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Background The risk of liver fibrosis in non-alcoholic fatty liver disease (NAFLD) can be easily evaluated by noninvasive scoring systems, of which the NAFLD fibrosis score (NFS) is the most commonly used. Proprotein convertase subtilisin/kexin type 9 (PCSK9), a new predictor of cardiovascular events, has been reported to be associated with cardiovascular outcomes and NAFLD. However, the relationship of NFS with PCSK9 and their prognostic abilities in cardiovascular risks are unknown. Methods A total of 2008 hospitalized subjects who had chest pain without lipid-lowering therapy were consecutively included. Baseline clinical data were collected, and the NFS was calculated. The circulating PCSK9 concentration was determined by enzyme immunoassay. The major adverse cardiovascular event (MACE) occurrences were recorded in the follow-up period. Associations of PCSK9 concentration with NFS were examined. All of the participants were categorized into three groups according to NFS levels and were further stratified by PCSK9 tertiles to evaluate the MACEs. Results 158 (7.87%) MACEs were observed during a mean of 3.2 years of follow-up. NFS levels were independently related to higher PCSK9 levels according to multivariable linear regression analysis. Furthermore, elevated PCSK9 and NFS concentrations were respectively associated with increased MACE incidence in multivariable Cox regression models. When combining NFS status with PCSK9 tertiles as a stratifying factor, patients with intermediate-high NFS and high PCSK9 levels had higher risks of events than those with low NFS and low PCSK9 levels. Conclusions This study revealed for the first time that NFS is positively related to PCSK9 and that the combination of NFS and PCSK9 greatly increased the risk of MACEs in patients with chest pain, providing a potential link between NFS and PCSK9 for predicting cardiovascular events.

Background Recent guidelines highlighted the association between atherosclerosis and triglyceride-enriched lipoproteins in patients with impaired glucose metabolism. However, evidence from prospective studies for long-term prognostic utility of low-density lipoprotein triglyceride (LDL-TG) in real-world patients with prediabetes (Pre-DM) or diabetes mellitus (DM) and coronary artery disease (CAD) is currently not available. The aim of the present study was to evaluate the impact of LDL-TG on major adverse cardiovascular events (MACEs) in patients with stable CAD under different glucose metabolism status. Methods A total of 4381 patients with CAD were consecutively enrolled and plasma LDL-TG level was measured by an automated homogeneous assay. They were categorized according to both status of glucose metabolism [DM, Pre-DM, normal glycaemia regulation (NGR)] and tertiles of LDL-TG. All subjects were followed up for the occurrence of MACEs. Results During a median of 5.1 (interquartile range 3.9 to 5.9) years’ follow-up, 507 (11.6%) MACEs occurred. Cubic spline models showed a significant association between LDL-TG and MACEs in DM and Pre-DM but not in NGR. When the combined effect of elevated LDL-TG and glucose disorders was considered for risk stratification, the medium tertile of LDL-TG plus DM, and the highest tertile of LDL-TG plus Pre-DM or plus DM subgroups were associated with significantly higher risk of MACEs after adjustment of confounders including triglyceride [hazard ratios (95% confidence intervals): 1.843 (1.149–2.955), 1.828 (1.165–2.867), 2.212 (1.396–3.507), all p Conclusions In this longitudinal cohort study on real-world practice, higher LDL-TG was associated with worse outcomes among Pre-DM and DM patients with stable CAD.

TG-rich lipoprotein (TRL)-related biomarkers, including TRL-cholesterol (TRL-C), remnant-like lipoprotein particle-cholesterol (RLP-C), and apoC-III have been associated with atherosclerosis. However, their prognostic values have not been fully determined, especially in patients with previous CAD. This study aimed to examine the associations of TRL-C, RLP-C, and apoC-III with incident cardiovascular events (CVEs) in the setting of secondary prevention of CAD. Plasma TRL-C, RLP-C, and total apoC-III were directly measured. A total of 4,355 participants with angiographically confirmed CAD were followed up for the occurrence of CVEs. During a median follow-up period of 5.1 years (interquartile range: 3.9–6.4 years), 543 (12.5%) events occurred. Patients with incident CVEs had significantly higher levels of TRL-C, RLP-C, and apoC-III than those without events. Multivariable Cox analysis indicated that a log unit increase in TRL-C, RLP-C, and apoC-III increased the risk of CVEs by 49% (95% CI: 1.16–1.93), 21% (95% CI: 1.09–1.35), and 40% (95% CI: 1.11–1.77), respectively. High TRL-C, RLP-C, and apoC-III were also independent predictors of CVEs in individuals with LDL-C levels ≤1.8 mmol/l (n = 1,068). The addition of RLP-C level to a prediction model resulted in a significant increase in discrimination, and all three TRL biomarkers improved risk reclassification. Thus, TRL-C, RLP-C, and apoC-III levels were independently associated with incident CVEs in Chinese CAD patients undergoing statin therapy.

ObjectiveWhether lipoprotein(a) (Lp(a)) is a predictor for recurrent cardiovascular events (RCVEs) in patients with coronary artery disease (CAD) has not been established. This study, hence, aimed to examine the potential impact of Lp(a) on RCVEs in a real-world, large cohort of patients with the first cardiovascular event (CVE).MethodsIn this multicentre, prospective study, 7562 patients with angiography-diagnosed CAD who had experienced a first CVE were consecutively enrolled. Lp(a) concentrations of all subjects were measured at admission and the participants were categorised according to Lp(a) tertiles. All patients were followed-up for the occurrence of RCVEs including cardiovascular death, non-fatal myocardial infarction and stroke.ResultsDuring a mean follow-up of 61.45±19.57 months, 680 (9.0%) RCVEs occurred. The results showed that events group had significantly higher Lp(a) levels than non-events group (20.58 vs 14.95 mg/dL, pConclusionsCirculating Lp(a) concentration was indeed a useful predictor for the risk of RCVEs in real-world treated patients with CAD, providing additional information concerning the future clinical application of Lp(a).

BackgroundThe aim of the present study is to examine the effects of free fatty acids (FFAs) on major cardiovascular events (MACEs) in patients with stable coronary artery disease (CAD) and different glucose metabolism status.MethodsIn this study, we consecutively enrolled 5443 patients from March 2011 to May 2015. Patients were categorized according to both status of glucose metabolism status [diabetes mellitus (DM), pre-diabetes (Pre-DM), normal glycaemia regulation (NGR)] and FFAs levels. All subjects were followed up for the occurrence of the MACEs.ResultsDuring a median of 6.7 years’ follow-up, 608 MACEs occurred. A twofold higher FFAs level was independently associated with MACEs after adjusting for confounding factors [Hazard Ratio (HR): 1.242, 95% confidence interval (CI) 1.084–1.424,pvalue = 0.002]. Adding FFAs to the Cox model increased the C-statistic by 0.015 (0.005–0.027). No significant difference in MACEs was observed between NGR and Pre-DM groups (p > 0.05). When patients were categorized by both status of glucose metabolism and FFAs levels, medium and high FFAs were associated with significantly higher risk of MACEs in Pre-DM [1.736 (1.018–2.959) and 1.779 (1.012–3.126), all p-value ConclusionsThe present data indicated that baseline FFAs levels were associated with the prognosis in DM and Pre-DM patients with CAD, suggesting that FFAs may be a valuable predictor in patients with impaired glucose metabolism.

Background It has been demonstrated that patients with type 2 diabetes mellitus (DM) is associated with increased cardiovascular risk. However, little is known regarding the long-term prognosis in diabetic patients who experience mild-to-intermediate coronary artery stenosis (CAS). This study was to assess the clinical outcomes of diabetic patients with different severity of CAS. Methods We consecutively enrolled 10,940 patients hospitalized due to angina-like chest pain and followed up for major adverse cardiovascular events (MACEs) covering cardiac death, myocardial infarction, ischemic stroke, unplanned coronary revascularization and angina-related hospitalization. According to coronary angiography, patients were divided into non-obstructive CAS (NOCAS, Results During a median follow-up of 40 months, 1,017 (11.1%) MACEs occurred. In patients with ICAS or SCAS, the incidence of events was higher when patients coexisted with DM (p Conclusions Diabetic patients with ICAS had the worse outcome, which was comparable to patients with SCAS alone.

Background The prognostic value of N-terminal pro-brain natriuretic peptide (NT-proBNP) in patients with coronary artery disease (CAD) with different glucose status has not been established. This study sought to evaluate the significance of NT-proBNP in predicting major adverse cardiovascular events (MACEs) in patients with chronic coronary syndrome (CCS) and normal left-ventricular systolic function (LVSF) according to different glucose status, especially in those with abnormal glucose metabolism. Methods A total of 8062 patients with CCS and normal LVSF were consecutively enrolled in this prospective study. Baseline plasma NT-proBNP levels were measured. The follow-up data of all patients were collected. Kaplan-Meier and Cox regression analyses were used to assess the risk of MACEs according to NT-proBNP tertiles stratified by glucose status. Results Over an average follow-up of 59.13 ± 18.23 months, 569 patients (7.1 %) suffered from MACEs, including cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke. Kaplan-Meier analysis showed that high NT-proBNP levels had a significant association with MACEs in subjects with prediabetes mellitus (pre-DM) or DM, but not in patients with normoglycemia. Multivariate Cox regression analysis revealed that NT-proBNP remained an independent predictor of MACEs in patients with pre-DM [hazard ratio (HR): 2.56, 95% confidence interval (CI): 1.34–4.91] or DM (HR: 2.34, 95% CI: 1.32–4.16). Moreover, adding NT-proBNP to the original Cox model including traditional risk factors significantly increased the C-statistic by 0.035 in pre-DM and DM, respectively. Conclusions The present study indicated that NT-proBNP could well predict worse outcomes in dysglycemic patients with CCS and normal LVSF, suggesting that NT-proBNP may help with risk stratification in this population.

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.

Background Achievement of low-density lipoprotein cholesterol (LDL-C) goal is the most important for the patients with atherosclerotic cardiovascular diseases (ASCVD) who received lipid-lowering therapy. It is unclear that whether combination of ezetimibe with statin is superior to double-dose of statin regarding both of the lipid-lowering efficacy and improvement of inflammation in Chinese patients with ASCVD. Therefore, this study was performed to compare the effects of these two regimes on lipid profiles and inflammation markers. Methods In this randomized control study, ninety eight patients with ASCVD, who were naïve to statins or other lipid-lowering agents, were enrolled into the study, and randomly assigned into two groups, A40 group (atorvastatin 40 mg/d, n = 50), A20E10 group (atorvastatin 20 mg/d combined with ezetimibe 10 mg/d, n = 48).The patients were followed up at week 4 and week 12 after treatment. The lipid profiles and oxidative low-density lipoprotein cholesterol (ox-LDL) were measured at the end of study. Results There were no differences in clinical characteristics including lipid, ox-LDL and hypersensitive C reactive protein (Hs-CRP) among groups at baseline. However, the average level of LDL-C was lower in group A20E10 than that in group A40 significantly (1.59 ± 0.44 mmol/L vs 1.99 ± 0.56 mmol/L, p = 0.001) during follow-up at week 12 after treatment. Importantly, the higher rate of achievement of LDL-C goal was attained at group of combination statin with ezetimibe (79.2% in group A20E10 vs 50.0% in group A40, p = 0.016). The difference of the level of ox-LDL between both the groups after 12 weeks treatment had not statistical significance (3.63 ± 1.13 U/L in group A20E10 vs 4.14 ± 1.32 U/L in group A40, p = 0.077).Similarly, the level of Hs-CRP between both the groups after treatment was not significantly different (p > 0.05). Conclusions In this randomized study, the data showed that a combination of moderate statin and ezetimibe achieved more reduction of LDL-C compared to the double-dose statin but similar impact on inflammation markers.

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.

ObjectiveThe aim of the study was to investigate the impacts of triglyceride (TG) and high-density lipoprotein cholesterol (HDL-C) dyslipidaemia on prognosis in coronary artery disease (CAD) patients with different glucose metabolism status.DesignAn observational cohort study.Setting/participantsA total of 3057 patients with stable CAD were consecutively enrolled and divided into three groups according to different glucose metabolism status. Atherogenic dyslipidaemia (AD) was defined as TG ≥1.7 mmol/L and HDL-C Primary outcome measuresThe primary endpoints were cardiovascular mortality, non-fatal myocardial infarction and non-fatal stroke.ResultsDuring a median follow-up of 6.1 years, 308 (10.1%) CVEs occurred. No significant difference in the occurrence of CVEs was observed between normal glucose regulation (NGR) and pre-diabetes (pre-DM) groups (HR: 1.25, 95% CI 0.89 to 1.76) while DM group presented 1.45-fold higher risk of CVEs (HR: 1.45, 95% CI 1.02 to 2.05). When the participants were categorised according to combined status of two parameters, the cardiovascular risk was significantly elevated in pre-DM or DM plus AD group compared with the NGR plus non-AD group (HR: 1.76, 95% CI 1.10 to 2.80 and HR: 1.87, 95% CI 1.17 to 2.98).ConclusionsThe present study suggested that the presence of AD might affect the prognosis in patients with DM or pre-DM and stable CAD.

Background Whether plasma proprotein convertase subtilisin/kexin type 9 (PCSK9) levels is a predictor for cardiovascular outcomes has currently been controversial. No data is currently available regarding the relation of PCSK9 to cardiovascular metabolic markers (CVMMs) and major adverse cardiovascular events (MACEs) in stable coronary artery disease (CAD) patients with diabetes or without diabetes. Methods A total 1225 untreated patients with stable CAD were consecutively enrolled and their baseline plasma PCSK9 levels were determined by ELISA. Patients were divided into high and low PCSK9 groups according to PCSK9 median. All patients followed up for the occurrence of MACEs and received standard therapy after admission. The associations of PCSK9 with CVMMs and MACEs were evaluated. Results PCSK9 levels were positively correlated with multiple CVMMs including total cholesterol, low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol and hemoglobin A1c at baseline (all p p p p p Conclusions The present study firstly showed that elevated PCSK9 levels were related to multiple CVMMs and MACEs in stable CAD with diabetes, suggesting that plasma PCSK9 measurement could help to identify diabetic patients with CAD at higher cardiovascular risk. More studies may be needed to confirm our findings.

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 The atherogenicity of remnant cholesterol (RC) has been underlined by recent guidelines, which was linked to coronary artery disease (CAD), especially for patients with diabetes mellitus (DM). This study aimed to examine the prognostic value of plasma RC in the patients with CAD under different glucose metabolism status. Methods Fasting plasma RC were directly calculated or measured in 4331 patients with CAD. Patients were followed for the occurrence of major adverse cardiovascular events (MACEs) and categorized according to both glucose metabolism status [DM, pre-DM, normoglycemia (NG)] and RC levels. Cox proportional hazards model was used to calculate hazard ratios (HRs) with 95% confidence intervals. Results During a mean follow-up of 5.1 years, 541 (12.5%) MACEs occurred. The risk for MACEs was significantly higher in patients with elevated RC levels after adjustment for potential confounders. No significant difference in MACEs was observed between pre-DM and NG groups (p > 0.05). When stratified by combined status of glucose metabolism and RC, highest levels of calculated and measured RC were significant and independent predictors of developing MACEs in pre-DM (HR: 1.64 and 1.98; both p Conclusions In this large-scale and long-term follow-up cohort study, data firstly demonstrated that higher RC levels were significantly associated with the worse prognosis in DM and pre-DM patients with CAD, suggesting that RC may be a target for patients with impaired glucose metabolism.

Background Merging studies have reported the association of lipoprotein(a) [Lp(a)] with poor outcomes of coronary artery disease (CAD) in patients with type 2 diabetes mellitus (T2DM). However, the prognostic importance of Lp(a) for recurrent cardiovascular events (CVEs) is currently undetermined in patients with T2DM and prior CVEs. Methods From April 2011 to March 2017, we consecutively recruited 2284 T2DM patients with prior CVEs. Patients were categorized into low, medium, and high groups by Lp(a) levels and followed up for recurrent CVEs, including nonfatal acute myocardial infarction, stroke, and cardiovascular mortality. Kaplan–Meier, Cox regression and C-statistic analyses were performed. Results During 7613 patient-years’ follow-up, 153 recurrent CVEs occurred. Lp(a) levels were significantly higher in patients with recurrent CVEs than counterparts (20.44 vs. 14.71 mg/dL, p = 0.002). Kaplan–Meier analysis revealed that the event-free survival rate was dramatically lower in high and medium Lp(a) groups than that in low group irrespective of HBA1c status ( Conclusions Our data, for the first time, confirmed that Lp(a) was an independent predictor for recurrent CVEs in T2DM patients with prior CVEs, suggesting that Lp(a) measurement may help to further risk stratification for T2DM patients after they suffered a first CVE.

Background Heart-type fatty acid-binding protein (H-FABP) is a novel marker of myocardial injury and has been reported to be associated with cardiovascular diseases (CVD) including patients with diabetes mellitus (DM). Unfortunately, its prognostic value in patients with CVD and impaired glucose metabolism (IGM) is unclear. The objective of this study was to investigate the prognostic value of H-FABP in CVD patients with IGM. Methods A total of 4594 patients with angiography-proven coronary artery disease (CAD) were enrolled and divided into subgroup according to glucose metabolism status (normal glucose regulation [NGR], pre-DM, and DM). Baseline levels of H-FABP were measured using latex immunoturbidimetric method. The cardiovascular events (CVE) were defined as cardiovascular death, myocardial infarction, stroke and coronary revascularization. Cox regression and Kaplan–Meier analysis were used to evaluate the relations of H-FABP and glucose metabolism status to CVEs. Results During the follow-up period with up to 7.1 years, 380 CVEs occurred. Patients with CVE had higher levels of H-FABP compared to those without CVE (p Conclusions Our data firstly showed that elevated H-FABP levels were associated with worse outcomes in CAD patients with pre-DM and DM, which provided the novel information that H-FABP might be a prognostic marker for clinical outcomes among patients with CAD and IGM.

Background Elevation in small dense low-density lipoprotein (sdLDL) is common in patients with diabetes mellitus (DM), which has already been reported to be associated with incidence of coronary artery disease (CAD). The aim of the present study was to investigate the prognostic value of plasma sdLDL level in patients with stable CAD and DM. Methods A total of 4148 consecutive patients with stable CAD were prospectively enrolled into the study and followed up for major cardiovascular events (MACEs) up to 8.5 years. Plasma sdLDL level was measured in each patient by a direct method using automated chemistry analyzer. The patients were subsequently divided into four groups by the quartiles of sdLDL and the association of sdLDL level with MACEs in different status of glucose metabolism [DM, Pre-DM, normal glycaemia regulation (NGR)] was evaluated. Results A total of 464 MACEs were documented. Both Kaplan–Meier analysis and Cox regression analysis indicated that the patients in quartile 4 but not quartile 2 or 3 of sdLDL level had significantly higher rate of MACEs than that in lowest quartile. When the prognostic value of high sdLDL was assessed in different glucose metabolism status, the results showed that the high sdLDL plus DM was associated with worse outcome after adjustment of confounding risk factors (hazard ratio: 1.83, 95% confident interval: 1.24–2.70, p Conclusions The present study firstly indicated that elevated levels of plasma sdLDL were associated with increased risk of MACEs among DM patients with proven CAD, suggesting that sdLDL may be useful for CAD risk stratification in DM.

Background Although several studies have indicated that lipoprotein(a) is a useful prognostic predictor for patients following percutaneous coronary intervention ( PCI ), previous observations have somewhat been limited by either small sample size or short‐term follow‐up. Hence, this study aimed to evaluate the impact of lipoprotein(a) on long‐term outcomes in a large cohort of stable coronary artery disease patients after PCI . Methods and Results In this multicenter and prospective study, we consecutively enrolled 4078 stable coronary artery disease patients undergoing PCI from March 2011 to March 2016. They were categorized according to both the median of lipoprotein(a) levels and lipoprotein(a) values of dL (high). All patients were followed up for occurrence of cardiovascular events, including cardiovascular death, nonfatal myocardial infarction, and stroke. During an average of 4.9 years of follow‐up, 315 (7.7%) cardiovascular events occurred. The events group had significantly higher lipoprotein(a) levels than the nonevents group. Compared with the low lipoprotein(a) group, Kaplan–Meier analysis showed that the high lipoprotein(a) group had a significantly lower cumulative event‐free survival rate, and multivariate Cox regression analysis further revealed that the high lipoprotein(a) group had significantly increased cardiovascular events risk. Moreover, adding continuous or categorical lipoprotein(a) to the Cox model led to a significant improvement in C‐statistic, net reclassification, and integrated discrimination. Conclusions With a large sample size and long‐term follow‐up, our data confirmed that high lipoprotein(a) levels could be associated with a poor prognosis after PCI in stable coronary artery disease patients, suggesting that lipoprotein(a) measurements may be useful for patient risk stratification before selective PCI .

Aim: To investigated the potential differences between probable and definite heterozygous familial hypercholesterolemia (HeFH) patients diagnosed by Dutch Lipid Clinic Network criteria. Methods: Clinical characteristics, lipid profile, severity of coronary artery stenosis and gene mutations were compared. Kaplan–Meier curve was performed to evaluate the cardiovascular events. Results: Overall, 325 participants were included and divided into two groups: probable (n = 233) and definite HeFH (n = 92). Definite HeFH patients had higher low-density lipoprotein cholesterol (LDL-C), oxidized-LDL and proprotein convertase subtilisin/kexin 9 levels, and higher prevalence of tendon xanthomas. The incidence of genetic mutations was statistically higher in definite HeFH than probable HeFH patients. The coronary stenosis calculated by Gensini score was statistically severer in definite HeFH patients. The best LDL-C threshold for predicting mutations was 5.14 mmol/l. Definite HeFH had lower event-free survival rates. Conclusion: Definite HeFH patients had higher severity of phenotype and genotype, and higher risk of cardiovascular events.

Background Reverse cholesterol transport (RCT) is an important cardioprotective mechanism and the decrease in cholesterol efflux can result in the dyslipidemia. Although liraglutide, a glucagon like peptide-1 analogue, has mainly impacted blood glucose, recent data has also suggested a beneficial effect on blood lipid. However, the exact mechanism by which liraglutide modulates lipid metabolism, especially its effect on RCT, remain undetermined. Hence, the aim of the present study was to investigate the potential impacts and potential underlying mechanisms of liraglutide on the cholesterol efflux in both db/db mice and HepG2 cells. Methods Six-week old db/db mice with high fat diet (HFD) and wild type mice were administered either liraglutide (200 μg/kg) or equivoluminal saline subcutaneously, twice daily for 8 weeks and body weight was measured every week. After the 8-week treatment, the blood was collected for lipid evaluation and liver was obtained from the mice for hematoxylin–eosin (HE) staining, red O staining and Western blotting. Cholesterol efflux was assessed by measuring the radioactivity in the plasma and feces after intraperitoneal injection of 3H-labeled cholesterol. HepG2 Cells were treated with different concentrations of glucose (0, 5, 25, and 50 mmol/L) with or without liraglutide (1000 nmol/L) for 24 h. The intracellular cholesterol efflux was detected by BODIPY-cholesterol fluorescence labeling. Real-time PCR or Western blotting was used to examine the expression levels of ABCA1, ABCG1 and SR-B1. Results Liraglutide significantly decreased blood glucose, serum total cholesterol (TC), triglyceride (TG) and low-density lipoprotein cholesterol (LDL-C). It also reduced liver lipid deposition in db/db mice fed with HFD. Moreover, the movement of 3H-cholesterol from macrophages to plasma and feces was significantly enhanced in db/db mice fed with HFD after liraglutide adminstration. In vitro study, liraglutide could promote the cholesterol efflux of HepG2 cells under high glucose, and also increase the expression of ABCA1 by activating the ERK1/2 pathway. Conclusions Liraglutide could improve lipid metabolism and hepatic lipid accumulation in db/db mice fed with HFD by promoting reversal of cholesterol transport, which was associated with the up-regulation of ABCA1 mediated by the ERK1/2 phosphorylation.

Familial hypercholesterolemia (FH) is one of the most common causes of premature myocardial infarction (MI). However, The patterns of FH remained unrecognized in clinical care, especially in very young patients (VYPs, ≤35 years) with MI. The present study enrolled a total of 1,093 VYPs (≤35 years) presenting a first MI. Clinical diagnosis of FH was made using Dutch Lipid Clinic Network criteria. Coronary severity was assessed by Gensini score (GS). Patients were followed for a median of 40-months with cardiac death, stroke, MI, post-discharge revascularization or unstable angina as primary endpoints. The detected rates of definite/probable FH were 6.5%. The prevalence reached up to 10.3% in patients ≤25 years. The FH had similar levels of comorbidities but was younger, more likely to be very high risk (VHR) and had higher GS (p

Background/Aims: Previous studies have suggested that leptin was associated with atherosclerosis and involved in inflammation. Gender differences between leptin and inflammatory markers have been evaluated less in untreated patients with stable coronary artery disease (CAD). Methods: In this study, a total of 394 consecutive Chinese patients who received coronary artery angiography were enrolled, including 243 patients with CAD and 151 non-CAD controls. The baseline clinical characteristics were collected and serum leptin levels were determined using ELISA. Results: The relation of serum leptin levels to inflammatory markers was found only in female patients. Leptin and white blood cell count (WBCC) as well as its subsets were significantly higher in female patients than female controls. In female patients, leptin was positively associated with C-reactive protein (CRP; r = 0.28, p = 0.016), WBCC (r = 0.261, p = 0.02), neutrophil, r = 0.268, p = 0.018, and monocyte, r = 0.228, p = 0.044. Multivariable regression analysis revealed that leptin was significantly and independently associated with CRP (β = 0.317, p = 0.004), WBCC (β = 0.278, p = 0.020), neutrophil (β = 0.262, p = 0.032), and monocyte (β = 0.245, p = 0.032). Conclusions: The serum leptin levels were higher in female patients and independently associated with CRP, WBCC, and its subsets, suggesting a potential interaction between leptin and inflammation in female CAD 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.

// Sha Li 1 , Xi Zhao 1 , Yan Zhang 1 , Cheng-Gang Zhu 1 , Yuan-Lin Guo 1 , Na-Qiong Wu 1 , Rui-Xia Xu 1 , Ping Qing 1 , Ying Gao 1 , Jing Sun 1 , Geng Liu 1 , Qian Dong 1 and Jian-Jun Li 1 1 Division of Dyslipidemia, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China Correspondence to: Jian-Jun Li, email: // Keywords : proprotein convertase subtilisin/kexin type 9; apolipoprotein CIII; small dense low density lipoprotein cholesterol; dyslipidemia; discordance Received : August 02, 2016 Accepted : September 29, 2016 Published : October 04, 2016 Abstract Plasma levels of proprotein convertase subtilisin/kexin type 9 (PCSK9), apolipoprotein C-III (apoC3) and small dense low density lipoprotein cholesterol (sdLDL-C), have been recently recognized as circulating atherosclerosis-related lipid measurements. We aimed to elucidate their associations with current dyslipidemias, and identify their levels at increased risk to dyslipidemia. A total of 1,605 consecutive, non-treated patients undergoing diagnostic/interventional coronary angiography were examined. Plasma PCSK9 and apoC3 levels were determined using a validated ELISA assay, and sdLDL-C was measured by the Lipoprint LDL System. Plasma levels of PCSK9, apoC3, and sdLDL-C were associated with the current dyslipidemias classification (all p

Background Proprotein convertase subtilisin/kexin 9 (PCSK9) has been proposed as a novel target for coronary artery disease (CAD). Familial hypercholesterolemia (FH) is characterized by high prevalence of CAD and major cardiovascular events (MACEs). However, no data is available on the association between PCSK9 levels and MACEs in FH patients with standard lipid lowering therapy. Methods A total of 338 consecutive heterozygous FH (Dutch Lipid Clinic Network score ≥ 6) was enrolled and followed up for the occurrence of MACEs. Multidetector CT and coronary angiography were performed to determine coronary artery calcification score (CACS) and Gensini score (GS). Multivariable Cox regression analyses were used to calculate hazard ratios (HRs) with 95% confidence intervals (CIs). Plasma PCSK9 concentrations were determined by enzyme immunoassay. Results PCSK9 was independently and positively associated CACS and GS at baseline. During a mean follow-up of 3 years, 33 (9.8%) events occurred. Patients with MACEs had higher median PCSK9 compared with those without (332.47 vs. 311.89 ng/mL, p = 0.038). Kaplan–Meier analysis revealed that patients with higher PCSK9 presented lower event-free survival (p = 0.0017). PCSK9 was statistically correlated with MACEs after adjusting for confounding factors, with the HR per SD being 1.86 (1.31–2.65) and 3.70 (1.16–11.82) for the highest tertile compared with the lowest tertile. Adding PCSK9 to Cox prediction model led to a statistical improvement in net reclassification and integrated discrimination. Conclusion Elevated levels of PCSK9 were positively associated with the development of CAD and future cardiovascular events, suggesting that measurement of PCSK9 concentration might be useful for cardiovascular risk stratification. Further studies are needed to confirm our results.

Lipoprotein(a) [Lp(a)] has been considered as a causal risk factor for cardiovascular disease (CVD) in the general population and levels vary in different ethnicities. However, no systemic analysis is currently available regarding the relation of plasma Lp(a) levels to cardiovascular events (CVEs) in Chinese patients with heterozygous familial hypercholesterolemia (HeFH).Three hundred and ninety-three patients with HeFH undergoing Lp(a) measurement at baseline were consecutively enrolled and followed prospectively for an average of 36.5 months. Lp(a) levels were determined using an immunoturbidimetry assay. Cox regression analysis with adjusted hazard ratios (HRs) and Kaplan-Meier analysis were used to evaluate the prognostic value of Lp(a) on CVEs.Thirty-five events occurred during follow-up. Lp(a) was significantly higher in patients with CVEs (53.3 mg/dL versus 31.7 mg/dL, p 0.001). In Kaplan-Meier analysis, patients with upper tertile of Lp(a) had a significant lower event-free survival (p = 0.004). After adjusting for confounding risk factors, per log unit increase in baseline Lp(a) was independently associated with CVEs [HR: 2.03(1.28-3.21), p = 0.002]. HRs remained unchanged after accounting for hard endpoints and did not vary too much in several relevant subgroups. Adding Lp(a) to the Cox model led to a significant improvement in C-statistic, net reclassification and integrated discrimination. Moreover, HR for upper versus lower tertile of change in Lp(a) was 2.68 (1.11-6.48) for CVEs after one year.Both baseline and on-statin treatment Lp(a) levels were associated with an increased risk of CVEs in patients with HeFH, suggesting that Lp(a) measurement might clinically help further risk stratification of FH patients.

It has been demonstrated that pitavastatin can significantly reduce low-density lipoprotein (LDL) cholesterol (LDL-C), but its impact on lipoprotein subfractions and oxidized low-density lipoprotein (oxLDL) has not been determined. The aim of the present study was to investigate the potential effects of pitavastatin on subfractions of LDL and high-density lipoprotein (HDL) as well as oxLDL in untreated patients with coronary atherosclerosis (AS). Thirty-six subjects were enrolled in this study. Of them, 18 patients with AS were administered pitavastatin 2 mg/day for 8 weeks and 18 healthy subjects without therapy served as controls. The plasma lipid profile, lipoprotein subfractions and circulating oxLDL were determined at baseline and 8 weeks respectively. The results showed that pitavastatin treatment indeed not only decreased LDL-C, total cholesterol (TC), triglycerides (TG) and apolipoprotein B (ApoB) levels, and increased HDL cholesterol (HDL-C), but also reduced the cholesterol concentration of all of the LDL subfractions and the percentage of intermediate and small LDL subfractions. Meanwhile, pitavastatin could decrease plasma oxLDL levels. Furthermore, a more close correlation was found between oxLDL and LDL-C as well as LDL subfractions after pitavastatin treatment. We concluded that a moderate dose of pitavastatin therapy not only decreases LDL-C and oxLDL concentrations but also improves LDL subfractions in patients with AS.

Sodium ferulate (SF) is the sodium salt of ferulic acid which is an active ingredient of Radix Angelica Sinensis and Ligusticum chuanxiong hort. Here, we investigated SF inhibition in a rat model of myocardial hypertrophy induced by coarctation of the abdominal aorta. Following coarctation, rats were given SF (20, 40, and 80 mg/kg/day) for 25 consecutive days. We characterized myocardial hypertrophy using myocardial hypertrophic parameters, histopathology, and gene expression of atrial natriuretic factor (ANF) ―a gene related to myocardial hypertrophy. We detected the levels of angiotensin II (Ang II) and endothelin-1 (ET-1), protein kinase C beta (PKC-β), Raf-1, extracellular regulated protein kinase 1/2 (ERK1/2), and mitogen-activated protein kinase phosphatase-1 (MKP-1) in myocardium. Notably, coarctation of the abdominal aorta increases myocardial hypertrophic parameters, cardiac myocyte diameter, the concentration of Ang II and ET-1 in myocardium, and gene expression of ANF. SF significantly ameliorates myocardial hypertrophy caused by coarctation of the abdominal aorta; reduces concentrations of Ang II and ET-1; suppresses the overexpression of ANF, PKC-β, Raf-1, and ERK1/2; and increases the expression of MKP-1. These results indicate that SF alleviates myocardial hypertrophy induced by coarctation of the abdominal aorta, and these protective effects could be related to the inhibition of PKC and mitogen-activated protein kinase (MAPK) signaling pathways.

Aim: The link of oxidized-low-density lipoprotein (ox-LDL) with premature coronary artery disease (CAD) has previously been less examined. Materials & methods: A total of 1217 patients with angiography-proven CAD were consecutively enrolled and divided into very-early CAD (VECAD), early CAD and late CAD subgroups. And 72 normal control of VECAD were examined. All the subjects were followed-up for an average of 31 months.Results: Patients with VECAD had higher ox-LDL levels; and logistic regression analysis indicated that ox-LDL was an independent risk factor for VECAD among patients with CAD (adjusted odds ratio: 1.024; p

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.

Recently, monocyte-to-high density lipoprotein ratio (MHR) has been proposed as a novel prognostic indicator of cardiovascular diseases. However, no study is currently available regarding the comparison between MHR and monocyte count (MC) in predicting the outcomes among patients undergoing coronary angiography.A total of 3798 patients scheduled for selective coronary angiography were enrolled and followed up to capture major adverse cardiovascular events (MACEs, death, acute myocardial infarction, unstable angina, stroke, heart failure, and unexpected coronary revascularization). Cox proportional hazards models were used to evaluate the risk of MHR or MC on MACEs.During a median of 24.6 months follow-up, 347 (9.1%) MACEs occurred. The upper tertiles of MC and MHR have a significant lower event-free survival (p = 0.011; p = 0.014, respectively). Significantly, both MC and MHR were associated with increased MACEs risk after adjusting for potential confounders [adjusted HR (95% CI): 2.734 (1.547-4.832); 2.031 (1.268-3.254), respectively]. Additionally, the area under the receiver-operating characteristic curves of MC or MHR in predicting MACEs were 0.574 (0.542-0.606) and 0.562 (0.530-0.594) (p 0.001, both), respectively.Our data firstly indicated that MHR was an independent predictor of MACEs whereas the prognostic impact was not superior to MC in patients who underwent coronary angiography. Key Messages MHR has been suggested as a novel prognostic indicator of several cardiovascular diseases. No study is currently available regarding the comparison of MHR to MC in predicting the outcomes in a large cohort of patients undergoing coronary angiography. Our data firstly indicate that MHR is independently associated with MACEs in patients undergoing coronary angiography whereas the prognostic impact is similar to MC.

Proprotein convertase subtilisin/kexin type 9 (PCSK9), a novel target for low-density lipoprotein cholesterol (LDL-C)-lowering therapy, has been found to possess multiple off-target effects in humans. The aim of the present study was to investigate the association of blood pressure (BP) with plasma PCSK9 levels in a large Chinese cohort and the relation of PCSK9 level to carotid intima-media thickness (cIMT) in hypertensive patients. A total of 805 patients without lipid-lowering drug therapy were consecutively enrolled. First, the relationship between BP and PCSK9 was evaluated in hypertensives and normotensives. Furthermore, we examined the relation of PCSK9 to cIMT in 256 enrolled patients who had received a carotid ultrasound test. Plasma PCSK9 levels were measured by enzyme-linked immunosorbent assay, and cITM of left and right carotid arteries was assessed by B-mode ultrasound. There was no significant difference in PCSK9 levels between hypertensives and normotensives. PCSK9 level was not associated with systolic and diastolic BP and pulse pressure in hypertensives and normotensives regardless of sex. A positive correlation between PCSK9 and maximum-IMT and mean-MIT in hypertensives was found in univariate analyses, whereas such an association was absent in normotensives. In addition, the positive association of PCSK9 with cIMT disappeared in hypertensives in multivariate analyses. PCSK9 level is not associated with systolic or diastolic BP in hypertensives or normotensives, but it positively correlates with cIMT in hypertensives in univariate but not multivariate analyses, and further researches are needed.

It has been reported that proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors can significantly reduce lipoprotein(a) [Lp(a)], and the mechanism for Lp(a) reduction remains unclear. Recently an interesting clinical research with a small sample showed a positive correlation between plasma PCSK9 and Lp(a) levels in diabetes. Here we aimed to use a relatively large sample to investigate whether such an association exists in Han Chinese. A total of 783 inpatients were consecutively enrolled and composed of 172 patients with type 2 diabetes mellitus (T2DM) and 611 non-T2DM subjects. Plasma PCSK9 level was measured by ELISA, and its association with Lp(a) was assayed by Spearman’s correlation and multiple regression. Clinical and biochemical parameters were determined in all subjects studied. No significant differences in PCSK9 and Lp(a) levels were found between T2DM and non-T2DM patients. PCSK9 level was not related to Lp(a) level either in T2DM or non-T2DM group in bivariate correlation and multiple linear regression analysis. Additionally, no association between the levels of PCSK9 and Lp(a) was found in well, poorly controlled T2DM patients or in T2DM patients with or without coronary artery disease (CAD). Besides, no difference was found among the PCSK9 values across tertiles of Lp(a) level. We found no association of plasma PCSK9 levels with Lp(a) level in Han Chinese with or without T2DM, suggesting that Lp(a) reduction by PCSK9 inhibitors may not be achieved simply through PCSK9 pathway at least in Chinese.

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.

Background: Elevated levels of proprotein convertase subtilisin/kexin type 9 (PCSK9) have been reported to be related to dyslipidemia, including patients with kidney dysfunction. However, its association with estimated glomerular filtration rate (eGFR) in individuals with normal serum creatinine (SCr) has not been determined. Methods: A total of 2,089 subjects with normal SCr and without lipid-lowering treatment were consecutively enrolled in this study. Plasma PCSK9 levels were measured by ELISA kit and eGFR was evaluated by the Chronic Kidney Disease Epidemiology Collaboration equation. Subjects were divided into a normal eGFR group (n = 1,205, ≥90 mL/min/1.73 m2) and a decreased eGFR group (n = 884, < 90 mL/min/1.73 m2). Baseline characteristics and laboratory findings were compared between the two groups. Spearman’s correlation and linear regression were performed to determine the association between PCSK9 and eGFR. Results: No significant difference in PCSK9 levels was found between the normal eGFR group and the decreased eGFR group (236.84 ± 67.87 vs. 239.98 ± 68.72 ng/mL, p = 0.303). In Spearman’s correlation and multivariable linear regression analysis, no association of PCSK9 levels with eGFR was detected in the total cohort (r = –0.039, p = 0.079; adjusted β = –0.013, p = 0.630). This result remained the same in the subgroups of normal eGFR (r = –0.038, p = 0.190; adjusted β = –0.031, p = 0.367) and decreased eGFR (r = –0.054, p = 0.109; adjusted β = –0.034, p = 0.319). Conclusion: In this single-center study with moderate sample size, the data showed no relationship of PCSK9 levels with normal or decreased eGFR in untreated patients with normal SCr, suggesting that further studies may be needed to understand the relationship between PCSK9 and lipid disorder in different stage of kidney dysfunction.

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 and aims: Elevated low-density lipoprotein cholesterol (LDL-C) is causal risk for coronary artery disease (CAD) and LDL-associated variables including LDL-C, apolipoprotein B (apoB), non-high-density lipoprotein cholesterol (non-HDL-C), lipoprotein a [Lp(a)], small dense LDL (sd-LDL), and oxidized LDL (ox-LDL) have been widely used for predicting the risk of CAD. This study was aimed to compare the values of six LDL-related variables for predicting the severity of CAD using untreated patients undergoing coronary angiography (CAG). Methods: A group of 1977 individuals were consecutively enrolled and divided into CAD (n = 1151) and non-CAD groups (n = 826) according to the results of CAG. LDL-C, apoB, non-HDL-C, Lp(a), sd-LDL and ox-LDL were measured, respectively. The numbers of stenotic arteries and Gensini Scores (GS) were used to calculate the severity of CAD and the associations of six variables with the severity of CAD and predicting value of these parameters were simultaneously examined. Results: CAD patients had significantly higher concentrations of LDL-related variables than non-CAD ones (all p ox-LDL > apoB > non-HDL-C > LDL-C > Lp(a) [area under curve (AUC): sd-LDL 0.641; ox-LDL 0.640; apoB 0.611; non-HDL-C 0.587; LDL-C 0.583; Lp(a) 0.554; respectively]. In multivariate logistic analysis, all variables showed as independent risk factors for the severity of CAD [odds ratio (OR): ox-LDL > sd-LDL > apoB > non-HDL-C > LDL-C > Lp(a)]. Conclusions: All of LDL-related variables could be useful marker for predicting the severity of CAD but sd-LDL and ox-LDL appeared to litter better. Further study may be needed to validate our results.

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.

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.

OBJECTIVE To assess the association between resting heart rate (RHR) and lipoprotein subfractions to provide potential evidence for the relationship between RHR and severity of CAD. METHODS A total of 1119 consecutive non-treated subjects scheduled for coronary angiography were enrolled. High-density lipoprotein (HDL) and low-density lipoprotein (LDL) separation were performed by Lipoprint System. The link of RHR with lipoprotein subfractions was assessed. RESULTS Increased RHR was significantly associated with higher triglyceride, total cholesterol, non-HDL-cholesterol, and apolipoprotein B (all p

Background Plasma proprotein convertase subtilisin/kexin type 9 (PCSK9) has been reported to be related to several risk factors and diseases such as inflammatory markers and coronary artery disease. The aim of present study was to investigate whether plasma PCSK9 concentration was associated with coronary artery calcification. Methods A total of 403 consecutive untreated patients with angina-like chest pain, who received electron beam computed tomography, were enrolled and a coronary artery calcification score (CACS) was also measured. The baseline clinical characteristics were collected and blood sample was taken after 12-h fasting. The plasma PCSK9 concentrations were determined by ELISA in all patients, and the relationship between plasma PCSK9 concentrations and CACS was investigated. Results Patients with coronary artery calcification (CACS > 0) had significant higher plasma PCSK9 concentrations compared with those (CACS = 0) without coronary artery calcification (258.58 ± 69.53 ng/mL vs. 202.53 ± 52.17 ng/mL, P Conclusion A positive association between plasma PCSK9 concentration and coronary artery calcification in untreated patients with angina-like chest pain was observed in our study, suggesting that further investigation may be needed in order to confirm our primary findings and explore the clinical implications.

Cigarette smoking is one of the established risk factors of atherosclerotic cardiovascular disease, however, its impact on lipids is not completely understood, especially in the Chinese population. Therefore, this study evaluated the impact of smoking status (non, former, and current smoking) on the distribution of lipoprotein subfractions in untreated patients with angina-like chest pain.A total of 877 patients were consecutively enrolled and divided into nonsmoking (n = 518), former smoking (n = 103), and current smoking (n = 256) groups. Both low- and high-density lipoprotein cholesterol (LDL-C and HDL-C) subfractions were measured using the Quantimetrix Lipoprint System. The distributions of lipoprotein subfractions were evaluated among the groups.Compared with nonsmoking subjects, the current smoking group had significantly lower large/medium HDL-C (both P0.001) concentration and large HDL subfraction percentage but higher small HDL-C and medium LDL-C concentrations as well as medium LDL subfraction percentage. Importantly, former smoking subjects showed elevated levels of large HDL-C concentration, large HDL particle percentage, and mean LDL particle size and attenuation in small HDL/LDL percentages and small LDL-C concentration, but these levels did not reach the optimal status compared with those of the non-smoking group (data not shown).Smoking has an adverse impact on the lipoprotein subfractions, presented as lower large HDL particles besides higher small HDL and medium LDL particles, whereas smoking cessation could reverse these change to a certain degree.

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.

To investigate the short- and long-term effects of Xuezhikang (血脂康, XZK), an extract of cholestin, on proprotein convertase subtilisin/kexin type 9 (PCSK9) level. Thirty rats were randomly divided into three groups and were given saline, XZK 1,200 mg/kg or lovastatin 10 mg/kg respectively by daily gavage for 3 days (n=10 for each). Sixteen patients without previous lipid-lowering drug treatment for dyslipidemia received XZK 1,200 mg daily for 8 weeks. Fasting blood samples and liver tissue were collected at day 3 for rats, while the blood samples were obtained at baseline and week 8 from patients. The serum PCSK9 and lipid profile were measured. The expression of hepatic low density lipoprotein (LDL) receptor and sterol regulatory element binding protein 2 (SREBP-2) were measured by real time-PCR. PCSK9 levels in rats were significantly increased in the XZK and lovastatin groups (P=0.002, P=0.003 vs. control) at day 3, while no significant differences were found in the levels of lipid parameters. PCSK9 levels in patients increased by 34% (P=0.006 vs. baseline) accompanied by total cholesterol and LDL-cholesterol decreased by 22% and 28% P=0.001, P=0.002 vs. baseline). The hepatic mRNA levels of LDL-receptor and SREBP-2 were significantly increased in the XZK and lovastatin groups. XZK has significant impact on PCSK9 in a short- and long-term manner in both rats and humans. Moreover, the data indicated that as lovastatin, XZK increased PCSK9 levels through SREBP-2 pathway.

Patients with familial hypercholesterolemia (FH) are often characterized by premature coronary artery disease (CAD) with heterogeneity at onset. The aim of the present study was to investigate the associations of lipoprotein (a) [Lp(a)] with the FH phenotype, genotype and roles of Lp(a) in determining CAD risk among patients with and without FH.We enrolled 8050 patients undergoing coronary angiography, from our Lipid clinic. Clinical FH was diagnosed using the Dutch Lipid Clinic Network criteria. Mutational analysis (LDLR, APOB, PCSK9) in definite/probable FH was performed by target exome sequencing.Lp(a) levels were increased, with a clinical FH diagnosis (unlikely, possible, definite/probable FH) independent of the patients status, with Lp(a)-hyperlipoproteinemia [Lp(a)-HLP] (median 517.70 vs. 570.98 vs. 604.65 mg/L, p 0.001) or without (median 89.20 vs. 99.20 vs. 133.67 mg/L, p 0.001). Patients with Lp(a)-HLP had a higher prevalence of definite/probable FH than those without (6.1% vs. 2.4%, p 0.05). However, no significant difference in Lp(a) was observed in patients with definite/probable FH phenotype carrying LDLR or LDLR-independent (APOB, PCSK9) or neither mutations (p 0.05). Multivariate analysis showed that Lp(a) and FH phenotype were both significant determinants in predicting the early onset and severity of CAD. Subsequently, patients with Lp(a)-HLP in definite/probable FH increased significantly the CAD risk (all p 0.05).Lp(a) levels were higher in patients with FH phenotype than in those without, but no difference were found in FH patients of different mutated backgrounds. Moreover, Lp(a) and FH played a synergistic role in predicting the early onset and severity of CAD.

Background It has been demonstrated that an elevated ratio of triglycerides (TG) to high-density lipoprotein cholesterol (HDL-C) is a risk factor of coronary artery disease (CAD) in patients with type 2 diabetes mellitus (T2DM) and is also found to be associated with cardiovascular events (CVEs) in the general population. However, its prognostic value in patients with T2DM along with CAD remains to be determined. Materials and Methods A total of 1,447 consecutive patients with T2DM with angiographic-proven stable CAD were enrolled in the present study and followed-up for an average of 20.3 months. The characteristics of all patients including fasting lipid profile were obtained at baseline and multivariate Cox proportional hazards models were constructed using log TG/HDL-C as a predictor variable. The relationships between CVEs and total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), non–HDL-C, TC/HDL-C, LDL-C/HDL-C and apolipoprotein B/ apolipoprotein AI (apoB/apoAI) were also explored. Results Compared with patients without CVEs, the ones who experienced CVEs had a higher TG/HDL-C ratio. Univariable regression revealed a significant association of log TG/HDL-C with CVEs (hazard ratio = 2.5, P = 0.015). After adjusting for multiple traditional risk factors of cardiovascular disease, the association was still found (hazard ratio = 2.47, P = 0.047). Moreover, results suggested that the ratios of non–HDL-C, TC/HDL-C, LDL-C/HDL-C and apoB/apoAI were not predictors for CVEs in T2DM. Conclusions In our primary study, data suggested that elevated TG/HDL-C value might be a useful predictor for future CVEs in Chinese patients with T2DM with stable CAD. Further study is needed to confirm our findings.

Several small studies have found that moderate- to high-dose statins (HMG-CoA reductase inhibitors) could increase the serum proprotein convertase subtilisin/kexin type 9 (PCSK9) level. However, little is known regarding the short-term, dose-dependent effects of low-dose atorvastatin and the rapid effects of a single dose of atorvastatin on PCSK9. The objective of this study was to investigate the short-term impact of low-dose atorvastatin on PCSK9 in humans.In this randomized study, data from 66 subjects were analyzed. In protocol I, 32 patients were randomized to atorvastatin 10 mg/day (n = 19) or 20 mg/day (n = 13) and eight healthy subjects without therapy were controls for 8 weeks. Serum PCSK9 and lipid profile were determined at day 0, week 4, and week 8. In protocol II, 26 patients were randomized to a single dose of atorvastatin 10 mg (n = 11) or 80 mg (n = 15), and serum levels of PCSK9 were measured at 24 h after treatment.Atorvastatin 10 mg/day decreased low-density lipoprotein cholesterol (LDL-C) by 32 % at 4 weeks and by 33 % at 8 weeks, and atorvastatin 20 mg/day resulted in reduction of LDL-C by 41 % at 4 weeks and by 38 % at 8 weeks. Atorvastatin 10 mg/day slightly increased serum PCSK9 by 5-7 % but without a significant difference, while atorvastatin 20 mg/day significantly increased serum PCSK9 by 30 % at 4 weeks and by 35 % at 8 weeks (p = 0.009 and p = 0.002, respectively). In addition, 24 h after a single dose, atorvastatin 10 mg significantly increased serum PCSK9 by 13 % and atorvastatin 80 mg by 27 % (p = 0.042 and p = 0.001, respectively).The short-term impact of low-dose atorvastatin on PCSK9 was time and dose dependent, with a rapid increase in PCSK9 levels being observed within 24 h of dosing.

We investigated simultaneously traditional and novel lipid indices, alone or in combination, in predicting coronary severity assessed by Gensini score (GS) in 1605 non-lipid-lowering-drug-treated patients undergoing coronary angiography. Firstly, levels of triglycerides (TG), total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), non high density lipoprotein cholesterol (non-HDL-C), apolipoprotein (apo) B, lipoprotein (a) [Lp(a)], proprotein convertase subtilisin/kexin type 9 (PCSK9), apoC3, small dense LDL (sdLDL) and large HDL were increased, while HDL-C and apoA1 levels were decreased as GS status (all p for trend