CD163+ Macrophages Induce Endothelial-to-Mesenchymal Transition in Atheroma.

BACKGROUND: Cell phenotype switching is increasingly being recognized in atherosclerosis. However, our understanding of the exact stimuli for such cellular transformations and their significance for human atherosclerosis is still evolving. Intraplaque hemorrhage is thought to be a major contributor to plaque progression in part by stimulating the influx of CD163+ macrophages. Here, we explored the hypothesis that CD163+ macrophages cause plaque progression through the induction of proapoptotic endothelial-to-mesenchymal transition (EndMT) within the fibrous cap. METHODS: Human coronary artery sections from CVPath's autopsy registry were selected for pathological analysis. Athero-prone ApoE-/- and ApoE-/-/CD163-/- mice were used for in vivo studies. Human peripheral blood mononuclear cell-induced macrophages and human aortic endothelial cells were used for in vitro experiments. RESULTS: In 107 lesions with acute coronary plaque rupture, 55% had pathological evidence of intraplaque hemorrhage in nonculprit vessels/lesions. Thinner fibrous cap, greater CD163+ macrophage accumulation, and a larger number of CD31/FSP-1 (fibroblast specific protein-1) double-positive cells and TUNEL (terminal deoxynucleotidyl transferase-dUTP nick end labeling) positive cells in the fibrous cap were observed in nonculprit intraplaque hemorrhage lesions, as well as in culprit rupture sections versus nonculprit fibroatheroma sections. Human aortic endothelial cells cultured with supernatants from hemoglobin/haptoglobin-exposed macrophages showed that increased mesenchymal marker proteins (transgelin and FSP-1) while endothelial markers (VE-cadherin and CD31) were reduced, suggesting EndMT induction. Activation of NF-κB (nuclear factor kappa ß) signaling by proinflammatory cytokines released from CD163+ macrophages directly regulated the expression of Snail, a critical transcription factor during EndMT induction. Western blot analysis for cleaved caspase-3 and microarray analysis of human aortic endothelial cells indicated that apoptosis was stimulated during CD163+ macrophage-induced EndMT. Additionally, CD163 deletion in athero-prone mice suggested that CD163 is required for EndMT and plaque progression. Using single-cell RNA sequencing from human carotid endarterectomy lesions, a population of EndMT was detected, which demonstrated significant upregulation of apoptosis-related genes. CONCLUSIONS: CD163+ macrophages provoke EndMT, which may promote plaque progression through fibrous cap thinning.

In-stent restenosis caused by a reprotruding calcified nodule and stent fracture in the hinged coronary artery.

Calcified nodules (CNs) cause in-stent restenosis (ISR) frequently. Although reprotrusion of CNs through stent struts is one of the mechanisms of ISR, the process of this phenomenon has not been understood. Furthermore, little is known about stent fracture (SF) occurring at the site of CNs. We are presenting a case of an 82-year-old male who developed early ISR due to the combination of an in-stent CN and SF in the hinged right coronary artery. The process of progression of the in-stent CN was recorded sequentially with angiography and intravascular ultrasound (IVUS). IVUS from the fulcrum of hinge motion revealed the repetitive protruding movement of the CN into the stent lumen.

Creatinine kinase-myocardial band (CK-MB) to creatinine kinase (CK) ratio for ST-segment elevation myocardial infarction in the era of the universal definition.

Although serum troponin level is the gold standard under the universal definition of acute myocardial infarction (AMI), serum creatinine kinase (CK) and creatine kinase-myocardial band (CK-MB) is still measured in clinical practice as the compliment of troponin level. The purpose of this retrospective study is to illustrate the dramatic change of CK-MB/CK ratio by comparing CK-MB/CK ratio in patients with ST-segment elevation myocardial infarction (STEMI) among ≤ 24 h before reaching peak CK, peak CK, ≤ 24 h after reaching peak CK, and 24-48 h after reaching peak CK. We included 502 patients with STEMI. We calculated each average CK-MB/CK ratio at ≤ 24 h before reaching peak CK, peak CK, ≤ 24 h after reaching peak CK, and 24-48 h after reaching peak CK. The average values were compared using Friedman test. The average CK-MB/CK ratio at ≤ 24 h before reaching peak CK, peak CK, ≤ 24 h after reaching peak CK, and 24-48 h after reaching peak CK was 0.096 (9.6% of CK), 0.098 (9.8% of peak CK), 0.076 (7.6% of CK), and 0.028 (2.8% of CK), respectively. The Friedman test suggested that the CK-MB/CK ratio significantly declined after reaching peak CK (p < 0.001). In conclusion, the CK-MB/CK ratio was around 0.1 (10% of CK) until CK-MB and CK reached the peak, but dropped sharply after reaching peak CK. The CK-MB/CK ratio less than 0.1 (10% of CK) cannot be used to rule out the possibility of AMI, when the onset of symptom is unclear or late presentation.

Determinants of serious in-hospital complications in patients with Killip class 1/2 ST-segment elevation myocardial infarction who underwent primary percutaneous coronary intervention.

Killip classification has been used to stratify the risk of patients with acute myocardial infarction (AMI). There were many reports that Killip class 3 or 4 is closely associated with poor clinical outcomes. In other words, Killip class 1 or 2 is associated with favorable clinical outcomes in patients with AMI, especially when patients received primary percutaneous coronary intervention (PCI). However, some patients with Killip class 1/2 suffer from serious in-hospital complications. This study aimed to identify factors associated with serious in-hospital complications of ST-segment elevation myocardial infarction (STEMI) in patients with Killip class 1/2. The primary endpoint was serious in-hospital complications defined as the composite of in-hospital death and mechanical complications. We included 809 patients with STEMI, and divided them into the non-complication group (n = 791) and the complication group (n = 18). In-hospital death was observed in 14 patients (1.7%), and mechanical complications were observed in 4 patients (0.5%). Final TIMI flow ≤ 2 was more frequently observed in the complication group (33.3%) than in the non-complication group (5.4%) (p < 0.001). Multivariate logistic regression analysis revealed that serious in-hospital complication was associated with final TIMI flow grade ≤ 2 (Odds ratio 6.040, 95% confidence interval 2.042-17.870, p = 0.001). In conclusion, serious in-hospital complication of STEMI was associated with insufficient final TIMI flow grade in patients with Killip class 1/2. If final TIMI flow grade is suboptimal after primary PCI, we may recognize the potential risk of serious complications even when patients presented as Killip class 1/2.

Development of a simple prediction model for mechanical complication in ST-segment elevation myocardial infarction patients after primary percutaneous coronary intervention.

Mechanical complication (MC) is a rare but serious complication in patients with ST-segment elevation myocardial infarction (STEMI). Although several risk factors for MC have been reported, a prediction model for MC has not been established. This study aimed to develop a simple prediction model for MC after STEMI. We included 1717 patients with STEMI who underwent primary percutaneous coronary intervention (PCI). Of 1717 patients, 45 MCs occurred after primary PCI. Prespecified predictors were determined to develop a tentative prediction model for MC using multivariable regression analysis. Then, a simple prediction model for MC was generated. Age ≥ 70, Killip class ≥ 2, white blood cell ≥ 10,000/µl, and onset-to-visit time ≥ 8 h were included in a simple prediction model as "point 1" risk score, whereas initial thrombolysis in myocardial infarction (TIMI) flow grade ≤ 1 and final TIMI flow grade ≤ 2 were included as "point 2" risk score. The simple prediction model for MC showed good discrimination with the optimism-corrected area under the receiver-operating characteristic curve of 0.850 (95% CI: 0.798-0.902). The predicted probability for MC was 0-2% in patients with 0-4 points of risk score, whereas that was 6-50% in patients with 5-8 points. In conclusion, we developed a simple prediction model for MC. We may be able to predict the probability for MC by this simple prediction model.

Association of peak C-reactive protein with long-term clinical outcomes in patients with ST-segment elevation myocardial infarction.

Peak C-reactive protein (CRP) levels following ST-segment elevation myocardial infarction (STEMI) are associated with left ventricular thrombus formation or cardiac rupture. However, the impact of peak CRP on long-term outcomes in patients with STEMI is not completely understood. The purpose of this retrospective study was to compare the long-term all-cause death after STEMI between patients with and without high peak CRP levels. We included 594 patients with STEMI, and divided them into the high CRP group (n = 119) and the low-moderate CRP group (n = 475) according to the quintile of peak CRP levels. The primary endpoint was all-cause death after the discharge of the index admission. The mean peak CRP level was 19.66 ± 5.14 mg/dL in the high CRP group, whereas that was 6.43 ± 3.86 mg/dL in the low-moderate CRP group (p < 0.001). During the median follow-up duration of 1045 days (Q1 284 days, Q3 1603 days), a total of 45 all-cause deaths were observed. The Kaplan-Meier curves showed that all-cause death was more frequently observed in the high CRP group than in the low-moderate CRP group (p = 0.002). The multivariate Cox hazard analysis revealed that high CRP was significantly associated with all-cause death (hazard ratio 2.325, 95% confidence interval 1.246-4.341, p = 0.008) after controlling for confounding factors. In conclusion, high peak CRP was significantly associated with all-cause death in patients with STEMI. Our results suggest that peak CRP may be useful to stratify patients with STEMI for the risk of future death.

Factors associated with intensive care unit delirium in patients with acute myocardial infarction.

Some patients admitted to intensive care units (ICU) would develop delirium, which is associated with poor prognosis. The purpose of this retrospective study was to identify factors associated with ICU delirium in patients with acute myocardial infarction (AMI). We included 753 AMI and divided those into the ICU-delirium group (n = 110) and the non-ICU-delirium group (n = 643) according to the presence of ICU delirium. The ICU delirium was evaluated by confusion assessment method for the intensive care unit. Patient characteristics and clinical outcomes were compared between the 2 groups, and factors associated with ICU delirium were sought by multivariate analysis. The prevalence of female sex was significantly higher in the ICU-delirium group (43.6%) than in the non-ICU-delirium group (20.2%) (p < 0.001). The incidence of in-hospital death was significantly higher in the ICU-delirium group (17.3%) than in the non-ICU-delirium group (0.5%) (p < 0.001). The multivariate logistic regression analysis revealed that age [every 10 years increase: odds ratio (OR) 1.439, 95% confidence interval (CI) 1.127-1.837, p = 0.004], female sex (OR 2.237, 95%CI 1.300-3.849, p = 0.004), triple vessel disease (OR 2.317, 95%CI 1.365-3.932, p = 0.002), body mass index < 18.5 kg/m2 (OR 2.910, 95%CI 1.410-6.008, p = 0.004), use of mechanical support (OR 2.812, 95%CI 1.500-5.270, p = 0.001), respiratory failure (OR 5.342, 95%CI 3.080-9.265, p < 0.001), and use of continuous renal replacement therapy (OR 5.901, 95%CI 2.520-13.819, p < 0.001) were significantly associated with ICU delirium. In conclusion, ICU delirium was associated with in-hospital death. Older age, female sex, triple vessel disease, leanness, use of mechanical support, respiratory failure, and continuous renal replacement therapy were significantly associated with the occurrence of ICU delirium.

Comparison of in-hospital outcomes of acute myocardial infarction between patients with cardiogenic shock and with cardiac arrest.

In-hospital mortality of acute myocardial infarction (AMI) complicated with cardiogenic shock (CS) remains high. Also, in-hospital mortality of AMI complicated with cardiac arrest (CA) has been reported to be highest among any AMI. However, there were few reports that compared in-hospital mortality directly between AMI complicated with CS and complicated with CA. The purpose of this study was to compare in-hospital outcomes between AMI complicated with CS and complicated with CA. We retrospectively included 195 AMI patients complicated by CS or CA, and divided those into the CA group (n = 109) and the CS group (n = 86). We also subdivided the CA group into CA with persistent CS (n = 83) and CA without persistent CS (n = 26). One-third of the study population died during the index admission. In-hospital death was more frequently observed in the CA group (45.0%) than in the CS group (20.9%) (p < 0.001). In-hospital mortality was highest in the CA with persistent CS group (68.7%), followed by the CS group (20.9%), and least in the CA without persistent CS group (11.5%) (p < 0.001). Favorable neurological function was more frequently observed in the CA without persistent CS group (76.9%) and the CS group (74.4%) than in the CA with persistent CS group (27.7%) (p < 0.001). In conclusion, in-hospital mortality was higher in AMI patients with CA than in those with CS. However, when we divided AMI patients with CA into those with and without persistent CS, in-hospital mortality was lowest in CA without persistent CS, followed by CS, and highest in CA with persistent CS.

Impact of intravascular ultrasound-incomplete stent apposition on stent failure.

OBJECTIVES: This study aimed to investigate the relationship between immediate incomplete stent apposition (ISA) detected by intravascular ultrasound (IVUS) and midterm stent failure. BACKGROUND: Stent failure is one of serious clinical events related to percutaneous coronary intervention (PCI). The previous studies using optical coherence tomography showed that ISA could be associated with stent thrombosis. However, the association between immediate ISA detected by IVUS and stent failure has not been fully investigated. METHODS: We included 396 lesions that underwent elective PCI, and divided those into the appropriate stent apposition (ASA) group (n = 290) and the ISA group (n = 106). The primary endpoint was stent failure, which was defined as a composite of ischemia-driven target lesion revascularization and stent thrombosis. We compared clinical and lesion characteristics between the two groups, and performed a multivariate COX hazard analysis to investigate the association between immediate ISA and stent failure. RESULTS: The median follow-up duration was 1296 days. The Kaplan-Meier curves revealed the higher incidence of stent failure in the ISA group than in the ASA group (p < 0.001). The multivariate stepwise COX hazard analysis showed that immediate ISA (hazard ratio 4.97, 95% confidence interval 1.31-18.82, p = 0.018) was significantly associated with stent failure. When we set the cut-off value of the immediate ISA distance as 0.25 mm, the distance ≥ 0.25 mm had 68.8% sensitivity and 85.0% specificity to predict stent failure. CONCLUSIONS: Immediate ISA detected by IVUS was associated with midterm stent failure. We should pay attention to reduce immediate ISA for improving the midterm outcomes.

Endothelial Recovery in Bare Metal Stents and Drug-Eluting Stents on a Single-Cell Level.

OBJECTIVE: Healing processes, particularly reendothelialization, are essential for vascular homeostasis after plain old balloon angioplasty and stent implantation. Drug-eluting stents (DES) are commonly used for percutaneous coronary intervention because restenosis rates are reduced as compared with bare metal stents (BMS). However, in addition to understanding the nature of regenerated endothelial cells, concerns over incomplete stent healing persist, and the molecular effects of antiproliferative drug coatings on endothelium remain poorly understood. APPROACH AND RESULTS: We used the rabbit iliac artery model to analyze differences in stent endothelialization in BMS and DES. Histology and immunohistochemistry confirmed that stent coverage was significantly greater in BMS than in DES at 30 days after stent implantation. Single-cell RNA sequencing revealed a more immature transcriptomic signature of neointimal endothelial cell harvested from stented arteries in comparison with native and plain old balloon angioplasty­ treated arteries. Whereas the genetic signature of BMS was overall proangiogenic with enrichment of genes involved in endothelial proliferation, sprouting, and migration, as well as extracellular matrix assembly, DES-derived endothelial cell showed upregulation of genes associated with angiogenesis inhibition and endothelial activation. CONCLUSIONS: Single-cell RNA sequencing analysis identified unique transcriptional changes within regenerated endothelium after plain old balloon angioplasty and stent implantation. These data suggest unique endothelial transcriptional differences, which characterize the different response of the endothelium to vascular injury and may help explain why long-term responses in DES remain suboptimal.

Comparison of Long-Term Clinical Outcomes in Patients Stratified by a Novel Acute Myocardial Infarction Risk Stratification (nARS) System.

BACKGROUND: As severity of acute myocardial infarction (AMI) varies widely, several risk stratifications for AMI have been reported. We have introduced a novel AMI risk stratification system linked to a rehabilitation program (novel AMI risk stratification; nARS), which stratified AMI patients into low (L)-, intermediate (I)-, and high (H)-risk groups. The purpose of this retrospective study was to compare the long-term clinical outcomes in patients with AMI among L-, I-, H-risk groups.Methods and Results: This study included 773 AMI patients, and assigned them into the L-risk group (n=332), the I-risk group (n=164), and the H-risk group (n=277). The primary endpoint was major cardiovascular events (MACE), defined as the composite of all-cause death, readmission for heart failure, non-fatal myocardial infarction, and target vessel revascularization after the discharge of index admission. The median follow-up duration was 686 days. MACE was most frequently observed in the H-risk group (39.4%), followed by the I-risk group (23.2%), and least in the L-risk group (19.9%) (P<0.001). The multivariate Cox hazard analysis revealed that the H-risk was significantly associated with MACE (HR 2.166, 95% CI 1.543-3.041, P<0.001) after controlling for multiple confounding factors. CONCLUSIONS: H-risk according to nARS was significantly associated with long-term adverse events after hospital discharge for patients with AMI. These results support the validity of nARS as a risk marker for long-term outcomes.

Association of collateral flow with clinical outcomes in patients with acute myocardial infarction.

Coronary collateral flow is an important prognostic marker in percutaneous coronary intervention (PCI) for chronic total occlusion. However, the role of collateral flow to the culprit lesion of acute myocardial infarction (AMI) has not been fully established yet. The purpose of this retrospective study was to examine the association between collateral flow and long-term clinical outcomes in patients with AMI. We included 937 patients with AMI, and divided those into the no-collateral group (n = 704) and the collateral group (n = 233) according to the presence or absence of collateral flow to the culprit lesion of AMI. The primary endpoint was the incidence of major adverse cardiac events (MACE), which was defined as a composite of all-cause death, non-fatal MI, re-admission for heart failure, and ischemia driven target vessel revascularization. The median follow-up duration was 473 days (Q1: 184 days- Q3: 1027 days), and a total of 263 MACE was observed during the study period. The incidence of MACE was significantly greater in the no-collateral group than in the collateral group (29.8% vs. 22.3%, p = 0.027). In the multivariate COX hazard model, the presence of collateral flow was inversely associated with MACE (HR 0.636, 95% CI 0.461-0.878, p = 0.006) after controlling multiple confounding factors. In conclusion, the presence of collateral flow to the culprit lesion of AMI was inversely associated with long-term adverse outcomes. Careful observation of collateral flow may be important in emergent coronary angiography to stratify a high-risk group among various patients with AMI.

Comparison of the Incidence of Periprocedural Myocardial Infarction in Bifurcation Lesions Between Medina (1,1,1) and (0,1,1) in Elective Percutaneous Coronary Intervention.

Periprocedural myocardial infarction (PMI) following percutaneous coronary intervention (PCI) is more frequently observed in true bifurcation lesions such as Medina (1,1,1) and (0,1,1). The aim of this study is to compare the incidence of PMI in elective PCI between Medina (1,1,1) and (0,1,1) bifurcation lesions. This was a retrospective, single-center study. We included 162 true bifurcation lesions, which were divided into the (1,1,1) group (n = 85) and the (0,1,1) group (n = 77). We compared the incidence of PMI between the two groups and performed multivariate logistic regression analysis using PMI as a dependent variable. The incidence of PMI was similar in the (1,1,1) group and the (0,1,1) group (12.9% versus 15.6%, P = 0.658). The final TIMI flow grade of the side branches and that of the main branches were also similar in the two groups. In multivariate logistic regression analysis, Medina classification (1,1,1) was not associated with PMI (odds ratio (OR), 0.996; 95% confidence interval (CI), 0.379-2.621; P = 0.994), but the angle of the side branch < 45° (OR, 3.569; 95% CI, 1.320-9.654; P = 0.012), lesion length in a main vessel (per 10-mm increase) (OR, 1.508; 95% CI, 1.104-2.060; P = 0.010), and absence of side branch protection (OR, 3.034; 95% CI, 1.095-8.409; P = 0.033) were significantly associated with PMI. In conclusion, the Medina (1,1,1) bifurcation lesions did not increase the incidence of PMI as compared to Medina (0,1,1). However, the narrow side branch angle, diffuse long lesion, and absence of side branch protection were significantly associated with PMI. We should pay attention to these high-risk features in the treatment of true bifurcation lesions.

Association of Increased Pulse Wave Velocity With Long-Term Clinical Outcomes in Patients With Preserved Ankle-Brachial Index After Acute Myocardial Infarction.

BACKGROUND: Low ankle-brachial index (ABI) is an established risk factor for long-term cardiovascular outcomes in patients with acute myocardial infarction (AMI), and brachial-ankle pulse wave velocity (ba-PWV) may also be a risk factor. However, there is a significant overlap between low ABI and high ba-PWV. The purpose of this retrospective study was to examine whether increased ba-PWV was associated with long-term clinical outcomes in AMI patients with normal ABI. METHODS: We included 932 AMI patients with normal ABI and divided them into the high PWV group (≥1,400 cm/s; n=646) and the low PWV group (<1400 cm/s; n=286) according to the ba-PWV values measured during the AMI hospitalisation. The primary endpoint was the major adverse cardiovascular events (MACE) defined as the composite of all-cause death, nonfatal myocardial infarction, and hospitalisation for heart failure. RESULTS: During the median follow-up duration of 541 days (Q1: 215 days-Q3: 1,022 days), a total of 154 MACE were observed. The Kaplan-Meier curves showed that MACE was more frequently observed in the high PWV group than in the low PWV group (p<0.001). The multivariate Cox hazard analysis revealed that high ba-PWV was significantly associated with MACE (hazard ratio [HR] 1.587; 95% CI 1.002-2.513; p=0.049) after controlling multiple confounding factors. CONCLUSIONS: High ba-PWV was significantly associated with long-term adverse events in AMI patients with normal ABI. Our results suggest the usefulness of PWV as a prognostic marker in AMI with normal ABI.

Clinical impact of calcified nodule in patients with heavily calcified lesions requiring rotational atherectomy.

OBJECTIVES: We sought to evaluate the incidence and clinical impact of calcified nodule (CN) in patients with heavily calcified lesions requiring rotational atherectomy (RA). BACKGROUND: It remains unclear whether CN impacts adversely on clinical outcomes in patients with heavily calcified lesions. METHODS: Between January 2011 and February 2014, 264 patients after second-generation drug-eluting stent (DES) implantation following RA were retrospectively enrolled. CN was defined as a convex shape of the luminal side of calcium as assessed by intravascular ultrasound. The primary endpoint was the cumulative 5-year incidence of major adverse cardiac events (MACE), defined as a composite of cardiac death, clinically driven target lesion revascularization (CDTLR), and definite stent thrombosis (ST). RESULTS: CN was observed in 128 patients (48.5%) with heavily calcified lesions. Cumulative 5-year incidence of MACE was significantly higher in the CN group than in the non-CN group, mainly driven by a higher rate of CDTLR and ST (35.4% vs. 18.8%, p < .001; 23.2% vs. 7.9%, p < .001; 7.0% vs. 0.93%, p = .009, respectively). Independent risk factors of 5-year MACE included hemodialysis (hazard ratio [HR] = 3.39, 95% confidence intervals [CI]: 2.00-5.73, p < .001), CN (HR = 2.53, 95% CI: 1.49-4.27, p < .001), ostial lesion (HR = 3.02, 95% CI: 1.58-5.78, p = .001), left ventricular ejection fraction ≤40% (HR = 2.17, 95% CI: 1.27-3.70, p = .005), and right coronary artery lesion (HR = 1.82, 95% CI: 1.07-3.11, p = .03). CONCLUSIONS: CN was observed in 48.5% of heavily calcified lesions, resulting in unfavorable long-term clinical outcomes after second-generation DES implantation following RA.

Vascular Response of a Polymer-Free Paclitaxel-Coated Stent (Zilver PTX) versus a Polymer-Coated Paclitaxel-Eluting Stent (Eluvia) in Healthy Swine Femoropopliteal Arteries.

PURPOSE: To compare the long-term vascular healing responses of healthy swine iliofemoral arteries treated with a polymer-free paclitaxel-eluting stent (Z-PES, Zilver PTX) or a fluoropolymer-based paclitaxel-eluting stent (FP-PES, Eluvia). MATERIALS AND METHODS: Bilateral iliofemoral arteries in 20 swine were treated with a Z-PES (n = 16) or a FP-PES (n = 24) and were examined histologically at 1, 3, 6, and 12 months. RESULTS: Morphometric analysis revealed larger external and internal elastic lamina, stent expansion, and lumen area in the FP-PES than in the Z-PES at all timepoints. Luminal narrowing was similar in the 2 groups at 1 month; however, greater stenosis was observed in the Z-PES group at 3 months, with significant regression thereafter, resulting in equivalent stenosis at 6 and 12 months. Greater drug effect and less complete vessel healing were found in the FP-PES group at all timepoints, including greater numbers of malapposed struts with excessive fibrin deposition at 1 and 3 months, than in the Z-PES group. Three of 12 FP-PESs from the 6- and 12-month cohorts also showed circumferential medial disruption with peri-strut inflammation, whereas no abnormal findings were observed in contralateral Z-PESs. CONCLUSIONS: Prolonged paclitaxel release with the presence of a permanent polymer may contribute to the differential vascular responses seen for the Z-PES and FP-PES groups, including medial layer disruption and aneurysmal vessel degeneration that was sometimes observed in the FP-PES group. These distinct features should be confirmed by pathology and in vivo imaging of human superficial femoral arteries to determine their clinical significance.

Co-Registration of Peripheral Atherosclerotic Plaques Assessed by Conventional CT Angiography, MicroCT and Histology in Patients with Chronic Limb Threatening Ischaemia.

OBJECTIVE: To co-register conventional computed tomography angiography (CTA), with ex vivo micro-computed tomography (microCT) and histology of popliteal atherosclerotic plaques. Improving the non-invasive imaging capabilities may be valuable to advance patient care with peripheral arterial obstructive disease towards lesion and individual based treatment. METHODS: In this prospective observational study, 12 popliteal arteries from 11 symptomatic patients who had undergone transfemoral amputations for chronic limb threatening ischaemia and who had pre-operative CTA, were analysed ex vivo by microCT and histology. A total of 353 histological cross sections were co-registered with microCT and CTA, and classified as: lipid rich (LP, n = 26), fibrous (FP, n = 80), or calcific (CP, n = 247) plaques. CTA and microCT plaque density was calculated in 791 regions of interest as Hounsfield units (HU). RESULTS: CTA and microCT could identify plaque components that were confirmed by histology such as fibrous tissue (FP), lipid pool/core (LP), and calcification (CP). MicroCT densities were 77.8 HU for FP (IQR 52.8, 129.5 HU), -28.4 HU for LP (IQR -87.1, 13.2 HU), and 3826.0 HU for CP (IQR 2989.0, 4501.0 HU). CTA densities of the three components of the plaque were: 78.0 HU for FP (IQR 59.5, 119.8 HU), 32.5 HU for LP (IQR 15.0, 42 HU), and 641.5 HU for CP (IQR 425.8, 1135 HU). The differences were statistically significant between the HU densitometric characteristics among the three groups (p < .0001) for both imaging modalities. Overall, microCT performed better diagnostically than conventional CTA for the three types of plaques: areas under the receiving operator characteristics curve were greater for microCT than CTA for FP (0.97 vs. 0.90), for LP (0.88 vs. 0.67), and for CP (0.97 vs. 0.90). CONCLUSION: CTA and microCT can be used to identify histological atherosclerotic plaque components, with better diagnostic performance for microCT. This study demonstrates the feasibility of using microCT to assess plaque morphology lesions in a manner that approaches histology thus becoming a useful tool for ex vivo assessment of atherosclerosis and towards lesion based treatment.

Diversity of macrophage phenotypes and responses in atherosclerosis.

The presence of macrophages within the plaque is a defining hallmark of atherosclerosis. Macrophages are exposed to various microenvironments such as oxidized lipids and cytokines which effect their phenotypic differentiation and activation. Classically, macrophages have been divided into two groups: M1 and M2 macrophages induced by T-helper 1 and T-helper 2 cytokines, respectively. However, for a decade, greater phenotypic heterogeneity and plasticity of these cells have since been reported in various models. In addition to M1 and M2 macrophage phenotypes, the concept of additional macrophage phenotypes such as M (Hb), Mox, and M4 has emerged. Understanding the mechanisms and functions of distinct phenotype of macrophages can lead to determination of their potential role in atherosclerotic plaque pathogenesis. However, there are still many unresolved controversies regarding their phenotype and function with respect to atherosclerosis. Here, we summarize and focus on the differential subtypes of macrophages in atherosclerotic plaques and their differing functional roles based upon microenvironments such as lipid, intraplaque hemorrhage, and plaque regression.

Vascular responses to coronary calcification following implantation of newer-generation drug-eluting stents in humans: impact on healing.

AIMS: Vascular calcification is routinely encountered in percutaneous coronary intervention (PCI) and severe coronary calcification is a known predictor of in-stent restenosis and stent thrombosis. However, the histopathologic mechanisms behind such events have not been systematically described. METHODS AND RESULTS: From our registry of 1211 stents, a total of 134 newer-generation drug-eluting stents (DES) (Xience, Resolute-Integrity, PROMUS-Element, and Synergy) with duration of implant ≥30 days were histologically analysed. The extent of calcification of the stented lesions was evaluated radiographically and divided into severe (SC, n = 46) and non-severely calcified lesions (NC, n = 88). The percent-uncovered struts per section {SC vs. NC; median 2.4 [interquartile range (IQR) 0.0-19.0] % vs. 0.0 (IQR 0.0-4.6) %, P = 0.02} and the presence of severe medial tears (MTs) (59% vs. 44%, respectively, P = 0.03) were greater in SC than NC. In addition, SC had a higher prevalence of ≥3 consecutive struts lying directly in contact with surface calcified area (3SC) (52% vs. 8%, respectively, P < 0.0001). Multivariate analysis demonstrated that sections with duration of implantation ≤6 months [odds ratio (OR): 7.7, P < 0.0001], 3SC (OR: 6.5, P < 0.0001), strut malapposition (OR: 5.0, P < 0.0001), and lack of MTs (OR: 2.5, P = 0.0005) were independent predictors of uncovered struts. Prevalence of neoatherosclerosis was significantly lower in SC than that of NC (24% vs. 44%, P = 0.02). CONCLUSION: Severe calcification, especially surface calcified area is an independent predictor of uncovered struts and delayed healing after newer-generation DES implantation. These data expand of knowledge of the vascular responses of stenting of calcified arteries and suggests further understand of how best to deal with calcification in patients undergoing PCI.

Factors Associated with In-Hospital Death in Patients with Killip Class 3 Acute Myocardial Infarction.

The clinical outcomes in acute myocardial infarction (AMI) patients with Killip class 3 are often inconsistent with those in the literature, and the factors associated with poor outcomes have not been sufficiently investigated. The purpose of this study was to identify factors associated with in-hospital death in AMI patients with Killip class 3. We included 205 AMI patients with Killip class 3, and divided them into a survived group (n = 189) and in-hospital death group (n = 16). The primary objective was to identify factors associated with in-hospital death using multivariate analysis. Age was significantly younger in the survived group than in the in-hospital death group (73.1 ± 11.2 versus 83.2 ± 6.2 years, P < 0.001). Systolic blood pressure (SBP) was significantly higher in the survived group than in the in-hospital death group (150.0 ± 31.2 versus 124.8 ± 25.3 mmHg, P = 0.002). The prevalence of TIMI thrombus grade ≥ 2 was significantly greater in the in-hospital death group than in the survived group (56.3 versus 22.2%, P = 0.005). In multivariate logistic regression analysis, in-hospital death was significantly associated with age [odds ratio (OR) 1.168, 95% confidence interval (CI) 1.061-1.287, P = 0.002] and TIMI thrombus grade ≥ 2 (versus ≤ 1: OR 5.743, 95% CI 1.717-19.214, P = 0.005), and inversely associated with SBP on admission (per 10 mmHg increase: OR 0.764, 95% CI 0.613-0.953, P = 0.017). In conclusion, in-hospital death was associated with age and coronary thrombus burden, and was inversely associated with SBP on admission in patients with Killip class 3. It may be important to recognize these high risk features to improve the clinical outcomes of patients with Killip class 3.