Complex electrophysiological remodeling in postinfarction ischemic heart failure

Bence Hegyi, Julie Bossuyt, Leigh G. Griffiths, Rafael Shimkunas, Zana Coulibaly, Zhong Jian, Kristin N. Grimsrud, Claus S. Sondergaard, Kenneth S. Ginsburg, Nipavan Chiamvimonvat, Luiz Belardinelli, András Varró (+8 others)
2018 Proceedings of the National Academy of Sciences of the United States of America  
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 largeanimal 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
more » ... ne model of post-MI HF. We recorded eight ionic currents during the cell's action potential (AP) under physiologically relevant conditions using self AP-clamp sequential dissection. Compared with healthy controls, HF-remote zone myocytes exhibited increased late Na + current, Ca 2+ -activated K + current, Ca 2+ -activated Cl − current, decreased rapid delayed rectifier K + current, and altered Na + /Ca 2+ exchange current profile. In HF-border zone myocytes, the above changes also occurred but with additional decrease of L-type Ca 2+ current, decrease of inward rectifier K + current, and Ca 2+ 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. ischemic heart failure | myocardial infarction | electrophysiology | action potential | ionic currents I schemic cardiomyopathy as a chronic consequence of myocardial infarction (MI) represents a leading cause of heart failure (HF). Ischemic HF is characterized by extensive structural and functional remodeling that leads to altered action potential (AP) and increased susceptibility for cardiac arrhythmias (1). Precision therapeutic interventions require in-depth understanding of the electrophysiological changes that promote arrhythmias. However, the changes of ionic currents in ischemic HF remain incompletely understood to date, especially in large-animal models that are needed for translational studies. Emerging evidence suggests differential myocardium remodeling in the infarct border and remote zones, leading to complex changes in ionic currents (2), Ca 2+ handling (3), and contractility (4). However, most previous studies were conducted either early after MI induction (in 2-7 d) or scar formation (within 8 wk) (2, 5), but not at the clinically relevant later stages of HF. Recently, we established a porcine MI model (6) that developed chronic HF (with reduced ejection fraction, EF) over 5 mo, providing a large-animal model for translational study of chronic post-MI HF. In this study, we systematically investigated the changes of ionic currents and AP in ventricular myocytes from the infarct border and remote zones to gain a comprehensive understanding of the electrophysiological remodeling. The AP of ventricular myocyte is shaped by a constellation of ionic currents that integrate at the cell level. The inward vs. outward currents counterbalance instantaneously to determine the AP profile. To gain a comprehensive view of remodeling, we developed an innovative self AP-clamp sequential dissection method (7) to record multiple inward and outward ionic currents during the cell's own AP under physiological conditions. We found that HF remote-zone myocytes exhibit decreased rapid delayed rectifier K + current (I Kr ), altered Na + /Ca 2+ exchange current (I NCX ), and increases of late Na + current (I NaL ), Ca 2+activated K + current [I K(Ca) ], and Ca 2+ -activated Cl − current [I Cl(Ca) ]. The border-zone myocytes also show the above changes, but with 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 Ca 2+ 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 channelblocker therapy may fail, and highlight the need to understand the integrated changes of ionic currents in treating arrhythmias in HF.
doi:10.1073/pnas.1718211115 pmid:29531045 fatcat:sqcalraem5awhklqentb736524