International Journal of Cardiology 177 (2014) 517–519
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Clinical relevance of decreased ratios of serum eicosapentaenoic acid/ arachidonic acid (AA) and docosahexaenoic acid/AA to impaired arterial stiffness Hiroshi Yoshida a,b,⁎, Kumie Ito b,c, Ryo Sato a,b, Hideo Kurosawa a,c, Yoshiharu Tomono b,d, Yuji Hirowatari e, Mitsuyuki Shimizu f, Norio Tada b a
Department of Laboratory Medicine, Jikei University Kashiwa Hospital, Japan Internal Medicine of Metabolism and Nutrition, Jikei University Graduate School of Medicine, Japan c Inzai General Hospital, Japan d Department of Nutrition, Jikei University Kashiwa Hospital, Japan e Bioscience Division, TOSOH Corporation, Japan f Division of Cardiology, Department of Internal Medicine, Jikei University Kashiwa Hospital, Japan b
a r t i c l e
i n f o
Article history: Received 12 August 2014 Accepted 15 August 2014 Available online 23 August 2014 Keywords: Eicosapentaenoic acid (EPA) Docosahexaenoic acid (DHA) Arachidonic acid (AA) Arterial stiffness CAVI Atherosclerosis
Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), n−3 polyunsaturated fatty acids (PUFAs), have beneficial effects on reduction of cardiovascular disease (CVD) risk in epidemiological studies [1,2]. Japan EPA Lipid Intervention Study (JELIS) reported that long-term use of purified EPA added on statins reduced the incidence of major coronary events compared with the statin monotherapy [3], and meta-analysis papers have demonstrated that EPA and DHA supplementations reduce the risk of fatal CVD by 10% [4]. However, arachidonic acid (AA), an n−6 PUFA, is a source of inflammatory mediators in contrast to n−3 PUFA EPA [5]. In the results of sub-analysis from the JELIS, the risk of cardiovascular death and myocardial infarction was significantly lower in subjects with a higher serum EPA/AA ratio [6]. Arterial stiffness is a functional biomarker of atherosclerosis and an important predictor of CVD [7]. However, the association between serum EPA/AA ratio and the arterial
⁎ Corresponding author at: Department of Laboratory Medicine, Jikei University Kashiwa Hospital, 163-1 Kashiwashita, Kashiwa, Chiba 277-8567, Japan. Tel.: + 81 4 7164 1111x2270; fax: +81 4 7164 1126. E-mail address: [email protected] (H. Yoshida).
http://dx.doi.org/10.1016/j.ijcard.2014.08.093 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
stiffness [cardio-ankle vascular index (CAVI)] has not been fully elucidated. Subjects of this study, approved by the Ethics Committee of Jikei University School of Medicine, were 136 non-obese persons (mean age: 67 ± 9 years, mean body mass index (BMI): 22.9 ± 2.8 kg/m2) who underwent a medical brain checkup at Jikei University Kashiwa hospital from April 2009 to March 2011. The medical records were investigated retrospectively. The patients, who took medications of EPA and DHA, were excluded from the study subjects. CAVI was examined with VaSera CAVI instrument (Fukuda Denshi, Tokyo, Japan), which simultaneously measured blood pressure levels in bilateral arms by an oscillometric method, and the coefficient of variation of CAVI was b5% [8]. The average data of bilateral values of CAVI and blood pressure were used for the statistical analysis. Fasting blood samples were collected, and serum total cholesterol (TC), triglyceride (TG), insulin, plasma glucose and glycohemoglobin A1c (HbA1c) were measured by conventional methods. Cholesterol levels of very lowdensity lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL), and other fractions were measured by high-performance liquid chromatography [9]. Fatty acids were determined by gas-chromatography. Serum creatinine was measured by the enzymatic method, and estimated glomerular filtration rate (eGFR) was calculated by the formula of the Japanese Society of Nephrology. CAVI in patients without signs of atherosclerosis was reported to be b8.0, and the cut-off point of CAVI for the presence of atherosclerotic diseases was reported to be 9.0 [8]. The study subjects with CAVI b 8.0, 8.0 to 8.9, and ≥9.0 were classified into Group 1 (n = 47), 2 (n = 50) and 3 (n = 41). Although 6, 7, and 2 subjects of the total subjects took lipid-lowering drugs, anti-hypertensives, and diabetic medicines, respectively, there were no significant differences in medications among the 3 groups. Table 1 shows the characteristics of study subjects. Age of Group 3 was highest, and smokers were found more frequently in Group 1 than in Group 2 whereas smoker numbers were scarce in the study subjects. Group 3 showed modestly lower eGFR. HDL-cholesterol was significantly lower in Group 3 than in Groups 1 and 2. However,
518
H. Yoshida et al. / International Journal of Cardiology 177 (2014) 517–519
Table 1 Characteristics of study subjects.
Basic data Male/female Age (years) Smoker (yes/no) Drink (yes/no) BMI (kg/m2) SBP (mm Hg) DBP (mm Hg) FPG (mg/dL) Hemoglobin A1c (%) Insulin (×10−3 U/L) Insulin resistance (HOMA-R) Estimated GFR (mL/min) Serum lipid data (mg/dL) TC TG Non-HDL cholesterol Lipoprotein cholesterol by anion-exchange liquid chromatography (mg/dL) HDL LDL IDL VLDL Others PUFAs AA (μg/mL) EPA (μg/mL) DHA (μg/mL) EPA/AA DHA/AA
All
Group 1 (CAVI b 8)
Group 2 (CAVI = 8–9)
Group 3 (CAVI N 9)
p value (T1 vs T2)
p value (T1 vs T3)
p value (T2 vs T3)
ANOVA or Kruskal–Wallis
60/76 67 ± 9 8/128 21/115 22.9 ± 2.8 133 ± 16 81 ± 9 102 ± 14 5.5 ± 0.4 6.0 ± 4.0 1.6 ± 1.2 75 ± 17
19/28 62 ± 11 6/41 10/37 23.4 ± 3.3 131 ± 17 81 ± 8 104 ± 18 5.4 ± 0.3 6.4 ± 4.4 1.7 ± 1.3 79 ± 18
19/31 68 ± 7 0/50 5/45 22.5 ± 2.6 135 ± 15 81 ± 9 101 ± 13 5.5 ± 0.5 6.0 ± 4.2 1.6 ± 1.2 77 ± 16
22/19 73 ± 7 2/37 6/33 22.9 ± 2.3 133 ± 17 80 ± 9 102 ± 10 5.5 ± 0.4 5.6 ± 3.1 1.4 ± 0.9 70 ± 17
NS b0.005 b0.01 NS NS NS NS NS NS NS NS NS
NS b0.0001 NS NS NS NS NS NS NS NS NS b0.05
NS b0.0005 NS NS NS NS NS NS NS NS NS NS
NS b0.0001 b0.05 NS NS NS NS NS NS NS NS NS
206 ± 35 120 ± 53 143 ± 32
207 ± 31 117 ± 60 141 ± 30
213 ± 39 120 ± 50 149 ± 36
195 ± 31 123 ± 50 138 ± 27
NS NS NS
NS NS NS
b0.05 NS NS
NS NS NS
62.4 ± 14.6 117.0 ± 29.3 5.9 ± 2.9 10.2 ± 6.9 6.6 ± 4.1
66.4 ± 14.4 115.0 ± 26.5 6.0 ± 3.9 10.9 ± 9.0 6.7 ± 5.0
63.2 ± 14.7 122.8 ± 33.8 5.8 ± 2.2 9.7 ± 5.2 6.6 ± 3.7
56.6 ± 13.2 112.0 ± 25.7 5.8 ± 2.2 10.1 ± 6.0 6.6 ± 3.5
NS NS NS NS NS
b0.005 NS NS NS NS
b0.05 NS NS NS NS
b0.01 NS NS NS NS
152.5 ± 36.7 78.2 ± 40.3 159.7 ± 50.0 0.53 ± 0.30 1.09 ± 0.38
134.1 ± 23.7 83.8 ± 39.5 164.2 ± 56.4 0.63 ± 0.31 1.29 ± 0.41
163.3 ± 37.3 78.8 ± 43.7 158.5 ± 42.2 0.50 ± 0.29 1.00 ± 0.29
160.7 ± 40.7 70.7 ± 36.6 155.7 ± 51.9 0.46 ± 0.28 1.01 ± 0.41
b0.0001 NS NS b0.05 b0.005
b0.001 NS NS b0.01 b0.05
NS NS NS NS NS
b0.0001 NS NS b0.05 b0.005
BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; FPG, fasting plasma glucose; HOMA-R, homeostasis model assessment ratio; GFR, glomerular filtration ratio; TC, total cholesterol; TG, triglyceride; HDL, high-density lipoprotein; LDL, low density lipoprotein; IDL, intermediate density lipoprotein; VLDL, very low density lipoprotein; PUFAs, polyunsaturated fatty acids; AA, arachidonic acid; EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid; NS, not significant. HOMA-R data were calculated by the formula [fasting insulin (mU/mL) × FPG/405], and estimated GFR data were calculated by the formula following the equation of the Japanese Society of Nephrology: eGFR = 194 × Creatinine − 1.094 × age−0.287 (× 0.739 if female). Others mean chylomicron, chylomicron remnant, and lipoprotein (a) [Lp(a)].
cholesterol levels of other lipoproteins were not different among the 3 groups. AA levels were significantly lower in Group 1 than in Groups 2 and 3, but EPA and DHA concentrations were not different (Table 1). However, the ratios of EPA/AA and DHA/AA were significantly higher in Group 1 than in Groups 2 and 3. In simple correlations of age, BMI, blood pressures, glucose metabolism-related parameters, and serum lipid data to CAVI, age and AA were positively correlated with CAVI. HDL-C, EPA/AA and DHA/AA were inversely correlated with CAVI. The influence of AA levels to CAVI might be considered. In the two subgroups divided by median of AA levels, EPA/AA and DHA/AA were not different among the 3 groups in the subgroup with lower AA values (n = 68). However, EPA/AA was significantly lower (p b 0.05) in Group 3 (n = 23, 0.41 ± 0.23) than in Group 1 (n = 12, 0.6 ± 0.23) in the subgroup with higher AA group (n = 68). Then, multivariate stepwise-regression analysis using EPA/AA, DHA/AA and HDL cholesterol, universal confounding factors (gender, age, smoking habit, BMI) and LDL-cholesterol globally regarded as treat target for atherosclerosis prevention as independent variables, showed that DHA/AA, age and HDL-cholesterol were found to be the significant factors for CAVI but not EPA/AA (Table 2). Ratios of EPA/AA and DHA/AA were higher in non-obese subjects with low CAVI expressing good arterial stiffness. Meanwhile, AA was higher in the subjects with higher CAVI, but EPA and DHA were not different among the 3 groups by CAVI levels. In the subgroup with higher AA group, EPA/AA was significantly lower in the higher CAVI group than in the lower CAVI group. EPA composed of 20 carbon chains in the structure acts as an inhibitor of AA-derived inflammatory mediators by competing with AA at the step of cyclooxygenases and lipoxygenases [5]. The Hisayama Study also demonstrated the significant association between EPA/AA ration and CVD risk, especially in subjects with higher levels of highly-sensitive C-reactive protein (CRP) [10]. Recently, EPA administration to obese patients with dyslipidemia has been reported
to improve arterial stiffness (CAVI), which shows that the improved CAVI is associated with the increased EPA/AA ratio and the decreased inflammation [11]. The present study shows similar findings that EPA/AA ratio is inversely correlated with CAVI in non-obese subjects, indicating the particular association of EPA/AA ratio to CAVI in subjects with higher AA levels presumably expressive of inflammation. The multivariate regression analysis revealed that DHA/AA, age and HDL-cholesterol significantly correlated with CAVI, but EPA/AA did not. The discrepancy between EPA/AA and DHA/AA is undefined but might be related to age and diet habits. EPA and DHA consumption and traditional Japanese diet intake increase with age [12]. In addition, serum DHA concentrations are naturally high compared with EPA. Including age in independent variables might attenuate the correlation of EPA/AA to CAVI. But, it remains unclear because the data of dietary intake were not obtained in this retrospective study.
Table 2 Multiple stepwise regression analysis between CAVI and fatty acid, and lipoprotein data.
Basic data Male/female Age (years) Smoker (yes/no) Body mass index (kg/m2) Fatty acid EPA/AA DHA/AA Lipoprotein data by anion-exchange liquid chromatography HDL cholesterol LDL cholesterol
Partial correlation coefficient
t value
p value
−0.0671 0.6187 −0.0920 −0.1060
0.7579 8.8744 1.0414 1.2016
0.4499 b0.0001 0.2997 0.2318
−0.0155 −0.1762
0.1745 2.0175
0.8618 0.0458
−0.3089 0.0971
3.6599 1.0993
0.0004 0.2737
H. Yoshida et al. / International Journal of Cardiology 177 (2014) 517–519
In conclusion, the present study suggests that DHA/AA ratio may be useful in the management of patients with impaired arterial stiffness, while EPA/AA could be helpful for patients with high serum AA concentrations presumably expressive of inflammation in non-obese subjects. Conflict of interest The authors report no conflict of interest for the present study. Acknowledgments We thank the medical staff for medical checkup of the brain at the Jikei University Kashiwa Hospital and also appreciate Daisuke Manita MS (Bioscience Division, TOSOH Corp, Japan) for the helpful assistance of lipoprotein cholesterol measurement by HPLC. Source of funding Research funds were provided by the Jikei University Research Fund and in part by Grant-in-Aid for Scientific Research (23591066) from the Japan Ministry of Education, Culture, Sports, Science and Technology (Yoshida H). References [1] Hu FB, Bronner L, Willett WC, et al. Fish and omega-3 fatty acid intake and risk of coronary heart disease in women. JAMA 2002;287:1815–21.
519
[2] Iso H, Kobayashi M, Ishihara J, et al. Intake of fish and n3 fatty acids and risk of coronary heart disease among Japanese: the Japan Public Health Center-based (JPHC) study cohort I. Circulation 2006;113:195–202. [3] Yokoyama M, Origasa H, Matsuzaki M, et al. lipid intervention study (JELIS) Investigators. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet 2007;369:1090–8. [4] Kromhout D, de Goede J. Update on cardiometabolic health effects of n−3 fatty acids. Curr Opin Lipidol 2014;25:85–90. [5] Harris WS, Miller M, Tighe AP, Davidson MH, Schaefer EJ. Omega-3 fatty acids and coronary heart disease risk: clinical and mechanistic perspectives. Atherosclerosis 2008;197:12–24. [6] Matsuzaki M, Yokoyama M, Saito Y, et al. Incremental effects of eicosapentaenoic acid on cardiovascular events in statin-treated patients with coronary artery disease. Circ J 2009;73:1283–90. [7] Vlachopoulos C, Aznaouridis K, Stefanadis C. Prediction of cardiovascular events and all-cause mortality with arterial stiffness: a systematic review and meta-analysis. J Am Coll Cardiol 2010;55:1318–27. [8] Shirai K, Hiruta N, Song M, et al. Cardio-ankle vascular index (CAVI) as a novel indicator of arterial stiffness: theory, evidence and perspectives. J Atheroscler Thromb 2011;18:924–38. [9] Ito K, Yoshida H, Yanai H, et al. Relevance of intermediate-density lipoprotein cholesterol to Framingham risk score of coronary heart disease in middle-aged men with increased non-HDL cholesterol. Int J Cardiol 2013;168:3853–8. [10] Ninomiya T, Nagata M, Hata J, et al. Association between ratio of serum eicosapentaenoic acid to arachidonic acid and risk of cardiovascular disease: the Hisayama study. Atherosclerosis 2013;231:261–7. [11] Ito R, Satoh-Asahara N, Yamakage H, et al. An increase in the EPA/AA ratio is associated with improved arterial stiffness in obese patients with dyslipidemia. J Atheroscler Thromb 2014;21:248–60. [12] Otsuka R, Kato Y, Imai T, Ando F, Shimokata H. Higher serum EPA or DHA, and lower ARA compositions with age independent fatty acid intake in Japanese aged 40 to 79. Lipids 2013;48:719–27.
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Clinical relevance of decreased ratios of serum eicosapentaenoic acid/ arachidonic acid (AA) and docosahexaenoic acid/AA to impaired arterial stiffness Hiroshi Yoshida a,b,⁎, Kumie Ito b,c, Ryo Sato a,b, Hideo Kurosawa a,c, Yoshiharu Tomono b,d, Yuji Hirowatari e, Mitsuyuki Shimizu f, Norio Tada b a
Department of Laboratory Medicine, Jikei University Kashiwa Hospital, Japan Internal Medicine of Metabolism and Nutrition, Jikei University Graduate School of Medicine, Japan c Inzai General Hospital, Japan d Department of Nutrition, Jikei University Kashiwa Hospital, Japan e Bioscience Division, TOSOH Corporation, Japan f Division of Cardiology, Department of Internal Medicine, Jikei University Kashiwa Hospital, Japan b
a r t i c l e
i n f o
Article history: Received 12 August 2014 Accepted 15 August 2014 Available online 23 August 2014 Keywords: Eicosapentaenoic acid (EPA) Docosahexaenoic acid (DHA) Arachidonic acid (AA) Arterial stiffness CAVI Atherosclerosis
Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), n−3 polyunsaturated fatty acids (PUFAs), have beneficial effects on reduction of cardiovascular disease (CVD) risk in epidemiological studies [1,2]. Japan EPA Lipid Intervention Study (JELIS) reported that long-term use of purified EPA added on statins reduced the incidence of major coronary events compared with the statin monotherapy [3], and meta-analysis papers have demonstrated that EPA and DHA supplementations reduce the risk of fatal CVD by 10% [4]. However, arachidonic acid (AA), an n−6 PUFA, is a source of inflammatory mediators in contrast to n−3 PUFA EPA [5]. In the results of sub-analysis from the JELIS, the risk of cardiovascular death and myocardial infarction was significantly lower in subjects with a higher serum EPA/AA ratio [6]. Arterial stiffness is a functional biomarker of atherosclerosis and an important predictor of CVD [7]. However, the association between serum EPA/AA ratio and the arterial
⁎ Corresponding author at: Department of Laboratory Medicine, Jikei University Kashiwa Hospital, 163-1 Kashiwashita, Kashiwa, Chiba 277-8567, Japan. Tel.: + 81 4 7164 1111x2270; fax: +81 4 7164 1126. E-mail address: [email protected] (H. Yoshida).
http://dx.doi.org/10.1016/j.ijcard.2014.08.093 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
stiffness [cardio-ankle vascular index (CAVI)] has not been fully elucidated. Subjects of this study, approved by the Ethics Committee of Jikei University School of Medicine, were 136 non-obese persons (mean age: 67 ± 9 years, mean body mass index (BMI): 22.9 ± 2.8 kg/m2) who underwent a medical brain checkup at Jikei University Kashiwa hospital from April 2009 to March 2011. The medical records were investigated retrospectively. The patients, who took medications of EPA and DHA, were excluded from the study subjects. CAVI was examined with VaSera CAVI instrument (Fukuda Denshi, Tokyo, Japan), which simultaneously measured blood pressure levels in bilateral arms by an oscillometric method, and the coefficient of variation of CAVI was b5% [8]. The average data of bilateral values of CAVI and blood pressure were used for the statistical analysis. Fasting blood samples were collected, and serum total cholesterol (TC), triglyceride (TG), insulin, plasma glucose and glycohemoglobin A1c (HbA1c) were measured by conventional methods. Cholesterol levels of very lowdensity lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL), and other fractions were measured by high-performance liquid chromatography [9]. Fatty acids were determined by gas-chromatography. Serum creatinine was measured by the enzymatic method, and estimated glomerular filtration rate (eGFR) was calculated by the formula of the Japanese Society of Nephrology. CAVI in patients without signs of atherosclerosis was reported to be b8.0, and the cut-off point of CAVI for the presence of atherosclerotic diseases was reported to be 9.0 [8]. The study subjects with CAVI b 8.0, 8.0 to 8.9, and ≥9.0 were classified into Group 1 (n = 47), 2 (n = 50) and 3 (n = 41). Although 6, 7, and 2 subjects of the total subjects took lipid-lowering drugs, anti-hypertensives, and diabetic medicines, respectively, there were no significant differences in medications among the 3 groups. Table 1 shows the characteristics of study subjects. Age of Group 3 was highest, and smokers were found more frequently in Group 1 than in Group 2 whereas smoker numbers were scarce in the study subjects. Group 3 showed modestly lower eGFR. HDL-cholesterol was significantly lower in Group 3 than in Groups 1 and 2. However,
518
H. Yoshida et al. / International Journal of Cardiology 177 (2014) 517–519
Table 1 Characteristics of study subjects.
Basic data Male/female Age (years) Smoker (yes/no) Drink (yes/no) BMI (kg/m2) SBP (mm Hg) DBP (mm Hg) FPG (mg/dL) Hemoglobin A1c (%) Insulin (×10−3 U/L) Insulin resistance (HOMA-R) Estimated GFR (mL/min) Serum lipid data (mg/dL) TC TG Non-HDL cholesterol Lipoprotein cholesterol by anion-exchange liquid chromatography (mg/dL) HDL LDL IDL VLDL Others PUFAs AA (μg/mL) EPA (μg/mL) DHA (μg/mL) EPA/AA DHA/AA
All
Group 1 (CAVI b 8)
Group 2 (CAVI = 8–9)
Group 3 (CAVI N 9)
p value (T1 vs T2)
p value (T1 vs T3)
p value (T2 vs T3)
ANOVA or Kruskal–Wallis
60/76 67 ± 9 8/128 21/115 22.9 ± 2.8 133 ± 16 81 ± 9 102 ± 14 5.5 ± 0.4 6.0 ± 4.0 1.6 ± 1.2 75 ± 17
19/28 62 ± 11 6/41 10/37 23.4 ± 3.3 131 ± 17 81 ± 8 104 ± 18 5.4 ± 0.3 6.4 ± 4.4 1.7 ± 1.3 79 ± 18
19/31 68 ± 7 0/50 5/45 22.5 ± 2.6 135 ± 15 81 ± 9 101 ± 13 5.5 ± 0.5 6.0 ± 4.2 1.6 ± 1.2 77 ± 16
22/19 73 ± 7 2/37 6/33 22.9 ± 2.3 133 ± 17 80 ± 9 102 ± 10 5.5 ± 0.4 5.6 ± 3.1 1.4 ± 0.9 70 ± 17
NS b0.005 b0.01 NS NS NS NS NS NS NS NS NS
NS b0.0001 NS NS NS NS NS NS NS NS NS b0.05
NS b0.0005 NS NS NS NS NS NS NS NS NS NS
NS b0.0001 b0.05 NS NS NS NS NS NS NS NS NS
206 ± 35 120 ± 53 143 ± 32
207 ± 31 117 ± 60 141 ± 30
213 ± 39 120 ± 50 149 ± 36
195 ± 31 123 ± 50 138 ± 27
NS NS NS
NS NS NS
b0.05 NS NS
NS NS NS
62.4 ± 14.6 117.0 ± 29.3 5.9 ± 2.9 10.2 ± 6.9 6.6 ± 4.1
66.4 ± 14.4 115.0 ± 26.5 6.0 ± 3.9 10.9 ± 9.0 6.7 ± 5.0
63.2 ± 14.7 122.8 ± 33.8 5.8 ± 2.2 9.7 ± 5.2 6.6 ± 3.7
56.6 ± 13.2 112.0 ± 25.7 5.8 ± 2.2 10.1 ± 6.0 6.6 ± 3.5
NS NS NS NS NS
b0.005 NS NS NS NS
b0.05 NS NS NS NS
b0.01 NS NS NS NS
152.5 ± 36.7 78.2 ± 40.3 159.7 ± 50.0 0.53 ± 0.30 1.09 ± 0.38
134.1 ± 23.7 83.8 ± 39.5 164.2 ± 56.4 0.63 ± 0.31 1.29 ± 0.41
163.3 ± 37.3 78.8 ± 43.7 158.5 ± 42.2 0.50 ± 0.29 1.00 ± 0.29
160.7 ± 40.7 70.7 ± 36.6 155.7 ± 51.9 0.46 ± 0.28 1.01 ± 0.41
b0.0001 NS NS b0.05 b0.005
b0.001 NS NS b0.01 b0.05
NS NS NS NS NS
b0.0001 NS NS b0.05 b0.005
BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; FPG, fasting plasma glucose; HOMA-R, homeostasis model assessment ratio; GFR, glomerular filtration ratio; TC, total cholesterol; TG, triglyceride; HDL, high-density lipoprotein; LDL, low density lipoprotein; IDL, intermediate density lipoprotein; VLDL, very low density lipoprotein; PUFAs, polyunsaturated fatty acids; AA, arachidonic acid; EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid; NS, not significant. HOMA-R data were calculated by the formula [fasting insulin (mU/mL) × FPG/405], and estimated GFR data were calculated by the formula following the equation of the Japanese Society of Nephrology: eGFR = 194 × Creatinine − 1.094 × age−0.287 (× 0.739 if female). Others mean chylomicron, chylomicron remnant, and lipoprotein (a) [Lp(a)].
cholesterol levels of other lipoproteins were not different among the 3 groups. AA levels were significantly lower in Group 1 than in Groups 2 and 3, but EPA and DHA concentrations were not different (Table 1). However, the ratios of EPA/AA and DHA/AA were significantly higher in Group 1 than in Groups 2 and 3. In simple correlations of age, BMI, blood pressures, glucose metabolism-related parameters, and serum lipid data to CAVI, age and AA were positively correlated with CAVI. HDL-C, EPA/AA and DHA/AA were inversely correlated with CAVI. The influence of AA levels to CAVI might be considered. In the two subgroups divided by median of AA levels, EPA/AA and DHA/AA were not different among the 3 groups in the subgroup with lower AA values (n = 68). However, EPA/AA was significantly lower (p b 0.05) in Group 3 (n = 23, 0.41 ± 0.23) than in Group 1 (n = 12, 0.6 ± 0.23) in the subgroup with higher AA group (n = 68). Then, multivariate stepwise-regression analysis using EPA/AA, DHA/AA and HDL cholesterol, universal confounding factors (gender, age, smoking habit, BMI) and LDL-cholesterol globally regarded as treat target for atherosclerosis prevention as independent variables, showed that DHA/AA, age and HDL-cholesterol were found to be the significant factors for CAVI but not EPA/AA (Table 2). Ratios of EPA/AA and DHA/AA were higher in non-obese subjects with low CAVI expressing good arterial stiffness. Meanwhile, AA was higher in the subjects with higher CAVI, but EPA and DHA were not different among the 3 groups by CAVI levels. In the subgroup with higher AA group, EPA/AA was significantly lower in the higher CAVI group than in the lower CAVI group. EPA composed of 20 carbon chains in the structure acts as an inhibitor of AA-derived inflammatory mediators by competing with AA at the step of cyclooxygenases and lipoxygenases [5]. The Hisayama Study also demonstrated the significant association between EPA/AA ration and CVD risk, especially in subjects with higher levels of highly-sensitive C-reactive protein (CRP) [10]. Recently, EPA administration to obese patients with dyslipidemia has been reported
to improve arterial stiffness (CAVI), which shows that the improved CAVI is associated with the increased EPA/AA ratio and the decreased inflammation [11]. The present study shows similar findings that EPA/AA ratio is inversely correlated with CAVI in non-obese subjects, indicating the particular association of EPA/AA ratio to CAVI in subjects with higher AA levels presumably expressive of inflammation. The multivariate regression analysis revealed that DHA/AA, age and HDL-cholesterol significantly correlated with CAVI, but EPA/AA did not. The discrepancy between EPA/AA and DHA/AA is undefined but might be related to age and diet habits. EPA and DHA consumption and traditional Japanese diet intake increase with age [12]. In addition, serum DHA concentrations are naturally high compared with EPA. Including age in independent variables might attenuate the correlation of EPA/AA to CAVI. But, it remains unclear because the data of dietary intake were not obtained in this retrospective study.
Table 2 Multiple stepwise regression analysis between CAVI and fatty acid, and lipoprotein data.
Basic data Male/female Age (years) Smoker (yes/no) Body mass index (kg/m2) Fatty acid EPA/AA DHA/AA Lipoprotein data by anion-exchange liquid chromatography HDL cholesterol LDL cholesterol
Partial correlation coefficient
t value
p value
−0.0671 0.6187 −0.0920 −0.1060
0.7579 8.8744 1.0414 1.2016
0.4499 b0.0001 0.2997 0.2318
−0.0155 −0.1762
0.1745 2.0175
0.8618 0.0458
−0.3089 0.0971
3.6599 1.0993
0.0004 0.2737
H. Yoshida et al. / International Journal of Cardiology 177 (2014) 517–519
In conclusion, the present study suggests that DHA/AA ratio may be useful in the management of patients with impaired arterial stiffness, while EPA/AA could be helpful for patients with high serum AA concentrations presumably expressive of inflammation in non-obese subjects. Conflict of interest The authors report no conflict of interest for the present study. Acknowledgments We thank the medical staff for medical checkup of the brain at the Jikei University Kashiwa Hospital and also appreciate Daisuke Manita MS (Bioscience Division, TOSOH Corp, Japan) for the helpful assistance of lipoprotein cholesterol measurement by HPLC. Source of funding Research funds were provided by the Jikei University Research Fund and in part by Grant-in-Aid for Scientific Research (23591066) from the Japan Ministry of Education, Culture, Sports, Science and Technology (Yoshida H). References [1] Hu FB, Bronner L, Willett WC, et al. Fish and omega-3 fatty acid intake and risk of coronary heart disease in women. JAMA 2002;287:1815–21.
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[2] Iso H, Kobayashi M, Ishihara J, et al. Intake of fish and n3 fatty acids and risk of coronary heart disease among Japanese: the Japan Public Health Center-based (JPHC) study cohort I. Circulation 2006;113:195–202. [3] Yokoyama M, Origasa H, Matsuzaki M, et al. lipid intervention study (JELIS) Investigators. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet 2007;369:1090–8. [4] Kromhout D, de Goede J. Update on cardiometabolic health effects of n−3 fatty acids. Curr Opin Lipidol 2014;25:85–90. [5] Harris WS, Miller M, Tighe AP, Davidson MH, Schaefer EJ. Omega-3 fatty acids and coronary heart disease risk: clinical and mechanistic perspectives. Atherosclerosis 2008;197:12–24. [6] Matsuzaki M, Yokoyama M, Saito Y, et al. Incremental effects of eicosapentaenoic acid on cardiovascular events in statin-treated patients with coronary artery disease. Circ J 2009;73:1283–90. [7] Vlachopoulos C, Aznaouridis K, Stefanadis C. Prediction of cardiovascular events and all-cause mortality with arterial stiffness: a systematic review and meta-analysis. J Am Coll Cardiol 2010;55:1318–27. [8] Shirai K, Hiruta N, Song M, et al. Cardio-ankle vascular index (CAVI) as a novel indicator of arterial stiffness: theory, evidence and perspectives. J Atheroscler Thromb 2011;18:924–38. [9] Ito K, Yoshida H, Yanai H, et al. Relevance of intermediate-density lipoprotein cholesterol to Framingham risk score of coronary heart disease in middle-aged men with increased non-HDL cholesterol. Int J Cardiol 2013;168:3853–8. [10] Ninomiya T, Nagata M, Hata J, et al. Association between ratio of serum eicosapentaenoic acid to arachidonic acid and risk of cardiovascular disease: the Hisayama study. Atherosclerosis 2013;231:261–7. [11] Ito R, Satoh-Asahara N, Yamakage H, et al. An increase in the EPA/AA ratio is associated with improved arterial stiffness in obese patients with dyslipidemia. J Atheroscler Thromb 2014;21:248–60. [12] Otsuka R, Kato Y, Imai T, Ando F, Shimokata H. Higher serum EPA or DHA, and lower ARA compositions with age independent fatty acid intake in Japanese aged 40 to 79. Lipids 2013;48:719–27.
