Familial hypercholesterolemia (FH) is a highly prevalent autosomal dominant hereditary disease, generally characterized by three major signs, hyper-low-density-lipoprotein (LDL) cholesterolemia, tendon/skin xanthomas and premature coronary artery disease (CAD). Because the risk of CAD is very high in these patients, they should be identified at an early stage of their lives and started on intensive treatment to control LDL-cholesterol. We here introduce a new guideline for the management of FH patients in Japan intending to achieve better control to prevent CAD. Diagnostic criteria for heterozygous FH are 2 or more of 1) LDL-cholesterol ≥180 mg/dL, 2) tendon/skin xanthoma(s), and 3) family history of FH or premature CAD within second degree relatives, for adults; and to have both 1) LDL-cholesterol ≥140 mg/dL and 2) family history of FH or premature CAD within second degree relatives, for children. For the treatment of adult heterozygous FH, intensive lipid control with statins and other drugs is necessary. Other risks of CAD, such as smoking, diabetes mellitus, hypertension etc., should also be controlled strictly. Atherosclerosis in coronary, carotid, or peripheral arteries, the aorta and aortic valve should be screened periodically. FH in children, pregnant women, and women who wish to bear a child should be referred to specialists. For homozygotes and severe heterozygotes resistant to drug therapies, LDL apheresis should be performed. The treatment cost of homozygous FH is authorized to be covered under the program of Research on Measures against Intractable Diseases by the Japanese Ministry of Health, Labour, and Welfare.

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Aim: The study aim was to evaluate the acute hemodynamic effects of intranasal 17-beta-estradiol on ophthalmic arterial circulation in postmenopausal women.
Methods: Twenty-one healthy women in natural menopause for at least 6 months (mean age: 53.2± 2.9 years) were investigated. Each patient received 300 µg intranasal 17-beta-estradiol. We evaluated the heart rate, systolic and diastolic blood pressure, ophthalmic artery velocity at systolic and diastolic peak and its flow curve integral (FCI) before and 30, 60 and 180 minutes after the administration of the drug.
Results: At all time points, the ophthalmic artery FCI showed statistically significant variations (p<0.001) of velocity (cm/sec) compared to T0 (speed recorded at baseline before drug administration). Moreover, systolic blood pressure, diastolic blood pressure and heart rate did not significantly differ each other after drug administration.
Conclusions: Administration of a single dose of intranasal 17-beta-estradiol to healthy postmenopausal women increases ophthalmic artery perfusion.

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Aim: Glycated hemoglobin (HbA1c) is associated with an increased risk of cardiovascular disease and death from any cause. The aim of this study was to examine the relationship between HbA1c value and coronary artery lesion complexity.
Methods: The subjects were 638 consecutive patients who underwent their first coronary angiography and had their HbA1c levels measured from December 2008 to August 2011. Sixty-one hemodialysis patients were excluded and 577 were analyzed. The complexity of the coronary artery lesions was evaluated using the SYNTAX score (SXscore). The subjects were divided into quartiles according to either the HbA1c or the fasting plasma glucose (FPG) values. Logistic regression analysis (with forced entry methods) was used to predict the prevalence of an intermediate or high SXscore.
Results: Both the higher HbA1c quartiles (Q1 to Q4) and higher FPG quartiles were significantly associated with a higher SXscore (p for trend <0.0001 and 0.026, respectively). The association between higher HbA1c quartiles and a higher SXscore was even observed in non-diabetic subjects (n= 433, Q1: 3.0±6.8, Q2: 6.9±15.6, Q3: 7.6±11.8, Q4: 7.4±13.4 p for trend= 0.004). In addition, a higher HbA1c quartile independently predicted patients with intermediate or high SXscores (SXscore ≥23) after adjusting for age, sex, hypertension, dyslipidemia, creatinine and FPG values (Odds ratio: Q1: 1.00 reference, Q2: 3.24, Q3: 3.03, Q4: 8.04).
Conclusion: HbA1c is significantly associated with the complexity of coronary lesions. This association is even observed in non-diabetic adults. A higher HbA1c value is an independent predictor of the prevalence of complex coronary lesions.

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Aim: This study investigated the impact of the circulating galectin-3 level on the 30-day prognostic outcome in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI).
Methods: From May 2009 to March 2011, blood samples for assessment of the circulating galectin-3 level were collected from 196 consecutive STEMI patients treated by primary PCI and from 30 healthy volunteers.
Results: The galectin-3 level was determined using ELISA. Our results demonstrated that the circulating level of galectin-3 was significantly higher in STEMI patients than in healthy control subjects (p<0.001). As compared with patients with galectin-3 <7.67 ng/mL, patients with galectin-3 ≥7.67 ng/mL were significantly older, had significantly lower left ventricular ejection fraction and significantly higher frequency of elevated white blood cell count, advanced Killip score (defined as ≥ score 3), congestive heart failure (defined as ≥ New York Heart Association Functional Class III), respiratory failure, unstable hemodynamics requiring a mechanical ventilator and intra-aortic balloon pump support, multiple vessel diseases and 30-day mortality (all p<0.04). Furthermore, multivariate analysis showed that elevated circulating level of galectin-3 was the strongest independent predictor of the combined 30-day major adverse clinical outcome (MACO) (defined as advanced CHF or 30-day mortality) (p<0.0001).
Conclusion: A high circulating galectin-3 level may serve as a useful biomarker for predicting 30-day MACO in patients with STEMI undergoing primary PCI.

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Aim: Lectin-like oxidized LDL receptor-1 (LOX-1) is a class E oxidized LDL specific scavenger receptor that recognizes multiple ligands. Advanced glycation end products (AGEs) have been recently identified as other ligands to LOX-1 and shown to increase LOX-1 expressions in diabetes; therefore, we investigated the underlying mechanism involved.
Methods: Confluent human aortic endothelial cells were treated with a fixed concentration of AGE-BSA or BSA as a control in the presence or absence of either antibody of the receptor for advanced glycation end products, mammalian target of rapamycin (mTOR) inhibitor rapamycin, NF-kB inhibitor, phosphoinositide 3-kinases (PI3K) inhibitor or anti-diabetic drug metformin. After stimulation, cells were lysed and Western blot protein expression on LOX-1, rapamycin-insensitive companion of mTOR (RICTOR), the phosphorylation status of p-mTOR, p-P70S6 kinase and p-Akt were determined.
Results: AGEs induced LOX-1 expression in endothelial cells. Pretreatment either with anti-RAGE antibody or LY294002 prior to AGE-BSA decreases LOX-1 and p-mTOR expressions. Incubating endothelial cells with AGE-BSA in the presence of rapamycin down-regulated the protein expression-level of p-mTOR by 41% (p<0.05) and LOX-1 expression by 61.5% (p<0.01). Knockdown of RICTOR by RNA silencing showed a 41.5% (p<0.01) and 71.2% (p<0.01) reduction in LOX-1 and p-Akt expressions, respectively. Preincubation of endothelial cells with AGE-BSA and metformin, an anti-diabetic drug known to have an mTOR inhibition effect, significantly reduced AGE-stimulated LOX-1 expression.
Conclusion: Our results indicated that LOX-1 up-regulation induced by AGE-BSA was a receptor mediated through RAGE and is via the PI3K/PDK1/mTORC2 pathway. Metformincan reduce AGE-stimulated LOX-1 expression in endothelial cells in vitro.

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Aim: Ezetimibe selectively blocks intestinal cholesterol absorption by inhibiting Niemann-Pick C1-like 1 (NPC1L1) and reducing LDL cholesterol (LDL-C). In animals, ezetimibe reversed diet-induced obesity, liver steatosis, and insulin resistance. In humans, its potential effects on liver steatosis and insulin resistance have been suggested. We investigated the effects of ezetimibe on postprandial hyperlipidaemia and hyperglycaemia in obese subjects with dyslipidaemia in a double-blind randomized crossover trial.
Methods: Twenty obese men with hypertriglyceridaemia were assigned randomly to an ezetimibe- or a placebo-precedence-treated group. Subjects in the ezetimibe group were treated with ezetimibe (10 mg/day) for the first 4 weeks, followed by a 4-week interval and then treated with placebo for another 4 weeks. The placebo group received these treatments in reverse order. Subjects were requested to fast for at least 12 hours and then received a standard meal. Blood samples were collected at 0, 30, 60, 120, 240, 360 and 480 minutes after the meal on Days 0, 28, 56 and 84 and were used to measure the lipid and glucose metabolism markers.
Results: Ezetimibe significantly decreased the postprandial serum triglyceride excursion (p=0.01) and fasting serum LDL-C, remnant-like particles(RLP) and ApoB48 levels (p<0.05). Postprandial glucose excursion, serum insulin levels, serum glucose-dependent insulinotropic polypeptide (GIP) and active glucagon-like peptide-1 (GLP-1) were not significantly affected by ezetimibe treatment.
Conclusion: Ezetimibe restored the postprandial dysregulation of lipid but did not affect glucose metabolism in a double-blind randomized crossover trial.

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Aims: Plasma fatty acid composition can change with age, reflecting diet and levels of desaturating enzymes such as stearoyl-CoA desaturase (SCD), delta-6 desaturase (D6D) and delta-5 desaturase (D5D), which contribute to the development of insulin resistance. This study analyzed longitudinal changes in fatty acid composition in Japanese children during early puberty and the association between changes in desaturase indices and changes in body fatness and insulin resistance.
Methods: The study included 77 children (38 boys and 39 girls) aged 9.6±0.5 years. Relative weight (RW) and waist-to-height ratio (WHtR) were determined. The fatty acid composition of plasma phospholipids was analyzed by gas chromatography, and the desaturase indices were calculated: SCD (16:1n-7/16:0: SCD16 and 18:1n-9/18:0: SCD18), D6D (20:3n-6/18:2n-6) and D5D (20:4n-6/20:3n-6) in 2006 and 2009.
Results: Obese children showed higher dihomo-gamma linolenic acid (DGLA; 20:3n-6), a higher D6D index and lower D5D index than non-obese children. Longitudinal changes in fatty acid com-position were generally similar in both sexes. Increased D6D index and DGLA and decreased D5D index were significantly associated with increased WHtR in boys and girls. In addition, increased D6D index was associated with an increased homeostasis model of assessment ratio (HOMA-R) only in girls.
Conclusion: The change in abdominal adiposity is a determinant of longitudinal changes in D6D and D5D indices and DGLA during early puberty.

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Aim: Endothelial lipase (EL) regulates plasma high-density lipoprotein-cholesterol (HDL-C) levels by promoting HDL catabolism. However, it remains unknown whether the inhibition of EL has beneficial effects on the genesis of vascular diseases. Here, we investigated the role of EL on vascular remodeling in mice.
Methods: Vascular remodeling was developed by ligation of the left common carotid artery and neointimal lesions were histologically compared between EL-knockout (ELKO), EL-transgenic (ELTg), and wild-type (WT) mice. HDL was isolated from these mice, and effects of the HDL on cell growth and Erk activation were evaluated in vitro using cultured vascular smooth muscle cells.
Results: Plasma HDL-C levels were 62% higher in ELKO and 13% lower in ELTg than in WT mice, after the carotid ligation. The size of neointimal lesion was significantly larger in ELTg and smaller in ELKO than in WT mice. Vascular expression of adhesion molecules was lower in ELKO and higher in ELTg compared with WT mice. Moreover, oxidative stress was attenuated in ELKO mice. HDL isolated from ELKO, ELTg, and WT mice inhibited expression of intercellular adhesion molecule-1, angiotensin II-induced activation of Erk, and growth of cultured vascular smooth muscle cells, whereas EL expression itself did not affect cell migration or growth.
Conclusion: EL expression modulates vascular remodeling as well as plasma HDL-C levels. EL inactivation may increase HDL particles that can inhibit smooth muscle cell growth and migration.

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Aim: Inherent mechanisms leading to vascular smooth muscle cells (VSMC) alterations in obesitylinked type 2 diabetes (T2D) situation remain to be clarified. This study evaluates the impact of supernatant of adipocytes extracted from mice fed high-fat-diets (HFD) on the proliferation and apoptosis of VSMC.
Methods: Adipocytes were extracted from visceral white fat pads of male and female C57Bl6 mice showing different stages of metabolic alterations after 20 weeks of vegetal or animal HFD feeding. These cells were stimulated or not with insulin or glucose to condition VSMC media. After 24h of stimulation with adipocyte supernatants (AdS), VSMC proliferation and sustainability were assessed in the absence and presence of AdS. CD36 and insulin receptor mRNA levels were also evaluated.
Results: Proliferation and viability of VSMC were significantly modulated by the nature of the AdS used and the gender of mice from which adipocytes have been extracted. The most extensive effects on VSMC were triggered by adipocytes from males fed animal HFD and females fed vegetal HFD. These effects were concurrent with increased leptin concentration and decreased adiponectin levels in AdS. In addition, adipocytes of HFD-fed mice increased caspase-3 activity and apoptosis in VSMC. Significant up-regulation of CD36 mRNA was also found in these cells.
Conclusion: Adipocytes of HFD-fed mice induce VSMC alterations. These changes involved mouse gender, most probably correlated to the diet-induced adipocyte secretion profile. Greater sensitivity to AdS effects in VSMC raises concerns about the more frequent cardiovascular events associated with obesity in the presence of T2D, which impairs adipocyte activity.

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Aim: Aspirin is an antiplatelet drug widely used for the prevention of cardiovascular disease; however, it is known to increase bleeding events. A low response to aspirin was reported to correlate with poor prognosis in patients undergoing antiplatelet therapy with aspirin. The aim of this study was to evaluate the impact of the antiplatelet activity of aspirin on cardiovascular and bleeding events in Japanese patients.
Methods: We analyzed the clinical course of 239 Japanese patients undergoing antiplatelet therapy with aspirin for a median of 64 months in this study. Their residual platelet reactivity was examined at enrollment and after 2 years. The co-primary endpoints were the occurrence of major adverse cardiac and cerebrovascular events (MACCEs) and bleeding events.
Results: The annual incidence of MACCEs and major bleeding events was 3.7% and 0.48%, respectively. With defined criteria, 67 patients (28%) were classified as low responders based on the platelet aggregability measured at enrollment. Low response to aspirin was not associated with increased MACCEs, while it clearly increased MACCEs in patients less than 70 years old (low responders 36.9% vs. responders 14.8%, log rank p=0.008). Five major types of bleeding occurred in the responders, but not in low responders, although the difference was not statistically significant (p= 0.07).
Conclusion: Low response to aspirin was not associated with the increase of long-term MACCEs, while it increased MACCEs in patients less than 70 years old; however, it tended to decrease major bleeding events in Japanese patients.

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