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Cardiac glycosides have been used for the treatment of heart failure because of their capabilities of inhibiting Na + /K +  ATPase (NKA), which raises [Na + ] i  and attenuates Ca 2+  extrusion  via  the Na + /Ca 2+  exchanger (NCX), causing [Ca 2+ ] i  elevation. The resulting [Ca 2+ ] i  accumulation further enhances Ca 2+ -induced Ca 2+  release, generating the positive inotropic effect. However, cardiac glycosides have some toxic and side effects such as arrhythmogenesis, confining their extensive clinical applications. The mechanisms underlying the proarrhythmic effect of glycosides are not fully understood. Here we investigated the mechanisms by which glycosides could cause cardiac arrhythmias  via  impairing mitochondrial energetics using an integrative computational cardiomyocyte model. In the simulations, the effect of glycosides was mimicked by blocking NKA activity. Results showed that inhibiting NKA not only impaired mitochondrial Ca 2+  retention (thus suppressed reactive oxygen species (ROS) scavenging) but also enhanced oxidative phosphorylation (thus increased ROS production) during the transition of increasing workload, causing oxidative stress. Moreover, concurrent blocking of mitochondrial Na + /Ca 2+  exchanger, but not enhancing of Ca 2+  uniporter, alleviated the adverse effects of NKA inhibition. Intriguingly, NKA inhibition elicited Ca 2+  transient and action potential alternans under more stressed conditions such as severe ATP depletion, augmenting its proarrhythmic effect. This computational study provides new insights into the mechanisms underlying cardiac glycoside-induced arrhythmogenesis. The findings suggest that targeting both ion handling and mitochondria could be a very promising strategy to develop new glycoside-based therapies in the treatment of heart failure.

Inhibiting Na+/K+ ATPase Can Impair Mitochondrial Energetics and Induce Abnormal Ca2+ Cycling and Automaticity in Guinea Pig Cardiomyocytes