Metformin Intervention Prevents Cardiac Dysfunction in a murine model of Adult Congenital Heart Disease

Abstract

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.

Metformin in patients with and without diabetes: a paradigm shift in cardiovascular disease management

“…Evidence backing the pleiotropic effects of metformin in reducing CVD-related events necessitates further exploration with regard to the mechanism of drug action in various tissue compartments. The recent evidence pointing towards its therapeutic benefit in heart failure with persevered ejection fraction in clinical and preclinical studies underlines the need to explore the breadth of the pleiotropic systemic effects of metformin [70]. Recent study also reported that metformin offers therapeutic benefit during heart failure with preserved ejection fraction by lowering titin-based passive stiffness in mice model [71], is associated with improved survival and decreased incidence of adverse cardiac events in peripheral arterial disease patients [72] and with a lower below-the-knee arterial calcification score [73].…”

“…Recent study also reported that metformin offers therapeutic benefit during heart failure with preserved ejection fraction by lowering titin-based passive stiffness in mice model [71], is associated with improved survival and decreased incidence of adverse cardiac events in peripheral arterial disease patients [72] and with a lower below-the-knee arterial calcification score [73]. Moreover, metformin is able to prevent cardiac dysfunction in a murine model of adult congenital heart disease [70]. A proper understanding of these pleotropic effects will allow us to tailor the dose of the drug and remain abreast about its potential side effects in patients receiving them.…”

Metformin and the heart: Update on mechanisms of cardiovascular protection with special reference to comorbid type 2 diabetes and heart failure

“…reduced the development of HF in spontaneously hypertensive, insulinresistant rats [118], prevented progression of cardiac dysfunction in a model of adult congenital heart disease [119], and improved myocardial function in a rat model of post-MI HF [120]. Finally, changes in the gut microbiome that may be specific to the pathogenesis of HF (including HFpEF) have been described during treatment with metformin, especially involving bacteria that produce short chain fatty acids [108,109].…”