Calmodulin kinase II (
CaMKII) mediates critical signaling pathways responsible for divergent functions in the heart including
calcium cycling,
hypertrophy and apoptosis. Dysfunction in the
CaMKII signaling pathway occurs in
heart disease and is associated with increased susceptibility to life-threatening
arrhythmia. Furthermore,
CaMKII inhibition prevents
cardiac arrhythmia and improves heart function following
myocardial infarction. Recently, a novel mechanism for oxidative
CaMKII activation was discovered in the heart. Here, we provide the first report of
CaMKII oxidation state in a well-validated, large-animal model of
heart disease. Specifically, we observe increased levels of oxidized
CaMKII in the
infarct border zone (BZ). These unexpected new data identify an alternative activation pathway for
CaMKII in common
cardiovascular disease. To study the role of oxidation-dependent
CaMKII activation in creating a pro-
arrhythmia substrate following
myocardial infarction, we developed a new mathematical model of
CaMKII activity including both oxidative and autophosphorylation activation pathways. Computer simulations using a multicellular mathematical model of the cardiac fiber demonstrate that enhanced
CaMKII activity in the
infarct BZ, due primarily to increased oxidation, is associated with reduced conduction velocity, increased effective refractory period, and increased susceptibility to formation of conduction block at the BZ margin, a prerequisite for reentry. Furthermore, our model predicts that
CaMKII inhibition improves conduction and reduces refractoriness in the BZ, thereby reducing vulnerability to conduction block and reentry. These results identify a novel oxidation-dependent pathway for
CaMKII activation in the
infarct BZ that may be an effective therapeutic target for improving conduction and reducing heterogeneity in the infarcted heart.