Structural determinants of re-entrant drivers in atrial fibrillation: insights from digital twins derived from 3D micrometre-resolution imaging of human heart.

Atrial fibrillation (AF) affects over 45 million people worldwide. Although catheter ablation is the most promising treatment, its outcomes in patients with persistent AF remain suboptimal. This is attributed to insufficient insights into how structural substrates in human atria sustain AF and the lack of precise methods to identify ablation targets. Here, we investigate how atrial wall thickness (AWT), myofibre organisation and fibrosis govern the stability and localisation of re-entrant drivers (RDs). Five human donor atria from individuals with cardiac co-morbidities were functionally characterised using optical mapping and structurally imaged at an isotropic resolution of 170-180 µm via 9.4T gadolinium-enhanced magnetic resonance imaging. Heart-specific digital twins with and without specific structural components were developed to evaluate their effects on RD stability and localisation. Simulations revealed that AWT variations had a global influence on RD dynamics, with RDs preferentially drifting toward and stabilising in atrial regions with smaller AWT values, more prominently in the right atrium (RA) than the left atrium (LA). Incorporating myofibre orientation further constrained RD localisation, particularly in the posterior LA and lateral RA, where well-aligned myofibres bordered regions of disorganised fibres. This effect was more pronounced in the RA than in the LA. In contrast, fibrosis had the most significant influence on RD localisation in the LA, with RDs anchoring at fibrotic border zones. This study highlights AWT as a key determinant of AF maintenance, with 3D myofibre orientation and fibrosis holding region-specific influences on RD localisation and stability. RDs were consistently localised in regions with smaller AWT, aligned myofibres adjacent to disorganised structures and/or fibrotic border zones. These findings provide mechanistic insights into human AF maintenance and potential structural substrate targets for mechanism-based improved ablation strategies. KEY POINTS: Digital twins of human atria ex vivo revealed that atrial wall thickness (AWT) has a global impact on re-entrant driver (RD) dynamics. RDs drifted toward and along AWT gradients, and tended to localise in regions with smaller AWT. This effect was more pronounced in the right atrium (RA) than in the left atrium (LA). Incorporating myofibre orientation into heart-specific AWT models further constrained RD localisation, particularly in the posterior LA and the lateral RA, where well-aligned myofibres bordered disorganised regions. This effect was most substantial in the RA due to the prominent myofibre bundle architecture in the lateral RA. Fibrosis had a lesser impact on RDs in the RA compared to the LA. Specifically, RD locations remain relatively stable in the RA, regardless of the presence or absence of fibrosis. In contrast, fibrosis in the LA significantly altered RD distribution, with RDs clustering near fibrotic border zones.