Metformin intervention prevents cardiac dysfunction in a murine model of adult congenital heart disease.

Julia C Wilmanns
Raghav Pandey, The Jackson Laboratory
Olivia Hon, The Jackson Laboratory
Anjana Chandran
Jan M Schilling
Elvira Forte, The Jackson Laboratory
Qizhu Wu
Gael Cagnone
Preeti Bais, The Jackson Laboratory
Vivek M. Philip, The Jackson Laboratory
David Coleman, The Jackson Laboratory
Heidi Kocalis, The Jackson Laboratory
Stuart K Archer
James T Pearson
Mirana Ramialison
Joerg Heineke
Hemal H Patel
Nadia Rosenthal, The Jackson Laboratory
Milena B Furtado, The Jackson Laboratory
Mauro W Costa, The Jackson Laboratory

We thank Pete A. Williams for providing mitochondrial antibodies and advice, and the In Vivo Physiology, histology and microscopy cores of the Jackson Laboratory for the generation of all metabolic and physiological data.

Abstract

OBJECTIVE: 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.

METHODS: 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.

RESULTS: 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.

CONCLUSIONS: 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.