Assessment of sex differences in associations between sleep duration and lipid/glucose metabolism in urban Japan: a cross-sectional study.

Inadequate sleep durations (short or long) are related to worsening of lipid/glucose metabolism, leading to atherosclerotic cardiovascular diseases (ASCVD). Few data exist on sex differences in this relationship that, to date, has been scarcely reported. This cross-sectional study included 6678 men and 4700 women at the Health Planning Center of Nihon University Hospital, located in the center of Tokyo, between September 2015 and October 2016. The prevalence of diabetes and dyslipidemia in the participants was 3.3% and 6.5%, respectively. Sleep duration was divided into five categories: < 5 h, 5-6 h, 6-7 h, 7-8 h, and ≥ 8 h. We examined the odds ratio (OR) and 95% confidence interval (CI) of lipid/glucose metabolism-related markers for the reference value defined in each guideline with 6-7 h as the reference of comparison. In men, a sleep duration of < 5 h was associated with ORs of 1.32 and 1.33 (95% CI, 1.01-1.73 and 1.02-1.74) for LDL-C level ≥ 120 mg/dL and non-HDL-C level of ≥ 150 mg/dL (defined as "borderline hyper" by the Japan Atherosclerosis Society Guidelines for Prevention of ASCVD 2017), respectively. Moreover, a sleep duration of < 5 h was associated with an OR of 1.77 (1.33-2.35) for fasting blood glucose of ≥ 100 mg/dL (defined as "high" by a specialized lifestyle checkup program in Japan). In women, sleep duration of < 5 h was associated with an OR of 1.70 (1.24-2.33) for HbA1c level of ≥ 5.6% (defined as "high" by a specialized life style checkup program in Japan). However, there was no association between sleep duration and serum lipid profile. Inadequate short sleep duration was as a potential risk factor of adverse lipid and/or glucose metabolism in both sexes. However, there were sex differences in associations between sleep duration and lipid/glucose metabolism in urban Japan. To further reduce risks of ASCVD, it is of particular importance to emphasize adequate sleep duration in both sexes.Trial registration UMIN ( http://www.umin.ac.jp/ ) Study ID: UMIN000037643 retrospectively registered on August 9, 2019.

Higher Frequency of Fish Intake May Be Associated with a Lower Neutrophil/Lymphocyte Ratio: Anti-Atherosclerotic Effects of Fish Consumption.

BACKGROUND: Higher fish consumption has been reported to be associated with a lower incidence of coronary artery disease (CAD). An elevated neutrophil/lymphocyte ratio (NLR), a marker of systemic inflammation, is reportedly associated with the development of adverse CAD events. We hypothesized that a higher fish intake was associated with a lower NLR. METHODS AND RESULTS: This cross-sectional study was conducted in a cohort of 8,237 Japanese subjects who had no history of atherosclerotic cardiovascular disease registered at the Health Planning Center of Nihon University Hospital between April 2018 and March 2019. The average weekly frequency of fish intake was 2.32 ± 1.31 days. The NLR decreased significantly as the weekly frequency of fish intake (0 day, 1-2 days, 3-4 days, or 5-7 days) increased (p = 0.001). A multiple stepwise regression analysis identified the weekly frequency of fish intake (ß = -0.045, p < 0.0001) and habitual alcohol intake (ß = -0.051, p < 0.0001) as significant but weak, negative, and independent determinants of the NLR. Conversely, the presence of metabolic syndrome (ß = 0.046, p < 0.0001), the presence of treatment for diabetes mellitus (ß = 0.054, p < 0.0001), and the presence of treatment for hypertension (ß = 0.043, p < 0.0001) were significant positive and independent determinants of the NLR. CONCLUSIONS: The present results suggest that a higher frequency of fish intake appears to be associated with a lower NLR, suggesting an anti-systemic inflammation effect. This association may partially explain the preventive effects of a higher fish intake on CAD events.

Gender differences in the associations among fish intake, lifestyle, and non-HDL-C level in Japanese subjects over the age of 50 years: Anti-atherosclerotic effect of fish consumption.

BACKGROUND AND AIMS: Higher fish consumption may lead to the suppression of atherogenesis. The present study was aimed at investigating the gender differences in association with the frequency of fish intake, lifestyle behaviors and serum non-high-density lipoprotein cholesterol (non-HDL-C) levels. METHODS AND RESULTS: This cross-sectional study was conducted in a cohort of 4320 (2479 males, 1570 females) healthy Japanese subjects over 50 years of age registered at the Health Planning Center of Nihon University Hospital between April 2018 and March 2019. The average weekly frequency of fish intake was 2.58 ± 1.39 days in males and 2.42 ± 1.36 days in females. In males, the serum non-HDL-C level decreased significantly as the weekly frequency of fish intake (0-1 days, 2-3 days, 4-5 days, or 6-7 days) increased (p < 0.0001). Multiple stepwise regression analysis identified the weekly frequency of fish intake (ß = -0.056, p = 0.004) and habitual aerobic exercise (ß = -0.063, p = 0.001) as independent determinants of the serum non-HDL-C level. On the other hand, no such associations were observed in females. However, the proportion of subjects engaging in habitual aerobic exercise increased as the frequency of fish intake increased even among females. CONCLUSIONS: A higher frequency of fish intake may be associated with healthier lifestyle behaviors and lower non-HDL-C levels in males, but not in females. There appear to be gender differences in the relationships between the intake of fish and lifestyle behaviors on lipid metabolism. CLINICAL TRIAL REGISTRATION: umin (http://www.umin.ac.jp/) Study ID: UMIN000035899.

Incremental Predictive Value of Coronary Calcium Score in Risk Stratification of Coronary Revascularization in Patients With Normal or Mild Ischemia Using Nuclear Myocardial Perfusion Single Photon Emission Computed Tomography.

BACKGROUND: The incremental predictive value of the coronary artery calcium score (CACS) for risk stratification of coronary revascularization in patients with normal or mildly abnormal nuclear myocardial perfusion single photon emission computed tomography (MPS) scores is unknown.Methods and Results:We analyzed 528 patients in whom CACS was calculated and who underwent stress MPS within 3 months. Patients with known coronary artery disease, prior coronary revascularization, and those undergoing hemodialysis were excluded. Patients were followed-up with coronary revascularization based on the evidence of physiological ischemia defined by fractional flow reserve or severe coronary stenosis (≥90%). CACS was significantly associated with the summed stress score (SSS) from MPS assessment. Multivariate logistic regression analysis showed that high CACS (≥300; odds ratio [OR] 5.44, 95% confidence interval [CI] 2.28-13.0) and SSS (OR 1.29, 95% CI 1.18-1.40) were significant (P<0.001) predictors of future coronary revascularization. The log-rank test showed that high CACS stratified coronary revascularization in normal SSS (0-3; P<0.001) or mildly abnormal SSS (4-8; P=0.028) groups, whereas high CACS did not significantly stratify coronary revascularization in moderate to severe SSS (≥9; P=0.757). CONCLUSIONS: Risk stratification using CACS with a cut-off value 300 may have incremental predictive value for revascularization in patients with normal or mildly abnormal MPS.

Association among daily fish intake, white blood cell count, and healthy lifestyle behaviors in an apparently healthy Japanese population: implication for the anti-atherosclerotic effect of fish consumption.

Higher fish consumption has been reported to be associated with a lower incidence of coronary artery disease. We hypothesized that a higher frequency of fish intake may be associated with lower peripheral white blood cell (WBC) counts, a marker of chronic inflammation, which is known to be involved in the development of atherosclerotic cardiovascular disease (ASCVD), and a healthy lifestyle. This cross-sectional study was conducted between April 2018 and August 2018 at the Health Planning Center of Nihon University Hospital in a cohort of 4105 apparently healthy subjects. The average frequency of fish intake was 2.3 ± 1.3 days per week. The WBC count decreased significantly as the frequency of fish intake (0-2 days, 3-4 days, or 5-7 days per week) increased (s < 0.0001). Multivariate linear regression analysis identified higher weekly frequency of fish intake as a significant independent determinant of a lower WBC count (ß = - 0.051, p = 0.001). Furthermore, as the weekly frequency of fish intake increased, the proportion of habitual cigarette smokers decreased (p = 0.021), that of subjects engaging in habitual aerobic exercises increased (p < 0.0001), and the weekly alcohol intake frequency increased (p < 0.0001). Moreover, the above-mentioned lifestyle behaviors were also independent determinants of the WBC count. These results suggest that a high frequency of fish intake might be associated with healthier lifestyle behaviors as well as lower WBC counts, and thus may both exert beneficial anti-inflammatory effects and represent a component of healthier lifestyle behaviors associated with a lower risk of ASCVD in Japanese. This association may be partially related to the preventive effects of a higher fish intake on ASCVD events. CLINICAL TRIAL REGISTRATION: UMIN ( http://www.umin.ac.jp/ ) Study ID: UMIN000039197 retrospectively registered 1 February 2020.

Administration of eicosapentaenoic acid may alter lipoprotein particle heterogeneity in statin-treated patients with stable coronary artery disease: A pilot 6-month randomized study.

BACKGROUND: We hypothesized that the addition of eicosapentaenoic acid (EPA) to ongoing statin therapy could change the particle heterogeneity of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) particles, even in stable coronary artery disease (CAD) patients. METHODS: We assigned CAD patients already receiving statin therapy to one of two groups: an EPA group (1800 mg/day; n = 30) and a control group (n = 30). A gel permeation high-performance liquid chromatography method was used to measure the particle concentration and number of lipoprotein subclasses. RESULTS: In the EPA group, significant decreases of both the concentration and number of medium LDL (p = 0.0002 and 0.0001), small LDL (p = 0.0004 and 0.0005) and very small LDL (p = 0.0005 and 0.002) particles were observed. Conversely, the concentration and number of large HDL particles increased significantly (p = 0.024 and 0.048). The concentration of very large HDL particles also increased significantly (p = 0.028). Furthermore, significant correlations between the variables that showed significant changes in the LDL and HDL particle subclasses, and the EPA/arachidonic acid (AA) ratio were found. No other significant associations of lipoprotein particle heterogeneity with the serum EPA/AA ratio were noted in either the control group or the EPA group. Interestingly, univariate and multivariate regression analyses revealed that increased serum lecithin-cholesterol acyltransferase activity, a key enzyme of HDL cholesterol efflux, was a predictor for increased above-mentioned HDL particles subclasses. CONCLUSIONS: Administration of EPA might alter both LDL and HDL particle heterogeneity, causing decreased concentration and number of smaller LDL particles and increased concentration and number of larger HDL particles. Furthermore, addition of EPA to ongoing statin therapy appears to be capable of increasing the EPA/AA ratio, which might have an anti-atherosclerotic effect on lipoprotein particle heterogeneity, even in stable CAD patients with well-controlled serum lipid levels. CLINICAL TRIAL REGISTRATION: UMIN (http://www.umin.ac.jp/) Study ID: UMIN000010452.

The serum uric acid level in females may be a better indicator of metabolic syndrome and its components than in males in a Japanese population　.

BACKGROUND: Although the level of uric acid (UA) is higher in males, increased UA level in females was reported to be closely associated with prevalence of metabolic syndrome (Mets) leading to atherosclerotic cardiovascular disease (ASCVD). Few data exist regarding the gender diferences in relationship between the serum UA levels and cardo-metabolic risk in the Japanese population, which generally contains a lower proportion of obesity than Western populations. METHODS: This cross-sectional study was designed to investigate, by gender, the association between the serum UA level and abdominal obesity, and thereby cardio-metabolic risk i.e. presence of Mets and its components using a sample of 8567 apparently healthy subjects females: n = 3334, males: n = 5233 at the Health Planning Center of Nihon University Hospital between September 2015 and August 2016. RESULTS: Receiver operating characteristic analysis was performed to reveal the accuracy of serum UA level as a predictor of abdominal obesity based on the Japanese criteria of Mets (females vs. males: area under the curve, 0.751 vs 0.609). Furthermore, the serum UA level and proportion of abdominal obesity rose with increasing age in females; in males, however, these parameters did not change in parallel with age. Furthermore, the serum UA levels in females reflected a status of cardio-metabolic risk when compared with males in a multi-logistic regression analysis. It is particularly worth noting that in the above-mentioned multivariate logistic regression analysis, the odds ratio of hyperuricemia in females was generally 1.3-2.5 times higher than that in males. CONCLUSIONS: Compared with males, increased serum UA level in females might be involved in abdominal obesity and cardio-metabolic risk, possibly leading to the development of ASCVD even in a Japanese population. This may be due to gender differences affecting the development of abdominal obesity and changes in the serum UA levels with age. CLINICAL TRIAL REGISTRATION: UMIN (http://www.umin.ac.jp/) Study ID:　UMIN000035901retrospectively registered 1 March 2018.

Administration of eicosapentaenoic acid may alter high-density lipoprotein heterogeneity in statin-treated patients with stable coronary artery disease: A 6-month randomized trial.

BACKGROUND: Combined statin plus eicosapentaenoic acid (EPA) therapy might be a potentially effective treatment option to prevent coronary artery disease (CAD). The serum EPA/arachidonic acid (AA) ratio has been identified as a potential new risk marker for CAD. Few data exist whether administration of EPA could affect high-density lipoprotein (HDL) particle size. We hypothesized that the addition of EPA to ongoing statin therapy may result in altered HDL heterogeneity. METHODS: We conducted this 6-month, single-center, prospective, randomized open-label clinical trial to investigate the effect of the additional administration of EPA on the HDL heterogeneity (HDL2, HDL3, and HDL2/HDL3 ratio) in stable CAD patients receiving treatment with statins. We assigned stable CAD patients already receiving statin therapy to the EPA group (1800mg/day: n=50) or the control group (n=50). RESULTS: A significant decrease in the serum HDL3 level (-4.7% vs. -0.5%, p=0.037), but not of the serum HDL2 level, and a significant increase in the HDL2/HDL3 ratio (5.5% vs. -5.1%, p=0.032) were observed in the EPA group as compared to the control group. Multiple regression analysis with adjustments for coronary risk factors identified the achieved EPA/ AA ratio as an independent and significant predictor of an increase of the HDL2/HDL3 ratio (ß=0.295, p=0.001). Furthermore, the change in the serum cholesterol ester transfer protein mass was positively correlated with the change in the EPA/AA ratio in the EPA group (r=0.286, p=0.044), but not in the control group (r=0.121, p=0.401). CONCLUSION: Administration of EPA might decrease the serum HDL3 level, resulting in an increase in the HDL2/HDL3 ratio. Furthermore, increased EPA/AA ratio by the addition of EPA to ongoing statin therapy might be an indicator of an increase in the HDL2/HDL3 ratio, thereby regulating HDL particle size. CLINICAL TRIAL REGISTRATION: UMIN (http://www.umin.ac.jp/) Study ID: UMIN000010452.

Association of daily fish intake with serum non-high-density lipoprotein cholesterol levels and healthy lifestyle behaviours in apparently healthy males over the age of 50 years in Japanese: Implication for the anti-atherosclerotic effect of fish consumption.

BACKGROUND AND AIM: Higher fish consumption has been reported to be associated with a lower incidence of coronary artery disease (CAD). We hypothesized that higher fish intake may be associated with lower serum level of non-high-density lipoprotein cholesterol (non-HDL-C) levels, representing the entire dyslipidemia spectrum, and a healthy lifestyle. METHODS AND RESULTS: This cross-sectional study was conducted in a population of 1270 apparently healthy males over the age of 50 years without lipid-modifying therapy at the Health Planning Center of Nihon University Hospital between April and August 2018. The average number of days of fish intake per week was 2.6 ± 1.4. We performed analysis of variance using fish consumption as a categorical variable (0-1 day, 2-3 days, 4-5 days, or 6-7 days per week). The serum non-HDL-C levels in the 6-7 days fish intake group were significantly lower than those in the 0-1 and 2-3days fish intake groups. Furthermore, with increasing frequency of fish intake per week, the proportion of subjects with cigarette smoking decreased (p = 0.026), that of subjects engaging in habitual aerobic exercises increased (p = 0.034), and the sleep duration of the subjects increased (p < 0.0001). CONCLUSIONS: These results suggest that a high frequency of fish intake, that is a fish intake of 6-7 days per week, was associated with healthier lifestyle behaviours as well as lower non-HDL-C levels, and thus may represent a component of a healthy lifestyle associated with a lower risk of CAD in Japanese males over the age of 50. CLINICAL TRIAL REGISTRATION: UMIN (http://www.umin.ac.jp/). STUDY ID: UMIN000035899.

Does administration of eicosapentaenoic acid increase soluble thrombomodulin level in statin-treated patients with stable coronary artery disease?

Interventions targeting the serum eicosapentaenoic acid (EPA)/arachidonic acid (AA) ratio could be useful for the prevention of coronary artery disease (CAD). Few data exist regarding the effects of administration of EPA on the serum levels of soluble thrombomodulin (sTM) as a marker of endothelial damage, or on the relationship between the sTM and EPA/AA ratio in patients with CAD receiving statin treatment. We assigned stable CAD patients already receiving statin therapy to an EPA group (1800 mg/day: n = 50) or control group (n = 50). A significant increase of the sTM level was observed in the EPA group as compared to that in the control group 0.40 (0.10/0.70) FU/mL vs. 0.20 (0/0.40) FU/mL, p = 0.004 at the 6-month follow-up examination. Multivariate regression analysis after adjustments for coronary risk factors and changes of the serum lipid levels identified an increased EPA/AA ratio as an independent predictor of increased serum sTM level (ß = 0.244, p = 0.02). The results suggest that an increased sTM level caused by additional administration of EPA to statin might be associated with an increased EPA/AA ratio. The increase of the serum sTM after administration of EPA might reflect an increase of the TM expression on the endothelial surface rather than endothelial damage in CAD patients under statin treatment.Clinical Trial Registration Information UMIN ( http://www.umin.ac.jp/ ), Study ID: UMIN000010452.

Increased triglyceride/high-density lipoprotein cholesterol ratio may be associated with reduction in the low-density lipoprotein particle size: assessment of atherosclerotic cardiovascular disease risk.

Hypertriglyceridemia, which often leads to both low-density lipoprotein (LDL) and high-density lipoprotein (HDL) metabolic disorders, is a strong risk factor for the development of atherosclerotic cardiovascular disease (ASCVD). We hypothesized that the triglyceride (TG)/HDL cholesterol (TG/HDL-C) ratio may be more useful for estimation of the LDL-particle size, as a well-known risk factor for ASCVD, as compared to the serum TG level per se. Polyacrylamide gel electrophoresis was used in this study to estimate the LDL-particle size [relative LDL migration (LDL-Rm value)] in 649 consecutive patients with one additional risk factor for ASCVD. Multivariable regression analysis identified both serum TG (ß = 0.556, p < 0.0001) and the serum TG/HDL-C ratio (ß = 0.607, p < 0.0001) as independent indicators of the LDL-particle size. In terms of evaluation of the accuracy of indicators of LDL-Rm values equal to or greater than 0.40, which are suggestive of the presence of large amounts of small-dense LDL and represent the upper limit (mean + 2 standard deviation) of the normal range in this population, both the serum TG level and serum TG/HDL-C ratio showed high accurate areas under the receiver-operating characteristic curve (0.900 vs. 0.914), but with a negative likelihood ratio of 0.506 vs. 0.039, indicating that the TG/HDL-C ratio model is superior for excluding patients with values below the cutoff value and with LDL-Rm values ≥ 0.40. Furthermore, in 456 patients followed up for at least 1 year, multivariable regression analysis identified increased serum TG/HDL-C ratio as an independent predictor of a decreased LDL-particle size. These results suggest that the serum TG/HDL-C ratio may be more useful for assessing the risk of ASCVD as compared to the serum TG level per se. To reduce the risk of ASCVD, it may be important to focus not only on changes of the serum LDL-C, but also on those of the serum TG/HDL-C ratio.

A longitudinal study of the association of the eicosapentaenoic acid/arachidonic acid ratio derived from fish consumption with the serum lipid levels: a pilot study.

It has been demonstrated that regular fish consumption is associated with a reduced mortality from atherosclerotic cardiovascular disease (ASCVD). However, data are scarce regarding the correlation between the changes in the serum eicosapentaenoic acid/arachidonic acid (EPA/AA) ratio associated with regular fish consumption and the changes in the serum lipid profile variables. This study was designed as a hospital-based longitudinal study to investigate the relationship between the changes in the serum EPA/AA ratio and changes of the serum lipid levels in patients with one or more risk factors for ASCVD. In 475 patients followed-up for at least 1 year, univariable and multivariable regression analyses conducted after adjustments for the risk factors of ASCVD revealed that the absolute change of the EPA/AA ratio (∆EPA/AA ratio) was independently and significantly associated with the changes of the serum levels of low-density lipoprotein cholesterol (LDL-C) (ß = - 0.129, p = 0.005), triglyceride (TG) (ß = - 0.108, p = 0.019), non-high-density lipoprotein cholesterol (non-HDL-C) (ß = - 0.149, p = 0.001), and TG/HDL-C ratio, a marker of the LDL particle size (ß = - 0.104, p = 0.02), while not being correlated with any other lipid parameters. On the other hand, while the ∆ docosahexaenoic acid (DHA)/AA ratio was inversely correlated with the changes of the serum HDL-C level and positively correlated with the changes of the TG/HDL-C ratio, possibly serving to promote development of atherosclerosis. The results suggest that an increase of the EPA/AA ratio might be associated with decrease of the serum levels of LDL-C, TG and non-HDL-C levels, as well as with an increase of the TG/HDL-C ratio, which represents increased LDL particle size, all of which play a role in the development of ASCVD. A high EPA/AA ratio, but not DHA/AA ratio, derived from fish consumption might reduce the risk of ASCVD through reducing the risk of development of atherosclerosis.Clinical Trial Registration Information: UMIN ( http://www.umin.ac.jp/ ), Study ID: UMIN000010603.

Association of lecithin-cholesterol acyltransferase activity and low-density lipoprotein heterogeneity with atherosclerotic cardiovascular disease risk: a longitudinal pilot study.

BACKGROUND: Lecithin-cholesterol acyltransferase (LCAT) is believed to be involved in reverse cholesterol transport, which is known to play a key role in suppression of atherosclerosis. However, recent investigations have demonstrated that higher LCAT activity, measured in terms of the serum cholesterol esterification rate by an endogenous substrate method, is associated with increased formation of triglyceride (TG)-rich lipoproteins (TRLs), leading to a decrease in the low-density lipoprotein (LDL) particle size. The purpose of this hospital-based longitudinal study was to clarify the causal relationship between changes in the LCAT activity and changes in the LDL-particle size. METHODS: The subjects were a total of 335 patients, derived from our previous study cohort, with one or more risk factors for atherosclerotic cardiovascular disease (ASCVD). For this study, we measured the LDL-particle size (relative LDL migration [LDL-Rm value]) by polyacrylamide gel electrophoresis in the subjects, along with the changes in the LCAT activity, at the end of a follow-up period of at least 1 year. RESULTS: The results revealed that the absolute change (Δ) in the LDL-particle size increased significantly as the quartile of Δ LCAT activity increased (p = 0.01). A multi-logistic regression adjusted-analysis revealed that Δ LCAT activity in the fourth quartile as compared to that in the first quartile was independently predictive of an increased LDL-particle size (odds ratio [95% confidence interval]: 2.03 [1.02/4.04], p = 0.04). Moreover, the ∆ LCAT activity was also positively correlated with ∆ TRL-related markers (i.e., TG, remnant particle-like cholesterol [RLP-C], apolipoprotein B, apolipoprotein C-2, and apolipoprotein C-3). CONCLUSIONS: The results lend support to the hypothesis that increased LCAT activity may be associated with increased formation of TRLs, leading to a reduction in the LDL-particle size in patients at a high risk for ASCVD. To reduce the risk of ASCVD, it may be important to focus not only on the quantitative changes in the serum LDL-cholesterol levels, but also on the LCAT activity. TRIAL REGISTRATION: UMIN ( https://upload.umin.ac.jp/cgi-bin/ctr/ctr_reg_list.cgi ) Study ID: UMIN000033228 retrospectively registered 2 July 2018.

A cross-sectional and longitudinal study between association of n-3 polyunsaturated fatty acids derived from fish consumption and high-density lipoprotein heterogeneity.

Decreased high-density lipoprotein (HDL) particle size, cholesterol poor, apolipoprotein A-I-rich HDL particles leading to smaller HDL particle size, may be associated with an anti-atherosclerotic effect. The data are sparse regarding the relationship between n-3 polyunsaturated fatty acids [n-3 PUFAs: eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA)] and HDL particle size. This study was designed as a hospital-based cross-sectional study to investigate the relationship between the serum levels of n-3 PUFAs and the HDL-cholesterol/apolipoprotein A-1 ratio, as estimated by the HDL particle size, in patients with the presence of one or more risk factors for atherosclerotic cardiovascular disease (ASCVD). Six hundred and forty sequential patients were enrolled in this study. The serum levels of EPA and DHA showed a strong correlation (r = 0.736, p < 0.0001). However, in a multivariate regression analysis after adjustment for ASCVD risk factors, increased serum DHA (ß = - 0.745, p = 0.021), but not serum EPA (ß = - 0.414, p = 0.139) or EPA + DHA (ß = 0.330, p = 0.557) level, was identified as an independent indicator of decreased HDL particle size. In 476 patients followed up for at least 6 months, the absolute change (Δ) in the HDL-cholesterol/apolipoprotein A-1 ratio decreased significantly as the quartile of the Δ DHA level increased (p = 0.014), whereas no significant difference in the Δ HDL-cholesterol/apolipoprotein A-1 ratio was noted with the increase in the quartile of the Δ EPA level. Moreover, a multivariate regression analysis identified increased DHA level and decreased estimated low-density lipoprotein (LDL) particle size measured relative to the mobility value of LDL with polyacrylamide gel electrophoresis (i.e., relative LDL migration: LDL-Rm value), as independent predictors of decreased HDL-cholesterol/apolipoprotein A-1 ratio (ß = - 0.171, p = 0.0003 and ß = - 0.142, p = 0.002). The results suggest that increased serum DHA level, but not EPA level, might be associated with decreased HDL-cholesterol/apolipoprotein A-1 ratio, an indicator of estimated HDL particle size. Further studies are needed to investigate the useful clinical indices and outcomes of these patients. Clinical Trial Registration Information UMIN ( http://www.umin.ac.jp/ ), Study ID: UMIN000010603.

Relation between low-density lipoprotein cholesterol/apolipoprotein B ratio and triglyceride-rich lipoproteins in patients with coronary artery disease and type 2 diabetes mellitus: a cross-sectional study.

BACKGROUND: The low-density lipoprotein cholesterol/apolipoprotein B (LDL-C/apoB) ratio has conventionally been used as an index of the LDL-particle size. Smaller LDL-particle size is associated with triglyceride (TG) metabolism disorders, often leading to atherogenesis. We investigated the association between the LDL-C/apoB ratio and TG metabolism in coronary artery disease (CAD) patients with diabetes mellitus (DM). METHODS: In the cross-sectional study, the LDL-C/apoB ratio, which provides an estimate of the LDL-particle size, was calculated in 684 consecutive patients with one additional risk factor. The patients were classified into 4 groups based on the presence or absence of CAD and DM, as follows: CAD (-) DM (-) group, n = 416; CAD (-) DM (+) group, n = 118; CAD (+) DM (-) group, n = 90; CAD (+) DM (+) group, n = 60. RESULTS: A multi-logistic regression analysis after adjustments for coronary risk factors revealed that the CAD (+) DM (+) condition was an independent predictor of the smallest LDL-C/apoB ratio among the four groups. Furthermore, multivariate regression analyses identified elevated TG-rich lipoprotein (TRL)-related markers (TG, very-LDL fraction, remnant-like particle cholesterol, apolipoprotein C-II, and apolipoprotein C-III) as being independently predictive of a smaller LDL-particle size in both the overall subject population and a subset of patients with a serum LDL-C level < 100 mg/dL. In the 445 patients followed up for at least 6 months, multi-logistic regression analyses identified increased levels of TRL-related markers as being independently predictive of a decreased LDL-C/apoB ratio, which is indicative of smaller LDL-particle size. CONCLUSIONS: The association between disorders of TG metabolism and LDL heterogeneity may account for the risk of CAD in patients with DM. Combined evaluation of TRL-related markers and the LDL-C/apoB ratio may be of increasing importance in the risk stratification of CAD patients with DM. Further studies are needed to investigate the useful clinical indices and outcomes of these patients. Clinical Trial Registration UMIN (http://www.umin.ac.jp/) Study ID: UMIN000028029 retrospectively registered 1 July 2017.

The Ratio of Eicosapentaenoic Acid (EPA) to Arachidonic Acid may be a Residual Risk Marker in Stable Coronary Artery Disease Patients Receiving Treatment with Statin Following EPA Therapy.

BACKGROUND: We investigated the relationship between the eicosapentaenoic acid (EPA)/arachidonic acid (AA) ratio and non-high-density lipoprotein cholesterol (non-HDL-C) level, a major residual risk of coronary artery disease (CAD), in statin-treated CAD patients following EPA therapy. METHODS: We conducted a 6-month, prospective, randomized clinical trial to investigate the effect of the additional administration of EPA on the EPA/AA ratio and the serum non-HDL-C level in stable CAD patients receiving statin treatment. We assigned CAD patients already receiving statin therapy to an EPA group (1800 mg/day; n = 50) or a control group (n = 50). RESULTS: A significant reduction in the serum non-HDL-C level was observed in the EPA group, compared with the control group (-9.7 vs. -1.2%, p = 0.01). A multiple-regression analysis with adjustments for coronary risk factors revealed that achieved EPA/AA ratio was more reliable as an independent and significant predictor of a reduction in the non-HDL-C level at a 6-month follow-up examination (ß = -0.324, p = 0.033) than the absolute change in the EPA/AA ratio. Interestingly, significant negative correlations were found between the baseline levels and the absolute change values of both non-HDL-C and triglyceride-rich lipoproteins, both markers of residual risk of CAD, indicating that patients with a higher baseline residual risk achieved a greater reduction. CONCLUSION: The present results suggest that the achieved EPA/AA ratio, but not the absolute change in EPA/AA ratio, following EPA therapy might be a useful marker for the risk stratification of CAD among statin-treated patients with a high non-HDL-C level. CLINICAL TRIAL REGISTRATION: UMIN ( http://www.umin.ac.jp/ ) Study ID: UMIN000010452.