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Apolipoprotein A-1 and arterial stiffness in metabolic syndrome
Clinica Chimica Acta 437 (2014) 115–119
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Association between Apolipoprotein B/Apolipoprotein A-1 and arterial stiffness in metabolic syndrome Min Kyung Kim a, Chul Woo Ahn a,b, Shinae Kang a,b, Ji Yoon Ha a, Haeri Baek a, Jong Suk Park a,b,⁎, Kyung Rae Kim a a b
Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea Severance Institute for Vascular and Metabolic Research, Yonsei University College of Medicine, Seoul, Republic of Korea
a r t i c l e
i n f o
Article history: Received 22 January 2014 Received in revised form 3 July 2014 Accepted 4 July 2014 Available online 12 July 2014 Keywords: Apolipoprotein B Apolipoprotein A-1 Apolipoprotein B/Apolipoprotein A-1 ratio Arterial stiffness Metabolic syndrome
a b s t r a c t Background: Apolipoprotein B/Apolipoprotein A-1 ratio (Apo B/Apo A-1) is known to be associated with atherosclerotic vascular disease. However, few studies have investigated the relationship between Apo B/Apo A-1 ratio and arterial stiffness, thus we investigated the relationships between Apo B/Apo A-1 and arterial stiffness in patients with metabolic syndrome (MetS). Methods: 1252 subjects with MetS according to the Adult Treatment Panel III were enrolled in our study. Anthropometric profiles and serum concentrations of Apo B, Apo A-1, fasting plasma glucose (FPG), total cholesterol (TC), triglycerides (TG), and high density lipoprotein cholesterol (HDL-C) were measured. Pulse wave velocity (PWV) was evaluated to assess arterial stiffness. Results: The subjects were stratified into four groups according to their Apo B/Apo A-1 ratios. PWV gradually increased according to Apo B/Apo A-1 quartiles. After adjusting for age, arterial stiffness was significantly correlated with systolic blood pressure, diastolic blood pressure, FPG, homeostasis model assessment (HOMAIR), Apo B and Apo B/Apo A-1. In multiple logistic regression analysis after adjusting for risk factors, Apo B/Apo A-1 ratio was a significant contributor to increased PWV. Conclusion: These results suggest that Apo B/Apo A-1 is independently associated with increased arterial stiffness in patients with MetS. © 2014 Elsevier B.V. All rights reserved.
1. Introduction Serum low density lipoprotein cholesterol (LDL-C) is associated with increased risk of cardiovascular disease [1], but recent studies indicate that Apolipoprotein B/Apolipoprotein A-1 (Apo B/Apo A-1) ratio is an even better indicator of atherosclerotic vascular disease [2–6]. Pulse wave velocity (PWV) is a non-invasive measurement method and is widely used as an index of arterial stiffness. Arterial stiffness is strongly associated with not only cardiovascular diseases and mortality [7–9], but also a marker of vascular damage caused by structural and functional changes within the arterial wall [10].
Abbreviations: MetS, metabolic syndrome; PWV, pulse wave velocity; FPG, fasting plasma glucose; TC, total cholesterol; HOMA-IR, homeostasis model assessment of insulin resistance; WC, waist circumference; cfPWV, carotid–femoral pulse wave velocity. ⁎ Corresponding author at: Division of Endocrinology, Department of Internal Medicine, Gangnam Severance Hospital, 146-92 Dogok-dong, Gangnam-ku, P.O. Box 135-720, Seoul, Republic of Korea. Tel.: +82 2 2019 4377; fax: +82 2 3463 3882. E-mail address: [email protected] (J.S. Park).
http://dx.doi.org/10.1016/j.cca.2014.07.005 0009-8981/© 2014 Elsevier B.V. All rights reserved.
Metabolic syndrome (MetS) is defined as the clustering of several cardiovascular risk factors including visceral obesity, impaired glucose intolerance, a high level of triglycerides (TG), a low level of high density cholesterol (HDL-C), and hypertension. The prevalence of metabolic syndrome is increasing worldwide. According to data from the National Health and Nutrition Examination Survey, the age-adjusted prevalence of metabolic syndrome is 34.2% in the U.S. [11]. This increasing trend also has been observed in Asian countries [12] and European populations [13]. MetS is considered common and is a recognized risk factor for atherosclerotic cardiovascular disease [14,15]. Although there have been numerous researches on the association between apo B and cardiovascular disease, there are a few reports with a small sample size on the direct relationship between Apo B and arterial stiffness [16,17]. Only one study reported an independent association between Apo B and arterial stiffness in general population [18]. There is no report of the relationship between Apo B/A1 ratio and arterial stiffness in patients with MetS. The present study was therefore designed to investigate the relationships between Apo B/Apo A-1 and arterial stiffness in Korean patients with MetS.
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2. Methods 2.1. Study participants We analyzed 1252 patients with MetS recruited from the Metabolic Syndrome Research Initiatives (MSRI) study. The MSRI study included 4253 participants who have more than one risk factor of MetS, recruited at 17 different tertiary medical centers from January 2006 through December 2007. This MSRI study is a population-based, multi-center cohort study, designed to evaluate the prevalence and characteristics of MetS and the occurrence of cardiovascular (CV) events in Seoul, Korea. Subjects were excluded if they were suspected of having a current acute illness including a clinically significant infectious disease or other malignancy, or if they were taking lipid-lowering medication (fibrate or statin). We also excluded subjects with a clinical history of cardiovascular disease, renal disease, or hepatic disease and pregnant or lactating women were also excluded. The Institutional Review Board of Yonsei University College of Medicine approved the study protocol, and written informed consent was obtained from all participants. 2.2. Definition of MetS MetS was defined according to the updated National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria applying Asia Pacific WHO guidelines for waist circumference (WC). Accordingly, subjects with three or more of the following characteristics were diagnosed with MetS: fasting plasma glucose ≥100 mg/dl or diabetes diagnosis, WC ≥90 cm for males and ≥80 cm for females, blood pressure (BP) ≥130/85 mm Hg or on BP medication, TG ≥ 150 mg/dl or on TG-lowering medication, and HDL-C b 40 mg/dl for males and b50 mg/dl for females. 2.3. Clinical characteristics Height, weight and WC were measured. Each personal medical history of acute and chronic illnesses and medication history were assessed using a standard questionnaire. Systolic and diastolic blood pressures were measured by an experienced technician by placing the arm at the height corresponding to the height of the heart after a 5 min rest period. Current smokers or drinkers were defined as those who answered that they currently smoke or drank alcohol regularly over the past 6 months. 2.4. Biochemical parameters Blood samples were taken from all subjects after 8 h of fasting. Samples were immediately centrifuged, and plasma and serum samples were stored at −70°C until analysis. Glucose was measured with a standard glucose oxidase reference method (747 Analyzer, Hitachi). Total cholesterol (TC), HDL-C and TG were measured with an enzymatic color test (Daiichi, Hitachi 747). Low density lipoprotein cholesterol (LDL-C) was calculated according to the Friedewald formula. Fasting serum insulin was determined by means of chemiluminescence (RIA kit, Daiichi, Japan), and insulin resistance was estimated using the homeostasis model assessment of insulin resistance (HOMA-IR) index, calculated from the following formula: HOMA-IR = fasting insulin (μU/ml) × fasting plasma glucose (mmol/l) / 22.5. Apo A-1 and Apo B were measured by an immunoturbidimetric method (Cobas Integra 800 Analyzer; Roche Diagnostics) using standard procedures [19]. 2.5. Pulse wave velocity (PWV) Arterial stiffness was measured using a PP-1000 pulse wave analyzer (Hanbyul Meditech Co.), as previously described [20]. The carotid– femoral (cf) PWV value was calculated automatically after 10 s of data was collected. For cfPWV, the carotid–femoral transit time and PWV
were calculated from the carotid–femoral distance divided by transit time. We used the mean cfPWV of right cfPWV and left cfPWV as a marker of arterial stiffness. 2.6. Statistical analysis Data were expressed as the mean ± S.D. One way ANOVA was used to compare continuous variables among groups. Continuous variables with skewed distribution were expressed as the median (and interquartile range) and log transformed for analysis. Age-adjusted cfPWV means and standard errors were calculated using analysis of covariance (ANCOVA) according to Apo B/Apo A-1 quartiles. A Pearson's correlation analysis was also performed to evaluate the relationship between Apo B/Apo A-1 ratio and various clinical factors where indicated. The logistic regression analyses were used to explore the associations of Apo B, Apo A-1 and Apo B/Apo A-1 with high cfPWV after adjusting for other risk factors. The associations of the Apo B/Apo A-1 with high cfPWV were further explored by categorizing the Apo B/Apo A-1 into quartiles and using the first quartile as the reference. Adjusted odds ratios (ORs) and corresponding 95% confidence intervals were estimated with the use of multivariate logistic regression analysis models. High cfPWV was designated as a value greater than the cut-off between the third and fourth quartiles. High cfPWV was defined as N 8.52 m/s. Statistical analyses were carried out using SPSS for Windows 18.0. A P b 0.05 was considered statistically significant. 3. Results 3.1. Clinical characteristics of the study population The clinical and biochemical characteristics of the study subjects are presented in Table 1. The subjects were stratified into four groups according to their Apo B/Apo A-1 ratios. There were significant differences in metabolic parameters among the groups. Age, SBP, DBP, BMI, WC, FPG, HOMA-IR, TC, TG, and LDL-C increased according to quartiles of Apo B/Apo A-1 ratio, whereas HDL-C decreased (Table 2). Fig. 1 showed the association of Apo B/Apo A-1 quartiles with arterial stiffness. The age-adjusted means of cfPWV showed an increasing trend across the Apo B/Apo A-1 quartiles in patients with MetS (Q1, Q2, Q3, Q4; 7.70 ± 1.26, 7.81 ± 1.21, 7.91 ± 1.36, 8.03 ± 1.23, P = 0.02). Table 1 Clinical and biochemical characteristics of subjects. Total (N = 1252) Age (y) Sex (M/F) SBP (mm Hg) DBP (mm Hg) BMI (kg/m2) WC (cm) FPG (mmol/l) HOMA-IR TC (mmol/l) TG (mmol/l) HDL-C (mmol/l) LDL-C (mmol/l) Apo B (g/l) Apo A-1 (g/l) Apo B/Apo A-1 cfPWV (m/s) Current smoker (%) Current drinker (%) Hypertension (%) Diabetes (%)
57.34 ± 10.84 610/642 131.38 ± 14.41 82.72 ± 10.19 26.37 ± 3.17 93.34 ± 8.02 6.53 ± 1.96 2.10 ± 2.76 4.98 ± 1.02 1.92 (1.48–2.79) 1.22 ± 0.29 2.86 ± 0.88 1.31 ± 0.41 1.83 ± 0.49 0.76 ± 0.38 7.86 ± 2.76 13.7 11.8 47.8 25.6
Data are means ± SD, median (interquartile range) for skewed distribution. SBP, systolic blood pressure; DBP, diastolic blood pressure; WC, waist circumference; FPG, fasting plasma glucose; HOMA-IR, homeostasis model assessment of insulin resistance; PWV, pulse wave velocity.
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Table 2 Clinical characteristics of subjects divided into quartiles according to Apo B/Apo A-1 quartiles.
N Age (years) M/F (N) SBP (mm Hg) DBP (mm Hg) BMI (kg/m2) WC (cm) FPG (mmol/l) HOMA-IR TC (mmol/l) TG (mmol/l) HDL-C (mmol/l) LDL-C (mmol/l) Apo B (g/l) Apo A-1 (g/l) Apo B/Apo A-1 Current smoker (%) Current drinker (%) Hypertension (%) Diabetes (%)
Q1
Q2
Q3
Q4
P value
313 55.89 ± 10.94 149/164 127.34 ± 10.94 78.57 ± 10.23 25.64 ± 3.24 90.22 ± 7.60 6.38 ± 1.86 1.65 ± 2.03 4.43 ± 0.96 1.68 (1.08–2.26) 1.33 ± 0.35 2.30 ± 0.88 0.98 ± 0.29 2.08 ± 0.54 0.48 ± 0.07 13.4 12.1 49.0 24.3
313 56.93 ± 10.68 160/153 129.36 ± 14.93 81.50 ± 10.67 26.14 ± 3.25 92.72 ± 8.03 6.44 ± 1.63 1.88 ± 2.48 4.81 ± 0.89 1.83 (1.34–2.58) 1.25 ± 0.30 2.74 ± 0.72 1.23 ± 0.30 1.90 ± 0.47 0.65 ± 0.03 12.7 9.7 46.6 25.6
313 57.65 ± 10.61 155/158 132.02 ± 13.88 84.06 ± 9.81 26.63 ± 3.16 94.16 ± 8.31 6.53 ± 1.89 2.07 ± 2.91 5.02 ± 0.90 2.00 (1.54–2.74) 1.17 ± 0.26 2.86 ± 0.73 1.39 ± 0.31 1.76 ± 0.39 0.79 ± 0.05 14.1 11.8 48.0 26.2
313 58.88 ± 11.12 146/167 136.79 ± 14.78 86.73 ± 10.18 27.05 ± 2.99 96.25 ± 8.12 6.76 ± 2.34 2.38 ± 3.37 5.65 ± 0.89 2.16 (1.73–2.88) 1.11 ± 0.25 3.54 ± 0.86 1.66 ± 0.41 1.56 ± 0.40 1.12 ± 0.09 14.6 13.2 48.0 26.2
b0.01 NS b0.01 b0.01 b0.01 b0.01 0.04 b0.01 b0.01 b0.01 b0.01 b0.01 b0.01 b0.01 b0.01 NS NS NS NS
Data are means ± SD, median (interquartile range) for skewed distribution. SBP, systolic blood pressure; DBP, diastolic blood pressure; BMI, body mass index; WC, waist circumference; FPG, fasting plasma glucose; HOMA-IR, homeostasis model assessment of insulin resistance; TC, total cholesterol; TG, triglyceride; HDL-C, high-density lipoprotein cholesterol; LDL-C, lowdensity lipoprotein cholesterol; Apo B, Apolipoprotein B; Apo A, Apolipoprotein A; PWV, pulse wave velocity.
3.2. Correlation and regression analysis Pearson correlation analyses revealed that cfPWV was significantly related with SBP, DBP, FPG, HOMA-IR, Apo B and Apo B/Apo A-1 after adjusting for age (Table 3). The strength of the association between high cfPWV and Apo B/Apo A-1 was examined in a logistic regression analysis, with high cfPWV as a dependent variable, including Apo B, Apo A-1 and Apo B/Apo A-1 and adjusting for cardiovascular risk factors. Only Apo B/Apo A-1 was shown to be significantly associated with high cfPWV (OR 1.56, 95% confidence intervals 1.07–2.31, P b 0.05). So we analyzed the association between high cfPWV and Apo B/Apo A-1. Logistic regression analysis revealed that the odds ratio for high PWV in the highest quartile group of Apo B/Apo A-1 was significantly increased compared to the lowest quartile based on an unadjusted model. These relationships remained significant after further adjustments for age, sex, smoking status, alcohol status, SBP, DBP, BMI, WC, FPG, TC, HDL-C, LDL-C, TG, HOMA-IR, the presence of antihypertensive medications and the presence of glucose lowering medications (Table 4). 4. Discussion In this study, we found that Apo B/Apo A-1 was significantly associated with arterial stiffness in patients with MetS. Our data are in
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Fig. 1. Age adjusted cfPWV according to Apo B/Apo A-1 quartiles. The age-adjusted means of cfPWV showed an increasing trend across the Apo B/Apo A-1 quartiles in patients with MetS (Q1, Q2, Q3, Q4; 7.70 ± 1.26, 7.81 ± 1.21, 7.91 ± 1.36, 8.03 ± 1.23, *P b 0.05 vs Q1, **P b 0.01 vs Q1).
agreement with several studies that have shown a significant association between Apo B/ApoA-1 and MetS [21–23]. We found significant differences in metabolic parameters according to quartiles of Apo B/ ApoA-1. Current guidelines for CVD prevention emphasize reduction of total cholesterol and LDL-C, but several studies have shown that Apo B performs better than TC or LDL-C in CVD risk prediction [24–26]. As each LDL particle contains one molecule of Apo B, Apo B may directly reflect the total number of atherogenic particles, including very lowdensity lipoproteins (VLDL), intermediate-density lipoproteins (IDL), and LDL [24]. Early detection and prevention of CVD are very important, and PWV is an early marker of subclinical atherosclerosis and a strong predictor of CVD [9,14]. In a French cross-sectional study of 247 patients with treatment for cardiovascular risk factors, PWV was positively correlated with Apo B [16]. Recently Koivistoinen et al. found that Apo B was also associated with PWV in healthy young adults [18]. In this study, we demonstrated that Apo B was associated with PWV in patients with MetS, but LDL-C levels were not statistically correlated with PWV. Apo A-1 is the major apolipoprotein in HDL particles and it has antiinflammatory and antioxidant effects [27–31]. The antiatherogenic Table 3 Age adjusted correlations between cfPWV and risk factors.
Sex (male = 1, female = 0) Current smoker (yes = 1, no = 0) Current drinker (yes = 1, no = 0) SBP DBP BMI WC FPG HOMA-IR TC TG HDL-C LDL-C Apo B Apo A-1 Apo B/Apo A-1
r
P value
0.16 0.09 0.07 0.24 0.20 0.10 0.06 0.13 0.12 0.08 0.09 −0.07 0.03 0.12 −0.10 0.14
b0.01 NS NS b0.01 b0.01 NS NS b0.01 b0.01 NS NS NS NS b0.01 NS b0.01
SBP, systolic blood pressure; DBP, diastolic blood pressure; WC, waist circumference; FPG, fasting plasma glucose; HOMA-IR, homeostasis model assessment of insulin resistance; TC, total cholesterol; PWV, pulse wave velocity.
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Table 4 Odds ratios and 95% confidence intervals for high cfPWV according to Apo B/Apo A-1 quartiles. Q1 Crude Adjusted OR
Q2
Q3
Q4
P value
1.00 1.34 (0.98–2.04) 1.68 (1.19–2.37) 1.94 (1.39–2.93) b0.01 1.00 1.18 (0.76–1.83) 1.41 (1.11–2.26) 1.57 (1.24–2.45) 0.01
PWV, pulse wave velocity; SBP, systolic blood pressure; DBP, diastolic blood pressure; WC, waist circumference; FPG, fasting plasma glucose; HOMA-IR, homeostasis model assessment of insulin resistance; High cfPWV was defined as N75th percentile. Adjusted for age, sex, smoking status, alcohol status, SBP, DBP, BMI, WC, FPG, TC, HDL-C, LDL-C, TG, HOMA-IR, the presence of antihypertensive medications, and the presence of glucose lowering medications.
community from Seoul, there was a possibility of selection bias. Although our study had limitations in generalizing its results, the present study was meaningful as the first study to clarify the association between Apo B/Apo A-1 ratio and arterial stiffness in patients with MetS. In conclusion, our results suggest that Apo B/Apo A-1 ratio is an independent marker of increased arterial stiffness in patients with MetS. Furthermore studies are needed to explore these findings and to elucidate the mechanism for these associations.
Acknowledgments This study was supported by a grant from the Seoul R&BD Program, Republic of Korea (10526).
References properties of Apo A-1 in coronary arteries were recently reported [32]. Previous studies demonstrated a reverse association between HDL-C and Apo-A1 and risk for vascular disease, but consistent superiority has not been shown for one versus the other [2,14,33–35]. Nevertheless, many studies have reported that HDL-C is not associated with PWV and we failed to demonstrate an association between HDL-C and PWV in this study. Few studies have evaluated the relationship between Apo A-1 and PWV, Taquet et al. reported that Apo A-1 did not appear to be significantly correlated with PWV in middle-aged women [36]. In another study by Koivistoinen et al., Apo A-1 was not significantly associated with PWV in healthy young adults [18]. The present study recorded similar data with these previous studies, as Apo A-1 was not shown to be related to arterial stiffness in patients with MetS. The American College of Cardiology Foundation/American Heart Association (ACCF/AHA) Guideline for lipoprotein management suggests treatment goals for Apo B [37]. However, the Apo B/Apo A-1 ratio represents both sides of the risk of CV events, since Apo B is an indicator of atherogenic particles and ApoA-1 reflects antiatherogenic particles. High Apo B/Apo A-1 ratio can contribute to an increased risk of a CV outcome [2,38,39]. However, there are few reports on the relationship between Apo B/Apo A-1 and PWV. In the Cardiovascular Risk in Young Finns Study, Koivistoinen et al. investigated the association of Apo B/ Apo A-1 ratio with PWV in a population of 1618 healthy young adults. They found that Apo B/Apo A-1 ratio was independently associated with PWV [18]. In our results, we demonstrated that Apo B/Apo A-1 was an independent determinant of increased arterial stiffness in patients with MetS, which is a novel information. But the mechanism underlying the relationship of Apo B/Apo A-1 and arterial stiffness is not completely understood, endothelial dysfunction by high Apo B/ Apo A-1 is one of the possible mechanisms for the associations, suggesting deterioration in vasoreactivity mainly in resistance arteries in subjects with high apoB/Apo A-1 [40]. The major limitation of this study is that the cross-sectional study design cannot explain the causal relationship between Apo B/Apo A-1 and arterial stiffness. In addition, many participants who used various doses of lipid-lowering drugs were excluded, resulting in a smaller number of subjects, and the study lacked a control group. Third, there are significant portion of the study population have several risk factors including hypertension and type 2 diabetes mellitus, because personal medical histories were based on self-administered questionnaire, we just analyzed regression analysis including the presence of antihypertensive and glucose lowering agents. So we could not eliminate the possible effect of medications used for these diseases on the present findings. There are some reports on the effects of diabetic medication, or antihypertensive medication on PWV. However, arterial stiffness was not significantly affected by the kinds of diabetic medications, or antihypertensive medications [41–43]. But since they were small sample sized studies, more researches are needed to confirm the results. Finally because most participants were residents of an urban
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Association between Apolipoprotein B/Apolipoprotein A-1 and arterial stiffness in metabolic syndrome Min Kyung Kim a, Chul Woo Ahn a,b, Shinae Kang a,b, Ji Yoon Ha a, Haeri Baek a, Jong Suk Park a,b,⁎, Kyung Rae Kim a a b
Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea Severance Institute for Vascular and Metabolic Research, Yonsei University College of Medicine, Seoul, Republic of Korea
a r t i c l e
i n f o
Article history: Received 22 January 2014 Received in revised form 3 July 2014 Accepted 4 July 2014 Available online 12 July 2014 Keywords: Apolipoprotein B Apolipoprotein A-1 Apolipoprotein B/Apolipoprotein A-1 ratio Arterial stiffness Metabolic syndrome
a b s t r a c t Background: Apolipoprotein B/Apolipoprotein A-1 ratio (Apo B/Apo A-1) is known to be associated with atherosclerotic vascular disease. However, few studies have investigated the relationship between Apo B/Apo A-1 ratio and arterial stiffness, thus we investigated the relationships between Apo B/Apo A-1 and arterial stiffness in patients with metabolic syndrome (MetS). Methods: 1252 subjects with MetS according to the Adult Treatment Panel III were enrolled in our study. Anthropometric profiles and serum concentrations of Apo B, Apo A-1, fasting plasma glucose (FPG), total cholesterol (TC), triglycerides (TG), and high density lipoprotein cholesterol (HDL-C) were measured. Pulse wave velocity (PWV) was evaluated to assess arterial stiffness. Results: The subjects were stratified into four groups according to their Apo B/Apo A-1 ratios. PWV gradually increased according to Apo B/Apo A-1 quartiles. After adjusting for age, arterial stiffness was significantly correlated with systolic blood pressure, diastolic blood pressure, FPG, homeostasis model assessment (HOMAIR), Apo B and Apo B/Apo A-1. In multiple logistic regression analysis after adjusting for risk factors, Apo B/Apo A-1 ratio was a significant contributor to increased PWV. Conclusion: These results suggest that Apo B/Apo A-1 is independently associated with increased arterial stiffness in patients with MetS. © 2014 Elsevier B.V. All rights reserved.
1. Introduction Serum low density lipoprotein cholesterol (LDL-C) is associated with increased risk of cardiovascular disease [1], but recent studies indicate that Apolipoprotein B/Apolipoprotein A-1 (Apo B/Apo A-1) ratio is an even better indicator of atherosclerotic vascular disease [2–6]. Pulse wave velocity (PWV) is a non-invasive measurement method and is widely used as an index of arterial stiffness. Arterial stiffness is strongly associated with not only cardiovascular diseases and mortality [7–9], but also a marker of vascular damage caused by structural and functional changes within the arterial wall [10].
Abbreviations: MetS, metabolic syndrome; PWV, pulse wave velocity; FPG, fasting plasma glucose; TC, total cholesterol; HOMA-IR, homeostasis model assessment of insulin resistance; WC, waist circumference; cfPWV, carotid–femoral pulse wave velocity. ⁎ Corresponding author at: Division of Endocrinology, Department of Internal Medicine, Gangnam Severance Hospital, 146-92 Dogok-dong, Gangnam-ku, P.O. Box 135-720, Seoul, Republic of Korea. Tel.: +82 2 2019 4377; fax: +82 2 3463 3882. E-mail address: [email protected] (J.S. Park).
http://dx.doi.org/10.1016/j.cca.2014.07.005 0009-8981/© 2014 Elsevier B.V. All rights reserved.
Metabolic syndrome (MetS) is defined as the clustering of several cardiovascular risk factors including visceral obesity, impaired glucose intolerance, a high level of triglycerides (TG), a low level of high density cholesterol (HDL-C), and hypertension. The prevalence of metabolic syndrome is increasing worldwide. According to data from the National Health and Nutrition Examination Survey, the age-adjusted prevalence of metabolic syndrome is 34.2% in the U.S. [11]. This increasing trend also has been observed in Asian countries [12] and European populations [13]. MetS is considered common and is a recognized risk factor for atherosclerotic cardiovascular disease [14,15]. Although there have been numerous researches on the association between apo B and cardiovascular disease, there are a few reports with a small sample size on the direct relationship between Apo B and arterial stiffness [16,17]. Only one study reported an independent association between Apo B and arterial stiffness in general population [18]. There is no report of the relationship between Apo B/A1 ratio and arterial stiffness in patients with MetS. The present study was therefore designed to investigate the relationships between Apo B/Apo A-1 and arterial stiffness in Korean patients with MetS.
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2. Methods 2.1. Study participants We analyzed 1252 patients with MetS recruited from the Metabolic Syndrome Research Initiatives (MSRI) study. The MSRI study included 4253 participants who have more than one risk factor of MetS, recruited at 17 different tertiary medical centers from January 2006 through December 2007. This MSRI study is a population-based, multi-center cohort study, designed to evaluate the prevalence and characteristics of MetS and the occurrence of cardiovascular (CV) events in Seoul, Korea. Subjects were excluded if they were suspected of having a current acute illness including a clinically significant infectious disease or other malignancy, or if they were taking lipid-lowering medication (fibrate or statin). We also excluded subjects with a clinical history of cardiovascular disease, renal disease, or hepatic disease and pregnant or lactating women were also excluded. The Institutional Review Board of Yonsei University College of Medicine approved the study protocol, and written informed consent was obtained from all participants. 2.2. Definition of MetS MetS was defined according to the updated National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria applying Asia Pacific WHO guidelines for waist circumference (WC). Accordingly, subjects with three or more of the following characteristics were diagnosed with MetS: fasting plasma glucose ≥100 mg/dl or diabetes diagnosis, WC ≥90 cm for males and ≥80 cm for females, blood pressure (BP) ≥130/85 mm Hg or on BP medication, TG ≥ 150 mg/dl or on TG-lowering medication, and HDL-C b 40 mg/dl for males and b50 mg/dl for females. 2.3. Clinical characteristics Height, weight and WC were measured. Each personal medical history of acute and chronic illnesses and medication history were assessed using a standard questionnaire. Systolic and diastolic blood pressures were measured by an experienced technician by placing the arm at the height corresponding to the height of the heart after a 5 min rest period. Current smokers or drinkers were defined as those who answered that they currently smoke or drank alcohol regularly over the past 6 months. 2.4. Biochemical parameters Blood samples were taken from all subjects after 8 h of fasting. Samples were immediately centrifuged, and plasma and serum samples were stored at −70°C until analysis. Glucose was measured with a standard glucose oxidase reference method (747 Analyzer, Hitachi). Total cholesterol (TC), HDL-C and TG were measured with an enzymatic color test (Daiichi, Hitachi 747). Low density lipoprotein cholesterol (LDL-C) was calculated according to the Friedewald formula. Fasting serum insulin was determined by means of chemiluminescence (RIA kit, Daiichi, Japan), and insulin resistance was estimated using the homeostasis model assessment of insulin resistance (HOMA-IR) index, calculated from the following formula: HOMA-IR = fasting insulin (μU/ml) × fasting plasma glucose (mmol/l) / 22.5. Apo A-1 and Apo B were measured by an immunoturbidimetric method (Cobas Integra 800 Analyzer; Roche Diagnostics) using standard procedures [19]. 2.5. Pulse wave velocity (PWV) Arterial stiffness was measured using a PP-1000 pulse wave analyzer (Hanbyul Meditech Co.), as previously described [20]. The carotid– femoral (cf) PWV value was calculated automatically after 10 s of data was collected. For cfPWV, the carotid–femoral transit time and PWV
were calculated from the carotid–femoral distance divided by transit time. We used the mean cfPWV of right cfPWV and left cfPWV as a marker of arterial stiffness. 2.6. Statistical analysis Data were expressed as the mean ± S.D. One way ANOVA was used to compare continuous variables among groups. Continuous variables with skewed distribution were expressed as the median (and interquartile range) and log transformed for analysis. Age-adjusted cfPWV means and standard errors were calculated using analysis of covariance (ANCOVA) according to Apo B/Apo A-1 quartiles. A Pearson's correlation analysis was also performed to evaluate the relationship between Apo B/Apo A-1 ratio and various clinical factors where indicated. The logistic regression analyses were used to explore the associations of Apo B, Apo A-1 and Apo B/Apo A-1 with high cfPWV after adjusting for other risk factors. The associations of the Apo B/Apo A-1 with high cfPWV were further explored by categorizing the Apo B/Apo A-1 into quartiles and using the first quartile as the reference. Adjusted odds ratios (ORs) and corresponding 95% confidence intervals were estimated with the use of multivariate logistic regression analysis models. High cfPWV was designated as a value greater than the cut-off between the third and fourth quartiles. High cfPWV was defined as N 8.52 m/s. Statistical analyses were carried out using SPSS for Windows 18.0. A P b 0.05 was considered statistically significant. 3. Results 3.1. Clinical characteristics of the study population The clinical and biochemical characteristics of the study subjects are presented in Table 1. The subjects were stratified into four groups according to their Apo B/Apo A-1 ratios. There were significant differences in metabolic parameters among the groups. Age, SBP, DBP, BMI, WC, FPG, HOMA-IR, TC, TG, and LDL-C increased according to quartiles of Apo B/Apo A-1 ratio, whereas HDL-C decreased (Table 2). Fig. 1 showed the association of Apo B/Apo A-1 quartiles with arterial stiffness. The age-adjusted means of cfPWV showed an increasing trend across the Apo B/Apo A-1 quartiles in patients with MetS (Q1, Q2, Q3, Q4; 7.70 ± 1.26, 7.81 ± 1.21, 7.91 ± 1.36, 8.03 ± 1.23, P = 0.02). Table 1 Clinical and biochemical characteristics of subjects. Total (N = 1252) Age (y) Sex (M/F) SBP (mm Hg) DBP (mm Hg) BMI (kg/m2) WC (cm) FPG (mmol/l) HOMA-IR TC (mmol/l) TG (mmol/l) HDL-C (mmol/l) LDL-C (mmol/l) Apo B (g/l) Apo A-1 (g/l) Apo B/Apo A-1 cfPWV (m/s) Current smoker (%) Current drinker (%) Hypertension (%) Diabetes (%)
57.34 ± 10.84 610/642 131.38 ± 14.41 82.72 ± 10.19 26.37 ± 3.17 93.34 ± 8.02 6.53 ± 1.96 2.10 ± 2.76 4.98 ± 1.02 1.92 (1.48–2.79) 1.22 ± 0.29 2.86 ± 0.88 1.31 ± 0.41 1.83 ± 0.49 0.76 ± 0.38 7.86 ± 2.76 13.7 11.8 47.8 25.6
Data are means ± SD, median (interquartile range) for skewed distribution. SBP, systolic blood pressure; DBP, diastolic blood pressure; WC, waist circumference; FPG, fasting plasma glucose; HOMA-IR, homeostasis model assessment of insulin resistance; PWV, pulse wave velocity.
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Table 2 Clinical characteristics of subjects divided into quartiles according to Apo B/Apo A-1 quartiles.
N Age (years) M/F (N) SBP (mm Hg) DBP (mm Hg) BMI (kg/m2) WC (cm) FPG (mmol/l) HOMA-IR TC (mmol/l) TG (mmol/l) HDL-C (mmol/l) LDL-C (mmol/l) Apo B (g/l) Apo A-1 (g/l) Apo B/Apo A-1 Current smoker (%) Current drinker (%) Hypertension (%) Diabetes (%)
Q1
Q2
Q3
Q4
P value
313 55.89 ± 10.94 149/164 127.34 ± 10.94 78.57 ± 10.23 25.64 ± 3.24 90.22 ± 7.60 6.38 ± 1.86 1.65 ± 2.03 4.43 ± 0.96 1.68 (1.08–2.26) 1.33 ± 0.35 2.30 ± 0.88 0.98 ± 0.29 2.08 ± 0.54 0.48 ± 0.07 13.4 12.1 49.0 24.3
313 56.93 ± 10.68 160/153 129.36 ± 14.93 81.50 ± 10.67 26.14 ± 3.25 92.72 ± 8.03 6.44 ± 1.63 1.88 ± 2.48 4.81 ± 0.89 1.83 (1.34–2.58) 1.25 ± 0.30 2.74 ± 0.72 1.23 ± 0.30 1.90 ± 0.47 0.65 ± 0.03 12.7 9.7 46.6 25.6
313 57.65 ± 10.61 155/158 132.02 ± 13.88 84.06 ± 9.81 26.63 ± 3.16 94.16 ± 8.31 6.53 ± 1.89 2.07 ± 2.91 5.02 ± 0.90 2.00 (1.54–2.74) 1.17 ± 0.26 2.86 ± 0.73 1.39 ± 0.31 1.76 ± 0.39 0.79 ± 0.05 14.1 11.8 48.0 26.2
313 58.88 ± 11.12 146/167 136.79 ± 14.78 86.73 ± 10.18 27.05 ± 2.99 96.25 ± 8.12 6.76 ± 2.34 2.38 ± 3.37 5.65 ± 0.89 2.16 (1.73–2.88) 1.11 ± 0.25 3.54 ± 0.86 1.66 ± 0.41 1.56 ± 0.40 1.12 ± 0.09 14.6 13.2 48.0 26.2
b0.01 NS b0.01 b0.01 b0.01 b0.01 0.04 b0.01 b0.01 b0.01 b0.01 b0.01 b0.01 b0.01 b0.01 NS NS NS NS
Data are means ± SD, median (interquartile range) for skewed distribution. SBP, systolic blood pressure; DBP, diastolic blood pressure; BMI, body mass index; WC, waist circumference; FPG, fasting plasma glucose; HOMA-IR, homeostasis model assessment of insulin resistance; TC, total cholesterol; TG, triglyceride; HDL-C, high-density lipoprotein cholesterol; LDL-C, lowdensity lipoprotein cholesterol; Apo B, Apolipoprotein B; Apo A, Apolipoprotein A; PWV, pulse wave velocity.
3.2. Correlation and regression analysis Pearson correlation analyses revealed that cfPWV was significantly related with SBP, DBP, FPG, HOMA-IR, Apo B and Apo B/Apo A-1 after adjusting for age (Table 3). The strength of the association between high cfPWV and Apo B/Apo A-1 was examined in a logistic regression analysis, with high cfPWV as a dependent variable, including Apo B, Apo A-1 and Apo B/Apo A-1 and adjusting for cardiovascular risk factors. Only Apo B/Apo A-1 was shown to be significantly associated with high cfPWV (OR 1.56, 95% confidence intervals 1.07–2.31, P b 0.05). So we analyzed the association between high cfPWV and Apo B/Apo A-1. Logistic regression analysis revealed that the odds ratio for high PWV in the highest quartile group of Apo B/Apo A-1 was significantly increased compared to the lowest quartile based on an unadjusted model. These relationships remained significant after further adjustments for age, sex, smoking status, alcohol status, SBP, DBP, BMI, WC, FPG, TC, HDL-C, LDL-C, TG, HOMA-IR, the presence of antihypertensive medications and the presence of glucose lowering medications (Table 4). 4. Discussion In this study, we found that Apo B/Apo A-1 was significantly associated with arterial stiffness in patients with MetS. Our data are in
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Fig. 1. Age adjusted cfPWV according to Apo B/Apo A-1 quartiles. The age-adjusted means of cfPWV showed an increasing trend across the Apo B/Apo A-1 quartiles in patients with MetS (Q1, Q2, Q3, Q4; 7.70 ± 1.26, 7.81 ± 1.21, 7.91 ± 1.36, 8.03 ± 1.23, *P b 0.05 vs Q1, **P b 0.01 vs Q1).
agreement with several studies that have shown a significant association between Apo B/ApoA-1 and MetS [21–23]. We found significant differences in metabolic parameters according to quartiles of Apo B/ ApoA-1. Current guidelines for CVD prevention emphasize reduction of total cholesterol and LDL-C, but several studies have shown that Apo B performs better than TC or LDL-C in CVD risk prediction [24–26]. As each LDL particle contains one molecule of Apo B, Apo B may directly reflect the total number of atherogenic particles, including very lowdensity lipoproteins (VLDL), intermediate-density lipoproteins (IDL), and LDL [24]. Early detection and prevention of CVD are very important, and PWV is an early marker of subclinical atherosclerosis and a strong predictor of CVD [9,14]. In a French cross-sectional study of 247 patients with treatment for cardiovascular risk factors, PWV was positively correlated with Apo B [16]. Recently Koivistoinen et al. found that Apo B was also associated with PWV in healthy young adults [18]. In this study, we demonstrated that Apo B was associated with PWV in patients with MetS, but LDL-C levels were not statistically correlated with PWV. Apo A-1 is the major apolipoprotein in HDL particles and it has antiinflammatory and antioxidant effects [27–31]. The antiatherogenic Table 3 Age adjusted correlations between cfPWV and risk factors.
Sex (male = 1, female = 0) Current smoker (yes = 1, no = 0) Current drinker (yes = 1, no = 0) SBP DBP BMI WC FPG HOMA-IR TC TG HDL-C LDL-C Apo B Apo A-1 Apo B/Apo A-1
r
P value
0.16 0.09 0.07 0.24 0.20 0.10 0.06 0.13 0.12 0.08 0.09 −0.07 0.03 0.12 −0.10 0.14
b0.01 NS NS b0.01 b0.01 NS NS b0.01 b0.01 NS NS NS NS b0.01 NS b0.01
SBP, systolic blood pressure; DBP, diastolic blood pressure; WC, waist circumference; FPG, fasting plasma glucose; HOMA-IR, homeostasis model assessment of insulin resistance; TC, total cholesterol; PWV, pulse wave velocity.
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Table 4 Odds ratios and 95% confidence intervals for high cfPWV according to Apo B/Apo A-1 quartiles. Q1 Crude Adjusted OR
Q2
Q3
Q4
P value
1.00 1.34 (0.98–2.04) 1.68 (1.19–2.37) 1.94 (1.39–2.93) b0.01 1.00 1.18 (0.76–1.83) 1.41 (1.11–2.26) 1.57 (1.24–2.45) 0.01
PWV, pulse wave velocity; SBP, systolic blood pressure; DBP, diastolic blood pressure; WC, waist circumference; FPG, fasting plasma glucose; HOMA-IR, homeostasis model assessment of insulin resistance; High cfPWV was defined as N75th percentile. Adjusted for age, sex, smoking status, alcohol status, SBP, DBP, BMI, WC, FPG, TC, HDL-C, LDL-C, TG, HOMA-IR, the presence of antihypertensive medications, and the presence of glucose lowering medications.
community from Seoul, there was a possibility of selection bias. Although our study had limitations in generalizing its results, the present study was meaningful as the first study to clarify the association between Apo B/Apo A-1 ratio and arterial stiffness in patients with MetS. In conclusion, our results suggest that Apo B/Apo A-1 ratio is an independent marker of increased arterial stiffness in patients with MetS. Furthermore studies are needed to explore these findings and to elucidate the mechanism for these associations.
Acknowledgments This study was supported by a grant from the Seoul R&BD Program, Republic of Korea (10526).
References properties of Apo A-1 in coronary arteries were recently reported [32]. Previous studies demonstrated a reverse association between HDL-C and Apo-A1 and risk for vascular disease, but consistent superiority has not been shown for one versus the other [2,14,33–35]. Nevertheless, many studies have reported that HDL-C is not associated with PWV and we failed to demonstrate an association between HDL-C and PWV in this study. Few studies have evaluated the relationship between Apo A-1 and PWV, Taquet et al. reported that Apo A-1 did not appear to be significantly correlated with PWV in middle-aged women [36]. In another study by Koivistoinen et al., Apo A-1 was not significantly associated with PWV in healthy young adults [18]. The present study recorded similar data with these previous studies, as Apo A-1 was not shown to be related to arterial stiffness in patients with MetS. The American College of Cardiology Foundation/American Heart Association (ACCF/AHA) Guideline for lipoprotein management suggests treatment goals for Apo B [37]. However, the Apo B/Apo A-1 ratio represents both sides of the risk of CV events, since Apo B is an indicator of atherogenic particles and ApoA-1 reflects antiatherogenic particles. High Apo B/Apo A-1 ratio can contribute to an increased risk of a CV outcome [2,38,39]. However, there are few reports on the relationship between Apo B/Apo A-1 and PWV. In the Cardiovascular Risk in Young Finns Study, Koivistoinen et al. investigated the association of Apo B/ Apo A-1 ratio with PWV in a population of 1618 healthy young adults. They found that Apo B/Apo A-1 ratio was independently associated with PWV [18]. In our results, we demonstrated that Apo B/Apo A-1 was an independent determinant of increased arterial stiffness in patients with MetS, which is a novel information. But the mechanism underlying the relationship of Apo B/Apo A-1 and arterial stiffness is not completely understood, endothelial dysfunction by high Apo B/ Apo A-1 is one of the possible mechanisms for the associations, suggesting deterioration in vasoreactivity mainly in resistance arteries in subjects with high apoB/Apo A-1 [40]. The major limitation of this study is that the cross-sectional study design cannot explain the causal relationship between Apo B/Apo A-1 and arterial stiffness. In addition, many participants who used various doses of lipid-lowering drugs were excluded, resulting in a smaller number of subjects, and the study lacked a control group. Third, there are significant portion of the study population have several risk factors including hypertension and type 2 diabetes mellitus, because personal medical histories were based on self-administered questionnaire, we just analyzed regression analysis including the presence of antihypertensive and glucose lowering agents. So we could not eliminate the possible effect of medications used for these diseases on the present findings. There are some reports on the effects of diabetic medication, or antihypertensive medication on PWV. However, arterial stiffness was not significantly affected by the kinds of diabetic medications, or antihypertensive medications [41–43]. But since they were small sample sized studies, more researches are needed to confirm the results. Finally because most participants were residents of an urban
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