Hepatic lipase (HL) is a key enzyme catalyzing the hydrolysis of triglycerides (TG) and phospholipids (PLs) in several lipoproteins. It is generally recognized that HL is involved in the remodeling of remnant, low-density lipoprotein (LDL), high-density lipoprotein (HDL) and the production of small, dense low-density lipoproteins (sd-LDLs).On the other hand, it is unclear whether HL accelerates or retards atherosclerosis. From the clinical point of view, HL deficiency may provide useful information on answering this question, but the rarity of this disease makes it impossible to conduct epidemiological study.In this review, we describe a comprehensive and updated view of the clinical significance of HL on lipid and lipoprotein metabolism.

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Chemokines and their receptors have become significant factors in atherosclerosis research. CXCL16 is a multifunctional agent located on a separate locus to all other known chemokines and binds only to its “unique” receptor named CXCR6. As a scavenger receptor, adhesion molecule, and chemokine, it quickly became an interesting target in atherosclerosis research as all its functions have a role in vascular pathology. The investigation of the role of CXCL16 in atherosclerosis, although shown in in vitro studies, animal knockout models, and CXCL16 gene polymorphisms, haplotypes, and circulating levels, still shows puzzling results. Genetic and epigenetic studies have just scratched the surface of research necessary for a better assessment of the significance and perspective of this marker in plaque development and progression. In this review, we will summarize current knowledge about CXCL16 in atherosclerosis. Additionally, we will point out the importance of bioinformatics tools for the detection of potentially new CXCL16 regulatory networks through microRNA activity. This review aims to provide a better understanding of the underlying mechanisms, define more specific biomarkers, and discover new therapeutic targets.

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Aim: To evaluate the effects of treatment for hyperlipidemia on total mortality, we examined the association with adjustments for multiple factors, including those related to general health, such as blood hemoglobin and serum levels of albumin, adiponectin, brain natriuretic peptide, and lipids, using a prospective cohort study of a general Japanese population.
Methods: The population-based, longitudinal Takahata study enrolled 3,291 Japanese individuals (1515 male, 1776 female; age: 62.5±10.3 years) between 2004 and 2006. The incidence and causes of death were annually monitored until January 10, 2012 (median follow-up period: 2,655 days).
Results: During the follow-up period, there were 169 deaths. The Cox proportional hazard regression model analysis used to adjust for factors related to general health condition, cardiovascular disease risks, and serum lipid levels showed a significant association between treatment for hyperlipidemia and decreased total mortality compared with no treatment for hyperlipidemia [hazard ratio (HR): 0.24; 95% confidence interval (CI): 0.08–0.69) and subjects without hyperlipidemia (HR: 0.34;95%CI: 0.12–0.96). The Cox proportional hazard regression model analysis with adjustments for factors related to general health conditions showed a significantly lower total mortality in subjects without hyperlipidemia than that in subjects with untreated hyperlipidemia (HR: 0.70; 95%CI: 0.50–0.99).
Conclusions: Not only antihyperlipidemic drugs used but also selection bias and non-evaluated factors, such as socio-economic status, educational level, health literacy, and daily nutrition, affected the results. Subjects taking treatment for hyperlipidemia were found to have reduced total mortality, which was independent of serum lipid levels.

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Aim: Arterial stiffness assessed by brachial-ankle pulse wave velocity (baPWV) is predictive of cardiovascular events. This study was designed to investigate whether baPWV has an additional prognostic value to single-photon emission computed tomography (SPECT) in patients with suspected coronary artery disease (CAD).
Methods: A total of 350 subjects (age, 66.2±10.5 years, 53.4% male) with suspected CAD undergoing myocardial SPECT and baPWV within 30 days were retrospectively analyzed. Cardiovascular events, including cardiovascular death, acute coronary syndrome and ischemic stroke, were assessed. Both fixed and reversible perfusion defects on SPECT were considered abnormal myocardial perfusion imaging (MPI) findings.
Results: During the median follow-up period of 441 days (interquartile range 169–719 days), cardiovascular events occurred in 21 patients (6.0%). In multivariable Cox regression analysis, abnormal MPI [hazard ratio (HR), 2.67; 95% confidence interval (CI), 1.21–10.37; p=0.024] and high baPWV (≥1,790 cm/s) (HR, 2.03; 95% CI, 1.08–6.38; p=0.007) were independent predictors of clinical events even after adjusting for possible confounders. Also, high baPWV had an incremental prognostic value to traditional risk factors and abnormal MPI in predicting cardiovascular events (overall Chi-square, from 24.08 to 27.42; p＜0.001). Kaplan–Meier survival curves stratified by baPWV and MPI proved significantly improved prediction of cardiovascular events (log-rank p=0.001).
Conclusions: baPWV has an incremental prognostic value to traditional risk factors and MPI. Therefore, baPWV can be used to identify subjects at higher risk of cardiovascular events in patients undergoing SPECT.

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Aim: There is a strong relationship between carotid atherosclerosis and future cardiovascular disease (CVD). This study sought to clarify the association of fatty liver and an elevated serum gamma-glutamyl transpeptidase (GGT) level with carotid atherosclerosis.
Methods: We reviewed the medical records of subjects who underwent medical checkups at our institute. Carotid atherosclerosis and fatty liver were assessed using ultrasound (US), and predictors of increased carotid intima-media thickness (IMT) and carotid plaque were identified using a logistic regression model.
Results: In total, 958 subjects (564 men, 394 women; median age, 59 years) were enrolled. The median value of the mean carotid IMT was 0.713 mm, and the frequency of carotid plaque was 19.5%. For the highest quartile of the mean carotid IMT (≥0.863 mm), a male sex, older age, hypertension (HT), dyslipidemia (DL) and type 2 diabetes mellitus (DM) were identified as independent predictors. A male sex, older age, HT and elevated serum GGT level were found to be significant predictors of the presence of carotid plaque. In addition, fatty liver correlated with the existence of carotid plaque. When the combination of the serum GGT level and presence or absence of fatty liver was included as a variable in the analysis, a male sex, older age, HT and fatty liver with a serum GGT level of ≥83 IU/L (90th percentile) (odds ratio 3.21, 95% confidence interval 1.27–8.12, p=0.014)were identified to be significantly associated with carotid plaque.
Conclusions: This study suggests that the simultaneous presence of an elevated serum GGT level and fatty liver is highly predictive of carotid plaque.

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Aims: Considering that cerebral infarction (CI) may share a common etiological basis with coronary artery disease (CAD), we evaluated six CAD-related single-nucleotide polymorphisms (SNPs) on 9p21 for investigating the effect of 9p21 on CI or carotid plaque in the Chinese Han population.
Methods: Altogether, 528 patients with noncardioembolic CI (375 with carotid plaque and 153 without carotid plaque) and 258 control subjects were genotyped. Six SNPs previously shown to be associated with CAD were sequenced and assessed for association with CI and carotid plaque using odds ratio (OR) and 95% confidence interval (CI) from logistic regression models.
Results: The G allele frequencies of rs2383206 (OR=1.472, p=0.021) and rs4977574 (OR=1.519, p=0.013) significantly increased in patients with CI without carotid plaque compared with middle-aged patients in the control group. The CI risk was higher among the GG genotype carriers than among GA＋AA genotype carriers (OR=1.794, 95% CI=1.059–3.039, p=0.030 for rs2383206; OR=1.866, 95% CI=1.088–3.201, p=0.023 for rs4977574). In comparison with the non-GG genotype, the GG genotype of rs2383206 and rs4977574 combined had a 1.733-fold greater risk of CI in the middle-aged group. SNPs rs2383206 and rs4977574 were also associated with a risk of carotid plaque among patients with CI aged ＞65 years (OR=2.329, p=0.018 and OR=1.997, p=0.049, respectively). Moreover, six SNPs were strongly correlated with linkage disequilibrium.
Conclusions: Genetic variations of rs2383206 and rs4977574 on 9p21 are potentially associated with CI and carotid plaque in the Chinese Han population. Our results provide further evidence that the 9p21 region represents a major risk locus for cerebrovascular diseases.

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Aim: Although it is understood that a looped wire technique using a 0.035-inch wire for femoropopliteal (FP) long chronic total occlusions (CTOs) goes to the subintima, there has been no systematic assessment of wire passages. The purpose of this study is to examine these passages by intravascular ultrasound (IVUS) after looped wire technique for FP long CTOs.
Methods: Between March 2012 and October 2014, 57 consecutive FP long CTO lesions (mean lesion length, 246±42 mm), involving the superficial femoral artery ostium and treated with IVUS-guided endovascular therapy, were enrolled. After IVUS confirmed that the initial wire passage was intraplaque, the looped wire technique was routinely conducted through the CTO body. Based on IVUS findings, the wire passage was classified into 3 types: intraplaque, subintimal, and intramedia.
Results: At the FP lesion in the proximal, middle, and distal segments, the wire proceeded intraplaque in 98%, 25%, and 20% cases; subintimal in 2%, 61%, and 52%; and intramedia in 0%, 14%, and 28%, respectively. The success rate of antegrade wiring was 74%, with the remaining 26% cases requiring an additional retrograde approach.
Conclusions: The looped wire technique variably proceeds to intraplaque, subintimal, or intramedia, even starting from intraplaque in FP long CTOs.

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Aim: To investigate the thrombolytic and antiplatelet effects of a novel plasminogen activator from the venom of the Gloydius brevicaudus viper (GBV-PA) in vitro and in vivo.
Methods: Thrombolytic experiments were performed in rabbit models of ear vein thrombosis and carotid artery thrombosis and in dog model of acute cerebral infarction. Inhibition of thrombus formation was evaluated in rat inferior vena cava thrombosis model and ferric chloride-induced arterial thrombosis. In vitro, we assayed the antithrombotic effect of GBV-PA on rabbit blood clots, euglobulin lysis time (ELT) of rabbit plasma, and ADP-induced platelet aggregation.
Results: GBV-PA intravenous administration significantly reduced vascular recanalization times of rabbit ear veins thrombosis and thrombus weight of rabbit carotid artery thrombosis. The arterial recanalization rates were dose- and time-dependently improved after the administration of GBV-PA in canine acute cerebral infarction model. Thrombus length and weight were significantly reduced by GBV-PA both in rat inferior vena cava and ferric chloride-induced arterial thrombosis models. Thrombus formation in the blood of rabbits that were administered of GBV-PA was also inhibited. GBV-PA radically reduced plasma ELT of the rabbit's blood clots. ADP-induced platelet aggregation was inhibited by GBV-PA in a dose-dependent manner with a half-maximal inhibitory concentration of 19.9 μg/mL.
Conclusion: This study demonstrates that GBV-PA is a thrombolytic and antiplatelet agent. It has significant antithrombotic effects on various in vitro and in vivo experimental models of thrombosis. The mechanisms that underline its antithrombotic effects were related to GBV-PA's capabilities of increasing fibrinolytic activity and inhibition of platelet aggregation.

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Aim: von Willebrand factor (VWF) plays an important role in the regulation of hemostasis and thrombosis formation, particularly under a high shear rate. However, the adhesive force due to the molecular interaction between VWF and glycoprotein Ibα (GPIbα) has not been fully explored. Thus, we employed atomic force microscopy to directly measure the adhesive force between VWF and GPIbα.
Methods: We measured the adhesive force between VWF and GPIbα at the molecular level using an atomic force microscope (AFM). An AFM cantilever was coated with recombinant N-terminus VWF binding site of GPIbα, whereas a cover glass was coated with native VWF.
Results: The adhesive force at the molecular level was measured using an AFM. In the presence of 1 μg/mL VWF, the adhesion force was nearly 200 pN. As per the Gaussian fit analysis, the adhesive force of a single bond could have been 54 or 107 pN.
Conclusion: Our consideration with the Gaussian fit analysis proposed that the adhesive force of a single bond could be 54 pN, which is very close to that obtained by optical tweezers (50 pN).

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Aim: Vasa vasorum neovascularization is a key feature of atherosclerosis (AS) and is strongly associated with inflammatory infiltration, lipid deposition, intraplaque hemorrhage, and hemosiderin deposit. Here we investigate the effects of Endostar, a strong anti-angiogenic drug, on vasa vasorum neovascularization in the experimental porcine model of early AS.
Methods: Eighteen adult male Ba-Ma mini pigs were randomized into three groups, with six animals in each group. The pigs in the normal (N) group were fed a normal diet for 18 weeks, without balloon injury surgery. The animals in the atherosclerotic (AS) control and AS＋Endostar groups were fed a hypercholesterolemic diet for 12 weeks after balloon injury surgery; they received either saline or Endostar for an additional six weeks, while continuing the hypercholesterolemic diet. The atherosclerotic abdominal aorta and levels of serum lipids, TNF-alpha, IL-6, and hs-CRP were analyzed at 18 weeks.
Results: The AS group had a significantly higher body weight and serum lipid concentration levels than the N group (p＜0.05), confirming the success of the hypercholesterolemic diet. However, no statistical differences were noted between the AS and AS＋Endostar groups. Histopathology results revealed that vasa vasorum density and intima–media thickness (IMT) had also increased in the AS group compared with those in the N group (p＜0.05). The Endostar treatment significantly alleviated AS with decreased vasa vasorum density and IMT (AS vs. AS＋Endostar, p＜0.05). Western blot analysis indicated that the expression of VEGF, β-catenin, and TNF-alpha in the atherosclerotic abdominal aorta was considerably reduced by the Endostar treatment. In addition, immunohistochemistry results showed that the angiogenesis markers VEGF and β-catenin were predominately localized in endothelial cells of the adventitial vasa vasorum. The levels of the serum inflammatory markers TNF-alpha, hs-CRP, and IL-6 were markedly higher in the AS group than in the N group (p＜0.05) but showed no marked difference during the Endostar treatment, suggesting that the local inhibition of angiogenesis was not accompanied by a change in serum inflammatory markers and that the inhibitive effect of Endostar on local TNF-alpha expression could be because of the prevention of vasa vasorum neovascularization.
Conclusions: Our results demonstrated that the Endostar treatment inhibited vasa vasorum neovascularization and AS progression in the experimental porcine model of early AS, supporting the role of vasa vasorum neovascularization in the development of AS and the therapeutic potential of anti-angiogenesis intervention in AS.

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