Heart failure (HF) following myocardial infarction (MI) is associated with high incidence of cardiac arrhythmias. Development of therapeutic strategy requires detailed understanding of electrophysiological remodeling. However, changes of ionic currents in ischemic HF remain incompletely understood, especially in translational large animal models. Here, we systematically measure the major ionic currents in ventricular myocytes from the infarct border and remote zones in a porcine model of post-MI HF. We recorded eight ionic currents during the cell’s action potential (AP) under physiologically relevant conditions using ^selfAP-clamp Sequential Dissection. Compared to healthy controls, HF-remote zone myocytes exhibited increased late Na⁺ current, Ca²⁺-activated K⁺ current, Ca²⁺-activated Cl^- current, decreased rapid delayed rectifier K⁺ current, and altered Na⁺/Ca²⁺ exchange current profile. In HF-border zone myocytes, the above changes also occurred but with additional decrease of L-type Ca²⁺ current, decrease of inward rectifier K⁺ current, and Ca²⁺ release-dependent delayed afterdepolarizations. Our data reveal that the changes in any individual current are relatively small, but the integrated impacts shift the balance between the inward and outward currents to shorten AP in the border zone but prolong AP in the remote zone. This differential remodeling in post-MI HF increases the inhomogeneity of AP repolarization which may enhance the arrhythmogenic substrate. Our comprehensive findings provide a new mechanistic framework for understanding why single channel blockers may fail to suppress arrhythmias, and highlight the need to consider the rich tableau and integration of many ionic currents in designing therapeutic strategies for treating arrhythmias in HF.

Electrophysiology data were collected using pClamp10 (Molecular Devices) software, then Clampfit 10 (Molecular Devices), Excel 2016 (Microsoft) and Origin 2016 (OriginLab) softwares were used for data processing and analysis.

Calcium and contraction data were collected using IonWizard (IonOptix) software, then IonWizard, Excel and Origin softwares were used for data processing and analysis.

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