Understanding the role of mitochondrial dysfunction in cardiac arrhythmias using a novel 3D panoramic optical mapping system

ABSTRACT Cardiac arrhythmias are a major cause of morbidity and mortality, and are increasingly prevalent due to an aging population with diabetes, heart failure and hypertension. Atrial fibrillation (AF) and ventricular fibrillation (VF), are chaotic arrhythmias, whereas, atrial tachycardia (AT), atrial flutter (AFL) and ventricular tachycardia (VT) are more organized, focal or macro-reentrant arrhythmias. Our grasp of the specific mechanisms that allow for the cardiac substrate to harbor organized and/or chaotic rhythms is incomplete. Causative factors of arrhythmias include fibrosis, increased late Na+ current and increased reactive oxidative stress (ROS) causing augmented mitophagy, which is a process of eliminating defective mitochondria to maintain the overall health of the mitochondrial pool. Our methodological breakthrough is to use 3D panoramic anatomical and optical mapping, in conjunction with mitophagy detection to characterize the interplay amongst electrical activation, substrate heterogeneity due to fibrosis and mitophagy, and action potential duration (APD) heterogeneity. Our proposed concept is that larger or greater number of areas of fibrosis, APD heterogeneity and/or mitophagy will allow for more chaotic atrial or ventricular arrhythmias. By individually disrupting these pathways and defining the consequences on arrhythmogenesis, we will determine how these three processes are co-regulated or functionally inter-dependent. We crossed mice with a reporter Keima protein which detects mitophagy, together with two lines of transgenic mice with spontaneous and sustained AF, AFL, AT, VT and VF due to mutations in the human cardiac NaV1.5 channel gene SCN5A. This project presents an integrated experimental approach using (1) multi-modality imaging of whole hearts of murine models of Na+ overload with AF, AFL, AT, VT and VF or myocardial infarction induced VT/VF to understand the mechanisms of organized and chaotic atrial and ventricular arrhythmogenesis, (2) AAV delivery of mitochondrial catalase to reverse increased mitophagy after myocardial infarction and (3) optogenetics via AAV delivery of channelrhodopsin-2 into whole murine hearts and use of focused light stimulation to trigger, prevent and terminate atrial and ventricular arrhythmias. The proposed experiments are highly significant and innovative in that co-registered 3D panoramic imaging will allow us to dissect the mechanisms that drive organized and chaotic cardiac arrhythmias, which may lead to new and effective treatment strategies of cardiac arrhythmias.