Clonal haematopoiesis of indeterminate potential and atrial fibrillation: an east Asian cohort study.

BACKGROUND AND AIMS: Both clonal haematopoiesis of indeterminate potential (CHIP) and atrial fibrillation (AF) are age-related conditions. This study investigated the potential role of CHIP in the development and progression of AF. METHODS: Deep-targeted sequencing of 24 CHIP mutations (a mean depth of coverage = 1000×) was performed in 1004 patients with AF and 3341 non-AF healthy subjects. Variant allele fraction ≥ 2.0% indicated the presence of CHIP mutations. The association between CHIP and AF was evaluated by the comparison of (i) the prevalence of CHIP mutations between AF and non-AF subjects and (ii) clinical characteristics discriminated by CHIP mutations within AF patients. Furthermore, the risk of clinical outcomes-the composite of heart failure, ischaemic stroke, or death-according to the presence of CHIP mutations in AF was investigated from the UK Biobank cohort. RESULTS: The mean age was 67.6 ± 6.9 vs. 58.5 ± 6.5 years in AF (paroxysmal, 39.0%; persistent, 61.0%) and non-AF cohorts, respectively. CHIP mutations with a variant allele fraction of ≥2.0% were found in 237 (23.6%) AF patients (DNMT3A, 13.5%; TET2, 6.6%; and ASXL1, 1.5%) and were more prevalent than non-AF subjects [356 (10.7%); P < .001] across the age. After multivariable adjustment (age, sex, smoking, body mass index, diabetes, and hypertension), CHIP mutations were 1.4-fold higher in AF [adjusted odds ratio (OR) 1.38; 95% confidence interval 1.10-1.74, P < .01]. The ORs of CHIP mutations were the highest in the long-standing persistent AF (adjusted OR 1.50; 95% confidence interval 1.14-1.99, P = .004) followed by persistent (adjusted OR 1.44) and paroxysmal (adjusted OR 1.33) AF. In gene-specific analyses, TET2 somatic mutation presented the highest association with AF (adjusted OR 1.65; 95% confidence interval 1.05-2.60, P = .030). AF patients with CHIP mutations were older and had a higher prevalence of diabetes, a longer AF duration, a higher E/E', and a more severely enlarged left atrium than those without CHIP mutations (all P < .05). In UK Biobank analysis of 21 286 AF subjects (1297 with CHIP and 19 989 without CHIP), the CHIP mutation in AF is associated with a 1.32-fold higher risk of a composite clinical event (heart failure, ischaemic stroke, or death). CONCLUSIONS: CHIP mutations, primarily DNMT3A or TET2, are more prevalent in patients with AF than non-AF subjects whilst their presence is associated with a more progressive nature of AF and unfavourable clinical outcomes.

Clonal Hematopoiesis and Acute Ischemic Stroke Outcomes.

OBJECTIVE: The effect of clonal hematopoiesis of indeterminate potential (CHIP) on the manifestation and clinical outcomes of acute ischemic stroke (AIS) has not been fully elucidated. METHODS: Patients with AIS were included from a prospective registry coupled with a DNA repository. Targeted next-generation sequencing on 25 genes that are frequently mutated in hematologic neoplasms was performed. The prevalence of CHIP was compared between patients with AIS and age-matched healthy individuals. A multivariate linear or logistic regression model was used to assess the association among CHIP and stroke severity, hemorrhagic transformation, and functional outcome at 90 days. RESULTS: In total, 380 patients with AIS (mean age = 67.2 ± 12.7 years; 41.3% women) and 446 age-matched controls (mean age = 67.2 ± 8.7 years; 31.4% women) were analyzed. The prevalence of CHIP was significantly higher in patients with AIS than in the healthy controls (29.0 vs 22.0%, with variant allele frequencies of 1.5%, p = 0.024). PPM1D was found to be most significantly associated with incident AIS (adjusted odds ratio [aOR] = 7.85, 95% confidence interval [CI] = 1.83-33.63, p = 0.006). The presence of CHIP was significantly associated with the initial National Institutes of Health Stroke Scale (NIHSS) score (ß = 1.67, p = 0.022). Furthermore, CHIP was independently associated with the occurrence of hemorrhagic transformation (65/110 clonal hematopoiesis positive [CH+] vs 56/270 CH negative [CH-], aOR = 5.63, 95% CI = 3.24-9.77, p < 0.001) and 90-day functional disability (72/110 [CH+] vs 99/270 [CH-], aOR = 2.15, 95% CI = 1.20-3.88, p = 0.011). INTERPRETATION: CH was significantly associated with incident AIS. Moreover, particularly, sequence variations in PPM1D, TET2, and DNMT3A represent a new prognostic factor for AIS. ANN NEUROL 2023;94:836-847.

Alcohol consumption and the risk of new-onset uterine leiomyomas: a nationwide population-based study in 2.5 million Korean women aged 20 to 39 years.

BACKGROUND: Uterine leiomyomas are the most common benign tumors in women of childbearing age. Although there are several studies reporting the positive association of drinking alcohol with the incidence of uterine leiomyomas, studies targeting Korean women are lacking. OBJECTIVE: This study aimed to investigate the association between alcohol consumption and the risk of new-onset uterine leiomyomas in Korean women of early reproductive-age. STUDY DESIGN: This was a retrospective nationwide population-based cohort study using the Korean National Health Insurance Service database. Participants comprised 2,512,384 asymptomatic Korean women aged 20 to 39 years who underwent a national health examination from 2009 to 2012. The follow-up period was from the date of the first national health examination to the date of diagnosis of new-onset uterine leiomyomas or December 2018 if no uterine leiomyomas were detected. The diagnosis of uterine leiomyomas required 2 outpatient records within a year or 1 inpatient record of International Classification of Diseases, Tenth Revision (ICD-10) codes of uterine leiomyomas (D25) in the Korean National Health Insurance Service. Exclusion criteria were previously diagnosed uterine leiomyomas during the screening period (January 2002 to the date of first health examination) or uterine leiomyoma diagnosis within 1 year of baseline examination. The associations of alcohol consumption, amount drunk per drinking session, and sustained drinking over time with the risk of new-onset uterine leiomyomas were investigated. RESULTS: Approximately 6.1% of women aged 20 to 39 years were diagnosed with uterine leiomyomas after an average of 4.3 years. Alcohol consumption was associated with an increased incidence of new-onset uterine leiomyomas of 12% to 16% (hazard ratio, 1.12; 95% confidence interval, 1.11-1.14 for mild-to-moderate drinkers; hazard ratio, 1.16; 95% confidence interval, 1.12-1.20 for heavy drinkers). Drinking ≥1 days per week was associated with increased risk of uterine leiomyomas (hazard ratio, 1.11; 95% confidence interval, 1.10-1.12 for drinking 1 day per week; hazard ratio, 1.15; 95% confidence interval, 1.12-1.17 for drinking ≥3 days per week), and the association increased proportionately to the amount of alcohol consumed per drinking session (hazard ratio, 1.17; 95% confidence interval, 1.15-1.19 for ≥7 glasses per drinking session). Women who also reported alcohol consumption in the questionnaire administered 2 years later (sustained drinkers) exhibited a 20% increased risk of new-onset uterine leiomyomas (hazard ratio, 1.20; 95% confidence interval, 1.17-1.22) compared with women who answered that they did not drink alcohol at both times (sustained nondrinkers). In women who discontinued drinking, the risk was 3% (hazard ratio, 1.03; 95% confidence interval, 1.01-1.06), whereas in women who became drinkers, the risk was 14% (hazard ratio, 1.14; 95% confidence interval, 1.11-1.16). CONCLUSION: Having an alcohol drinking habit, the amount of alcohol consumed per drinking session, and sustained drinking over 2 years were significantly associated with the risk of new-onset uterine leiomyomas. Avoiding or discontinuing drinking could lower the risk of new-onset uterine leiomyomas in early reproductive-age women.

Incremental prognostic value of triglyceride glucose index additional to coronary artery calcium score in asymptomatic low-risk population.

BACKGROUND: The triglyceride glucose (TyG) index has been suggested as a reliable surrogate marker of insulin resistance which is a substantial risk factor for atherosclerotic cardiovascular disease (ASCVD). Several recent studies have shown the relationship between the TyG index and cardiovascular disease; however, the role of the TyG index in coronary artery calcification (CAC) progression has not been extensively assessed especially in low-risk population. METHODS: We enrolled 5775 Korean adults who had at least two CAC evaluations. We determined the TyG index using ln (fasting triglycerides [mg/dL] x fasting glucose [mg/dL]/2). The CAC progression was defined as either incident CAC in a CAC-free population at baseline or an increase of ≥ 2.5 units between the square roots of the baseline and follow-up coronary artery calcium scores (CACSs) of subjects with detectable CAC at baseline. RESULTS: CAC progression was seen in 1,382 subjects (23.9%) during mean 3.5 years follow-up. Based on the TyG index, subjects were stratified into four groups. Follow-up CACS and incidence of CAC progression were markedly elevated with rising TyG index quartiles (group I [lowest]:17.6% vs. group II:22.2% vs. group III:24.6% vs. group IV [highest]: 31.3%, p < 0.001). In multivariate logistic regression analysis, the TyG index was independent predictor of CAC progression (odds ratio: 1.57; 95% confidence interval: 1.33 to 1.81; p < 0.001) especially in baseline CACS ≤ 100 group. CONCLUSION: The TyG index is an independent predictor of CAC progression in low-risk population. It adds incremental risk stratification over established factors including baseline CACS.

Mildly Abnormal Lipid Levels, but Not High Lipid Variability, Are Associated With Increased Risk of Myocardial Infarction and Stroke in "Statin-Naive" Young Population A Nationwide Cohort Study.

RATIONALE: In young adults, the role of mildly abnormal lipid levels and lipid variability in the risk of atherosclerotic cardiovascular diseases remains uncertain. OBJECTIVE: To investigate the association of these abnormalities in lipid profiles with the risk of myocardial infarction (MI) and stroke in young population. METHODS AND RESULTS: From the Korean National Health Insurance Service, a nationwide population-based cohort of 1 934 324 statin-naive adults aged 20 to 39 years, with ≥3 lipid profile measurements and without a history of MI and stroke, were followed-up until the date of MI or stroke, or December 31, 2017. The primary measure of lipid variability was variability independent of the mean. Higher baseline total cholesterol, LDL-C (low-density lipoprotein-cholesterol), and triglycerides and lower HDL-C (high-density lipoprotein-cholesterol) levels were significantly associated with increased MI risk; respective adjusted hazard ratios and 95% CIs comparing the highest versus lowest quartiles were 1.35 (1.20-1.53) for total cholesterol, 1.41 (1.25-1.60) for LDL-C, 1.28 (1.11-1.47) for triglycerides, and 0.82 (0.72-0.94) for HDL-C. Adjusted analyses for deciles of lipid profiles showed that MI risk was significantly elevated among participants with total cholesterol ≥223.4 mg/dL, LDL-C ≥139.5 mg/dL, HDL-C ≤41.8 mg/dL, and triglycerides ≥200.1 mg/dL. The associations between lipid levels and stroke risk were less prominent. Multivariable-adjusted restricted cubic spline analysis demonstrated that the increase in MI risk was not exclusively driven by extreme values of lipid profiles. Similar results were obtained on sensitivity analyses of baseline lipid levels. However, associations between lipid variability and the risk of MI and stroke varied depending on the measure of lipid variability used. CONCLUSIONS: Mildly abnormal baseline lipid levels were associated with an increased future risk of atherosclerotic cardiovascular disease events, particularly MI, whereas measures of lipid variability were not. Therefore, in young adults, achieving optimal lipid levels could be valuable in the prevention of atherosclerotic cardiovascular disease.

Haploinsufficiency of Cyfip2 Causes Lithium-Responsive Prefrontal Dysfunction.

OBJECTIVE: Genetic variants of the cytoplasmic FMR1-interacting protein 2 (CYFIP2) encoding an actin-regulatory protein are associated with brain disorders, including intellectual disability and epilepsy. However, specific in vivo neuronal defects and potential treatments for CYFIP2-associated brain disorders remain largely unknown. Here, we characterized Cyfip2 heterozygous (Cyfip2+/- ) mice to understand their neurobehavioral phenotypes and the underlying pathological mechanisms. Furthermore, we examined a potential treatment for such phenotypes of the Cyfip2+/- mice and specified a neuronal function mediating its efficacy. METHODS: We performed behavioral analyses of Cyfip2+/- mice. We combined molecular, ultrastructural, and in vitro and in vivo electrophysiological analyses of Cyfip2+/- prefrontal neurons. We also selectively reduced CYFIP2 in the prefrontal cortex (PFC) of mice with virus injections. RESULTS: Adult Cyfip2+/- mice exhibited lithium-responsive abnormal behaviors. We found increased filamentous actin, enlarged dendritic spines, and enhanced excitatory synaptic transmission and excitability in the adult Cyfip2+/- PFC that was restricted to layer 5 (L5) neurons. Consistently, adult Cyfip2+/- mice showed increased seizure susceptibility and auditory steady-state responses from the cortical electroencephalographic recordings. Among the identified prefrontal defects, lithium selectively normalized the hyperexcitability of Cyfip2+/- L5 neurons. RNA sequencing revealed reduced expression of potassium channel genes in the adult Cyfip2+/- PFC. Virus-mediated reduction of CYFIP2 in the PFC was sufficient to induce L5 hyperexcitability and lithium-responsive abnormal behavior. INTERPRETATION: These results suggest that L5-specific prefrontal dysfunction, especially hyperexcitability, underlies both the pathophysiology and the lithium-mediated amelioration of neurobehavioral phenotypes in adult Cyfip2+/- mice, which can be implicated in CYFIP2-associated brain disorders. ANN NEUROL 2020;88:526-543.

Association of the new visceral adiposity index with coronary artery calcification and arterial stiffness in Korean population.

BACKGROUND AND AIMS: The new visceral adiposity index (NVAI) is an indirect marker of visceral adipose tissue recently developed using a Korean population. Here we examined the association of NVAI with coronary artery calcification and arterial stiffness in asymptomatic Korean patients. METHODS AND RESULTS: We analyzed data from 60,938 asymptomatic Korean adults. Odds ratios and 95% confidence intervals (CIs) for coronary artery calcification score (CACS) > 100 and brachial-ankle pulse wave velocity (baPWV) ≥14 m/s were calculated across NVAI tertiles using multiple logistic regression analysis. Receiver operating characteristic (ROC) and area under the curve (AUC) analyses were used to assess the ability of NVAI to predict moderate to high risk of cardiovascular disease. The prevalence of moderate and high risk of cardiovascular disease increased significantly as the NVAI tertile increased. The odds ratio (95% CI) of the highest NVAI tertile for CACS >100 was 5.840 (5.101-6.686) for men and 18.916 (11.232-31.855) for women, after adjusting for confounders. All NVAI AUC values were significantly higher than the AUC values for other visceral adiposity markers. CONCLUSIONS: This study provides the evidence that NVAI is independently and positively associated with coronary calcification and arterial stiffness in asymptomatic Korean adults.

Melanin decolorization by lysosome-related extract in Saccharomyces cerevisiae modified to overproduce glutathione peroxidase.

All eukaryotes have lysosomes that contain hydrolytic enzymes, such as protease, that degrade waste materials and cellular fragments. As a cellular organelle, lysosomes function as the digestive system of the cell, serving both to degrade material taken up from outside the cell and to digest obsolete components of the cell itself. In a previous study, melanin compounds were bleached using lysosome-related organelle extract (LOE) in which glutathione peroxidase (GPX) contributed decisively to melanin decolorization. In this study, Saccharomyces cerevisiae was engineered to overproduce GPX, which increases the melanin color reduction activity of LOE. In addition, the peroxidase activity of the recombinant yeast was measured for each compartment. In spite of the modification to overexpress the GPX protein, with the peroxidase activity of the lysosome fraction specifically higher, the overall peroxidase activity of the cells remained constant. The overexpression of GPX2 among the GPX present in S. cerevisiae increased both the melanin-decolorization activity and the peroxidase activity of LOE. These results indicate that the peroxidase activity is related to the melanin decomposition and antioxidant enzymes such as GPX. In an artificial skin tissue test, the LOE extracted from the recombinant yeast was efficient in reducing the melanin. These results confirmed the enzyme's ability to penetrate corneous tissue, and they suggest the possibility of further development as a new whitening cosmetic. KEY POINTS: • Modification of Saccharomyces cerevisiae to overexpress glutathione peroxidase (GPX). • The lysosome fraction of the recombinant strain enhanced the decolorizing function. • The LOE penetrates the skin barrier and works effectively on artificial skin tissue.

Concurrent smoking and alcohol consumers had higher triglyceride glucose indices than either only smokers or alcohol consumers: a cross-sectional study in Korea.

BACKGROUND: The triglyceride glucose (TyG) index is a noninsulin-based marker for insulin resistance (IR) in general practice. Although smoking and heavy drinking have been regarded as major risk factors for various chronic diseases, there is limited evidence regarding the combined effects of smoking and alcohol consumption on IR. This study aimed to investigate the relationship between the TyG index and smoking and alcohol consumption using two Korean population-based datasets. METHODS: This study included 10,568 adults in the Korean National Health and Nutrition Examination Survey (KNHANES) and 9586 adults in the Korean Initiatives on Coronary Artery Calcification (KOICA) registry datasets. Multivariate logistic analysis was conducted to explore the relationship between smoking and alcohol consumption and the TyG index. To assess the predictive value of smoking and alcohol consumption on high TyG index, the area under the curve (AUC) were compared and net reclassification improvement (NRI) and integrated discrimination improvement (IDI) analyses were derived. RESULTS: The combined effect of smoking and alcohol consumption was an independent risk factor of a higher TyG index in the KNHANES (adjusted odds ratio: 4.33, P < .001) and KOICA (adjusted odds ratio: 1.94, P < .001) datasets. Adding smoking and alcohol consumption to the multivariate logistic models improved the model performance for the TyG index in the KNHANES (AUC: from 0.817 to 0.829, P < .001; NRI: 0.040, P < .001; IDI: 0.017, P < .001) and KOICA (AUC: from 0.822 to 0.826, P < .001; NRI: 0.025, P = .006; IDI: 0.005, P < .001) datasets. CONCLUSIONS: Smoking and alcohol consumption were independently associated with the TyG index. Concurrent smokers and alcohol consumers were more likely to have a TyG index that was ≥8.8 and higher than the TyG indices of non-users and those who exclusively consumed alcohol or smoking tobacco.

Triglyceride glucose index is an independent predictor for the progression of coronary artery calcification in the absence of heavy coronary artery calcification at baseline.

BACKGROUND: Data on the relationship between the triglyceride glucose (TyG) index and coronary artery calcification (CAC) progression is limited. This longitudinal study evaluated the association of TyG index with CAC progression in asymptomatic adults. METHODS: We enrolled 12,326 asymptomatic Korean adults who had at least two CAC evaluations. The TyG index was determined using ln (fasting triglycerides [mg/dL] × fasting glucose [mg/dL]/2). CAC progression was defined as a difference ≥ 2.5 between the square roots (√) of the baseline and follow-up coronary artery calcium score (CACS) (Δ√transformed CACS). Annualized Δ√transformed CACS was defined as Δ√transformed CACS divided by the inter-scan period. RESULTS: During a mean 3.3 years, the overall incidence of CAC progression was 30.6%. The incidence of CAC progression (group I [lowest]: 22.7% versus [vs.] group II: 31.7% vs. group III [highest]: 37.5%, P < 0.001) and annualized Δ√transformed CACS (group I: 0.46 ± 1.44 vs. group II: 0.71 ± 2.02 vs. group III: 0.87 ± 1.75, P < 0.001) were markedly elevated with increasing TyG index tertiles. Multivariate linear regression analysis showed that TyG index was associated with annualized Δ√transformed CACS (ß = 0.066, P = 0.036). In multivariate logistic regression analysis, the TyG index was significantly associated with CAC progression in baseline CACS ≤ 100. CONCLUSION: The TyG index is an independent predictor of CAC progression, especially in adults without heavy baseline CAC.

Hypoxia-induced cancer stemness acquisition is associated with CXCR4 activation by its aberrant promoter demethylation.

BACKGROUND: A hypoxic microenvironment leads to an increase in the invasiveness and the metastatic potential of cancer cells within tumors via the epithelial-mesenchymal transition (EMT) and cancer stemness acquisition. However, hypoxia-induced changes in the expression and function of candidate stem cell markers and their possible molecular mechanism is still not understood. METHODS: Lung cell lines were analyzed in normoxic or hypoxic conditions. For screening among the stem cell markers, a transcriptome analysis using next-generation sequencing was performed. For validation, the EMT and stem cell characteristics were analyzed. To determine whether an epigenetic mechanism was involved, the cell lines were treated with a DNA methyltransferase inhibitor (AZA), and methylation-specific PCR and bisulfite sequencing were performed. RESULTS: Next-generation sequencing revealed that the CXCR4 expression was significantly higher after the hypoxic condition, which functionally resulted in the EMT and cancer stemness acquisition. The acquisition of the EMT and stemness properties was inhibited by treatment with CXCR4 siRNA. The CXCR4 was activated by either the hypoxic condition or treatment with AZA. The methylation-specific PCR and bisulfite sequencing displayed a decreased CXCR4 promoter methylation in the hypoxic condition. CONCLUSIONS: These results suggest that hypoxia-induced acquisition of cancer stem cell characteristics was associated with CXCR4 activation by its aberrant promoter demethylation.

Arterial stiffness measured by cardio-ankle vascular index in Korean women with polycystic ovary syndrome.

Many studies have reported an increased arterial stiffness using pulse wave velocity (PWV) in women with polycystic ovary syndrome (PCOS). However, PWV is essentially dependent on blood pressure (BP) at the time of measurement. The cardio-ankle vascular index (CAVI) is a relatively new index for measuring arterial stiffness, and its conspicuous feature is its independency from the BP at the time of measurement. The aim of this study was to evaluate arterial stiffness by CAVI in PCOS patients (n = 26) and in the age-matched controls (n = 59). The CAVI was measured by a single medical professional. The mean age of the women with PCOS was 33.3 (±6.6) years, and that of the matched controls was 33.1 (±5.9) years (p = .861). The mean CAVIs were similar between the patients and controls (6.49 ± 0.41 and 6.39 ± 0.65, respectively, p = .452). The CAVI increased linearly with age in both groups, but in the women with PCOS, CAVI showed relatively strong negative correlations with body mass index (BMI) in both the unadjusted (r = -0.537, p = .005) and adjusted models (r = -0.474, p = .003 after age and BMI adjustment and r = -0.604, p = .033 after age, BMI, sitting auscultatory systolic BP and square root hs-CRP adjustment). In conclusion, relatively young women with PCOS may not have increased arterial stiffness. A negative correlation between CAVI and BMI in women with PCOS requires further study to determine whether vascular adaptation to adiposity occurred in these women. Impact Statement What is already known on this subject? Increased arterial stiffness is one of the earliest adverse structural and functional alterations in blood vessels, potentially leading to later cardiovascular disease. Many studies have reported an increased arterial stiffness using pulse wave velocity (PWV) in women with polycystic ovary syndrome (PCOS). However, PWV is essentially dependent on blood pressure (BP) at the time of measurement. The cardio-ankle vascular index (CAVI) is a relatively new index for measuring arterial stiffness, and its conspicuous feature is its independency from the BP at the time of measurement. What do the results of this study add? The CAVIs were similar between the women with PCOS and the age-matched controls. The CAVI increased linearly with age in both groups, but in women with PCOS, CAVI showed a relatively strong negative correlation with the body mass index (BMI). What are the implications of these findings for clinical practice and/or further research? Relatively young women with PCOS may not have increased arterial stiffness. However, CAVI showed a negative correlation with BMI only in the women with PCOS, suggesting that adiposity itself is associated with the decreased arterial stiffness in these women. This finding requires a replication, and whether adaptation to the hemodynamic consequences of adiposity occurred in the PCOS patients remains to be established. Further longitudinal studies are needed to verify the relationships among vascular stiffness, adiposity and PCOS.

Evaluation of the impact of glycemic status on the progression of coronary artery calcification in asymptomatic individuals.

BACKGROUND: Data on the influence of glycemic status on the progression of coronary calcification, an important marker for future adverse cardiovascular events, are limited. METHODS: Data from the Korea Initiatives on Coronary Artery Calcification (KOICA) registry on 12,441 asymptomatic Korean adults (52 ± 9 years, 84.2% males) without previous history of coronary artery disease and stroke, who underwent serial coronary artery calcification (CAC) screening examinations, were included in this study. The median inter-scan period was 3.0 (2.0-4.8) years. All participants were categorized into three groups based on their glycemic status: normal (n = 6578), pre-diabetes (n = 4146), and diabetes (n = 1717). CAC progression was defined as a difference ≥ 2.5 between the square roots (√) of the baseline and follow-up CAC scores. RESULTS: The incidence of CAC progression was significantly different between the three groups (normal, 26.3%; pre-diabetes, 30.9%; and diabetes, 46.9%; p < 0.001). In the univariate logistic analysis, the risk of CAC progression was higher in the pre-diabetes (odds ratio [OR] 1.253; 95% confidential interval [CI] 1.150-1.366) and diabetes (OR 2.471; 95% CI 2.215-2.758) groups than in the normal group (p < 0.001, both). In the multivariate logistic analysis, the risk of CAC progression was not significantly different between the normal and pre-diabetes groups but was significantly higher in the diabetes group than in the normal group. CONCLUSIONS: In asymptomatic subjects, diabetes had an incremental impact on CAC progression; however, pre-diabetes did not increase the risk of CAC progression after adjusting for confounding factors.

Asymmetric Synthesis of Dihydropyranones via Gold(I)-Catalyzed Intermolecular [4+2] Annulation of Propiolates and Alkenes.

Intermolecular asymmetric gold catalysis involving alkyne activation presents a significant challenge due to its distinct mechanistic mode from other metals. Herein, we report a highly enantioselective synthesis of α,ß-unsaturated δ-lactones from [4+2] annulation of propiolates and alkenes in upto 95 % ee. Notably, for the desired chiral recognition, the choice of 1,1,2,2-tetrachloroethane as solvent was found to be crucial. Furthermore, an anionic surfactant (sodium dodecyl sulfate) improved the product selectivity in the divergence of the cyclopropyl gold carbene intermediate.

Impact of metabolic syndrome on the progression of coronary calcium and of coronary artery disease assessed by repeated cardiac computed tomography scans.

BACKGROUND: It is not clear how severe metabolic syndrome (MS) affects the development of coronary atherosclerosis. METHODS: This was an observational, retrospective cohort study with Koreans who received health check-ups voluntarily. A total of 2426 subjects had baseline and follow-up coronary artery calcium score (CACS) data. Among them, 1079 had coronary computed tomography angiography (CCTA) data. We compared baseline CACS and any progression in subjects with and without MS. A more detailed analysis was conducted for coronary artery disease (CAD), which was defined by coronary artery stenosis (≥50 %), multivessel involvement, and coronary plaques in those patients with CCTA data. RESULTS: At baseline, subjects with MS (34.0 %, n = 825) had higher CACS and more significant coronary artery stenosis, multivessel involvement, and atheromatous plaques than those without MS (P < 0.05 for all). In the follow-up (median 1197 days), subjects with MS showed significant increases in CACS and progression of CAD compared with counterparts without MS, in parallel with the numbers of MS components. Finally, MS was a significant predictor for the progression of CACS (hazard ratio 1.32; 95 % confidence interval 1.06-1.64) and progression of coronary artery stenosis and/or development of vulnerable plaque (hazard ratio 1.47, 95 % confidence interval 1.01-2.15) after adjusting for other cardiovascular risk factors. CONCLUSIONS: Subjects with MS showed progression of CAD as assessed by CACS and CCTA over ~3 years. Therefore, more vigilant screening for coronary vascular health is needed among those with MS.

Prevalence and Distribution of Coronary Artery Calcification in Asymptomatic United States and Korean Adults　- Cross-Sectional Propensity-Matched Analysis.

BACKGROUND: The incidence of coronary artery disease (CAD) varies depending on ethnicity, but the precise differences remain to be firmly established. This study therefore evaluated the disparity in coronary artery calcification (CAC), as a marker of CAD, in asymptomatic US and Korean adults.Methods and Results:CAC score was compared between asymptomatic Korean (n=15,128) and US (n=7,533) adults. Propensity score matching was performed according to age, gender, hypertension, diabetes, dyslipidemia, and current smoking, which generated 2 cohorts of 5,427 matched pairs. Both cohorts were categorized according to age group: 45-54, 55-64, and 65-74 years. Overall, the prevalence of CAC score >0, >100, and >400 in Korean adults was lower than in US adults (P<0.001, all). According to increasing age groups, the likelihood of CAC was most often lower in Korean adults, especially in Korean women. The odds of having CAC >400 in Korean adults aged 65-74 years was 0.66 (95% CI: 0.48-0.91) overall, 0.78 (95% CI: 0.52-1.19) in men, and 0.50 (95% CI: 0.29-0.86) in women, compared with US counterparts. CONCLUSIONS: Korean adults have a lower prevalence and severity of atherosclerotic burden as assessed on CAC, compared with US adults, but the disparity in CAC according to ethnicity may decline with older age. (Circ J 2016; 80: 2349-2355).

Warranty Period of Zero Coronary Artery Calcium Score for Predicting All-Cause Mortality According to Cardiac Risk Burden in Asymptomatic Korean Adults.

BACKGROUND: The aim of this study was to examine whether zero coronary artery calcium (CAC) score is associated with favorable prognosis of all-cause mortality (ACM) according to a panel of conventional risk factors (RF) in asymptomatic Korean adults.Methods and Results:A total of 48,215 individuals were stratified according to presence/absence of CAC, and the following RF were examined: hypertension, diabetes, current smoking, high low-density lipoprotein cholesterol, and low high-density lipoprotein cholesterol. The RF were summed on composite score as 0, 1-2, or ≥3 RF present. The warranty period was defined as the time to cumulative mortality rate >1%. Across a median follow-up of 4.4 years (IQR, 2.7-6.6), 415 (0.9%) deaths occurred. Incidence per 1,000 person-years for ACM was consistently higher in subjects with any CAC, irrespective of number of RF. The warranty period was substantially longer (eg, 9 vs. 5 years) for CAC=0 compared with CAC >0. The latter observation did not change materially according to pre-specified RF, but difference in warranty period according to presence/absence of CAC reduced somewhat when RF burden increased. CONCLUSIONS: In asymptomatic Korean adults, the absence of CAC evoked a strong protective effect against ACM as reflected by longer warranty period, when no other RF were present. The usefulness of zero CAC score and its warranty period requires further validation in the presence of multiple RF. (Circ J 2016; 80: 2356-2361).

Bis Expression in Patients with Surgically Resected Lung Cancer and its Clinical Significance.

BACKGROUND: Bis, also known as BAG3, has been identified as a Bcl-2-interacting protein that enhances cellular anti-apoptotic activity. It is involved in cellular differentiation, angiogenesis, migration, and invasion in various tumors. The purpose of this study was to investigate the Bis expression pattern, and the clinical significance thereof, in patients with resected lung cancer. METHODS: We studied 121 lung cancer patients who underwent curative surgical resection. Patient clinicopathological characteristics were reviewed retrospectively from medical records, including tumor recurrence and survival. The expression of Bis protein in lung cancer tissues was evaluated by immunohistochemical staining and was assessed using a four-tiered intensity score system (negative, weak, moderate, strong). Enhanced Bis expression at the periphery of a tumor facing the adjacent nontumor region was referred as "marginal activity." RESULTS: Although Bis expression was higher in squamous cell carcinoma than in adenocarcinoma, marginal activity was higher in adenocarcinoma than in squamous cell carcinoma. All of the small cell carcinomas and lung cancer with neuroendocrine differentiation examined were negative for Bis expression. Compared with stage I lung cancer, patients with stage II and IIIA lung cancer exhibited higher Bis protein levels in lung tissues. Recurrence and survival rates did not differ significantly according to Bis expression intensity score or marginal activity. CONCLUSIONS: Our study demonstrated that Bis expression differed according to the histological type and pathological stage of the lung cancer. Further studies are needed to assess its use as a biomarker and its role in the molecular pathogenesis of lung cancer.

Incremental benefit of coronary artery calcium score above traditional risk factors for all-cause mortality in asymptomatic Korean adults.

BACKGROUND: Coronary artery calcium score (CACS) is a well-recognized marker for subclinical coronary atherosclerosis, particularly in asymptomatic populations. To date, however, the added prognostic benefit of CACS compared with traditional risk factors in an Asian population remains unknown. This study therefore investigated the benefit of CACS over traditional risk factors for all-cause mortality in a large multicenter registry of asymptomatic Korean adults. METHODS AND RESULTS: A total of 34,386 individuals were retrospectively enrolled to participate in a general health examination. The Framingham 10-year risk score (FRS) was calculated according to the traditional risk stratification algorithm and CACS was calculated in log(CACS+1) for continuous data and categorized as 0, 1-100, 101-400 and >400. During a median follow-up of 4.9 years (IQR, 3.0-7.1), there were 303 all-cause deaths (0.9%). Following adjustment, CACS was independently associated with all-cause death (hazard ratio, 1.10; 95% confidence interval (CI): 1.05-1.17; P<0.001). Notably, CACS added further prognostic value above and beyond FRS (likelihood ratio, χ(2)=75.42, P<0.001; continuous net reclassification improvement=0.40, 95% CI: 0.29-0.51, P≤0.001; improving C-statistic from 0.64, 95% CI: 0.61-0.67 to 0.68, 95% CI: 0.64-0.71; ∆C=0.04, 95% CI: 0.01-0.06, P=0.002). CONCLUSIONS: In an asymptomatic Korean population, CACS improved prediction of all-cause mortality over and above that of a conventional risk tool.

Association of epicardial fat with left ventricular diastolic function in subjects with metabolic syndrome: assessment using 2-dimensional echocardiography.

BACKGROUND: Metabolic syndrome (MetS) is related with left ventricular diastolic dysfunction (LVDD) and poor cardiovascular outcome. Epicardial adipose tissue (EAT) thickness, measured by echocardiography, is increased in subjects with MetS. However, the association of EAT with LV diastolic function has not been evaluated in subjects with MetS. METHODS: In this retrospective study, EAT thickness was measured in 1,486 consecutive asymptomatic patients with no known heart disease who had transthoracic echocardiography during a self-referred healthcare exam. Subjects with a history of ischemic heart disease, cardiomyopathy or significant valvular heart disease were excluded. LVDD was defined as E/e' ratio ≥ 15. Subjects were grouped into two groups, those with MetS and those without. RESULTS: MetS was present in 346 subjects. There was no difference in LV systolic function between the two groups. However compared to patients without MetS, patients with MetS had larger left atrium (LA) size and higher E/e' ratio (38 ± 5 versus 35 ± 5 mm for LA and 10.0 ± 3.3 versus 8.7 ± 2.7 for E/e' ratio in subjects with versus without MetS both p < 0.001). LVDD was found in 27 (7.8%) subjects with MetS, compared to 30 (2.6%) subjects without MetS (p < 0.001). In subjects with MetS, EAT was significantly correlated with LVDD, even after adjusting for other cardiometabolic risk factors such as age, systolic blood pressure, BMI, blood glucose and LDL cholesterol (OR 1.845, 95% CI 1.153-2.951, p = 0.011). CONCLUSION: Greater EAT is found in subjects with MetS. EAT is significantly associated with LVDD in subjects with MetS, even after adjusting for other risk factors.