Neointimal proliferation can occur within a coronary stent. Chronic inflammation within the neointima with infiltration of macrophages leads to neoatherosclerosis and result in in-stent restenosis. Disruption of neoatheroma can cause acute thrombotic occlusion [1]. Hence neoatherosclerosis is a complication of percutaneous coronary intervention and can present with recurrence of angina or acute coronary syndrome.

Occurrence of neoatherosclerosis is earlier in drug eluting stents than in bare metal stents and has a greater prevalence. Late stent thrombosis due to rupture of the plaques with thin fibrous cap is associated with high mortality [2]. Thus in-stent neoatherosclerosis is an important contributing factor to late vascular complications of very late stent thrombosis and late in-stent restenosis. Neoatherosclerosis is characterized by plenty of lipid laden foamy macrophages, with or without calcification and a necrotic core in the neointima. While native coronary atherosclerosis takes decades to develop, neoatherosclerosis may develop in months to years after stent placement [3]. Lesions of neoatherosclerosis can be detected by optical coherence tomography.

A study of 406 neoatherosclerotic lesions from 299 autopsies in the CVPath stent registry included 197 bare metal stents and 209 drug eluting stents. 103 were sirolimus eluting stents and 106 paclitaxel eluting stents. Neoatherosclerosis was noted in 31% of drug eluting stent lesions and 16% of bare metal stent lesions (p < 0.001). Median stent duration was shorter in case of drug eluting stents. Unstable lesions with thin cap fibroatheromas or plaque rupture were more frequent in drug eluting stents. Mean implant duration was 1.5 years in drug eluting stents and 6.1 years in bare metal stents. Younger age, longer implant durations, drug eluting stents and underlying unstable plaques were the independent determinants of neoatherosclerosis identified by multiple logistic regression [4].

Reformation of an endothelial cover is delayed after drug eluting stent implantation. Hence the neointima is more prone to become lipid laden and develop neoatherosclerosis, increasing plaque vulnerability. Thus neoatherosclerosis is an important mechanism for drug eluting stent failure. Near-infrared spectroscopy with intravascular ultrasound was used along with optical coherence tomography to characterize neoatherosclerotic lesions in 65 consecutive patients with symptomatic in-stent restenosis in a study [5]. 51 had drug eluting stents and 14 bare metal stents. Neoatherosclerosis was confirmed by optical coherence tomography in 40 stents of which 68% were drug eluting stents. Thin cap atheroma was noted in 47% with drug eluting stents and 7% with bare metal stents. Near infrared spectroscopy showed that total lipid core burden index and density of lipid core burden index were higher in drug eluting stents, compared to bare metal stents. Neoatherosclerosis was classified into thin cap (type I), thick cap (type II) and peri-strut neoatherosclerosis (type III). Type I thin cap neoatheroma was more common in drug eluting stents and in areas of stented segments without significant in-stent restenosis. It was associated with more of periprocedural myocardial infarction.

In study of 313 in-stent restenosis between 2009 and 2017 in patients undergoing optical coherence guided percutaneous coronary intervention (PCI), neoatherosclerosis was defined as a lipid neointima or calcified neointima. eGFR, time from PCI to in-stent restenosis and drug eluting stent in-stent restenosis were independent predictors for neoatherosclerosis in this study [6]. Intravascular lithotripsy has been used to treat recurrent restenosis due to severe calcific neoatherosclerosis in one report [7].

A study of 185 patients with in-stent restenosis suggested that low density lipoprotein cholesterol (LDL-C) levels may be related to the formation and progression of early neoatherosclerosis. They suggested that poor control of LDL-C may be a risk factor for the occurrence of early neoatherosclerosis following drug eluting stent implantation [8].

Intensive therapy with rosuvastatin plus eicosapentaenoic acid was used in a study evaluating in-stent neoatherosclerosis with optical coherence tomography. In that study of 42 patients, intensive therapy prevented atherosclerotic progression more effectively in native coronary plaques in patients with neoatherosclerosis [9].


  1. Mazin I, Paul G, Asher E. Neoatherosclerosis – From basic concept to clinical implication. Thromb Res. 2019 Jun;178:12-16.
  2. Yahagi K, Kolodgie FD, Otsuka F, Finn AV, Davis HR, Joner M, Virmani R. Pathophysiology of native coronary, vein graft, and in-stent atherosclerosis. Nat Rev Cardiol. 2016 Feb;13(2):79-98.
  3. Otsuka F, Byrne RA, Yahagi K, Mori H, Ladich E, Fowler DR, Kutys R, Xhepa E, Kastrati A, Virmani R, Joner M. Neoatherosclerosis: overview of histopathologic findings and implications for intravascular imaging assessment. Eur Heart J. 2015 Aug 21;36(32):2147-59.
  4. Nakazawa G, Otsuka F, Nakano M, Vorpahl M, Yazdani SK, Ladich E, Kolodgie FD, Finn AV, Virmani R. The pathology of neoatherosclerosis in human coronary implants bare-metal and drug-eluting stents. J Am Coll Cardiol. 2011 Mar 15;57(11):1314-22.
  5. Ali ZA, Roleder T, Narula J, Mohanty BD, Baber U, Kovacic JC, Mintz GS, Otsuka F, Pan S, Virmani R, Sharma SK, Moreno P, Kini AS. Increased thin-cap neoatheroma and periprocedural myocardial infarction in drug-eluting stent restenosis: multimodality intravascular imaging of drug-eluting and bare-metal stents. Circ Cardiovasc Interv. 2013 Oct 1;6(5):507-17.
  6. Nakamura D, Dohi T, Ishihara T, Kikuchi A, Mori N, Yokoi K, Shiraki T, Mizote I, Mano T, Higuchi Y, Yamada T, Nishino M, Sakata Y. Predictors and outcomes of neoatherosclerosis in patients with in-stent restenosis. EuroIntervention. 2020 Sep 29:EIJ-D-20-00539.
  7. Salazar C, Escaned J, Tirado G, Gonzalo N. Intravascular lithotripsy for recurrent restenosis caused by severe calcific neoatherosclerosis. EuroIntervention. 2020 Jul 17;16(4):e351-e352.
  8. Meng L, Liu X, Yu H, Wei G, Gu X, Chang X, Xie M, Qu W, Peng X, Sun Y, Tian J, Yu B. Incidence and Predictors of Neoatherosclerosis in Patients with Early In-Stent Restenosis Determined Using Optical Coherence Tomography. Int Heart J. 2020 Sep 29;61(5):872-878.
  9. Sugizaki Y, Otake H, Kuroda K, Kawamori H, Toba T, Nagasawa A, Takeshige R, Nakano S, Matsuoka Y, Tanimura K, Takahashi Y, Fukuyama Y, Hirata KI. Concomitant Use of Rosuvastatin and Eicosapentaenoic Acid Significantly Prevents Native Coronary Atherosclerotic Progression in Patients With In-Stent Neoatherosclerosis. Circ J. 2020 Sep 25;84(10):1826-1836.
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