Response by Kass et al to Letter Regarding Article, "Chronic Atrial and Ventricular Pacing in the Mouse: Application to Model Cardiac Dyssynchrony and Resynchronization in Heart Failure".

May 2019 1 In Response: Drs Etzion and Mulla note limitations from our use of right ventricular (RV) pacing with atrial ventricular (AV) dissociation rather than AV pacing with a shortened AV delay.1 We agree these are limitations. The ideal approach would be to sense the atria, pace the RV with a shortened AV delay, and then resynchronize either with biventricular stimulation and the same short AV delay (best) or revert to normal sinus (next best). By contrast, our approach combined both dyssynchrony/resynchronization and loss/recovery of AV timing. However, the impact of each factor differs, the former being on intrinsic left ventricular (LV) systolic performance, the latter on preload. In their prior rat study, Mulla et al2 compared acute AV sequential to RV-only pacing. RV-only pacing predictably reduced preload relative to AV sequential pacing because of loss of proper atrial timing and was thus associated with lower systolic pressure, stroke volume, stroke work, and dP/dtmax. However, less preload-sensitive measures of systole, such as ejection fraction or end-systolic pressure/volume ratio (the latter can be estimated from their Table 1) were if anything higher with RV-only pacing. It is also unlikely lower preload from RV-pacing would be sustained over weeks (as we studied) given that homeostatic mechanisms would raise preload to help restore arterial pressure and cardiac output. The mouse heart is 10× smaller than the rat, making multi-chamber stimulation an extreme technical challenge. The commercial pacing unit in Hulsman et al3 cannot be used as it provides only one lead, and while our method can handle dual chamber stimulation, lead implantation remains difficult. Importantly, our mouse data matches well with reported findings from canine models (the source of most published molecular/cellular data) using RV tachypacing and ignoring AV coordination. Organ and limited available molecular human data also matches well with findings from this animal model.4 The canine work also found transitioning from RV tachypacing to either biventricular or atrial tachypacing, yields similar improvements. Together, this suggests the dominant effect from single-site ventricular pacing and its reversal to atrial pacing stems from dyssynchrony, whereas atrial ventricular coordination is a secondary contributor. Pending advances in microlead technology, we feel our model provides the key elements of dyssynchrony/resynchronization physiology but does so in mice providing the added advantage being amenable to genetic engineering. RESPONSE TO LETTER TO THE EDITOR