- Academic Editor
†These authors contributed equally.
Background: Neoatherosclerosis (NA)
is associated with stent failure. However, systematic studies on the
manifestations of NA and neovascularization (NV) at different stages after
drug-eluting stent (DES) implantation are lacking. Moreover, the relationship
between NA and NV in in-stent restenosis (ISR) has not been reported. This study
aimed to characterize NA and NV in patients with ISR at different post-DES stages
and compare the association between NA and NV in ISR lesions. Methods: A
total of 227 patients with 227 lesions who underwent follow-up optical coherence
tomography before percutaneous coronary intervention for DES ISR were enrolled
and divided into early (E-ISR:
Despite the ongoing evolution and various iterations of
drug-eluting stent (DES) technologies, the prevalence of in-stent restenosis
(ISR) remains high, accounting for approximately 10% of percutaneous coronary
interventions (PCI) [1, 2, 3]. Therefore, even the latest DES implants cannot
prevent stent failure. With the development and wide application of endovascular
imaging techniques, increasing evidence shows that in-stent neoatherosclerosis
(NA) is a major cause of stent failure, especially in the extended phase after
stent implantation [4, 5, 6, 7]. Neovascularization (NV) is associated with plaque
vulnerability [8, 9]; however, no reports have been found on the relationship
between NA and NV in ISR lesions. Moreover, elevated low-density lipoprotein
cholesterol (LDL-C) levels have been reported to increase the risk of plaque
rupture in de novo lesions. Lee et al. [5] showed LDL-C levels
In this single-center retrospective study, we consecutively screened 497
patients with ISR confirmed by coronary angiography (CAG) at the Affiliated
Hospital of Zunyi Medical University between January 2018 and October 2022. ISR was defined as a percent diameter stenosis exceeding 50%
within the stent implantation segment [10, 11, 12]. The inclusion
criteria were first ISR on CAG follow-up and availability of
OCT images before re-PCI. The exclusion criteria were combined multiple ISRs, ISR
occurring
Study flow diagram. ISR, in-stent restenosis; CAG, coronary angiography; DES, drug-eluting stents; E-ISR, early in-stent restenosis; LDL-C, low-density lipoprotein cholesterol; L-ISR, late in-stent restenosis; NV, neovascularization; OCT, optical coherence tomography; PCI, percutaneous coronary intervention; VL-ISR, very late in-stent restenosis.
Quantitative coronary angiographic (QCA) and OCT analyses are
presented in the Supplementary Materials. NA was
defined as neointimal formation in the presence of lipids or calcifications
in
Representative optical coherence tomography images of restenosis. (A) Homogeneous neointima. (B) Heterogeneous neointima. (C) Layered neointima. (D) Calcified neoatherosclerosis. (E) Both lipidic (asterisks) and calcified neoatherosclerosis (arrowhead). (F) Neoatherosclerosis (asterisks) with neovascularization (arrowheads). (G) Intraintima neovascularization (white arrowhead), peri-stent neovascularization (yellow arrowhead), and PLIA (asterisk). (H) Lipidic neoatherosclerosis (asterisks) with intimal disruption (arrowhead). (I) Macrophage infiltration (arrowhead). PLIA, peri-stent low intensity area.
Details of data analyses are presented in the Supplementary Materials.
A total of 227 patients with 227 lesions were included, with 55, 78, and 94
cases in the E-ISR, L-ISR, and VL-ISR groups, respectively. A comparative
analysis of the basic data and QCA analysis of the three groups showed no
significant differences among the groups, except for the clinical manifestations
during OCT follow-up and the time of stent implantation. The
number of patients presenting with acute coronary syndrome (ACS) at the early,
late, and very late stages of CAG follow-up was 10 (15.4%), 17
(21.8%), and 42 (44.7%), respectively (p
Overall (n = 227) | E-ISR (n = 55) | L-ISR (n = 78) | VL-ISR (n = 94) | p value | p value* | ||||
① vs. ② | ① vs. ③ | ② vs. ③ | |||||||
General information | |||||||||
Age, year | 64.00 (56.00–71.00) | 62.00 (54.00–70.00) | 63.00 (53.00–71.00) | 66.00 (58.00–72.00) | 0.065 | ||||
Male | 175 (77.1) | 40 (72.7) | 60 (76.9) | 75 (79.8) | 0.612 | ||||
Smoking | 125 (55.1) | 34 (61.8) | 42 (53.8) | 49 (52.1) | 0.499 | ||||
Hypertension | 138 (60.8) | 34 (61.8) | 44 (56.4) | 60 (63.8) | 0.602 | ||||
Diabetes mellitus | 70 (30.8) | 17 (30.9) | 18 (23.1) | 35 (37.2) | 0.135 | ||||
LDL-C (mmol/L) | 2.33 (1.95–2.90) | 2.27 (1.82–2.70) | 2.29 (1.96–2.76) | 2.42 (1.99–3.20) | 0.139 | ||||
Creatinine (µmol/L) | 84.00 (70.00–100.00) | 84.00 (69.00–97.00) | 84.00 (72.00–96.00) | 84.00 (69.00–105.25) | 0.832 | ||||
LVEF (%) | 56.00 (44.00–61.00) | 55.00 (43.00–60.00) | 56.00 (42.00–61.00) | 56.00 (51.75–60.00) | 0.612 | ||||
Time from implantation (months) | 38.00 (13.00–72.00) | 11.00 (8.00–11.00) | 35.00 (24.00–39.00) | 84.00 (63.00–120.00) | |||||
Clinical presentation | |||||||||
ACS at stenting | 115 (50.7) | 32 (58.2) | 38 (48.7) | 45 (47.9) | 0.437 | ||||
ACS at ISR | 69 (29.1) | 10 (15.4) | 17 (21.8) | 42 (44.7) | 0.329 | 0.002 | |||
Medication at follow-up | |||||||||
Aspirin | 185 (81.5) | 48 (87.3) | 66 (84.6) | 71 (75.5) | 0.14 | ||||
P2Y12 inhibitor | 174 (76.7) | 47 (85.5) | 59 (75.6) | 68 (72.3) | 0.182 | ||||
Statin | 195 (85.9) | 50 (90.9) | 70 (89.7) | 75 (79.8) | 0.082 |
Data are expressed as the median [interquartile range] or n (%). *A p
value of
The OCT analysis data for the entire stent are summarized in
Table 2 and Fig. 3. The kappa coefficients for inter- and
intra-observer agreement for the assessment of NA, lipid NA, calcified NA, NV,
intraintima NV, and peri-stent NV were 0.92/0.93, 0.89/0.92, 0.91/0.93,
0.93/0.94, 0.93/0.93, and 0.90/0.93, respectively. No significant differences
were observed in the quantitative analysis results among the three groups. In the
qualitative analysis, the overall prevalence of NA and NV was 52.9% (49.3%
lipidic, 20.3% calcified, and 16.7% were both lipidic and calcific) and 41.0%
(intimal, 30.0%; peri-stent, 31.7%; and 20.7% were both intimal and
peri-stent), respectively (Supplementary Fig. 1). The prevalence of NA
(E-ISR, 40.0%; L-ISR, 51.3%; LV-ISR, 61.7%) and NV (E-ISR, 25.5%; L-ISR,
41.0%; VL-ISR 50.0%) increased with time after stenting. NA mainly manifested
as lipidic, while the prevalence of calcified NA was not significantly different
among the three groups. Moreover, heterogeneous intima, thin-cap fibroatheroma
(TCFA), intimal rupture, plaque erosion, macrophage infiltration, red thrombus,
and white thrombus were more common in the VL-ISR than in the E-ISR group
(p
Overall (n = 227) | E-ISR (n = 55) | L-ISR (n = 78) | VL-ISR (n = 94) | p value | p value* | |||||
① vs. ② | ① vs. ③ | ② vs. ③ | ||||||||
Quantitative analysis | ||||||||||
Mean lumen area, mm |
3.46 (2.41–4.72) | 3.38 (2.38–4.78) | 3.52 (2.50–4.70) | 3.47 (2.34–4.70) | 0.405 | |||||
Mean stent area, mm |
7.12 (5.81–8.58) | 7.02 (5.60–8.29) | 7.21 (6.02–8.58) | 7.11 (5.77–8.90) | 0.081 | |||||
Neointimal area, mm |
3.31 (2.33–4.72) | 3.23 (2.34–4.66) | 3.36 (2.39–4.73) | 3.32 (2.27–4.72) | 0.688 | |||||
Neointimal burden (%) | 49.13 (36.06–62.88) | 48.40 (36.32–61.99) | 49.41 (37.20–61.88) | 49.28 (35.25–64.43) | 0.903 | |||||
Qualitative analysis | ||||||||||
Predominantly homogeneous | 105 (46.3) | 41 (74.5) | 38 (48.7) | 26 (27.7) | 0.03 | 0.004 | ||||
Predominantly | 122 (53.7) | 14 (25.5) | 40 (51.3) | 68 (72.3) | 0.03 | 0.004 | ||||
heterogeneous | ||||||||||
Layered | 45 (19.8) | 9 (16.4) | 11 (14.1) | 25 (26.6) | 0.094 | |||||
NA | 120 (52.9) | 22 (40.0) | 40 (51.3) | 58 (61.7) | 0.035 | 0.199 | 0.01 | 0.169 | ||
Lipidic | 112 (49.3) | 18 (32.7) | 39 (50.0) | 55 (58.5) | 0.01 | 0.047 | 0.002 | 0.264 | ||
Calcified | 46 (20.3) | 8 (14.5) | 12 (15.4) | 26 (27.7) | 0.066 | |||||
TCFA | 45 (19.8) | 5 (9.1) | 13 (16.7) | 27 (28.7) | 0.01 | 0.208 | 0.005 | 0.062 | ||
Intimal disruption | 41 (18.1) | 4 (7.3) | 12 (15.4) | 25 (26.6) | 0.009 | 0.157 | 0.004 | 0.075 | ||
Plaque erosion | 63 (27.8) | 8 (14.5) | 22 (28.2) | 33 (35.1) | 0.026 | 0.063 | 0.007 | 0.334 | ||
Macrophage | 43 (18.9) | 3 (5.5) | 13 (16.7) | 27 (28.7) | 0.002 | 0.05 | 0.001 | 0.062 | ||
Cholesterol crystal | 35 (15.4) | 5 (9.1) | 12 (15.4) | 18 (19.1) | 0.26 | |||||
PLIA | 31 (13.7) | 10 (18.2) | 12 (15.4) | 9 (9.6) | 0.289 | |||||
NV | 93 (41.0) | 14 (25.5) | 32 (41.0) | 47 (50.0) | 0.013 | 0.063 | 0.003 | 0.24 | ||
Intraintima | 68 (30.0) | 8 (14.5) | 24 (30.8) | 36 (38.3) | 0.009 | 0.031 | 0.002 | 0.302 | ||
Peri-stent | 72 (31.7) | 12 (21.8) | 22 (28.2) | 38 (40.4) | 0.045 | 0.406 | 0.02 | 0.094 | ||
Thrombus | 58 (25.6) | 6 (10.9) | 17 (21.8) | 35 (37.2) | 0.001 | 0.102 | 0.001 | 0.028 | ||
Red | 39 (17.2) | 3 (5.5) | 12 (15.4) | 24 (25.5) | 0.006 | 0.075 | 0.002 | 0.103 | ||
White | 49 (21.6) | 6 (10.9) | 15 (19.2) | 28 (29.8) | 0.021 | 0.195 | 0.008 | 0.111 |
Data are expressed as the median [interquartile range] or n (%). *A p
value of
OCT analysis of the entire stent. The prevalence of NA
and NV in an entire stent. E-ISR, early in-stent restenosis; L-ISR, late in-stent
restenosis; NA, neoatherosclerosis; NV, neovascularization; VL-ISR, very late
in-stent restenosis; OCT, optical coherence tomography.
The OCT analysis data for the MLA site are summarized in Supplementary Table 2. The results are similar to those of the entire stent analysis. Quantitative analysis showed no significant differences among the three groups. Qualitative analysis showed that from E-ISR to VL-ISR, the incidences of NA and NV increased gradually, NA was still mainly lipidic, and NV mostly manifested as endointimal microvessels. Moreover, heterogeneous intima, TCFA, intimal rupture, macrophage infiltration, endointimal NV, and red thrombosis were more common in the VL-ISR group.
Before comparing the relationship between NA and NV, we first compared the
characteristics of NA and non-NA patients, and found that the NA group had higher
LDL-C and creatinine levels and longer stent implantation time compared with
those in the non-NA group (p
Next, we compared the relationship between NA and NV and found no significant differences in general
clinical data, CAG, and quantitative OCT findings of the MLA site between NV and
non-NV groups, except for stent implantation time, MLA, and stent area; the median stent implantation time was longer in
the NV group than in the non-NV group (60.0 months vs. 36.0 months, p =
0.008); the MLA and stent area of the NV group were larger than those of the
non-NV group (p
Comparison of OCT characteristics of ISR lesions in the
NV and non-NV groups. NA, neoatherosclerosis; NV, neovascularization; PLIA,
peri-low intensity area; TCFA, thin-cap fibroatheroma; OCT, optical coherence tomography.
***p
Overall (n =227) | NV (n = 93) | Non-NV (n = 134) | p value | |||
General information | ||||||
Age, year | 64.00 (56.00–71.00) | 64.00 (57.00–71.50) | 63.00 (54.00–70.25) | 0.233 | ||
Male | 175 (77.1) | 72 (77.4) | 103 (76.9) | 0.922 | ||
Smoking | 125 (55.1) | 50 (53.8) | 75 (56.0) | 0.742 | ||
Hypertension | 138 (60.8) | 57 (61.3) | 81 (60.4) | 0.898 | ||
Diabetes mellitus | 70 (30.8) | 32 (34.4) | 38 (28.4) | 0.332 | ||
LDL-C (mmol/L) | 2.33 (1.95–2.90) | 2.27 (1.83–3.05) | 2.38 (1.98–2.88) | 0.389 | ||
Creatinine (µmol/L) | 84.00 (70.00–100.00) | 85.00 (71.50–100.00) | 83.50 (69.00–100.25) | 0.42 | ||
LVEF (%) | 56.00 (44.00–61.00) | 56.00 (50.00–61.00) | 56.00 (42.75–60.00) | 0.136 | ||
Time from implantation (months) | 38.00 (13.00–72.00) | 60.00 (24.00–96.00) | 36.00 (11.00–63.25) | 0.008 | ||
CAG finding | ||||||
Length, mm | 12.10 (8.70–17.90) | 11.80 (8.75–17.10) | 12.35 (8.60–18.53) | 0.564 | ||
Reference vessel diameter, mm | 3.18 |
3.23 |
3.14 |
0.107 | ||
MLD, mm | 1.14 |
1.15 |
1.13 |
0.496 | ||
Diameter stenosis (%) | 63.48 (60.06–67.68) | 63.31 (59.99–67.63) | 63.56 (60.05–67.70) | 0.962 | ||
Previous stent type | 0.416 | |||||
First-generation DES | 172 (75.8) | 72 (77.4) | 100 (74.6) | |||
New-generation DES | 44 (19.4) | 15 (16.1) | 29 (21.6) | |||
Unknown | 11 (4.8) | 6 (6.5) | 5 (3.7) | |||
OCT finding | ||||||
MLA, mm |
1.64 |
1.75 |
1.57 |
0.016 | ||
Stent area (MLA site), mm |
6.74 |
7.11 |
6.47 |
0.016 | ||
Neointimal area (MLA site), mm |
4.80 (3.84–6.12) | 5.12 (4.05–6.34) | 4.66 (3.80–5.93) | 0.111 | ||
Neointimal burden (MLA site), % | 74.54 |
74.34 |
74.68 |
0.773 | ||
Predominantly homogeneous | 105 (46.3) | 31 (33.3) | 74 (55.2) | 0.001 | ||
Predominantly heterogeneous | 122 (53.7) | 62 (66.7) | 60 (44.8) | |||
NA | 120 (52.9) | 64 (68.8) | 56 (41.8) | |||
Non-NA | 107 (47.1) | 29 (31.2) | 78 (58.2) | |||
TCFA | 45 (19.8) | 28 (30.1) | 17 (12.7) | 0.001 | ||
Intimal rupture | 41 (18.1) | 26 (28.0) | 15 (11.2) | 0.001 | ||
Macrophage | 43 (18.9) | 31 (33.3) | 12 (9.0) | |||
Cholesterol crystal | 35 (15.4) | 19 (20.4) | 16 (11.9) | 0.082 | ||
PLIA | 31 (13.7) | 18 (19.4) | 13 (9.7) | 0.037 | ||
Thrombus | 58 (25.6) | 35 (37.6) | 23 (17.2) | 0.001 |
Data are expressed as the median [interquartile range], mean
Comparison of the general data and CAG
findings between the two groups revealed that the prevalence of diabetes mellitus
(DM) was higher in the LDL-C
Overall (n = 227) | LDL-C |
LDL-C |
p value | |||
General information | ||||||
Age, year | 64.00 (56.00–71.00) | 65.00 (56.00–73.00) | 64.00 (55.75–71.00) | 0.488 | ||
Male | 175 (77.1) | 35 (85.4) | 140 (75.3) | 0.164 | ||
Smoking | 125 (55.1) | 25 (61.0) | 100 (53.8) | 0.401 | ||
Hypertension | 138 (60.8) | 24 (58.5) | 114 (61.3) | 0.744 | ||
Diabetes mellitus | 70 (30.8) | 18 (43.9) | 52 (28.0) | 0.045 | ||
Creatinine (µmol/L) | 84.00 (70.00–100.00) | 85.00 (72.00–100.50) | 84.00 (69.00–100.00) | 0.471 | ||
LVEF (%) | 56.00 (44.00–61.00) | 58.00 (43.00–62.50) | 55.00 (44.75–60.00) | 0.306 | ||
Time from implantation (months) | 38.00 (13.00–72.00) | 36.00 (11.00–68.50) | 48.00 (15.00–84.00) | 0.149 | ||
Previous stent type | 0.406 | |||||
First-generation DES | 172 (75.8) | 28 (68.3) | 144 (77.4) | |||
New-generation DES | 44 (19.4) | 11 (26.8) | 33 (17.7) | |||
Unknown | 11 (4.8) | 2 (4.9) | 9 (4.8) | |||
CAG finding | ||||||
Length, mm | 12.10 (8.70–17.90) | 10.40 (8.45–16.20) | 12.85 (8.80–18.33) | 0.058 | ||
Reference vessel diameter, mm | 3.18 |
3.23 |
3.17 |
0.341 | ||
MLD, mm | 1.14 |
1.16 |
1.13 |
0.515 | ||
Diameter stenosis (%) | 63.48 (60.06–67.68) | 61.95 (59.33–68.09) | 63.64 (60.24–67.55) | 0.402 | ||
OCT finding | ||||||
Predominantly homogeneous | 105 (46.3) | 34 (82.9) | 71 (38.2) | |||
Predominantly heterogeneous | 122 (53.7) | 7 (17.1) | 115 (61.8) | |||
NA | 120 (52.9) | 12 (29.3) | 108 (58.1) | 0.001 | ||
Lipidic | 112 (49.3) | 11 (26.8) | 101 (54.3) | 0.001 | ||
Calcified | 46 (20.3) | 7 (17.1) | 39 (21.0) | 0.574 | ||
TCFA | 45 (19.8) | 3 (7.3) | 42 (22.6) | 0.026 | ||
Intimal rupture | 41 (18.1) | 3 (7.3) | 38 (20.4) | 0.048 | ||
Plaque erosion | 63 (27.8) | 7 (17.1) | 56 (30.1) | 0.092 | ||
Macrophage | 43 (18.9) | 4 (9.8) | 39 (21.0) | 0.097 | ||
Cholesterol crystal | 35 (15.4) | 5 (12.2) | 30 (16.1) | 0.528 | ||
PLIA | 31 (13.7) | 7 (17.1) | 24 (12.9) | 0.482 | ||
NV | 93 (41.0) | 21 (51.2) | 72 (38.7) | 0.14 | ||
Intraintima | 68 (30.0) | 11 (26.8) | 57 (30.6) | 0.629 | ||
Peri-stent | 72 (31.7) | 18 (43.9) | 54 (29.0) | 0.064 | ||
Thrombus | 58 (25.6) | 4 (9.8) | 54 (29.0) | 0.01 | ||
Red | 39 (17.2) | 2 (4.9) | 37 (19.9) | 0.021 | ||
White | 49 (21.6) | 4 (9.8) | 45 (24.2) | 0.042 |
Data are expressed as the median [interquartile range], mean
Comparison of
plaque characteristics between LDL-C
The main findings of the study are as follows: (1) the
prevalence of lipidic (not calcified) NA and intimal NV increased over time after
stenting. Additionally, the homogeneous intima decreased gradually, while the
heterogeneous intima increased from E-ISR to VL-ISR. TCFA, intimal rupture,
plaque erosion, macrophage infiltration, and thrombus were more common in the
VL-ISR group than in the E-ISR group; (2) the prevalence of NA was higher in
patients with ISR and NV lesions than in those without. Moreover, patients with
ISR plus NV had a higher incidence of macrophage infiltration, TCFA, intimal
rupture, and thrombosis; (3) patients with ISR with poorly controlled LDL-C
levels had a higher incidence of plaque vulnerability than those with LDL-C
A previous study found that the incidences of NA after the first- and
second-generation of DES implants were 45.5% and 10.8%, respectively; moreover,
the incidence of NA gradually increased with the extension of follow-up time [5].
Nakamura et al. [4] reported the NA incidence of 47.0% among 64
bare-metal stent (BMS) ISR and 241 DES ISR lesions. Chen et al. [16]
reported an NA incidence as high as 75% after
Although evidence suggests that the incidence of NA is
time-dependent, systematic studies on the manifestations of NA at different
stages are lacking. Previous studies by Yonetsu et al. [20] reported
that the incidence of lipid-rich neointima (lipid NA) in BMS/DES was
time-dependent, with 8%/37%, 28%/63%, and 77%/75% in the early (
Previous studies showed that first-generation DES implants significantly reduced
the prevalence of BMS-associated ISR but also increased the incidence of stent
thrombosis [23]. Second-generation DES is associated with fewer stent thrombotic
events, but NA formation remained unavoidable [24, 25]. Lee et al. [5]
also showed that second-generation DES did not prevent NA better than the
first-generation DES. Furthermore, the development of NA after DES implantation
has been described as a late catch-up phenomenon, as it has been observed that
neointimal growth is highly inhibited in the first year after DES implantation; however, subsequently, it shows sustained progression,
accompanied by rapid lipid-laden macrophage deposition, thus becoming the final
common pathway for stent failure in the late stages [6, 26]. Therefore, both
pathological studies and endovascular imaging findings have shown that NA
formation was an important cause of late failure of BMS, first-
and second-generation DES [6, 27]. In an OCT analysis of 2139 patients with ACS,
Amabile et al. [28] showed that NA is common in patients with very late
stent thrombosis. Habara et al. [10] showed that VL-ISR (
Consequently, NA formation may lead to stent failure and can trigger MACEs [29, 30, 31]. In this study, the number of patients presenting with ACS at follow-up was significantly higher in the VL-ISR group than in the E-ISR group; this may be related to the significantly higher prevalence of NA in the VL-ISR than in the E-ISR group. The incidence of NA with intimal rupture and thrombus in the VL-ISR group (21 intimal ruptures and 30 thrombi among 58 NA lesions) was significantly higher than that in the E-ISR group (3 intimal ruptures and 5 thrombi among 22 NA lesions), suggesting that NA plays an important role in stent failure and MACE. Notably, both the incidence of NA and NV are time-dependent, and there may be a potential relationship between them, but no reports have been found on the relationship between NA and NV in ISR lesions. Based on an in situ lesion study, the incidence of NA is reportedly associated with the formation of NV [32]. Therefore, we hypothesized that there might be a correlation between the occurrence of NA and the presence of NV in ISR lesions. To investigate and verify this hypothesis, we further explored the relationship between NA and NV in ISR lesions.
NV has been regarded as an important pathway for the delivery of erythrocytes and inflammatory cells involved in lipid plaque formation and has been identified as a contributor of plaque vulnerability [33]. In this study, NV, especially intraintimal NV, increased gradually from E-ISR to VL-ISR. Another study found that NV dilatation in the plaques for native coronary arteries was closely related to plaque vulnerability; plaques with NV have thinner fibrous caps and a higher incidence of plaque rupture [8]. NV inhibition effectively prevents atherosclerosis in situ [34]. Lipid-laden intima is thought to be closely associated with intimal NV after BMS implantation [17]. Tian et al. [32] also reported that NA was more common in stents with NV within the intima. In addition, Gao et al. [35] reported no difference in the incidence of NA between diabetic and non-diabetic patients, but NV in NA lesions was more common in diabetic patients. Our results also showed that the prevalence of NA was similar in diabetic and non-diabetic patients, and no difference in the incidence of NA was observed in diabetic patients with and without NV lesions; this may be related to the inclusion of a special population (ISR patients) in this study, which is expected to be further confirmed by randomized studies. Significantly, we found that NA was more frequently observed in ISR patients with NV lesions. Moreover, patients with ISR plus NV had higher incidences of macrophage infiltration, TCFA, intimal rupture, and thrombosis. These findings suggest that NV formation and dilatation in ISR lesions may be associated with NA progression and plaque vulnerability.
LDL-C is well known to be involved in atherosclerosis development and
progression, and high levels promote cardiovascular events. In situ
studies have shown that active control of LDL-C levels can stabilize or reverse
coronary plaque, thus reducing the risk of MACE [36, 37, 38]. A
first- and second-generation DES study showed that LDL-C
The current research has some limitations. First, this was a single-center, retrospective study with a relatively limited sample size. Second, some individuals diagnosed with ISR were excluded from the study owing to the absence of OCT imaging, which may introduce a potential selection bias, and the data derived from this study may not represent the wider patient population. Consequently, the findings of this investigation are solely descriptive and intended to generate hypotheses, which require further validation through large-sample randomized prospective trials. Third, not reporting the clinical results of these patients is an important limitation of this study. However, we are currently collecting the clinical follow-up data of these patients, and the data are not yet complete. Therefore, they were not included in the analysis of this study. We will continue to collect and analyze the clinical outcomes of these patients and report the results in future studies. Last, there was a lack of histological validation of neointimal tissue characteristics. Although OCT is the preferred intravascular imaging method for diagnosing NA in vivo, it has its own limitations and may not accurately assess qualitative neointimal characteristics.
Progression of lipidic NA was associated with L-ISR and VL-ISR but may not be related to calcified NA. NV formation may be associated with NA progression and plaque vulnerability in ISR lesions. Moreover, patients with poorly controlled LDL-C had lesions with more vulnerable features; consequently, patients with ISR also need aggressive lipid-lowering therapy. However, further randomized controlled trials are needed to determine target LDL-C levels for different populations in clinical practice.
ACS, acute coronary syndrome; BMS, bare-metal stent; CAG, coronary angiography; DES, drug-eluting stent; DM, diabetes mellitus; ISR, in-stent restenosis; LAD, left anterior descending artery; LCX, left circumflex artery; LDL-C, low-density lipoprotein cholesterol; LVEF, left ventricular ejection fraction; MACE, major adverse cardiovascular event; MLA, minimum lumen area; MLD, minimal lumen diameter; NA, neoatherosclerosis; NV, neovascularization; OCT, optical coherence tomography; PCI, percutaneous coronary intervention; PLIA, peri-stent low intensity area; QCA, quantitative coronary analysis; RCA, right coronary artery.
The datasets generated during the current study are not publicly available due to their confidential nature. However, they can be obtained from the corresponding author upon reasonable request.
BS, RZ, and YZ conceptualized the study. CD, ZL, WZ, and YD performed the methodology. HL, JR, WD, NG, YS, and XH conducted the investigation. Data curation was carried out by HL, ZB, YS and CD. ZB, HL and NG conducted formal analysis. The original draft was written by CD and ZL. BS, YZ, and RZ reviewed and edited the draft. Funding acquisition was carried out by ZB, YZ, and CD. BS and RZ provided resources for this study. BS, ZL, RZ, and YZ supervised the study. All authors contributed to the manuscript’s editorial changes, have read and approved the published version, and agreed to be accountable for all aspects of the work.
This study was approved by the Ethics Committee of the Affiliated Hospital of Zunyi Medical University (ZMU[2022] 1-177) and informed consent was obtained from all patients.
We would like to express our gratitude to all those who helped us during the writing of this manuscript. Thanks to all the peer reviewers for their opinions and suggestions.
This research was supported by the National Natural Science Foundation of China (Grant Numbers: 82260106, 82200290), the Science and Technology Program of the Guizhou Province (Grant Numbers: ZK [2022] 671, LC [2021] 026), the Excellent Young Talent Cultivation Project of Zunyi City (Grant Number: HZ (2022) 366), and the Master Research Foundation of the Affiliated Hospital of Zunyi Medical University (Grant Number: [2016] 32).
The authors declare no conflict of interest.
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