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Angioscopic findings 1 year after percutaneous coronary intervention for chronic total occlusion

Open AccessPublished:September 01, 2022DOI:https://doi.org/10.1016/j.jjcc.2022.08.008

      Highlights

      • This study suggests delayed healing of stents implanted for chronic total occlusion (CTO) lesions.
      • Longer duration of dual-antiplatelet therapy (DAPT) may be beneficial for these patients.
      • Delayed healing for stents implanted for acute coronary syndrome lesions.
      • Extended DAPT may be useful in cases of percutaneous coronary intervention for CTO lesions.

      Abstract

      Background

      Chronic total occlusion (CTO) is a high-risk factor for stent thrombosis, but little is known about the difference in neointimal healing between CTO and non-CTO lesions regarding implanted stents. We investigated factors affecting neointimal healing after stent implantation for CTO and non-CTO lesions using angioscopy.

      Methods

      We retrospectively evaluated 106 stents in 85 consecutive patients between March 2016 and July 2020. Their average age was 68 ± 11 years, and participants (73 male and 12 female) underwent follow-up angiography and angioscopy 1 year after percutaneous coronary intervention (PCI). The stents (n = 106) were divided into three groups according to the lesion status at the previous PCI: CTO (n = 17), acute coronary syndrome (ACS) (n = 35), and stable coronary artery disease without CTO or non-CTO (n = 54).

      Results

      The neointimal stent coverage grade was significantly lower in the CTO and ACS groups than in the non-CTO group (0.4 ± 0.5, 0.9 ± 0.8, and 1.4 ± 0.8, respectively, p < 0.001). Thrombi were significantly more frequent in CTO and ACS than in non-CTO (71 %, 51 %, and 15 %, respectively, p < 0.001). The yellow grade in CTO was comparable to that in ACS but significantly higher in CTO than in non-CTO (CTO vs. ACS vs. non-CTO 1.5 ± 0.7, 1.4 ± 0.6, and 0.9 ± 0.7, respectively, p = 0.007).

      Conclusions

      Delayed healing occurs in stents implanted for CTO lesions. Longer dual-antithrombotic therapy may be beneficial.

      Graphical abstract

      Keywords

      Introduction

      The success rate of percutaneous coronary intervention (PCI) for chronic total occlusion (CTO) lesions has notably increased owing to the widespread use of the bidirectional approach [
      • Maeremans J.
      • Walsh S.
      • Knaapen P.
      • Spratt J.C.
      • Avran A.
      • Hanratty C.G.
      • et al.
      The hybrid algorithm for treating chronic total occlusions in Europe: the RECHARGE registry.
      ]. Studies have demonstrated that successful recanalization of coronary CTO lesions may improve long-term outcomes [
      • Jones D.A.
      • Weerackody R.
      • Rathod K.
      • Behar J.
      • Gallagher S.
      • Knight C.J.
      • et al.
      Successful recanalization of chronic total occlusions is associated with improved long-term survival.
      ,
      • Mashayekhi K.
      • Nührenberg T.G.
      • Toma A.
      • Gick M.
      • Ferenc M.
      • Hochholzer W.
      • et al.
      A randomized trial to assess regional left ventricular function after stent implantation in chronic total occlusion: the REVASC trial.
      ], although CTO is still considered a notable risk factor of stent thrombosis [
      • Giustino G.
      • Chieffo A.
      • Palmerini T.
      • Valgimigli M.
      • Feres F.
      • Abizaid A.
      • et al.
      Efficacy and safety of dual antiplatelet therapy after complex PCI.
      ]. Current guidelines recommend that the duration of dual antiplatelet therapy (DAPT) after PCI should consider both bleeding and thrombotic risks. Although thrombotic risk factors are listed in the guidelines, and CTO is included as a thrombotic risk factor, it is uncertain how each individual factor affects stent healing [
      • Valgimigli M.
      • Bueno H.
      • Byrne R.A.
      • Collet J.P.
      • Costa F.
      • Jeppsson A.
      • et al.
      2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: the task force for dual antiplatelet therapy in coronary artery disease of the european Society of Cardiology (ESC) and of the european Association for Cardio-Thoracic Surgery (EACTS).
      ,
      • Nakamura M.
      • Kimura K.
      • Kimura T.
      • Ishihara M.
      • Otsuka F.
      • Kozuma K.
      • et al.
      JCS 2020 guideline focused update on antithrombotic therapy in patients with coronary artery disease.
      ].
      Coronary angioscopy is a unique diagnostic modality that allows the direct visualization of the internal surface of a vessel, provides detailed information about the characteristics of a plaque or thrombus and the degree of neointimal healing of the stent, and produces a full-color, three-dimensional image [
      • Mizuno K.
      • Takano M.
      Coronary angioscopy.
      ,
      • Mitsutake Y.
      • Yano H.
      • Ishihara T.
      • Matsuoka H.
      • Ueda Y.
      • Ueno T.
      Consensus document on the standard of coronary angioscopy examination and assessment from the japanese Association of Cardiovascular Intervention and Therapeutics.
      ]. A previous angioscopic study revealed delayed neointimal stent coverage and a higher incidence of thrombus on the stent strut in first-generation drug-eluting stents (DES) [
      • Takano M.
      • Ohba T.
      • Inami S.
      • Seimiya K.
      • Sakai S.
      • Mizuno K.
      Angioscopic differences in neointimal coverage and in persistence of thrombus between sirolimus-eluting stents and bare metal stents after a 6-month implantation.
      ]. Acute coronary syndrome (ACS) is also known as a cause of delayed neointimal stent coverage after DES implantation [
      • Räber L.
      • Zanchin T.
      • Baumgartner S.
      • Taniwaki M.
      • Kalesan B.
      • Moschovitis A.
      • et al.
      Differential healing response attributed to culprit lesions of patients with acute coronary syndromes and stable coronary artery after implantation of drug-eluting stents: an optical coherence tomography study.
      ]. Therefore, we conducted a study to investigate the difference in neointimal healing between stents implanted for CTO lesions and those implanted for non-CTO or ACS lesions using coronary angioscopy to assess the thrombotic risk of CTO lesions.

      Methods

      Our retrospective study included 106 stents in 85 consecutive patients who underwent follow-up angiography and angioscopy 1 year after PCI between March 2016 and July 2020 at our hospital. Of the 85 patients, 73 were males and 12 were female. The average age of the selected patients was 68 ± 11 years. The examined stents were divided into three groups according to the lesion status at the previous PCI: CTO group (n = 17), ACS group (n = 35), and stable coronary artery disease without CTO (non-CTO group, n = 54). The patients' cases were reviewed at a 1-year follow-up using medical records, and the angioscopic findings were evaluated. Coronary interventions were performed in accordance with standard techniques and international guidelines. Intravascular ultrasound guidance was used in all CTO interventions. This study was performed in accordance with the Declaration of Helsinki. The institutional review committee of Nippon Medical School approved the study (Approval number: B-2021-418), and all patients provided written informed consent.
      Catheterization was performed via a transradial approach using 4-Fr catheters. Selective coronary angiography was performed after administering 3000 units of heparin. Coronary angioscopy was performed with a 3.6-Fr rapid-exchange angioscope (SMART-i®, Fibertech, Tokyo, Japan). Irrigation with low-molecular-weight dextran solution was continuously performed from a deeply engaged 4-Fr guiding catheter (Kiwami®, Terumo, Tokyo, Japan) to get a clear field of view devoid of blood during imaging (Fig. 1). Low-molecular-weight dextran solution was injected into the left (40 to 50 mL at 4 to 5 mL/s) and right (30 to 40 mL at 3 to 4 mL/s) coronary arteries using an auto-powered injector. Before observation, the white balance was adjusted for optimal color image collection. The light power was adjusted to avoid reflection and to obtain images with adequate brightness for the determination of the plaque color. During the angioscopy procedure, an assistant adjusted the light power to maintain a constant brightness level on the target plaque or lesion. Angioscopic and fluoroscopic images were recorded simultaneously on a digital recorder for future analysis.
      Fig. 1
      Fig. 1Angioscopy procedure (right anterior oblique cranial view).
      Fluoroscopy shows an everolimus-eluting stent implanted in the proximal left descending artery (blue line). Irrigation with low-molecular-weight dextran solution was continuously performed from a deeply engaged 4-Fr guiding catheter (the red arrow indicates the tip of the catheter) to clear the field of view of blood during imaging (angioscope, yellow arrow shows the tip of the angioscope).
      We assessed the degree of neointimal stent coverage, yellow color grade of the plaque, and the presence of thrombi [
      • Mitsutake Y.
      • Yano H.
      • Ishihara T.
      • Matsuoka H.
      • Ueda Y.
      • Ueno T.
      Consensus document on the standard of coronary angioscopy examination and assessment from the japanese Association of Cardiovascular Intervention and Therapeutics.
      ]. The degree of neointimal stent coverage of the stent struts was evaluated using a grading system as follows: grade 0 (stent struts with complete exposure, similar to findings immediately after implantation), grade 1 (transparent stent struts with dull light reflection), grade 2 (stent struts slightly visible, with no light reflection from the struts), and grade 3 (stent struts completely covered and not visible through the neointima) (Fig. 2). The minimum grade was assessed and the struts located at the orifice of the side branches were excluded from this evaluation. The level of intensity of the yellow color grade represents the increased risk of an atherosclerotic plaque or lesion, as well as being a predictor for stent failure [
      • Ueda Y.
      • Matsuo K.
      • Nishimoto Y.
      • Sugihara R.
      • Hirata A.
      • Nemoto T.
      • et al.
      In-stent yellow plaque at 1 year after implantation is associated with future event of very late stent failure: the DESNOTE study (Detect the event of very late stent failure from the drug-eluting stent not well covered by neointima determined by angioscopy).
      ]. The yellow color grade was classified semi-quantitatively according to the surface color as: grade 0 (white), grade 1 (light yellow), grade 2 (yellow), and grade 3 (intense yellow) (Fig. 2). The maximum color grade of the plaques was assessed. Thrombus is defined as a red and/or white solid material adhering to the intima or protruding into the inner lumen despite flushing with clear liquid (Fig. 2, white arrow). A previous study revealed that thrombus was detected on yellow and/or Grade-0/1 neointima, but never on the white Grade-2 neointima [
      • Higo T.
      • Ueda Y.
      • Oyabu J.
      • Okada K.
      • Kashiwase K.
      • Kodama K.
      • et al.
      Atherosclerotic and thrombogenic neointima formed over sirolimus drug-eluting stent: an angioscopic study.
      ]. The presence of thrombus reflects insufficient neointimal healing and the increased potential risk of stent thrombosis. Angioscopic evaluations were made by two angioscopy specialists blinded to the clinical status.
      Fig. 2
      Fig. 2Angioscopic grading of neointimal stent coverage and grading of yellow plaque, and representative image of thrombus.
      Top – Angioscopic grading of neointimal stent coverage. Grade 0: stent struts with complete exposure (similar to immediately after implantation). Grade 1: transparent stent struts with dull light reflection. Grade 2: stent struts slightly visible, with no light reflection from the stent struts. Grade 3: completely covered stent struts not visible through the neointima.
      Right – thrombus (white arrow).
      Bottom – Grading of yellow plaque. The color of the plaques was graded as 0 (white), 1 (light yellow), 2 (yellow), and 3 (bright yellow).
      The data are expressed as mean ± SD for continuous variables and as number (%) for categorical variables. For continuous variables, the differences between groups were compared using one-way analysis of variance followed by the Student t-test with Bonferroni correction for intergroup comparisons. For categorical variables, the differences between the groups were compared using the chi-square test. For multivariate analysis, logistic regression was used to investigate the factors associated with neointimal stent coverage, presence of thrombi, and yellow color grade. All analyses were conducted with SPSS version 25 (IBM, Armonk, NY, USA), and p-values <0.05 were considered significant.

      Results

      The baseline patients' characteristics of each group at 1-year follow-up are shown in Table 1. The CTO, ACS, and non-CTO groups included 17 (16 %), 35 (33 %), and 54 (51 %) cases, respectively. Patients in the non-CTO group tended to be older than those in the ACS group (69 ± 10 years vs. 64 ± 11 years, p = 0.063). The prevalence of coronary risk factors was comparable between the three groups, but the incidence of hyperuricemia was significantly higher in the CTO group (p = 0.040). DAPT was continued in all patients in the CTO group, in 94 % of the ACS group, and in 85 % of the non-CTO group. Statins were administered to almost all patients. Prescription rates of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, β-blockers, and diuretics were significantly higher in the ACS (p = 0.017), CTO and ACS (p = 0.019), and CTO (p < 0.001) groups, respectively. There were no significant differences in the levels of low- and high-density lipoprotein-cholesterol, triglyceride, HbA1c, uric acid, and serum creatinine between the three groups. Left ventricular ejection fraction assessed by echocardiography was significantly lower in CTO group than in the non-CTO group (p = 0.035). Lesion location and stent types were similar between the three groups. The number of stents was significantly larger in the CTO group than in the ACS and non-CTO groups (1.9 ± 0.9, 1.3 ± 0.5, and 1.3 ± 0.5, respectively, p = 0.001). Stent length was significantly greater in the CTO group than in the non-CTO group (49 ± 28 mm vs. 34 ± 21 mm, p = 0.030). The minimum stent diameter was significantly smaller in the CTO group than in the non-CTO group (2.7 ± 0.3 mm vs. 3.0 ± 0.4 mm, p = 0.017).
      Table 1Patients' characteristics at 1-year follow-up.
      CTO (n = 17)ACS (n = 35)Non-CTO (n = 54)p-Value
      Age (years)67 ± 1264 ± 1169 ± 100.063
      Male (%)15 (88 %)28 (80 %)50 (93 %)0.209
      BMI (kg/m2)25.4 ± 3.623.6 ± 3.224 ± 3.50.297
      AF (%)2 (1 %)1 (3 %)3 (6 %)0.427
      CHF (%)2 (1 %)1 (3 %)2 (4 %)0.321
      Coronary risk factors
      Hypertension (%)15 (88 %)29 (83 %)45 (83 %)0.870
      Dyslipidemia (%)15 (88 %)33 (94 %)48 (89 %)0.653
      Diabetes mellitus (%)6 (35 %)12 (34 %)22 (41 %)0.848
      Smoking (%)13 (76 %)20 (57 %)37 (69 %)0.332
      Family history (%)5 (29 %)8 (23 %)17 (31 %)0.673
      Hyperuricemia (%)11 (65 %)10 (29 %)20 (37 %)0.040
      Medications
      DAPT use (%)17 (100 %)33 (94 %)46 (85 %)0.124
      Aspirin (%)17 (100 %)33 (94 %)47 (87 %)0.191
      P2Y12 inhibitors (%)17 (100 %)35 (100 %)53 (98 %)0.615
      DOAC (%)2 (12 %)1 (3 %)2 (4 %)0.321
      Statin (%)17 (100 %)35 (100 %)50 (93 %)0.135
      ACE-I/ARB (%)13 (76 %)34 (97 %)40 (74 %)0.017
      β-Blocker (%)16 (94 %)26 (74 %)32 (59 %)0.019
      CCB (%)6 (35 %)10 (28 %)25 (46 %)0.233
      Insulin (%)1 (6 %)1 (3 %)5 (9 %)0.490
      Diuretics (%)8 (47 %)3 (9 %)3 (6 %)<0.001
      Laboratory data
      Hb (mg/dL)14.3 ± 1.613.7 ± 1.413.7 ± 1.30.305
      LDL-C (mg/dL)83 ± 1571 ± 2271 ± 270.199
      HDL-C (mg/dL)52 ± 1550 ± 1449 ± 110.804
      TG (mg/dL)157 ± 117151 ± 79147 ± 820.923
      HbA1c (%)6.3 ± 0.76.0 ± 0.76.2 ± 0.50.380
      Uric acid (mg/dL)6.0 ± 1.45.4 ± 1.15.4 ± 1.30.232
      CRP (mg/dL)0.26 ± 0.430.09 ± 0.140.14 ± 0.220.087
      S-Cre (mg/dL)0.96 ± 0.220.88 ± 0.251.28 ± 1.570.239
      Echocardiography
      LVEF (%)52 ± 1458 ± 1260 ± 110.035
      Lesion location0.120
      LAD (%)7 (41 %)22 (63 %)37 (69 %)
      LCX (%)1 (6 %)5 (14 %)5 (9 %)
      RCA (%)9 (53 %)8 (23 %)12 (22 %)
      Stent type0.254
       2nd generation DES12 (71 %)23 (66 %)28 (52 %)
       3rd generation DES5 (29 %)12 (34 %)26 (48 %)
      Number of stents1.9 ± 0.91.3 ± 0.51.3 ± 0.50.001
      Number of stents ≥34 (24 %)1 (3 %)2 (4 %)0.009
      Stent length (mm)49 ± 2835 ± 1634 ± 210.031
      Stent length ≥ 60 mm5 (29 %)3 (9 %)4 (7 %)0.036
      Minimum stent diameter (mm)2.7 ± 0.32.9 ± 0.53.0 ± 0.40.021
      Minimum stent diameter < 3 mm12 (71 %)16 (46 %)20 (37 %)0.053
      ACE-I, angiotensin-converting enzyme inhibitor; AF, atrial fibrillation; ARB, angiotensin II receptor blocker; BMI, body mass index; CCB, calcium channel blocker; CHF, congestive heart failure; CRP, C-reactive protein; CTO, chronic total occlusion; DAPT, dual antiplatelet therapy; DES, drug-eluting stent; DOAC, direct oral anticoagulants; Hb, hemoglobin; HbA1C, hemoglobin A1c; HDL-C, high-density lipoprotein cholesterol; LAD, left anterior descending artery; LCX, left circumflex artery; LDL-C, low-density lipoprotein cholesterol; LVEF, left ventricular ejection fraction; RCA, right coronary artery; S-Cre, serum creatinine; TG, triglyceride.
      A representative case of the CTO group is shown in Fig. 3. The patient, a male in his late 60s, was diagnosed with effort angina pectoris. Coronary angiography during a previous PCI showed total occlusion of the proximal left anterior descending artery and a collateral from the right coronary artery (Fig. 3a). PCI was performed, and a guidewire was passed via an antegrade approach; thereafter, a DES was deployed. Fig. 3b shows the follow-up coronary angiography 1 year after PCI. No in-stent restenosis was observed. Fig. 3c shows the angioscopic findings of the stent. The neointimal stent coverage was very poor (grade 0), and the intima color was intense yellow (grade 3). These findings indicated delayed neointimal healing.
      Fig. 3
      Fig. 3(a)-(c) Representative case: angioscopic findings 12 months after everolimus-eluting stent implantation for chronic total occlusion of the LAD. (a) CAG performed during a previous PCI showed total occlusion at the proximal LAD and a collateral from the right coronary artery. (b) Follow-up CAG 1 year after PCI. No in-stent restenosis was observed (c) Angioscopy: neointimal stent coverage: grade 0, yellow color: grade 3.
      CAG, coronary angiography; LAD, left anterior descending artery; PCI, percutaneous coronary intervention.
      The grade of neointimal stent coverage was significantly lower in the CTO and ACS groups than in the non-CTO group (0.4 ± 0.5, 0.9 ± 0.8, and 1.4 ± 0.8, respectively, p < 0.001, Fig. 4a ). More than half of the patients in the CTO group (59 %) showed very poor (grade 0) neointimal stent coverage (Table 2).
      Fig. 4
      Fig. 4(a) Grade of neointimal stent coverage. (b) Frequency of thrombus. (c) Yellow color grade.
      ACS, acute coronary syndrome; CTO, chronic total occlusion.
      Table 2Angioscopic findings.
      CTO (n = 17)ACS (n = 35)Non-CTO (n = 54)
      Neointimal stent coverage
      Grade 010123
      Grade 171731
      Grade 20514
      Grade 3016
      Yellow color grade
      Grade 01114
      Grade 181931
      Grade 27149
      Grade 3110
      ACS, acute coronary syndrome; CTO, chronic total occlusion.
      The frequency of thrombus occurrence was significantly higher in the CTO and ACS groups than in the non-CTO group (71 %, 51 %, and 15 %, respectively, p < 0.001, Fig. 4b).
      The yellow grade was significantly higher in the CTO and ACS groups than in the non-CTO group (1.5 ± 0.7, 1.4 ± 0.6, and 0.9 ± 0.7, respectively, p < 0.001, Fig. 4c). Approximately half of the patients in the CTO group (47 %) had a yellow grade of 2 or 3, while a majority of the patients (83 %) in the non-CTO group had a yellow color grade of 0 or 1 (Table 2). Trends that the presence of thrombus was mainly related to neointimal stent coverage in CTO group, and related to both neointimal coverage and yellow color grade in ACS group were observed (Table 3).
      Table 3Frequency of thrombus in each grade of neointimal coverage and yellow color.
      CTO (n = 17)ACS (n = 35)
      Neointimal stent coverage
      Grade 07 (70 %)10 (83 %)
      Grade 15 (71 %)7 (41 %)
      Grade 20 (0 %)1 (20 %)
      Grade 30 (0 %)0 (0 %)
      Yellow color grade
      Grade 01 (100 %)0 (0 %)
      Grade 18 (100 %)7 (37 %)
      Grade 23 (43 %)11 (79 %)
      Grade 30 (0 %)0 (0 %)
      ACS, acute coronary syndrome; CTO, chronic total occlusion.
      Although there were significant differences between the groups in the number of stents, stent length, and minimum stent diameter, multivariate analysis revealed that stents implanted for either CTO and ACS lesions were at significant risk of neointimal stent coverage grade 0, presence of thrombus, and yellow color grade ≥ 2 (Table 4).
      Table 4Multivariate analysis.
      Odds ratio95 % CIp-Value
      Factors associated with neointimal stent coverage grade 0
      Age1.0571.000–1.1160.050
      Male1.3120.246–7.0070.751
      CTO43.6167.833–242.859<0.001
      ACS13.0742.927–58.4030.001
      Stent length ≥ 60 mm1.7710.319–9.8190.513
      Minimum stent diameter < 3 mm0.3330.090–1.2280.099
      Factors associated with the presence of thrombus
      Age0.9720.928–1.0180.235
      Male0.2480.062–0.9830.047
      CTO14.5303.553–59.428<0.001
      ACS5.2211.799–15.1490.002
      Stent length ≥ 60 mm3.5880.671–19.1980.135
      Minimum stent diameter < 3 mm0.5260.173–1.6000.258
      Factors associated with presence of yellow color grade ≥ 2
      Age1.0060.960–1.0540.810
      Male0.3000.081–1.1150.072
      CTO5.3691.426–20.2170.013
      ACS3.4541.213–9.8320.020
      Stent length ≥ 60 mm0.2920.049–1.7230.174
      Minimum stent diameter < 3 mm1.3470.499–3.6390.557
      ACS, acute coronary syndrome; CTO, chronic total occlusion.

      Discussion

      The main findings of the present study are as follows: First, delayed neointimal stent healing was observed (insufficient neointimal stent coverage and presence of thrombus) 1 year after PCI in the stents were deployed for CTO lesions. Second, the yellow color grade was higher where stents were implanted 1 year after PCI for CTO lesions compared to stents for non-CTO lesions. Finally, the above two findings were similar in the case of ACS lesions. To our knowledge, this is the first study to investigate delayed stent healing and neoatherosclerosis in stents implanted for CTO lesions using coronary angioscopy.
      Stent thrombosis was a major problem in first-generation DES [
      • McFadden E.P.
      • Stabile E.
      • Regar E.
      • Cheneau E.
      • Ong A.T.
      • Kinnaird T.
      • et al.
      Late thrombosis in drug-eluting coronary stents after discontinuation of antiplatelet therapy.
      ], and several angioscopic studies revealed delayed neointimal stent coverage and presence of thrombus in first-generation DES [
      • Takano M.
      • Ohba T.
      • Inami S.
      • Seimiya K.
      • Sakai S.
      • Mizuno K.
      Angioscopic differences in neointimal coverage and in persistence of thrombus between sirolimus-eluting stents and bare metal stents after a 6-month implantation.
      ,
      • Kotani J.
      • Awata M.
      • Nanto S.
      • Uematsu M.
      • Oshima F.
      • Minamiguchi H.
      • et al.
      Incomplete neointimal coverage of sirolimus-eluting stents: angioscopic findings.
      ,
      • Takano M.
      • Mizuno K.
      Angioscopic findings after drug-eluting stent implantation.
      ]. A pathological study reported that impaired neointimal healing extended the window during which stents were prone to thrombosis [
      • Farb A.
      • Burke A.P.
      • Kolodgie F.D.
      • Virmani R.
      Pathological mechanisms of fatal late coronary stent thrombosis in humans.
      ]. Second- and third-generation DES have shown better neointimal coverage and fewer thrombi compared to first-generation DES [
      • Miyoshi T.
      • Matsuoka H.
      • Kawakami H.
      • Dai K.
      • Sato T.
      • Watanabe K.
      • et al.
      Assessment of second- and third-generation drug-eluting stents on chronic coronary angioscopy – multicenter study on intra-coronary angioscopy after stent (MICASA) prospective data analysis.
      ,
      • Iannaccone M.
      • D’Ascenzo F.
      • Templin C.
      • Omedè P.
      • Montefusco A.
      • Guagliumi G.
      • et al.
      Optical coherence tomography evaluation of intermediate-term healing of different stent types: systemic review and meta-analysis.
      ], and with second-generation DES, neointimal stent coverage proceeds quickly, even in a few months [
      • Takahara M.
      • Kitahara H.
      • Nishi T.
      • Miura K.
      • Miyayama T.
      • Sugimoto K.
      • et al.
      Very early tissue coverage after drug-eluting stent implantation: an optical coherence tomography study.
      ]. Therefore, the duration of DAPT after implantation of stents is getting shorter. Nevertheless, the risk of thrombosis still exists. Current guidelines recommend that the duration of DAPT should be based on the balance between bleeding and thrombotic risks. Although thrombotic risk factors have been noted in the guidelines, it is uncertain how each factor will affect stent healing [
      • Valgimigli M.
      • Bueno H.
      • Byrne R.A.
      • Collet J.P.
      • Costa F.
      • Jeppsson A.
      • et al.
      2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: the task force for dual antiplatelet therapy in coronary artery disease of the european Society of Cardiology (ESC) and of the european Association for Cardio-Thoracic Surgery (EACTS).
      ,
      • Nakamura M.
      • Kimura K.
      • Kimura T.
      • Ishihara M.
      • Otsuka F.
      • Kozuma K.
      • et al.
      JCS 2020 guideline focused update on antithrombotic therapy in patients with coronary artery disease.
      ]. The present study revealed that neointimal stent coverage was insufficient, and thrombi were more frequently seen in the stents deployed for CTO lesions, as compared to those deployed for stable lesions. Our study also revealed that the yellow grade of stents was higher for CTO lesions than for stable lesions. A yellow plaque that is newly formed inside a stent is defined as neoatherosclerosis [
      • Kawakami H.
      • Matsuoka H.
      • Oshita A.
      • Kono T.
      • Shigemi S.
      A case of a newly developed yellow neointima at stent implanted site 1 year after sirolimus-eluting stent placement: angioscopic findings.
      ], and the presence of a yellow plaque in an implanted stent is considered a predictor of stent failure [
      • Ueda Y.
      • Matsuo K.
      • Nishimoto Y.
      • Sugihara R.
      • Hirata A.
      • Nemoto T.
      • et al.
      In-stent yellow plaque at 1 year after implantation is associated with future event of very late stent failure: the DESNOTE study (Detect the event of very late stent failure from the drug-eluting stent not well covered by neointima determined by angioscopy).
      ]. This also indicates that CTO lesions should be regarded as high-risk factor for late coronary events. Aggressive lipid-lowering therapy may be considered after PCI for CTO lesions.
      ACS is a known high-risk factor for ischemic events, and extended DAPT is recommended for ACS patients. The long-term risk for recurrent events is higher among patients with ACS than among those with stable coronary artery disease after DES implantation. There is a difference in arterial healing between ACS and stable coronary artery disease. Uncovered struts, fibrin deposition, and inflammation are more frequently observed with ACS in autopsy specimens [
      • Nakazawa G.
      • Finn A.V.
      • Joner M.
      • Ladich E.
      • Kutys R.
      • Mont E.K.
      • et al.
      Delayed arterial healing and increased late stent thrombosis at culprit sites after drug-eluting stent placement for acute myocardial infarction patients: an autopsy study.
      ]. A previous study using optical coherence tomography showed delayed stent healing in ACS culprit lesions [
      • Räber L.
      • Zanchin T.
      • Baumgartner S.
      • Taniwaki M.
      • Kalesan B.
      • Moschovitis A.
      • et al.
      Differential healing response attributed to culprit lesions of patients with acute coronary syndromes and stable coronary artery after implantation of drug-eluting stents: an optical coherence tomography study.
      ]. Another angioscopic study showed poor neointimal stent coverage in DES deployed on vulnerable plaques compared to those on stable plaques [
      • Kawai K.
      • Ichikawa M.
      • Masuyama T.
      • Kijima Y.
      Angioscopic comparison of arterial repair after second-generation drug-eluting stent implantation into vulnerable and stable coronary plaques.
      ]. The present study revealed that the neointimal stent coverage grade and the frequency of thrombi in deployed stents were similar in CTO and ACS lesions. A separate histopathologic study suggested that many CTO lesions evolve from ACS and might be caused by plaque rupture and thrombotic occlusion [
      • Katsuragawa M.
      • Fujiwara H.
      • Miyamae M.
      • Sasayama S.
      Histologic studies in percutaneous transluminal coronary angioplasty for chronic total occlusion: comparison of tapering and abrupt types of occlusion and short and long occluded segments.
      ]. An angioscopic study also found more frequent intense yellow color plaques and protruding thrombi in the middle segment of CTO lesions [
      • Kimura S.
      • Sugiyama T.
      • Hishikari K.
      • Nakagama S.
      • Nakamura S.
      • Misawa T.
      • et al.
      Intravascular ultrasound and angioscopy assessment of coronary plaque components in chronic totally occluded lesions.
      ], which is in accordance with the histopathological findings. Therefore, CTO lesions have a vulnerable plaque component as also noted in ACS lesions; this may explain the delayed healing after implanting a stent for both ACS and CTO lesions observed in the present study.
      The present study suggests that both CTO and ACS lesions are high-risk factors for stent thrombosis. Longer DAPT may be considered after PCI for CTO lesions in the same way as that for ACS lesions. There were several differences in angioscopic findings between CTO and ACS, further investigation for more detailed risk stratification is desired.
      This study had several limitations. First, it was a single-center retrospective study with a small sample size. However, the present study could identify a significant difference in the neointimal stent healing between the groups. A large-scale prospective study is desirable to provide further information in this regard. Second, the stent type was not unified and second- and third-generation DES were included in the present study. However, we did not observe a significant difference in neointimal healing between the second- and third-generation DES.

      Conclusions

      The present study confirmed the presence of delayed neointimal healing of stents implanted for CTO lesions. Longer duration of DAPT may be beneficial for these patients.

      Declaration of competing interest

      The authors declare that there is no conflict of interest.

      Acknowledgments

      None.

      Funding

      This research received no grant from any funding agency in the public, commercial or not-for-profit sectors.

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