Pathophysiology and therapeutic relevance of PI3K(p110α) protein in atrial fibrillation

Genetically modified animal studies have revealed specific expression patterns and unequivocal roles of class I PI3K isoenzymes. PI3K(p110α), a catalytic subunit of class I PI3Ks is ubiquitously expressed and is well characterised in the cardiovascular system. Given that genetic inhibition of PI3K(p110α) causes lethal phenotype embryonically, the catalytic subunit is critically important in housekeeping and biological processes. A growing number of studies underpin crucial roles of PI3K(p110α) in cell survival, proliferation, hypertrophy and arrhythmogenesis. While the studies provide great insights, the precise mechanisms involved in PI3K(p110α) hypofunction and atrial fibrillation (AF) are not fully known. AF is a well recognised clinical problem with significant management limitations. In this translational review, we attempted a narration of PI3K(p110α) hypofunction in the molecular basis of AF pathophysiology. We sought to cautiously highlight the relevance of this molecule in the therapeutic approaches for AF management per se (i.e without conditions associate with cell proliferation, like cancer), and in mitigating effects of clinical risk factors in atrial substrate formation leading to AF progression. We also considered PI3K(p110α) in AF gene association, with the aim of identifying mechanistic links between the ever increasingly well-defined genetic loci (regions and genes) and AF. Such mechanisms will aid in identifying new drug targets for arrhythmogenic substrate and AF.