Augmentation of myocardial If dysregulates calcium homeostasis and causes adverse cardiac remodeling

Pessah Yampolsky; Michael Koenen; Matias Mosqueira; Pascal Geschwill; Sebastian Nauck; Monika Witzenberger; Claudia Seyler; Thomas Fink; Mathieu Kruska; Claus Bruehl; Alexander P. Schwoerer; Heimo Ehmke; Rainer H.A. Fink; Andreas Draguhn; Dierk Thomas; Hugo A. Katus; Patrick A. Schweizer

doi:10.1038/s41467-019-11261-2

Augmentation of myocardial I_f dysregulates calcium homeostasis and causes adverse cardiac remodeling

Pessah Yampolsky, Michael Koenen, Matias Mosqueira, Pascal Geschwill, Sebastian Nauck, Monika Witzenberger, Claudia Seyler, Thomas Fink, Mathieu Kruska, Claus Bruehl, Alexander P. Schwoerer, Heimo Ehmke, Rainer H.A. Fink, Andreas Draguhn, Dierk Thomas, Hugo A. Katus, Patrick A. Schweizer^*

^*Corresponding author for this work

Clinic of Internal Medicine II - Cardiology

30 Citations (Scopus)

Abstract

HCN channels underlie the depolarizing funny current (I_f) that contributes importantly to cardiac pacemaking. I_f is upregulated in failing and infarcted hearts, but its implication in disease mechanisms remained unresolved. We generated transgenic mice (HCN4^tg/wt) to assess functional consequences of HCN4 overexpression-mediated I_f increase in cardiomyocytes to levels observed in human heart failure. HCN4^tg/wt animals exhibit a dilated cardiomyopathy phenotype with increased cellular arrhythmogenicity but unchanged heart rate and conduction parameters. I_f augmentation induces a diastolic Na⁺ influx shifting the Na⁺/Ca²⁺ exchanger equilibrium towards ‘reverse mode’ leading to increased [Ca²⁺]_i. Changed Ca²⁺ homeostasis results in significantly higher systolic [Ca²⁺]_i transients and stimulates apoptosis. Pharmacological inhibition of I_f prevents the rise of [Ca²⁺]_i and protects from ventricular remodeling. Here we report that augmented myocardial I_f alters intracellular Ca²⁺ homeostasis leading to structural cardiac changes and increased arrhythmogenicity. Inhibition of myocardial I_fper se may constitute a therapeutic mechanism to prevent cardiomyopathy.

Original language	English
Article number	3295
Journal	Nature Communications
Volume	10
Issue number	1
ISSN	1751-8628
DOIs	https://doi.org/10.1038/s41467-019-11261-2
Publication status	Published - 01.12.2019

Funding

We gratefully acknowledge the excellent technical work of Simone Bauer and Ulrike Mersdorf. This work was supported in parts by grants from the Medical Faculty of the University of Heidelberg and the German Cardiac Society (postdoc fellowship and research scholarship to P.Y.), from the German Heart Foundation (Kaltenbach scholarship to T.F.), from the German Cardiac Society and the Hengstberger Foundation (Klaus-Georg and Sigrid Hengstberger Scholarship to D.T.), from the Joachim Siebe-neicher Foundation (to D.T.), from the Deutsche Forschungsgemeinschaft (SCHW 1611/ 1-1 to P.A.S. and TH 1120/8-1 to D.T.), from the Max-Planck-Society (TANDEM project to P.A.S. and M.K.O.) and from the German Centre for Cardiovascular Research (DZHK) (to S.N., C.S., A.P.S., H.E., D.T., H.A.K., P.A.S.). S.N. is recipient of a DZHK doctoral student scholarship. P.A.S. is recipient of the Heidelberg Research Center for Molecular Medicine (HRCMM) Senior Career Fellowship.

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SDG 3 Good Health and Well-being

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10.1038/s41467-019-11261-2

Cite this

Yampolsky, P., Koenen, M., Mosqueira, M., Geschwill, P., Nauck, S., Witzenberger, M., Seyler, C., Fink, T., Kruska, M., Bruehl, C., Schwoerer, A. P., Ehmke, H., Fink, R. H. A., Draguhn, A., Thomas, D., Katus, H. A., & Schweizer, P. A. (2019). Augmentation of myocardial I_f dysregulates calcium homeostasis and causes adverse cardiac remodeling. Nature Communications, 10(1), Article 3295. https://doi.org/10.1038/s41467-019-11261-2

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title = "Augmentation of myocardial If dysregulates calcium homeostasis and causes adverse cardiac remodeling",

abstract = "HCN channels underlie the depolarizing funny current (If) that contributes importantly to cardiac pacemaking. If is upregulated in failing and infarcted hearts, but its implication in disease mechanisms remained unresolved. We generated transgenic mice (HCN4tg/wt) to assess functional consequences of HCN4 overexpression-mediated If increase in cardiomyocytes to levels observed in human heart failure. HCN4tg/wt animals exhibit a dilated cardiomyopathy phenotype with increased cellular arrhythmogenicity but unchanged heart rate and conduction parameters. If augmentation induces a diastolic Na+ influx shifting the Na+/Ca2+ exchanger equilibrium towards {\textquoteleft}reverse mode{\textquoteright} leading to increased [Ca2+]i. Changed Ca2+ homeostasis results in significantly higher systolic [Ca2+]i transients and stimulates apoptosis. Pharmacological inhibition of If prevents the rise of [Ca2+]i and protects from ventricular remodeling. Here we report that augmented myocardial If alters intracellular Ca2+ homeostasis leading to structural cardiac changes and increased arrhythmogenicity. Inhibition of myocardial Ifper se may constitute a therapeutic mechanism to prevent cardiomyopathy.",

author = "Pessah Yampolsky and Michael Koenen and Matias Mosqueira and Pascal Geschwill and Sebastian Nauck and Monika Witzenberger and Claudia Seyler and Thomas Fink and Mathieu Kruska and Claus Bruehl and Schwoerer, \{Alexander P.\} and Heimo Ehmke and Fink, \{Rainer H.A.\} and Andreas Draguhn and Dierk Thomas and Katus, \{Hugo A.\} and Schweizer, \{Patrick A.\}",

note = "Funding Information: We gratefully acknowledge the excellent technical work of Simone Bauer and Ulrike Mersdorf. This work was supported in parts by grants from the Medical Faculty of the University of Heidelberg and the German Cardiac Society (postdoc fellowship and research scholarship to P.Y.), from the German Heart Foundation (Kaltenbach scholarship to T.F.), from the German Cardiac Society and the Hengstberger Foundation (Klaus-Georg and Sigrid Hengstberger Scholarship to D.T.), from the Joachim Siebe-neicher Foundation (to D.T.), from the Deutsche Forschungsgemeinschaft (SCHW 1611/ 1-1 to P.A.S. and TH 1120/8-1 to D.T.), from the Max-Planck-Society (TANDEM project to P.A.S. and M.K.O.) and from the German Centre for Cardiovascular Research (DZHK) (to S.N., C.S., A.P.S., H.E., D.T., H.A.K., P.A.S.). S.N. is recipient of a DZHK doctoral student scholarship. P.A.S. is recipient of the Heidelberg Research Center for Molecular Medicine (HRCMM) Senior Career Fellowship. Publisher Copyright: {\textcopyright} 2019, The Author(s). Copyright: Copyright 2019 Elsevier B.V., All rights reserved.",

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Yampolsky, P, Koenen, M, Mosqueira, M, Geschwill, P, Nauck, S, Witzenberger, M, Seyler, C, Fink, T, Kruska, M, Bruehl, C, Schwoerer, AP, Ehmke, H, Fink, RHA, Draguhn, A, Thomas, D, Katus, HA & Schweizer, PA 2019, 'Augmentation of myocardial I_f dysregulates calcium homeostasis and causes adverse cardiac remodeling', Nature Communications, vol. 10, no. 1, 3295. https://doi.org/10.1038/s41467-019-11261-2

TY - JOUR

T1 - Augmentation of myocardial If dysregulates calcium homeostasis and causes adverse cardiac remodeling

AU - Yampolsky, Pessah

AU - Koenen, Michael

AU - Mosqueira, Matias

AU - Geschwill, Pascal

AU - Nauck, Sebastian

AU - Witzenberger, Monika

AU - Seyler, Claudia

AU - Fink, Thomas

AU - Kruska, Mathieu

AU - Bruehl, Claus

AU - Schwoerer, Alexander P.

AU - Ehmke, Heimo

AU - Fink, Rainer H.A.

AU - Draguhn, Andreas

AU - Thomas, Dierk

AU - Katus, Hugo A.

AU - Schweizer, Patrick A.

N1 - Funding Information: We gratefully acknowledge the excellent technical work of Simone Bauer and Ulrike Mersdorf. This work was supported in parts by grants from the Medical Faculty of the University of Heidelberg and the German Cardiac Society (postdoc fellowship and research scholarship to P.Y.), from the German Heart Foundation (Kaltenbach scholarship to T.F.), from the German Cardiac Society and the Hengstberger Foundation (Klaus-Georg and Sigrid Hengstberger Scholarship to D.T.), from the Joachim Siebe-neicher Foundation (to D.T.), from the Deutsche Forschungsgemeinschaft (SCHW 1611/ 1-1 to P.A.S. and TH 1120/8-1 to D.T.), from the Max-Planck-Society (TANDEM project to P.A.S. and M.K.O.) and from the German Centre for Cardiovascular Research (DZHK) (to S.N., C.S., A.P.S., H.E., D.T., H.A.K., P.A.S.). S.N. is recipient of a DZHK doctoral student scholarship. P.A.S. is recipient of the Heidelberg Research Center for Molecular Medicine (HRCMM) Senior Career Fellowship. Publisher Copyright: © 2019, The Author(s). Copyright: Copyright 2019 Elsevier B.V., All rights reserved.

PY - 2019/12/1

Y1 - 2019/12/1

N2 - HCN channels underlie the depolarizing funny current (If) that contributes importantly to cardiac pacemaking. If is upregulated in failing and infarcted hearts, but its implication in disease mechanisms remained unresolved. We generated transgenic mice (HCN4tg/wt) to assess functional consequences of HCN4 overexpression-mediated If increase in cardiomyocytes to levels observed in human heart failure. HCN4tg/wt animals exhibit a dilated cardiomyopathy phenotype with increased cellular arrhythmogenicity but unchanged heart rate and conduction parameters. If augmentation induces a diastolic Na+ influx shifting the Na+/Ca2+ exchanger equilibrium towards ‘reverse mode’ leading to increased [Ca2+]i. Changed Ca2+ homeostasis results in significantly higher systolic [Ca2+]i transients and stimulates apoptosis. Pharmacological inhibition of If prevents the rise of [Ca2+]i and protects from ventricular remodeling. Here we report that augmented myocardial If alters intracellular Ca2+ homeostasis leading to structural cardiac changes and increased arrhythmogenicity. Inhibition of myocardial Ifper se may constitute a therapeutic mechanism to prevent cardiomyopathy.

AB - HCN channels underlie the depolarizing funny current (If) that contributes importantly to cardiac pacemaking. If is upregulated in failing and infarcted hearts, but its implication in disease mechanisms remained unresolved. We generated transgenic mice (HCN4tg/wt) to assess functional consequences of HCN4 overexpression-mediated If increase in cardiomyocytes to levels observed in human heart failure. HCN4tg/wt animals exhibit a dilated cardiomyopathy phenotype with increased cellular arrhythmogenicity but unchanged heart rate and conduction parameters. If augmentation induces a diastolic Na+ influx shifting the Na+/Ca2+ exchanger equilibrium towards ‘reverse mode’ leading to increased [Ca2+]i. Changed Ca2+ homeostasis results in significantly higher systolic [Ca2+]i transients and stimulates apoptosis. Pharmacological inhibition of If prevents the rise of [Ca2+]i and protects from ventricular remodeling. Here we report that augmented myocardial If alters intracellular Ca2+ homeostasis leading to structural cardiac changes and increased arrhythmogenicity. Inhibition of myocardial Ifper se may constitute a therapeutic mechanism to prevent cardiomyopathy.

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U2 - 10.1038/s41467-019-11261-2

DO - 10.1038/s41467-019-11261-2

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AN - SCOPUS:85069688568

SN - 1751-8628

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