Voxel-scale diffusion tensor phenomapping of the healthy and pressure-overloaded human heart

Diffusion tensor magnetic resonance imaging of the heart is typically performed at millimetre-scale resolution, yielding only four to five voxels across the ventricular wall, limiting the measurement of local spatial variation in cardiomyocyte organization. Here we present a submillimetre in vivo cardiac diffusion tensor imaging method achieved during free breathing that facilitates voxel-level characterization of myocardial microstructure. We introduce a phenomapping framework that combines voxelwise diffusion magnitude and anisotropy with radial and circumferential gradients of cardiomyocyte helix angle to identify distinct microstructural environments. The approach was developed in healthy volunteers and applied to patients with severe aortic valve stenosis, who had preserved cardiac function and marked myocardial thickening. Comparisons to conventional resolution imaging, together with downsampling analyses and ex vivo and histological validation, show that these voxel-scale features are less optimally detected using standard techniques. Four data-driven microstructural classes, defined by combined diffusion properties and orientation gradients, were observed in both healthy and pressure-overloaded hearts. Despite substantial hypertrophy, pressure overload was associated with preserved cardiomyocyte spatial organization. This framework supports studies of myocardial microstructural remodelling in vivo.