Metformin prevents ischaemic ventricular fibrillation in metabolically normal pigs
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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.
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.
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).
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.
KeywordsAction potential ATP Ischaemia Metformin Ventricular fibrillation
AMP-activated protein kinase
Left anterior descending coronary artery
Monophasic action potential
The authors appreciate the contributions of M. Kusumah, surgical/anaesthesia assistant at the Denver VA Medical Center.
All data generated or analysed during this study are included in this published article (and its ESM files).
GGS and RLS are supported by National Institutes of Health grants 5R01HL049944 and 4T32HL007171. GGS, JEBR and CRG are supported by the Medical Research Service of the US Department of Veterans Affairs. JEBR is supported by the University of Colorado Center for Women’s Health.
Duality of interest
The authors declare that there is no duality of interest associated with this manuscript.
All authors fulfilled ICMJE uniform requirements for manuscripts submitted to medical journals based upon substantial contributions to conception and design or acquisition and interpretation of data, drafting the article or critically revising it for intellectual content, and provision of approval of the submitted work. GGS is the guarantor of this work.
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