Table 2.
Effects of metformin on atrial arrhythmias: reports from in vivo studies
| Model | Metformin (dose/ duration) | Key results and major findings | Interpretation | References | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Energy homeostasis | ROS | Ion channel | Inflammation | Cx43 | EP changes | Structural remodel | AF | ||||
| Non-DM dogs with atrial rapid pacing (1200 bpm for 6 h) | 100 mg/kg/days for 2 weeks |
↑↑AMPK -↑PPARα, PGC-1α, VLCAD, CPT-1 |
– | – | – | – | ↑AERP ↓AERPd | ↓FFA/TG /lipid deposition in LAA | – | Metformin improved EP disorders caused by atrial rapid pacing via ↓lipid accumulation and promoted FAO in AF models through AMPK/PPAR-α/VLCAD pathway | [41] |
| Non-DM dogs with rapid atrial pacing (400 bpm for 6 weeks) | 100 mg/kg/days for 1 week prior then 6 weeks | – | ↓ in LA/EAT | – | – ↑APN, adipoR1 – ↓ IL-6, NF-kB, TNFα, TGFβ1 | – | ↑AERP ↓AERPd | ↓LA fibrosis and EAT | ↓ | Metformin reduced AF and atrial fibrosis by inhibited ROS/NF-kB, reduced epicardial fat, pro-inflammatory adipokines, and upregulated adiponectin in LA/EAT | [45] |
| Non-DM dogs with rapid atrial pacing 400 bpm | 100 mg/kg/days for 1 week then pace for 180/ 360 min (acute) | – | – | – | – | ↑ |
↔ AERPd |
– | – | Metformin reduced AF by preventing adverse electrical remodeling via increase AMPK and Cx43 expression in chronic AF model. Metformin mildly increased Cx43 in acute pacing and could not attenuate AERPd | [42] |
| 100 mg/kg/days with pace for 6 weeks (chronic) |
↑AMPK ↔ mito-chondrial morphology |
– | – | – | ↑↑ | ↑AERP ↓AERPd | ↔Irregular myocardial fibers | ↓ | |||
| GK T2DM rats | 300 mg/kg/days for 3 months |
- ↔ SK1, ↑SK2,↓SK3 -↑SK current -↓distorted current-voltage relationship |
↓ APD | ↓ Atrial myofilament irregularity and fibrosis | ↓ | Metformin reduced atrial arrhythmia in DM GK rats via decreased atrial remodeling and normalized APD via restoring SK current | [53] | ||||
adipoR1 adiponectin receptor 1, AERP atrial effective refractory period, AERPd AERP dispersion, AMPK 5' adenosine monophosphate-activated protein kinase, APD action potential duration, bpm beats per minutes, APN adiponectin, Ca calcium, CPT-1 Carnitine palmitoyltransferase I, EAT epicardial adipose tissue, EP electrophysiologic, FAO fatty acid oxidation, FFA free fatty acid, GK Goto-Kakizaki, LA left atrium, LAA left atrial appendage, PGC-1α peroxisome proliferator-activated receptor-gamma coactivator 1α, PPAR-α peroxisome proliferator-activated receptor α, ROS reactive oxygen species, SK channels small conductance calcium-activated potassium channels, TG triglyceride, TGFβ1 transforming growth factor beta1, TNFα tumor necrosis factor alpha, VLCAD Very long-chain specific acyl-CoA dehydrogenase