Abstract 275: Modulation of Energy Metabolism by Metformin Prevents Diet Induced Cardiac Dysfunction in a Mouse Model of Adult Congenital Heart Disease

Abstract

Objective: Congenital heart disease (CHD) is the most frequent birth defect worldwide. Improved surgical and treatment interventions have led to a significant increase in the number of adult patients with CHD, now referred to as ACHD. 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 and metabolic intervention studies by metformin. 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. 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 lead to improved liver function in both control and ACHD mice and prevented the development of heart dysfunction in ACHD predisposed mice. Metabolomic analysis of these animals revealed that metformin leads to an ACHD specific increase in metabolites associated with fat acid oxidation, likely reflecting upregulation of FAO. 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 current hypothesis is that metformin treatment leads to normalization of energy use by ACHD heart by enhancing FAO and we are currently performing CRISPR/Cas9 mediated deletion of key metabolic genes to characterize their role in ACHD. This data indicates that 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.