Plaque Lesions Research Articles

Clinical and epidemiological aspects in equine aural plaques.

The association between aural plaques, Equus caballus papillomavirus (EcPV), and the different breeds of horses and risk factors is poorly described. The objective of this study was to determine the clinical prevalence of aural plaques in Mangalarga Marchador (MM) and Quarter Horse (QH) horses in Brazil, to evaluate the association of this prevalence with some risk factors, and to detect the presence of EcPV DNA (types 1-10) in aural plaques biopsies. A total of 400 MM and 425 QH horses, were clinically evaluated. For each horse, an identification form was completed, containing information on breeding, sex, age, presence, and classification of aural plaque lesions, presence of ectoparasites, management type, ear clipping performed, and sensitivity to ear palpation. Biopsies of the lesions were taken from 30 horses and assessed for the presence of EcPV DNA using PCR. Among the MM and QH horses evaluated, 41.5% and 33.6%, respectively, had aural plaques. The MM horses showed a higher frequency of plaques than QH (p = 0.02). At least one viral type was identified in 90% of all aural plaque biopsies, with EcPV4 being the most frequently detected in both breeds, followed by EcPV6, EcVP5, EcVP3 and EcPV1 respectively. In one sample, EcPV1 was detected alone, although it had previously been described only in copresence. The copresence of viral DNA the MM 73% (11/15) QH 27% (4/15) horses. Aural plaques are widely distributed, with a higher prevalence of EcPV4. Additionally, MM horses have higher susceptibility and frequency of the disease than QH horses.

Abstract 4132968: CCR5 modulation enhances M-MDSCs functionality in early atherosclerosis

Background: The role of immune suppressive microenvironment, promulgated by the presence of Myeloid Derived Suppressor Cells (MDSC) have been the major focus of research delineating the underlying mechanisms of cardiovascular diseases (CVD). CCR5, a chemokine receptor, has been associated with both immunosuppressive and inflammatory phenotypes, however, the possible role of CCR5 pertaining to MDSCs in the development of atherosclerosis has not been elucidated yet. Therefore, we investigated the therapeutic potential of CCR5 modulation in early atherosclerosis progression. Methods: CCR5 receptor-ligand expression was studied with flow cytometry, real time PCR and immunocytochemistry in 65 individuals (25 Healthy controls, 20 young hypercholesterolemic individuals, and 20 stable [Coronary Artery Disease] CAD patients). To induce atherosclerosis, mice were fed high fat diet (HFD) for 6 weeks following partial ligation of left carotid artery in C57BL6 mice. MDSCs phenotype and functionality were assessed using CCR5 inhibitor in vitro (10 -8 M) and in vivo (i.p 3ng/day for 15 days) . M-MDSCs phenotype switch, atherosclerotic lesion development and plaque phenotype was studied in vivo . Results: We observed CCR5 elevation on Monocytic-MDSCs in the early phase of atherosclerosis. M-MDSCs displayed an intermediate phenotype with expression of both pro and anti-inflammatory mediators in early atherosclerosis, a similar trend was observed in inflammatory cytokines stimulated M-MDSCs ( in vitro ). Notably, DAPTA treatment shifted phenotype of M-MDSCs to anti-inflammatory profile with elevated expression of IL-10 and reduced expression of IFNγ, IL4, and IL22. Further, CCR5 modulation expanded IL10+M-MDSC in vivo . Additionally, DAPTA reduced the migratory potential, reduced cholesterol uptake and improved the functionality (suppression of T cell) of M-MDSCs. Blocking CCR5 with DAPTA led to the formation of stable plaque in HFD-fed mice. Conclusion: Increased expression of CCR5 coupled with inflammatory cytokine secretion by regulatory cells lead to dysfunctional M-MDSCs in CVD risk factor population. Possibly this dysfunctionality contributes to the development and progression of CVD including atherosclerosis. Our findings show targeting of CCR5 with DAPTA reduces atherogenesis, increases plaque stabilization and corrects phenotypic alterations in immune suppressive M-MDSCs. The functionality and phenotype of M-MDSCs in atherosclerosis, may be ameliorated by targeting CCR5.

Enhanced Macrophages Engulfment by Peptide‐Templated Nanoassemblies Targeting SIRPα and Suppressing Oxidative Stress for Atherosclerosis Pro‐Efferocytotic Therapy

AbstractPrompt removal of apoptotic cells via macrophage‐mediated efferocytosis is an emerging approach for atherosclerosis treatment, because these diseased cells directly contribute to vascular inflammation and secondary necrosis in plaques. Despite blocking CD47 can restore impaired efferocytosis by inhibiting “don't eat me” signals, the currently available CD47 antibody (CD47‐Ab)‐based therapy may accelerate off‐target clearance of healthy cells due to the ubiquitous expression of CD47 on viable cells. Here, a peptide‐templated nanoassembly (PTna‐1) engineered to induce synergistic enhancement of engulfment by macrophages is reported. Through self‐assembled polypeptides with multiple functional motifs, the nanoassembly can specifically target p32‐overexpressing macrophages and bind to the Ig‐V‐like domain of SIRPα but not to CD47, thereby normalizing intraplaque efferocytosis and alleviating persistent inflammation. Concurrently, disassembled PTna‐1 released manganese porphyrins with photoacoustic/magnetic resonance imaging capability to suppress oxidative stress and synergistically enhance macrophage phagocytosis through the RhoA/ROCK1 pathway. Compared with CD47‐Abs, PTna‐1 promoted a more significant reduction in lesion area and plaque stabilization without affecting the incidence of anemia in atherosclerotic mice. Proteomic analysis revealed that PTna‐1 treatment decreased the expression of inflammation‐related proteins in plaques. Overall, these peptide‐driven nanoassemblies employing a SIRPα‐specific blockade strategy provide a distinct paradigm of pro‐efferocytotic therapy for atherosclerosis.

Coronary artery plaque characteristics in smokers assessed by intracoronary multi-modality imaging: a NIRS-IVUS guided PROSPECT II substudy

Abstract Background Smoking is a risk factor for coronary artery disease and myocardial infarction. Purpose Among patients with myocardial infarction, we hypothesized smokers would have increased prevalence of nonculprit high-risk plaque characteristics as assessed by intracoronary multimodality imaged when compared to nonsmokers. Method This is a prespecified post-hoc analysis of the PROSPECT II (Providing Regional Observations to Study Predictors of Events in the Coronary Tree). Altogether 898 patients with acute myocardial infarction with or without ST-segment elevation who after successful percutaneous coronary intervention had near-infrared spectroscopy and intravascular ultrasound imaging performed. Data on lesion location, plaque burden, and lipid content were collected. Current, former, and nonsmokers were examined regarding the presence of high-risk plaques in both culprit and nonculprit lesions as well as plaque location. High-risk plaque characteristics were defined as a maximum plaque burden (maxPB) of ≥70% and a maximum 4 mm lipid core burden index (maxLCBI4mm) of ≥324.7. Results Out of 886 patients with known smoking history, 32% were smokers, 32% former, and 37% nonsmokers. Smokers were younger (median age: smokers 59.0; former 65.5; nonsmokers 64.0 years, p<0.001) with fewer co-morbidities and presented more often with STEMI (% presenting with STEMI: smokers 22.2%; former 18.9%; nonsmokers 19.4%, p=0.006). LDL was similar but CRP was higher in smokers (median µg/mL: smokers 4.0; former 3.1; nonsmokers 2.9, p=0.004). In multivariate models of nonculprit lesion morphology smoking history was not associated with maxPB or maxLCBI4mm but was associated with presence of calcified nodules (OR: 2.88 (95% CI 1.46–5.69) p=0.002 [smokers vs nonsmokers]). Calcified nodules were also associated with number of years smoked (OR: 1.02 (95% CI 1.01–1.03) p=0.004). Smoking was not associated with presence of ≥1 lesions with MaxLCBI4mm, ≥ 324.7, maxPB >=70% or the combination of both. Smoking was not associated with presence of plaque rupture or thrombus. Right coronary artery culprit lesions were more common in smokers and former smokers (smokers 29.9%; former 30.9%; nonsmokers 21.6%; OR: 1.12 (95% CI 1.04–1.21) p<0.001 [smokers vs nonsmokers]). Conclusion In this prospective intracoronary multimodality imaging study of patients with recent acute myocardial infarction, smoking was not associated with a higher rate of high-risk nonculprit plaques based on lipid content by NIRS or PB by IVUS when compared to former or nonsmokers. However, smoking was associated with higher presence of IVUS-detected calcified nodules, higher CRP-levels, and the right coronary artery as it angiographically was a more common site for culprit lesions. These results indicate that the elevated risk in smokers is unrelated to vulnerable plaque morphology defined by high PB and lipid content, and instead possibly related to inflammation, calcification, or hemodynamic changes.Table 1

Different treatment modalities for underexpanded stents-Effectiveness and outcomes: A practical guide.

Underexpanded stents are a dreaded complication of percutaneous coronary intervention (PCI) and are a major predictor of stent thrombosis and in-stent restenosis. Lesion preparation and plaque modification before stent implantation are essential to prevent stent underexpansion and optimize the technical outcomes of PCI. Once stent underexpansion occurs, the treatment options are limited. New devices for the treatment of complex calcified lesions have emerged in the past few years, and experience has accumulated with their use in the treatment of underexpanded stents. This review aims to provide an evidence-based, practical summary of the approach to stent underexpansion, with particular attention to the expected luminal gain, complication rates, and technical nuances of various treatment options. These modalities include the ultrahigh pressure OPN noncompliant balloon, excimer laser coronary angioplasty, rotational and orbital atherectomy, and intravascular lithotripsy. The data gathered for each of these modalities and our experience in treating this complex condition were used to formulate a treatment algorithm for such cases.

Myeloid GSK3α Deficiency Reduces Lesional Inflammation and Neovascularization during Atherosclerotic Progression.

The molecular mechanisms by which cardiovascular risk factors promote the development of atherosclerosis are poorly understood. We have recently shown that genetic ablation of myeloid glycogen synthase kinase (GSK)-3α attenuates atherosclerotic lesion development in low-density lipoprotein receptor-deficient (Ldlr-/-) mice. However, the precise contributions of GSK3α/β in atherogenesis are not known. The aim of this study is to investigate the effect of GSK3α and/or β deficiency on lesional inflammation and plaque vascularization. Five-week-old female Ldlr-/- mice were fed a high-fat diet for 10 weeks to establish atherosclerotic lesions. Mice were harvested at 15 weeks of age and atherosclerotic lesions were characterized. The results indicate that, in addition to significantly reducing plaque volume, GSK3α-deficiency decreases inflammation, reduces vasa vasorum density at the aortic sinus, and reduces plasma c-reactive protein (CRP) levels. GSK3β-deficiency is associated with decreased plasma CRP levels but does not affect lesional inflammation or vascularization. These results suggest GSK3α may be an applicable target for the development of novel anti-atherogenic therapies.

Matrix vesicles from osteoblasts promote atherosclerotic calcification

Atherosclerotic calcification often coincides with osteoporosis, suggesting a potential interplay between bone and vascular mineralization. Osteoblast-derived matrix vesicles (Ost-MVs), pivotal in bone mineralization, have emerged as potential contributors to ectopic vascular calcification. However, the precise role of Ost-MVs in vascular calcification and the underlying mechanisms remain elusive. In this study, we observed a concomitant increase in atherosclerotic calcification and bone loss, accompanied by elevated release of Ost-MVs into circulation. We demonstrate that circulating Ost-MVs target plaque lesions in the setting of atherosclerosis. Mechanistically, vascular injury facilitates transendothelial transport of Ost-MVs, collagen І remodeling promotes Ost-MVs aggregation, and vascular smooth muscle cell (VSMC) phenotypic switching enhances MV uptake. These pathological changes during atherosclerosis collectively contribute to Ost-MVs recruitment into the vasculature. Furthermore, Ost-MVs and VSMC-derived matrix vesicles (VSMC-MVs) exacerbate calcification via the Ras-Raf-ERK pathway. Our findings unveil a novel Ost-MVs-mediated mechanism participating in vascular calcification and enriching our understanding of bone-vascular crosstalk.

Overview and Future Direction of Embolic Stroke of Undetermined Source from the Insights of CHALLENGE ESUS/CS Registry.

Cryptogenic stroke (CS) accounts for approximately one-fourth of acute ischemic strokes, with most cases derived from embolic etiologies. In 2014, embolic stroke of undetermined source (ESUS) was advocated and the efficacy of anticoagulant therapy was anticipated. However, 3 large-scale clinical trials failed to demonstrate the superiority of direct oral anticoagulants (DOACs) over aspirin, potentially due to the heterogeneous and diverse pathologies of ESUS, including paroxysmal atrial fibrillation (AF), arteriogenic sources such as nonstenotic carotid plaque and aortic complicated lesion (ACL), patent foramen oval (PFO), and nonbacterial thrombotic endocarditis (NBTE) related to active cancer.Transesophageal echocardiography (TEE) is one of the most effective imaging modalities for assessing embolic sources in ESUS and CS. The Mechanisms of Embolic Stroke Clarified by Transesophageal Echocardiography for Embolic Stroke of Undetermined Source/Cryptogenic Stroke (CHALLENGE ESUS/CS) registry is a multicenter registry that enrolled consecutive patients with CS who underwent TEE at 8 hospitals in Japan between April 2014 and December 2016. Their mean age was 68.7±12.8 years, and 455 patients (67.2%) were male. The median National Institutes of Health Stroke Scale (NIHSS) score was 2. Since 7 analyses have been conducted from each institution to date, novel and significant insights regarding embolic origins and pathophysiologies of ESUS and CS were elucidated from this multicenter registry. This review discusses the diagnosis and treatment of ESUS and CS, tracing their past and future directions. Meaningful insights from the CHALLENGE ESUS/CS registry are also referenced and analyzed.

Novel Role of Endothelial CD45 in Regulating Endothelial-to-Mesenchymal Transition in Atherosclerosis.

Protein-tyrosine-phosphatase CD45 is exclusively expressed in all nucleated cells of the hematopoietic system but is rarely expressed in endothelial cells. Interestingly, our recent study indicated that activation of the endogenous CD45 promoter in human endothelial colony forming cells (ECFCs) induced expression of multiple EndoMT marker genes. However, the detailed molecular mechanisms underlying CD45 that drive EndoMT and the therapeutic potential of manipulation of CD45 expression in atherosclerosis are entirely unknown. We generated a tamoxifen-inducible EC-specific CD45 deficient mouse strain (EC-iCD45KO) in an ApoE-deficient (ApoE-/-) background and fed with a Western diet (C57BL/6) for atherosclerosis and molecular analyses. We isolated and enriched mouse aortic endothelial cells with CD31 beads to perform single-cell RNA sequencing. Biomedical, cellular, and molecular approaches were utilized to investigate the role of endothelial CD45-specific deletion in the prevention of EndoMT in ApoE-/- model of atherosclerosis. Single-cell RNA sequencing revealed that loss of endothelial CD45 inhibits EndoMT marker expression and transforming growth factor-β signaling in atherosclerotic mice. which is associated with the reductions of lesions in the ApoE-/- mouse model. Mechanistically, the loss of endothelial cell CD45 results in increased KLF2 expression, which inhibits transforming growth factor-β signaling and EndoMT. Consistently, endothelial CD45 deficient mice showed reduced lesion development, plaque macrophages, and expression of cell adhesion molecules when compared to ApoE-/- controls. These findings demonstrate that the loss of endothelial CD45 protects against EndoMT-driven atherosclerosis, promoting KLF2 expression while inhibiting TGFβ signaling and EndoMT markers. Thus, targeting endothelial CD45 may be a novel therapeutic strategy for EndoMT and atherosclerosis.

Rapid Efficacy of riSankizumab in pretibial psoriasis invOLVEment: RESOLVE.

Despite extraordinary improvements in the management of psoriasis in recent times, some areas of the body, such as the pretibial area, still show an unsatisfactory response and a more significant impact on patient quality of life. This multicentre study focuses on psoriasis affecting sensitive areas (particularly the pretibial area), its impact on quality of life and the therapeutic response to risankizumab. This multicentre prospective observational study recruited patients with moderate-to-severe psoriasis with pretibial area involvement. All patients underwent treatment with risankizumab (150 mg every 3 weeks), and efficacy was assessed after 24 weeks. The study included 128 patients with a mean age of 51 years, suffering from moderate-to-severe psoriasis with involvement of the pretibial area with median total Psoriasis Area Severity Index score of 17.05 and Dermatology Life Quality Index of 16.27. The group was further divided into two sub-groups: the 'mother patch' group, in whom the very first psoriatic plaque appeared in the pretibial region (45 patients), and the 'non-mother patch' group, in whom the psoriatic lesion in the pretibial region was present but not as the first manifestation (83 patients). In order to better assess the involvement of psoriasis in the pretibial area, the pretibial plaque lesion severity index was also calculated at baseline in all patients: extent 2.75, erythema 2.64, infiltration 2.45 and desquamation 2.38. All participants in this study showed a good therapeutic response, with a reduction in all scores. The pretibial area is becoming an object of therapeutic interest due to some resistance to clearance and the consequent impairment of patient quality of life. This study showed that risankizumab can give favourable therapeutic results not only in patients with moderate-to-severe psoriasis with involvement of the difficult-to-treat areas but particularly in patients with recalcitrant plaques in the pretibial area.

Evaluation of Lesion Burden in Pediatric Patients with Multiple Sclerosis by Computer Aided Algorithm and Comparison with Standard Detection Methods

Background: The aim of this retrospective study was to assess the lesion burden in pediatric patients with multiple sclerosis (pMS) using a computer-assisted algorithm, specifically the VolBrain program. The study aimed to compare the performance of this automated tool with traditional detection methods performed by neuroimaging analysts, providing valuable insights into the potential of automated tools for lesion quantification in pMS. Materials and Methods: The study cohort consisted of 20 PMS patients, aged 10-18 years, registered at Atatürk University Research Hospital. Lesion assessment was performed using the VolBrain program (by an anatomist) and standard detection methods (by a neuroradiologist) using T2 SPACE dark matter sequences. Statistical analysis included Wilcoxon and Pearson correlation tests, and the study adhered to ethical considerations and standardised magnetic resonance imaging (MRI) protocols. Results: In this study, pMS patients aged 10-18 years, the cohort consisted of 60% females (n=12) and 40% males (n=8). The mean age for females was 15.67±1.969 and for males 14.50±2.20 years (p=0.24). Plaque count analysis showed a statistically significant difference between radiologist and VolBrain assessment in all pMS patients (p=0.021). Significant differences were also observed in female pMS patients (p=0.034) but not in males (p=0.362). Correlations between radiologist and VolBrain assessments showed significant associations in both female and male patients, with strong correlations observed for plaque number, lesion burden and Expanded Disability Status Scale (EDSS) scores (p<0.01). Conclusions: This study demonstrates the potential of the VolBrain programme in assessing lesion burden in pMS patients. The observed correlations with traditional methods and clinical parameters support the concurrent validity of VolBrain and emphasise its potential clinical relevance. Incorporating automated tools into routine clinical practice could improve the accuracy of lesion quantification and thus contribute to improved monitoring and management of pMS.

Fractal geometry of culprit coronary plaque images within optical coherence tomography in patients with acute coronary syndrome vs stable angina pectoris.

The main cause of acute coronary syndrome (ACS) is plaque rupture and thrombus formation. However, it has not been fairly successful to identify vulnerable plaque to rupture using conventional parameters of intravascular imaging modalities. Fractal analysis is one of the mathematical models to examine geometrical features of picture image using a specific parameter called as fractal dimension (FD) which suggests geometric complexity of the image. This study examined FD of the optical coherence tomography (OCT)-derived images of the culprit plaque in patients with ACS vs stable angina pectoris (SAP) to evaluate the feasibility of FD for identifying vulnerable coronary plaques prone to provoke ACS distinguished from stable plaques only provoking SAP. We examined 65 cases (34 ACS patients, 31 SAP patients) in which the culprit lesion was imaged by OCT before percutaneous coronary intervention in patients with ACS and SAP. The culprit plaque lesion in the ACS group had a significantly larger mean lipid arc (203.8 ± 39.4° vs 152.3 ± 34.5°, p < 0.001) and a larger lipid plaque length (12.6 ± 5.1mm vs 7.7 ± 2.7mm, p < 0.001) and a thinner fibrous cap thickness (75.3 ± 22.3μm vs 134.8 ± 53.2μm, p < 0.001) than those in the SAP group. The prevalence of OCT-derived macrophage infiltration (Mph) in the entire culprit coronary vessel as well as that of the OCT-derived thin-cap fibroatheroma (TCFA) at the culprit lesion were significantly greater in the ACS group than those in the SAP group, respectively (Mph: 61.8% vs 35.5%, p = 0.048; TCFA: 44.1% vs 6.4%, p < 0.001). The FD of culprit plaque in the ACS group was significantly greater than in the SAP group (2.401 ± 0.073 vs 2.341 ± 0.051, p < 0.001). In multivariate regression analysis, the presence of Mph was a significant determinant of FD (regression coefficient estimate 0.049, CI 0.018-0.079, p = 0.002). The FD of OCT-derived image of culprit coronary plaque in the ACS group was significantly greater than that in the SAP group, indicating that the culprit plaque in ACS were structurally more complex. Therefore, fractal analysis of coronary OCT images might be clinically useful for identifying coronary plaques prone to provoke ACS.

Comparison between the diagnostic utility of three-dimensional fluid attenuated inversion recovery (3D FLAIR) and three dimensional double inversion recovery (3D DIR) magnetic resonance sequences in the assessment of overall load of multiple sclerosis lesions in the brain

BackgroundMultiple sclerosis (MS) is a complex CNS demyelinating disease. Assessment of MS plaques in specific anatomic locations in the brain was challenging to detect by conventional MRI sequences. So, this study aimed to compare the diagnostic accuracy of 3D FLAIR (Fluid attenuation inversion recovery), or 3D DIR (Double inversion recovery) sequences to conventional 2D FLAIR and T2 sequences in detecting MS plaques in different anatomic sites, as well as counting the total lesion burden.MethodsA comparative cross-sectional study enrolled 30 MS patients on the basis of McDonald’s criteria 2017. All participants underwent a brain MRI study including 3D FLAIR or 3D DIR sequences, conventional 2D FLAIR, and T2 sequences.ResultsNo statistically significant difference between the 3D DIR and 3D FLAIR in total lesion (plaque) burden results; however, when each is compared to the conventional ones, both are superior. 3D FLAIR detected the most significant number of plaques in the periventricular region, followed by 2D FLAIR and T2W sequences, with 3D DIR being the least accurate in this region. Meanwhile, 3D DIR was the most precise and can detect a statistically significant number of cortical plaques compared to the 3D FLAIR and the conventional sequences. No statistically significant results on which sequence is best in regard to infratentorial plaque detection.Conclusion3D FLAIR and 3D DIR were superior to 2D FLAIR and T2 sequences in detecting overall lesion burden in MS. Moreover, the 3D DIR sequence was the most precise in the detection of the cortical plaques.

Abstract Tu015: Angiopoietin-like 4 Stabilizes Atherosclerotic Plaques by Modulating the Phenotypic Transition of Endothelial Cells and Vascular Smooth Muscle Cells

Atherosclerosis, the leading cause of death, is a vascular disease of chronic inflammation. We recently showed that angiopoietin-like 4 (ANGPTL4) promotes cardiac repair by suppressing pathological inflammation. Given the fundamental contribution of inflammation to atherosclerosis, we assessed the role of ANGPTL4 in the development of atherosclerosis and determined whether ANGPTL4 regulates atherosclerotic plaque stability. We injected ANGPTL4 protein twice a week into atherosclerotic Apoe-/- mice and analyzed the atherosclerotic lesion size, endothelial dysfunction, inflammation, and plaque stability. In atherosclerotic mice, ANGPTL4 reduced the atherosclerotic plaque size, endothelial dysfunction, and vascular inflammation. Furthermore, ANGPTL4 was associated with maintenance of vascular integrity and attenuated endothelial-to-mesenchymal transition (EndMT) in both HUVEC and atherosclerotic plaque of Apoe-/- mice. In the atherosclerotic lesions and fibrous caps, the number of α-SMA(+), SM22α(+), and SM-MHC(+) cells was higher, while the number of CD68(+) and Mac2(+) cells was lower in the ANGPTL4 group. Most importantly, the fibrous cap was significantly thicker in the ANGPTL4 group than in the PBS group. Smooth muscle cells (SMCs) isolated from atherosclerotic aortas showed significantly increased expression of CD68 and Krüppel-like factor 4 (KLF4), a modulator of the vascular SMC phenotype, along with downregulation of α-SMA, and these changes were attenuated by ANGPTL4 treatment. Furthermore, ANGPTL4 reduced TNFa-induced NADPH oxidase 1 (NOX1), a major source of reactive oxygen species, resulting in attenuation of KLF4-mediated SMC phenotypic changes. Our results reveal that ANGPTL4 treatment inhibits atherogenesis and suggest that targeting vascular stability and inflammation may serve as a novel therapeutic strategy to prevent and treat atherosclerosis. Even more importantly, ANGPTL4 treatment inhibited the phenotypic changes of SMCs into macrophage-like cells by downregulating NOX1 activation of KLF4, leading to the formation of more stable plaques.

Early and short-term use of proprotein convertase anti-subtilisin-kexin type 9 inhibitors on coronary plaque stability in acute coronary syndrome.

Proprotein convertase anti-subtilisin-kexin type 9 inhibitors (PCSK9Is) improve plaque volume and composition and reduce major adverse coronary events in chronic coronary artery disease. We evaluated the effects of the short-term use of PCSK9Is on coronary plaque stability in patients with acute coronary syndrome (ACS) using optical coherence tomography (OCT). This is a multicentre, open-label randomized controlled trial. The enrolled 80 subjects met the inclusion criteria. Of these, 52 patients (age 60 ± 11 years, 38 men, 14 women) with ST-elevated ACS had undergone successful primary percutaneous coronary intervention with LDL-cholesterol (LDL-C) levels > 70 mg/dL while receiving high-intensity statins. Participants were randomly assigned to the PCSK9I group (evolocumab 420 mg for 3 months, n = 29) or the standard of care (SoC) group (n = 23). Optical coherence tomography was performed at baseline (BL) and 3 and 9 months after randomization to assess lipid-rich plaques in non-culprit lesions. The change in the minimum fibrous cap thickness (MFCT) from BL to 9 months was the primary endpoint. The percentage change in LDL-C levels from BL to 3 months was significantly greater in the PCSK9I group (-67.8 ± 21.5% in the PCSK9I group vs. -16.3 ± 21.8% in the SoC group; P < 0.0001), and the difference between the two groups disappeared from BL to 9 months (-20.0 ± 37.8% in the PCSK9I group vs. -6.7 ± 34.2% in the SoC group; P = 0.20). The changes in MFCT from BL to 9 months were significantly greater in the PCSK9I group, even after PCSK9I discontinuation {100 μm [interquartile range (IQR): 45-180 μm] vs. 50 μm [IQR: 0-110 μm]; P = 0.032}. Combination treatment with PCSK9Is and statins resulted in more marked plaque stabilization after ACS than SoC alone, and this effect persisted for 6 months after PCSK9I discontinuation. Adage-Joto study, UMIN ID No. 26516.

Anti-Lipoprotein Lipase Antibody as a Useful Marker for Plaque Vulnerability in Patients with Stable Angina.

Identifying patients with vulnerable plaque who have poor prognosis among those with coronary artery disease (CAD) is crucial to deciding future therapeutic interventions. We previously reported that male CAD patients with low anti-apolipoprotein B-100 autoantibody (anti-apoB-100 Ab) levels were at an increased risk of developing unstable plaque lesions. This study focused on the autoantibodies against lipoprotein lipase (LPL), a key enzyme in triglyceride metabolism, which is another risk factor for atherosclerosis, and investigated their association with plaque characteristics. We measured serum anti-LPL Ab levels using a homemade enzyme-linked immunosorbent assay in 80 male CAD patients. Coronary plaque properties were evaluated using iMAP®-intravascular ultrasound. Serum anti-LPL Ab levels were not correlated with plaque burden but were significantly negatively and positively correlated with fibrotic and necrotic plaques, respectively. High-risk patients with low anti-apoB-100 Ab levels were divided into groups according to their anti-LPL Ab levels. The group with high anti-LPL Ab levels exhibited more necrotic plaques and fewer fibrotic plaques as well as higher remnant-like lipoprotein particle levels than the group with low anti-LPL Ab levels. Serum anti-LPL Ab levels can serve as a marker of plaque instability in CAD patients and can help identify higher-risk cases when combined with anti-apoB-100 Ab levels.

Effect of Serum IL-6 Levels on the Progression of Non-Target Lesions in Patients after Coronary Stenting.

percutaneous coronary intervention (PCI) has become the mainstay of treatment for atherosclerotic cardiovascular disease (ASCVD). Inflammatory factors have been shown to be involved in the initiation and progression of ASCVD. After PCI, the persistence of inflammation, especially the inflammation released at the target lesion, may affect the stability of non-target lesion plaques. Interleukin-6 (IL-6) is one of the most common inflammatory factors, however studies about the influence of IL-6 on the progression of non-target lesions (NTLs) of coronary artery are limited. This study investigated whether serum IL-6 levels can affect the progression of NTLs after coronary stent implantation. We performed a retrospective cohort study including 441 patients undergoing coronary angiography (CAG) and stent implantation, who had at least one NTL, between January 2019 and December 2021. They underwent followup CAG 9 to 12 months after PCI. Quartile grouping was based on serum IL-6 levels following readmission. The relationship between serum IL-6 levels and the progression of NTLs after coronary stent implantation was analyzed by using logistic regression analysis and restricted cubic spline regression. Predictive value of IL-6 on NTL progression was evaluated using the receiver operating characteristic (ROC) curve. When compared to the first quartile (Q1) group, the probability of NTL progression was increased in Q2 (adjusted odds ratio (aOR) 3.06, 95% CI 1.29-7.29), Q3 (aOR 3.55, 95% CI 1.52-8.26), and Q4 group (aOR 7.51, 95% CI 3.30-17.05), with a trend test p 0.001. With the increase of IL-6 levels, the risk of progression of NTLs gradually increased, and there was a non-linear relationship between IL-6 and progression of NTLs (p 0.001). The ROC curve showed that the critical value of the serum IL-6 level was 12.652 pg/mL (area under the curve is 0.673, sensitivity is 54.5%, specificity is 70.9%, p 0.05). A high serum IL-6 level is an independent risk factor for the progression of NTLs after coronary stent implantation, and has certain predictive value for the progression of NTLs.

Macrophage Membrane-Encapsulated Dopamine-Modified Poly Cyclodextrin Multifunctional Biomimetic Nanoparticles for Atherosclerosis Therapy.

Atherosclerotic plaques exhibit high cholesterol deposition and oxidative stress resulting from high reactive oxygen species (ROS). These are the major components in plaques and the main pro-inflammatory factor. Therefore, it is crucial to develop an effective therapeutic strategy that can simultaneously address the multiple pro-inflammatory factors via removing cholesterol and inhibiting the overaccumulated ROS. In this study, we constructed macrophage membrane-encapsulated biomimetic nanoparticles (MM@DA-pCD@MTX), which not only alleviate cholesterol deposition at the plaque lesion via reverse cholesterol transport but also scavenge the overaccumulated ROS. β-Cyclodextrin (β-CD) and the loaded methotrexate (MTX) act synergistically to induce cholesterol efflux for inhibiting the formation of foam cells. Among them, MTX up-regulated the expression of ABCA1, CYP27A1, and SR-B1. β-CD increased the solubility of cholesterol crystals. In addition, the ROS scavenging property of dopamine (DA) was perfectly preserved in MM@DA-pCD@MTX, which could scavenge the overaccumulated ROS to alleviate the oxidative stress at the plaque lesion. Last but not least, MM-functionalized "homing" targeting of atherosclerotic plaques not only enables the targeted drug delivery but also prolongs in vivo circulation time and drug half-life. In summary, MM@DA-pCD@MTX emerges as a potent, multifunctional therapeutic platform for AS treatment, offering a high degree of biosafety and efficacy in addressing the complex pathophysiology of atherosclerosis.

Effectiveness of narrowband ultraviolet B monotherapy versus combination therapy with systemic agents in patients with early-stage mycosis fungoides and the association with plaque lesions.

Narrowband ultraviolet B (NB-UVB) has been recommended as first-line therapy for early-stage mycosis fungoides (MF) in international guidelines. NB-UVB can be used as monotherapy or part of a multimodality treatment regimen. There is limited evidence on the effectiveness and optimal patients of NB-UVB in combination with systemic therapies in MF. We aimed to assess the effectiveness of the combination versus NB-UVB monotherapy in early-stage MF and if plaque lesion status was related to these effects. This observational cohort study included 247 early-stage MF patients who had received NB-UVB combined with systemic therapies vs. NB-UVB monotherapy from 2009 to 2021. The primary outcome was partial or complete response. Overall response rate and median time to response were calculated. Hazard ratios (HRs) were estimated using the Cox model. In 139 plaque-stage patients, the response rate for combination therapy group was higher than that of monotherapy group (79.0%vs. 54.3%, p=0.006). The adjusted HR for combination therapy compared with NB-UVB monotherapy was 3.11 (95% CI 1.72-5.63). The combination therapy group also showed shorter time to response (4vs. 6 months, p=0.002). In 108 patch-stage patients, the response rate and time to response in two treatment groups showed no significant difference. There was therefore an observed interaction with patients' plaque lesion status for the effect size of NB-UVB combination therapy. No serious adverse events were observed. Adding systemic treatments to NB-UVB did not improve the treatment outcome of patch-stage patients, but it surpassed NB-UVB monotherapy for early-stage patients with plaques.

Hemodynamic coupling between a primary atherosclerotic plaque and subsequent secondary lesions

Atherosclerosis is one of the most common diseases of the arterial tree, especially in the coronary arteries. Stenoses exceeding 50% area reduction are shown to alternate the downstream coronary flow, and hemodynamics will lead to further atherogenesis. Clinical evidence also confirms that vascular stenoses are not stagnant since they are usually associated with downstream lesions. In this study, it is hypothesized that the formation of secondary plaques, or aneurysms downstream of a primary stenosis, compensates for the abnormal ranges of hemodynamic forces caused by the primary stenosis. An experimental setup captured the hemodynamics of non-Newtonian blood flow in three-dimensional (3D) printed phantoms of coronary arteries with various sequences of lesions. Then, based on the collected data, in silico models of these lesions were simulated using computational fluid dynamics. For the proposed cases, time-averaged wall shear stress, velocity profile, oscillatory shear index, and relative residence time were extracted at the plaque side and the plaque front walls and compared to the reference model with only the primary plaque. The secondary plaque postulated the abnormal hemodynamic conditions to its downstream, which implies endothelial activation and onset of further pathologic events. However, the secondary aneurysm restored flow conditions to normal after its distal shoulder, preventing more damage to the endothelium. Examined angiograms of patients with developed atherosclerotic lesions unveiled that a sequence of plaques is formed over time, and most interestingly, the series stopped after the formation of an aneurysm.