Toll-like receptor 2, hyaluronan, and neutrophils play a key role in plaque erosion: the OPTICO-ACS study.

BACKGROUND AND AIMS: In one-third of patients with acute coronary syndrome (ACS), thrombosis occurs despite an intact fibrous cap (IFC) (IFC-ACS, 'plaque erosion'). Recent studies emphasize neutrophils as the immediate inflammatory response in this pathology, but their exact molecular activation patterns are still poorly understood and may represent future therapeutic targets. METHODS AND RESULTS: Thirty-two patients with IFC-ACS and matched patients with ACS with ruptured fibrous cap (RFC) (RFC-ACS) from the OPTICO-ACS study were included, and blood samples were collected from the local site of the culprit lesion and the systemic circulation. Neutrophil surface marker expression was quantified by flow cytometry. Neutrophil cytotoxicity towards endothelial cells was examined in an ex vivo co-culture assay. Secretion of active matrix metalloproteinase 9 (MMP9) by neutrophils was evaluated using zymography in supernatants and in plasma samples. Optical coherence tomography (OCT)-embedded thrombi were used for immunofluorescence analysis. Toll-like receptor 2 (TLR2) expression was higher on neutrophils from IFC-ACS than RFC-ACS patients. TLR2 stimulation increased the release of active MMP9 from local IFC-ACS-derived neutrophils, which also aggravated endothelial cell death independently of TLR2. Thrombi of IFC-ACS patients exhibited more hyaluronidase 2 with concomitant increase in local plasma levels of the TLR2 ligand: hyaluronic acid. CONCLUSION: The current study provides first in-human evidence for distinct TLR2-mediated neutrophil activation in IFC-ACS, presumably triggered by elevated soluble hyaluronic acid. Together with disturbed flow conditions, neutrophil-released MMP9 might be promoting endothelial cell loss-triggered thrombosis and therefore providing a potential future target for a phenotype-specific secondary therapeutic approach in IFC-ACS.

Culprit plaque morphology determines inflammatory risk and clinical outcomes in acute coronary syndrome.

AIMS: Rupture of the fibrous cap (RFC) and erosion of an intact fibrous cap (IFC) are the two predominant mechanisms causing acute coronary syndromes (ACS). It is uncertain whether clinical outcomes are different following RFC-ACS vs. IFC-ACS and whether this is affected by a specific inflammatory response. The prospective, translational OPTIcal-COherence Tomography in Acute Coronary Syndrome study programme investigates the impact of the culprit lesion phenotype on inflammatory profiles and prognosis in ACS patients. METHODS AND RESULTS: This analysis included 398 consecutive ACS patients, of which 62% had RFC-ACS and 25% had IFC-ACS. The primary endpoint was a composite of cardiac death, recurrent ACS, hospitalization for unstable angina, and target vessel revascularization at 2 years [major adverse cardiovascular events (MACE+)]. Inflammatory profiling was performed at baseline and after 90 days. Patients with IFC-ACS had lower rates of MACE+ than those with RFC-ACS (14.3% vs. 26.7%, P = 0.02). In 368-plex proteomic analyses, patients with IFC-ACS showed lower inflammatory proteome expression compared with those with RFC-ACS, including interleukin-6 and proteins associated with the response to interleukin-1ß. Circulating plasma levels of interleukin-1ß decreased from baseline to 3 months following IFC-ACS (P < 0.001) but remained stable following RFC-ACS (P = 0.25). Interleukin-6 levels decreased in patients with RFC-ACS free of MACE+ (P = 0.01) but persisted high in those with MACE+. CONCLUSION: This study demonstrates a distinct inflammatory response and a lower risk of MACE+ following IFC-ACS. These findings advance our understanding of inflammatory cascades associated with different mechanisms of plaque disruption and provide hypothesis generating data for personalized anti-inflammatory therapeutic allocation to ACS patients, a strategy that merits evaluation in future clinical trials.

The correlation between sub-epidermal moisture measurement and other early indicators of pressure ulcer development-A prospective cohort observational study. Part 1. The correlation between sub-epidermal moisture measurement and ultrasound.

The correlation between sub-epidermal moisture (SEM) and other early indicators of pressure ulcer (PU) development is yet to be determined. This three-part series aims to bridge this knowledge gap, through investigating SEM and its correlation with evidence-based technologies and assessments. This article focuses on the correlation between SEM and ultrasound. A prospective cohort observational study was undertaken between February and November 2021. Patients undergoing three surgery types were consecutively enrolled to the study following informed consent. Assessments were performed prior to and following surgery for 3 days at the sacrum, both heels and a control site, using a SEM scanner and high-frequency ultrasound scanner (5-15 MHz). Spearman's rank (rs ) explored the correlation between SEM and ultrasound. A total of 60 participants were included; 50% were male with a mean age of 58 years (±13.46). A statistically significant low to moderately positive correlation was observed between SEM and ultrasound across all anatomical sites (rs range = 0.39-0.54, p < 0.05). The only exception was a correlation between SEM and ultrasound on day 0 at the right heel (rs = 0.23, p = 0.09). These results indicate that SEM and ultrasound agreed in the presence of injury; however, SEM was able to identify abnormalities before ultrasound.

Interleukin-10 -1082 G/A polymorphism and its association with early or severe presentation of coronary artery disease: A systematic review and meta-analysis.

INTRODUCTION: Interleukin-10 (IL-10) is an anti-inflammatory cytokine with potent deactivating properties on macrophages and T cells; and plays an important role in atherosclerotic plaque maturation and rupture. A guanine (G) to adenine (A) substitution in the IL-10 gene at -1082 bp (rs1800896) has been associated with reduced in IL-10 production in vitro. Against this background, we tested the association of IL-10 -1082G/A with early or severe presentation of coronary artery disease (CAD) using a systematic review and updated meta-analysis of published association studies. MATERIALS AND METHODS: Relevant studies were identified following a comprehensive online search on PubMed, EMBASE, MEDLINE, Scopus, Cochrane library and Web of Science databases and stratified into two subgroups based on mode of CAD presentation: early or severe and non-severe. Study level odds ratios (ORs) and their 95% confidence intervals (CI) were pooled using random effects employing a Z test. RESULTS: A total of 24 studies were included for quantitative synthesis with a cumulative sample of 19,135 (11,143 cases / 7,992 controls). A significant association was derived for IL-10 -1082G/A and early or severe CAD via dominant, recessive, and allelic genetic model comparisons [OR 1.24 (95 % CI 1.02, 1.50), p = 0.03; OR 1.32 (95 % CI 1.03, 1.69), p = 0.03 and OR 1.18 (95 % CI 1.02, 1.36), p = 0.02 respectively]. In contrast, no significant association was seen for the pooled group or non-severe CAD subgroup (p = NS). Sensitivity analysis showed consistent results. CONCLUSIONS: IL-10 -1082G/A appears to be associated with early or severe presentation of CAD. Further studies are warranted to confirm this association.

Glu298Asp variant of the endothelial nitric oxide synthase gene and acute coronary syndrome or premature coronary artery disease: A systematic review and meta-analysis.

INTRODUCTION: Several published studies have reported an association between the Glu298Asp polymorphism (rs1799983), residing in the endothelial nitric oxide synthase (NOS3) gene, and lower levels of circulating nitric oxide, as well as an increased risk of coronary artery disease (CAD). However, association status of this genetic variant with acute coronary syndrome (ACS) or premature CAD (PCAD) is still unclear. Against this background, we conducted a systematic review and study level meta-analysis to assess the association of the NOS3 Glu298Asp polymorphism with ACS or PCAD. MATERIALS AND METHODS: A comprehensive online search to identify relevant studies was performed on several databases including PubMed, EMBASE, MEDLINE, Scopus, Cochrane library and Web of Science. The identified studies were stratified into two ancestral subgroups: 'European ancestry' and 'All other ancestries combined'. Study level odds ratios (ORs) and their 95% confidence intervals (CI) were pooled using random/fixed effects employing a Z test. RESULTS: Out of a total of 195 distinct records identified through online search, 37 articles with 39 different studies, with a total sample size of 27,441 (11,516 cases/15,925 controls) were included for quantitative synthesis. Pooled results suggested significant associations of the NOS3 Glu298Asp polymorphism with ACS or PCAD through dominant as well as allelic genetic models (p ≤ 0.002), primarily driven by the 'All other ancestries combined' subgroup. The 'All other ancestries combined' subgroup demonstrated an additional risk of 36% for ACS or PCAD, through both dominant and allelic genetic models (OR = 1.36, 95%CI = 1.13, 1.63, p = 0.001 and OR = 1.36, 95%CI = 1.14, 1.61, p = 0.0005 respectively). On the other hand, the 'European ancestry' subgroup did not show any significant associations. Sensitivity analysis and a sub-analysis for the myocardial infarction endpoint further supported these observed associations. CONCLUSIONS: This meta-analysis indicates towards an association between the NOS3 Glu298Asp polymorphism and ACS or PCAD, predominantly driven by 'All other ancestries combined' subgroup. In contrast, the 'European ancestry' subgroup did not demonstrate any significant association. Further large-scale investigations are required to confirm our derived results.

Emerging evidence on Omicron (B.1.1.529) SARS-CoV-2 variant.

COVID's Omicron variant has sparked a slew of concerns across the globe. This review aims to provide a brief overview of what we know about the Omicron variant right now. The new variant has been discovered in 149 countries across all six World Health Organization (WHO) regions since its discovery in South Africa on November 24, 2021 and became the dominant variant in the country in less than 3 weeks. The WHO has warned that the B.1.1.529 variant is spreading at an unprecedented rate, and has urged countries to prepare for the worst. Over the course of this time, researchers from Africa and around the world have uncovered a wealth of information about the virus's epidemiology and biological properties. Case numbers are increasing exponentially in hard-hit areas such as South Africa, United Kingdom, and USA (overtaking the delta variant), implying that the variant is highly transmissible. Initial research has provided some insights into the efficacy of vaccines against the Omicron variant and whether it produces major illness, however, much remains unknown, and additional work is needed to investigate what the initial reports represent in real-world situations.

A prospective trial of a novel low-dose paclitaxel-coated balloon therapy in patients with restenosis in drug-eluting coronary stents Intracoronary Stenting and Angiographic Results: Optimizing Treatment of Drug Eluting Stent In-stent REstenosis 3A (ISAR-DESIRE 3A).

OBJECTIVES: We investigated the clinical efficacy of a paclitaxel-coated balloon (PCB) with a novel matrix coating and reduced drug concentration in comparison with a widely used PCB with iopromide excipient. METHODS: We prospectively enrolled patients with restenosis in drug-eluting stents. All patients were treated with a novel low-dose PCB with citrate-based excipient (Agent PCB). Angiographic follow-up was scheduled at 6-8 months. Outcomes were compared against those of patients treated with iopromide excipient PCB (SeQuent Please PCB) enrolled in a trial with identical inclusion and exclusion criteria. The primary endpoint was percent diameter stenosis (%DS) at follow-up angiography. The primary hypothesis was that the investigational device would be non-inferior to the control device (ClinicalTrials.gov Identifier: NCT02367495). RESULTS: One hundred twenty-five patients with 151 lesions were enrolled. Mean age was 68.1 ± 10.2 years, 40.8% had diabetes mellitus and 80.1% had focal morphology in-stent restenosis. Follow-up angiography data at 6-8 months was available for 102 (81.6%) patients. The Agent PCB was non-inferior to the SeQuent Please PCB in terms of the primary endpoint (38.9 ± 17.5 vs. 38.1 ± 21.5%; p non-inferiority  = 0.0056). Late lumen loss was also comparable between the groups (0.35 ± 0.55 vs. 0.37 ± 0.59; p = 0.71). There was no difference between the groups in the incidence of TLR (27.7% vs. 22.1%; p = 0.31), death or myocardial infarction (4.2% vs. 4.4%; p = 0.92) or target lesion thrombosis (1.0% vs. 0.7%; p = 0.93). CONCLUSION: In patients with DES restenosis, angioplasty with a novel PCB with citrate-based excipient was non-inferior to PCB with iopromide excipient in terms of angiographic outcome.

Angiographic performance of everolimus-eluting stents for the treatment of coronary in-stent restenosis in daily practice.

OBJECTIVES: The present study aims to analyze the angiographic anti-restenotic performance of durable polymer everolimus-eluting stents (EES) for the treatment of in-stent restenosis (ISR) in daily practice. BACKGROUND: Randomized data is available supporting the use of drug-coated balloons and drug-eluting stents for the treatment of ISR; however, additional real-world data including angiographic follow-up is needed. METHODS: Patients who underwent EES-implantation for the treatment of drug-eluting stent ISR and attended for a 6-8 months angiographic surveillance were analyzed. Off-line assessment of the angiograms was conducted at a central quantitative coronary angiographic core laboratory. RESULTS: A total of 426 patients with ISR were treated with EES and had undergone angiographic follow-up. The mean age was 66.8 ± 9.9 years and 27.5% suffered from diabetes. A total of 459 lesions were treated. The diameter stenosis decreased from 64.3 ± 19.1% (preprocedural) to 12.0 ± 6.4% (postprocedural). At 6-8 months angiographic follow-up, the in-segment diameter stenosis was 38.3 ± 21.7% and the in-stent late luminal loss was 0.54 ± 0.74 mm in the treated area analysis. The rate of recurrent binary restenosis was 25.7%. CONCLUSIONS: In the setting of ISR, the angiographic anti-restenotic efficacy of stenting with EES is comparable to that observed in randomized clinical trials and less favorable than its performance in patients undergoing stenting for de novo disease.

Association of interleukin 6 -174 G/C polymorphism with coronary artery disease and circulating IL-6 levels: a systematic review and meta-analysis.

INTRODUCTION: Circulating IL-6 levels and at least one polymorphic form of IL6 gene (IL6 -174 G/C, rs1800795) have been shown to be independently associated with coronary artery disease (CAD) by several investigators. Despite more than 12 published meta-analyses on this subject, association of -174 G/C with CAD, especially amongst distinct ancestral population groups remain unclear. We, therefore, conducted a systematic review and an updated meta-analysis to comprehensively ascertain the association of IL6 -174 G/C with CAD and circulating IL-6 levels. MATERIALS AND METHODS: Relevant case-control/cohort studies investigating association of -174 G/C with CAD and circulating IL-6 levels were identified following a comprehensive online search. Association status for CAD was determined for the pooled sample, as well as separately for major ancestral subgroups. Association status for circulating IL-6 levels was assessed for the pooled sample, as well as separately for CAD cases and CAD free controls. Study-level odds ratios (OR) and 95% confidence intervals (CI) were pooled using random/fixed-effects model. RESULTS: Quantitative synthesis for the CAD endpoint was performed using 55 separate qualifying studies with a collective sample size of 51,213 (19,160 cases/32,053 controls). Pooled association of -174 G/C with CAD was found to be statistically significant through dominant (OR 1.15; 95% CI 1.05-1.25, p = 0.002) as well as allelic genetic model comparisons (OR 1.13, 95% CI 1.06-1.21, p = 0.0003). This effect was largely driven by Asian and Asian Indian ancestral subgroups, which also showed significant association with CAD in both genetic model comparisons (OR range 1.29-1.53, p value range ≤ 0.02). Other ancestral subgroups failed to show any meaningful association. Circulating IL-6 levels were found to be significantly higher amongst the 'C' allele carriers in the pooled sample (Standard mean difference, SMD 0.11, 95% CI 0.01-0.22 pg/ml, p = 0.009) as well as in the CAD free control subgroup (SMD 0.10, 95% CI 0.02-0.17 pg/ml, p = 0.009), though not in the CAD case subgroup (SMD 0.17, 95% CI = - 0.02 to 0.37, p = 0.12). CONCLUSIONS: The present systematic review and meta-analysis demonstrate an overall association between IL6 -174 G/C polymorphism and CAD, which seems to be mainly driven by Asian and Asian Indian ancestral subgroups. Upregulation of plasma IL-6 levels in the 'C' allele carriers seems to be at least partly responsible for this observed association. This warrants further investigations with large, structured case-control studies especially amongst Asian and Asian Indian ancestral groups.

Molecular docking, binding mode analysis, molecular dynamics, and prediction of ADMET/toxicity properties of selective potential antiviral agents against SARS-CoV-2 main protease: an effort toward drug repurposing to combat COVID-19.

The importance of the main protease (Mpro) enzyme of SARS-CoV-2 in the digestion of viral polyproteins introduces Mpro as an attractive drug target for antiviral drug design. This study aims to carry out the molecular docking, molecular dynamics studies, and prediction of ADMET properties of selected potential antiviral molecules. The study provides an insight into biomolecular interactions to understand the inhibitory mechanism and the spatial orientation of the tested ligands and further, identification of key amino acid residues within the substrate-binding pocket that can be applied for structure-based drug design. In this regard, we carried out molecular docking studies of chloroquine (CQ), hydroxychloroquine (HCQ), remdesivir (RDV), GS441524, arbidol (ARB), and natural product glycyrrhizin (GA) using AutoDock 4.2 tool. To study the drug-receptor complex's stability, selected docking possesses were further subjected to molecular dynamics studies with Schrodinger software. The prediction of ADMET/toxicity properties was carried out on ADMET Prediction™. The docking studies suggested a potential role played by CYS145, HIS163, and GLU166 in the interaction of molecules within the active site of COVID-19 Mpro. In the docking studies, RDV and GA exhibited superiority in binding with the crystal structure of Mpro over the other selected molecules in this study. Spatial orientations of the molecules at the active site of Mpro exposed the significance of S1-S4 subsites and surrounding amino acid residues. Among GA and RDV, RDV showed better and stable interactions with the protein, which is the reason for the lesser RMSD values for RDV. Overall, the present in silico study indicated the direction to combat COVID-19 using FDA-approved drugs as promising agents, which do not need much toxicity studies and could also serve as starting points for lead optimization in drug discovery.

Differential immunological signature at the culprit site distinguishes acute coronary syndrome with intact from acute coronary syndrome with ruptured fibrous cap: results from the prospective translational OPTICO-ACS study.

AIMS: Acute coronary syndromes with intact fibrous cap (IFC-ACS), i.e. caused by coronary plaque erosion, account for approximately one-third of ACS. However, the underlying pathophysiological mechanisms as compared with ACS caused by plaque rupture (RFC-ACS) remain largely undefined. The prospective translational OPTICO-ACS study programme investigates for the first time the microenvironment of ACS-causing culprit lesions (CL) with intact fibrous cap by molecular high-resolution intracoronary imaging and simultaneous local immunological phenotyping. METHODS AND RESULTS: The CL of 170 consecutive ACS patients were investigated by optical coherence tomography (OCT) and simultaneous immunophenotyping by flow cytometric analysis as well as by effector molecule concentration measurements across the culprit lesion gradient (ratio local/systemic levels). Within the study cohort, IFC caused 24.6% of ACS while RFC-ACS caused 75.4% as determined and validated by two independent OCT core laboratories. The IFC-CL were characterized by lower lipid content, less calcification, a thicker overlying fibrous cap, and largely localized near a coronary bifurcation as compared with RFC-CL. The microenvironment of IFC-ACS lesions demonstrated selective enrichment in both CD4+ and CD8+ T-lymphocytes (+8.1% and +11.2%, respectively, both P < 0.05) as compared with RFC-ACS lesions. T-cell-associated extracellular circulating microvesicles (MV) were more pronounced in IFC-ACS lesions and a significantly higher amount of CD8+ T-lymphocytes was detectable in thrombi aspirated from IFC-culprit sites. Furthermore, IFC-ACS lesions showed increased levels of the T-cell effector molecules granzyme A (+22.4%), perforin (+58.8%), and granulysin (+75.4%) as compared with RFC plaques (P < 0.005). Endothelial cells subjected to culture in disturbed laminar flow conditions, i.e. to simulate coronary flow near a bifurcation, demonstrated an enhanced adhesion of CD8+T cells. Finally, both CD8+T cells and their cytotoxic effector molecules caused endothelial cell death, a key potential pathophysiological mechanism in IFC-ACS. CONCLUSIONS: The OPTICO-ACS study emphasizes a novel mechanism in the pathogenesis of IFC-ACS, favouring participation of the adaptive immune system, particularly CD4+ and CD8+ T-cells and their effector molecules. The different immune signatures identified in this study advance the understanding of coronary plaque progression and may provide a basis for future development of personalized therapeutic approaches to ACS with IFC. TRIAL REGISTRATION: The study was registered at clinicalTrials.gov (NCT03129503).

Optimistic bias, risky behavior, and social norms among Indian college students during COVID-19.

Using survey data of college students in India, we investigate whether COVID-19 optimistic bias among individuals increases risky behavior. We also explore whether participants' optimistic bias differs depending on their degree of closeness with others. We found that the presence of friends instead of neighbors/strangers make participants with high COVID-19 optimistic bias inclined to take more risks. Besides, it has been found that preventive behavioral norms followed by peers minimize risky behavior among participants with high optimistic bias. Our findings offer important implications for policymakers to minimize the transmission of the disease among college students.

Prospective, randomized trial of bioresorbable scaffolds vs. everolimus-eluting stents in patients undergoing coronary stenting for myocardial infarction: the Intracoronary Scaffold Assessment a Randomized evaluation of Absorb in Myocardial Infarction (ISAR-Absorb MI) trial.

Aims: Bioresorbable scaffolds (BRS) provide short-term coronary artery scaffolding and drug delivery. Although prior trials showed a higher rate of device failure compared with conventional drug-eluting stents (DES), only a single trial investigated patients undergoing percutaneous coronary intervention (PCI) for acute myocardial infarction (MI). We aimed to compare outcomes with BRS vs. DES in patients undergoing PCI for MI. Methods and results: We did a prospective, randomized, multicentre, non-inferiority, clinical trial of everolimus-eluting BRS vs. durable polymer everolimus-eluting stents (EES) in patients with acute MI. Patients were eligible for enrolment if they presented with ST-elevation MI, or non-ST-elevation MI with thrombosis visual at angiography and were randomly allocated to treatment with BRS or EES in 2:1 proportion. Angiographic follow-up was scheduled at 6-8 months and clinical follow-up was done at 12 months. The primary endpoint was percentage diameter stenosis in-segment at follow-up. A total of 262 patients were enrolled and were allocated to BRS (n = 173) or EES (n = 89). Angiographic follow-up was available for 213 (81.3%) patients. Mean diameter stenosis was 24.6 ± 12.2% with BRS vs. 27.3 ± 11.7% with EES (mean difference -2.7%, upper limit of one-sided 97.5% confidence limit 0.7%, pre-specified margin of non-inferiority 5%, Pnon-inferiority <0.001). The rate of the device-oriented composite of cardiac death/target vessel MI/target lesion revascularization [BRS: 12 (7.0%) vs. EES: 6 (6.7%), hazard ratio (HR) 1.04, 95% confidence interval (CI) 0.39-2.78] and definite/probable stent thrombosis [3 (1.7%) vs. 2 (2.3%), HR 0.76, 95% CI 0.13-4.56] were comparable in both groups. Conclusion: In patients undergoing PCI for acute MI BRS were non-inferior to EES for percentage diameter stenosis at angiographic follow-up. Rates of clinical events were comparable between the treatment groups, although the study was not powered to detect differences in clinical outcomes. Clinical trial registration: The trial was registered at www.clinicaltrials.gov (NCT01942070).

Differential Release Kinetics of Cardiac Biomarkers in Patients Undergoing Valve Replacement Surgery.

BACKGROUND: Differential release kinetics of cardiac biomarkers including brain natriuretic peptide (BNP), Troponin-I, and CK-MB following valve replacement (VR) are not well characterized. METHODS AND RESULTS: We serially measured these biomarkers 24 hours prior, six hours, 24 hours, 48 hours, and one month following mitral/aortic VR in 100 patients. Baseline BNP, Tn-I, and CK-MB levels were 304.01 pg/mL, 0.03 ng/mL, and 0.99 ng/mL, respectively. While BNP levels decreased at six hours, and then peaked at 24 hours, Tn-I and CK-MB levels increased within six hours and then showed declining trends by 24 hours. While Tn-I and CK-MB levels normalized at one month, 33% patients still had BNP >200 pg/mL. Those with baseline BNP >200 pg/mL more commonly had AF, higher RV systolic pressure, longer inotrope and ventilator duration, and longer mean ICU/hospital stay as compared to those with lower BNP, although echocardiographic left ventricular ejection fraction and Tn-I/CK-MB levels were similar. Inotrope duration >42 hours, ventilation time >29 hours, and ICU stay >4 days was seen in 42% versus 19%, 30% versus 9%, and 33% versus 14%, respectively, in those with BNP >/<200 pg/mL. Baseline BNP had a significant positive correlation with mean inotrope duration, ICU, and hospital stay. Baseline BNP was also a significant predictor of inotrope duration (odds ratio [OR]=5.9, 95% confidence interval [CI]=1.20-29.68, p=0.01) and ventilation time (OR=4.7, 95% CI=1.76-17.21, p=0.02). CONCLUSION: Release kinetics of cardiac biomarkers is significantly different following VR; BNP levels increase following an initial transient decline. Only BNP was a predictor of postoperative variables.

Transforming friction: unveiling sliding-induced phase transitions in CVD-grown WS2 monolayers under single-asperity sliding nanocontacts.

Transition metal dichalcogenides (TMDs) exhibit diverse properties across different phases, making them promising materials for various engineering applications. In the present work, we employed a comprehensive approach, combining experimental investigations and computational simulations to elucidate the remarkable tunable frictional characteristics of chemical vapor deposition (CVD) grown WS2 monolayers through the sliding-induced transitions between the 1H and 1T' phases. Our atomic force microscopy (AFM) measurements reveal a significant contrast in friction between the two phases, with the 1H phase displaying higher friction (∼52%) than the 1T' phase. Surprisingly, under repeated scanning at constant stress, the friction of the 1H phase decreases, eventually matching the lower friction values of the 1T' phase. It was observed that the phase transformation is irreversible and is strongly dependent on contact stresses and is accelerated as the contact stress is increased by increasing the applied normal load. Molecular dynamics (MD) simulations provide further insights into the phase transition mechanism, highlighting the role of localized lateral stress and strain induced by sliding an AFM tip on the 1H phase. The simulations confirm that sliding induced localized lateral strain plays a crucial role in the phase transition, ultimately resulting in a decrease in friction. Moreover, our simulations unveil an intriguing connection between friction, potential energy surfaces, and the localized lateral strain during the phase transformation process. Our findings not only offer insights into the tribological properties of TMD materials but also open new possibilities for tailoring their performance in various applications where reducing friction and wear is crucial.

Coronary microevaginations characterize culprit plaques and their inflammatory microenvironment in a subtype of acute coronary syndrome with intact fibrous cap: results from the prospective translational OPTICO-ACS study.

AIMS: Coronary microevaginations (CMEs) represent an outward bulge of coronary plaques and have been introduced as a sign of adverse vascular remodelling following coronary device implantation. However, their role in atherosclerosis and plaque destabilization in the absence of coronary intervention is unknown. This study aimed to investigate CME as a novel feature of plaque vulnerability and to characterize its associated inflammatory cell-vessel-wall interactions. METHODS AND RESULTS: A total of 557 patients from the translational OPTICO-ACS study programme underwent optical coherence tomography imaging of the culprit vessel and simultaneous immunophenotyping of the culprit lesion (CL). Two hundred and fifty-eight CLs had a ruptured fibrous cap (RFC) and one hundred had intact fibrous cap (IFC) acute coronary syndrome (ACS) as an underlying pathophysiology. CMEs were significantly more frequent in CL when compared with non-CL (25 vs. 4%, P < 0.001) and were more frequently observed in lesions with IFC-ACS when compared with RFC-ACS (55.0 vs. 12.7%, P < 0.001). CMEs were particularly prevalent in IFC-ACS-causing CLs independent of a coronary bifurcation (IFC-ICB) when compared with IFC-ACS with an association to a coronary bifurcation (IFC-ACB, 65.4 vs. 43.7%, P = 0.030). CME emerged as the strongest independent predictor of IFC-ICB (relative risk 3.36, 95% confidence interval 1.67-6.76, P = 0.001) by multivariable regression analysis. IFC-ICB demonstrated an enrichment of monocytes in both culprit blood analysis (culprit ratio: 1.1 ± 0.2 vs. 0.9 ± 0.2, P = 0.048) and aspirated culprit thrombi (326 ± 162 vs. 96 ± 87 cells/mm2, P = 0.017), while IFC-ACB confirmed the accumulation of CD4+ T cells, as recently described. CONCLUSION: This study provides novel evidence for a pathophysiological involvement of CME in the development of IFC-ACS and provides first evidence for a distinct pathophysiological pathway for IFC-ICB, driven by CME-derived flow disturbances and inflammatory activation involving the innate immune system. TRIAL REGISTRATION: Registration of the study at clinicalTrials.gov (NCT03129503).

Cholesterol crystals at the culprit lesion in patients with acute coronary syndrome are associated with worse cardiovascular outcomes at two years follow up - results from the translational OPTICO-ACS study program.

BACKGROUND: Cholesterol crystals (CCs) represent a feature of advanced atherosclerotic plaque and may be assessed by optical coherence tomography (OCT). Their impact on cardiovascular outcomes in patients presenting with acute coronary syndromes (ACS) is yet unknown. METHODS: The culprit lesion (CL) of 346 ACS-patients undergoing preintervention OCT imaging were screened for the presence of CCs and divided into two groups accordingly. The primary end-point was the rate of major adverse cardiac events plus (MACE+) consisting of cardiac death, myocardial infarction, target vessel revascularization and re-hospitalization due to unstable or progressive angina at two years. RESULTS: Among 346 patients, 57.2% presented with CCs at the CL. Patients with CCs exhibited a higher prevalence of ruptured fibrous caps (RFC-ACS) (79.8% vs. 56.8%; p < 0.001) and other high-risk features such as thin cap fibroatheroma (80.8% vs. 64.9%; p = 0.001), presence of macrophages (99.0% vs. 85.1%; p < 0.001) as well as a greater maximum lipid arc (294.0° vs. 259.3°; p < 0.001) at the CL as compared to patients without CCs. MACE+ at two years follow-up occurred more often in CC-patients (29.2% vs. 16.1%; p = 0.006) as compared to patients without CCs at the culprit site. Multivariable cox regression analysis identified CCs as independent predictor of MACE+ (HR 1.705; 1.025-2.838 CI, p = 0.040). CONCLUSIONS: CCs were associated with conventional high-risk plaque features and associated with increased MACE+-rates at two years follow up. The identification of CCs might be useful as prognostic marker in patients with ACS and assist "precision prevention" in the future.

Pharmacological measures to increase HDL-C among high risk isolated low HDL cases: a randomized study amongst north Indians.

BACKGROUND & OBJECTIVES: Low serum levels of high density lipoprotein cholesterol (HDL-C) is an established risk factor for coronary heart disease (CHD). Among a variety of lipid modifying drugs, the best single drug therapy to increase HDL-C levels, especially among high risk, isolated low HDL-C (ILHDL-C) cases is yet to be identified. The objectives of the present study were to evaluate the best pharmacological measure among atorvastatin, fenofibrate and niacin aimed to raise HDL-C and its effect in decreasing the estimated Framingham-10-year CHD risk percentage (CHD-RP) among high risk ILHDL-C cases in north India. METHODS: Two hundred CHD equivalent (CHD-RP≥20), ILHDL-C cases were randomly assigned for treatment either with atorvastatin 10 mg/day (n=70), micronized fenofibrate 160 mg/day (n=65) or niacin-extended release (ER) 750 mg/day (n=65). After 6 wk of treatment, the dosages of drugs were doubled and the patients were finally assessed after 12 wk for their lipid values. RESULTS: Baseline characteristics were similar in the three groups. Niacin therapy 750 mg and 1.5 g/day resulted in a significant rise in HDL-C by 8.10 ± 3.19 and 12.41 ± 4.39 per cent (P<0.001), respectively. Fenofibrate 160 and 320 mg/day also resulted in a significant rise in HDL-C by 3.85 ± 3.48 and 6.24 ± 4.43 per cent (P<0.001), respectively, while atorvastatin 10 and 20 mg/day resulted in a non-significant increase in HDL-C by 0.13 ± 2.92 per cent and 0.51 ± 2.63 per cent, respectively. By increasing HDL-C values, niacin was found to be most effective in reduction of 10-year CHD-RP (P<0.001), followed by fenofibrate (P=0.010), while atorvastatin had no effect. INTERPRETATION & CONCLUSIONS: Our findings indicate that niacin rather than fibrates or statins seems to provide a safe and effective therapy for increasing HDL-C, thus reducing the cumulative CHD risk among ILHDL-C cases.

Nanoscale friction and wear behavior of a CVD-grown aged WS2 monolayer: the role of wrinkles and surface chemistry.

Friction reduction by transition metal dichalcogenide (TMD) monolayers is well documented; however, wrinkle formation on the surface of TMDs takes place due to strain relaxation over time and leads to the deterioration of the tribological properties at a small scale. Herein, we report the role of wrinkles on the wear behavior of a chemical vapor deposition (CVD) grown aged WS2 monolayer and the comparison with wrinkle-free regions. Atomic force microscopy (AFM) was utilized to perform load-dependent experiments, and we noticed that the wear initiated near wrinkles resulted in the disintegration of the monolayer. In contrast, in the wrinkle-free regions, wear occurred at significantly higher loads, similar to that of freshly grown WS2, although the coefficient of friction (COF) was increased due to the changes in surface chemistry as a result of aging, which was confirmed using X-ray photoelectron spectroscopy (XPS). In the presence of wrinkles, a ten-fold reduction in the load-carrying capacity was observed compared to the wrinkle-free regions. Molecular dynamics (MD) simulations were used to corroborate experimental findings, which demonstrate the role of wrinkles in the initiation of wear due to the stress concentration under sliding nanocontacts near the wrinkles. In addition, simulations help establish a relationship between the adsorbed chemical species on the surface and increased COF.