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Background and Aims: To examine whether smoking habits, including smoking amount and cessation duration at baseline, are associated with atherosclerosis progression., Methods: At baseline (2006-08, Japan), we obtained smoking status, amount of smoking and time since cessation for quitters in a community-based random sample of Japanese men initially aged 40-79 years and free of cardiovascular disease. Coronary artery calcification (CAC) and aortic artery calcification (AAC) as biomarker of atherosclerosis was quantified using Agatston's method at baseline and after 5 years of follow-up. We defined progression of CAC and AAC (yes/no) using modified criteria by Berry., Results: A total of 781 participants was analyzed. Multivariable adjusted odds ratios (ORs) of CAC and AAC progression for current smokers were 1.73 (95% CI, 1.09-2.73) and 2.47 (1.38-4.44), respectively, as compared to never smokers. In dose-response analyses, we observed a graded positive relationship of smoking amount and CAC progression in current smokers (multivariable adjusted ORs: 1.23, 1.72, and 2.42 from the lowest to the highest tertile of pack-years). Among the former smokers, earlier quitters (≥10.7 years) had similar ORs of the progression of CAC and AAC to that of participants who had never smoked., Conclusions: Compared with never smokers, current smokers especially those with greater pack-years at baseline had higher risk of atherosclerosis progression in community-dwelling Japanese men. Importantly, the residual adverse effect appears to be present for at least ten years after smoking cessation. The findings highlight the importance of early avoidance or minimizing smoking exposure for the prevention of atherosclerotic disease., Competing Interests: Declaration of competing interest We do not have conflicts of interest to disclose. Funding support Our study has been supported by Grants-in-aid for Scientific Research (A) 13307016, (A) 17209023, (A) 21249043, (A) 23249036, (A) 25253046, (A) 15H02528, (A) 15H04773, (B) 26293140, (B) 23390174, and (C) 23590790 from the Ministry of Education, Culture, Sports, Science, and Technology Japan, and by grant R01HL 068200 from Glaxo-Smith Klein., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: The mechanisms by which exercise reduces the risk of coronary heart disease remain poorly understood. Irisin, an exercise-induced polypeptide secreted from skeletal muscles, is proposed to potentially mediate beneficial effects of exercise, especially in metabolic regulation and development of atherosclerosis. We examined whether higher serum irisin levels are associated with lower prevalence and progression of coronary atherosclerosis., Methods and Results: We performed a prospective, population-based study of Japanese men aged 40-79 years without known coronary heart disease. We measured baseline serum irisin levels using an enzyme-linked immunosorbent assay and quantified coronary artery calcification (CAC) from serial computed tomography scans. Of 1038 participants (mean age, 63.9 years) at baseline, 670 (64.6%) had prevalent CAC. Of 810 participants at follow-up (median, 5.1 years), 407 (50.3%) experienced CAC progression. In Poisson regression with robust error variance adjusted for age and behavioral factors, serum irisin levels were inversely associated with CAC prevalence (relative risk [RR] of 4th versus 1st quartiles [95% confidence interval], 0.88 [0.78-0.99]; trend P = 0.016) and CAC progression (RR, 0.76 [0.63-0.91]; trend P = 0.002). After further adjustment for cardiometabolic risk factors, the inverse association with CAC prevalence disappeared (RR, 0.95 [0.84-1.08]; trend P = 0.319), but that with CAC progression persisted (RR, 0.77 [0.64-0.93]; trend P = 0.003). These associations were consistent when we applied ordinal logistic regression and across subgroups by cardiometabolic risk factor status., Conclusions: Higher serum irisin levels were associated with less burden of coronary atherosclerosis. This association would be mediated through and beyond traditional cardiometabolic pathways., (Copyright © 2018. Published by Elsevier B.V.)

Background: Low-density lipoprotein particle (LDL-P) has recently been found to be a stronger predictor of cardiovascular disease (CVD) than LDL-cholesterol (LDL-C)., Objectives: Whether LDL-P is associated with subclinical atherosclerosis, independent of LDL-C, as well as other lipid measures has not been fully examined. We aimed to analyze LDL-P associations with measures of subclinical atherosclerosis., Methods: We examined 870 Japanese men randomly selected from Kusatsu City, Shiga, Japan, aged 40-79 years from 2006-2008, free of clinical CVD and not using lipid-lowering medication. Cross-sectional associations of lipid measures with carotid intima-media thickness (cIMT) and coronary artery calcification (CAC; >0 Agatston score) were examined., Results: LDL-P was significantly positively associated with cIMT and maintained this association after adjustments for LDL-C and other lipid measures. Although these lipid measures were positively associated with cIMT, model adjustment for LDL-P removed any significant relationships. Higher LDL-P was associated with a significantly higher odds ratio of CAC and further adjustment for LDL-C did not affect this relationship. In contrast, the LDL-C association with CAC was no longer significant after adjustment for LDL-P. Other lipid measures attenuated associations of LDL-P with CAC. Likewise, associations of these measures with CAC were attenuated when model adjustments for LDL-P were made., Conclusions: In a community-based sample of Japanese men, free of clinical CVD, LDL-P was a robust marker for subclinical atherosclerosis, independent of LDL-C and other lipid measures. Associations of LDL-C and other lipid measures with either cIMT or CAC were generally not independent of LDL-P., Competing Interests: None., (Copyright © 2016 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Objective: Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an enzyme predominantly bound to low-density lipoprotein (LDL). Lp-PLA2 is recognized as playing a key role in inflammatory processes and the development of atherosclerosis. This study aimed to investigate whether Lp-PLA2 is related to subclinical atherosclerosis, independently from traditional risk factors, in a general Japanese population by analyses of both the observational study and Mendelian randomization using V279F polymorphism., Methods and Results: We cross-sectionally examined community-based sample of 929 Japanese men aged 40-79 years, without statin treatment, who were randomly selected from the resident registration. Multiple regression analyses of Lp-PLA2 activity and concentration were undertaken separately for men aged 40-49 years and 50-79 years, to clarify interactions of age and Lp-PLA2. Lp-PLA2 activity for men aged 50-79 years was significantly and positively related to intima-media thickness (IMT) (P = 0.013) and plaque index (P = 0.008) independent of traditional risk factors including small LDL particles, but not to coronary artery calcification (CAC) score. Associations with Lp-PLA2 concentration were qualitatively similar to those of activity. Corresponding relationships were not observed in men aged 40-49 years. Mendelian randomization analyses based on V279F genotype did not show any significant associations with subclinical atherosclerosis, although the homozygote and heterozygote of V279F showed low Lp-PLA2 activity and concentration., Conclusions: Lp-PLA2 activity in Japanese men aged 50-79 years was associated significantly and positively with IMT and plaque in the carotid artery but Mendelian randomization did not support that Lp-PLA2 is a causative factor for subclinical atherosclerosis., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Objective: The utility of lipoprotein particle profiles measured by nuclear magnetic resonance (NMR) spectroscopy beyond standard serum lipids remains inconclusive. Furthermore, few studies have compared NMR measurements with standard lipids in association with coronary artery calcification (CAC) in Japanese, where the coronary atherosclerotic burden is low. We examined whether NMR-based lipoprotein particle profiles are associated with CAC, and compared them with standard lipid and lipid ratios in the Japanese general population., Methods and Results: We conducted a cross-sectional study in 851 men aged 40-79 years without cardiovascular diseases and lipid-lowering therapies. Adjusted odds ratios (ORs) (95% confidence intervals) for the top versus the bottom quartile of NMR-measured particle concentrations were 2.01 (1.24-3.23) for low-density lipoprotein (LDL-P), 1.04 (0.62-1.75) for high-density lipoprotein (HDL-P), 1.82 (1.13-2.95) for very-low-density lipoprotein (VLDL-P), and 1.92 (1.18-3.17) for LDL-P/HDL-P ratio. Similarly adjusted ORs of NMR-measured particle sizes were 0.59 (0.36-0.97) for LDL-P, 0.66 (0.40-1.10) for HDL-P, and 0.67 (0.40-1.12) for VLDL-P. The corresponding ORs were 1.82 (1.14-2.90) for total cholesterol (TC), 2.06 (1.28-3.30) for low-density lipoprotein cholesterol (LDL-C), 0.56 (0.34-0.91) for high-density lipoprotein cholesterol (HDL-C), 2.02 (1.24-3.29) for triglycerides, 2.08 (1.29-3.36) for non-high-density lipoprotein cholesterol (non-HDL-C), 2.27 (1.37-3.78) for TC/HDL-C ratio, and 1.73 (1.06-2.85) for LDL-C/HDL-C ratio. After mutual adjustment for total LDL-P concentration and TC/HDL-C ratio or non-HDL-C, LDL-P was no longer associated, whereas TC/HDL-C ratio remained significantly associated with CAC., Conclusions: In community-based Japanese men, the overall association of CAC with NMR-measured lipoprotein indices is comparable, but not superior, to that with standard lipids., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: We recently reported that Japanese had higher liver fat at a lower level of BMI compared with non-Hispanic whites (NHW)., Objective: We hypothesize that ethnic difference in fat storage capacity contributes to this ethnic difference in liver fat., Design: To examine this, we assessed liver fat among 244 Japanese-American aged 40-49, using regional computed-tomography images, along with metabolic variables., Results: Despite the similar BMI between Japanese-Americans and NHW men, Japanese-Americans had more liver fat (liver to spleen attenuation ratio: 1.03 ± 0.22 for Japanese-Americans, and 1.07 ± 0.15 for NHW men; p < 0.05) and tended to have a greater disposition for fatty liver with an increase in BMI than NHW, indicating a clear difference between the two groups. In addition, liver fat is less in Japanese-Americans compared with Japanese men (1.03 ± 0.22 vs. 1.01 ± 0.16; p < 0.05), despite of a much higher BMI. These ethnic differences support the hypothesis that higher fat storage capacity indeed seems to be associated with less liver fat. In all the groups, liver fat content strongly correlated with triglycerides, homeostasis model assessment-insulin resistance, and C-reactive protein (CRP). Nevertheless, these metabolic variables were worse in Japanese-Americans, despite of less liver fat, compared with Japanese. Moreover, CRP levels were least among Japanese with highest liver fat, and highest among NHW men with least liver fat, despite of a strong positive association between CRP and fatty liver within each population., Conclusions: Fat content in the liver is intermediate for Japanese-Americans compared with Japanese and NHW men, which supports the hypothesis of less fat storage capacity among Japanese, closely linked to ethnic difference in predisposition to fatty liver., (© 2011 Asian Oceanian Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.)

Background: The association of serum polyunsaturated fatty acids (PUFAs) with lipids in different populations is not known., Objective: Our aim was to examine the association of serum n-6 (omega-6) or n-3 (omega-3) PUFAs with triglycerides or HDL-cholesterol concentrations in 261 white, 285 Japanese, and 212 Japanese American men aged 40-49 y., Design: We used a population-based cross-sectional study. Of the original sample (n = 926), those taking lipid-lowering medications or who had diabetes (n = 168) were excluded. Serum fatty acids were analyzed by capillary gas-liquid chromatography. Multiple regression models as a function of tertile groups of each PUFA were used., Results: Serum n-6 PUFAs were significantly inversely associated with triglycerides across populations after adjustment for age, body mass index, pack-years of smoking, and ethanol consumption [beta = -0.39 (P < 0.001), -0.38 (P < 0.001), and -0.33 (P < 0.001) in whites, Japanese, and Japanese Americans, respectively]. Marine n-3 PUFAs were significantly inversely associated with triglycerides across populations [beta = -0.15 (P < 0.001), -0.22 (P < 0.001), and -0.13 (P < 0.001) in whites, Japanese, and Japanese Americans, respectively]. n-6 PUFAs were significantly positively associated with HDL cholesterol in whites (beta = 4.49, P < 0.001) and Japanese (beta = 3.73, P < 0.01). Marine n-3 PUFAs were significantly positively associated with HDL cholesterol in Japanese (beta = 2.15, P < 0.05), and eicosapentaenoic acid was significantly positively associated with HDL cholesterol in whites (beta = 2.68, P < 0.01)., Conclusion: Serum n-6 and n-3 PUFAs are inversely associated with triglycerides across populations.