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Human iPSC modelling of a familial form of atrial fibrillation reveals a gain of function of If and ICaL in patient-derived cardiomyocytes

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Benzoni, P, Campostrini, G, Landi, S, Bertini, V, Marchina, E, Iascone, M, Ahlberg, G, Olesen, MS, Crescini, E, Mora, C, Bisleri, G, Muneretto, C, Ronca, R, Presta, M, Poliani, PL, Piovani, G, Verardi, R, Pasquale, ED, Consiglio, A, Raya, A, Torre, E, Lodrini, AM, Milanesi, R, Rocchetti, M, Baruscotti, M, DiFrancesco, D, Memo, M, Barbuti, A & Dell'Era, P 2020, 'Human iPSC modelling of a familial form of atrial fibrillation reveals a gain of function of If and ICaL in patient-derived cardiomyocytes' Cardiovascular Research, bind 116, nr. 6, s. 1147-1160. https://doi.org/10.1093/cvr/cvz217

APA

CBE

Benzoni P, Campostrini G, Landi S, Bertini V, Marchina E, Iascone M, Ahlberg G, Olesen MS, Crescini E, Mora C, Bisleri G, Muneretto C, Ronca R, Presta M, Poliani PL, Piovani G, Verardi R, Pasquale ED, Consiglio A, Raya A, Torre E, Lodrini AM, Milanesi R, Rocchetti M, Baruscotti M, DiFrancesco D, Memo M, Barbuti A, Dell'Era P. 2020. Human iPSC modelling of a familial form of atrial fibrillation reveals a gain of function of If and ICaL in patient-derived cardiomyocytes. Cardiovascular Research. 116(6):1147-1160. https://doi.org/10.1093/cvr/cvz217

MLA

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Author

Benzoni, Patrizia ; Campostrini, Giulia ; Landi, Sara ; Bertini, Valeria ; Marchina, Eleonora ; Iascone, Maria ; Ahlberg, Gustav ; Olesen, Morten Salling ; Crescini, Elisabetta ; Mora, Cristina ; Bisleri, Gianluigi ; Muneretto, Claudio ; Ronca, Roberto ; Presta, Marco ; Poliani, Pier Luigi ; Piovani, Giovanna ; Verardi, Rosanna ; Pasquale, Elisa Di ; Consiglio, Antonella ; Raya, Angel ; Torre, Eleonora ; Lodrini, Alessandra Maria ; Milanesi, Raffaella ; Rocchetti, Marcella ; Baruscotti, Mirko ; DiFrancesco, Dario ; Memo, Maurizio ; Barbuti, Andrea ; Dell'Era, Patrizia. / Human iPSC modelling of a familial form of atrial fibrillation reveals a gain of function of If and ICaL in patient-derived cardiomyocytes. I: Cardiovascular Research. 2020 ; Bind 116, Nr. 6. s. 1147-1160.

Bibtex

@article{274ca026f03f4332bc0a627278e469fa,
title = "Human iPSC modelling of a familial form of atrial fibrillation reveals a gain of function of If and ICaL in patient-derived cardiomyocytes",
abstract = "AIMS: Atrial fibrillation (AF) is the most common type of cardiac arrhythmias, whose incidence is likely to increase with the aging of the population. It is considered a progressive condition, frequently observed as a complication of other cardiovascular disorders. However, recent genetic studies revealed the presence of several mutations and variants linked to AF, findings that define AF as a multifactorial disease. Due to the complex genetics and paucity of models, molecular mechanisms underlying the initiation of AF are still poorly understood. Here we investigate the pathophysiological mechanisms of a familial form of AF, with particular attention to the identification of putative triggering cellular mechanisms, using patient's derived cardiomyocytes (CMs) differentiated from induced pluripotent stem cells (iPSCs).METHODS AND RESULTS: Here we report the clinical case of three siblings with untreatable persistent AF whose whole-exome sequence analysis revealed several mutated genes. To understand the pathophysiology of this multifactorial form of AF we generated three iPSC clones from two of these patients and differentiated these cells towards the cardiac lineage. Electrophysiological characterization of patient-derived CMs (AF-CMs) revealed that they have higher beating rates compared to control (CTRL)-CMs. The analysis showed an increased contribution of the If and ICaL currents. No differences were observed in the repolarizing current IKr and in the sarcoplasmic reticulum calcium handling. Paced AF-CMs presented significantly prolonged action potentials and, under stressful conditions, generated both delayed after-depolarizations of bigger amplitude and more ectopic beats than CTRL cells.CONCLUSIONS: Our results demonstrate that the common genetic background of the patients induces functional alterations of If and ICaL currents leading to a cardiac substrate more prone to develop arrhythmias under demanding conditions. To our knowledge this is the first report that, using patient-derived CMs differentiated from iPSC, suggests a plausible cellular mechanism underlying this complex familial form of AF.",
author = "Patrizia Benzoni and Giulia Campostrini and Sara Landi and Valeria Bertini and Eleonora Marchina and Maria Iascone and Gustav Ahlberg and Olesen, {Morten Salling} and Elisabetta Crescini and Cristina Mora and Gianluigi Bisleri and Claudio Muneretto and Roberto Ronca and Marco Presta and Poliani, {Pier Luigi} and Giovanna Piovani and Rosanna Verardi and Pasquale, {Elisa Di} and Antonella Consiglio and Angel Raya and Eleonora Torre and Lodrini, {Alessandra Maria} and Raffaella Milanesi and Marcella Rocchetti and Mirko Baruscotti and Dario DiFrancesco and Maurizio Memo and Andrea Barbuti and Patrizia Dell'Era",
note = "{\circledC} The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.",
year = "2020",
month = "5",
day = "1",
doi = "10.1093/cvr/cvz217",
language = "English",
volume = "116",
pages = "1147--1160",
journal = "Cardiovascular Research",
issn = "0008-6363",
publisher = "Oxford University Press",
number = "6",

}

RIS

TY - JOUR

T1 - Human iPSC modelling of a familial form of atrial fibrillation reveals a gain of function of If and ICaL in patient-derived cardiomyocytes

AU - Benzoni, Patrizia

AU - Campostrini, Giulia

AU - Landi, Sara

AU - Bertini, Valeria

AU - Marchina, Eleonora

AU - Iascone, Maria

AU - Ahlberg, Gustav

AU - Olesen, Morten Salling

AU - Crescini, Elisabetta

AU - Mora, Cristina

AU - Bisleri, Gianluigi

AU - Muneretto, Claudio

AU - Ronca, Roberto

AU - Presta, Marco

AU - Poliani, Pier Luigi

AU - Piovani, Giovanna

AU - Verardi, Rosanna

AU - Pasquale, Elisa Di

AU - Consiglio, Antonella

AU - Raya, Angel

AU - Torre, Eleonora

AU - Lodrini, Alessandra Maria

AU - Milanesi, Raffaella

AU - Rocchetti, Marcella

AU - Baruscotti, Mirko

AU - DiFrancesco, Dario

AU - Memo, Maurizio

AU - Barbuti, Andrea

AU - Dell'Era, Patrizia

N1 - © The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.

PY - 2020/5/1

Y1 - 2020/5/1

N2 - AIMS: Atrial fibrillation (AF) is the most common type of cardiac arrhythmias, whose incidence is likely to increase with the aging of the population. It is considered a progressive condition, frequently observed as a complication of other cardiovascular disorders. However, recent genetic studies revealed the presence of several mutations and variants linked to AF, findings that define AF as a multifactorial disease. Due to the complex genetics and paucity of models, molecular mechanisms underlying the initiation of AF are still poorly understood. Here we investigate the pathophysiological mechanisms of a familial form of AF, with particular attention to the identification of putative triggering cellular mechanisms, using patient's derived cardiomyocytes (CMs) differentiated from induced pluripotent stem cells (iPSCs).METHODS AND RESULTS: Here we report the clinical case of three siblings with untreatable persistent AF whose whole-exome sequence analysis revealed several mutated genes. To understand the pathophysiology of this multifactorial form of AF we generated three iPSC clones from two of these patients and differentiated these cells towards the cardiac lineage. Electrophysiological characterization of patient-derived CMs (AF-CMs) revealed that they have higher beating rates compared to control (CTRL)-CMs. The analysis showed an increased contribution of the If and ICaL currents. No differences were observed in the repolarizing current IKr and in the sarcoplasmic reticulum calcium handling. Paced AF-CMs presented significantly prolonged action potentials and, under stressful conditions, generated both delayed after-depolarizations of bigger amplitude and more ectopic beats than CTRL cells.CONCLUSIONS: Our results demonstrate that the common genetic background of the patients induces functional alterations of If and ICaL currents leading to a cardiac substrate more prone to develop arrhythmias under demanding conditions. To our knowledge this is the first report that, using patient-derived CMs differentiated from iPSC, suggests a plausible cellular mechanism underlying this complex familial form of AF.

AB - AIMS: Atrial fibrillation (AF) is the most common type of cardiac arrhythmias, whose incidence is likely to increase with the aging of the population. It is considered a progressive condition, frequently observed as a complication of other cardiovascular disorders. However, recent genetic studies revealed the presence of several mutations and variants linked to AF, findings that define AF as a multifactorial disease. Due to the complex genetics and paucity of models, molecular mechanisms underlying the initiation of AF are still poorly understood. Here we investigate the pathophysiological mechanisms of a familial form of AF, with particular attention to the identification of putative triggering cellular mechanisms, using patient's derived cardiomyocytes (CMs) differentiated from induced pluripotent stem cells (iPSCs).METHODS AND RESULTS: Here we report the clinical case of three siblings with untreatable persistent AF whose whole-exome sequence analysis revealed several mutated genes. To understand the pathophysiology of this multifactorial form of AF we generated three iPSC clones from two of these patients and differentiated these cells towards the cardiac lineage. Electrophysiological characterization of patient-derived CMs (AF-CMs) revealed that they have higher beating rates compared to control (CTRL)-CMs. The analysis showed an increased contribution of the If and ICaL currents. No differences were observed in the repolarizing current IKr and in the sarcoplasmic reticulum calcium handling. Paced AF-CMs presented significantly prolonged action potentials and, under stressful conditions, generated both delayed after-depolarizations of bigger amplitude and more ectopic beats than CTRL cells.CONCLUSIONS: Our results demonstrate that the common genetic background of the patients induces functional alterations of If and ICaL currents leading to a cardiac substrate more prone to develop arrhythmias under demanding conditions. To our knowledge this is the first report that, using patient-derived CMs differentiated from iPSC, suggests a plausible cellular mechanism underlying this complex familial form of AF.

U2 - 10.1093/cvr/cvz217

DO - 10.1093/cvr/cvz217

M3 - Journal article

VL - 116

SP - 1147

EP - 1160

JO - Cardiovascular Research

JF - Cardiovascular Research

SN - 0008-6363

IS - 6

ER -

ID: 59172720