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BACKGROUND: The Society of Cardiovascular Angiography and Intervention (SCAI) has defined 5 stages of cardiogenic shock (CS). In patients with acute myocardial infarction (AMI) who initially present in stable hemodynamic condition (SCAI CS stage: A or B), CS stages could deteriorate despite therapeutic management. However, deterioration of SCAI CS stages after AMI remains to be fully characterized. Therefore, the current study sought to investigate the frequency and clinical characteristics about deterioration of SCAI CS stages after AMI. METHODS: We retrospectively analyzed 347 patients in a derivation cohort and 163 patients in a validation cohort who had AMI (SCAI shock stage upon arrival: A/B) and underwent percutaneous coronary intervention (PCI) at National Cerebral and Cardiovascular Center, Suita, Japan (enrolment period of study subjects: 2019.07.01-2022.09.30). Deterioration of CS (D-CS) was defined as SCAI shock stage C-E after PCI. Clinical characteristics and in-hospital mortality were compared according to D-CS status. Adjusted hazard ratios (HRs) for in-hospital mortality were calculated with multivariate Cox proportional hazards models that included variables with P<0.10 in univariate models. Uni- and multivariate logistic regression analyses were used to identify predictors of D-CS. RESULTS: D-CS occurred in 17.3% (60/347) of the derivation cohort. Patients with D-CS had lower systolic blood pressure (BP) (P<0.001) and left ventricular ejection fraction (LVEF) (P<0.001) upon arrival with a higher proportion of initial Thrombolysis in Myocardial Infarction (TIMI) grade flow 0 or 1 (P=0.002). During hospitalization (13.9±9.4 days), D-CS was associated with higher in-hospital mortality [adjusted HR, 12.95; 95% confidence interval (CI): 1.46-114.97; P=0.02]. Initial systolic BP, LVEF, and TIMI grade flow 0 or 1 independently predicted D-CS. The D-CS risk score including these variables satisfactorily predicted D-CS [area under the curve (AUC), 0.749; 95% CI: 0.651-0.848] and in-hospital mortality (AUC, 0.961; 95% CI: 0.914-1.000) in the validation cohort. CONCLUSIONS: D-CS occurred in 17.3% of patients with AMI initially presenting in stable condition and increased the risk of in-hospital mortality. Our D-CS risk score (initial systolic BP, LVEF, and TIMI grade flow) could be helpful to predict D-CS.

DOI： 10.21037/cdt-24-226

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BACKGROUND: Acute autoimmune pericarditis (AAP) is an uncommon disease with diverse etiology. Data regarding AAP diagnosis and outcomes are scant. OBJECTIVES: This study sought to describe the diagnosis and the rates of in-hospital mortality, cardiac tamponade, and readmission of AAP. METHODS: This study used a nationwide Japanese claim-based database to identify patients with AAP from April 2016 to March 2020 compared with patients with acute idiopathic pericarditis (AIP). RESULTS: Of 20,469 hospitalized patients with acute pericarditis, 170 had AAP and 5,027 had AIP of new onset. The diagnosis for AAP was systemic lupus erythematosus in 23.5% (40 of 170), rheumatoid arthritis in 19.4% (33 of 170), systemic sclerosis in 8.2% (14 of 170), other in 17.7% (30 of 170), and undifferentiated in 31.2% (53 of 170). During hospitalization, 1.8% (3 of 170) of patients with AAP and 1.5% (73 of 5,027) of patients with AIP died, and cardiac tamponade occurred in 8.8% (15 of 170) of AAP patients and 4.7% (237 of 5,027) of AIP patients. The incidence of cardiac tamponade was highest in patients with systemic lupus erythematosus (15.0%; 6 of 40). AAP was more associated with cardiac tamponade than AIP (adjusted OR: 1.82; 95% CI: 1.02-3.23). There was no difference between the AAP and AIP groups with regard to rehospitalization, although this was more common in patients with undifferentiated forms of autoimmune disease (P = 0.001). CONCLUSIONS: This Japanese national registry study of acute pericarditis revealed no differences in rehospitalization for recurrence between patients with AAP and AIP. It also underscored the diversity in AAP diagnosis, with more than 30% of patients lacking a differentiated diagnosis.

DOI： 10.1016/j.jacasi.2024.06.008

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BACKGROUND: Left ventricular (LV) thrombus is not common but poses significant risks of embolic stroke or systemic embolism. However, the distinction in embolic risk between nonischemic cardiomyopathy (NICM) and ischemic cardiomyopathy (ICM) remains unclear. METHODS AND RESULTS: In total, 2738 LV thrombus patients from the JROAD-DPC (Japanese Registry of All Cardiac and Vascular Diseases Diagnosis Procedure Combination) database were included. Among these patients, 1037 patients were analyzed, with 826 (79.7%) having ICM and 211 with NICM (20.3%). Within the NICM group, the distribution was as follows: dilated cardiomyopathy (DCM; 41.2%), takotsubo cardiomyopathy (27.0%), hypertrophic cardiomyopathy (18.0%), and other causes (13.8%). The primary outcome was a composite of embolic stroke or systemic embolism (SSE) during hospitalization. The ICM and NICM groups showed no significant difference in the primary outcome (5.8% vs. 7.6%, p = 0.34). Among NICM, SSE occurred in 12.6% of patients with DCM, 7.0% with takotsubo cardiomyopathy, and 2.6% with hypertrophic cardiomyopathy. Multivariate logistic regression analysis for SSE revealed an odds ratio of 1.4 (95% confidence interval [CI], 0.7-2.7, p = 0.37) for NICM compared to ICM. However, DCM exhibited a higher adjusted odds ratio for SSE compared to ICM (2.6, 95% CI 1.2-6.0, p = 0.022). CONCLUSIONS: This nationwide shows comparable rates of embolic events between ICM and NICM in LV thrombus patients, with DCM posing a greater risk of SSE than ICM. The findings emphasize the importance of assessing the specific cause of heart disease in NICM, within LV thrombus management strategies.

DOI： 10.1016/j.ijcard.2024.132329

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Language：Japanese   Publisher：(一社)日本集中治療医学会  

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Background: Cardiovascular events still occur at intermediate stenosis with fractional flow reserve (FFR) ≥0.81, underscoring the additional measure to evaluate this residual risk. A reduction in distal coronary artery pressure/aortic pressure from baseline to hyperemia (i.e., change in Pd/Pa) reflects lipidic burden within vessel walls. We hypothesized that this physiological measure might stratify the risk of future cardiac events at deferrable lesions. Methods: Lesion- (899 intermediate lesions) and patient-based (899 deferred patients) analyses in those with FFR ≥0.81 were conducted to investigate the association between change in Pd/Pa and target lesion failure (TLF) and major adverse cardiac events (MACE) at 7 years, respectively. Results: The occurrence of TLF and MACE was 6.7% and 13.4%, respectively. The incidence of target lesion-related non-fatal myocardial infarction was 0.6%. Lesions with TLF had greater change in Pd/Pa (0.11±0.03 vs. 0.09±0.04; P=0.002), larger diameter stenosis (51.0±9.2% vs. 46.4±12.4%; P=0.048), and smaller FFR (0.84 (0.82-0.87) vs. 0.86 (0.83-0.90); P=0.02). Change in Pd/Pa (per 0.01 increase) predicted TLF (odds ratio, 1.16; 95% confidence interval (CI), 1.05-1.28; P=0.002) and MACE (odds ratio, 1.08; 95% CI, 1.01-1.16; P=0.03). Lesions with change in Pd/Pa ≥0.10 had 2.94- and 1.85-fold greater likelihood of TLF (95% CI, 1.30-6.69; P=0.01) and MACE (95% CI, 1.08-3.17; P=0.03), respectively. Lesions with FFR ≤0.85 had substantially higher likelihood of TLF when change in Pd/Pa ≥0.10 (12.4% vs. 2.9%; hazard ratio, 3.60, 95% CI, 1.01-12.80; P=0.04). However, change in Pd/Pa did not affect TLF risk in lesions with FFR ≥0.86 (3.8% vs. 3.7%; hazard ratio, 0.56; 95% CI, 0.06-5.62; P=0.62). Conclusions: Despite deferrable FFR values, lesions and patients with change in Pd/Pa ≥0.10 had higher cardiovascular risk. Change in Pd/Pa might help stratify lesion- and patient-level risk of future cardiac events in those with FFR ≥0.81.

DOI： 10.1161/CIRCINTERVENTIONS.124.013830

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BACKGROUND AND AIMS: Randomized clinical trials have demonstrated the ability of glucagon-like peptide-1 analogues (GLP-1RAs) to reduce atherosclerotic cardiovascular disease events in patients with type 2 diabetes (T2D). How GLP-1RAs modulate diabetic atherosclerosis remains to be determined yet. METHODS: The OPTIMAL study was a prospective randomized controlled study to compare the efficacy of 48-week continuous glucose monitoring- and HbA1c-guided glycemic control on near infrared spectroscopty (NIRS)/intravascular ultrasound (IVUS)-derived plaque measures in 94 statin-treated patients with T2D (jRCT1052180152, UMIN000036721). Of these, 78 patients with evaluable serial NIRS/IVUS images were analyzed to compare plaque measures between those treated with (n = 16) and without GLP-1RAs (n = 72). RESULTS: All patients received a statin, and on-treatment LDL-C levels were similar between the groups (66.9 ± 11.6 vs. 68.1 ± 23.2 mg/dL, p = 0.84). Patients receiving GLP-1RAs demonstrated a greater reduction of HbA1c [-1.0 (-1.4 to -0.5) vs. -0.4 (-0.6 to -0.2)%, p = 0.02] and were less likely to demonstrate a glucose level >180 mg/dL [-7.5 (-14.9 to -0.1) vs. 1.1 (-2.0 - 4.2)%, p = 0.04], accompanied by a significant decrease in remnant cholesterol levels [-3.8 (-6.3 to -1.3) vs. -0.1 (-0.8 - 1.1)mg/dL, p = 0.008]. On NIRS/IVUS imaging analysis, the change in percent atheroma volume did not differ between the groups (-0.9 ± 0.25 vs. -0.2 ± 0.2%, p = 0.23). However, GLP-1RA treated patients demonstrated a greater frequency of maxLCBI4mm regression (85.6 ± 0.1 vs. 42.0 ± 0.6%, p = 0.01). Multivariate analysis demonstrated that the GLP-1RA use was independently associated with maxLCBI4mm regression (odds ratio = 4.41, 95%CI = 1.19-16.30, p = 0.02). CONCLUSIONS: In statin-treated patients with T2D and CAD, GLP-1RAs produced favourable changes in lipidic plaque materials, consistent with its stabilization.

DOI： 10.1016/j.athplu.2024.03.001

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INTRODUCTION: Cerebral microbleeds (CMBs) on brain magnetic resonance imaging (MRI) are predictive of intracerebral hemorrhage (ICH). However, the risk of ICH in patients with CMBs who undergo percutaneous coronary intervention (PCI) while receiving dual antiplatelet therapy (DAPT) is unclear. MATERIALS AND METHODS: We conducted a study on 329 consecutive patients with coronary artery disease who underwent PCI and were evaluated using a 3T MRI scanner. Based on T2*-weighted imaging, patients were classified into three groups: no CMBs, < 5 CMBs, or ≥ 5 CMBs. We determined the occurrence of ICH during follow-up. RESULTS: At least 1 CMB was found in 109 (33%) patients. The mean number of CMBs per patient was 2.9 ± 3.6. Among the 109 patients with CMBs, 16 (15%) had ≥ 5 CMBs. Coronary stent implantation was performed in 321 patients (98%). DAPT was prescribed for 325 patients (99%). During a mean follow-up period of 2.3 years (interquartile range, 1.9-2.5 years), ICH occurred in one patient (1.1%) with four CMBs. There were no significant differences in the incidence of ICH (0% vs. 1.1% vs. 0%; p = 0.28). However, the rate of DAPT at 6 months of follow-up was significantly lower in patients with ≥ 5 CMBs than in patients with no CMBs or < 5 CMBs (89% vs. 91% vs. 66%, p = 0.026). Furthermore, there were no significant differences in systemic blood pressure during follow-up (123 ± 16 vs. 125 ± 16 vs. 118 ± 11 mmHg; p = 0.40). CONCLUSION: Although a substantial number of patients who underwent PCI had cerebral microbleeds, at approximately two years of follow-up, intracerebral hemorrhage was very rare in our study population.

DOI： 10.1007/s00380-024-02404-7

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Language：English   Publisher：(一社)日本循環器学会  

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Objective Earlobe crease (ELC) is an easily detectable physical sign of cardiovascular risk and coronary artery disease (CAD). However, the relationship between ELC and CAD severity in patients with ST-segment elevation myocardial infarction (STEMI) requiring urgent clinical judgment is unknown. Using the residual synergy between percutaneous coronary intervention with taxus and cardiac surgery (SYNTAX) score, we investigated the relationship between ELC and anatomical severity of CAD. Methods, patients or materials We studied 219 consecutive patients with STEMI (median age, 71 years old) and divided them into 2 groups according to the presence of ELC (ELC group, n=161; non-ELC group, n=58). Results The ELC group had a significantly higher number of diseased vessels than the non-ELC group (≥2 diseased vessels, 79% vs. 46%; ≥3 diseased vessels, 35% vs. 12%; P<0.001). In addition, a higher median residual SYNTAX score was observed after primary percutaneous coronary intervention than the non-ELC group [8 (4-12) vs. 3 (0-8), P<0.001]. Furthermore, a multivariable regression analysis showed that ELC was an independent predictor of the residual SYNTAX score (β=3.620, P<0.001). Conclusions The presence of ELC was significantly associated with the anatomical severity of diseased coronary vessels in patients with STEMI who required emergency clinical judgment and treatment.

DOI： 10.2169/internalmedicine.2997-23

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AIM: Omega-3 fatty acids have emerged as a new option for controlling the residual risk for coronary artery disease (CAD) in the statin era. Eicosapentaenoic acid (EPA) is associated with reduced CAD risk in the Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention trial, whereas the Statin Residual Risk with Epanova in High Cardiovascular Risk Patients with Hypertriglyceridemia trial that used the combination EPA/docosahexaenoic acid (DHA) has failed to derive any clinical benefit. These contradictory results raise important questions about whether investigating the antiatherosclerotic effect of omega-3 fatty acids could help to understand their significance for CAD-risk reduction. METHODS: The Attempts at Plaque Vulnerability Quantification with Magnetic Resonance Imaging Using Noncontrast T1-weighted Technic EPA/DHA study is a single-center, triple-arm, randomized, controlled, open-label trial used to investigate the effect of EPA/DHA on high-risk coronary plaques after 12 months of treatment, detected using cardiac magnetic resonance (CMR) in patients with CAD receiving statin therapy. Eligible patients were randomly assigned to no-treatment, 2-g/day, and 4-g/day EPA/DHA groups. The primary endpoint was the change in the plaque-to-myocardium signal intensity ratio (PMR) of coronary high-intensity plaques detected by CMR. Coronary plaque assessment using computed tomography angiography (CTA) was also investigated. RESULTS: Overall, 84 patients (mean age: 68.2 years, male: 85%) who achieved low-density lipoprotein cholesterol levels of ＜100 mg/dL were enrolled. The PMR was reduced in each group over 12 months. There were no significant differences in PMR changes among the three groups in the primary analysis or analysis including total lesions. The changes in CTA parameters, including indexes for detecting high-risk features, also did not differ. CONCLUSION: The EPA/DHA therapy of 2 or 4 g/day did not significantly improve the high-risk features of coronary atherosclerotic plaques evaluated using CMR under statin therapy.

DOI： 10.5551/jat.64063

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BACKGROUND: While internal mammary artery (IMA) has become a major conduit of coronary artery bypass graft (CABG) surgery, subclavian artery stenosis (SAS) could cause subsequent coronary events due to ischemia of myocardial territory supplied by IMA. Clinical characteristics and cardiovascular outcomes of SAS-related IMA failure (SAS-IMAF) remain to be fully determined yet. Therefore, the current study was designed to characterize SAS-IMAF in patients receiving CABG with IMA. METHODS: This is a retrospective observational study which analyzed 380 patients who presented acute coronary syndrome/stable ischemic heart disease (ACS/SIHD) after CABG using IMA (2005.01.01-2020.10.31). SAS-IMAF was defined as the presence of myocardial ischemia/necrosis caused by SAS. Clinical characteristics and cardiovascular outcomes [major adverse cardiovascular events (MACE) = cardiac death + non-fatal myocardial infarction + non-fatal ischemic stroke], were compared in subjects with and without SAS-IMAF. Multivariate Cox proportional hazards model and propensity score-matched analyses were used to compare cardiovascular outcomes between those with and without SAS-IMAF. RESULTS: SAS-IMAF was identified in 5.5% (21/380) of study subjects. Patients with SAS-IMAF are more likely had a history of hemodialysis (P<0.001), stroke (P<0.001) and lower extremity artery disease (P<0.001). Furthermore, SAS-IMAF patients more frequently presented ACS (P=0.002) and required mechanical support (P=0.02). Despite SAS as a culprit lesion causing ACS/SIHD, percutaneous coronary intervention was firstly selected in 47.6% (10/21) of them. Consequently, 33.3% (7/21) of SAS-IMAF patients required additional revascularization procedure (vs. 0.3%, P<0.001). During 4.9-year observational period, SAS-IMAF exhibited a 5.82-fold [95% confidence interval (CI): 2.31-14.65, P<0.001] increased risk of MACE. Multivariate Cox proportional hazards model [hazard ratio (HR) 4.04, 95% CI: 1.44-11.38, P=0.008] and propensity score-matched analyses (HR 2.67, 95% CI: 1.06-6.73, P=0.038) consistently demonstrated the association of SAS-IMAF with MACE. CONCLUSIONS: SAS-IMAF reflects a high-risk phenotype of polyvascular disease, underscoring meticulous evaluation of subclavian artery after CABG using IMA.

DOI： 10.21037/cdt-23-211

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BACKGROUND: Non-contrast T1-weighted imaging (T1WI) with cardiac magnetic resonance enables to evaluate the intensity of coronary plaque. Plaque-to-myocardial signal intensity ratio (PMR) has been shown to associate with an elevated risk of future coronary events. Of note, PMR >1.4 is a best cut-off value to identify high-risk plaque causing future coronary events. One recent study has reported intraluminal thrombus as a contributor to PMR. However, whether plaque material itself is associated with PMR has not been fully characterized yet. We present three cases with coronary artery stenosis evaluated by non-contrast T1WI-magnetic resonance imaging, optical coherence tomography (OCT) and near-infrared spectroscopy (NIRS)-intravascular ultrasound (IVUS) imaging. CASE DESCRIPTION: Case 1 exhibited one lesion with high PMR (2.79) at the proximal segment of left anterior descending (LAD) artery. OCT imaging did not identify any obvious intra-luminal thrombus but the presence of lipid-rich plaque harboring cholesterol crystal at the corresponding lesion. In addition, an elevated maximum 4-mm lipid-core burden index (maxLCBI4mm) (=873) was observed at this lesion by NIRS/IVUS imaging. In case 2, PMR of coronary stenosis at the middle segment of LAD artery was 1.88. This lesion harboured lipidic materials without any thrombus on OCT imaging. NIRS-derived maxLCBI4mm was 725. Case 3 had a severe stenosis at the middle segment of LAD artery. This lesion exhibited a low PMR (0.90). On OCT and NIRS/IVUS imaging, this lesion was characterized as the presence of small lipid arc with a low maxLCBI4mm (=386). CONCLUSIONS: These cases showed the possible relationship of T1WI-derived PMR with the degree of lipidic plaque components.

DOI： 10.21037/cdt-23-125

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BACKGROUND: Continuous glucose monitoring (CGM) improves glycemic fluctuation and reduces hypoglycemic risk. Whether CGM-guided glycemic control favorably modulates coronary atherosclerosis in patients with type 2 diabetes (T2DM) remains unknown. METHODS: The OPTIMAL trial was a prospective, randomized, single-center trial in which 94 T2DM patients with CAD were randomized to CGM- or HbA1c-guided glycemic control for 48 weeks (jRCT1052180152). The primary endpoint was the nominal change in total atheroma volume (TAV) measured by serial IVUS. The secondary efficacy measure was the nominal change in maxLCBI4mm on near-infrared spectroscopy imaging. RESULTS: Among the 94 randomized patients, 82 had evaluable images at 48 weeks. Compared to HbA1c-guided glycemic control, CGM-guided control achieved a greater reduction in %coefficient of variation [-0.1 % (-1.8 to 1.6) vs. -3.3 % (-5.1 to -1.5), p = 0.01] and a greater increase in the duration with glucose between 70 and 180 mg/dL [-1.5 % (-6.0 to 2.9) vs. 6.7 % (1.9 to 11.5), p = 0.02]. TAV increased by 0.11 ± 1.9 mm3 in the HbA1c-guided group and decreased by -3.29 ± 2.00 mm3 in the CGM-guided group [difference = -3.4 mm3 (95%CI: -8.9 to 2.0 mm3), p = 0.22]. MaxLCBI4mm, increased by 90.1 ± 25.6 in the HbA1c-guided group and by 50.6 ± 25.6 in the CGM-guided group (difference = -45.6 (95%CI: -118.1 to 26.7) p = 0.21]. A post-hoc exploratory analysis showed a greater regression of maxLCBI4mm in the CGM-guided group [difference = 20.4 % (95%CI:1.3 to 39.5 %), p = 0.03]. CONCLUSIONS: CGM-guided control for 48 weeks did not slow disease progression in T2DM patients with CAD. A greater regression of lipidic plaque under CGM-guided glycemic control in the post-hoc analysis requires further investigation.

DOI： 10.1016/j.jdiacomp.2023.108592

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Language：English   Publisher：(一社)日本心血管インターベンション治療学会  

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Language：English   Publisher：(一社)日本心血管インターベンション治療学会  

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Language：English   Publisher：(一社)日本心血管インターベンション治療学会  

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Language：English   Publisher：(一社)日本心血管インターベンション治療学会  

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Nitroglycerin dilates the radial artery and prevents spasm, which increases the success rate of sheath cannulation through the conventional transradial approach. However, the effects of nitroglycerin on distal radial approach (DRA) procedures are not known. The aim of this study is to elucidate whether a transdermal nitroglycerin patch improves the rate of successful DRA cannulation. A total of 92 patients scheduled for coronary angiography by means of DRA randomly received (1:1) a transdermal nitroglycerin patch preintegrated with the covering material or only the covering material on their upper arm on the side of the puncture. The diameter of the distal radial artery was evaluated with ultrasound at baseline and after application. DRA procedures were performed in a double-blind fashion. The primary outcome was the rate of successful palpation-guided distal radial artery cannulation with the first puncture. The nitroglycerin group had larger distal radial artery diameter after patch application than that of the no-treatment group (mean, 3.21 mm vs 2.71 mm, p <0.001), but not at baseline (mean, 2.64 mm vs 2.64 mm, p = 0.965).The nitroglycerin group had a significantly higher success rate of DRA cannulation with the first puncture than that of the no-treatment group (59% vs 24%, p = 0.001; odds ratio 4.5, 95% confidence interval 1.9 to 11.0). The nitroglycerin group required fewer punctures than did the no-treatment group (median, 1 vs 3, p = 0.019). There were no significant differences in the occurrence of hypotension between the 2 groups. No patients experienced radial artery occlusion. In conclusion, transdermal nitroglycerin patch application safely facilitates DRA cannulation. Trial Registration: Japan Registry of Clinical Trials, https://jrct.niph.go.jp/ (identifier: jRCTs051210128).

DOI： 10.1016/j.amjcard.2023.07.068

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Inflammation has been considered to promote atheroma instability. Coronary computed tomography angiography (CCTA) visualizes pericoronary adipose tissue (PCAT) attenuation, which reflects coronary artery inflammation. While PCAT attenuation has been reported to predict future coronary events, plaque phenotypes exhibiting high PCAT attenuation remains to be fully elucidated. The current study aims to characterize coronary atheroma with a greater vascular inflammation. We retrospectively analyzed culprit lesions in 69 CAD patients receiving PCI from the REASSURE-NIRS registry (NCT04864171). Culprit lesions were evaluated by both CCTA and near-infrared spectroscopy/intravascular ultrasound (NIRS/IVUS) imaging prior to PCI. PCAT attenuation at proximal RCA (PCATRCA) and NIRS/IVUS-derived plaque measures were compared in patients with PCATRCA attenuation ≥ and < -78.3 HU (median). Lesions with PCATRCA attenuation ≥ -78.3 HU exhibited a greater frequency of maxLCBI4mm ≥ 400 (66% vs. 26%, p < 0.01), plaque burden ≥ 70% (94% vs. 74%, p = 0.02) and spotty calcification (49% vs. 6%, p < 0.01). Whereas positive remodeling (63% vs. 41%, p = 0.07) did not differ between two groups. On multivariable analysis, maxLCBI4mm ≥ 400 (OR = 4.07; 95%CI 1.12-14.74, p = 0.03), plaque burden ≥ 70% (OR = 7.87; 95%CI 1.01-61.26, p = 0.04), and spotty calcification (OR = 14.33; 95%CI 2.37-86.73, p < 0.01) independently predicted high PCATRCA attenuation. Of note, while the presence of only one plaque feature did not necessarily elevate PCATRCA attenuation (p = 0.22), lesions harboring two or more features were significantly associated with higher PCATRCA attenuation. More vulnerable plaque phenotypes were observed in patients with high PCATRCA attenuation. Our findings suggest PCATRCA attenuation as the presence of profound disease substrate, which potentially benefits from anti-inflammatory agents.

DOI： 10.1007/s10554-023-02907-w

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Calcified atheroma has been viewed conventionally as stable lesion which less likely increases no-reflow phenomenon. Given that lipidic materials triggers the formation of calcification, lipidic materials could exist within calcified lesion, which may cause no-reflow phenomenon after PCI. The REASSURE-NIRS registry (NCT04864171) employed near-infrared spectroscopy and intravascular ultrasound imaging to evaluate maximum 4-mm lipid-core burden index (maxLCBI4mm) at target lesions containing small (maximum calcification arc < 180°: n = 272) and large calcification (maximum calcification arc ≥ 180°: n = 189) in stable CAD patients. The associations of maxLCBI4mm with corrected TIMI frame count (CTFC) and no-reflow phenomenon after PCI were analyzed in patients with target lesions containing small and large calcification, respectively. No-reflow phenomenon occurred in 8.0% of study population. Receiver-operating characteristics curve analyses revealed that optimal cut-off values of maxLCBI4mm for predicting no-reflow phenomenon were 585 at small calcification (AUC = 0.72, p < 0.001) and 679 at large calcification (AUC = 0.76, p = 0.001). Target lesions containing small calcification with maxLCBI4mm ≥ 585 more likely exhibited a greater CTFC (p < 0.001). In those with large calcification, 55.6% of them had maxLCBI4mm ≥ 400 [vs. 56.2% (small calcification), p = 0.82]. Furthermore, a higher CTFC (p < 0.001) was observed in association with maxLCBI4mm ≥ 679 at large calcification. On multivariable analysis, maxLCBI4mm at large calcification still independently predicted no-reflow phenomenon (OR = 1.60, 95%CI = 1.32-1.94, p < 0.001). MaxLCBI4mm at target lesions exhibiting large calcification elevated a risk of no-reflow phenomenon after PCI. Calcified plaque containing lipidic materials is not necessarily stable lesion, but could be active and high-risk one causing no-reflow phenomenon.

DOI： 10.1007/s10554-023-02905-y

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The feasibility of rotational atherectomy (RA) during percutaneous coronary intervention (PCI) in patients who present with acute coronary syndrome (ACS) remains fully unsettled. We retrospectively evaluated 198 consecutive patients who underwent RA during PCI from 2009 to 2020. All patients underwent intracoronary imaging (intravascular ultrasound 96.5%, optical coherence tomography 9.1%, both 5.6%) during PCI. Patients who underwent RA during PCI were divided into two groups: ACS (n = 49; unstable angina pectoris, n = 27; non-ST-elevation myocardial infarction, n = 18, and ST-elevation myocardial infarction, n = 4) and chronic coronary syndrome (CCS) (n = 149). The RA procedural success rate was comparable between in the ACS and CCS groups (93.9 vs. 89.9%, P = 0.41). No significant differences were observed in procedural complications and in-hospital death between the groups. The incidence of major adverse cardiovascular event (MACE) after 2 years was significantly higher in ACS group compared with CCS group (38.7 vs. 17.4%, log-rank P = 0.002). Multivariable Cox regression analysis identified SYNTAX score or CABG SYNTAX score > 22 (hazard ratio (HR) 2.66, 95% confidence interval (CI) 1.40-5.06, P = 0.002) and mechanical circulatory support during the procedure (HR 2.61, 95% CI 1.21-5.59, P = 0.013) as predictors of MACE at 2 years, but not ACS on index admission (HR 1.58, 95% CI 0.84-2.99, P = 0.151). RA procedure is feasible as a bail-out strategy for ACS lesions. However, more complexed coronary atherosclerosis and mechanical circulatory support during RA procedure, but no ACS lesions were associated with worse mid-term clinical outcomes.

DOI： 10.1007/s00380-023-02272-7

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BACKGROUND: Current guidelines recommend prophylactic defibrillator implantation in patients with acute myocardial infarction (AMI) and left ventricular ejection fraction (LVEF) ≤40% or LVEF ≤35% plus heart failure symptoms or inducible ventricular tachyarrhythmias during an electrophysiology study at 40 days after AMI or 90 days after revascularization. In-hospital predictors of sudden cardiac death (SCD) after AMI during the index hospitalization remain unsettled. We sought to examine in-hospital predictors of SCD in patients with AMI and LVEF ≤40% evaluated during the index hospitalization. METHODS: We retrospectively evaluated 441 consecutive patients with AMI and LVEF ≤40% admitted to our hospital between 2001 and 2014 (77% male gender; median age: 70 years; median hospitalization length: 23 days). The primary endpoint was a composite of SCD or aborted SCD at ≥30 days after AMI onset (composite arrhythmic event). LVEF and QRS duration (QRSd) on electrocardiography were measured at a median of 12 days and 18 days, respectively. RESULTS: During a median follow-up of 7.6 years, the incidence of composite arrhythmic events was 7.3% (32 of 441 patients). In multivariable analysis, QRSd ≥100 msec (beta-coefficient=1.54, p=0.003), LVEF ≤23% (beta-coefficient=1.14, p=0.007), and onset-reperfusion time >5.5 hours (beta-coefficient=1.16, p=0.035) were independent predictors of composite arrhythmic events. The combination of these 3 factors was associated with the highest rate of composite arrhythmic events compared with 0-2 factors (p<0.001). CONCLUSIONS: The combination of QRSd ≥100 msec, LVEF ≤23%, and onset-reperfusion time >5.5 hours during the index hospitalization provides precise risk stratification for SCD in patients early after AMI.

DOI： 10.1016/j.jjcc.2023.05.003

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BACKGROUND: Intravascular imaging has shown better response of coronary atheroma to statin-mediated lowering of low-density lipoprotein cholesterol in women. However, its detailed mechanism remains to be determined yet. Modifiability of coronary atheroma under lipid-lowering therapies is partly driven by lipidic plaque component. Given a smaller plaque volume in women, lipidic plaque features including their density may differ between sex. Therefore, the current study sought to characterize sex-related differences in the density of lipidic plaque. METHODS: We analyzed 1429 coronary lesions (culprit/nonculprit lesions=825/604) in 758 coronary artery disease patients (men/women=608/150) from the REASSURE-NIRS multicenter registry (Revelation of Pathophysiological Phenotypes of Vulnerable Lipid-Rich Plaque on Near-Infrared Spectroscopy). Total atheroma volume at 4-mm segment, maximum 4-mm-lipid-core burden index, and lipid plaque density index (=maximum 4-mm-lipid-core burden index/total atheroma volume at 4-mm segment) on near-infrared spectroscopy/intravascular ultrasound imaging at culprit and nonculprit lesions were compared in men and women. RESULTS: Statin and high-intensity statin were used in 72.4 (P=0.81) and 22.9% (P=0.32) of study subjects, respectively. Women exhibited a smaller adjusted total atheroma volume at 4-mm segment (culprit lesions: 50.3±0.4 versus 54.2±0.3mm3, P<0.001, nonculprit lesions: 31.5±3.0 versus 44.4±2.1mm3, P<0.001), whereas their adjusted maximum 4-mm-lipid-core burden index did not differ between sex (culprit lesions: 544.7±29.9 versus 501.7±19.1, P=0.11, nonculprit lesions: 288.8±26.7 versus 272.7±18.9, P=0.51). Furthermore, a greater adjusted lipid plaque density index was observed in women (culprit lesions: 18.2±0.9 versus 9.8±0.6, P<0.001, nonculprit lesions: 23.0±2.0 versus 7.8±1.4, P<0.001). These adjustments of total atheroma volume at 4-mm segment, maximum 4-mm-lipid-core burden index, and lipid plaque density index included age, body mass index, hypertension, dyslipidemia, diabetes, smoking, a history of myocardial infarction and chronic kidney disease, low-density lipoprotein cholesterol level, statin and ezetimibe use, vessel volume, and hospital unit. The aforementioned plaque features consistently existed in both acute coronary syndrome and stable coronary artery disease subjects. CONCLUSIONS: Women harbored greater condensed lipidic plaque features, accompanied by smaller atheroma volume. These observations indicate potentially better modifiable disease in women, which underscores the need to intensify their lipid-lowering therapies for further improving their outcomes. REGISTRATION: URL: https://www. CLINICALTRIALS: gov/; Unique identifier: NCT04864171.

DOI： 10.1161/CIRCIMAGING.122.015107

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BACKGROUND: Acute pericarditis occasionally requires invasive treatment, and may recur after discharge. However, there are no studies on acute pericarditis in Japan, and its clinical characteristics and prognosis are unknown. METHODS: This was a single-center, retrospective cohort study of clinical characteristics, invasive procedures, mortality, and recurrence in patients with acute pericarditis hospitalized from 2010 to 2022. The primary in-hospital outcome was adverse events (AEs), a composite of all-cause mortality and cardiac tamponade. The primary outcome in the long-term analysis was hospitalization for recurrent pericarditis. RESULTS: The median age of all 65 patients was 65.0 years [interquartile range (IQR), 48.0-76.0 years], and 49 (75.3 %) were male. The etiology of acute pericarditis was idiopathic in 55 patients (84.6 %), collagenous in 5 (7.6 %), bacterial in 1 (1.5 %), malignant in 3 (4.6 %), and related to previous open-heart surgery in 1 (1.5 %). Of the 8 patients (12.3 %) with in-hospital AE, 1 (1.5 %) died during hospitalization and 7 (10.8 %) developed cardiac tamponade. Patients with AE were less likely to have chest pain (p = 0.011) but were more likely to have symptoms lasting 72 h after treatment (p = 0.006), heart failure (p < 0.001), and higher levels of C-reactive protein (p = 0.040) and B-type natriuretic peptide (p = 0.032). All patients complicated with cardiac tamponade were treated with pericardial drainage or pericardiotomy. We analyzed 57 patients for recurrent pericarditis after excluding 8 patients: 1 with in-hospital death, 3 with malignant pericarditis, 1 with bacterial pericarditis, and 3 lost to follow-up. During a median follow-up of 2.5 years (IQR 1.3-3.0 years), 6 patients (10.5 %) had recurrences requiring hospitalization. The recurrence rate of pericarditis was not associated with colchicine treatment or aspirin dose or titration. CONCLUSIONS: In acute pericarditis requiring hospitalization, in-hospital AE and recurrence were each observed in >10 % of patients. Further large studies on treatment are warranted.

DOI： 10.1016/j.jjcc.2023.03.002

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Language：English   Publisher：(一社)日本循環器学会  

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Background Acute myocardial infarction (AMI) infrequently occurs after acute stroke. The Heart-brain team approach has a potential to appropriately manage this poststroke cardiovascular complication. However, clinical outcomes of AMI complicating acute stroke (AMI-CAS) with the heart-brain team approach have not been characterized. The current study investigated cardiovascular outcomes in patients with AMI-CAS managed by a heart-brain team. Methods and Results We retrospectively analyzed 2390 patients with AMI at our institute (January 1, 2007-September 30, 2020). AMI-CAS was defined as the occurrence of AMI within 14 days after acute stroke. Major adverse cerebral/cardiovascular events (cardiac-cause death, nonfatal myocardial infarction, and nonfatal stroke) and major bleeding events were compared in subjects with  AMI-CAS and those without acute stroke. AMI-CAS was identified in 1.6% of the subjects. Most AMI-CASs (37/39=94.9%) presented ischemic stroke. Median duration of AMI from the onset of acute stroke was 2 days. Patients with AMI-CAS less frequently received primary percutaneous coronary intervention (43.6% versus 84.7%; P<0.001) and dual-antiplatelet therapy (38.5% versus 85.7%; P<0.001), and 33.3% of them did not receive any antithrombotic agents (versus 1.3%; P<0.001). During the observational period (median, 2.4 years [interquartile range, 1.1-4.4 years]), patients with AMI-CAS exhibited a greater likelihood of experiencing major adverse cerebral/cardiovascular events (hazard ratio [HR], 3.47 [95% CI, 1.99-6.05]; P<0.001) and major bleeding events (HR, 3.30 [95% CI, 1.34-8.10]; P=0.009). These relationships still existed even after adjusting for clinical characteristics and medication use (major adverse cerebral/cardiovascular event: HR, 1.87 [95% CI, 1.02-3.42]; P=0.04; major bleeding: HR, 2.67 [95% CI, 1.03-6.93]; P=0.04). Conclusions Under the heart-brain team approach, AMI-CAS was still a challenging disease, reflected by less adoption of primary percutaneous coronary intervention and antithrombotic therapies, with substantially elevated cardiovascular and major bleeding risks. Our findings underscore the need for a further refined approach to mitigate their ischemic/bleeding risks.

DOI： 10.1161/JAHA.122.027156

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BACKGROUND: Indwelling urethral catheters (IUCs) are used to measure urine volume, keep patients on bed rest, or keep the groin area clean in patients with acute myocardial infarction (AMI). However, the association between IUC use and in-hospital urinary-related complications is unknown. METHODS: This was a single-center retrospective analysis of 303 patients admitted to our hospital in 2018-2020 who had AMI without cardiogenic shock. An IUC was inserted in the emergency room upon initiation of invasive catheter treatment and removed as soon as possible. The primary outcome was in-hospital adverse urinary event (IHAUE), which consisted of in-hospital urinary tract infection and in-hospital gross hematuria. RESULTS: Of 303 patients, 243 patients (80.2 %) underwent IUC insertion. A lower proportion of patients with IUCs were male (72 % vs. 85 %, p = 0.044). A higher proportion had Killip classification 2 or 3 (13 % vs. 0 %, p = 0.003) or ST-elevation myocardial infarction (65 % vs. 32 %, p < 0.001). IHAUEs occurred significantly more commonly in patients with IUCs than without IUCs (11 % vs. 2 %, p = 0.023). Kaplan-Meier analysis showed that IHAUEs occurred more frequently in patients with IUCs than patients without IUCs (log-rank test p = 0.033). Furthermore, IUC use longer than the median of 2 days was associated with a higher odds ratio (OR) for IHAUE when compared with those without IUC use (OR, 3.65; 95 % confidence interval, 1.28-10.4; p = 0.015). There were no significant differences in in-hospital mortality by IUC status. CONCLUSIONS: IUC use is associated with a higher risk of IHAUEs in patients with uncomplicated AMI. Routine IUC use might not be recommended.

DOI： 10.1016/j.jjcc.2022.12.007

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Language：Japanese   Publisher：医学図書出版(株)  

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BACKGROUND: Recent clinical studies are testing strategies for short (1-3 months) dual antiplatelet therapy following newer-generation drug-eluting stent (DES) placement. However, detailed biological responses to newer-generation DES remain unknown in humans. AIMS: We sought to evaluate early pathologic responses to abluminal biodegradable polymer-coated (BP-) DES compared with circumferential durable polymer-coated (DP-) DES in human autopsy cases. METHODS: The study included 38 coronary lesions with newer-generation DES implanted for <90 days (DP-DES=24, BP-DES=14) in 26 autopsy cases. The degree of strut coverage was defined as follows: grade 0 (bare), grade 1 (with fibrin or tissues/cells without endothelium), grade 2 (with single-layered endothelium), and grade 3 (with endothelium and underlying smooth muscle cell layers). RESULTS:  The duration following implantation was similar in DP- and BP-DES (median=20 vs 17 days). A total of 2,022 struts (DP-DES=1,297, BP-DES=725) were pathologically analysed. Focal grade 2 coverage was observed as early as 5 days after the implantation in both stents. The multilevel mixed-effects ordered logistic regression model demonstrated that BP-DES exhibited greater strut coverage compared with DP-DES (odds ratio [OR]: 3.64, 95% confidence interval [CI]: 1.37-9.67; p=0.009), which remained significant after adjustment for the duration following implantation and underlying tissue characteristics (OR: 2.74, 95% CI: 1.10-6.80; p=0.030). The predictive probability of grade 2 and 3 coverage was comparably limited at 30 days (DP-DES=17.1%, BP-DES=28.7%) and increased at 90 days (DP-DES=76.5%, BP-DES=86.6%). Both stents showed low inflammation and a similar degree of fibrin deposition. CONCLUSIONS: Single-layered endothelial coverage begins in the days after newer-generation DES placement, and BP-DES potentially exhibit faster strut coverage with smooth muscle cell infiltration than DP-DES in humans. Nevertheless, vessel healing remains suboptimal in both stents at 30 days.

DOI： 10.4244/EIJ-D-22-00650

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BACKGROUND: Although screening for coronary artery disease (CAD) using computed tomography coronary angiography in patients with stable chest pain has been reported to be beneficial, patients with chronic kidney disease (CKD) might have limited benefit due to complications of contrast agent nephropathy and decreased diagnostic accuracy as a result of coronary artery calcifications. Cardiac magnetic resonance (CMR) has emerged as a novel imaging modality for detecting coronary stenosis and high-risk coronary plaques without contrast media that is not affected by coronary artery calcification. However, the clinical use of this technology has not been robustly evaluated. METHODS: AQUAMARINE-CKD is an open parallel-group prospective multicenter randomized controlled trial of 524 patients with CKD at high risk for CAD estimated based on risk factor categories for a Japanese urban population (Suita score) recruited from 6 institutions. Participants will be randomized 1:1 to receive a CMR examination that includes non-contrast T1-weighted imaging and coronary magnetic angiography (CMR group) or standard examinations that include stress myocardial scintigraphy (control group). Randomization will be conducted using a web-based system. The primary outcome is a composite of cardiovascular events at 1 year after study examinations: all-cause death, death from CAD, nonfatal myocardial infarction, nonfatal ischemic stroke, and ischemia-driven unplanned coronary intervention (percutaneous coronary intervention or coronary bypass surgery). DISCUSSION: If the combination of T1-weighted imaging and coronary magnetic angiography contributes to the risk assessment of CAD in patients with CKD, this study will have major clinical implications for the management of patients with CKD at high risk for CAD. TRIAL REGISTRATION: Japan Registry of Clinical Trials (jRCT) 1,052,210,075. Registered on September 10, 2021.

DOI： 10.1186/s13063-022-06820-w

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BACKGROUND: Mechanism of femoropopliteal in-stent restenosis has been underappreciated. AIM: The aim of this animal study was to elucidate vascular response after femoropopliteal bare nitinol self-expanding stents (SESs) implantation. METHODS: Misago, Smart Flex, or Innova stent was randomly implanted in 36 swine femoropopliteal arteries. At week 4, quantitative vessel analysis (QVA) was performed on 36 legs, of which 18 underwent histological evaluation after angiography. The remaining 18 legs underwent QVA and histological evaluation at week 13. RESULTS: Fibrin deposition was excessive at week 4. Internal elastic lamina (IEL) progressively enlarged over time, and vessel injury developed from mild level at week 4 to moderate level at week 13. Vessel inflammatory reaction was mild to moderate at week 4, and was moderate to severe at week 13. Increased fibrin deposition was an early-acting, IEL enlargement and increased vessel inflammation were long-acting, and increased vessel injury and giant cells infiltration were late-acting contributors to neointimal hyperplasia (NIH). Stent type altered time-dependent process of vessel injury, vessel inflammation, eosinophils and giant cells infiltration. Misago had less fibrin deposition and vessel enlargement, and less progressive vessel injury, vessel inflammation, and eosinophils and giant cells infiltration. Net lumen as assessed by percent diameter stenosis or minimum lumen diameter was preserved with Misago, but was not preserved with the other stents. CONCLUSIONS: In the context of bare nitinol SES platform with less progressive mechanical stress and inflammatory reaction, the advantage of less NIH outweighed the disadvantage of less vessel enlargement, leading to net lumen preservation.

DOI： 10.1007/s12928-022-00889-5

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BACKGROUND: Lipid-rich plaque is an important substrate that causes future coronary events. However, the clinical implications of underlying plaque characteristics in coronary lesions after newer-generation drug-eluting stent (DES) implantation remain unknown. METHODS: The current study analyzed 445 target lesions after newer-generation DES implantation in 416 patients with coronary artery disease (CAD) (chronic coronary syndrome/acute coronary syndrome = 264/181) from the REASSURE-NIRS multicentre registry. Near-infrared spectroscopy (NIRS) imaging was used to evaluate maximum lipid core burden index after stent implantation in target lesions (residual maxLCBI4mm). The primary and secondary outcomes were 3-year lesion-oriented clinical outcomes (LOCO): cardiac death, nonfatal target-lesion-related myocardial infarction (MI), or ischemia-driven target-lesion revascularization (ID-TLR) and patient-oriented clinical outcomes (POCO): all-cause death, nonfatal MI, or ID unplanned revascularization. Outcomes were compared by residual maxLCBI4mm tertile. RESULTS: Median residual maxLCBI4mm was 183; 16% of lesions had residual maxLCBI4mm > 400. Higher residual maxLCBI4mm was not associated with a greater likelihood of LOCO or POCO during the observational period (LOCO, log-rank P = 0.76; POCO, log-rank P = 0.84). Mixed-effects logistic regression demonstrated that residual maxLCBI4mm does not predict LOCO (odds ratio [OR], 1.000; 95% confidence interval [CI], 0.997-1.003; P = 0.95). There was no significant relationship between residual maxLCBI4mm and POCO (OR, 1.001; 95% CI, 0.999-1.002; P = 0.30). CONCLUSIONS: Residual maxLCBI4mm is not associated with LOCO or POCO in patients with CAD after newer-generation DES implantation. Our findings suggest that NIRS-derived underlying lipid-rich plaque is not associated with the risk of stent-related events and patient-based outcomes in patients with CAD who have received newer-generation DESs.

DOI： 10.1016/j.cjca.2022.07.004

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AME PUBLISHING COMPANY  

Background: Active cancer associates with increased cardiovascular and bleeding risks in patients with acute myocardial infarction (AMI). Recent chemotherapeutic agents have improved survival rate which enables to induce inactive status of cancer. However, whether cardiovascular and bleeding risks still exist in AMI patients with inactive cancer remains unknown.Methods: The current study is a retrospective cross-sectional study including 712 AMI patients receiving primary percutaneous coronary intervention (PCI) with drug-eluting stent between 2007 and 2017. Primary PCI in ST-segment elevation myocardial infarction and non-ST-segment elevation myocardial infarction subjects was defined as PCI performed within 48 and 72 hours of symptom onset, respectively. Cardiovascular (= all-cause death + non-fatal MI + stroke) and bleeding events were compared in AMI patients with and without inactive cancer.Results: Inactive cancer was identified in 11.1% of study subjects. Patients with inactive cancer were older (P<0.001) with atrial fibrillation (P<0.001), chronic kidney disease (P<0.001), anemia (P<0.001) and a higher prevalence of Killip class IV (P<0.001). Dual (82 vs. 87%) and triple (18 vs. 13%, P=0.34) antithrombotic therapies were commenced. Nearly 80% of subjects switched to single antithrombotic therapy around 1.5 years after dual/triple antithrombotic therapies (77 vs. 77%, P=0.99). During the 2.9-year observational period, inactive cancer was associated with 3.59-fold elevated risk for experiencing a composite of cardiovascular and bleeding events (95% CI: 2.13-6.04, P<0.001). Furthermore, after adjusting clinical characteristics, inactive cancer was an independent predictor for bleeding events (HR: 3.98, 95% CI: 1.90- 8.34, P<0.001). Of particular interests, even after switching to single antithrombotic therapy, an elevated bleeding risk was still observed in inactive cancer subjects (P<0.001).Conclusions: Inactive cancer worsened clinical outcome, especially bleeding risks in AMI subjects, underscoring to further optimize their antithrombotic managements.

DOI： 10.21037/cdt-22-306

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Publisher：株式会社 医学書院  

DOI： 10.11477/mf.1438200603

CiNii Research

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DOI： 10.1016/j.jcmg.2022.02.005

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BACKGROUND: The distal radial approach (DRA) is a novel catheter cannulation technique to access the distal radial artery for coronary angiography (CAG). It is associated with less occurrence of puncture site occlusion than the conventional transradial approach. However, cannulation failure occasionally occurs due to difficulty in puncturing the smaller distal radial artery. Nitroglycerin is expected to improve the rate of successful DRA via its vasodilative and vasospasm-preventive effects. METHODS: The DRA in CAG using transdermal NitroGlycerin patch (DRANG) study is a single-center, double-arm, parallel-assignment, double-blinded, randomized, controlled trial. Eligible patients with angina pectoris who are scheduled to receive CAG via DRA at the National Cerebral and Cardiovascular Center will be enrolled and allocated to the nitroglycerin group (n = 46) or the no-treatment group (n = 46). The nitroglycerin group will receive a transdermal nitroglycerin patch pre-integrated with a covering material that completely conceals the patch on their upper arm on the puncture side. The no-treatment group will receive only the covering material. Applications are performed 2-8 h before puncture while the patient wears an eye mask. Physicians who are blinded to the allocation and have similar experience with DRA puncture will perform DRA using the Seldinger technique with a 22-gauge needle. The primary outcome is the rate of successful palpation-guided distal radial artery cannulation with the first puncture. The secondary outcomes are the rate of successful distal radial artery cannulation, number of punctures, procedure time, use of ultrasound guidance, diameter of the distal radial artery and changes before and after patch application, and occurrence of arterial vasospasm, occlusion, or hypotension. CONCLUSIONS: This study will allow us to determine the impact of a transdermal nitroglycerin patch on the rate of successful DRA and validate its effectiveness as a DRA pretreatment. TRIAL REGISTRATION: jRCTs051210128.

DOI： 10.1016/j.carrev.2022.05.010

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DOI： 10.1016/j.carrev.2021.11.025

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BACKGROUND AND AIMS: The residual risk of atherosclerotic cardiovascular disease (ASCVD) in patients with diabetes on statin therapy warrants identification of other pro-atherogenic drivers. Lipoprotein(a) [Lp(a)] promotes the formation of necrotic cores within vessel walls. Given that patients with diabetes have an Lp(a)-associated ASCVD risk, Lp(a) might lead to plaque vulnerability in patients with diabetes on statin therapy. METHODS: We analyzed target lesions that underwent PCI in 312 patients with coronary artery disease (CAD) on statin treatment from the REASSURE-NIRS registry (NCT04864171). Maximum 4-mm lipid-core-burden index (maxLCBI4mm) in target lesions was measured with near-infrared spectroscopy (NIRS) imaging. The relationship between Lp(a) levels and maxLCBI4mm was investigated in patients with and without diabetes. RESULTS: High-intensity statin use (p = 0.49) and on-treatment low-density lipoprotein cholesterol (LDL-C) (p = 0.32) and Lp(a) levels (p = 0.09) were comparable between patients with and without diabetes. Lp(a) levels were significantly associated with maxLCBI4mm in patients with diabetes (p = 0.01) but not in patients without diabetes (p = 0.96). Multivariate analysis showed that LDL-C levels (p = 0.03) predict maxLCBI4mm in patients without diabetes, but not Lp(a) levels (p = 0.91). Both LDL-C (p = 0.01) and Lp(a) (p = 0.04) levels were independent predictors of maxLCBI4mm in patients with diabetes. Even in patients with diabetes achieving LDL-C <1.8 mmol/L (70 mg/dL), Lp(a) levels remained associated with maxLCBI4mm (p = 0.04). CONCLUSIONS: A significant relationship between Lp(a) and maxLCBI4mm exists in patients with diabetes and CAD on statin treatment, even with LDL-C <1.8 mmol/L (70 mg/dL). Lp(a) might be associated with more vulnerable coronary atheroma in patients with diabetes despite receiving statin therapy.

DOI： 10.1016/j.atherosclerosis.2022.03.033

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DOI： 10.1093/ehjci/jeab295

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DOI： 10.1253/circj.CJ-20-1282

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AIMS: Although comprehensive cardiac rehabilitation (CCR) is recommended for patients with heart failure (HF), participants often show low adherence. The aim of this study was to evaluate the association of CCR completion and response with long-term clinical outcomes. METHODS AND RESULTS: We screened 824 HF patients who participated in a 3 month CCR programme and underwent baseline assessment, including cardiopulmonary exercise testing (CPX). After excluding 52 participants who experienced all-cause death or HF hospitalization within 180 days, long-term outcomes were compared between those who attended 3 month follow-up assessment including CPX (completers) and those who did not (non-completers). We also compared the prognostic value of the changes in peak oxygen uptake (VO2 ) vs. quadriceps muscle strength (QMS) during the 3 month CCR programme. Among the 772 study patients, there were no significant differences in baseline characteristics, including left ventricular ejection fraction, B-type natriuretic peptide levels, and peak VO2 , between the completers (n = 561) and non-completers (n = 211), except for a higher age (63.2 ± 14.2 vs. 59.4 ± 16.2 years; P = 0.0015) and proportion of females (27% vs. 17%; P = 0.0030) among the completers. During a median follow-up of 55.4 months, the completers had lower rates of the composite of all-cause death or HF hospitalization (34.4% vs. 44.6%; P = 0.0015) and all-cause death (16.9% vs. 24.6%; P = 0.0037) than the non-completers. After adjustment for prognostic baseline characteristics, including age and sex, CCR completion was associated with 34% and 44% reductions in the composite outcome and all-cause death, respectively. Among the completers, peak VO2 and QMS increased significantly (8.9 ± 15.8% and 10.5 ± 17.9%, respectively) over 3 months. Patients who had an increase in peak VO2  ≥ 6.3% (median value) during the CCR programme had significantly lower rates of the composite outcome (27.0% vs. 33.8%; P = 0.048) and all-cause mortality (10.0% vs. 17.4%; P = 0.0069) than those who did not. No statistically significant difference was observed in the composite outcome (30.5% vs. 30.4%; P = 0.76) or all-cause mortality (13.0% vs. 14.4%; P = 0.39) between those with and without an increase in QMS ≥8.3% (median value). CONCLUSIONS: In HF patients who participated in a 3 month CCR programme, its completion was associated with lower risks of subsequent HF hospitalization and death. Within the group of patients who completed the programme, the improvement in exercise capacity, but not in skeletal muscle strength, over the 3-month period was associated with better outcomes. These findings highlight the importance of the post-CCR follow-up assessment, including CPX, to identify a patient's adherence and response to the CCR programme.

DOI： 10.1002/ehf2.13838

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OBJECTIVES: To determine the characteristics of thyroid storm patients with acute decompensated heart failure who should be candidates for temporary percutaneous mechanical circulatory support in addition to beta-blocker treatment to prevent cardiogenic shock. DESIGN: A single-center, retrospective review of treatment details and data collected from electronic medical records. SETTING: Thyrotoxicosis complicated with acute decompensated heart failure. PATIENTS: Eight consecutive patients who were admitted to our hospital for acute decompensated heart failure with thyroid storm between December 2011 and August 2020 were retrospectively reviewed. Of the eight patients, four were treated with percutaneous mechanical circulatory support. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Compared with thyroid storm patients who did not require percutaneous mechanical circulatory support, those who did had a significantly higher initial plasma brain natriuretic peptide level (1,231 [911-3,387] vs 447 pg/mL [243-653 pg/mL], respectively; p = 0.015), as well as a significantly larger left ventricular end-diastolic diameter (56 [54-63] vs 48 mm [38-48 mm], respectively; p = 0.029) and end-systolic diameter (50 [49-58] vs 28 mm [28-30 mm], respectively; p = 0.029) on echocardiogram. In terms of thyroid storm severity, the Burch-Wartofsky score was higher in patients with percutaneous mechanical circulatory support than in those without, although the difference was not significant. All patients survived this index admission. CONCLUSIONS: In thyroid storm patients, the presence of a high brain natriuretic peptide level, "left ventricular dilatation," or both may necessitate hemodynamic assessment to determine the indication of percutaneous mechanical circulatory support before beta-blocker administration.

DOI： 10.1097/CCE.0000000000000599

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Language：Japanese   Publisher：(一社)日本動脈硬化学会  

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DOI： 10.1016/j.hrcr.2021.04.015

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A 75-year-old man had recurrent in-stent restenosis (ISR) attributable to calcified nodule. Near-infrared spectroscopy (NIRS) showed a gradual decrease in yellow signals during the process of repeated percutaneous coronary intervention for recurrent ISR that eventually halted. The case indicates that NIRS signals may represent lesion instability even in calcified nodule, and may be potentially predictive of recurrent ISR.

DOI： 10.1016/j.cjca.2021.07.012

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Background Statin-mediated efficacy of lowering low-density lipoprotein (LDL) cholesterol varies in each individual, and its diminished response is associated with worse outcomes. However, there is no established approach to predict hyporesponse to statins. PCSK9 (proprotein convertase subxilisin/kexin type 9) is a serine-protease associated with LDL metabolism, which circulates as mature and furin-cleaved PCSK9. Since mature PCSK9 more potently degrades the LDL receptor, its evaluation may enable the identification of statin hyporesponders. Methods and Results We analyzed 101 statin-naive patients with coronary artery disease who commenced a statin. PCSK9 subtypes at baseline and 1 month after statin use were measured by ELISA. Hyporesponse to statins was defined as a percent reduction in LDL cholesterol <15%. The relationship between each PCSK9 subtype level and hyporesponse to statins was investigated. Statins significantly lowered LDL cholesterol level (percent reduction, 40%±21%), whereas 11% of study participants exhibited a hyporeseponse to statins. Multivariable logistic regression analysis demonstrated that baseline mature PCSK9 level was an independent predictor for hyporesponse to statins even after adjusting clinical characteristics (mature PCSK9 per 10-ng/mL increase: odds ratio [OR], 1.12; 95% CI, 1.01-1.24 [P=0.03]), whereas furin-cleaved level was not (per 10-ng/mL increase: OR, 1.37; 95% CI, 0.73-2.58 [P=0.33]). Receiver operating characteristic curve analysis identified mature PCSK9 level of 228 ng/mL as an optimal cutoff to predict hyporesponse to statins (area under the curve, 0.73 [sensitivity, 0.91; specificity, 0.56]). Conclusions Baseline mature PCSK9 level >228 ng/mL is associated with hyporesponse to statins. This finding suggests that mature PCSK9 might be a potential determinant of hyporesponse to statins.

DOI： 10.1161/JAHA.120.019525

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BACKGROUND: Calcified nodule (CN) has a unique plaque morphology, in which an area of nodular calcification causes disruption of the fibrous cap with overlying luminal thrombus. CN is reported to be the least frequent cause of acute coronary thrombosis, and the pathogenesis of CN has not been well studied. OBJECTIVES: The purpose of this study is to provide a comprehensive morphologic assessment of the CN in addition to providing an evolutionary perspective as to how CN causes acute coronary thrombosis in patients with acute coronary syndromes. METHODS: A total of 26 consecutive CN lesions from 25 subjects from our autopsy registry were evaluated. Detailed morphometric analysis was performed to understand the plaque characteristics of CN and nodular calcification. RESULTS: The mean age was 70 years, with a high prevalence of diabetes and chronic kidney disease. CNs were equally distributed between men and women, with 61.5% of CNs found in the right coronary artery (n = 16), mainly within its mid-portion (56%). All CNs demonstrated surface nonocclusive luminal thrombus, consisting of multiple nodular fragments of calcification, protruding and disrupting the overlying fibrous cap, with evidence of endothelial cell loss. The degree of circumferential sheet calcification was significantly less in the culprit section (89° [interquartile range: 54° to 177°]) than in the adjacent proximal (206° [interquartile range: 157° to 269°], p = 0.0034) and distal (240° [interquartile range: 178° to 333°], p = 0.0004) sections. Polarized picrosirius red staining showed the presence of necrotic core calcium at culprit sites of CNs, whereas collagen calcium was more prevalent at the proximal and distal regions of CNs. CONCLUSIONS: Our study suggests that fibrous cap disruption in CN with overlying thrombosis is initiated through the fragmentation of necrotic core calcifications, which is flanked-proximally and distally-by hard, collagen-rich calcification in coronary arteries, which are susceptible to mechanical stress.

DOI： 10.1016/j.jacc.2021.02.016

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Background: Vulnerable plaque features including lipidic plaque have been shown to affect fractional flow reserve (FFR). Given that formation and propagation of lipid plaque is accompanied by endothelial dysfunction which impairs vascular tone, the degree of lipidic burden may affect vasoreactivity during hyperemia, potentially leading to reduced FFR. Our aim is to elucidate the relationship of the extent of lipidic plaque burden with coronary physiological vasoreactivity measure. Methods: We analyzed 89 subjects requeuing PCI due to angiographically intermediate coronary stenosis with FFR ≤0.80. Near-infrared spectroscopy (NIRS) and intravascular ultrasound were used to evaluate lipid-core burden index (LCBI) and atheroma volume at both target lesion (maxLCBI4mm; maximum value of LCBI within any 4 mm segments) and entire target vessel (LCBIvessel: LCBI within entire vessel). In addition to FFR, delta-FFR was measured by difference of distal coronary artery pressure/aortic pressure (Pd/Pa) between baseline and hyperemic state. Results: The averaged FFR and delta-FFR was 0.74 (0.69-0.77), and 0.17±0.05, respectively. On target lesion-based analysis, maxLCBI4mm was negatively correlated to FFR (ρ=-0.213, P=0.040), and it was positively correlated to delta-FFR (ρ=0.313, P=0.002). Furthermore, target vessel-based analysis demonstrated similar relationship of LCBIvessel with FFR (ρ=-0.302, P=0.003) and delta-FFR (ρ=0.369, P<0.001). Even after adjusting clinical characteristics and lesion/vessel features, delta-FFR (by 0.10 increase) was independently associated with maxLCBI4mm (β=57.2, P=0.027) and LCBIvessel (β=24.8, P=0.007) by mixed linear model analyses. Conclusions: A greater amount of lipidic plaque burden at not only "target lesion" alone but "entire target vessel" was associated with a greater delta-FFR. The accumulation of lipidic plaque materials at both local site and entire vessel may impair hyperemia-induced vasoreactivity, which causes a reduced FFR.

DOI： 10.21037/cdt-20-1024

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BACKGROUND: Coronary computed tomography angiography (CCTA) non-invasively visualizes lipid-rich plaque. However, this ability is not fully validated in vivo. The current study aimed to elucidate the association of CCTA features with near-infrared spectroscopy-derived lipidic plaque measure in patients with coronary artery disease. METHODS: 95 coronary lesions (culprit/non-culprit = 51/44) in 35 CAD subjects were evaluated by CCTA and NIRS imaging. CT density, positive remodeling, spotty calcification, napkin-ring sign and NIRS-derived maximum 4-mm lipid-core burden index (maxLCBI4mm) were analyzed by two independent physicians. The association of CCTA-derived plaque features with maxLCBI4mm ≥ 400 was evaluated. RESULTS: The median CT density and maxLCBI4mm were 57.7 Hounsfield units (HU) and 304, respectively. CT density (r = -0.75, p < 0.001) and remodeling index (RI) (r = 0.58, p < 0.001) were significantly associated with maxLCBI4mm, respectively. Although napkin-ring sign (p < 0.001) showed higher prevalence of maxLCBI4mm ≥ 400 than those without it, spotty calcification did not (p = 0.13). On multivariable analysis, CT density [odds ratio (OR) = 0.95, 95% confidence interval (CI) = 0.93-0.97; p < 0.001] and positive remodeling [OR = 7.71, 95%CI = 1.37-43.41, p = 0.02] independently predicted maxLCBI4mm ≥ 400. Receiver operating characteristic curve analysis demonstrated CT density <32.9 HU (AUC = 0.92, sensitivity = 85.7%, specificity = 91.7%) and RI ≥ 1.08 (AUC = 0.83, sensitivity = 74.3%, specificity = 85.0%) as optimal cut-off values of maxLCBI4mm ≥ 400. Of note, only 52.6% at lesions with one of these plaque features exhibited maxLCBI4mm ≥ 400, whereas the frequency of maxLCBI4mm ≥ 400 was highest at those with both features (88.5%, p < 0.001 for trend). CONCLUSIONS: CT density <32.9 HU and RI ≥ 1.08 were associated with lipid-rich plaque on NIRS imaging. Our findings underscore the synergistic value of CT density and positive remodeling to detect lipid-rich plaque by CCTA.

DOI： 10.1016/j.atherosclerosis.2021.02.019

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Language：English   Publisher：(一社)日本循環器学会  

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OBJECTIVE: Although there are regional reports that the COVID-19 pandemic is associated with a reduction in acute myocardial infarction presentations and primary percutaneous coronary intervention (PCI) procedures, little is known about the impact of the COVID-19 pandemic on mechanical complications resulting from ST-segment elevation myocardial infarction (STEMI) and mortality. METHODS: This single-centre retrospective cohort study analysed presentations, incidence of mechanical complications, and mortality in patients with STEMI before and after a state of emergency was declared due to the COVID-19 pandemic by the Japanese government on 7 April 2020. RESULTS: We analysed 359 patients with STEMI hospitalised before the declaration and 63 patients hospitalised after the declaration. The proportion of patients with late presentation was significantly higher after the declaration than before (25.4% vs 14.2%, p=0.03). The incidence of late presentation was significantly higher during the COVID-19 pandemic than before (incidence rate ratio (IRR), 2.41; 95% CI, 1.37 to 4.05; p=0.001, even after adjusting for month (IRR, 2.61; 95% CI, 1.33 to 5.13; p<0.01). Primary PCI was performed significantly less often after the declaration than before (68.3% vs 82.5%, p=0.009). The mechanical complication resulting from STEMI occurred in 13 of 359 (3.6%) patients before the declaration and 9 of 63 (14.3%) patients after the declaration (p<0.001). However, the incidence of in-hospital death (before, 6.2% vs after, 6.4%, p=0.95) was comparable. CONCLUSIONS: Following the COVID-19 pandemic, an increased incidence of mechanical complications resulting from STEMI was observed. Instructing people to stay at home, without effectively educating them to immediately seek medical attention when suffering symptoms of a heart attack, may worsen outcomes in patients with STEMI.

DOI： 10.1136/openhrt-2020-001497

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DOI： 10.1093/eurheartj/ehaa632

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BACKGROUND AND AIMS: Calcified nodule (CN) is an eruptive calcified mass causing acute coronary syndrome (ACS). Since coronary calcification is associated with an elevated cardiac event's risk, ACS attributable to CN may exhibit worse clinical outcome following percutaneous coronary intervention (PCI). METHODS: We retrospectively analyzed 657 ACS patients receiving PCI with newer-generation drug-eluting stent (DES) implantation under intravascular ultrasound (IVUS) guidance. CN was defined as (1) protruding calcification with its irregular surface and (2) the presence of calcification at adjacent proximal and distal segments. The primary endpoint was a composite of major adverse cardiac event [MACE = cardiac death + ACS recurrence + target lesion revascularization (TLR)]. RESULTS: CN was identified in 5.3% (=35/657) of the study subjects. CN patients were more likely to have coronary risk factors including hypertension (p = 0.005), chronic kidney disease (p < 0.001), maintenance hemodialysis (p < 0.001) and a history of PCI (p < 0.001). During the observational period (median = 1304 days), CN was associated with an increased risk of MACE (HR = 7.68, 95%CI = 4.61-12.80, p < 0.001), ACS recurrence (HR = 12.32, 95%CI = 6.05-25.11, p < 0.001) and TLR (HR = 10.48, 95%CI = 5.80-18.94, p < 0.001). These cardiac risks related to CN were consistently observed by Cox proportional hazards model (MACE: p < 0.001, ACS recurrence: p < 0.001, TLR: p < 0.001) and a propensity score-matched cohort analysis (MACE: p = 0.002, ACS recurrence: p = 0.01, TLR: p = 0.005). Of note, over 80% of TLR at the CN lesion was driven by its re-appearance within the implanted DES. CONCLUSIONS: ACS patients attributable to CN have an increased risk of ACS recurrence and TLR, mainly driven by the continuous growth and protrusion of the calcified mass.

DOI： 10.1016/j.atherosclerosis.2020.11.005

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DOI： 10.1016/j.jcin.2020.06.026

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A 75-year-old female patient on hemodialysis presented with non-ST-segment elevation myocardial infarction. After successful primary percutaneous coronary intervention, in-stent restenosis (ISR) occurred 3 consecutive times. Intravascular imaging assessment during the repeated percutaneous coronary intervention indicated that the ISR was not associated with neointimal hyperplasia but was mainly attributed to a calcified nodule, which protruded into the lumen. We applied excimer laser catheter ablation to avoid another ISR. (Level of Difficulty: Intermediate.).

DOI： 10.1016/j.jaccas.2020.06.035

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In vivo imaging of plaque instability has been considered to have a great potential to predict future coronary events and evaluate the stabilization effect of novel anti-atherosclerotic medical therapies. Currently, there are several intravascular imaging modalities which enable to visualize plaque components associated with its vulnerability. These include virtual histology intravascular ultrasound (VH-IVUS), integrated backscatter IVUS (IB-IVUS), optical coherence tomography (OCT), near-infrared spectroscopy and coronary angioscopy. Recent studies have shown that these tools are applicable for risk stratification of cardiovascular events as well as drug efficacy assessment. However, several limitation exists in each modality. The current review paper will outline advantages and limitation of VH-IVUS, IB-IVUS, OCT, NIRS and coronary angioscopy imaging.

DOI： 10.21037/cdt-20-238

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DOI： 10.21037/cdt-20-415

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Background: Lowering low-density lipoprotein cholesterol (LDL-C) levels using a statin is a cornerstone of preventive therapeutic management following acute myocardial infarction (AMI). In addition to its anti-atherosclerotic effects, recent studies reported a lower occurrence of heart failure (HF) under statin therapy. However, there is a wide variability in statin response. The association between the response to statin and the occurrence of HF in AMI subjects remains unclear. The purpose of present study is to examine whether the variability in statin response affects HF risk after AMI. Methods: We analyzed 505 statin-naïve AMI subjects undergoing primary percutaneous coronary intervention (PCI) who commenced atorvastatin, rosuvastatin, or pitavastatin. Statin hyporesponse was defined as a reduction in LDL-C levels <15% from baseline to 1 month after statin therapy. HF outcomes were compared between patients with and without statin hyporesponse. Results: Statin hyporesponse was identified in 15.2% (77/505) of study subjects. During a median 4.4-year observational period, statin hyporesponse was associated with a greater likelihood of HF [hazard ratio (HR) =3.01, 95% confidence interval (CI): 1.27-6.79, P=0.01]. This increased HF risk in statin hyporesponders was consistently observed in a multivariate Cox proportional hazards model (HR =2.74, 95% CI: 1.01-6.75, P=0.04), a propensity score-matched cohort (HR =12.30, 95% CI: 1.50-100.3, P=0.01) and in an inverse probability of treatment weights analysis with average treatment effects (coefficient =7.02, 95% CI: 2.29-21.58, P=0.0006). Conclusions: Hyporesponse to statins increases HF risk after AMI. Our findings highlight statin hyporesponse as a high-risk feature associated with HF events.

DOI： 10.21037/cdt-20-415

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DOI： 10.1007/s12928-019-00601-0

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In the original publication of the article, the first author name "Yuji Nishimoto" was repeated in the author group.

DOI： 10.1007/s12928-019-00605-w

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BACKGROUND: Struts have been considered as covered when tissue overlying the struts is >0 μm by optical coherence tomography (OCT). However, there is no confirmatory study to validate this definition by histology which is the gold standard. The aim of the present study was to assess the appropriate cutoff value of neointimal thickness of stent strut coverage by OCT with histology confirmation. METHODS: We performed ex vivo OCT imaging of human coronary arteries with stents at autopsy. A total of 46 stents in 39 vessels from 25 patients were examined in this study, and a total of 165 cross-sectional images were co-registered with histology to determine the optimal cutoff value for strut coverage by OCT which was defined as luminal endothelial cells with 2 abluminal layers of smooth muscles cells and matrix. Considering the resolution of OCT is 10 to 20 μm, the cutoff values were assessed at ≥20, ≥40, and ≥60 μm. RESULTS: A total of 2235 struts were reviewed by histology, 1216 were considered as well-matched struts which were analyzed in this study. By histology, 160 struts were identified as uncovered, while 1056 struts were covered. The OCT assessment without consideration of neointimal thickness yielded a poor specificity of 37.5% and sensitivity 100%. Of 3 cutoff values, the cutoff value of ≥40 μm yielded the best sensitivity (99.3%), specificity (91.0%), positive predictive value (98.6%), and negative predictive value (95.6%) as compared with ≥20 and ≥60 μm. CONCLUSIONS: Neointimal thickness ≥40 μm by OCT yielded the most accurate cutoff value to identify stent strut coverage validated by histology.

DOI： 10.1161/CIRCINTERVENTIONS.119.008869

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In the original publication of this article [1] the wording of '3Di-PMR' was different between the text and figures.

DOI： 10.1186/s12968-020-00620-4

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DOI： 10.1253/circj.CJ-19-1109

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BACKGROUND: Periprocedural myocardial injury (pMI) is a common complication of elective percutaneous coronary intervention (PCI) that reduces some of the beneficial effects of coronary revascularization and impacts the risk of cardiovascular events. We developed a 3-dimensional volumetric cardiovascular magnetic resonance (CMR) method to evaluate coronary high intensity plaques and investigated their association with pMI after elective PCI. METHODS: Between October 2012 and October 2016, 141 patients with stable coronary artery disease underwent T1-weighted CMR imaging before PCI. A conventional 2-dimensional CMR plaque-to-myocardial signal intensity ratio (2D-PMR) and the newly developed 3-dimensional integral of PMR (3Di-PMR) were measured. 3Di-PMR was determined as the sum of PMRs above a threshold of > 1.0 for voxels in a target plaque. pMI was defined as high-sensitivity cardiac troponin T > 0.07 ng/mL. RESULTS: pMI following PCI was observed in 46 patients (33%). 3Di-PMR was significantly higher in patients with pMI than those without pMI. The optimal 3Di-PMR cutoff value for predicting pMI was 51 PMR*mm3 and the area under the receiver operating characteristic curve (0.753) was significantly greater than that for 2D-PMR (0.683, P = 0.015). 3Di-PMR was positively correlated with lipid volume (r = 0.449, P < 0.001) based on intravascular ultrasound. Stepwise multivariable analysis showed that 3Di-PMR ≥ 51 PMR*mm3 and the presence of a side branch at the PCI target lesion site were significant predictors of pMI (odds ratio [OR], 11.9; 95% confidence interval [CI], 4.6-30.4, P < 0.001; and OR, 4.14; 95% CI, 1.6-11.1, P = 0.005, respectively). CONCLUSIONS: 3Di-PMR coronary assessment facilitates risk stratification for pMI after elective PCI. TRIAL REGISTRATION: retrospectively registered.

DOI： 10.1186/s12968-019-0588-6

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DOI： 10.1007/s10554-019-01641-6

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Introduction: In CKD subjects, atherosclerotic cardiovascular disease (ASCVD) is a major cause of their morbidity and mortality (1-3). Current therapeutic guidelines recommend lowering LDL-C level to prevent ASCVD (4, 5). However, it remains uncertain how this therapeutic approach effectively modifies atherosclerosis of CKD. These findings suggest the need to further understand pathophysiology of atherosclerosis. Given that intravascular imaging modalities have contributed to characterize the natural history of coronary atherosclerosis (13-23), the integration of plaque imaging is expected to help to elucidate targets associated with stabilizing atheroma.Areas covered: This review will outline atherogenic stimuli in patients with CKD. In addition, the characteristics of their coronary atheroma will be presented from finding in clinical studies using a variety of intravascular imaging modalities. The efficacy of current guideline recommended anti-atherosclerotic therapies in CKD patients will be also summarized. All related articles were searched through PubMed.Expert opinion: Integration of intravascular imaging has a great potential to establish effective therapies for slowing progression of atherosclerosis in subjects with CKD. More efforts toward searching therapeutic target associated with atherosclerosis of CKD are required. In particular, identifying drivers associated with plaque calcification will lead to the development of new agents which regress calcium accumulation.

DOI： 10.1080/14779072.2019.1676150

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Background: Histopathological studies have reported the presence of cholesterol crystals in the culprit lesion in patients with sudden cardiac death. Given that cholesterol crystals themselves promote pro-inflammatory cascades, they may destabilize atherosclerotic plaques, leading to the occurrence of acute coronary events. Case summary: A 60-year-old man presented with ST-segment elevation myocardial infarction. Emergent coronary angiography revealed a severely stenotic lesion (=culprit lesion) and another non-obstructive lesion in the proximal and middle segments of the left anterior descending artery (LAD), respectively. Optical coherence tomography (OCT) imaging showed that both lesions exhibited lipid-rich plaque with cholesterol crystals, and the non-obstructive lesion in the mid-LAD did not have a thin fibrous cap (its thickness = 230 μm). A drug-eluting stent was successfully implanted at the culprit lesion in the proximal LAD. On non-contrast T1-weighted magnetic resonance imaging performed 10 days after percutaneous coronary intervention (PCI), a high-intensity signal was identified at the non-obstructive mid-LAD lesion. This lesion was medically managed with aspirin, clopidogrel, and rosuvastatin due to the absence of myocardial ischaemia. However, 12 months after PCI, the patient was hospitalized again due to unstable angina pectoris. Coronary angiography revealed substantial progression of the mid-LAD lesion. Optical coherence tomography imaging prior to the second PCI showed a severely narrowed lesion containing cholesterol crystals and covered by organized thrombus. This lesion harbored an extensive amount of lipidic materials on near-infrared spectroscopy (maximum 4-mm lipid core burden index = 809). Discussion: In our case, atherosclerotic plaques containing cholesterol crystals was associated with the occurrence of acute coronary syndrome. Our findings suggest that plaque with cholesterol crystals is a potential precursor to future acute coronary events.

DOI： 10.1093/ehjcr/ytz128

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The association between low-dose combined oral contraceptives (COCs) and anticoagulation factors in Japanese women has been rarely studied. A total of 394 Japanese women with a new beginning cycle of COC use were enrolled, of whom 335 women visited the clinic within 4 weeks after starting the first cycle of COC. Visits occurred in the active phase (272 women) and the placebo phase (63 women). Free protein S (PS) antigen and activity levels and antithrombin activity levels decreased significantly in both the active and placebo phase groups. Protein C (PC) activity levels increased significantly in both groups. Larger reductions in free PS antigen and activity levels occurred with COC comprising either 30 µg ethinylestradiol/desogestrel or 20 µg ethinylestradiol/drospirenone than that comprising 35 µg ethinylestradiol/norethisterone. In four women with the Japanese-specific PS K196E mutation, mean PS activity was 65% before COC use and 57% during COC use, indicating further decrease with COC use. In conclusion, decreased antigen and activity levels of PS and antithrombin and increased activity levels of PC were observed even during the first cycle of low-dose COC use. The effects on PS and PC activities were also observed in the hormone-free interval.

DOI： 10.1007/s12185-019-02633-x

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Language：English   Publisher：(一社)日本循環器学会  

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Aims: Coronary high-intensity plaques (HIPs) with a high plaque-to-myocardial signal intensity ratio (PMR) on non-contrast T1-weighted imaging in patients with stable coronary artery disease (CAD) are associated with future coronary events. To characterize the morphological substrate of HIP, we performed a correlative optical coherence tomography (OCT) study. Methods and results: We examined 137 lesions in 105 patients with stable angina pectoris or silent myocardial ischaemia scheduled for percutaneous coronary intervention (PCI) using a 3 T magnetic resonance scanner. Pre-interventional OCT was performed for PCI target lesions. HIP was defined as PMR ≥ 1.4. Of the 137 lesions, 34% were HIP and 66% were non-HIP. The prevalence of lipid-rich plaque (96% vs. 70%, P < 0.001), macrophage accumulation (65% vs. 46%, P = 0.046), cholesterol crystals (46% vs. 22%, P = 0.006), and healed plaque rupture (multiple layers of different optical densities overlaying a large lipid accumulation, 72% vs. 18%, P < 0.001) was significantly higher in the HIP group than the non-HIP group; no significant differences were observed for the presence of thin cap fibroatheroma, intracoronary thrombus, and plaque rupture between the two groups. Multivariable stepwise logistic regression analysis showed that HIP was significantly associated with the presence of healed plaque rupture [odds ratio (OR) 9.32; 95% confidence interval (95% CI) 4.05-22.71; P < 0.001] and lipid-rich plaque (OR 4.38; 95% CI 1.08-29.77; P = 0.038). Conclusions: The significant association between HIP- and OCT-derived healed plaque rupture and large lipid core provides new insights into the characteristics of high-risk plaques, even in clinically stable CAD.

DOI： 10.1093/ehjci/jey035

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BACKGROUND: The histopathological validation of optical coherence tomography (OCT) in visualizing atherosclerotic plaques has been reported only in ex vivo studies. We sought to evaluate the accuracy of OCT in tissue characterization in vivo. METHODS AND RESULTS: A total of 25 patients with stable angina pectoris who underwent directional coronary atherectomy (DCA) were included in the investigation, whereby OCT was performed before and after a single debulking. The debulked region was determined on OCT and classified into fibrous tissue, lipid, calcification, thrombus, and macrophage accumulation, which were compared with histology. Changes in OCT signal intensity in the deeper intimal region after DCA were also visually evaluated. Fibrous tissues were detected in all cases, while thrombus was identified only in 1 case, by both OCT and histology. The sensitivity, specificity, positive and negative predictive values, and predictive accuracy for lipid detection by OCT were 88.9%, 75.0%, 66.7%, 92.3%, and 80.0%; those for calcification were 50.0%, 100%, 100%, 91.3%, and 92.0%; and those for macrophage accumulation were 85.7%, 88.9%, 75.0%, 94.1%, and 88.0%, respectively. The false positive diagnoses for lipid were mostly attributed to the extracellular matrix accumulation containing less collagen. The false negative diagnoses for calcification were explained by the presence of lipid around the calcification. The OCT signal intensity in the deeper intimal region substantially increased after DCA in all cases. CONCLUSIONS: The current study showed excellent predictive accuracy of in vivo OCT in tissue characterization, whereas the limitations of OCT were highlighted by an over-detection of lipid, under-detection of calcification, and underestimation of the deeper intimal matrix.

DOI： 10.1016/j.ijcard.2018.05.022

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A 53-year-old male presented with acute myocardial infarction and was subsequently implanted with a 4.0 × 28 mm everolimus-eluting platinum chromium stent in his proximal left anterior descending artery. Eight months after the implantation, he developed exertional angina and underwent coronary angiography, which revealed significant in-stent restenosis (ISR). Percutaneous coronary intervention was performed 1 month later, and the pre-procedural optical coherence tomography (OCT) revealed a diffusely bordered and rapidly attenuated signal-poor region with invisible stent struts at ISR site, potentially indicating a "lipid-laden" neointima. The ISR lesion was excised using a novel directional coronary atherectomy catheter. The histological analysis of the retrieved restenotic tissues revealed substantial inflammation characterized by abundant foamy macrophages and T-cell infiltration. This "inflammatory" neointimal tissue with numerous macrophages (without a necrotic core) detected on OCT was not expected owing to the absence of a known feature of macrophages on OCT (i.e., high backscattering with remarkable attenuation). The current histological confirmation of in vivo OCT findings of restenotic neointima indicated that a "lipid-laden" neointima on OCT may not necessarily reflect necrotic core accumulation, and this could be attributed to substantial inflammation with abundant macrophages.

DOI： 10.1536/ihj.17-602

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Language：English   Publisher：(一社)日本心血管インターベンション治療学会  

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Early identification of high-risk or vulnerable atherosclerotic plaques prone to rupture and performing preemptive therapy prior to catastrophic cardiovascular events are optimal goals of plaque imaging. Despite the advances in imaging modalities to identify vulnerable characteristics, the predictive value of the imaging techniques in the clinical setting is still developing. In this regard, reliable and high-sensitive imaging modalities identifying vulnerable plaque characters that may lead to future cardiovascular events will be useful. In this review article, we describe a current non-invasive plaque imaging technique to identify high-risk coronary plaque features.

DOI： 10.5551/jat.RV17019

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Intake of hemoglobin by the hemoglobin-haptoglobin receptor CD163 leads to a distinct alternative non-foam cell antiinflammatory macrophage phenotype that was previously considered atheroprotective. Here, we reveal an unexpected but important pathogenic role for these macrophages in atherosclerosis. Using human atherosclerotic samples, cultured cells, and a mouse model of advanced atherosclerosis, we investigated the role of intraplaque hemorrhage on macrophage function with respect to angiogenesis, vascular permeability, inflammation, and plaque progression. In human atherosclerotic lesions, CD163+ macrophages were associated with plaque progression, microvascularity, and a high level of HIF1α and VEGF-A expression. We observed irregular vascular endothelial cadherin in intraplaque microvessels surrounded by CD163+ macrophages. Within these cells, activation of HIF1α via inhibition of prolyl hydroxylases promoted VEGF-mediated increases in intraplaque angiogenesis, vascular permeability, and inflammatory cell recruitment. CD163+ macrophages increased intraplaque endothelial VCAM expression and plaque inflammation. Subjects with homozygous minor alleles of the SNP rs7136716 had elevated microvessel density, increased expression of CD163 in ruptured coronary plaques, and a higher risk of myocardial infarction and coronary heart disease in population cohorts. Thus, our findings highlight a nonlipid-driven mechanism by which alternative macrophages promote plaque angiogenesis, leakiness, inflammation, and progression via the CD163/HIF1α/VEGF-A pathway.

DOI： 10.1172/JCI93025

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DOI： 10.1161/CIRCINTERVENTIONS.117.006175

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BACKGROUND: Despite the success of HMG-CoA reductase inhibitor (statin) therapy in reducing atherosclerotic cardiovascular events, a residual risk for cardiovascular events in patients with coronary artery disease (CAD) remains. Long-chain n-3 polyunsaturated fatty acids (LC n-3 PUFAs), especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are promising anti-atherosclerosis agents that might reduce the residual CAD risk. Non-contrast T1-weighted imaging (T1WI) with cardiac magnetic resonance (CMR) less invasively identifies high-risk coronary plaques as high-intensity signals. These high-intensity plaques (HIPs) are quantitatively assessed using the plaque-to-myocardium signal intensity ratio (PMR). Our goal is to assess the effect of EPA/DHA on coronary HIPs detected with T1WI in patients with CAD on statin treatment. METHODS/DESIGN: This prospective, controlled, randomized, open-label study examines the effect of 12 months of EPA/DHA therapy and statin treatment on PMR of HIPs detected with CMR and computed tomography angiography (CTA) in patients with CAD. The primary endpoint is the change in PMR after EPA/DHA treatment. Secondary endpoints include changes in Hounsfield units, plaque volume, vessel area, and plaque area measured using CTA. Subjects are randomly assigned to either of three groups: the 2 g/day EPA/DHA group, the 4 g/day EPA/DHA group, or the no-treatment group. DISCUSSION: This trial will help assess whether EPA/DHA has an anti-atherosclerotic effect using PMR of HIPs detected by CMR. The trial outcomes will provide novel insights into the effect of EPA/DHA on high-risk coronary plaques and may provide new strategies for lowering the residual risk in patients with CAD on statin therapy. TRIAL REGISTRATION: The University Hospital Medical Information Network (UMIN) Clinical Trials Registry, ID: UMIN000015316 . Registered on 2 October 2014.

DOI： 10.1186/s13063-017-2353-1

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER IRELAND LTD  

BACKGROUND AND AIMS: Lipoprotein-associated phospholipase A2 (Lp-PLA2), an enzymatic inflammatory biomarker primarily bound to low-density lipoprotein cholesterol, is associated with an approximate twofold increased risk of cardiovascular disease and stroke. Despite indications that circulating Lp-PLA2 is sensitive to statins, it remains largely unknown whether statin usage exerts local effects on Lp-PLA2 expression at the site of atheromatous plaque. METHODS: Carotid plaques (n = 38) were prospectively collected from symptomatic (n = 18) and asymptomatic (n = 20) patients with (n = 20) or without (n = 18) documented statin history. In all cases, endarterectomy was performed where the primary stenosis was removed in an undisturbed manner. Serial cryosections of the presenting lesion were assessed histologically for macrophages, Lp-PLA2, and cell death (apoptotic index). RESULTS: Symptomatic lesions exhibited less calcification, with greater inflammation characterized by increased expression of CD68+ and CD163+ macrophage subsets, and Lp-PLA2. Symptomatic plaques also exhibited greater necrotic core area and increased apoptosis, as compared with asymptomatic lesions. In contrast, statin treatment did not appear to influence any of these parameters, except for the extent of apoptosis, which was less in statin treated as compared with statin naïve lesions. Overall, Lp-PLA2 expression correlated positively with necrotic core area, CD68+ and CD163+ macrophage area, and cell death. Finally, in vitro assays and dual immunofluorescence staining confirmed CD163-expressing monocytes/macrophages are also a major source of Lp-PLA2. CONCLUSIONS: Statin treatment has no effect on local atherosclerotic lesion Lp-PLA2 activity, therefore, the addition of anti-inflammatory treatments to further decrease macrophage Lp-PLA2 expression in atherosclerotic lesions may reduce lesional inflammation and cell death, and prevent necrotic core expansion and lesion progression.

DOI： 10.1016/j.atherosclerosis.2017.10.014

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INTRODUCTION: Polymers are an essential component of drug-eluting stents (DES) used to control drug release but remain the most controversial component of DES technology. There are two types of polymers employed in DES: durable polymer based DES (DP-DES) and biodegradable polymer DES (BP-DES). First-generation DES were exclusively composed of DP and demonstrated increased rates of late stent failure due in part to poor polymer biocompatibility. Newer generations DES use more biocompatible durable polymers or biodegradable polymers. Areas covered: We will cover issues identified with 1st-generation DP-DES, areas of success and failure in 2nd-generation DP-DES and examine the promise and shortcomings of BP-DES. Briefly, fluorinated polymers used in 2nd-generation DP-DES have excellent anti-thrombogenicity and better biocompatibility than 1st-generation DES polymers. However, these devices lead to persistent drug exposure to the endothelium which impairs endothelial function and predisposes towards neoatherosclerosis. Meanwhile, BP-DES has shortened the duration of drug exposure which might be beneficial for endothelial functional recovery leading to less neoatherosclerosis. However, it remains uncertain whether the long-term biocompatibility of bare metal surfaces is better than that of polymer-coated metals. Expert commentary: Each technology has distinct advantages, which can be optimized depending upon the particular characteristics of the patient being treated.

DOI： 10.1080/14779072.2017.1386098

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Language：Japanese   Publisher：(一社)日本心臓病学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPANESE CIRCULATION SOC  

DOI： 10.1253/circj.CJ-16-1175

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

Aim: To optimize conventional coronary optical coherence tomography (OCT) images using the attenuation-compensated technique to improve identification of plaques and the external elastic lamina (EEL) contour. Methods and Results: The attenuation-compensated technique was optimized via manipulating contrast exponent C, and compression exponent N, to achieve an optimal contrast and signal-to-noise ratio (SNR). This was applied to 60 human coronary lesions (38 native and 22 stented) ex vivo conventional coronary OCT images acquired from heart autopsies of 10 patients and matching histology was available as reference. Three independent reviewers assessed the conventional and attenuation-compensated OCT images blindly for plaque characteristics and EEL detection. Conventional OCT and compensated OCT assessment were compared against histology. Using an optimized algorithm, the attenuation-compensated OCT images had a 2-fold improvement in contrast between different tissues in both stented and non-stented epicardial coronaries (P < 0.05). Overall sensitivity and specificity for plaque classification increased from 84 to 89% and from 92 to 94%, respectively, with substantial agreement among the three reviewers (Fleiss' Kappa k, 0.72 and 0.71, respectively). Furthermore, operators were 2.5 times more likely to identify the EEL contour in the attenuation-compensated OCT images (k = 0.72) than in the conventional OCT images (k = 0.36). Conclusion: The attenuation-compensated technique can be retrospectively applied to conventional OCT images and improves the detection of plaque characteristics and the EEL contour. This approach could complement conventional OCT imaging in the evaluation of plaque characteristics and quantify plaque burden in the clinical setting.

DOI： 10.1093/ehjci/jew153

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DOI： 10.1016/j.jccase.2016.10.016

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Language：Japanese   Publisher：(株)メジカルビュー社  

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The process of early atherosclerotic plaque progression is characterized by the development of pathologic intimal thickening (PIT) with lipid pool that may transform into the necrotic core to form fibroatheroma, where infiltration of foamy macrophages plays a crucial role. The expansion of the necrotic core is also attributable to intraplaque hemorrhage. Thin-cap fibroatheroma (TCFA) is characterized by a relatively large necrotic core with an overlying thin fibrous cap measuring <65 µm typically containing numerous macrophages, and is considered to be the precursor lesion of plaque rupture which is the most common cause of coronary thrombosis. The second common cause of acute thrombosis is plaque erosion, while calcified nodules is known to be the least frequent cause of coronary thrombosis. Coronary thrombosis can occur without symptoms to form healed lesions, which contributes to an increase in plaque burden and luminal narrowing. The process of plaque progression is generally accompanied by the progression of calcification. An understanding of the histomorphological characteristics of coronary plaques should provide important insights into the pathogenesis, diagnosis, and treatment of atherosclerotic coronary disease for both basic and clinical researchers as well as for clinicians.

DOI： 10.21037/cdt.2016.06.01

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Language：English   Publisher：(一社)日本心血管インターベンション治療学会  

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Language：Japanese   Publishing type：Research paper (scientific journal)  

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Language：Japanese   Publishing type：Research paper (scientific journal)  

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Language：English   Publisher：ELSEVIER SCIENCE INC  

DOI： 10.1016/j.jcmg.2015.01.012

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

OBJECTIVES: This study sought to evaluate the diagnostic performance of optical frequency domain imaging (OFDI) for recognition of coronary plaque morphologies and to assess additive values of integrated backscatter intravascular ultrasound (IB-IVUS) in detection of vulnerable plaque. BACKGROUND: Precise diagnosis of coronary lesions susceptible to plaque rupture and thrombosis may serve to stratify the risk of future coronary events and to make decisions for appropriate treatment of choice. METHODS: Twenty-seven coronary arteries from 14 human autopsy hearts were interrogated ex vivo by OFDI and IB-IVUS. Imaged segments were sectioned at 3 mm intervals where a total of 360 pairs of cross-sectional images coregistered to histology were investigated. RESULTS: Overall, OFDI could depict various plaque components and structures such as fibrous tissue, sheet and nodular calcification, lipid, cholesterol crystals, and healed plaque rupture. OFDI could detect 14 of 18 thin-cap fibroatheroma (TCFA), however, the diagnostic accuracy was not high (positive predictive value [PPV] = 60.9%, κ = 0.664; area under the curve [AUC]: 0.88) mainly because of signal interference from macrophages. Further, we defined IB-IVUS-derived TCFA by recursive partitioning analysis as: 1) cross-sectional % lipid area >65.1%; 2) % lipid area >32.3 but <65.1% with plaque area >10.5 mm(2), where TCFA detection by IB-IVUS alone was marginal (PPV = 50.0%, κ = 0.545; AUC: 0.82). However, when IB-IVUS was combined with OFDI, all pseudo OFDI-derived TCFA (non-TCFA on histology) were excluded. Accordingly, PPV of TCFAs diagnosed by both OFDI and IB-IVUS was improved to 100.0% (κ = 0.704; AUC: 0.93). CONCLUSIONS: OFDI could recognize detailed morphologies of human coronary plaque. However, diagnostic accuracy of both OFDI alone and IB-IVUS alone to identify TCFA is limited. Combination of IB-IVUS with OFDI improved the accuracy for TCFA detection, suggesting hybrid imaging or further development of novel devices will be required to identify coronary lesions responsible for future events.

DOI： 10.1016/j.jcmg.2015.07.011

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Plaque rupture, usually of a precursor lesion known as a 'vulnerable plaque' or 'thin-cap fibroatheroma', is the leading cause of thrombosis. Less-frequent aetiologies of coronary thrombosis are erosion, observed with greatest incidence in women aged <50 years, and eruptive calcified nodules, which are occasionally identified in older individuals. Various treatments for patients with coronary artery disease, such as CABG surgery and interventional therapies, have led to accelerated atherosclerosis. These processes occur within months to years, compared with the decades that it generally takes for native disease to develop. Morphological identifiers of accelerated atherosclerosis include macrophage-derived foam cells, intraplaque haemorrhage, and thin fibrous cap. Foam-cell infiltration can be observed within 1 year of a saphenous vein graft implantation, with subsequent necrotic core formation and rupture ensuing after 7 years in over one-third of patients. Neoatherosclerosis occurs early and with greater prevalence in drug-eluting stents than in bare-metal stents and, although rare, complications of late stent thrombosis from rupture are associated with high mortality. Comparison of lesion progression in native atherosclerotic disease, atherosclerosis in saphenous vein grafts, and in-stent neoatherosclerosis provides insight into the pathogenesis of atheroma formation in natural and iatrogenic settings.

DOI： 10.1038/nrcardio.2015.164

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Language：English   Publisher：OXFORD UNIV PRESS  

DOI： 10.1093/eurheartj/ehv223

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

Despite the reduction in late thrombotic events with newer-generation drug-eluting stents (DES), late stent failure remains a concern following stent placement. In-stent neoatherosclerosis has emerged as an important contributing factor to late vascular complications including very late stent thrombosis and late in-stent restenosis. Histologically, neoatherosclerosis is characterized by accumulation of lipid-laden foamy macrophages within the neointima with or without necrotic core formation and/or calcification. The development of neoatherosclerosis may occur in months to years following stent placement, whereas atherosclerosis in native coronary arteries develops over decades. Pathologic and clinical imaging studies have demonstrated that neoatherosclerosis occurs more frequently and at an earlier time point in DES when compared with bare metal stents, and increases with time in both types of implant. Early development of neoatherosclerosis has been identified not only in first-generation DES but also in second-generation DES. The mechanisms underlying the rapid development of neoatherosclerosis remain unknown; however, either absence or abnormal endothelial functional integrity following stent implantation may contribute to this process. In-stent plaque rupture likely accounts for most thrombotic events associated with neoatherosclerosis, while it may also be a substrate of in-stent restenosis as thrombosis may occur either symptomatically or asymptomatically. Intravascular optical coherence tomography is capable of detecting neoatherosclerosis; however, the shortcomings of this modality must be recognized. Future studies should assess the impact of iterations in stent technology and risk factor modification on disease progression. Similarly, refinements in imaging techniques are also warranted that will permit more reliable detection of neoatherosclerosis.

DOI： 10.1093/eurheartj/ehv205

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OBJECTIVES: This study sought to evaluate whether the permanent fluoropolymer-coated Xience Xpedition everolimus-eluting stent (Xience-EES) exhibits lower acute thrombogenicity compared with contemporary drug-eluting stents (DES) with biodegradable polymer coatings in an acute swine shunt model. BACKGROUND: Previous pre-clinical and clinical experience suggests that several factors may influence the predisposition for acute thrombus formation of polymer-coated DES, including stent design and the polymer coating technology. It remains unclear whether relevant differences exist with respect to acute thrombogenicity, particularly between current commercial stent designs using permanent polymers and those using biodegradable polymers. METHODS: An ex vivo carotid to jugular arteriovenous porcine shunt model involving a test circuit of 3 in-line stents, was used to test acute thrombogenicity, where Xience-EES (n = 24) was compared with 4 CE-marked DES with biodegradable polymer coatings (BioMatrix Flex, Synergy, Nobori, and Orsiro [n = 6 each]). After 1 h of circulation, platelet aggregation in whole mount stents was evaluated by confocal microscopy with immunofluorescent staining against dual platelet markers (CD61/CD42b) along with scanning electron microscopy. RESULTS: Xience-EES showed the least percentage of thrombus-occupied area as compared with the biodegradable polymer-coated DES, with a significant difference compared with BioMatrix Flex and Synergy (mean differences: [BioMatrix Flex: 15.54, 95% confidence interval [CI]: 11.34 to 19.75, p < 0.001; Synergy: 8.64, 95% CI: 4.43 to 12.84, p < 0.001; Nobori: 4.22, 95% CI: -0.06 to 8.49, p = 0.055; Orsiro: 2.95, 95% CI: -1.26 to 7.15, p = 0.286). The number of cell nuclei on strut surfaces was also the least in Xience-EES, with a significant difference relative to BioMatrix Flex, Nobori, and Orsiro (mean ratios: BioMatrix Flex: 4.73, 95% CI: 2.46 to 9.08, p < 0.001; Synergy: 1.44, 95% CI: 0.75 to 2.76, p = 0.51; Nobori: 5.97, 95% CI: 3.11 to 11.44, p < 0.001; Orsiro: 5.16, 95% CI: 2.69 to 9.91, p < 0.001). CONCLUSIONS: Xience-EES's overall design confers acute thromboresistance relative to contemporary DES with biodegradable coatings, with less platelet aggregation versus BioMatrix Flex and Synergy, and less inflammatory cell attachment versus BioMatrix Flex, Nobori, and Orsiro, in an ex vivo swine shunt model, which lends support to reported clinical findings of lower early stent thrombosis.

DOI： 10.1016/j.jcin.2015.03.029

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER IRELAND LTD  

OBJECTIVE: Smooth muscle cells, macrophage infiltration and accumulation of lipids, proteoglycans, collagen matrix and calcification play a central role in atherosclerosis. The early histologic changes of plaque progression from pathologic intimal thickenings (PIT) to late fibroatheroma lesions have not been fully characterized. METHODS: A total of 151 atherosclerotic coronary lesions were collected from 67 sudden death victims. Atherosclerotic plaques were classified as PIT without macrophage infiltration, PIT with macrophages, and early and late fibroatheromas. Presence of macrophages and proteoglycans (versican, decorin and biglycan) were recognized by specific antibodies while hyaluronan was detected by affinity histochemistry. Lipid deposition was identified by oil-red-O, and calcification was assessed following von Kossa and alizarin red staining. RESULTS: Lesion progression from PIT to late fibroatheroma was associated with increase in macrophage accumulation (p < 0.001) and decreasing apoptotic body clearance by macrophages (ratio of engulfed-to-total apoptotic bodies) (p < 0.001). Lipid deposition in lipid pool of PIT had a microvesicular appearance whereas those in the necrotic core were globular in nature. Overall, the accumulation of hyaluronan (p < 0.001), and proteoglycan versican (p < 0.001) and biglycan (p = 0.013) declined along with lesion progression from PIT to fibroatheromas. Microcalcification was first observed only within areas of lipid pools and its presence and size increased in lesions with necrotic core. CONCLUSIONS: PIT to fibroatheroma lesions are accompanied by early lipid accumulation, followed by macrophage infiltration with defective clearance of apoptotic bodies along with decrease in proteoglycan and hyaluronan in lipid pools that convert to necrotic cores. Calcification starts in PIT and increases with plaque progression.

DOI： 10.1016/j.atherosclerosis.2015.05.011

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

DOI： 10.1161/CIRCULATIONAHA.114.012658

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

OBJECTIVES: To evaluate whether iterative reconstruction algorithms improve the diagnostic accuracy of coronary CT angiography (CCTA) for detection of lipid-core plaque (LCP) compared to histology. METHODS AND MATERIALS: CCTA and histological data were acquired from three ex vivo hearts. CCTA images were reconstructed using filtered back projection (FBP), adaptive-statistical (ASIR) and model-based (MBIR) iterative algorithms. Vessel cross-sections were co-registered between FBP/ASIR/MBIR and histology. Plaque area <60 HU was semiautomatically quantified in CCTA. LCP was defined by histology as fibroatheroma with a large lipid/necrotic core. Area under the curve (AUC) was derived from logistic regression analysis as a measure of diagnostic accuracy. RESULTS: Overall, 173 CCTA triplets (FBP/ASIR/MBIR) were co-registered with histology. LCP was present in 26 cross-sections. Average measured plaque area <60 HU was significantly larger in LCP compared to non-LCP cross-sections (mm(2): 5.78 ± 2.29 vs. 3.39 ± 1.68 FBP; 5.92 ± 1.87 vs. 3.43 ± 1.62 ASIR; 6.40 ± 1.55 vs. 3.49 ± 1.50 MBIR; all p < 0.0001). AUC for detecting LCP was 0.803/0.850/0.903 for FBP/ASIR/MBIR and was significantly higher for MBIR compared to FBP (p = 0.01). MBIR increased sensitivity for detection of LCP by CCTA. CONCLUSION: Plaque area <60 HU in CCTA was associated with LCP in histology regardless of the reconstruction algorithm. However, MBIR demonstrated higher accuracy for detecting LCP, which may improve vulnerable plaque detection by CCTA. KEY POINTS: • A low attenuation plaque area is associated with the presence of lipid-core plaque • MBIR leads to higher diagnostic accuracy for detecting lipid-core plaque • The benefit of MBIR is mainly due to increased sensitivity at high specificities • Semiautomated CCTA assessment can detect vulnerable plaques non-invasively.

DOI： 10.1007/s00330-014-3404-6

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

BACKGROUND: The long-term efficacy of radiofrequency ablation of renal autonomic nerves has been proven in nonrandomized studies. However, long-term safety of the renal artery (RA) is of concern. The aim of our study was to determine if cooling during radiofrequency ablation preserved the RA while allowing equivalent nerve damage. METHODS AND RESULTS: A total of 9 swine (18 RAs) were included, and allocated to irrigated radiofrequency (n=6 RAs, temperature setting: 50°C), conventional radiofrequency (n=6 RAs, nonirrigated, temperature setting: 65°C), and high-temperature radiofrequency (n=6 RAs, nonirrigated, temperature setting: 90°C) groups. RAs were harvested at 10 days, serially sectioned from proximal to distal including perirenal tissues and examined after paraffin embedding, and staining with hematoxylin-eosin and Movat pentachrome. RAs and periarterial tissue including nerves were semiquantitatively assessed and scored. A total of 660 histological sections from 18 RAs were histologically examined by light microscopy. Arterial medial injury was significantly less in the irrigated radiofrequency group (depth of medial injury, circumferential involvement, and thinning) than that in the conventional radiofrequency group (P<0.001 for circumference; P=0.003 for thinning). Severe collagen damage such as denatured collagen was also significantly less in the irrigated compared with the conventional radiofrequency group (P<0.001). Nerve damage although not statistically different between the irrigated radiofrequency group and conventional radiofrequency group (P=0.36), there was a trend toward less nerve damage in the irrigated compared with conventional. Compared to conventional radiofrequency, circumferential medial damage in highest-temperature nonirrigated radiofrequency group was significantly greater (P<0.001). CONCLUSIONS: Saline irrigation significantly reduces arterial and periarterial tissue damage during radiofrequency ablation, and there is a trend toward less nerve damage.

DOI： 10.1161/CIRCINTERVENTIONS.114.001720

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPANESE CIRCULATION SOC  

DOI： 10.1253/circj.CJ-14-0897

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPANESE CIRCULATION SOC  

DOI： 10.1253/circj.CJ-14-1069

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Language：English   Publisher：ELSEVIER SCIENCE INC  

DOI： 10.1016/j.jcmg.2014.08.005

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：EUROPA EDITION  

AIMS: We aimed to investigate a fully bioresorbable poly-l-lactide (PLLA) scaffold to assess vascular remodelling in comparison to a permanent polymeric metal DES. METHODS AND RESULTS: Twenty-five New Zealand white rabbits received an Absorb bioresorbable vascular scaffold (BVS, 1.0 and 1.1) or a CYPHER sirolimus-eluting stent (SES) in the iliac arteries. Twelve arteries were harvested at one month for scanning electron microscopy (SEM) analysis (BVS 1.1). The other implanted (BVS 1.0) arteries (n=32) were explanted at three, six and 36 months for light microscopic analysis. Re-endothelialisation assessed at one month was incomplete in both BVS and SES by SEM, with a trend towards greater coverage in SES (endothelialisation above strut: 32.2% vs. 60.6%, p=0.10). However, light microscopic analysis at later time points revealed greater endothelial coverage in BVS than in SES at 36 months (100.0% vs. 93.3%, p=0.05). Inflammation scores were comparable between arteries implanted with BVS and SES at three months (1.1 vs. 1.1, p=0.99), which decreased over time in the BVS implanted arteries (36 months: 0.0 vs. 0.2, p=0.05). At 36 months, BVS were completely resorbed, and resorption sites were replaced by connective tissue. CONCLUSIONS: BVS in the rabbit iliac artery model demonstrated ongoing vascular healing at three and six months, and complete vessel restoration, re-endothelialisation and no to minimal vascular inflammation at 36 months.

DOI： 10.4244/EIJV10I7A143

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Language：English   Publisher：NATURE PUBLISHING GROUP  

DOI： 10.1038/nrcardio.2014.62-c2

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：EUROPA EDITION  

AIMS: Biodegradable polymer-based drug-eluting stents are thought to be safer than durable polymer-based stents. However, the long-term vascular response remains unclear. The aim of this study was to compare the biocompatibility of durable polymer-based sirolimus-eluting (SES) and everolimus-eluting (EES) stents with biodegradable polymer-based biolimus-eluting (BES) stents in a porcine coronary model. Stents were implanted in porcine coronaries. Acetylcholine challenge tests and optical coherence tomography (OCT) examination were performed at one month. Animals were sacrificed at three and six months (n=6 each), and the stents were analysed histologically. At one month, acetylcholine challenge tests revealed a trend towards greatest vasoconstriction in SES, less in BES, and least in EES, but the differences were not significant. OCT analysis demonstrated the highest incidence of uncovered struts in SES, followed by BES, while EES showed almost complete strut coverage (41.7±27.0%, 24.5±23.8%, 0.4±0.8%, respectively; p=0.004). Upon histological analysis at three months, SES showed a significantly higher inflammatory score than BES and EES (2.9±1.4, 0.8±0.9, 0.5±0.4, respectively; p=0.001), and this was maintained at six months (1.6±1.5, 0.3±0.3, 0.4±0.6, respectively; p=0.049). While SES showed an increased inflammatory reaction, EES and BES showed minimal inflammation. These results indicate that the late inflammatory reaction does not necessarily depend on degradability of the polymer, if the combination of the drug, metal, and polymer is biocompatible.

DOI： 10.4244/EIJV10I6A124

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BACKGROUND: Although renal sympathetic denervation therapy has shown promising results in patients with resistant hypertension, the human anatomy of peri-arterial renal nerves is poorly understood. OBJECTIVES: The aim of our study was to investigate the anatomic distribution of peri-arterial sympathetic nerves around human renal arteries. METHODS: Bilateral renal arteries were collected from human autopsy subjects, and peri-arterial renal nerve anatomy was examined by using morphometric software. The ratio of afferent to efferent nerve fibers was investigated by dual immunofluorescence staining using antibodies targeted for anti-tyrosine hydroxylase and anti-calcitonin gene-related peptide. RESULTS: A total of 10,329 nerves were identified from 20 (12 hypertensive and 8 nonhypertensive) patients. The mean individual number of nerves in the proximal and middle segments was similar (39.6 ± 16.7 per section and 39.9 ± 1 3.9 per section), whereas the distal segment showed fewer nerves (33.6 ± 13.1 per section) (p = 0.01). Mean subject-specific nerve distance to arterial lumen was greatest in proximal segments (3.40 ± 0.78 mm), followed by middle segments (3.10 ± 0.69 mm), and least in distal segments (2.60 ± 0.77 mm) (p < 0.001). The mean number of nerves in the ventral region (11.0 ± 3.5 per section) was greater compared with the dorsal region (6.2 ± 3.0 per section) (p < 0.001). Efferent nerve fibers were predominant (tyrosine hydroxylase/calcitonin gene-related peptide ratio 25.1 ± 33.4; p < 0.0001). Nerve anatomy in hypertensive patients was not considerably different compared with nonhypertensive patients. CONCLUSIONS: The density of peri-arterial renal sympathetic nerve fibers is lower in distal segments and dorsal locations. There is a clear predominance of efferent nerve fibers, with decreasing prevalence of afferent nerves from proximal to distal peri-arterial and renal parenchyma. Understanding these anatomic patterns is important for refinement of renal denervation procedures.

DOI： 10.1016/j.jacc.2014.03.059

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

AIMS: The aim of our study was to investigate chronic total occlusion (CTO) in human coronary arteries to clarify the difference between CTO with prior coronary artery bypass graft (CABG) and those without prior CABG. METHODS AND RESULTS: A total of 95 CTO lesions from 82 patients (61.6 ± 14.0 years, male 87.8%) were divided into the following three groups: CTO with CABG (n = 34) (CTO+CABG), CTO without CABG--of long-duration (n = 49) (LD-CTO) and short-duration (n = 12) (SD-CTO). A histopathological comparison of the plaque characteristics of CTO, proximal and distal lumen morphology, and negative remodelling between groups was performed. A total of 1127 sections were evaluated. Differences in plaque characteristics were observed between groups as follows: necrotic core area was highest in SD-CTO (18.6%) (LD-CTO: 7.8%; CTO+CABG: 4.5%; P = 0.02); calcified area was greatest in CTO+CABG (29.2%) (LD-CTO: 16.8%; SD-CTO: 12.1%; P = 0.009); and negative remodelling was least in SD-CTO [remodelling index (RI) 0.86] [CTO+CABG (RI): 0.72 and LD-CTO (RI): 0.68; P < 0.001]. Approximately 50% of proximal lumens showed characteristics of abrupt closure, whereas the majority of distal lumen patterns were tapered (79%) (P < 0.0001). CONCLUSION: These pathological differences in calcification, negative remodelling, and presence of necrotic core along with proximal and distal tapering, which has been associated with greater success, help explain the differences in success rates of percutaneous coronary intervention in CTO patients with and without CABG.

DOI： 10.1093/eurheartj/eht422

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

In published post-mortem pathological studies, more than two-thirds of acute coronary events are associated with the rupture of lipid-rich, voluminous, and outwardly remodelled plaques covered by attenuated and inflamed fibrous caps in the proximal part of coronary arteries. Superficial erosion of the plaques is responsible for most of the remaining events; the eroded plaques usually do not demonstrate much lipid burden, do not have thin fibrous caps, are not positively remodelled, and are not critically occlusive. Both noninvasive and invasive imaging studies have been performed to clinically define the plaque characteristics in acute coronary syndromes in an attempt to identify the high-risk plaque substrate susceptible to development of an acute coronary event. Optical coherence tomography (OCT)--an intravascular imaging modality with high resolution--can be used to define various stages of plaque morphology, which might allow its use for the identification of high-risk plaques vulnerable to rupture, and their amenability to pre-emptive interventional treatment. OCT might also be employed to characterize plaque pathology at the time of intervention, to provide a priori knowledge of the mechanism of the acute coronary syndrome and, therefore, to enable improved management of the condition.

DOI： 10.1038/nrcardio.2014.62

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

OBJECTIVES: The study interrogated an autopsy registry to investigate the histopathologic features of early stent thrombosis (ST) in patients presenting with acute coronary syndrome (ACS). BACKGROUND: The occurrence of early ST following percutaneous coronary intervention (PCI) for ACS remains a clinical problem despite advances in stent technology in both bare-metal and drug-eluting stents. METHODS: Sixty-seven stented coronary lesions from 59 patients who presented with ACS and died within 30 days were included. Stented segments were cross sectioned at 3 to 4 mm intervals and evaluated by light microscopy, and morphometric analysis was performed. RESULTS: Early ST (<30 days of PCI) was identified in 34 (58%) of the 59 patients. Early ST was dependent on the underlying plaque morphology and underlying thrombus burden: presence of necrotic core prolapse was more frequent in thrombosed lesions compared with patent lesions (70% vs. 43%, p = 0.045) and maximal underlying thrombus thickness was significantly greater in thrombosed versus patent lesions. All 3 patients with false lumen stenting had ST. Detailed analysis revealed that the percent of necrotic core prolapse, medial tear, or incomplete apposition was significantly greater in the early ST compared with patent group (28% vs.11%, p < 0.001; 27% vs. 15% p = 0.004; and 34% vs. 18% p = 0.008, respectively). Multivariate analysis revealed that maximal depth of strut penetration, % strut with medial tear, and % struts with incomplete apposition were the primary indicators of early ST. CONCLUSIONS: The current autopsy study highlights the impact of thrombus burden and suboptimal stent implantation in unstable lesions as a trigger of early ST, suggesting that improvement in implantation technique and refinement of stent design may improve clinical outcomes of ACS patients.

DOI： 10.1016/j.jacc.2014.02.607

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Atherosclerosis causes clinical disease through luminal narrowing or by precipitating thrombi that obstruct blood flow to the heart (coronary heart disease), brain (ischemic stroke), or lower extremities (peripheral vascular disease). The most common of these manifestations is coronary heart disease, including stable angina pectoris and the acute coronary syndromes. Atherosclerosis is a lipoprotein-driven disease that leads to plaque formation at specific sites of the arterial tree through intimal inflammation, necrosis, fibrosis, and calcification. After decades of indolent progression, such plaques may suddenly cause life-threatening coronary thrombosis presenting as an acute coronary syndrome. Most often, the culprit morphology is plaque rupture with exposure of highly thrombogenic, red cell-rich necrotic core material. The permissive structural requirement for this to occur is an extremely thin fibrous cap, and thus, ruptures occur mainly among lesions defined as thin-cap fibroatheromas. Also common are thrombi forming on lesions without rupture (plaque erosion), most often on pathological intimal thickening or fibroatheromas. However, the mechanisms involved in plaque erosion remain largely unknown, although coronary spasm is suspected. The calcified nodule has been suggested as a rare cause of coronary thrombosis in highly calcified and tortious arteries in older individuals. To characterize the severity and prognosis of plaques, several terms are used. Plaque burden denotes the extent of disease, whereas plaque activity is an ambiguous term, which may refer to one of several processes that characterize progression. Plaque vulnerability describes the short-term risk of precipitating symptomatic thrombosis. In this review, we discuss mechanisms of atherosclerotic plaque initiation and progression; how plaques suddenly precipitate life-threatening thrombi; and the concepts of plaque burden, activity, and vulnerability.

DOI： 10.1161/CIRCRESAHA.114.302721

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

BACKGROUND: The Absorb everolimus-eluting bioresorbable vascular scaffold (Absorb) has shown promising clinical results; however, only limited preclinical data have been published. We sought to investigate detailed pathological responses to the Absorb versus XIENCE V (XV) in a porcine coronary model with duration of implant extending from 1 to 42 months. METHODS AND RESULTS: A total of 335 devices (263 Absorb and 72 XV) were implanted in 2 or 3 main coronary arteries of 136 nonatherosclerotic swine and examined by light microscopy, scanning electron microscopy, pharmacokinetics, and gel permeation chromatography analyses at various time points. Vascular responses to Absorb and XV were largely comparable at all time points, with struts being sequestered within the neointima. Inflammation was mild to moderate (with absence of inflammation at 1 month) for both devices, although the scores were greater in Absorb at 6 to 36 months. Percent area stenosis was significantly greater in Absorb than XV at all time points except at 3 months. The extent of fibrin deposition was similar between Absorb and XV, which peaked at 1 month and decreased rapidly thereafter. Histomorphometry showed expansile remodeling of Absorb-implanted arteries starting after 12 months, and lumen area was significantly greater in Absorb than XV at 36 and 42 months. These changes correlated with dismantling of Absorb seen after 12 months. Gel permeation chromatography analysis confirmed that degradation of Absorb was complete by 36 months. CONCLUSIONS: Absorb demonstrates comparable long-term safety to XV in porcine coronary arteries with mild to moderate inflammation. Although Absorb was associated with greater percent stenosis relative to XV, expansile remodeling was observed after 12 months in Absorb with significantly greater lumen area at ≥ 36 months. Resorption is considered complete at 36 months.

DOI： 10.1161/CIRCINTERVENTIONS.113.000990

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：INFORMA HEALTHCARE  

OBJECTIVES: Patients previously treated with coronary stents may suffer an acute coronary syndrome (ACS) without any evidence of thrombus formation on coronary angiography (CAG). This may be due to partial, nonocclusive stent thrombosis with microembolization. In this paper, we illustrate possible mechanisms both with optical coherence tomography (OCT) and histology. DESIGN: We present two cases with ACS from very late stent thrombosis who have been previously treated with first-generation drug-eluting stents (DES). RESULTS: The first patient had ACS 15 months after DES implantation. The angiogram (CAG) was near normal with slight peri-stent contrast staining. OCT revealed abnormalities including thrombus not visible on CAG. These are findings that may explain the ACS. The second patient had subclinical episodes with chest pain after DES implantation. The patient died from stent thrombosis in a DES. Postmortem histological examination of the coronary arteries revealed stent struts with little or no neointimal coverage, persistent peri-strut fibrin deposition, inflammatory cells, malapposition, and small luminal platelet-rich thrombi. Old spotty myocardial infarctions were found in the supplied territory possibly caused by earlier episodes of embolizing thrombus. CONCLUSIONS: In patients with previous implanted DES presenting with ACS, OCT may detect abnormalities and thrombus formation not visible on CAG. Such findings may impact the treatment strategy in these patients.

DOI： 10.3109/14017431.2014.900185

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Acute coronary syndrome is the leading cause of death worldwide and plaque rupture is the most common underlying mechanism of coronary thrombosis. During the last 2 decades the understanding of atherosclerotic plaque progression advanced dramatically and pathology studies provided fundamental insights of underlying plaque morphology, which paved the way for invasive imaging modalities, which bring a new area of atherosclerotic plaque characterization in vivo. The development of intravascular ultrasound (IVUS) allowed the field to evaluate the principles of vascular anatomy, which is often underestimated by coronary angiography. Furthermore, IVUS image technologies were developed to obtain improved characterization of plaque composition. However, since spatial resolution of IVUS is insufficient to distinguish details of plaque morphology, a broad adoption of this technology in clinical practice was missing. Optical coherence tomography is a light-based imaging modality with higher spatial resolution compared to IVUS, which enables the assessment of vascular anatomy with great detail.

DOI： 10.1586/14779072.2014.902749

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Coronary artery calcification is a well-established predictor of future cardiac events; however, it is not a predictor of unstable plaque. The intimal calcification of the atherosclerotic plaques may begin with smooth muscle cell apoptosis and release of matrix vesicles and is almost always seen microscopically in pathological intimal thickening, which appears as microcalcification (≥0.5 μm, typically <15 μm in diameter). Calcification increases with macrophage infiltration into the lipid pool in early fibroatheroma where they undergo apoptosis and release matrix vesicles. The confluence of calcified areas involves extracellular matrix and the necrotic core, which can be identified by radiography as speckled (≤2 mm) or fragmented (>2, <5 mm) calcification. The calcification in thin-cap fibroatheromas and plaque rupture is generally less than what is observed in stable plaques and is usually speckled or fragmented. Fragmented calcification spreads into the surrounding collagen-rich matrix forming calcified sheets, the hallmarks of fibrocalcific plaques. The calcified sheets may break into nodules with fibrin deposition, and when accompanied by luminal protrusion, it is associated with thrombosis. Calcification is highest in fibrocalcific plaques followed by healed plaque rupture and is the least in erosion and pathological intimal thickening. The extent of calcification is greater in men than in women especially in the premenopausal period and is also greater in whites compared with blacks. The mechanisms of intimal calcification remain poorly understood in humans. Calcification often occurs in the presence of apoptosis of smooth muscle cells and macrophages with matrix vesicles accompanied by expression of osteogenic markers within the vessel wall.

DOI： 10.1161/ATVBAHA.113.302642

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

OBJECTIVES: We sought to evaluate the pathologic findings of the percutaneous Parachute device implanted in patients with severe heart failure (HF). BACKGROUND: Currently, most treatments of HF rest on optimal medical therapy with adjunctive interventional or surgical palliative treatments. One such treatment is the Parachute device, which partitions the left ventricle excluding the scarred myocardium from functioning myocardium, and has shown promise in clinical studies. METHODS: We have examined histopathologically seven cases [six males (age range 43–74 years; mean 56 years) and one female (55 years)] of Parachute device that were either retrieved at autopsy (n = 4) or during transplantation (n = 3); implant duration, 15-1,533 days. RESULTS: Three patients died of cardiac causes and none died from complications. Histologic early changes (<30 days, n = 1) included adherent thrombus, with focal neutrophil infiltration and degenerating inflammatory cells. Over time (31–300 days, n = 4), there was organized thrombus and development of neoendocardial thickening especially at the free-edge of the device and its contact with the adjacent endocardium while the base of the device showed varying degrees of fibrin thrombus. The greatest organization of thrombus was observed in devices removed at >300 days (680 and 1533 days); both had fractures of the foot along with strut fracture and one had tearing of the expanded polytetrafluoroethylene. CONCLUSIONS: The percutaneous Parachute device appears as a promising adjunctive treatment for patients suffering from severe HF. The pathologic changes are those of organizing thrombus with and without inflammation with minor complications of foot and strut fracture.

DOI： 10.1002/ccd.25010

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

BACKGROUND: Clinical trials have demonstrated that the second-generation cobalt-chromium everolimus-eluting stent (CoCr-EES) is superior to the first-generation paclitaxel-eluting stent (PES) and is noninferior or superior to the sirolimus-eluting stent (SES) in terms of safety and efficacy. It remains unclear whether vascular responses to CoCr-EES are different from those to SES and PES because the pathology of CoCr-EES has not been described in humans. METHODS AND RESULTS: A total of 204 lesions (SES=73; PES=85; CoCr-EES=46) from 149 autopsy cases with duration of implantation >30 days and ≤3 years were pathologically analyzed, and comparison of vascular responses was corrected for duration of implantation. The observed frequency of late and very late stent thrombosis was less in CoCr-EES (4%) versus SES (21%; P=0.029) and PES (26%; P=0.008). Neointimal thickness was comparable among the groups, whereas the percentage of uncovered struts was strikingly lower in CoCr-EES (median=2.6%) versus SES (18.0%; P<0.0005) and PES (18.7%; P<0.0005). CoCr-EES showed a lower inflammation score (with no hypersensitivity) and less fibrin deposition versus SES and PES. The observed frequency of neoatherosclerosis, however, did not differ significantly among the groups (CoCr-EES=29%; SES=35%; PES=19%). CoCr-EES had the least frequency of stent fracture (CoCr-EES=13%; SES=40%; PES=19%; P=0.007 for CoCr-EES versus SES), whereas fracture-related restenosis or thrombosis was comparable among the groups (CoCr-EES=6.5%; SES=5.5%; PES=1.2%). CONCLUSIONS: CoCr-EES demonstrated greater strut coverage with less inflammation, less fibrin deposition, and less late and very late stent thrombosis compared with SES and PES in human autopsy analysis. Nevertheless, the observed frequencies of neoatherosclerosis and fracture-related adverse pathological events were comparable in these devices, indicating that careful long-term follow-up remains important even after CoCr-EES placement.

DOI： 10.1161/CIRCULATIONAHA.113.001790

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

OBJECTIVES: This study was designed to evaluate the safety of a novel drug-coated balloon (DCB) with 2 µg/mm(2) paclitaxel and a carrier comprised of polysorbate and sorbitol in a swine femoral artery model. BACKGROUND: DCB have emerged as a therapeutic alternative in the treatment of peripheral vascular disease. METHODS: The femoral arteries of 45 swine were treated with low pressure balloon inflation either 1× clinical dose (single inflation, 2 µg/mm(2) paclitaxel) or 4× dose (2 DCBs, each with 4 µg/mm(2) paclitaxel) or control (uncoated) balloons. The treated arteries, downstream vascular beds, and organs were assessed histologically at 28, 90, and 180-days. Twenty-four swine were treated with 1× dose for pharmacokinetic analysis through 30 days. RESULTS: Arterial tissue paclitaxel concentration was 58.8 ± 54.2 ng/mg at 1-hr and 0.3 ± 0.4 ng/mg at 30 days, whereas plasma paclitaxel could no longer be detected after 1 day. The treated arteries displayed minimal endothelial loss, fibrin deposition, and inflammation with long-term dose-dependent drug effect (medial smooth muscle cell loss) peaking at 90 days for both 1× (1.1 ± 1.4 vs. 0.0 ± 0.0, P = 0.008) and 4× dose (2.0 ± 1.5 vs. 0.0 ± 0.0, P < 0.001). In parallel, healing of the treated arteries was evident by significantly greater medial proteoglycan and collagen deposition at 180 days. No evidence of ischemia from downstream emboli or systemic toxicity was observed even for 4× DCB groups. CONCLUSIONS: The findings indicate desired pharmacologic levels with biologic effects at early and healing at late time points in the treated arteries, without evidence of significant downstream emboli or systemic toxicity, consistent with safety of the Lutonix DCB.

DOI： 10.1002/ccd.24995

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Language：English   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

DOI： 10.1161/CIRCULATIONAHA.113.007267

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Language：English   Publisher：OXFORD UNIV PRESS  

This editorial refers to 'Mast cells in human carotid atherosclerotic plaques are associated with intraplaque microvessel density and the occurrence of future cardiovascular events'(dagger), by S. Willems et al., on page 3699-3706

DOI： 10.1093/eurheartj/eht259

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AIMS: Restenosis in drug-eluting stents (DESs) occurs infrequently, however, it remains a pervasive clinical problem. We interrogated our autopsy registry to determine the underlying mechanisms of DES restenosis, and further we investigated the neointimal characteristics of DESs and compared with bare metal stents (BMSs). METHODS AND RESULTS: Coronary lesions from patients with DES implants (n = 82) were categorized into four groups based on cross-sectional area narrowing: patent (<50%), intermediate (50-74%), restenotic (≥ 75% with residual lumen), and total occlusion (organized thrombus within the stent). Restenosis and occlusion were significantly dependent on the total stented length: restenosis (26.7 mm) and occlusion (25.7 mm) compared with patent DESs (17.3 mm). Further, restenotic and occluded lesions were located more distally in the coronary arteries and had greater vessel injury and uneven strut distribution suggesting local drug gradient. Multivariate analysis revealed that normalized maximum inter-strut distance was associated with DES restenosis (OR: 17.4, P = 0.04) while medial tear length was a predictor of DES occlusion (OR: 5.1, P = 0.03). No differences were observed between different DESs (sirolimus-, paclitaxel-, and everolimus-eluting stents) for restenosis and occlusion. Further, neointimal compositions of restenotic DESs demonstrated greater proteoglycan deposition and less smooth muscle cellularity over time, when compared with BMS with greater cell density and collagen deposition. CONCLUSIONS: Our study indicates the impacts of inadequate drug concentration due to wider inter-strut distance and vessel injury as primary mechanisms of DES restenosis and occlusion, respectively. Moreover, the differences in neointimal compositions between DESs and BMSs might serve as a potential target for the suppression of late neointima growth via inhibition of proteoglycans in DESs.

DOI： 10.1093/eurheartj/eht241

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Mice with homozygous null mutations in the HDL receptor (scavenger receptor class B, type I, or SR-BI) and apolipoprotein E (apoE) genes [SR-BI/apoE double KO (SR-BI(-/-)/apoE(-/-) or dKO) mice] spontaneously develop occlusive, atherosclerotic coronary artery disease (CAD) and die prematurely (50% mortality at 42 d of age). Using microarray mRNA expression profiling, we identified genes whose expression in the hearts of dKO mice changed substantially during disease progression [at 21 d of age (no CAD), 31 d of age (small myocardial infarctions), and 43 d of age (extensive myocardial infarctions) vs. CAD-free SR-BI(+/-)/apoE(-/-) controls]. Expression of most genes that increased >sixfold in dKO hearts at 43 d also increased after coronary artery ligation. We examined the influence and potential mechanism of action of apolipoprotein D (apoD) whose expression in dKO hearts increased 80-fold by 43 d. Analysis of ischemia/reperfusion-induced myocardial infarction in both apoD KO mice and wild-type mice with abnormally high plasma levels of apoD (adenovirus-mediated hepatic overexpression) established that apoD reduces myocardial infarction. There was a correlation of apoD's ability to protect primary cultured rat cardiomyocytes from hypoxia/reoxygenation injury with its potent ability to inhibit oxidation in a standard antioxidation assay in vitro. We conclude that dKO mice represent a useful mouse model of CAD and apoD may be part of an intrinsic cardioprotective system, possibly as a consequence of its antioxidation activity.

DOI： 10.1073/pnas.1315986110

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BACKGROUND: Re-endothelialization is delayed after drug-eluting stent (DES) implantation. In this setting, neointima is more prone to become lipid laden and develop neoatherosclerosis (NA), potentially increasing plaque vulnerability. METHODS AND RESULTS: Optical coherence tomography and near-infrared spectroscopy with intravascular ultrasound were used to characterize NA in 65 (51 DES and 14 bare-metal stents) consecutive symptomatic patients with in-stent restenosis. Median duration poststent implantation was 33 months. Optical coherence tomography-verified NA was observed in 40 stents with in-stent restenosis (62%), was more prevalent in DES than bare-metal stents (68% versus 36%; P=0.02), and demonstrated significantly higher prevalence of thin-cap neoatheroma (47% versus 7%; P=0.01) in DES. Near-infrared spectroscopy assessment demonstrated that the total lipid core burden index (34 [interquartile range, 12-92] versus 9 [interquartile range, 0-32]; P<0.001) and the density of lipid core burden index (lipid core burden index/4 mm, 144 [interquartile range, 60-285] versus 26 [interquartile range, 0-86]; P<0.001) were higher in DES compared with bare-metal stents. Topographically, NA was classified as I (thin-cap NA), II (thick-cap NA), and III (peri-strut NA). Type I thin-cap neoatheroma was more common in DES (20% versus 3%; P=0.01) and in areas of the stented segment without significant in-stent restenosis (71%). Periprocedural myocardial infarction occurred only in DES (11 versus 0; P=0.05), of which 6 (55%) could be attributed to segments with >70% in-stent restenosis. By logistic regression, prior DES was the only independent predictor of both NA (odds ratio, 7.0; 95% confidence interval, 1.7-27; P=0.006) and periprocedural myocardial infarction (odds ratio, 1.8; 95% confidence interval, 1.1-2.4; P=0.05). CONCLUSIONS: In-stent thin-cap neoatheroma is more prevalent, is distributed more diffusely across the stented segment, and is associated with increased periprocedural myocardial infarction in DES compared with bare-metal stents. These findings support NA as a mechanism for late DES failure.

DOI： 10.1161/CIRCINTERVENTIONS.112.000248

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：H M P COMMUNICATIONS  

OBJECTIVES: This study was designed to evaluate the pharmacokinetic and vascular healing of a second-generation everolimus-eluting stent (EES) and slow-release zotarolimus-eluting stent (R-ZES). BACKGROUND: Second-generation DESs have alleviated the safety concerns of late stent thrombosis by addressing issues of polymer biocompatibility and stent design, and optimizing drug loads and release kinetics. No preclinical comparison study exists between these stents. METHODS: Rabbit iliac artery stent implantation was performed using Xience Prime EES and Resolute R-ZES. Histomorphometric evaluation was performed at 28 and 60 days after implantation in an induced atheroma model. Endothelial coverage and maturation were assessed by scanning electron microscopy and immuno-labeling at 14 and 28 days following deployment. For pharmacokinetic studies, arterial tissue and stents were retrieved at 3, 14, 28, and 90 days, and blood samples were obtained during the first 24 hours. RESULTS: Vascular remodeling (percent stenosis, neointimal thickness) was similar in arteries implanted with either stent group. At 28 days, inflammation was significantly less in the EES group as compared to the R-ZES group (inflammation score: 1.59 ± 0.52 vs 2.22 ± 0.69, respectively; P=.044), with no differences observed at 60 days. Endothelial coverage was similar between both groups; however, endothelial maturation above stent struts was significantly higher in the EES group vs R-ZES group at 28 days (33 ± 20% vs 22 ± 21%, respectively; P=.040). Arterial drug level concentrations were also shown to be significantly less in the EES group vs the R-ZES group (P<.0001). CONCLUSIONS: Overall, EES and R-ZES displayed similar remodeling properties with lower arterial drug levels observed in the EES group vs the R-ZES group, which may have led to more rapid endothelial maturation.

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Vascular walls change their dimension and mechanical properties in response to injury such as balloon angioplasty and endovascular stent implantation. Placement of bare metal stents induces neointimal proliferation/restenosis which progresses through different phases of repair with time involving a cascade of cellular reactions. These phases just like wound healing comprise distinct steps consisting of thrombosis, inflammation, proliferation, and migration followed by remodelling. It is noteworthy that animals show a rapid progression of healing after stent deployment compared with man. During stenting, endothelial cells are partially to completely destroyed or crushed along with medial wall injury and stretching promoting activation of platelets, and thrombus formation accompanied by inflammatory reaction. Macrophages and platelets play a central role through the release of cytokines and growth factors that induce vascular smooth muscle cell accumulation within the intima. Smooth muscle cells undergo complex phenotypic changes including migration and proliferation from the media towards the intima, and transition from a contractile to a synthetic phenotype; the molecular mechanisms responsible for this change are highlighted in this review. Since studies in animals and man show that smooth muscle cells play a dominant role in restenosis, drugs like rapamycin and paclitaxel have been coated on stent with polymers to allow local slow release of drugs, which have resulted in dramatic reduction of restenosis that was once the Achilles' heel of interventional cardiologists.

DOI： 10.1093/cvr/cvt115

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The internal mammary artery (IMA) grafts have been associated with long-term patency and improved survival as compared to saphenous vein grafts (SVGs). Early failure of IMA is attributed to poor surgical technique and less with thrombosis. Similarly, bypass surgery especially with the use of IMA has also been shown to be superior at 1-year as well as over five years compared to percutaneous procedures, including the use of drug-eluting stents for the treatment of coronary artery disease. The superiority of IMAs over SVGs can be attributed to its striking resistance to the development of atherosclerosis. Structurally its endothelial layer shows fewer fenestrations, lower intercellular junction permeability, greater anti-thrombotic molecules such as heparin sulfate and tissue plasminogen activator, and higher endothelial nitric oxide production, which are some of the unique ways that make the IMA impervious to the transfer of lipoproteins, which are responsible for the development of atherosclerosis. A better comprehension of the molecular resistance to the generation of adhesion molecules that are involved in the transfer of inflammatory cells into the arterial wall that also induce smooth muscle cell proliferation is needed. This basic understanding is crucial to championing the use of IMA as the first line of defense for the treatment of coronary artery disease.

DOI： 10.3978/j.issn.2225-319X.2013.07.06

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER IRELAND LTD  

DOI： 10.1016/j.atherosclerosis.2012.12.032

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

BACKGROUND: Recent transcatheter aortic valve replacement studies have raised concerns about adverse cerebrovascular events. The etiopathology of the embolized material is currently unknown. METHODS AND RESULTS: A total of 40 patients underwent transcatheter aortic valve replacement with the use of a dual filter-based embolic protection device (Montage Dual Filter System, Claret Medical, Inc). Macroscopic material liberated during the transcatheter aortic valve replacement procedure was captured in the device filter baskets in 30 (75%) patients and sent for histopathologic analysis. The captured material varied in size from 0.15 to 4.0 mm. Amorphous calcified material (size, 0.55-1.8 mm) was identified in 5 patients (17%). In 8 patients (27%), the captured material (size, 0.25-4.0 mm) contained valve tissue composed of loose connective tissue (collagen and elastic fibers) with focal areas of myxoid stroma, with or without coverage by endothelial cells and intermixed with fibrin. In another 13 (43%) patients, collagenous tissue, which may represent elements of vessel wall and valvelike structures, was identified. In 9 patients (30%), thrombotic material was intermixed with neutrophils (size, 0.15-2.0 mm). Overall, thrombotic material was found in 52% of patients, and tissue fragments compatible with aortic valve leaflet or aortic wall origin were found in 52% (21/40) of patients. CONCLUSIONS: Embolic debris traveling to the brain was captured in 75% of transcatheter aortic valve replacement procedures where a filter-based embolic protection device was used. The debris consisted of fibrin, or amorphous calcium and connective tissue derived most likely from either the native aortic valve leaflets or aortic wall.

DOI： 10.1161/CIRCULATIONAHA.112.001091

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

Atherosclerotic plaque rupture with luminal thrombosis is the most common mechanism responsible for the majority of acute coronary syndromes and sudden coronary death. The precursor lesion of plaque rupture is thought to be a thin cap fibroatheroma (TCFA) or "vulnerable plaque". TCFA is characterised by a necrotic core with an overlying thin fibrous cap (≤65 μm) that is infiltrated by macrophages and T-lymphocytes. Intraplaque haemorrhage is a major contributor to the enlargement of the necrotic core. Haemorrhage is thought to occur from leaky vasa vasorum that invades the intima from the adventitia as the intima enlarges. The early atherosclerotic plaque progression from pathologic intimal thickening (PIT) to a fibroatheroma is thought to be the result of macrophage infiltration. PIT is characterised by the presence of lipid pools which consist of proteoglycan with lipid insudation. The conversion of the lipid pool to a necrotic core is poorly understood but is thought to occur as a result of macrophage infiltration which releases matrix metalloproteinase (MMPs) along with macrophage apoptosis that leads to the formation of a acellular necrotic core. The fibroatheroma has a thick fibrous cap that begins to thin over time through macrophage MMP release and apoptotic death of smooth muscle cells converting the fibroatheroma into a TCFA. Other causes of thrombosis include plaque erosion which is less frequent than plaque rupture but is a common cause of thrombosis in young individuals especially women <50 years of age. The underlying lesion morphology in plaque erosion consists of PIT or a thick cap fibroatheroma. Calcified nodule is the least frequent cause of thrombosis, which occurs in older individuals with heavily calcified and tortious arteries.

DOI： 10.1016/j.hlc.2013.03.001

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OBJECTIVES: This study sought to determine whether the classification of human coronary atherosclerotic plaques with T1, T2, and ultrashort echo time (UTE) cardiac magnetic resonance (CMR) would correlate well with atherosclerotic plaque classification by histology. BACKGROUND: CMR has been extensively used to classify carotid plaque, but its ability to characterize coronary plaque remains unknown. In addition, the detection of plaque calcification by CMR remains challenging. Here, we used T1, T2, and UTE CMR to evaluate atherosclerotic plaques in fixed post-mortem human coronary arteries. We hypothesized that the combination of T1, T2, and UTE CMR would allow both calcified and lipid-rich coronary plaques to be accurately detected. METHODS: Twenty-eight plaques from human donor hearts with proven coronary artery disease were imaged at 9.4-T with a T1-weighted 3-dimensional fast low-angle shot (FLASH) sequence (250-μm resolution), a T2-weighted rapid acquisition with refocused echoes (RARE) sequence (in-plane resolution 0.156 mm), and an UTE sequence (300-μm resolution). Plaques showing selective hypointensity on T2-weighted CMR were classified as lipid-rich. Areas of hypointensity on the T1-weighted images, but not the UTE images, were classified as calcified. Hyperintensity on the T1-weighted and UTE images was classified as hemorrhage. Following CMR, histological characterization of the plaques was performed with a pentachrome stain and established American Heart Association criteria. RESULTS: CMR showed high sensitivity and specificity for the detection of calcification (100% and 90%, respectively) and lipid-rich necrotic cores (90% and 75%, respectively). Only 2 lipid-rich foci were missed by CMR, both of which were extremely small. Overall, CMR-based classification of plaque was in complete agreement with the histological classification in 22 of 28 cases (weighted κ = 0.6945, p < 0.0001). CONCLUSIONS: The utilization of UTE CMR allows plaque calcification in the coronary arteries to be robustly detected. High-resolution CMR with T1, T2, and UTE contrast enables accurate classification of human coronary atherosclerotic plaque.

DOI： 10.1016/j.jcmg.2012.09.015

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Saphenous vein grafts (SVGs) are the most used conduits in coronary artery bypass graft (CABG) surgery; however, they are susceptible to accelerated atherosclerosis. Clinical studies have shown 10-year patency rates of SVG can be as low as 50% to 60%. This article highlights changes that are observed following CABG surgery using SVG, including intimal thickening to the development of atherosclerotic changes, and how these changes in vein graft are different from those observed in native atherosclerosis. It also discusses the role of risk factors that contribute to acceleration of SVG atherosclerosis.

DOI： 10.1016/j.iccl.2012.11.002

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

OBJECTIVES: This study sought to examine the effect of oral metformin (Mf) therapy on endothelialization in the setting of drug-eluting stents (DES). BACKGROUND: Mf is a commonly used therapy in diabetic patients receiving DES. Mf and locally eluted mammalian target of rapamycin (mTOR) inhibitors used in DES have convergent molecular signaling; however, the impact of this drug interaction on stent endothelialization is unknown. METHODS: We examined human endothelial aortic cells (HAECs) and a rabbit model of stenting to determine points on molecular convergence between these 2 agents and their impact on stent endothelialization. RESULTS: Western blotting of HAECs treated with Mf and the mTOR inhibitor sirolimus and 14-day rabbit iliacs treated with the combination of zotarolimus-eluting stents (ZES) and oral Mf demonstrated greater inhibition of S6 kinase (S6K), a downstream effector of mTOR complex 1, than either treatment alone. HAEC proliferation was significantly inhibited by Mf or sirolimus treatments alone and further reduced when they were combined. Knockdown of S6K via short interfering RNA in HAECs impaired cell proliferation via a cyclin D1-dependent mechanism, whereas its overexpression rescued the antiproliferative effects of both agents. Last, endothelialization and endothelial cell proliferation at 14 days were assessed in rabbits receiving ZES or bare-metal stents and Mf or placebo by scanning electron microscopy and bromodeoxyuridine/CD31 labeling, respectively. Both endpoints were inhibited by ZES treatment alone and were further reduced by the combination of Mf and ZES. CONCLUSIONS: Significant convergence of signaling occurs between Mf and locally delivered mTOR inhibitors at S6K. This further impairs endothelial recovery/proliferation via an S6K-dependent mechanism. Patients receiving Mf in combination with stents that elute mTOR inhibitors are potentially at increased risk of delayed endothelial healing and stent thrombosis.

DOI： 10.1016/j.jacc.2012.12.018

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

The relationships between oxidation-specific epitopes (OSE) and lipoprotein (a) [Lp(a)] and progressive atherosclerosis and plaque rupture have not been determined. Coronary artery sections from sudden death victims and carotid endarterectomy specimens were immunostained for apoB-100, oxidized phospholipids (OxPL), apo(a), malondialdehyde-lysine (MDA), and MDA-related epitopes detected by antibody IK17 and macrophage markers. The presence of OxPL captured in carotid and saphenous vein graft distal protection devices was determined with LC-MS/MS. In coronary arteries, OSE and apo(a) were absent in normal coronary arteries and minimally present in early lesions. As lesions progressed, apoB and MDA epitopes did not increase, whereas macrophage, apo(a), OxPL, and IK17 epitopes increased proportionally, but they differed according to plaque type and plaque components. Apo(a) epitopes were present throughout early and late lesions, especially in macrophages and the necrotic core. IK17 and OxPL epitopes were strongest in late lesions in macrophage-rich areas, lipid pools, and the necrotic core, and they were most specifically associated with unstable and ruptured plaques. Specific OxPL were present in distal protection devices. Human atherosclerotic lesions manifest a differential expression of OSEs and apo(a) as they progress, rupture, and become clinically symptomatic. These findings provide a rationale for targeting OSE for biotheranostic applications in humans.

DOI： 10.1194/jlr.P030890

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OBJECTIVES: This study sought to determine the accuracy of plaque pattern assessment by coronary computed tomography angiography (CCTA) to differentiate between early and advanced atherosclerotic lesions as defined by histology. BACKGROUND: A ringlike attenuation pattern of coronary atherosclerotic plaques termed as napkin-ring sign (NRS) was described in CCTA of patients who had acute coronary syndrome. METHODS: All procedures were performed in accordance with local and federal regulations and the Declaration of Helsinki. Approval of the local ethics committees was obtained. We investigated 21 coronary arteries of 7 donor hearts. Overall, 611 histological sections were obtained and coregistered with CCTA images. The CCTA cross sections were read in random order for conventional plaque categories (noncalcified [NCP], mixed [MP], calcified [CP]) and plaque patterns (homogenous, heterogeneous with no napkin-ring sign [non-NRS], and heterogeneous with NRS). RESULTS: No plaque was detected in 134 (21.9%), NCP in 254 (41.6%), MP in 191 (31.3%), and CP in 32 (5.2%) CCTA cross sections. The NCP and MP were further classified into homogenous plaques (n = 207, 46.5%), non-NRS plaques (n = 200, 44.9%), and NRS plaques (n = 38, 8.6%). The specificities of NCP and MP to identify advanced lesions were moderate (57.9%, 95% confidence interval [CI]: 50.1% to 65.6%, and 72.1%, 95% CI: 64.7% to 79.4%, respectively), which were similar to the homogenous and heterogeneous plaques (62.6%, 95% CI: 54.8% to 70.3%, and 67.3%, 95% CI: 58.6% to 76.1%, respectively). In contrast, the specificity of the NRS to identify advanced lesions was excellent (98.9%, 95% CI: 97.6% to 100%). The diagnostic performance of the pattern-based scheme to identify advanced lesions was significantly better than that of the conventional plaque scheme (area under the curve: 0.761 vs. 0.678, respectively; p = 0.001). CONCLUSIONS: The assessment of the plaque pattern improves diagnostic accuracy of CCTA to identify advanced atherosclerotic lesions. The CCTA finding of NRS has a high specificity and high positive predictive value for the presence of advanced lesions.

DOI： 10.1016/j.jcmg.2012.03.019

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Atherosclerotic vascular disease not only remains the leading cause of death in the Western countries, but it has become the most common cause of morbidity and mortality in the low- and middle-income countries as well. Therefore, better understanding of the pathogenesis of atherosclerotic disease and its prevention are of fundamental importance. It is well known that it affects sequentially the aorta followed by coronary, carotid, peripheral, and intracerebral arteries, with some individual variability. The mechanisms of progression are similar in each of the beds, with increasing lipid accumulation in the arterial wall along with macrophages and T-cell infiltration, paucity of smooth-muscle cell proliferation and collagen deposition, and endothelial-cell dysfunction and hypercoagulability playing an important role at the time of acute manifestations of the disease. Fundamental to this inflammatory process is the presence of classic risk factors, regardless of the involved territory. Therefore, the concept of palliative treatment must be reserved for only those who have progressed beyond preventive measures. Mt Sinai J Med 79:641653, 2012. (C) 2012 Mount Sinai School of Medicine

DOI： 10.1002/msj.21353

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER IRELAND LTD  

OBJECTIVE: The purpose of this study was to identify histologic characteristics of advanced coronary atherosclerotic plaques that are related with the detection of the napkin-ring sign (NRS) in coronary CT angiography (CCTA). METHODS: CCTA was performed in 7 human donor hearts. Histological slicing and stainings were performed in 1 mm increments of each major coronary artery. Histology was co-registered with the CT-data and classified according to the modified AHA classification. RESULTS: Advanced plaques (types IV-VI) were present in 139 (23%) of 611 cross sections. Of these 33 (24%) demonstrated an NRS in CCTA. NRS plaques were associated with greater non-core plaque area (median 10.2 vs. 6.4 mm(2), p < 0.01) and larger vessel area (median 17.1 vs. 13.0 mm(2), p < 0.01). The area of the necrotic/lipid core was larger in plaques with NRS (median 1.1 vs. 0.5 mm(2), p = 0.05). Angiogenesis tended to be more frequent in plaques with NRS (48% vs. 30%) whereas micro-calcifications tended to be more frequent in plaques without NRS (27% vs. 46%) (p = 0.06 and 0.07 respectively). In a multivariate analysis, necrotic/lipid core area (OR = 1.9), non-core plaque area (OR = 1.6), and total vessel area (OR = 0.9) independently predicted the appearance of the NRS in coronary CT angiography. CONCLUSION: Delineation of NRS in CCTA is independently linked to the size of the necrotic/lipid core, the size of the non-core plaque and to the vessel area as measured in histology of advanced coronary atherosclerotic plaques.

DOI： 10.1016/j.atherosclerosis.2012.06.021

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER IRELAND LTD  

DOI： 10.1016/j.atherosclerosis.2012.04.028

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Deployment of drug-eluting stents instead of bare-metal stents has dramatically reduced restenosis rates, but rates of very late stent thrombosis (>1 year postimplantation) have increased. Vascular endothelial cells normally provide an efficient barrier against thrombosis, lipid uptake, and inflammation. However, endothelium that has regenerated after percutaneous coronary intervention is incompetent in terms of its integrity and function, with poorly formed cell junctions, reduced expression of antithrombotic molecules, and decreased nitric oxide production. Delayed arterial healing, characterized by poor endothelialization, is the primary cause of late (1 month-1 year postimplantation) and very late stent thrombosis following implantation of drug-eluting stents. Impairment of vasorelaxation in nonstented proximal and distal segments of stented coronary arteries is more severe with drug-eluting stents than bare-metal stents, and stent-induced flow disturbances resulting in complex spatiotemporal shear stress can also contribute to increased thrombogenicity and inflammation. The incompetent endothelium leads to late stent thrombosis and the development of in-stent neoatherosclerosis. The process of neoatherosclerosis occurs more rapidly, and more frequently, following deployment of drug-eluting stents than bare-metal stents. Improved understanding of vascular biology is crucial for all cardiologists, and particularly interventional cardiologists, as maintenance of a competently functioning endothelium is critical for long-term vascular health.

DOI： 10.1038/nrcardio.2012.64

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It has been more than 3 decades since the introduction of percutaneous transluminal coronary angioplasty for the treatment of coronary artery disease, and the introduction of bare metal stents and drug-eluting stents (DES) has significantly improved clinical outcomes by decreasing rates of acute vessel closure and restenosis. This article reviews pathologic findings from male and female patients who had received coronary stents for acute coronary syndrome and died suddenly with or without complications of stent implantation, at early (<30 days) and late (>30 days) time points after DES implantation.

DOI： 10.1016/j.iccl.2012.01.003

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Language：English   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

DOI： 10.1161/CIRCINTERVENTIONS.111.967927

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

OBJECTIVE: We recently reported that lowering of macrophage free intracellular iron increases expression of cholesterol efflux transporters ABCA1 and ABCG1 by reducing generation of reactive oxygen species. In this study, we explored whether reducing macrophage intracellular iron levels via pharmacological suppression of hepcidin can increase macrophage-specific expression of cholesterol efflux transporters and reduce atherosclerosis. METHODS AND RESULTS: To suppress hepcidin, increase expression of the iron exporter ferroportin, and reduce macrophage intracellular iron, we used a small molecule inhibitor of bone morphogenetic protein (BMP) signaling, LDN 193189 (LDN). LDN (10 mg/kg IP b.i.d.) was administered to mice, and its effects on atherosclerosis, intracellular iron, oxidative stress, lipid efflux, and foam cell formation were measured in plaques and peritoneal macrophages. Long-term LDN administration to apolipoprotein E-/- mice increased ABCA1 immunoreactivity within intraplaque macrophages by 3.7-fold (n=8; P=0.03), reduced Oil Red O-positive lipid area by 50% (n=8; P=0.02), and decreased total plaque area by 43% (n=8; P=0.001). LDN suppressed liver hepcidin transcription and increased macrophage ferroportin, lowering intracellular iron and hydrogen peroxide production. LDN treatment increased macrophage ABCA1 and ABCG1 expression, significantly raised cholesterol efflux to ApoA-1, and decreased foam cell formation. All preceding LDN-induced effects on cholesterol efflux were reversed by exogenous hepcidin administration, suggesting modulation of intracellular iron levels within macrophages as the mechanism by which LDN triggers these effects. CONCLUSIONS: These data suggest that pharmacological manipulation of iron homeostasis may be a promising target to increase macrophage reverse cholesterol transport and limit atherosclerosis.

DOI： 10.1161/ATVBAHA.111.240101

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

OBJECTIVES: The purpose of this study was to examine selective macrophage differentiation occurring in areas of intraplaque hemorrhage in human atherosclerosis. BACKGROUND: Macrophage subsets are recognized in atherosclerosis, but the stimulus for and importance of differentiation programs remain unknown. METHODS: We used freshly isolated human monocytes, a rabbit model, and human atherosclerotic plaques to analyze macrophage differentiation in response to hemorrhage. RESULTS: Macrophages characterized by high expression of both mannose and CD163 receptors preferentially exist in atherosclerotic lesions at sites of intraplaque hemorrhage. These hemoglobin (Hb)-stimulated macrophages, M(Hb), are devoid of neutral lipids typical of foam cells. In vivo modeling of hemorrhage in the rabbit model demonstrated that sponges exposed to red cells showed an increase in mannose receptor-positive macrophages only when these cells contained Hb. Cultured human monocytes exposed to Hb:haptoglobin complexes, but not interleukin-4, expressed the M(Hb) phenotype and were characterized by their resistance to cholesterol loading and up-regulation of ATP-binding cassette (ABC) transporters. M(Hb) demonstrated increased ferroportin expression, reduced intracellular iron, and reactive oxygen species (ROS). Degradation of ferroportin using hepcidin increased ROS and inhibited ABCA1 expression and cholesterol efflux to apolipoprotein A-I, suggesting reduced ROS triggers these effects. Knockdown of liver X receptor alpha (LXRα) inhibited ABC transporter expression in M(Hb) and macrophages differentiated in the antioxidant superoxide dismutase. Last, LXRα luciferase reporter activity was increased in M(Hb) and significantly reduced by overnight treatment with hepcidin. Collectively, these data suggest that reduced ROS triggers LXRα activation and macrophage reverse cholesterol transport. CONCLUSIONS: Hb is a stimulus for macrophage differentiation in human atherosclerotic plaques. A decrease in macrophage intracellular iron plays an important role in this nonfoam cell phenotype by reducing ROS, which drives transcription of ABC transporters through activation of LXRα. Reduction of macrophage intracellular iron may be a promising avenue to increase macrophage reverse cholesterol transport.

DOI： 10.1016/j.jacc.2011.10.852

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OBJECTIVES: This study sought to examine the capability of optical frequency domain imaging (OFDI) to characterize various morphological and histological responses to stents implanted in human coronary arteries. BACKGROUND: A precise assessment of vascular responses to stents may help stratify the risk of future adverse events in patients who have been treated with coronary stents. METHODS: Fourteen human stented coronary segments with implant duration ≥ 1 month from 10 hearts acquired at autopsy were interrogated ex vivo by OFDI and intravascular ultrasound (IVUS). Comparison with histology was assessed in 134 pairs of images where the endpoints were to investigate: 1) accuracy of morphological measurements; 2) detection of uncovered struts; and 3) characterization of neointima. RESULTS: Although both OFDI and IVUS provided a good correlation of neointimal area with histology, the correlation of minimum neointimal thickness was inferior in IVUS (R(2) = 0.39) as compared with OFDI (R(2) = 0.67). Similarly, IVUS showed a weak correlation of the ratio of uncovered to total stent struts per section (RUTSS) (R(2) = 0.24), whereas OFDI maintained superiority (R(2) = 0.66). In a more detailed analysis by OFDI, identification of individual uncovered struts demonstrated a sensitivity of 77.9% and specificity of 96.4%. Other important morphological features such as fibrin accumulation, excessive inflammation (hypersensitivity), and in-stent atherosclerosis were characterized by OFDI; however, the similarly dark appearance of these tissues did not allow for direct visual discrimination. The quantitative analysis of OFDI signal reflections from various in-stent tissues demonstrated distinct features of organized thrombus and accumulation of foamy macrophages. CONCLUSIONS: The results of the present study reinforce the potential of OFDI to detect vascular responses that may be important for the understanding of long-term stent performance, and indicate the capability of this technology to serve as a diagnostic indicator of clinical success.

DOI： 10.1016/j.jcmg.2011.09.015

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DOI： 10.1016/j.carrev.2011.08.001

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Several randomized and observational studies have reported steady increase in cumulative incidence of late and very late ST (LST/VLST) following first-generation drug-eluting stents (DES: sirolimus-(SES) and paclitaxel-(PES)) up to 5 years. Pathologic studies have identified uncovered struts as the primary substrate responsible for LST/VLST following DES, where delayed arterial healing is associated with stent struts penetrating into the necrotic core, long/overlapping stents, and bifurcation stenting especially in flow divider region. Grade V stent fracture also induces LST/VLST and restenosis. Hypersensitivity reaction is exclusive to SES as an etiology of LST/VLST, whereas malapposition secondary to excessive fibrin deposition is associated with PES. Uncovered struts can be identified in SES and PES with duration of implant beyond 12 months, particularly in stents placed for "off-label" indications. Neoatherosclerosis is another important contributing factor for VLST in DES and bare metal stents (BMS); however, DES shows rapid and more frequent development of neoatherosclerosis than BMS. Future pathologic studies should address the long-term safety of newer generation DES including zotarolimus- and everolimus-eluting stents in terms of the improvement in reendothelialization, decreased inflammation and fibrin deposition as well as a lower incidence of stent fracture-related adverse events, and reduced neoatherosclerosis, which likely contribute to the decreased risk of LST/VLST and better patient outcomes.

DOI： 10.1155/2012/608593

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DOI： 10.1161/CIRCULATIONAHA.111.048736

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Language：English   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

DOI： 10.1161/CIRCIMAGING.111.969683

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

DOI： 10.1016/j.jcin.2011.05.020

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

OBJECTIVES: We sought to assess whether hyperinsulinemia is associated with percentage lipid and coronary plaque burden in nondiabetic patients with acute coronary syndromes (ACS). BACKGROUND: Hyperinsulinemia carries an increased risk of cardiovascular disease even in pre-diabetic patients, but the precise mechanisms of its effects remain unclear. METHODS: Nonculprit coronary lesions associated with mild-to-moderate stenosis in 82 nondiabetic patients with ACS were examined by integrated backscatter intravascular ultrasound (IB-IVUS), using a 40-MHz intravascular catheter. Conventional IVUS and IB-IVUS measurements from the worst 10-mm segment (1-mm intervals) were calculated. All patients underwent a 75-g oral glucose tolerance test (OGTT) to calculate the area under the insulin concentration-time curve (AUC insulin) from 0 to 120 min. RESULTS: Patients in the high tertile of AUC insulin had a significantly greater percentage lipid area and absolute lipid volume than did patients in the intermediate and low tertiles (tertile 3 vs. tertile 2 vs. tertile 1; 37.6 ± 16.6% vs. 25.8 ± 11.9% vs. 27.5 ± 14.7%, p < 0.01 by analysis of variance [ANOVA], and 29.9 ± 22.6 mm(3) vs. 15.3 ± 12.6 mm(3) vs. 17.7 ± 12.7 mm(3), p < 0.01 by ANOVA, respectively) and a smaller percentage fibrosis area (55.0 ± 11.5% vs. 61.7 ± 9.4% vs. 60.7 ± 9.4%, p = 0.03 by ANOVA). Multiple regression analysis showed that the high tertile of AUC insulin was independently associated with an increased percentage lipid area (p < 0.05). On conventional IVUS analysis, external elastic membrane cross-sectional area was significantly increased with greater plaque volume in patients in the high tertile of AUC insulin (both p < 0.05 by ANOVA). CONCLUSIONS: Hyperinsulinemia is associated with an increased lipid content and a greater plaque volume of nonculprit intermediate lesions in nondiabetic patients with ACS, suggesting that plaque vulnerability is increased in this subgroup of patients.

DOI： 10.1016/j.jcmg.2011.02.004

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

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.

DOI： 10.1016/j.jacc.2011.01.011

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

BACKGROUND: Although atherosclerotic models, especially in the rabbit, have existed for a long time, a comparative study of various drug-eluting stent (DES) implantations in atherosclerotic arteries have not been systematically studied. METHODS AND RESULTS: New Zealand White rabbits (n=44) with induced atheroma received bilateral iliac artery stents: bare metal stent (BMS) (Driver) or a stent eluting zotarolimus (ZES) (Endeavor), sirolimus (SES) (Cypher), or everolimus (EES) (Xience V). After 28 days, tissues were harvested for histomorphometric analyses, en face analysis of endothelial coverage, and expression of endothelial nitric oxide synthase (eNOS). Area measurements of external elastic lamina and stent area were similar. Neointimal area was significantly less in all DES versus BMS, which was least in SES and EES; similar trends were noted for cell proliferation. Uncovered struts were greater for SES and EES and least in BMS, whereas ZES were in between and associated with the least fibrin. Macrophages of the neointima were significantly less for all DES relative to BMS. Plaque calcification underneath stents, however, was significantly greater in SES and ZES than in BMS. Although endothelial coverage in between struts was comparable between BMS and DES, there was significantly greater expression of eNOS in BMS and ZES relative to EES and SES. CONCLUSIONS: The rabbit atherosclerotic model of stenting showed delayed healing and significantly greater reduction of neointima following implantation of SES and EES; however, delayed healing was less in ZES with greater neointima (but less than BMS), endothelial regrowth, and eNOS expression.

DOI： 10.1161/CIRCINTERVENTIONS.110.957654

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OBJECTIVE: Several studies in experimental animals have shown that statins stabilize atheromatous plaques by increasing fibrous-cap thickness. However, direct evidence linking the use of statins to the incidence of plaque rupture in humans is lacking. We investigated whether statin treatment before the onset of ST-elevation myocardial infarction (STEMI) influences the incidence of plaque rupture detected by intravascular ultrasound (IVUS). METHODS: The study enrolled 458 patients with STEMI who were admitted within 6h from symptom onset. IVUS interrogation was performed before percutaneous coronary intervention. RESULTS: Plaque ruptures were detected in 262 patients (57%). Patients with statin pretreatment (n=68) had a lower incidence of plaque rupture than those without (37% vs. 61%, p<0.001). Univariate analysis revealed that smoking (p=0.003), lower high-density lipoprotein cholesterol (p=0.001), and a lack of statin pretreatment (p<0.001) were associated with a higher incidence of plaque rupture. Multivariate logistic regression analysis identified statin pretreatment as a negative determinant of plaque rupture independent of age, gender, coronary risk factors, and all other medications (odds ratio 0.35; 95% CI 0.19-0.66, p=0.001). Positive remodeling was also associated with plaque rupture (p<0.001), and the relationship between statin pretreatment and a lower incidence of plaque rupture persisted after adjustment for positive remodeling (odds ratio 0.42; 95% CI 0.22-0.80, p=0.009). CONCLUSIONS: Statin treatment before the onset of STEMI is associated with a lower incidence of plaque rupture, suggesting that the prevention of plaque rupture may be a crucial mechanism underlying clinical benefits associated with statins.

DOI： 10.1016/j.atherosclerosis.2010.09.005

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：EUROPA EDITION  

First generation drug-eluting stents (DES) have significantly improved the treatment options for patients with symptomatic coronary artery disease by decreasing rates of restenosis after percutaneous coronary revascularisation procedures. However, early enthusiasm was tempered by reports of late stent thrombosis, primarily in "off-label" use. In particular, the treatment of atherosclerotic plaques at coronary bifurcations has been challenging for interventional cardiologists regardless of the stent choice due to the underlying nature of the atherosclerotic disease and the use of multiple stents. In this article we illustrate the location and severity of plaque and investigate the healing following both bare metal stents (BMS) and drug-eluting stents (DES) at bifurcations using post-mortem specimens. The presented data will demonstrate that neointimal growth following stent implantation correlate to flow conditions, as there is less underlying atherosclerotic disease at high shear regions and subsequently less neointimal growth is observed in these regions versus low shear regions. The occurrence of late stent thrombosis in DES is also shown to be associated with greater presence of uncovered stent struts at the high shear region, which is likely due to local flow mechanics.

DOI： 10.4244/EIJV6SUPJA5

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Language：Japanese   Publisher：(一社)日本心臓病学会  

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OBJECTIVES: The aim of this study was to assess whether ultrasound attenuation and plaque rupture as detected by intravascular ultrasound (IVUS) are associated with the incidence of no-reflow phenomenon after percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI). BACKGROUND: No-reflow phenomenon is associated with worse long-term outcomes after STEMI. Therefore, reliable and feasible intravascular imaging techniques are needed to identify patient subgroups that would be at high risk for no-reflow phenomenon. METHODS: One hundred seventy consecutive patients with STEMI who underwent PCI within 12 h after symptom onset were enrolled. The IVUS interrogation was performed before PCI. RESULTS: No-reflow phenomenon occurred in 30 patients (18%), who had a higher incidence of no ST-segment resolution (50% vs. 9%; p < 0.001), a higher peak creatine kinase level (4,090 IU/l vs. 2,823 IU/l; p < 0.001), and a lower left ventricular ejection fraction in the chronic phase (51% vs. 59%; p < 0.01). Multivariate logistic regression analysis revealed that ultrasound attenuation with a longitudinal length of > or =5 mm, plaque rupture, and reperfusion time correlated with no-reflow phenomenon (all p < 0.05). In patients with both ultrasound attenuation > or =5 mm and plaque rupture, the incidence of no-reflow phenomenon was 88%, and the risk of decreased coronary reflow was higher than that predicted by either factor alone (p = 0.004 for interaction). CONCLUSIONS: In patients with STEMI, a longer ultrasound attenuation and plaque rupture on IVUS are associated with an increased incidence of no-reflow phenomenon, suggesting that this subset of patients might be at high risk for distal embolism.

DOI： 10.1016/j.jcin.2010.01.015

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Idiopathic pulmonary arterial hypertension (IPAH) is a progressive disease characterized by inappropriate increase of pulmonary artery smooth muscle cells (PASMCs) leading to occlusion of pulmonary arterioles. Inhibition of platelet-derived growth factor (PDGF) signaling is starting to garner attention as a targeted therapy for IPAH. We assessed the inhibitory effects of simvastatin, a 3-hydroxy-3-methylglutanyl coenzyme A reductase inhibitor, on PDGF-induced proliferation and migration of PASMCs obtained from 6 patients with IPAH who underwent lung transplantation. PDGF stimulation caused a significantly higher growth rate of PASMCs from patients with IPAH than that of normal control PASMCs as assessed by H-3-thymidine incorporation. Simvastatin (0.1 mu mol/L) significantly inhibited PDGF-induced cell proliferation of PASMCs from patients with IPAH but did not inhibit proliferation of normal control cells at the same concentration. Western blot analysis revealed that simvastatin significantly increased the expression of cell cycle inhibitor p27. PDGF significantly increased the migration distance of IPAH-PASMCs compared with that of normal PASMCs, and simvastatin (1 mu mol/L) significantly inhibited PDGF-induced migration. Immunofluorescence staining revealed that simvastatin (1 mu mol/L) inhibited translocation of Rho A from the cytoplasm to membrane and disorganized actin fibers in PASMCs from patients with IPAH. In conclusion, simvastatin had inhibitory effects oil inappropriate PDGF signaling in PASMCs from patients with IPAH.

DOI： 10.1097/FJC.0b013e3181c0419c

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPANESE CIRCULATION SOC  

BACKGROUND: Ruptured plaque and culprit lesions associated with anterior acute myocardial infarction cluster mainly in the proximal segment of the left anterior descending coronary artery (LAD). This study investigated whether the tissue characteristics of plaque in the proximal LAD differs from that of plaque in the distal LAD as assessed by integrated backscatter (IB)-intravascular ultrasound (IVUS). METHODS AND RESULTS: IVUS interrogation was used to study 107 non-culprit intermediate plaques in 68 patients with angina pectoris who underwent percutaneous coronary interventions. Proximal and distal segments were defined as <30 mm and > or =30 mm from the ostium, respectively. IB-IVUS images were recorded, and the average percentage values of each plaque component (lipid, fibrosis, dense fibrosis, and calcification) were compared between segments. Plaques in the proximal segment (n=51) had a higher %lipid content (36 vs 19%, P<0.01) and a lower %fibrosis content (57 vs 64%, P<0.01) than did plaques in the distal segment (n=56). Multiple linear regression analysis showed that proximal plaques had a higher %lipid content, independently of other coronary risk factors and plaque burden (P<0.01). CONCLUSIONS: The %lipid and %fibrosis contents differ significantly between plaques in the proximal segment and those in the distal segment of the LAD. (Circ J 2010; 74: 142 - 147).

DOI： 10.1253/circj.CJ-09-0389

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OBJECTIVES: Low levels of adiponectin, an adipocytokine with anti-diabetic and anti-atherogenic properties, are associated with increased risk of future myocardial infarction in men. Previous studies have demonstrated that cigarette smoking is involved in the development of insulin resistance, and current smokers have been shown to have reduced plasma adiponectin levels. However, the influence of smoking cessation on adiponectin levels remains unknown. We sought to assess whether smoking cessation is associated with increased plasma adiponectin levels in men. METHODS: The study includes 72 men (47 non-smokers and 25 current smokers at baseline) with stable angina pectoris who underwent percutaneous coronary intervention and follow-up coronary angiography 6 months later. During the 6-month follow-up period, all 47 non-smokers remained non-smokers, while 15 men of the 25 baseline current smokers successfully quit smoking. We evaluated plasma adiponectin levels at coronary intervention and 6 months later. RESULTS: Plasma adiponectin levels at coronary intervention were comparable to those after 6 months in non-smokers (4.22 [3.15-6.43] vs. 4.58 [3.03-6.26] microg/mL, P=0.124) and in persistent smokers (4.77 [4.25-10.53] vs. 5.16 [4.11-8.10] microg/mL, P=0.721). Meanwhile, an increase in adiponectin level was observed in patients who quit smoking for 6 months (4.24 [3.30-5.70] vs. 5.50 [4.03-8.00] microg/mL, P=0.002). Univariate analysis revealed that the percent increase in adiponectin levels correlated positively with smoking cessation (P=0.003) and negatively with additional use of beta-blockers (P=0.049). In addition, increases in adiponectin levels were closely associated with increase in high-density lipoprotein cholesterol (P=0.148), decrease in triglycerides (P=0.140), and additional use of renin-angiotensin system inhibitors (P=0.069). Multivariate analysis demonstrated that smoking cessation was an independent determinant of the increase in adiponectin (P=0.036). CONCLUSIONS: Smoking cessation is associated with increased plasma adiponectin levels in men with stable angina, suggesting that the significance of smoking cessation may be partly explained by the increase in adiponectin level.

DOI： 10.1016/j.jjcc.2008.11.004

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BACKGROUND: In patients with acute myocardial infarction (AMI), the relationship of serial changes in ST-segment elevation after reperfusion to left ventricular (LV) function remains unclear. METHODS AND RESULTS: The study group comprised 164 patients with reperfused anterior AMI within 6 h of symptom onset. The sum of ST-segment deviation was calculated on admission (SigmaST-admission), and 1 h (SigmaST-1 h) and 24 h (SigmaST-24 h) after reperfusion. ST resolution was defined as a reduction in SigmaST-1 h of > or =50% as compared with SigmaST-admission. Patients were classified into 3 groups: group A, 82 patients with ST resolution in whom SigmaST-1 h > or = SigmaST-24 h; group B, 37 patients with ST resolution in whom SigmaST-1 h < SigmaST-24 h; group C, 45 patients without ST resolution. Peak creatine kinase were higher in groups B and C than in group A (4,578+/-2,176, 4,236+/-2,638, 2,222+/-1,926 mU/ml, p<0.01). At 6 months follow-up, the LV ejection fraction were lower in groups B and C than in group A (53+/-8, 54+/-12, 62+/-9%, p<0.01). CONCLUSIONS: An increase in ST-segment elevation 1-24 h after reperfusion, despite ST resolution, is associated with a larger infarction and poorer LV function in patients with reperfused anterior AMI.

DOI： 10.1253/circj.72.409

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Language：English   Publisher：Japanese Circulation Society  

DOI： 10.1253/circj.72.505

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Other Link： http://search.jamas.or.jp/link/ui/2008214974

Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPANESE CIRCULATION SOC  

BACKGROUND: Impaired glucose tolerance (IGT) is a significant risk factor for cardiovascular disease, but is not always recognized in the clinical setting. An anti-atherogenic adipocytokine, adiponectin, is decreased in type 2 diabetes mellitus, but its role in non-diabetic subjects has not been clarified. The hypothesis investigated in the present study was that plasma adiponectin levels correlate with IGT and coronary artery disease (CAD) in non-diabetic men. METHODS AND RESULTS: Glucose intolerance was evaluated by an oral glucose tolerance test and plasma adiponectin levels were measured in 232 non-diabetic men who underwent coronary angiography. Patients with IGT (n=102) had significantly lower adiponectin levels than those with normal glucose tolerance (n=130) (4.47 [3.23-6.39] vs 5.85 [3.99-8.65] mug/ml, p=0.003). Plasma adiponectin levels were associated with IGT in multiple logistic regression analysis (odds ratio (OR) 0.623, 95% confidence interval (CI) 0.397-0.980; p=0.041). Non-diabetic patients with CAD (n=122) had lower adiponectin levels than those without CAD (n=110) (4.60 [3.32-6.38] vs 6.08 [4.10-9.88] microg/ml, p<0.001). Multiple logistic regression analysis demonstrated adiponectin independently correlated with the presence of CAD (OR 0.432, 95% CI 0.256-0.728; p=0.002). CONCLUSIONS: Hypoadiponectinemia is associated with IGT and CAD in non-diabetic men, suggesting that the adiponectin level can provide valuable information regarding the risk of CAD even in non-diabetic subjects.

DOI： 10.1253/circj.71.1703

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Reduced incidence of type-2 diabetes has been shown in patients treated with pravastatin. Adiponectin can exhibit beneficial effects on glucose metabolism. We investigated whether pravastatin could improve glucose tolerance associated with increasing adiponectin levels in patients with impaired glucose tolerance (IGT). This study consisted of 40 coronary artery disease (CAD) patients with IGT assessed by oral glucose tolerance test (OGTT). Patients were randomized to receive pravastatin (n=20) or no lipid-lowering medications (control group, n=20) for 6 months, after which OGTT was repeated and adiponectin levels were measured. Pravastatin treatment significantly decreased levels of total cholesterol (16%), low-density lipoprotein cholesterol (23%) and high-sensitivity C-reactive protein (37%) (p<0.01, respectively). At 2h in OGTT, pravastatin significantly improved hyperglycemia (-14%) and hyperinsulinemia (-23%). Pravastatin treatment significantly elevated plasma adiponectin levels (35%; p<0.001) but not in the control group. The glucose reduction at 2h post-OGTT was significantly associated with increased levels of adiponectin (r=-0.462; p=0.003). Pravastatin treatment is an independent predictor for improvement of post-loaded hyperglycemia (odds ratio; 5.7; 95% confidence interval 1.7-19.3; p=0.003) and achieved beneficial conversion from IGT to normal glucose tolerance (40%; p=0.03). Pravastatin exhibits beneficial effects on glucose metabolism especially in the postprandial state associated with increasing plasma adiponectin levels in CAD patients with IGT.

DOI： 10.1016/j.atherosclerosis.2006.08.023

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There is conflicting information about whether mortality after AMI is higher in women than men. We investigated the significance of plasma adiponectin concentrations on major adverse cardiac events (MACE) after acute myocardial infarction (AMI) to delineate any differences between men and women. The study patients consisted of 114 men and 42 women with AMI. The incidence of MACE was significantly higher in women than men during the entire follow-up period (p<0.05). Compared with men for post-AMI MACE, the hazard ratio for women was 5.6 after adjustment for prognostic factors. Killip class (p<0.001) and sex differences (p<0.05) were independent predictors of MACE at 1 year post-AMI. Plasma adiponectin levels in women were significantly higher than men on admission (8.66 microg/mL [range: 6.6-14.08] versus 4.71 microg/mL [range: 3.47-7.27], p<0.0001) and during the post-AMI course (all p<0.0001). Multivariate analysis identified plasma adiponectin level on admission as an independent predictor of MACE in men (p<0.001) and the difference between plasma adiponectin levels at discharge and on admission in women (p<0.05). Patterns of serial changes in plasma adiponectin concentrations are different between men and women and plasma adiponectin concentrations can be used to predict future adverse cardiac events in AMI patients.

DOI： 10.1016/j.atherosclerosis.2006.07.028

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Language：Japanese   Publisher：Japan Heart Foundation  

DOI： 10.11281/shinzo1969.39.Supplement3_54

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OBJECTIVES: We sought to assess whether plasma adiponectin levels correlate with angiographic coronary lesion complexity in patients with coronary artery disease (CAD). BACKGROUND: Metabolic disorders, including diabetes mellitus and metabolic syndrome, are important risk factors for acute cardiovascular events, and adiponectin is a key molecule of metabolic disorders, with anti-atherogenic properties. Low plasma adiponectin levels are associated with CAD and future incidence of myocardial infarction. The involvement of adiponectin in coronary plaque vulnerability, which may be reflected by angiographic complex lesions, remains to be elucidated. METHODS: We measured plasma adiponectin levels in 207 men (152 with stable CAD and 55 with acute coronary syndromes [ACS]). Coronary lesions were classified as of simple or complex appearance. RESULTS: Plasma adiponectin levels were significantly lower in stable CAD patients with complex coronary lesions (n = 60) than in those with simple lesions (n = 92) (4.14 [range 2.95 to 6.02] vs. 5.27 [range 3.67 to 8.12] microg/ml, p = 0.006). Multiple logistic regression analysis demonstrated that adiponectin level was independently associated with complex lesions (odds ratio 0.514, 95% confidence interval 0.278 to 0.951; p = 0.034). Polytomous logistic regression revealed that adiponectin correlated independently with both single and multiple complex lesions. Among patients with ACS, who had lower adiponectin levels than stable CAD patients, those with multiple complex lesions had significantly lower adiponectin than those with a single complex lesion (3.26 [range 2.26 to 4.46] vs. 4.21 [range 3.36 to 5.41] microg/ml, p = 0.032). CONCLUSIONS: Plasma adiponectin levels are significantly associated with coronary lesion complexity in men with CAD. Low adiponectin levels may contribute to coronary plaque vulnerability.

DOI： 10.1016/j.jacc.2006.05.054

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BACKGROUND: The relationship between adiponectin and coronary spastic angina (CSA), both of which are closely involved in coronary endothelial dysfunction, has not been elucidated. METHODS AND RESULTS: Plasma adiponectin concentrations were examined in 55 men with CSA and 55 with chest pain syndrome (CPS). The plasma log-adiponectin levels were significantly lower in patients with CSA than with CPS (0.61+/-0.28 vs 0.80+/-0.21 microg/ml, p < 0.0001). The prevalence of smoking was significantly higher in the CSA patients than in those with CPS (50.9% vs 29.1%, p = 0.0195). In multiple logistic regression analysis, log-adiponectin (p = 0.0008) and smoking (p = 0.0210) were independent determinants of CSA. Conclusions Hypoadiponectinemia is a potential risk factor for CSA in men, independent of smoking.

DOI： 10.1253/circj.69.1154

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Other Link： http://search.jamas.or.jp/link/ui/2017380440

Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ELSEVIER SCIENCE INC  

DOI： 10.1016/j.jacc.2017.09.501

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DOI： 10.1016/S0735-1097(17)34388-7

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Language：Japanese   Publisher：(一社)日本集中治療医学会  

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Language：Japanese   Publisher：日本心臓血管内視鏡学会  

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Language：English   Publisher：INFORMA HEALTHCARE  

DOI： 10.3109/14017431.2014.954825

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Language：English   Publisher：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

DOI： 10.1194/jlr.P030890ERR

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Language：English   Publishing type：Book review, literature introduction, etc.   Publisher：EDIZIONI MINERVA MEDICA  

Peripheral artery disease (PAD) is an emerging problem especially with aging population and increase in the incidence of diabetes and metabolic syndrome. The disease is histologically characterized by the presence of moderate to severe calcification and fibrous plaques as compared to coronary and carotid atherosclerotic disease, which are richer in necrotic core. Endovascular therapy for the superficial femoral artery (SFA), at least in the United States, has been largely limited to balloon angioplasty and stenting and these are considered safe and relatively effective therapies. However, the patency rates remain low even at one year and restenosis is a growing and challenging problem. Recently the development of newer devices, i.e., drugeluting stent, and drug coated balloon are showing greater efficacy and are being adopted into daily practice. In this review, we will present the morphologic characteristics of the underlying SFA atherosclerotic disease and discuss in-stent restenosis and the mechanisms that may be involved in the induction of excessive smooth muscle cell proliferation and deposition of proteoglycans and collagen, that lead to restenosis.

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DOI： 10.1016/j.hlc.2013.03.001

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DOI： 10.1161/CIRCULATIONAHA.111.048736

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DOI： 10.1016/S0735-1097(11)60629-3

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Objective - To examine the left ventricular regional wall motion abnormality and to evaluate dispersion of this abnormality in patients with long QT syndrome. Design - Left ventricular short axis images at basal and middle levels were recorded on videotape and digitised to reconstruct digitised M mode echocardiograms, from which left ventricular wall thickness curves were obtained. The wall thickening time (ThT) was defined as the period in which the instantaneous wall thickness exceeded 90% of the maximum wall thickness. ThT was measured at three segments in each of the septal and free wall sides of the left ventricle, a total of 12 segments. To examine the mechanical dispersion of the left ventricle, the difference between the maximum and minimum ThT of 12 segments in each subject was obtained. Patients - Eight patients with congenital long QT syndrome (averaged QTc interval (SD) 509 (27) ms(1/2)) and 10 control subjects (QTc interval 397 (26) ms(1/2)) were examined. Results - The averaged ThT values of the 12 segments pooled from all subjects were correlated with the QT intervals (r = 0.72, p &lt
0.005). Thus the averaged ThT in the long QT syndrome patients was longer than in the control subjects (p &lt
0.005). The segmental variation of ThT in the patients was greater than in the control subjects (p &lt
0.001). The dispersion of ThT in the patients was therefore larger than in control subjects (p &lt
0.005). However, the pattern of ThT variation in the patients varied according to the individual subject. Conclusions - There is not only electrical but also mechanical dispersion in the left ventricle of long QT syndrome patients. Regional assessment of ventricular wall motion may allow quantification of the spatial variation of wall motion abnormality.

DOI： 10.1136/hrt.80.3.245

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