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Purpose: This study aimed to investigate the relationships of moderate-to-vigorous physical activity (MVPA) with all-cause and disease-specific mortality. We also investigated how the association between MVPA at leisure time (LT-MVPA) and health outcomes differs at different MVPA at work (WT-MVPA) levels., Methods: The 81,601 community-dwelling Japanese persons age 50-79 yr who responded to a questionnaire in 2000-2003 were followed until 2018. Cox proportional hazard model was used to examine the association of total MVPA with risks of all-cause, cancer, heart disease, stroke, and respiratory disease mortality. Then, we compared the mortality risk according to the tertile of LT-MVPA, stratified by the tertile of WT-MVPA., Results: During the 15.1 yr of average follow-up, 16,951 deaths were identified. Even total MVPA below the recommended volume (i.e., 0.1-1.49 MET·h·d -1 ) was associated with 11% to 24% reductions in all-cause (hazard ratio [HR], 0.89; 95% confidence interval [CI], 0.82-0.96) and heart disease mortality (HR, 0.76; 95% CI, 0.61-0.94), compared with no MVPA at all. The further reduced risks were seen in MVPA up to 10 MET·h·d -1 . The inverse association between LT-MVPA and mortality risks was more evident at lower WT-MVPA, which was also inversely associated with the risks., Conclusions: Health benefits were observed at low levels of MVPA and up to 10 MET·h·d -1 , although the fine threshold for excessive MVPA was not clear. LT-MVPA had distinct health benefits especially for persons with lower WT-MVPA., (Copyright © 2023 by the American College of Sports Medicine.)

Rationale: A cervical pedicle screw (CPS) serves as an important anchor for cervical surgeries. Its placement requires the development of a highly safe and easy-to-handle method. Considering that the lateral end of the cortical bone of the spinal canal (LE point) is the most crucial for CPS placement, we devised a U-shaped wire capable of identifying LE points under direct vision and reliably confirming the site with C-arm lateral fluoroscopy., Patient Concerns: A 65-year-old male, who had been aware of numbness in both hands, mild finger dexterity disorder, and gait disturbance for half a year, visited our hospital due to the progression of his symptoms in the previous 2 months., Diagnosis: The patient presented with mild muscle weakness and tendon hyperreflexia in the upper and lower extremities on both sides, and magnetic resonance imaging revealed moderate spinal canal stenosis at the C4/5 and 5/6 levels. Based on the local third cervical vertebra (C3)/4 angle of -10 degrees and the C2/7 angle of -15 degrees, the patient was diagnosed with cervical myelopathy with cervical kyphosis. He had a Japanese Orthopaedic Association score for cervical myelopathy of 10., Interventions: We placed CPSs at C3 using a U-shaped wire. After placing an anchor in the range of C3-T1, laminectomy from C4 to C7 was performed. Subsequently, corrective fixation was performed to reduce kyphosis, followed by bone grafting in the range of C3-T1 and complete posterior cervical decompression fixation., Outcomes: The CPSs were placed at C3 without deviation and intra- or postoperative complications. The surgery resulted in improvement in kyphosis with a C2/7 angle of -5 degrees and recovery in spinal cord disorder with a Japanese Orthopedic Association score for cervical myelopathy of 13., Lessons: A U-shaped wire, which can be prepared inexpensively and easily, is a useful tool, especially for inexperienced surgeons, for safe CPS placement by capture of LE points accurately., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background and Purpose: Several prospective cohort studies and a randomized clinical trial have shown the beneficial effects of peanut consumption on cardiovascular disease and its risk factors. We examined the association between peanut consumption and risk of cardiovascular disease in Japanese men and women., Methods: We analyzed data of 74 793 participants aged 45 to 74 years who completed a lifestyle questionnaire including the validated food frequency questionnaire in the Japan Public Health Center–based Prospective Study. They were followed up from 1995 to 2009 for cohort I and from 1998 to 1999 to 2012 for cohort II. Peanut consumption was calculated from the food frequency questionnaire, and the end points were incidence of stroke, ischemic heart disease, and cardiovascular disease (stroke and ischemic heart disease)., Results: During a median follow-up of 14.8 years, 3,599 strokes and 849 ischemic heart diseases were reported. Higher peanut consumption was associated with reduced risks of total stroke, ischemic stroke, and cardiovascular disease among men and women. The multivariable hazard ratios (95% CIs) for the highest versus lowest quartiles of peanut consumption after adjustment for age, sex, public health center, smoking, alcohol consumption, perceived stress level, physical activity, vegetable, fruit, fish, soy, sodium and total energy intakes, body mass index, history of hypertension, history of diabetes, and cholesterol-lowering drug were 0.84 (0.77–0.93, P for trend=0.002) for total stroke, 0.80 (0.71–0.90, P for trend=0.002) for ischemic stroke, 0.93 (0.79–1.08, P for trend=0.27) for hemorrhagic stroke, 0.97 (0.80–1.17, P for trend=0.81) for ischemic heart disease and 0.87 (0.80–0.94, P for trend=0.004) for cardiovascular disease, and these associations were similarly observed in both sexes., Conclusions: Higher peanut consumption was associated with reduced risk of stroke, especially ischemic stroke, but not ischemic heart disease in Japanese men and women.

Objective: To investigate the relation between body mass index (BMI) and dry eye disease (DED)., Methods: We conducted a cross-sectional questionnaire-based survey in 85,264 Japanese men and women aged 40 to 74 years who participated in the Japan Public Health Center-based Prospective Study for the Next Generation (JPHC-NEXT Study). Dry eye disease was defined as the presence of severe symptoms or clinical diagnosis. A multivariable logistic regression model was used to estimate the odds ratios (ORs) of DED associated with BMI and their two-sided 95% confidence intervals (CIs). We adjusted for age, cohort area, visual display terminal time, smoking status, alcohol intake, education status, income status, as well as history of hormone replacement therapy for women., Results: Prevalence of DED was 23.4% (n = 19,985; 6,289 men, 13,696 women). Higher BMI was correlated with a lower prevalence of DED in a dose-response fashion, with an adjusted OR of DED (95% CI) per 1 kg/m2 increment of BMI of 0.98 (95% CI: 0.97-0.99) for men and 0.97 (95% CI: 0.97-0.98) for women., Conclusions: This large population-based study showed an inverse relationship between BMI and prevalence of DED in a Japanese population. Underestimation of DED is warned, especially for participants with high BMI., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2021 Contact Lens Association of Ophthalmologists.)

Background: Genome-wide association studies provided many biological insights into coronary artery disease (CAD), but these studies were mainly performed in Europeans. Genome-wide association studies in diverse populations have the potential to advance our understanding of CAD., Methods: We conducted 2 genome-wide association studies for CAD in the Japanese population, which included 12 494 cases and 28 879 controls and 2808 cases and 7261 controls, respectively. Then, we performed transethnic meta-analysis using the results of the coronary artery disease genome-wide replication and meta-analysis plus the coronary artery disease 1000 Genomes meta-analysis with UK Biobank. We then explored the pathophysiological significance of these novel loci and examined the differences in CAD-susceptibility loci between Japanese and Europeans., Results: We identified 3 new loci on chromosome 1q21 ( CTSS ), 10q26 ( WDR11-FGFR2 ), and 11q22 ( RDX - FDX1 ). Quantitative trait locus analyses suggested the association of CTSS and RDX - FDX1 with atherosclerotic immune cells. Tissue/cell type enrichment analysis showed the involvement of arteries, adrenal glands, and fat tissues in the development of CAD. We next compared the odds ratios of lead variants for myocardial infarction at 76 genome-wide significant loci in the transethnic meta-analysis and a moderate correlation between Japanese and Europeans, where 8 loci showed a difference. Finally, we performed tissue/cell type enrichment analysis using East Asian-frequent and European-frequent variants according to the risk allele frequencies and identified significant enrichment of adrenal glands in the East Asian-frequent group while the enrichment of arteries and fat tissues was found in the European-frequent group. These findings indicate biological differences in CAD susceptibility between Japanese and Europeans., Conclusions: We identified 3 new loci for CAD and highlighted the genetic differences between the Japanese and European populations. Moreover, our transethnic analyses showed both shared and unique genetic architectures between the Japanese and Europeans. While most of the underlying genetic bases for CAD are shared, further analyses in diverse populations will be needed to elucidate variations fully.

We aimed to assess the association between cruciferous vegetable intake and colorectal cancer (CRC) development among Japanese adults aged between 45 and 74 years in the Japan Public Health Center-based Prospective Study. During 1 325 853 person-years of follow-up, 2612 CRC cases were identified. The association of cruciferous vegetable intake with CRC risk was assessed using a Cox proportional hazard regression model to compute hazard ratios (HRs) and 95% confidence intervals (CIs), adjusted for potential confounders. No significant association was observed between the highest cruciferous vegetable intake quartile (compared with the lowest) and CRC risk in men (multivariate HRs: 1.08; 95% CI: 0.91, 1.29) and women (multivariate HRs: 0.99; 95% CI: 0.80, 1.22) and its subsites. Women showed a marginal negative association between cruciferous vegetable intake and the risk of colon cancer (CC) after excluding participants who developed CC in the first 3 years of follow-up (P for trend = 0.08); a positive association was found with proximal CC in men. Cruciferous vegetable intake does not have a significant association with CRC risk in the Japanese general population.

Evidence on the association between BMI, height, and endometrial cancer risk, including by subtypes, among Asian populations remains limited. We evaluated the impact of BMI and height on the risk of endometrial cancer, overall and by histological subtype. We prospectively investigated 53 651 Japanese women aged 40-69 years. With an average follow-up duration of 18.6 years, 180 newly diagnosed endometrial cancers were reported, including 119 type 1 and 21 type 2. The association between BMI, height, and endometrial cancer risk was assessed using a Cox proportional hazards regression model with adjustment for potential confounders. Overweight and obesity were associated positively with the risk of endometrial cancer. Compared with BMI of 23.0-24.9 kg/m, hazard ratios (HRs) (95% confidence intervals) were 1.93 (1.17-3.16) for BMI of 27.0-29.9 kg/m and 2.37 (1.20-4.66) for BMI of at least 30.0 kg/m. On analysis by histological subtype, with each increase in BMI of 5 U, the estimated HR of type 1 endometrial cancer increased (HR=1.54, 95% confidence interval: 1.21-1.98), but HR of type 2 endometrial cancer was unaffected. There was no statistically significant association between height and endometrial cancer risk. In conclusion, the risk of endometrial cancer was elevated in women with a BMI of at least 27.0 kg/m. By histological subtype, BMI was associated with type 1, but not type 2 endometrial cancer risk among a population with a relatively low BMI compared with western populations.

The association between plasma C-peptide concentration and prostate cancer is unclear. Inconsistency of results from previous studies motivates this study. Using the Japan Public Health Center-based Prospective study, 201 prostate cancer cases and 402 controls were matched by age, public health center area, residence, date and time of blood collection, and fasting duration before blood collection. Odds ratios (OR) and 95% confidence intervals (CIs) were estimated by conditional logistic regression models. Out of 201 cases, 144 were localized and 48 were advanced. The overall association between median plasma C-peptide concentration and prostate cancer was not significant (OR for the highest tertile=0.81, 95% CI: 0.43-1.56, P-trend=0.54). Although stratification of prostate cancer by stage indicated different effects of plasma C-peptide on localized and advanced cases, there was no association between plasma C-peptide concentration and advanced prostate cancer (OR=2.82, 95% CI: 0.30-26.36 for the highest category, P-trend=0.37) and localized cases (OR=0.49, 95% CI: 0.23-1.04 for the highest category, P-trend=0.06) for patients fasting at the time of blood collection. The association between plasma C-peptide concentration and prostate cancer risk differed by cancer stage. Differentiation of localized and advanced prostate cancer cases is crucial when investigating the association between plasma C-peptide concentration and the risk of prostate cancer.

The aim of this study was to evaluate the associations between menstrual and reproductive factors and thyroid cancer risk among Japanese women. A total 54 776 women aged 40-69 years completed a self-administered questionnaire, which included menstrual and reproductive history. During 1990-2012, 187 newly diagnosed cases of thyroid cancer were identified. Hazard ratios (HRs) and 95% confidence intervals (CIs) for menstrual and reproductive factors and incidence of thyroid cancer were estimated using Cox proportional hazards regression. Postmenopausal women who had natural menopause were at reduced risk of thyroid cancer than premenopausal women in the age-area-adjusted model (HR: 0.62 per 1 year increase, 95% CI: 0.39-0.99), but this association was slightly attenuated and no longer statistically significant in the multivariable-adjusted model. On analysis by menopausal status, an inverse association between age at menarche and risk of thyroid cancer was observed for premenopausal women (HR: 0.83 per 1 year increase, 95% CI: 0.70-0.98, P trend=0.03), but not for postmenopausal women. The risk of thyroid cancer increased with surgical menopause compared with natural menopause (HR: 2.34, 95% CI: 1.43-3.84). Although increasing age at menopause and duration of fertility were associated with an increased risk of thyroid cancer, this association was not observed among postmenopausal women. This study confirmed that early age at menarche for premenopausal women and surgical menopause and late age at natural menopause for postmenopausal women were associated with the development of thyroid cancer. Our results support the hypothesis that exposure to estrogens increases the risk of thyroid cancer.

Purpose: Physical activity guidelines recommend at least 150 min of moderate-intensity physical activity (MPA), 75 min of vigorous-intensity physical activity (VPA), or combination of MPA and VPA. However, few epidemiological studies have examined whether the general population can derive equal health benefits from MPA or VPA. This study examined the associations of different activity intensities with mortality., Methods: In this prospective cohort study, a total of 83,454 community-dwelling Japanese who answered a questionnaire in 2000-2003 were followed for all-cause mortality through 2012. Subjects were classified into four groups by physical activity guidelines and also by the proportion of VPA to total MVPA, that is, physically inactive, physically active without any VPA (0% VPA), and active with some VPA (30% or less) or with more VPA (more than 30%). Hazard ratios of all-cause mortality were calculated with adjustment for potential confounders including physical activity volume., Results: During 894,718 person-years of follow-up, 8891 deaths were identified. Compared with physically inactive subjects, the adjusted hazard ratios for all-cause mortality were 0.75 (95% confidence interval, 0.68-0.83), 0.73 (0.65-0.82), and 0.74 (0.62-0.89) among men, and 0.71 (0.62-0.81), 0.75 (0.64-0.88), and 0.74 (0.58-0.94) among women. For "0% VPA," "30% or less" and "more than 30%," respectively., Conclusions: Meeting the guidelines in either pattern of physical activity is important for lowering mortality risk. It may be suggested that people can receive comparable health benefit by MPA or VPA as long as they meet the guideline.

The effects of cigarette smoking and alcohol drinking on the incidence of oral cavity and pharyngeal cancer (OCPC) in the Asian population have been poorly understood. To assess the effects of cigarette smoking, alcohol drinking, and facial flushing response on incidence of OCPC, a total of 95 525 middle-aged and older eligible individuals were followed in a large-scale population-based cohort study in Japan from 1990 to 2010. In this study, the person-years of observation were 698 006 in men and 846 813 in women, and a total of 222 cases (men=160, women=62) of OCPC were newly diagnosed during the study period. A multivariate Cox proportional-hazards model was used to assess the incidence risk of OCPC and subsites by cigarette smoking and alcohol drinking. The result showed that cigarette smoking and regular alcohol drinking were associated significantly with the incidence of OCPC in men. Compared with nonsmokers and nondrinkers, current male smokers showed a hazard ratio (HR) of 2.37 [95% confidence interval (CI)=1.51-3.70] and regular male drinkers showed an HR of 1.82 (95% CI=1.20-2.76). Cigarette smoking also increased the risk of OCPC among male heavy alcohol drinkers (HR=4.05, 95% CI=2.31-7.11). However, there was no significant association between facial flushing response and OCPC. In conclusion, cigarette smoking and alcohol drinking are independent risk factors for OCPC and its subsites in the male Japanese population.

Background: Appropriate initial dosing of vancomycin (VCM) is important in improving survival and in preventing nephrotoxicity in critically ill patients, but the potential relationship between initial VCM trough levels and early-onset nephrotoxicity remains unclear. We examined the relationship between initial VCM trough levels and early-onset VCM-associated nephrotoxicity., Methods: We performed a retrospective study of patients who had therapeutic drug monitoring of VCM with initial trough levels within 4 days after the beginning of VCM administration. We excluded patients who received renal replacement therapy from 2 days before to 7 days after the beginning of VCM administration, were younger than 18 years, or had renal dysfunction before the beginning of VCM administration. Early-onset VCM-associated nephrotoxicity was defined as an increase in serum creatinine level of ≥0.5 mg/dL (44.2 μmol/L) or 50% above baseline for 2 or more consecutive days within 7 days after the beginning of VCM administration., Results: Among 109 enrolled patients, 13 patients had early-onset VCM-associated nephrotoxicity. Its incidence rate was 31.3% in patients with initial trough levels of ≥20g/mL, which was significantly higher than 6.3% in patients with initial trough levels of <10 mg/L. Multiple logistic regression analysis demonstrated that early-onset VCM-associated nephrotoxicity was associated with initial trough levels of ≥20 mg/L (odds ratio, 5.0; 95% confidence interval, 1.3-19.1) and with vasopressor use (odds ratio, 5.0; 95% confidence interval, 1.3-19.1). Kaplan-Meier analysis showed that the probability of nonnephrotoxicity for patients with initial VCM trough levels of ≥20 mg/L was lower compared with patients with trough levels of <15 mg/L., Conclusions: Initial trough levels of ≥20 mg/L but not ≥15 mg/L were associated with early-onset VCM-associated nephrotoxicity in critically ill patients. Future prospective studies are needed to examine outcomes in critically ill patients achieving initial VCM trough levels of 15-20 mg/L.

An association between female reproductive factors, exogenous hormone use, and pancreatic cancer risk has long been suggested in laboratory settings, but epidemiological findings remain mixed and inconclusive. Studies carried out on Asian populations are also limited. In this study, 45 617 women aged 40-69 years were followed for an average of 18.4 years in the Japan Public Health Center-based prospective cohort and 211 pancreatic cases were identified as of 31 December 2011. We applied multivariate-adjusted Cox proportional hazards regression models using age as a time-scale to assess the association between female reproductive factors (menstrual status, menarche age, menopause age, number of births, age at first birth, total years of fertility, history of breastfeeding) and exogenous hormone use with the incidence of pancreatic cancer through hazard ratios and confidence intervals. No significant associations were found between our examined female reproductive factors and pancreatic cancer incidence. The use of exogenous hormones was found to be associated with an increased risk of pancreatic cancer in a multivariate-adjusted model (hazard ratio: 1.47; 95%; confidence interval: 1.00-2.14) in the Japanese female population. Our results suggest that exogenous hormones may play a role in the formation of pancreatic cancer, and further prospective studies are warranted for clarification.

Background and Purpose: There is limited evidence on the association between total physical activity and stroke in Asian populations experiencing a greater burden of hemorrhagic stroke than Western populations. We aimed to understand their optimal level of physical activity for stroke prevention., Methods: A total of 74 913 Japanese people 50 to 79 years of age without histories of cardiovascular disease or cancer were followed from 2000 to 2012., Results: During the 698 946 person-years of follow-up, we documented a total of 2738 incident cases of stroke, including 1007 hemorrhagic strokes (747 intraparenchymal and 260 subarachnoid hemorrhages) and 1721 ischemic strokes (1206 nonembolic and 515 embolic infarctions). Individuals in the second or third metabolic equivalents of task-hours per day quartile had the lowest risks of total stroke (hazard ratio [HR], 0.83; 95% confidence interval [CI], 0.75-0.93), intraparenchymal hemorrhage (HR, 0.79; 95% CI, 0.64-0.97), subarachnoid hemorrhage (HR, 0.78; CI, 0.55-1.11), and nonembolic infarction (HR, 0.78; CI, 0.67-0.92), whereas those in the fourth quartile had the lowest risk of embolic infarction (HR, 0.76; CI, 0.59-0.97). Cubic spline graphs revealed a steep decrease in stroke risk (30% risk reduction) from the lowest level to a plateau at 5 to 10 metabolic equivalents of task-hours per day (50th percentile). The associations of total physical activity level with hemorrhage stroke showed U or J shape, which were because of vigorous-intensity activities, whereas the association with ischemic stroke showed L shape., Conclusions: For Japanese people, moderate levels of total physical activity, particularly achieved by moderate-intensity activities, may be optimal for stroke prevention because excessive vigorous-intensity activities might not be beneficial or even disadvantageous for prevention of hemorrhagic stroke., (© 2017 American Heart Association, Inc.)

Reproductive/menstrual factors may be involved in the etiology of gallbladder cancer (GBC) and bile duct cancer (BDC). However, the results from previous epidemiological studies have been inconsistent. We investigated the association of reproductive/menstrual factors with the risk for GBC and BDC in a population-based prospective cohort study in Japan. Data on reproductive/menstrual factors were collected through a self-administered questionnaire at baseline. The hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using the Cox proportional hazard model. A total of 55 786 women enrolled between 1990 and 1994 were included in the analysis, and 115 GBC and 113 BDC cases were identified, with 944 861 person-years follow-up until 2010. For GBC, irregular and longer cycles were moderately associated with an increased risk [HR=2.12 (95% CI: 1.30-3.47) and HR=1.76 (95% CI: 1.08-2.89), respectively]. This effect tended to be greater in premenopausal than in postmenopausal women. Furthermore, older age at first pregnancy tended to be associated with an increased risk [HR=1.84 (95% CI: 1.03-3.29), P-trend=0.036], whereas increased duration of fertility tended to be associated with a decreased risk [HR=0.59 (95% CI: 0.35-1.01), P-trend=0.055] of GBC. No clear association with BDC was observed. This finding suggests that women with irregular or longer cycles may have an increased risk for GBC and female hormones may play an important role in the etiology of GBC.

Background and Purpose: Because of limited evidence, we investigated a long-term impact of changes in employment status on risk of stroke., Methods: This was a prospective study of 21 902 Japanese men and 19 826 women aged 40 to 59 years from 9 public health centers across Japan. Participants were followed up from 1990 to 1993 to the end of 2009 to 2014. Cox proportional hazard ratio of stroke (incidence and mortality) and its types (hemorrhagic and ischemic) was calculated according to changes in the employment status within 5 years interval between 1990 to 1993 and 1995 to 1998 (continuously employed, job loss, reemployed, and continuously unemployed)., Results: During the follow-up period, 973 incident cases and 275 deaths from stroke in men and 460 cases and 131 deaths in women were documented. Experiencing 1 spell of unemployment was associated with higher risks of morbidity and mortality from total, hemorrhagic, and ischemic stroke in both men and women, even after propensity score matching. Compared with continuously employed subjects, the multivariable hazard ratio (95% confidence interval) for total stroke incidence in job lost men was 1.58 (1.18-2.13) and in job lost women was 1.51 (1.08-2.29), and those for total stroke mortality were 2.22 (1.34-3.68) in men and 2.48 (1.26-4.77) in women. The respective hazard ratio (95% confidence interval) in reemployed men was 2.96 (1.89-4.62) for total stroke incidence and 4.21 (1.97-8.97) for mortality, whereas those in reemployed women were 1.30 (0.98-1.69) for incidence and 1.28 (0.76-2.17) for mortality., Conclusions: Job lost men and women and reemployed men had increased risks for both hemorrhagic and ischemic stroke incidence and mortality., (© 2017 American Heart Association, Inc.)

Background and Purpose: The prediction of genetic predispositions to ischemic stroke (IS) may allow the identification of individuals at elevated risk and thereby prevent IS in clinical practice. Previously developed weighted multilocus genetic risk scores showed limited predictive ability for IS. Here, we investigated the predictive ability of a newer method, polygenic risk score (polyGRS), based on the idea that a few strong signals, as well as several weaker signals, can be collectively informative to determine IS risk., Methods: We genotyped 13 214 Japanese individuals with IS and 26 470 controls (derivation samples) and generated both multilocus genetic risk scores and polyGRS, using the same derivation data set. The predictive abilities of each scoring system were then assessed using 2 independent sets of Japanese samples (KyushuU and JPJM data sets)., Results: In both validation data sets, polyGRS was shown to be significantly associated with IS, but weighted multilocus genetic risk scores was not. Comparing the highest with the lowest polyGRS quintile, the odds ratios for IS were 1.75 (95% confidence interval, 1.33-2.31) and 1.99 (95% confidence interval, 1.19-3.33) in the KyushuU and JPJM samples, respectively. Using the KyushuU samples, the addition of polyGRS to a nongenetic risk model resulted in a significant improvement of the predictive ability (net reclassification improvement=0.151; P<0.001)., Conclusions: The polyGRS was shown to be superior to weighted multilocus genetic risk scores as an IS prediction model. Thus, together with the nongenetic risk factors, polyGRS will provide valuable information for individual risk assessment and management of modifiable risk factors., (© 2016 The Authors.)

Objective: Fatty acid-binding protein 4 (FABP4) is expressed in adipocytes and macrophages, and elevated circulating FABP4 level is associated with obesity-mediated metabolic phenotype. We systematically investigated roles of FABP4 in the development of coronary artery atherosclerosis., Approach and Results: First, by immunohistochemical analyses, we found that FABP4 was expressed in macrophages within coronary atherosclerotic plaques and epicardial/perivascular fat in autopsy cases and macrophages within thrombi covering ruptured coronary plaques in thrombectomy samples from patients with acute myocardial infarction. Second, we confirmed that FABP4 was secreted from macrophages and adipocytes cultured in vitro. Third, we investigated the effect of exogenous FABP4 on macrophages and human coronary artery-derived smooth muscle cells and endothelial cells in vitro. Treatment of the cells with recombinant FABP4 significantly increased gene expression of inflammatory markers in a dose-dependent manner. Finally, we measured serum FABP4 level in the aortic root (Ao-FABP4) and coronary sinus (CS-FABP4) of 34 patients with suspected or known coronary artery disease. Coronary stenosis score assessed by the modified Gensini score was weakly correlated with CS-FABP4 but was not correlated with Ao-FABP4. A stronger correlation (r=0.59, P<0.01) was observed for the relationship between coronary stenosis score and coronary veno-arterial difference in FABP4 level, (CS-Ao)-FABP4, indicating local production of FABP4 during coronary circulation in the heart. Multivariate analysis indicated that (CS-Ao)-FABP4 was an independent predictor of the severity of coronary stenosis after adjustment of conventional risk factors., Conclusions: FABP4 locally produced by epicardial/perivascular fat and macrophages in vascular plaques contributes to the development of coronary atherosclerosis., (© 2016 American Heart Association, Inc.)

Background and Purpose: There have been consistent findings reported that marital transition (ie, change in marital status during a given time period) is associated with risk of cardiovascular disease; however, few studies have been conducted on stroke risk, particularly stroke subtypes. Moreover, no studies have examined the moderating effect of living arrangement and employment status on the association between marital transition and stroke risk., Methods: We examined sex-specific associations between marital transition and stroke risk using data from Japan Public Health Center-based Prospective Study. We included 24 162 men and 25 626 women who were married at prebaseline (5 years before baseline). Marital transition was determined by marital status at baseline. Weighted hazard ratios of stroke risk were estimated by Cox proportional regression analysis with inverse probability of weighting using a propensity score., Results: An increased risk of stroke, particularly hemorrhagic stroke, was observed among men and women with marital transition (ie, married to unmarried); weighted hazard ratios (95% confidence interval [CI]) for men and women were 1.26 (1.13-1.41) and 1.26 (1.09-1.45), respectively. Participants with marital transition and lived with children had increased stroke risk. Living with parents buffered the increased stroke risk owing to marital transition among men; however, no such effect was identified among women. Elevated stroke risk owing to marital transition was magnified among women if they were unemployed; weighted hazard ratio=2.98 (95% CI, 1.66-5.33)., Conclusions: Living arrangement and employment status modified the positive associations between marital transition and stroke risk, which differed by sex., (© 2016 American Heart Association, Inc.)

Background and Purpose: The association between breakfast intake and the risk of cardiovascular disease, including stroke, among Asian people remains unknown. We sought to prospectively investigate whether the omission of breakfast is related to increased risks of stroke and coronary heart disease in general Japanese populations., Methods: A total of 82,772 participants (38,676 men and 44,096 women) aged 45 to 74 years without histories of cardiovascular disease or cancer were followed up from 1995 to 2010. Participants were classified as having breakfast 0 to 2, 3 to 4, 5 to 6, or 7 times/wk. The hazard ratios of cardiovascular disease were estimated using Cox proportional hazards models., Results: During the 1 050 030 person-years of follow-up, we documented a total of 4642 incident cases, 3772 strokes (1051 cerebral hemorrhages, 417 subarachnoid hemorrhages, and 2286 cerebral infarctions), and 870 coronary heart disease. Multivariable analysis showed that those consuming no breakfast per week compared with those consuming breakfast everyday had hazard ratios (95% confidence interval; P for trend) of 1.14 (1.01-1.27; 0.013) for total cardiovascular disease, 1.18 (1.04-1.34; 0.007) for total stroke, and 1.36 (1.10-1.70; 0.004) for cerebral hemorrhage. Similar results were observed even after exclusion of early cardiovascular events. No significant association between the frequency of breakfast intake and the risk of coronary heart disease was observed., Conclusions: The frequency of breakfast intake was inversely associated with the risk of stroke, especially cerebral hemorrhage in Japanese, suggesting that eating breakfast everyday may be beneficial for the prevention of stroke., (© 2016 American Heart Association, Inc.)

High hemoglobin A1c (HbA1c) levels are strongly associated with an increased risk of cardiovascular disease (CVD) in people with and without diabetes. However, information regarding the relationship between low HbA1c levels and the risk of CVD among people without known diabetes is limited. The aim of this large-scale, prospective, population-based cohort study was to clarify the association between HbA1c levels and CVD risk among people without known diabetes.We followed-up 10,980 men and 18,079 women (46-80 years old and free of CVD and cancer at baseline) in the Japan Public Health Center-based Prospective Study. Using Cox models, we estimated the hazard ratios for CVD risk with adjustments for age, sex, geographic areas, body mass index, smoking status, sports and physical exercise, alcohol intake, systolic blood pressure, non-high-density lipoprotein cholesterol, and high-density lipoprotein cholesterol.During the median follow-up of 9.4 years, 935 CVD events (770 strokes and 165 coronary heart diseases) occurred. We observed a nonlinear association between HbA1c levels and CVD risk in participants without known diabetes. Compared with HbA1c levels of 5.0 to 5.4% (31-36 mmol/mol), the hazard ratios for CVD in participants without known diabetes were 1.50 (95% confidence interval: 1.15-1.95), 1.01 (0.85-1.20), 1.04 (0.82-1.32), and 1.77 (1.32-2.38) for HbA1c levels of <5.0% (<31 mmol/mol), 5.5 to 5.9% (37-41 mmol/mol), 6.0 to 6.4% (42-47 mmol/mol), and ≥6.5% (≥48 mmol/mol), respectively (P value for nonlinear trend: <0.001). In addition, the hazard ratio for CVD was 1.81 (1.43-2.29) in patients with known diabetes compared with participants with HbA1c levels of 5.0 to 5.4% and without known diabetes. This nonlinear relation persisted after excluding people with kidney dysfunction, liver dysfunction, anemia, body mass index <18.5 kg/m, or early events within 3 years of follow-up (P value for nonlinear trend: <0.01 for all tests).In conclusion, both low and high levels of HbA1c were associated with a higher risk of CVD in a Japanese general population without known diabetes.

Background and Purpose: Little research has been conducted to examine the effect of inconsistencies in socioeconomic status on cardiovascular health. In particular, no studies have been reported in Asian countries, including Japan, which is thought to have high socioeconomic status inconsistency among women., Methods: We examined the effect of status inconsistency between education level and occupation on stroke risk in a prospective 20-year study of 14 742 middle-aged Japanese women included in the prospective Japan Public Health Center-based (JPHC) Study Cohort I in 1990. Status inconsistency between education level and occupation was determined (qualified, overqualified, and underqualified), and the association with risk of stroke was examined. Cox proportional regression analysis was used to determine hazard ratios, which were adjusted for age, marital status, and geographical area., Results: Adjusted hazard ratio for stroke in overqualified compared with qualified women was 2.06 (95% confidence interval, 1.13-3.78). Adjusted hazard ratios for stroke among highly educated manual workers and workers in service industry were 3.47 (95% confidence interval, 1.54-7.84) and 3.21 (95% confidence interval, 1.49-6.90), respectively, when compared with highly educated professionals/managers., Conclusions: High academic qualifications without an appropriate job could be a risk factor for stroke among Japanese women. Our result suggests that status inconsistency could be a potential explanation for the increased stroke risk among highly educated women., (© 2014 American Heart Association, Inc.)

Background and Purpose: An individualized risk score for the development of stroke may be a useful tool to motivate patients to modify their risk behaviors. We developed and validated a point-based prediction model (risk score) for stroke incidence using a Japanese cohort of general men and women., Methods: The Japan Public Health Center-based prospective study cohort II (age range, 40-69 years at baseline in 1993-1994; n=15 672) was used to derive the point-based model according to Cox regression results. The model was externally validated using the Japan Public Health Center study cohort I and also by bootstrap methods within cohort II. The model discrimination was evaluated by the area under the receiver operating characteristic curve, model calibration, by the Grønnesby-Borgan χ(2) statistic. Vascular age was also calculated., Results: During 14 years of follow-up, 790 incident stroke cases occurred. Variables selected for the model were age, sex, current smoking, body mass index, blood pressure, antihypertensive medication use, and diabetes mellitus. Interactions of sex with current smoking and of antihypertensive medication use with systolic blood pressure were statistically significant. The point-based model discriminated reasonably well (area under the receiver operating characteristic curve, 0.73). The area under the receiver operating characteristic curve of the point-based model applied externally to cohort I was reasonably good: 0.69. A 50-year-old man with diabetes mellitus and hypertension has an estimated vascular age of 69 years. High normal blood pressure and grade 1 hypertension accounted for one third of the stroke incidence., Conclusions: We developed score to predict 10-year stroke risk using variables that are easily available in the community setting.

Iodine is a suspected risk factor for thyroid cancer. Seaweed accounts for about 80% of Japanese people's iodine intake. We examined the association between seaweed consumption and the risk of thyroid cancer in Japanese women. Women participating in the Japan Public Health Center-based Prospective Study (n=52 679; age: 40-69 years) were followed up for a mean of 14.5 years; 134 new thyroid cancer cases, including 113 papillary carcinoma cases, were identified. Seaweed consumption was assessed using a food-frequency questionnaire and divided into three categories: 2 days/week or less (reference); 3-4 days/week; and almost daily. The Cox proportional hazards model was applied to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Seaweed consumption was clearly associated with an increased risk of papillary carcinoma (HR for almost daily consumption compared with 2 days/week or less=1.71; 95% CI: 1.01-2.90; trend P=0.04). After stratification for menopausal status, an increased risk was observed in postmenopausal women (papillary carcinoma HR for almost daily consumption compared with 2 days/week or less=3.81, 95% CI: 1.67-8.68; trend P<0.01), but not in premenopausal women (HR=0.91, 95% CI: 0.44-1.91; trend P=0.76). This study identified a positive association between seaweed consumption and the risk of thyroid cancer (especially for papillary carcinoma) in postmenopausal women.

Diminished bioavailability of nitric oxide is a hallmark of endothelial dysfunction and is associated with a broad spectrum of vascular disorders such as impaired angiogenesis. Because Rac1, a Rho family member, mediates cellular motility and generation of reactive oxygen species, it could be involved in the regulation of endothelial nitric oxide production. However, the pathophysiological consequences of postnatal endothelial Rac1 deletion on endothelial function have not been determined. We generated endothelial-specific Rac1 haploinsufficient mice (EC-Rac1(+/-)) using Cre-loxP technology. The EC-Rac1(+/-) mice have decreased expression and activity of endothelial nitric oxide synthase (eNOS), impaired endothelium-dependent vasorelaxation, and mild hypertension compared with control (Rac1(+/flox)) mice. Hind limb ischemia model and aortic capillary sprouting assay showed that eNOS activity and angiogenesis was impaired in EC-Rac1(+/-) mice. Indeed, Rac1 promotes eNOS gene transcription through p21-activated kinase but not NADPH oxidase, increases eNOS mRNA stability, and enhances eNOS activity by promoting endothelial uptake of l-arginine. These findings indicate that endothelial Rac1 is essential for endothelium-dependent vasomotor response and ischemia-induced angiogenesis. These effects of Rac1 on endothelial function are largely due to the upregulation of eNOS through multiple mechanisms that are mediated, in part, by p21-activated kinase. Therapeutic strategies to enhance Rac1 function, therefore, may be important for preventing endothelial dysfunction.

Objective: We demonstrated previously that mouse embryonic stem (ES) cell-derived vascular endothelial growth factor receptor-2 (VEGF-R2)-positive cells can differentiate into both vascular endothelial cells and mural cells. This time, we investigated kinetics of differentiation of human ES cells to vascular cells and examined their potential as a source for vascular regeneration., Methods and Results: Unlike mouse ES cells, undifferentiated human ES cells already expressed VEGF-R2, but after differentiation, a VEGF-R2-positive but tumor rejection antigen 1-60 (TRA1-60)-negative population emerged. These VEGF-R2-positive but tumor rejection antigen 1-60-negative cells were also positive for platelet-derived growth factor receptor alpha and beta chains and could be effectively differentiated into both VE-cadherin+ endothelial cell and alpha-smooth muscle actin+ mural cell. VE-cadherin+ cells, which were also CD34+ and VEGF-R2+ and thought to be endothelial cells in the early differentiation stage, could be expanded while maintaining their maturity. Their transplantation to the hindlimb ischemia model of immunodeficient mice contributed to the construction of new blood vessels and improved blood flow., Conclusions: We could identify the differentiation process from human ES cells to vascular cell components and demonstrate that expansion and transplantation of vascular cells at the appropriate differentiation stage may constitute a novel strategy for vascular regenerative medicine.

Background: We demonstrated that vascular endothelial growth factor receptor 2 (VEGF-R2)-positive cells derived from mouse embryonic stem (ES) cells can differentiate into both endothelial cells and mural cells to suffice as vascular progenitor cells (VPCs). Here we examined whether VPCs occur in primate ES cells and investigated the differences in VPC differentiation kinetics between primate and mouse ES cells., Methods and Results: In contrast to mouse ES cells, undifferentiated monkey ES cells expressed VEGF-R2. By culturing these undifferentiated ES cells for 4 days on OP9 feeder layer, VEGF-R2 expression disappeared, and then reappeared after 8 days of differentiation. We then isolated these VEGF-R2-positive and vascular endothelial cadherin (VEcadherin)-negative cells by flow cytometry sorting. Additional 5-day reculture of these VEGF-R2+ VEcadherin- cells on OP9 feeder layer resulted in the appearance of platelet endothelial cell adhesion molecule-1 (PECAM1)-positive, VEcadherin-positive, endothelial nitric oxide synthase (eNOS)-positive endothelial cells. On a collagen IV-coated dish in the presence of serum, these cells differentiated into smooth muscle actin (SMA)-positive and calponin-positive mural cells (pericytes or vascular smooth muscle cells). Addition of 50 ng/mL VEGF to the culture on a collagen IV-coated dish resulted in the appearance of PECAM1+ cells surrounded by SMA+ cells. In addition, these differentiated VEGF-R2+ cells can form tube-like structures in a 3-dimensional culture., Conclusions: Our findings indicate that differentiation kinetics of VPCs derived from primate and mouse ES cells were different. Differentiated VEGF-R2+ VEcadherin- cells can act as VPCs in primates. To seek the clinical potential of VPCs for vascular regeneration, investigations of primate ES cells are indispensable.

Background: Vein graft disease limits the late results of coronary revascularization. C-type natriuretic peptide (CNP) inhibits the growth of vascular smooth muscle cells. Given the effects of CNP on cGMP cascade, we hypothesized that transfected CNP genes modulate endothelial repair and thrombogenicity in the vein graft., Methods and Results: Autologous rabbit jugular vein grafts were incubated ex vivo in a solution of adenovirus vectors containing CNP gene (Ad.CNP) or Escherichia coli lac Z gene (Ad.LacZ) and then interposed in the carotid artery. Reendothelialization, mural thrombi formation, and intima/media ratio were evaluated on the 14th and 28th postoperative days. More reendothelialization was seen in Ad.CNP-infected grafts than in Ad.LacZ-infected grafts both at 14 days (0.81+/-0.05 versus 0.30+/-0.14, P<0.01) and at 28 days (0.96+/-0.01 versus 0.45+/-0.08, P<0.001). The mural thrombus area was smaller in Ad.CNP-infected grafts than in Ad.LacZ-infected grafts. Neointimal thickening was significantly suppressed in the Ad.CNP group. The in vitro wound assay with human coronary artery endothelial cells revealed significant potentiation of the wound repair process by CNP and atrial natriuretic peptide administration., Conclusions: Infected Ad.CNP accelerated reendothelialization and suppressed thrombosis and neointimal hyperplasia. The method may potentially prevent vein graft disease in patients undergoing coronary artery revascularization.

We recently reported that C-type natriuretic peptide (CNP) occurs in vascular endothelial cells and acts as a vascular-type natriuretic peptide. In the present study, we stimulated the cGMP cascade in proliferating smooth muscle cells (SMCs), in which particulate guanylate cyclase-B, the specific receptor for CNP, is predominantly expressed, by use of an adenovirus encoding rat CNP cDNA (Ad.CNP). In the Ad.CNP-treated cultured SMCs, CNP caused the growth inhibition of SMCs at G(1) phase with an early increase of p21(CIP1/WAF1) expression and subsequent upregulation of p16(INK4a). The expression of smooth muscle myosin heavy chain-2, which is the molecular marker of highly differentiated SMCs, was reinduced in the Ad.CNP-treated SMCs. The Ad.CNP-treated SMCs also reexpressed particulate guanylate cyclase-A, which shows high affinity to atrial and brain natriuretic peptide and is exclusively expressed in well-differentiated SMCs. CNP, which was overexpressed in rabbit femoral arteries in vivo at the time of balloon injury, significantly suppressed neointimal formation. Furthermore, an enhancement of the expression of smooth muscle myosin heavy chain-2 occurred in the residual neointima. In addition, early regeneration of endothelial cells was observed in the Ad.CNP-infected group. Thus, stimulation of cGMP cascade in proliferating dedifferentiated SMCs can induce growth inhibition and redifferentiation of SMCs with accelerated reendothelialization.

Vascular endothelial growth factor (VEGF) has been recognized as an angiogenic factor that induces endothelial proliferation and vascular permeability. Recent studies have also suggested that VEGF can promote macrophage migration, which is critical for atherosclerosis. We have reported that VEGF is remarkably expressed in activated macrophages, endothelial cells, and smooth muscle cells within human coronary atherosclerotic lesions, and we have proposed the significance of VEGF in the progression of atherosclerosis. To clarify the mechanism of VEGF expression in atherosclerotic lesions, we examined the regulation of VEGF expression by oxidized low density lipoprotein (Ox-LDL), which is abundant in atherosclerotic arterial walls. A recent report has revealed that peroxisome proliferator-activated receptor-gamma (PPARgamma) is expressed not only in adipocytes but also in monocytes/macrophages and has suggested that PPARgamma may have a role in the differentiation of monocytes/macrophages. Furthermore, 9- and 13-hydroxy-(S)-10,12-octadecadienoic acid (9- and 13-HODE, respectively), the components of Ox-LDL, may be PPARgamma ligands. Therefore, we investigated the involvement of PPARgamma in the regulation of VEGF by Ox-LDL. PPARgamma expression was detected in human monocyte/macrophage cell lines, human acute monocytic leukemia (THP-1) cells, and human coronary artery endothelial cells (HCAECs). Ox-LDL (10 to 50 microg/mL) upregulated VEGF secretion from THP-1 dose-dependently. VEGF mRNA expression in HCAECs was also upregulated by Ox-LDL. The mRNA expression of VEGF in THP-1 cells and HCAECs was also augmented by PPARgamma activators, troglitazone (TRO), and 15-deoxy-(12,14)-prostaglandin J(2) (PGJ2). In contrast, VEGF expression in another monocyte/macrophage cell line, human histiocytic lymphoma cells (U937), which lacks PPARgamma expression, was not augmented by TRO or PGJ2. We established the U937 cell line, which permanently expresses PPARgamma (U937T). TRO and Ox-LDL augmented VEGF expression in U937T. In addition, VEGF production by THP-1 cells was significantly increased by exposure to 9-HODE and 13-HODE. In conclusion, Ox-LDL upregulates VEGF expression in macrophages and endothelial cells, at least in part, through the activation of PPARgamma.

The effects of a highly selective Na+/H+ exchange inhibitor cariporide on the reperfused in situ heart were assessed. Male Sprague-Dawley (SD) rats weighing 200-300 g were anesthetized with pentobarbital sodium (60 mg/kg, i.p.) and divided into four groups; sham-operated (n = 6), vehicle (n = 15), 0.1 mg/kg (n = 15), and 1.0 mg/kg (n = 15) groups. The left coronary artery was ligated for 5 min and then released with ECG and blood pressure monitoring. Cariporide was intravenously given as a bolus 2 min before the reperfusion. The heart was rapidly excised and frozen 3 min after the onset of ventricular fibrillation, otherwise 10 min after the reperfusion. The adenosine triphosphate (ATP), creatine phosphate (CP), and glycogen contents were measured in the reperfused ischemic myocardium by using an enzymatic fluorometric assay technique. The incidence of the lethal ventricular fibrillation was 53% in the vehicle, 27% in the low-dose and 7% in the high-dose group. The concentrations (mean+/-SEM) of ATP, CP (nmol/mg protein), and glycogen (nmol as glucose/mg protein) were 74+/-4, 255+/-19, and 164+/-21 in the sham, 23+/-4, 763+/-70, and 61+/-7 in the vehicle, 27+/-4, 180+/-16, and 104+/-14 in the low-dose, and 32+/-4, 178+/-24, and 108+/-8 in the high-dose groups, respectively, indicating that cariporide significantly blunted CP overshoot as well as glycogenolysis during reperfusion. Thus cariporide can be expected to depress arrhythmogenesis and protect the metabolic status of the heart.

Shear stress dilates blood vessels and exerts an antiproliferative effect on vascular walls. These effects are ascribed to shear stress-induced, endothelium-derived vasoactive substances. Endothelin-converting enzymes (ECEs), the enzymes that convert big endothelin-1 (ET-1) to ET-1, have recently been isolated and the corresponding proteins have been termed ECE-1 and ECE-2. Furthermore, two isoforms of human ECE-1 have been demonstrated and termed ECE-1 alpha and ECE-1 beta. In this study, to elucidate the role of ECE-1 under shear stress we examined the effect of physiologic shear stress on the mRNA expression of ECE-1 and ET-1 in cultured bovine carotid artery endothelial cells (BAECs) and human umbilical veins (HUVECs), and also ECE-1 alpha mRNA expression in HUVECs. ECE-1 mRNA expression was significantly downregulated by shear stress in 24 h, both in BAECs and HUVECs, in a shear stress intensity-dependent manner. The expression of ECE-1 alpha mRNA was also attenuated by shear stress in HUVECs. ET-1 mRNA expression showed a concordant decrease with ECE-1 mRNA expression. These results suggest that shear stress-induced gene regulation of ET-1 and ECE-1 mRNA expression can contribute to the decrease of ET-1 peptide level by shear stress.