Complex electrophysiological remodeling in postinfarction ischemic heart failure

Bence Hegyi, Julie B C 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, Julius G. Papp, Piero Pollesello, Jouko Levijoki, Leighton T Izu, Walter D Boyd, Tamás Bányász, Donald M Bers, Ye Chen-Izu

Research output: Contribution to journalArticle

8 Citations (Scopus)

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 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 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.

Original languageEnglish (US)
Pages (from-to)E3036-E3044
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number13
DOIs
StatePublished - Mar 27 2018

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Heart Failure
Action Potentials
Muscle Cells
Cardiac Arrhythmias
Myocardial Infarction
Dissection
Swine
Incidence
Therapeutics

Keywords

  • Action potential
  • Electrophysiology
  • Ionic currents
  • Ischemic heart failure
  • Myocardial infarction

ASJC Scopus subject areas

  • General

Cite this

Complex electrophysiological remodeling in postinfarction ischemic heart failure. / Hegyi, Bence; Bossuyt, Julie B C; Griffiths, Leigh G.; Shimkunas, Rafael; Coulibaly, Zana; Jian, Zhong; Grimsrud, Kristin N; Sondergaard, Claus S.; Ginsburg, Kenneth S; Chiamvimonvat, Nipavan; Belardinelli, Luiz; Varró, András; Papp, Julius G.; Pollesello, Piero; Levijoki, Jouko; Izu, Leighton T; Boyd, Walter D; Bányász, Tamás; Bers, Donald M; Chen-Izu, Ye.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 115, No. 13, 27.03.2018, p. E3036-E3044.

Research output: Contribution to journalArticle

Hegyi, B, Bossuyt, JBC, Griffiths, LG, Shimkunas, R, Coulibaly, Z, Jian, Z, Grimsrud, KN, Sondergaard, CS, Ginsburg, KS, Chiamvimonvat, N, Belardinelli, L, Varró, A, Papp, JG, Pollesello, P, Levijoki, J, Izu, LT, Boyd, WD, Bányász, T, Bers, DM & Chen-Izu, Y 2018, 'Complex electrophysiological remodeling in postinfarction ischemic heart failure', Proceedings of the National Academy of Sciences of the United States of America, vol. 115, no. 13, pp. E3036-E3044. https://doi.org/10.1073/pnas.1718211115
Hegyi, Bence ; Bossuyt, Julie B C ; Griffiths, Leigh G. ; Shimkunas, Rafael ; Coulibaly, Zana ; Jian, Zhong ; Grimsrud, Kristin N ; Sondergaard, Claus S. ; Ginsburg, Kenneth S ; Chiamvimonvat, Nipavan ; Belardinelli, Luiz ; Varró, András ; Papp, Julius G. ; Pollesello, Piero ; Levijoki, Jouko ; Izu, Leighton T ; Boyd, Walter D ; Bányász, Tamás ; Bers, Donald M ; Chen-Izu, Ye. / Complex electrophysiological remodeling in postinfarction ischemic heart failure. In: Proceedings of the National Academy of Sciences of the United States of America. 2018 ; Vol. 115, No. 13. pp. E3036-E3044.
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AU - Bossuyt, Julie B C

AU - Griffiths, Leigh G.

AU - Shimkunas, Rafael

AU - Coulibaly, Zana

AU - Jian, Zhong

AU - Grimsrud, Kristin N

AU - Sondergaard, Claus S.

AU - Ginsburg, Kenneth S

AU - Chiamvimonvat, Nipavan

AU - Belardinelli, Luiz

AU - Varró, András

AU - Papp, Julius G.

AU - Pollesello, Piero

AU - Levijoki, Jouko

AU - Izu, Leighton T

AU - Boyd, Walter D

AU - Bányász, Tamás

AU - Bers, Donald M

AU - Chen-Izu, Ye

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N2 - 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 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.

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