The evidence for the impact of saturated fat intake on cardiovascular disease remains inconsistent. One reason for this inconsistency may be the large difference in the distribution of saturated fat intake between the East and West. In this review, we focus on the published literature on this topic among Japanese population. Three studies have examined the link between saturated fat intake and intraparenchymal hemorrhage, consistently showing an inverse association. However, the association for ischemic stroke is less clear, although it is generally inverse. As for myocardial infarction, the findings in Japanese studies are inconsistent, as are those of Western studies. The JPHC study, however, found a positive association, the first report in Asia. Taken together with the results of the JPHC and Western studies, a saturated fat intake of around 20 g/day (approximately 10% of total energy) may be optimal, which corresponds to 200 g of milk a day and 150 g of meat every other day.

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Aim: The consumption of n-3 polyunsaturated fatty acids (PUFA), including docosahexaenoic acid DHA), reduces the incidence of cardiovascular events, and reduced serum levels of n-3 PUFA may be associated with an increased risk of cardiovascular events. However, controversy remains regarding which components of PUFA are associated with the endothelial function in patients with coronary artery disease (CAD). We therefore examined the associations between the n-3 and n-6 PUFA levels and CAD.
Methods: We retrospectively reviewed 160 consecutive Japanese patients with CAD whose endothelial function was measured according to the percent change in flow-mediated dilation (FMD) and the serum levels of n-3 PUFA, including eicosapentaenoic acid (EPA) and DHA, and n-6 PUFA, including arachidonic acid (AA) and dihomo-gamma-linolenic acid (DHLA).
Results: A single regression analysis showed no relationships between the FMD and the serum levels of PUFA, including EPA, DHA, AA and DHLA. In contrast, a multiple regression analysis showed that the DHA level was a positive (P＜0.01) and age was a negative (P＜0.001) contributor to an increased FMD; however, sex, body mass index, systolic and diastolic blood pressure, current/past smoking and the levels of HbA1c, triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, EPA, AA and DHLA did not significantly affect the outcome.
Conclusions: The serum level of DHA is associated with the endothelial function evaluated according to the FMD in patients with CAD, thus suggesting that a low serum level of DHA may be a predictive biomarker for endothelial dysfunction.

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Aim: It is challenging to identify causal (or target) genes at individual loci detected using genome-wide association studies (GWAS). In order to follow up GWAS loci, we investigated functional genes at homologous loci identified using human lipid GWAS that responded to a high-fat, high-cholesterol diet (HFD) intervention in an animal model.
Methods: The HFD intervention was carried out for four weeks in male rats of the spontaneously hypertensive rat strain. The liver and adipose tissues were subsequently excised for analyses of changes in the gene expression as compared to that observed in rats fed normal rat chow (n=8 per group). From 98 lipid-associated loci reported in previous GWAS, 280 genes with rat orthologs were initially selected as targets for the two-staged analysis involving screening with DNA microarray and validation with quantitative PCR (qPCR). Consequently, genes showing a differential expression due to HFD were examined for changes in the expression induced by atorvastatin, which was independently administered to the rats.
Results: Using the HFD intervention in the rats, seven known (Abca1, Abcg5, Abcg8, Lpl, Nr1h3, Pcsk9 and Pltp) and three novel (Madd, Stac3 and Timd4) genes were identified as potential significant targets, with an additional list of 23 suggestive genes. Among these 33 genes, Stac3, Fads1 and six known genes exhibited nominally significant expression changes following treatment with atorvastatin. Six (of 33) genes overlapped with those previously detected in the expression QTL studies.
Conclusions: Our experimental in vivo approach increases the ability to identify target gene(s), when combined with other functional studies, thus improving understanding of the mechanisms by which GWAS variants act.

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Aim: It has been reported that beta-blockers (BB) reduce cardiovascular events in patients with atherosclerotic disease. However, little is known about the efficacy of these drugs in patients with critical limb ischemia (CLI). We investigated whether beta-blocker therapy affects the clinical outcomes of CLI patients.
Methods: Between March 2004 and December 2011, 1,873 consecutive CLI patients who received endovascular therapy (EVT) (394 BB-treated patients and 1,479 non-BB-treated patients) for de novo infrainguinal lesions were identified retrospectively. A propensity score analysis was used for risk adjustment in a multivariable analysis and one-to-one matching (BB: 305, non-BB 305). The primary endpoint was amputation-free survival (AFS), and the secondary endpoints were overall survival and the rates of limb salvage and freedom from major adverse limb events (MALE; including repeat reintervention, surgical conversion and major amputation). The mean follow-up period was 22±15 months.
Results: In the propensity score-matched pair analysis, there were no significant differences in AFS between the patients treated with and without beta-blockers (58.8% vs. 58.5% at three years, log-rank p=0.76). There were also no significant differences in the limb salvage rate (88.3% vs. 88.8 at three years, log-rank P=0.41), overall survival (63.0% vs. 62.4% at three years, log-rank P=0.70) and freedom from MALE (43.6% vs. 44.9% at three years, log-rank P=0.58) between the patients treated with and without beta-blockers.
Conclusions: The present results suggest that beta-blocker therapy does not worsen the clinical outcomes after EVT in CLI patients.

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Aim: Although our recent cross-sectional study demonstrated that the CHADS₂ score is associated with an ankle-brachial index of ＜0.9 in patients without atrial fibrillation (AF), the true cause-effect relationship between these parameters remains to be evaluated. Hence, the aim of this study was to investigate whether the CHADS₂ score is a useful predictor of new-onset PAOD in non-AF patients.
Methods: From January 1, 2000 to December 31, 2001, a total of 723,750 patients older than 18years of age with no past history of PAOD, rheumatic heart disease or AF were surveyed from the “National Health Insurance Research Database.” The CHADS₂ score was calculated for each patient. Finally, 581,997 (score 0), 84,971 (score 1), 31,473 (score 2), 14,432 (score 3), 8,156 (score 4), 2,430 (score 5) and 291 (score 6) patients were studied and followed for the onset of PAOD. We further divided the study patients into four groups: group 1 (score 0), group 2 (score 1-2), group 3 (score 3-4) and group 4 (score 5-6).
Results: During the follow-up period of 9.83±0.01 years, 24,775 (3.4%) patients experienced new-onset PAOD. The overall incidence of PAOD was 0.6 per 1,000 patient-years. The rate of PAOD increased from 1.8% (group 1) to 18.7% (group 4) (p＜0.001). According to a multivariate analysis, groups 2-4 were significantly associated with new-onset PAOD (all p＜0.001). In addition, the hazard ratio of each two-point increment in the CHADS₂ score for predicting PAOD was 2.51 (p＜0.001).
Conclusions: The CHADS₂ score is a useful predictor of new-onset PAOD in non-AF patients.

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Aims: Lectin-like oxidized low-density lipoprotein (LDL) receptor-1 ligands containing apolipoprotein B (LAB) and lectin-like oxidized LDL receptor-1 (LOX-1) are known as LOX-1-related modified LDL indicators. These indicators play an important role in the early phase atherosclerosis, but the relationship between these indicators and subclinical atherosclerosis, as represented by the cardioankle vascular index (CAVI), has not been assessed. We herein investigated the association of LOX-1- related modified LDL indicators and the CAVI in healthy, Japanese urban community inhabitants who were considered to be at low risk for cardiovascular disease (CVD).
Methods: The participants were 515 healthy Japanese (310 men and 205 women) without a history of CVD, cancer or the use of medication for hypertension, diabetes or dyslipidaemia. To estimate the association between LOX-1-related modified LDL indicators (LAB, soluble form of LOX-1 (sLOX-1)) and the CAVI, we performed multivariable linear regression analyses with possible confounders such as the serum LDL cholesterol level.
Results: The plasma LAB showed a positive association with the CAVI in men (standardized coefficient: 0.11, p=0.04). This relationship was not observed in women. On the other hand, no clear association was observed between the CAVI and the plasma sLOX-1 level in either sex.
Conclusions: The plasma LAB levels may represent a useful marker for detecting potential atherosclerosis in healthy individuals considered to be at low risk for atherosclerosis and CVD. Further studies are needed to confirm the present findings.

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Aim: Deep pontine lacunar infarction (DPLI) not involving the basal pial surface of the medial part of the pons, is known to be a small vessel disease in the territory of the basilar artery (BA). In the present study, we examined whether morphological features of the BA differ in individuals with an advanced age and may be associated with DPLI.
Methods: This study included 338 healthy subjects and 78 patients with DPLI treated at the stroke centers of three university hospitals in Korea. Time-Of-Flight magnetic resonance angiographic images were transported to a central lab and analyzed blind to obtain the clinical data. For the quantitative analysis, the BA was projected two-dimensionally in the anteroposterior and lateral views and perceived as triangles of the vertebrobasilar junction, angulation point and BA division. The angles and triangular areas were summated into angulation indexes and used to quantify the degree of BA tortuosity.
Results: The BA showed a more acute angle at the angulation point in the elderly patients than in the healthy subjects. Compared to the healthy subjects, the DPLI patients exhibited significantly larger angles at the vertebrobasilar junction, in addition to the acute angles noted at the angulation point. A unit increase in the BA angle indexes at the vertebrobasilar junction and angulation points for DPLI was found to have an odds ratio of 1.15 (95% confidence interval, 1.05-1.26) and 0.95 (95% CI, 0.91-0.99), respectively, even after adjusting for potential confounders.
Conclusions: The angulation point of the BA becomes more acute in elderly individuals. In this study, the vertebrobasilar junction showed a larger angle in the patients with DPLI than in the healthy controls.

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Aim: Lysophospholipids, particularly sphingosine 1-phosphate and lysophosphatidic acid, are known to be involved in the pathogenesis of atherosclerosis; however, the role of lysophosphatidylserine (LysoPS) in the onset of atherosclerotic diseases remains uncertain.
Methods: We investigated the effects of LysoPS on the uptake of oxidized low-density lipoprotein (oxLDL) and the modulation of inflammatory mediators and ER stress utilizing RAW264.7 cells and mouse peritoneal macrophages (MPMs).
Results: We found that LysoPS augmented cholesterol accumulation in both models. Consistent with these findings, LysoPS increased the expression of scavenger receptors (CD36, MSR1, LOX1 and TLR4). Regarding the involvement of these lipids in inflammation, LysoPS significantly decreased the expression of inflammatory mediators in lipopolysaccharide (LPS)-treated RAW264.7 cells and MPMs. LysoPS also attenuated ER stress in LPS-untreated RAW264.7 cells. The expression patterns of LysoPS receptors differed considerably among the LPS-untreated RAW264.7 cells, LPS-treated RAW264.7 cells and MPMs.
Conclusions: LysoPS may have proatherosclerotic properties in the setting of foam cell formation as well as antiatherosclerotic effects on inflammation in macrophages.

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Aim: In addition to type 2 diabetes, an elevated Lp(a) level is known to be a surrogate biomarker of cardiovascular disease. However, recent studies have demonstrated that the Lp(a) levels are lower in type 2 diabetic patients than in non-diabetic subjects. Therefore, we sought to evaluate the prognostic value of elevated lipoprotein(a) [Lp(a)] in type 2 diabetic patients with symptomatic coronary artery disease (CAD).
Methods: A total of 1494 diabetic patients with CAD (62.3% men, mean age: 63.5±10.3 years) were enrolled. CAD was diagnosed using invasive coronary angiography, and laboratory values for lipid parameters, including Lp(a), were obtained on the day of coronary angiography. The patients were divided into tertile groups according to the individual Lp(a) level. The baseline characteristics, coronary angiographic findings, duration of follow-up and major adverse cardiovascular events (MACEs) were recorded.
Results: Over a mean follow-up period of 4.4±2.6 years, there were 59 MACEs (35 cardiac deaths and 24 cases of non-fatal myocardial infarction), for an event rate of 3.9%. A survival probability plot according to the Lp(a) tertile revealed that an elevated Lp(a) level was associated with a worse prognosis (p=0.008), after adjusting for age, gender, hypertension, hyperlipidemia, smoking and the extent of CAD. Furthermore, the addition of an elevated Lp(a) level to the reference model improved the integrated discrimination improvement (0.0216, p＜0.001), continuous net reclassification improvement (NRI) (0.5721, p=0.012) and NRI (0.1549, p=0.004) values.
Conclusions: In terms of the prognosis, elevated Lp(a) is associated with worse outcomes in type 2 diabetic patients with symptomatic CAD. Furthermore, an elevated Lp(a) level has incremental prognostic value in type 2 diabetic patients with symptomatic CAD.

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Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common human enzyme defect, affecting more than 400 million people worldwide. In patients with G6PD deficiency, the use of aspirin is controversial, since past studies have reported a potential risk of haemolysis related to its administration, even at low doses. More recent publications have shown that low-dose aspirin administration is safe in these patients. At the same time, no authors have previously reported more than single cases regarding low-dose aspirin treatment in patients with G6PD deficiency undergoing percutaneous coronary intervention (PCI), and most physicians are still sceptical about aspirin administration in these patients. In this paper, we report a case series of five patients with G6PD deficiency receiving PCI with drug-eluting stents (DES) and treatment with dual antiplatelet therapy (DAPT) containing low-dose aspirin, without clinical complications. Moreover, we discuss our internal protocol for managing these patients and provide an overview of the available data.

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