PI3K(p110a) regulates atrial function independent of fibrosis and is a critical regulator of atrial enlargement in a setting of pressure overload-Implications for atrial myopathy & atrial fibrillation

Background Phosphoinositide 3-kinase (PI3K, p110α) is a critical regulator of normal heart size in mice, and is conserved in humans. Under basal conditions, cardiomyocyte-specific heterozygote transgenic mice expressing a dominant negative PI3K (dnPI3K) mutant have reduced cardiac PI3K activity and smaller heart weights, but left ventricular (LV) function is relatively normal. With advances in ultrasound, we recently identified atrial dysfunction in dnPI3K mice (>40% drop in left atrial (LA) reservoir and booster pump function) despite atria weight being smaller vs. non-transgenic (Ntg, control) and no elevation in atrial fibrosis. We also characterized dnPI3K homozygote transgenic mice with two copies of the dnPI3K transgene, designed to inhibit PI3K activity further. DnPI3K homozygote mice presented with LV dysfunction, significant fibrosis (LV and LA), and a subset of mice presented with arrhythmia including intermittent atrial fibrillation, atrial enlargement and atrial thrombi. LA function was also depressed in homozygote dnPI3K, but not dramatically reduced vs. dnPI3K heterozygote mice. In another study, heterozygote dnPI3K mice and mice with increased PI3K due to expression of a constitutively active PI3K (caPI3K) mutant were subjected to pressure overload (aortic banding) for 1 week. Atrial enlargement (based on raw atria weight alone) appeared to be greater in banded heterozygote dnPI3K vs. Ntg and lower in caPI3K. However, analysis of normalized atrial weights and atrial weight/heart weight ratios had not been assessed. Purpose 1) To more comprehensively characterize collagen deposition in atria from heterozygote and homozygote dnPI3K mice, and 2) evaluate atrial enlargement in heterozygote dnPI3K and caPI3K in response to pressure overload. Methods 1) LA from 20 week old female dnPI3K (heterozygote & homozygote) and Ntg were fixed and stained with Masson’s trichrome or the predominant collagens in the heart (collagen I and III by immunohistochemistry). 2) Atria weight/tibia length (AW/TL) and atria weight/heart weight (AW/HW) were analyzed from a prior study in adult male Ntg, heterozygote dnPI3K and caPI3K that were subjected to ascending aortic-constriction (AAC/Band) or sham for 1 week. This procedure leads to pathological cardiac hypertrophy within 1 week in Ntg. Results 1) Fibrosis, collagen I and collagen III expression were elevated in atria from homozygote dnPI3K vs. heterozygote dnPI3K and Ntg (Fig 1A). 2) Normalized AW/TL and AW/HW were elevated in control Ntg in response to AAC (Band), elevated further in heterozygote dnPI3K (dnP Band), but not elevated in caPI3K (caP Band, Figure 1B). Conclusions Reduced PI3K(p110α) in cardiomyocytes alone leads to atrial dysfunction in the absence of atrial fibrosis and increased collagen expression. In a setting of pressure overload, increased PI3K(p110α) protects against atrial enlargement whereas reduced PI3K(p110α) accelerates atrial enlargement.