International Journal of Cardiology Proarrhythmic proclivity of left-stellate ganglion stimulation in a canine model of drug- induced long-QT syndrome type 1  Rachel M.A. ter Bekke, Annerie M.E. Moers, Monique M.J. de Jong, Daniel M. Johnson, Peter J. Schwartz, Emilio Vanoli, Paul G.A. Volders  International Journal of Cardiology  DOI: 10.1016/j.ijcard.2019.01.098 Copyright © 2019 The Authors Terms and Conditions

Fig. 1 Representative examples of effects of LSGS and RSGS on ECG, LVP, and RVP characteristics. Upon LSGS, a junctional tachycardia appeared after 6 s (*), which was interspersed by ventricular extrasystoles. The EMW, being positive at baseline, turned negative during LSGS (−40 ms, red), but not during RSGS (89 ms, green). LSG indicates left-stellate ganglion; RSG, right stellate ganglion; EMW, electromechanical window; LVP, left-ventricular pressure; RVP, right-ventricular pressure. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.) International Journal of Cardiology DOI: (10.1016/j.ijcard.2019.01.098) Copyright © 2019 The Authors Terms and Conditions

Fig. 2 Bar graph demonstrating the mean QT, QLVP, and EMW changes after LSGS, HMR1556, and LSGS during IKs inhibition. * P < 0.05. Abbreviations as in Fig. 1. International Journal of Cardiology DOI: (10.1016/j.ijcard.2019.01.098) Copyright © 2019 The Authors Terms and Conditions

Fig. 3 Vagal rebound post-LSGS at baseline. Upon termination of LSGS, and during a protracted positive inotropic response (upper panel), sinus and junctional bradycardia, ventricular extrasystoles and idioventricular rhythm occurred, indicating a vagal response by a baroreflex loop and/or sympathetic withdrawal. The lower ECG traces A, B, C, and D are ECG examples at different stages of the vagal rebound. LVP indicates left-ventricular pressure. International Journal of Cardiology DOI: (10.1016/j.ijcard.2019.01.098) Copyright © 2019 The Authors Terms and Conditions

Fig. 4 Top, LV MAPs and first derivative (dV/dt) of MAP signal. After HMR1556, EADs followed after an initial delay in repolarization (arrowheads). Upon concomitant LSGS at 10–15 Hz, frank EAD upstrokes were absent but a discernable delay in repolarization (arrows) remained present, contributing to MAPD90 prolongation. Bottom, rate dependency of MAPD90 at baseline (square), during HMR1556 (circle) and simultaneous LSGS (triangle). Black symbols: EAD present; gray symbols: initial delay in repolarization. LSGS indicates left-stellate ganglion stimulation; APD90, action potential duration at 90% repolarization; CL, cycle length. International Journal of Cardiology DOI: (10.1016/j.ijcard.2019.01.098) Copyright © 2019 The Authors Terms and Conditions

Fig. 5 Induction of TdP, degenerating into VF, after a short-coupled non-pause dependent PVC during LSGS in drug-induced LQT1. Abbreviations as in Fig. 1. International Journal of Cardiology DOI: (10.1016/j.ijcard.2019.01.098) Copyright © 2019 The Authors Terms and Conditions

Fig. 6 Top, beat-to-beat changes in RR interval, QT interval, QLVP90, and EMW during HMR1556 and LSGS just prior to TdP (left) or at 26 s and maximal chronotropic response (no TdP; right). Pre-LSGS QT and EMW were significantly more pronounced in TdP-susceptible animals. TdP initiation was fast-rate dependent due to short-coupled non-pause dependent PVCs. # indicates P < 0.05. Below, simultaneous recording of ECG lead II and LVP to illustrate EMW variations. International Journal of Cardiology DOI: (10.1016/j.ijcard.2019.01.098) Copyright © 2019 The Authors Terms and Conditions

Fig. 7 Outflow-tract origins of TdP/VF-triggering (non-pause dependent) PVC. Left, 6‑lead ECG recording showing an intermediate QRS axis with a relatively short duration. Right, box plot of interventricular activation delay of the junctional beats versus the TdP/VF-triggering extrasystoles demonstrating the earliest electrical activation in the RV in all but one case. International Journal of Cardiology DOI: (10.1016/j.ijcard.2019.01.098) Copyright © 2019 The Authors Terms and Conditions