Po-02-212 twisted fibrotically-insulated myobundles create the common track and pivoting points for reentrant drivers maintaining persistent af in-vivo

Localized reentrant drivers have been suggested to maintain persistent atrial fibrillation (perAF). However, their existence, electrophysiological mechanisms, and structural substrates in-vivo are controversial. Define AF driving mechanism in-vivo and ex-vivo in a perAF canine model. A clinically relevant canine model (n=5) of self-sustained (4 months) perAF was developed to study AF maintaining mechanisms both in-vivo and ex-vivo by integrated 3D imaging, including high-resolution near-infrared optical mapping (NIOM, 0.3-0.5mm resolution), contrast-enhanced magnetic resonance imaging (CE-MRI, 0.15mm resolution). Transmural fibrosis was validated with histology. CE-MRI was used to quantitatively analyze 3D atrial structure, including transmural fiber orientation and fibrosis content in the sub-epi, intramural, and sub-endocardial layers. In all canine models (n=5), sequential in-vivo to ex-vivo sub-surface NIOM and 3D CE-MRI revealed that the self-sustained perAF was primarily maintained by localized reentrant drivers with temporal stability 53±17% (n=10), which recurrent on the same arrhythmogenic hubs. The 3D structure of the arrhythmogenic driver hubs includes a common intramural reentry track and multiple return paths formed by fibrotically-insulated bundles. The in-vivo spatio-temporal activation patterns of reentrant drivers were preserved ex-vivo (Figure A), including driver AFCL (91±7 ms vs 96±12 ms, p>0.05) and temporal driver stability (51±8% vs 52±6%, n=4, p>0.05). Targeted ablation of the driver reentrant tracks terminated or converted AF to slower tachycardia. Quantitative CE-MRI analysis of 3D myofiber orientations revealed that the transmural fiber twist along the common reentry tracks and pivoting points is greater than in non-driver regions (Figure B-C). The driver reentrant tracks had increased interstitial fibrotic strands and significantly higher intramural fibrosis than the neighboring non-driver regions (Figure D-E). Our results provide in-vivo proof-of-concept that spatially stable reentrant drivers are a mechanism of perAF maintenance. Intramural fibrotic strands and fibrotically-insulated myobundles in regions with the highest transmural myofiber twist which may form the common tracks and pivoting points for return paths of the spatially-stable reentrant AF driver.