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.

Plaque features of the middle cerebral artery are associated with periprocedural complications of intracranial angioplasty and stenting.

PURPOSE: The identification of plaque features in the middle cerebral artery (MCA) may help minimize periprocedural complications and select patients suitable for percutaneous transluminal angioplasty and stenting (PTAS). However, relevant research is lacking. METHODS: We retrospectively included patients with symptomatic MCA stenosis who received PTAS. All patients underwent intracranial vessel wall MRI (VWMRI) before surgery. Periprocedural complications (PC) included ischemic and hemorrhagic stroke within 30 days. Stenosis location, MCA shape, plaque eccentricity and distribution, plaque thickness and length, and enhancement ratio were compared between patients with and without PC. RESULTS: Sixty-six patients were included in the study, of which 12.1% (8/66) had PC. Of the eight patients with PC, seven (87.5%) had superior wall plaques. In the non-PC group (n = 58), nine (17%) patients had superior wall plaques. Compared with patients without PC, those with PC had more frequent superior wall plaques (17% vs 87.5%, p < 0.001) and s-shaped MCAs (19% vs 50%, p = 0.071), different stenosis locations (p = 0.012), thicker plaques (1.58 [1.35, 2.00] vs 1.98 [1.73, 2.43], p = 0.038), and less frequent inferior wall plaques (79.2% vs 12.5%, p < 0.001). Multivariate analysis showed that only the presence of superior wall plaques (OR = 41.54 [2.31, 747.54]) was independently associated with PC. CONCLUSION: MCA plaque features were highly correlated with PC in patients with symptomatic MCA stenosis who underwent PTAS.

DNA methylation and histone post-translational modifications in atherosclerosis and a novel perspective for epigenetic therapy.

Atherosclerosis, which is a vascular pathology characterized by inflammation and plaque build-up within arterial vessel walls, acts as the important cause of most cardiovascular diseases. Except for a lipid-depository and chronic inflammatory, increasing evidences propose that epigenetic modifications are increasingly associated with atherosclerosis and are of interest from both therapeutic and biomarker perspectives. The chronic progressive nature of atherosclerosis has highlighted atherosclerosis heterogeneity and the fact that specific cell types in the complex milieu of the plaque are, by far, not the only initiators and drivers of atherosclerosis. Instead, the ubiquitous effects of cell type are tightly controlled and directed by the epigenetic signature, which, in turn, is affected by many proatherogenic stimuli, including low-density lipoprotein, proinflammatory, and physical forces of blood circulation. In this review, we summarize the role of DNA methylation and histone post-translational modifications in atherosclerosis. The future research directions and potential therapy for the management of atherosclerosis are also discussed. Video Abstract.

Effect of plaque morphological characteristics on the outcomes of carotid artery stenting.

Carotid artery stenting (CAS) represents today an accepted option for the treatment of severe carotid artery stenosis. The evolution of materials, techniques, perioperative medical management and patients' selection, has allowed to progressively reduce CAS complications. However, the main drawback of CAS is still represented by the risk of cerebral embolization, that may occur during several steps of the procedure and also in the early postoperative period. Preoperative carotid plaque morphological characteristics may have a great role in determining the risk of embolization during CAS. This review summarizes the current knowledge on carotid plaque characteristics that may influence the risk of complication during CAS. This information may be important for the optimization of CAS patients' selection and adaptation of the materials and techniques.

Allogeneic Adipose-Derived Mesenchymal Stem Cell Transplantation Alleviates Atherosclerotic Plaque by Inhibiting Ox-LDL Uptake, Inflammatory Reaction and Endothelial Damage in Rabbits.

Atherosclerosis (AS) is a chronic inflammatory disease of arteries fueled by lipids. It is a major cause of cardiovascular morbidity and mortality. Mesenchymal stem cells have been used for the treatment of atherosclerotic lesions. Adipose-derived stem cells (ADSCs) have been shown to regulate the activation state of macrophages and exhibit anti-inflammatory capabilities. However, the effect of allogeneic ADSCs in the treatment of AS have not been investigated. In this study, the early treatment effect and preliminary mechanism analysis of allogeneic rabbit ADSCs intravenous transplantation were investigated in a high-fat diet rabbit model. The polarization mechanism of rabbit ADSCs on the macrophage was further analyzed in vitro. Compared with the model group, blood lipid levels declined, the plaque area, oxidized low-density lipoprotein (ox-LDL) uptake, scavenger receptor A1 and cluster of differentiation (CD) 36 levels were all significantly reduced, and the accumulation of inflammatory M1 macrophages, apoptosis, interleukin (IL)-6 and tumor necrosis factor (TNF)-α expression were decreased. The endothelial cells (CD31), M2 macrophages, IL-10 and the transforming growth factor (TGF)-ß levels increased. In vitro, ADSCs can promote the M1 macrophage phenotypic switch toward the M2 macrophage through their secreted exosomes, and the main mechanism includes increasing arginase 1 expression and IL-10 secretion, declining inducible nitric oxide synthase (iNOS) expression and TNF-α secretion, and activating the STAT6 pathway. Therefore, allogeneic rabbit ADSC transplantation can transmigrate to the aortic atherosclerotic plaques and show a good effect in lowering blood lipids and alleviating atherosclerotic plaque in the early stage of AS by inhibiting ox-LDL uptake, inflammatory response, and endothelial damage.

Preventive PCI or medical therapy alone for vulnerable atherosclerotic coronary plaque: Rationale and design of the randomized, controlled PREVENT trial.

BACKGROUND: Acute coronary syndromes are commonly caused by the rupture of vulnerable plaque, which often appear angiographically not severe. Although pharmacologic management is considered standard therapy for stabilizing plaque vulnerability, the potential role of preventive local treatment for vulnerable plaque has not yet been determined. The PREVENT trial was designed to compare preventive percutaneous coronary intervention (PCI) plus optimal medical therapy (OMT) with OMT alone in patients with functionally nonsignificant high-risk vulnerable plaques. METHODS: The PREVENT trial is a multinational, multicenter, prospective, open-label, active-treatment-controlled randomized trial. Eligible patients have at least 1 angiographically significant stenosis (diameter stenosis >50% by visual estimation) without functional significance (fractional flow reserve [FFR] >0.80). Target lesions are assessed by intracoronary imaging and must meet at least 2 imaging criteria for vulnerable plaque; (1) minimal lumen area <4.0 mm2; (2) plaque burden >70%; (3) maximal lipid core burden index in a 4 mm segment >315 by near infrared spectroscopy; and (4) thin cap fibroatheroma as determined by virtual histology or optical coherence tomography. Enrolled patients are randomly assigned in a 1:1 ratio to either preventive PCI with either bioabsorbable vascular scaffolds or metallic everolimus-eluting stents plus OMT or OMT alone. The primary endpoint is target-vessel failure, defined as the composite of death from cardiac causes, target-vessel myocardial infarction, ischemic-driven target-vessel revascularization, or hospitalization for unstable or progressive angina, at 2 years after randomization. RESULTS: Enrollment of a total of 1,608 patients has been completed. Follow-up of the last enrolled patient will be completed in September 2023 and primary results are expected to be available in early 2024. CONCLUSIONS: The PREVENT trial is the first large-scale, randomized trial to evaluate the effect of preventive PCI on non-flow-limiting vulnerable plaques containing multiple high-risk features that is appropriately powered for clinical outcomes. PREVENT will provide compelling evidence as to whether preventive PCI of vulnerable plaques plus OMT improves patient outcomes compared with OMT alone. CLINICAL TRIAL REGISTRATION: URL: https://www. CLINICALTRIALS: gov. Unique identifier: NCT02316886. KEY POINTS: The PREVENT trial is the first, large-scale randomized clinical trial to evaluate the effect of preventive PCI on non-flow-limiting vulnerable plaque with high-risk features. It will provide compelling evidence to determine whether PCI of focal vulnerable plaques on top of OMT improves patient outcomes.

Nanotransportadores activos de cannabinoides para el tratamiento de la aterosclerosis / Active cannabinoid nanocarriers for the treatment of atherosclerosis

Con la intención de vehiculizar fármacos cannabinoides (agonistas CB2) de forma selectiva hacia la placa de ateroma, se han obtenido nanopartículas biocompatibles y biodegradables. Para ello, las nanopartículas PEGyladas, han sido funcionalizadas con un péptido capaz de unirse selectivamente a proteínas endoteliales de adhesión sobreexpresadas en la placa aterosclerótica (vascular cell adhesion molecule 1, VCAM-1). Las partículas han sido caracterizadas fisicoquímicamente, in vitro en cultivos celulares e in vivo en un modelo animal de aterosclerosis (ratones deficientes en apolipoproteína E, ApoE-/-), demostrando un óptimo control espacio-temporal de la liberación del cannabinoide y una respuesta farmacológica superior. Dado que los fármacos agonistas CB2 presentan alta lipofilia y baja disponibilidad, la introducción de nanosistemas selectivos para la vehiculización de estos fármacos antiaterogénicos, mejoraría su biodisponibilidad y eficacia.El trabajo presentado muestra parte de los resultados obtenidos de un proyecto previo. Estos resultados nos han avalado para la concesión de una nueva ayuda de financiación para abordar una estrategia más avanzada que implica la introducción de elementos de diagnóstico y de un fitocannabinoide. (AU)

In order to selectively deliver cannabinoid drugs (CB2 agonists) to the atherosclerotic plaque, biocompatible and biodegradable nanoparticles have been obtained. For this purpose, the PEGylated nanoparticles have been functionalized with a peptide capable of selectively binding to endothelial adhesion proteins overexpressed in the atherosclerotic plaque (vascular cell adhesion molecules 1, VCAM-1). The particles have been characterized physicochemically, in vitro in cell cultures and in vivo in an animal model of atherosclerosis (apolipoprotein E-deficient ApoE-/- mice), demonstrating optimal spatiotemporal control of cannabinoid release and superior pharmacological response. Given that CB2 agonist drugs present high lipophilicity and low availability, the introduction of selective nanosystems for the vehiculation of these antiatherogenic drugs would improve their bioavailability and efficacy.The work presented shows part of the results obtained from a previous project. These results have supported us for the award of a new funding grant to address a more advanced strategy involving the introduction of diagnostic elements and a phytocannabinoid. (AU)

Pathophysiology and Optimal Treatment of Intracranial Branch Atheromatous Disease.

Intracranial branch atheromatous disease (BAD) is a pathological condition characterized by the occlusion of a relatively large perforating branch (700-800 µm) near the orifice of a parent artery due to atherosclerotic plaque-based thrombus (microatheroma). BAD is refractory to treatment and follows a course of progressive exacerbation, especially motor paralysis. Uniform treatment for common atherothrombotic cerebral infarction or lacunar infarction does not prevent the progressive exacerbation of BAD, and consequently affects functional prognosis. To date, various combinations of treatments have been investigated and proposed to attenuate the worsening symptoms of BAD. However, no therapy with established efficacy is yet available for BAD. Since it is the most difficult condition to treat in the area of cerebral infarction, the establishment of optimal treatment methods for BAD is keenly awaited. This review presents an overview of the acute treatments available for BAD and discusses the prospects for optimal treatment.

Human Basilar Arterial Plaque Detected by Near-Infrared Spectroscopy: Clinical Image.

A patient in their 70s presented with weakness of the left limb and aphasia. Left vertebral angiography showed acute basilar artery occlusion. After mechanical thrombectomy, basilar artery trunk stenosis was evident and catheter-based near-infrared spectroscopy (NIRS) showed lipid-rich atherosclerotic plaque extending to almost 220° of the vessel circumference in the culprit lesion. Loading doses of dual antiplatelet therapy and aggressive medical treatment were started because additional intervention might have increased risk of plaque protrusion and thrombotic reocclusion. The patient presented with minor stroke caused by restenosis of the basilar artery 4 months later; balloon angioplasty and stenting were performed without thromboembolic complications. The patient was discharged without any new neurologic deficits. NIRS visualizes the distribution of lipids in the culprit lesion and the plaque burden of residual stenosis, identifies mechanisms of in situ thrombosis, and provides suggestions for the timing of additional interventions.

Ultrasound-assisted biomimetic nanobubbles for targeted treatment of atherosclerosis.

Cardiovascular disease caused by atherosclerosis remains the main reason of death in the worldwide scale. Although oxidative stress plays a key role in the initiation and progression of atherosclerosis, current antioxidant drugs have limited efficacy. To resolve this problem, we constructed Nox2 siRNA-loaded nanobubbles (PNBs-siNox2) coated with platelet membranes to utilize their antioxidant stress activity and targeting effect for atherosclerosis treatment. After platelet membranes modification, the capacity of PNBs-siNox2 to target collagen, foam cells, or human umbilical vein endothelial cells (HUVECs) was significantly increased. Moreover, our study demonstrated that under ultrasonic irradiation, biomimetic nanobubbles were more effective at targeting atherosclerotic plaques and delivering genes into cells. In the present study, we provided a biomimetic gene loading strategy based on nanoplatform for noninvasive, precise and efficient therapy of atherosclerosis, which further improved the efficiency of gene transfection and effectively slowed the progression of atherosclerotic plaques when combined with ultrasound.

Enhanced Local Delivery of microRNA-145a-5P into Mouse Aorta via Ultrasound-Targeted Microbubble Destruction Inhibits Atherosclerotic Plaque Formation.

Abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) play a key role in the formation and rupture of atherosclerotic plaques. Previous studies have confirmed that microRNA-145 (miR-145) is involved in the phenotypic regulation of VSMCs and reduction of atherosclerosis. At present, seeking safe and effective gene delivery remains a key problem restricting the development of gene therapy. In recent years, ultrasound-targeted microbubble destruction (UTMD) has become a safe and effective transfection method that is widely used in the basic research of gene therapy for heart and tumor diseases. Here, we synthesized cationic microbubbles to encapsulate miR-145 and targeted their release into VSMCs in vitro and in vivo using ultrasound. The feasibility of this gene therapy was verified by fluorescence microscopy and an in vivo imaging system. The results showed that treatment with miR-145 delivered via UTMD considerably improved the gene transfection efficiency and promoted the contraction phenotype of VSMCs in vitro. In vivo, this treatment reduced the atherosclerotic plaque area by 48.04% compared with treatment with free miR-145. Therefore, UTMD-mediated miRNA therapy may provide a new targeted therapeutic approach for atherosclerotic plaques.

Recent Advances: From Cell Biology to Cell Therapy in Atherosclerosis Plaque via Stent Implantation.

Atherosclerosis is a multifactorial result of complicated pathophysiology. Changes in the expression of polygenes, coupled with environmental and lifestyle factors, trigger a cascade of adverse events involving a variety of cell types, such as vascular endothelial cells, smooth muscle cells, and macrophages. In this review, we summarize the function and therapeutic targets of atherosclerotic cells. This article reviews the role of endothelial cells, smooth muscle cells, macrophages and foam cells in the development of atherosclerosis and the progress in the treatment of atherosclerosis by targeting these cells. Atherosclerotic plaque involves a variety of cells and biomolecules, and its complex biological environment is a difficult point for the study and treatment of atherosclerosis. For treating atherosclerosis, a large number of studies emerged based on blocking or inhibiting factors affecting the formation and development of plaque. Cardiovascular stent intervention is currently the main method for the treatment of atherosclerosis. In recent decades, numerous studies on cardiovascular, stents mainly involve drug coating or biomolecular modification of stents to enhance anti-thrombosis, anti-restenosis and endothelialization. This paper introduces the research status of cardiovascular stents and new strategies for surface modification. The treatment of atherosclerosis based on the level of molecular biology and cell biology is becoming a research hotspot in the coming decades.

Outcomes of non-ischaemic coronary lesions with high-risk plaque characteristics on coronary CT angiography.

BACKGROUND: The integrative implications of quantitative and qualitative plaque characteristics on clinical outcomes and therapeutic guidance have not been fully investigated. AIMS: We aimed to investigate the combined prognostic value of quantitative and qualitative plaque measures and their interactions with treatment modalities and physiological lesion severity. METHODS: Among 697 vessels from 458 patients who underwent fractional flow reserve (FFR)-guided treatment, quantitative high-risk plaque (qn-HRP; plaque burden ≥70% and minimum lumen area <3.3 mm2) and qualitative HRP (ql-HRP; low-attenuation plaque or positive remodelling) were defined on coronary computed tomography angiography (CCTA). The primary endpoint was the vessel-oriented composite outcome (VOCO; a composite of cardiac death, myocardial infarction, or revascularisation). RESULTS: The mean baseline FFR was 0.85±0.12, and 25.8% underwent percutaneous coronary intervention (PCI) during the index procedure. In medically treated lesions, both qn-HRP and ql-HRP were associated with an increased risk of VOCO (p<0.05). Relative to the lesions with qn-HRP(-)/ql-HRP(-),those with qn-HRP(+)/ql-HRP(+) showed a higher risk of VOCO (hazard ratio [HR] 8.36, 95% confidence interval [CI]: 2.86-24.44). The PCI group showed a lower risk for VOCO than the medical treatment group (HR 0.31, 95% CI: 0.11-0.91) in lesions with qn-HRP(+)/ql-HRP(+). This difference was consistent in lesions with an FFR of 0.81-0.90 (HR 0.19, 95 CI: 0.04-0.90), but not in those with an FFR of>0.90. CONCLUSIONS: In non-ischaemic lesions, ql-HRP and qn-HRP showed a synergistic impact on risk assessment and had prognostic interactions with FFR and treatment modalities. Therefore, they need to be integrated into risk stratification and the optimisation of a treatment strategy. CLINICALTRIALS: gov: NCT04037163.

Plaque modification and stabilization after drug-coated balloon angioplasty for intracranial atherosclerotic lesions.

OBJECTIVES: A drug-coated balloon (DCB) has potential applications in the treatment of intracranial atherosclerotic disease (ICAD). We aimed to evaluate changes of vessel wall features of ICAD lesions after DCB treatment by using vessel wall MRI (VWMRI). METHODS: We retrospectively included patients with symptomatic ICAD who underwent DCB angioplasty alone. The incidences of stenosis of the lumen area, vessel wall thickening, hyperintense plaques, and prominent wall enhancement were compared between the baseline and follow-up VWMRI. RESULTS: There were 29 ICAD lesions from 29 patients, of which 22 were stenosis and 7 were occlusion. The median interval between DCB treatment and follow-up VWMRI was 4.1 [3.3, 6.7] months. After DCB treatment, follow-up VWMRI showed a significant decrease in the stenosis degree of the lumen area (83% [71%, 96%] vs 15% [3%, 41%], p < 0.001). Thirty-eight percent (11/29) of the patients observed normal appearance of the target vessel wall on follow-up VWMRI. In the stenosis group, the prevalence of hyperintense plaques decreased from 66.7% (14/21) at baseline to 23.8% (5/21) at follow-up, and prominent wall enhancement decreased from 66.7% (14/21) at baseline to 19.0%(4/21) at follow-up. The incidence of hyperintense plaques (p = 0.028) and vessel wall thickening (p = 0.018) tended to decrease with follow-up time. Although not significant (p = 0.106), a similar trend was observed between the incidence of prominent wall enhancement and follow-up time. CONCLUSION: Vascular healing with plaque modification and stabilization occurred following DCB treatment of ICAD lesions. KEY POINTS: • A drug-coated balloon (DCB) has potential applications in the treatment of intracranial atherosclerotic disease (ICAD). • Vascular healing with plaque modification and stabilization occurred following DCB treatment of ICAD lesions.

Efficacy of medical treatment and balloon angioplasty for severe intracranial atherosclerosis: a high-resolution MR vessel wall imaging.

OBJECTIVES: To investigate the efficacy of medical treatment and balloon angioplasty for intracranial atherosclerosis using high-resolution MR vessel wall imaging (HR-MRI). METHODS: In this prospective study, patients with symptomatic severe stenosis from January 2018 to August 2021 were treated with medical treatment or balloon angioplasty. The patients underwent HR-MRI at baseline and at 3, 6, and 12 months. Plaque characteristics at follow-up were compared with those at baseline using paired sample T-test or Wilcoxon rank sum test. The difference in the recurrence of ischemic events between two groups was compared. RESULTS: A total of 37 patients (26 males; mean age = 60.5 ± 11.6 years) were evaluated. Of 68 plaques, 42 (61.8%) were treated with medication only. At 12 months of medical treatment, maximum plaque length (p = 0.004), maximum wall thickness (p = 0.036), and plaque enhancement (p = 0.001) were significantly reduced than baseline. At 3 months after balloon angioplasty, luminal stenosis (p = 0.048) was significantly reduced compared to baseline. At 6 months after balloon angioplasty, maximum plaque length (p = 0.011), maximum wall thickness (p = 0.003), and luminal stenosis (p = 0.001) were significantly reduced than baseline. No difference was found in the recurrence of ischemic events between two groups (p = 0.458). CONCLUSION: Intracranial atherosclerotic plaque shrank and tended to be stable at 12 months of medical treatment. Plaque burden was significantly reduced 6 months after balloon angioplasty. This may provide evidence for the application and selection of treatment strategies for intracranial atherosclerotic disease. KEY POINTS: • Plaque burden and plaque enhancement were significantly reduced at 12 months of medical treatment compared to baseline. • Plaque burden was significantly reduced at 6 months after balloon angioplasty compared with baseline. • No significant difference in the recurrence rate of ischemic stroke between patients treated with medication and balloon angioplasty.

Fundamental Pathobiology of Coronary Atherosclerosis and Clinical Implications for Chronic Ischemic Heart Disease Management-The Plaque Hypothesis: A Narrative Review.

Importance: Recent clinical and imaging studies underscore that major adverse cardiac events (MACE) outcomes are associated not solely with severe coronary obstructions (ischemia hypothesis or stenosis hypothesis), but with the plaque burden along the entire coronary tree. New research clarifies the pathobiologic mechanisms responsible for plaque development/progression/destabilization leading to MACE (plaque hypothesis), but the translation of these insights to clinical management strategies has lagged. This narrative review elaborates the plaque hypothesis and explicates the current understanding of underlying pathobiologic mechanisms, the provocative destabilizing influences, the diagnostic and therapeutic implications, and their actionable clinical management approaches to optimize the management of patients with chronic coronary disease. Observations: Clinical trials of management strategies for patients with chronic coronary artery disease demonstrate that while MACE rate increases progressively with the anatomic extent of coronary disease, revascularization of the ischemia-producing obstruction does not forestall MACE. Most severely obstructive coronary lesions often remain quiescent and seldom destabilize to cause a MACE. Coronary lesions that later provoke acute myocardial infarction often do not narrow the lumen critically. Invasive and noninvasive imaging can identify the plaque anatomic characteristics (plaque burden, plaque topography, lipid content) and local hemodynamic/biomechanical characteristics (endothelial shear stress, plaque structural stress, axial plaque stress) that can indicate the propensity of individual plaques to provoke a MACE. Conclusions and Relevance: The pathobiologic construct concerning the culprit region of a plaque most likely to cause a MACE (plaque hypothesis), which incorporates multiple convergent plaque features, informs the evolution of a new management strategy capable of identifying the high-risk portion of plaque wherever it is located along the course of the coronary artery. Ongoing investigations of high-risk plaque features, coupled with technical advances to enable prognostic characterization in real time and at the point of care, will soon enable evaluation of the entire length of the atheromatous coronary artery and broaden the target(s) of our therapeutic intervention to include all regions of the plaque (both flow limiting and nonflow limiting).

Heparanase: A Novel Therapeutic Target for the Treatment of Atherosclerosis.

Cardiovascular disease (CVD) is the leading cause of death and disability worldwide, and its management places a huge burden on healthcare systems through hospitalisation and treatment. Atherosclerosis is a chronic inflammatory disease of the arterial wall resulting in the formation of lipid-rich, fibrotic plaques under the subendothelium and is a key contributor to the development of CVD. As such, a detailed understanding of the mechanisms involved in the development of atherosclerosis is urgently required for more effective disease treatment and prevention strategies. Heparanase is the only mammalian enzyme known to cleave heparan sulfate of heparan sulfate proteoglycans, which is a key component of the extracellular matrix and basement membrane. By cleaving heparan sulfate, heparanase contributes to the regulation of numerous physiological and pathological processes such as wound healing, inflammation, tumour angiogenesis, and cell migration. Recent evidence suggests a multifactorial role for heparanase in atherosclerosis by promoting underlying inflammatory processes giving rise to plaque formation, as well as regulating lesion stability. This review provides an up-to-date overview of the role of heparanase in physiological and pathological processes with a focus on the emerging role of the enzyme in atherosclerosis.

Sonodynamic Therapy With Concentric Ultrasound Imaging Array for Precision Theranostics for Atherosclerotic Plaque.

Atherosclerotic cardiovascular disease is a major cause of human disability and mortality. Our previous study demonstrated the safety and efficacy of sonodynamic therapy (SDT) on atherosclerotic plaques. However, traditional single-element therapeutic transducer has single acoustic field, and positioning therapeutic and imaging transducers in the same position is difficult during ultrasound imaging-guided SDT. Continuously changing the position of transducers to intervene lesions in different positions is required, increasing the difficulty of treatment. Thus, an SDT device with precise theranostics is required. Therefore, we designed and fabricated a "concentric ultrasound transducer for theranostics" (CUST-T), comprising a central 8-MHz linear array transducer for ultrasound imaging, and a peripheral 1-MHz hollow two-dimensional (2-D) planar array transducer for generating phased-array focused ultrasound (PAFUS). The CUST-T exhibited high imaging resolution at a distance of up to 20 mm from the transducer and could generate a personalized complex PAFUS acoustic field to match various lesions. In vitro biomedical results showed that PAFUS-SDT induced RAW264.7-derived foam cell apoptosis leading to a targeting field apoptotic rate 4.36-6.24 times that of the nontargeting field and the significant apoptotic region was consistent with the PAFUS acoustic field. In vivo, PAFUS-SDT guided by ultrasound imaging significantly increased the lumen area ( ) and collagen level ( ), whereas the wall thickness ( ) and lipid content ( ) of rabbit femoral artery were reduced. In conclusion, CUST-T provided image guidance sufficient for accurate SDT for atherosclerotic plaques in peripheral arteries and could be applied in clinical practice.

Macrophage-Targeted Sonodynamic/Photothermal Synergistic Therapy for Preventing Atherosclerotic Plaque Progression Using CuS/TiO2 Heterostructured Nanosheets.

Sonodynamic therapy (SDT) and photothermal therapy (PTT) are two effective strategies for the treatment of atherosclerotic plaques. However, the low yield of reactive oxygen species (ROS) of conventional organic sonosensitizers and the low biosafety of hyperthermia limit the therapeutic efficacy of SDT and PTT. Herein, we report copper sulfide/titanium oxide heterostructure nanosheets modified with hyaluronic acid (HA) and PEG (HA-HNSs) for low-intensity sonodynamic and mild-photothermal synergistic therapy for early atherosclerotic plaques. CuS/TiO2 heterostructure nanosheets (HNSs) show high electron-hole separation efficiency and superior sonodynamic performance, because it has high surface energy crystal facets as well as a narrow band. Moreover, HNSs exhibit intense absorbance in the NIR-II region, which endows the nanosheets with excellent photothermal performance. With a further modification of HA, HA-HNSs can selectively target intraplaque proinflammatory macrophages through CD44-HA interaction. Because SDT reduces the expression of heat shock protein 90 and PTT facilitates the sonocatalytic process, the combination of SDT and PTT based on HA-HNSs could synergistically induce proinflammatory macrophage apoptosis. More importantly, the synergistic therapy prevents the progression of early atherosclerotic plaque by removing lesional macrophages and mitigating inflammation. Taken together, this work provides a macrophage-targeting sonodynamic/photothermal synergistic therapy, which is an effective translational clinical intervention for early atherosclerotic plaques.

Atherosclerosis: From Molecular Biology to Therapeutic Perspective.

Atherosclerosis is a chronic and progressive inflammatory disease of the arteries initiated by the functional and structural alteration of the endothelial layer responsible for promoting the subendothelial retention of modified low-density lipoproteins (LDL), which in turn generate an active proinflammatory state in which environmental factors, such as oxidizing agents, growth factors, cytokines, monocyte-macrophages and smooth muscle cells (SMCs), work in cooperation to promote the formation of plaque [...].