Nerve sprouting, defibrillation and calcium waves

Abstract

Zoll et al. first reported the successful termination of ventricular fibrillation (VF) by externally applied electrical countershocks. In the same seminal report, the authors also discovered that recurrent VF may occur shortly after successful ventricular de fibrillation. Due to the general availability of the implantable cardioverter-de fibrillator (ICD), patients may survive the initial VF episodes but suffer from multiple recurrent VF and de fibrillation shocks within a short period of time. The clustering of recurrent VF episodes (electrical storm) after initial successful de fibrillation suggests that the first episode of VF begets subsequent episodes of VF. The mechanisms by which VF begets VF remains poorly understood. In this chapter we will discuss the mechanisms of neural remodeling after myocardial infarction (MI). We propose that nerve sprouting and sympathetic hyperinnervation occur after MI. The increased sympathetic nerve densities in the heart is highly heterogeneous, with portions of the heart showing increased nerve densities while the remaining portions of the heart showing denervation. During sympathetic nerve activation, there is increased heart rate and augmented intracellular calcium (Ca i) concentration. In addition, we found that the action potential duration (APD) is abbreviated after a fibrillation-de fibrillation episode in failing ventricles. The shortened APD and the elevated Ca i promotes late phase 3 early afterdepolarization (EAD) and Ca 2+-transient triggered firing (CTTF), leading to recurrent cardiac fibrillation. We also propose that the mechanisms of APD shortening after fibrillation-de fibrillation episodes in the failing (but not in the normal) ventricles are due to the upregulation of small conductance Ca 2+ activated potassium (SK) currents. We hope that these discussions will help the readers better understand the relevance of cardiac neural remodeling and electrical remodeling in the mechanisms of arrhythmogenesis.