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.
Sapra, G., Tham, Y. K., Cemerlang, N., Matsumoto, A., Kiriazis, H., Bernardo, B. C., Henstridge, D. C.
, Ooi, J. Y. Y., Pretorius, L.
, Boey, E. J. H., Lim, L., Sadoshima, J., Meikle, P. J.
, Mellett, N. A., Woodcock, E. A., Marasco, S.
, Ueyama, T., Du, X-J., Febbraio, M. A., & McMullen, J. R.
(2014). The small-molecule BGP-15 protects against heart failure and atrial fibrillation in mice
. Nature Communications
, 1 - 16. . https://doi.org/10.1038/ncomms6705