A Hybrid Hierarchical Framework for Quantifying Mechanical Markers in Atherosclerotic Disease Progression: A New Approach for Diagnosis and Risk Assessment

ABSTRACT Atherosclerosis is the primary pathological basis for cardiovascular diseases. Despite advances in diagnosis and treatment, current methods primarily focus on late‐stage intervention, missing critical opportunities for early detection. Recently, the dynamic mechanical properties of arterial tissue have been recognized as a novel approach for assessing vascular status, and offer an opportunity to employ the mechanical properties of atherosclerotic lesions for evaluating disease status and monitoring disease progression. Here, we employed a Hybrid Hierarchical theory–Microrheology (HHM) framework to quantify multiscale mechanical markers during lesion progression. The results revealed a two‐stage power‐law rheology, with short‐ and long‐timescale exponents ( α short , α long ) as key mechanical markers of lesion composition and mechanical gradients. We further applied a self‐similar hierarchical framework to capture plaque heterogeneity across cytoplasmic, cellular, and tissue scales, yielding additional mechanical markers (e.g., E 1 , η , E 2 , E 3 ) from subcellular to tissue scales. Based on these markers, we built a multiparametric diagnostic model that outperforms traditional elastic modulus criterion. This model captures stage‐ and region‐specific trajectories, coupling mechanical signatures with histology for improved staging and risk assessment, establishing an operational framework for enhanced prediction and diagnosis of atherosclerosis.