Fig. 1.

Proposed mechanisms involved in intermittent hypoxia-mediated arrhythmia. Reactive oxygen species (ROS), increased by intermittent hypoxia, trigger Ca²⁺ release from the sarcoplasmic reticulum (SR) and mitochondria and causes Ca²⁺ influx through voltage-dependent Ca²⁺ channels (VDCC) and transient receptor potential vanilloid (TRPV) channels. The resulting increase in cytosolic free Ca²⁺ concentration ([Ca²⁺]_cyt) then activates calpain, a Ca²⁺-dependent, non-lysosomal cysteine protease, which causes degradation of human ERG (hERG) channels and decrease in whole cell K⁺ currents through hERG channels. Reduced hERG K⁺ current then leads to prolongation of the Q-T interval and ultimately to arrhythmia and sudden cardiac death. The reduced hERG K⁺ current also causes membrane depolarization that opens VDCC, enhances Ca²⁺ influx through VDCC, and further increases [Ca²⁺]_cyt in the cardiomyocytes. The loop formed by the initial ROS-mediated increase in [Ca²⁺]_cyt and the calpain-mediated decrease in whole cell hERG K⁺ currents may serve as a pathogenic sequence of events for ROS-mediated arrhythmia in patients with OSA or individuals exposed to intermittent hypoxia.