Fibrous Cap Thickness Research Articles

Atherosclerotic Plaque Segmentation Based on Strain Gradients: A Theoretical Framework

Background: Atherosclerotic plaque detection is a clinical and technological problem that has been approached by different studies. Nowadays, intravascular ultrasound (IVUS) is the standard used to capture images of the coronary walls and to detect plaques. However, IVUS images are difficult to segment, which complicates obtaining geometric measurements of the plaque. Objective: IVUS, in combination with new techniques, allows estimation of strains in the coronary section. In this study, we have proposed the use of estimated strains to develop a methodology for plaque segmentation. Methods: The process is based on the representation of strain gradients and the combination of the Watershed and Gradient Vector Flow algorithms. Since it is a theoretical framework, the methodology was tested with idealized and real IVUS geometries. Results: We achieved measurements of the lipid area and fibrous cap thickness, which are essential clinical information, with promising results. The success of the segmentation depends on the plaque geometry and the strain gradient variable (SGV) that was selected. However, there are some SGV combinations that yield good results regardless of plaque geometry such as ▽εvMises+▽εrθ, ▽εyy+▽εrr or ▽εmin+▽εTresca. These combinations of SGVs achieve good segmentations, with an accuracy between 97.10% and 94.39% in the best pairs. Conclusions: The new methodology provides fast segmentation from different strain variables, without an optimization step.

Morphological and clinical implications of the optical coherence tomography-derived lipid core burden index

Abstract Background Intracoronary optical coherence tomography (OCT) is a valuable tool for vulnerable plaque assessment and morphology-guided risk stratification. However the groundbreaking impact of OCT in clinical practice may be offset by its inherent limitation, the subjectivity in plaque interpretation. Recent studies reported a semi-automated method to assess fibrous cap thickness but data regarding an automated assessment of lipid component at OCT, such a lipid core burden index (LCBI), are lacking. Purpose The aim of this study was to assess the morphological characteristics and prognostic implications of an OCT-derived LCBI (OCT-LCBI). Methods In order to assess OCT-LCBI in 1003 patients with 1-year follow-up from the CLIMA multicenter registry (clinicaltrial.gov identifier NCT02883088) we used a novel previously validated software able to automate obtain a maximum OCT-LCBI in 4 mm (maxOCT-LCBI4mm). A maxOCT-LCBI4mm cut-off of 400 was used, based on previous literature on this topic. Primary composite clinical endpoint included cardiac death, myocardial infarction and target vessel revascularization. A secondary analysis using clinical outcomes of CLIMA study was performed. Results Patients with a maxOCT-LCBI4mm ≥400 showed higher prevalence of fibrous cap thickness <75μm (FCT, odds ratio [OR] 1.43, 95% confidence interval [CI] 1.03–1.99; p=0.034), lipid pool arc >180°(OR 3.93, 95% CI 2.97–5.21; p<0.001), minimum lumen area <3.5 mm2 (OR 1.5, 1.16–1.94; p=0.002), macrophage infiltration (OR 2.38, 95% CI 1.81–3.13; p<0.001) and intra-plaque intimal vasculature (OR 1.34, 95% CI 1.05–1.72, p=0.021). A maxOCT-LCBI4mm ≥400 predicted the primary endpoint (adjusted hazard ratio [HR] 1.86, 95% CI 1.1–3.2; p=0.019) as well as the CLIMA endpoint (HR 2.56, 95% CI 1.24–5.29; p=0.011). Patients with high lipid content and thin FCT <75 μm were at higher risk for adverse events (HR 4.88, 95% CI 2.44–9.72; p<0.001) (Figure 1). Conclusions We applied for the first time in a large population with clinical follow-up a software able to automatically obtain a maxOCT-LCBI4mm. A high maxOCT-LCBI4mm was related to vulnerable plaque features and further clinical events. This study represents a step further towards a comprehensive automated assessment of the coronary plaque risk profile. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Supported by a grant from the Centro per la Lotta contro l'Infarto – Fondazione Onlus, Rome, Italy

Interrelation between baseline plaque characteristics and changes in coronary atherosclerosis with the PCSK9-inhibitor alirocumab: insights from the PACMAN-AMI randomized trial

Abstract Background Patients with acute myocardial infarction (AMI) frequently experience recurrent atherothrombotic events, largely attributable to non-culprit lesions with high-risk characteristics. Statins can halt the progression of coronary atherosclerosis, and addition of protein convertase subtilisin/kexin type 9-inhibitors (PCSK9i) results in incremental low-density lipoprotein cholesterol (LDL-C) lowering and atheroma regression. Purpose We sought to examine the interrelation between baseline imaging characteristics, on-treatment LDL-C levels, and changes in coronary atherosclerosis as assessed by serial, multi-modality intracoronary imaging in patients with AMI. Methods This is a post hoc analysis from the PACMAN-AMI randomized trial. Patients were randomly allocated to biweekly alirocumab 150 mg vs. placebo on top of high-intensity statin initiated within 24h of presentation with AMI, and underwent serial imaging of the two non-infarct-related arteries at baseline and after 52 weeks. The primary endpoint was percent atheroma volume (PAV) by intravascular ultrasound (IVUS). Powered secondary endpoints were maximal lipid core burden index (maxLCBI4mm) by near-infrared spectroscopy (NIRS) and minimum fibrous cap thickness (FCTmin) by optical coherence tomography (OCT). Results Of 300 randomized patients (mean age 58.5±9.8 years, 18.7% women, baseline LDL-C 3.94±0.87 mmol/L), IVUS was serially performed in 265 patients (537 arteries). LDL-C levels decreased to 1.92±0.79 mmol/L with placebo and 0.61±0.61 mmol/L with alirocumab (p<0.001). Compared with placebo (statin alone), alirocumab added to statin resulted in greater PAV reduction (−2.13% vs. −0.92%; p<0.001), greater maxLCBI4mm reduction (−79.42 vs. −37.60; p=0.006), and greater increase in FCTmin (62.67 vs. 33.19 μm; p=0.001). Changes in PAV and maxLCBI4mm were inversely related to on-treatment LDL-C levels, and change in FCTmin was positively related to on-treatment LDL-C levels (Figure 1). Across all patients, we found significant, inverse relationships between change in PAV and baseline PAV [slope: −0.072 (95% CI −0.101 to −0.042); p<0.001], between change in maxLCBI4mm and baseline maxLCBI4mm [slope: −0.437 (95% CI −0.505 to −0.369); p<0.001], and between change in FCTmin and baseline FCTmin [slope: −0.436 (95% CI −0.541 to −0.332); p<0.001]; these findings indicate greater PAV and maxLCBI4mm regression in lesions with greater PAV and LCBI4mm at baseline, and greater fibrous cap thickening in lesions with thinner fibrous caps at baseline. Conclusion In this study of intensive LDL-C lowering treatment initiated in the acute AMI setting, more favorable plaque changes were observed in patients with lower on-treatment LDL-C levels and in lesions with more adverse baseline plaque characteristics. Whether AMI patients with high-risk plaque features might derive greater clinical benefit from early initiation of intensive LDL-C-lowering therapies requires further investigation. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Sanofi, Regeneron

Brussels Chicory Stabilizes Unstable Atherosclerotic Plaques and Reshapes the Gut Microbiota in Apoe−/− Mice

Adherence to a Mediterranean dietary pattern can protect against atherosclerosis in part by reducing intestinal permeability and gut microbial LPS production. Brussels chicory, a typical Mediterranean vegetable, has been shown to inhibit the formation of early-stage atherosclerosis in mice. We evaluated whether Brussels chicory affects advanced atherosclerosis progression, intestinal permeability, and gut microbial LPS production. Thirty-week-old male apoE-deficient mice with unstable atherosclerotic plaques in the brachiocephalicarterywere fed the AIN-93G diet alone (control) or supplemented with 0.5% freeze-dried Brussels chicory for 20 wk. Plaque volume and features of plaque stability, plaque macrophage polarization, fecal and serum LPS concentrations, serum lipid profiles and inflammation-related cytokines, and gut microbial profiles were measured. Compared with the control treatment, Brussels chicory consumption did not significantly change plaque volume and serum lipid profiles. However, it increased plaque stability (P < 0.05), as evidenced by reduced necrotic core size (42.3%), and increased fibrous cap thickness (55.0%) and collagen content (68.4%). Moreover, Brussels chicory consumption reduced intestinal permeability (56.3%), fecal and serum LPS concentrations (52.2% and 39.4%), serum IL1β and TNFα (52.0% and 33.8%), promoted plaquemacrophage polarization towards the M2-likephenotype, and altered gut microbial composition, the latter indicated by increased relative abundance of certain members of the Ruminococcaceae family, such as Ruminiclostridium_9, Ruminiclostridium_5, and Intestinimonas (P < 0.05). Spearman correlation analyses further showed that these bacterial genera were significantly correlated with intestinal permeability, fecal and serum LPS, serum proinflammatory cytokines, and several features of plaque stability. Brussels chicory might help stabilize atherosclerotic plaques in mice by reducing intestinal permeability and gut microbial LPS production. This study provides a promising approach to slow the progression of atherosclerosis.

Correlation Between Serum Uric Acid Levels and Coronary Plaque Characteristics on Optical Coherence Tomography.

Elevated serum uric acid (sUA) is associated with increasing risk of coronary heart disease (CHD). However, existing research is limited by potential confounders. Herein, our study aims to probe the association between sUA levels and the morphological characteristics of coronary plaque by a propensity score matching (PSM) analysis.All 420 patients with CHD who had undergone optical coherence tomography of culprit lesions were included. Eligible patients were assigned into 2 groups according to sUA level: high-sUA group (sUA ≥ 6.0 mg/dL) and low-sUA group (sUA < 6.0 mg/dL). PSM was applied to control the balance of baseline characteristics.After PSM, a total of 112 patients were included in our study (56 in each group). The high-sUA group showed a higher prevalence of TCFA (35.7% versus 16.1%, P = 0.03) and macrophage infiltration (33.9% versus 14.3%, P = 0.026) compared with the low-sUA group. Plaques in the high-sUA group had a wider maximum lipid arc (166.51° (115.77°, 224.14°) versus 142.29° (93.95°, 169.06°), P = 0.048), longer calcification length (6.77 (3.90, 20.55) mm versus 4.20 (1.95, 7.45) mm, P = 0.040), and thinner minimum fibrous cap thickness (43.81 (28.17, 62.26) μm versus 92.57 (46.25, 135.37) μm, P = 0.003). Correlation analysis indicated that the sUA value was inversely associated with the minimum fibrous cap thickness (r = -0.332, P = 0.015) and positively associated with the maximum lipid arc (r = 0.399, P = 0.003), average lipid arc (r = 0.347, P = 0.011), and calcification length (r = 0.386, P = 0.006).The relationship between high-sUA levels and typical vulnerable features of plaques persisted after balancing the traditional risk factors.

Early Enhancement with Contrast-Enhanced Ultrasonography Relates to the Number of Small-Diameter Neovessels in the Carotid Plaque

Background and Purpose: Intraplaque neovessels (INVs) have been recognized as a major cause of intraplaque hemorrhage and subsequent vulnerability of the carotid plaque. However, the exact mechanisms by which INVs cause intraplaque hemorrhage remain unclear. Various sizes of INVs coexist in carotid plaques pathologically, and we hypothesized that the size of INVs would be associated with carotid plaque histology, particularly in terms of intraplaque hemorrhage. Detection method of INV is important when determining whether carotid plaques are vulnerable, and contrast-enhanced ultrasonography (CEUS) is one of the most useful methods to detect them. The purpose of this study was to examine the relationship between findings from CEUS and vascular pathology obtained by carotid endarterectomy (CEA). We focused on associations between small and large INVs evaluated by CEUS and histologically defined intraplaque hemorrhage. Methods: Participants comprised 115 patients (mean age, 73.0 ± 7.2 years; 96 men) who underwent preoperative CEUS and underwent CEA. CEUS findings were evaluated as vascular grade at 0 min (Vas-G0) and 10 min (Vas-G10) after contrast injection. Plaques were histologically evaluated quantitatively for the total area of intraplaque hemorrhage, cholesterol, and calcification and the thinnest fibrous cap. Immunohistochemical studies were conducted using anti-CD-34 antibody as a marker for endothelial cells. INVs were divided into two groups depending on diameter: small INVs, <50 μm; and large INVs, ≥50 μm. The numbers of small and large blood vessels in the plaque were quantified histologically. Associations of small and large INVs with CEUS, plaque histology, and clinical findings were assessed by uni- and multivariable analyses. Results: Multivariable analyses indicated that CEUS Vas-G0 was associated with the 4th quartile of the number of small INVs compared with other quartiles, and Vas-G10 was associated with the 4th quartile of the number of large INVs. Histologically, the presence and area of intraplaque hemorrhage were associated with the number of small INVs, while the increased number of large INVs was associated with infrequent plaque disruption and thicker fibrous cap. Conclusions: Our study showed that early phase enhancement in the CEUS can help identify plaque vulnerability by predicting a larger number of small INVs. This information can also help determine treatment strategies for carotid plaque.

Fibrous Cap Thickness Predicts Stable Coronary Plaque Progression: Early Clinical Validation of a Semiautomated OCT Technology.

Imaging-based characteristics associated with the progression of stable coronary atherosclerotic lesions are poorly defined. Utilizing a combination of optical coherence tomography (OCT) and intravascular ultrasound (IVUS) imaging, we aimed to characterize the lesions prone to progression through clinical validation of a semiautomated OCT computational program. Patients with stable coronary artery disease underwent nonculprit vessel imaging with IVUS and OCT at baseline and IVUS at the 12-month follow-up. After coregistration of baseline and follow-up IVUS images, paired 5-mm segments from each patient were identified, demonstrating the greatest plaque progression and regression as measured by the change in plaque burden. Experienced readers identified plaque features on corresponding baseline OCT segments, and predictors of plaque progression were assessed by multivariable analysis. Each segment then underwent volumetric assessment of the fibrous cap (FC) using proprietary software. Among 23 patients (70% men; median age, 67 years), experienced-reader analysis demonstrated that for every 100 μm increase in mean FC thickness, plaques were 87% less likely to progress (P = .01), which persisted on multivariable analysis controlling for baseline plaque burden (P = .05). Automated FC analysis (n = 17 paired segments) confirmed this finding (P = .01) and found thinner minimal FC thickness (P = .01) and larger FC surface area of <65 μm (P = .02) and <100 μm (P = .04) in progressing segments than in regressing segments. No additional imaging features predicted plaque progression. A semiautomated FC analysis tool confirmed the significant association between thinner FC and stable coronary plaque progression along entire vessel segments, illustrating the diffuse nature of FC thinning and suggesting a future clinical role in predicting the progression of stable coronary artery disease.

Correlation of lipoprotein (a) levels and plaque morphology in very young acute coronary syndrome patients using optical coherence tomography

IntroductionLevels of lipoprotein (LP) (a) are useful marker for risk stratification of cardiovascular disease. This genetic biomarker is suggestive of patient predisposition to acute coronary event. The present study was to study correlation of LP(a) levels and plaque morphology in very young patients (<35 years) with acute coronary syndrome (ACS). MethodsA prospective, single-center, observational study consisting of very young patients with ACS and fit for optical coherence tomography (OCT) guided invasive coronary angiography was conducted at tertiary-care centre. LP(a) levels were compared between healthy controls and very young ACS patients. Correlation of LP(a) levels and plaque characteristics in very young ACS patients was done using OCT imaging. ResultsOut of enrolled 80 subjects, 40 were very young ACS and 40 were matched healthy controls. In very young patients, plaque rupture and erosion were mechanism of ACS in 67.5% and 32.5% patients, respectively. Mean levels of LP(a) were 28.10 ± 13.96 nmol/l in healthy controls and 47.19 ± 29.85 nmol/l in very young patients with ACS (p = 0.022). Among very young ACS patients, patients with LP(a) levels<75 nmol/l and ≥75 nmol/l had mean thin cap fibroatheroma thickness of 117.08 ± 52.542 μm and 95.00 ± 36.286 μm, respectively (p = 0.2355). ConclusionHigher levels of LP(a) were seen in younger patients with ACS compared with matched healthy individuals. Plaque rupture was the commonest mechanism of ACS in very young ACS patients. Patients with high LP(a) levels had lesser thickness of fibrous cap in OCT imaging compared with low levels of LP(a).

Patient-specific biomechanical analysis of atherosclerotic plaques enabled by histologically validated tissue characterization from computed tomography angiography: A case study

BackgroundRupture of unstable atherosclerotic plaques with a large lipid-rich necrotic core and a thin fibrous cap cause myocardial infarction and stroke. Yet it has not been possible to assess this for individual patients. Clinical guidelines still rely on use of luminal narrowing, a poor indicator but one that persists for lack of effective means to do better. We present a case study demonstrating the assessment of biomechanical indices pertaining to plaque rupture risk non-invasively for individual patients enabled by histologically validated tissue characterization. MethodsRoutinely acquired clinical images of plaques were analyzed to characterize vascular wall tissues using software validated by histology (ElucidVivo, Elucid Bioimaging Inc.). Based on the tissue distribution, wall stress and strain were then calculated at spatial locations with varied fibrous cap thicknesses at diastolic, mean and systolic blood pressures. ResultsThe von Mises stress of 152 [131, 172] kPa and the equivalent strain of 0.10 [0.08, 0.12] were calculated where the fibrous cap thickness was smallest (560 μm) (95% CI in brackets). The stress at this location was at a level predictive of plaque failure. Stress and strain at locations with larger cap thicknesses were calculated to be lower, demonstrating a clinically relevant range of risk levels. ConclusionPatient specific tissue characterization can identify distributions of stress and strain in a clinically relevant range. This capability may be used to identify high-risk lesions and personalize treatment decisions for individual patients with cardiovascular disease and improve prevention of myocardial infarction and stroke.

Tribbles 3 deficiency promotes atherosclerotic fibrous cap thickening and macrophage-mediated extracellular matrix remodelling.

Tribbles 3 (TRIB3) modulates lipid and glucose metabolism, macrophage lipid uptake, with a gain-of-function variant associated with increased cardiovascular risk. Here we set out to examine the role of this pseudokinase in atherosclerotic plaque development. Human endarterectomy atherosclerotic tissue specimens analysed by immunofluorescence showed upregulated TRIB3 in unstable plaques and an enrichment in unstable regions of stable plaques. Atherosclerosis was induced in full body Trib3KO and Trib3WT littermate mice by injecting mPCSK9 expressing adeno-associated virus and western diet feeding for 12 weeks. Trib3KO mice showed expanded visceral adipose depot while circulatory lipid levels remained unaltered compared to wildtype mice. Trib3KO mice aortae showed a reduced plaque development and improved plaque stability, with increased fibrous cap thickness and collagen content, which was accompanied by increased macrophage content. Analysis of both mouse and human macrophages with reduced TRIB3 expression showed elongated morphology, increased actin expression and altered regulation of genes involved in extracellular matrix remodelling. In summary, TRIB3 controls plaque development and may be atherogenic in vivo. Loss of TRIB3 increases fibrous cap thickness via altered metalloproteinase expression in macrophages, thus inhibiting collagen and elastic fibre degradation, suggesting a role for TRIB3 in the formation of unstable plaques.

Gut Microbiota and Coronary Plaque Characteristics.

BackgroundThe relationship between gut microbiota and in vivo coronary plaque characteristics has not been reported. This study was conducted to investigate the relationship between gut microbiota and coronary plaque characteristics in patients with coronary artery disease.Methods and ResultsPatients who underwent both optical coherence tomography and intravascular ultrasound imaging and provided stool and blood specimens were included. The composition of gut microbiota was evaluated using 16S rRNA sequencing. A total of 55 patients were included. At the genus level, 2 bacteria were associated with the presence of thin‐cap fibroatheroma, and 9 bacteria were associated with smaller fibrous cap thickness. Among them, some bacteria had significant associations with inflammatory/prothrombotic biomarkers. Dysgonomonas had a positive correlation with interleukin‐6, Paraprevotella had a positive correlation with fibrinogen and negative correlation with high‐density lipoprotein cholesterol, Succinatimonas had positive correlations with fibrinogen and homocysteine, and Bacillus had positive correlations with fibrinogen and high‐sensitivity C‐reactive protein. In addition, Paraprevotella, Succinatimonas, and Bacillus were also associated with greater plaque volume. Ten bacteria were associated with larger fibrous cap thickness. Some were associated with protective biomarker changes; Anaerostipes had negative correlations with trimethylamine N‐oxide, tumor necrosis factor α, and interleukin‐6, and Dielma had negative correlations with trimethylamine N‐oxide, white blood cells, plasminogen activator inhibitor‐1, and homocysteine, and a positive correlation with high‐density lipoprotein cholesterol.ConclusionsBacteria that were associated with vulnerable coronary plaque phenotype and greater plaque burden were identified. These bacteria were also associated with elevated inflammatory or prothrombotic biomarkers.RegistrationURL: https://www.umin.ac.jp/ctr/; Unique identifier: UMIN000041692.

A Plaque Instability Index Calculated by Histological Marker Analysis of the Endarterectomy Carotid Artery

(1) Background: Atherosclerosis is a pandemic condition that causes the development of ischemic syndromes including myocardial infarctions and many strokes, in addition to disabling peripheral artery disease. Progression of atheroma plaques has been associated with an increased risk of mortality. It is a challenge to determine in advance if atherosclerotic plaque will become unstable by calculating an index of instability. We proposed a score of ten parameters for the assessment of high-risk plaques, by quantification of 10 risk factors for acute cardiovascular events, most of them representing histological variables. (2) Methods: Carotid endarterectomy samples were collected from 10 highly symptomatic patients who matched for gender, age, risk factors, and plaque morphology. Samples were stained with hematoxylin-eosin, elastic van Gieson, Perls, and Mallory. Immunohistochemistry was performed using specific antibodies, such as CD31 for endothelial cells, CD68 for macrophages, and CD3 for T cells. (3) Results: For each plaque, the presence and/or number of histological features (fibrous cap thickness, lipid core size, plaque and cap infiltration with macrophages and lymphocytes, neovessels, intraplaque hemorrhage, parietal thrombi, and calcium deposits) were recorded on a simple semi-quantitative one- or two-grade scale. The study identified four stable plaques (SPs), two vulnerable plaques (VPs), and four unstable plaques (USPs). We found significantly more macrophages and neovessels in unstable plaques compared with stable plaques. The score for unstable plaques was higher than that for VP. (4) Conclusions: The study showed that symptomatic carotid disease is associated with an increased index score. The proposed algorithm for carotid plaque assessment may be useful for an imaging application.

Potential of optical frequency domain imaging for differentiation between early and advanced coronary atherosclerosis.

This study evaluated whether optical frequency domain imaging (OFDI) accurately distinguish between fibroatheroma (FA) and pathological intimal thickening (PIT) compared with histopathology. A total of 631 histological cross-sections from 14 autopsy hearts were analyzed for the comparison between OFDI and histological images. Of those, 190 (30%) sections were diagnosed with PIT and 120 (19%) with FA. The OFDI signal attenuation rate was calculated from an exponential. The lipid length was measured longitudinally by detection of sequential OFDI frames within a plaque segment containing lipids. The lipid arc was measured with a protractor centered in the center of the lumen. The fibrous cap thickness was defined as the minimum thickness of the signal rich band overlying PIT and FA. There was no significant difference in the OFDI signal attenuation rate between FA and PIT (3.09 ± 1.04 versus 2.79 ± 1.20, p = 0.13). However, the lipid length was significantly longer, the maximum lipid arc was significantly larger, and the fibrous cap thickness was significantly thinner in FA than in PIT (7.5 [4.3-10.3] mm versus 4.3 [2.7-5.8] mm, p < 0.0001, 125 [101-174]° versus 96 [74-131]°, p < 0.0001, and 220 [167-280] µm versus 260 [190-332] µm, p = 0.019). This study revealed OFDI may have the potential capability for discriminating FA from PIT based on the longitudinal and circumferential extent of lipid plaque, although the OFDI signal attenuation rate was similar between FA and PIT.

Early Diagnosis and Treatment of Coronary Heart Disease with Image Features of Optical Coherence Tomography under Adaptive Segmentation Algorithm.

This research was aimed at exploring the application value of optical coherence tomography (OCT) images under adaptive segmentation algorithm in the early diagnosis of coronary heart disease (CHD). Eighty-two patients with CHD were included, who were to undergo coronary angiography (CAG) to confirm their condition. According to the diagnostic criteria of CHD in the American Coronary Artery Surgery Study (CASS), the patients were divided into the stable plaque group (41 cases) and unstable plaque group (41 cases). Besides, 20 healthy volunteers were selected as the control group, and all of them underwent OCT scans. On the basis of a fourth-order partial differential equation (PDE) and active contour (AC) model, a novel adaptive image segmentation algorithm PDE-AC was constructed and used for OCT image processing. No significant difference was found in general clinical data and serological indicators in the control group compared to the other two groups (P > 0.05). The lipid plaque length, degree of stenosis, and lipid pool angle, macrophages and intimal erosion, and plaque fissure in the unstable plaque group were highly greater than those in the stable plaque group. The fibrous cap thickness (FCT) was significantly thinner than that in the stable plaque group (P < 0.05). The diagnostic sensitivity, specificity, and accuracy of OCT under PDE-AC algorithm for CHD (91.53%, 84.08%, and 95.38%) were markedly higher than those of single OCT (83.46%, 75.11%, and 88.02%) (P < 0.05). In summary, OCT images under PDE-AC algorithm did better than simple OCT images in the diagnosis of CHD. Lipid plaque length, degree of stenosis, and lipid pool angle, macrophage and intimal erosion, plaque fissure, and FCT were important indicators for judging plaque stability, having the better clinical application value.

Abstract P3010: Angptl4 Reduces Atherosclerosis And Promotes Fibrous Cap Stability By Targeting Klf4 In Vascular Smooth Muscle Cells

Background: Atherosclerosis is vascular disease of chronic inflammation, and we recently showed that angiopoietin-like 4 (ANGPTL4) promote cardiac repair by suppressing pathological inflammation. Given the contribution of inflammation to atherosclerosis, we assessed the effect of ANGPTL4 on atherosclerosis development. Methods: We injected recombinant ANGPTL4 protein or PBS to atherosclerotic Apoe-/- mice twice a week fed a high-fat diet for 8 weeks, and analyzed atherosclerotic lesion size, inflammation, and plaque stability. The effect of ANGPTL4 on vascular smooth muscle cells (VSMCs) was studied, and plasma levels of ANGPTL4 in patients were measured. Results: ANGPTL4 treatment reduced the atherosclerotic plaque size and vascular inflammation. In the atherosclerotic lesions, the number of α-SMA(+)MYH11(+) cells was higher, while the number of CD68(+)cells was lower in the ANGPTL4 group than in the vehicle-treated group. Moreover, α-SMA-expressing fibrous cap was significantly thicker in the ANGPTL4 group than in the PBS group. Then, we isolated VSMCs from atherosclerotic aortas, and found that CD68 and Krüppel-like factor 4 (KLF4) were significantly upregulated in the PBS group. As KLF4 is a phenotypic modulator and an inducer of NADP oxidase 1 (Nox1) in VSMCs, the effect of ANGPTL4 on VSMCs was assessed. Cholesterol-induced upregulations of Nox1 and KLF4 were substantially inhibited by ANGPTL4 treatment. Then, we analyzed the circulating ANGPTL4 levels of the cardiovascular disease patients, and found the positive correlation between high ANGPTL4 and low incidence of vascular events. Conclusions: Our results showed that ANGPTL4 inhibited atherogenesis by increasing the fibrous cap thickness. KLF4 and Nox1 were suggested as targets of ANGPTL4 in VSMCs to confer plaque stability by attenuating phenotypic changes of VSMCs toward inflammatory macrophage-like cells. Taken together, circulating ANGPTL4 may be associated with regulation of vascular events.

Exercise training inhibits atherosclerosis progression and reduces VE-cadherin levels within atherosclerotic plaques in hypercholesterolemic mice

Vascular endothelial-cadherin (VE-cadherin), matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) have emerged as key-factors of atherogenesis. The aim of this study was to evaluate the effects of exercise training (ET) on those key-factors in relation to the progression of atherosclerotic lesions in hypercholesterolemic mice. Thirty male, apoE knockout (apoE−/−) mice were randomly assigned to the following equivalent groups: 1) CO-control: High-fat diet (HFD) administration for 12 weeks. 2) EX-exercise: HFD administration as in CO, and during the last 4 weeks (9th −12th week) ET on treadmill (5sessions/week, 60min/session). At the end of study, blood samples were obtained and all mice were sacrificed. Aortic roots were excised and analysed regarding the percentage of aortic stenosis, and the relative concentrations of collagen, elastin, VE-cadherin, MMP-8,-9 and TIMP-1,-2 within the atherosclerotic lesions. Aortic stenosis was significantly lower in the EX than the CO group (39.63 ± 7.22% vs 62.04 ± 8.55%; p < 0.001), along with considerable increase in fibrous cap thickness and of collagen and elastin contents within plaques (p < 0.05). Compared to controls, exercised-treated mice showed reduced intra-plaque relative concentrations of VE-cadherin (15.09 ± 1.89% vs 23.49 ± 3.01%, p < 0.001), MMP-8 (8.51 ± 2.24% vs 18.51 ± 4.08%, p < 0.001) and MMP-9 (12.1 ± 4.86% vs 18.88 ± 6.23%, p < 0.001). Inversely, the relative concentrations of TIMP-1 and TIMP-2 in the ET group were considerably higher by 62.5% and 31.2% than in the EX group (p < 0.05), respectively. Finally, body weight and lipids concentrations did not differ between groups at the end of the study (p > 0.05). ET treatment induced regression of established atherosclerotic lesions in apoE−/− mice and improved their stability. Those effects seemed to be mediated by favourable modification of VE-cadherin, MMPs and TIMPs.

Interventional hepatic apoC-III knockdown improves atherosclerotic plaque stability and remodeling by triglyceride lowering.

Apolipoprotein C-III (apoC-III) is a critical regulator of triglyceride metabolism and correlates positively with hypertriglyceridemia and cardiovascular disease (CVD). It remains unclear if therapeutic apoC-III lowering reduces CVD risk and if the CVD correlation depends on the lipid-lowering or antiinflammatory properties. We determined the impact of interventional apoC-III lowering on atherogenesis using an apoC-III antisense oligonucleotide (ASO) in 2 hypertriglyceridemic mouse models where the intervention lowers plasma triglycerides and in a third lipid-refractory model. On a high-cholesterol Western diet apoC-III ASO treatment did not alter atherosclerotic lesion size but did attenuate advanced and unstable plaque development in the triglyceride-responsive mouse models. No lesion size or composition improvement was observed with apoC-III ASO in the lipid-refractory mice. To circumvent confounding effects of continuous high-cholesterol feeding, we tested the impact of interventional apoC-III lowering when switching to a cholesterol-poor diet after 12 weeks of Western diet. In this diet switch regimen, apoC-III ASO treatment significantly reduced plasma triglycerides, atherosclerotic lesion progression, and necrotic core area and increased fibrous cap thickness in lipid-responsive mice. Again, apoC-III ASO treatment did not alter triglyceride levels, lesion development, and lesion composition in lipid-refractory mice after the diet switch. Our findings suggest that interventional apoC-III lowering might be an effective strategy to reduce atherosclerosis lesion size and improve plaque stability when lipid lowering is achieved.

Optical coherence tomography-derived lipid core burden index and clinical outcomes: results from the CLIMA registry.

The aim of this study was to assess the morphological characteristics and prognostic implications of the optical coherence tomography (OCT)-derived lipid core burden index (LCBI). OCT-LCBI was assessed in 1003 patients with 1-year follow-up from the CLIMA multicentre registry using a validated software able to automatically obtain a maximum OCT-LCBI in 4 mm (maxOCT-LCBI4mm). Primary composite clinical endpoint included cardiac death, myocardial infarction, and target-vessel revascularization. A secondary analysis using clinical outcomes of CLIMA study was performed. Patients with a maxOCT-LCBI4mm ≥ 400 showed higher prevalence of fibrous cap thickness (FCT) <75 μm [odds ratio (OR) 1.43, 95% confidence interval (CI) 1.03-1.99; P = 0.034], lipid pool arc >180° (OR 3.93, 95%CI 2.97-5.21; P < 0.001), minimum lumen area <3.5 mm2 (OR 1.5, 95%CI 1.16-1.94; P = 0.002), macrophage infiltration (OR 2.38, 95%CI 1.81-3.13; P < 0.001), and intra-plaque intimal vasculature (OR 1.34, 95%CI 1.05-1.72; P = 0.021). A maxOCT-LCBI4mm ≥400 predicted the primary endpoint [adjusted hazard ratio (HR) 1.86, 95%CI 1.1-3.2; P = 0.019] as well as the CLIMA endpoint (HR 2.56, 95%CI 1.24-5.29; P = 0.011). Patients with high lipid content and thin FCT < 75 µm were at higher risk for adverse events (HR 4.88, 95%CI 2.44-9.72; P < 0.001). A high maxOCT-LCBI4mm was related to poor outcome and vulnerable plaque features. This study represents a step further in the automated assessment of the coronary plaque risk profile.

Cholesterol crystals in non-culprit plaques of STEMI patients: A 3-vessel OCT study

BackgroundCholesterol crystals (CCs) are regular microstructures found within the necrotic core of atherosclerotic plaques and have been hypothesized to be related to plaque destabilization. We attempted to investigate the potential association between CCs and non-culprit plaque vulnerability in patients with ST-segment elevated myocardial infarction (STEMI) and study morphological features of CCs in ruptured non-culprit plaques. MethodsA total of 261 patients with ST-segment elevation myocardial infarction who underwent 3-vessel optical coherence tomography (OCT) imaging were included. Non-culprit plaques were divided into two groups according to the presence or absence of CCs in the plaque to compare the morphological characteristics of the plaques. The differences in parameters of the non-culprit plaque CCs were explored between ruptured plaques and unruptured plaques. ResultsTotally, 530 non-culprit plaques (29 ruptured plaques and 501 unruptured plaques) were identified by OCT. The incidence of CCs was 21.1%. Compared with non-culprit plaques without CCs, those with CCs had a larger lipid burden. Macrophages (p < 0.001) and spotty calcification (p = 0.002) were more frequently observed in non-culprit plaques with CCs. The frequency of CCs was significantly higher (p = 0.001) and the CCs were larger (p = 0.046) and more superficial (p = 0.005) in ruptured non-culprit plaques than in unruptured non-culprit plaques. The maximum lipid arc and fibrous cap thickness were independent predictors of plaque rupture, but the presence of CCs was not. ConclusionsNon-culprit plaques with CCs have more vulnerable features. CCs are more frequently found in ruptured non-culprit plaques and larger and more superficial CCs are associated with plaque rupture.

The characteristics of intracranial plaques of unilateral, anterior circulation embolic stroke of undetermined source: An analysis of different subtypes based on high-resolution imaging.

The aim was to investigate the characteristics of non-stenotic intracranial plaque (NSIP) in embolic stroke of undetermined source (ESUS) subtypes by high-resolution magnetic resonance imaging. Consecutive patients with ESUS who were mandatory for high-resolution magnetic resonance imaging were retrospectively enrolled. Based on the location and arterial supply of the infarct, the ESUS were categorized into three types: cortical ESUS, subcortical ESUS and mixed ESUS. The NSIP parameters including plaque location, morphology (plaque distribution, remodeling index and plaque burden) and composition (thick fibrous cap, discontinuity of plaque surface, intraplaque hemorrhage and complicated plaque) were evaluated amongst the subtypes. Of 243 patients, there were 87 (35.8%) cortical ESUS, 127 (52.3%) subcortical ESUS and 29 (11.9%) mixed ESUS. Significant differences were found in plaque location (p &lt; 0.001), plaque quadrant (p &lt; 0.001), remodeling index (p &lt; 0.001), plaque burden (p &lt; 0.001), discontinuity of plaque surface (p &lt; 0.001), intraplaque hemorrhage (p=0.001) and complicated plaque (p &lt; 0.001) of ipsilateral NISP amongst the different ESUS subtypes, except for fibrous cap (p=0.135). However, no differences were found amongst contralateral NISP. In addition, the clinical characteristics of the differences between ESUS subtypes were striking, including age (p=0.004), initial National Institutes of Health Stroke Scale (p &lt; 0.001), coronary artery disease (p=0.039), serum urea (p=0.011) and creatinine (p=0.002). This is the first report of significantly heterogeneous characteristics of ipsilateral NSIP and clinical findings amongst ESUS subtypes, which may suggest their different underlying mechanisms.