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Increased association of coronary artery calcification in apparently healthy Korean adults with hypertriglyceridemic waist phenotype: The Kangbuk Samsung Health Study
International Journal of Cardiology 194 (2015) 78–82
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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Increased association of coronary artery calcification in apparently healthy Korean adults with hypertriglyceridemic waist phenotype: The Kangbuk Samsung Health Study Byung Sub Moon, Hye-Jeong Park, Min-Kyung Lee, Won Seon Jeon, Se Eun Park, Cheol-Young Park, Won-Yong Lee, Ki-Won Oh, Sung-Woo Park, Eun-Jung Rhee ⁎ Department of Endocrinology and Metabolism, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
a r t i c l e
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Article history: Received 9 January 2015 Received in revised form 11 May 2015 Accepted 17 May 2015 Available online 19 May 2015 Keywords: Hypertriglyceridemia Abdominal obesity Coronary artery calcification
a b s t r a c t Background: Hypertriglyceridemic waist phenotype is a simple screening parameter to identify people at increased risk for cardiovascular disease. We evaluated whether hypertriglyceridemic waist (HTGW) phenotype increases the risk for coronary artery calcification (CAC) in apparently healthy Korean adults. Methods: A total of 32,186 participants (mean age 41.3, 80.2% men) in a health screening program, in whom the coronary artery calcium score (CACS) was measured, were analyzed. Subjects were divided into four groups: 1) normal waist circumference (WC)–normal triglyceride (TG) (NWNT), 2) normal WC–high TG (NWHT), 3) enlarged WC–normal TG (EWNT), and 4) enlarged WC–high TG (EWHT). Enlarged WC was defined as WC ≥ 90 cm for men and ≥ 85 cm for women; high serum TG was defined as TG ≥ 150 mg/dL. The presence of CAC was defined by CACS N0, and CACS was analyzed in a logarithmized form of CACS plus 1 {ln(CACS + 1)}. Results: A total of 14.9% of the participants had CAC. The EWHT group showed the highest mean value for ln(CACS + 1) among the four groups. The EWHT group showed the highest odds ratio for CAC, with NWHT group the second, and with EWNT group the third compared with the NWNT group after adjusting for confounding variables (1.579, 1.302, and 1.266 vs. NWNT). Conclusions: The EWHT group showed the highest association for CAC, suggesting this HTGW phenotype as a useful marker for the detection of subjects with high cardiometabolic risk in healthy Korean adults. © 2015 Published by Elsevier Ireland Ltd.
1. Introduction Metabolic syndrome (MetS) represents a constellation of metabolic derangements including abdominal obesity, high triglyceride (TG), low high-density lipoprotein cholesterol (HDL-C), hypertension, and glucose intolerance. The National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) report recommended the use of five variables to diagnose MetS, including waist circumference (WC), serum TG concentration, serum HDL-C concentration, blood pressure, and fasting glucose concentration. Individuals meeting three of these five criteria were classified as having MetS [1]. Although MetS is Abbreviations: HTGW, Hypertriglyceridemic waist; CAC, Coronary artery calcification; CACS, Coronary artery calcium score; WC, Waist circumference; TG, Triglyceride; NWNT, Normal waist circumference, normal triglyceride; EWNT, Enlarged waist circumference, normal triglyceride; NWHT, Normal waist circumference, high triglyceride; EWHT, Enlarged waist circumference, high triglyceride; MetS, Metabolic syndrome; CVD, Cardiovascular disease. ⁎ Corresponding author at: Department of Endocrinology and Metabolism, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, 108 Pyungdong, Jongro-ku, Seoul 110-746, Republic of Korea. E-mail address: [email protected] (E.-J. Rhee).
http://dx.doi.org/10.1016/j.ijcard.2015.05.104 0167-5273/© 2015 Published by Elsevier Ireland Ltd.
important in understanding the pathophysiology of the interrelated cardiovascular risk factors, its practical value is debatable. Some studies indicate that MetS is less effective in predicting cardiovascular disease (CVD) than the established predicting models that are designed specifically for these purposes [2]. From a clinical or public health perspective, MetS is useful only if it identifies individuals at high risk of disease. The Quebec Cardiovascular Study group introduced “hypertriglyceridemic waist,” defined as both hypertriglyceridemia and increased WC, as a marker of atherogenic metabolic profile in men and demonstrated its value in estimating the 5-year risk for cardiovascular events [3–5]. A 7.5-year prospective study of 3430 middle-aged men, using low WC and low TG concentrations as a reference group, reported that the risk of developing CVD over the follow-up period was significantly increased only among men with the hypertriglyceridemic waist (HTGW) phenotype [6]. There have been many efforts to find the appropriate atherosclerosis screening marker for early detection and prevention of overt CVD. Both the presence and degree of coronary artery calcification are strong predictors of incident coronary heart disease, as markers for atherosclerosis, and are positively associated with CVD events [7,8]. To date, few studies have investigated the relationship between HTGW phenotype
B.S. Moon et al. / International Journal of Cardiology 194 (2015) 78–82
and coronary artery calcium score (CACS), especially in healthy Korean adults. In this article, we evaluated the relationship between HTGW phenotype and coronary artery calcification assessed by multidetector computed tomography (MDCT) in apparently healthy Korean adults.
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For the assessment of remnant renal function, estimated glomerular filtration rate (eGFR) was calculated by the formula from Modification of Diet in Renal Disease Study Group [10]: −1:154
eGFR ¼ 186 Serum Crðmg=dLÞ ½0:742 if female
Age−0:203
2. Methods 2.1. Study subjects
2.3. Measurement of CACS
This was a cross-sectional study, and subjects were participants in the Kangbuk Samsung Health Study, a large database of a medical health checkup program at the Health Promotion Center of Kangbuk Samsung Hospital, Sungkyunkwan University, Seoul, Korea. The purpose of the medical health checkup program is to promote the health of employees through a regular health checkup and to enhance early detection of existing diseases. Of the 34,462 subjects who participated in the checkup program between January 2010 and December 2012, we excluded subjects with a self-reported history of ischemic heart disease (n = 419) or ischemic stroke (n = 270) and subjects who were taking aspirin (n = 38) or a statin (n = 1249). Final analyses were performed in 32,186 subjects (25,823 men and 6363 women) with a mean age of 41.3 years. The participants provided their written informed consent for the usage of the medical check-up data for the research. The design, protocol and the consent procedure of this study were reviewed and approved by Institutional Review Board of Kangbuk Samsung Hospital (KBS12089) and is in accordance with the Helsinki Declaration of 1975.
MDCT for coronary calcium scoring was undertaken by a 64-slice, spiral computed tomography scan (GE Health Care, Tokyo, Japan), using the software HEARTBEAT-CS (Philips, Cleveland, Ohio, USA). The 64-slice MDCT was performed using the following protocol: 0.625 mm slice thickness, 120 kVP, 800 effective mAs, and a 400 msec rotational speed. Severity of coronary artery calcification was assessed by the Agatston score [11]. The total CACS was determined by the sum of the individual scores for the four major epicardial coronary arteries: left main, left anterior descending, left circumflex, and right coronary artery. The technicians who perform MDCT are blinded to any information of patients, and CACS is automatically detected using the above software. The presence of coronary artery calcification was defined by CACS N0 and further subdivided into 0 b CACS b 100 and CACS ≥ 100. CACS was analyzed in logarithmized form of CACS plus 1 {ln(CACS + 1)}.
2.2. Anthropometric and laboratory measurements
2.4. Definition of HTGW phenotype Participants were divided into four groups according to their TG and WC measurements: normal WC–normal TG (NWNT), normal WC–high TG (NWHT), enlarged WC–normal TG (EWNT), and enlarged WC–high TG (EWHT). Enlarged WC was defined as WC ≥90 cm for men and WC ≥85 cm for women; and high serum TG was defined as TG ≥150 mg/dL. 2.5. Statistical analysis
Height and weight were measured by well-trained nurses with subjects wearing lightweight gowns. The participants' WC was measured at the midpoint between the top of the iliac crest and the lower border of the last palpable rib by a well-trained examiner. Body mass index (BMI) was calculated by dividing the weight (kg) by the square of the height (m). Blood pressure was measured using a standardized sphygmomanometer after 5 min of rest. Systolic blood pressure and diastolic blood pressure were measured three times with participants in the seated position, with 1 min of rest between each measurement. The average of the second and third measurements was used in the analysis. Blood samples were taken from the antecubital vein after an overnight fast. The hexokinase method was used to test fasting glucose concentrations (Hitachi Modular D2400; Roche, Tokyo, Japan). Fasting insulin concentrations were determined by electrochemiluminescence immunoassay (Hitachi Modular E170; Roche, Tokyo, Japan). An enzymatic calorimetric test was used to measure total cholesterol and TG concentrations. The selective inhibition method was used to measure HDL-C levels, and a homogeneous enzymatic calorimetric test was used to measure low-density lipoprotein cholesterol levels. Serum high-sensitivity C-reactive protein (hs-CRP) levels were measured using a nephelometric assay with a BNII nephelometer (Dade Behring, Deerfield, IL). Insulin resistance was measured using the homeostatic model of the assessment of insulin resistance (HOMA-IR) and was obtained by applying the following formula: HOMA-IR = fasting insulin (uIU/mL) × fasting blood glucose (mmol/L) / 22.5 [9]. Lifestyle habits were assessed by a selfquestionnaire. A smoker was defined as a subject who had ever smoked at least five packs of cigarettes in his or her life. Alcohol drinking was defined as a subject who drank more than 20 g of alcohol every day. Doing regular exercise was defined as exercise of moderate intensity at least three times every week.
All data were analyzed using SPSS Windows, version 18.0 (SPSS Inc., Chicago, IL, USA). Bivariate correlation analyses were performed
Table 1 General characteristics of the participants. Variables (N = 32,186)
Mean ± SD or N (%)
Age (y) Sex: male (%) BMI (kg/m2) SBP (mm Hg) FBS (mg/dL) Fasting insulin (uIU/mL) TC (mg/dL) TG (mg/dL) HDL-C (mg/dL) LDL-C (mg/dL) HbA1c (%) HOMA-IR hs-CRP (mg/dL) eGFR (mL/min) Subjects who have ever smoked (%) Alcohol drinking (%) Regular exercise (%) Calcification (%) CACS = 0 (%) 0 b CACS b 100 (%) CACS ≥ 100 (%)
41.3 ± 7.5 25,823 (80.2) 24.3 ± 3.1 113.5 ± 13.0 98.5 ± 16.4 6.2 ± 6.8 202.6 ± 35.1 135.6 ± 89.7 53.9 ± 13.5 129.3 ± 31.9 5.7 ± 0.5 1.5 ± 1.5 0.12 ± 0.4 92.0 ± 14.4 15,783 (49.0) 5545 (17.2) 6090 (18.9) 4543 (14.1) 27,643 (85.9) 3779 (11.7) 764 (2.4)
SD, standard deviation; BMI, body mass index; SBP, systolic blood pressure; FBS, fasting blood sugar; TC, total cholesterol; TG, triglyceride; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; HbA1c, glycated hemoglobin; HOMA-IR, homeostatic model of the assessment of insulin resistance; hs-CRP, high-sensitivity C-reactive protein; eGFR, estimated glomerular filtration rate; CACS, coronary artery calcium score.
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3.2. Correlation of CACS with variable parameters
Table 2 Bivariate correlation of ln(CACS + 1) with various parameters. Parameters
Correlation coefficient
Age BMI SBP FBS Fasting insulin TG HDL-C LDL-C HbA1c HOMA-IR hs-CRP eGFR
0.350⁎ 0.094⁎ 0.141⁎ 0.156⁎ 0.025⁎ 0.084⁎ −0.063⁎ 0.090⁎ 0.155⁎ 0.058⁎ 0.013⁎ −0.089⁎
Model 1 0.059⁎ 0.091⁎ 0.086⁎ 0.029⁎ 0.053⁎ −0.029⁎ 0.047⁎ 0.092⁎ 0.054⁎ 0.008 0.022⁎
Model 1, adjustment for age, sex, smoking, alcohol drinking, and regular exercise status. ln(CACS + 1), logarithmized form of coronary artery calcium score plus 1; BMI, body mass index; SBP, systolic blood pressure; FBS, fasting blood sugar; TG, triglyceride; LDL-C, low-density lipoprotein cholesterol; HbA1c, glycated hemoglobin; HOMA-IR, homeostatic model of the assessment of insulin resistance; hs-CRP, high-sensitivity C-reactive protein; eGFR, estimated glomerular filtration rate. ⁎ P b 0.05.
between ln(CACS + 1) and the variables using Pearson's correlation and partial correlation analyses. Comparisons of the mean values and the prevalence of metabolic variables among the four groups were performed with a one-way analysis of variance test and posthoc analyses with Tukey's b method; data that did not follow normal distribution were analyzed after logarithmic transformation. Binary logistic regression analysis was performed with coronary artery calcification as the dependent variable and other confounding variables included in the model. Statistical significance was defined as P value b 0.05.
3. Results 3.1. Baseline characteristics Participants' general characteristics are presented in Table 1. The mean age of the participants was 41.3 years (range 23–88 years), and 80.2% of the participants were male. The mean BMI was 24.3 kg/m2. Forty-nine percent of the study population had ever smoked at least five packs of cigarettes in his or her life. A total of 4543 (14.1%) subjects in the study population had coronary artery calcification (CACS N 0).
Bivariate correlation analyses were performed between CACS and multiple variables (Table 2). Age showed the highest correlation with CACS. When partial correlation analyses were performed with adjustment for age, sex, smoking, alcohol drinking, and regular exercise status, most of the parameters showed significant correlations with CACS except for the hs-CRP level. 3.3. Comparison of participants' baseline characteristics in groups according to WC and serum TG Subjects were divided into four groups according to their WC and serum TG measurements (Table 3): at baseline, there were 17,276 (53.7%) subjects in the NWNT group; 5434 (16.9%) in the NWHT group; 4957 (15.4%) in the EWNT group; and 4519 (14.0%) in the EWHT group. The proportion of subjects with coronary artery calcification (CACS N 0) was highest in the EWHT group (20.6%) and lowest in the NWNT group (10.9%). 3.4. Comparison of coronary artery calcification in groups according to TG levels and WC In a binary logistic regression analysis with coronary artery calcification as the dependent variable, the EWHT group showed the highest odds ratio (OR) at 1.579, the NWHT group showed an OR of 1.302, and the EWNT group showed an OR of 1.266—with NWNT group as the reference group—after adjusting for baseline confounding factors (Table 4). We compared coronary artery calcification among the four groups by natural logarithmic transformation. The EWHT group showed the highest mean value for ln(CACS + 1) (0.63 ± 1.42); the NWNT group showed the lowest mean value for ln(CACS + 1) (0.34 ± 1.09) among the four groups (P b 0.05 in post-hoc analysis, Fig. 1). However, there was no statistically significant difference between the NWHT and EWNT groups in post-hoc analysis, which showed mean values of 0.52 ± 1.31 and 0.51 ± 1.31, respectively. 4. Discussion In this large study of healthy Korean adults participating in a medical health screening program, the EWHT group showed the
Table 3 Comparison of baseline characteristics between the groups. N = 32,186
NWNT (n = 17,276)
NWHT (n = 5434)
EWNT (n = 4957)
EWHT (n = 4519)
P value
Age (y) Sex: male (%) BMI (kg/m2) SBP (mm Hg) FBS (mg/dL) Fasting insulin (uIU/mL) TC (mg/dL) TG (mg/dL) HDL-C (mg/dL) LDL-C (mg/dL) HbA1c (%) HOMA-IR hs-CRP (mg/dL) eGFR (mL/min) Subjects who have ever smoked (%) Alcohol drinking (%) Regular exercise (%) CACS N 0 (%)
41.0 ± 7.6a 12,562 (72.7%) 22.6 ± 2.2 110.1 ± 12.5 95.6 ± 12.9 4.7 ± 7.8 194.6 ± 32.4 89.4 ± 29.0 59.2 ± 13.4 122.5 ± 30.2 5.6 ± 0.4 1.1 ± 1.5 0.1 ± 0.4a 93.0 ± 14.6a 7115 (41.2%) 2451 (14.2%) 3598 (20.8%) 1875 (10.9%)
41.7 ± 6.8bc 5031 (92.6%) 23.9 ± 1.8 115.2 ± 12.0 101.5 ± 20.0 6.7 ± 3.3 215.5 ± 34.7 221.9 ± 91.5 46.4 ± 10.1 138.2 ± 31.8 5.8 ± 0.6a 1.7 ± 1.0 0.1 ± 0.2a 91.1 ± 14.2bc 3346 (61.6%)a 1153 (21.2%) 851 (15.7%)a 923 (17.0%)
41.9 ± 8.3b 4034 (81.4%) 27.3 ± 2.4 117.0 ± 12.3 99.7 ± 14.8 7.5 ± 4.4 201.4 ± 33.5 104.7 ± 27.0 52.6 ± 11.3 132.8 ± 30.9 5.8 ± 0.5a 1.9 ± 1.3 0.2 ± 0.4b 91.0 ± 14.2bd 2438 (49.2%) 880 (17.8%) 956 (19.3%) 813 (16.4%)
41.3 ± 7.1ac 4196 (92.9%) 28.0 ± 2.5 120.4 ± 12.4 104.8 ± 22.2 10.0 ± 5.6 218.8 ± 36.8 242.2 ± 117.0 44.0 ± 8.9 140.8 ± 33.0 5.9 ± 0.7 2.6 ± 1.8 0.1 ± 0.2b 90.6 ± 14.0cd 2884 (63.8%)a 1061 (23.5%) 685 (15.2%)a 932 (20.6%)
b0.01 b0.01 b0.01 b0.01 b0.01 b0.01 b0.01 b0.01 b0.01 b0.01 b0.01 b0.01 b0.01 b0.01 b0.01 b0.01 b0.01 b0.01
The same superscripted letters denote that there were no significant differences in the post-hoc analyses. BMI, body mass index; SBP, systolic blood pressure; FBS, fasting blood sugar; TC, total cholesterol; TG, triglyceride; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; HbA1c, glycated hemoglobin; HOMA-IR, homeostatic model of the assessment of insulin resistance; hs-CRP, high-sensitivity C-reactive protein; eGFR, estimated glomerular filtration rate; CACS, coronary artery calcium score.
B.S. Moon et al. / International Journal of Cardiology 194 (2015) 78–82 Table 4 Logistic regression analyses with coronary artery calcification as the dependent variable. 95% CI
NWNT NWHT EWNT EWHT
P value
Odds ratio
Lower
Upper
b0.001 b0.001 b0.001
1 1.322 1.284 1.587
1.200 1.156 1.430
1.457 1.426 1.760
Adjusted for age, sex, systolic blood pressure, fasting glucose, eGFR, smoking, alcohol drinking, and regular exercise status. CI, confidence interval; NWNT, normal waist circumference–normal triglyceride; NWHT, normal waist circumference–high triglyceride; EWNT, enlarged waist circumference–normal triglyceride; EWHT, enlarged waist circumference–high triglyceride; eGFR, estimated glomerular filtration rate.
highest association for coronary artery calcification among four groups divided by WC and serum TG. Since the Quebec Cardiovascular Study introduced the concept of the HTGW phenotype, there have been several studies suggesting a relationship between the HTGW phenotype and CVD [3–5]. Tanko et al. reported that an enlarged waist combined with elevated TG in postmenopausal women was associated with a 4.7-fold increased risk for fatal CVD events and suggested the relative advantage of the HTGW phenotype compared with the NCEP ATP III criteria for easier accessibility in general practice [12]. The Hoorn Study showed that the HTGW phenotype was associated with CVD in subjects with both normal and abnormal glucose metabolisms [13]. Czernichow et al. reported that the HTGW phenotype was associated with the risk of CVD after 7.5 years of follow-up in a low-risk, middle-aged male population [6]. Recently, Wang et al. analyzed 95,015 Asian participants in the Kailuan Study and reported that the HTGW phenotype was associated with the risk of CVD [14]. Arsenault et al. reported that the HTGW phenotype was predictive of increased coronary heart disease risk in both men and women who were followed for 9.8 years [15]. Results of our study are in line with previous studies. From these previous studies and the results of our study, we can conclude that the HTGW phenotype contributes to the development of atherosclerosis in healthy adults. Tanko et al. investigated the relative utility of EWHT compared with MetS (NCEP ATP III criteria) in estimating fatal CVD events and the annual progression rate of aortic calcification in 557 menopausal women [12]. The presence of EWHT was associated with a 4.7-fold increased risk for fatal CVD events and, among participants who were discordant for EWHT and MetS at baseline, those with EWHT alone had a higher annual progression rate of aortic calcification compared with those with MetS alone. Therefore, EWHT may be a better indicator of a CVD event than MetS, and other MetS components have little value for screening. This result is in line with our study that the HTGW phenotype may be
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a valuable diagnostic tool in identifying people at increased risk for CVD events. Recent studies have highlighted the importance of intra-abdominal adipose tissue, which is not simply a fat mass, but instead, is an active endocrine organ that modifies metabolic status [16]. Therefore, visceral adipose tissue accumulation may be a strong risk factor for MetS, especially subsequent CVD [17]. NCEP ATP III identified CVD as the primary clinical outcome of MetS [1], and future risk of CVD events can be reflected by the CACS [18]. Cao et al. reported in a community-based, natural population study that MetS increases the risk of coronary artery calcification and that the risk of coronary artery calcification increases with increased numbers of MetS components [19]. In our study, CACS was measured in more than 30,000 subjects of both genders, and we adopted various components that reflect metabolic health, including lipid profiles, hs-CRP, and HOMA-IR. However, this study has several limitations. First, because the study population was not representative of the Korean population, the results of our study cannot be extrapolated to the entire Korean population. Second, because our study was cross-sectional, a cause-and-effect relationship cannot be determined from it. Third, our study lacked substantial numbers of female subjects (25,823 men and 6363 women). Fourth, we lacked data on other cardiac markers besides CACS. Therefore, we could not identify the cardiac functional status of each groups. Fifth, subjects were classified into simple two groups according to CACS: zero of CACS or over. Because participants of our study were relative fit in medical health checkup program, there were small portion of subjects with CACS over zero (n = 4543, 14.1%). Sixth, there could be a possibility of ‘within subject variability’ for subjects with very low CACS, that is, lower than 10 but higher than 0. In a previous study performed in subjects from MESA study, interscan variability was considerably high for patients with calcium scores lower than 30 [20]. Although it is well-known that compared with subjects with zero calcium score, the presence of CAC at very low levels (N 0 to 10 Agatston units) is correlated with higher risk for CAC progression and CVD, the reliability for the predictive value of very low CACS needs further validation [21]. Despite these limitations, the results of our study have significant clinical implication. In conclusion, we found that the EWHT group showed the highest correlation with coronary artery calcification among the four groups in this study. This suggests the HTGW phenotype as not only a screening tool for metabolic derangement, but also a simple marker of early atherosclerosis in apparently healthy Korean subjects. Future research is needed to determine whether the HTGW phenotype is associated with CVD in various study populations. Conflict of interest This paper has not been published in part or in its entirety and is not under consideration by another journal. All authors have nothing to declare. References
Fig. 1. Comparison of the coronary artery calcium score according to the four groups divided by TG levels and WC in this study. TG, triglyceride; WC, waist circumference; ANOVA, analysis of variance; EWHT, enlarged waist circumference–high triglyceride; EWNT, enlarged waist circumference–normal triglyceride; ln(CACS + 1), logarithmized form of coronary artery calcium score plus 1; NWHT, normal waist circumference–high triglyceride; NWNT, normal waist circumference–normal triglyceride.
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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Increased association of coronary artery calcification in apparently healthy Korean adults with hypertriglyceridemic waist phenotype: The Kangbuk Samsung Health Study Byung Sub Moon, Hye-Jeong Park, Min-Kyung Lee, Won Seon Jeon, Se Eun Park, Cheol-Young Park, Won-Yong Lee, Ki-Won Oh, Sung-Woo Park, Eun-Jung Rhee ⁎ Department of Endocrinology and Metabolism, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
a r t i c l e
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Article history: Received 9 January 2015 Received in revised form 11 May 2015 Accepted 17 May 2015 Available online 19 May 2015 Keywords: Hypertriglyceridemia Abdominal obesity Coronary artery calcification
a b s t r a c t Background: Hypertriglyceridemic waist phenotype is a simple screening parameter to identify people at increased risk for cardiovascular disease. We evaluated whether hypertriglyceridemic waist (HTGW) phenotype increases the risk for coronary artery calcification (CAC) in apparently healthy Korean adults. Methods: A total of 32,186 participants (mean age 41.3, 80.2% men) in a health screening program, in whom the coronary artery calcium score (CACS) was measured, were analyzed. Subjects were divided into four groups: 1) normal waist circumference (WC)–normal triglyceride (TG) (NWNT), 2) normal WC–high TG (NWHT), 3) enlarged WC–normal TG (EWNT), and 4) enlarged WC–high TG (EWHT). Enlarged WC was defined as WC ≥ 90 cm for men and ≥ 85 cm for women; high serum TG was defined as TG ≥ 150 mg/dL. The presence of CAC was defined by CACS N0, and CACS was analyzed in a logarithmized form of CACS plus 1 {ln(CACS + 1)}. Results: A total of 14.9% of the participants had CAC. The EWHT group showed the highest mean value for ln(CACS + 1) among the four groups. The EWHT group showed the highest odds ratio for CAC, with NWHT group the second, and with EWNT group the third compared with the NWNT group after adjusting for confounding variables (1.579, 1.302, and 1.266 vs. NWNT). Conclusions: The EWHT group showed the highest association for CAC, suggesting this HTGW phenotype as a useful marker for the detection of subjects with high cardiometabolic risk in healthy Korean adults. © 2015 Published by Elsevier Ireland Ltd.
1. Introduction Metabolic syndrome (MetS) represents a constellation of metabolic derangements including abdominal obesity, high triglyceride (TG), low high-density lipoprotein cholesterol (HDL-C), hypertension, and glucose intolerance. The National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) report recommended the use of five variables to diagnose MetS, including waist circumference (WC), serum TG concentration, serum HDL-C concentration, blood pressure, and fasting glucose concentration. Individuals meeting three of these five criteria were classified as having MetS [1]. Although MetS is Abbreviations: HTGW, Hypertriglyceridemic waist; CAC, Coronary artery calcification; CACS, Coronary artery calcium score; WC, Waist circumference; TG, Triglyceride; NWNT, Normal waist circumference, normal triglyceride; EWNT, Enlarged waist circumference, normal triglyceride; NWHT, Normal waist circumference, high triglyceride; EWHT, Enlarged waist circumference, high triglyceride; MetS, Metabolic syndrome; CVD, Cardiovascular disease. ⁎ Corresponding author at: Department of Endocrinology and Metabolism, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, 108 Pyungdong, Jongro-ku, Seoul 110-746, Republic of Korea. E-mail address: [email protected] (E.-J. Rhee).
http://dx.doi.org/10.1016/j.ijcard.2015.05.104 0167-5273/© 2015 Published by Elsevier Ireland Ltd.
important in understanding the pathophysiology of the interrelated cardiovascular risk factors, its practical value is debatable. Some studies indicate that MetS is less effective in predicting cardiovascular disease (CVD) than the established predicting models that are designed specifically for these purposes [2]. From a clinical or public health perspective, MetS is useful only if it identifies individuals at high risk of disease. The Quebec Cardiovascular Study group introduced “hypertriglyceridemic waist,” defined as both hypertriglyceridemia and increased WC, as a marker of atherogenic metabolic profile in men and demonstrated its value in estimating the 5-year risk for cardiovascular events [3–5]. A 7.5-year prospective study of 3430 middle-aged men, using low WC and low TG concentrations as a reference group, reported that the risk of developing CVD over the follow-up period was significantly increased only among men with the hypertriglyceridemic waist (HTGW) phenotype [6]. There have been many efforts to find the appropriate atherosclerosis screening marker for early detection and prevention of overt CVD. Both the presence and degree of coronary artery calcification are strong predictors of incident coronary heart disease, as markers for atherosclerosis, and are positively associated with CVD events [7,8]. To date, few studies have investigated the relationship between HTGW phenotype
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and coronary artery calcium score (CACS), especially in healthy Korean adults. In this article, we evaluated the relationship between HTGW phenotype and coronary artery calcification assessed by multidetector computed tomography (MDCT) in apparently healthy Korean adults.
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For the assessment of remnant renal function, estimated glomerular filtration rate (eGFR) was calculated by the formula from Modification of Diet in Renal Disease Study Group [10]: −1:154
eGFR ¼ 186 Serum Crðmg=dLÞ ½0:742 if female
Age−0:203
2. Methods 2.1. Study subjects
2.3. Measurement of CACS
This was a cross-sectional study, and subjects were participants in the Kangbuk Samsung Health Study, a large database of a medical health checkup program at the Health Promotion Center of Kangbuk Samsung Hospital, Sungkyunkwan University, Seoul, Korea. The purpose of the medical health checkup program is to promote the health of employees through a regular health checkup and to enhance early detection of existing diseases. Of the 34,462 subjects who participated in the checkup program between January 2010 and December 2012, we excluded subjects with a self-reported history of ischemic heart disease (n = 419) or ischemic stroke (n = 270) and subjects who were taking aspirin (n = 38) or a statin (n = 1249). Final analyses were performed in 32,186 subjects (25,823 men and 6363 women) with a mean age of 41.3 years. The participants provided their written informed consent for the usage of the medical check-up data for the research. The design, protocol and the consent procedure of this study were reviewed and approved by Institutional Review Board of Kangbuk Samsung Hospital (KBS12089) and is in accordance with the Helsinki Declaration of 1975.
MDCT for coronary calcium scoring was undertaken by a 64-slice, spiral computed tomography scan (GE Health Care, Tokyo, Japan), using the software HEARTBEAT-CS (Philips, Cleveland, Ohio, USA). The 64-slice MDCT was performed using the following protocol: 0.625 mm slice thickness, 120 kVP, 800 effective mAs, and a 400 msec rotational speed. Severity of coronary artery calcification was assessed by the Agatston score [11]. The total CACS was determined by the sum of the individual scores for the four major epicardial coronary arteries: left main, left anterior descending, left circumflex, and right coronary artery. The technicians who perform MDCT are blinded to any information of patients, and CACS is automatically detected using the above software. The presence of coronary artery calcification was defined by CACS N0 and further subdivided into 0 b CACS b 100 and CACS ≥ 100. CACS was analyzed in logarithmized form of CACS plus 1 {ln(CACS + 1)}.
2.2. Anthropometric and laboratory measurements
2.4. Definition of HTGW phenotype Participants were divided into four groups according to their TG and WC measurements: normal WC–normal TG (NWNT), normal WC–high TG (NWHT), enlarged WC–normal TG (EWNT), and enlarged WC–high TG (EWHT). Enlarged WC was defined as WC ≥90 cm for men and WC ≥85 cm for women; and high serum TG was defined as TG ≥150 mg/dL. 2.5. Statistical analysis
Height and weight were measured by well-trained nurses with subjects wearing lightweight gowns. The participants' WC was measured at the midpoint between the top of the iliac crest and the lower border of the last palpable rib by a well-trained examiner. Body mass index (BMI) was calculated by dividing the weight (kg) by the square of the height (m). Blood pressure was measured using a standardized sphygmomanometer after 5 min of rest. Systolic blood pressure and diastolic blood pressure were measured three times with participants in the seated position, with 1 min of rest between each measurement. The average of the second and third measurements was used in the analysis. Blood samples were taken from the antecubital vein after an overnight fast. The hexokinase method was used to test fasting glucose concentrations (Hitachi Modular D2400; Roche, Tokyo, Japan). Fasting insulin concentrations were determined by electrochemiluminescence immunoassay (Hitachi Modular E170; Roche, Tokyo, Japan). An enzymatic calorimetric test was used to measure total cholesterol and TG concentrations. The selective inhibition method was used to measure HDL-C levels, and a homogeneous enzymatic calorimetric test was used to measure low-density lipoprotein cholesterol levels. Serum high-sensitivity C-reactive protein (hs-CRP) levels were measured using a nephelometric assay with a BNII nephelometer (Dade Behring, Deerfield, IL). Insulin resistance was measured using the homeostatic model of the assessment of insulin resistance (HOMA-IR) and was obtained by applying the following formula: HOMA-IR = fasting insulin (uIU/mL) × fasting blood glucose (mmol/L) / 22.5 [9]. Lifestyle habits were assessed by a selfquestionnaire. A smoker was defined as a subject who had ever smoked at least five packs of cigarettes in his or her life. Alcohol drinking was defined as a subject who drank more than 20 g of alcohol every day. Doing regular exercise was defined as exercise of moderate intensity at least three times every week.
All data were analyzed using SPSS Windows, version 18.0 (SPSS Inc., Chicago, IL, USA). Bivariate correlation analyses were performed
Table 1 General characteristics of the participants. Variables (N = 32,186)
Mean ± SD or N (%)
Age (y) Sex: male (%) BMI (kg/m2) SBP (mm Hg) FBS (mg/dL) Fasting insulin (uIU/mL) TC (mg/dL) TG (mg/dL) HDL-C (mg/dL) LDL-C (mg/dL) HbA1c (%) HOMA-IR hs-CRP (mg/dL) eGFR (mL/min) Subjects who have ever smoked (%) Alcohol drinking (%) Regular exercise (%) Calcification (%) CACS = 0 (%) 0 b CACS b 100 (%) CACS ≥ 100 (%)
41.3 ± 7.5 25,823 (80.2) 24.3 ± 3.1 113.5 ± 13.0 98.5 ± 16.4 6.2 ± 6.8 202.6 ± 35.1 135.6 ± 89.7 53.9 ± 13.5 129.3 ± 31.9 5.7 ± 0.5 1.5 ± 1.5 0.12 ± 0.4 92.0 ± 14.4 15,783 (49.0) 5545 (17.2) 6090 (18.9) 4543 (14.1) 27,643 (85.9) 3779 (11.7) 764 (2.4)
SD, standard deviation; BMI, body mass index; SBP, systolic blood pressure; FBS, fasting blood sugar; TC, total cholesterol; TG, triglyceride; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; HbA1c, glycated hemoglobin; HOMA-IR, homeostatic model of the assessment of insulin resistance; hs-CRP, high-sensitivity C-reactive protein; eGFR, estimated glomerular filtration rate; CACS, coronary artery calcium score.
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3.2. Correlation of CACS with variable parameters
Table 2 Bivariate correlation of ln(CACS + 1) with various parameters. Parameters
Correlation coefficient
Age BMI SBP FBS Fasting insulin TG HDL-C LDL-C HbA1c HOMA-IR hs-CRP eGFR
0.350⁎ 0.094⁎ 0.141⁎ 0.156⁎ 0.025⁎ 0.084⁎ −0.063⁎ 0.090⁎ 0.155⁎ 0.058⁎ 0.013⁎ −0.089⁎
Model 1 0.059⁎ 0.091⁎ 0.086⁎ 0.029⁎ 0.053⁎ −0.029⁎ 0.047⁎ 0.092⁎ 0.054⁎ 0.008 0.022⁎
Model 1, adjustment for age, sex, smoking, alcohol drinking, and regular exercise status. ln(CACS + 1), logarithmized form of coronary artery calcium score plus 1; BMI, body mass index; SBP, systolic blood pressure; FBS, fasting blood sugar; TG, triglyceride; LDL-C, low-density lipoprotein cholesterol; HbA1c, glycated hemoglobin; HOMA-IR, homeostatic model of the assessment of insulin resistance; hs-CRP, high-sensitivity C-reactive protein; eGFR, estimated glomerular filtration rate. ⁎ P b 0.05.
between ln(CACS + 1) and the variables using Pearson's correlation and partial correlation analyses. Comparisons of the mean values and the prevalence of metabolic variables among the four groups were performed with a one-way analysis of variance test and posthoc analyses with Tukey's b method; data that did not follow normal distribution were analyzed after logarithmic transformation. Binary logistic regression analysis was performed with coronary artery calcification as the dependent variable and other confounding variables included in the model. Statistical significance was defined as P value b 0.05.
3. Results 3.1. Baseline characteristics Participants' general characteristics are presented in Table 1. The mean age of the participants was 41.3 years (range 23–88 years), and 80.2% of the participants were male. The mean BMI was 24.3 kg/m2. Forty-nine percent of the study population had ever smoked at least five packs of cigarettes in his or her life. A total of 4543 (14.1%) subjects in the study population had coronary artery calcification (CACS N 0).
Bivariate correlation analyses were performed between CACS and multiple variables (Table 2). Age showed the highest correlation with CACS. When partial correlation analyses were performed with adjustment for age, sex, smoking, alcohol drinking, and regular exercise status, most of the parameters showed significant correlations with CACS except for the hs-CRP level. 3.3. Comparison of participants' baseline characteristics in groups according to WC and serum TG Subjects were divided into four groups according to their WC and serum TG measurements (Table 3): at baseline, there were 17,276 (53.7%) subjects in the NWNT group; 5434 (16.9%) in the NWHT group; 4957 (15.4%) in the EWNT group; and 4519 (14.0%) in the EWHT group. The proportion of subjects with coronary artery calcification (CACS N 0) was highest in the EWHT group (20.6%) and lowest in the NWNT group (10.9%). 3.4. Comparison of coronary artery calcification in groups according to TG levels and WC In a binary logistic regression analysis with coronary artery calcification as the dependent variable, the EWHT group showed the highest odds ratio (OR) at 1.579, the NWHT group showed an OR of 1.302, and the EWNT group showed an OR of 1.266—with NWNT group as the reference group—after adjusting for baseline confounding factors (Table 4). We compared coronary artery calcification among the four groups by natural logarithmic transformation. The EWHT group showed the highest mean value for ln(CACS + 1) (0.63 ± 1.42); the NWNT group showed the lowest mean value for ln(CACS + 1) (0.34 ± 1.09) among the four groups (P b 0.05 in post-hoc analysis, Fig. 1). However, there was no statistically significant difference between the NWHT and EWNT groups in post-hoc analysis, which showed mean values of 0.52 ± 1.31 and 0.51 ± 1.31, respectively. 4. Discussion In this large study of healthy Korean adults participating in a medical health screening program, the EWHT group showed the
Table 3 Comparison of baseline characteristics between the groups. N = 32,186
NWNT (n = 17,276)
NWHT (n = 5434)
EWNT (n = 4957)
EWHT (n = 4519)
P value
Age (y) Sex: male (%) BMI (kg/m2) SBP (mm Hg) FBS (mg/dL) Fasting insulin (uIU/mL) TC (mg/dL) TG (mg/dL) HDL-C (mg/dL) LDL-C (mg/dL) HbA1c (%) HOMA-IR hs-CRP (mg/dL) eGFR (mL/min) Subjects who have ever smoked (%) Alcohol drinking (%) Regular exercise (%) CACS N 0 (%)
41.0 ± 7.6a 12,562 (72.7%) 22.6 ± 2.2 110.1 ± 12.5 95.6 ± 12.9 4.7 ± 7.8 194.6 ± 32.4 89.4 ± 29.0 59.2 ± 13.4 122.5 ± 30.2 5.6 ± 0.4 1.1 ± 1.5 0.1 ± 0.4a 93.0 ± 14.6a 7115 (41.2%) 2451 (14.2%) 3598 (20.8%) 1875 (10.9%)
41.7 ± 6.8bc 5031 (92.6%) 23.9 ± 1.8 115.2 ± 12.0 101.5 ± 20.0 6.7 ± 3.3 215.5 ± 34.7 221.9 ± 91.5 46.4 ± 10.1 138.2 ± 31.8 5.8 ± 0.6a 1.7 ± 1.0 0.1 ± 0.2a 91.1 ± 14.2bc 3346 (61.6%)a 1153 (21.2%) 851 (15.7%)a 923 (17.0%)
41.9 ± 8.3b 4034 (81.4%) 27.3 ± 2.4 117.0 ± 12.3 99.7 ± 14.8 7.5 ± 4.4 201.4 ± 33.5 104.7 ± 27.0 52.6 ± 11.3 132.8 ± 30.9 5.8 ± 0.5a 1.9 ± 1.3 0.2 ± 0.4b 91.0 ± 14.2bd 2438 (49.2%) 880 (17.8%) 956 (19.3%) 813 (16.4%)
41.3 ± 7.1ac 4196 (92.9%) 28.0 ± 2.5 120.4 ± 12.4 104.8 ± 22.2 10.0 ± 5.6 218.8 ± 36.8 242.2 ± 117.0 44.0 ± 8.9 140.8 ± 33.0 5.9 ± 0.7 2.6 ± 1.8 0.1 ± 0.2b 90.6 ± 14.0cd 2884 (63.8%)a 1061 (23.5%) 685 (15.2%)a 932 (20.6%)
b0.01 b0.01 b0.01 b0.01 b0.01 b0.01 b0.01 b0.01 b0.01 b0.01 b0.01 b0.01 b0.01 b0.01 b0.01 b0.01 b0.01 b0.01
The same superscripted letters denote that there were no significant differences in the post-hoc analyses. BMI, body mass index; SBP, systolic blood pressure; FBS, fasting blood sugar; TC, total cholesterol; TG, triglyceride; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; HbA1c, glycated hemoglobin; HOMA-IR, homeostatic model of the assessment of insulin resistance; hs-CRP, high-sensitivity C-reactive protein; eGFR, estimated glomerular filtration rate; CACS, coronary artery calcium score.
B.S. Moon et al. / International Journal of Cardiology 194 (2015) 78–82 Table 4 Logistic regression analyses with coronary artery calcification as the dependent variable. 95% CI
NWNT NWHT EWNT EWHT
P value
Odds ratio
Lower
Upper
b0.001 b0.001 b0.001
1 1.322 1.284 1.587
1.200 1.156 1.430
1.457 1.426 1.760
Adjusted for age, sex, systolic blood pressure, fasting glucose, eGFR, smoking, alcohol drinking, and regular exercise status. CI, confidence interval; NWNT, normal waist circumference–normal triglyceride; NWHT, normal waist circumference–high triglyceride; EWNT, enlarged waist circumference–normal triglyceride; EWHT, enlarged waist circumference–high triglyceride; eGFR, estimated glomerular filtration rate.
highest association for coronary artery calcification among four groups divided by WC and serum TG. Since the Quebec Cardiovascular Study introduced the concept of the HTGW phenotype, there have been several studies suggesting a relationship between the HTGW phenotype and CVD [3–5]. Tanko et al. reported that an enlarged waist combined with elevated TG in postmenopausal women was associated with a 4.7-fold increased risk for fatal CVD events and suggested the relative advantage of the HTGW phenotype compared with the NCEP ATP III criteria for easier accessibility in general practice [12]. The Hoorn Study showed that the HTGW phenotype was associated with CVD in subjects with both normal and abnormal glucose metabolisms [13]. Czernichow et al. reported that the HTGW phenotype was associated with the risk of CVD after 7.5 years of follow-up in a low-risk, middle-aged male population [6]. Recently, Wang et al. analyzed 95,015 Asian participants in the Kailuan Study and reported that the HTGW phenotype was associated with the risk of CVD [14]. Arsenault et al. reported that the HTGW phenotype was predictive of increased coronary heart disease risk in both men and women who were followed for 9.8 years [15]. Results of our study are in line with previous studies. From these previous studies and the results of our study, we can conclude that the HTGW phenotype contributes to the development of atherosclerosis in healthy adults. Tanko et al. investigated the relative utility of EWHT compared with MetS (NCEP ATP III criteria) in estimating fatal CVD events and the annual progression rate of aortic calcification in 557 menopausal women [12]. The presence of EWHT was associated with a 4.7-fold increased risk for fatal CVD events and, among participants who were discordant for EWHT and MetS at baseline, those with EWHT alone had a higher annual progression rate of aortic calcification compared with those with MetS alone. Therefore, EWHT may be a better indicator of a CVD event than MetS, and other MetS components have little value for screening. This result is in line with our study that the HTGW phenotype may be
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a valuable diagnostic tool in identifying people at increased risk for CVD events. Recent studies have highlighted the importance of intra-abdominal adipose tissue, which is not simply a fat mass, but instead, is an active endocrine organ that modifies metabolic status [16]. Therefore, visceral adipose tissue accumulation may be a strong risk factor for MetS, especially subsequent CVD [17]. NCEP ATP III identified CVD as the primary clinical outcome of MetS [1], and future risk of CVD events can be reflected by the CACS [18]. Cao et al. reported in a community-based, natural population study that MetS increases the risk of coronary artery calcification and that the risk of coronary artery calcification increases with increased numbers of MetS components [19]. In our study, CACS was measured in more than 30,000 subjects of both genders, and we adopted various components that reflect metabolic health, including lipid profiles, hs-CRP, and HOMA-IR. However, this study has several limitations. First, because the study population was not representative of the Korean population, the results of our study cannot be extrapolated to the entire Korean population. Second, because our study was cross-sectional, a cause-and-effect relationship cannot be determined from it. Third, our study lacked substantial numbers of female subjects (25,823 men and 6363 women). Fourth, we lacked data on other cardiac markers besides CACS. Therefore, we could not identify the cardiac functional status of each groups. Fifth, subjects were classified into simple two groups according to CACS: zero of CACS or over. Because participants of our study were relative fit in medical health checkup program, there were small portion of subjects with CACS over zero (n = 4543, 14.1%). Sixth, there could be a possibility of ‘within subject variability’ for subjects with very low CACS, that is, lower than 10 but higher than 0. In a previous study performed in subjects from MESA study, interscan variability was considerably high for patients with calcium scores lower than 30 [20]. Although it is well-known that compared with subjects with zero calcium score, the presence of CAC at very low levels (N 0 to 10 Agatston units) is correlated with higher risk for CAC progression and CVD, the reliability for the predictive value of very low CACS needs further validation [21]. Despite these limitations, the results of our study have significant clinical implication. In conclusion, we found that the EWHT group showed the highest correlation with coronary artery calcification among the four groups in this study. This suggests the HTGW phenotype as not only a screening tool for metabolic derangement, but also a simple marker of early atherosclerosis in apparently healthy Korean subjects. Future research is needed to determine whether the HTGW phenotype is associated with CVD in various study populations. Conflict of interest This paper has not been published in part or in its entirety and is not under consideration by another journal. All authors have nothing to declare. References
Fig. 1. Comparison of the coronary artery calcium score according to the four groups divided by TG levels and WC in this study. TG, triglyceride; WC, waist circumference; ANOVA, analysis of variance; EWHT, enlarged waist circumference–high triglyceride; EWNT, enlarged waist circumference–normal triglyceride; ln(CACS + 1), logarithmized form of coronary artery calcium score plus 1; NWHT, normal waist circumference–high triglyceride; NWNT, normal waist circumference–normal triglyceride.
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