Over half of heart failure patients die of arrhythmic death, which claims about 20% of total mortalities worldwide, and 100,000 lives a year in UK, more than breast cancer, lung cancer and AIDS combined. Current anti-arrhythmic agents are designed to block ion channel activity, which can cause pro-arrhythmic effects, culminating in greater overall mortality risk. Our current work provides important evidence supporting an emerging concept by targeting “upstream regulators” of ion channels as a new treatment route against ventricular arrhythmias. We recently discovered a novel mechanism underlying gene regulation of a set of potassium (K+) channels through a signalling complex comprised of mitogen-activated kinase kinase 7 (MKK7), histone deacetylase 2 (HDAC2) and Krϋppel-like factor 4 (KLF4). Gain and loss of function studies demonstrate a critical link of stress signalling pathways through the MKK7/HDAC2/KLF4 mechanism with repression of cardiac K+ channels, repolarisation delay and susceptibility to arrhythmias. Our data in an arrhythmic mouse model further reveal the effect of HDAC2 inhibition by pharmacological inhibitors on restoring K+ activity and reducing arrhythmic propensity. This study suggests a gene regulatory avenue for treatment of cardiac arrhythmias.