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Proc Natl Acad Sci U S A. 2018 Mar 27;115(13):E3036-E3044. doi: 10.1073/pnas.1718211115. Epub 2018 Mar 12.

Complex electrophysiological remodeling in postinfarction ischemic heart failure.

Author information

1
Department of Pharmacology, University of California, Davis, CA 95616.
2
Department of Veterinary Medicine and Epidemiology, University of California, Davis, CA 95616.
3
Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN 55902.
4
College of Medicine, Mayo Clinic, Rochester, MN 55902.
5
Department of Biomedical Engineering, University of California, Davis, CA 95616.
6
Department of Surgery, University of California, Davis, Sacramento, CA 95817.
7
Division of Cardiovascular Medicine, Department of Internal Medicine, University of California, Davis, CA 95616.
8
Department of Veterans Affairs, Northern California Health Care System, Mather, CA 95655.
9
Department of Clinical Research, Gilead Sciences, Inc., Foster City, CA 94404.
10
Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Szeged, H-6720 Szeged, Hungary.
11
MTA-SZTE Research Group of Cardiovascular Pharmacology, Hungarian Academy of Sciences, H-6720 Szeged, Hungary.
12
Critical Care Proprietary Products, Orion Pharma, FI-02200 Espoo, Finland.
13
Department of Physiology, Faculty of Medicine, University of Debrecen, H-4012 Debrecen, Hungary.
14
Department of Pharmacology, University of California, Davis, CA 95616; ychenizu@ucdavis.edu.

Abstract

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.

KEYWORDS:

action potential; electrophysiology; ionic currents; ischemic heart failure; myocardial infarction

PMID:
29531045
PMCID:
PMC5879679
DOI:
10.1073/pnas.1718211115
[Indexed for MEDLINE]
Free PMC Article

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