Sudden cardiac death (SCD) and cardiac arrhythmias remain a daunting public health problem. It is estimated that there are between 250,000 and 400,000 SCDs in the United States each year1, most of which occur in the setting of heart failure or as a complication of ischemic heart disease, such as after myocardial infarction. Oxidant stress is recognized to have a central role in the development and progression of myocardial dysfunction—but the molecular targets of reactive oxidative species (ROS) remain obscure. Furthermore, knowledge of how disorders of the reduction-oxidation balance contribute mechanistically to disorders of cardiac electrophysiology and the risk of arrhythmias continues to evolve. Ion channels underlie the fundamental electrical properties of the heart, including cellular excitability and impulse propagation. Pharmacological therapies for SCD, targeting ion channels, have been uniformly disappointing, showing either no benefit in survival or even an increase in the incidence of ventricular tachyarrhythmias and SCD2. In contrast, considerable advances have been achieved either with pharmacological therapies, which affect regulatory pathways ‘upstream’of ion channels (for instance, β-blockers, statins, angiotensin-converting enzyme and aldosterone inhibitors), or with ‘downstream’device-based therapies (implantable cardioverter defibrillators). Two recent studies in Circulation Research3 and Cell4 unravel the complexities of the molecular pathways involved in the arrhythmogenesis in heart failure. These mechanistic findings have implications for our understanding of how ion channels are affected by upstream regulatory circuits. ROS are evanescent signaling molecules that are by-products of cellular metabolism and have an important role in cellular and tissue excitability and the progression of heart failure. As a result of activity in the electron transfer chain, it is estimated that up to 5% of the molecular oxygen consumed in mitochondria is converted to superoxide anions5, 6. Thus, ROS are important mediators linking metabolic activity to various cell signaling pathways, and a number of these pathways affect cellular and tissue excitability.

Arguably, the most comprehensively established link between ROS, injury and arrhythmias is in ischemia and reperfusion of the myocardium—as occurs frequently in manifestations of coronary heart disease, such as unstable angina pectoris and myocardial infarction. Additionally, ROS-induced disturbances in the cardiac rhythm have been proposed in a number of other circumstances, such as atrial fibrillation and arrhythmias in the failing heart. The cellular intermediates that are affected by changes in ROS are numerous but prominently include ion channels and their regulators. A particularly intriguing example is the multifunctional Ca2+–calmodulin kinase II (CaMKII), which couples increases in intracellular Ca2+ to activation of ion channels by phosphorylation of a large and diverse set of effector targets. A growing body of evidence suggests that CaMKII may be a key link between increased levels of oxidant stress in heart failure and cardiac arrhythmias (Fig. 1). The two recent studies add to this body of evidence.