Introduction: ATF6a and ATF6b are endoplasmic reticulum (ER) type II transmembrane proteins that sense the accumulation of toxic misfolded proteins in the ER of cardiac myocytes during ER stress. Upon ER stress, ATF6a is cleaved into an active transcription factor which increases the expression of adaptive genes. ATF6b is an isoform of ATF6a, which is also cleaved similar manner as ATF6a during ER stress. However, while a great deal is known about the biological role and significance of ATF6a in the heart, the role of ATF6b remains unknown. Hence, the overall objective of this research was to elucidate the role of ATF6b in cardiac myocyte viability and survival. Hypothesis: If ATF6b is important for cell viability, then knocking down endogenous ATF6b in cardiac myocytes will increase cell death. Methods: To determine the role of endogenous ATF6b, a loss-of-function strategy in cardiac myocytes was used. Combinations of viability assays, as well as assays for specific kinds of cell death were used in conjunction with immunoblotting and quantitative real time- polymerase chain reaction to assess the roles for ATF6b. Mechanistic studies were done using gain-of-function approaches wherein the activated form of ATF6b was ectopically expressed in cultured cardiac myocytes. Results: In NRVMs, knockdown of ATF6b resulted in cell death in both the absence and presence of the thapsigargin. This cell death was determined to be associated with the induction of numerous pro-apoptotic genes, including Puma, Bax and Bak. Use of highly specific inhibitors or apoptosis and necrosis showed that ATF6b knockdown leads to apoptotic cell death, which was shown to be mediated at least partly by induction of Puma. Gain and loss-of-function analyses of ATF6b showed that ATF6b inhibited p53 transcription Furthermore, this inhibition was due to the ability of ATF6b ability to inhibit NF-kB, a transcription factor that is known to bind to the p53 promoter and stimulate its transcription. Conclusion: This study showed that ATF6b maintains cardiac myocyte viability under basal and ER stress conditions. Mechanistically, it was shown that ATF6b transcriptionally represses the NF-kB-p53-Puma axis. In doing so, ATF6b inhibits the NF- kB mediated p53 induction, thereby inhibiting Puma- and caspase-mediated apoptosis.