g(m3)-ganglioside and Atrial-Fibrillation

Heart failure (HF) and atrial fibrillation (AF) share common risk factors, frequently coexist and are associated with high mortality. Treatment of HF with AF represents a major unmet need. Here we show that a small molecule, BGP-15, improves cardiac function and reduces arrhythmic episodes in two independent mouse models, which progressively develop HF and AF. In these models, BGP-15 treatment is associated with increased phosphorylation of the insulin-like growth factor 1 receptor (IGF1R), which is depressed in atrial tissue samples from patients with AF. Cardiac-specific IGF1R transgenic overexpression in mice with HF and AF recapitulates the protection observed with BGP-15. We further demonstrate that BGP-15 and IGF1R can provide protection independent of phosphoinositide 3-kinase-Akt and heat-shock protein 70; signalling mediators often defective in the aged and diseased heart. As BGP-15 is safe and well tolerated in humans, this study uncovers a potential therapeutic approach for HF and AF.

Topics: Animals; Atrial Fibrillation; Caveolin 1; Caveolin 3; Disease Models, Animal; Electrocardiography; G(M3) Ganglioside; Heart Failure; HSP70 Heat-Shock Proteins; Humans; Male; Mice; Mice, Knockout; Mice, Transgenic; Microarray Analysis; Oximes; Phosphatidylinositol 3-Kinases; Phosphorylation; Piperidines; Proto-Oncogene Proteins c-akt; Receptor, IGF Type 1; Receptors, Somatomedin; Risk Factors; Signal Transduction; Transgenes