Autonomic modulation of ventricular repolarization in Long QT syndrome

Arrhythmias in Long QT syndrome are known to occur during autonomic activity. The changes in repolarization of the myocardium under autonomic activity are thought to influence arrhythmia mechanisms. Although autonomic modulation of the ventricle is modulated by both humoral and nervous components, yet, due to technical difficulties a detailed understanding of the underlying mechanisms of the neuronal modulation is still elusive. This work is a description of the evolution of a novel model and early results of studies pertaining to the effects of the autonomic nerve stimulation on ventricular repolarization, in the context of long QT pathophysiology. These neuro-cardiology studies were performed using a combination of isolated innervated heart preparation and optical mapping for the first time. Two important repolarization characteristics namely physiological restitution and dispersion of repolarization were studied. The early results suggest that during sympathetic nerve stimulation, physiological restitution curve show unique characteristics of a negative slope at peak heart rates, not reported by classical restitution studies. Also, the action potential duration adaptation at peak heart rates showed heterogeneity over the surface of the myocardium and in addition, exhibited some features of a possible reduction of repolarization reserve, especially during ion channel inhibition. Another set of data obtained using this novel model revealed the autonomic nerve stimulation modulated the dispersion of repolarization in a unique way, and differed from pharmacological autonomic stimulation significantly. Interestingly, preliminary data evaluating the myocardial substrate suggests heterogeneity to be at more than one level i.e. key ion channel distributions, nerve terminal distribution over the myocardium and a possible interaction between them. When the hearts were treated with key repolarization inhibitors, the dispersion of repolarization showed a generically similar response rather than a characteristic response of individual ion currents. In these studies, the substrate changes of repolarization seem to dominate that of neuromodulation of the ventricle.