TET2 mutation, but not DNMT3A, is associated with adverse atrial remodeling and postoperative atrial fibrillation following cardiac surgery
A Tazibet, S Ninni, E Wotrain, D Montaigne, B StaelsAbstract
Introduction
Hematopoietic somatic mosaicism (HSM) is a recently identified risk factor for cardiovascular diseases and atrial fibrillation (AF). TET2 mutation is one of the most common mutation in HSM. Its role in postoperative atrial fibrillation (POAF) after cardiac surgery remains unclear.
Objective
The aim of the study is to assess the impact of TET2 mutation on preoperative atrial remodeling and POAF incidence after cardiac surgery.
Method
Blood DNA from 656 patients referred for cardiac surgery was genotyped on a large genes panel to assess HSM, including TET2 mutation. Atrial remodeling was assessed based on multiparametric approach including interatrial block (IAB) assessment (P wave duration > 120ms on ECG), left atrium (LA) echocardiography evaluation and right atrial fibrosis assessment using Red Sirius staining on fresh atrial tissue collected during surgery.
Results
656 patients were included. 282 patients (43%) carried HSM (HSM+). DNMT3A (18.5%) and TET2 mutation (12.5%) were more prevalent. HSM+ patients were older (70y [64;76] vs 66y [58;72], p<0.001) and present more often AF prior to surgery (18% vs 9%, p=0.001). HSM+ status was associated with a higher incidence of POAF (41% vs 30%, p=0.005) with a higher incidence observed in patients carrying TET2 mutation (age-adjusted OR 2.20; 95% CI 1.31-3.72, p<0.01). Preoperative IAB trended to be more frequent in HSM+ patients (27% vs 21%, p=0.06) and was significantly more prevalent in patients carrying TET2 mutation (prevalence 37%, age-adjusted OR 1.82; 95% CI 1.01-3.19, p=0.04). Severe LA enlargement (indexed LA volume.> 50mL/m2) was more prevalent in HSM+ patients (34% vs 27%, p=0.048) and was significantly more prevalent in patients carrying TET2 mutation (prevalence 44.5%, adjusted OR 1.75, CI 95% 1.01-3.01, p=0.04). In a subgroup of 23 patients who underwent aortic valve replacement and had available fresh atrial tissue, TET2-mutated patients presented a trend toward increased atrial fibrosis compared to other patients. Moreover, HSM+ patients had higher preoperative circulating TGFβ (16693.3 ± 5141 ng/mL vs 13662.1 ± 4726 ng/mL, p=0.01) with higher level for TET2-mutated patients. K-medoid clustering patients analysis observed a synergic worsening effect of severe LA enlargement, HSM status and "high" TGFβ level on POAF incidence, with a majority of these patients carrying TET2mutation (56%).
Conclusion
TET2 mutation is associated with a higher risk of POAF following cardiac surgery with an adverse atrial remodeling substrate and trend toward increased atrial fibrosis and preoperative circulating TGFβ expression. These data suggest that TET2 mutation could be associated with a higher degree of atrial fibrosis leading to POAF after cardiac surgery.POAF and TET2 mutationAtrial remodeling and TET2 mutation