TCT-75 Novel Fully-Quantitative Virtual Histology Analysis of Confluent Necrotic Core Size and Fibrous Cap Thickness in Relation to Conventional Phenotypic Plaque Type Assessment and Cerebral Symptom Occurrence/Timing: The CRACK-VH Study in 252 Consecutive Patients with Atheromatous Carotid Stenosis

Abstract Background Activating transcription factor 3 (ATF3) is an early response gene that is activated in response to atherosclerotic stimulation and may be an important factor in inhibiting the progression of atherosclerosis. In this study, we directly measured the expression of ATF3 and inflammatory factors in human coronary atherosclerotic plaques to examine the relationship between ATF3 expression, inflammation and structural stability in human coronary atherosclerotic plaques. Methods A total of 68 coronary artery specimens were collected from the autopsy group, including 36 cases of sudden death from coronary heart disease (SCD group) and 32 cases of acute death caused by mechanical injury with coronary atherosclerosis (CHD group). Twenty-two patients who had no coronary heart disease were collected as the control group (Con group). The histological structure of the coronary artery was observed under a light microscope after routine HE staining, and the intimal and lesion thicknesses, thickness of the fibrous cap, thickness of necrosis core, degree of lumen stenosis were assessed by image analysis software. Western blotting and immunohistochemistry were used to measure the expression and distribution of ATF3, inflammatory factors (CD45, IL-1β, TNF-α) and matrix metalloproteinase-9 (MMP-9) and vascular cell adhesion molecule 1 (VCAM1) in the coronary artery. The Pearson correlation coefficient was used to analyse the correlation between ATF3 protein expression and inflammatory factors and between ATF3 protein expression and structure-related indexes in the lesion group. Results Compared with those in the control group, the intima and necrotic core in the coronary artery were thickened, the fibrous cap became thin and the degree of vascular stenosis was increased in the lesion group, while the intima and necrotic core became thicker and the fibrous cap became thinner in the SCD group than in the CHD group (P < 0.05). There was no or low expression of ATF3, inflammatory factors, VCAM1 and MMP-9 in the control group, and the expression of inflammatory factors, VCAM1 and MMP-9 in the SCD group was higher than that in CHD group, while the expression of ATF3 in the SCD group was significantly lower than that in CHD group (P < 0.05). In the lesion group, the expression of ATF3 was negatively correlated with intimal and necrotic focus thickness, positively correlated with fibrous cap thickness (P < 0.01), and negatively correlated with inflammatory factors, VCAM1 and MMP-9 (P < 0.01). Conclusions The expression of ATF3 may be related to the progression and stability of atherosclerotic plaques, and may affect the structural stability of atherosclerotic plaques by regulating the inflammatory response, thus participating in the regulation of atherosclerotic progression.

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Utility of high-resolution MR imaging to assess fibrous cap thickness, lipid-rich necrotic core and haemorrhage of carotid atheroma

British Journal of Surgery ◽

10.1002/bjs.6488 ◽

2009 ◽

Vol 96 (S1) ◽

pp. 1-1

Author(s):

U. Sadat ◽

V. E. Young ◽

M. J. Graves ◽

M. E. Gaunt ◽

K. Varty ◽

...

Keyword(s):

High Resolution ◽

Mr Imaging ◽

Necrotic Core ◽

Fibrous Cap ◽

Fibrous Cap Thickness

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Abstract 2286: Ultrasonographic And Pathological Measurement Of Fibrous Cap In Rupture-prone Carotid Plaques Using Advanced Ultrasound Technology

Stroke ◽

10.1161/str.43.suppl_1.a2286 ◽

2012 ◽

Vol 43 (suppl_1) ◽

Author(s):

Akihiro Watanabe ◽

Kozue Saito ◽

Koji Iihara ◽

Hatsue Ueda ◽

Kazuyuki Nagatsuka

Keyword(s):

Carotid Endarterectomy ◽

Carotid Stenosis ◽

Plaque Rupture ◽

Ultrasound Image ◽

Short Axis ◽

Short Axis View ◽

Fibrous Cap ◽

Fibrous Cap Thickness ◽

Unstable Plaques ◽

Axis View

[Background and Purpose] In carotid stenosis, thin fibrous cap, as one of the characteristics of unstable plaques, have been thought to be an important risk factor for plaque rupture and acute cerebral ischemic events. A study reported there was good agreement between ultrasonographic and pathological fibrous cap thickness(FCT). The fibrous cap of ultrasound image in this study, however, was not measured at the same location in pathology. So, we precisely aligned ultrasonographic images with pathology in carotid plaques by advanced ultrasound with global position system (GPS)-like positon-sensing technology, and examined the characteristics of fibrous cap in rupture-prone plaques. [Methods and Results] 24 patients(symptomatic=18, asymptomatic=6) undergoing carotid endarterectomy for carotid stenosis between June 2010 and January 2011 were subjected in this study. We performed carotid ultrasound using a LOGIQ E9(GE Healthcare) within three days before carotid endarterectomy. Three-dimensinal images with the positonal information were obtained using an electromagnetic transmitter and sensors mounted on a linear probe. Endarterectomy specimens were cut every 3mm from carotid bifurcation in the short axis view. The three-dimensinal images alined with the specimens were extracted every 3mm of the same location in the short axis view. We measured maximal and minimal FCT in these ultrasonographic and pathological images. There was a positive relation(r=0.74) between fibrous cap thickness in pathology(maximal FCT =571μm[93 to 1062]) and ultrasound(maximal FCT =439μm[242 to 809]). Maximal FCT in pathology was significantly less in the pathologically ruptured plaques(n=16) than in the nonrupured plaques(n=8) (456μm VS 803μm, P<0.05). In contrast, maximal FCT in ultrasound had no difference in the two groups(389μm VS 497μm, P=0.09). In pathology fibrous cap was ruptured in 16 patients(67%, minimal FCT=0μm), and thin, restored and sparse though nonruptured in other 5 patients(21%, minimal FCT=177μm[50 to 339]). At the same location, the fibrous cap of ultrasound image disappeared in all these 21 patients. The other 3 patients(13%) without plaque rupture showed thick fibrous cap in pathology(minimal FCT =301μm[279 to 325]) and ultrasound(minimal FCT =283μm[250 to 300]). [Conclusions] Using advanced ultrasound with GPS-like technology, we were able to examine the pathological characteristics of fibrous cap in ultrasound in detail. It is difficult to sort out preoperatively more pathologically unstable plaques only by measuring FCT in ultrasound. Ultrasonographic disappearance of fibrous cap is more significant sign of pathologically unstable plaques.

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Abstract 13: Macrophage Erk5 Activation Induced by Apoptotic Cells and Statins Promotes Efferocytosis and Inhibits Atherosclerosis Formation

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.33.suppl_1.a13 ◽

2013 ◽

Vol 33 (suppl_1) ◽

Author(s):

Kyungsun Heo ◽

Hannah Cushman ◽

Chang-Hoon Woo ◽

Masashi Akaike ◽

Xin Wang ◽

...

Keyword(s):

Apoptotic Cell ◽

Cardiac Risk ◽

Necrotic Core ◽

High Cholesterol Diet ◽

Apoptotic Cells ◽

Phagocytic Capacity ◽

Fibrous Cap ◽

Cell Accumulation ◽

Fibrous Cap Thickness ◽

Dying Cells

Backgrounds Defective efferocytosis (phagocytic clearance of dying cells) is critically linked to progression of advanced atherosclerotic lesions. Although it has been well known that efferocytosis is processed by molecules including eat-me and find-me signals, it is unclear how efferocytosis becomes defective in advanced lesion. Methods and Results Here, we found that bone marrow-derived macrophages (BMDM) from macrophage-specific ERK5 knockout (ERK5 fl/fl LysM Cre +/- ; ERK5-MKO) mice reduced mRNA and proteins levels of efferocytosis-related signaling molecules such as Mer-tK, C1qa, C1qb, C1qc, Gas6, Mfg-e8, Thbs1, and Anxa1 compared with BMDM from non-transgenic control (NLC) mice. Interestingly, addition of apoptotic cells and pitavastatin activate ERK5 kinase activity and increase opsonins, eat-me and find-me signals, and phagocytic capacity toward apoptotic cells in normal macrophage, but macrophages from ERK5-MKO failed to respond in this manner. ERK5-MKO crossed to LDLR -/- mice and fed a high cholesterol diet for 16-week accelerated atherosclerosis formation with an increased level of apoptotic cell accumulation and necrotic core formation, which was accompanied by a significant reduction in collagen content and fibrous cap thickness. We also found lower levels of expression for Mfg-e8 and Thbs1 in the advanced necrotic core of ERK5-MKO mice compared to NLC mice. Conclusion Our study shows that apoptotic cells and statins-activated ERK5 plays a key role in coordinating the process of efferocytosis. Our results provide a mechanistic understanding of the clinically well-described cardiac risk of acute atherothrombotic events in advanced lesions. 1

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Necrotic core thickness and positive arterial remodeling index: emergent biomechanical factors for evaluating the risk of plaque rupture

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00005.2008 ◽

2008 ◽

Vol 295 (2) ◽

pp. H717-H727 ◽

Cited By ~ 150

Author(s):

Jacques Ohayon ◽

Gérard Finet ◽

Ahmed M. Gharib ◽

Daniel A. Herzka ◽

Philippe Tracqui ◽

...

Keyword(s):

Plaque Rupture ◽

Necrotic Core ◽

Plaque Morphology ◽

Arterial Remodeling ◽

Plaque Instability ◽

Fibrous Cap ◽

Remodeling Index ◽

Core Thickness ◽

Fibrous Cap Thickness ◽

Biomechanical Factors

Fibrous cap thickness is often considered as diagnostic of the degree of plaque instability. Necrotic core area (Corearea) and the arterial remodeling index (Remodindex), on the other hand, are difficult to use as clinical morphological indexes: literature data show a wide dispersion of Corearea thresholds above which plaque becomes unstable. Although histopathology shows a strong correlation between Corearea and Remodindex, it remains unclear how these interact and affect peak cap stress (Capstress), a known predictor of rupture. The aim of this study was to investigate the change in plaque vulnerability as a function of necrotic core size and plaque morphology. Capstress value was calculated on 5,500 idealized atherosclerotic vessel models that had the original feature of mimicking the positive arterial remodeling process described by Glagov. Twenty-four nonruptured plaques acquired by intravascular ultrasound on patients were used to test the performance of the associated idealized morphological models. Taking advantage of the extensive simulations, we investigated the effects of anatomical plaque features on Capstress. It was found that: 1) at the early stages of positive remodeling, lesions were more prone to rupture, which could explain the progression and growth of clinically silent plaques and 2) in addition to cap thickness, necrotic core thickness, rather than area, was critical in determining plaque stability. This study demonstrates that plaque instability is to be viewed not as a consequence of fibrous cap thickness alone but rather as a combination of cap thickness, necrotic core thickness, and the arterial remodeling index.

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Correction to: Mitochondrial Respiration Is Reduced in Atherosclerosis, Promoting Necrotic Core Formation and Reducing Relative Fibrous Cap Thickness

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atv.0000000000000071 ◽

2018 ◽

Vol 38 (7) ◽

Keyword(s):

Mitochondrial Respiration ◽

Necrotic Core ◽

Core Formation ◽

Fibrous Cap ◽

Fibrous Cap Thickness

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Abstract P408: Mesenchymal Stem Cell-derived Angptl4 Improves Endothelial Permeability And Resolution Of Inflammation In Atherosclerosis

Circulation Research ◽

10.1161/res.129.suppl_1.p408 ◽

2021 ◽

Vol 129 (Suppl_1) ◽

Author(s):

Dong-im Cho ◽

Yong Sook Kim ◽

Youngkeun Ahn

Keyword(s):

Endothelial Permeability ◽

Necrotic Core ◽

Vascular Lesions ◽

Blue Dye ◽

Vascular Events ◽

Vascular Integrity ◽

Fibrous Cap ◽

Vascular Stability ◽

Fibrous Cap Thickness ◽

Inflammatory Molecules

Objective: Given the fundamental contribution of inflammation to atherosclerosis, we studied the effect of ANGPTL4 in regulating vascular lesions during atherosclerosis. Methods and Results: We analyzed plasma levels of ANGPTL4 and found that acute myocardial infarction (AMI) patients with higher levels of ANGPTL4 had fewer vascular events than did patients with lower ANGPTL4 levels ( p <0.05). Moreover, in AMI patients with heart failure (HF) at admission, the recurrence of HF was lower in patients with a higher level of ANGPTL4. We then investigated the therapeutic application of ANGPTL4 in an atherosclerosis model. Apoe-/- mice fed a high-fat diet were injected with PBS or ANGPTL4 protein (2 μg per mouse, i.p. ) three times per week for 7 weeks. En face staining and mRNA analysis showed that plaque size, necrotic core area, lipid accumulation, and inflammatory molecules were greatly reduced in the ANGPTL4 group. Aortic permeability, measured by leakage of Evans blue dye, was significantly decreased in the ANGPTL4 group. The induction of pro-inflammatory mediators was significantly inhibited in endothelial cells, vascular smooth muscle cells, and macrophages by ANGPTL4 treatment. Endothelial Krüppel-like factor 2 (KLF2) and VE-cadherin were restored to contribute to maintenance of vascular integrity by ANGPTL4 treatment. Elevated levels of circulating leptin, interleukin-6, and interleukin-1β were profoundly reduced. Most importantly, the fibrous cap was significant thicker in the ANGPTL4 group than in the PBS group. Conclusions: ANGPTL4 treatment attenuated atherogenesis, which suggests that targeting vascular stability and inflammation may serve as a novel therapeutic strategy to prevent and treat atherosclerosis. More importantly, ANGPTL4 treatment inhibits necrotic core formation in lesions, leading to the formation of more stable plaques as evidenced by increased fibrous cap thickness.

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In Vivo Quantitative Measurement of Intact Fibrous Cap and Lipid-Rich Necrotic Core Size in Atherosclerotic Carotid Plaque

Circulation ◽

10.1161/circulationaha.104.528174 ◽

2005 ◽

Vol 112 (22) ◽

pp. 3437-3444 ◽

Cited By ~ 367

Author(s):

Jianming Cai ◽

Thomas S. Hatsukami ◽

Marina S. Ferguson ◽

William S. Kerwin ◽

Tobias Saam ◽

...

Keyword(s):

Carotid Plaque ◽

Quantitative Measurement ◽

Necrotic Core ◽

Core Size ◽

Fibrous Cap

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3284Quantification of macrophage presence and identification of thin-cap fibroatheroma by optical coherence tomography image: histopathological validation study

European Heart Journal ◽

10.1093/eurheartj/ehz745.0055 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

K Fujii ◽

R Kawakami ◽

T Imanaka ◽

H Shibutani ◽

K Kawai ◽

...

Keyword(s):

Optical Coherence Tomography ◽

Predictive Value ◽

Vulnerable Plaque ◽

Necrotic Core ◽

Macrophage Infiltration ◽

Optical Coherence ◽

Signal Attenuation ◽

Fibrous Cap ◽

Attenuation Ratio ◽

Fibrous Cap Thickness

Abstract Background Intracoronary optical coherence tomography (OCT) is thought to be capable of identifying a vulnerable, rupture-prone plaque based on the presence of a thin-cap fibroatheroma (TCFA). Moreover, recent studies have reported that OCT may be able to identify macrophage infiltration of the fibrous cap, a key characteristic of vulnerable plaque. Purpose This study evaluated the accuracy of OCT image for characterizing TCFA and identifying macrophage infiltration in comparison with histopathology. Methods A total of 924 focal plaques in 206 coronary arteries from 78 autopsy hearts were examined to compare OCT and histological images. By histology, 16 plaques (1.7%) were classified as TCFAsthat contained a large necrotic core covered by a thin (<65μm) fibrous-cap. Correlating OCT-histological sections were identified and OCT-derived tissue property indexes named normalized standard deviation (NSD) and signal attenuation ratio were applied on the fibrous-cap to identify inflamed fibrous-cap defined as a macrophage percentage >10% by histology. Results With histology as standard, the sensitivity, specificity, and negative-predictive-value of TCFAs were extremely high (more than 90%). However, the positive-predictive-value of TCFAs was only 32%, which indicated a high proportion of false-positives. Most false-positive diagnoses of OCT for TCFAs contained large amounts of foam cell accumulations on luminal surface without necrotic core. Twelve of 16 fibrous-caps were considered as inflamed and the remaining 4 were non-inflamed on histology. However, no significant difference in NSD and signal attenuation ratio were identified between them. There was moderate correlation of the fibrous-cap thickness between OCT and histology (r2 = 0.41 and p<0.01). Conclusions OCT is a promising intracoronary imaging modality for differentiating tissue characteristics (fibrous, calcified, or lipid-rich plaque) and identifying TCFA. However, it is still challenging to precisely identify inflammation, fibrous-cap thickness, and necrotic core in the native coronary artery. Therefore, careful interpretation is required to assess coronary vulnerable plaque by OCT. Acknowledgement/Funding None

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The impact of vildagliptin on the daily glucose profile and coronary plaque stability in impaired glucose tolerance patients with coronary artery disease: VOGUE—A multicenter randomized controlled trial

BMC Cardiovascular Disorders ◽

10.1186/s12872-021-01902-0 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Hiroyuki Yamamoto ◽

Akihide Konishi ◽

Toshiro Shinke ◽

Hiromasa Otake ◽

Masaru Kuroda ◽

...

Keyword(s):

Coronary Artery Disease ◽

Controlled Trial ◽

Control Group ◽

Randomized Controlled ◽

Fibrous Cap ◽

Multicenter Randomized Controlled Trial ◽

The Mean ◽

Artery Disease ◽

Fibrous Cap Thickness ◽

The Impact

Abstract Background The impact of reduction in glycemic excursion on coronary plaques remains unknown. This study aimed to elucidate whether a dipeptidyl peptidase 4 inhibitor could reduce the glycemic excursion and stabilize the coronary plaques compared with conventional management in coronary artery disease (CAD) patients with impaired glucose tolerance (IGT). Methods This was a multicenter, randomized controlled trial including CAD patients with IGT under lipid-lowering therapy receiving either vildagliptin (50 mg once a day) or no medication (control group) regarding glycemic treatment. The primary endpoint was changes in the minimum fibrous cap thickness and lipid arc in non-significant native coronary plaques detected by optical coherence tomography at 6 months after intervention. Glycemic variability expressed as the mean amplitude of glycemic excursion (MAGE) measured with a continuous glucose monitoring system was evaluated before and 6 months after intervention. Results A total of 20 participants with 47 lesions were allocated to either the vildagliptin group (10 participants, 22 lesions) or the control group (10 participants, 25 lesions). The adjusted difference of mean changes between the groups was − 18.8 mg/dl (95% confidence interval, − 30.8 to − 6.8) (p = 0.0064) for the MAGE (vildagliptin, − 20.1 ± 18.0 mg/dl vs. control, 2.6 ± 12.7 mg/dl), − 22.8° (− 40.6° to − 5.1°) (p = 0.0012) for the mean lipid arc (vildagliptin, − 9.0° ± 25.5° vs. control, 15.8° ± 16.8°), and 42.7 μm (15.3 to 70.1 μm) (p = 0.0022) for the minimum fibrous cap thickness (vildagliptin, 35.7 ± 50.8 μm vs. control, − 15.1 ± 25.2 μm). Conclusions Vildagliptin could reduce the MAGE at 6 months and may be associated with the decreased lipid arc and increased minimum FCT of the coronary plaques in CAD patients with IGT as compared with the control group. These findings may represent its potential stabilization effect on coronary plaques, which are characteristic in this patient subset. Trial registration Registered in the UMIN clinical trial registry (UMIN000008620), Name of the registry: VOGUE trial, Date of registration: Aug 6, 2012, URL: https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000010058

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