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Atherosclerosis is a chronic inflammatory disease characterized by thickening of the arterial wall. However, a limited number of studies have been conducted on metabolic profiling of human aortic tissue.We applied liquid chromatography/mass spectrometry to perform global and targeted profiling of plaque-containing aortic tissue. The aorta samples included plaque-containing (n = 18) and control plaque-free (n = 24) aortic tissue from patients undergoing aortic surgery.The metabolic patterns of atherosclerotic and control vessels were significantly different. Metabolites in the purine and glutathione pathways showed dysregulation of oxidative stress in plaques, and levels of glucosylceramide, tryptophan, and kynurenine, which are related to inflammation, were also altered. Interestingly, an increased level of quinic acid was observed in plaques (p 0.000), and we demonstrated an inhibitory effect of quinic acid on inflammatory activation and oxidative stress in macrophages.Our study provides insight into the disease mechanism and potential markers of atherosclerosis through comprehensive metabolic profiling of human aortic tissue samples containing plaque.

Background and aims Limited data is available on the benefit of statin for primary prevention in the elderly. The aim of this study is to investigate whether statin for primary prevention is effective in lowering the cardiovascular risk and all-cause death in individuals aged >75 years. Methods This was a retrospective, propensity score-matched study and data were acquired between 2005 and 2016 in a tertiary university hospital. Of the 6414 patients screened, 1559 statin-naive patients without a history of atherosclerotic cardiovascular disease before the index visit were included. After propensity score matching, 1278 patients (639 statin users, 639 statin non-users) were finally analyzed. Primary outcome variables included major adverse cardiovascular and cerebrovascular events (MACCE) and all-cause death. MACCE included cardiovascular death, nonfatal myocardial infarction, coronary revascularization, and nonfatal stroke or transient ischemic attack. Results At a median follow-up of 5.2 years, statin users had lower rates of MACCE (2.15 vs. 1.25 events/100 person-years; hazard ratio, 0.59; p = 0.005) and all-cause death (1.19 vs. 0.65 events/100 person-years; hazard ratio, 0.56; p = 0.02), as well as lower levels of low-density lipoprotein-cholesterol than did non-users. The Kaplan-Meier curves revealed lower event rates in statin users (hazard ratio: 0.59 for MACCE and 0.56 for all-cause death). The incidence of myocardial infarction and coronary revascularization were lower in statin users. Conclusions Statin therapy for primary prevention was clearly associated with lower risk of cardiovascular events and all-cause death in individuals aged >75 years. These results support more active statin use in this population.

Background and aims Although the importance of the functional properties of high-density lipoprotein (HDL) has been increasingly emphasized, studies on the genetic factors associated with HDL function are highly limited. The aim of this study was to identify genetic variants associated with an individual's cholesterol efflux capacity (CEC) using a genome-wide association study approach. Methods This study included a discovery group of 607 subjects with coronary artery disease and an independent replication group of 158 subjects. CEC was assessed using a radioisotope and ApoB-depleted serum. Genome-wide associations between the adjusted CEC and genotyped and imputed variants were examined with linear regression, assuming an additive genetic model. Finally, adjustments were made for confounding parameters to assess the independence of associations and to determine R2 of overall model on CEC. Results In the discovery group, 631 variants showed significant association with CEC, and five of them were found to correlate with CEC in the replication group. One of them was located near LOC541471 in 2q13, whereas the other four (rs117835232, rs117252933, rs118064592, and rs150434350) were located in CDKAL1 in 6p22.3. The association between the presence of any CDKAL1 variant and CEC was significant after adjustment for clinical and laboratory variables. High-density lipoprotein-cholesterol levels also showed a very significant association with CEC. Body mass index, current alcohol use, triglycerides levels, low-density lipoprotein-cholesterol levels and statin use showed borderline associations with CEC. Conclusions We identified and replicated genetic variants associated with CEC using a genome-wide association study-based approach. CDKAL1 variants showed correlations with CEC independent of HDL-cholesterol levels and other clinical characteristics.

In end-stage renal disease, deleterious effect of sarcopenia on cardiovascular disease has been explained mainly by chronic inflammation. However, evidence emerged that skeletal muscles mediate their protective effect against sarcopenia by secreting myokines. Therefore, we sought to investigate the effect of irisin, a recently introduced myokine, on the association between sarcopenia and cardiovascular disease in peritoneal dialysis (PD) patients.Serum irisin concentrations were assessed by enzyme-linked immunosorbent assay in 102 prevalent PD patients and 35 age- and sex-matched controls. To determine sarcopenia and cardiovascular disease, anthropometric indices including mid-arm muscle circumference (MAMC) and carotid intima-media thickness (cIMT) were measured.Serum irisin concentrations were significantly lower in PD patients than in controls (184.2 ± 88.0 vs. 457.2 ± 105.5 ng/mL, P0.001). In PD patients, univariate linear regression analysis showed that serum irisin was positively correlated with MAMC and thigh circumference, but negatively correlated with residual renal function and cIMT. Multivariate analysis revealed that MAMC (per 1 cm increase, B = 8.78, 95% confidence interval [CI] = 0.77-16.79, P = 0.03) had an independent association with serum irisin. In addition, serum irisin was a significant independent predictor for carotid atherosclerosis even after adjustment for high-sensitivity C-reactive protein in PD patients (per 1 g/mL increase, odds ratio = 0.990, 95% CI = 0.982-0.997, P = 0.007).This study demonstrated that serum irisin was significantly associated with sarcopenia and carotid atherosclerosis in PD patients. Additional studies to provide a confirmation and examine possible mechanisms are warranted.

Background Effects of peroxisome proliferator-activated receptor alpha (PPARα) agonists on cardiovascular outcome have been controversial. Although these agents primarily affect lipoprotein metabolism, their pleiotropic anti-inflammatory effect is one of the potential anti-atherosclerotic mechanisms. This study aimed to evaluate the effect of fenofibrate and gemfibrozil on inflammation in macrophages and reveal pathways these agents may affect. Methods and results The two PPARα agonists inhibited secretion of CXCL2, TNF-α, IL-6, activation of p65 of NF-κB, ERK, and TLR4 expression. These changes occurred simultaneously with upregulation and secretion of β-defensin 1, an inflammation-modulating peptide. To demonstrate the role of β-defensin 1, it was knocked-down by target-specific siRNA. The effects of PPARα agonists on TLR4 expression and chemokine secretion were obviously abrogated with this treatment. In experiments investigating whether β-defensin 1 acts extracellularly, inflammatory chemokines decreased significantly after the addition of recombinant β-defensin 1 or conditioned media to cells. In experiments designed to clarify if the effects of the two agents are PPARα-dependent, induction of mRNA and secretion β-defensin 1 and inhibition of chemokine release were clearly reduced with GW6471, a PPARα blocker. Conclusions Our results reveal the pathways by which fenofibrate and gemfibrozil inhibit LPS-induced inflammatory activation of macrophages. This study elucidated a novel anti-inflammatory mechanism that acts through PPARα, β-defensin 1, and TLR4 pathways.

Objective We investigated the association of polymorphisms in FADS genes with polyunsaturated fatty acids (PUFAs) in serum phospholipids, lipid peroxides, and coronary artery disease (CAD) in Koreans. Methods In this case–control study, CAD patients ( n =756, 40–79 years) and healthy controls ( n =890) were genotyped for rs174537 near FADS1 ( FEN1 rs174537G>T), FADS2 (rs174575, rs2727270), and FADS3 (rs1000778). We calculated the odds ratios (ORs) for CAD risk and measured serum PUFA composition and lipid peroxide. Results Among four SNPs, only rs174537G>T differed in allele frequencies between controls and CAD patients after adjustment for age, BMI, cigarette smoking, alcohol consumption, hypertension, diabetes mellitus, and hyperlipidemia ( P =0.017). The minor T allele was associated with a lower risk of CAD [OR 0.75 (95%CI 0.61–0.92), P =0.006] after adjustment. rs174537T carriers had a significantly higher proportion of linoleic acid (LA, 18:2ω6), lower arachidonic acid (AA, 20:4ω6), and lower ratios of AA/dihomo-γ-linolenic acid (DGLA, 20:3ω6) and AA/LA than G/G subjects in both control and CAD groups. In the control group, 174537T carriers had significantly lower levels of total- and LDL-cholesterol, malondialdehyde, and ox-LDL. In CAD patients, rs174537T carriers showed a larger LDL particle size than G/G subjects. The proportion of AA in serum phospholipids positively correlated with LDL-cholesterol, ox-LDL, and malondialdehyde in controls and with 8-epi-prostaglandin F 2α in both control and CAD groups. Conclusion The rs174537T is associated with a lower proportion of AA in serum phospholipids and reduced CAD risk, in association with reduced total- and LDL-cholesterol and lipid peroxides.

Visceral adipose tissue has emerged as a key organ contributing to the development of coronary artery disease (CAD). However, defining central obesity by waist circumference (WC) may underestimate visceral adiposity in lean patients. The aim of this study was to investigate the relationship between visceral adiposity and severity of CAD in subjects with normal WC.Among 365 patients with documented CAD, 90 male subjects with normal WC (90 cm) were selected and their visceral fat areas (VFA) were examined using computed tomography. Lipid profiles and levels of adipokines including lipocalin-2, high molecular weight adiponectin, and monocyte chemoattractant protein (MCP)-1 were measured. Patients were divided into tertiles based on VFA at the L4 vertebra level.Patients with single-vessel disease had significantly lower VFA than those with multi-vessel disease (P0.05; 86.0 vs. 97.5 vs. 99.6 cm(2) for single- , double- , and triple-vessel diseases, respectively). Positive association between the extent of CAD and VFA was clearly demonstrated and logistic regression analysis showed that subjects in the upper tertile for VFA had a 4.5-fold higher risk of having multi-vessel disease compared with those in the lowest tertile (P0.05; odds ratio=4.51; 95% confidence interval=1.10-18.45). Circulating levels of lipocalin-2 and MCP-1 were significantly higher in the upper tertiles of VFA.Increased visceral adiposity is significantly associated with the severity of CAD, even in subjects without central obesity as determined by WC measurements. Abnormalities in adipokine regulation may provide a novel mechanistic connection between visceral adiposity and associated cardiovascular complications.

Emerging evidence suggests a role of lycopene in the primary prevention of cardiovascular disease. This study aimed to investigate the association of serum lycopene concentration with brachial-ankle pulse wave velocity (baPWV), a marker of arterial stiffness and markers of oxidative stress and inflammation.healthy women (n=264, 31-75 yrs) were classified into tertiles according to serum lycopene concentration. Multivariate linear regression analyses were used to assess the relationship between serum lycopene and baPWV.Subjects in middle tertile (T2) and upper tertile (T3) had lower baPWV (1263+/-23 and 1265+/-14 cm/s vs. 1338+/-21 cm/s; p=0.009) and lower oxidized LDL (oxLDL) (53+/-3 and 55+/-3 U/L vs. 66+/-3 U/L; p0.001) than those in lower tertile (T1). Subjects in T3 showed higher LDL particle size (24.3+/-0.08 nm vs. 24.0+/-0.07 nm, p=0.005) and lower C-reactive protein (hs-CRP) (0.80+/-0.25mg/dL vs. 1.27+/-0.24 mg/dL, p=0.015), compared with those in T1. Logistic regression analysis showed that baPWV decreased with the increment of lycopene concentration; log baPWV decreased by 0.21 cm/s (95% CI -0.168;-0.045, p=0.001) per unit change in lycopene. After adjustment for age, BMI, smoking, drinking, menopause and blood pressure, the estimated effect was attenuated by 35%, but remained statistically significant [-0.13 cm/s (95% CI -0.112;-0.018, p=0.006)]. Further adjustment for beta-carotene, alpha-tocopherol, oxLDL, LDL particle size, and hs-CRP increased the strength of the association [beta=-0.221 (95% CI -0.215;-0.012, p=0.029)].This study supports the presence of an independent inverse relationship between circulating lycopene and baPWV. Additionally, reduced oxidative modification of LDL may be one of mediators on the mechanisms how lycopene reduces arterial stiffness.

Background Proper screening and diagnosis of familial hypercholesterolemia (FH) is of critical importance for cardiovascular prevention. However, the clinical diagnosis of FH remains difficult partly because its phenotype can vary between different ethnicities. The aim of this study was to determine the clinical features and the best diagnostic approach in Korean FH patients. The predictors of putative pathogenic mutations and coronary artery disease (CAD) were also identified. Methods and Results Ninety-seven patients with low-density lipoprotein-cholesterol >190 mg/dL and xanthoma or FH-compatible family history were included. Putative pathogenic mutations in LDLR , APOB , or PCSK9 genes were identified in 32% of the enrolled patients. The subjects were classified according to four sets of clinical criteria (Simon Broome, Dutch, MEDPED, Japanese). The mutation rates in definite type FH of Simon Broome or Dutch criteria were 35%–37% and lower in our patients than in those of other countries. The mutation detection rate by MEDPED criteria was 67%–75% and higher than those based on other criteria. The best low-density lipoprotein-cholesterol (LDL-C) threshold for predicting mutations was 225 mg/dL. LDL-C was found to be the only independent predictor of mutation carriers, while hypertension and low high-density lipoprotein-cholesterol were predictive of CAD. Conclusions The conventional clinical criteria showed limited mutation detection power and low specificities in Korean FH patients, in whom the best LDL-C threshold for putative mutation was 225 mg/dL. Traditional cardiovascular risk factors were also significantly associated with CAD risk in this population.

Background/Objective Familial hypercholesterolemia (FH) is an autosomal dominant disorder caused by mutations in LDLR, APOB, or PCSK9 . Polygenicity is a plausible cause in mutation-negative FH patients based on LDL cholesterol (LDL-C)-associated single nucleotide polymorphisms (SNPs) identified by the Global Lipids Genetics Consortium (GLGC). However, there are limited data regarding the polygenic cause of FH in Asians. Methods We gathered data from 66 mutation-negative and 31 mutation-positive Korean FH patients, as well as from 2274 controls who participated in the Korean Health Examinee (HEXA) shared control study. We genotyped the patients for six GLGC SNPs and four East Asian LDL-C-associated SNPs and compared SNP scores among patient groups and controls. Results Weighted mean 6- and 4-SNP scores (0.67 [SD = 0.07] and 0.46 [0.11], respectively) were both significantly associated with LDL-C levels in controls ( p = 2.1 × 10 −4 , R 2 = 0.01 and p = 5.0 × 10 −12 , R 2 = 0.02, respectively). Mutation-negative FH patients had higher 6-SNP (0.72 [0.07]) and 4-SNP (0.49 [0.08]) scores than controls ( p = 1.8 × 10 −8 and p = 3.6 × 10 −3 , respectively). We also observed higher scores in mutation-positive FH patients compared with controls, but the difference did not reach statistical significance. Conclusion The present study demonstrates the utility of SNP score analysis for identifying polygenic FH in Korean patients by showing that small-effect common SNPs may cumulatively elevate LDL-C levels.

Objective The aim of this study is to compare the non-lipid effects of rosuvastatin–fenofibrate combination therapy with rosuvastatin monotherapy in high-risk Asian patients with mixed hyperlipidemia. Methods A total of 236 patients were initially screened. After six weeks of diet and life style changes, 180 of these patients were randomly assigned to receive one of two regimens: rosuvastatin 10mg plus fenofibrate 160mg or rosuvastatin 10mg. The primary outcome variables were the incidences of muscle or liver enzyme elevation. The patients were followed for 24 weeks during drug treatment and for an additional four weeks after drug discontinuation. Results The rates of the primary outcome variables were similar between the two groups (2.8% and 3.9% in the combination and the rosuvastatin groups, respectively, p =1.00). The combination group had more, but not significantly, common treatment-related adverse events (AEs) (13.3% and 5.6%, respectively) and drug discontinuation due to AEs (10.0% and 3.3%, respectively) than the rosouvastatin group. Combination therapy was associated with higher elevations in homocysteine, blood urea nitrogen, and serum creatinine, whereas elevation in alanine aminotransferase was greater in the rosuvastatin group. Leukocyte count and hemoglobin level decreased to a greater extent in the combination group. The combination group showed greater reductions in TG and elevation in HDL-cholesterol. Conclusion In our study population, the rosuvastatin–fenofibrate combination resulted in comparable incidences of myo- or hepatotoxicity as rosuvastatin monotherapy. However, this combination may need to be used with caution in individuals with underlying pathologies such as renal dysfunction (NCT01414803).