Metformin intervention prevents cardiac dysfunction in a murine model of adult congenital heart disease.
Adult congenital heart disease
Metabolism
Metformin
Obesity
Journal
Molecular metabolism
ISSN: 2212-8778
Titre abrégé: Mol Metab
Pays: Germany
ID NLM: 101605730
Informations de publication
Date de publication:
02 2019
02 2019
Historique:
received:
21
08
2018
revised:
06
11
2018
accepted:
10
11
2018
pubmed:
30
11
2018
medline:
26
11
2019
entrez:
29
11
2018
Statut:
ppublish
Résumé
Congenital heart disease (CHD) is the most frequent birth defect worldwide. The number of adult patients with CHD, now referred to as ACHD, is increasing with improved surgical and treatment interventions. However the mechanisms whereby ACHD predisposes patients to heart dysfunction are still unclear. ACHD is strongly associated with metabolic syndrome, but how ACHD interacts with poor modern lifestyle choices and other comorbidities, such as hypertension, obesity, and diabetes, is mostly unknown. We used a newly characterized mouse genetic model of ACHD to investigate the consequences and the mechanisms associated with combined obesity and ACHD predisposition. Metformin intervention was used to further evaluate potential therapeutic amelioration of cardiac dysfunction in this model. ACHD mice placed under metabolic stress (high fat diet) displayed decreased left ventricular ejection fraction. Comprehensive physiological, biochemical, and molecular analysis showed that ACHD hearts exhibited early changes in energy metabolism with increased glucose dependence as main cardiac energy source. These changes preceded cardiac dysfunction mediated by exposure to high fat diet and were associated with increased disease severity. Restoration of metabolic balance by metformin administration prevented the development of heart dysfunction in ACHD predisposed mice. This study reveals that early metabolic impairment reinforces heart dysfunction in ACHD predisposed individuals and diet or pharmacological interventions can be used to modulate heart function and attenuate heart failure. Our study suggests that interactions between genetic and metabolic disturbances ultimately lead to the clinical presentation of heart failure in patients with ACHD. Early manipulation of energy metabolism may be an important avenue for intervention in ACHD patients to prevent or delay onset of heart failure and secondary comorbidities. These interactions raise the prospect for a translational reassessment of ACHD presentation in the clinic.
Identifiants
pubmed: 30482476
pii: S2212-8778(18)30836-6
doi: 10.1016/j.molmet.2018.11.002
pmc: PMC6358551
pii:
doi:
Substances chimiques
Hypoglycemic Agents
0
Metformin
9100L32L2N
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
102-114Informations de copyright
Copyright © 2018 The Authors. Published by Elsevier GmbH.. All rights reserved.
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