Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD (M.S., R.N., D.B., G.Z., B.L.L., A.S., D.I.L., D.A.K.).
Department of Medicine, Karolinska Institutet, Solna, Sweden (M.S.).
Circ Heart Fail. 2019 Feb;12(2):e005655. doi: 10.1161/CIRCHEARTFAILURE.118.005655.
The mouse is the most widely used mammal in experimental biology. Although many clinically relevant in vivo cardiac stressors are used, one that has eluded translation is long-term cardiac pacing. Here, we present the first method to chronically simulate and simultaneously record cardiac electrical activity in conscious mobile mice. We then apply it to study right ventricular pacing induced electromechanical dyssynchrony and its reversal (resynchronization).
The method includes a custom implantable bipolar stimulation and recording lead and flexible external conduit and electrical micro-commutator linked to a pulse generator/recorder. This achieved continuous pacing for at least 1 month in 77% of implants. Mice were then subjected to cardiac ischemia/reperfusion injury to depress heart function, followed by 4 weeks pacing at the right ventricle (dyssynchrony), right atrium (synchrony), or for 2 weeks right ventricle and then 2 weeks normal sinus (resynchronization). Right ventricular pacing-induced dyssynchrony substantially reduced heart and myocyte function compared with the other groups, increased gene expression heterogeneity (>10 fold) comparing septum to lateral walls, and enhanced growth and metabolic kinase activity in the late-contracting lateral wall. This was ameliorated by restoring contractile synchronization.
The new method to chronically pace conscious mice yields stable atrial and ventricular capture and a means to dissect basic mechanisms of electromechanical physiology and therapy. The data on dyssynchrony and resynchronization in ischemia/reperfusion hearts is the most comprehensive to date in ischemic heart disease, and its similarities to nonischemic canine results support the translational utility of the mouse.
老鼠是实验生物学中最广泛使用的哺乳动物。尽管使用了许多与临床相关的体内心脏应激源，但有一种方法一直未能转化，即长期心脏起搏。在这里，我们首次提出了一种在清醒可移动小鼠中慢性模拟和同时记录心脏电活动的方法。然后，我们将其应用于研究右室起搏诱导的机电失同步及其逆转（再同步）。
该方法包括定制的可植入双极刺激和记录引线以及柔性外部导管和与脉冲发生器/记录器相连的电微接触器。在 77%的植入物中，这种方法至少能实现 1 个月的连续起搏。然后，将小鼠进行心脏缺血/再灌注损伤以抑制心脏功能，随后进行 4 周的右心室起搏（失同步）、右心房起搏（同步）或 2 周的右心室起搏和 2 周的正常窦性起搏（再同步）。与其他组相比，右室起搏诱导的失同步显著降低了心脏和心肌功能，使隔室与外侧壁之间的基因表达异质性增加了 10 倍以上，并增强了晚期收缩的外侧壁的生长和代谢激酶活性。通过恢复收缩同步性，这种情况得到了改善。
该方法能够对清醒小鼠进行长期起搏，从而获得稳定的心房和心室捕获，并提供了解机电生理学和治疗基本机制的手段。在缺血/再灌注心脏中，关于失同步和再同步的数据是迄今为止最全面的，与非缺血犬的结果相似，支持了该方法在缺血性心脏病中的转化应用。
