Familial hypercholesterolemia is a genetic disorder associated with elevated LDL-cholesterol and high lifetime cardiovascular risk. Both clinical and molecular cascade screening programs have been implemented to increase early definition and treatment. In this systematic review, we discuss the main issues found in 65 different articles related to cascade screening and familial hypercholesterolemia, covering a range of topics including different types/strategies, considerations both positive and negative regarding cascade screening in general and associated with the different strategies, cost and coverage consideration, direct and indirect contact with patients, public policy around life insurance and doctor–patient confidentiality, the “right to know,” and public health concerns regarding familial hypercholesterolemia.

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Aim: Whole exome sequencing (WES) is a recently developed method for discovering rare mutations associated with hereditary disorders. However, the feasibility and utilization of this method in identifying familial hypertriglyceridemia is not well known. The purpose of the study was to identify the genetic locus that causes hypertriglyceridemia and assess its prevalence in Taiwanese subjects with hypertriglyceridemia.
Methods: We performed WES among two individuals with hypertriglyceridemia and one control subject in an index family (22 members). Based on the WES findings, we extended the study to genotype 65 unrelated adult index patients with a fasting serum triglyceride level of ＞500 mg/dL and 125 normal controls using polymerase chain reaction.
Results: Using WES alignment, variant calling and annotation, 15 presumptive causal variants were initially identified, including 13 cases by the autosomal dominant model and two cases by the autosomal recessive model. Only APOA5 c.553 G＞T (rs2075291), resulting in the amino acid mutation Gly185Cys, co-segregated well with hypertriglyceridemia in terms of autosomal recessive inheritance (homozygote TT: mean triglyceride level: 1,071 mg/dL vs non TT (GT and GG): mean triglyceride level: 118 mg/dL; p＜0.001) in the index family. In the unrelated cohorts, the frequency of the TT genotype of rs2075291 was 12.3% in the hypertriglyceridemic group; however, no TT genotype was found in the control group.
Conclusions: Our results demonstrate that WES is feasible for identifying the genetic locus that causes hypertriglyceridemia. The TT genotype of APOA5 c.553G＞T acts as an important indicator of hypertriglyceridemia in patients in Taiwan.

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Aim: We assessed whether there is an association between the cardio-ankle vascular index (CAVI) score and the carotid intima media thickness (IMT), the pulse wave velocity (PWV) and the central augmentation index (CAIx) that is independent of the subject's cardiovascular risk and pharmacological treatment.
Methods: The CAVI score was measured in 500 subjects using a VaSera device and the brachial ankle PWV (ba-PWV) was calculated. A carotid ultrasound was used to measure the IMT. A Mobil-O-Graph device was used to measure the carotid femoral PWV (cf-PWV) and the CAIx. The Framingham-D'Agostino and SCORE scales were used to measure the subject's cardiovascular risk.
Results: The mean value of the CAVI score was 8.59±1.1. IMT, CAIx and PWV maintained a positive association with the CAVI score (p＜0.01) in a multiple linear regression analysis, after adjusting for the subject's cardiovascular risk, body mass index and pharmacological treatment. The cut-off level that gave the maxima sensitivity and specificity to detect a mean IMT of ＞0.90 mm was 8.95 (AUC=0.67) for the CAVI score, 8.85 (AUC=0.66) for cf-PWV and 15.10 (AUC=0.66) for ba-PWV. The cut-off to detect a maxima IMT of ＞0.90 mm was 8.60 (AUC=0.62) for the CAVI score, 8.85 (AUC=0.64) for cf-PWV and 15.75 (AUC=0.70) for ba-PWV.
Conclusion: There was a positive association of the CAVI score with vascular structure and function parameters that was independent of cardiovascular risk and any medications being used by the subject. The ability of the CAVI score to predict carotid atherosclerosis is similar to that of cf-PWV and ba-PWV in Caucasian adults.

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Aim: The aim of this study was to perform a meta-analysis to investigate the association between PPARγ rs1801282/rs3856806 polymorphisms and atherosclerotic diseases.
Methods: The meta-analysis was performed by searching the PubMed, Embase and Web of Science databases from the first available year to September 10, 2013. Additionally, reference lists from the identified articles, reviews and abstracts presented at the meetings of related scientific societies were also checked. All case-control studies investigating the association between PPARγ rs1801282/rs3856806 polymorphisms and the risk of atherosclerotic disease were included. The association was assessed according to the odds ratio (OR) with a 95% confidence interval (CI). Publication bias was analyzed using Begg's funnel plot and Egger's regression test.
Results: A total of 29 studies reporting PPARγ rs1801282/rs3856806 polymorphism were included in the final meta-analysis. Neither the rs1801282 (Pro12Ala) nor rs3856806 (C161T) polymorphisms showed any significant associations with susceptibility to atherosclerotic diseases. In the meta-analysis performed to assess the association between the rs3856806 gene polymorphism and atherosclerotic disease based on ethnicity and the type of disease, significant associations were found in the Caucasian subgroup, Asian, CAD and MI subgroups.
Conclusions: The present data suggest that there is no statistical evidence of a significant association between the PPARγ gene rs1801282/rs3856806 polymorphism and the risk of atherosclerotic disease. In contrast, the rs3856806 polymorphism was associated with an increased risk in the Caucasian and MI subgroups, whereas decreased risks were noted in the Asian and CAD subgroups. Due to significant between-study heterogeneity, further studies with a larger sample size involving homogeneous AS patients and well-matched controls are required in the future.

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Aim: Chitosan-oligosaccharides (COS) treatment showed lipid lowering effects in rats and reverse cholesterol transport (RCT) promotion in mice, suggested that COS might be a potential atheroprotective material. In this study, we investigated the effects of COS treatment on atherosclerosis (AS) in apolipoprotein E deficient mice (apoE-/-).
Methods: After feeding high fat (HF) diet for 12 weeks with the gastric gavages administration of COS or vehicle, respectively, the mice were sacrificed for the assessment of atherosclerosis, plaque stability, and the mechanism investigation.
Results: Cholesterol and TG in non-high density lipoprotein (non-HDL) fractions were reduced dramatically in COS groups. The COS treatment decreased the lesion areas of aortic enface, plaque areas in aortic root, and increased plaque stability in apoE-/-. Furthermore, the COS treatment significantly enhanced the expression of liver low density lipoprotein receptor (LDL-R), scavenger receptor BI (SR-BI) as well as the expression of macrophage SR-BI and ATP binding cassette transporter A1(ABCA1). We also found that the COS treatment did not affect the plasma lipid level in LDL-R deficient mice and cholesterol absorption in wild type mice.
Conclusions: COS treatment attenuated AS and decreased plasma non-HDL level in apoE-/-, and the potential mechanism might be involved with enhanced expression of hepatic LDL-R and SR-BI, and macrophage ABCA1.

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Aim: In patients with carotid plaque, intraplaque hemorrhage arising from ruptured neovascular vessels within the neointima is an important cause of stroke. The expression of Vasohibin-1 (VASH1), a negative feedback regulator of angiogenesis, occurs in the microvessel endothelial cells of various solid tumors and the arterial wall. However, the roles of VASH1 in the pathogenesis of atherosclerotic diseases remain unclear. The present study aimed to clarify the relevance of the VASH1 expression and plaque instability in human carotid plaques.
Methods: We used quantitative real-time PCR and immunostaining to examine 12 atheromatous plaque specimens obtained via carotid endarterectomy. The distal areas of specimens lacking macroscopic atherosclerotic lesions served as controls.
Results: Compared with that observed in the controls, the VASH1 gene expression increased significantly in the atheromatous plaque (p=0.018). Moreover, the VASH1 mRNA levels correlated positively with those of VEGFA, CD31 and VCAM1 (r=0.788, p=0.004; r=0.99, p＜0.001; r=0.94, p＜0.001, respectively). Finally, the immunohistochemical analyses revealed the VASH1 expression in the neointimal microvessel endothelial cells of carotid plaque.
Conclusions: The VASH1 expression levels in atheroma reflect both enhanced neovascularization and the inflammatory burden. Therefore, the VASH1 level may be a novel biomarker for evaluating plaque instability in patients with carotid arteriosclerosis and predicting ischemic stroke.

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Aim: According to the Japan Atherosclerosis Society 2012 guidelines (JAS2012-GL), chronic kidney disease (CKD) has newly been added to the high-risk group in terms of atherosclerotic cardiovascular diseases. We therefore explored the lipid target level achievement rates under the JAS2012-GL in real-world clinical practice.
Methods: We retrospectively reviewed the medical charts of patients who were hospitalized at the Nephrology Department at Kobe City Medical Center General Hospital in the period from April 1, 2012 to May 31, 2013 and explored the serum lipid target level achievement rates. Patients without lipid data or those undergoing regular dialysis because of chronic renal failure were excluded. In this study, the CKD group (CKD-G) did not include CKD patients under secondary prevention for coronary heart disease (CHD) or diabetes mellitus (DM).
Results: The CKD-G included 146 (81.1%) of the 180 enrolled patients. According to the JAS2012-GL, 100% of the CKD-G patients were categorized into the high-risk group, although only 12.1% of the CKD-G subjects were at high risk according to the JAS2007-GL. Under the JAS2012-GL, the LDL cholesterol (LDL-C) and non-HDL cholesterol (non-HDL-C) target level achievement rates for CKD-G were 71.4% and 68.1%, respectively. According to the JAS2007-GL, these rates were 81.3% and 79.1%, respectively, and, under both guidelines, these rates were 71.7% and 72.1% for primary prevention DM and 66.7% and 66.7% for CHD, respectively.
Conclusions: After the revision of the JAS-GL in 2012, the LDL-C and non-HDL-C target level achievement rates for CKD-G were reduced by approximately 10%; however, they remained similar to those for DM and higher than those for CHD.

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Aim: Resveratrol has been shown to mimic the beneficial effects of dietary restriction (DR). We previously reported that DR delays stroke onset and extends the lifespan in Stroke-Prone Spontaneously Hypertensive rats (SHRSP). Therefore, we examined whether resveratrol mimics DR and delays stroke onset in SHRSP.
Methods: Cerebrovascular endothelial cells (CVECs) from SHRSP were treated with resveratrol, and the inflammatory gene expression levels and NFκB protein levels were measured. In order to address the effects of resveratrol in vivo, SHRSP (male, 10 weeks of age) were fed an experimental diet containing several doses of resveratrol (0 - 0.05% (w/w)), after which we measured the plasma cytokine levels and examined the stroke onset and lifespan.
Results: Treatment with resveratrol (100 μM, 24 hours) in CVECs from SHRSP significantly decreased the interleukin (IL)-1β-induced monocyte chemoattractant protein-1 (MCP-1) mRNA expression levels and p50 and p65 protein levels in the nuclear fraction. When the SHRSP were fed a diet containing resveratrol for one week, the resveratrol treatment did not affect the plasma lipid and glucose levels, body weight or weight of each tissue. Resveratrol slightly, but not significantly, decreased the plasma levels of IL-1β and MCP-1 compared with that observed in the control group. In addition, resveratrol decreased the IL-1β and MCP-1 mRNA expression levels in the brain versus the control animals. However, no doses of resveratrol delayed stroke onset or extended the lifespan in SHRSP.
Conclusions: In this study, resveratrol did not delay stroke onset in SHRSP, although it partially suppressed systemic and cerebral inflammation. These results suggest that resveratrol does not mimic the beneficial effects of DR on stroke in vivo.

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Aim: We statistically investigated whether the impact of cardiovascular risk factors on arterial stiffness would be different from that on arterial wall thickness.
Methods: We analyzed 1648 Japanese type 2 diabetic patients. Arterial stiffness was evaluated by pulse wave verbosity (PWV) and wall thickness was assessed with carotid intima-media thickness (IMT) by ultrasonography. We developed a common regression model to PWV and IMT by extending the linear mixed model and statistically detected the difference in the impact of cardiovascular risk factors between the two indices.
Results: There was a significant correlation between PWV and IMT (r=0.365, p＜0.001). Sex, diabetic duration, hemoglobin A1c levels, and the presence of retinopathy and cardiovascular disease were comparable independent risk factors for elevated PWV and IMT. On the other hand, the impact of age, systolic blood pressure, and low- and high-density lipoprotein cholesterol levels were significantly different between the two measurements (all p＜0.05). Cholesterol levels were significantly associated with IMT but not with PWV. Age and systolic blood pressure had a significant impact on both measurements, but the impact on PWV was significantly greater than that on IMT. Indeed, patients with low IMT but with advanced age and high systolic pressure had high PWV, whereas patients with low PWV but with impaired cholesterol levels had high IMT.
Conclusion: The extended linear mixed model statistically confirmed that the impact of cardiovascular risk factors on elevated PWV and IMT were not identical in Japanese patients with type 2 diabetes mellitus.

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Aim: The circulating RNA levels are predictive markers in several diseases. We determined the levels of circulating p53-related genes in patients with acute ST-segment elevation myocardial infarction (STEMI), indicating major heart muscle damage.
Methods: Plasma RNA was extracted from the patients (n=45) upon their arrival to the hospital (STEMI 0h) and at four hours post-catheterization (STEMI 4h) as well as from controls (n=34).
Results: Of 18 circulating p53-related genes, nine genes were detectable. A significantly lower incidence of circulating p21 (p＜0.0001), Notch1 (p=0.042) and BTG2 (p＜0.0001) was observed in the STEMI 0h samples in comparison to the STEMI 4h and control samples. Lower expression levels (2.1-fold) of circulating BNIP3L (p=0.011), p21 (3.4-fold, p=0.005) and BTG2 (6.3-fold, p=0.0001) were observed in the STEMI 0h samples in comparison to the STEMI 4h samples, with a 7.4-fold lower BTG2 expression (p＜0.001) and 2.6-fold lower p21 expression (p=0.034) compared to the control samples. Moreover, the BNIP3L expression (borderline significance, p=0.0655) predicted the level of peak troponin, a marker of myocardial infarction. In addition, the BNIP3L levels on admission (p=0.0025), at post-catheterization (p=0.020) and the change between the groups (p=0.0079) were inversely associated with troponin. The BNIP3L (p=0.0139) and p21 levels (p=0.0447) were also associated with a longer time to catheterization.
Conclusions: Our results suggest that circulating downstream targets of p53 are inhibited during severe AMI and subsequently re-expressed after catheterization, uncovering possible novel death-or-survival decisions regarding the fate of p53 in the heart and the potential use of its target genes as prognostic biomarkers for oxygenation normalization.

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