Role of PI3K in Atrial Myopathy: Insights from Transgenic Mouse Models and Identification of a Dysregulated PI3K Lipid Profile in Individuals with Atrial Fibrillation
In a serendipitous discovery, we identified atrial enlargement, fibrosis and thrombi in a subset of transgenic mice with reduced phosphoinositide 3-kinase (PI3K, class IA) in cardiac myocytes. Understanding mechanisms underlying atrial myopathy has important implications for understanding and preventing atrial fibrillation (AF). Prior work had shown that PI3K is an essential regulator of exercise-induced ventricular enlargement and protection, but the role in the atria was unknown. Further, while targeting IGF1-PI3K-Akt signaling has been considered a potential therapeutic strategy for the failing heart, growing evidence suggests fine-tuning IGF1-PI3K signaling would be necessary. Here, we undertook comprehensive physiological and molecular analyses in cardiac-specific transgenic mice with increased or decreased PI3K to assess the dose response impact of directly regulating PI3K. Elevated PI3K was associated with a dose-dependent increase in heart size, and preserved/enhanced function. In contrast, reduced PI3K led to cardiac dysfunction, fibrosis, arrhythmia, and increased susceptibility to atrial enlargement and thrombi. This phenotype was associated with dysregulation of a lipid species (GM3) that regulates the IGF1-PI3K pathway, cardiac stress and contractility genes. Proteomic profiling identified distinct signatures across atria with varying degrees of atrial dysfunction, enlargement, and presence of atrial thrombi. To assess the potential relevance in humans we assessed circulating PI3K-related lipids in plasma from athletes with/without AF. Dysregulation of GM3 and PI3K-related lipids were identified in athletes with AF. Collectively, this work advances our understanding of mechanisms underpinning atrial pathophysiology, offers new insights for therapeutic approaches targeting atrial myopathy and AF, and has identified potential new lipid markers for identifying individuals at risk of AF. Overall design: Target-locus-amplification of genomic DNA from dnPI3K transgenic mice to reveal transgene insertion site