The pathology of neoatherosclerosis in human coronary implants bare-metal and drug-eluting stents

Abstract

Objectives: Human coronary bare-metal stents (BMS) and drug-eluting stents (DES) from autopsy cases with implant duration >30 days were examined for the presence of neointimal atherosclerotic disease.

Background: Neointimal atherosclerotic change (neoatherosclerosis) after BMS implantation is rarely reported and usually occurs beyond 5 years. The incidence of neoatherosclerosis after DES implantation has not been reported.

Methods: All available cases from the CVPath stent registry (n = 299 autopsies), which includes a total of 406 lesions-197 BMS, 209 DES (103 sirolimus-eluting stents [SES] and 106 paclitaxel-eluting stents [PES])-with implant duration >30 days were examined. Neoatherosclerosis was recognized as clusters of lipid-laden foamy macrophages within the neointima with or without necrotic core formation.

Results: The incidence of neoatherosclerosis was significantly greater in DES lesions (31%) than BMS lesions (16%; p < 0.001). The median stent duration with neoatherosclerosis was shorter in DES than BMS (DES, 420 days [interquartile range [IQR]: 361 to 683 days]; BMS, 2,160 days [IQR: 1,800 to 2,880 days], p < 0.001). Unstable lesions characterized as thin-cap fibroatheromas or plaque rupture were more frequent in BMS (n = 7, 4%) than in DES (n = 3, 1%; p = 0.17), with relatively shorter implant durations for DES (1.5 ± 0.4 years) compared to BMS (6.1 ± 1.5 years). Independent determinants of neoatherosclerosis identified by multiple logistic regression included younger age (p < 0.001), longer implant durations (p < 0.001), SES usage (p < 0.001), PES usage (p = 0.001), and underlying unstable plaques (p = 0.004).

Conclusions: Neoatherosclerosis is a frequent finding in DES and occurs earlier than in BMS. Unstable features of neoatherosclerosis are identified for both BMS and DES with shorter implant durations for the latter. The development of neoatherosclerosis may be yet another rare contributing factor to late thrombotic events.

Figure 1. Representative images of the various stages of newly formed atherosclerotic changes within the neointima after stent implantation are illustrated

Foamy macrophage clusters in the peri-strut region of sirolimus-eluting stents (SES) implanted for13 months antemortem is seen in A. Fibroatheroma with foamy macrophage rich lesion and early necrotic core formation in SES of 13 months duration (B). Fibroatheroma with peri-strut early necrotic core, cholesterol clefts, surface foamy macrophages, and early calcification (arrow) in SES at 13 months (C). Peri-strut late necrotic core in the neointima characterized by large aggregate of cholesterol cleft in SES at 17 months (D). Fibroatheroma with calcification in the necrotic core in SES of 10 months duration (E). A peri-strut calcification (arrow) with fibrin in SES of 7 months duration (F). (G and H) A low (H) and high power (G) magnification image of a severely narrowed bare metal stents (BMS) implanted 61 months with a thin-cap fibroatheroma. Note macrophage infiltration and a discontinuous thin fibrous cap (G). (I and J) A low magnification image shows a plaque rupture with an acute thrombus that has totally occluded the lumen in BMS implanted for 61 months antemortem (I). A high magnification image shows a discontinuous thin-cap with occlusive luminal thrombus (J).

Figure 2. Representative cases showing atherosclerotic change following BMS, SES, and PES implantation

(A to C) Histologic sections from a 65-year-old woman with a paclitaxel-eluting stent (PES) implanted in the left circumflex artery 14 months antemortem, who died of traumatic brain injury. A low power image shows a patent lumen with moderate neointimal growth (A), foamy macrophage infiltration and necrotic core formation with cholesterol clefts is seen at high magnification in B. (C) Same section as B showing CD68 positive macrophages in the neointima. (D to F) Histological sections from a 59-year-old male with sirolimus-eluting stents (SES) (Patient 10 in Table 4) implanted for 23 months who died from stent thrombosis (D). Note thin-cap fibroatheroma with fibrous cap disruption in E (arrows) from boxed area in D. The thrombus (Th) was more apparent in the distal section taken 3 mm apart (D). F shows CD 68 positive macrophages in the fibrous cap and in the underlying necrotic core. (G to I) Histologic section from a 47-year-old male who had a bare metal stents (BMS) implanted 8 years prior to death (Case 8 in Table 4). Note occlusive thrombus (Th) in the lumen and ruptured plaque (boxed area in G), which is shown at higher magnification in H with large number of macrophages within the lumen as well as at the ruptured cap. Note large number of CD 68 positive macrophages at the site of rupture (I).

Figure 3. Bar graph showing cumulative incidence of atherosclerotic change with time following implantation of BMS vs. SES, and PES

Both sirolimus-eluting stents (SES) and paclitaxel-eluting stents (PES) show earlier onset of neoatherosclerosis and a higher incidence of lesion formation as compared to bare metal stents (BMS). No drug-eluting stents (DES) was available beyond 6 years.