The role of the unfolded protein response in arrhythmias

Human heart failure is characterized by arrhythmogenic electrical remodeling consisting mostly of ion channel downregulations. Reversing these downregulations is a logical approach to antiarrhythmic therapy, but understanding the pathophysiological mechanisms of the reduced currents is crucial for finding the proper treatments. The unfolded protein response (UPR) is activated by endoplasmic reticulum (ER) stress and has been found to play pivotal roles in different diseases including neurodegenerative diseases, diabetes mellitus, and heart disease. Recently, the UPR is reported to regulate multiple cardiac ion channels, contributing to arrhythmias in heart disease. In this review, we will discuss which UPR modulators and effectors could be involved in regulation of cardiac ion channels in heart disease, and how the understanding of these regulating mechanisms may lead to new antiarrhythmic therapeutics that lack the proarrhythmic risk of current ion channel blocking therapies.