr after reanimation. This treatment strategy model allowed us to observe the effects of pharmacological agents that may decrease the incidence of cardiac arrhythmias and/or ischemic damage, during and after open-heart surgery.

We have developed a swine model for the target delivery of pharmacological agents within the pericardial space/fluid. Using this approach, the relative benefits of administered agents on induced atrial fibrillation, relative refractory periods and/or ischemic protection can be investigated.

药理试验药物的疗效在心包目标交付模型在猪

To date, many pharmacological agents used to treat or prevent arrhythmias in open-heart cases create undesired systemic side effects. For example, ...

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 ...

Evaluation of Cardiac Contractility Modulation Therapy in 2D Human Stem Cell-Derived Cardiomyocytes

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are currently being explored for multiple in vitro applications and have been used in regulatory submissions. Here, we extend their use to cardiac medical device safety or performance assessments. We developed a novel method to evaluate cardiac medical device contractile properties in robustly contracting 2D hiPSC-CMs monolayers plated on a flexible extracellular matrix (ECM)-based hydrogel substrate. This tool enables the quantification of the effects of cardiac electrophysiology device signals on human cardiac function (e.g., contractile properties) with standard laboratory equipment. The 2D hiPSC-CM monolayers were cultured for 2-4 days on a flexible hydrogel substrate in a 48-well format.
The hiPSC-CMs were exposed to standard cardiac contractility modulation (CCM) medical device electrical signals and compared to control (i.e., pacing only) hiPSC-CMs. The baseline contractile properties of the 2D hiPSC-CMs were quantified by video-based detection analysis based on pixel displacement. The CCM-stimulated 2D hiPSC-CMs plated on the flexible hydrogel substrate displayed significantly enhanced contractile properties relative to baseline (i.e., before CCM stimulation), including an increased peak contraction amplitude and accelerated contraction and relaxation kinetics. Furthermore, the utilization of the flexible hydrogel substrate enables the multiplexing of the video-based cardiac-excitation contraction coupling readouts (i.e., electrophysiology, calcium handling, and contraction) in healthy and diseased hiPSC-CMs. The accurate detection and quantification of the effects of cardiac electrophysiological signals on human cardiac contraction is vital for cardiac medical device development, optimization, and de-risking. This method enables the robust visualization and quantification of the contractile properties of the cardiac syncytium, which should be valuable for nonclinical cardiac medical device safety or effectiveness testing. This paper describes, in detail, the methodology to generate 2D hiPSC-CM hydrogel substrate monolayers.

Here, we demonstrate a non-invasive cardiac medical device contractility evaluation method using 2D human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) monolayers, plated on a flexible substrate, coupled with video-based microscopy. This tool will be useful for the in vitro evaluation of the contractile properties of cardiac electrophysiology devices.

2D人干细胞来源心肌细胞中心脏收缩力调节疗法的评估

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are currently being explored for multiple in vitro applications and have been used ...

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

In this article, we describe an optimized, Langendorff-based procedure for the isolation of single-cell atrial cardiomyocytes (ACMs) from a rat model of metabolic syndrome (MetS)-related heart failure with preserved ejection fraction (HFpEF). The prevalence of MetS-related HFpEF is rising, and atrial cardiomyopathies associated with atrial remodeling and atrial fibrillation are clinically highly relevant as atrial remodeling is an independent predictor of mortality. Studies with isolated single-cell cardiomyocytes are frequently used to corroborate and complement in vivo findings. Circulatory vessel rarefication and interstitial tissue fibrosis pose a potentially limiting factor for the successful single-cell isolation of ACMs from animal models of this disease.
We have addressed this issue by employing a device capable of manually regulating the intraluminal pressure of cardiac cavities during the isolation procedure, substantially increasing the yield of morphologically and functionally intact ACMs. The acquired cells can be used in a variety of different experiments, such as cell culture and functional Calcium imaging (i.e., excitation-contraction-coupling).
We provide the researcher with a step-by-step protocol, a list of optimized solutions, thorough instructions to prepare the necessary equipment, and a comprehensive troubleshooting guide. While the initial implementation of the procedure might be rather difficult, a successful adaptation will allow the reader to perform state-of-the-art ACM isolations in a rat model of MetS-related HFpEF for a broad spectrum of experiments.

Here, we describe an optimized, Langendorff-based procedure for the isolation of single-cell atrial cardiomyocytes from a rat model of metabolic syndrome-related heart failure with preserved ejection fraction. A manual regulation of intraluminal pressure of cardiac cavities is implemented to yield functionally intact myocytes suitable for excitation-contraction-coupling studies.

代谢综合征心力衰竭模型大鼠心房心肌细胞的分离与保留射血分数的关系

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

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

Although advances have been achieved in the treatment of heart failure (HF) following myocardial infarction (MI), HF following MI remains one of the major causes of mortality and morbidity around the world. Cell-based therapies for cardiac repair and improvement of left ventricular function after MI have attracted considerable attention. Accordingly, the safety and efficacy of these cell transplantations should be tested in a preclinical large animal model of HF prior to clinical use. Pigs are widely used for cardiovascular disease research due to their similarity to humans in terms of heart size and coronary anatomy. Therefore, we sought to present an effective protocol for the establishment of a porcine chronic HF model using closed-chest coronary balloon occlusion of the left circumflex artery (LCX), followed by rapid ventricular pacing induced with pacemaker implantation. Eight weeks later, the stem cells were administered by intramyocardial injection in the peri-infarct area. Then the infarct size, cell survival, and left ventricular function (including echocardiography, hemodynamic parameters, and electrophysiology) were evaluated. This study helps establish a stable preclinical large animal HF model for stem cell treatment.

We sought to establish a swine model of heart failure induced by left circumflex artery blockage and rapid pacing to test the effect and safety of intramyocardial administration of stem cells for cell-based therapies.

建立干细胞治疗心肌梗塞心力衰竭的猪模型

Although advances have been achieved in the treatment of heart failure (HF) following myocardial infarction (MI), HF following MI remains one of the major ...

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 ...

A New Model of Heart Failure Post-Myocardial Infarction in the Rat

Ligation of the left anterior descending (LAD) coronary artery has been widely used to establish the rat model of heart failure (HF) post myocardial infarction (MI). However, the disadvantages of this model include high mortality rate after ligation and larger variations both in the infarct size and the degree of impaired cardiac function. In addition, a ventilator or exteriorization of the heart is indispensable for the previous models, which complicates the procedure during the ligation. In this study, we developed a reliable and reproducible model without the ventilator or exteriorization of the heart by ligating the LAD coronary artery. Four weeks after the procedure, we found that the serum concentrations of CK-MB, NT-proBNP, and Renin, which were used to assist diagnoses of MI and HF, were significantly higher in the MI group compared to the sham group. In contrast, the value of left ventricle ejection fraction (LVEF) in the MI group was obviously less than in the sham group. Furthermore, the infarct size and cardiac fibrosis area were individually confirmed and quantitatively analyzed by TTC staining and Masson's trichrome staining. Smaller variations were found in either infarct size or fibrosis area in the MI group, which helped to develop a reliable and reproducible model of HF post-MI. This new model of HF post-MI in the rat is vital for studying the potential mechanisms of MI and HF. This new method can be used to develop the new drug for treatment of MI and HF in rats by using pharmacological strategies.

We successfully developed a reliable and reproducible model of heart failure post-myocardial infarction in the rat without ventilation or exteriorization of the heart. This simplifies the procedure and benefits the further studies about the potential mechanisms behind the heart failure.

Ligation of the left anterior descending (LAD) coronary artery has been widely used to establish the rat model of heart failure (HF) post myocardial ...

Modified Heterotopic Abdominal Heart Transplantation and a Novel Aortic Regurgitation Model in Rats

Over the past 50 years, many researchers have reported heterotopic abdominal heart transplantation in mice and rats, with some variations in the surgical technique. Modifying the transplantation procedure to strengthen the myocardial protection could prolong the ischemia time while preserving the donor&#39;s cardiac function. This technique&#39;s key points are as follows: transecting the donor&#39;s abdominal aorta before harvesting to unload the donor&#39;s heart; perfusing the donor&#39;s coronary arteries with a cold cardioplegic solution; and topical cooling of the donor&#39;s heart during the anastomosis procedure. Consequently, since this procedure prolongs the acceptable ischemia time, beginners can easily perform it and achieve a high success rate.
Moreover, a new aortic regurgitation (AR) model was established in this work using a technique different from the existing one,&#160;which is created by inserting a catheter from the right carotid artery and puncturing the native aortic valve under continuous echocardiographic guidance. A heterotopic abdominal heart transplantation was performed using the novel AR model. In the protocol, after the donor&#39;s heart is harvested, a stiff guidewire is inserted into the donor&#39;s brachiocephalic artery and advanced toward the aortic root. The aortic valve is punctured by pushing the guidewire further even after the resistance is felt, thus inducing AR. It is easier to damage the aortic valve using this method than with the procedure described in the conventional AR model. Additionally, this novel AR model does not contribute to the recipient&#39;s circulation; therefore, this method is expected to produce a more severe AR model than the conventional procedure.

This study demonstrates a reproducible heterotopic abdominal heart transplantation technique in rats that beginners can learn and perform. Additionally, a novel aortic regurgitation model in rats is generated by performing heterotopic abdominal heart transplantation and damaging the donor's aortic valve using a guidewire after harvesting.

改良异位腹心移植及新型大鼠主动脉瓣反流模型

Over the past 50 years, many researchers have reported heterotopic abdominal heart transplantation in mice and rats, with some variations in the surgical ...

<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.