NATURE COMMUNICATIONS | DOI: 10.1038/ncomms6705
Received 15 Sep 2014 | Accepted 30 Oct 2014 | Published 9 Dec 2014
Geeta Sapra, Yow Keat Tham, Nelly Cemerlang, Aya Matsumoto, Helen Kiriazis, Bianca C. Bernardo, Darren C. Henstridge, Jenny Y.Y. Ooi, Lynette Pretorius, Esther J.H. Boey, Lydia Lim, Junichi Sadoshima, Peter J. Meikle, Natalie A. Mellet, Elizabeth A. Woodcock, Silvana Marasco, Tomomi Ueyama, Xiao-Jun Du, Mark A. Febbraio & Julie R. McMullen
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.