Abstract
Aim: Omega-3 polyunsaturated fatty acids (PUFAs) such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been reported to reduce the risk of cardiovascular disease. However, whether omega-3 PUFAs are involved in the pathogenesis of abdominal aortic aneurysms (AAA) remains unclear.
Methods: We analyzed 67 consecutive patients admitted for the elective surgical repair of AAA. We investigated the association of serum EPA and DHA levels as well as the EPA/AA ratio with the size of AAA assessed using three-dimensional reconstructed computed tomography images.
Results: Mean patient age was 70 ± 9 years and 60 patients were male. Serum EPA and DHA levels were 75.2 ± 35.7 µg/mL and 146.1 ± 48.5 µg/mL, respectively. EPA/AA ratio was 0.44 ± 0.22, which was lower than those in healthy Japanese subject and equivalent to those in Japanese patients with coronary artery disease as previously reported. Mean of the maximum AAA diameter was 56.4 ± 8.9 mm, and serum EPA levels and EPA/AA ratio negatively correlated with it (r = −0.32 and r = −0.32, respectively). Multiple liner regression analysis showed that EPA levels were significant independent factor contributing to the maximum AAA diameter. Furthermore, low serum EPA levels and low EPA/AA ratio were significantly associated with the growth rate of AAA diameter (r = −0.43 and r = −0.33, respectively).
Conclusion: EPA levels in patients with AAA were relatively low. Low serum EPA levels and EPA/AA ratio were associated with the size and growth rate of AAA.
Keywords: Polyunsaturated fatty acids, Atherosclerosis, Inflammation, Coronary artery disease
See editorial vol. 24: 908–909
Introduction
Dietary intake of fish-derived omega-3 polyunsaturated fatty acids (PUFAs) such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) has been recommended to reduce the risk of cardiovascular disease1–4). Omega-3 PUFAs have been demonstrated to possess anti-inflammatory, anti-fibrotic, and cardioprotective properties and improve vascular function5–9). Atherosclerosis and inflammation are reported to be implicated in the pathogenesis of aortic aneurysms10, 11). However, it is still unclear omega-3 PUFAs are implicated in the pathogenesis of aortic aneurysms as well as coronary artery disease (CAD). We previously reported that dietary intake of EPA and DHA prevented development of abdominal aortic aneurysms (AAAs) through the inhibition of macrophagemediated inflammation in a mouse model12). Therefore, we assessed serum levels of omega-3 PUFAs in patients with AAA and investigated the association with size of AAA.
Methods
Study Subjects
We enrolled 86 consecutive patients who were admitted to Juntendo University Hospital for the purpose of treatment for AAA by elective Endovascular Aneurysm Repair (EVAR) and conventional surgical repair from January 2013 to June 2016. We measured serum concentrations of PUFAs [EPA, DHA, and arachidonic acid (AA)] on admission. Eleven patients were excluded because 1 patient had an infected aneurysm, 1 patient had an endoleak after previous EVAR, 7 patients had taken pure EPA and 2 patients had received hemodialysis. Eight patients had not undergone three-dimensional (3D) reconstructed computed tomographic (CT) scan imaging before surgery. Finally, we analyzed 67 patients. We investigated whether serum omega-3 PUFAs (EPA and DHA), AA and the EPA/AA ratio are associated with the size of AAA. All subjects provided informed consent, the study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki, and the study was approved by the ethical committee of Juntendo University Hospital.
Blood pressure (BP) was measured using a standard mercury sphygmomanometer. Height and weight were measured using an automated scale, and body mass index (BMI) was calculated as the weight in kilograms divided by the square of the height in meters. Hypertension was defined as systolic blood pressure ≥ 140 mmHg, diastolic blood pressure ≥ 90 mmHg, or currently taking antihypertensive medications. Dyslipidemia was defined as a low-density lipoprotein cholesterol (LDL-C) level ≥ 140 mg/dL, a high-density lipoprotein cholesterol (HDL-C) level < 40 mg/dL, a triglycerides (TG) level ≥ 150 mg/dL, or currently taking lipid-lowering medications. Diabetes mellitus (DM) was defined as a documented history of diabetes treated with medications or hemoglobin A1c (HbA1c) of National Glycohemoglobin Standardization Program (NGSP) level ≥ 6.5%, fasting plasma glucose level ≥ 126 mg/dL, or non-fasting plasma glucose level ≥ 200 mg/dL.
Blood Sampling
Whole blood samples were drawn after overnight fasting within 24 h of admission. Serum levels of total cholesterol (TC), TG, and HDL-C were measured using standard enzymatic methods, and LDL-C values were calculated using the Friedewald formula13). Plasma glucose concentrations and HbA1c, C-reactive protein (CRP), and creatinine (Cr) levels were measured using standardized methods. The estimated glomerular filtration rate was calculated based on the Japanese equation that uses serum Cr level, age, and gender as follows: estimated glomerular filtration rate (mL/min/1.73 m2) = 194 × Cr−1.094 × age−0.287 (female × 0.739)14). Serum concentrations of EPA, DHA, and AA levels were measured by SRL Inc. (Tokyo, Japan) using standard laboratory protocols.
Computed Tomography, Measuring Aneurysm Diameter
All 67 patients had undergone 3D reconstructed CT scan imaging before surgery. All CT angiographies were performed on a multidetector row CT scanner with 64 detectors (Aquilion; Toshiba, Tokyo, Japan). These CT images were reviewed on a 3D workstation (Synapse Vincent; Fujifilm, Tokyo, Japan). The aneurysm's maximum diameter was evaluated, with measurements obtained perpendicular to the centerline of aorta and aneurysm15, 16). The centerline of aorta and aneurysm was identified, and a curved multiplanar reconstruction (CPR) image was created. Then, the maximum diameter on CPR was determined using the cross section perpendicular to the centerline in this CPR image17). Representative images used to determine the maximum diameter of AAA are shown in Fig. 1.
Coronary Artery Disease
CAD was defined as patients with a documented history of acute myocardial infarction, coronary artery bypass graft surgery, or documented presence of significant coronary artery stenosis (luminal narrowing ≥ 50%) in at least one major coronary artery by coronary angiography or multidetector computed tomographic angiography18, 19). Coronary angiography was performed according to standard methods20). Coronary segments were analyzed according to the model of the American College of Cardiology/American Heart Association21).
Statistical Analysis
Continuous variables were expressed as mean ± standard deviation (SD), and categorical variables were reported as percentages. Statistical differences between the groups were analyzed by unpaired Student's t-test, the chi-square test, Fisher's exact test, or the Mann–Whitney–Wilcoxon rank-sum test, as appropriate. Correlations between 2 variables were determined by simple linear regression analysis. Spearman correlations were used when variables were not normally distributed. Multiple linear regression analysis was used to determine the factors independently contributing to the maximum AAA diameter among the variables with a P value < 0.1 in univariate analysis (BMI, EPA and using β blocker). All statistical analyses were performed using JMP 12 software for Windows (SAS Institute, Cary, NC, USA.). Statistical significance was defined as a P-value < 0.05.
Results
Clinical Characteristics of Patients
The baseline characteristics of all patients are shown in Table 1. Over all 67 patients, the mean age was 70 ± 9 years, BMI was 24.8 ± 2.9 kg/m2, and 60 (89.6%) were male. Nineteen (28.4%) patients had a history of current smoking. The number of hypertension, dyslipidemia, diabetes mellitus, and coronary artery disease patients were 52 (77.6%), 59 (88.1%), 13 (19.4%), and 40 (59.7%), respectively.
Table 1. Characteristics of the patients.
All patients | CAD group | Non-CAD group | P value | |
---|---|---|---|---|
N = 67 | N = 40 | N = 27 | ||
Age, (years) | 70 ± 9 | 71 ± 9 | 70 ± 9 | 0.53 |
Male, n (%) | 60 (89.6) | 38 (95.0) | 22 (81.5) | 0.1 |
Body mass index (kg/m2) | 24.8 ± 2.9 | 24.4 ± 2.9 | 25.2 ± 2.9 | 0.26 |
Systolic blood pressure (mmHg) | 120 ± 13 | 119 ± 14 | 123 ± 11 | 0.19 |
Diastolic blood pressure (mmHg) | 69 ± 11 | 66 ± 11 | 73 ± 11 | 0.008 |
Current smoking, n (%) | 19 (28.4) | 13 (32.5) | 6 (22.2) | 0.41 |
Hypertension, n (%) | 52 (77.6) | 30 (75) | 22 (81.5 | 0.76 |
Dyslipidemia, n (%) | 59 (88.1) | 37 (92.5) | 22 (81.5) | 0.25 |
Diabetes mellitus, n (%) | 13 (19.4) | 10 (25.0) | 3 (11.1) | 0.21 |
Coronary artery disease, n (%) | 40 (59.7) | |||
Total cholesterol (mg/dL) | 176 ± 31 | 169 ± 26 | 187 ± 34 | 0.015 |
HDL-cholesterol (mg/dL) | 45 ± 13 | 45 ± 14 | 46 ± 11 | 0.93 |
LDL-cholesterol (mg/dL) | 102 ± 28 | 96 ± 24 | 111 ± 32 | 0.028 |
Triglyceride (mg/dL) | 143 ± 64 | 140 ± 61 | 149 ± 70 | 0.56 |
HbA1c (NGSP) (%) | 6.0 ± 0.6 | 6.1 ± 0.7 | 5.9 ± 0.5 | 0.17 |
Creatinine (mg/dL) | 0.86 ± 0.22 | 0.88 ± 0.24 | 0.82 ± 0.19 | 0.62 |
eGFR (mL/min/1.73 m2) | 70.1 ± 17.6 | 68.7 ± 16.8 | 72.3 ± 18.8 | 0.41 |
CRP (mg/dL) | 0.28 ± 0.45 | 0.31 ± 0.53 | 0.24 ± 0.32 | 0.34 |
EPA (µg/mL) | 75.2 ± 35.7 | 71.7 ± 29.7 | 80.5 ± 43.2 | 0.6 |
DHA (µg/mL) | 146.1 ± 48.5 | 142.7 ± 45.3 | 151.0 ± 53.4 | 0.53 |
AA (µg/mL) | 184.3 ± 53.7 | 182.8 ± 54.9 | 186.5 ± 52.8 | 0.74 |
EPA/AA ratio | 0.44 ± 0.22 | 0.43 ± 0.22 | 0.45 ± 0.23 | 0.72 |
Maximum AAA diameter (mm) | 56.4 ± 8.9 | 56.9 ± 8.7 | 55.6 ± 9.2 | 0.69 |
Medications | ||||
Antiplatelet, n (%) | 23 (34.3) | 20 (50.0) | 3 (11.1) | 0.001 |
Calcium channel blocker, n (%) | 31 (46.3) | 14 (35.0) | 17 (63.0) | 0.028 |
β-blocker, n (%) | 24 (35.8) | 19 (47.5) | 5 (18.5) | 0.019 |
ACE inhibitor or ARB, n (%) | 36 (53.7) | 23 (57.5) | 13 (48.2) | 0.46 |
Statin, n (%) | 46 (68.7) | 33 (82.5) | 13 (48.2) | 0.006 |
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Values are presented as means ± standard deviations. HDL = high-density lipoprotein, LDL = low-density lipoprotein, HbA1c = hemoglobin A1c, NGSP = national glycohemoglobin standardization program, eGFR = estimated glomerular filtration rate, CRP = C-reactive protein, EPA = eicosapentaenoic acid, DHA = docosahexaenoic acid, AA = arachidonic acid, AAA = abdominal aortic aneurysm, ACE = angiotensin converting enzyme, ARB = angiotensin II receptor blocker.
Serum PUFA Levels in Patients with AAA
As shown in Table 1, serum levels of EPA, DHA, and AA were 75.2 ± 35.7, 146.1 ± 48.5, and 184.3 ± 53.7 µg/mL, respectively. The EPA/AA ratio was 0.44 ± 0.22, and the median value was 0.41. We have previously reported serum levels of PUFAs in a healthy Japanese population living in an urban area. In subjects aged over 65 years, serum levels of EPA, DHA, and AA were 81.9 ± 31.1, 123.2 ± 27.0, and 119.8 ± 22.7 µg/mL, respectively. The EPA/AA ratio was 0.68 ± 0.2222). Therefore, serum levels of EPA had a tendency to decrease with age, those of DHA, and AA had a tendency to increase with age, and the EPA/AA ratio was also relatively lower than in healthy Japanese subjects.
Correlations between Serum PUFA Levels and AAA Diameter
Mean of the maximum AAA diameter was 56.4 ± 8.9 mm. There were no significant correlations between maximum AAA diameter and conventional risk factors (e.g., hypertension, dyslipidemia, diabetes mellitus, current smoking, and coronary artery disease). There were no significant correlations between serum levels of TC, HDL-C, LDL-C, TG, HbA1c, creatinine and CRP, and maximum AAA diameter. Although statins, β blockers, and angiotensin pathway inhibition (angiotensin converting enzyme inhibitors or angiotensin II receptor blockers) were pharmacological treatment strategy for AAA, only β blocker usage was associated with AAA diameter (Table 2).
Table 2. Univariate linear regression analysis for correlates of maximum AAA diameter.
r | P value | |
---|---|---|
Age | −0.043 | 0.73 |
Gender | 0.009 | 0.94 |
Body mass index | 0.24 | 0.05 |
Systolic blood pressure | −0.091 | 0.46 |
Diastolic blood pressure | −0.15 | 0.22 |
Current smoking | 0.088 | 0.47 |
Hypertension | 0.075 | 0.54 |
Dyslipidemia | −0.11 | 0.36 |
Diabetes mellitus | −0.037 | 0.77 |
Coronary artery disease | 0.05 | 0.69 |
Total cholesterol | 0.077 | 0.53 |
HDL-cholesterol | −0.13 | 0.28 |
LDL-cholesterol | 0.16 | 0.18 |
Triglyceride | 0.088 | 0.48 |
HbA1c | 0.007 | 0.95 |
Creatinine | −0.054 | 0.66 |
eGFR | 0.091 | 0.46 |
CRP | −0.039 | 0.75 |
EPA | −0.32 | 0.007 |
DHA | −0.14 | 0.25 |
AA | 0.026 | 0.83 |
EPA/AA ratio | −0.32 | 0.008 |
Antiplatelet | 0.021 | 0.87 |
Calcium channel blocker | 0.15 | 0.23 |
β-blocker | 0.21 | 0.091 |
ACE inhibitor or ARB | 0.015 | 0.91 |
Statin | −0.032 | 0.79 |
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Values are presented as means ± standard deviations. CAD = coronary artery disease, HDL = high-density lipoprotein, LDL = low-density lipoprotein, HbA1c = hemoglobin A1c, NGSP = national glycohemoglobin standardization program, eGFR = estimated glomerular filtration rate, CRP = C-reactive protein, EPA = eicosapentaenoic acid, DHA = docosahexaenoic acid, AA = arachidonic acid, ACE = angiotensin converting enzyme, ARB = angiotensin II receptor blocker.
As shown in Fig. 2, serum levels of EPA and the EPA/AA ratio were negatively correlated with maximum AAA diameter (r = −0.32, P = 0.0073, and r = −0.32, P = 0.0075, respectively). However, there were no significant correlations between maximum AAA diameter and serum levels of DHA and AA. Multiple liner regression analysis showed that serum levels of EPA were significant independent factor contributing to maximum AAA diameter (EPA: β = −0.269, P = 0.02, BMI: β = 0.125, P = 0.2, using β blocker: β = −0.109, P = 0.3) (Table 3).
Table 3. Multiple liner regression analysis for correlates of maximum AAA diameter.
β | SE | P value | |
---|---|---|---|
EPA | −0.269 | 0.03 | 0.28 |
BMI | 0.125 | 0.364 | 0.29 |
β blocker | −0.109 | 1.1 | 0.36 |
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R2 = 0.11, P = 0.05
Multiple linear regression analysis was performed among variables with a P value < 0.1 in univariate analysis (BMI, EPA and using β blocker). Using β blocker was assigned a value of 1. Non using β blocker was assigned a value of 0.
Comparison between Serum PUFA Levels between the CAD and the Non-CAD Groups
The patients were also divided into a CAD group and a non-CAD group. Characteristics of the patients in both groups are shown in Table 1. The EPA/AA ratio was not significantly different between the two groups (0.43 ± 0.22 vs. 0.45 ± 0.23, P = 0.72). Serum levels of EPA in the non-CAD group tended to correlate with maximum AAA diameter (r = −0.38, P = 0.050), and the EPA/AA ratio in the non-CAD group was negatively correlated with maximum AAA diameter (r = −0.42, P = 0.030). Whereas maximum AAA diameter tended to be associated with both serum levels of EPA and the EPA/AA ratio (r = −0.26, P = 0.10, and r = −0.28, P = 0.079, respectively) in the CAD group (Fig. 3).
Correlations between Serum PUFA Levels and Growth Rate of AAA Diameter
We investigated the rate of AAA expansion. Among all study subjects, for 41 patients previously performed CT scans over at least six-month intervals could be reviewed retrospectively. We evaluated aneurysms by measuring the traditional maximum minor-axis diameter using the cross sectional slice. Mean of the maximum minor-axis AAA diameter was 48.8 ± 6.1 mm. Mean follow-up time was 30.6 ± 22.5 months (range 6–77 months). The mean monthly growth rate of maximum minor-axis AAA diameter was 0.28 ± 0.12 mm/month (range 0.11–0.64 mm). Systolic blood pressure and diastolic blood pressure were positively correlated with monthly growth rate of maximum minor-axis AAA diameter (r = 0.39, P = 0.0097, and r = 0.31, P = 0.045, respectively) and serum levels of creatinine was negatively correlated with monthly growth rate of maximum minor-axis AAA diameter (r = −0.33, P = 0.035). Serum levels of EPA and the EPA/AA ratio were negatively correlated with AAA growth rate (r = −0.43, P = 0.0056, and r = −0.33, P = 0.033, respectively), as shown in Fig. 4.
Discussion
To our knowledge, this is the first study to assess the association between serum levels of PUFAs and the development of AAA in a clinical setting. In patients with AAA, serum levels of EPA had a tendency to decrease with age, DHA, and AA, had a tendency to increase with age, and the EPA/AA ratio was also relatively lower than in healthy Japanese subject22). Moreover, there were significant negative correlations between serum levels of EPA and the EPA/AA ratio and maximum AAA diameter and growth rate of AAA diameter.
Compared with our previous report of serum PUFA levels in healthy Japanese subjects22), patients with AAA showed low EPA levels and EPA/AA ratios. Several previous studies have demonstrated that serum levels of EPA and EPA/AA ratios in patients with CAD are lower than those in normal subjects. The JELIS study showed that the average ratio of EPA/AA serum levels was 0.6 in the primary and secondary prevention study2, 23). In the Tochigi Ryoma EPA/AA Trial in Coronary Artery Disease (TREAT-CAD), the EPA/AA ratio was measured in 428 patients who underwent diagnostic coronary angiography because they were suspected to have CAD. The average EPA/AA ratio was 0.49, and its median value was 0.3724). We also evaluated serum PUFA levels in patients with acute coronary syndrome in a metropolitan area in Japan. The EPA/AA ratio was 0.46 in 72 patients25). The EPA/AA ratio of serum levels in our study subjects was 0.44 ± 0.22, which is equivalent to previous reports in patients with CAD. In addition, serum levels of EPA and the EPA/AA ratio in patients with AAA in the non-CAD group were equivalent to those, in the CAD group, suggesting that serum levels of EPA, and the EPA/AA ratio in patients with AAA is relatively low regardless of the presence of CAD.
Serum levels of EPA and the EPA/AA ratio were significantly negatively correlated with maximum AAA diameter and the growth rate of AAA. AAA formation is associated with chronic aortic wall inflammation, which is linked to the production of elastinand collagen-degrading enzymes such as matrix metalloproteinases (MMP)-2 and MMP-926, 27). We have reported that, in the AAA model that was developed by angiotensin II infusion in apolipoprotein E-deficient mice, administration of both EPA and DHA suppressed the infiltration of macrophages and that down-regulation of inflammatory cytokines and enzymes in the aortic wall resulted in inhibition of the development of AAA12). Wang et al. have also demonstrated that an EPA-rich diet can attenuate AAA formation in a murine CaCl2-induced AAA model by suppressing tissue remodeling28). These results from in vivo studies could account for the association between lower EPA and EPA/AA ratio and the severity of AAA.
Although DHA as well as EPA has been recommended to reduce the risk of cardiovascular disease, Yagi et al. reported that the serum levels of DHA, but not EPA, are associated with the endothelial function in patients with CAD29). Furthermore, we have reported that both EPA and DHA inhibited the development of AAA in a mouse model12). However, serum DHA levels did not correlate with AAA formation in our study population. The mechanism(s) by which only EPA levels were associated with AAA formation is unclear. Therefore, further studies will be required to clarify the different role between DHA and EPA in the pathogenesis of AAA.
Conventional risk factors for AAA are advanced age, male gender, smoking, hypertension, dyslipidemia, and CAD. Pharmacological treatment strategies for AAA are statins, β blockers, and angiotensin pathway inhibition. Several cohort studies have implicated that statins are associated with lower AAA growth rates30, 31). In this study, the CAD group tended to have more conventional risk factors than the non-CAD group, and the CAD group tended to use more pharmacological treatment for AAA than the non-CAD group, especially statins and β blockers. There were stronger correlations of serum levels of EPA and EPA/AA ratio with maximum AAA diameter in the non-CAD group than in the CAD group. These results suggest that low serum levels of EPA and a low EPA/AA ratio contribute more to the development of AAA in patients with fewer conventional risk factors.
This study has several limitations. Firstly, this study was a cross-sectional survey. Therefore, we could not show the causal relationship between PUFA levels and the development of AAA. Secondly, the study sample size was relatively small. Although this study showed a significant correlation between EPA and AAA, a larger prospective study is needed to confirm our results.
Conclusion
The EPA level and EPA/AA ratio may be relatively lower in patients with AAA than in healthy Japanese subjects and equivalent to those in patients with CAD previously reported. Low levels of serum EPA and a low EPA/AA ratio are associated with the severity of AAA. Further investigation would be required to assess whether low serum levels of EPA and a low EPA/AA ratio are potential therapeutic targets.
Acknowledgements
The authors would like to thank Enago (www.enago.jp) for the English language review.
Conflict of Interest
Dr. Daida and Dr. Shimada have received scholarship funds and lecture fees from Takeda Pharmaceutical Company Ltd. and Mochida Pharmaceutical Company Ltd. Dr. Daida has also received clinical research fundings from Takeda Pharmaceutical Company Ltd. The remaining authors report no conflicts of interest.
References
- 1).Teramoto T, Sasaki J, Ueshima H, Egusa G, Kinoshita M, Shimamoto K, Daida H, Biro S, Hirobe K, Funahashi T, Yokote K, Yokode M: Treatment - therapeutic lifestyle modification. J Atheroscler Thromb, 2008; 15: 109-115 [DOI] [PubMed] [Google Scholar]
- 2).Yokoyama M, Origasa H, Matsuzaki M, Matsuzawa Y, Saito Y, Ishikawa Y, Oikawa S, Sasaki J, Hishida H, Itakura H, Kita T, Kitabatake A, Nakaya N, Sakata T, Shimada K, Shirato K: Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet (London, England), 2007; 369: 1090-1098 [DOI] [PubMed] [Google Scholar]
- 3).Rizos EC, Ntzani EE, Bika E, Kostapanos MS, Elisaf MS: Association between omega-3 fatty acid supplementation and risk of major cardiovascular disease events: az systematic review and meta-analysis. JAMA, 2012; 308: 1024-1033 [DOI] [PubMed] [Google Scholar]
- 4).Ishida T, Naoe S, Nakakuki M, Kawano H, Imada K: Eicosapentaenoic Acid Prevents Saturated Fatty Acid-Induced Vascular Endothelial Dysfunction: Involvement of Long-Chain Acyl-CoA Synthetase. J Atheroscler Thromb, 2015; 22: 1172-1185 [DOI] [PubMed] [Google Scholar]
- 5).Schwab JM, Chiang N, Arita M, Serhan CN: Resolvin E1 and protectin D1 activate inflammation-resolution programmes. Nature, 2007; 447: 869-874 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6).Bagnall RD, Weintraub RG, Ingles J, Duflou J, Yeates L, Lam L, Davis AM, Thompson T, Connell V, Wallace J, Naylor C, Crawford J, Love DR, Hallam L, White J, Lawrence C, Lynch M, Morgan N, James P, du Sart D, Puranik R, Langlois N, Vohra J, Winship I, Atherton J, McGaughran J, Skinner JR, Semsarian C: A Prospective Study of Sudden Cardiac Death among Children and Young Adults. N Engl J Med, 2016; 374: 2441-2452 [DOI] [PubMed] [Google Scholar]
- 7).Kris-Etherton PM, Harris WS, Appel LJ: Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Circulation, 2002; 106: 2747-2757 [DOI] [PubMed] [Google Scholar]
- 8).Saravanan P, Davidson NC, Schmidt EB, Calder PC: Cardiovascular effects of marine omega-3 fatty acids. Lancet (London, England), 2010; 376: 540-550 [DOI] [PubMed] [Google Scholar]
- 9).Matsumoto M, Sata M, Fukuda D, Tanaka K, Soma M, Hirata Y, Nagai R: Orally administered eicosapentaenoic acid reduces and stabilizes atherosclerotic lesions in ApoE-deficient mice. Atherosclerosis, 2008; 197: 524-533 [DOI] [PubMed] [Google Scholar]
- 10).Eliason JL, Hannawa KK, Ailawadi G, Sinha I, Ford JW, Deogracias MP, Roelofs KJ, Woodrum DT, Ennis TL, Henke PK, Stanley JC, Thompson RW, Upchurch GR, Jr.: Neutrophil depletion inhibits experimental abdominal aortic aneurysm formation. Circulation, 2005; 112: 232-240 [DOI] [PubMed] [Google Scholar]
- 11).Kajimoto K, Miyauchi K, Kasai T, Shimada K, Kojima Y, Shimada A, Niinami H, Amano A, Daida H: Short-term 20-mg atorvastatin therapy reduces key inflammatory factors including c-Jun N-terminal kinase and dendritic cells and matrix metalloproteinase expression in human abdominal aortic aneurysmal wall. Atherosclerosis, 2009; 206: 505-511 [DOI] [PubMed] [Google Scholar]
- 12).Yoshihara T, Shimada K, Fukao K, Sai E, Sato-Okabayashi Y, Matsumori R, Shiozawa T, Alshahi H, Miyazaki T, Tada N, Daida H: Omega 3 Polyunsaturated Fatty Acids Suppress the Development of Aortic Aneurysms Through the Inhibition of Macrophage-Mediated Inflammation. Circ J, 2015; 79: 1470-1478 [DOI] [PubMed] [Google Scholar]
- 13).Friedewald WT, Levy RI, Fredrickson DS: Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem, 1972; 18: 499-502 [PubMed] [Google Scholar]
- 14).Matsuo S, Imai E, Horio M, Yasuda Y, Tomita K, Nitta K, Yamagata K, Tomino Y, Yokoyama H, Hishida A: Revised equations for estimated GFR from serum creatinine in Japan. American journal of kidney diseases : the official journal of the National Kidney Foundation, 2009; 53: 982-992 [DOI] [PubMed] [Google Scholar]
- 15).Halazun KJ, Bofkin KA, Asthana S, Evans C, Henderson M, Spark JI: Hyperhomocysteinaemia is associated with the rate of abdominal aortic aneurysm expansion. Eur J Vasc Endovasc Surg, 2007; 33: 391-394; discussion 395–396 [DOI] [PubMed] [Google Scholar]
- 16).Chaikof EL, Blankensteijn JD, Harris PL, White GH, Zarins CK, Bernhard VM, Matsumura JS, May J, Veith FJ, Fillinger MF, Rutherford RB, Kent KC: Reporting standards for endovascular aortic aneurysm repair. J Vasc Surg, 2002; 35: 1048-1060 [DOI] [PubMed] [Google Scholar]
- 17).Ihara T, Komori K, Yamamoto K, Kobayashi M, Banno H, Kodama A: Three-dimensional workstation is useful for measuring the correct size of abdominal aortic aneurysm diameters. Ann Vasc Surg, 2013; 27: 154-161 [DOI] [PubMed] [Google Scholar]
- 18).Miller JM, Rochitte CE, Dewey M, Arbab-Zadeh A, Niinuma H, Gottlieb I, Paul N, Clouse ME, Shapiro EP, Hoe J, Lardo AC, Bush DE, de Roos A, Cox C, Brinker J, Lima JA: Diagnostic performance of coronary angiography by 64-row CT. N Engl J Med, 2008; 359: 2324-2336 [DOI] [PubMed] [Google Scholar]
- 19).Budoff MJ, Dowe D, Jollis JG, Gitter M, Sutherland J, Halamert E, Scherer M, Bellinger R, Martin A, Benton R, Delago A, Min JK: Diagnostic performance of 64-multidetector row coronary computed tomographic angiography for evaluation of coronary artery stenosis in individuals without known coronary artery disease: results from the prospective multicenter ACCURACY (Assessment by Coronary Computed Tomographic Angiography of Individuals Undergoing Invasive Coronary Angiography) trial. J Am Coll Cardiol, 2008; 52: 1724-1732 [DOI] [PubMed] [Google Scholar]
- 20).Dohi T, Miyauchi K, Ohkawa R, Nakamura K, Kurano M, Kishimoto T, Yanagisawa N, Ogita M, Miyazaki T, Nishino A, Yaginuma K, Tamura H, Kojima T, Yokoyama K, Kurata T, Shimada K, Daida H, Yatomi Y: Increased lysophosphatidic acid levels in culprit coronary arteries of patients with acute coronary syndrome. Atherosclerosis, 2013; 229: 192-197 [DOI] [PubMed] [Google Scholar]
- 21).Austen WG, Edwards JE, Frye RL, Gensini GG, Gott VL, Griffith LS, McGoon DC, Murphy ML, Roe BB: A reporting system on patients evaluated for coronary artery disease. Report of the Ad Hoc Committee for Grading of Coronary Artery Disease, Council on Cardiovascular Surgery, American Heart Association. Circulation, 1975; 51: 5-40 [DOI] [PubMed] [Google Scholar]
- 22).Yanagisawa N, Shimada K, Miyazaki T, Kume A, Kitamura Y, Ichikawa R, Ohmura H, Kiyanagi T, Hiki M, Fukao K, Sumiyoshi K, Hirose K, Matsumori R, Takizawa H, Fujii K, Mokuno H, Inoue N, Daida H: Polyunsaturated fatty acid levels of serum and red blood cells in apparently healthy Japanese subjects living in an urban area. J Atheroscler Thromb, 2010; 17: 285-294 [DOI] [PubMed] [Google Scholar]
- 23).Itakura H, Yokoyama M, Matsuzaki M, Saito Y, Origasa H, Ishikawa Y, Oikawa S, Sasaki J, Hishida H, Kita T, Kitabatake A, Nakaya N, Sakata T, Shimada K, Shirato K, Matsuzawa Y: Relationships between plasma fatty acid composition and coronary artery disease. J Atheroscler Thromb, 2011; 18: 99-107 [DOI] [PubMed] [Google Scholar]
- 24).Kitagawa Y, Abe S, Toyoda S, Watanabe S, Ebisawa K, Murakami Y, Takahashi T, Sugimura H, Taguchi I, Inoue T: Gender differences in the ratio of eicosapentaenoic acid to arachidonic acid in an inland prefecture, Tochigi: Tochigi Ryomo EPA/AA Trial in Coronary Artery Disease (TREAT-CAD). Internal medicine (Tokyo, Japan), 2014; 53: 177-182 [DOI] [PubMed] [Google Scholar]
- 25).Nishizaki Y, Shimada K, Tani S, Ogawa T, Ando J, Takahashi M, Yamamoto M, Shinozaki T, Miyauchi K, Nagao K, Hirayama A, Yoshimura M, Komuro I, Nagai R, Daida H: Significance of imbalance in the ratio of serum n-3 to n-6 polyunsaturated fatty acids in patients with acute coronary syndrome. Am J Cardiol, 2014; 113: 441-445 [DOI] [PubMed] [Google Scholar]
- 26).Longo GM, Xiong W, Greiner TC, Zhao Y, Fiotti N, Baxter BT: Matrix metalloproteinases 2 and 9 work in concert to produce aortic aneurysms. The Journal of clinical investigation, 2002; 110: 625-632 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27).Freestone T, Turner RJ, Coady A, Higman DJ, Greenhalgh RM, Powell JT: Inflammation and matrix metalloproteinases in the enlarging abdominal aortic aneurysm. Arterioscler Thromb Vasc Biol, 1995; 15: 1145-1151 [DOI] [PubMed] [Google Scholar]
- 28).Wang JH, Eguchi K, Matsumoto S, Fuji K, Komuro I, Nagai R, Manade I: The ω-3 Polyunsaturated fatty acid, eicosapentaenoic acid, attenuates abdominal aortic aneurysm development via suppression of tissue remodeling. PLoS One, 2014; 9: e96286. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29).Yagi S, Aihara K, Fukuda D, Takashima A, Hara T, Hotchi J, Ise T, Yamaguchi K, Tobiume T, Iwase T, Yamada H, Soeki T, Wakatsuki T, Shimabukuro M, Akaike M, Sata M: Effects of docosahexaenoic Acid on the endothelial function in patients with coronary artery disease. J Atheroscler Thromb, 2015; 22: 447-454 [DOI] [PubMed] [Google Scholar]
- 30).Moll FL, Powell JT, Fraedrich G, Verzini F, Haulon S, Waltham M, van Herwaarden JA, Holt PJ, van Keulen JW, Rantner B, Schlosser FJ, Setacci F, Ricco JB: Management of abdominal aortic aneurysms clinical practice guidelines of the European society for vascular surgery. Eur J Vasc Endovasc Surg, 2011; 41 Suppl 1: S1-s58 [DOI] [PubMed] [Google Scholar]
- 31).Golledge J, Norman PE: Current status of medical management for abdominal aortic aneurysm. Atherosclerosis, 2011; 217: 57-63 [DOI] [PubMed] [Google Scholar]