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Background: An electrical storm of Torsade de Pointes arrhythmias (TdP) can be reproducibly induced in the anesthetized chronic AV-block (CAVB) dog by infusion of the IKr-blocker dofetilide. Earlier studies showed that these arrhythmias 1) arise from locations with high spatial dispersion in repolarization (SDR) and 2) can be suppressed by high-rate pacing. We examined whether suppression of TdP by high-rate pacing is established through a decrease in SDR in the CAVB dog.Methods: Dofetilide (25 μg/kg in 5 min) was administered to 5 anesthetized CAVB dogs to induce TdP arrhythmias. During the experiments, animals were continuously paced from the right ventricular apex at 50 beats/minute (RVA50). Upon TdP occurrence and conversion, RVA pacing was consecutively set to 100, 80 and 60 beats/minute for 2 min, referred to as pacing blocks. To determine the additional anti-arrhythmic effects of HRP over defibrillation alone, the number of arrhythmic events and SDR at RVA100 were compared to data from three previously conducted experiments, in which dogs underwent the same experimental protocol but were paced at RVA60 upon TdP occurrence (RVA60retro). In all experiments, recordings included surface electrocardiogram and mapping by 56 intramural needles, each recording four electrograms, evenly inserted into the ventricular walls and septum. For each pacing block, the number of ectopic beats (EB), and TdP severity were scored. SDR was quantified as the average difference in repolarization time within four squared needles (SDRcubic).Results: In 4 out of 5 animals, pacing at RVA100 suppressed TdP occurrence. One dog could not be converted by defibrillation after the initial TdP. Compared to RVA50, pacing at RVA100, but not RVA80 and RVA60, significantly reduced the TdP score (78 ± 33 vs. 0 ± 0, p < 0.05 and vs. 12.5 ± 25 and 25 ± 50, both p > 0.05). The reduction in TdP score was reflected by a significant decrease in SDRcubic (125 ± 46 ms before TdP vs. 49 ± 18 ms during RVA100, p < 0.05), and SDR was smaller than in the RVA60retro animals (101 ± 52 ms, p < 0.05 vs. RVA100).Conclusion: In CAVB dogs, high-rate pacing effectively suppresses TdP, which, at least in part, results from a spatial homogenization of cardiac repolarization, as reflected by a decrease in SDR.

Abstract Neural coupled oscillators are a useful building block in numerous models and applications. They were analyzed extensively in theoretical studies and more recently in biologically realistic simulations of spiking neural networks. The advent of mixed-signal analog/digital neuromorphic electronic circuits provides new means for implementing neural coupled oscillators on compact, low-power, spiking neural network hardware platforms. However, their implementation on this noisy, low-precision and inhomogeneous computing substrate raises new challenges with regards to stability and controllability. In this work, we present a robust, spiking neural network model of neural coupled oscillators and validate it with an implementation on a mixed-signal neuromorphic processor. We demonstrate its robustness showing how to reliably control and modulate the oscillator’s frequency and phase shift, despite the variability of the silicon synapse and neuron properties. We show how this ultra-low power neural processing system can be used to build an adaptive cardiac pacemaker modulating the heart rate with respect to the respiration phases and compare it with surface ECG and respiratory signal recordings from dogs at rest. The implementation of our model in neuromorphic electronic hardware shows its robustness on a highly variable substrate and extends the toolbox for applications requiring rhythmic outputs such as pacemakers.

Long QT syndrome type 1 with affected IKs is associated with a high risk for developing Torsade de Pointes (TdP) arrhythmias and eventually sudden cardiac death. Therefore, it is of high interest to explore drugs that target IKs as antiarrhythmics. We examined the antiarrhythmic effect of IKs channel activator ML277 in the chronic atrioventricular block (CAVB) dog model. TdP arrhythmia sensitivity was tested in anesthetized mongrel dogs (n = 7) with CAVB in series: (1) induction experiment at 4 ± 2 weeks CAVB: TdP arrhythmias were induced with our standardized protocol using dofetilide (0.025 mg/kg), and (2) prevention experiment at 10 ± 2 weeks CAVB: the antiarrhythmic effect of ML277 (0.6–1.0 mg/kg) was tested by infusion for 5 min preceding dofetilide. ML277: (1) temporarily prevented repolarization prolongation induced by dofetilide (QTc: 538 ± 65 ms at induction vs. 393 ± 18 ms at prevention, p < 0.05), (2) delayed the occurrence of the first arrhythmic event upon dofetilide (from 129 ± 28 s to 180 ± 51 s, p < 0.05), and (3) decreased the arrhythmic outcome with a significant reduction in the number of TdP arrhythmias, TdP score, arrhythmia score and total arrhythmic events (from 669 ± 132 to 401 ± 228, p < 0.05). IKs channel activation by ML277 temporarily suppressed QT interval prolongation, delayed the occurrence of the first arrhythmic event and reduced the arrhythmic outcome in the CAVB dog model.

Degradation of cellular material by lysosomes is known as autophagy, and its main function is to maintain cellular homeostasis for growth, proliferation and survival of the cell. In recent years, research has focused on the characterization of autophagy pathways. Targeting of autophagy mediators has been described predominantly in cancer treatment, but also in neurological and cardiovascular diseases. Although the number of studies is still limited, there are indications that activity of autophagy pathways increases under arrhythmic conditions. Moreover, an increasing number of antiarrhythmic and non-cardiac drugs are found to affect autophagy pathways. We, therefore, suggest that future work should recognize the largely unaddressed effects of antiarrhythmic agents and other classes of drugs on autophagy pathway activation and inhibition.