Mechanistic enquiry into the effect of increased pacing rate on the upper limit of vulnerability

The goal of this study is to investigate the mechanisms responsible for the increase in the upper limit of vulnerability (ULV; highest shock strength that induces arrhythmia) following the increase in pacing rate. To accomplish this goal, the study employs a three-dimensional bidomain finite element model of a slice through the canine ventricles. The preparation was paced eight times at a basic cycle length (BCL) of either 80 or 150 ms followed by delivery of shocks of various strengths and timings. Our results demonstrate that the shock strength, which induced an arrhythmia 50% of the time, increased 20% for the faster pacing compared to the slower pacing. Analysis of the mechanisms underlying the increased vulnerability revealed that delayed post-shock activations originating in the tissue depths appear as breakthrough activations on the surfaces of the preparation following an isoelectric window (IW). However, the IW duration was consistently shorter in the faster-paced preparation. Consequently, breakthrough activations appeared on the surfaces of this preparation earlier, when the tissue was less recovered, resulting in higher probability of unidirectional block and reentry. This explains why shocks of the same strength were more likely to result in arrhythmia induction when delivered to a preparation that was rapidly paced.

Mechanistic inquiry into decrease in probability of defibrillation success with increase in complexity of preshock reentrant activity

Energy requirements for successful antiarrhythmia shocks are arrhythmia specific. However, it remains unclear why the probability of shock success decreases with increasing arrhythmia complexity. The goal of this research was to determine whether a diminished probability of shock success results from an increased number of functional reentrant circuits in the myocardium, and if so, to identify the responsible mechanisms. To achieve this goal, we assessed shock efficacy in a bidomain defibrillation model of a 4-mm-thick slice of canine ventricles. Shocks were applied between a right ventricular cathode and a distant anode to terminate either a single scroll wave (SSW) or multiple scroll waves (MSWs). From the 160 simulations conducted, dose-response curves were constructed for shocks given to SSWs and MSWs. The shock strength that yielded a 50% probability of success (ED50) for SSWs was found to be 13% less than that for MSWs, which indicates that a larger number of functional reentries results in an increased defibrillation threshold. The results also demonstrate that an isoelectric window exists after both failed and successful shocks; however, shocks of strength near the ED50 value that were given to SSWs resulted in 16.3% longer isoelectric window durations than the same shocks delivered to MSWs. Mechanistic inquiry into these findings reveals that the two main factors underlying the observed relationships are 1) smaller virtual electrode polarizations in the tissue depth, and 2) differences in preshock tissue state. As a result of these factors, intramural excitable pathways leading to delayed breakthrough on the surface were formed earlier after shocks given to MSWs compared with SSWs and thus resulted in a lower defibrillation threshold for shocks given to SSWs.

Mechanisms of shock-induced arrhythmogenesis during acute global ischemia

Little is known about the mechanisms of vulnerability and defibrillation under ischemic conditions. We investigated these mechanisms in 18 Langendorff-perfused rabbit hearts during 75% reduced-flow ischemia. Electrical activity was optically mapped from the anterior epicardium during right ventricular shocks applied at various phases of the cardiac cycle while the excitation-contraction decoupler 2,3-butanedione monoxime (BDM; 15 mM) was used to suppress motion artifacts caused by contraction of the heart. During ischemia, vulnerable window width increased [from 30–90% of the action potential duration (APD) in the control to −10 to 100% of the APD in ischemia]. Moreover, arrhythmia severity increased along with the reduction of APD (176 ± 9 ms in control and 129 ± 26 ms in ischemia, P < 0.01) and increased dispersion of repolarization (45 ± 17 ms in control and 73 ± 28 ms in ischemia, P < 0.01). Shock-induced virtual electrode polarization was preserved. Depolarizing (contrary to hyperpolarizing) response time constants increased. Virtual electrode-induced wavefronts of excitation had much more tortuous pathways leading to wavefront fractionation. Defibrillation failure at all shock strengths was observed in four hearts. Optical mapping revealed that the shock extinguished the arrhythmia; however, the arrhythmia self-originated after an isoelectric window of 339 ± 189 ms. In conclusion, in most cases, virtual electrode-induced phase singularity (VEIPS) was responsible for shock-induced arrhythmogenesis during acute global ischemia. Enhancement of arrhythmogenesis was associated with an increased dispersion of repolarization and altered deexcitation. In four hearts, arrhythmogenesis could not be explained by VEIPS.