PortalPublikationenPITX2 Knockout Induces Key Findings of Electrical Remodeling...

PITX2 Knockout Induces Key Findings of Electrical Remodeling as Seen in Persistent Atrial Fibrillation

Standard

PITX2 Knockout Induces Key Findings of Electrical Remodeling as Seen in Persistent Atrial Fibrillation. / Schulz, Carl; Lemoine, Marc D; Mearini, Giulia; Koivumäki, Jussi; Sani, Jascha; Schwedhelm, Edzard; Kirchhof, Paulus; Ghalawinji, Amer; Stoll, Monika; Hansen, Arne; Eschenhagen, Thomas; Christ, Torsten.

in: CIRC-ARRHYTHMIA ELEC, Jahrgang 16, Nr. 3, 03.2023, S. e011602.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Schulz, C, Lemoine, MD, Mearini, G, Koivumäki, J, Sani, J, Schwedhelm, E, Kirchhof, P, Ghalawinji, A, Stoll, M, Hansen, A, Eschenhagen, T & Christ, T 2023, 'PITX2 Knockout Induces Key Findings of Electrical Remodeling as Seen in Persistent Atrial Fibrillation', CIRC-ARRHYTHMIA ELEC, Jg. 16, Nr. 3, S. e011602. https://doi.org/10.1161/CIRCEP.122.011602

APA

Schulz, C., Lemoine, M. D., Mearini, G., Koivumäki, J., Sani, J., Schwedhelm, E., Kirchhof, P., Ghalawinji, A., Stoll, M., Hansen, A., Eschenhagen, T., & Christ, T. (2023). PITX2 Knockout Induces Key Findings of Electrical Remodeling as Seen in Persistent Atrial Fibrillation. CIRC-ARRHYTHMIA ELEC, 16(3), e011602. https://doi.org/10.1161/CIRCEP.122.011602

Vancouver

Schulz C, Lemoine MD, Mearini G, Koivumäki J, Sani J, Schwedhelm E et al. PITX2 Knockout Induces Key Findings of Electrical Remodeling as Seen in Persistent Atrial Fibrillation. CIRC-ARRHYTHMIA ELEC. 2023 Mär;16(3):e011602. https://doi.org/10.1161/CIRCEP.122.011602

Bibtex

@article{9fe5a35a85a349fcaa889ac231b7b697,
title = "PITX2 Knockout Induces Key Findings of Electrical Remodeling as Seen in Persistent Atrial Fibrillation",
abstract = "BACKGROUND: Electrical remodeling in human persistent atrial fibrillation is believed to result from rapid electrical activation of the atria, but underlying genetic causes may contribute. Indeed, common gene variants in an enhancer region close to PITX2 (paired-like homeodomain transcription factor 2) are strongly associated with atrial fibrillation, but the mechanism behind this association remains unknown. This study evaluated the consequences of PITX2 deletion (PITX2-/-) in human induced pluripotent stem cell-derived atrial cardiomyocytes.METHODS: CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat-associated 9) was used to delete PITX2 in a healthy human iPSC line that served as isogenic control. Human induced pluripotent stem cell-derived atrial cardiomyocytes were differentiated with unfiltered retinoic acid and cultured in atrial engineered heart tissue. Force and action potential were measured in atrial engineered heart tissues. Single human induced pluripotent stem cell-derived atrial cardiomyocytes were isolated from atrial engineered heart tissue for ion current measurements.RESULTS: PITX2-/- atrial engineered heart tissue beats slightly slower than isogenic control without irregularity. Force was lower in PITX2-/- than in isogenic control (0.053±0.015 versus 0.131±0.017 mN, n=28/3 versus n=28/4, PITX2-/- versus isogenic control; P<0.0001), accompanied by lower expression of CACNA1C and lower L-type Ca2+ current density. Early repolarization was weaker (action potential duration at 20% repolarization; 45.5±13.2 versus 8.6±5.3 ms, n=18/3 versus n=12/4, PITX2-/- versus isogenic control; P<0.0001), and maximum diastolic potential was more negative (-78.3±3.1 versus -69.7±0.6 mV, n=18/3 versus n=12/4, PITX2-/- versus isogenic control; P=0.001), despite normal inward rectifier currents (both IK1 and IK,ACh) and carbachol-induced shortening of action potential duration.CONCLUSIONS: Complete PITX2 deficiency in human induced pluripotent stem cell-derived atrial cardiomyocytes recapitulates some findings of electrical remodeling of atrial fibrillation in the absence of fast beating, indicating that these abnormalities could be primary consequences of lower PITX2 levels.",
author = "Carl Schulz and Lemoine, {Marc D} and Giulia Mearini and Jussi Koivum{\"a}ki and Jascha Sani and Edzard Schwedhelm and Paulus Kirchhof and Amer Ghalawinji and Monika Stoll and Arne Hansen and Thomas Eschenhagen and Torsten Christ",
note = "doi: 10.1161/CIRCEP.122.011602",
year = "2023",
month = mar,
doi = "10.1161/CIRCEP.122.011602",
language = "English",
volume = "16",
pages = "e011602",
journal = "CIRC-ARRHYTHMIA ELEC",
issn = "1941-3149",
publisher = "Lippincott Williams and Wilkins",
number = "3",

}

RIS

TY - JOUR

T1 - PITX2 Knockout Induces Key Findings of Electrical Remodeling as Seen in Persistent Atrial Fibrillation

AU - Schulz, Carl

AU - Lemoine, Marc D

AU - Mearini, Giulia

AU - Koivumäki, Jussi

AU - Sani, Jascha

AU - Schwedhelm, Edzard

AU - Kirchhof, Paulus

AU - Ghalawinji, Amer

AU - Stoll, Monika

AU - Hansen, Arne

AU - Eschenhagen, Thomas

AU - Christ, Torsten

N1 - doi: 10.1161/CIRCEP.122.011602

PY - 2023/3

Y1 - 2023/3

N2 - BACKGROUND: Electrical remodeling in human persistent atrial fibrillation is believed to result from rapid electrical activation of the atria, but underlying genetic causes may contribute. Indeed, common gene variants in an enhancer region close to PITX2 (paired-like homeodomain transcription factor 2) are strongly associated with atrial fibrillation, but the mechanism behind this association remains unknown. This study evaluated the consequences of PITX2 deletion (PITX2-/-) in human induced pluripotent stem cell-derived atrial cardiomyocytes.METHODS: CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat-associated 9) was used to delete PITX2 in a healthy human iPSC line that served as isogenic control. Human induced pluripotent stem cell-derived atrial cardiomyocytes were differentiated with unfiltered retinoic acid and cultured in atrial engineered heart tissue. Force and action potential were measured in atrial engineered heart tissues. Single human induced pluripotent stem cell-derived atrial cardiomyocytes were isolated from atrial engineered heart tissue for ion current measurements.RESULTS: PITX2-/- atrial engineered heart tissue beats slightly slower than isogenic control without irregularity. Force was lower in PITX2-/- than in isogenic control (0.053±0.015 versus 0.131±0.017 mN, n=28/3 versus n=28/4, PITX2-/- versus isogenic control; P<0.0001), accompanied by lower expression of CACNA1C and lower L-type Ca2+ current density. Early repolarization was weaker (action potential duration at 20% repolarization; 45.5±13.2 versus 8.6±5.3 ms, n=18/3 versus n=12/4, PITX2-/- versus isogenic control; P<0.0001), and maximum diastolic potential was more negative (-78.3±3.1 versus -69.7±0.6 mV, n=18/3 versus n=12/4, PITX2-/- versus isogenic control; P=0.001), despite normal inward rectifier currents (both IK1 and IK,ACh) and carbachol-induced shortening of action potential duration.CONCLUSIONS: Complete PITX2 deficiency in human induced pluripotent stem cell-derived atrial cardiomyocytes recapitulates some findings of electrical remodeling of atrial fibrillation in the absence of fast beating, indicating that these abnormalities could be primary consequences of lower PITX2 levels.

AB - BACKGROUND: Electrical remodeling in human persistent atrial fibrillation is believed to result from rapid electrical activation of the atria, but underlying genetic causes may contribute. Indeed, common gene variants in an enhancer region close to PITX2 (paired-like homeodomain transcription factor 2) are strongly associated with atrial fibrillation, but the mechanism behind this association remains unknown. This study evaluated the consequences of PITX2 deletion (PITX2-/-) in human induced pluripotent stem cell-derived atrial cardiomyocytes.METHODS: CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat-associated 9) was used to delete PITX2 in a healthy human iPSC line that served as isogenic control. Human induced pluripotent stem cell-derived atrial cardiomyocytes were differentiated with unfiltered retinoic acid and cultured in atrial engineered heart tissue. Force and action potential were measured in atrial engineered heart tissues. Single human induced pluripotent stem cell-derived atrial cardiomyocytes were isolated from atrial engineered heart tissue for ion current measurements.RESULTS: PITX2-/- atrial engineered heart tissue beats slightly slower than isogenic control without irregularity. Force was lower in PITX2-/- than in isogenic control (0.053±0.015 versus 0.131±0.017 mN, n=28/3 versus n=28/4, PITX2-/- versus isogenic control; P<0.0001), accompanied by lower expression of CACNA1C and lower L-type Ca2+ current density. Early repolarization was weaker (action potential duration at 20% repolarization; 45.5±13.2 versus 8.6±5.3 ms, n=18/3 versus n=12/4, PITX2-/- versus isogenic control; P<0.0001), and maximum diastolic potential was more negative (-78.3±3.1 versus -69.7±0.6 mV, n=18/3 versus n=12/4, PITX2-/- versus isogenic control; P=0.001), despite normal inward rectifier currents (both IK1 and IK,ACh) and carbachol-induced shortening of action potential duration.CONCLUSIONS: Complete PITX2 deficiency in human induced pluripotent stem cell-derived atrial cardiomyocytes recapitulates some findings of electrical remodeling of atrial fibrillation in the absence of fast beating, indicating that these abnormalities could be primary consequences of lower PITX2 levels.

U2 - 10.1161/CIRCEP.122.011602

DO - 10.1161/CIRCEP.122.011602

M3 - SCORING: Journal article

C2 - 36763906

VL - 16

SP - e011602

JO - CIRC-ARRHYTHMIA ELEC

JF - CIRC-ARRHYTHMIA ELEC

SN - 1941-3149

IS - 3

ER -