Human iPSC modelling of a familial form of atrial fibrillation reveals a gain of function of If and ICaL in patient-derived cardiomyocytes.
Action Potentials
/ drug effects
Anti-Arrhythmia Agents
/ therapeutic use
Atrial Fibrillation
/ drug therapy
Calcium Channels, L-Type
/ genetics
Case-Control Studies
Cell Differentiation
Cells, Cultured
Drug Resistance
/ genetics
Genetic Predisposition to Disease
Heart Rate
/ drug effects
Humans
Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
/ genetics
Induced Pluripotent Stem Cells
/ metabolism
Middle Aged
Mutation
Myocytes, Cardiac
/ metabolism
Siblings
Exome Sequencing
Arrhythmias
Atrial fibrillation
Ion channels
Precision medicine
iPSC-derived cardiomyocytes
Journal
Cardiovascular research
ISSN: 1755-3245
Titre abrégé: Cardiovasc Res
Pays: England
ID NLM: 0077427
Informations de publication
Date de publication:
01 05 2020
01 05 2020
Historique:
received:
15
11
2018
revised:
19
07
2019
accepted:
26
08
2019
pubmed:
11
9
2019
medline:
9
2
2021
entrez:
11
9
2019
Statut:
ppublish
Résumé
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). 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. 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.
Identifiants
pubmed: 31504264
pii: 5555813
doi: 10.1093/cvr/cvz217
pmc: PMC7177512
doi:
Substances chimiques
Anti-Arrhythmia Agents
0
Calcium Channels, L-Type
0
Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1147-1160Commentaires et corrections
Type : CommentIn
Informations de copyright
© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.
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