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

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Pages (from-to)102-114
Number of pages13
JournalMolecular Metabolism
Volume20
DOIs
Publication statusPublished - Feb 2019

Keywords

  • Adult congenital heart disease
  • Metabolism
  • Metformin
  • Obesity

Cite this

Wilmanns, Julia C. ; Pandey, Raghav ; Hon, Olivia ; Chandran, Anjana ; Schilling, Jan M. ; Forte, Elvira ; Wu, Qizhu ; Cagnone, Gael ; Bais, Preeti ; Philip, Vivek ; Coleman, David ; Kocalis, Heidi ; Archer, Stuart K. ; Pearson, James T. ; Ramialison, Mirana ; Heineke, Joerg ; Patel, Hemal H. ; Rosenthal, Nadia A. ; Furtado, Milena B. ; Costa, Mauro W. / Metformin intervention prevents cardiac dysfunction in a murine model of adult congenital heart disease. In: Molecular Metabolism. 2019 ; Vol. 20. pp. 102-114.
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title = "Metformin intervention prevents cardiac dysfunction in a murine model of adult congenital heart disease",
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",
author = "Wilmanns, {Julia C.} and Raghav Pandey and Olivia Hon and Anjana Chandran and Schilling, {Jan M.} and Elvira Forte and Qizhu Wu and Gael Cagnone and Preeti Bais and Vivek Philip and David Coleman and Heidi Kocalis and Archer, {Stuart K.} and Pearson, {James T.} and Mirana Ramialison and Joerg Heineke and Patel, {Hemal H.} and Rosenthal, {Nadia A.} and Furtado, {Milena B.} and Costa, {Mauro W.}",
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Wilmanns, JC, Pandey, R, Hon, O, Chandran, A, Schilling, JM, Forte, E, Wu, Q, Cagnone, G, Bais, P, Philip, V, Coleman, D, Kocalis, H, Archer, SK, Pearson, JT, Ramialison, M, Heineke, J, Patel, HH, Rosenthal, NA, Furtado, MB & Costa, MW 2019, 'Metformin intervention prevents cardiac dysfunction in a murine model of adult congenital heart disease', Molecular Metabolism, vol. 20, pp. 102-114. https://doi.org/10.1016/j.molmet.2018.11.002

Metformin intervention prevents cardiac dysfunction in a murine model of adult congenital heart disease. / Wilmanns, Julia C.; Pandey, Raghav; Hon, Olivia; Chandran, Anjana; Schilling, Jan M.; Forte, Elvira; Wu, Qizhu; Cagnone, Gael; Bais, Preeti; Philip, Vivek; Coleman, David; Kocalis, Heidi; Archer, Stuart K.; Pearson, James T.; Ramialison, Mirana; Heineke, Joerg; Patel, Hemal H.; Rosenthal, Nadia A.; Furtado, Milena B.; Costa, Mauro W.

In: Molecular Metabolism, Vol. 20, 02.2019, p. 102-114.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Metformin intervention prevents cardiac dysfunction in a murine model of adult congenital heart disease

AU - Wilmanns, Julia C.

AU - Pandey, Raghav

AU - Hon, Olivia

AU - Chandran, Anjana

AU - Schilling, Jan M.

AU - Forte, Elvira

AU - Wu, Qizhu

AU - Cagnone, Gael

AU - Bais, Preeti

AU - Philip, Vivek

AU - Coleman, David

AU - Kocalis, Heidi

AU - Archer, Stuart K.

AU - Pearson, James T.

AU - Ramialison, Mirana

AU - Heineke, Joerg

AU - Patel, Hemal H.

AU - Rosenthal, Nadia A.

AU - Furtado, Milena B.

AU - Costa, Mauro W.

PY - 2019/2

Y1 - 2019/2

N2 - 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.

AB - 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.

KW - Adult congenital heart disease

KW - Metabolism

KW - Metformin

KW - Obesity

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U2 - 10.1016/j.molmet.2018.11.002

DO - 10.1016/j.molmet.2018.11.002

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JO - Molecular Metabolism

JF - Molecular Metabolism

SN - 2212-8778

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