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

doi:10.1016/j.molmet.2018.11.002

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

Mol Metab. 2019 Feb:20:102-114. doi: 10.1016/j.molmet.2018.11.002. Epub 2018 Nov 15.

Authors

Julia C Wilmanns¹, Raghav Pandey², Olivia Hon², Anjana Chandran³, Jan M Schilling⁴, Elvira Forte², Qizhu Wu⁵, Gael Cagnone⁶, Preeti Bais², Vivek Philip², David Coleman², Heidi Kocalis², Stuart K Archer⁷, James T Pearson⁸, Mirana Ramialison⁹, Joerg Heineke¹⁰, Hemal H Patel⁴, Nadia A Rosenthal¹¹, Milena B Furtado¹², Mauro W Costa¹³

Affiliations

¹ Australian Regenerative Medicine Institute, Monash University, Australia; Department of Cardiology and Angiology, Experimental Cardiology, Hannover Medical School, Germany.
² The Jackson Laboratory, USA.
³ Australian Regenerative Medicine Institute, Monash University, Australia.
⁴ VA San Diego Healthcare System and Department of Anesthesiology, University of California San Diego, USA.
⁵ Monash Biomedical Imaging, Monash University, Australia.
⁶ Department of Pharmacology, Research Center of CHU Sainte-Justine, Canada.
⁷ Monash Bioinformatics Platform, Monash University, Australia; Biomedicine Discovery Institute, Faculty of Medicine, Nursing and Health Sciences, Monash University, Australia.
⁸ Monash Biomedical Imaging, Monash University, Australia; Department of Physiology, Monash University, Australia; National Cerebral & Cardiovascular Center, Suita 565-8565, Japan.
⁹ Australian Regenerative Medicine Institute, Monash University, Australia; Systems Biology Institute, Australia.
¹⁰ Department of Cardiology and Angiology, Experimental Cardiology, Hannover Medical School, Germany.
¹¹ The Jackson Laboratory, USA; Australian Regenerative Medicine Institute, Monash University, Australia; National Heart and Lung Institute, Imperial College London, W12 0NN, UK.
¹² The Jackson Laboratory, USA; Australian Regenerative Medicine Institute, Monash University, Australia.
¹³ The Jackson Laboratory, USA; Australian Regenerative Medicine Institute, Monash University, Australia. Electronic address: mauro.costa@jax.org.

Abstract

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.

Keywords: Adult congenital heart disease; Metabolism; Metformin; Obesity.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cardiac Output
Energy Metabolism
Heart Defects, Congenital / complications*
Hypoglycemic Agents / administration & dosage
Hypoglycemic Agents / therapeutic use*
Male
Metabolic Syndrome / complications
Metabolic Syndrome / drug therapy*
Metformin / administration & dosage
Metformin / therapeutic use*
Mice
Mice, Inbred C57BL
Ventricular Dysfunction, Left / drug therapy
Ventricular Dysfunction, Left / etiology
Ventricular Dysfunction, Left / prevention & control*

Substances

Hypoglycemic Agents
Metformin