Cardiac phenotype in familial partial lipodystrophy.
LMNA
arrhythmia
atrial fibrillation
conduction disease
lipodystrophy
Journal
Clinical endocrinology
ISSN: 1365-2265
Titre abrégé: Clin Endocrinol (Oxf)
Pays: England
ID NLM: 0346653
Informations de publication
Date de publication:
06 2021
06 2021
Historique:
revised:
21
01
2021
received:
06
10
2020
accepted:
22
01
2021
pubmed:
28
1
2021
medline:
30
9
2021
entrez:
27
1
2021
Statut:
ppublish
Résumé
LMNA variants have been previously associated with cardiac abnormalities independent of lipodystrophy. We aimed to assess cardiac impact of familial partial lipodystrophy (FPLD) to understand the role of laminopathy in cardiac manifestations. Retrospective cohort study. Clinical data from 122 patients (age range: 13-77, 101 females) with FPLD were analysed. Mature human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from a patient with an LMNA variant were studied as proof-of-concept for future studies. Subjects with LMNA variants had a higher prevalence of overall cardiac events than others. The likelihood of having an arrhythmia was significantly higher in patients with LMNA variants (OR: 3.77, 95% CI: 1.45-9.83). These patients were at higher risk for atrial fibrillation or flutter (OR: 5.78, 95% CI: 1.04-32.16). The time to the first arrhythmia was significantly shorter in the LMNA group, with a higher HR of 3.52 (95% CI: 1.34-9.27). Non-codon 482 LMNA variants were more likely to be associated with cardiac events (vs. 482 LMNA: OR: 4.74, 95% CI: 1.41-15.98 for arrhythmia; OR: 17.67, 95% CI: 2.45-127.68 for atrial fibrillation or flutter; OR: 5.71, 95% CI: 1.37-23.76 for conduction disease). LMNA mutant hiPSC-CMs showed a higher frequency of spontaneous activity and shorter action potential duration. Functional syncytia of hiPSC-CMs displayed several rhythm alterations such as early afterdepolarizations, spontaneous quiescence and spontaneous tachyarrhythmia, and significantly slower recovery in chronotropic changes induced by isoproterenol exposure. Our results highlight the need for vigilant cardiac monitoring in FPLD, especially in patients with LMNA variants who have an increased risk of developing cardiac arrhythmias. In addition, hiPSC-CMs can be studied to understand the basic mechanisms for the arrhythmias in patients with lipodystrophy to understand the impact of specific mutations.
Identifiants
pubmed: 33502018
doi: 10.1111/cen.14426
pmc: PMC9003538
mid: NIHMS1787972
doi:
Substances chimiques
Lamin Type A
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1043-1053Subventions
Organisme : NCATS NIH HHS
ID : UL1 TR000433
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK125513
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK088114
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK089503
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK034933
Pays : United States
Organisme : NCATS NIH HHS
ID : TL1 TR000435
Pays : United States
Informations de copyright
© 2021 John Wiley & Sons Ltd.
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