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

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


Patients with adult congenital heart disease (ACHD) have a higher risk of developing progressive cardiac dysfunction. Not much is currently known about how ACHD predisposes patients to heart failure upon metabolic stress. Using genetically predisposed mice and diet as a cardiac stressor, Wilmanns, Pandey, and colleagues describe a preexisting imbalance in the metabolic state of ACHD hearts. The interaction between genetic and metabolic factors ultimately leads to the clinical presentation of heart failure in ACHD. Modulation of energy utilization by Metformin, a drug widely used to treat type 2 diabetes, prevents cardiac dysfunction in the ACHD/obesity model and could therefore be considered a preventive intervention for heart failure in ACHD.

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.