Targeted Therapy of Atherosclerosis Vulnerable Plaque By ROS-Scavenging Nanoparticles And MR/Fluorescence Dual-Modality Imaging Tracing

Background: Cardiovascular diseases are currently the leading cause of death and disability worldwide, and the key pathological basis is atherosclerosis (AS). Especially, the rupture of vulnerable plaques is the main cause of acute cardiovascular and cerebrovascular events such as myocardial infarction and stroke. Thus, the early identifying and therapy of vulnerable plaques are necessary. Results: In this study, we developed a novel multimodal imaging platform (GPRD) based on Gd doped Prussian blue (GPB) and rhodamine (Rd) to specifically target and identify the vulnerable plaques with the help of dextran sulfate (DS), one of the excellent ligands of scavenger receptor class A (SR-A). It is more important that the nano-enzyme capacity of GPRD NPs realized the elimination of the excessive production of ROS in cells, and the following reduction of ROS-induced oxidative stress, inflammation, apoptosis, and the formation of macrophage-derived foam cells, presenting an inhibition of plaque progress eventually. Conclusions: The ROS-scavenging multimodal imaging nanoprobe provided a new avenue for the diagnosis and treatment of AS vulnerable plaques.

NR1D1 Deletion Induces Rupture-Prone Vulnerable Plaques by Regulating Macrophage Pyroptosis via the NF-κB/NLRP3 Inflammasome Pathway

Vulnerable plaque rupture is the main trigger of most acute cardiovascular events. But the underlying mechanisms responsible for the transition from stable to vulnerable plaque remain largely unknown. Nuclear receptor subfamily 1 group D member 1 (NR1D1), also known as REV-ERB α, is a nuclear receptor that has shown the protective role in cardiovascular system. However, the effect of NR1D1 on vulnerable plaque rupture and its underlying mechanisms are still unclear. By generating the rupture-prone vulnerable plaque model in hypercholesterolemic ApoE−/− mice and NR1D1−/−ApoE−/− mice, we demonstrated that NR1D1 deficiency significantly augmented plaque vulnerability/rupture, with higher incidence of intraplaque hemorrhage (78.26% vs. 47.82%, P = 0.0325 ) and spontaneous plaque rupture with intraluminal thrombus formation (65.21% vs. 39.13%, P = 0.1392 ). In vivo experiments indicated that NR1D1 exerted a protective role in the vasculature. Mechanically, NR1D1 deficiency aggravates macrophage infiltration, inflammation, and oxidative stress. Compared with the ApoE−/− mice, NR1D1−/−ApoE−/− mice exhibited a significantly higher expression level of pyroptosis-related genes in macrophages within the plaque. Further investigation based on mice bone marrow-derived macrophages (BMDMs) confirmed that NR1D1 exerted a protective effect by inhibiting macrophage pyroptosis in a NLRP3-inflammasome-dependent manner. Besides, pharmacological activation of NR1D1 by SR9009, a specific NR1D1 agonist, prevented plaque vulnerability/rupture. In general, our findings provide further evidences that NR1D1 plays a protective role in the vasculature, regulates inflammation and oxidative stress, and stabilizes rupture-prone vulnerable plaques.

Assessment of Carotid Plaque Stability Using Contrast-Enhanced Ultrasound and Its Correlation With the Expression of CD147 and MMP-9 in the Plaque

This study aims to investigate the correlation between the enhancement degree of contrast-enhanced ultrasound (CEUS) and the expression of CD147 and MMP-9 in carotid atherosclerotic plaques in patients with carotid endarterectomy and evaluate the diagnostic efficacy of CEUS using pathological results as the gold standard. Thirty-eight patients who underwent carotid endarterectomy (CEA) for carotid stenosis in the Department of Neurovascular Surgery of the Second People’s Hospital of Shenzhen from July 2019 to June 2020 were selected. Preoperatively, two-dimensional (2D) ultrasound scan was performed on all patients to assess the characteristics of the plaque and degree of stenosis, and CEUS was used to evaluate the surface morphology of the plaque and the distribution of neovascularization. Postoperatively, pathological sections and immunohistochemical analysis of CD147 and MMP-9 levels in the plaque were performed on the stripped plaque tissue, and the results were analyzed against the CEUS grading and pathological results. Among the 38 patients, pathological results showed that 10 and 28 were in the stable and vulnerable plaque groups, respectively. There were more smokers in the vulnerable plaque group than in the stable plaque group, with higher intraplaques CD147 and MMP-9. The difference in ultrasound plaque surface morphology grading and CEUS grading between the two groups was statistically significant. There was no significant difference in age, sex, incidence of complications such as hypertension, diabetes, and coronary heart disease between the two groups. CD147 was higher in the CEUS grade IV group than in the grades I (P = 0.040) and II (P = 0.010) groups. MMP-9 was higher in the CEUS grade IV group than in the grade II group (P = 0.017); MMP-9 was higher in the grade III group than in the grade II group (P = 0.015). Intraplaque contrast enhancement intensity was positively correlated with CD147 (r = 0.462, P = 0.003) and MMP-9 (r = 0.382, P = 0.018) levels. There was moderate consistency between the assessment of plaque vulnerability by 2D-ultrasound and by histopathological hematoxylin-eosin (HE) (kappa = 0.457, P > 0.05). 2D diagnosis of vulnerable plaque had a sensitivity of 85.7%, a specificity of 60.0%, a positive predictive value of 85.7%, a negative predictive value of 60.0%, and an accuracy of 78.0%. There was a strong consistency between the assessment of plaque vulnerability by CEUS and histopathological HE (kappa = 0.671, P < 0.01). CEUS had a sensitivity of 89.2%, a specificity of 80.0%, a positive predictive value of 92.6%, a negative predictive value of 72.7%, and an accuracy of 86.8% for the diagnosis of vulnerable plaques; CEUS is a reliable, non-invasive test that can show the distribution of neovascularization within vulnerable plaques, evaluate the vulnerability and risk of intraplaque hemorrhage, with a high consistency with pathological findings. The degree of intraplaque enhancement and the levels of CD147 and MMP-9 in the tissue were positively correlated.

Cavitation on top of collision breaks the cover of coronary plaques and triggers acute coronary syndrome

Background Coronary injuries are hypothesized to be caused by the cavitation phenomenon (explosion of air bubbles) which is seen frequently in industrial pipes. Based on hydraulics principles applied to the coronary circulation. during distal negative suctioning in diastole, if the coronary static pressure decreases below the vapor pressure (VP), bubbles will form. They explode when the coronary static pressure recovers > the VP during systole. These explosions create jet waves weakening and rupturing the cover of the coronary plaques, triggering acute coronary syndrome (ACS). How could these events be observed, recorded and compared? Methods Coronary angiograms of patients with ACS and stable coronary artery disease (CAD) (control) were selected. The arteries were recorded at 15 frames per second and saved in the electronic health records and reviewed image by image. After the index artery was completely filled with contrast, the following images showed the blood in white moving in on a background of black contrast. The flow could be laminar, turbulent (mixing of blood in white and contrast in black), antegrade or RETROGRADE (black column traveling backward). At the same time, an artificial intelligence (AI) program was used to detect and identify the flow. Results There were 104 patients with ACS enrolled and 20 patients with stable CAD as control. First, in the ACS group, 84 lesions (80%) were in the end of the proximal segment of the left anterior descending artery (LAD) and mid-segment of the right coronary artery (RCA). 20 lesions (19%) were at the distal RCA. Second, during diastole, 95% of the flow were laminar. The flow became turbulent at the beginning of systole. The turbulence was caused by the COLLISION of the antegrade flow (end of diastole) and the retrograde flow (at the beginning of systole). These collisions were seen in 95% at the location of vulnerable plaques of patients with ACS. In the control patients, there were only 2 cases (10%) with collision. Third, in the 20 patients with lesions at the distal RCA, the lesions were seen to be located at the areas of recirculating flow, at the ostium of the posterior descending artery (PDA) or proximal to the origin of the PDA. The cause of turbulence was most likely due to cavitation on top of collision. The cavitation happened because of continuous steady forward flow (of the PDA) in the myocardium during systole, while at the proximal RCA the blood flew forward more slowly. (Fig.1) The DSICREPANCY of velocities at the proximal and distal RCA allowed the formation of an empty gap (bubble of air). When the flow reversed during systole, this retrograde flow slammed on the bubble which collapsed violently, injured, ruptured the cover of the plaque and started ACS. Conclusions Rupture of bubbles (cavitation) on top of collision was most likely the cause of injury to the cover of vulnerable plaques, triggering ACS. Understanding the mechanism will help to better manage ACS. FUNDunding Acknowledgement Type of funding sources: None. Cavity formation and collision Formation of cavitation at the PDA

Carotid plaque vulnerability assessed by combined shear wave elastography and ultrafast doppler compared to histology: the UF-plaque study

Purpose New biomarkers are needed to assess the vulnerability of carotid plaque to guide carotid surgery decision. Ultrafast Ultrasound Imaging (UUI) provides an estimation of plaque stiffness by Shear Wave Elastography (SWE) and the quantification of wall shear stress (WSS) by ultrafast Doppler. We aimed at evaluating the plaque stiffness and WSS applied on the plaque as potential biomarkers of plaque vulnerability. Methods Patients were referred for carotid endarterectomy because of symptomatic or asymptomatic carotid stenosis. Their plaques were evaluated by UUI within 48 hours before surgery. For each plaque, WSS and SWE were obtained on a longitudinal view at the stenosis. After endarterectomy, gross analysis and histology were performed on each removed plaque. Results 46 plaques with SWE data and 29 with WSS data were analysed. Histological analysis revealed 29 vulnerable and 17 stable plaques. Analysis of the Gray Scale Median by B mode, mean and standard deviation of stiffness by SWE were not helpful in identifying vulnerable plaques. Figure 1 presents the SWE acquisition on one plaque (A) and the distribution of plaque's stiffness average over all plaques showing the 4 ranges of stiffness (B). SWE analysis revealed that the percentage of stiffness range of [3–5] m/s was significantly increased in vulnerable plaques (p=0.048) (Figure 2A). WSS alone showed no significant difference between stable and vulnerable plaques regardless of which segment of the plaque was analysed. A multiparametric score using maximal WSS at the peak of the plaque associated with SWE texture analysis parameters was created by a stepwise analysis, leading to a score with a sensitivity of 80% and a specificity of 78%. The ROC curve of this score found an AUC of 0.85 (Figure 2B). Conclusions Multiparameter scoring including plaque stiffness and flow analysis using ultrafast ultrasound imaging allows an effective identification of histologically vulnerable carotid plaques. FUNDunding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Fédération Française de cardiologieSociété Française de Cardiologie Figure 1 Figure 2

Plaque Erosion: A Distinctive Pathological Mechanism of Acute Coronary Syndrome

Plaque erosion (PE) is one of the most important pathological mechanisms underlying acute coronary syndrome (ACS). The incidence of PE is being increasingly recognized owing to the development and popularization of intracavitary imaging. Unlike traditional vulnerable plaques, eroded plaques have unique pathological characteristics. Moreover, recent studies have revealed that there are differences in the physiopathological mechanisms, biomarkers, and clinical outcomes between PE and plaque rupture (PR). Accurate diagnosis and treatment of eroded plaques require an understanding of the pathogenesis of PE. In this review, we summarize recent scientific discoveries of the pathological characteristics, mechanisms, biomarkers, clinical strategies, and prognosis in patients with PE.

Recent Trends in Artificial Intelligence-Assisted Coronary Atherosclerotic Plaque Characterization

Coronary artery disease is a major cause of morbidity and mortality worldwide. Its underlying histopathology is the atherosclerotic plaque, which comprises lipid, fibrous and—when chronic—calcium components. Intravascular ultrasound (IVUS) and intravascular optical coherence tomography (IVOCT) performed during invasive coronary angiography are reference standards for characterizing the atherosclerotic plaque. Fine image spatial resolution attainable with contemporary coronary computed tomographic angiography (CCTA) has enabled noninvasive plaque assessment, including identifying features associated with vulnerable plaques known to presage acute coronary events. Manual interpretation of IVUS, IVOCT and CCTA images demands scarce physician expertise and high time cost. This has motivated recent research into and development of artificial intelligence (AI)-assisted methods for image processing, feature extraction, plaque identification and characterization. We performed parallel searches of the medical and technical literature from 1995 to 2021 focusing respectively on human plaque characterization using various imaging modalities and the use of AI-assisted computer aided diagnosis (CAD) to detect and classify atherosclerotic plaques, including their composition and the presence of high-risk features denoting vulnerable plaques. A total of 122 publications were selected for evaluation and the analysis was summarized in terms of data sources, methods—machine versus deep learning—and performance metrics. Trends in AI-assisted plaque characterization are detailed and prospective research challenges discussed. Future directions for the development of accurate and efficient CAD systems to characterize plaque noninvasively using CCTA are proposed.

Association between apolipoprotein B/A1 ratio and coronary plaque vulnerability in patients with atherosclerotic cardiovascular disease: an intravascular optical coherence tomography study

Background Apolipoprotein (Apo) A1 and Apo B are strongly associated with the risk of atherosclerotic cardiovascular disease (ASCVD). However, the relationship between the Apo B/A1 ratio and the morphology of coronary vulnerable plaques has not been fully elucidated in patients with ASCVD. Methods A total of 320 patients with ASCVD undergoing percutaneous coronary intervention were enrolled and assigned into acute coronary syndrome (ACS) or chronic coronary syndrome (CCS) group. The morphology of culprit plaque was analyzed by intravascular optical coherence tomography. Association between the Apo B/A1 ratio and coronary vulnerable plaques were evaluated using logistic regression models and receiver operator characteristic (ROC) curve analyses. Results The Apo B/A1 ratio was higher in ACS patients than CCS patients (0.77 ± 0.28 vs. 0.64 ± 0.22, P < 0.001) and it was also higher in patients with plaque rupture, erosion or thrombus than those without culprit plaques. The high Apo B/A1 ratio was associated with high percent of vulnerable plaques compared with low ratio group. The Apo B/A1 ratio was negatively related to fibrous cap thickness in lipid-rich plaque (r = − 0.228, P = 0.043). Univariate and multivariate logistic regression analyses revealed that the Apo B/A1 ratio was an independent factor of plaque rupture, erosion, and thrombus. The area under the ROC curve of the Apo B/A1 ratio for plaque rupture, erosion, and thrombus were 0.632, 0.624, and 0.670 respectively (P < 0.001 for all), which were higher than that of low-density lipoprotein cholesterol. Conclusions The Apo B/A1 ratio is an independent predictor for plaque rupture, erosion, and thrombus in patients with ASCVD.