Assessment of Normal Systolic Blood Pressure Maintenance with the Risk of Coronary Artery Calcification Progression in Asymptomatic Metabolically Healthy Korean Adults with Normal Weight, Overweight, and Obesity.

Metabolically healthy obesity (MHO) is known to have a close association with subclinical coronary atherosclerosis. Despite recent data on the benefit of intensive systolic blood pressure (SBP) control in diverse clinical conditions, little is known regarding the association of normal SBP maintenance (SBPmaintain) with coronary artery calcification (CAC) progression in MHO. This study included 2724 asymptomatic adults (48.8 ± 7.8 years; 77.9% men) who had no metabolic abnormalities except overweight and obesity. Participants with normal weight (44.2%), overweight (31.6%), and obesity (24.2%) were divided into two groups: normal SBPmaintain (follow-up SBP < 120 mm Hg) and ≥elevated SBPmaintain (follow-up SBP ≥ 120 mm Hg). CAC progression was defined using the SQRT method, a difference of ≥2.5 between the square root (√) of the baseline and follow-up coronary artery calcium score. During a mean follow-up of 3.4 years, the proportion of normal SBPmaintain (76.2%, 65.2%, and 59.1%) and the incidence of CAC progression (15.0%, 21.3%, and 23.5%) was different in participants with normal weight, overweight, and obesity (all p < 0.05, respectively). The incidence of CAC progression was lower in the normal SBPmaintain group than in the ≥elevated SBPmaintain group in only participants with obesity (20.8% vs. 27.4%, p = 0.048). In multiple logistic models, compared to participants with normal weight, those with obesity had a higher risk of CAC progression. Normal SBPmaintain was independently associated with the decreased risk of CAC progression in participants with obesity. MHO had a significant association with CAC progression. Normal SBPmaintain reduced the risk of CAC progression in asymptomatic adults with MHO.

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.

Comparison of the effectiveness of Martin's equation, Friedewald's equation, and a Novel equation in low-density lipoprotein cholesterol estimation.

Low-density-lipoprotein cholesterol (LDL-C) is the main target in atherosclerotic cardiovascular disease (ASCVD). We aimed to validate and compare a new LDL-C estimation equation with other well-known equations. 177,111 samples were analysed from two contemporary population-based cohorts comprising asymptomatic Korean adults who underwent medical examinations. Performances of the Friedewald (FLDL), Martin (MLDL), and Sampson (SLDL) equations in estimating direct LDL-C by homogenous assay were assessed by measures of concordance (R2, RMSE, and mean absolute difference). Analyses were performed according to various triglyceride (TG) and/or LDL-C strata. Secondary analyses were conducted within dyslipidaemia populations of each database. MLDL was superior or at least similar to other equations regardless of TG/LDL-C, in both the general and dyslipidaemia populations (RMSE = 11.45/9.20 mg/dL; R2 = 0.88/0.91; vs FLDL: RMSE = 13.66/10.42 mg/dL; R2 = 0.82/0.89; vs SLDL: RMSE = 12.36/9.39 mg/dL; R2 = 0.85/0.91, per Gangnam Severance Hospital Check-up/Korea Initiatives on Coronary Artery Calcification data). MLDL had a slight advantage over SLDL with the lowest MADs across the full spectrum of TG levels, whether divided into severe hyper/non-hyper to moderate hypertriglyceridaemia samples or stratified by 100-mg/dL TG intervals, even up to TG values of 500-600 mg/dL. MLDL may be a readily adoptable and cost-effective alternative to direct LDL-C measurement, irrespective of dyslipidaemia status. In populations with relatively high prevalence of mild-to-moderate hypertriglyceridaemia, Martin's equation may be optimal for LDL-C and ASCVD risk estimation.

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.

Sex differences in coronary artery calcium progression: The Korea Initiatives on Coronary Artery Calcification (KOICA) registry.

Even with increasing awareness of sex-related differences in atherosclerotic cardiovascular disease (ASCVD), it remains unclear whether the progression of coronary atherosclerosis differs between women and men. We sought to compare coronary artery calcium (CAC) progression between women and men. From a retrospective, multicentre registry of consecutive asymptomatic individuals who underwent CAC scoring, we identified 9,675 men and 1,709 women with follow-up CAC scoring. At baseline, men were more likely to have a CAC score >0 than were women (47.8% vs. 28.6%). The probability of CAC progression at 5 years, defined as [√CAC score (follow-up)-√CAC score (baseline)] ≥2.5, was 47.4% in men and 29.7% in women (p<0.001). When we stratified subjects according to the 10-year ASCVD risk (<5%, ≥5% and <7.5%, and ≥7.5%), a sex difference was observed in the low risk group (CAC progression at 5 years, 37.6% versus 17.9%; p<0.001). However, it became weaker as the 10-year ASCVD risk increased (64.2% versus 46.2%; p<0.001, and 74.8% versus 68.7%; p = 0.090). Multivariable analysis demonstrated that male sex was independently associated with CAC progression rate among the entire group (p<0.001). Subgroup analyses showed an independent association between male sex and CAC progression rate only in the low-risk group. The CAC progression rate is higher in men than in women. However, the difference between women and men diminishes as the 10-year ASCVD risk increases.

Association between blood pressure classification defined by the 2017 ACC/AHA guidelines and coronary artery calcification progression in an asymptomatic adult population.

Aims: Coronary artery calcium score (CACS) is widely used for cardiovascular risk stratification in asymptomatic population. We assessed the association of new blood pressure (BP) classification using the 2017 American College of Cardiology/American Heart Association guidelines with coronary artery calcification (CAC) progression according to age in asymptomatic adults. Methods and results: Overall, 10 839 asymptomatic Korean adults (23.4% aged ≤45 years) who underwent at least two CACS evaluations for health check-up were enrolled. Participants were categorized by age (≤45 and >45 years) and BP [normal (<120/<80 mmHg, untreated), elevated (120-129/<80 mmHg, untreated), Stage 1 hypertension (untreated BP 130-139/80-89 mmHg) or Stage 2 hypertension (BP ≥140/≥90 mmHg or anti-hypertensive use)] groups. CAC progression was defined as a difference of ≥2.5 between the square root (√) of the baseline and follow-up CACS. During a mean 3.3-year follow-up, the incidence of CAC progression was 13.5% and 36.3% in individuals aged ≤45 and >45 years, respectively. After adjustment for age, sex, diabetes, dyslipidaemia, obesity, current smoking, and baseline CACS, hazard ratios (95% confidence interval) for CAC progression in elevated BP, Stage 1 hypertension, and Stage 2 hypertension compared to normal BP were 1.43 (0.96-2.14) (P = 0.077), 1.64 (1.20-2.23) (P = 0.002), and 2.38 (1.82-3.12) (P < 0.001) in the ≤45 years group and 1.11 (0.95-1.30) (P = 0.179), 1.17 (1.04-1.32) (P = 0.009), and 1.52 (1.39-1.66) (P < 0.001) in the >45 years group, respectively. Conclusion: Newly defined Stage 1 hypertension is independently associated with CAC progression in asymptomatic adults regardless of age.

Atherogenic index of plasma and coronary artery calcification progression beyond traditional risk factors according to baseline coronary artery calcium score.

This study aimed to evaluate the association between the atherogenic index of plasma (AIP), which has been suggested as a novel marker for atherosclerosis, and coronary artery calcification (CAC) progression according to the baseline coronary artery calcium score (CACS). We included 12,326 asymptomatic Korean adults who underwent at least two CAC evaluations from December 2012 to August 2016. Participants were stratified into four groups according to AIP quartiles, which were determined by the log of (triglyceride/high-density lipoprotein cholesterol). Baseline CACSs were divided into three groups: 0, 1 - 100, and > 100. CAC progression was defined as a difference ≥ 2.5 between the square roots (√) of the baseline and follow-up CACSs (Δ√transformed CACS). Annualized Δ√transformed CACS was defined as Δ√transformed CACS divided by the inter-scan period. During a mean 3.3-year follow-up period, the overall incidence of CAC progression was 30.6%. The incidences of CAC progression and annualized Δ√transformed CACS were markedly elevated with increasing AIP quartile in participants with baseline CACSs of 0 and 1 - 100, but not in those with a baseline CACS > 100. The AIP level was associated with the annualized Δ√transformed CACS in participants with baseline CACSs of 0 (ß = 0.016; P < 0.001) and 1 - 100 (ß = 0.035; P < 0.001), but not in those with baseline CACS > 100 (ß = 0.032; P = 0.385). After adjusting for traditional risk factors, the AIP was significantly associated with CAC progression in those with baseline CACS ≤ 100. The AIP has value for predicting CAC progression in asymptomatic adults without heavy baseline CAC.

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.

Machine learning based risk prediction model for asymptomatic individuals who underwent coronary artery calcium score: Comparison with traditional risk prediction approaches.

BACKGROUND: Machine learning (ML) is a computer algorithm used to identify patterns for prediction in various tasks, and ML methods have been beneficial for developing prediction models when applied to heterogeneous and large datasets. We aim to examine the prognostic ability of a ML-based prediction algorithm utilizing routine health checkup data to predict all-cause mortality (ACM) compared to established risk prediction approaches. METHODS: A total 86155 patients with seventy available parameters (35 clinical, 32 laboratory, and 3 coronary artery calcium score [CACS] parameters) were analyzed. ML involved feature selection, splitting data randomly into a training (70%) and test set (30%), and model building with a boosted ensemble algorithm. The developed ML model was validated in a separate cohort of 4915 patients. The performance of ML for predicting ACM was compared with the following models: (i) the Framingham risk score (FRS) + CACS, (ii) atherosclerotic cardiovascular disease (ASCVD) + CACS, with (iii) logistic regression (LR) model. RESULTS: In the derivation dataset, 690 patients died during the median 4.6-year follow-up (interquartile range, 3.0-6.6 years). The AUC value in the ML model was significantly higher than the other models in test set (ML: 0.82, FRS + CACS: 0.70, ASCVD + CACS: 0.74; LR model: 0.79, p < 0.05 for all), but not statistically significantly higher in validation set (ML: 0.78, FRS + CACS: 0.62, ASCVD + CACS: 0.72; LR model: 0.74, p: 0.572 and 0.625 for ASCVD + CACS and LR model, respectively). The ML model improved reclassification over the other models in low to intermediate risk patients (p < 0.001 for all). CONCLUSION: The prediction algorithm derived by ML methods showed a robust ability to predict ACM and improved reclassification over established conventional risk prediction approaches in asymptomatic population undergoing a health checkup.

Impact of optimal glycemic control on the progression of coronary artery calcification in asymptomatic patients with diabetes.

BACKGROUND: Data on the impact of optimal glycemic control (OGC) on the progression of coronary artery calcification, an important marker for future adverse cardiovascular events in individuals with diabetes are limited. METHODS: We investigated 1637 asymptomatic adults with diabetes (56 ±â€¯8 years, 88.8% men) and no history of coronary artery disease or stroke, who underwent serial coronary artery calcium (CAC) screening. The median inter-scan period was 3.0 (2.0-4.4) years. The change in CAC was compared base on OGC status. OGC was defined as a follow-up hemoglobin A1C (HbA1C) of <7.0%, and CAC progression was defined by a square root (√) transformed difference between the baseline and follow-up CAC scores (Δ âˆštransformed CAC) of ≥2.5. RESULTS: Despite no significant difference in the baseline CAC scores, the incidence of CAC progression was lower in the OGC group than in the non-OGC group (45.4% vs. 51.7%; p < 0.013). The two groups differed in the Δ âˆštransformed (OGC, 3.8 ±â€¯6.4; non-OGC, 4.7 ±â€¯6.9; p = 0.016) and annualized Δ âˆštransformed CAC (OGC, 1.1 ±â€¯2.4; non-OGC, 1.4 ±â€¯2.6; p = 0.010) scores. Subgroup analysis showed that OGC significantly reduced the risk of CAC progression in patients aged <65 years and in: smokers, and patients with a body mass index of <25 kg/m2, dyslipidemia, and baseline CAC scores between 1-100 and >400. In multivariate regression analysis, OGC was independently associated with a reduced risk of CAC progression (odds ratio, 0.745, 95% confidence interval, 0.601-0.924; p = 0.007). CONCLUSION: OGC attenuated the progression of coronary artery calcification in asymptomatic patients with diabetes.

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.

Prevalence and severity of coronary artery calcification based on the epidemiologic pattern: A propensity matched comparison of asymptomatic Korean and Chinese adults.

BACKGROUND: Lifestyle, environmental, and genetic factors substantially influence cardiovascular disease (CVD) risk. We aimed to explore epidemiologic trends in coronary artery calcium scores (CACS), as a marker of CVD, along with possible differences by geographic area and study period in separate East Asian populations. METHODS: We generated 3 matched groups (n=702) using a propensity scoring approach derived from a Korean (N=48,901) and Chinese cohort (N=927) as follows: (1) A recent Chinese group and (2) recent Korean group, both of whom underwent CACS scanning from 2012-2014; and (3) a past Korean group who underwent CACS scanning 8-10years before the index group (2002-2006). We used logistic regression to generate odds ratios (OR) with 95% confidence intervals (95% CI) to estimate the likelihood of having CACS between the groups, based on CACS stratified by severity: >0 (any), >100 (moderate), and >400 (severe). RESULTS: The prevalence of any, moderate, or severe CACS did not differ significantly between the recent Chinese and Korean groups. Notably, the odds of the presence of moderate CACS in the recent Chinese group (OR: 3.05, 95% CI: 1.49-6.71, P-value<0.001) and the presence of any CACS in the recent Korean group (OR: 1.58, 95% CI: 1.17-2.15, P-value<0.001) were significantly higher than in the past Korean group. CONCLUSIONS: In this study involving separate East Asian populations, there were no geographic differences in the prevalence of CACS. However, changes in other unmeasured factors over time are likely the culprits for the elevated prevalence of CACS in asymptomatic East Asians.

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).

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).

Associations between elevated resting heart rate and subclinical atherosclerosis in asymptomatic Korean adults undergoing coronary artery calcium scoring.

Elevated resting heart rate (RHR) and the presence of coronary artery calcium (CAC) are closely related with inflammatory activity and cardiovascular disease outcomes. To date, however, the relationship between a high RHR and CAC has not been well studied, especially in non-western populations. We therefore aimed to examine the cross-sectional relationship between high RHR and the burden of subclinical atherosclerosis as measured by CAC score in a large sample of Korean adults. A total 26,018 subjects were enrolled and underwent CAC screening as part of a broader general health examination. RHR was categorized into four groups as: <60, 60-69, 70-79, and ≥80 beats per minute. Multivariable logistic regression models were employed to estimate the odds of having a CAC score of either >0, >100, or >400 based on RHR. Mean age of the study population was 53.9 ± 8.2 years, and 79.7 % were male. After adjustment, each 10 beat per minute increment in RHR was associated with greater odds of having a CAC score above 100 (OR 1.13, 95 % CI 1.08-1.18) or 400 (OR 1.22, 95 % CI 1.13-1.31). Likewise, following adjustment, the odds of having a CAC >100 or >400 for those with a RHR ≥80 beats per minute were 1.42 (95 % CI 1.19-1.69) and 1.86 (95 % CI 1.42-2.47), respectively, compared with those who had a RHR <60 beats per minute. In a large cohort of Korean adults, elevations in the RHR, particularly above 80 beats per minute, were found to be independently associated with the presence of subclinical atherosclerosis as measured by CAC scoring.

Effect of imatinib on airway smooth muscle thickening in a murine model of chronic asthma.

BACKGROUND: Asthma is characterized by airway hyperresponsiveness (AHR), inflammation and remodeling. The tyrosine kinase inhibitor imatinib mesylate was developed to inhibit BCR-ABL kinase activity; however, it also has potent inhibitory activity against the c-Kit and platelet-derived growth factor receptors. The present study aimed to determine whether imatinib suppresses airway smooth muscle (ASM) remodeling and whether its effect is associated with growth factors such as transforming growth factor (TGF)-ß1 and stem cell factor (SCF). METHODS: We developed a mouse model of airway remodeling, which includes smooth muscle thickening, in which ovalbumin (OVA)-sensitized mice were repeatedly exposed to intranasal OVA administration twice a week for 3 months. Mice were treated with imatinib during the OVA challenge. RESULTS: Mice chronically exposed to OVA developed sustained eosinophilic airway inflammation and AHR compared with control mice. In addition, the mice chronically exposed to OVA developed features of airway remodeling, including thickening of the peribronchial smooth muscle layer. Administration of imatinib significantly inhibited the development of AHR, eosinophilic inflammation and, importantly, ASM remodeling in mice chronically exposed to OVA. Imatinib treatment significantly reduced the levels of interleukin-4, -5 and -13. In addition, TGF-ß1 and SCF were significantly reduced in the imatinib-treated animals. CONCLUSIONS: These results suggest that imatinib administration can prevent not only airway inflammation, but also airway remodeling associated with chronic allergen challenge. Imatinib may provide a clinically attractive therapy for chronic severe asthma.

Inhibitory effects of anti-immunoglobulin E antibodies on airway remodeling in a murine model of chronic asthma.

BACKGROUND: Airway remodeling is one of the cardinal features of asthma and is thought to play a pivotal role in refractory or persistent asthma. Immunoglobulin E (IgE) has a major effect on the pathogenesis of asthma. The aim of this study was to investigate the effects of anti-IgE antibody not only on airway inflammation and bronchial hyperresponsiveness, but also on airway remodeling in a murine model of chronic asthma. METHODS: The authors developed a mouse model of chronic asthma in which ovalbumin (OVA)-sensitized female BALB/c-mice were exposed to intranasal OVA administration twice a week for 3 months. Anti-IgE antibodies were administered intravenously starting on the 38th day and once a month thereafter for 3 months during the intranasal OVA challenge. RESULTS: Mice that were chronically exposed to OVA developed sustained eosinophilic airway inflammation and airway hyperresponsiveness (AHR) to methacholine and showed increased levels of collagen, hydroxyproline, and alpha-smooth muscle actin, as compared with control mice. Treatment with anti-IgE antibody inhibited the development of AHR, eosinophilic inflammation, and airway remodeling. Moreover, anti-IgE antibody treatment reduced the levels of interleukin (IL)-5 and IL-13 in the bronchoalveolar lavage fluids, although it did not affect the levels of IL-10, transforming growth factor-beta, and activin A. CONCLUSION: These results suggest that anti-IgE antibody treatment modulates the airway inflammation and remodeling associated with chronic allergen challenge. The inhibition of inflammation may be related to the regulation of Th2 cytokines. However, the mechanisms underlying the blocking of airway remodeling by anti-IgE antibody remain to be elucidated.

Inhibitory effect of CXC chemokine receptor 4 antagonist AMD3100 on bleomycin induced murine pulmonary fibrosis.

CXC chemokine receptor 4 (CXCR4), which binds the stromal cell-derived factor-1 (SDF-1), has been shown to play a critical role in mobilizing the bone marrow (BM)-derived stem cells and inflammatory cells. We studied the effects of AMD3100, CXCR4 antagonist, on a murine bleomycin-induced pulmonary fibrosis model. Treatment of mice with AMD3100 in bleomycin-treated mice resulted in the decrease of SDF-1 in bronchoalveolar lavage (BAL) fluids at an early stage and was followed by the decrease of fibrocytes in the lung. AMD3100 treatment decreased the SDF-1 mRNA expression, fibrocyte numbers in the lung at an early stage (day 3) and CXCR4 expression at the later stage (day 7 and 21) after bleomycin injury. The collagen content and pulmonary fibrosis were significantly attenuated by AMD3100 treatment in later stage of bleomycin injury. AMD3100 treatment also decreased the murine mesenchymal and hematopoietic stem cell chemotaxis when either in the stimulation with bleomycin treated lung lysates or SDF-1 in vitro. In BM stem cell experiments, the phosphorylation of p38 MAPK which was induced by SDF-1 was significantly blocked by addition of AMD3100. Our data suggest that AMD3100 might be effective in preventing the pulmonary fibrosis by inhibiting the fibrocyte mobilization to the injured lung via blocking the SDF-1/CXCR4 axis.

14th congress of the APSR and 3rd Joint Congress of the APSR/ACCP.

The Asian Pacific Society of Respirology (APSR) held its 14th Congress and 3rd Joint Congress of the APSR/American College of Chest Physicians (ACCP) in Seoul, Korea, between 14 and 18 November 2009. It was attended by 1906 delegates from around the world and was particularly well represented by people from the Asia-Pacific Rim. The Congress was highlighted by an excellent scientific program, preceded by an educational course on manuscript preparation and several postgraduate courses. Office Bearers representing the American Thoracic Society, European Respiratory Society and ACCP, amongst others, made significant contributions, further enhancing the high-quality faculty.

Effects of elastase inhibitor on the epithelial cell apoptosis in bleomycin-induced pulmonary fibrosis.

Alveolar epithelial cell injury and apoptosis is consistent findings in human idiopathic pulmonary fibrosis (IPF). Epithelial cell apoptosis is known to be induced by leukocyte elastase in vitro. The authors hypothesized that synthetic neutrophil elastase inhibitor, sivelestat (ONO-5046), can inhibit the bleomycin-induced pulmonary fibrosis in rats by blocking the apoptotic pathways in epithelial cells. Adult rats were injected with intratracheal bleomycin. Sivelestat was given for 13 days intraperitoneally after bleomycin treatments. Similar experiments were carried out in which A549 cells, a human alveolar type II epithelial cell line, were treated with bleomycin or neutrophil elastase. In rats, sivelestat decreased neutrophil counts and the cytokine-induced neutrophil chemoattractant (CINC)-1 in the bronchoalveolar lavage (BAL) fluid of bleomycin-treated rats. Sivelestat also decreased the bleomycin-induced lung inflammatory cell apoptosis by decreasing caspase-3 and -9 activities. In A549 cells, sivelestat decreased the elastase-induced epithelial cell apoptosis but not the bleomycin-induced epithelial cell apoptosis. Similarly, sivelestat inhibited the elastase-induced cell death but not the bleomycin-induced cell death in MTT assays. Sivelestat also inhibited the elastase-induced caspase-3 and -9 activities and cytochrome c release from the mitochondria but did not inhibit the bleomycin-induced caspase activities in A549 cells. In conclusion, bleomycin caused the lung inflammatory cell apoptosis through the caspase-9 and -3 pathways in rats. Sivelestat inhibited pulmonary fibrosis by blocking these mitochondria-mediated apoptotic pathways in bleomycin-treated rats and in elastase-treated A549 cells. These findings suggest that sivelestat can suppress the bleomycin-induced pulmonary fibrosis by blocking neutrophil chemotaxis and by inhibiting the neutrophil elastase-induced lung cell apoptosis in rats.