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

Abstract

ObjectiveCongenital 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.MethodsWe 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.ResultsACHD 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.ConclusionsThis 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.

Metformin use and cardiovascular outcomes after acute myocardial infarction in patients with type 2 diabetes: a cohort study

“…Despite these findings, metformin treatment has been shown to be advantageous in several pre-clinical and clinical studies of various cardiovascular diseases [44–47]. Beneficial effects on mortality have been reported in patients started on metformin after AMI, independent of its hypoglycaemic actions [31].…”

Cardiovascular Protection by Metformin: Latest Advances in Basic and Clinical Research

“…Metformin, at clinically relevant doses, has been shown to exert beneficial effects in various forms of myocardial injury, including myocardial ischemic injury [18], diabetic cardiomyopathy [19], cardiotoxicity [20], and ventricular dysfunction/HF [21, 22]. While activation of AMPK and the consequent suppression of inflammation and oxidative stress have been shown to be a primary mechanism by which metformin protects against myocardial pathologies [4, 5], detailed signaling cascades only begin to be delineated recently.…”