Fibrous Cap Thickness Research Articles

Analysis of risk factors in high-risk plaque in acute coronary syndrome based on LASSO regression

Abstract Background The CLIMA Study (Relationship between OCT Coronary Plaque Morphology and Clinical Outcome) put forward the concept of High-risk plaque (HRP) and demonstrated that HRP were correlated with the high risk of major coronary events[1, 2]. HRP were defined as the presence of four simultaneous characteristics: minimum lumen area (MLA) <3.5mm2, fibrous cap thickness (FCT) <75 μm, lipid arc circumferential extension >180°, and the presence of macrophage infiltration. Early prediction of HRP formation are of great significance for the prevention and treatment of Acute Coronary Syndrome (ACS), but there are no relevant studies. Purpose To identify the risk factors related to OCT HRP in ACS and establish risk prediction model for HRPs in ACS. Methods A prospective observational cohort study was carried out on the patients with ACS from September 2019 to August 2022. A total of 169 patients were divided into OCT HRP (n=55) and OCT non-HRP (n=114) groups. Clinical information, laboratory examination and the OCT characteristics of the patients were collected. LASSO regression was used to screen variables, and multivariate logistic regression was used to establish risk prediction model. A nomogram was formulated, use the ROC curve to evaluate the discrimination of the model and the Bootstrap method to internally validate the model. Results The most frequently observed HRP characteristic was Lipid plague>180°(147 patients），followed by MLA<3.5mm2(141 patients), macrophages(127 patients), FCT<75μm(64 patients). The LASSO regression model was used to screen variables and construct an HRP risk factor model. This final model included age, BMI≥25, TC, LDL-C and Log NT-proBNP. The model is well differentiated (AUC 0.780, 95%CI 0.705-0.855) and calibrated. Decision Curve Analysis shows that the model has good net benefits. Conclusion This prediction model can accurately predict the risk of OCT HRP in patients with ACS, and is expected to assist clinicians in diagnosis and prevention of plaque stability.

Characterization of plaque hemorrhage with optical coherence tomography imaging in statin-treated patients with coronary artery disease: comparison with noncontrast T1-weighted MRI

Abstract Background Plaque hemorrhage is a phenotypic feature of coronary lesions associated with future coronary events. Noncontrast T1-weighted MRI has a potential to non-invasively identify plaque hemorrhage. Plaque to myocardium ratio (PMR) evaluated by noncontrast T1-weighted MRI has been shown to pathohistologically correspond to plaque hemorrhage. In several case reports comparing OCT images with coronary specimens, low intensity area without its attenuation was observed at lesions presenting plaque hemorrhage. However, whether the association of this OCT-derived feature with PMR remains to be elucidated yet. Purpose To characterize plaque hemorrhage in vivo by comparing with OCT and noncontrast T1-weighted MRI. Methods The current study prospectively enrolled 80 statin-treated patients with coronary artery disease requiring elective PCI. A total of 103 target lesions were imaged by both noncontrast T1-weighted MRI and OCT prior to PCI. Plaque hemorrhage on noncontrast T1-weighted MRI was defined as PMR>1.0. On OCT imaging analysis, low intensity area without attenuation (LIA) was defined according to the following criteria; (1) area presenting homogeneous low intensity signals, (2) clear border and (3) no signal attenuation behind its area. The maximum arc of LIA was manually measured. OCT-derived plaque features were compared in lesions with and without PMR>1.0. Results PMR>1.0 was observed at 49.5% of analyzed lesions. Patients with PMR>1.0 were more likely older (72 vs. 66 years, p=0.02), whereas there was no significant difference in on-treatment LDL-C levels (median: 80 vs. 77 mg/dL, p=0.62) (Table). On lesion-based analysis, while fibrous cap thickness was similar between the two groups (80 vs. 100um, p=0.10), a larger lipid arc (270 vs. 230º, p=0.02) and a greater frequency of macrophage (90.2 vs. 53.9%, p<0.01), layered plaque (62.8 vs. 32.7%, p=0.003) and cholesterol crystal (70.6 vs. 30.8%, p<0.001) were observed at lesions with PMR>1.0. Furthermore, lesions with PMR>1.0 more frequently exhibited LIA (66.7 vs. 19.2%, p<0.001) and its greater maximum arc (33 vs. 0º, p<0.001) (Figure). Of note, PMR was significantly correlated to the maximum arc of LIA (r=0.51, p<0.001) (Figure). Multivariate analysis demonstrated LIA and cholesterol crystal as independent OCT-derived features associated with PMR>1.0 (Table). Conclusion In statin-treated patients, 49.5% of analyzed lesions presented PMR>1.0. Coronary lesions with PMR>1.0 more frequently harbored LIA and cholesterol crystals, in addition to other vulnerable OCT features. Our findings suggest OCT-derived LIA as a potential signature of plaque hemorrhage. Given that cholesterol crystal was another feature of PMR>1.0, plaque inflammation driven by cholesterol crystallization may exist at plaque hemorrhage despite statin use. Whether anti-inflammation agent could modulate plaque hemorrhage requires future investigation.

PCSK9 inhibitors and coronary atherosclerotic plaque modification: a meta-analysis

Abstract Introduction Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have emerged as a promising class of medications, primarily recognized for their potent cholesterol-lowering effects. Beyond their established role in reducing low-density lipoprotein cholesterol levels, recent studies suggest a potential impact of PCSK9 inhibitors on the modification of coronary atherosclerotic plaques. Purpose The purpose of this meta-analysis is to comprehensively synthesize data from relevant clinical studies and trials that have investigated the effects of PCSK9 inhibitors on coronary atherosclerotic plaque characteristics. Methods We performed a literature search for studies assessing the evolution of coronary atherosclerotic plaques after treatment with a PCSK9 inhibitor compared to a control group. We excluded reviews, editorials, case reports/case series, and studies that did not use PCSK9 inhibitors or did not have a control group for comparison. The main outcomes of interest were the changes in percent atheroma volume (PAV), total atheroma volume (TAV), minimal fibrous cap thickness (FCT), lipid arch, as well as the number of patients with improved PAV at follow-up. Effect sizes are presented as standardized mean difference (SMD) or risk ratio (RR) with their corresponding 95% confidence intervals (CIs) and were pooled based on a random-effects model. Publication bias was assessed by funnel plot inspection and egger’s regression test. Results The literature search yielded 189 results. After application of the exclusion criteria, a total of 8 studies were selected for data extraction and inclusion in the meta-analysis. Concerning the intravascular ultrasound findings PCSK9 inhibitors induced greater reductions in PAV (SMD -2.70, 95% CI -5.24 to -0.15, p=0.04) (Figure 1) and TAV (SMD -2.46, 95% CI -4.68 to -0.23, p=0.03) (Figure 2), with a greater proportion of patients exhibiting an improvement in PAV (RR 1.30, 95% CI 1.20 to 1.41, p<0.01). Moving to optical coherence tomography parameters, patients treated with PCSK9 inhibitors had an increase in minimal FCT (SMD 2.09, 95% CI 0.12 to 4.07, p=0.04) and a lower lipid arch (SMD -0.64, 95% CI -0.97 to -0.32, p<0.01). Funnel plot inspection and egger’s regression test did not indicate the presence of publication bias. Conclusion This meta-analysis suggests that PCSK9 inhibitors use is associated with a favorable coronary atherosclerotic plaque remodeling.Figure 1Figure 2

Differences in non-flow limiting non-culprit plaque characteristics after myocardial infarction in patients with versus without chronic kidney disease

Abstract Background Patients with chronic kidney disease (CKD) are at increased risk for recurrent cardiovascular events after myocardial infarction compared to patients with preserved renal function. This disparity may be related to differences in plaque morphology. Purpose To compare non-flow limiting non-culprit (NC) plaque characteristics as assessed by optical coherence tomography in patients with versus without chronic kidney disease presenting with myocardial infarction. Methods 438 patients presenting with myocardial infarction with additional non-flow limiting (defined as a fractional flow reserve >0.80) NC lesions were included in the prospective observational PECTUS-obs study after treatment of the infarct related artery. An independent core laboratory performed all quantitative and qualitative OCT analyses. For the present subgroup analysis, patients were grouped according to the presence or absence of CKD, which was defined as an estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m². Baseline characteristics were compared between groups on a patient-level and OCT characteristics were compared on a lesion-level while accounting for within-patient clustering. Results Out of 420 patients with at least one analyzable OCT, baseline renal function was known in 416. Among them, there were 55 patients with and 361 patients without CKD (mean eGFR 47.4 ± 9.2 vs 84.7 ± 15.0 ml/min/1.73 m², p<0.001). Patients with CKD were older (mean age 73 ± 9 vs 62 ± 10 years, p<0.001), more frequently were female (29.1% vs 17.2%, p=0.035) and predominantly presented with a non-ST-segment elevation myocardial infarction (72.2% vs 44.9%, p<0.001). Comorbid disease was more prevalent among patients with CKD, including a higher prevalence of hypertension (p=0.010), hypercholesterolemia (p=0.020), diabetes (p<0.001), history of myocardial infarction (p<0.001), carotid artery disease (p=0.019) and peripheral artery disease (p=0.002). Coronary lesions in patients with CKD on average had a larger maximal calcium arc (188 ± 114 vs 137 ± 87º, p=0.003) and length (11.9 ± 10.3 vs 8.4 ± 7.4 mm, p=0.021). Lipid plaques were less prevalent among lesions in patients with CKD (63.6% vs 78.0%, p=0.016) and less frequently had a lipid arc ≥90º (60.6% vs 76.1%, p=0.018). Although the mean minimal fibrous cap thickness was lower in patients with CKD (p=0.025), no difference was observed in the prevalence of thin-cap fibroatheromas (p=0.984) or high-risk plaques according to the PECTUS-obs criteria (p=0.665). Conclusion Non-flow limiting NC lesions in patients with CKD differ from those in patients without CKD in a cohort of patients presenting with myocardial infarction. Overall, plaques in patients with CKD show more extensive calcification, whereas lesions in patients without CKD more often consist of lipid plaques, but the prevalence of high-risk plaques was comparable.

Prognostic value of diffuse high-risk plaque in patients with acute myocardial infarction: a three-vessel optical coherence tomography study

Abstract Background Existing evidence has identified that high-risk plaque (HRP) characterized by a thin-cap fibroatheroma and/or a minimal lumen area ≤ 3.5 mm² were indicative of future cardiovascular events. Diffuse coronary artery disease also contributes to the poor prognosis. Purpose The present study aims to assess the prognostic value of diffuse HRP in patients with acute myocardial infarction (AMI) by using three-vessel optical coherence tomography (OCT). Methods A total of 674 patients with AMI who underwent OCT examination of three major epicardial arteries between January 2017 and December 2018 were consecutively studied. Among 2843 nonculprit lesions detected by OCT, 1375 (48.4%) HRPs were identified and divided into diffuse HRP group (lesion length >20mm, n=443) and focal HRP group (lesion length ≤20mm, n=932). Patients were followed up for a median period of 5 years. Major adverse cardiovascular event (MACE) was defined as the composite of cardiac death, nonculprit lesion-related nonfatal myocardial infarction, and unplanned coronary revascularization. Results The average age of all enrolled patients is 56.7±11.4 years, with 74.9% of male. As compared with focal HRP group, diffuse HRP group had longer lesion length [25.8(23.0,30.8) mm vs. 13.2(9.8,16.1) mm, P<0.001], longer lipid length [18.6(12.3,24.9) mm vs. 7.0(4.5,10.5) mm, P<0.001], and thinner minimal fibrous cap thickness [73.3(53.3,106.7) μm vs. 93.3(60.0,130.0) μm, P<0.001], whereas mean lipid arc was comparable between the two groups. The prevalence of nonculprit plaque rupture (14.2% vs. 7.8%, P<0.001) was significantly higher in diffuse HRP group than that in the focal HRP group. Nonculprit lesions in diffuse HRP group had higher incidence of macrophage accumulation, microvessels, cholesterol crystals, calcification, and layered plaque phenotype than those in focal HRP group (all P<0.001). The incidence of nonculprit lesion-related MACE was 4.7% in diffuse HRP group and 1.7% in focal HRP group [HR: 3.155, 95% confidence interval: 1.579 to 6.301, P=0.002]. Conclusions In patients with AMI, diffuse HRP at nonculprit segment has higher levels of plaque vulnerability and is predictive of future adverse cardiovascular events. Further studies are warranted to investigate the individual treatment strategy of diffuse and focal HRP.Figure 1.Nonculprit plaque vulnerabilityFigure 2.MACE

Real-Time Imaging Assessment of Stress-Induced Vascular Inflammation Using Heartbeat-Synchronized Motion Compensation.

Chronic mental stress accelerates atherosclerosis through complicated neuroimmune pathways, needing for advanced imaging techniques to delineate underlying cellular mechanisms. While histopathology, ex vivo imaging, and snapshots of in vivo images offer promising evidence, they lack the ability to capture real-time visualization of blood cell dynamics within pulsatile arteries in longitudinal studies. An electrically tunable lens was implemented in intravital optical microscopy, synchronizing the focal plane with heartbeats to follow artery movements. ApoE-/- mice underwent 2 weeks of restraint stress before baseline imaging followed by 2 weeks of stress exposure in the longitudinal imaging, while nonstressed mice remained undisturbed. The progression of vascular inflammation was assessed in the carotid arteries through intravital imaging and histological analyses. A 4-fold reduction of motion artifact, assessed by interframe SD, and an effective temporal resolution of 25.2 Hz were achieved in beating murine carotid arteries. Longitudinal intravital imaging showed chronic stress led to a 6.09-fold (P=0.017) increase in myeloid cell infiltration compared with nonstressed mice. After 3 weeks, we observed that chronic stress intensified vascular inflammation, increasing adhered myeloid cells by 2.45-fold (P=0.031), while no significant changes were noted in nonstressed mice. Microcirculation imaging revealed increased circulating, rolling, and adhered cells in stressed mice's venules. Histological analysis of the carotid arteries confirmed the in vivo findings that stress augmented plaque area, myeloid cell and macrophage accumulation, and necrotic core volume while reducing fibrous cap thickness indicating accelerated plaque formation. We visualized the 3-dimensional structure of the carotid artery and 4-dimensional dynamics of the venules in the cremaster muscle. Dynamic focusing motion compensation intravital microscopy enabled subcellular resolution in vivo imaging of blood cell dynamics in beating arteries under chronic restraint stress in real time. This novel technique emphasizes the importance of advanced in vivo imaging for understanding cardiovascular disease.

Electrochemical impedance spectroscopy unmasks high-risk atherosclerotic features in human coronary artery disease.

Coronary plaque rupture remains the prominent mechanism of myocardial infarction. Accurate identification of rupture-prone plaque may improve clinical management. This study assessed the discriminatory performance of electrochemical impedance spectroscopy (EIS) in human cardiac explants to detect high-risk atherosclerotic features that portend rupture risk. In this single-center, prospective study, n = 26 cardiac explants were collected for EIS interrogation of the three major coronary arteries. Vessels in which advancement of the EIS catheter without iatrogenic plaque disruption was rendered impossible were not assessed. N = 61 vessels underwent EIS measurement and histological analyses. Plaques were dichotomized according to previously established high rupture-risk parameter thresholds. Diagnostic performance was determined via receiver operating characteristic areas-under-the-curve (AUC). Necrotic cores were identified in n = 19 vessels (median area 1.53 mm2) with a median fibrous cap thickness of 62 μm. Impedance was significantly greater in plaques with necrotic core area ≥1.75 mm2 versus <1.75 mm2 (19.8 ± 4.4 kΩ vs. 7.2 ± 1.0 kΩ, p = .019), fibrous cap thickness ≤65 μm versus >65 μm (19.1 ± 3.5 kΩ vs. 6.5 ± 0.9 kΩ, p = .004), and ≥20 macrophages per 0.3 mm-diameter high-power field (HPF) versus <20 macrophages per HPF (19.8 ± 4.1 kΩ vs. 10.2 ± 0.9 kΩ, p = .002). Impedance identified necrotic core area ≥1.75 mm2, fibrous cap thickness ≤65 μm, and ≥20 macrophages per HPF with AUCs of 0.889 (95% CI: 0.716-1.000) (p = .013), 0.852 (0.646-1.000) (p = .025), and 0.835 (0.577-1.000) (p = .028), respectively. Further, phase delay discriminated severe stenosis (≥70%) with an AUC of 0.767 (0.573-0.962) (p = .035). EIS discriminates high-risk atherosclerotic features that portend plaque rupture in human coronary artery disease and may serve as a complementary modality for angiography-guided atherosclerosis evaluation.

Effect of Colchicine on Coronary Plaque Stability in Acute Coronary Syndrome as Assessed by Optical Coherence Tomography: The COLOCT Randomized Clinical Trial.

Colchicine has been approved to reduce cardiovascular risk in patients with coronary heart disease on the basis of its potential benefits demonstrated in the COLCOT (Colchicine Cardiovascular Outcomes Trial) and LoDoCo2 (Low-Dose Colchicine 2) studies. Nevertheless, there are limited data available about the specific impact of colchicine on coronary plaques. This was a prospective, single-center, randomized, double-blind clinical trial. From May 3, 2021, until August 31, 2022, a total of 128 patients with acute coronary syndrome aged 18 to 80 years with lipid-rich plaque (lipid pool arc >90°) detected by optical coherence tomography were included. The subjects were randomly assigned in a 1:1 ratio to receive either colchicine (0.5 mg once daily) or placebo for 12 months. The primary end point was the change in the minimal fibrous cap thickness from baseline to the 12-month follow-up. Among 128 patients, 52 in the colchicine group and 52 in the placebo group completed the study. The mean age of the 128 patients was 58.0±9.8 years, and 25.0% were female. Compared with placebo, colchicine therapy significantly increased the minimal fibrous cap thickness (51.9 [95% CI, 32.8 to 71.0] μm versus 87.2 [95% CI, 69.9 to 104.5] μm; difference, 34.2 [95% CI, 9.7 to 58.6] μm; P=0.006), and reduced average lipid arc (-25.2° [95% CI, -30.6° to -19.9°] versus -35.7° [95% CI, -40.5° to -30.8°]; difference, -10.5° [95% CI, -17.7° to -3.4°]; P=0.004), mean angular extension of macrophages (-8.9° [95% CI, -13.3° to -4.6°] versus -14.0° [95% CI, -18.0° to -10.0°]; difference, -6.0° [95% CI, -11.8° to -0.2°]; P=0.044), high-sensitivity C-reactive protein level (geometric mean ratio, 0.6 [95% CI, 0.4 to 1.0] versus 0.3 [95% CI, 0.2 to 0.5]; difference, 0.5 [95% CI, 0.3 to 1.0]; P=0.046), interleukin-6 level (geometric mean ratio, 0.8 [95% CI, 0.6 to 1.1] versus 0.5 [95% CI, 0.4 to 0.7]; difference, 0.6 [95% CI, 0.4 to 0.9]; P=0.025), and myeloperoxidase level (geometric mean ratio, 1.0 [95% CI, 0.8 to 1.2] versus 0.8 [95% CI, 0.7 to 0.9]; difference, 0.8 [95% CI, 0.6 to 1.0]; P=0.047). Our findings suggested that colchicine resulted in favorable effects on coronary plaque stabilization at optical coherence tomography in patients with acute coronary syndrome. URL: https://www.clinicaltrials.gov; Unique identifier: NCT04848857.

Enhanced Plaque Stabilization Effects of Alirocumab - Insights From Artificial Intelligence-Aided Optical Coherence Tomography Analysis of the Alirocumab for Thin-Cap Fibroatheroma in Patients With Coronary Artery Disease Estimated by Optical Coherence Tomography (ALTAIR) Study.

Proprotein convertase subtilisin/kexin type 9 inhibitors stabilize vulnerable plaque, reducing cardiovascular events. However, manual optical coherence tomography (OCT) analysis of drug efficacy is challenging because of signal attenuation within lipid plaques. Twenty-four patients with thin-cap fibroatheroma were prospectively enrolled and randomized to receive alirocumab (75 mg every 2 weeks) plus rosuvastatin (10 mg/day) or rosuvastatin (10 mg/day) alone. OCT images at baseline and 36 weeks were analyzed manually and with artificial intelligence (AI)-aided software. AI-aided OCT analysis showed significantly greater percentage changes in the alirocumab+rosuvastatin vs. rosuvastatin-alone group in fibrous cap thickness (FCT; median [interquartile range] 212.3% [140.5-253.5%] vs. 88.6% [63.0-119.6%]; P=0.006) and lipid volume (median [interquartile range] -30.8% [-51.8%, -16.6%] vs. -2.1% [-21.6%, 4.3%]; P=0.015). Interobserver reproducibility for changes in minimum FCT and lipid index was relatively low for manual analysis (interobserver intraclass correlation coefficient [ICC] 0.780 and 0.499, respectively), but high for AI-aided analysis (interobserver ICC 0.999 and 1.000, respectively). Agreements between manual and AI-aided OCT analyses of FCT and the lipid index were acceptable (concordance correlation coefficients 0.859 and 0.833, respectively). AI-aided OCT analysis objectively showed greater plaque stabilization of adding alirocumab to rosuvastatin. Our results highlight the benefits of a fully automated AI-assisted approach for assessing drug efficacy, offering greater objectivity in evaluating serial changes in plaque stability vs. conventional OCT assessment.

Optical coherence tomography assessment of the impact of colchicine on non-culprit coronary plaque composition after myocardial infarction.

Low-dose colchicine reduces the risk of cardiovascular events after myocardial infarction (MI). The purpose of this study was to assess the effect of colchicine post-MI on coronary plaque morphology in non-culprit segments by optical coherence tomography (OCT). COCOMO-ACS was a double-blind, placebo-controlled trial that randomized 64 patients (median age 61.5 years; 9.4% female) with acute non-ST-segment elevation MI to colchicine 0.5 mg daily or placebo for a median of 17.8 months in addition to guideline-recommended therapy. Participants underwent serial OCT imaging within a matched segment of non-culprit coronary artery which contained at least one lipid-rich plaque causing ≥20% stenosis. The primary outcome was the change in minimum fibrous cap thickness (FCT) in non-culprit segments from baseline to final visit. Of those randomized, 57 (29 placebo, 28 colchicine) had evaluable imaging at baseline and follow-up. Overall, colchicine had no effect on relative (placebo +48.0±35.1% vs. colchicine +62.4±38.1%, P=0.18) or absolute changes in minimum FCT (+29.2±20.9 µm vs. +37.2±21.3 µm, P=0.18), or change in maximum lipid arc (-38.8±32.2° vs. -54.8±46.9°, P=0.18) throughout the imaged non-culprit segment. However, in patients assigned colchicine, cap rupture was less frequent (placebo 27.6% vs. colchicine 3.6%, P=0.03). In post-hoc analysis of 43 participants who had been followed for at least 16 months, minimum FCT increased to a greater extent in the colchicine group (placebo +38.7±25.4% vs. colchicine +64.7±34.1%, P=0.005). In this study, OCT failed to detect an effect of colchicine on the minimum FCT or maximum lipid arc of plaques in non-culprit segments post-MI. The post-hoc observation that minimum FCT increased to a greater extent with colchicine after more prolonged treatment suggests longer-term studies may be required to detect the effect of anti-inflammatory therapies on plaque morphology by OCT. Australian New Zealand Clinical Trials Registry Identifier, ACTRN12618000809235, registered on the 11th of May 2018.

Sex differences in plaque characteristics of fractional flow reserve-negative non-culprit lesions after myocardial infarction

Background and aimsRecurrent events after myocardial infarction (MI) are common and often originate from native non-culprit (NC) lesions that are non-flow limiting. These lesions consequently pose as targets to improve long-term outcome. It is, however, largely unknown whether these lesions differ between sexes. The aim of this study was to assess such potential differences. MethodsFrom the PECTUS-obs study, we assessed sex-related differences in plaque characteristics of fractional flow reserve (FFR)-negative intermediate NC lesions in 420 MI-patients. ResultsAmong the included patients, 80 (19.1 %) were female and 340 (80.9 %) male. Women were older and more frequently had hypertension and diabetes. In total, 494 NC lesions were analyzed. After adjustment for clinical characteristics and accounting for within-patients clustering, lesion length was longer in female patients (20.8 ± 10.0 vs 18.3 ± 8.5 mm, p = 0.048) and minimum lumen area (2.30 ± 1.42 vs 2.78 ± 1.54 mm2, p < 0.001) and minimum lumen diameter (1.39 ± 0.45 vs 1.54 ± 0.44 mm, p < 0.001) were smaller. The minimum fibrous cap thickness was smaller among females (96 ± 53 vs 112 ± 72 μm, p = 0.025), with more lesions harboring a thin cap fibroatheroma (39.3 % vs 24.9 %, p < 0.001). Major adverse cardiovascular events at two years occurred in 6.3 % of female patients and 11.8 % of male patients (p = 0.15). ConclusionsFFR-negative NC lesions after MI harbored more high-risk plaque features in female patients. Although this did not translate into an excess of recurrent events in female patients in this modestly sized cohort, it remains to be investigated whether this difference affects clinical outcome.

Fractal geometry of culprit coronary plaque images within optical coherence tomography in patients with acute coronary syndrome vs stable angina pectoris.

The main cause of acute coronary syndrome (ACS) is plaque rupture and thrombus formation. However, it has not been fairly successful to identify vulnerable plaque to rupture using conventional parameters of intravascular imaging modalities. Fractal analysis is one of the mathematical models to examine geometrical features of picture image using a specific parameter called as fractal dimension (FD) which suggests geometric complexity of the image. This study examined FD of the optical coherence tomography (OCT)-derived images of the culprit plaque in patients with ACS vs stable angina pectoris (SAP) to evaluate the feasibility of FD for identifying vulnerable coronary plaques prone to provoke ACS distinguished from stable plaques only provoking SAP. We examined 65 cases (34 ACS patients, 31 SAP patients) in which the culprit lesion was imaged by OCT before percutaneous coronary intervention in patients with ACS and SAP. The culprit plaque lesion in the ACS group had a significantly larger mean lipid arc (203.8 ± 39.4° vs 152.3 ± 34.5°, p < 0.001) and a larger lipid plaque length (12.6 ± 5.1mm vs 7.7 ± 2.7mm, p < 0.001) and a thinner fibrous cap thickness (75.3 ± 22.3μm vs 134.8 ± 53.2μm, p < 0.001) than those in the SAP group. The prevalence of OCT-derived macrophage infiltration (Mph) in the entire culprit coronary vessel as well as that of the OCT-derived thin-cap fibroatheroma (TCFA) at the culprit lesion were significantly greater in the ACS group than those in the SAP group, respectively (Mph: 61.8% vs 35.5%, p = 0.048; TCFA: 44.1% vs 6.4%, p < 0.001). The FD of culprit plaque in the ACS group was significantly greater than in the SAP group (2.401 ± 0.073 vs 2.341 ± 0.051, p < 0.001). In multivariate regression analysis, the presence of Mph was a significant determinant of FD (regression coefficient estimate 0.049, CI 0.018-0.079, p = 0.002). The FD of OCT-derived image of culprit coronary plaque in the ACS group was significantly greater than that in the SAP group, indicating that the culprit plaque in ACS were structurally more complex. Therefore, fractal analysis of coronary OCT images might be clinically useful for identifying coronary plaques prone to provoke ACS.

Potential of diagnostic electron microscopy of calcification, pathological neovascularization and elastolysis in combination with phenotyping of cell populations in large arteries

Aim. To determine the potential of diagnostic electron microscopy of intraplaque processes (severity of lipid damage, fibrous cap thickness and condition, severity of pathological neovascularization, presence, nature and severity of calcification, ratio and distribution of various cell populations).Material and methods. The study objects were plaques removed during endar­terectomy from the human carotid artery and segments of the human internal mammary artery removed during coronary bypass surgery. Whole specimens were subjected to chemical fixation, staining with heavy metal salts, embedding in epoxy resin followed by layer-by-layer grinding, polishing, contrasting, visualization using back-scattered electron scanning electron microscopy and three-dimensional reconstruction with color mapping (modified EM-BSEM).Results. The use of a modified EM-BSEM made it possible to: 1) visualize the fibrous cap thickness and assess the extracellular matrix; 2) analyze the neointimal lipid distribution; 3) perform three-dimensional reconstruction and analyze the microenvironment of calcifications of various sizes; 4) visualize endothelial cells, defects in interendothelial contacts and the basement membrane of neointimal capillaries with their subsequent three-dimensional reconstruction; 5) perform an analysis of age-dependent defects in the basement membrane and internal elastic membrane of the internal mammary artery. The resolution of the obtained images was significantly superior to intravascular imaging methods (intravascular ultrasound and optical coherence tomography), allowing additional assessment of capillary fluidity, the degree of calcification encapsulation and the condition of elastic fibers. Three-dimensional reconstruction of calcifications, neointimal capillaries and elastic fibers made it possible to assess their spatial density and heterogeneity. Simultaneously with the identification and assessment of these histological structures, objective phenotyping of cell populations was performed, which made it possible to isolate macrophages and foam cells, vascular smooth muscle cells, fibroblasts and endothelial cells in atherosclerotic plaques and automatically identify them through color mapping determined by their electronic contrast distribution signatures.Conclusion. The modified EM-BSEM method allows for universal electron microscopic diagnosis of atherosclerotic and elastolytic lesions of large arteries with high information content about vascular remodeling and high accuracy. Electronic contrast distribution signatures unique for each cell population indicate the possibility of their automated phenotyping using specialized neural network algorithms.

Role of imaging techniques in the assessment of vulnerable plaques and the effectiveness of lipid-lowering therapy

The aim was to evaluate the potential of various imaging methods in the diagnosis of vulnerable coronary plaques and their stabilization using various lipid-lowering therapy regimens.The sources were searched in the PubMed database using the following keywords: "vulnerable (unstable) plaque" AND "PCSK9 inhibitors" AND "intravascular ultrasound" OR "optical coherence tomography" OR "computed tomography angiography". As a result, 8 original clinical trials were selected that corresponded to the review purpose. We assessed the results of following studies on plaque imaging and their regression with various lipid-lowering therapy regimens: GLAGVO, ODYSSEY J, PACMAN-AMI, HUYGENS, ALTAIR, ARCHITECT, etc. The results of most studies have established the advantages of a combined regimen of lipid-lowering therapy (statin+PCSK9 inhibitor) in reducing the rate of cardiovascular events in com­parison with statin monotherapy. The reduction in plaque volume ranged from 0,95% to 2,13% in patients receiving a combination of lipid-lowering drugs, while in monotherapy, it increased from 0,05% to 0,92% (GLAGOV, PACMAN-AMI). The changes of minimum fibrous cap thickness varied from 18,0-62,67 µm with combined therapy and 13,2-33,19 µm with monotherapy (PACMAN-AMI, Gao F). Lipid arc regression was 57,5о in combination therapy (statin+PCSK9 inhibitor) and 31,4о in statin monotherapy (HUYGENS). Imaging diagnostic methods makes it possible to identify vulnerable plaques, which helps in consideration of combination lipid-lowering therapy. In addition, plaque visualization makes it possible to evaluate the treatment effectiveness.

Abstract Tu012: Innate Immune Pathway cGAS-STING in Macrophage Function in Atherosclerosis

Macrophages are key cells in atherosclerotic cardiovascular disease. Macrophages within a single plaque are heterogenous: some are lipid-laden “foam cells” with varying ability to recycle lipoproteins or clear dead cells while others secrete traditional “pro-inflammatory” signals. Determining what signals bias macrophages to one phenotype versus another could identify a therapeutic target. Our lab showed that after acute myocardial infarction, macrophages are skewed to a reparative phenotype by loss of cGAS-STING signaling. cGAS-STING are a pattern recognition receptor-adaptor pair that are activated by double stranded DNA in a sequence-independent manner. Global deletion of Sting and Cgas have been shown to protect against atherosclerosis in mice. We hypothesize that hematopoietic-specific loss of Cgas will reduce plaque burden by biasing macrophages to a less inflammatory phenotype and upregulating pro-resolving functions. To test this, B6.129S7- Ldlr tm1Her /J ( Ldlr -/-) mice (female, age 8-12 weeks, 9 per group) underwent total body irradiation followed by bone marrow transplant from C57BL6/N- Cgas -/- ( Cgas -/-) or wildtype donor mice (female, age 6-8 weeks). After bone marrow reconstitution, recipient mice were started on Western diet. Mice will continue Western diet for 12 weeks (through April 24, 2024). Then, aortas, peripheral blood, spleen, and bone marrow will be collected for further analysis including plaque burden, fibrous cap thickness, and macrophage phenotype. We will also perform in vitro studies using primary macrophages to determine how Cgas -/- affects macrophage effector functions critical for atherosclerosis. To date, mice that received Cgas -/- or wildtype donor bone marrow had similar baseline cell count, triglyceride and total cholesterol levels. Bone marrow derived macrophages (BMDM) from Cgas -/- mice have increased expression of fibronectin. Thus, at baseline Cgas -/- BMDM express high levels of a marker associated with pro-reparative macrophages. More studies are needed to characterize this phenotype and determine the consequence for in vivo atherosclerosis.

Peritoneal Dialysis Aggravates and Accelerates Atherosclerosis in Uremic ApoE-/- Mice.

Atherosclerosis is highly prevalent in people with chronic kidney disease (CKD), including those receiving peritoneal dialysis (PD). Although it is lifesaving, PD induces profound systemic inflammation, which may aggravate atherosclerosis. Therefore, the hypothesis is that this PD-induced inflammation aggravates atherosclerosis via immune cell activation. ApoE-/- mice were subjected to a 5/6 nephrectomy to induce CKD. Three weeks later, mice were fed a high-cholesterol diet. Half of the nephrectomized mice then received daily peritoneal infusions of 3.86% Physioneal for 67 further days (CKD+PD) until the end of the experiment, and were compared with mice without CKD. Sham operated and PD-only mice were additional controls. CKD+PD mice displayed more severe atherosclerotic disease than control mice. Plaque area increased, and plaques were more advanced with a vulnerable phenotype typified by decreased collagen content and decreased fibrous cap thickness. Increased CD3+ T-cell numbers were present in plaques and perivascular adipose tissue of CKD and CKD+PD mice. Plaques of CKD+PD mice contained more iNOS+ immune cells. Spleens of CKD+PD mice showed more CD4+ central memory, terminally differentiated type 1 T-helper (Th1), Th17, and CX3C motif chemokine receptor 1+ (CX3CR1) CD4+ T-cells with less regulatory and effector T-cells. PD-fluid exposure in uremic mice potentiates systemic and vascular T-cell-driven inflammation and aggravates atherosclerosis. PD polarized CD4+ T-cells toward an inflammatory Th1/Th17 phenotype, and increased CX3CR1+ CD4+ T-cells, which are associated with vascular homing in CKD-associated atherosclerosis. Targeting CD4+ T-cell activation and CX3CR1+ polarization has the potential to attenuate atherosclerosis in PD patients.

Melatonin Ameliorates Atherosclerotic Plaque Vulnerability by Regulating PPARδ-Associated Smooth Muscle Cell Phenotypic Switching.

Vulnerable atherosclerotic plaque rupture, the leading cause of fatal atherothrombotic events, is associated with an increased risk of mortality worldwide. Peroxisome proliferator-activated receptor delta (PPARδ) has been shown to modulate vascular smooth muscle cell (SMC) phenotypic switching, and, hence, atherosclerotic plaque stability. Melatonin reportedly plays a beneficial role in cardiovascular diseases; however, the mechanisms underlying improvements in atherosclerotic plaque vulnerability remain unknown. In this study, we assessed the role of melatonin in regulating SMC phenotypic switching and its consequential contribution to the amelioration of atherosclerotic plaque vulnerability and explored the mechanisms underlying this process. We analyzed features of atherosclerotic plaque vulnerability and markers of SMC phenotypic transition in high-cholesterol diet (HCD)-fed apolipoprotein E knockout (ApoE-/-) mice and human aortic SMCs (HASMCs). Melatonin reduced atherosclerotic plaque size and necrotic core area while enhancing collagen content, fibrous cap thickness, and smooth muscle alpha-actin positive cell coverage on the plaque cap, which are all known phenotypic characteristics of vulnerable plaques. In atherosclerotic lesions, melatonin significantly decreased the synthetic SMC phenotype and KLF4 expression and increased the expression of PPARδ, but not PPARα and PPARγ, in HCD-fed ApoE-/- mice. These results were subsequently confirmed in the melatonin-treated HASMCs. Further analysis using PPARδ silencing and immunoprecipitation assays revealed that PPARδ plays a role in the melatonin-induced SMC phenotype switching from synthetic to contractile. Collectively, we provided the first evidence that melatonin mediates its protective effect against plaque destabilization by enhancing PPARδ-mediated SMC phenotypic switching, thereby indicating the potential of melatonin in treating atherosclerosis.

Early and short-term use of proprotein convertase anti-subtilisin-kexin type 9 inhibitors on coronary plaque stability in acute coronary syndrome.

Proprotein convertase anti-subtilisin-kexin type 9 inhibitors (PCSK9Is) improve plaque volume and composition and reduce major adverse coronary events in chronic coronary artery disease. We evaluated the effects of the short-term use of PCSK9Is on coronary plaque stability in patients with acute coronary syndrome (ACS) using optical coherence tomography (OCT). This is a multicentre, open-label randomized controlled trial. The enrolled 80 subjects met the inclusion criteria. Of these, 52 patients (age 60 ± 11 years, 38 men, 14 women) with ST-elevated ACS had undergone successful primary percutaneous coronary intervention with LDL-cholesterol (LDL-C) levels > 70 mg/dL while receiving high-intensity statins. Participants were randomly assigned to the PCSK9I group (evolocumab 420 mg for 3 months, n = 29) or the standard of care (SoC) group (n = 23). Optical coherence tomography was performed at baseline (BL) and 3 and 9 months after randomization to assess lipid-rich plaques in non-culprit lesions. The change in the minimum fibrous cap thickness (MFCT) from BL to 9 months was the primary endpoint. The percentage change in LDL-C levels from BL to 3 months was significantly greater in the PCSK9I group (-67.8 ± 21.5% in the PCSK9I group vs. -16.3 ± 21.8% in the SoC group; P < 0.0001), and the difference between the two groups disappeared from BL to 9 months (-20.0 ± 37.8% in the PCSK9I group vs. -6.7 ± 34.2% in the SoC group; P = 0.20). The changes in MFCT from BL to 9 months were significantly greater in the PCSK9I group, even after PCSK9I discontinuation {100 μm [interquartile range (IQR): 45-180 μm] vs. 50 μm [IQR: 0-110 μm]; P = 0.032}. Combination treatment with PCSK9Is and statins resulted in more marked plaque stabilization after ACS than SoC alone, and this effect persisted for 6 months after PCSK9I discontinuation. Adage-Joto study, UMIN ID No. 26516.

Safety and efficacy of PCSK9 inhibitor (evolocumab) in patients with non-ST segment elevation acute coronary syndrome and non-culprit artery critical lesions: a randomised controlled trial protocol (SPECIAL study)

IntroductionPatients with non-ST segment elevation acute coronary syndrome (NSTE-ACS) and concomitant multivessel coronary artery disease (CAD) are considered patients with extremely high-risk atherosclerotic cardiovascular disease (ASCVD), and current guidelines specify...

Urolithin A promotes atherosclerotic plaque stability by limiting inflammation and hypercholesteremia in Apolipoprotein E-deficient mice.

Urolithin A (UroA), a dietary phytochemical, is produced by gut bacteria from fruits rich in natural polyphenols ellagitannins (ETs). The efficiency of ETs metabolism to UroA in humans depends on gut microbiota. UroA has shown a variety of pharmacological activities. In this study we investigated the effects of UroA on atherosclerotic lesion development and stability. Apolipoprotein E-deficient (ApoE-/-) mice were fed a high-fat and high-cholesterol diet for 3 months to establish atherosclerosis model. Meanwhile the mice were administered UroA (50 mg·kg-1·d-1, i.g.). We showed that UroA administration significantly decreased diet-induced atherosclerotic lesions in brachiocephalic arteries, macrophage content in plaques, expression of endothelial adhesion molecules, intraplaque hemorrhage and size of necrotic core, while increased the expression of smooth muscle actin and the thickness of fibrous cap, implying features of plaque stabilization. The underlying mechanisms were elucidated using TNF-α-stimulated human endothelial cells. Pretreatment with UroA (10, 25, 50 μM) dose-dependently inhibited TNF-α-induced endothelial cell activation and monocyte adhesion. However, the anti-inflammatory effects of UroA in TNF-α-stimulated human umbilicalvein endothelial cells (HUVECs) were independent of NF-κB p65 pathway. We conducted RNA-sequencing profiling analysis to identify the differential expression of genes (DEGs) associated with vascular function, inflammatory responses, cell adhesion and thrombosis in UroA-pretreated HUVECs. Human disease enrichment analysis revealed that the DEGs were significantly correlated with cardiovascular diseases. We demonstrated that UroA pretreatment mitigated endothelial inflammation by promoting NO production and decreasing YAP/TAZ protein expression and TEAD transcriptional activity in TNF-α-stimulated HUVECs. On the other hand, we found that UroA administration modulated the transcription and cleavage of lipogenic transcription factors SREBP1/2 in the liver to ameliorate cholesterol metabolism in ApoE-/- mice. This study provides an experimental basis for new dietary therapeutic option to prevent atherosclerosis.