Autosomal recessive hypercholesterolemia (ARH) is an extremely rare inherited disorder, the cause of which is mutations in the low-density lipoprotein (LDL) receptor adaptor protein 1 (LDLRAP1) gene. Only 36 families with 14 different mutations have been reported in the literature to date. The clinical phenotype of ARH is milder than that of homozygous familial hypercholesterolemia (FH) caused by LDL receptor gene mutations. Recently, the lipoprotein metabolism of ARH was investigated in both humans and mice by several investigators, including ourselves. Based on these findings the preserved clearance of LDL receptor-dependent very-LDL (VLDL) may be a possible mechanism underlying the responsiveness to statins and the milder phenotype of ARH. Although ARH has been described as being “recessive,” several studies, including ours, have indicated that a heterozygous carrier status of the LDLRAP1 gene is associated with mild hypercholesterolemia and exacerbates the phenotype of FH resulting from LDL receptor gene mutations. This review summarizes current understanding regarding ARH and its causative gene, LDLRAP1, and attempts to provide new insight into novel pharmacological targets for treating dyslipidemic patients.

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Aim: Chemokine CXC ligand 16 (CXCL16) has chemoattractive, adhesive and scavenging properties and may play a role in the formation of atherosclerotic lesions. However, studies of CXCL16 polymorphisms in patients with atherosclerosis are scarce. The missense polymorphisms I123T and A181V are potentially important factors in the regulation of presentation and shedding of the CXCL16 chemokine domain. The aim of this study was to analyze the association between I123T and A181V polymorphism haplotypes and the accumulation of carotid plaque as well as the effect of the haplotype on the CXCL16 mRNA expression in carotid plaques in patients with advanced atherosclerosis. Additionally, we performed a bioinformatic prediction analysis of the impact of CXCL16 protein sequence variation on CXCL16-CXCR6 interactions and analyzed the soluble CXCL16 plasma levels according to the CXCL16 haplotype.
Methods: This study evaluated a total of 733 participants, including 283 controls and 450 patients with carotid atherosclerosis (CA) undergoing endarterectomy. Analyses of the polymorphisms and the gene expression were performed using real-time PCR. The soluble CXCL16 levels were measured with ELISA.
Results: The missense allele haplotype, T123V181, was found to be significantly and independently associated with the occurrence of CA plaque (OR=1.27;1.02-1.57, p=0.03). This haplotype was predicted to significantly change the CXCL16-CXCR6 interaction, compared to I123A181. Neither the CXCL16 mRNA expression in the human plaques nor the soluble CXCL16 plasma levels differed according to the haplotype.
Conclusions: These results indicate that the CXCL16 T123V181 haplotype is a moderate genetic risk factor for the development of carotid plaque. Further functional and replication studies are needed to clarify the mechanisms by which this combination of alleles promotes advanced CA and validate its impact on disease progression.

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Aims: Recently, a number of studies have shown an increased red blood cell distribution width (RDW) to be a strong and independent predictor of the prognosis of coronary artery disease. The aim of this study was to investigate the underlying mechanisms responsible for the relationship between the RDW and a poor prognosis of coronary artery disease.
Methods: Four hundred and twenty-four patients with ST elevation myocardial infarction treated with primary percutaneous coronary intervention (pPCI) were analyzed retrospectively. We evaluated the relationships between the RDW and the high-sensitivity C-reactive protein (hsCRP) N-terminal pro-brain natriuretic peptide (NTpro-BNP), fasting blood glucose and lipid levels, as well as other parameters of blood examinations and angiographic manifestations.
Results: There were 85 patients in the RDW ≥14% group (mean age 60.62±11.29 years, and men: 87%) and 339 patients in the RDW ＜14% group (mean age: 59.74±11.55 years, and men: 78%). The RDW ≥14% group had higher platelet distribution width (PDW), NTpro-BNP and hsCRP values on admission, a heavier intracoronary thrombotic burden and a higher incidence of three-branch vascular lesions than the RDW ＜14% group. In the multiple logistic regression analysis, the associations between the RDW and the NTpro-BNP level, incidence of three-branch and left main lesions and intracoronary thrombotic burden remained.
Conclusions: A high RDW may be associated with the severity and instability of acute myocardial infarction.

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Aim: Limited data are available regarding the prognostic value of the brachial-ankle index (ABI) in patients with a history of drug-eluting stent (DES) implantation. This study sought to determine the relationship between the ABI and coronary events in patients with DES.
Methods: A total of 322 patients who underwent both DES implantation and ABI measurement during initial hospitalization were reviewed. Cardiovascular events, including cardiac death, non-fatal acute myocardial infarction and coronary revascularization, were assessed.
Results: During the mean follow-up period of 298±58 days, there were 32 cases of cardiovascular events (9.9%). The patients with a lower ABI had more events (2.8% in the highest tertile versus　10.3% in the middle tertile versus 16.8% in the lowest tertile, p=0.001). According to the multiple Cox regression analysis, the ABI was independently associated with clinical events (the lowest tertile versus the highest tertile of ABI, hazard ratio: 6.35, 95% confidence interval: 1.37-29.32, p=0.018).　In addition, the cumulative event rate according to the ABI tertile differed significantly in the Kaplan-Meier curves (log-rank p=0.009), whereas the receiver-operating characteristic curve analysis showed a sensitivity and specificity for predicting cardiovascular events of 62.5% and 66.2%, respectively, with an ABI of 1.057 as the best cut-off value.
Conclusions: A lower ABI is associated with poorer cardiovascular outcomes in patients with DES implantation. As a simple and non-invasive parameter, the ABI has the benefit of predicting future cardiovascular events in this population.

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Aim: Highly concentrated carbon dioxide (CO₂) is thought to be useful for ischemic diseases. We investigated whether treatment with a few micrometers of CO₂ molecules atomized via two fluidnozzles (CO₂ mist) exerts an angiogenic effect in a mouse ischemic hindlimb model.
Methods: Mice with unilateral hindlimb ischemia were divided into untreated (UT), 100% CO₂ gas alone-treated (CG), mixed air (O₂; 20%, N₂; 80%) mist-treated (AM) and 100% CO₂ mist-treated (CM) groups. The lower body of the mice was encased in a polyethylene bag filled with each gaseous agent using a gas mist generator for 10 minutes daily.
Results: According to a laser Doppler analysis, the ischemic hindlimb blood flow was persistently higher after the seventh day of induction of ischemia in the CM group than in the UT group. The capillary density was also greater in the CM group on day 28 compared with that observed in the UT group. In addition, the parameters in the AM and CG groups were similar to those obtained in the UT group. The observed effects were abolished by the administration of an inhibitor of nitric oxide synthase (NOS). The vascular endothelial growth factor mRNA expression and protein levels and the phosphorylated endothelial NOS level were increased in the CM group compared with that observed in the UT group. A proteomic analysis using liquid chromatography-tandem mass spectrometry identified novel protein candidates regulated by CO₂ mist.
Conclusion: Percutaneous CO₂ mist therapy may be useful for treating ischemia-induced angiogenesis.

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Aim: Previous clinical trials have demonstrated the effectiveness of eicosapentaenoic acid (EPA) in preventing cardiovascular events. The aim of the present study was to investigate the effects of EPA treatment on the accumulation of coronary atherosclerotic plaque using optical coherence tomography (OCT).
Methods: A total of 46 acute coronary syndrome (ACS) patients without dyslipidemia were divided into two groups: those who received 1,800 mg/day of EPA (n=15) or the control group (n=31). Serial OCT examinations were performed at baseline and after eight months of follow-up. The target for the OCT analysis was non-culprit plaque with a percent diameter of stenosis of 30% to 70% in non-culprit vessels of ACS.
Results: Between the baseline and follow-up visits, the serum EPA levels increased (50±26 mg/dL to 200±41 mg/dL, p＜0.001) in the EPA group, although they did not change in the control group. According to the OCT analysis, the lipid arc did not change in the EPA group (131±52 degrees to 126±54 degrees, p=0.106) or the control group (137±50 degrees to 138±50 degrees, p=0.603). In contrast, the fibrous cap thickness significantly increased in both the EPA group (169±70 μm to 201±49 μm, p＜0.001) and the control group (164±63 μm to 174±72 μm, p=0.018); however, the relative change in the fibrous cap thickness was significantly greater in the EPA group than in the control group (131±35% vs. 106±15%, p=0.001).
Conclusions: In the present study, the administration of EPA for eight months significantly increased the fibrous cap thickness in patients with coronary atherosclerotic plaque.

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Aim: The aim of this analysis was to investigate the relationships between dyslipidemia, achieved blood pressure (BP) values and the lipid levels, as well as the control of four cardiovascular risk factors (BP, low-density lipoprotein: LDL cholesterol, hemoglobin A1c: HbA1c and smoking) and the incidence of cardiovascular disease (CVD), in Japanese patients receiving antihypertensive therapy.
Methods: A total of 13,052 patients with no history of CVD were included in this subanalysis of the prospective observational OMEGA study in Japanese hypertensive patients treated with olmesartan. Multivariable Cox regression models were used to evaluate the relationship with the risk of CVD.
Results: The incidence of CVD during the 36-month study period was 5.59/1,000 patient-years among the patients with dyslipidemia (n=6,297) and 5.57/1,000 patient-years among the patients without dyslipidemia (n=6,755), with no significant differences between the two groups. Higher achieved BP values tended to be associated with an increased CVD risk in both the patients with and without dyslipidemia. In addition, the risk of CVD tended to be higher in the patients with an achieved LDL cholesterol level of ≥120 mg/dL than in those with an LDL level of ＜120 mg/dL (trend p=0.0005) and in the patients with an achieved high-density lipoprotein cholesterol level of ＜60 mg/dL than in those with an HDL level of ≥60 mg/dL (trend p=0.0017). Furthermore, the risk of CVD was higher among the patients with fewer controlled risk factors than among those with control of all four risk factors (trend p＜0.0001).
Conclusions: In order to prevent CVD in olmesartan-treated hypertensive patients with no history of CVD, it is important to control both the lipid and BP levels and aim for comprehensive risk factor control.

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Aim: Recent studies have shown that platelet indices are linked to metabolic and cardiovascular diseases, in addition to being markers of hemostasis. These studies suggested that they could be modified by various biomolecules, including lipids. Proprotein convertase subtilisin/kexin type 9 (PCSK9), a newly-identified member, plays a key role in lipid metabolism and atherosclerosis. Therefore, we evaluated the relationship between the plasma PCSK9 level and platelet indices.
Methods: In this cross-sectional study, a total of 330 consecutive, stable coronary artery disease (CAD) patients were enrolled at our center between October 2012 and April 2014. The baseline clinical characteristics were collected, and the plasma PCSK9 levels were determined using an ELISA. The associations between PCSK9 and the platelet indices were investigated.
Results: The plasma PCSK9 levels were positively correlated with the platelet (PLT) count and plateletcrit (PCT) (r=0.218, p＜0.001; r=0.250, p＜0.001; respectively), while no correlation of PCSK9 with either the mean platelet volume (MPV) or platelet distribution width (PDW) was found. The association of PCSK9 with the PLT and PCT remained after adjusting for cardiometabolic risk factors (β=0.300, p＜0.001; β=0.269, p＜0.01; respectively), but the latter disappeared when further adjusted for inflammatory markers (β=0.212, p＜0.05; β=0.151, p=NS). Additionally, a correlation analysis performed according to the number of diseased vessels showed that PCSK9 was related to the PLT and PCT in patients with single-, two- or multi-vessel disease, with a particularly strong correlation with two-vessel disease.
Conclusions: The plasma PCSK9 levels are positively associated with the PLT count in CAD patients, suggesting a potential link between PCSK9 and platelets that may be involved in atherosclerosis and metabolic disorders.

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Aim: To investigate the acute effects of the ingestion of a fructose-containing beverage combined with fat on postprandial lipoprotein metabolism.
Methods: Twelve young healthy Japanese women with apolipoprotein E phenotype 3/3 were enrolled in this study. At each of four sessions, the subjects ingested one of four sugar beverages containing fructose and/or glucose (total: 0.5 g/kg body weight) combined with OFTT cream (1 g/kg, 0.35 g/kg as fat) in a randomized crossover design. The four sugar beverages were as follows: 100% (w/w) fructose (F100), 90% fructose＋10% glucose (F90G10), 55% fructose＋45% glucose (F55G45) and 100% glucose (G100). Venous blood samples were obtained at baseline and 0.5, one, two, four and six hours after ingestion.
Results: The serum concentrations of TG in the F100, F90G10 and F55G45 trials were significantly higher than each fasting value at two and four hours, and returned to baseline at six hours, except in the F100 trial. The concentrations at four hours and the incremental areas under the curve for the hepatic triglyceride-rich lipoprotein-triglyceride (VLDL-TG^TM) levels in the F100 and F90G10 trials were significantly higher and larger, respectively, than those observed in the G100 trial. Meanwhile, the concentrations of RLP-TG and apolipoprotein B-48 peaked at two hours in the G100 trial, versus four hours in the other trials, and did not return to baseline at six hours, except in the G100 trial. At four hours, the ⊿apoB48 tended to be higher in the F100 trial than in the G100 trial.
Conclusions: The ingestion of a high-fructose-containing beverage with fat cream delays the clearance of chylomicron and its remnant derived from the intestine and enhances the secretion of triglyceride-rich lipoprotein particles from the liver, thereby inducing postprandial lipidemia, even in young healthy women.

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Aims: The population-attributable fraction (PAF) is an indicator of the disease burden. In Western countries, the PAF of hypercholesterolemia in cardiovascular disease (CVD) is the highest among that for traditional risk factors; however, data for Asian populations are limited.
Methods: A 24-year cohort study was conducted among 9,209 randomly selected participants who were not taking statins. We estimated the hazard ratio (HR) after adjusting for covariates and PAF associated with the serum total cholesterol (TC) levels in relation to CVD mortality.
Results: The TC level was found to be positively associated with an increased risk of CVD, coronary heart disease (CHD) and cardiac death (CHD plus heart failure), with an HR of 1.08 (95% confidence interval [CI]: 1.00-1.16), 1.33 (95% CI: 1.14-1.55) and 1.21 (95% CI: 1.08-1.35) for a 1-SD increment in the serum TC level, respectively. Similar positive associations between the TC level and both CHD and cardiac death were observed after classifying the patients by age and sex. Furthermore, the highest serum TC level (≥6.72 mmol/L) was positively associated with CVD death, with an HR of 1.76 (95% CI: 1.25-2.47), as well as both CHD death and cardiac death. In contrast, no significant relationships were observed between the serum TC level and stroke. Meanwhile, the PAF for CVD, CHD, and cardiac deaths due to hypercholesterolemia (serum TC level ≥5.69 mmol/L, defined by the Japan Atherosclerosis Society) was 1.7%, 10.6% and 5.6%, respectively.
Conclusions: The estimated PAF of CVD death due to hypercholesterolemia is moderately high, but lower than that for other risk factors, such as hypertension.

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