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Serum fatty acids and ischemic stroke subtypes in middle- and late-onset acute stroke patients
Clinical Nutrition Experimental xxx (2018) 1e11
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Serum fatty acids and ischemic stroke subtypes in middleand late-onset acute stroke patients Takahisa Mori*, Yuhei Tanno, Shigen Kasakura, Kazuhiro Yoshioka, Noriyoshi Nakai Department of Stroke Treatment, Shonan Kamakura General Hospital Stroke Centre, Okamoto 1370-1, Kamakura City, Kanagawa, 247-8533, Japan
a r t i c l e i n f o
s u m m a r y
Article history: Received 19 November 2017 Accepted 26 September 2018 Available online xxx
Introduction: Among stroke patients, the dietary lipid content is likely associated with the age at stroke onset and ischemic stroke subtype. Specifically, middle-onset stroke patients may have a higher serum level of saturated fatty acids and higher incidence of lacunar or atherosclerotic stroke, whereas late-onset stroke patients may have a higher serum level of n-3 polyunsaturated fatty acids (PUFA; a fish oil component) and lower incidence of lacunar or atherosclerotic stroke. This retrospective study aimed to investigate the relationships among serum fatty acid levels, age at stroke onset and stroke subtype in ischemic stroke patients. Methods: Our analysis included ischemic stroke patients aged 50 years who were admitted to our institution within 24 h of stroke onset between September 2015 and March 2017 and underwent blood evaluations of saturated fatty acids (lauric, myristic, palmitic, stearic acids), a monounsaturated fatty acid (MUFA; oleic acid), n-6 PUFAs [linoleic, arachidonic acids (AA)] and n-3 PUFAs [alphalinoleic, eicosapentaenoic (EPA), docosahexaenoic acids (DHA)]. We excluded patients who used statins, n-3 PUFA supplements or purified EPA drugs, fibrates or ezetimibe at onset. To compare serum levels of fatty acids and incidence rates of stroke subtypes, we stratified patients by age at stroke onset as Middle onset (50 e74 years) or Late onset (75 years). Results: One hundred ninety-one patients with an average age of 74.4 years met our inclusion criteria. Ninety-one and 100 patients
Keywords: Serum fatty acids Ischemic stroke subtype Middle-onset stroke Late-onset stroke
Abbreviations: MBP, mean blood pressure; SBP, systolic blood pressure; DBP, diastolic blood pressure; BMI, body mass index; BS, blood sugar; TCHO, total cholesterol; TG, triglyceride; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; MUFA, monounsaturated fatty acid; PUFA, polyunsaturated fatty acid; AA, arachidonic acid; EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid; SD, standard deviation; mRS, modified Rankin scale. * Corresponding author. Fax: þ81 467478243. E-mail address: [email protected] (T. Mori). https://doi.org/10.1016/j.yclnex.2018.09.001 2352-9393/© 2018 The Authors. Published by Elsevier Ltd on behalf of European Society for Clinical Nutrition and Metabolism. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Please cite this article in press as: Mori T, et al., Serum fatty acids and ischemic stroke subtypes in middleand late-onset acute stroke patients, Clinical Nutrition Experimental (2018), https://doi.org/10.1016/ j.yclnex.2018.09.001
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T. Mori et al. / Clinical Nutrition Experimental xxx (2018) 1e11
were classified as Middle- and Late-onset, respectively, and these groups differed significantly in terms of mean body mass index values (23.9 vs. 22.9 kg/m2, p < 0.05). Significant differences were also observed in the serum levels of various fatty acids between the Middle- and Late-onset groups, with the following respective serum levels (all mg/ml): myristic, 25.2 and 20.9 (p < 0.05); palmitic, 763 and 663 (p < 0.001); stearic, 224 and 193 (p < 0.0001); oleic, 702 and 586 (p < 0.0001); linoleic, 882 and 746 (p < 0.0001); AA, 158 and 140 (p < 0.005); EPA, 64 and 79 (p < 0.05) and DHA, 131 and 142 (p ¼ 0.09). The EPA/AA and n-6/n-3 ratios also differed significantly (0.43 vs. 0.57, p < 0.001; 5.2 vs. 4.0, p < 0.0001). Middle- and Late-onset patients had respective lacunar or atherosclerotic stroke incidence rates of 66% and 42% and cardiogenic stroke incidence rates of 16% and 36% (p < 0.01). Conclusions: People with higher serum levels of saturated fatty acids, MUFAs and n-6 PUFAs more frequently experienced lacunar or atherosclerotic stroke during middle age, whereas those with lower serum levels of these fatty acids and higher serum levels of n-3 PUFAs, such as EPA, more frequently experienced all types of ischemic stroke at an older age. © 2018 The Authors. Published by Elsevier Ltd on behalf of European Society for Clinical Nutrition and Metabolism. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).
1. Introduction According to previous studies, n-3 polyunsaturated fatty acids (PUFAs) may reduce the incidence of coronary heart disease or stroke or the mortality associated with cardiovascular disease [1e4]. By contrast, saturated fatty acids (SFAs) can increase the risks of these conditions [5], and the effects of n-6 PUFAs remain controversial [6]. Despite these findings, the serum concentrations of fatty acids in normally healthy people remain uncertain. Furthermore, although the concentrations of fatty acids such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) continue to increase with age in women, no validated model has linked age with fatty acid levels in men [7]. In patients with hypercholesterolemia, the Japan EPA Lipid Intervention Study (JELIS) reported approximate plasma concentrations of 34, 748, 690, 835, 162, 95 and 170 mg/ml for myristic acid, palmitic acid, oleic acid, linoleic acid, arachidonic acid (AA), EPA and DHA, respectively [8]. Arteriosclerosis progression is a known consequence of dyslipidaemia, and rapid progression can lead to vascular disease at a younger age. By contrast, slower arteriosclerosis progression can delay the onset of vascular disease until later ages. As dietary lipids are constructed from triacylglycerols (i.e., triglycerides), which are composed of three fatty acids and a single glycerol molecule, the dietary lipid content may be associated with the age at stroke onset and ischemic stroke subtype. Specifically, patients with a stroke onset during middle age (50e74 years) may have higher serum levels of saturated fatty acids and a higher incidence of lacunar or atherosclerotic stroke, whereas those with onset at a later age (75 years) may have lower serum levels of saturated fatty acids, higher serum levels of n-3 PUFAs and a lower incidence of lacunar or atherosclerotic stroke. This retrospective study aimed to investigate the relationships among serum levels of fatty acids, age at stroke onset and stroke subtype.
2. Patients and methods 2.1. Study design and subjects We conducted a cross-sectional study of acute ischemic stroke patients aged 50 years who 1) were admitted to our institution within 24 h of stroke onset between September 2015 and March 2017, 2) Please cite this article in press as: Mori T, et al., Serum fatty acids and ischemic stroke subtypes in middleand late-onset acute stroke patients, Clinical Nutrition Experimental (2018), https://doi.org/10.1016/ j.yclnex.2018.09.001
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had a pre-hospital modified Rankin scale (mRS) score of 2, 3) had a body mass index (BMI) of 18.5 and 4) underwent evaluations of serum fatty acid levels at admission. 2.2. Exclusion criteria We excluded patients who used statins, n-3 PUFA supplements or drugs such as highly purified EPA, fibrates or ezetimibe at stroke onset. Additionally, we excluded those with a BMI <18.5, which was defined as underweight according to the World Health Organisation (WHO) guidelines, as we determined that possible malnutrition was not appropriate to our investigation. 2.3. Variables The following fatty acid-related variables were examined: serum levels of SFAs, including lauric acid, myristic acid, palmitic acid and stearic acid; monounsaturated fatty acids (MUFAs) such as oleic acid; n-6 PUFAs such as linoleic acid and AA and n-3 PUFAs such as alpha-linolenic acid, EPA and DHA. MBP was calculated using the following formula: DBP plus (SBP-DBP) divided by 3. 2.4. Evaluation After stratifying patients by the age at stroke onset into Middle-onset (50e74 years) and Late-onset groups (75 years), the baseline characteristics, serum levels of fatty acids and incidence of stroke subtypes were compared between the groups. 2.5. Ethics The relevant institutional ethics committee approved the access of medical records for our retrospective analysis. Informed consent was not required because of the retrospective design and anonymisation of patient identifiers. 2.6. Statistical analysis Continuous variables are expressed as means ± standard deviations (SDs) and were compared using the unpaired Student's t test. Categorical data were compared using the chi-square test. A p value of <0.05 was considered statistically significant. We used the JMP software program (version 14.1; SAS Institute, Cary, NC, USA) to perform the statistical analyses. 3. Results A total of 463 patients with ischemic stroke were admitted to our stroke centre during the study period. Among them, 129 patients were excluded from our analysis because of a pre-hospital mRS score of 3, 37 were excluded with a BMI of <18.5, 57 were excluded because they did not undergo a serum fatty acid analysis at admission and 49 were excluded for using medication for dyslipidaemia. Finally, 191 patients (Table 1) met our inclusion criteria. The included patients had an average age of 74.4 years and a slight male predominance (63.3%). In this group, the serum levels of total cholesterol (TCHO), triglycerides, low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) were 203.4 ± 40.2, 116.2 ± 71.2, 121.2 ± 33.5 and 58.5 ± 17.5 mg/dl, respectively. Regarding stroke subtype, 102 (53.4%) and 50 patients (26.1%) experienced lacunar/atherosclerotic or cardiogenic stroke, respectively. Upon age stratification (Table 2), 91 and 100 patients were classified into the Middle- and Late-onset groups, respectively. These groups both exhibited a slight male predominance (60% and 66%, respectively, p > 0.05). Regarding anthropomorphic factors, the Middle- and Late-onset groups had the following respective mean values: height, 162.0 ± 8.5 and 159.7 ± 10.1 cm (p ¼ 0.09); body weight, 63.0 ± 11.2 and 58.9 ± 11.5 kg (p < 0.05); and BMI, 24.0 ± 3.8 and 22.9 ± 2.9 kg/m2 (p < 0.05). The Middle- and Late-onset groups also had the following respective mean laboratory values at admission: Please cite this article in press as: Mori T, et al., Serum fatty acids and ischemic stroke subtypes in middleand late-onset acute stroke patients, Clinical Nutrition Experimental (2018), https://doi.org/10.1016/ j.yclnex.2018.09.001
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T. Mori et al. / Clinical Nutrition Experimental xxx (2018) 1e11 Table 1 All patients' characteristics. n Age (m ± SD) years Male gender Height (m ± SD) cm Body Weight (m ± SD) kg BMI (m ± SD) kg/m2 Mean blood pressure (m ± SD) mmHg BS (m ± SD) mg/dl HbA1c (m ± SD) % TCHO (m ± SD) mg/dl TG (m ± SD) mg/dl LDL-C (m ± SD) mg/dl HDL-C (m ± SD) mg/dl Saturated fatty acids Lauric acid (m ± SD) mg/ml Myristic acid (m ± SD) mg/ml Palmitic acid (m ± SD) mg/ml Stearic acid (m ± SD) mg/ml Monounsaturated fatty acid oleic acid (m ± SD) mg/ml n-6 Polyunsaturated fatty acids Linoleic acid (m ± SD) mg/ml Arachidonic acid (m ± SD) mg/ml n-3 Polyunsaturated fatty acids Alpha-linolenic acid (m ± SD) mg/ml Eicosapentaenoic acid (m ± SD) mg/ml Docosahexaenoic acid (m ± SD) mg/ml EPA/AA ratio (m ± SD) n-6/n-3 ratio (m ± SD)
191 74.4 ± 10.4 121 (63.3%) 160.8 ± 9.4 60.8 ± 11.5 23.4 ± 3.4 115.0 ± 19.5 136.8 ± 50.9 6.1 ± 1.1 203.4 ± 40.2 116.2 ± 71.2 121.2 ± 33.5 58.5 ± 17.5 2.7 ± 5.6 22.9 ± 14.2 711.1 ± 182.5 207.8 ± 49.5 641.2 ± 193.8 810.6 ± 207.8 149.0 ± 39.2 24.3 ± 12.9 72.7 ± 41.1 136.9 ± 43.2 0.503 ± 0.282 4.6 ± 1.9
BMI: body mass index, BS: blood sugar, TCHO: Total cholesterol, TG: Triglyceride. LDL-C: low density lipoprotein cholesterol, HDL-C: high density lipoprotein cholesterol. EPA: eicosapentaenoic acid, AA: arachidonic acid, n-6: n-6 polyunsaturated fatty acids. n-3: n-3 polyunsaturated fatty acids, m: mean, SD: standard deviation.
MBP, 119.2 ± 20.0 and 111.1 ± 18.3 mmHg (p < 0.01); glycated haemoglobin (HbA1c, 6.4 ± 1.4 and 6.0 ± 0.8% (p < 0.05); TCHO, 212.4 ± 41.7 and 195.1 ± 37.1 mg/dl (p < 0.01); triglyceride, 135.5 ± 86.7 and 98.5 ± 48.3 mg/dl (p < 0.001) and HDL-C, 61.2 ± 17.8 and 56.0 ± 16.9 mg/dl (p < 0.05) (Table 2). A comparative analysis of SFA levels between the Middle- and Late-onset groups revealed the following respective values (all mg/ml) (Table 3): lauric acid, 2.8 ± 5.5 and 2.5 ± 5.8 (ns); myristic acid, 25.2 ± 16.1 and 20.9 ± 12.0 (p < 0.05); palmitic acid, 763 ± 211.4 and 663.5 ± 136.0 (p < 0.001) and stearic acid, 223.7 ± 54.2 and 193.3 ± 39.7 (p < 0.0001). The respective serum levels of the MUFA oleic acid were 702.3 ± 212.4 and 585.7 ± 156.5 mg/ml (p < 0.0001). The Middle- and Late-onset groups also had the following respective serum levels of n-6 PUFAs (all mg/ml): linoleic acid, 881.7 ± 217.9 and 745.8 ± 175.5 (p < 0.0001) and AA, 158.4 ± 41.6 and 140.4 ± 35.1 (p < 0.005). Finally, the two groups had the following respective serum levels of n-3 PUFAs (all mg/ml): alpha-linolenic acid, 27.0 ± 13.8 and 21.8 ± 11.5 (p < 0.01); EPA, 66.4 ± 37.7 and 78.5 ± 43.5 mg/ml (p < 0.05) and DHA, 131.3 ± 43.4 and 142.0 ± 42.6 (p ¼ 0.09). The Middle- and Late-onset groups had respective EPA/AA ratios of 0.427 ± 0.233 and 0.573 ± 0.305 (p < 0.001) and respective n-6/n-3 ratios of 5.2 ± 2.3 and 4.0 ± 1.4 (p < 0.0001) (Table 3). Middle- and Late-onset patients differed significantly in terms of the incidence of lacunar or atherosclerotic stroke and of cardiogenic stroke (n ¼ 60, 66% vs. 42, 42% and 14, 15.4% vs. 36, 36%, respectively; p < 0.01) (Table 2). In a stepwise regression analysis, the n-6 PUFAs AA and linoleic acid were significant determinants of an elevated TCHO level, while the MUFA oleic acid was a significant determinant of a reduced TCHO level (Table 4) (Fig. 1). Oleic acid was also the most significant determinant of an elevated triglyceride level, followed by myristic acid (Table 5) (Fig. 2). Please cite this article in press as: Mori T, et al., Serum fatty acids and ischemic stroke subtypes in middleand late-onset acute stroke patients, Clinical Nutrition Experimental (2018), https://doi.org/10.1016/ j.yclnex.2018.09.001
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Table 2 Comparison of baseline features in middle onset patients with in late onset patients.
n Age (m ± SD) years Male gender Female gender Height (m ± SD) cm Body Weight (m ± SD) kg BMI (m ± SD) kg/m2 Mean blood pressure (m ± SD) mmHg BS (m ± SD) mg/dl HbA1c (m ± SD) % TCHO (m ± SD) mg/dl TG (m ± SD) mg/dl LDL-C (m ± SD) mg/dl HDL-C (m ± SD) mg/dl Stroke subtypes Lacuna or atherosclerosis Cardiogenic embolism Others
Middle onset
Late onset
(50e74 years old)
(75 years or older)
91 65.5 ± 6.6 55 (60.4%) 36 (39.6%%) 162.0 ± 8.5 63.0 ± 11.2 24.0 ± 3.8 119.2 ± 20.0 140.7 ± 62.9 6.4 ± 1.4 212.4 ± 41.7 135.5 ± 86.7 124.1 ± 37.1 61.2 ± 17.8
100 82.6 ± 5.4 66 (66.0%) 34 (34.0%) 159.7 ± 10.1 58.9 ± 11.5 22.9 ± 2.9 111.1 ± 18.3 133.3 ± 36.7 6.0 ± 0.8 195.1 ± 37.1 98.5 ± 48.3 119.4 ± 29.9 56.0 ± 16.9
60 14 17
42 36 22
p
<0.0001 ns 0.09 <0.05 <0.05 <0.01 ns <0.05 <0.01 <0.001 ns <0.05 <0.01
Bold: Significantly higher. BMI: body mass index, BS: blood sugar, TCHO: Total cholesterol, TG: Triglyceride. LDL-C: low density lipoprotein cholesterol, HDL-C: high density lipoprotein cholesterol. p: probability, m: mean, SD: standard deviation. Table 3 Comparison of fatty acids in middle onset patients with in Late onset patients.
Saturated fatty acids Lauric acid (m ± SD) mg/ml Myristic acid (m ± SD) mg/ml Palmitic acid (m ± SD) mg/ml Stearic acid (m ± SD) mg/ml Monounsaturated fatty acid Oleic acid (m ± SD) mg/ml n-6 Polyunsaturated fatty acids Linoleic acid (m ± SD) mg/ml Arachidonic acid (m ± SD) mg/ml n-3 Polyunsaturated fatty acids Alpha-linolenic acid (m ± SD) mg/ml Eicosapentaenoic acid (m ± SD) mg/ml Docosahexaenoic acid (m ± SD) mg/ml EPA/AA ratio (m ± SD) n-6/n-3 ratio (m ± SD)
Middle onset (n ¼ 91)
Late onset (n ¼ 100)
(50e74 years old)
(75 years or older)
2.8 ± 5.5 25.2 ± 16.1 763.3 ± 211.4 223.7 ± 54.2
2.5 ± 5.8 20.9 ± 12.0 663.5 ± 136.0 193.3 ± 39.7
ns <0.05 <0.001 <0.0001
702.3 ± 212.4
585.7 ± 156.5
<0.0001
881.7 ± 217.9 158.4 ± 41.6
745.8 ± 175.5 140.4 ± 35.1
<0.0001 <0.01
27.0 ± 13.8 66.4 ± 37.7 131.3 ± 43.4 0.427 ± 0.233 5.2 ± 2.3
21.8 ± 11.5 78.5 ± 43.5 142.0 ± 42.6 0.573 ± 0.305 4.0 ± 1.4
<0.01 <0.05 <0.1 <0.001 <0.0001
p
Bold: Significantly higher. EPA: eicosapentaenoic acid, AA: arachidonic acid, n-6: n-6 polyunsaturated fatty acids. n-3: n-3 polyunsaturated fatty acids, SD: standard deviation, p: probability.
Next, we stratified the two age groups by sex. Among women, Middle-onset patients had a higher mean blood pressure and serum levels of HbA1c, TCHO, LDL-C, HDL-C and linoleic acid; a lower EPA/AA ratio and were most likely to suffer from arteriosclerotic stroke (Table 6). By contrast, women in the Late-onset group had a lower mean blood pressure and serum levels of HbA1c, triglyceride, palmitic acid, oleic acid and linoleic acid; higher levels of EPA and DHA; a lower n-6/n-3 ratio; higher EPA/AA ratio and a lower incidence of arteriosclerotic stroke (Table 6). No differences in the serum levels of fatty acids were observed between men and women in the Middle-onset group, whereas female Late-onset patients had higher serum levels of stearic acid, AA Please cite this article in press as: Mori T, et al., Serum fatty acids and ischemic stroke subtypes in middleand late-onset acute stroke patients, Clinical Nutrition Experimental (2018), https://doi.org/10.1016/ j.yclnex.2018.09.001
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Table 4 Stepwise regression analysis for independet determinants of total cholesterol. Variables
t-value
95% CI
p
Arachidonic acid Linoleic acid Oleic acid Stearic acid
5.64 5.17 3.93 3.31
0.235e0.489 0.053e0.119 0.107 to 0.036 0.102e0.403
<0.0001 <0.0001 <0.001 <0.01
CI: Confidence Interval.
Fig. 1. Relationship between the serum levels of arachidonic acid and total cholesterol. The analysis revealed a strong correlation between these parameters.
Table 5 Stepwise regression analysis for independet determinants of triglyceride. Variables
t-value
95% CI
p
Oleic acid Myristic acid
11.5 3.9
0.203e0.287 0.570e1.729
<0.0001 <0.001
CI: Confidence Interval.
and DHA relative to their male counterparts (Table 7). Furthermore, the serum levels of some fatty acids were higher among Middle-onset male patients relative to their Late-onset counterparts. Late-onset female patients had higher serum levels of EPA and DHA, a higher EPA/AA ratio, a lower serum level of linoleic acid and a lower n-6/n-3 ratio relative to their Middle-onset counterparts (Table 8). 4. Discussion Our results demonstrate significant differences in the levels of various serum lipid and fatty acid levels and the types of stroke among stroke patients according to the age at stroke onset. Furthermore, Please cite this article in press as: Mori T, et al., Serum fatty acids and ischemic stroke subtypes in middleand late-onset acute stroke patients, Clinical Nutrition Experimental (2018), https://doi.org/10.1016/ j.yclnex.2018.09.001
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Fig. 2. Relationship between the serum levels of oleic acid and triglyceride. This analysis revealed a strong correlation between these parameters.
we observed that the serum level of total cholesterol exhibited significant positive correlations with the serum levels of the n-6 PUFAs AA and linoleic acid and the SFA stearic acid, as well as a negative correlation with the MUFA oleic acid. Moreover, the serum level of triglyceride correlated significantly with the serum level of oleic acid. Previous studies have reported that dietary supplementation with n-3 PUFAs could effectively reduce the risk of cardiovascular death [9], whereas the consumption of SFAs increases this risk [5]. Another study reported that the administration of highly purified EPA appeared to reduce the risk of recurrent stroke in a Japanese population of hypercholesterolemic patients receiving low-dose statin therapy [3]. Furthermore, in a 24-year follow-up of NIPPON DATA80, the intake of n-3 PUFAs was inversely and independently associated with the long-term risk of total cerebrovascular disease (CVD) mortality in a representative sample of Japanese subjects with a high intake of n-3 PUFAs [4]. Furthermore, a low serum n-3/n-6 ratio at admission was identified as a potential predictor of neurological deterioration in Japanese patients with acute ischemic stroke [10]. Therefore, patients with severe metabolic disorders were expected to suffer from early arteriosclerosis progression and arteriosclerotic stroke during Middle age, while patients with mild metabolic disorders were expected to experience a delayed arteriosclerotic progression and stroke at a later age. Indeed, Middle-onset patients in our study had higher mean values for the parameters of BMI, mean blood pressure, HbA1c, TCHO, triglyceride and HDL-C when compared to Late-onset patients, as well as higher levels of all fatty acids except EPA, particularly high levels of stearic, oleic, and linoleic acids and a high n-6/n-3 ratio. Approximately 66% of Middle-onset patients suffered from lacunar or atherosclerotic stroke. Current dietary recommendations suggest avoiding the overconsumption of vegetable oils containing high levels of linoleic acid or meat containing high levels of AA. Conversely, these guidelines encourage the increased consumption of foods containing high levels of oleic acid, such as extra virgin olive oil (a common component of Mediterranean cuisine). We observed a correlation of a higher serum level of oleic or myristic acid with a higher serum level of triglyceride (Table 5, Fig. 2). Therefore, a high level of consumption of vegetable oil containing oleic acid or coconut oil containing myristic acid may contribute to hypertriglyceridemia.
Please cite this article in press as: Mori T, et al., Serum fatty acids and ischemic stroke subtypes in middleand late-onset acute stroke patients, Clinical Nutrition Experimental (2018), https://doi.org/10.1016/ j.yclnex.2018.09.001
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Table 6 Comparison of variables in male and female patients according to onset age.
n Age (m±SD) years Height (m±SD) cm Body Weight (m±SD) kg BMI (m±SD) kg/m2 Mean blood pressure (m ± SD) mmHg BS (m±SD) mg/dl HbA1c (m ± SD) % TCHO (m ± SD) mg/dl TG (m ± SD) mg/dl LDL-C (m ± SD) mg/dl HDL-C (m ± SD) mg/dl Stroke subtypes Lacuna or atherosclerosis Cardiogenic embolism Others Saturated fatty acids Lauric acid (m ± SD) mg/ml Myristic acid (m ± SD) mg/ml Palmitic acid (m ± SD) mg/ml Stearic acid (m ± SD) mg/ml Monounsaturated fatty acid Oleic acid (m ± SD) mg/ml n-6 Polyunsaturated fatty acids Linoleic acid (m ± SD) mg/ml Arachidonic acid (m ± SD) mg/ml n-3 Polyunsaturated fatty acids Alpha-linolenic acid (m ± SD) mg/ml Eicosapentaenoic acid (m ± SD) mg/ml Docosahexaenoic acid (m ± SD) mg/ml EPA/AA ratio (m ± SD) n-6/n-3 ratio (m ± SD)
Middle onset (n ¼ 91)
Late onset (n ¼ 100)
(50e74 years old)
(75 years or older)
p
Male Female Male Female 55 (60.4%, 55/91) 36 (40.0%, 36/91) 66 (66%, 66/100) 34 (34%, 34/100) ns 166.9 ± 5.9 66.5 ± 8.7 23.9 ± 2.6 119.6 ± 19.9 142.2 ± 71.4 6.2 ± 1.3 203.6 ± 41.6 151.9 ± 95.8 114.6 ± 36.4 58.6 ± 19.4
154.7 ± 6.3 57.7 ± 12.6 24.1 ± 5.2 118.5 ± 20.3 138.4 ± 47.9 6.6 ± 1.5 225.9 ± 38.4 110.4 ± 64.1 138.7 ± 33.8 65.2 ± 14.6
165.0 ± 6.8 63.7 ± 10.3 23.3 ± 2.8 112.2 ± 19.1 135.9 ± 37.6 6.1 ± 0.9 187.0 ± 35.9 101.8 ± 51.8 112.6 ± 28.7 54.1 ± 15.6
149.4 ± 7.0 49.6 ± 7.2 22.2 ± 3.0 109.1 ± 16.7 128.4 ± 34.9 5,7 ± 0.4 210.5 ± 34.9 92.2 ± 41.0 132.4 ± 28.0 59.7 ± 18.9
<0.0001 <0.0001 0.08 <0.05 ns <0.05 <0.0001 <0.0001 <0.001 <0.05
35 10 10
25 4 7
27 26 13
15 10 9
<0.05
3.46 ± 6.91 27.1 ± 18.5 786.7 ± 231.7 228.1 ± 61.7
1.90 ± 1.87 22.3 ± 18.5 727.6 ± 173.0 217.1 ± 40.3
2.84 ± 6.92 20.9 ± 12.6 658.4 ± 146.2 184.4 ± 37.3
1.93 ± 2.18 21.0 ± 10.9 673.4 ± 115.0 210.5 ± 39.1
ns 0.07 <0.001 <0.0001
722.5 ± 231.3
671.4 ± 178.4
588.3 ± 170.2
580.5 ± 128.0
<0.001
875.3 ± 228.4 156.6 ± 46.3
891.2 ± 203.7 161.2 ± 33.5
738.1 ± 182.5 134.1 ± 37.2
760.8 ± 162.6 152.7 ± 27.2
<0.0001 <0.01
27.9 ± 14.7 68.3 ± 43.0 128.0 ± 48.0 0.449 ± 0.274 5.36 ± 2.59
25.6 ± 12.3 63.6 ± 28.0 136.3 ± 35.4 0.394 ± 0.145 4.98 ± 1.60
21.0 ± 9.7 72.0 ± 42.9 131.9 ± 40.0 0.552 ± 0.309 4.20 ± 1.32
23.3 ± 14.4 91.2 ± 42.5 161.6 ± 41.8 0.614 ± 0.298 3.62 ± 1.32
<0.05 <0.05 <0.01 <0.01 <0.0001
Bold: Significantly higher. EPA: eicosapentaenoic acid, AA: arachidonic acid, n-6: n-6 polyunsaturated fatty acids, n-3: n-3 polyunsaturated fatty acids, SD: standard deviation, p: probability.
Patients in the Late-onset group had a higher level of EPA, higher EPA/AA ratio and lower incidence of arteriosclerotic stroke, compared to their younger counterparts. These results suggest that the excess intake of SFAs, MUFAs and n-6 PUFAs and insufficient intake of EPA contributes to the early progression of arteriosclerosis and middle-age onset of arteriosclerotic stroke. By contrast, the appropriate intake of the indicated fatty acids and EPA delay the progression of arteriosclerosis. Furthermore, Middle-onset patients were more likely to harbour multiple cardiovascular risk factors, compared with Late-onset patients. A previous study reported that Japanese men harbouring 3 or 4 cardiovascular risk factors had a higher risk of stroke mortality relative to their counterparts with none of these factors (hazard ratio: 5.1) [11]. In 2016, the World Health Statistics reported that Japanese women had the longest life expectancy worldwide, with a value of 86.8 years in 2015; moreover, Japanese men had the sixth-longest life expectancy of 80.5 years in the same year. The statistics bureau of the Japanese Ministry of Internal Affairs and Communications further reported that as of March 1, 2017, 10,457,000 Japanese women and 6,685,000 Japanese men were aged 75 years or older. Although the general Japanese population aged 75 years or older has a female predominance (61% vs. 39% men), the corresponding age group in our study cohort comprised only 34% women and 66% men (Table 6). This suggests that the incidence of ischemic stroke is much lower among women than among men. We might attribute this finding to the higher levels of EPA and DHA, higher EPA/AA ratio and lower n-6/n-3 ratio detected among female subjects aged 75 years or older in our study, compared to their male counterparts (Table 6). Please cite this article in press as: Mori T, et al., Serum fatty acids and ischemic stroke subtypes in middleand late-onset acute stroke patients, Clinical Nutrition Experimental (2018), https://doi.org/10.1016/ j.yclnex.2018.09.001
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Table 7 Comparison of fatty acids in male and female patients according to onset age. Middle onset (n ¼ 91)
n Saturated fatty acids Lauric acid (m ± SD) mg/ml Myristic acid (m ± SD) mg/ml Palmitic acid (m ± SD) mg/ml Stearic acid (m ± SD) mg/ml Monounsaturated fatty acid Oleic acid (m ± SD) mg/ml n-6 Polyunsaturated fatty acids Linoleic acid (m ± SD) mg/ml Arachidonic acid (m ± SD) mg/ml n-3 Polyunsaturated fatty acids Alpha-linolenic acid (m ± SD) mg/ml Eicosapentaenoic acid (m ± SD) mg/ml Docosahexaenoic acid (m ± SD) mg/ml EPA/AA ratio (m ± SD) n-6/n-3 ratio (m ± SD)
p
Late onset (n ¼ 100)
(50e74 years old)
(75 years or older)
Male Female 55 (60.4%, 55/91) 36 (40.0%, 36/91)
Male Female 66 (66%, 66/100) 34 (34%, 34/100)
p
3.46 ± 6.91 27.1 ± 18.5 786.7 ± 231.7 228.1 ± 61.7
1.90 ± 1.87 22.3 ± 18.5 727.6 ± 173.0 217.1 ± 40.3
ns ns ns ns
2.84 ± 6.92 20.9 ± 12.6 658.4 ± 146.2 184.4 ± 37.3
1.93 ± 2.18 21.0 ± 10.9 673.4 ± 115.0 210.5 ± 39.1
ns ns ns 0.0015
722.5 ± 231.3
671.4 ± 178.4
ns 588.3 ± 170.2
580.5 ± 128.0
ns
875.3 ± 228.4 156.6 ± 46.3
891.2 ± 203.7 161.2 ± 33.5
ns 738.1 ± 182.5 ns 134.1 ± 37.2
760.8 ± 162.6 152.7 ± 27.2
ns 0.0112
27.9 ± 14.7 68.3 ± 43.0 128.0 ± 48.0 0.449 ± 0.274 5.36 ± 2.59
25.6 ± 12.3 63.6 ± 28.0 136.3 ± 35.4 0.394 ± 0.145 4.98 ± 1.60
ns ns ns ns ns
21.0 ± 9.7 72.0 ± 42.9 131.9 ± 40.0 0.552 ± 0.309 4.20 ± 1.32
23.3 ± 14.4 91.2 ± 42.5 161.6 ± 41.8 0.614 ± 0.298 3.62 ± 1.32
ns 0.0354 0.0007 ns 0.0431
Bold: Significantly higher. EPA: eicosapentaenoic acid, AA: arachidonic acid, n-6: n-6 polyunsaturated fatty acids, n-3: n-3 polyunsaturated fatty acids, SD: standard deviation, p: probability. Table 8 Comparison of fatty acids in middle- or late-onset patients according to gender. n
Saturated fatty acids Lauric acid (m ± SD) mg/ml Myristic acid (m ± SD) mg/ml Palmitic acid (m ± SD) mg/ml Stearic acid (m ± SD) mg/ml Monounsaturated fatty acid Oleic acid (m ± SD) mg/ml n-6 Polyunsaturated fatty acids linoleic acid (m ± SD) mg/ml arachidonic acid (m ± SD) mg/ml n-3 Polyunsaturated fatty acids Alpha-linolenic acid (m ± SD) mg/ml Eicosapentaenoic acid (m ± SD) mg/ml Docosahexaenoic acid (m ± SD) mg/ml EPA/AA ratio (m ± SD) n-6/n-3 ratio (m ± SD)
Male (n ¼ 121)
p
Female (n ¼ 70)
p
Middle onset
Late onset
Middle onset
Late onset
(50e74 years old)
(75 years or older)
(50e74 years old)
(75 years or older)
55
66
36
34
3.46 ± 6.91 27.1 ± 18.5 786.7 ± 231.7 228.1 ± 61.7
2.84 ± 6.92 20.9 ± 12.6 658.4 ± 146.2 184.4 ± 37.3
ns 0.0293 0.0003 <0.0001
1.90 ± 1.87 22.3 ± 18.5 727.6 ± 173.0 217.1 ± 40.3
1.93 ± 2.18 21.0 ± 10.9 673.4 ± 115.0 210.5 ± 39.1
ns ns ns ns
722.5 ± 231.3
588.3 ± 170.2
0.0004
671.4 ± 178.4
580.5 ± 128.0
0.0175
875.3 ± 228.4 156.6 ± 46.3
738.1 ± 182.5 134.1 ± 37.2
0.0004 0.0037
891.2 ± 203.7 161.2 ± 33.5
760.8 ± 162.6 152.7 ± 27.2
0.0042 ns
27.9 ± 14.7 68.3 ± 43.0 128.0 ± 48.0 0.449 ± 0.274 5.36 ± 2.59
21.0 ± 9.7 72.0 ± 42.9 131.9 ± 40.0 0.552 ± 0.309 4.20 ± 1.32
0.0023 ns ns 0.0571 0.0019
25.6 ± 12.3 63.6 ± 28.0 136.3 ± 35.4 0.394 ± 0.145 4.98 ± 1.60
23.3 ± 14.4 91.2 ± 42.5 161.6 ± 41.8 0.614 ± 0.298 3.62 ± 1.32
ns 0.002 0.0081 0.0002 0.0003
Bold: Significantly higher. EPA: eicosapentaenoic acid, AA: arachidonic acid, n-6: n-6 polyunsaturated fatty acids, n-3: n-3 polyunsaturated fatty acids, SD: standard deviation, p: probability.
A previous study reported a much lower level of coronary heart disease-related mortality in Japan relative to the USA and suggested that this difference might be attributed to differences in the levels of fish intake and serum omega-3 fatty acid levels between the two populations [12]. These findings suggest that Japanese women aged 75 years or older who consume more fish and have a higher serum level of omega-3 fatty acid may live longer than their male counterparts. This speculation is supported by our finding that among Late-onset patients in our study, women had higher serum levels of EPA and Please cite this article in press as: Mori T, et al., Serum fatty acids and ischemic stroke subtypes in middleand late-onset acute stroke patients, Clinical Nutrition Experimental (2018), https://doi.org/10.1016/ j.yclnex.2018.09.001
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DHA; by contrast, no sex-related differences in these parameters were observed among Middle-onset patients (Tables 7 and 8). 5. Study limitations Our study had several limitations of note. First, this study included a small number of patients. Moreover, all patients were of East Asian ethnicity and were most likely of Japanese ancestry. In addition to genetic differences attributable to race, our patients likely had different dietary intakes from populations in Western countries. These factors may limit the generalisability of our results. Second, our study design was retrospective and cross-sectional, rather than prospective. Therefore, the appropriate dietary intakes of SFA, MUFA, n-6 PUFA and n-3 PUFA (especially EPA) and consequent serum levels that protect against arteriosclerotic progression could not be confirmed. The appropriate daily intake of these fatty acids from dietary sources may prevent abnormal increases in the serum levels of TCHO or TG and atherosclerosis would thus inhibit the rapid progression of atherosclerosis. Therefore, further prospective study is needed to determine the appropriate levels of SFAs, MUFAs and n-6 PUFAs and sufficient levels of n-3 PUFAs, especially EPA. 6. Conclusion People with higher serum levels of saturated fatty acids, MUFAs, and n-6 PUFAs more frequently experienced lacunar or atherosclerotic stroke during middle age, whereas those with lower serum levels of these fatty acids and higher serum levels of n-3 PUFAs, such as EPA, more frequently experienced all types of ischemic stroke at an older age. Conflict of interest The authors have no conflicts of interest to disclose. Statement of authorship Takahisa Mori, MD, had full access to all data in the study and takes responsibility for the integrity of the data and accuracy of the data analysis. Study concept and design: T. Mori. Acquisition of data: T. Mori, Y. Tanno, S. Kasakura, K. Yoshioka, N. Nakai. Interpretation of data and statistical analysis: T. Mori. Drafting the manuscript: T. Mori. Critical revision of the manuscript for important intellectual content: T. Mori. Final approval of the submitted version: T. Mori, Y. Tanno, S. Kasakura, K. Yoshioka, N. Nakai. Acknowledgement The authors wish to thank Miss Nozomi Chiba, BA, for her secretarial support. Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.yclnex.2018.09. 001. References [1] Dyerberg J, Bang HO. A hypothesis on the development of acute myocardial infarction in Greenlanders. Scand J Clin Lab Investig Suppl 1982;161:7e13. [2] Kromhout D, Bosschieter EB, de Lezenne Coulander C. The inverse relation between fish consumption and 20-year mortality from coronary heart disease. N Engl J Med 1985;312:1205e9. [3] Tanaka K, Ishikawa Y, Yokoyama M, Origasa H, Matsuzaki M, Saito Y, et al. Reduction in the recurrence of stroke by eicosapentaenoic acid for hypercholesterolemic patients: subanalysis of the JELIS trial. Stroke J Cerebr Circ 2008;39: 2052e8.
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[4] Miyagawa N, Miura K, Okuda N, Kadowaki T, Takashima N, Nagasawa SY, et al. Long-chain n-3 polyunsaturated fatty acids intake and cardiovascular disease mortality risk in Japanese: a 24-year follow-up of NIPPON DATA80. Atherosclerosis 2014;232:384e9. [5] Sacks FM, Lichtenstein AH, Wu JHY, Appel LJ, Creager MA, Kris-Etherton PM, et al. Dietary fats and cardiovascular disease: a presidential advisory from the American heart association. Circulation 2017;136:e1e23. [6] Harris WS, Mozaffarian D, Rimm E, Kris-Etherton P, Rudel LL, Appel LJ, et al. Omega-6 fatty acids and risk for cardiovascular disease: a science advisory from the American heart association nutrition subcommittee of the council on nutrition, physical activity, and metabolism; council on cardiovascular nursing; and council on epidemiology and prevention. Circulation 2009;119:902e7. [7] Rajalahti T, Lin C, Mjos SA, Kvalheim OM. Serum fatty acid and lipoprotein subclass concentrations and their associations in prepubertal healthy Norwegian children. Metabolomics Off J Metabolomic Soc 2016;12:81. [8] Itakura H, Yokoyama M, Matsuzaki M, Saito Y, Origasa H, Ishikawa Y, et al. Relationships between plasma fatty acid composition and coronary artery disease. J Atherosclerosis Thromb 2011;18:99e107. [9] Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico. Lancet 1999;354: 447e55. [10] Suda S, Katsumata T, Okubo S, Kanamaru T, Suzuki K, Watanabe Y, et al. Low serum n-3 polyunsaturated fatty acid/n-6 polyunsaturated fatty acid ratio predicts neurological deterioration in Japanese patients with acute ischemic stroke. Cerebrovasc Dis 2013;36:388e93. [11] Nakamura Y, Yamamoto T, Okamura T, Kadowaki T, Hayakawa T, Kita Y, et al. Combined cardiovascular risk factors and outcome: NIPPON DATA80, 1980-1994. Circ J Off J Jpn Circ Soc 2006;70:960e4. [12] Iso H, Sato S, Folsom AR, Shimamoto T, Terao A, Munger RG, et al. Serum fatty acids and fish intake in rural Japanese, urban Japanese, Japanese American and Caucasian American men. Int J Epidemiol 1989;18:374e81.
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Clinical Nutrition Experimental journal homepage: http:// www.clinicalnutritionexperimental.com
Serum fatty acids and ischemic stroke subtypes in middleand late-onset acute stroke patients Takahisa Mori*, Yuhei Tanno, Shigen Kasakura, Kazuhiro Yoshioka, Noriyoshi Nakai Department of Stroke Treatment, Shonan Kamakura General Hospital Stroke Centre, Okamoto 1370-1, Kamakura City, Kanagawa, 247-8533, Japan
a r t i c l e i n f o
s u m m a r y
Article history: Received 19 November 2017 Accepted 26 September 2018 Available online xxx
Introduction: Among stroke patients, the dietary lipid content is likely associated with the age at stroke onset and ischemic stroke subtype. Specifically, middle-onset stroke patients may have a higher serum level of saturated fatty acids and higher incidence of lacunar or atherosclerotic stroke, whereas late-onset stroke patients may have a higher serum level of n-3 polyunsaturated fatty acids (PUFA; a fish oil component) and lower incidence of lacunar or atherosclerotic stroke. This retrospective study aimed to investigate the relationships among serum fatty acid levels, age at stroke onset and stroke subtype in ischemic stroke patients. Methods: Our analysis included ischemic stroke patients aged 50 years who were admitted to our institution within 24 h of stroke onset between September 2015 and March 2017 and underwent blood evaluations of saturated fatty acids (lauric, myristic, palmitic, stearic acids), a monounsaturated fatty acid (MUFA; oleic acid), n-6 PUFAs [linoleic, arachidonic acids (AA)] and n-3 PUFAs [alphalinoleic, eicosapentaenoic (EPA), docosahexaenoic acids (DHA)]. We excluded patients who used statins, n-3 PUFA supplements or purified EPA drugs, fibrates or ezetimibe at onset. To compare serum levels of fatty acids and incidence rates of stroke subtypes, we stratified patients by age at stroke onset as Middle onset (50 e74 years) or Late onset (75 years). Results: One hundred ninety-one patients with an average age of 74.4 years met our inclusion criteria. Ninety-one and 100 patients
Keywords: Serum fatty acids Ischemic stroke subtype Middle-onset stroke Late-onset stroke
Abbreviations: MBP, mean blood pressure; SBP, systolic blood pressure; DBP, diastolic blood pressure; BMI, body mass index; BS, blood sugar; TCHO, total cholesterol; TG, triglyceride; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; MUFA, monounsaturated fatty acid; PUFA, polyunsaturated fatty acid; AA, arachidonic acid; EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid; SD, standard deviation; mRS, modified Rankin scale. * Corresponding author. Fax: þ81 467478243. E-mail address: [email protected] (T. Mori). https://doi.org/10.1016/j.yclnex.2018.09.001 2352-9393/© 2018 The Authors. Published by Elsevier Ltd on behalf of European Society for Clinical Nutrition and Metabolism. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Please cite this article in press as: Mori T, et al., Serum fatty acids and ischemic stroke subtypes in middleand late-onset acute stroke patients, Clinical Nutrition Experimental (2018), https://doi.org/10.1016/ j.yclnex.2018.09.001
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were classified as Middle- and Late-onset, respectively, and these groups differed significantly in terms of mean body mass index values (23.9 vs. 22.9 kg/m2, p < 0.05). Significant differences were also observed in the serum levels of various fatty acids between the Middle- and Late-onset groups, with the following respective serum levels (all mg/ml): myristic, 25.2 and 20.9 (p < 0.05); palmitic, 763 and 663 (p < 0.001); stearic, 224 and 193 (p < 0.0001); oleic, 702 and 586 (p < 0.0001); linoleic, 882 and 746 (p < 0.0001); AA, 158 and 140 (p < 0.005); EPA, 64 and 79 (p < 0.05) and DHA, 131 and 142 (p ¼ 0.09). The EPA/AA and n-6/n-3 ratios also differed significantly (0.43 vs. 0.57, p < 0.001; 5.2 vs. 4.0, p < 0.0001). Middle- and Late-onset patients had respective lacunar or atherosclerotic stroke incidence rates of 66% and 42% and cardiogenic stroke incidence rates of 16% and 36% (p < 0.01). Conclusions: People with higher serum levels of saturated fatty acids, MUFAs and n-6 PUFAs more frequently experienced lacunar or atherosclerotic stroke during middle age, whereas those with lower serum levels of these fatty acids and higher serum levels of n-3 PUFAs, such as EPA, more frequently experienced all types of ischemic stroke at an older age. © 2018 The Authors. Published by Elsevier Ltd on behalf of European Society for Clinical Nutrition and Metabolism. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).
1. Introduction According to previous studies, n-3 polyunsaturated fatty acids (PUFAs) may reduce the incidence of coronary heart disease or stroke or the mortality associated with cardiovascular disease [1e4]. By contrast, saturated fatty acids (SFAs) can increase the risks of these conditions [5], and the effects of n-6 PUFAs remain controversial [6]. Despite these findings, the serum concentrations of fatty acids in normally healthy people remain uncertain. Furthermore, although the concentrations of fatty acids such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) continue to increase with age in women, no validated model has linked age with fatty acid levels in men [7]. In patients with hypercholesterolemia, the Japan EPA Lipid Intervention Study (JELIS) reported approximate plasma concentrations of 34, 748, 690, 835, 162, 95 and 170 mg/ml for myristic acid, palmitic acid, oleic acid, linoleic acid, arachidonic acid (AA), EPA and DHA, respectively [8]. Arteriosclerosis progression is a known consequence of dyslipidaemia, and rapid progression can lead to vascular disease at a younger age. By contrast, slower arteriosclerosis progression can delay the onset of vascular disease until later ages. As dietary lipids are constructed from triacylglycerols (i.e., triglycerides), which are composed of three fatty acids and a single glycerol molecule, the dietary lipid content may be associated with the age at stroke onset and ischemic stroke subtype. Specifically, patients with a stroke onset during middle age (50e74 years) may have higher serum levels of saturated fatty acids and a higher incidence of lacunar or atherosclerotic stroke, whereas those with onset at a later age (75 years) may have lower serum levels of saturated fatty acids, higher serum levels of n-3 PUFAs and a lower incidence of lacunar or atherosclerotic stroke. This retrospective study aimed to investigate the relationships among serum levels of fatty acids, age at stroke onset and stroke subtype.
2. Patients and methods 2.1. Study design and subjects We conducted a cross-sectional study of acute ischemic stroke patients aged 50 years who 1) were admitted to our institution within 24 h of stroke onset between September 2015 and March 2017, 2) Please cite this article in press as: Mori T, et al., Serum fatty acids and ischemic stroke subtypes in middleand late-onset acute stroke patients, Clinical Nutrition Experimental (2018), https://doi.org/10.1016/ j.yclnex.2018.09.001
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had a pre-hospital modified Rankin scale (mRS) score of 2, 3) had a body mass index (BMI) of 18.5 and 4) underwent evaluations of serum fatty acid levels at admission. 2.2. Exclusion criteria We excluded patients who used statins, n-3 PUFA supplements or drugs such as highly purified EPA, fibrates or ezetimibe at stroke onset. Additionally, we excluded those with a BMI <18.5, which was defined as underweight according to the World Health Organisation (WHO) guidelines, as we determined that possible malnutrition was not appropriate to our investigation. 2.3. Variables The following fatty acid-related variables were examined: serum levels of SFAs, including lauric acid, myristic acid, palmitic acid and stearic acid; monounsaturated fatty acids (MUFAs) such as oleic acid; n-6 PUFAs such as linoleic acid and AA and n-3 PUFAs such as alpha-linolenic acid, EPA and DHA. MBP was calculated using the following formula: DBP plus (SBP-DBP) divided by 3. 2.4. Evaluation After stratifying patients by the age at stroke onset into Middle-onset (50e74 years) and Late-onset groups (75 years), the baseline characteristics, serum levels of fatty acids and incidence of stroke subtypes were compared between the groups. 2.5. Ethics The relevant institutional ethics committee approved the access of medical records for our retrospective analysis. Informed consent was not required because of the retrospective design and anonymisation of patient identifiers. 2.6. Statistical analysis Continuous variables are expressed as means ± standard deviations (SDs) and were compared using the unpaired Student's t test. Categorical data were compared using the chi-square test. A p value of <0.05 was considered statistically significant. We used the JMP software program (version 14.1; SAS Institute, Cary, NC, USA) to perform the statistical analyses. 3. Results A total of 463 patients with ischemic stroke were admitted to our stroke centre during the study period. Among them, 129 patients were excluded from our analysis because of a pre-hospital mRS score of 3, 37 were excluded with a BMI of <18.5, 57 were excluded because they did not undergo a serum fatty acid analysis at admission and 49 were excluded for using medication for dyslipidaemia. Finally, 191 patients (Table 1) met our inclusion criteria. The included patients had an average age of 74.4 years and a slight male predominance (63.3%). In this group, the serum levels of total cholesterol (TCHO), triglycerides, low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) were 203.4 ± 40.2, 116.2 ± 71.2, 121.2 ± 33.5 and 58.5 ± 17.5 mg/dl, respectively. Regarding stroke subtype, 102 (53.4%) and 50 patients (26.1%) experienced lacunar/atherosclerotic or cardiogenic stroke, respectively. Upon age stratification (Table 2), 91 and 100 patients were classified into the Middle- and Late-onset groups, respectively. These groups both exhibited a slight male predominance (60% and 66%, respectively, p > 0.05). Regarding anthropomorphic factors, the Middle- and Late-onset groups had the following respective mean values: height, 162.0 ± 8.5 and 159.7 ± 10.1 cm (p ¼ 0.09); body weight, 63.0 ± 11.2 and 58.9 ± 11.5 kg (p < 0.05); and BMI, 24.0 ± 3.8 and 22.9 ± 2.9 kg/m2 (p < 0.05). The Middle- and Late-onset groups also had the following respective mean laboratory values at admission: Please cite this article in press as: Mori T, et al., Serum fatty acids and ischemic stroke subtypes in middleand late-onset acute stroke patients, Clinical Nutrition Experimental (2018), https://doi.org/10.1016/ j.yclnex.2018.09.001
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T. Mori et al. / Clinical Nutrition Experimental xxx (2018) 1e11 Table 1 All patients' characteristics. n Age (m ± SD) years Male gender Height (m ± SD) cm Body Weight (m ± SD) kg BMI (m ± SD) kg/m2 Mean blood pressure (m ± SD) mmHg BS (m ± SD) mg/dl HbA1c (m ± SD) % TCHO (m ± SD) mg/dl TG (m ± SD) mg/dl LDL-C (m ± SD) mg/dl HDL-C (m ± SD) mg/dl Saturated fatty acids Lauric acid (m ± SD) mg/ml Myristic acid (m ± SD) mg/ml Palmitic acid (m ± SD) mg/ml Stearic acid (m ± SD) mg/ml Monounsaturated fatty acid oleic acid (m ± SD) mg/ml n-6 Polyunsaturated fatty acids Linoleic acid (m ± SD) mg/ml Arachidonic acid (m ± SD) mg/ml n-3 Polyunsaturated fatty acids Alpha-linolenic acid (m ± SD) mg/ml Eicosapentaenoic acid (m ± SD) mg/ml Docosahexaenoic acid (m ± SD) mg/ml EPA/AA ratio (m ± SD) n-6/n-3 ratio (m ± SD)
191 74.4 ± 10.4 121 (63.3%) 160.8 ± 9.4 60.8 ± 11.5 23.4 ± 3.4 115.0 ± 19.5 136.8 ± 50.9 6.1 ± 1.1 203.4 ± 40.2 116.2 ± 71.2 121.2 ± 33.5 58.5 ± 17.5 2.7 ± 5.6 22.9 ± 14.2 711.1 ± 182.5 207.8 ± 49.5 641.2 ± 193.8 810.6 ± 207.8 149.0 ± 39.2 24.3 ± 12.9 72.7 ± 41.1 136.9 ± 43.2 0.503 ± 0.282 4.6 ± 1.9
BMI: body mass index, BS: blood sugar, TCHO: Total cholesterol, TG: Triglyceride. LDL-C: low density lipoprotein cholesterol, HDL-C: high density lipoprotein cholesterol. EPA: eicosapentaenoic acid, AA: arachidonic acid, n-6: n-6 polyunsaturated fatty acids. n-3: n-3 polyunsaturated fatty acids, m: mean, SD: standard deviation.
MBP, 119.2 ± 20.0 and 111.1 ± 18.3 mmHg (p < 0.01); glycated haemoglobin (HbA1c, 6.4 ± 1.4 and 6.0 ± 0.8% (p < 0.05); TCHO, 212.4 ± 41.7 and 195.1 ± 37.1 mg/dl (p < 0.01); triglyceride, 135.5 ± 86.7 and 98.5 ± 48.3 mg/dl (p < 0.001) and HDL-C, 61.2 ± 17.8 and 56.0 ± 16.9 mg/dl (p < 0.05) (Table 2). A comparative analysis of SFA levels between the Middle- and Late-onset groups revealed the following respective values (all mg/ml) (Table 3): lauric acid, 2.8 ± 5.5 and 2.5 ± 5.8 (ns); myristic acid, 25.2 ± 16.1 and 20.9 ± 12.0 (p < 0.05); palmitic acid, 763 ± 211.4 and 663.5 ± 136.0 (p < 0.001) and stearic acid, 223.7 ± 54.2 and 193.3 ± 39.7 (p < 0.0001). The respective serum levels of the MUFA oleic acid were 702.3 ± 212.4 and 585.7 ± 156.5 mg/ml (p < 0.0001). The Middle- and Late-onset groups also had the following respective serum levels of n-6 PUFAs (all mg/ml): linoleic acid, 881.7 ± 217.9 and 745.8 ± 175.5 (p < 0.0001) and AA, 158.4 ± 41.6 and 140.4 ± 35.1 (p < 0.005). Finally, the two groups had the following respective serum levels of n-3 PUFAs (all mg/ml): alpha-linolenic acid, 27.0 ± 13.8 and 21.8 ± 11.5 (p < 0.01); EPA, 66.4 ± 37.7 and 78.5 ± 43.5 mg/ml (p < 0.05) and DHA, 131.3 ± 43.4 and 142.0 ± 42.6 (p ¼ 0.09). The Middle- and Late-onset groups had respective EPA/AA ratios of 0.427 ± 0.233 and 0.573 ± 0.305 (p < 0.001) and respective n-6/n-3 ratios of 5.2 ± 2.3 and 4.0 ± 1.4 (p < 0.0001) (Table 3). Middle- and Late-onset patients differed significantly in terms of the incidence of lacunar or atherosclerotic stroke and of cardiogenic stroke (n ¼ 60, 66% vs. 42, 42% and 14, 15.4% vs. 36, 36%, respectively; p < 0.01) (Table 2). In a stepwise regression analysis, the n-6 PUFAs AA and linoleic acid were significant determinants of an elevated TCHO level, while the MUFA oleic acid was a significant determinant of a reduced TCHO level (Table 4) (Fig. 1). Oleic acid was also the most significant determinant of an elevated triglyceride level, followed by myristic acid (Table 5) (Fig. 2). Please cite this article in press as: Mori T, et al., Serum fatty acids and ischemic stroke subtypes in middleand late-onset acute stroke patients, Clinical Nutrition Experimental (2018), https://doi.org/10.1016/ j.yclnex.2018.09.001
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Table 2 Comparison of baseline features in middle onset patients with in late onset patients.
n Age (m ± SD) years Male gender Female gender Height (m ± SD) cm Body Weight (m ± SD) kg BMI (m ± SD) kg/m2 Mean blood pressure (m ± SD) mmHg BS (m ± SD) mg/dl HbA1c (m ± SD) % TCHO (m ± SD) mg/dl TG (m ± SD) mg/dl LDL-C (m ± SD) mg/dl HDL-C (m ± SD) mg/dl Stroke subtypes Lacuna or atherosclerosis Cardiogenic embolism Others
Middle onset
Late onset
(50e74 years old)
(75 years or older)
91 65.5 ± 6.6 55 (60.4%) 36 (39.6%%) 162.0 ± 8.5 63.0 ± 11.2 24.0 ± 3.8 119.2 ± 20.0 140.7 ± 62.9 6.4 ± 1.4 212.4 ± 41.7 135.5 ± 86.7 124.1 ± 37.1 61.2 ± 17.8
100 82.6 ± 5.4 66 (66.0%) 34 (34.0%) 159.7 ± 10.1 58.9 ± 11.5 22.9 ± 2.9 111.1 ± 18.3 133.3 ± 36.7 6.0 ± 0.8 195.1 ± 37.1 98.5 ± 48.3 119.4 ± 29.9 56.0 ± 16.9
60 14 17
42 36 22
p
<0.0001 ns 0.09 <0.05 <0.05 <0.01 ns <0.05 <0.01 <0.001 ns <0.05 <0.01
Bold: Significantly higher. BMI: body mass index, BS: blood sugar, TCHO: Total cholesterol, TG: Triglyceride. LDL-C: low density lipoprotein cholesterol, HDL-C: high density lipoprotein cholesterol. p: probability, m: mean, SD: standard deviation. Table 3 Comparison of fatty acids in middle onset patients with in Late onset patients.
Saturated fatty acids Lauric acid (m ± SD) mg/ml Myristic acid (m ± SD) mg/ml Palmitic acid (m ± SD) mg/ml Stearic acid (m ± SD) mg/ml Monounsaturated fatty acid Oleic acid (m ± SD) mg/ml n-6 Polyunsaturated fatty acids Linoleic acid (m ± SD) mg/ml Arachidonic acid (m ± SD) mg/ml n-3 Polyunsaturated fatty acids Alpha-linolenic acid (m ± SD) mg/ml Eicosapentaenoic acid (m ± SD) mg/ml Docosahexaenoic acid (m ± SD) mg/ml EPA/AA ratio (m ± SD) n-6/n-3 ratio (m ± SD)
Middle onset (n ¼ 91)
Late onset (n ¼ 100)
(50e74 years old)
(75 years or older)
2.8 ± 5.5 25.2 ± 16.1 763.3 ± 211.4 223.7 ± 54.2
2.5 ± 5.8 20.9 ± 12.0 663.5 ± 136.0 193.3 ± 39.7
ns <0.05 <0.001 <0.0001
702.3 ± 212.4
585.7 ± 156.5
<0.0001
881.7 ± 217.9 158.4 ± 41.6
745.8 ± 175.5 140.4 ± 35.1
<0.0001 <0.01
27.0 ± 13.8 66.4 ± 37.7 131.3 ± 43.4 0.427 ± 0.233 5.2 ± 2.3
21.8 ± 11.5 78.5 ± 43.5 142.0 ± 42.6 0.573 ± 0.305 4.0 ± 1.4
<0.01 <0.05 <0.1 <0.001 <0.0001
p
Bold: Significantly higher. EPA: eicosapentaenoic acid, AA: arachidonic acid, n-6: n-6 polyunsaturated fatty acids. n-3: n-3 polyunsaturated fatty acids, SD: standard deviation, p: probability.
Next, we stratified the two age groups by sex. Among women, Middle-onset patients had a higher mean blood pressure and serum levels of HbA1c, TCHO, LDL-C, HDL-C and linoleic acid; a lower EPA/AA ratio and were most likely to suffer from arteriosclerotic stroke (Table 6). By contrast, women in the Late-onset group had a lower mean blood pressure and serum levels of HbA1c, triglyceride, palmitic acid, oleic acid and linoleic acid; higher levels of EPA and DHA; a lower n-6/n-3 ratio; higher EPA/AA ratio and a lower incidence of arteriosclerotic stroke (Table 6). No differences in the serum levels of fatty acids were observed between men and women in the Middle-onset group, whereas female Late-onset patients had higher serum levels of stearic acid, AA Please cite this article in press as: Mori T, et al., Serum fatty acids and ischemic stroke subtypes in middleand late-onset acute stroke patients, Clinical Nutrition Experimental (2018), https://doi.org/10.1016/ j.yclnex.2018.09.001
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Table 4 Stepwise regression analysis for independet determinants of total cholesterol. Variables
t-value
95% CI
p
Arachidonic acid Linoleic acid Oleic acid Stearic acid
5.64 5.17 3.93 3.31
0.235e0.489 0.053e0.119 0.107 to 0.036 0.102e0.403
<0.0001 <0.0001 <0.001 <0.01
CI: Confidence Interval.
Fig. 1. Relationship between the serum levels of arachidonic acid and total cholesterol. The analysis revealed a strong correlation between these parameters.
Table 5 Stepwise regression analysis for independet determinants of triglyceride. Variables
t-value
95% CI
p
Oleic acid Myristic acid
11.5 3.9
0.203e0.287 0.570e1.729
<0.0001 <0.001
CI: Confidence Interval.
and DHA relative to their male counterparts (Table 7). Furthermore, the serum levels of some fatty acids were higher among Middle-onset male patients relative to their Late-onset counterparts. Late-onset female patients had higher serum levels of EPA and DHA, a higher EPA/AA ratio, a lower serum level of linoleic acid and a lower n-6/n-3 ratio relative to their Middle-onset counterparts (Table 8). 4. Discussion Our results demonstrate significant differences in the levels of various serum lipid and fatty acid levels and the types of stroke among stroke patients according to the age at stroke onset. Furthermore, Please cite this article in press as: Mori T, et al., Serum fatty acids and ischemic stroke subtypes in middleand late-onset acute stroke patients, Clinical Nutrition Experimental (2018), https://doi.org/10.1016/ j.yclnex.2018.09.001
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Fig. 2. Relationship between the serum levels of oleic acid and triglyceride. This analysis revealed a strong correlation between these parameters.
we observed that the serum level of total cholesterol exhibited significant positive correlations with the serum levels of the n-6 PUFAs AA and linoleic acid and the SFA stearic acid, as well as a negative correlation with the MUFA oleic acid. Moreover, the serum level of triglyceride correlated significantly with the serum level of oleic acid. Previous studies have reported that dietary supplementation with n-3 PUFAs could effectively reduce the risk of cardiovascular death [9], whereas the consumption of SFAs increases this risk [5]. Another study reported that the administration of highly purified EPA appeared to reduce the risk of recurrent stroke in a Japanese population of hypercholesterolemic patients receiving low-dose statin therapy [3]. Furthermore, in a 24-year follow-up of NIPPON DATA80, the intake of n-3 PUFAs was inversely and independently associated with the long-term risk of total cerebrovascular disease (CVD) mortality in a representative sample of Japanese subjects with a high intake of n-3 PUFAs [4]. Furthermore, a low serum n-3/n-6 ratio at admission was identified as a potential predictor of neurological deterioration in Japanese patients with acute ischemic stroke [10]. Therefore, patients with severe metabolic disorders were expected to suffer from early arteriosclerosis progression and arteriosclerotic stroke during Middle age, while patients with mild metabolic disorders were expected to experience a delayed arteriosclerotic progression and stroke at a later age. Indeed, Middle-onset patients in our study had higher mean values for the parameters of BMI, mean blood pressure, HbA1c, TCHO, triglyceride and HDL-C when compared to Late-onset patients, as well as higher levels of all fatty acids except EPA, particularly high levels of stearic, oleic, and linoleic acids and a high n-6/n-3 ratio. Approximately 66% of Middle-onset patients suffered from lacunar or atherosclerotic stroke. Current dietary recommendations suggest avoiding the overconsumption of vegetable oils containing high levels of linoleic acid or meat containing high levels of AA. Conversely, these guidelines encourage the increased consumption of foods containing high levels of oleic acid, such as extra virgin olive oil (a common component of Mediterranean cuisine). We observed a correlation of a higher serum level of oleic or myristic acid with a higher serum level of triglyceride (Table 5, Fig. 2). Therefore, a high level of consumption of vegetable oil containing oleic acid or coconut oil containing myristic acid may contribute to hypertriglyceridemia.
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Table 6 Comparison of variables in male and female patients according to onset age.
n Age (m±SD) years Height (m±SD) cm Body Weight (m±SD) kg BMI (m±SD) kg/m2 Mean blood pressure (m ± SD) mmHg BS (m±SD) mg/dl HbA1c (m ± SD) % TCHO (m ± SD) mg/dl TG (m ± SD) mg/dl LDL-C (m ± SD) mg/dl HDL-C (m ± SD) mg/dl Stroke subtypes Lacuna or atherosclerosis Cardiogenic embolism Others Saturated fatty acids Lauric acid (m ± SD) mg/ml Myristic acid (m ± SD) mg/ml Palmitic acid (m ± SD) mg/ml Stearic acid (m ± SD) mg/ml Monounsaturated fatty acid Oleic acid (m ± SD) mg/ml n-6 Polyunsaturated fatty acids Linoleic acid (m ± SD) mg/ml Arachidonic acid (m ± SD) mg/ml n-3 Polyunsaturated fatty acids Alpha-linolenic acid (m ± SD) mg/ml Eicosapentaenoic acid (m ± SD) mg/ml Docosahexaenoic acid (m ± SD) mg/ml EPA/AA ratio (m ± SD) n-6/n-3 ratio (m ± SD)
Middle onset (n ¼ 91)
Late onset (n ¼ 100)
(50e74 years old)
(75 years or older)
p
Male Female Male Female 55 (60.4%, 55/91) 36 (40.0%, 36/91) 66 (66%, 66/100) 34 (34%, 34/100) ns 166.9 ± 5.9 66.5 ± 8.7 23.9 ± 2.6 119.6 ± 19.9 142.2 ± 71.4 6.2 ± 1.3 203.6 ± 41.6 151.9 ± 95.8 114.6 ± 36.4 58.6 ± 19.4
154.7 ± 6.3 57.7 ± 12.6 24.1 ± 5.2 118.5 ± 20.3 138.4 ± 47.9 6.6 ± 1.5 225.9 ± 38.4 110.4 ± 64.1 138.7 ± 33.8 65.2 ± 14.6
165.0 ± 6.8 63.7 ± 10.3 23.3 ± 2.8 112.2 ± 19.1 135.9 ± 37.6 6.1 ± 0.9 187.0 ± 35.9 101.8 ± 51.8 112.6 ± 28.7 54.1 ± 15.6
149.4 ± 7.0 49.6 ± 7.2 22.2 ± 3.0 109.1 ± 16.7 128.4 ± 34.9 5,7 ± 0.4 210.5 ± 34.9 92.2 ± 41.0 132.4 ± 28.0 59.7 ± 18.9
<0.0001 <0.0001 0.08 <0.05 ns <0.05 <0.0001 <0.0001 <0.001 <0.05
35 10 10
25 4 7
27 26 13
15 10 9
<0.05
3.46 ± 6.91 27.1 ± 18.5 786.7 ± 231.7 228.1 ± 61.7
1.90 ± 1.87 22.3 ± 18.5 727.6 ± 173.0 217.1 ± 40.3
2.84 ± 6.92 20.9 ± 12.6 658.4 ± 146.2 184.4 ± 37.3
1.93 ± 2.18 21.0 ± 10.9 673.4 ± 115.0 210.5 ± 39.1
ns 0.07 <0.001 <0.0001
722.5 ± 231.3
671.4 ± 178.4
588.3 ± 170.2
580.5 ± 128.0
<0.001
875.3 ± 228.4 156.6 ± 46.3
891.2 ± 203.7 161.2 ± 33.5
738.1 ± 182.5 134.1 ± 37.2
760.8 ± 162.6 152.7 ± 27.2
<0.0001 <0.01
27.9 ± 14.7 68.3 ± 43.0 128.0 ± 48.0 0.449 ± 0.274 5.36 ± 2.59
25.6 ± 12.3 63.6 ± 28.0 136.3 ± 35.4 0.394 ± 0.145 4.98 ± 1.60
21.0 ± 9.7 72.0 ± 42.9 131.9 ± 40.0 0.552 ± 0.309 4.20 ± 1.32
23.3 ± 14.4 91.2 ± 42.5 161.6 ± 41.8 0.614 ± 0.298 3.62 ± 1.32
<0.05 <0.05 <0.01 <0.01 <0.0001
Bold: Significantly higher. EPA: eicosapentaenoic acid, AA: arachidonic acid, n-6: n-6 polyunsaturated fatty acids, n-3: n-3 polyunsaturated fatty acids, SD: standard deviation, p: probability.
Patients in the Late-onset group had a higher level of EPA, higher EPA/AA ratio and lower incidence of arteriosclerotic stroke, compared to their younger counterparts. These results suggest that the excess intake of SFAs, MUFAs and n-6 PUFAs and insufficient intake of EPA contributes to the early progression of arteriosclerosis and middle-age onset of arteriosclerotic stroke. By contrast, the appropriate intake of the indicated fatty acids and EPA delay the progression of arteriosclerosis. Furthermore, Middle-onset patients were more likely to harbour multiple cardiovascular risk factors, compared with Late-onset patients. A previous study reported that Japanese men harbouring 3 or 4 cardiovascular risk factors had a higher risk of stroke mortality relative to their counterparts with none of these factors (hazard ratio: 5.1) [11]. In 2016, the World Health Statistics reported that Japanese women had the longest life expectancy worldwide, with a value of 86.8 years in 2015; moreover, Japanese men had the sixth-longest life expectancy of 80.5 years in the same year. The statistics bureau of the Japanese Ministry of Internal Affairs and Communications further reported that as of March 1, 2017, 10,457,000 Japanese women and 6,685,000 Japanese men were aged 75 years or older. Although the general Japanese population aged 75 years or older has a female predominance (61% vs. 39% men), the corresponding age group in our study cohort comprised only 34% women and 66% men (Table 6). This suggests that the incidence of ischemic stroke is much lower among women than among men. We might attribute this finding to the higher levels of EPA and DHA, higher EPA/AA ratio and lower n-6/n-3 ratio detected among female subjects aged 75 years or older in our study, compared to their male counterparts (Table 6). Please cite this article in press as: Mori T, et al., Serum fatty acids and ischemic stroke subtypes in middleand late-onset acute stroke patients, Clinical Nutrition Experimental (2018), https://doi.org/10.1016/ j.yclnex.2018.09.001
T. Mori et al. / Clinical Nutrition Experimental xxx (2018) 1e11
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Table 7 Comparison of fatty acids in male and female patients according to onset age. Middle onset (n ¼ 91)
n Saturated fatty acids Lauric acid (m ± SD) mg/ml Myristic acid (m ± SD) mg/ml Palmitic acid (m ± SD) mg/ml Stearic acid (m ± SD) mg/ml Monounsaturated fatty acid Oleic acid (m ± SD) mg/ml n-6 Polyunsaturated fatty acids Linoleic acid (m ± SD) mg/ml Arachidonic acid (m ± SD) mg/ml n-3 Polyunsaturated fatty acids Alpha-linolenic acid (m ± SD) mg/ml Eicosapentaenoic acid (m ± SD) mg/ml Docosahexaenoic acid (m ± SD) mg/ml EPA/AA ratio (m ± SD) n-6/n-3 ratio (m ± SD)
p
Late onset (n ¼ 100)
(50e74 years old)
(75 years or older)
Male Female 55 (60.4%, 55/91) 36 (40.0%, 36/91)
Male Female 66 (66%, 66/100) 34 (34%, 34/100)
p
3.46 ± 6.91 27.1 ± 18.5 786.7 ± 231.7 228.1 ± 61.7
1.90 ± 1.87 22.3 ± 18.5 727.6 ± 173.0 217.1 ± 40.3
ns ns ns ns
2.84 ± 6.92 20.9 ± 12.6 658.4 ± 146.2 184.4 ± 37.3
1.93 ± 2.18 21.0 ± 10.9 673.4 ± 115.0 210.5 ± 39.1
ns ns ns 0.0015
722.5 ± 231.3
671.4 ± 178.4
ns 588.3 ± 170.2
580.5 ± 128.0
ns
875.3 ± 228.4 156.6 ± 46.3
891.2 ± 203.7 161.2 ± 33.5
ns 738.1 ± 182.5 ns 134.1 ± 37.2
760.8 ± 162.6 152.7 ± 27.2
ns 0.0112
27.9 ± 14.7 68.3 ± 43.0 128.0 ± 48.0 0.449 ± 0.274 5.36 ± 2.59
25.6 ± 12.3 63.6 ± 28.0 136.3 ± 35.4 0.394 ± 0.145 4.98 ± 1.60
ns ns ns ns ns
21.0 ± 9.7 72.0 ± 42.9 131.9 ± 40.0 0.552 ± 0.309 4.20 ± 1.32
23.3 ± 14.4 91.2 ± 42.5 161.6 ± 41.8 0.614 ± 0.298 3.62 ± 1.32
ns 0.0354 0.0007 ns 0.0431
Bold: Significantly higher. EPA: eicosapentaenoic acid, AA: arachidonic acid, n-6: n-6 polyunsaturated fatty acids, n-3: n-3 polyunsaturated fatty acids, SD: standard deviation, p: probability. Table 8 Comparison of fatty acids in middle- or late-onset patients according to gender. n
Saturated fatty acids Lauric acid (m ± SD) mg/ml Myristic acid (m ± SD) mg/ml Palmitic acid (m ± SD) mg/ml Stearic acid (m ± SD) mg/ml Monounsaturated fatty acid Oleic acid (m ± SD) mg/ml n-6 Polyunsaturated fatty acids linoleic acid (m ± SD) mg/ml arachidonic acid (m ± SD) mg/ml n-3 Polyunsaturated fatty acids Alpha-linolenic acid (m ± SD) mg/ml Eicosapentaenoic acid (m ± SD) mg/ml Docosahexaenoic acid (m ± SD) mg/ml EPA/AA ratio (m ± SD) n-6/n-3 ratio (m ± SD)
Male (n ¼ 121)
p
Female (n ¼ 70)
p
Middle onset
Late onset
Middle onset
Late onset
(50e74 years old)
(75 years or older)
(50e74 years old)
(75 years or older)
55
66
36
34
3.46 ± 6.91 27.1 ± 18.5 786.7 ± 231.7 228.1 ± 61.7
2.84 ± 6.92 20.9 ± 12.6 658.4 ± 146.2 184.4 ± 37.3
ns 0.0293 0.0003 <0.0001
1.90 ± 1.87 22.3 ± 18.5 727.6 ± 173.0 217.1 ± 40.3
1.93 ± 2.18 21.0 ± 10.9 673.4 ± 115.0 210.5 ± 39.1
ns ns ns ns
722.5 ± 231.3
588.3 ± 170.2
0.0004
671.4 ± 178.4
580.5 ± 128.0
0.0175
875.3 ± 228.4 156.6 ± 46.3
738.1 ± 182.5 134.1 ± 37.2
0.0004 0.0037
891.2 ± 203.7 161.2 ± 33.5
760.8 ± 162.6 152.7 ± 27.2
0.0042 ns
27.9 ± 14.7 68.3 ± 43.0 128.0 ± 48.0 0.449 ± 0.274 5.36 ± 2.59
21.0 ± 9.7 72.0 ± 42.9 131.9 ± 40.0 0.552 ± 0.309 4.20 ± 1.32
0.0023 ns ns 0.0571 0.0019
25.6 ± 12.3 63.6 ± 28.0 136.3 ± 35.4 0.394 ± 0.145 4.98 ± 1.60
23.3 ± 14.4 91.2 ± 42.5 161.6 ± 41.8 0.614 ± 0.298 3.62 ± 1.32
ns 0.002 0.0081 0.0002 0.0003
Bold: Significantly higher. EPA: eicosapentaenoic acid, AA: arachidonic acid, n-6: n-6 polyunsaturated fatty acids, n-3: n-3 polyunsaturated fatty acids, SD: standard deviation, p: probability.
A previous study reported a much lower level of coronary heart disease-related mortality in Japan relative to the USA and suggested that this difference might be attributed to differences in the levels of fish intake and serum omega-3 fatty acid levels between the two populations [12]. These findings suggest that Japanese women aged 75 years or older who consume more fish and have a higher serum level of omega-3 fatty acid may live longer than their male counterparts. This speculation is supported by our finding that among Late-onset patients in our study, women had higher serum levels of EPA and Please cite this article in press as: Mori T, et al., Serum fatty acids and ischemic stroke subtypes in middleand late-onset acute stroke patients, Clinical Nutrition Experimental (2018), https://doi.org/10.1016/ j.yclnex.2018.09.001
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DHA; by contrast, no sex-related differences in these parameters were observed among Middle-onset patients (Tables 7 and 8). 5. Study limitations Our study had several limitations of note. First, this study included a small number of patients. Moreover, all patients were of East Asian ethnicity and were most likely of Japanese ancestry. In addition to genetic differences attributable to race, our patients likely had different dietary intakes from populations in Western countries. These factors may limit the generalisability of our results. Second, our study design was retrospective and cross-sectional, rather than prospective. Therefore, the appropriate dietary intakes of SFA, MUFA, n-6 PUFA and n-3 PUFA (especially EPA) and consequent serum levels that protect against arteriosclerotic progression could not be confirmed. The appropriate daily intake of these fatty acids from dietary sources may prevent abnormal increases in the serum levels of TCHO or TG and atherosclerosis would thus inhibit the rapid progression of atherosclerosis. Therefore, further prospective study is needed to determine the appropriate levels of SFAs, MUFAs and n-6 PUFAs and sufficient levels of n-3 PUFAs, especially EPA. 6. Conclusion People with higher serum levels of saturated fatty acids, MUFAs, and n-6 PUFAs more frequently experienced lacunar or atherosclerotic stroke during middle age, whereas those with lower serum levels of these fatty acids and higher serum levels of n-3 PUFAs, such as EPA, more frequently experienced all types of ischemic stroke at an older age. Conflict of interest The authors have no conflicts of interest to disclose. Statement of authorship Takahisa Mori, MD, had full access to all data in the study and takes responsibility for the integrity of the data and accuracy of the data analysis. Study concept and design: T. Mori. Acquisition of data: T. Mori, Y. Tanno, S. Kasakura, K. Yoshioka, N. Nakai. Interpretation of data and statistical analysis: T. Mori. Drafting the manuscript: T. Mori. Critical revision of the manuscript for important intellectual content: T. Mori. Final approval of the submitted version: T. Mori, Y. Tanno, S. Kasakura, K. Yoshioka, N. Nakai. Acknowledgement The authors wish to thank Miss Nozomi Chiba, BA, for her secretarial support. Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.yclnex.2018.09. 001. References [1] Dyerberg J, Bang HO. A hypothesis on the development of acute myocardial infarction in Greenlanders. Scand J Clin Lab Investig Suppl 1982;161:7e13. [2] Kromhout D, Bosschieter EB, de Lezenne Coulander C. The inverse relation between fish consumption and 20-year mortality from coronary heart disease. N Engl J Med 1985;312:1205e9. [3] Tanaka K, Ishikawa Y, Yokoyama M, Origasa H, Matsuzaki M, Saito Y, et al. Reduction in the recurrence of stroke by eicosapentaenoic acid for hypercholesterolemic patients: subanalysis of the JELIS trial. Stroke J Cerebr Circ 2008;39: 2052e8.
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[4] Miyagawa N, Miura K, Okuda N, Kadowaki T, Takashima N, Nagasawa SY, et al. Long-chain n-3 polyunsaturated fatty acids intake and cardiovascular disease mortality risk in Japanese: a 24-year follow-up of NIPPON DATA80. Atherosclerosis 2014;232:384e9. [5] Sacks FM, Lichtenstein AH, Wu JHY, Appel LJ, Creager MA, Kris-Etherton PM, et al. Dietary fats and cardiovascular disease: a presidential advisory from the American heart association. Circulation 2017;136:e1e23. [6] Harris WS, Mozaffarian D, Rimm E, Kris-Etherton P, Rudel LL, Appel LJ, et al. Omega-6 fatty acids and risk for cardiovascular disease: a science advisory from the American heart association nutrition subcommittee of the council on nutrition, physical activity, and metabolism; council on cardiovascular nursing; and council on epidemiology and prevention. Circulation 2009;119:902e7. [7] Rajalahti T, Lin C, Mjos SA, Kvalheim OM. Serum fatty acid and lipoprotein subclass concentrations and their associations in prepubertal healthy Norwegian children. Metabolomics Off J Metabolomic Soc 2016;12:81. [8] Itakura H, Yokoyama M, Matsuzaki M, Saito Y, Origasa H, Ishikawa Y, et al. Relationships between plasma fatty acid composition and coronary artery disease. J Atherosclerosis Thromb 2011;18:99e107. [9] Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico. Lancet 1999;354: 447e55. [10] Suda S, Katsumata T, Okubo S, Kanamaru T, Suzuki K, Watanabe Y, et al. Low serum n-3 polyunsaturated fatty acid/n-6 polyunsaturated fatty acid ratio predicts neurological deterioration in Japanese patients with acute ischemic stroke. Cerebrovasc Dis 2013;36:388e93. [11] Nakamura Y, Yamamoto T, Okamura T, Kadowaki T, Hayakawa T, Kita Y, et al. Combined cardiovascular risk factors and outcome: NIPPON DATA80, 1980-1994. Circ J Off J Jpn Circ Soc 2006;70:960e4. [12] Iso H, Sato S, Folsom AR, Shimamoto T, Terao A, Munger RG, et al. Serum fatty acids and fish intake in rural Japanese, urban Japanese, Japanese American and Caucasian American men. Int J Epidemiol 1989;18:374e81.
Please cite this article in press as: Mori T, et al., Serum fatty acids and ischemic stroke subtypes in middleand late-onset acute stroke patients, Clinical Nutrition Experimental (2018), https://doi.org/10.1016/ j.yclnex.2018.09.001