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

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

Manhong Yi 1,† Hongjiu Zhang 2,† Keyi Fan 2 Jiang Han 2 Shirong Zhu 2 Yuwen Wang 2,* Heng Wang 3,4,* Guoping Zheng 3,4,*

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1
Department of Nephrology, The Second Hospital of Shanxi Medical University, Taiyuan 030001, China
2
Department of Vascular Surgery, The Second Hospital of Shanxi Medical University, Taiyuan 030001, China
3
Centre for Transplant and Renal Research, Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW 2145, Australia
4
Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2006, Australia
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.

Received: 19 January 2026 Revised: 28 April 2026 Accepted: 06 August 2026 Published: 14 August 2026

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© 2026 The authors. This is an open access article under the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).

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Cardiovasc. Sci. 2026, 3(3), 10013; DOI: 10.70322/cvs.2026.10013
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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