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Background and aim Diallyl disulfide (DADS), a volatile sulfide extracted from garlic, has been suggested as a chemical of anti-atherosclerotic drugs, while its molecular mechanism for this benefit has not fully been understood. The aim of the present study was to investigate the effects of DADS on lipid metabolism and its potential mechanisms in HepG2 cells induced by lipopolysaccharides (LPS). Methods and results HepG2 cells were treated with LPS with or without different concentrations of DADS (0, 20, 40, 80, 160 μg/ml) for 24 h. The cell activity was detected by CCK8, and Dil-LDL uptake assay was used to examine the LDL uptake. Real-time PCR and Western blot were used to detect the expression of LDLR, PCSK9 SREBP2 and HMGCR. In addition, we examined the effect of the combination of DADS with atorvastatin on PCSK9 expression. The results showed that LPS significantly increased PCSK9 and SREBP2 expressions in a dose-dependent manner in HepG2 cells. DADS attenuated PCSK9, SREBP2 and HMGCR expressions and up-regulated the expression of LDLR. Moreover, DADS reversed the expressions of PCSK9, SREBP2, HMGCR and LDLR induced by LPS and DADS could promote the LDL uptake in HepG2 cells. Furthermore, DADS decreased the expression of PCSK9 by activating the PI3K/Akt-SREBP2 signal pathway. Notably, DADS could reduce PCSK9 expression induced by atorvastatin in HepG2 cells. Conclusion DADS could significantly attenuated PCSK9 expression in a dose-dependent manner induced by LPS and increased the LDLR expression in HepG2 cells, which was associated with the activation of PI3K/Akt-SREBP2 signaling pathway.

Aim Calcific aortic valve disease (CAVD) is the most common valvular disease worldwide. The osteoblastic transdifferentiation of aortic valve interstitial cells (VICs) is the essential process of CAVD, but the underlying mechanisms are poorly understood. Aortic VICs are generated from epithelial-to-mesenchymal transition (EMT) and migration of neural crest cells (NCCs).Meis2 has been associated with EMT and NCCs migration during development, but its role in CAVD is unknown. This study aims to elucidate the specific functions of Meis2 and its downstream targets in aortic valve calcification. Material and methods Levels of Meis2 were examined in calcified (n = 30) and normal (n = 30) human aortic valve tissues, respectively. Meis2 was inhibited in porcine aortic VICs in vitro, and the effect on osteoblastic transdifferentiation and its downstream pathway were studied. Results Meis2 gene and protein expression decreased significantly in calcified human aortic valve tissue compared with the normal ones. Inhibiting Meis2 by siRNAs reduced the gene and protein expression of Notch1 and Twist1, and induced the osteoblastic transdifferentiation of the porcine aortic VICs in vitro. Conclusions The present study indicated that Meis2 repress the osteoblastic transdifferentiation of aortic VICs through the Notch1/Twist1 signaling pathway. The Results identify Meis2 as a potential intervention target for the prevention of CAVD.

Lipoprotein (a) [Lp(a)] is a causal risk factor for cardiovascular diseases, while its role in vascular calcification has not been well-established. Here, we investigated an association of Lp(a) with vascular calcification using population-based and in vitro study designs.A total of 2806 patients who received coronary computed tomography were enrolled to assess the correlation of Lp(a) with the severity of coronary artery calcification (CAC). Human aortic smooth muscle cells (HASMCs) were used to explore mechanisms of Lp(a)-induced vascular calcification.In the population study, Lp(a) was independently correlated with the presence and severity of CAC (all p 0.05). In vitro study showed that cell calcific depositions and alkaline phosphatase (ALP) activity were increased and the expression of pro-calcific proteins, including bone morphogenetic protein-2 (BMP2) and osteopontin (OPN), were up-regulated by Lp(a) stimulation. Interestingly, Lp(a) activated Notch1 signaling, resulting in cell calcification, which was inhibited by the Notch1 signaling inhibitor, DAPT. Lp(a)-induced Notch1 activation up-regulated BMP2-Smad1/5/9 pathway. In contrast, Noggin, an inhibitor of BMP2-Smad1/5/9 pathway, significantly blocked Lp(a)-induced HASMC calcification. Notch1 activation also induced translocation of nuclear factor-κB (NF-κB) accompanied by OPN overexpression and elevated inflammatory cytokines production, while NF-κB silencing alleviated Lp(a)-induced vascular calcification.Elevated Lp(a) concentrations are independently associated with the presence and severity of CAC and the impact of Lp(a) on vascular calcification is involved in the activation of Notch1-NF-κB and Notch1-BMP2-Smad1/5/9 pathways, thus implicating Lp(a) as a potential novel therapeutic target for vascular calcification.

Background: Currently, no data is available regarding the predictive role of N-terminal pro-brain natriuretic peptide (NT-proBNP) in patients with prediabetes mellitus (pre-DM) and coronary artery disease (CAD). We aimed to evaluate the significance of NT-proBNP in predicting major adverse cardiovascular events (MACEs) in patients with stable CAD (SCAD) and normal left-ventricular systolic function (LVSF) according to different glucose status, especially in ones with pre-DM. Methods: In this prospective study, a total of 8062 patients with SCAD and normal LVSF were consecutively enrolled. They were categorized according to glucose status and further stratified by NT-proBNP tertiles. The follow-up data of all patients were collected. Findings: Over an average follow-up of 59·13±18·23 months, 569 patients suffered from MACEs, including cardiovascular death, non-fatal myocardial infarction, and stroke. Kaplan-Meier analysis showed that high NT-proBNP levels had a significant association with MACEs in subjects with pre-DM or DM (both p 0·05). Multivariate Cox regression analysis suggested that NT-proBNP remained an independent predictor for MACEs in patients with pre-DM [hazard ratio (HR): 2·68, 95% confidence interval (CI): 1·72-4·19] or DM (HR: 2·32, 95% CI: 1·55-3·51). Moreover, adding NT-proBNP to the original model increased the C-statistic by 0·024 and 0·036 in pre-DM and DM respectively (both p

Background and aims The relation of lipoprotein (a) [Lp(a)] and proprotein convertase substilisin/kexin type 9 (PCSK9) levels to coronary artery disease (CAD) has been well established in the general population, while little is known about the association between Lp(a) or PCSK9 and atherosclerotic lesions of different artery sites in patients with familial hypercholesterolemia (FH). Methods One hundred and fifty-one patients with verified genotyped heterozygous FH (HeFH) were enrolled. There were available data regarding coronary angiography and carotid ultrasonography in 151 patients and femoral ultrasonography in 55 patients. Coronary and carotid severity was evaluated by Gensini score and Crouse score. PCSK9 and Lp(a) concentrations were determined by ELISA and immunoturbidimetry, respectively. Finally, the correlation of PCSK9 and Lp(a) with the presence and severity of CAD and peripheral artery disease (PAD) was assessed. Results The distributions of PCSK9 and Lp(a) were skewed and a close correlation between them in HeFH patients was found. PCSK9 levels were significantly higher in patients with coronary and carotid atherosclerotic lesions compared to their non-atherosclerotic groups, while no difference was found in femoral atherosclerotic lesions groups. Lp(a) levels only differed between patients with or without coronary atherosclerotic lesions. Patients with highest PCSK9 and Lp(a) concentrations had the highest prevalence and severity of atherosclerotic lesions. Multivariate regression analysis showed that PCSK9 was independently associated with CAD and PAD, while Lp(a) was only associated with CAD. Conclusions Circulating PCSK9 concentrations were associated with an increased risk of CAD and PAD, while Lp(a) was only a marker for CAD in HeFH patients.

Background Big endothelin-1 (ET-1) has been proposed as a novel prognostic indicator of acute coronary syndrome, while its predicting role of cardiovascular outcomes in patients with stable coronary artery disease (CAD) is unclear. Methods and results A total of 3154 consecutive patients with stable CAD were enrolled and followed up for 24months. The outcomes included all-cause death, non-fatal myocardial infarction, stroke and unplanned revascularization (percutaneous coronary intervention and coronary artery bypass grafting). Baseline big ET-1 was measured using sandwich enzyme immunoassay method. Cox proportional hazard regression analysis and Kaplan–Meier analysis were used to evaluate the prognostic value of big ET-1 on cardiovascular outcomes. One hundred and eighty-nine (5.99%) events occurred during follow-up. Patients were divided into two groups: events group ( n =189) and non-events group ( n =2965). The results indicated that the events group had higher levels of big ET-1 compared to non-events group. Multivariable Cox proportional hazard regression analysis showed that big ET-1 was positively and statistically correlated with clinical outcomes (Hazard Ratio: 1.656, 95% confidence interval: 1.099–2.496, p =0.016). Additionally, the Kaplan–Meier analysis revealed that patients with higher big ET-1 presented lower event-free survival ( p =0.016). Conclusions The present study firstly suggests that big ET-1 is an independent risk marker of cardiovascular outcomes in patients with stable CAD. And more studies are needed to confirm our findings.

Background It has been demonstrated that diabetic dyslipidaemia is the chief bridge between diabetes and incremental risk of cardiovascular disease in patients with diabetes. However, the characteristics of lipoprotein subfractions distribution in patients with type 2 diabetes (T2D) have not been fully investigated. The aim of present study was to evaluate the distributions of lipoprotein subfractions in T2D patients. Methods A total of 920 patients, who have not received lipid-lowering drug treatment previously, were consecutively enrolled in this study. Based on the evidence of diabetes, patients were divided into T2D group (n=204) and non-T2D group (n=716). Both low- and high-density lipoprotein cholesterol (LDL- and HDL-C) subfractions were analysed using the Quantimetrix Lipoprint System. The distributions of lipoprotein subfractions were evaluated in patients with and without T2D. Results Compared with non-T2D individuals, the T2D group manifested significantly lower large HDL-C concentration/HDL subfraction percentage, smaller mean LDL particle size but higher small HDL-C and LDL-C concentrations as well as small HDL and LDL subfraction percentages. Moreover, the data indicated that the small HDL-C/ LDL-C concentrations, the small and large HDL subfraction percentages along with the mean LDL particle size were independently related to the existence of T2D (95% CI=1.009–1.067, p=0.009; 95% CI=0.938-0.983, p=0.001; 95% CI=1.023–1.135, p=0.005; 95% CI= 1.005–1.048, p=0.014; 95% CI=0.940-0.999, p=0.040; respectively) assessed by logistic regression analysis. Conclusions The present study indicated that the changes of lipid profile in patients with T2D are characterised by abnormal distributions of lipoprotein subfractions apart from clinically atherogenic dyslipidaemia.

It has been proposed that plasma fibrinogen is associated with lipid levels and increased cardiovascular risk. However, the interrelationship has not been well-elucidated. We hypothesise that lipids may be potential mediators.We enrolled 4748 consecutive subjects scheduled for coronary angiography in this study. The severity of coronary atherosclerosis was assessed by Gensini score (GS). By principle component analysis, a multi-marker lipid index was extracted weighting the coefficients of six atherogenic lipid parameters: total cholesterol (TC), low-density lipoprotein-cholesterol, non-high-density lipoprotein-cholesterol (non-HDL-C), apolipoprotein (apo) B, apoB/apoA1, and TC/HDL-C ratio. Moreover, using mediation analysis, the relationship between fibrinogen and lipids with high GS was evaluated.Fibrinogen was positively associated with GS after adjustment (β=0.100, p0.001). We stratified our analyses by statin use status and found that subjects in the upper fibrinogen tertiles had higher levels of atherogenic lipid parameters irrespective of statin status (p0.001, all). Significantly, we observed a synergistic effect of fibrinogen and concurrent elevated lipid index for high GS. The adjusted odds ratios were greater in participants who had high fibrinogen levels and also high lipid index compared to those with low lipid index [on statin: 1.725(1.258-2.364) vs. 1.261(0.962-1.652); not on statin: 2.197(1.450-3.328) vs. 1.166(0.417-3.258)]. Specifically, mediation analysis indicated that around 24% of the effect of fibrinogen on high GS was mediated by lipid index, which was attenuated to 13% by statin status.The increased risk of fibrinogen on coronary atherosclerosis appeared to be enhanced by the high atherogenic lipid levels, which mediated around 24% of this effect.

Coronary collateral circulation (CCC) plays an important role in protecting myocardium from ischemic damage. The studies on factors which impact on CCC might be of great clinical interest. The aim of the present study was to evaluate endothelin-1 (ET-1) as a potential predictor for poor or good CCC in patients with angiography-proven ≥95% coronary occlusion.We screened 1038 consecutive patients with ≥95% occlusion in at least one major epicardial coronary artery detected by coronary angiography. Of these, 663 patients were classified into the poor CCC group with Rentrop 0-2 grade collateral circulation and 375 patients into the good CCC group with Rentrop 3 grade. The association of plasma ET-1 levels with collateral status was assessed.We found that patients in the poor CCC group had a higher ET-1 level than those in the good CCC group (0.59±0.48 vs. 0.39±0.32pmol/L, p0.001), and the ET-1 values increased with the descent of the Rentrop grades (p for trend0.001). Moreover, multivariate logistic regression analysis revealed an independent association between ET-1 and collateral status (odds ratio [95% CI] for poor CCC 2.27 [1.60-3.22], p0.001). Additionally, the association presented significance in both men (odds ratio [95% CI] for poor CCC 3.18 [2.20-4.74], p0.001) and women (odds ratio [95% CI] for poor CCC 3.10 [1.36-7.85], p=0.011) when the sex-specific analysis was performed.Plasma ET-1 level may be a useful, easily available marker for predicting the degree of CCC in patients with ≥95% coronary chronic occlusion.

Conflicting results have been yielded as to whether low-density lipoprotein (LDL) cholesterol (LDL-C) or non-high-density lipoprotein (HDL) cholesterol (non-HDL-C) is a better marker of coronary artery disease (CAD) risk. Recently, plasma LDL and HDL subfractions have been suggested to be more accurately reflecting the lipoproteins' atherogenicity.We sought to compare the relationship between LDL-C or non-HDL-C and lipoprotein subfractions.We conducted a cross-sectional study in 351 consecutive stable CAD patients without lipid-lowering therapy. The LDL and HDL separations were performed using the Lipoprint System. The LDL-C levels were measured directly, and the non-HDL-C levels were calculated.The cholesterol concentrations of LDL (large, medium, and small) and HDL (small) particles were increased (all P .001) by non-HDL-C or LDL-C quartiles, whereas the mean LDL particle size and cholesterol concentrations of HDL (large) were decreased (both P .001) by non-HDL-C quartiles. In age- and gender-adjusted analysis, the cholesterol in small LDL was much strongly related to non-HDL-C than to LDL-C (r = 0.539 vs 0.397, both P .001). Meanwhile, the mean LDL particle size was more closely associated with non-HDL-C than LDL-C (r = -0.336 vs r = -0.136, both P .05). Significantly, the cholesterol in large HDL was negatively correlated with non-HDL-C (r = -0223, P .001) but not with LDL-C. These correlations were further confirmed by the fully adjusted multivariable linear regression analysis.Non-HDL-C, in comparison to LDL-C, was more relevant to atherogenic lipoprotein subfractions in patients with stable CAD, supporting that it may be better in assessing cardiovascular risk.

Myocardial injury after percutaneous coronary intervention (PCI) has previously been reported to be associated with a worse outcome and Heart-type fatty acid binding protein (H-FABP) has recently been considered as a new predictor for myocardial injury in patients with coronary artery disease (CAD

Triglyceride-rich lipoproteins (TRL)-related markers, containing cholesterol subset [TRL-cholesterol (TRL-C) and remnant-like lipoprotein particles cholesterol (RLP-C)] and apolipopoprotein C-III (apoC-III), were reported to be involved in atherosclerosis. This multicenter prospective cohort study

Elevated plasma lipoprotein(a) [Lp(a)] and fibrinogen (Fib) levels are both associated with cardiovascular disease (CVD) and the atherogenicity of Lp(a) can be partly due to the potentially antifibrinolytic categories. We hypothesize that patients with higher Lp(a) and Fib may have worse outcomes.

Although several studies have indicated that lipoprotein(a) (Lp(a)) is a useful prognostic predictor for patients who underwent percutaneous coronary intervention (PCI), the previous observations have somewhat been limited by either small sample size or short-term follow-up. This study, hence, aimed

It has been well established that low density lipoprotein triglyceride (LDL-TG) is associated with hyperglycaemia. No current data, however, is available regarding the impact of LDL-TG on major adverse cardiovascular events (MACEs) in patients with stable CAD under different glucose metabolism

Proprotein convertase subtilisin/kexin type 9 (PCSK9), a newly-identified member that plays an essential role in cholesterol homeostasis and holds decent promise for hyperlipidemia and coronary artery disease (CAD) treatment. However, the determining factors of PCSK9 are not well-characterized. It is well established that ABO blood group is associated with cholesterol metabolism. Therefore, the relationship between ABO blood groups and plasma PCSK9 level was examined.A group of 507 consecutive patients undergoing diagnostic or interventional coronary angiography were enrolled in this cross-sectional study. The baseline clinical characteristics were collected, and the plasma PCSK9 levels were determined using ELISA. As a result, subjects of non-O type had higher levels of total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), non high density lipoprotein cholesterol (NHDL-C), apolipoprotein B (apo B), and PCSK9 compared with that of O type (p0.05, all). PCSK9 levels were significantly and positively related to TC, LDL, NHDL-C, and apo B (r = 0.253, p0.001; r = 0.262, p0.001; r = 0.215, p0.001; r = 0.187, p0.001; respectively). Multivariable regression analysis revealed that ABO group was significantly and independently associated with PCSK9 level (β = 7.91, p = 0.009). Additionally, mediation analysis indicated that ≈8%-19% of the effect of ABO blood group on PCSK9 levels was mediated by TC, LDL-C or NHDL-C levels.These data firstly suggested that the ABO blood group might be a significant determinant factor for plasma PCSK9 level. It is also possible that the observed association between PCSK9 and ABO blood group might be in part involved in their CAD susceptibility.

Background Both proprotein convertase subtilisin/kexin type 9 (PCSK9) and fibrinogen have been established as novel markers for atherosclerotic diseases. However, no data are available regarding the relationship between circulating PCSK9 and fibrinogen concentration up to now. Objective To explore the potential link of the circulating PCSK9 concentration to fibrinogen in patients with stable coronary artery disease (CAD). Methods We studied 219 eligible consecutive patients with angiographically proven stable CAD. Baseline clinical and laboratory data were collected. Plasma PCSK9 concentration was measured by enzyme-linked immunosorbent assay. High-sensitivity C-reactive protein (hs-CRP), erythrocyte sedimentation rate, D-dimer, and albumin were also measured in all subjects as inflammatory markers. The relation of the circulating PCSK9 concentration to fibrinogen was evaluated. Results The data indicated that the patients with high PCSK9 concentration tended to have higher fibrinogen levels according to PCSK9 tertiles ( P = .037). Spearman correlation analysis revealed a positive relation between plasma PCSK9 concentration and fibrinogen (r = 0.211, P = .002). Additionally, the circulating PCSK9 concentration also correlated positively with total cholesterol, low-density lipoprotein cholesterol, and hs-CRP levels (r = 0.333, P P P = .023, respectively). In the stepwise multivariate regression analysis, the association between PCSK9 and fibrinogen remained significant (β = 0.168, P = .011) after adjustment for conventional cardiovascular risk factors including lipid profiles, hs-CRP, and D-dimer. Conclusion The present study first demonstrated that the circulating PCSK9 concentration was positively associated with fibrinogen in patients with stable CAD, suggesting that the interactions of PCSK9 and fibrinogen in the status of atherosclerosis may need further investigation.

Oxidized-low-density lipoprotein (ox-LDL), as well as high-density lipoprotein (HDL) and its subfractions play important role in the development of coronary artery disease (CAD).A total of 1417 individuals who received selective coronary angiography (CAG) without lipids-lowering treatments were consecutively enrolled. Patients were divided into CAD (n = 942) and non-CAD group (n = 475). The severity of CAD was assessed by Gensini Scores (GS) system. The correlations of ox-LDL with HDL subfractions were analyzed.Compared with non-CAD subjects, CAD patients had higher ox-LDL but lower concentrations of HDL cholesterol (p = 0.002) and large HDL subfractions (p = 0.004). And ox-LDL was negatively correlated with large HDL subfractions in patients with severe CAD (p 0.05). Moreover, ox-LDL was elevated and large HDL subfractions decreased with the increase of the number of stenotic coronary arteries and GS (p 0.05, respectivelly).The correlations between ox-LDL and cholesterol level of large HDL particles varied among CAD and non-CAD, and CAD with different severities of atherosclerosis.

Background The purpose of this study was to gain a better understanding of molecular changes associated with the beneficial reverse remodeling through heterotopic transplantation model of rat hypertrophic hearts. Methods Stable cardiac hypertrophy was induced by abdominal aortic constriction (AAC) in Lewis rats (6 weeks). Left ventricular (LV) pressure unloading was induced by heterotopic transplantation of hypertrophic hearts (AAC–HT) (2 weeks). We measured heart weight (HW), LV weight (LVW) and the LV-to-final body weight ratio (LVW/BW). Cross-sectional areas of cardiomyocyte and collagen content were assessed by hematoxylin/eosin staining and picrosirius red staining, respectively. We further analyzed the signaling pathways of mitogen-activated protein kinases (MAPKs), Akt/GSK3β, NF-κB, metalloproteinase-2,9 (MMP-2, 9) and tissue inhibitors of metalloproteinase-1 (TIMP-1) by Western blot. Results The HW, LVW and LVW/BW in AAC hearts were higher than normal hearts, but the transplanted hearts showed a significant reduction in HW, LVW and LVW/BW compared to AAC hearts. Unloading induced a decrease in cardiomyocyte size and an increase in collagen content in AAC–HT hearts. A significant decrease in phosphorylation of p44/p42 MAP kinases (ERK), Akt, GSK3β and NF-κB was detected in AAC–HT hearts, but the phosphorylation of p38 MAP kinase and Jun-N-terminal kinase (JNK) was not changed. MMP-2, MMP-9 and TIMP-1 activity also increased accompanied by unloading. Conclusions Pressure unloading of the hypertrophic heart caused a reverse remodeling through regulating the ERK, Akt/GSK3β, and NFκB signal pathways, revealing these as potential target pathways for reversal of LV hypertrophy.