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Cardiac Arrhythmia After Myocardial Infarction: Insights From a Dynamic Canine Ventricular Myocyte Model

["Background: Electrophysiological remodeling of sarcolemmal ion channels in myocytes neighboring a myocardial infarct is thought to create a substrate for life-threatening arrhythmias. Computational biology is a powerful tool in elucidating arrhythmogenic mechanisms at the cellular level, where complex interactions between ionic processes determine behavior. Methods and Results: A novel theoretical model of canine cardiac ventricular action potential (AP) and calcium cycling is used to investigate ionic mechanisms underlying Ca 2+ transient (CaT) and AP duration (APD) rate dependence. Remodeling changes measured in the 5-day old canine infarct epicardial border zone (BZ) are integrated into the model to study ionic mechanisms underlying altered rate dependence of AP and CaT in BZ myocytes. For the first time, Ca 2+ /calmodulin-dependent protein kinase (CaMKII) regulatory pathway is integrated into a whole-cell model, which is paced over the physiological and arrhythmic range of cycle lengths (CL). Decreasing CL from 8,000 ms to 300 ms shortens APD due primarily to I Ca(L) reduction, with additional contributions from I to1 , I NaK , and late I Na . CaT amplitude increases as CL decreases from 8,000 ms to 500 ms. This positive force-frequency property depends on CaMKII activity. We test the hypothesis that CaMKII dysfunction during infarction contributes to abnormal rate-dependent properties of BZ myocytes. CaMKII suppression results in greater L-type calcium current reduction at fast pacing rates compared to control, loss of normal rate-dependent abbreviation of CaT, a negative relationship between CaT amplitude and frequency, and abnormal CaT restitution. Conclusions: The model of CaMKII regulation serves as a paradigm for modeling other regulatory pathways and effects on cell function. This study identifies CaMKII dysfunction as a potential root component of the remodeling process, suggesting that pharmacological interventions targeting CaMKII may reduce heterogeneity in cardiac tissue post-infarction."]