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Spatiotemporal Deep Video-Phenomapping Decodes Microvascular Rarefaction in Middle-Aged and Elder Renovascular
Lingjie Ju1, Ri Ji2, Hong Meng3
1Department of Sonography, Beijing Hospital, National Center for Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China.
Abstract:
In middle-aged and older atherosclerotic renal artery stenosis (ARAS), the anatomical severity of stenosis is a poor surrogate for microvascular competence, and the renal benefit of revascularization is unpredictable. We developed Renal-Video-AI, a self-supervised deep learning framework (Video Swin Transformer with VideoMAE pretraining) that extracts spatiotemporal hemodynamic features from contrast-enhanced ultrasound, and applied it to a multi-center Discovery Cohort (N = 1,226), an independent External Validation Cohort (N = 122), a prospective Multimodal Cohort with paired 10x Visium spatial transcriptomics (N = 57), and an aged two-kidney-one-clip (2K1C) murine model. Unsupervised phenomapping identified 3 intrinsic hemodynamic phenotypes-Preserved, Delayed, and Rarefied. The Rarefied phenotype predicted major adverse renal events (MAREs) independently of anatomical stenosis [hazard ratio (HR) 4.82, 95% confidence interval (CI) 3.10 to 6.50; Fine-Gray subdistribution HR (sHR) 5.1], and adding the phenotype to a standard clinical model improved the C-statistic from 0.72 to 0.88. A significant phenotype-by-treatment interaction (P < 0.01) showed that stenting reduced events only in the Delayed phenotype (HR 0.52, 95% CI 0.35 to 0.78), not in the Preserved (HR 0.98) or Rarefied (HR 1.05) phenotypes. In absolute terms, stenting reduced the 3-year cumulative incidence of MARE in the Delayed phenotype from 25.4% to 13.2% (absolute risk reduction 12.2%; number needed to treat = 8, 95% CI 6 to 13), with no benefit in the Preserved (8.4% versus 8.0%) or Rarefied (38.6% versus 39.4%) phenotypes. Spatial transcriptomics localized a hypoxia and pyroptosis signature to rarefied tissue, and the aged 2K1C model revealed a mitochondrial reactive oxygen species (ROS)-NLRP3-pyroptosis axis whose pharmacological inhibition (MCC950) restored microvascular perfusion. AI video-phenomapping thus reframes the revascularization decision around microvascular competence rather than anatomy, identifying both therapeutic futility (Rarefied) and a treatable window (Delayed), and nominates NLRP3-driven pyroptosis as a therapeutic target.
