IGF1–PI3K-induced physiological cardiac hypertrophy: Implications for new heart failure therapies, biomarkers, and predicting cardiotoxicity

Highlights • The IGF1–PI3K pathway mediates exercise induced heart growth and protection. • Strategies to mimic the benefits of exercise on the heart are of substantial interest. • Characterizing animal models of altered cardiac PI3K activity can identify new drug targets for heart disease, and biomarkers which distinguish the healthy and diseased heart. • Therapies that increase PI3K activity may provide a promising approach to improve function in the failing heart. • Systemic therapies that reduce PI3K activity, such as some cancer agents, may lead to cardiotoxicity.
Heart failure represents the end point of a variety of cardiovascular diseases. It is a growing health burden and a leading cause of death worldwide. To date, limited treatment options exist for the treatment of heart failure, but exercise has been well-established as one of the few safe and effective interventions, leading to improved outcomes in patients. However, a lack of patient adherence remains a significant barrier in the implementation of exercise-based therapy for the treatment of heart failure. The insulin-like growth factor 1 (IGF1)–phosphoinositide 3-kinase (PI3K) pathway has been recognized as perhaps the most critical pathway for mediating exercised-induced heart growth and protection. Here, we discuss how modulating activity of the IGF1–PI3K pathway may be a valuable approach for the development of therapies that mimic the protective effects of exercise on the heart. We outline some of the promising approaches being investigated that utilize PI3K-based therapy for the treatment of heart failure. We discuss the implications for cardiac pathology and cardiotoxicity that arise in a setting of reduced PI3K activity. Finally, we discuss the use of animal models of cardiac health and disease, and genetic mice with increased or decreased cardiac PI3K activity for the discovery of novel drug targets and biomarkers of cardiovascular disease.