Layered plaque is associated with high levels of vascular inflammation and vulnerability in patients with stable angina pectoris.

Layered plaque, a signature of previous plaque destabilization and healing, is a known predictor for rapid plaque progression; however, the mechanism of which is unknown. The aim of the current study was to compare the level of vascular inflammation and plaque vulnerability in layered plaques to investigate possible mechanisms of rapid plaque progression. This is a retrospective, observational, single-center cohort study. Patients who underwent both coronary computed tomography angiography (CTA) and optical coherence tomography (OCT) for stable angina pectoris (SAP) were selected. Plaques were defined as any tissue (noncalcified, calcified, or mixed) within or adjacent to the lumen. Perivascular inflammation was measured by pericoronary adipose tissue (PCAT) attenuation at the plaque levels on CTA. Features of plaque vulnerability were assessed by OCT. Layered plaques were defined as plaques presenting one or more layers of different optical densities and a clear demarcation from underlying components on OCT. A total of 475 plaques from 195 patients who presented with SAP were included. Layered plaques (n = 241), compared with non-layered plaques (n = 234), had a higher level of vascular inflammation (-71.47 ± 10.74 HU vs. -73.69 ± 10.91 HU, P = 0.026) as well as a higher prevalence of the OCT features of plaque vulnerability, including lipid-rich plaque (83.8% vs. 66.7%, P < 0.001), thin-cap fibroatheroma (26.1% vs. 17.5%, P = 0.026), microvessels (61.8% vs. 34.6%, P < 0.001), and cholesterol crystals (38.6% vs. 25.6%, P = 0.003). Layered plaque was associated with a higher level of vascular inflammation and a higher prevalence of plaque vulnerability, which might play an important role in rapid plaque progression.Clinical trial registration: https://classic.clinicaltrials.gov/ct2/show/NCT04523194 .

Clinical Significance of Coronary Healed Plaques in Stable Angina Pectoris Patients Undergoing Percutaneous Coronary Intervention.

BACKGROUND: Coronary healed plaques (HPs) reportedly have high vulnerability or show advanced atherosclerosis and a risk of rapid plaque progression. However, the prognosis of stable angina pectoris (SAP) patients with HPs undergoing percutaneous coronary intervention (PCI) remains under-investigated.Methods and Results: We analyzed 417 consecutive lesions from SAP patients undergoing pre- and post-intervention optical coherence tomography (OCT) for which HPs were defined as having a layered appearance. We investigated the differences in clinical and lesion characteristics, and post-PCI outcomes between HPs and non-HPs. To account for differences in clinical characteristics, propensity score matching was performed between the groups. HPs were observed in 216 lesions (51.8%) in the total cohort. In the propensity-matched cohort (n=294), HPs had higher rates of angiographic-B2/C lesions (77.6% vs. 59.2%, P<0.001), OCT-lipid-rich plaques (40.8% vs. 25.9%, P=0.007), macrophages (78.2% vs. 44.2%, P<0.001), greater luminal area stenosis (73.5±11.0% vs. 71.5±10.3%, P=0.002), and a higher prevalence of post-stenting irregular tissue protrusion (45.1% vs. 14.7%, P<0.001) than non-HPs. In the total cohort, target lesion revascularization (TLR)-free survival was poorer for HPs (log-rank test 7.66; P=0.006), and Cox proportional hazards analysis showed HP as an independent predictor of TLR (hazard ratio, 5.98; 95% confidence interval, 1.72-20.82; P=0.005). CONCLUSIONS: In SAP patients, HPs had greater complexity of lesions and higher vulnerability, which may have contributed to the poorer post-PCI outcomes.

Predictors and morphological properties of culprit healed plaques in patients with angina pectoris.

BACKGROUND: Plaque healing may serve a vital function in the natural progression of atherosclerotic disease. This study sought to investigate predictors and morphological characteristics of healed plaque (HP) among angina pectoris (AP) patients. METHODS: Patients who presented with AP and received preintervention optical coherence tomography (OCT) imaging were consecutively selected for this single-center retrospective observational study. Patient's demographic and clinical information was collected from the hospital's electronic medical records. Coronary angiograms and OCT images were compared via offline software. RESULTS: A total of 390 patients were chosen as the final study population. HP was identified in 186 patients (47.7%) and was relatively less in cases of unstable angina pectoris (UAP) than in stable angina pectoris (SAP) (89/233 [38.2%] vs. 97/157[61.8%]). The HP group had greater prevalence rates of previous myocardial infarction and SAP and higher levels of triglycerides and uremia (median, 1.67 vs. 1.31 mmol/L [p = .01] and 364.22 ± 91.80 vs. 341.53 ± 77.64 µmol/L [p = .01], respectively). Using multivariate analysis, SAP and long lesion length were shown to be stand-alone indicators of HP. HP presented with more severe stenosis as well as a longer lesion length and had more vulnerable and more complex features. In HP lesions, UAP patients had more plaque ruptures and thrombosis, whereas SAP patients had lower uric acid levels and more multiple HPs(≥3 HPs). CONCLUSION: Clinical presentation of SAP and long lesion length were strong predictors for HP in patients with AP. Patients with HP presented with more severe stenosis, longer lesion lengths, greater inflammation, and vulnerability.

Involvement of enhanced expression of classical complement C1q in atherosclerosis progression and plaque instability: C1q as an indicator of clinical outcome.

Activation of the classical complement pathway plays a major role in regulating atherosclerosis progression, and it is believed to have both proatherogenic and atheroprotective effects. This study focused on C1q, the first protein in the classical pathway, and examined its potentialities of plaque progression and instability and its relationship with clinical outcomes. To assess the localization and quantity of C1q expression in various stages of atherosclerosis, immunohistochemistry, western blotting, and real-time polymerase chain reaction (PCR) were performed using abdominal aortas from eight autopsy cases. C1q immunoreactivity in relation to plaque instability and clinical outcomes was also examined using directional coronary atherectomy (DCA) samples from 19 patients with acute coronary syndromes (ACS) and 18 patients with stable angina pectoris (SAP) and coronary aspirated specimens from 38 patients with acute myocardial infarction. C1q immunoreactivity was localized in the extracellular matrix, necrotic cores, macrophages and smooth muscle cells in atherosclerotic lesions. Western blotting and real-time PCR illustrated that C1q protein and mRNA expression was significantly higher in advanced lesions than in early lesions. Immunohistochemical analysis using DCA specimens revealed that C1q expression was significantly higher in ACS plaques than in SAP plaques. Finally, immunohistochemical analysis using thrombus aspiration specimens demonstrated that histopathological C1q in aspirated coronary materials could be an indicator of poor medical condition. Our results indicated that C1q is significantly involved in atherosclerosis progression and plaque instability, and it could be considered as one of the indicators of cardiovascular outcomes.

Detection of an anti-angina therapeutic module in the effective population treated by a multi-target drug Danhong injection: a randomized trial.

It's a challenge for detecting the therapeutic targets of a polypharmacological drug from variations in the responsed networks in the differentiated populations with complex diseases, as stable coronary heart disease. Here, in an adaptive, 31-center, randomized, double-blind trial involving 920 patients with moderate symptomatic stable angina treated by 14-day Danhong injection(DHI), a kind of polypharmacological drug with high quality control, or placebo (0.9% saline), with 76-day following-up, we firstly confirmed that DHI could increase the proportion of patients with clinically significant changes on angina-frequency assessed by Seattle Angina Questionnaire (ΔSAQ-AF ≥ 20) (12.78% at Day 30, 95% confidence interval [CI] 5.86-19.71%, P = 0.0003, 13.82% at Day 60, 95% CI 6.82-20.82%, P = 0.0001 and 8.95% at Day 90, 95% CI 2.06-15.85%, P = 0.01). We also found that there were no significant differences in new-onset major vascular events (P = 0.8502) and serious adverse events (P = 0.9105) between DHI and placebo. After performing the RNA sequencing in 62 selected patients, we developed a systemic modular approach to identify differentially expressed modules (DEMs) of DHI with the Zsummary value less than 0 compared with the control group, calculated by weighted gene co-expression network analysis (WGCNA), and sketched out the basic framework on a modular map with 25 functional modules targeted by DHI. Furthermore, the effective therapeutic module (ETM), defined as the highest correlation value with the phenotype alteration (ΔSAQ-AF, the change in SAQ-AF at Day 30 from baseline) calculated by WGCNA, was identified in the population with the best effect (ΔSAQ-AF ≥ 40), which is related to anticoagulation and regulation of cholesterol metabolism. We assessed the modular flexibility of this ETM using the global topological D value based on Euclidean distance, which is correlated with phenotype alteration (r2: 0.8204, P = 0.019) by linear regression. Our study identified the anti-angina therapeutic module in the effective population treated by the multi-target drug. Modular methods facilitate the discovery of network pharmacological mechanisms and the advancement of precision medicine. (ClinicalTrials.gov identifier: NCT01681316).

Machine Learning Identifies Metabolic Signatures that Predict the Risk of Recurrent Angina in Remitted Patients after Percutaneous Coronary Intervention: A Multicenter Prospective Cohort Study.

Recurrent angina (RA) after percutaneous coronary intervention (PCI) has few known risk factors, hampering the identification of high-risk populations. In this multicenter study, plasma samples are collected from patients with stable angina after PCI, and these patients are followed-up for 9 months for angina recurrence. Broad-spectrum metabolomic profiling with LC-MS/MS followed by multiple machine learning algorithms is conducted to identify the metabolic signatures associated with future risk of angina recurrence in two large cohorts (n = 750 for discovery set, and n = 775 for additional independent discovery cohort). The metabolic predictors are further validated in a third cohort from another center (n = 130) using a clinically-sound quantitative approach. Compared to angina-free patients, the remitted patients with future RA demonstrates a unique chemical endophenotype dominated by abnormalities in chemical communication across lipid membranes and mitochondrial function. A novel multi-metabolite predictive model constructed from these latent signatures can stratify remitted patients at high-risk for angina recurrence with over 89% accuracy, sensitivity, and specificity across three independent cohorts. Our findings revealed reproducible plasma metabolic signatures to predict patients with a latent future risk of RA during post-PCI remission, allowing them to be treated in advance before an event.

Correlation of Serum Adipolin with Epicardial Fat Thickness and Severity of Coronary Artery Diseases in Acute Myocardial Infarction and Stable Angina Pectoris Patients.

OBJECTIVE: Adipolin/C1q/TNF-related protein-12 is a family of CTRPs highly expressed in adipose tissue with glucose-lowering and anti-inflammatory effects. Various risk factors have been suggested in the incidence of cardiovascular diseases, such as a decrease in anti-inflammatory or an increase in inflammatory factors. The purpose of the present study was to investigate the correlation of adipolin with anthropometric, angiographic, echocardiographic, and biochemical parameters. SUBJECT AND METHODS: A total of 90 patients who were candidates for angiography were included in the study and divided into 3 groups: 30 patients with acute myocardial infarction (AMI), 30 patients with stable angina pectoris (SAP), and 30 subjects as a control group with a history of chest pain but normal angiography. Anthropometric, angiographic, echocardiographic, and biochemical parameters were measured in all subjects. RESULTS: Serum adipolin levels were significantly decreased in patients with AMI compared with the SAP and control groups (p < 0.001 for both). In addition, there was a negative association between serum levels of adipolin and epicardial fat thickness (EFT) and Gensini score in CAD patients. The results of multivariate linear regression analysis revealed that EFT values were independently associated with serum adipolin levels. CONCLUSION: The current study showed an independent association of adipolin with EFT for the first time in patients with AMI. Decreased adipolin levels in patients with AMI may be involved in the process of atherosclerosis, which requires further study.

Increased Serum Malondialdehyde-Modified Low-Density Lipoprotein and Coronary Angiographic Progression After Drug-Eluting Stent Implantation in Patients With Stable Angina.

BACKGROUND: Cardiac events can occur after drug-eluting stent (DES) implantation due to coronary plaque progression at non-stented sites. Malondialdehyde-modified low-density lipoprotein (MDA-LDL) is suggested to be an atherogenic marker. This study investigated the relationship between serum MDA-LDL and angiographic progression after DES implantation.Methods and Results:In total, 207 patients who underwent percutaneous coronary intervention (PCI) using DES and follow-up coronary angiography were retrospectively analyzed. MDA-LDL was serially measured before PCI and at follow up. Persistent high MDA-LDL was defined as a MDA-LDL level more than the median value both before PCI and at follow up. Angiographic progression was assessed by serial analysis of quantitative coronary angiography. Angiographic progression occurred in 35 patients (16.9%). MDA-LDL before PCI was significantly higher in the progression group than the non-progression group in all patients (143.4±35.8 U/L vs. 103.0±33.5U/L, P<0.001) and in patients with controlled LDL-cholesterol (LDL-C <100 mg/dL both before PCI and at follow up; 121.8±32.7 U/L vs. 84.9±24.9 U/L, P<0.001). There were positive correlations between % diameter stenosis changes and serum MDA-LDL before PCI in all patients (r=0.33, P<0.01) and those with controlled LDL-C (r=0.23, P=0.04). In multivariate logistic regression analysis, persistent high MDA-LDL was an independent predictor of plaque progression. CONCLUSIONS: Increased serum MDA-LDL was associated with angiographic progression after DES implantation.

An extracellular vesicle epitope profile is associated with acute myocardial infarction.

The current standard biomarker for myocardial infarction (MI) is high-sensitive troponin. Although powerful in clinical setting, search for new markers is warranted as early diagnosis of MI is associated with improved outcomes. Extracellular vesicles (EVs) attracted considerable interest as new blood biomarkers. A training cohort used for diagnostic modelling included 30 patients with STEMI, 38 with stable angina (SA) and 30 matched-controls. Extracellular vesicle concentration was assessed by nanoparticle tracking analysis. Extracellular vesicle surface-epitopes were measured by flow cytometry. Diagnostic models were developed using machine learning algorithms and validated on an independent cohort of 80 patients. Serum EV concentration from STEMI patients was increased as compared to controls and SA. EV levels of CD62P, CD42a, CD41b, CD31 and CD40 increased in STEMI, and to a lesser extent in SA patients. An aggregate marker including EV concentration and CD62P/CD42a levels achieved non-inferiority to troponin, discriminating STEMI from controls (AUC = 0.969). A random forest model based on EV biomarkers discriminated the two groups with 100% accuracy. EV markers and RF model confirmed high diagnostic performance at validation. In conclusion, patients with acute MI or SA exhibit characteristic EV biomarker profiles. EV biomarkers hold great potential as early markers for the management of patients with MI.

Healed Plaques in Patients With Stable Angina Pectoris.

OBJECTIVE: Healed plaques, signs of previous plaque destabilization, are frequently found in the coronary arteries. Healed plaques can now be diagnosed in living patients. We investigated the prevalence, angiographic, and optical coherence tomography features of healed plaques in patients with stable angina pectoris. Approach and Results: Patients with stable angina pectoris who had undergone optical coherence tomography imaging were included. Healed plaques were defined as plaques with one or more signal-rich layers of different optical density. Patients were divided into 2 groups based on layered or nonlayered phenotype at the culprit lesion. Among 163 patients, 87 (53.4%) had layered culprit plaque. Patients with layered culprit plaque had more multivessel disease (62.1% versus 44.7%, P=0.027) and more angiographically complex culprit lesions (64.4% versus 35.5%, P<0.001). Layered culprit plaques had higher prevalence of lipid plaque (83.9% versus 64.5%, P=0.004), macrophage infiltration (58.6% versus 35.5%, P=0.003), calcifications (78.2% versus 63.2%, P=0.035), and thrombus (28.7% versus 14.5%, P=0.029). Lipid index (P=0.001) and percent area stenosis (P=0.015) were greater in the layered group. The number of nonculprit plaques, evaluated using coronary angiograms, tended to be greater in patients with layered culprit plaque (4.2±2.5 versus 3.5±2.1, P=0.053). Nonculprit plaques in patients with layered culprit lesion had higher prevalence of layered pattern (P=0.002) and lipid phenotype (P=0.005). Lipid index (P=0.013) and percent area stenosis (P=0.002) were also greater in this group. CONCLUSIONS: In patients with stable angina pectoris, healed culprit plaques are common and have more features of vulnerability and advanced atherosclerosis both at culprit and nonculprit lesions.

Extracellular ubiquitin levels are increased in coronary heart disease and associated with the severity of the disease.

Aim: This study aimed to evaluate concentration of plasma extracellular ubiquitin (UB) in coronary heart disease (CHD) patients and its correlation with the disease severity.Methods: Levels of UB and stromal cell-derived factor-1a (SDF-1a) were measured in 60 healthy controls and 67 CHD cases. Coronary atherosclerosis was assessed with Gensini scoring system. Spearman correlation was used to evaluate the correlation between UB and low-density lipoprotein cholesterol (LDL-C), C-reactive protein (CRP), creatine kinase-MB (CK-MB), cardiac troponin I (cTnI) or SDF-1a. The receiver-operating characteristic (ROC) curve was established to assess the predictive value of UB.Results: Plasma UB levels were significantly higher in CHD patients than in controls (p < .0001), and the levels in those with acute myocardial infarction (AMI) were higher than stable angina pectoris (SAP) and unstable angina pectoris (UAP) groups (both p < .01). UB was also positively correlated with Gensini score, CRP, CK-MB and cTnI in CHD. ROC analysis of UB showed that the area under the curve (AUC) were 0.711 (95%CI, 0.623-0.799) and 0.778 (95%CI, 0.666-0.890) for CHD and acute coronary syndrome (ACS), respectively. Plasma SDF-1a levels were elevated in CHD patients but showed no significant correlation with UB concentration or the severity of the disease.Conclusion: Plasma UB concentration was increased in CHD and the change of UB levels may reflect the progression of CHD.

Prevalence and Clinical Significance of Layered Plaque in Patients With Stable Angina Pectoris　- Evaluation With Histopathology and Optical Coherence Tomography.

BACKGROUND: Healed plaques are identified as a layered pattern with optical coherence tomography (OCT) imaging, but the exact relationship between healed plaques and the development of significant coronary stenosis in stable angina pectoris (SAP) is not fully understood.Methods and Results:A retrospective clinincal study investigated the OCT characteristics of culprit lesions of SAP patients (n=205), and a prospective study examined the histopathological characteristics of layered plaque in directional coronary atherectomy (DCA) samples (42 samples from 18 SAP patients). In the retrospective study, layered plaque was observed in 36.6% of the SAP culprit lesions. Compared with patients with non-layered plaque, male sex and smoking were more frequent, and HbA1c level was significantly higher in the patients with layered plaque (81.3% vs. 65.9%, P<0.05; 62.7% vs. 41.8%, P<0.05; 6.6±1.3% vs. 6.2±1.0%, P<0.05, respectively). Furthermore, layered plaque was accompanied by higher plaque vulnerability and smaller minimal lumen area. In the histopathological study, the layered plaques had a significantly higher rate of intramural thrombus and macrophages infiltration than non-layered plaques (75.0% vs. 14.3%, P<0.05; 75.0% vs. 38.1%, P<0.05, respectively). CONCLUSIONS: Healed plaque containing intramural thrombus is identified as layered plaque by OCT, and was frequently observed, even in SAP patients. Intramural thrombus might play an important role in the development of coronary plaque with a high degree of stenosis in SAP patients.

Expression profiles and potential functions of long non-coding RNA in stable angina pectoris patients from Uyghur population of China.

Long non-coding RNAs (lncRNAs) are transcripts longer than 200 nt that are involved in cardiovascular diseases (CVDs). To determine whether lncRNAs are involved in stable angina pectoris (SAP), we analysed the expression profile of lncRNAs and mRNAs on a genome-wide scale in SAP of Uyghur population. Five pairs of SAP patients and healthy controls were screened by an Agilent microarray (human lncRNA + mRNA Array V4.0). Quantitative real-time polymerase chain reaction (qRT-PCR) was used to validate the lncRNA expression levels in 50 SAP and 50 controls. Data analyses were performed using R and Bioconductor. A total of 1871 up- and 231 down-regulated lncRNAs were identified to be differentially expressed in the peripheral blood mononuclear cells (PBMCs). Microarray analysis results identified the lncRNAs NR_037652.1, ENST00000607654.1, ENST00000589524.1 and uc004bhb.3, which were confirmed by qRT-PCR. Among screened lncRNAs, the annotation result of their co-expressed mRNAs showed that the most significantly related pathways were the NF-κB signalling pathway, apoptosis and the p53 signalling pathway, while the main significantly related diseases were the cholesterol, calcium and coronary disease. Our study indicated that clusters of lncRNAs were significantly differentially expressed between SAP patients and matched controls. These lncRNAs may play a significant role in SAP development and could serve as biomarkers and potential targets for the future treatment of SAP.

NLRP3 inflammasome expression in peripheral blood monocytes of coronary heart disease patients and its modulation by rosuvastatin.

Nucleotide­binding oligomerization domain, leucine rich repeat, and pyrin domain­containing protein 3 (NLRP3) inflammasome has been implicated in a series of physiological and pathological processes. However, its correlation in coronary heart disease (CHD) still remains to be elucidated. The present study aimed to determine the expression of NLRP3 inflammasome in peripheral blood monocytes (PBMCs) of stable angina pectoris (SAP) and acute myocardial infarction (AMI) patients. In addition, the effect of rosuvastatin on their activities was analyzed in vitro. A total of 60 participants with SAP (n=20), AMI (n=20) and non­CHD controls (n=20) were enrolled. Fluorescence­activated cell sorting, real­time PCR, western blotting and enzyme­linked immunosorbent assay were performed to reveal the role of NLRP3 inflammasome. NLRP3 inflammasome was expressed in the PBMCs, and revealed an increased expression along the downstream interleukin (IL)­1ß and IL­18 in both SAP and AMI groups, compared to the control group. Moreover, there was a more marked increase in the expression of these indicators in AMI patients when compared to SAP patients. Interference with rosuvastatin in vitro revealed that the expression of NLRP3 inflammasome and its downstream cytokines were significantly downregulated in both SAP and AMI groups in a time­dependent manner. The activation of NLRP3 inflammasome may be involved in the development of CHD, and rosuvastatin could attenuate the inflammatory process of atherosclerosis by downregulating NLRP3 expression and its downstream mediators. These findings indicated a potential role of NLRP3 in the pathogenesis and management of CHD, and also provided new insights into the mechanistic framework of rosuvastatin activity.

DNA Damage and Repair in Patients With Coronary Artery Disease: Correlation With Plaque Morphology Using Optical Coherence Tomography (DECODE Study).

OBJECTIVE: The aim of this study was to examine DNA ligase activity and expression of DNA damage response pathway (DDR) genes in patients with stable angina (SA) and non-ST elevation myocardial infarction (NSTEMI) and determine whether they correlate with plaque morphology. BACKGROUND: Patients with coronary artery disease (CAD) have evidence of deoxyribonucleic acid (DNA) damage in peripheral blood mononuclear cells (PBMCs). It is unclear whether this represents excess damage or defective DNA repair activity. METHODS: DNA ligase activity and the expression of 22 DDR genes were measured in PBMCs of patients (both SA (n = 47) and NSTEMI (n = 42)) and in age and gender-matched controls (n = 35). Target lesion anatomical assessment was undertaken with frequency domain optical coherent tomography. RESULTS: DNA ligase activity was different across the three groups of patients (control = 119 ±â€¯53, NSTEMI = 115.6 ±â€¯85.1, SA = 81 ±â€¯55.7 units/g of nuclear protein; ANOVA p = 0.023). Pair wise comparison demonstrated that this significance is due to differences between the control and SA patients (p = 0.046). Genes involved in double strand break repair and nucleotide excision repair pathways were differentially expressed in patients with SA and NSTEMI. In SA patients, fibrocalcific plaques were strongly associated with GTSE1, DDB1, MLH3 and ERCC1 expression. By contrast, in NSTEMI patients the strongest association was observed between fibrous plaques and ATM and XPA expression. CONCLUSION: PBMCs from patients with CAD exhibit differences in DNA ligase activity and expression of DDR genes. Expression levels of certain DDR genes are strongly associated with plaque morphology and may play a role in plaque development and progression. Trial Registration Number URL: www.Clinicaltrials.gov; NCT02335086.

Association of calciprotein particles measured by a new method with coronary artery plaque in patients with coronary artery disease: A cross-sectional study.

BACKGROUND: Calciprotein particles (CPPs) have been suggested to be associated with the degree of coronary atherosclerosis, and have also been established as a molecular marker for clinical outcome in patients with chronic kidney disease (CKD). However, there are several concerns with regard to conventional measurement of CPPs. We therefore developed a new CPP measurement system that can detect both smaller and lower-density CPPs. METHODS: We analyzed 71 consecutive patients who underwent percutaneous coronary intervention for acute coronary syndrome (ACS, n=29) and/or stable angina pectoris (AP, n=42) who did not have CKD of stage 4 or greater. CPP measurement was made using an infrared fluorescent bisphosphonate (OsteoSense, PerkinElmer, Waltham, MA, USA) and a gel filtration method. The coronary artery plaque was analyzed by gray-scale intravascular ultrasound (IVUS) and integrated backscatter (IB)-IVUS. RESULTS: The median CPP level (interquartile range) was 40,953 (19,171-74,131) arbitrary units (AU). When we divided the CPP level into quintiles, the total and lipid plaque volume were incrementally higher with increasing quintile from lowest to highest (both p<0.02). After adjustment by age, body mass index, and estimated glomerular filtration rate, which factors were correlated with the above-described plaque components, the top quintile of CPP (>86,751AU) had significantly higher total plaque (263mm3 vs. 161mm3; p=0.001) and lipid plaque volume (156mm3 vs. 89mm3; p<0.001) than the other quintiles. However, these associations were not found for the fibrous or calcified plaque volume. The CPP level was higher in the ACS group than the stable AP group (p=0.02), and the total and lipid plaque volume were also higher in the ACS group than the stable AP group (both p<0.05). CONCLUSIONS: The results suggested that a high CPP level, as measured by the novel assay, is a surrogate marker for coronary atherosclerosis, especially in lipid-rich plaques, contributing to an increased risk of plaque vulnerability.

Characteristics and significance of healed plaques in patients with acute coronary syndrome and stable angina: an in vivo OCT and IVUS study.

AIMS: The aim of this study was to determine the prevalence and significance of plaque with a multilayered (ML) pattern in patients with acute coronary syndrome (ACS) versus stable angina pectoris (SAP) using OCT. METHODS AND RESULTS: Two hundred and four patients (144 ACS and 60 SAP) with OCT imaging of the culprit lesions before intervention were studied. ML plaques were identified by OCT as plaque with multiple layers of distinct optical signals. ML plaque was identified in 119 out of 204 (58.3%) patients. ML plaques were more frequently observed in SAP than ACS (75% vs 51.4%, p=0.001). Patients with prior myocardial infarction (MI) had a higher incidence of ML plaque compared with those without (74.4% vs 54.5%, p=0.024). ML plaque had a higher degree of luminal stenosis (p=0.006), longer lesion length (p=0.025), more complex lesion type (B2/C) (p<0.001) on angiography and non-significant larger plaque burden (p=0.07) on IVUS compared with those without an ML pattern. CONCLUSIONS: ML plaques, indicative of prior thrombosis, were frequently identified in patients with CAD, particularly more so in SAP and those with prior MI compared with ACS. The presence of an ML pattern is a marker of a greater extent and severity of CAD, suggesting a pathogenic link between plaque healing and lesion progression.

Three-Dimensional Fibrous Cap Structure of Coronary Lipid Plaque　- ST-Elevation Myocardial Infarction vs. Stable Angina.

BACKGROUND: Fibrous cap thickness (FCT) is one of the key features of coronary vulnerable plaque. FCT is measured at an arbitrary point, determined on visual assessment of 2-D cross-sectional imaging. This method has poor reproducibility. The aim of this study was to compare the 3-D structure of FC in non-culprit lipid plaques between patients with ST-elevation myocardial infarction (STEMI) and with stable angina (SA) on optical coherence tomography. Methods and Results: A total of 54 non-culprit plaques from 23 STEMI and 23 SA patients were evaluated. Thin cap fibroatheroma (TCFA), defined as lipid plaque with FCT <80 µm, was identified using a novel algorithm. The number of TCFA, surface area of each TCFA, and the sum total area of TCFA in the target vessel were measured. Patients with STEMI had a greater median number of TCFA (9, IQR 1-17 vs. 2, IQR 0-5; P=0.002), the largest median single TCFA area (0.40, IQR 0.14-0.69 vs. 0.08, IQR 0.04-0.16 mm2; P<0.001) and median sum total area of TCFA (1.04, IQR 0.41-1.95 vs. 0.24, IQR 0.08-0.48 mm2, P<0.004). CONCLUSIONS: Patients with STEMI, as compared with those with SA, have greater vulnerability to non-culprit plaque.

Coronary Atherosclerotic Phenotype and Plaque Healing in Patients With Recurrent Acute Coronary Syndromes Compared With Patients With Long-term Clinical Stability: An In Vivo Optical Coherence Tomography Study.

Importance: At one end of the coronary artery disease (CAD) spectrum, there are patients with multiple recurrent acute coronary syndromes (rACS), and at the other end there are those with long-standing clinical stability. Predicting the natural history of these patients is challenging because unstable plaques often heal without resulting in ACS. Objective: To assess in vivo the coronary atherosclerotic phenotype as well as the prevalence and characteristics of healed coronary plaques by optical coherence tomography (OCT) imaging in patients at the extremes of the CAD spectrum. Design, Setting, and Participants: This is an observational, single-center cohort study with prospective clinical follow-up. From a total of 823 consecutive patients enrolled in OCT Registry of the Fondazione Policlinico A. Gemelli-IRCCS, Rome, Italy, from March 2009 to February 2016, 105 patients were included in the following groups: (1) patients with rACS, defined as history of at least 3 acute myocardial infarctions (AMIs) or at least 4 ACS with at least 1 AMI; (2) patients with long-standing stable angina pectoris (ls-SAP), defined as a minimum 3-year history of stable angina; and (3) patients with a single unheralded AMI followed by a minimum 3-year period of clinical stability (sAMI). Data were analyzed from January to August 2018. Exposures: Intracoronary OCT imaging of nonculprit coronary segments. Main Outcomes and Measures: Coronary plaque features and the prevalence of healed coronary plaques in nonculprit segments as assessed by intracoronary OCT imaging. Results: Of 105 patients, 85 were men (81.0%); the median (interquartile range) age was 68 (63-75) years. Median (interquartile range) time of clinical stability was 9 (5.0-15.0) years in the ls-SAP group and 8 (4.5-14.5) years in the sAMI group. Patients in the rACS and sAMI groups showed similar prevalence of lipid-rich plaque and thin-cap fibroatheroma, which was significantly higher than in those with ls-SAP (lipid-rich plaque 80.0% [n = 24 of 30] vs 76.3% [n = 29 of 38] vs 37.8% [n = 14 of 37], respectively; P < .001; thin-cap fibroatheroma 40.0% [n = 12 of 30] vs 34.2% [n = 13 of 38] vs 8.1% [n = 3 of 37], respectively; P = .006). Spotty calcifications were more frequently observed in patients with rACS than in those with ls-SAP and sAMI (70.0% [n = 21 of 30] vs 40.5% [n = 15 of 37] vs 44.7% [n = 17 of 38], respectively; P = .04). Healed coronary plaques were rarely observed in patients with rACS, whereas their prevalence was significantly higher in patients with ls-SAP and sAMI (3.3% [n = 1 of 30] vs 29.7% [n = 11 of 37] vs 28.9% [n = 11 of 38], respectively; P = .01). Conclusions and Relevance: Patients with rACS have a distinct atherosclerotic phenotype compared with those with ls-SAP, including higher prevalence of thin-cap fibroatheroma and lower prevalence of healed coronary plaques, suggesting that atherosclerotic profile and plaque healing may play a role in leading the natural history of patients with CAD.

Low Blood Content of IL-10-Producing CD4+ T Cells as a Risk Factor for Progression of Coronary Atherosclerosis.

In a 2-year prospective study, prognostic significance of the blood content of IL-10-producing CD4+ T lymphocytes for progression of coronary artery atherosclerosis was assessed. Patients with verified stable angina (n=36) admitted for scheduled coronary angiography and coronary stenting were enrolled. The blood levels of CD4+FoxpP3+ Treg, CD4+IFNγ+ Th1, CD4+IL17+ Th17, CD4+IL10+ cells, sCD25, IL-10, IL-17, C-reactive protein, and lipoprotein (a) were assayed before endovascular interventions. The blood content of CD4+IL10+ T cells below 3.3% was associated with progression of coronary artery atherosclerosis (OR 12.0 (2.3, 61.0), sensitivity 77%, specificity 78%, p=0.003). No differences in other immunological parameters and common atherosclerosis risk factors in the groups were revealed. We hypothesize that the content of CD4+IL10+ T cells can be an important predictive marker for the progression of coronary atherosclerosis.