Complex electrophysiological remodeling in postinfarction ischemic heart failure

Significance Cardiac arrhythmias often occur in heart failure (HF) patients, but drug therapies using selective ion channel blockers have failed clinical trials and effective drug therapies remain elusive. Here we systematically study the major ionic currents during the cardiac action potential (AP) and arrhythmogenic Ca2+ release in postinfarction HF. We found that changes in any individual current are relatively small, and alone could mislead as to consequences. However, differential changes in multiple currents integrate to shorten AP in the infarct border zone but prolong AP in the remote zone, increasing AP repolarization inhomogeneity. Our findings help explain why single channel-blocker therapy may fail, and highlight the need to understand the integrated changes of ionic currents in treating arrhythmias in HF. 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 with 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 after-depolarizations. 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 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.