Comprehensive biomechanical and anatomical atherosclerotic plaque metrics predict major adverse cardiovascular events: A new tool for clinical decision making.

BACKGROUND AND AIMS: Anatomical imaging alone of coronary atherosclerotic plaques is insufficient to identify risk of future adverse events and guide management of non-culprit lesions. Low endothelial shear stress (ESS) and high plaque structural stress (PSS) are associated with events, but individually their predictive value is insufficient for risk prediction. We determined whether combining multiple complementary, biomechanical and anatomical plaque characteristics improves outcome prediction sufficiently to inform clinical decision-making. METHODS: We examined baseline ESS, ESS gradient (ESSG), PSS, and PSS heterogeneity index (HI), and plaque burden in 22 lesions that developed subsequent events and 64 control lesions that remained quiescent from the PROSPECT study. RESULTS: 86 fibroatheromas were analysed from 67 patients. Lesions with events showed higher PSS HI (0.32 vs. 0.24, p<0.001), lower local ESS (0.56Pa vs. 0.91Pa, p = 0.007), and higher ESSG (3.82 Pa/mm vs. 1.96 Pa/mm, p = 0.007), while high PSS HI (hazard ratio [HR] 3.9, p = 0.006), high ESSG (HR 3.4, p = 0.007) and plaque burden>70 % (HR 2.6, p = 0.02) were independent outcome predictors in multivariate analysis. Combining low ESS, high ESSG, and high PSS HI gave both high positive predictive value (80 %), which increased further combined with plaque burden>70 %, and negative predictive value (81.6 %). Low ESS, high ESSG, and high PSS HI co-localised spatially within 1 mm in lesions with events, and importantly, this cluster was distant from the minimum lumen area site. CONCLUSIONS: Combining complementary biomechanical and anatomical metrics significantly improves risk-stratification of individual coronary lesions. If confirmed from larger prospective studies, our results may inform targeted revascularisation vs. conservative management strategies.

Heterogeneous plaque-lumen geometry is associated with major adverse cardiovascular events.

Aims: Prospective studies show that only a minority of plaques with higher risk features develop future major adverse cardiovascular events (MACE), indicating the need for more predictive markers. Biomechanical estimates such as plaque structural stress (PSS) improve risk prediction but require expert analysis. In contrast, complex and asymmetric coronary geometry is associated with both unstable presentation and high PSS, and can be estimated quickly from imaging. We examined whether plaque-lumen geometric heterogeneity evaluated from intravascular ultrasound affects MACE and incorporating geometric parameters enhances plaque risk stratification. Methods and results: We examined plaque-lumen curvature, irregularity, lumen aspect ratio (LAR), roughness, PSS, and their heterogeneity indices (HIs) in 44 non-culprit lesions (NCLs) associated with MACE and 84 propensity-matched no-MACE-NCLs from the PROSPECT study. Plaque geometry HI were increased in MACE-NCLs vs. no-MACE-NCLs across whole plaque and peri-minimal luminal area (MLA) segments (HI curvature: adjusted P = 0.024; HI irregularity: adjusted P = 0.002; HI LAR: adjusted P = 0.002; HI roughness: adjusted P = 0.004). Peri-MLA HI roughness was an independent predictor of MACE (hazard ratio: 3.21, P < 0.001). Inclusion of HI roughness significantly improved the identification of MACE-NCLs in thin-cap fibroatheromas (TCFA, P < 0.001), or with MLA ≤ 4 mm2 (P < 0.001), or plaque burden (PB) ≥ 70% (P < 0.001), and further improved the ability of PSS to identify MACE-NCLs in TCFA (P = 0.008), or with MLA ≤ 4 mm2 (P = 0.047), and PB ≥ 70% (P = 0.003) lesions. Conclusion: Plaque-lumen geometric heterogeneity is increased in MACE vs. no-MACE-NCLs, and inclusion of geometric heterogeneity improves the ability of imaging to predict MACE. Assessment of geometric parameters may provide a simple method of plaque risk stratification.

Plaque Structural Stress: Detection, Determinants and Role in Atherosclerotic Plaque Rupture and Progression.

Atherosclerosis remains a major cause of death worldwide, with most myocardial infarctions being due to rupture or erosion of coronary plaques. Although several imaging modalities can identify features that confer risk, major adverse cardiovascular event (MACE) rates attributable to each plaque are low, such that additional biomarkers are required to improve risk stratification at plaque and patient level. Coronary arteries are exposed to continual mechanical forces, and plaque rupture occurs when plaque structural stress (PSS) exceeds its mechanical strength. Prospective studies have shown that peak PSS is correlated with acute coronary syndrome (ACS) presentation, plaque rupture, and MACE, and provides additional prognostic information to imaging. In addition, PSS incorporates multiple variables, including plaque architecture, plaque material properties, and haemodynamic data into a defined solution, providing a more detailed overview of higher-risk lesions. We review the methods for calculation and determinants of PSS, imaging modalities used for modeling PSS, and idealized models that explore structural and geometric components that affect PSS. We also discuss current experimental and clinical data linking PSS to the natural history of coronary artery disease, and explore potential for refining treatment options and predicting future events.

Correlation between change in central subfield thickness and change in visual acuity in macular edema due to retinal vein occlusion: post hoc analysis of COPERNICUS, GALILEO, and VIBRANT.

PURPOSE: Assess correlation between change in central subfield thickness (CST) and change in best-corrected visual acuity (BCVA) in eyes with macular edema due to retinal vein occlusion (RVO) that received intravitreal aflibercept injections (IAI). METHODS: Post hoc analysis of COPERNICUS and GALILEO trials for CRVO and VIBRANT trial for BRVO with relationships determined using Pearson correlation coefficient. RESULTS: In COPERNICUS, correlations (r) between change in CST and change in BCVA from baseline at weeks 12, 24, 52, and 100 were -0.36 (95% CI: -0.52, -0.18; P < 0.001), -0.38 (95% CI: -0.53, -0.20; P < 0.001), -0.44 (95% CI: -0.58, -0.27; P < 0.001), and -0.41 (95% CI: -0.56, -0.23; P < 0.001), respectively. CST changes accounted for only 21% of the variance in BCVA changes; every 100-µm decrease in CST was associated with a 2.1-letter increase in BCVA (P = 0.003). Similar findings were noted for GALILEO (r, -0.45 to -0.23) and VIBRANT (r, -0.36 to -0.32) trials. CONCLUSION: In eyes treated with IAI for macular edema due to RVO, correlation between change in CST and change in BCVA was weak to moderate. While change in CST may be helpful in determining the need for anti-VEGF therapy, these findings do not support using changes in CST as a surrogate for changes in visual acuity outcomes.

Correlation of Change in Central Subfield Thickness and Change in Visual Acuity in Neovascular AMD: Post Hoc Analysis of VIEW 1 and 2.

PURPOSE: Determine correlation between change in central subfield thickness (CST) and change in best-corrected visual acuity (BCVA) in neovascular age-related macular degeneration receiving anti-vascular endothelial growth factor agents. DESIGN: A post hoc analysis of VIEW 1 and 2 randomized clinical trials. METHODS: This analysis included participants randomized to ranibizumab 0.5 mg every 4 weeks (Rq4), intravitreal aflibercept injection 2 mg every 4 weeks (2q4), and intravitreal aflibercept injection 2 mg every 8 weeks after 3 monthly doses (2q8) to week 52, followed by capped as-needed (at least every 12 weeks) dosing to week 96. Relationship between changes in CST and BCVA was determined using Pearson correlation coefficient. RESULTS: Of 1815 eyes, 595 were assigned to the Rq4, 613 to 2q4, and 607 to 2q8 arms. Correlations (95% confidence intervals [CI]) at weeks 12, 52, and 96 were -0.08 (95% CI, -0.17 to 0.00), -0.05 (95% CI, -0.14 to 0.04), and -0.15 (95% CI, -0.24 to -0.06) for Rq4; -0.13 (95% CI, -0.21 to -0.04), -0.06 (95% CI, -0.14 to 0.03) and -0.04 (95% CI, -0.13 to 0.05) for 2q4, and -0.04 (95% CI, -0.12 to 0.05), -0.01 (95% CI, -0.09 to 0.08), and -0.01 (95% CI, -0.10 to 0.09) for 2q8. Linear regression analysis adjusted for relevant baseline factors showed CST changes accounted for 11% of BCVA changes. Every 100 µm decrease in CST was associated with a 0.3 letter decrease (P = .25) at week 52 and a 0.14 letter decrease (P = .69) at week 96. CONCLUSIONS: Weak or no correlation was found between changes in CST and BCVA with either agent or regimen, suggesting changes in CST should not be used as a surrogate for visual acuity outcomes in neovascular age-related macular degeneration.

Correlation of Change in Macular Thickness With Change in Visual Acuity in Diabetic Macular Edema: Post Hoc Analysis of VISTA and VIVID Trials.

Purpose: To assess the correlation between the change in central subfield thickness (CST) and change in best-corrected visual acuity (BCVA) in eyes with diabetic macular edema (DME) treated with fixed-dosing intravitreal aflibercept injection (IAI). Methods: This post hoc analysis of the VISTA and VIVID randomized controlled clinical trials, in which 862 eyes with central-involved DME were randomly assigned to IAI 2 mg every 4 weeks (2q4; 290 eyes), IAI 2 mg every 8 weeks after 5 initial monthly doses (2q8; 286 eyes), or macular laser (286 eyes) and followed through 100 weeks. Correlations between the change in CST and change in BCVA from baseline to weeks 12, 52, and 100 were assessed using the Pearson correlation. Results: The respective correlations (r [95% CI]) at weeks 12, 52, and 100 were -0.39 (-0.49 to -0.29), -0.27 (-0.38 to -0.15), and -0.30 (-0.41 to -0.17) in the 2q4 arm and -0.28 (-0.39 to -0.17), -0.29 (-0.41 to -0.17), and -0.33 (-0.44 to -0.20) in the 2q8 arm. Linear regression analysis of the correlation at week 100, adjusted for relevant baseline factors, showed CST changes accounted for 17% of the variance in BCVA changes; every 100-µm decrease in CST was associated with a 1.2-letter increase in BCVA (P = .001). Conclusions: Correlations between the change in CST and change in BCVA after 2q4 or 2q8 fixed-dosing IAI for DME were modest. Although a change in CST might be important in determining the need for antivascular endothelial growth factor for DME at follow-up, it was not a good surrogate for VA outcomes.

Screening first-degree relatives of glaucoma patients reveals barriers to participation.

PURPOSE: To report the results of a glaucoma screening campaign targeting first-degree relatives of glaucoma patients in South India. METHODS: 1598 glaucoma patients were contacted via letter or letter and phone call and asked to bring their siblings and children to a glaucoma screening. Participants underwent standardised eye examinations and completed questionnaires that assessed barriers to participation and awareness of glaucoma risk. Two-proportion z-tests were used to compare categorical data. Costs associated with the screening were recorded. RESULTS: 206 probands (12.9%) attended the screening along with 50 siblings and children. Probands were nearly twice as likely to attend if they had been contacted via both letter and phone call rather than letter only. Over half of probands reported that their relatives could not participate because they did not live in the region, and one-fifth reported that their relatives had other commitments. Fifty-eight per cent of the siblings and children who attended did not know that they were at increased risk for glaucoma due to their family history, and 32.0% did not know that the relative who had invited them to the screening had glaucoma. Thirteen siblings and children (26.0% of those who attended) were found to have findings concerning for glaucoma. The average cost per first-degree relative who was screened was INR2422 (£26). CONCLUSION: Participation in this glaucoma screening campaign was poor. The major barrier to participation was distance from the screening site and associated indirect costs. Better strategies for bringing first-degree relatives in for examinations are needed.

High-intensity statin treatment is associated with reduced plaque structural stress and remodelling of artery geometry and plaque architecture.

Aims: Plaque structural stress (PSS) is a major cause of atherosclerotic plaque rupture and major adverse cardiovascular events (MACE). We examined the predictors of changes in peak and mean PSS (ΔPSSpeak, ΔPSSmean) in three studies of patients receiving either standard medical or high-intensity statin (HIS) treatment. Methods and results: We examined changes in PSS, plaque size, and composition between 7348 co-registered baseline and follow-up virtual-histology intravascular ultrasound images in patients receiving standard medical treatment (controls, n = 18) or HIS (atorvastatin 80 mg, n = 20, or rosuvastatin 40 mg, n = 22). The relationship between changes in PSSpeak and plaque burden (PB) differed significantly between HIS and control groups (P < 0.001). Notably, PSSpeak increased significantly in control lesions with PB >60% (P = 0.04), but not with HIS treatment. However, ΔPSSpeak correlated poorly with changes in lumen and plaque area or PB, plaque composition, or lipid lowering. In contrast, ΔPSSpeak correlated significantly with changes in lumen curvature, irregularity, and roughness (P < 0.05), all of which were reduced in HIS patients. ΔPSSmean correlated with changes in lumen area, PA, PB, and circumferential calcification, and was unchanged with either treatment. Conclusion: Our observational study shows that PSSpeak changes over time were associated with baseline disease severity and treatment. The PSSpeak increase seen in advanced lesions with standard treatment was associated with remodelling artery geometry and plaque architecture, but this was not seen after HIS treatment. Smoothing plaques by reducing plaque/lumen roughness, irregularity, and curvature represents a novel mechanism whereby HIS may reduce PSS and, thus may protect against plaque rupture and MACE.

Development of a Prognostic Model to Identify the Suitable Definitive Radiation Therapy Candidates in de Novo Metastatic Nasopharyngeal Carcinoma: A Real-World Study.

PURPOSE: We aimed to develop an accurate prognostic model to identify suitable candidates for definitive radiation therapy (DRT) in addition to palliative chemotherapy (PCT) among patients with de novo metastatic nasopharyngeal carcinoma (mNPC). METHODS AND MATERIALS: Patients with de novo mNPC who received first-line PCT with or without DRT were included. Overall survival for patients who received PCT alone versus PCT plus DRT was estimated using inverse probability of treatment weighting-adjusted survival analyses. We developed and validated a prognostic model to predict survival and stratify risks in de novo mNPC. A model-based trees approach was applied to estimate stratified treatment effects using prognostic scores obtained from the prognostic model and to identify suitable DRT candidates. Dominance analysis was used to determine the relative importance of each predictor of receiving DRT. RESULTS: A total of 460 patients were enrolled; 244 received PCT plus DRT and 216 received PCT alone. The 6-month conditional landmark, inverse probability of treatment weighting-adjusted Cox regression analysis showed that PCT plus DRT was associated with a significant survival benefit (hazard ratio: 0.516; 95% confidence interval, 0.403-0.660; P < .001). A prognostic model based on 5 independent prognostic factors, including serum lactate dehydrogenase, number of metastatic sites, presence of liver metastasis, posttreatment Epstein-Barr virus DNA level, and response of metastases to chemotherapy was developed and subsequently validated. Prognostic scores obtained from the prognostic model were used for risk stratification and efficacy estimation. High-risk patients identified using the proposed model would not benefit from additional DRT, whereas low-risk patients experienced significant survival benefits. Socioeconomic factors, including insurance status and education level, played an important role in receipt of DRT. CONCLUSIONS: Additional DRT after PCT was associated with increased overall survival in patients with de novo mNPC, especially low-risk patients identified with a newly developed prognostic model.

Six-Year Incidence and Causes of Low Vision and Blindness in a Rural Chinese Adult Population: The Handan Eye Study.

PURPOSE: To determine the six-year incidence, risk factors, and causes of visual impairment in a Chinese population. METHODS: This was a population-based study of eye disease in Chinese adults in a rural district of Handan in China. 6,830 individuals were invited to participate in 2006 and 5,394 returned for follow-up in 2012. All participants underwent standardized eye examinations. Visual impairment was defined according to WHO criteria. The incidence of visual impairment was age- and gender-standardized to the 2010 China Census. Multivariable logistic regression analysis was used to determine risk factors for visual impairment. RESULTS: The leading causes of visual impairment were cataract and refractive error. Based on presenting visual acuity (PVA), the six-year incidence rates of low vision and blindness were 5.2% and 0.5%, respectively. Incidence of low vision was associated with older age (p < .001), less education (p < .001), diabetes (p < .05), and lower BMI (p < .001). The incidence of blindness was associated with diabetes (p < .05). Based on best-corrected visual acuity (BCVA), the six-year incidence rates of low vision and blindness were 0.8% and 0.1%, respectively. Incidence of low vision was associated with older age (p < .001) and lower BMI (p < .05). None of these factors were associated with the incidence of blindness. CONCLUSION: In Handan, the incidence of visual impairment was high and associated with older age, less education, diabetes, and lower BMI. The majority of cases were due to unoperated cataract and uncorrected refractive error, reflecting the need for improved eye care in this region.

Targeting cancer stem cells in cholangiocarcinoma (Review).

The incidence of cholangiocarcinoma has been increasing steadily over the past 50 years, but the survival rates remained low due to the disease being highly resistant to non­surgical treatment interventions. Cancer stem cell markers are expressed in cholangiocarcinoma, suggesting that they serve a significant role in the physiology of the disease. Cancer stem cells are frequently implicated in tumor relapse and acquired resistance to a number of therapeutic strategies, including chemotherapy, radiation and immune checkpoint inhibitors. Novel targeted therapies to eradicate cancer stem cells may assist in overcoming treatment resistance in cholangiocarcinoma and reduce the rates of relapse and recurrence. Several signaling pathways have been previously documented to regulate the development and survival of cancer stem cells, including Notch, janus kinase/STAT, Hippo/yes­associated protein 1 (YAP1), Wnt and Hedgehog signaling. Although pharmacological agents have been developed to target these pathways, only modest effects were reported in clinical trials. The Hippo/YAP1 signaling pathway has come to the forefront in the field of cancer stem cell research due to its reported involvement in epithelium­mesenchymal transition, cell adhesion, organogenesis and tumorigenesis. In the present article, recent findings in terms of cancer stem cell research in cholangiocarcinoma were reviewed, where the potential therapeutic targeting of cancer stem cells in this disease was discussed.

Coronary artery lesion phenotype in frail older patients with non-ST-elevation acute coronary syndrome undergoing invasive care.

AIMS: The association of frailty with coronary plaque phenotype among older patients with non-ST-elevation acute coronary syndrome (NSTEACS) is not known. The aim of this study was to evaluate the association of frailty with coronary plaque phenotype among older patients with NSTEACS. METHODS AND RESULTS: Older patients with NSTEACS who underwent invasive angiography were recruited. Frailty was measured using the Fried frailty score. Following angiography, patients underwent greyscale and virtual histology intravascular ultrasound (VH-IVUS) imaging. Of the 90 patients, 26 (28.9%) were robust, 49 (54.4%) patients were pre-frail, and 15 (16.7%) were frail. Mean age was 80.9±3.8 years; 59 (65.6%) were male. Compared to robust patients, the pre-frail group had a significantly greater presence of high-risk lesions including VH thin-cap fibroatheroma (TCFA, p=0.011), minimum lumen area (MLA) ≤4 mm2 (p=0.016), TCFA+MLA ≤4 mm2 (p=0.005), TCFA+plaque burden (PB) ≥70% (p=0.005) and TCFA+PB ≥70%+MLA ≤4 mm2 (p=0.003). By age- and sex-adjusted logistic regression analysis, frailty was found to be strongly and independently associated with the presence of TCFA (odds ratio [OR] 2.81, 95% confidence interval [CI]:1.06-7.48, p=0.039). CONCLUSIONS: This is the first study to report the relationship between frailty phenotype and coronary plaque morphology among frail older NSTEACS patients. ClinicalTrials.gov Identifier: NCT01933581.

Cognitive Decline in Older Patients With Non- ST Elevation Acute Coronary Syndrome.

Background Dementia is a growing health burden of an aging population. This study aims to evaluate the prevalence of cognitive impairment and the predictors of cognitive decline at 1 year in older patients with non-ST-elevation acute coronary syndrome undergoing invasive care. Methods and Results Older patients with non-ST-elevation acute coronary syndrome were recruited into the ICON1 study. Cognition was evaluated using Montreal Cognitive Assessment. The composite major adverse cardiovascular events comprised death, myocardial infarction, unplanned revascularization, stroke, and significant bleeding at 1 year. Of 298 patients, 271 had cognitive assessment at baseline, and 211 (78%) had follow-up Montreal Cognitive Assessment at 1 year. Mean age was 80.5±4.8 years. There was a high prevalence (n=130, 48.0%) of undiagnosed cognitive impairment (Montreal Cognitive Assessment score <26) at baseline. Cognitive impairment patients were more likely to reach major adverse cardiovascular events by Kaplan-Meier analysis ( P=0.047). Seventy-four patients (35.1%) experienced cognitive decline (Montreal Cognitive Assessment score drop by ≥2 points) at 1 year. Recurrent myocardial infarction was independently associated with cognitive decline at 1 year (odds ratio 3.19, 95% confidence interval 1.18-8.63, P=0.02) after adjustment for age and sex. Conclusions In older patients undergoing invasive management of non-ST-elevation acute coronary syndrome, there is a high prevalence of undiagnosed cognitive impairment at baseline. Recurrent myocardial infarction is independently associated with cognitive decline at 1 year. Clinical Trial Registration URL: http://www.clinicaltrials.gov . Unique identifier: NCT01933581.