Metformin Intervention Prevents Cardiac Dysfunction in a Murine Model of Adult Congenital Heart Disease

Congenital heart disease (CHD) is the most frequent birth defect worldwide and the number of adult patients with CHD, now referred to as ACHD, is increasing. 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. Using a genetic mouse model of ACHD we showed that ACHD mice placed under metabolic stress (high fat diet) displayed decreased heart function. Comprehensive physiological, biochemical and molecular analysis showed that ACHD hearts exhibited early changes in energy metabolism that preceded cardiac dysfunction. Restoration of metabolic balance by metformin prevented the development of heart dysfunction in ACHD 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 and may be an important avenue for intervention in ACHD.