Diabetologia

, Volume 60, Issue 8, pp 1550–1558 | Cite as

Metformin prevents ischaemic ventricular fibrillation in metabolically normal pigs

  • Li Lu
  • Shuyu Ye
  • Rebecca L. Scalzo
  • Jane E. B. Reusch
  • Clifford R. Greyson
  • Gregory G. Schwartz
Article

Abstract

Aims/hypothesis

Metformin is the drug most often used to treat type 2 diabetes. Evidence suggests that metformin may reduce mortality of individuals with type 2 diabetes, but the mechanism of such an effect is unknown and outcomes of metformin treatment in people without diabetes have not been determined. If metformin favourably affected mortality of non-diabetic individuals, it might have even broader therapeutic utility. We evaluated the effect of metformin on myocardial energetics and ischaemic ventricular fibrillation (VF) in metabolically normal pigs.

Methods

Domestic farm pigs were treated with metformin (30 mg kg−1 day−1 orally for 2–3 weeks; n = 36) or received no treatment (n = 37). Under anaesthesia, pigs underwent up to 90 min low-flow regional myocardial ischaemia followed by 45 min of reperfusion. Pigs were monitored for arrhythmia, monophasic action potential morphology, haemodynamics and myocardial substrate utilisation, AMP-activated protein kinase (AMPK) phosphorylation activity and ATP concentration.

Results

Death due to VF occurred in 12% of pigs treated with metformin compared with 50% of untreated controls (p = 0.03). The anti-fibrillatory effect of metformin was associated with attenuation of action potential shortening in ischaemic myocardium (p = 0.02) and attenuation of the difference in action potential duration between ischaemic and non-ischaemic regions (p < 0.001) compared with untreated controls. Metformin had no effect on myocardial contractile function, oxygen consumption, or glucose or lactate utilisation. During ischaemia, however, metformin treatment amplified the activation of AMPK and preserved ATP concentration in myocardium compared with untreated controls (each p < 0.05).

Conclusions/interpretation

Chronic treatment of metabolically normal pigs with metformin at a clinically relevant dose reduces mortality from ischaemic VF. This protection is associated with preservation of myocardial energetics during ischaemia. Maintenance of myocardial ATP concentration during ischaemia is likely to prevent action potential shortening, heterogeneity of repolarisation, and propensity for lethal arrhythmia. The findings suggest that metformin might be protective in non-diabetic individuals with coronary heart disease.

Keywords

Action potential ATP Ischaemia Metformin Ventricular fibrillation 

Abbreviations

AMPK

AMP-activated protein kinase

CS

Citrate synthase

KATP

ATP-sensitive potassium

LAD

Left anterior descending coronary artery

LV

Left ventricle

MAP

Monophasic action potential

VF

Ventricular fibrillation

Supplementary material

125_2017_4287_MOESM1_ESM.pdf (21 kb)
ESM Table 1(PDF 21.0 kb)

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Copyright information

© Springer-Verlag (outside the USA) 2017

Authors and Affiliations

  • Li Lu
    • 1
    • 2
  • Shuyu Ye
    • 1
    • 2
  • Rebecca L. Scalzo
    • 2
    • 3
  • Jane E. B. Reusch
    • 2
    • 3
  • Clifford R. Greyson
    • 1
    • 2
  • Gregory G. Schwartz
    • 1
    • 2
  1. 1.Cardiology SectionDenver VA Medical CenterDenverUSA
  2. 2.University of Colorado School of MedicineAuroraUSA
  3. 3.Endocrinology/Metabolism SectionDenver VA Medical CenterDenverUSA

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