Diagnostics Accuracy of Magnetic Resonance Imaging in Detection of Atherosclerotic Plaque Characteristics in Carotid Arteries Compared to Histology: A Systematic Review.

Carotid plaque composition represents one of the main risk factors of future ischemic stroke. MRI provides excellent soft tissue contrast that can distinguish plaque characteristics. Our objective was to analyze the diagnostic accuracy of MRI imaging in the detection of carotid plaque characteristics compared to histology in patients with symptomatic and asymptomatic carotid atherosclerosis through a systematic review. After prospective registration in PROSPERO (ID CRD42022329690), Medline Ovid, Embase.com, Cochrane Library, and Web of Science Core were searched without any search limitation up to May 27, 2022 to identify eligible articles. Of the 8168 studies, 53 (37 × 1.5 T MRI, 17 × 3 T MRI) evaluated MRI accuracy in the detection of 13 specific carotid plaque characteristics in 169 comparisons. MRI demonstrated high diagnostic accuracy for detection of calcification (3 T MRI: mean sensitivity 92%/mean specificity 90%; 1.5 T MRI: mean sensitivity 81%/mean specificity 91%), fibrous cap (1.5 T: 89%/87%), unstable plaque (1.5 T: 89%/87%), intraplaque hemorrhage (1.5 T: 86%/88%), and lipid-rich necrotic core (1.5 T: 89%/79%). MRI also proved to have a high level of tissue discrimination for the carotid plaque characteristics investigated, allowing potentially for a better risk assessment and follow-up of patients who may benefit from more aggressive treatments. These results emphasize the role of MRI as the first-line imaging modality for comprehensive assessment of carotid plaque morphology, particularly for unstable plaque. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 2.

Cyclophilin D induces necrotic core formation by mediating mitochondria-associated macrophage death in advanced atherosclerotic lesions.

BACKGROUND AND AIMS: In advanced atherosclerotic lesions, macrophage deaths result in necrotic core formation and plaque vulnerability. Cyclophilin D (CypD) is a mitochondria-specific cyclophilin involved in the process of cell death after organ ischemia-reperfusion. However, the role of CypD in atherosclerosis, especially in necrotic core formation, is unknown. Therefore, this experiment aims to clarify the role of CypD in necrotic core formation. METHODS: To clarify the specific role of CypD, encoded by Ppif in mice, apolipoprotein-E/CypD-double knockout (Apoe-/-Ppif-/-) mice were generated. These mice were fed a high-fat diet containing 0.15 % cholesterol for 24 weeks to accelerate atherosclerotic lesion development. RESULTS: Deletion of CypD decreased the necrotic core size, accompanied by a reduction of macrophage apoptosis compared to control Apoe-/- mice. In RAW264.7 cells, siRNA-mediated knockdown of CypD attenuated the release of cytochrome c from the mitochondria to the cytosol induced by endoplasmic reticulum stress inducer thapsigargin. In addition, necroptosis, induced by TNF-α and caspase inhibitor, was attenuated by knockdown of CypD. Ly-6Chigh inflammatory monocytes in peripheral blood leukocytes and mRNA expression of Il1b in the aorta were decreased by deletion of CypD. In contrast, siRNA-mediated knockdown of CypD did not significantly decrease Il1b nor Ccl2 mRNA expression in RAW264.7 cells treated with LPS and IFN-γ, suggesting that inhibition of inflammation in vivo is likely due to decreased cell death in the atherosclerotic lesions rather than a direct action of CypD deletion on the macrophage. CONCLUSIONS: These results indicate that CypD induces macrophage death and mediates necrotic core formation in advanced atherosclerotic lesions. CypD could be a novel therapeutic target for treating atherosclerotic vascular diseases.

Computational model of the cancer necrotic core formation in a tumor-on-a-chip device.

The mechanisms underlying the formation of necrotic regions within avascular tumors are complex and poorly understood. In this paper, we investigate the formation of a necrotic core in a 3D tumor cell culture within a microfluidic device, considering oxygen, nutrients, and the microenvironment acidification by means of a computational-mathematical model. Our objective is to simulate cell processes, including proliferation and death inside a microfluidic device, according to the microenvironmental conditions. We employed approximation utilizing finite element models taking into account glucose, oxygen, and hydrogen ions diffusion, consumption and production, as well as cell proliferation, migration and death, addressing how tumor cells evolve under different conditions. The resulting mathematical model was examined under different scenarios, being capable of reproducing cell death and proliferation under different cell concentrations, and the formation of a necrotic core, in good agreement with experimental data reported in the literature. This approach not only advances our fundamental understanding of necrotic core formation but also provides a robust computational platform to study personalized therapeutic strategies, offering an important tool in cancer research and treatment design.

Establishment and Validation of a Model for Fetal Neural Ischemia Using Necrotic Core-Free Human Spinal Cord Organoids.

Fetal spinal cord ischemia is a serious medical condition that can result in significant neurological damage and adverse outcomes for the fetus. However, the lack of an appropriate experimental model has hindered the understanding of the pathology and the development of effective treatments. In our study, we established a system for screening drugs that affect fetal spinal cord ischemia using spinal cord organoids. Importantly, we produced necrotic core-free human spinal cord organoids (nf-hSCOs) by reducing the organoid size to avoid potential complications of spontaneous necrosis in large organoids. Exposing nf-hSCOs to CoCl2 as a hypoxia mimetic and hypoglycemic conditions resulted in significant neuronal damage, as assessed by multiple assay batteries. By utilizing this model, we tested chemicals that have been reported to exhibit beneficial effects in brain organoid-based ischemia models. Surprisingly, these chemicals did not provide sufficient benefit, and we discovered that rapamycin is a mild neuroprotective reagent for both axon degeneration and neuronal survival. We propose that nf-hSCO is suitable for large-scale screening of fetal neural ischemia due to its scalability, ease of ischemic induction, implementation of quantifiable assay batteries, and the absence of spontaneous necrosis.

Haemodynamic Effects on the Development and Stability of Atherosclerotic Plaques in Arterial Blood Vessel.

Studying the formation and stability of atherosclerotic plaques in the hemodynamic field is essential for understanding the growth mechanism and preventive treatment of atherosclerotic plaques. In this paper, based on a multiplayer porous wall model, we established a two-way fluid-solid interaction with time-varying inlet flow. The lipid-rich necrotic core (LRNC) and stress in atherosclerotic plaque were described for analyzing the stability of atherosclerotic plaques during the plaque growth by solving advection-diffusion-reaction equations with finite-element method. It was found that LRNC appeared when the lipid levels of apoptotic materials (such as macrophages, foam cells) in the plaque reached a specified lower concentration, and increased with the plaque growth. LRNC was positively correlated with the blood pressure and was negatively correlated with the blood flow velocity. The maximum stress was mainly located at the necrotic core and gradually moved toward the left shoulder of the plaque with the plaque growth, which increases the plaque instability and the risk of the plaque shedding. The computational model may contribute to understanding the mechanisms of early atherosclerotic plaque growth and the risk of instability in the plaque growth.

Metastasis from the tumor interior and necrotic core formation are regulated by breast cancer-derived angiopoietin-like 7.

Necrosis in the tumor interior is a common feature of aggressive cancers that is associated with poor clinical prognosis and the development of metastasis. How the necrotic core promotes metastasis remains unclear. Here, we report that emergence of necrosis inside the tumor is correlated temporally with increased tumor dissemination in a rat breast cancer model and in human breast cancer patients. By performing spatially focused transcriptional profiling, we identified angiopoietin-like 7 (Angptl7) as a tumor-specific factor localized to the perinecrotic zone. Functional studies showed that Angptl7 loss normalizes central necrosis, perinecrotic dilated vessels, metastasis, and reduces circulating tumor cell counts to nearly zero. Mechanistically, Angptl7 promotes vascular permeability and supports vascular remodeling in the perinecrotic zone. Taken together, these findings show that breast tumors actively produce factors controlling central necrosis formation and metastatic dissemination from the tumor core.

Association of Circulating Neutrophils with Relative Volume of Lipid-Rich Necrotic Core of Coronary Plaques in Stable Patients: A Substudy of SMARTool European Project.

BACKGROUND AND AIMS: Coronary atherosclerosis is a chronic non-resolving inflammatory process wherein the interaction of innate immune cells and platelets plays a major role. Circulating neutrophils, in particular, adhere to the activated endothelium and migrate into the vascular wall, promoting monocyte recruitment and influencing plaque phenotype and stability at all stages of its evolution. We aimed to evaluate, by flow cytometry, if blood neutrophil number and phenotype-including their phenotypic relationships with platelets, monocytes and lymphocytes-have an association with lipid-rich necrotic core volume (LRNCV), a generic index of coronary plaque vulnerability, in a group of stable patients with chronic coronary syndrome (CCS). METHODS: In 55 patients, (68.53 ± 1.07 years of age, mean ± SEM; 71% male), the total LRNCV in each subject was assessed by a quantitative analysis of all coronary plaques detected by computed tomography coronary angiography (CTCA) and was normalized to the total plaque volume. The expression of CD14, CD16, CD18, CD11b, HLA-DR, CD163, CCR2, CCR5, CX3CR1, CXCR4 and CD41a cell surface markers was quantified by flow cytometry. Adhesion molecules, cytokines and chemokines, as well as MMP9 plasma levels, were measured by ELISA. RESULTS: On a per-patient basis, LRNCV values were positively associated, by a multiple regression analysis, with the neutrophil count (n°/µL) (p = 0.02), neutrophil/lymphocyte ratio (p = 0.007), neutrophil/platelet ratio (p = 0.01), neutrophil RFI CD11b expression (p = 0.02) and neutrophil-platelet adhesion index (p = 0.01). Significantly positive multiple regression associations of LRNCV values with phenotypic ratios between neutrophil RFI CD11b expression and several lymphocyte and monocyte surface markers were also observed. In the bivariate correlation analysis, a significantly positive association was found between RFI values of neutrophil-CD41a+ complexes and neutrophil RFI CD11b expression (p < 0.0001). CONCLUSIONS: These preliminary findings suggest that a sustained increase in circulating neutrophils, together with the up-regulation of the integrin/activation membrane neutrophil marker CD11b may contribute, through the progressive intra-plaque accumulation of necrotic/apoptotic cells exceeding the efferocytosis/anti-inflammatory capacity of infiltrating macrophages and lymphocytes, to the relative enlargement of the lipid-rich necrotic core volume of coronary plaques in stable CAD patients, thus increasing their individual risk of acute complication.

Bifurcation analysis of a free boundary model of vascular tumor growth with a necrotic core and chemotaxis.

A considerable number of research works has been devoted to the study of tumor models. Several biophysical factors, such as cell proliferation, apoptosis, chemotaxis, angiogenesis and necrosis, have been discovered to have an impact on the complicated biological system of tumors. An indicator of the aggressiveness of tumor development is the instability of the shape of the tumor boundary. Complex patterns of tumor morphology have been explored in Lu et al. (J Comput Phys 459:111153, 2022). In this paper, we continue to carry out a bifurcation analysis on such a vascular tumor model with a controlled necrotic core and chemotaxis. This bifurcation analysis, to the parameter of cell proliferation, is built on the explicit formulas of radially symmetric steady-state solutions. By perturbing the tumor free boundary and establishing rigorous estimates of the free boundary system, we prove the existence of the bifurcation branches with Crandall-Rabinowitz theorem. The parameter of chemotaxis is found to influence the monotonicity of the bifurcation point as the mode l increases both theoretically and numerically.

Differences in Plaque Characteristics and Myocardial Mass: Implications for Physiological Significance.

Background: The mechanism of the fractional flow reserve (FFR) difference according to sex has not been clearly understood. Objectives: This study sought to evaluate sex differences in coronary stenosis, plaque characteristics, and left ventricular (LV) mass and their implications for physiological significance. Methods: This was a post hoc analysis of a pooled population of multicenter, international prospective cohorts. Patients (166 women and 489 men) underwent coronary computed tomography angiography (CCTA) within 90 days before invasive FFR measurements were included. The minimal lumen area, percent of plaque burden, whole vessel plaque volume by composition, high-risk plaque characteristics, and LV mass were analyzed from CCTA images. Results: Among 1,188 vessels analyzed, the FFR value was higher in women than that in men (0.85 ± 0.13 vs 0.82 ± 0.14; P = 0.001) despite a similar percentage of diameter stenosis between the sexes (45.9% ± 18.9% vs 46.1% ± 17.7%; P = 0.920). The composition of fibrofatty plaque + necrotic core (13.1% ± 16.9% vs 21.2% ± 19.9%; P < 0.001) and frequencies of low attenuation plaque (12.7% vs 24.5%; P < 0.001) and positive remodeling (33.8% vs 45.5%; P = 0.001) were lower in women than in men. Vessel, plaque, and lumen volumes were significantly smaller in women than that in men (all P < 0.001); however, no sex difference was observed in any of these parameters after adjustment for LV mass (all P > 0.10). Sex was not an independent predictor of the FFR value after adjustment for stenosis severity, plaque characteristics, and LV mass. Conclusions: Higher FFR values for the same stenosis severity in women can be explained by fewer high-risk plaque characteristics and smaller myocardial mass in women than that in men. (CCTA-FFR Registry for Risk Prediction; NCT04037163).

Assessing Efferocytosis in Atherosclerotic Lesions In Situ.

Whereas most atherosclerotic lesions are relatively benign, some plaques with large necrotic cores and thin fibrous caps are vulnerable to rupture, which results in many cardiovascular events and sudden death. Defects in the clearance of apoptotic cells, termed "efferocytosis," is the leading cause of necrotic core expansion. This chapter describes a method that identifies macrophage-associated terminal deoxynucleotidyl transferase (TUNEL)-positive events (i.e., efferocytosis events) and TUNEL events free from association with macrophages (i.e., uncleared apoptotic events) in atherosclerotic lesions. This assay has been critical to the understanding of how clinically dangerous atherosclerotic plaques form and will remain a crucial assay that reveals new insights into how macrophages carry out efferocytosis and how this process becomes defective as atherosclerosis advances.

Elimination of Ox-LDL through the liver inhibits advanced atherosclerotic plaque progression.

Aim: In the late stage of atherosclerosis, the endothelial barrier of plaque is destroyed. The rapid deposition of oxidized lipids in the circulation leads to migration of numerous smooth muscle cells and macrophages, as well as foaming necrosis. The plaque progresses rapidly, and vulnerable plaques can easily induce adverse cardiovascular events. Here, we take the principle of gene editing to transfer the liver to express the LOX-1 receptor which is more sensitive to Ox-LDL by using AAV8 containing a liver-specific promoter. In this way, we want to explore whether the progress of advanced atherosclerosis and the stability of advanced plaque can be improved when the liver continues to clear Ox-LDL from the circulation. Methods and Results: In order to explore the effect of the physiological and continuous elimination of Ox-LDL through the liver on advanced atherosclerosis, we chose ApoE-/- mice in high-fat diet for 20 weeks. After 16 weeks of high-fat diet, the baseline group was sacrificed and the specimens were collected. The virus group and the control group were injected with the same amount of virus dilution and normal saline through the tail vein, and continued to feed until 20 weeks of high-fat diet, and then sacrificed to collect specimens. The results showed that LOX-1 was ectopically and functionally expressed in the liver as an Ox-LDL receptor, reducing the content of it in circulation. Compared with the control group, the degree of plaque progression in the virus group was significantly reduced, similar to the baseline group, the plaque necrosis core decreased, and the collagen fiber content increased. In addition, there are more contractile smooth muscle cells in the plaques of the virus group instead of synthetic ones, and the content of macrophages was also reduced. These data suggested that the virus group mice have greatly increased advanced plaque stability compared with the control group mice. Conclusions: Due to the destruction of endothelial barrier in advanced plaques, rapid deposition of Ox-LDL can result in fast plaque progression, increased necrotic cores, and decreased stability. Our research shows that the use of AAV8 through gene editing allows the liver to express LOX-1 receptors that are more sensitive to Ox-LDL, so that it can continue to bind Ox-LDL in the circulation and exploit the liver's strong lipid metabolism ability to physiologically clear Ox-LDL, which can inhibit the rapid progress of advanced plaque and increase the stability of plaque.

Considerations for Whole-Slide Analysis of Murine Xenografts Experiments.

Histochemistry of tumor sections is a widely employed technique utilized to examine cell death in preclinical xenograft animal models of cancer. However, this is under the assumption that tumors are homogeneous, leading to practices such as automatic cell counting across the entire section. We have noted that in our experiments the core of the tumor is largely or partially necrotic, and lacks evidence of vascularization (in contrast to the outer areas of the tumor). We note that this can bias and confound immunohistochemical analyses that do not take care to sample areas of interest in a way to take this into account. Design-based stereology with image analysis techniques is an alternative process that could be used to measure the volume of the necrotic region compared to the volume of the whole tumor.

Myeloid-associated lipin-1 transcriptional co-regulatory activity is atheroprotective.

BACKGROUND AND AIMS: Atherosclerosis is the most prominent underlying cause of cardiovascular disease (CVD). It is initiated by cholesterol deposition in the arterial intima, which causes macrophage recruitment and proinflammatory responses that promote plaque growth, necrotic core formation, and plaque rupture. Lipin-1 is a phosphatidic acid phosphohydrolase for glycerolipid synthesis. We have shown that lipin-1 phosphatase activity promotes macrophage pro-inflammatory responses when stimulated with modified low-density lipoprotein (modLDL) and accelerates atherosclerosis. Lipin-1 also independently acts as a transcriptional co-regulator where it enhances the expression of genes involved in ß-oxidation. In hepatocytes and adipocytes, lipin-1 augments the activity of transcription factors such as peroxisome proliferator-activated receptor (PPARs). PPARs control the expression of anti-inflammatory genes in macrophages and slow or reduce atherosclerotic progression. Therefore, we hypothesize myeloid-derived lipin-1 transcriptional co-regulatory activity reduces atherosclerosis. METHODS: We used myeloid-derived lipin-1 knockout (lipin-1mKO) and littermate control mice and AAV8-PCSK9 along with high-fat diet to elicit atherosclerosis. RESULTS: Lipin-1mKO mice had larger aortic root plaques than littermate control mice after 8 and 12 weeks of a high-fat diet. Lipin-1mKO mice also had increased serum proinflammatory cytokine concentrations, reduced apoptosis in plaques, and larger necrotic cores in the plaques compared to control mice. CONCLUSIONS: Combined, the data suggest lipin-1 transcriptional co-regulatory activity in myeloid cells is atheroprotective.

Dead cell and debris clearance in the atherosclerotic plaque: Mechanisms and therapeutic opportunities to promote inflammation resolution.

Phagocytic clearance of dead cells and debris is critical for inflammation resolution and maintenance of tissue homeostasis. Consequently, defective clearance of dead cells and debris is associated with initiation and exacerbation of several autoimmune disorders and chronic inflammatory diseases such as atherosclerosis. The progressive loss of dead cell clearance capacity within the atherosclerotic plaque leads to accumulation of necrotic cells, chronic non-resolving inflammation, and expansion of the necrotic core, which triggers atherosclerotic plaque rupture and clinical manifestation of acute thrombotic cardiovascular adverse events. In this review, we describe the fundamental molecular and cellular mechanisms of dead cell clearance and how it goes awry in atherosclerosis. Finally, we highlight novel therapeutic strategies that enhance dead cell and debris clearance within the atherosclerotic plaque to promote inflammation resolution and atherosclerotic plaque stabilization.

Micro Optical Coherence Tomography for Coronary Imaging.

Intravascular optical coherence tomography (IVOCT) that produces images with 10 µm resolution has emerged as a significant technology for evaluating coronary architectural morphology. Yet, many features that are relevant to coronary plaque pathogenesis can only be seen at the cellular level. This issue has motivated the development of a next-generation form of OCT imaging that offers higher resolution. One such technology that we review here is termed micro-OCT (µOCT) that enables the assessment of the cellular and subcellular morphology of human coronary atherosclerotic plaques. This chapter reviews recent advances and ongoing works regarding µOCT in the field of cardiology. This new technology has the potential to provide researchers and clinicians with a tool to better understand the natural history of coronary atherosclerosis, increase plaque progression prediction capabilities, and better assess the vessel healing process after revascularization therapy.

Classifications of atherosclerotic plaque components with T1 and T2* mapping in 11.7 T MRI.

BACKGROUND AND AIMS: Histopathology is the gold standard for analysis of atherosclerotic plaques but has drawbacks due to the destructive nature of the method. Ex vivo MRI is a non-destructive method to image whole plaques. Our aim was to use quantitative high field ex vivo MRI to classify plaque components, with histology as gold standard. METHODS: Surgically resected carotid plaques from 12 patients with recent TIA or stroke were imaged at 11.7 T MRI. Quantitative T1/T2* mapping sequences and qualitative T1/T2* gradient echo sequences with voxel size of 30 × 30 × 60 µm3 were obtained prior to histological preparation, sectioning and staining for lipids, inflammation, hemorrhage, and fibrous tissue. Regions of interest (ROI) were selected based on the histological staining at multiple levels matched between histology and MRI. The MRI parameters of each ROI were then analyzed with quadratic discriminant analysis (QDA) for classification. RESULTS: A total of 965 ROIs, at 70 levels matched between histology and MRI, were registered based on histological staining. In the nine plaques where three or more plaque components were possible to co-localize with MRI, the mean degree of misclassification by QDA was 16.5 %. One of the plaques contained mostly fibrous tissue and lipids and had no misclassifications, and two plaques mostly contained fibrous tissue. QDA generally showed good classification for fibrous tissue and lipids, whereas plaques with hemorrhage and inflammation had more misclassifications. CONCLUSION: 11.7 T ex vivo high field MRI shows good visual agreement with histology in carotid plaques. T1/T2* maps analyzed with QDA is a promising non-destructive method to classify plaque components, but with a higher degree of misclassifications in plaques with hemorrhage or inflammation.

Prognostic Implications of Comprehensive Whole Vessel Plaque Quantification Using Coronary Computed Tomography Angiography.

Background: The prognostic value of whole vessel plaque quantification has not been fully understood. Objectives: We aimed to investigate the clinical relevance of whole vessel plaque quantification on coronary computed tomography angiography. Methods: In a total of 1,013 vessels with fractional flow reserve (FFR) measurement and available coronary computed tomography angiography, high-risk plaque characteristics (HRPC) included minimum lumen area <4 mm2, plaque burden ≥70%, low attenuation plaque, positive remodeling, spotty calcification, and napkin-ring sign; and high-risk vessel characteristics (HRVC) included total plaque volume ≥306.5 mm3, fibrofatty and necrotic core volume ≥4.46 mm3, or percent total atheroma volume ≥32.2% in a target vessel, based on corresponding optimal cutoff values. Survival analysis for vessel-oriented composite outcome (VOCO) (a composite of cardiac death, target vessel myocardial infarction, or target vessel revascularization) at 5 years was performed using marginal Cox proportional hazard models. Results: Whole vessel plaque quantification had incremental predictability in addition to % diameter stenosis and HRPC (P < 0.001) in predicting FFR ≤0.80. Among 517 deferred vessels based on FFR >0.80, the number of HRVC was significantly associated with the risk of VOCO (HR: 2.54; 95% CI: 1.77-3.64) and enhanced the predictability for VOCO of % diameter stenosis and the number of HRPC (P < 0.001). In a landmark analysis at 2 years, the number of HRVC showed sustained prognostic implications beyond 2 years, but the number of HRPC did not. Conclusions: Whole vessel plaque quantification can provide incremental predictability for low FFR and additive prognostic value in deferred vessels with high FFR over anatomical severity and lesion plaque characteristics. (CCTA-FFR Registry for Risk Prediction; NCT04037163).

The Interplay between Features of Plaque Vulnerability and Hemodynamic Relevance of Coronary Artery Stenoses.

Fractional flow reserve (FFR) may not be immune from hemodynamic perturbations caused by both vessel and lesion related factors. The aim of this study was to investigate the impact of plaque- and vessel wall-related features of vulnerability on the hemodynamic effect of intermediate coronary stenoses. Methods and Results: In this cross-sectional study, patients referred to catheterization laboratory for clinically indicated coronary angiography were prospectively screened for angiographically intermediate stenosis (50-80%). Seventy lesions from 60 patients were evaluated. Mean angiographic stenosis was 62.1 ± 16.3%. After having performed FFR assessment, intravascular ultrasound (IVUS) was performed over the FFR wire. Virtual histology IVUS was used to identify the plaque components and thin cap fibroatheroma (TCFA). TCFA was significantly more frequent (65 vs. 38%, p = 0.026), and necrotic core volume (26.15 ± 14.22 vs. 16.21 ± 8.93 mm3, p = 0.04) was significantly larger in the positively remodeled than non-remodeled vessels. Remodeling index correlated with necrotic core volume (r = 0.396, p = 0.001) and with FFR (r = -0. 419, p = 0.001). With respect to plaque components, only necrotic core area (r = -0.262, p = 0.038) and necrotic core volume (r = -0.272, p = 0.024) were independently associated with FFR. In the multivariable model, presence of TCFA was independently associated with significantly lower mean FFR value as compared to absence of TCFA (adjusted, 0.71 vs. 0.78, p = 0.034). Conclusion: The current study demonstrated that for a given stenosis geometry, features of plaque vulnerability such as necrotic core volume, TCFA, and positive remodeling may influence the hemodynamic relevance of intermediate coronary stenoses.

Association of culprit lesion plaque characteristics with flow restoration post-fibrinolysis in ST-segment elevation myocardial infarction: an intravascular ultrasound-virtual histology study.

BACKGROUND: Not every patient achieves normal coronary flow following fibrinolysis in STEMI (ST-segment elevation myocardial infarction). The culprit lesion plaque characteristics play a prominent role in the coronary flow before and during percutaneous coronary intervention. The main purpose was to determine the culprit lesion plaque features by virtual histology-intravascular ultrasound (VH-IVUS) in patients with STEMI following fibrinolysis in relation to baseline coronary angiogram TIMI (thrombolysis in myocardial infarction) flow. Pre-intervention IVUS was undertaken in 61 patients with STEMI after successful fibrinolysis. After the coronary angiogram, they were separated into the TIMI1-2 flow group (n = 31) and TIMI 3 flow group (n = 30). Culprit lesion plaque composition was evaluated by VH-IVUS. RESULTS: On gray-scale IVUS, the lesion external elastic membrane cross-sectional area (EEM CSA) was significantly higher in the TIMI 1-2 groups as compared to the TIMI 3 group (15.71 ± 3.73 mm2 vs 13.91 ± 2.94 mm2, p = 0.041) with no significant difference in plaque burden (82.42% vs. 81.65%, p = 0.306) and plaque volume (108.3 mm3 vs. 94.3 mm3, p = 0.194). On VH-IVUS, at the minimal luminal area site (MLS), the fibrous area (5.83 mm2 vs. 4.37 mm2, p = 0.024), necrotic core (NC) area (0.95 mm2 vs. 0.59 mm2, p < 0.001), and NC percentage (11% vs. 7.1%, p = 0.024) were higher in the TIMI 1-2 groups in contrast to the TIMI 3 group. The absolute necrotic core (NC) volume (8.3 mm3 vs. 3.65 mm3, p < 0.001) and NC percentage (9.3% vs. 6.0%, p = 0.007) were significantly higher in the TIMI 1-2 groups as compared to the TIMI 3 group. Absolute dense calcium (DC) volume was higher in TIMI 1-2 groups with a trend towards significance (1.0 mm3 vs.0.75 mm3, p = 0.051). In multivariate analysis, absolute NC volume was the only independent predictor of TIMI 1-2 flow (odds ratio = 1.561; 95% CI 1.202-2.026, p = 0.001). Receiver operating characteristic curves showed absolute NC volume has best diagnostic accuracy (AUC = 0.816, p < 0.001) to predict TIMI 1-2 flow with an optimal cutoff value of 4.5 mm3 with sensitivity and specificity of 79% and 61%, respectively. CONCLUSIONS: This study exemplifies that the necrotic core component of the culprit lesion plaque in STEMI is associated with the coronary flow after fibrinolysis. The absolute necrotic core volume is a key determinant of flow restoration post-fibrinolysis and aids in prognostication of less than TIMI 3 flow.

An integrated approach to simulating the vulnerable atherosclerotic plaque.

Analyses of individual atherosclerotic plaques are mostly descriptive, relying, for example, on histological classification by spectral analysis of ultrasound waves or staining and observing particular cellular components. Such passive methods have proved useful for characterizing the structure and vulnerability of plaques but have little quantitative predictive power. Our aim is to introduce and discuss a computational framework to provide insight to clinicians and help them visualize internal plaque dynamics. We use partial differential equations (PDEs) with macrophages, necrotic cells, oxidized lipids, oxygen concentration, and platelet-derived growth factor (PDGF) as primary variables coupled to a biomechanical model to describe vessel growth. The model is deterministic, providing mechanical, morphological, and histological characteristics of an atherosclerotic vessel at any desired future time point. We use our model to create computer-generated animations of a plaque evolution that are in qualitative agreement with published serial ultrasound images and hypothesize possible atherogenic mechanisms. A systems biology model consisting of five differential equations is able to capture the morphology of necrotic cores residing within vulnerable atherosclerotic plaque. In the context of the model, the distribution of oxidized low-density lipoprotein (Ox-LDL) particles, endothelial inflammation, plaque oxygenation (via the presence of vasa vasora), and intimal oxygenation are four important factors that drive changes in core morphology.NEW & NOTEWORTHY In this article, we propose a quantitative framework to describe the evolution of atherosclerotic plaque. We use partial differential equations (PDEs) with macrophages, necrotic cells, oxidized lipids, oxygen concentration, and PDGF as primary variables coupled to a biomechanical model to describe vessel growth. A feature of our method is that it outputs color-coded vessel sections corresponding to regions of the plaque that are necrotic and fibrous, qualitatively similar to images generated by enhanced intravascular ultrasound.