Yuni Choi

Metabolically-healthy obesity and coronary artery calcification.

OBJECTIVES The purpose of this study was to compare the coronary artery calcium (CAC) scores of metabolically-healthy obese (MHO) and metabolically healthy normal-weight individuals in a large sample of apparently healthy men and women. BACKGROUND The risk of cardiovascular disease among obese individuals without obesity-related metabolic abnormalities, referred to as MHO, is controversial. METHODS We conducted a cross-sectional study of 14,828 metabolically-healthy adults with no known cardiovascular disease who underwent a health checkup examination that included estimation of CAC scores by cardiac tomography. Being metabolically healthy was defined as not having any metabolic syndrome component and having a homeostasis model assessment of insulin resistance <2.5. RESULTS MHO individuals had a higher prevalence of coronary calcification than normal weight subjects. In multivariable-adjusted models, the CAC score ratio comparing MHO with normal-weight participants was 2.26 (95% confidence interval: 1.48 to 3.43). In mediation analyses, further adjustment for metabolic risk factors markedly attenuated this association, which was no longer statistically significant (CAC score ratio 1.24; 95% confidence interval: 0.79 to 1.96). These associations did not differ by clinically-relevant subgroups. CONCLUSIONS MHO participants had a higher prevalence of subclinical coronary atherosclerosis than metabolically-healthy normal-weight participants, which supports the idea that MHO is not a harmless condition. This association, however, was mediated by metabolic risk factors at levels below those considered abnormal, which suggests that the label of metabolically healthy for obese subjects may be an artifact of the cutoff levels used in the definition of metabolic health.

Metabolically Healthy Obesity and Development of Chronic Kidney Disease: A Cohort Study.

Context The risk for chronic kidney disease (CKD) among obese patients without metabolic abnormalities is unknown. Contribution In this cohort study of South Korean men and women, metabolically healthy overweight and obese participants had increased incidence of CKD compared with normal-weight participants. Caution Body mass index was a marker of obesity and was assessed only once at baseline. Implication Physicians should monitor metabolically healthy obese and overweight patients for CKD and counsel them about maintaining a healthy weight and lifestyle. Chronic kidney disease (CKD) is a major clinical and public health problem (1). It is a precursor for end-stage renal disease and a strong risk factor for cardiovascular morbidity and mortality (2). Its prevalence is increasing worldwide along with the growing prevalence of obesity and metabolic disease (3). Indeed, obesitymediated by hypertension, insulin resistance, hyperglycemia, dyslipidemia, and other metabolic abnormalitiesis a major risk factor for CKD (4). Although the role of obesity-induced metabolic abnormalities in CKD development is well-established, metabolically healthy obese (MHO) persons, seem to have a favorable profile with no metabolic abnormalities (5, 6). The association between MHO and CKD, however, is largely unknown. The only study available found no association (7), but the comparison between MHO and normal-weight participants could be biased because the reference group included overweight participants, and metabolically healthy participants were defined as those with fewer than 2 metabolic components. Therefore, we examined the association between categories of body mass index (BMI) and CKD in a large sample of metabolically healthy men and women who had health screening examinations. Methods Study Population The Kangbuk Samsung Health Study is a cohort study of South Korean men and women aged 18 years or older who had a comprehensive annual or biennial health examination at the clinics of the Kangbuk Samsung Hospital Health Screening Centers in Seoul and Suwon, South Korea (8). More than 80% of participants were employees of various companies and local governmental organizations and their spouses. In South Korea, the Industrial Safety and Health Act requires all employees to receive annual or biennial health screening examinations, offered free of charge. The remaining participants registered for the screening examinations on their own. Our analysis included all persons who had comprehensive health examinations from 1 January 2002 to 31 December 2009 and had at least 1 other screening examination before 31 December 2013 (that is, they all had a baseline visit and 1 follow-up visit [n=175859]) (Figure 1). We excluded persons who had metabolic abnormalities (5, 9, 10) or evidence of kidney disease at baseline (n=108263). We excluded those with fasting glucose levels of 100 mg/dL or greater or who used glucose-lowering agents; blood pressure (BP) of 130/85 mm Hg or greater or who used BP-lowering agents; triglyceride levels of 150 mg/dL or greater or who used lipid-lowering agents; high-density lipoprotein (HDL) cholesterol levels less than 40 mg/dL in men or less than 50 mg/dL in women; insulin resistance, defined as homeostasis model assessment of insulin resistance (HOMA-IR) scores of 2.5 or greater (11); estimated glomerular filtration rate (GFR) less than 60 mL/min/1.73 m2; proteinuria; history of CKD; or history of cancer. Among eligible participants (n=67596), we further excluded those with missing values in any of the study variables (n=5347 [7.9%]). The final sample size was 62249 participants (Figure 1), all of whom were metabolically healthy and did not have markers of kidney disease at baseline. This study was approved by the Institutional Review Board of the Kangbuk Samsung Hospital, which exempted the requirement for informed consent because we only accessed deidentified data routinely collected as part of health screening examinations. Figure 1. Study flow diagram. CKD = chronic kidney disease; HDL = high-density lipoprotein. * Participants in the screening program could have >1 criterion that made them ineligible for the study. Eligible participants could have missing data in >1 study variable. Measurements Data on medical history, medication use, family history, physical activity, alcohol intake, smoking habits, and education level were collected by a standardized, self-administered questionnaire. Anthropometry data, BP, and blood samples were obtained by trained staff during the examinations (8, 12). Smoking status was categorized as never, former, or current. Alcohol consumption was categorized as none, moderate (20 g per day), or high (>20 g per day). The weekly frequency of moderate- or vigorous-intensity physical activity was also assessed. Sitting BP, height, and weight were measured by trained nurses. Height was measured to the nearest 1 cm with a stadiometer while the participant stood barefoot. Weight was measured to the nearest 0.1 kg on a bioimpedance analyzer (InBody 3.0 and Inbody 720, Biospace), which was validated for reproducibility and accuracy of body composition measurements (13) and calibrated every morning before testing started. Body mass index was calculated as weight in kilograms divided by height in meters squared and was classified according to Asian-specific criteria (14) (underweight, BMI <18.5 kg/m2; normal weight, BMI of 18.5 to 22.9 kg/m2; overweight, BMI of 23 to 24.9 kg/m2; and obese, BMI 25 kg/m2). Blood specimens were sampled from the antecubital vein after at least a 10-hour fast. The methods for measuring serum levels of glucose, uric acid, total cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, HDL cholesterol, aspartate aminotransferase, alanine aminotransferase, -glutamyltransferase, insulin, and high-sensitivity C-reactive protein (hsCRP) have been reported elsewhere (8, 12). The Department of Laboratory Medicine of the Kangbuk Samsung Hospital has been accredited by the Korean Society for Laboratory Medicine and the Korean Association of Quality Assurance for Clinical Laboratories and participates in the College of American Pathologists Proficiency Testing survey. Insulin resistance was assessed with the HOMA-IR equation (fasting insulin [uU/mL]fasting glucose [mmol/L] 22.5). An ultrasonographic diagnosis of fatty liver was defined as a diffuse increase of fine echoes in the liver parenchyma compared with the kidney or spleen parenchyma (15, 16). During the study period, serum creatinine levels were measured with the kinetic alkaline picrate method (Jaffe method) in an automated chemistry analyzer (from 2002 to 2009, we used the Advia 1650a Autoanalyzer [Bayer Diagnostics]; from 2010 to 2013, we used the Modular D2400 [Roche]). The within-batch and total coefficients of variation were 1.8% to 3.9% for low-level and 1.4% to 1.8% for high-level quality control specimens throughout the study. Because the laboratory method that was used to measure serum creatinine levels from 2002 to 2009 was not traceable to isotope-dilution mass spectrometry, we estimated GFR by using the 4-variable Modification of Diet in Renal Disease Study equation (17). The conclusions did not change if we used the Chronic Kidney Disease Epidemiology Collaboration equation (18) for GFR estimation (data not shown). Urine protein was measured semiquantitatively by urine dipstick (URiSCAN Urine test strips, YD Diagnostics) tested on fresh, midstream urine samples and was reported in the following 6 grades: absent, trace, 1+, 2+, 3+, and 4+ (corresponding to protein levels of undetectable, 10 mg/dL, 30 mg/dL, 100 mg/dL, 300 mg/dL, and 1000 mg/dL, respectively). Proteinuria was defined as a grade of 1+ or greater. Statistical Analysis Person-years of follow-up were calculated from the date of the baseline health examination until the date of CKD diagnosis or the last screening examination, whichever came first. The cumulative incidence of CKD for baseline BMI categories (<18.5, 18.5 to 22.9, 23.0 to 24.9, or 25.0 kg/m2) were standardized to the empirical distribution of baseline confounders in the overall study sample with inverse probability weighting (19, 20). We first fitted a multinomial logistic regression to estimate each participants probability of being in his or her own BMI category given the observed confounders. Stabilized weights were then calculated as the inverse of the estimated conditional probabilities of exposure, further rescaled by the overall proportion of participants in each BMI category to reduce variability of weights across groups and to avoid influential observations involving extremely obese persons (19). For risk analyses, we fitted a spline-based, parametric survival model (21) according to the stabilized weights and stratified by BMI category to obtain smooth estimates of the CKD cumulative incidence curves that would have been seen in the entire population if every participant had been in each category (20). This survival model parameterized stratum-specific log cumulative hazards as distinct natural cubic splines of log time with 3 internal knots at the 25th, 50th, and 75th percentiles; allowed for interval-censored events (incident CKD occurred at an unknown time point between the visit at which CKD was diagnosed and the previous visit); and used robust SEs for spline parameters that accounted for the correlation induced by weighting (21). For comparison, we also applied weighted KaplanMeier methods to estimate nonparametric cumulative incidence curves for each BMI category. We used the previously mentioned weighted, spline-based survival model to calculate adjusted differences in cumulative incidences of CKD at 2, 5, and 10 years of follow-up of normal-weight participants compared with those in the other BMI categories. We calculated 95% CIs by applying delta methods to the robust variance estimates of spline parameters. In addition to risk differences, we

Relationship of sitting time and physical activity with non-alcoholic fatty liver disease

BACKGROUND & AIMS The goal of this study was to examine the association of sitting time and physical activity level with non-alcoholic fatty liver disease (NAFLD) in Korean men and women and to explore whether any observed associations were mediated by adiposity. METHODS A cross-sectional study was performed on 139,056 Koreans, who underwent a health examination between March 2011 and December 2013. Physical activity level and sitting time were assessed using the validated Korean version of the international Physical Activity Questionnaire Short Form. The presence of fatty liver was determined using ultrasonographic findings. Poisson regression models with robust variance were used to evaluate the association of sitting time and physical activity level with NAFLD. RESULTS Of the 139,056 subjects, 39,257 had NAFLD. In a multivariable-adjusted model, both prolonged sitting time and decreased physical activity level were independently associated with increasing prevalence of NAFLD. The prevalence ratios (95% CIs) for NAFLD comparing 5-9 and ⩾10 h/day sitting time to <5h/day were 1.04 (1.02-1.07) and 1.09 (1.06-1.11), respectively (p for trend <0.001). These associations were still observed in subjects with BMI <23 kg/m(2). The prevalence ratios (95% CIs) for NAFLD comparing minimally active and health-enhancing physically active groups to the inactive group were 0.94 (0.92-0.95) and 0.80 (0.78-0.82), respectively (p for trend <0.001). CONCLUSIONS Prolonged sitting time and decreased physical activity level were positively associated with the prevalence of NAFLD in a large sample of middle-aged Koreans, supporting the importance of reducing time spent sitting in addition to promoting physical activity.

Dietary Intake of Calcium and Phosphorus and Serum Concentration in Relation to the Risk of Coronary Artery Calcification in Asymptomatic Adults

Objective— The current data regarding the association between calcium and phosphorus and cardiovascular disease are lacking. The aim of this study was to explore whether dietary calcium and phosphorus intake and their serum levels are associated with the prevalence of coronary artery calcification (CAC) using cardiac computed tomography in asymptomatic participants without a history of chronic kidney disease or cardiovascular disease. Approach and Results— A cross-sectional study was performed in 23 652 Korean participants (40.8±7.3 years, male 83.5%) without chronic kidney disease (estimated glomerular filtration rate≥60 mL/min per 1.73 m2) or clinically overt cardiovascular disease, who underwent cardiac computed tomographic estimation of CAC scores as part of a general health checkup in addition to completing a self-administered food frequency questionnaire. We assessed the relationship of dietary calcium and phosphorus intake and serum levels with CAC scores using both multivariate-adjusted Tobit models and multinomial logistic regression models. Neither dietary calcium nor phosphorus intake was consistently associated with CAC scores. However, the serum calcium, phosphorus, and calcium–phosphorus product levels were significantly associated with the CAC score ratios. In multivariable-adjusted models, the CAC score ratios (95% confidence intervals) comparing the highest quartiles of serum calcium, phosphorus, and calcium–phosphorus product levels to the lowest quartiles were 1.89 (1.36–2.64), 3.33 (2.55–4.35), and 3.98 (3.00–5.28), respectively (P for trend <0.001). Conclusions— Elevated serum levels of calcium, phosphorus, and calcium–phosphorus product, but not dietary consumption, are associated with increased CAC scores. Our findings should be explored in further research.

Sleep Duration, Sleep Quality, and Markers of Subclinical Arterial Disease in Healthy Men and Women

Objective—Short and long sleep duration are associated with increased risk of clinical cardiovascular events, but the association between sleep duration and subclinical cardiovascular disease is not well established. We examined the association between sleep duration and sleep quality with coronary artery calcification (CAC) and with brachial–ankle pulse wave velocity (PWV) in a large sample of young and middle-aged asymptomatic adults. Approach and Results—We conducted a cross-sectional study of adult men and women who underwent a health checkup examination, including assessment of sleep duration and quality and coupled with either CAC (n=29 203) or brachial–ankle PWV (n=18 106). The multivariate-adjusted CAC score ratios (95% confidence interval) comparing sleep durations of ⩽5, 6, 8, and ≥9 hours with 7 hours of sleep were 1.50 (1.17–1.93), 1.34 (1.10–1.63), 1.37 (0.99–1.89), and 1.72 (0.90–3.28), respectively (P for quadratic trend=0.002). The corresponding average differences in brachial–ankle PWV were 6.7 (0.75–12.6), 2.9 (−1.7 to 7.4), 10.5 (4.5–16.5), and 9.6 (−0.7 to 19.8) cm/s, respectively (P for quadratic trend=0.019). Poor subjective sleep quality was associated with CAC in women but not in men, whereas the association between poor subjective sleep quality and brachial–ankle PWV was stronger in men than in women. Conclusions—In this large study of apparently healthy men and women, extreme sleep duration and poor subjective sleep quality were associated with increased prevalence of CAC and higher PWV. Our results underscore the importance of an adequate quantity and quality of sleep to maintain cardiovascular health.

Age at menarche and non-alcoholic fatty liver disease

BACKGROUND & AIMS The goal of this study was to examine the association between age at menarche and non-alcoholic fatty liver disease (NAFLD) in Korean women and to explore whether any observed associations were mediated by adult adiposity. METHODS A cross-sectional study was performed for 95,183 Korean women, aged 30 or older, who underwent a regular health screening examination between March 2011 and April 2013. Information regarding age at menarche was collected using standardized, self-administered questionnaires. The presence of fatty liver was determined using ultrasonographic findings. Poisson regression models with robust variance were used to evaluate the association between age at menarche and NAFLD. RESULTS Of the 76,415 women evaluated in this study, 9601 had NAFLD. Age at menarche was inversely associated with the prevalence of NAFLD. In a multivariable-adjusted model, the prevalence ratios (95% CIs) for NAFLD comparing menarche at <12, 12, 14, 15, and 16-18 years to menarche at 13 years were 1.31 (1.18-1.45), 1.05 (0.97-1.13), 0.93 (0.87-0.99), 0.87 (0.82-0.93), and 0.78 (0.73-0.84), respectively (p for trend <0.001). Adjusting for adult BMI or percent fat mass (%) substantially reduced these associations; however, they remained statistically significant. The association between age at menarche and NAFLD was modified by age. CONCLUSIONS We identified an inverse association between age at menarche and NAFLD in a large sample of middle-aged women. This association was partially mediated by adiposity. The findings of this study suggest that obesity prevention strategies are needed in women who undergo early menarche to reduce the risk of NAFLD.

Coffee consumption and coronary artery calcium in young and middle-aged asymptomatic adults

Objective To investigate the association between regular coffee consumption and the prevalence of coronary artery calcium (CAC) in a large sample of young and middle-aged asymptomatic men and women. Methods This cross-sectional study included 25 138 men and women (mean age 41.3 years) without clinically evident cardiovascular disease who underwent a health screening examination that included a validated food frequency questionnaire and a multidetector CT to determine CAC scores. We used robust Tobit regression analyses to estimate the CAC score ratios associated with different levels of coffee consumption compared with no coffee consumption and adjusted for potential confounders. Results The prevalence of detectable CAC (CAC score >0) was 13.4% (n=3364), including 11.3% prevalence for CAC scores 1–100 (n=2832), and 2.1% prevalence for CAC scores >100 (n=532). The mean ±SD consumption of coffee was 1.8±1.5 cups/day. The multivariate-adjusted CAC score ratios (95% CIs) comparing coffee drinkers of <1, 1–<3, 3–<5, and ≥5 cups/day to non-coffee drinkers were 0.77 (0.49 to 1.19), 0.66 (0.43 to 1.02), 0.59 (0.38 to 0.93), and 0.81 (0.46 to 1.43), respectively (p for quadratic trend=0.02). The association was similar in subgroups defined by age, sex, smoking status, alcohol consumption, status of obesity, diabetes, hypertension, and hypercholesterolaemia. Conclusions In this large sample of men and women apparently free of clinically evident cardiovascular disease, moderate coffee consumption was associated with a lower prevalence of subclinical coronary atherosclerosis.

Prevalence and severity of menopause symptoms and associated factors across menopause status in Korean women.

Objective:The present study investigated the prevalence and severity of menopause symptoms experienced by Korean women aged 44 to 56 years and their associated factors. Methods:A cross-sectional study was performed on 2,201 women aged 44 to 56 years in health checkup centers between November 2012 and March 2013. The 29-item Menopause-Specific Quality of Life Questionnaire was used to assess vasomotor, psychosocial, physical, and sexual symptoms related to menopause. The guidelines for the classification of reproductive aging stages proposed at the Stages of Reproductive Aging Workshop were used. Multivariable linear regression analyses were performed to identify factors associated with severity of menopause symptoms. Results:Among participants, 42.6% were premenopausal, 36.7% were perimenopausal, and 20.7% were postmenopausal. Although physical symptoms were the most severe menopause symptoms experienced by premenopausal and perimenopausal women, postmenopausal women reported sexual symptoms as the most bothersome. The mean scores for each domain increased from the premenopausal period through the postmenopausal period (P for trend < 0.001). The regression model revealed that age (for vasomotor and sexual symptoms) and obesity (for vasomotor and physical symptoms) were significantly associated with severity of menopause symptoms (P < 0.05). Physically active women had fewer severe physical symptoms related to menopause than inactive women. Conclusions:Postmenopausal women experience the most severe symptoms. Obesity and physical activity are the main modifiable factors associated with symptom severity. Further studies are needed to examine the effects of physical activity promotion and weight control interventions on preventing menopause symptoms in Korean women.

Menopausal stages and non-alcoholic fatty liver disease in middle-aged women

OBJECTIVES There is no established evidence regarding the influence of the menopausal transition period on non-alcoholic fatty liver disease (NAFLD). The goal of this study was to examine the association between menopausal stages and the prevalence of NAFLD in middle-aged Korean women. METHODS This study was a cross-sectional analysis of 1559 women aged 44-56 years, who underwent a comprehensive health screening examination in the Kangbuk Samsung Hospital Total Healthcare Centers during 2012 and 2013. Information regarding menopause status was collected using a standardized, self-administered questionnaire. The presence of fatty liver was determined using ultrasonography. Menopausal stages were defined according to the criteria of the Stages of Reproductive Aging Workshop (STRAW+10) as follows: early menopausal transition was defined as a persistent difference in consecutive menstrual cycle length of seven or more days; late menopausal transition was defined as having an interval of amenorrhea of 60 days or more; post-menopause was defined as the absence of menstrual periods for 12 or more months since the last period; pre-menopause was defined as having a regular menstrual cycle and not meeting the above criteria. Odds ratios and 95% confidence intervals for NAFLD were estimated by menopausal stages. RESULTS Of the 1559 women, 334 had NAFLD. A higher prevalence of NAFLD was observed across menopausal stages (p for trend <0.05). After adjusting for age, center, BMI, smoking status, alcohol intake, physical activity, educational level, parity and age at menarche, the odds ratios (95% CIs) for NAFLD comparing early transition, late transition, and post-menopause to pre-menopause were 1.07 (0.68-1.67), 1.87 (1.23-2.85), and 1.67 (1.01-2.78), respectively. CONCLUSIONS This study performed in middle-aged Korean women suggests that there is an increased prevalence of NAFLD in the late menopausal transition as well as post-menopausal stages, independent of a variety of potential confounders. The findings of this study suggest that early intervention strategies implemented before women begin to experience the menopausal transition are needed to reduce the risk of NAFLD.

Dietary sodium and potassium intake in relation to non-alcoholic fatty liver disease.

A few epidemiological data are available assessing the associations of intakes of sodium (Na) and potassium (K) with non-alcoholic fatty liver disease (NAFLD). We aimed to examine the associations of dietary intake of Na and K with the prevalence of ultrasound-diagnosed NAFLD. We performed a cross-sectional study of 100 177 participants (46 596 men and 53 581 women) who underwent a health screening examination and completed a FFQ at the Kangbuk Samsung Hospital Total Healthcare Centers, South Korea, between 2011 and 2013. NAFLD was defined by ultrasonographic detection of fatty liver in the absence of excessive alcohol intake or other known causes of liver disease. The proportion of NAFLD was 35·6 % for men and 9·8 % for women. Increasing prevalence of NAFLD was observed with increasing Na intake. The multivariable-adjusted prevalence ratios (PR) of NAFLD comparing the highest with the lowest quintile of energy-adjusted Na intake were 1·25 (95 % CI 1·18, 1·32; P trend<0·001) in men and 1·32 (95 % CI 1·18, 1·47; P trend <0·001) in women. However, when we additionally adjusted for body fat percentage, the association became attenuated; the corresponding PR of NAFLD were 1·15 (95 % CI 1·09, 1·21) in men and 1·06 (95 % CI 0·95, 1·17) in women. No inverse association was observed for energy-adjusted K intake. Our findings suggest that higher Na intake is associated with a greater prevalence of NAFLD in young and middle-aged asymptomatic adults, which might be partly mediated by adiposity.