Plaque Components Research Articles

Plaque heterogeneity and the spatial distributions of its components dictate drug-coated balloon therapy

Drug-coated balloon (DCB) angioplasty is one of the potential approaches to alleviating in-stent restenosis and treating peripheral artery disease. An in-silico model has been developed for sirolimus drug eluted from an inflated balloon in a patient-specific arterial cross-section consisting of fibrous tissue, fibrofatty tissue, dense calcium, necrotic core, and healthy tissue. The convection-diffusion-reaction equation represents the transport of drug, while drug binding, both specific and non-specific, can be modelled as a reaction process. The Brinkman equations describe the interstitial flow in porous tissue. An image processing technique is leveraged for reconstructing the computational domain. The Marker and Cell, and Immersed Boundary Methods are used to solve the set of governing equations. The no-flux interface condition and convection do amplify the tissue content, and the regions of dense calcium and necrotic core limited to or extremely close to the interface pose a clinical threat to DCB therapy. Simulations predict the effects of the positioning and clustering of plaque components in the domain. This study demands extensive intravascular ultrasound-derived virtual histology (VH-IVUS) imaging to understand the plaque morphology and determine the relative positions of different plaque compositions about the lumen-tissue interface, which have a significant impact on arterial pharmacokinetics.

Identification of binding partners that facilitate membrane-type 5 matrix metalloproteinase (MT5-MMP) processing of amyloid precursor protein.

One of the pathological hallmarks of Alzheimer's disease (AD) is the presence of extracellular deposits of amyloid beta (Aβ) peptide. In addition to Aβ as the core component of the amyloid plaque, the amyloid precursor protein (APP) processing fragment Aβ was also found accumulated around the plaque. The APPη pathway, mainly mediated by membrane-type 5 matrix metalloproteinase (MT5-MMP), represents an important factor in AD pathogenesis. The proamyloidogenic features of MT5-MMP could result from interactions with APP when trafficking between organelles, so determination of the location within the cell of APPη cleavage and interacting proteins of MT5-MMP affecting this process will be of priority in understanding the role of MT5-MMP in AD. In the present study,MT5-MMP was found to be located in the nucleus, cytosol, and cytosolic subcellular granules of CHO cells that stably expressed wild-type human APP751. MT5-MMP fusion proteins were constructed that could localize enzyme production in the Golgi apparatus, endosome, ER, mitochondria, or plasma membrane. The fusion proteins significantly increased sAPPη when directed to the endosome, Golgi apparatus, plasma membrane, or mitochondria. Since the C-terminal region of MT5-MMP is responsible for its intracellular location and trafficking, this domain was used as the bait in a yeast two-hybrid screen to identify MT5-MMP protein partners in a human brain cDNA library. Identified binding partners included N4BP2L1, TMX3, EIG121, bridging Integrator 1(BIN1), RUFY4, HTRA1, and TMEM199. The binding of N4BP2L1, EIG121, BIN1, or TMX3 to MT5-MMP resulted in the most significant increase in sAPPη production. Thus, the action of MT5-MMP on APP occurs in multiple locations within the cell and is facilitated by site-specific binding partners.

Photodynamic Therapy for Atherosclerosis.

Atherosclerosis, which currently contributes to 31% of deaths globally, is of critical cardiovascular concern. Current diagnostic tools and biomarkers are limited, emphasizing the need for early detection. Lifestyle modifications and medications form the basis of treatment, and emerging therapies such as photodynamic therapy are being developed. Photodynamic therapy involves a photosensitizer selectively targeting components of atherosclerotic plaques. When activated by specific light wavelengths, it induces localized oxidative stress aiming to stabilize plaques and reduce inflammation. The key advantage lies in its selective targeting, sparing healthy tissues. While preclinical studies are encouraging, ongoing research and clinical trials are crucial for optimizing protocols and ensuring long-term safety and efficacy. The potential combination with other therapies makes photodynamic therapy a versatile and promising avenue for addressing atherosclerosis and associated cardiovascular disease. The investigations underscore the possibility of utilizing photodynamic therapy as a valuable treatment choice for atherosclerosis. As advancements in research continue, photodynamic therapy might become more seamlessly incorporated into clinical approaches for managing atherosclerosis, providing a blend of efficacy and limited invasiveness.

14-3-3 proteins-a moonlight protein complex with therapeutic potential in neurological disorder: in-depth review with Alzheimer's disease.

Alzheimer's disease (AD) affects millions of people worldwide and is a gradually worsening neurodegenerative condition. The accumulation of abnormal proteins, such as tau and beta-amyloid, in the brain is a hallmark of AD pathology. 14-3-3 proteins have been implicated in AD pathology in several ways. One proposed mechanism is that 14-3-3 proteins interact with tau protein and modulate its phosphorylation, aggregation, and toxicity. Tau is a protein associated with microtubules, playing a role in maintaining the structural integrity of neuronal cytoskeleton. However, in the context of Alzheimer's disease (AD), an abnormal increase in its phosphorylation occurs. This leads to the aggregation of tau into neurofibrillary tangles, which is a distinctive feature of this condition. Studies have shown that 14-3-3 proteins can bind to phosphorylated tau and regulate its function and stability. In addition, 14-3-3 proteins have been shown to interact with beta-amyloid (Aβ), the primary component of amyloid plaques in AD. 14-3-3 proteins can regulate the clearance of Aβ through the lysosomal degradation pathway by interacting with the lysosomal membrane protein LAMP2A. Dysfunction of lysosomal degradation pathway is thought to contribute to the accumulation of Aβ in the brain and the progression of AD. Furthermore, 14-3-3 proteins have been found to be downregulated in the brains of AD patients, suggesting that their dysregulation may contribute to AD pathology. For example, decreased levels of 14-3-3 proteins in cerebrospinal fluid have been suggested as a biomarker for AD. Overall, these findings suggest that 14-3-3 proteins may play an important role in AD pathology and may represent a potential therapeutic target for the disease. However, further research is needed to fully understand the mechanisms underlying the involvement of 14-3-3 proteins in AD and to explore their potential as a therapeutic target.

Development of physiologically-informed computational coronary artery plaques for use in virtual imaging trials.

As a leading cause of death, worldwide, cardiovascular disease is of great clinical importance. Among cardiovascular diseases, coronary artery disease (CAD) is a key contributor, and it is the attributed cause of death for 10% of all deaths annually. The prevalence of CAD is commensurate with the rise in new medical imaging technologies intended to aid in its diagnosis and treatment. The necessary clinical trials required to validate and optimize these technologies require a large cohort of carefully controlled patients, considerable time to complete, and can be prohibitively expensive. A safer, faster, less expensive alternative is using virtual imaging trials (VITs), utilizing virtual patients or phantoms combined with accurate computer models of imaging devices. In this work, we develop realistic, physiologically-informed models for coronary plaques for application in cardiac imaging VITs. Histology images of plaques at micron-level resolution were used to train a deep convolutional generative adversarial network (DC-GAN) to create a library of anatomically variable plaque models with clinical anatomical realism. The stability of each plaque was evaluated by finite element analysis (FEA) in which plaque components and vessels were meshed as volumes, modeled as specialized tissues, and subjected to the range of normal coronary blood pressures. To demonstrate the utility of the plaque models, we combined them with the whole-body XCAT computational phantom to perform initial simulations comparing standard energy-integrating detector (EID) CT with photon-counting detector (PCD) CT. Our results show the network is capable of generating realistic, anatomically variable plaques. Our simulation results provide an initial demonstration of the utility of the generated plaque models as targets to compare different imaging devices. Vast, realistic, and variable CAD pathologies can be generated to incorporate into computational phantoms for VITs. There they can serve as a known truth from which to optimize and evaluate cardiac imaging technologies quantitatively.

Abstract WP116: Plaque Features and Infarct Pattern in Ischemic Stroke With Bilateral Carotid Artery Atherosclerosis

Objective: to compare the carotid artery plaque characteristics between ipsilateral and contralateral infarct in ischemic stroke with bilateral carotid artery atherosclerosis, and explore the association between plaque characteristics and infarct pattern. Methods: a total of 186 ischemic stroke patients with bilateral carotid artery atherosclerosis were included, carotid artery plaque burden (the degree of stenosis, maximum wall thickness, lumen area, wall area, normalized wall index (NWI=wall area/[lumen area+ wall area]), and eccentricity index), and vulnerability (intraplaque hemorrhage [IPH], calcification, irregular surface, thin or ruptured fibrous cap[TRFC], and lipid-rich necrotic core[LRNC]) were obtained by MR vessel wall imaging, infarct pattern was divided as single and multiple/recurrent infarcts in infarct ipsilateral carotid artery. Ipsilateral and contralateral carotid artery plaque features were compared, then the carotid artery plaque characteristics on the infarct side were correlated with the infarct pattern. Results: the mean age of subjects included was 68 years old, 79.6% of them were male. Compared with contralateral carotid artery plaque, plaque burden at the ipsilateral carotid artery was much heavy, presented with a higher degree of stenosis, smaller lumen area (0.22±0.15 vs. 0.28±0.15), larger wall area (0.50±0.19 vs.0.42±0.17), and higher eccentricity index (0.67±0.13 vs. 0.58±0.23), all p values<0.05. The vulnerable plaques were also more prevalent at ipsilateral infarct, with a high percentage of IPH (47.8% vs. 19.8%), irregular surface (36.3% vs. 17.5%), TRFC (38.5% vs.12.3%), and LRNC (38.1% vs. 15.9%), all p values were <0.05. After adjusting for covariates, the degree of stenosis (OR=1.590, 95% CI 1.048-2.410) and LRNC (OR=0.259, 95% CI 0.087-0.769) were associated with multiple or recurrent infarcts independently. Conclusion: in ischemic stroke with bilateral carotid atherosclerosis, the atherosclerotic plaque burden at ipsilateral infarct was much heavier and more vulnerable. Both lumen stenosis and plaque components were correlated with multiple or recurrent infarcts in this population.

Advances in Artificial Intelligence-Assisted Coronary Computed Tomographic Angiography for Atherosclerotic Plaque Characterization.

Coronary artery disease is a leading cause of death worldwide. Major adverse cardiac events are associated not only with coronary luminal stenosis but also with atherosclerotic plaque components. Coronary computed tomography angiography (CCTA) enables non-invasive evaluation of atherosclerotic plaque along the entire coronary tree. However, precise and efficient assessment of plaque features on CCTA is still a challenge for physicians in daily practice. Artificial intelligence (AI) refers to algorithms that can simulate intelligent human behavior to improve clinical work efficiency. Recently, cardiovascular imaging has seen remarkable advancements with the use of AI. AI-assisted CCTA has the potential to facilitate the clinical workflow, offer objective and repeatable quantitative results, accelerate the interpretation of reports, and guide subsequent treatment. Several AI algorithms have been developed to provide a comprehensive assessment of atherosclerotic plaques. This review serves to highlight the cutting-edge applications of AI-assisted CCTA in atherosclerosis plaque characterization, including detecting obstructive plaques, assessing plaque volumes and vulnerability, monitoring plaque progression, and providing risk assessment. Finally, this paper discusses the current problems and future directions for implementing AI in real-world clinical settings.

Comparison of Two Contemporary Quantitative Atherosclerotic Plaque Assessment Tools for Coronary Computed Tomography Angiography: Single-Center Analysis and Multi-Center Patient Cohort Validation.

Coronary computed tomography angiography (CCTA) provides non-invasive quantitative assessments of plaque burden and composition. The quantitative assessment of plaque components requires the use of analysis software that provides reproducible semi-automated plaque detection and analysis. However, commercially available plaque analysis software can vary widely in the degree of automation, resulting in differences in terms of reproducibility and time spent. To compare the reproducibility and time spent of two CCTA analysis software tools using different algorithms for the quantitative assessment of coronary plaque volumes and composition in two independent patient cohorts. The study population included 100 patients from two different cohorts: 50 patients from a single-center (Siemens Healthineers, SOMATOM Force (DSCT)) and another 50 patients from a multi-center study (5 different > 64 slice CT scanner types). Quantitative measurements of total calcified and non-calcified plaque volume of the right coronary artery (RCA), left anterior descending (LAD), and left circumflex coronary artery (LCX) were performed on a total of 300 coronaries by two independent readers, using two different CCTA analysis software tools (Tool #1: Siemens Healthineers, syngo.via Frontier CT Coronary Plaque Analysis and Tool #2: Siemens Healthineers, successor CT Coronary Plaque Analysis prototype). In addition, the total time spent for the analysis was recorded with both programs. The patients in cohorts 1 and 2 were 62.8 ± 10.2 and 70.9 ± 11.7 years old, respectively, 10 (20.0%) and 35 (70.0%) were female and 34 (68.0%) and 20 (40.0%), respectively, had hyperlipidemia. In Cohort #1, the inter- and intra-observer variabilities for the assessment of plaque volumes per patient for Tool #1 versus Tool #2 were 22.8%, 22.0%, and 26.0% versus 2.3%, 3.9%, and 2.5% and 19.7%, 21.4%, and 22.1% versus 0.2%, 0.1%, and 0.3%, respectively, for total, noncalcified, and calcified lesions (p < 0.001 for all between Tools #1 and 2 both for inter- and intra-observer). The inter- and intra-observer variabilities using Tool #2 remained low at 2.9%, 2.7%, and 3.0% and 3.8%, 3.7%, and 4.0%, respectively, for total, non-calcified, and calcified lesions in Cohort #2. For each dataset, the median processing time was higher for Tool #1 versus Tool #2 (459.5 s IQR = 348.0-627.0 versus 208.5 s; IQR = 198.0-216.0) (p < 0.001). The plaque analysis Tool #2 (CT-guided PCI) encompassing a higher degree of automated support required less manual editing, was more time-efficient, and showed a higher intra- and inter-observer reproducibility for the quantitative assessment of plaque volumes both in a representative single-center and in a multi-center validation cohort.

Thin Calcification Predicts Lipid Component in Carotid Plaque—Relationship Between Lipid Distribution and Thin Calcification

BackgroundAccurately evaluating plaque characteristics is essential because lesions with lipid-rich plaque put patients at risk of thromboembolic complications from carotid artery stenting (CAS). Near-infrared spectroscopy (NIRS) is a diagnostic imaging modality that identifies lipid components from the near-infrared absorption pattern, but does not reveal the distribution of calcification. The purpose of this study was to investigate the calcification characteristics of unstable carotid plaques, focusing on relationships between the calcification characteristics revealed by computed tomography angiography (CTA) and the lipid core distribution derived from NIRS. MethodsParticipants in this retrospective analysis comprised 35 patients (29 men, 6 women; mean age, 76.0 years; range, 52–89 years) who underwent CAS in our institute between January 2021 and December 2022. We evaluated the thickness and length of carotid calcifications at the minimal lumen level from preoperative CTA and analyzed the relationship with maximal lipid core burden index (max-LCBI) from NIRS. ResultsStrong, negative linear correlations were observed between the thickness of calcification and max-LCBI at Area (any segment in a target lesion) (r=-0.795, p<0.001), max-LCBI at minimal lumen area (MLA) (r=-0.795, p<0.001) and LCBI at Lesion (rate of LCBI in entire plaque lesion) (r=-0.788, p<0.001), respectively. Significant negative linear correlations were observed between distribution of calcification length and max-LCBI at Area (r=-0.429, p=0.01), max-LCBI at MLA (r=-0.373, p=0.027) and LCBI at Lesion (r=-0.443, p=0.008). ConclusionsThin and ubiquitous carotid calcification was associated with LCBI values derived from NIRS indicative of carotid lipid plaque distribution, implying the possibility of predicting lesion instability.

The expression of renin-angiotensin system components in human carotid plaque

Background/Aim. The renin-angiotensin system (RAS) is linked to the development of atherosclerosis (As), including its initiation and progression. Besides the well-known angio-tensin-converting enzyme (ACE), two newer RAS family members are related to vascular remodeling - ACE2 as a homolog of ACE and collectrin [transmembrane protein 27 (TMEM27)] as a homolog of ACE2. Up to now, a limited number of studies have examined the expression of these RAS components in advanced carotid plaque (CP) tissue based on the sex of the patients and plaque phenotypes (PPs). There are two ultrasonographically defined PPs - the hypoechogenic plaque (HoP) and the hyperechogenic plaque (HerP) phenotype. The aim of the study was to investigate whether there was a correlation between the expression of RAS components in the CP and the sex and PPs of patients. Methods. We examined 74 patients with advanced CP who underwent carotid endarterectomy. The intraplaque expression of RAS components was determined with the real-time polymerase chain reaction, using the TaqMan? gene expression assays and Western blot. A two-way ANOVA followed by a post-hoc Tukey test was performed for the statistical analysis of results. Results. No interaction was recorded between the sex of the patients and PPs in influencing the relative expression of ACE and TMEM27 messenger RNA (mRNA) (p &gt; 0.05). In 56.06% of plaque samples, no expression of ACE2 mRNA was detected. Among the plaques where ACE2 mRNA expression was detected, its expression level was higher in females with the HoP phenotype compared to females with the HerP phenotype (p &lt; 0.001). In patients with the HoP phenotype, females had higher expression of ACE2 mRNA than males (p &lt; 0.05). In the male study group, ACE protein levels were significantly lower in the HoP phenotype compared to the HerP phenotype (p &lt; 0.001). Fe-males with the HoP phenotype had significantly higher ACE protein levels than males with the HoP phenotype (p &lt; 0.0001). Conclusion. Our results revealed alterations in the expression levels of ACE and ACE2, at the mRNA and protein levels, in advanced carotid As. These alterations are impacted by sex and PP and may indicate a switch from the balanced RAS/ACE/ACE2 axis in the healthy blood vessel to the unbalanced axis in vascular remodeling due to As.

Effect of Ayurveda-based Dietary Modification and Panchakarma Therapy on Plaque Stabilization in patients with coronary artery disease – A Prospective Study

Abstract Background: Lifestyle modification, particularly diet modification, has a significant impact on coronary artery disease (CAD) progression. Ayurveda, traditional Indian medical literature, provides a guide to a balanced lifestyle with detailed dietary instructions. Objective: This study was designed to evaluate the effect of the Ayurveda-based diet kit on components of atheroma plaque: calcified and soft plaque, individually. Methods: This prospective, single-arm, multicenter study was conducted in January 2021–December 2021. Patients were assessed for demographic and clinical characteristics and underwent routine 128-slice multi-detector coronary computed tomography angiography with plaque volumetric analysis for CAD diagnosis and to reflect the extent of plaque deposition at the time of recruitment (baseline) and posttherapy. Patients were prescribed appropriate Panchakarma therapy and a high protein, low carbohydrate diet plan provided with the reverse diet kit that is known to have a high oxidative radical absorption capacity (64,000 units per day). Results: Out of 280 known CAD patients, 246 patients (mean ± standard deviation: 57.63 ± 9.82 years) completed the study. The mean weight and body mass index significantly decreased poststudy intervention. The mean total cholesterol, mean serum triglycerides, and the mean low-density lipoprotein were noted to be significantly and substantially lowered. The fibrotic plaque volume, the fibrofatty plaque volume, and the overall soft plaque volume were also significantly lowered. The mean total atheroma volume (baseline: 541.33 mm3 vs. end of study: 469.57 mm3) was found to be significantly lowered. Conclusion: This study provides an objective world evidence of the effect of Ayurveda-based diet as assessed by the currently available high-end diagnostic tools.

Multifunctional liposomes Co-encapsulating epigallocatechin-3-gallate (EGCG) and miRNA for atherosclerosis lesion elimination.

Atherosclerosis (AS) is a chronic inflammatory disease, characterized by a lipid accumulated plaque. Anti-oxidative and anti-inflammation and lipid metabolism promoting therapeutic strategies have been applied for atherosclerosis treatment. However, the therapeutic effect of a single therapeutic method is limited. It is suggested that a combination of these two strategies could help prevent lipid accumulation caused by inflammation and oxidative stress, and also promote lipid efflux from atherosclerotic plaque, to normalize arteries to the maximum extent. Hence, a strategy involving a multifunctional liposome co-encapsulating an antioxidant and anti-inflammatory drug epigallocatechin-3-gallate (EGCG) and a lipid-efflux-promoting gene miR-223 was established. The system (lip@EGCG/miR-223) could encapsulate miR-223 in core areas of the liposomes to provide a protective effect for gene drugs. Moreover, lip@EGCG/miR-223 was smaller in size (91.28 ± 2.28 nm characterized by DLS), making it easier to target AS lesions, which have smaller vascular endothelial spaces. After being efficiently internalized into the cells, lip@EGCG/miR-223 exhibited excellent antioxidant and anti-inflammatory effects in vitro by eliminating overproduced ROS and decreasing the level of inflammatory cytokines (TNF-α, IL-1β, and MCP-1), which was due to the effect of EGCG. Besides, the lipid-efflux-promoting protein ABCA1 was upregulated when treated with lip@EGCG/miR-223. Through the two therapies mentioned, lip@EGCG/miR-223 could effectively inhibit the formation of foam cells, which are a main component of atherosclerotic plaques. In AS model mice, after intravenous (i.v.) administration, lip@EGCG/miR-223 was effectively accumulated in atherosclerotic plaques, and the distribution of drugs in the heart and aorta compared to that in the kidney was significantly increased when compared with free drugs (the ratio was 6.27% for the free miR-223-treated group, which increased to 66.10% for the lip@EGCG/miR-223-treated group). By decreasing the inflammation level and lipid accumulation, the arterial vessels in AS were normalized, with less macrophages and micro-angiogenesis, when treated with lip@EGCG/miR-223. Overall, this study demonstrated that lip@EGCG/miR-223 could be developed as a potential system for atherosclerosis treatment by a combined treatment of antioxidant, anti-inflammatory, and lipid-efflux-promoting effects, which provides a novel strategy for the safe and efficient management of atherosclerosis.

Lipid Content Distribution and its Clinical Implication in Patients with Acute Myocardial Infarction-Plaque Erosion: Results from the Prospective OCTAMI Study.

Plaque erosion (PE) is one of the main plaque phenotypes of acute coronary syndrome (ACS). However, the underlying plaque component and distribution have not been systematically analysed. This study aims to investigate the distribution of lipid and calcium content in culprit lesions assessed by optical coherence tomography (OCT) in patients with PE and explore its relationship with prognosis in a cohort of ST segment elevation myocardial infarction (STEMI) patients. A prospective cohort of 576 patients with STEMI was enrolled in our study. After exclusion, 152 PE patients with clear underlying plaque components were ultimately analysed. The culprit lesion was divided into the border zone, external erosion zone and erosion site in the longitudinal view. Each pullback of the culprit lesions was assessed by 3 independent investigators frame-by-frame, and the quantity and distribution of lipid and calcium components were recorded. Of the 152 PE patients, lipid and calcium contents were more likely to exist in the external erosion zone than in the other regions. In particular, a high level of lipid content proximal to the erosion site was significantly associated with plaque vulnerability and a higher incidence of MACEs. This study revealed that high level of lipid content in the proximal external erosion zone was related to high-risk plaque characteristics and poor prognosis, which provided a novel method for risk stratification and precise management in patients with plaque erosion.

Pathophysiology and Treatment of the No-Reflow Phenomenon in ST-Segment Elevation Myocardial Infarction: Focus on Low-Dose Fibrinolysis during Primary Percutaneous Intervention.

Primary percutaneous coronary intervention (PCI) is the current class I therapeutic approach to treat acute ST-elevation myocardial infarction (STEMI). While primary PCI can restore adequate flow in the infarcted artery in the majority of cases, some patients experience the 'no-reflow' phenomenon, i.e., an abnormal myocardial reperfusion occurring even after the occluded coronary artery has been opened. No-reflow occurs when microvascular obstruction arises from embolization of thrombus or components of the atheromatous plaques. These embolic materials travel downstream within the infarct-related artery at time of primary PCI, leading to compromised blood flow. Currently, no expert consensus documents exist to outline an optimal strategy to prevent or treat no-reflow. Interventional cardiologists frequently employ intracoronary adenosine, calcium channel blockers, nicorandil, nitroprusside or glycoprotein IIb/IIIa inhibitors. However, evidence suggests that these interventions consistently enhance myocardial blood flow in only a specific subset of patients experiencing no-reflow. A recent and innovative therapeutic approach gaining attention is low-dose fibrinolysis during primary PCI, which offers the potential to augment coronary flow post-myocardial revascularization.

Ganglioside Micelles Affect Amyloid β Aggregation by Coassembly.

Amyloid β peptide (Aβ) is the crucial protein component of extracellular plaques in Alzheimer's disease. The plaques also contain gangliosides lipids, which are abundant in membranes of neuronal cells and in cell-derived vesicles and exosomes. When present at concentrations above its critical micelle concentration (cmc), gangliosides can occur as mixed micelles. Here, we study the coassembly of the ganglioside GM1 and the Aβ peptides Aβ40 and 42 by means of microfluidic diffusional sizing, confocal microscopy, and cryogenic transmission electron microscopy. We also study the effects of lipid-peptide interactions on the amyloid aggregation process by fluorescence spectroscopy. Our results reveal coassembly of GM1 lipids with both Aβ monomers and Aβ fibrils. The results of the nonseeded kinetics experiments show that Aβ40 aggregation is delayed with increasing GM1 concentration, while that of Aβ42 is accelerated. In seeded aggregation reactions, the addition of GM1 leads to a retardation of the aggregation process of both peptides. Thus, while the effect on nucleation differs between the two peptides, GM1 may inhibit the elongation of both types of fibrils. These results shed light on glycolipid-peptide interactions that may play an important role in Alzheimer's pathology.

3D patient-specific modeling and structural finite element analysis of atherosclerotic carotid artery based on computed tomography angiography

The assessment of carotid plaque vulnerability is a relevant clinical information that can help prevent adverse cerebrovascular events. To this aim, in this study, we propose a patient-specific computational workflow to quantify the stress distribution in an atherosclerotic carotid artery, by means of geometric modeling and structural simulation of the plaque and vessel wall. Ten patients were involved in our study. Starting with segmentation of the lumen, calcific and lipid plaque components from computed tomography angiography images, the fibrous component and the vessel wall were semi-automatically reconstructed with an ad-hoc procedure. Finite element analyses were performed using local pressure values derived from ultrasound imaging. Simulation outputs were analyzed to assess how mechanical factors influence the stresses within the atherosclerotic wall. The developed reconstruction method was first evaluated by comparing the results obtained using the automatically generated fibrous component model and the one derived from image segmentation. The high-stress regions in the carotid artery wall around plaques suggest areas of possible rupture. In mostly lipidic and heterogeneous plaques, the highest stresses are localized at the interface between the lipidic components and the lumen, in the fibrous cap.

LIGHT/TNFSF14 levels in carotid atherosclerotic plaques are associated with symptomatic cerebrovascular disease

Abstract Background Plaque rupture is the underlying cause of most cardiovascular events, such as stroke and myocardial infarction. Co-stimulatory molecules, the immune checkpoints, are emerging as strong candidates to battle atherosclerosis progression. The co-stimulatory molecule LIGHT (tumour necrosis factor 14; TNFSF14) exists in foam cell-rich regions of atherosclerotic plaques, but whether it has a driving role in promoting a high-risk plaque phenotype is not known. Purpose This study investigates the association between intra-plaque LIGHT and plaque vulnerability. Methods Plaque levels of LIGHT/TNFSF14 were measured in homogenised carotid endarterectomy plaques by Proximity Extension Assay (PEA) in subjects from the Carotid Plaque Imaging Cohort (CPIP; N=201). Homogenates were further examined by multi-plex cytokine analysis and ELISA, and tissue plaque sections through histology/immunohistochemistry. Results Plaque levels of LIGHT were associated with the occurrence of pre-operative cerebrovascular symptoms (p=0.00014). Furthermore, LIGHT correlated strongly with the histological plaque vulnerability index (p=5x10-15): a ratio between the sum of destabilising versus stabilising plaque components (i.e. macrophages, intra-plaque haemorrhage and lipids versus smooth muscle cells and collagen) as well as with necrotic core size and the inflammatory cytokines interleukin(IL)-1β, IL-6, chemokine (C-C motif) ligand (CCL)-2, CCL4 and CCL5. Moreover, plaque LIGHT levels correlated with several components of the extracellular matrix turnover machinery, including cleaved collagen, the collagen cross-linking proteoglycans fibromodulin and lumican, the matricellular protein COMP (cartilage oligomeric matrix protein), and the remodelling regulator ADAMTS7 (a disintegrin and metalloproteinase with thrombospondin motifs-7). Levels also correlated with matrix metalloproteinases (MMPs) 1, 2, 9 and 10, and tissue inhibitor of metalloproteinase (TIMP)-1. Conclusion Expression of LIGHT in atherosclerotic plaques does not only correlate with markers of plaque destabilisation¸ but is also significantly elevated in plaques from symptomatic, compared to asymptomatic, patients. These results connect LIGHT content to a rupture-prone plaque phenotype and suggest the LIGHT signalling pathway as a potential therapeutic target to promote atherosclerotic plaque stability.

Characterization of lipidic coronary atheroma under control of low-density lipoprotein &amp;lt;1.8 mmol/l and lipoprotein (a) &amp;lt;50 mg/dl in patients with coronary artery disease

Abstract Background Lp(a) has been considered as a potential therapeutic target associated with atherosclerosis. In particular, Lp(a) ≧50 mg/dL has been shown to predict an elevated cardiovascular risk even under lowering LDL-C level, indicating that lowering of both LDL-C and Lp(a) may be more beneficial to halt atherogenesis. However, atherosclerotic features with favorable control of these lipid targets have not been fully characterized yet. The REASSURE-NIRS registry (NCT04864171) is an on-going multi-center registry which enrolls CAD patients receiving near-infrared spectroscopy (NIRS)/IVUS-guided PCI in Japan. Given that NIRS enables to quantitatively evaluate lipidic plaque materials, this registry provides an opportunity to investigate lipidic plaque features in association with LDL-C and Lp(a) levels. Objectives The aim of this study was to elucidate NIRS-derived characteristics of coronary atheroma in patients with CAD who exhibited both LDL-C&amp;lt;1.8 mmol/L and Lp(a) &amp;lt;50 mg/dL. Methods From the REASSURE-NIRS registry (n=1013), we investigated 549 culprit lesions in 498 patients with measurement of both LDL-C and Lp(a) levels at the index of PCI. Maximum 4-mm lipid core burden index (max LCBI4mm) at culprit lesions were measured with NIRS imaging prior to PCI. Study subjects were stratified into 4 groups according to LDL-C and Lp(a) levels: LDL-C&amp;lt;1.8mmol/L and Lp(a)&amp;lt;50mg/dL, LDL-C≧1.8mmol/ and Lp(a)&amp;lt;50mg/dL, LDL-C&amp;lt;1.8mmol/L and Lp(a)≧50mg/dL, LDL-C≧1.8mmol/L and Lp(a)≧50mg/dL. Clinical characteristics and max LCBI4mm were compared in 4 groups. Results In the current study, 30.6% of patients was ACS. Under the use of lipid-lowering therapies (statin: 68.4% and high-intensity statin: 26.0%), 33.1% of study population exhibited both LDL-C&amp;lt;1.8mmol/L and Lp(a)&amp;lt;50mg/dL. Patients with LDL-C&amp;lt;1.8mmol/L and Lp(a)&amp;lt;50mg/dL were more likely to be male (p=0.002) and smoker (p=0.002) and have a history of previous MI (p&amp;lt;0.001). As expected, statin was more frequently used in those with both LDL-C&amp;lt;1.8mmol/L and Lp(a)&amp;lt;50mg/dL (p&amp;lt;0.001). On NIRS imaging analysis, patients with low LDL-C&amp;lt;1.8mmol/L and Lp(a)&amp;lt;50mg/dL were associated with significantly lower max LCBI4mm (Figure). Of note, even in patients with LDL-C&amp;lt;1.8mmol/L, max LCBI4mm was lower in those achieving Lp(a) &amp;lt;50 mg/dL compared to those with Lp(a) ≧50 mg/dL (p=0.001). Multivariate analysis adjusting for ACS, LDL-C levels and statin use, Lp(a) levels revealed emerged as independent predictor of maxLCBI4mm (β=1.0, 95%CI: 0.06 to 2.04, p=0.04). Conclusion Patients with LDL-C&amp;lt;1.8mmol/L and Lp(a)&amp;lt;50mg/dL more likely exhibited a smaller amount of lipidic plaque materials on NIRS imaging. Our findings support that lowering both LDL-C and Lp(a) may be more beneficial to modulate lipidic plaque component, which ultimately results in the further reduction of ASCVD risks.Comparison of clinical characteristics

The natural history and prediction of 10-year plaque progression on serial coronary CT angiography

Abstract Background Several studies have shown that plaque subcomponents such as low-attenuation or non-calcified plaque volume from coronary CT angiography (CCTA) are associated with the occurrence of major adverse cardiovascular events. However, it remains unknown how plaque morphology progresses over the long-term. Furthermore, it is unknown which plaque characteristics put patients at increased risk of plaque progression which would require more intensive image-guided follow-up. This study investigated the natural history and predictors of long-term coronary plaque progression in a serial CCTA cohort of patients with suspected coronary artery disease (CAD). Methods In this follow-up study, 539 patients from an earlier published CCTA cohort (Diemen, 2021) were invited for repeat CCTA imaging per-protocol, regardless of symptoms. A total of 299 patients underwent follow-up CCTA imaging with a median scan interval of 10.2 [8.7-11.2] years. Patients who underwent coronary artery bypass grafting (CABG) between baseline and follow-up imaging were excluded. All scans were analyzed using artificial intelligence-guided quantitative CCTA (AI-QCT). Revascularized vessels were excluded. Quantitative plaque volumes (total, low-density, non-calcified and calcified plaque) depicted by AI-QCT were divided by the total vessel volume to represent percent atheroma volume (PAV). PAV progression was calculated subtracting baseline PAV from follow-up PAV. The association of the plaque components with PAV progression was evaluated in a multivariate linear regression model adjusted for clinical risk characteristics (age, sex, hypertension, hypercholesterolemia, diabetes, BMI, smoking, family history of CAD and statin use). Results In total, 274 patients without CABG were used for the serial analysis, mean age was 57 years, 42% were women. At baseline, median PAV was 2.5% [IQR 0.7-8.1], which increased to 6.1% [IQR 1.2-12.9] at follow-up (Figure). The mean PAV progression was 0.4±0.5% per year. Adjusted for clinical risk characteristics and other plaque volumes, baseline percent non-calcified plaque volume (NCP) was the only plaque volume associated with PAV progression (0.5% PAV progression increase per % increase in baseline non-calcified plaque volume). Conclusion Using an unique long-term serial CCTA cohort undergoing per-protocol repeat imaging with a 10-year scan interval, we found that coronary plaque burden more than doubled. Interestingly, the amount of non-calcified plaque volume at baseline was the only predictor for disease progression.Figure

Advancing Antiamyloidogenic Activity by Fine-Tuning Macromolecular Topology.

Amyloid β peptide can aggregate into thin β-sheet fibrils or plaques deposited on the extracellular matrix, which is the hallmark of Alzheimer's disease. Multifunctional macromolecular structures play an important role in inhibiting the aggregate formation of amyloidogenic materials and thus are promising candidates with antiamyloidogenic characteristics for the development of next-generation therapeutics. In this study, we evaluate how small differences in the dendritic topology of these structures influence their antiamyloidogenic activity by the comparison of "perfectly dendritic" and "pseudodendritic" macromolecules, both decorated with mannose units. Their compactness, the position of surface units, and the size of glyco-architectures influence their antiamyloidogenic activity against Aβ 40, a major component of amyloid plaques. For the advanced analysis of the aggregation of the Aβ peptide, we introduce asymmetric flow field flow fractionation as a suitable method for the quantification of large and delicate structures. This alternative method focuses on the quantification of complex aggregates of Aβ 40 and glycodendrimer/glyco-pseudodendrimer over different time intervals of incubation, showing a good correlation to ThT assay and CD spectroscopy results. Kinetic studies of the second-generation glyco-pseudodendrimer revealed maximum inhibition of Aβ 40 aggregates, verified with atomic force microscopy. The second-generation glyco-pseudodendrimer shows the best antiamyloidogenic properties confirming that macromolecular conformation in combination with optimal functional group distribution is the key to its performance. These molecular properties were validated and confirmed by molecular dynamics simulation.