The cellular environment of the mammalian heart constantly is challenged with environmental and intrinsic pathological insults, which affect the proper folding of proteins in heart failure. The effects of damaged or misfolded proteins on the cell can be profound and result in a process termed “proteotoxicity”. While proteotoxicity is best known for its role in mediating the pathogenesis of neurodegenerative diseases such as Alzheimer’s disease, its role in human heart failure also has been recognized. The UPR involves three branches, including PERK, ATF6, and IRE1. In the presence of a misfolded protein, the GRP78 molecular chaperone that normally interacts with the receptors PERK, ATF6, and IRE-1 in the endoplasmic reticulum detaches to attempt to stabilize the protein. Mouse models of cardiac hypertrophy, ischemia, and heart failure demonstrate increases in activity of all three branches after removing GRP78 from these internal receptors. Recent studies have linked elevated PERK and CHOP in vitro with regulation of ion channels linked with human systolic heart failure. With this in mind, we specifically investigated ventricular myocardium from 10 patients with a history of conduction system defects or arrhythmias for expression of UPR and autophagy genes compared to myocardium from non-failing controls. We identified elevated Chop, Atf3, and Grp78 mRNA, along with XBP-1-regulated Cebpa mRNA, indicative of activation of the UPR in human heart failure with arrhythmias.