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Pathophysiology of native coronary, vein graft, and in-stent atherosclerosis

Key Points

  • The aetiology of luminal thrombosis in native coronary arteries is predominately plaque rupture, but can also be surface erosion and, least frequently, calcified nodules

  • The main precursor lesion with potential for rupture is identified as a 'vulnerable plaque' or 'thin-cap fibroatheroma', and is considered an appropriate therapeutic target for patients at risk of future coronary events

  • Native coronary disease develops over decades, whereas accelerated atherosclerosis is observed in saphenous vein grafts and in stents within months to years

  • In saphenous vein grafts and stents, accelerated atherosclerosis is likely to develop from resident macrophage-derived foam cells, which undergo apoptosis and form necrotic cores; pathological intimal thickening is rarely observed

  • By contrast, native coronary disease is thought to progress from lipid pools associated with pathological intimal thickening; necrotic cores arise from macrophage infiltration of these lipid pools

  • Important morphological identifiers of accelerated plaque progression include macrophage foam cells, intraplaque haemorrhage, and fibrous cap thickness

Abstract

Plaque rupture, usually of a precursor lesion known as a 'vulnerable plaque' or 'thin-cap fibroatheroma', is the leading cause of thrombosis. Less-frequent aetiologies of coronary thrombosis are erosion, observed with greatest incidence in women aged <50 years, and eruptive calcified nodules, which are occasionally identified in older individuals. Various treatments for patients with coronary artery disease, such as CABG surgery and interventional therapies, have led to accelerated atherosclerosis. These processes occur within months to years, compared with the decades that it generally takes for native disease to develop. Morphological identifiers of accelerated atherosclerosis include macrophage-derived foam cells, intraplaque haemorrhage, and thin fibrous cap. Foam-cell infiltration can be observed within 1 year of a saphenous vein graft implantation, with subsequent necrotic core formation and rupture ensuing after 7 years in over one-third of patients. Neoatherosclerosis occurs early and with greater prevalence in drug-eluting stents than in bare-metal stents and, although rare, complications of late stent thrombosis from rupture are associated with high mortality. Comparison of lesion progression in native atherosclerotic disease, atherosclerosis in saphenous vein grafts, and in-stent neoatherosclerosis provides insight into the pathogenesis of atheroma formation in natural and iatrogenic settings.

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Figure 1
Figure 2: Simplified scheme for classifying atherosclerotic lesions in human coronary arteries.
Figure 3: Human coronary lesion morphologies categorized as 'nonatherosclerotic intimal lesions'.
Figure 4: Human coronary lesion morphologies categorized as 'progressive atherosclerotic lesions'.
Figure 5: Progression of coronary calcification.
Figure 6: Human coronary lesion morphologies categorized as 'lesions with acute thrombi'.
Figure 7: Episodic rupture and healing can lead to chronic total occlusion.
Figure 8: Nonocclusive propagated thrombi that heal can contribute to the formation of fibrous plaques.
Figure 9: Plaque morphologies that can lead to necrotic core expansion.
Figure 10: Histological pattern of coronary calcification in progressive and stable plaques.
Figure 11: Advanced lesions complicated by calcification presenting as 'fibrocalcific' and/or 'nodual calcification' can arise from fibroatheromas.
Figure 12: Accelerated atherosclerotic disease in saphenous vein grafts.
Figure 13: Causes of late and very late stent thrombosis attributed to neoatherosclerosis and 'restenosis' (panels a–d) and progression of neoatherosclerosis (panels e–i).
Figure 14: Plaque progression and frequency of plaque rupture in native atherosclerotic disease, vein-graft atherosclerosis, and in-stent neoatherosclerosis.

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Acknowledgements

CVPath Institute Inc., a private non-profit research organization, provided major support for this work, which was also partially supported by National Institutes of Health grant R01 DK094434-01A1.

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K.Y. and F.D.K. contributed equally to this work. K.Y., F.D.K., F.O., and R.V. substantially contributed to discussion of content. K.Y., F.D.K., F.O., and R.V. wrote the manuscript. F.D.K., F.O., A.V.F., H.R.D., M.J., and R.V. reviewed and edited the manuscript before submission.

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Correspondence to Renu Virmani.

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Competing interests

F.O. has received speaking honoraria from Abbott Vascular, Bayer, Merck, and Terumo Corporation. A.V.F. receives research support from Boston Scientific and Medtronic, and is a consultant to St. Jude Medical. M.J. is a consultant for Biotronik and Cardionovum, and has received speaking honoraria from Abbott Vascular, Biotronik, Medtronic, and St. Jude Medical. R.V. receives research support from 480 Biomedical, Abbott Vascular, Atrium, Biosensors International, Biotronik, Boston Scientific, Cordis Johnson & Johnson, GSK, Kona, Medtronic, Microport Medical, OrbusNeich Medical, ReCor, SINO Medical Technology, Terumo Corporation, and W. L. Gore; has speaking engagements with Merck; receives honoraria from 480 Biomedical, Abbott Vascular, Biosensors International, Boston Scientific, CeloNova BioSciences, Claret Medical, Cordis Johnson & Johnson, Lutonix Bard, Medtronic, Terumo Corporation, and W. L.Gore; and is a consultant to 480 Biomedical, Abbott Vascular, Medtronic, and W. L. Gore. The other authors declare no competing interests.

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Yahagi, K., Kolodgie, F., Otsuka, F. et al. Pathophysiology of native coronary, vein graft, and in-stent atherosclerosis. Nat Rev Cardiol 13, 79–98 (2016). https://doi.org/10.1038/nrcardio.2015.164

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