The Four-Hit Framework of Aortic Aneurysm Progression: From Wall Injury to Imaging and Targeted Intervention

Abstract

Aortic aneurysm (AA) is a life-threatening vascular disease characterized by progressive aortic dilatation, wall degeneration, and risk of rupture. Although diameter-based imaging remains central to clinical decision-making, it does not fully reflect the biological processes underlying aneurysm initiation, expansion, and rupture. Recent advances in omics, vascular biology, functional imaging, and nanomedicine provide new opportunities to reinterpret AA pathogenesis. In this review, we propose the Four-Hit Hypothesis as an integrative framework for understanding AA progression. The four hits include disruption of the aortic barrier environment, immune-inflammatory invasion, maladaptive proliferative repair, and aging-associated structural destruction. We discuss their roles across disease stages, the differences between abdominal and thoracic aortic aneurysms, and their implications for biomarkers, imaging, and therapeutic development. This review aims to organize current evidence on AA biology and highlight potential directions for future studies in risk assessment, imaging, and targeted intervention.

Keywords

Aortic aneurysm / Vascular inflammation / Functional imaging

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