Abstract 199: Whole-Transcript Genomics Reveals Atrial KCNE1 Downregulation in a Model of Postoperative Atrial Fibrillation Susceptibility
Lone atrial fibrillation (AF) is associated with various ion channel gene sequence variants, notably the common S38G loss-of-function polymorphism in the KCNE1 K+ channel ancillary subunit gene. New-onset postoperative AF (PAF) generally occurs 48-72 hours after major surgery, particularly following procedures within the chest, but its molecular bases remain poorly understood. Here, to begin to address this gap in knowledge, we analyzed molecular changes in the left atrium (LA) three days following left upper lung lobectomy in Sinclair swine in relation to simultaneous changes in hemodynamics, LA effective refractory period (ERP), and the capacity to sustain electrically-induced AF. Relative to control pigs (no previous surgery), lobectomy increased mean pulmonary artery pressure (16 ± 3 vs 22 ± 5 mm Hg; P= 0.045) and pulmonary vascular resistance (273 ± 93 vs 481 ± 142 dyn¶s/cm5; P = 0.025), whereas other hemodynamic parameters were unchanged. Left atrial ERP measured from a 300 ms cycle length trended toward reduction in lobectomy animals (187 ± 37 vs 170 ± 44 ms, P>0.05). None of the lobectomy pigs developed spontaneous postoperative AF as assessed by telemetric ECG. However, all lobectomy pigs, but none of the controls, were able to sustain AF induced by a 10 s burst of rapid pacing for ≥30 s (P=0.0079), independent of atrial ERP; AF was sustained ≥60 s in 3/5 postoperative pigs versus 0/5 controls and correlated with a shorter ERP overall (P=0.023). Whole-transcript genomics of left atrial tissue using 25 probes per transcript revealed 13 genes with expression changes ≥2-fold in postoperative pigs. Strikingly, of these, atrial KCNE1 showed the statistically strongest link to surgery, and was the most downregulated gene in the postoperative group compared to controls (2.2-fold reduced, P=0.0027), recapitulated at the protein level with western blotting (P=0.039). The data suggest KCNE1 remodeling as a potential marker or influencing factor in the early progression of, or susceptibility to, PAF [[Unable to Display Character: –]] uncovering a possible common predisposing genetic factor in PAF and lone AF.
- © 2012 by American Heart Association, Inc.