Abstract Body: Cardiac arrhythmias, which are disruptions in the heart's electrical activities, critically affect the ventricular conduction system, impairing efficient blood circulation. These disturbances result in irregular heartbeats, contributing to patient mortality or causing harm to distant organs via embolic events. Given the severe implications, a profound understanding of the molecular mechanisms driving arrhythmia is crucial for devising specific treatments. This study unveils a pioneering link between the overexpression of IPP2 (Protein Phosphatase 1 Regulatory Inhibitor Subunit 2), driven by the Myh6 promoter (termed TgIPP2), and the onset of age-dependent cardiac arrhythmias. The electrical abnormalities observed in TgIPP2 overexpressing mice include a spectrum of dysfunctions such as axis deviations, elongated QRS and PR intervals, absence of P waves, AV dissociation, ventricular tachyarrhythmia, and heightened T waves. Investigating the pathophysiology behind these electrical anomalies, we subjected young adult mice to catecholamine challenges at low doses and conducted surface electrocardiogram (EKG) monitoring. TgIPP2 mice demonstrated a notable increase in arrhythmogenic episode frequency and duration following 0.2 mg/kg isoproterenol injection compared to their control counterparts. Through a protein phosphorylation analysis, we identified a key regulator of the ryanodine receptor, which modulates calcium release from the sarcoplasmic reticulum, correlating with the extended PR intervals and the delayed peaking of T waves. Therapeutic trials employing RyR blockers, specifically dantrolene, successfully normalized the erratic cardiac rhythms in aged TgIPP2 mice. However, beta blockers or L-type calcium channel blockers induced sudden cardiac death in this model. The study reveals that IPP2-induced aberrant phosphorylation disrupts calcium homeostasis, leading to arrhythmias.
In conclusion, our research marks a significant advancement in understanding arrhythmogenic mechanisms, demonstrating that IPP2 overexpression directly triggers arrhythmia, particularly affecting the atrioventricular (AV) node, atria, and ventricles. The discovery that aberrant phosphorylation, especially of the RyR regulator, plays a pivotal role in initiating cardiac arrhythmias opens new pathways for targeted anti-arrhythmic therapies.