RT Journal Article SR Electronic T1 The multifaceted process of human coronary atherosclerotic cap destabilisation JF bioRxiv FD Cold Spring Harbor Laboratory SP 2024.07.21.604507 DO 10.1101/2024.07.21.604507 A1 Bruijn, L.E. A1 Neves, N. Fonseca A1 van Rhijn, C.M. A1 Hamming, J.F. A1 van den Bogaerdt, AJ A1 Lindeman, J.H.N. YR 2024 UL http://biorxiv.org/content/early/2024/07/23/2024.07.21.604507.abstract AB Introduction Plaque rupture is the primary trigger of the acute clinical manifestations of atherosclerotic disease. So far, factual insight in the processes leading up to cap destabilization is largely missing. In order to overcome this knowledge gap, a pseudo-timeline of atherosclerosis progression was established in order to systematically map the qualitative changes in cap characteristics during lesion progression and destabilization.Material and Methods A pseudo-timeline was created by randomly selecting preclassified (revised AHA classification, at least 10 per stage) left coronary artery FFPE specimens obtained during tissue donation (aortic valve procurement). Qualitative changes were visualized by (immuno)histochemistry, immunofluorescence and confocal microscopy. Scoring was performed by two observers using semiquantitative scoring estimates.Results The median age of the donors was 56 years (IQR 51.5-59), and 67% of the patients was male. Movat staining indicated a consistent pattern of cap formation, maturation and destabilization. A distinctive cap emerged in the early fibroatheroma stage of progressive atherosclerosis. Disease progression was accompanied by profound fibrotic changes in the gap, and a progressive presence of inanotic (nutritional deprivation leading to dissolution) mesenchymal cells. Plaque rupture was preceded by thinning of the collagen fibers and accumulation of foam cells in the central portion of the thin cap. No evidence was found for a direct involvement of neovascularization in the destabilization process.Conclusion The pseudo-time line of atherosclerotic lesion development characterizes the development of an unstable cap as a degenerative and fibrotic process with progressive exhaustion of the mesenchymal cell population. This study provides a rationale for the limited efficacy of medical strategies aimed at plaque stabilization.Competing Interest StatementThe authors have declared no competing interest.Nonstandard Abbreviations and AcronymsEFAEarly FibroatheromaLFALate FibroatheromaLDLLow-density lipoproteinPITPathological Intimal ThickeningPRPlaque RuptureTCFAThin Cap Fibroatheroma