Various environmental stress including reactive oxygen species (ROS) causes nuclear DNA damage. Increased production of ROS is observed in the failing heart and is considered as one of the causes of heart failure. Accumulating evidences suggest the presence of DNA damage in the failing heart, however, mechanistic link that connects DNA damage and heart failure remains elusive. Here, we show that DNA single strand break (SSB) accumulates in the failing heart and that SSB accumulation induces cell-autonomous inflammation through activation of DNA damage response (DDR) signaling pathway. Using alkaline- and neutral comet assay, we found that SSB is increased in the failing heart of pressure overload. Using in vitro model, we found that SSB accumulation activates ataxia talengiectasia mutated (ATM) kinase, which in turn induces nuclear translocation of NF-kB and increases the expression of inflammatory cytokines. Our findings suggest that SSB accumulation in cardiomyocytes plays an important role in the pathogenesis of heart failure by activating DDR pathway and subsequent cell-autonomous inflammation. SSB accumulation is supposed to be characteristic to post-mitotic cells like cardiomyocytes because unrepaired SSB usually develops into DNA double strand break and lead to catastrophic cellular death in mitotic cells. Approaches targeting efficient SSB repair or DDR pathway may become a novel therapeutic strategy against heart failure.