Sudden cardiac arrest (SCA) due to malignant ventricular arrhythmias remains a major cause of mortality in the US. While the majority of SCA patients have significant coronary artery disease (CAD), nearly one in three patients present with lethal arrhythmias as their first and only manifestation of heart disease without prior cardiovascular symptoms. Moreover, these arrhythmic events exhibit a diurnal variation but the mechanisms responsible for this remain unclear. We hypothesize that chronic ischemia results in circadian misalignment between ischemic and non-ischemic (healthy) regions and is a mechanism of increased cardiac arrhythmias mediated by circadian phase shift in the intracellular calcium-calcineurin signaling.
The goal of this project is to determine whether cardiac circadian disruption is a viable therapeutic target for arrhythmias. Successful completion of the proposed studies will provide unique insight regarding the impact of circadian misalignment on arrhythmia vulnerability and illuminate opportunities for pharmacological interventions to manage, prevent, or even restore the loss of cardiac circadian alignment and consequently attenuate time-of-day incidence of cardiac arrhythmias and SCA.