Akihide Konishi

Stabilizing effect of combined eicosapentaenoic acid and statin therapy on coronary thin-cap fibroatheroma

BACKGROUND The addition of highly purified eicosapentaenoic acid (EPA) to statin therapy prevents cardiovascular events. However, the impact of this treatment on vulnerable plaques remains unclear. The aim of this study was to assess the impact of adding EPA to a standard statin therapy on vulnerable plaques by serial optical coherence tomography (OCT). METHODS Forty-nine non-culprit thin-cap fibroatheroma (TCFA) lesions in 30 patients with untreated dyslipidemia were included. Patients were randomly assigned to EPA (1800 mg/day) + statin (23 TCFA, 15 patients) or statin only (26 TCFA, 15 patients) treatment. The statin (rosuvastatin) dose was adjusted to achieve a target low-density lipoprotein (LDL) level of <70 mg/dL. Post-percutaneous intervention and 9-month follow-up OCT were performed to evaluate morphological changes of TCFAs. The EPA/arachidonic acid (EPA/AA) ratio and pentraxin-3 (PTX3) levels were also evaluated. RESULTS Despite similar follow-up LDL levels, the EPA + statin group had higher EPA/AA ratios and lower PTX3 levels than the statin group. OCT analysis showed that the EPA + statin group had a greater increase in fibrous-cap thickness, with a greater decrease in lipid arc and lipid length. Macrophage accumulation was less frequently detected in the EPA + statin group than in the statin group at follow-up. When the patients were categorized according to their follow-up PTX3 tertiles, fibrous-cap thickness showed significant increase, and the incidence of macrophages accumulation decreased with lower PTX3 levels. CONCLUSION The concomitant use of EPA and rosuvastatin may stabilize vulnerable plaques better than the statin alone, possibly by suppressing arterial inflammation.

Effect of Daily Glucose Fluctuation on Coronary Plaque Vulnerability in Patients Pre-Treated With Lipid-Lowering Therapy: A Prospective Observational Study

OBJECTIVES This study sought to investigate the effect of daily glucose fluctuation on coronary plaque properties in patients with coronary artery disease (CAD) pre-treated with lipid-lowering therapy. BACKGROUND There is growing evidence that glucose fluctuation, as a residual risk apart from dyslipidemia, is an important factor contributing to the development of CAD. METHODS This prospective study enrolled 70 consecutive CAD patients who were referred for percutaneous coronary intervention and whose low-density lipoprotein cholesterol level was <120 mg/dl under statin treatment or <100 mg/dl without statins. Daily glucose fluctuation was analyzed by measuring the mean amplitude of glycemic excursion (MAGE). The plaque properties in the culprit and nonculprit lesions were assessed by virtual histology intravascular ultrasound, and the volume percentage of necrotic core within the plaque (%NC) and the presence of thin-cap fibroatheroma were evaluated. RESULTS In total, 165 lesions were evaluated in 70 patients (40 diabetic and 30 nondiabetic patients). %NC was well correlated with MAGE (r = 0.490, p <0.001). A linear mixed effect model showed that MAGE had the strongest effect on %NC (coefficient β = 0.080 ± 0.020 [standard error], p < 0.001). The generalized linear mixed effect model revealed that MAGE was the only independent predictor of the presence of thin-cap fibroatheroma (odds ratio: 1.037; 95% confidence interval: 1.010 to 1.065; p = 0.007). CONCLUSIONS Daily glucose fluctuation may have an effect on coronary plaque vulnerability in patients with CAD pre-treated with lipid-lowering therapy. Further investigations should address the rationale for the early detection and control of glucose fluctuation in the era of universal statin use for CAD patients.

The impact of in-stent neoatherosclerosis on long-term clinical outcomes: an observational study from the Kobe University Hospital optical coherence tomography registry

AIMS Although pathological studies have indicated the development of neoatherosclerosis (NA) after stenting, its risk factors and impact on future clinical events remain unclear. We aimed to clarify the possible risk factors for NA development and to evaluate the impact of NA in a large Japanese observational OCT database of patients with coronary heart disease. METHODS AND RESULTS One hundred and seventy-five consecutive patients (314 lesions) who underwent OCT examination >1 year after bare metal or drug-eluting stent implantation were enrolled. We assessed the presence of NA by follow-up OCT and compared adverse clinical events between NA+ and NA- patients. Forty-six patients had NA at the follow-up OCT. These patients had higher low-density lipoprotein (LDL) cholesterol and C-reactive protein (CRP) levels at follow-up. In multivariate logistic analysis, LDL cholesterol and CRP levels at follow-up were independently associated with the presence of NA (odds ratio [OR]: 1.022, p=0.008, OR 1.022, p=0.001, respectively). Moreover, patients with NA had a higher incidence of major adverse cardiac events (MACE) at follow-up. Multivariate Cox hazard analysis showed that the presence of NA was an independent risk factor for MACE (hazard ratio: 2.909, p=0.012). CONCLUSIONS High LDL cholesterol and CRP levels may be risk factors for NA development in patients treated with coronary stents. Moreover, the presence of NA was independently associated with MACE, suggesting the need for careful clinical follow-up of these patients.

Two-year vessel healing after everolimus-eluting stent implantation: Serial assessment by optical coherence tomography

BACKGROUND Previous reports have suggested the importance of delayed arterial healing and the development of neoatherosclerosis as major contributors to stent thrombosis and delayed restenosis. The difference of in vivo assessment of long-term vessel healing between first-generation drug-eluting stents and current generation everolimus-eluting stents (EESs) is limited. The aim of this study was to evaluate long-term arterial healing in EES in comparison with the first generation sirolimus-eluting stents (SES). METHODS We evaluated 31 EES (23 patients) and 8 SES (7 patients) by serial optical coherence tomography at 12 months (mid-phase) and 24 months (late-phase) after stenting and evaluated the change in neointimal thickness (NIT), the percentages of uncovered struts, peri-strut low intensity area (PLIA; region around stent struts homogenously lower-intensity appearance than surrounding tissue), and thrombus. RESULTS Although the average NIT showed no significant changes from the mid- to the late-phase follow-up in both EES and SES groups, the change in NIT and minimum lumen area was significantly larger in SES than EES (5.2±29.4 vs. 37.2±48.9; p=0.02, -0.06±0.36 vs. -0.45±0.74; p=0.04, respectively). The incidence of uncovered struts and struts with PLIA of EES was lower than those of SES, at both phases. Stents with in-stent thrombus of EES tended to be lower than that of SES at both phase follow-ups. CONCLUSION Although both SES and EES showed progressive luminal narrowing from the mid- to the late-phase follow-up, the extent of delayed lumen narrowing and delayed neointimal proliferation was significantly less in the second generation EES than the first generation SES. EESs seem to offer sustained stability in efficacy, without sacrificing safety, up to 2 years after implantation.

Serial Optical Coherence Tomography Evaluation at 6, 12, and 24 Months After Biolimus A9-Eluting Biodegradable Polymer-Coated Stent Implantation

BACKGROUND The Nobori (Terumo Corporation, Tokyo, Japan) is a biolimus A9-eluting stent (BES) featured with a biodegradable polymer coated on the abluminal side only. We previously reported that favourable vessel healing was achieved at 6-12 months after BES implantation. However, detailed long-term vessel reaction after BES deployment is unclear. METHODS Twenty-two BESs were serially evaluated using optical coherence tomography (OCT) at 6, 12, and 24 months after stenting. Average neointimal thickness, uncovered struts, and neointimal unevenness score (each cross-section as maximum neointimal thickness in 1 cross section divided by the average neointimal thickness of the same cross-section) were manually measured. In addition, we evaluated the percentage of struts with peri-strut low-intensity area (a region around stent struts that homogenously showed less intensity than the surrounding tissue, which suggests fibrin deposition or impaired neointima maturation), thrombi, and atherogenic neointimas (neointimas containing a diffuse border and poor-signal region with invisible struts due to marked signal attenuation). RESULTS Serial OCT observation revealed a small gradual increase in neointimal thickness from 6 to 24 months (73 ± 24 μm; 81 ± 26 μm; and 108 ± 35 μm, respectively, P = 0.001) with a nonsignificant decrease in the lumen area (6.36 ± 1.98 mm(2); 6.18 ± 2.04 mm(2); and 5.87 ± 2.06 mm(2); P = 0.72). Frequency of uncovered struts (3.89 ± 3.91%; 1.55 ± 1.63%; and 0.23 ± 0.67%; P = 0.001), neointimal unevenness score (1.95 ± 0.18% to 1.86 ± 0.19% to 1.78 ± 0.17; P = 0.012), percentage of thrombi (5%, 0%, and 0%; P = 0.37) and peri-strut low-intensity area (6.8%, 5.1%, and 1.6%; P = 0.017) decreased from 6 to 12 and 24 months. Atherogenic neointima was not observed in the event-free OCT cohort. CONCLUSIONS The Nobori stent achieved acceptable long-term vessel healing, mostly without adverse vessel reactions.

Analysis by Optical Coherence Tomography of Long-term Arterial Healing After Implantation of Different Types of Stents

BACKGROUND Although drug-eluting stents have significantly reduced the midterm incidence of target lesion revascularization (TLR), in vivo studies on long-term vessel healing of sirolimus-eluting stents (SESs) and paclitaxel-eluting stents (PESs) are limited. The aim of this study was to compare long-term arterial healing with SESs and PESs. METHODS We evaluated 27 SESs (23 patients) and 21 PESs (20 patients) by serial optical coherence tomography at 6 months (midphase) and ≥ 3 years (late phase) after stenting and evaluated the change of neointimal thickness (NIT), the percentages of uncovered and malapposed struts, peristrut low-intensity area (region around stent struts with a homogeneously lower intensity appearance than surrounding tissue), thrombus, and atherogenic neointima. RESULTS At follow-up, most SESs showed a progressive increase in the average NIT, whereas PESs showed variable changes. Between midphase and late phase, NIT increased significantly in SESs (midphase, 94.1 ± 49.3; late phase, 130.2 ± 78.7; P = 0.001) but decreased significantly in PESs (midphase, 167.4 ± 122.9; late phase, 136.0 ± 77.7; P = 0.04). The percentages of uncovered struts decreased significantly in SESs; conversely, variable changes were observed in PESs. Peristrut low-intensity area and thrombus formation decreased in SESs but remained largely unchanged in PESs. The prevalence of atherogenic neointima was greater in the late phase than in the midphase in both groups but was similar for both stents. CONCLUSIONS Long-term vessel healing was different for SESs and PESs. Progressive vessel healing was consistently observed in SESs, whereas a heterogeneous process of delayed vessel healing was noted for PESs.

Impact of cytochrome P450 2C19 loss-of-function polymorphism on intra-stent thrombi and lesion outcome after everolimus-eluting stent implantation compared to that after first-generation drug-eluting stent implantation

BACKGROUND The contribution of clopidogrel response due to cytochrome P450 (CYP) 2C19 loss-of-function polymorphism after drug-eluting stent (DES) implantation is unclear. METHODS A total of 196 patients who had undergone optical coherence tomography (OCT) at 8 months following first-generation DES (120 lesions) and current-generation everolimus-eluting stent (EES) implantation (127 lesions) were enrolled. Patients were divided into 3 groups by CYP2C19 polymorphism: extensive metabolizers (EMs), intermediate metabolizers (IMs), and poor metabolizers (PMs). OCT findings were compared among the 3 groups. Responsiveness to clopidogrel was assessed by VerifyNow platelet reactivity unit (PRU). RESULTS The incidence of intra-stent thrombi was significantly higher after first-generation DES implantation compared with EES implantation (35% vs 13%, respectively; p=0.0001). In the first-generation DES group, the incidence of intra-stent thrombi significantly increased among EMs, IMs, and PMs (21% vs 36% vs 63%, respectively; p=0.007), while there was no significant difference among the 3 groups after EES implantation (10% vs 13% vs 20%, respectively; p=0.55). The PRU significantly increased among EMs, IMs, and PMs in each stent group. In multivariate analyses, although PMs had a 3-fold higher risk of thrombi formation compared with non-PMs after first-generation DES implantation, there were no significant differences in thrombi formation between the 2 groups after EES implantation. The optimal PRU cutoff values for the prediction of intra-stent thrombi with first-generation DES and EES were 234 and 256, respectively. CONCLUSION CYP2C19 loss-of-function polymorphism is associated with a higher incidence of intra-stent thrombi after first-generation DES implantation, while the impact is attenuated following EES implantation.

Impact of hemodialysis on local vessel healing and thrombus formation after drug-eluting stent implantation

BACKGROUND Although hemodialysis (HD) is a suggested risk factor for stent thrombosis, its contribution to local vessel healing after drug-eluting stent (DES) implantation is unclear. METHODS A total of 121 patients (152 lesions treated with DES) who underwent 8-month follow-up coronary angiography with optical coherence tomography (OCT) were enrolled, and the findings were compared between patients with and without HD. To match baseline differences, mid-term OCT findings of 42 propensity score-matched lesions (21 non-HD vs. 21 HD) were compared. Effects of HD on the efficacy of antiplatelet therapy were also evaluated by VerifyNow assay (Accumetrics, San Diego, CA, USA). RESULTS Patients with HD had a significantly higher rate of thrombus formation than those without (64% vs. 33%, p = 0.007), although the baseline parameters and lesion characteristics differed between the groups. Multivariate logistic regression analysis revealed that HD was associated with an increased risk of thrombus formation (odds ratio 5.991, 95% confidence interval: 1.972-18.199, p = 0.002). Even after propensity-matching for patient background and balancing of angiographic and OCT variables, the risk of thrombus formation remained significantly higher in HD patients. The P2Y12-reaction unit was significantly increased after HD (Pre HD: 211 ± 75 vs. Post HD: 262 ± 59, p = 0.01), but patients without HD showed no increase during the same elapsed time (221 ± 88 vs. 212 ± 96, p = 0.19). CONCLUSIONS HD is a potential risk factor for subclinical thrombus attachment after DES therapy. Systemic problems, such as residual platelet reactivity, associated with HD as well as local vessel features in HD patients might contribute to the increased incidence of thrombus attachment and subsequent onset of thrombotic event after DES implantation.

Paraoxonase-1 activity affects the clopidogrel response in CYP2C19 loss-of-function carriers

BACKGROUND The impact of paraoxonase-1 (PON1) activity on the response to clopidogrel may differ in patients treated with drug-eluting stents (DES) in association with CYP2C19 loss-of-function (LOF) polymorphisms. METHODS This study included 112 Japanese patients receiving clopidogrel (75 mg/day) and aspirin (100mg/day) who underwent optical coherence tomography (OCT) examination 9 months after DES implantation. The CYP2C19 genotype was analyzed and LOF carriers (1/2, 1/3, 2/2, 3/3, 2/3) were identified. At the 9-month follow-up, platelet reactivity was determined by measuring the P2Y12 reactivity unit (PRU) using a VerifyNow P2Y12 assay, PON1 activity was evaluated and intra-stent thrombus was evaluated by OCT. RESULTS Of the 112 Japanese patients, 75 were LOF carriers (67.0%). The patients were divided into tertiles according to the PON1 activity (tertile 1; <230 U/L, tertile 2; 230-283U/L, tertile 3; >283 U/L). In the VerifyNowP2Y12 analysis, tertile 1 had a higher PRU than tertiles 2 and 3 in LOF carriers, and there was no difference among tertiles in non-carriers. The highest incidence of intra-stent thrombus was observed in tertile 1 followed by tertiles 2 and 3 in LOF carriers, whereas there was no such difference in non-carriers. Multivariate analysis revealed that LOF carriers and PON1 activity tertile 1 were independent predictors of intra-stent thrombus in all patients. In LOF carriers, tertile 1 was the only independent predictor for intra-stent thrombus. CONCLUSION Low PON1 activity is associated with a low response to clopidogrel and a high frequency of intra-stent thrombus only in LOF carriers.

Impact of residual platelet reactivity under clopidogrel treatment for lesions and the clinical outcome after drug-eluting stent implantation in patients with hemodialysis

BACKGROUND Hemodialysis (HD) patients are at high risk for adverse clinical outcomes after drug-eluting stent (DES) implantation. However, the impact of residual platelet reactivity under dual anti-platelet therapy in this subset of patients remains unclear. METHODS We enrolled 142 stable angina patients (194 lesions) treated with DES, who were taking aspirin and 75mg clopidogrel and had undergone 8-month angiography with optical coherence tomography (OCT). OCT findings and major adverse cardiac events (MACEs) at 1 year (cardiac death, acute coronary syndrome, target lesion and vessel revascularization, and stent thrombosis) were compared between 28 HD patients and 114 non-HD patients. Responsiveness to clopidogrel was assessed by measuring P2Y12 reaction unit (PRU) at 8 months. RESULTS PRU was significantly higher in HD patients than in non-HD patients (p=0.006), even though proportion of cytochrome P450 2C19 genotype was equivalent. HD patients had a significantly higher rate of thrombi formation (assessed using OCT) and MACEs than non-HD patients (thrombi: p=0.001; MACEs: p=0.0001). The PRU value was independently associated with MACEs in both groups. The optimal cutoff values of PRU for predicting MACEs were 235 for HD patients and 259 for non-HD patients. CONCLUSIONS HD was associated with a high residual platelet reactivity, which may contribute to the higher incidence of MACEs after DES implantation in HD patients. HD may be a patient profile that merits a more potent anti-platelet regimen.