Transcriptomics analysis reveals atrial KCNE1 downregulation following lung lobectomy

摘要

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 (POAF) generally occurs 48–72 hours after major surgery, particularly following procedures within the chest, but its molecular bases remain poorly understood. To begin to address this gap in knowledge, we analyzed molecular changes in the left atrium (LA) in relation to simultaneous changes in hemodynamics, LA effective refractory period (ERP), and the capacity to sustain electrically-induced AF following left upper lung lobectomy in swine. Relative to control pigs (no previous surgery), 3 days after lobectomy higher values for mean pulmonary artery pressure (16 ± 1 vs 22 ± 2 mm Hg; P = 0.045) and pulmonary vascular resistance (273 ± 47 vs 481 ± 63 dyn·s/cm⁵; P = 0.025) were evident, whereas other hemodynamic variables were unchanged. LA ERP trended toward reduction in lobectomy animals (187 ± 16 vs 170 ± 20 ms, P > 0.05). None of the lobectomy pigs developed spontaneous POAF 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 LA 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). Transcriptomic analysis of LA tissue revealed 23 up-regulated and 10 down-regulated transcripts (≥1.5-fold, P<0.05) in lobectomy pigs. Strikingly, of the latter, KCNE1 down-regulation showed the statistically strongest link to surgery (2.0-fold, P=0.009), recapitulated at the protein level with western blotting (P=0.039), suggesting KCNE1 down-regulation as a possible common mechanistic factor in POAF and lone AF. Of the up-regulated transcripts, while Teneurin-2 was the strongest linked (1.5-fold change, P=0.001), DSCR5 showed the highest induction (2.7-fold, P=0.02); this and other hits will be targeted in future functional studies.