A Miniaturized, Programmable Pacemaker for Long-Term Studies in the Mouse

Abstract

Rationale: Cardiac pacing is a critical technology for the treatment of arrhythmia and heart failure. The impact of specific pacing strategies on myocardial function is an area of intense research and high clinical significance. Mouse models have proven extremely useful for probing mechanisms of heart disease, but there is currently no reliable technology for long-term pacing in the mouse. Objective: We sought to develop a device for long-term pacing studies in mice. We evaluated the device for i) treating 3rd-degree atrioventricular block after macrophage depletion, ii) ventricular pacing-induced cardiomyopathy, and iii) high-rate atrial pacing. Methods and Results: We developed a mouse pacemaker by refashioning a 26 mm × 6.7 mm clinical device powered by a miniaturized, highly efficient battery. The electrode was fitted with a single flexible lead, and custom software extended the pacing rate to up to 1200 beats per minute. The wirelessly programmable device was implanted in the dorsal subcutaneous space of 39 mice. The tunneled lead was passed through a left thoracotomy incision and attached to the epicardial surface of the apex (for ventricular pacing) or the left atrium (for atrial pacing). Mice tolerated the implantation and both long-term atrial and ventricular pacing over weeks. We then validated the pacemaker’s suitability for the treatment of atrioventricular block after macrophage depletion in Cd11bDTR mice. Ventricular pacing increased the heart rate from 313±59 to 550 beats per minute (P<0.05). In addition, we characterized tachypacing-induced cardiomyopathy in mice. Four weeks of ventricular pacing resulted in reduced left ventricular function, fibrosis, and an increased number of cardiac leukocytes and endothelial activation. Finally, we demonstrated the feasibility of chronic atrial pacing at 1200 beats per minute. Conclusions: Long-term pacing with a fully implantable, programmable, and battery-powered device enables previously impossible investigations of arrhythmia and heart failure in the mouse.

Rapid Atrial Pacing Promotes Atrial Fibrillation Substrate in Unanesthetized Instrumented Rats

“…In contrast to the experiments in rats, which demonstrated increased AF substrate following more than 2 days of RAP, we did not find any indications for increased AF substrate formation in unanesthetized mice exposed to RAP for up to 7 consecutive days at 1200 bpm. These findings seem consistent with the recently reported results of Hulsmans et al (2018). While Hulsmans et al (2018) managed to perform long-lasting LA pacing using a leadless Medtronic pacemaker adapted for mice experimentation, AF inducibility tested in the anesthetized state at the end of 28 days demonstrated only a mild tendency of increase, which did not reach statistical significance.…”

“…These findings seem consistent with the recently reported results of Hulsmans et al (2018). While Hulsmans et al (2018) managed to perform long-lasting LA pacing using a leadless Medtronic pacemaker adapted for mice experimentation, AF inducibility tested in the anesthetized state at the end of 28 days demonstrated only a mild tendency of increase, which did not reach statistical significance. Interestingly, Hulsmans et al (2018) also report molecular findings which are consistent with increased inflammatory response in the atrial tissue and are in line with our current microarray findings in the rats (discussed below).…”

“…Using a bi-atrial implantable device developed in our group, we previously managed to apply continuous RAP in unanesthetized rats under online confirmation of 1:1 atrial capture and serial measurements of AERP for up to 24 h (Etzion et al, 2008). Recently, a system based on a human leadless pacemaker was introduced for long-term single site pacing studies in rodents (Hulsmans et al, 2018). While this elegant and technically-advanced system demonstrated remarkable long-term pacing capabilities, the pacer itself could not be used for EP evaluation which was therefore done conventionally as a terminal invasive procedure under deep anesthesia (Hulsmans et al, 2018).…”

“…Recently, a system based on a human leadless pacemaker was introduced for long-term single site pacing studies in rodents (Hulsmans et al, 2018). While this elegant and technically-advanced system demonstrated remarkable long-term pacing capabilities, the pacer itself could not be used for EP evaluation which was therefore done conventionally as a terminal invasive procedure under deep anesthesia (Hulsmans et al, 2018).…”

An implantable system for long-term assessment of atrial fibrillation substrate in unanesthetized rats exposed to underlying pathological conditions

“…in the unanesthetized state) has not been reported thus far to the best of our knowledge. Recently, Hulsmans et al 19 reported the development of a miniaturized pacemaker for long-term pacing studies in rodents. However, although this technically-advanced system may open remarkable new opportunities, the currently introduced pacer could not be used for the electrophysiological (EP) testing, which was done conventionally under deep anesthesia as a single terminal procedure.…”