Mechanical pacing (MP) leads to higher cardiac output than chest compressions and, unlike electrical pacing (EP), avoids off-target effects. Thus, MP may be useful for bridging to equipment-based treatment in the emergency setting. However, only a finite number of beats can be stimulated with MP before the heart will no longer reliably respond (loss of capture, LoC).¹ In this work, we investigate the dynamics of LoC to gain insight into possible mechanisms and modulators of MP.

Langendorff-perfused rabbit hearts were mechanically or electrically paced at the mid-left ventricular free-wall using direct epicardial mechanical (MS) or electrical (ES) stimuli. Experiments included MP alone, MP interspersed with ES, MP preceded by sub-threshold and supra-threshold (constant indentation) MS, MP with altered left ventricular diastolic pressure (0 - 20 mmHg), and MP in the presence of the Piezo1 channel agonist Yoda1 (20 μM), and TRPA1 channel agonist allyl isothiocyanate (AITC; 60 μM) and antagonist HC030031 (20 μM).

The number of consecutive mechanically captured beats (MC) decreased with increasing pacing frequency from 2.5 Hz to 6.0 Hz. Interspersed ES increased the number of MC before LoC. Tissue pre-stretching before MP by sub-/supra threshold MS or increased left ventricular diastolic pressure reduced the number of MC. Application of Yoda1 and of AITC increased the number of MC, however HC-030031 did not affect the number of MC, nor did it prevent the increase in MC with Yoda1.

In line with previous reports, we observed a frequency dependence of LoC during MP. Contrary to prior studies, we found that prolonging the MS-MS intervals by interspersing ES increased the number of MC before LoC.¹ Moreover, mechanical tissue pre-stretching caused faster LoC, indicating a stretching-related mechanism. The mechanism underlying the LoC is not known. However, the prevailing hypothesis is that cation non-selective stretch-activated channels (SAC_ns) underlie MC, and their rundown results in LoC.¹ Interestingly, the SAC_ns Piezo1 has previously been shown to have peak currents that decrease with increasing stimulation rate² and with a plateau from approximately 5.0 Hz, matching the frequency after which MP becomes unreliable. In our study, we found Yoda1 increased the number of MC, which suggests Piezo1 is a contributor, combined with a study showing that the application of Grammostola spatulata MechanoToxin-4 (500 nmol/L) reduced mechanically-induced excitation in rabbit.³ Sensitizing Piezo1 while blocking TRPA1 increased MC, suggesting that Piezo1 can contribute independently to MC without sensitizing TRPA1 via calcium. However, AITC and HC-030031 did not show opposite effects on the number of MC, indicating that TRPA1 might not (or rarely) contribute to MP under physiological conditions. In future work, we will perform multi-site MP, which will aid in understanding the mechanisms underlying LoC, and potentially provide evidence for or against the utility of MP in the first aid setting.
References
1. Quinn TA, et al. Europace. 2016;18(suppl 4):iv85-iv93.

2. Lewis AH, et al. Cell Rep. 2017;19(12):2572-2585. 

3. Quinn TA, et al. Circ Arrhythm Electrophysiol. 2017;10(8):e004777.