Synergetic impact of lipoprotein(a) and fibrinogen on stroke in coronary artery disease patients.

BACKGROUND: Emerging data suggested that lipoprotein(a) [Lp(a)] is an independent risk factor for atherosclerotic cardiovascular disease. Previous studies indicated fibrinogen (Fib) had synergetic effect on Lp(a)-induced events. However, combined impact of Fib and Lp(a) on ischemic stroke has not been elucidated. METHODS: In this prospective study, we consecutively enrolled 8263 patients with stable coronary artery diseases (CAD) from 2011 to 2017. Patients were categorized into three groups according to tertiles of Lp(a) levels [Lp(a)-low, Lp(a)-medium, and Lp(a)-high] and further divided into nine groups by Lp(a) and Fib levels. All subjects were followed up for the occurrence of ischemic stroke. RESULTS: During a median follow-up of 37.7 months, 157 (1.9%) ischemic strokes occurred. Stroke incidence increased by Lp(a) (1.1 vs. 2.1 vs. 2.5%, Cochran-Armitage p < .001) and Fib (1.1 vs. 2.0 vs. 2.6%, Cochran-Armitage p < .001) categories. When further classified into nine groups by Lp(a) and Fib levels, the incidence of ischemic stroke in group 9 [Lp(a)-high and Fib-high] was significantly higher than that in group 1 [Lp(a)-low and Fib-low] (3.1 vs. 6%, p < .001). The group 9 was associated with a highest risk for ischemic stroke (adjusted HR 4.907, 95% CI: 2.154-11.18, p < .001), compared with individuals in the Lp(a)-high (adjusted HR 2.290, 95% CI: 1.483-3.537, p < .001) or Fib-high (adjusted HR 1.184, 95% CI: 1.399-3.410, p = .001). Furthermore, combining Lp(a) with Fib increased C-statistics by .045 (p = .004). CONCLUSIONS: Current study first demonstrated that elevated Lp(a) combining with Fib evaluation enhanced the risk of ischemic stroke in patients with CAD beyond Lp(a) or Fib alone.

Synergistic effect of the commonest residual risk factors, remnant cholesterol, lipoprotein(a), and inflammation, on prognosis of statin-treated patients with chronic coronary syndrome.

BACKGROUND: Currently, remnant cholesterol (RC), lipoprotein(a) [Lp(a)], and inflammation are considered the principal residual cardiovascular risk (RCVR) factors. This study sought to evaluate the combined impact of RC, Lp(a), and inflammation on prognosis of statin-treated patients with chronic coronary syndrome (CCS), which has not been investigated. METHODS: A total of 6839 patients with CCS were consecutively enrolled. Baseline RC, Lp(a), and high-sensitivity C-reactive protein (hsCRP) concentrations were measured and their medians were used for categorizations. All patients were followed for the major adverse cardiovascular events (MACEs), including cardiovascular death, non-fatal myocardial infarction, and stroke. The individual and combined effects of RC, Lp(a), and hsCRP on MACEs were examined and stratification analysis according to low-density lipoprotein cholesterol (LDL-C) was performed. RESULTS: Over an average of 54.93 ± 18.59 months follow-up, 462 MACEs were recorded. Multivariate Cox analysis showed that elevated RC and Lp(a) levels were significantly associated with an increased risk of MACEs, while high hsCRP levels were related to a slightly but non-significantly increased MACEs risk. Moreover, when participants were subgrouped according to RC, Lp(a), and hsCRP levels together, only High RC-High Lp(a)-High hsCRP group had significantly higher risk of MACEs [hazard ratio (HR) 1.99, 95% confidence interval (CI) 1.15-3.47] compared with the reference group (Low RC-Low Lp(a)-Low hsCRP), especially in patients with LDL-C < 2.6 mmol/L. CONCLUSIONS: The combination of elevated levels of RC, Lp(a), and hsCRP potentiated the adverse effect on MACEs among statin-treated patients with CCS, suggesting that multiple RCVR factors assessment may be a better strategy to improve stratification in very-high risk population.

SORBS2 as a molecular target for atherosclerosis in patients with familial hypercholesterolemia.

BACKGROUND: Familial hypercholesterolemia (FH) is a metabolic disease in which patients are prone to develop premature atherosclerosis (AS). Sorbin and SH3 Domain Containing 2 (SORBS2) is known to play a role in coronary heart disease (CHD). However, the mechanism underlying SORBS2 involvement in the development of hypercholesterolemia remains unknown. Here, we investigated the effects of SORBS2 on inflammation and foam cell formation and its underlying mechanisms. METHODS: Using Bioinformatics analysis, we established that SORBS2 is upregulated in patients with FH. Circulating concentrations of SORBS2 were measured using ELISA kit (n = 30). The association between circulating SORBS2 levels and inflammatory factors or lipid indexes were conducted using Spearman correlation analysis. We further conducted in vitro experiments that the expression of SORBS2 were analyzed, and SORBS2 siRNA were transfected into oxidized LDL (OxLDL)-induced macrophages, followed by western blot and immunofluorescence. RESULTS: Circulating SORBS2 levels were positively associated with inflammatory factors and lipid indexes. We also observed that high in vitro expression of SORBS2 in OxLDL-induced macrophages. After SORBS2 silencing, Nod like receptor family pyrin domain-containing 3 protein(NLRP3)-Caspase1 activation and NF-κB activation were attenuated, and secretion of pro-inflammatory cytokines (IL-1ß and IL-18) was decreased. Moreover, SORBS2 silencing blocked reactive oxygen species (ROS) production and lipid accumulation, and promoted cholesterol efflux through ABCG1-PPARγ pathway. CONCLUSIONS: SORBS2 regulates lipid-induced inflammation and foam cell formation, and is a potential therapeutic target for hypercholesterolemia.

NAFLD fibrosis score is correlated with PCSK9 and improves outcome prediction of PCSK9 in patients with chest pain: a cohort study.

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.

Relations of physical signs to genotype, lipid and inflammatory markers, coronary stenosis or calcification, and outcomes in patients with heterozygous familial hypercholesterolemia.

BACKGROUND: Although the presence of physical signs [tendon xanthomas and/or corneal arcus (TX/CA)], are associated with the risk of coronary artery disease in patients with heterozygous familial hypercholesterolemia (HeFH), their relationship with genotypes and clinical characteristics has not been fully determined. This study aimed to examine the association of TX/CA with genetic mutation, lipid- and inflammation-related markers, the severity of coronary stenosis or calcification, and cardiovascular events (CVEs) in patients with HeFH. METHODS: LDLR, APOB, and PCSK9 genes were screened in 523 HeFH patients, and patients with TX/CA (n = 50) were 1:4 propensity score-matched to patients without TX/CA (n = 200) to adjust for age and sex. Laboratory markers (proprotein convertase subtilisin/kexin type 9 [PCSK9], lipoprotein(a) and high-sensitivity C-reactive protein [hsCRP]), computed tomography angiography, coronary angiography, and follow-up for CVEs were performed. RESULTS: Patients with physical signs had significantly higher low-density lipoprotein cholesterol levels; higher PCSK9 or hsCRP concentrations; more LDLR positive mutations; and higher prevalence of high tertiles of Gensini, SYNTAX and Jeopardy scores as well as coronary artery calcium scores than did those without. Over an average follow-up of 3.7 years, the incidence of CVEs was significantly higher in patients with TX/CA (log-rank p < 0.001). Patients with physical signs and mutation positivity had threefold higher risks of CVEs (adjusted hazard ratio 3.34, 95% confidence interval 1.04-10.72, p = 0.024). CONCLUSIONS: Physical signs were associated with genotypes and phenotypes, and worse outcomes in patients with HeFH, suggesting that these signs may help in risk stratification in these patients.

The predictive utility of circulating PCSK9 levels on diabetes mellitus.

Increasing data including ours have suggested that proprotein convertase subtilisin/kexin type 9 (PCSK9), a novel regulator of cholesterol metabolism, may also play an important role in the development of type 2 diabetes mellitus (T2DM) and is associated with clinical outcomes in diabetic patients. Previous studies revealed that elevated plasma PCSK9 levels had a higher incidence of new-onset T2DM. Moreover, the results of available epidemiological, preclinical, and clinical studies have indicated that plasma PCSK9 concentration is correlated with glycemic parameters and can predict the adverse cardiovascular events in diabetic patients with coronary artery disease. However, there is currently no general agreement about the association of PCSK9 with T2DM. The usefulness of the circulating PCSK9 concentration as a predictor for the risk of new-onset T2DM should be clinically prudential.

Association of diabetes mellitus with clinical outcomes in patients with different coronary artery stenosis.

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, < 50% stenosis), intermediate CAS (ICAS, 50-69% stenosis), and severe CAS (SCAS, 70-100% stenosis) subgroups, and were further categorized into six groups as NOCAS with DM and non-DM, ICAS with DM and non-DM, and SCAS with DM and non-DM. 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 < 0.05, respectively). In subgroup analyses, patients with ICAS and DM, SCAS and non-DM, SCAS and DM had increased risk of events [adjusted hazard ratio (HR): 1.709, 95% confidence interval (CI) 1.106-2.641, p = 0.016; HR: 1.911, 95% CI 1.460-2.501, p < 0.001; HR: 2.053, 95% CI 1.514-2.782, p < 0.001] compared to ones with NOCAS and non-DM. Besides, the Kaplan-Meier curves indicated the highest risk of MACEs in patients with SCAS and DM than others (p < 0.001). CONCLUSIONS: Diabetic patients with ICAS had the worse outcome, which was comparable to patients with SCAS alone.

Prognostic value of NT-proBNP in patients with chronic coronary syndrome and normal left ventricular systolic function according to glucose status: a prospective cohort study.

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.

Early radial artery occlusion following the use of a transradial 7-French sheath for complex coronary interventions in Chinese patients.

OBJECTIVES: We aimed to explore the impact of 7-Fr sheaths on the incidence of early radial artery occlusion (RAO) after transradial coronary intervention (TRI) in Chinese patients. BACKGROUND: RAO precludes future use of the vessel for vascular access. Transradial catheterization is usually performed via 5-Fr or 6-Fr catheters; 7-Fr sheath insertion enables complex coronary interventions but may increase the RAO risk. METHODS: We prospectively enrolled 130 consecutive patients undergoing complex TRI using 7-Fr sheaths. Radial artery ultrasound assessment was performed before and after TRI. Early RAO was defined as the absence of flow on ultrasound within 6-24 hr after TRI. Multivariate logistic regression was used to determine the factors related to early RAO after TRI. RESULTS: 7-Fr sheaths were mainly used for chronic total occlusion (44.6%), bifurcation (30.0%), and tortuous calcification (25.4%) lesions. All patients were successfully sheathed. Percutaneous coronary intervention (PCI) procedural success was 96.2%; 119 patients (91.5%) had preserved radial artery patency after TRI. All 11 RAO cases (8.5%) were asymptomatic. The radial artery diameter was significantly larger postoperatively (3.1 ± 0.4 mm) than preoperatively (2.6 ± 0.5 mm) (p < .001). No parameters significantly differed between patients with and without RAO. TRI history was the only independent risk factor of early RAO (odds ratio: 6.047, 95% confidence interval: 1.100-33.253, p = .039). CONCLUSIONS: 7-Fr sheath use after transradial access for complex PCI is feasible and safe. Evaluating the radial artery within 24 hr after TRI allows timely RAO recognition, important for taking measures to maintain radial artery patency and preserve access for future TRIs.

Impact of liver fibrosis score on prognosis in patients with previous myocardial infarction: A prospective cohort study.

BACKGROUND & AIMS: Liver fibrosis score (LFS) has been used for predicting the cardiovascular outcomes (CVOs) in diverse populations. However, the association of LFS with CVOs in patients with previous myocardial infarction (MI) remains undetermined. We aimed to examine the prognostic value of LFS in patients with prior MI in a prospective cohort. METHODS: A total of 3718 patients with previous MI were consecutively enrolled from March 2009 to January 2019. Five LFSs including the fibrosis-4 (FIB-4) score, non-alcohol fatty liver disease fibrosis score (NFS), Forns score, HUI score and BARD score were used. The CVOs covered major adverse cardiac event (MACEs), cardiovascular mortality and all-cause mortality. Cox proportional hazards model was used to calculate hazard ratios (HRs) with 95% confidence intervals (CIs). RESULTS: During a mean follow-up of 47.4 ± 24.8 months, 431 (11.6%) MACEs occurred. Kaplan-Meier analysis demonstrated that higher LFSs resulted in a significantly higher probability of CVOs. Compared to the lowest score group, multivariable-adjusted HRs (95% CIs) of the highest group of FIB-4, NFS, Forns score, HUI score and BARD score were 1.75 (1.32-2.33), 2.37 (1.70-3.33), 2.44 (1.61-3.73), 1.58 (1.16-2.14) and 1.27 (1.03-1.57) respectively. These LFSs were also independent predictors of cardiovascular mortality and all-cause mortality. Similar results were observed across subgroups analysis. The addition of LFSs to a prediction model significantly increased the C-statistic for CVOs. CONCLUSIONS: The present study firstly demonstrated that LFS could be used as a risk stratification tool for predicting CVOs in patients with previous MI, which should be evaluated further.

Association of circulating proprotein convertase subtilisin/kexin type 9 concentration, prothrombin time and cardiovascular outcomes: a prospective cohort study.

BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is considered to have multiple roles in the development of atherosclerosis, which is recently reported to participate in the thrombotic process. We aimed to examine the relationship between PCSK9 concentration, coagulation indexes and cardiovascular events. METHODS: A total of 2293 consecutive patients with angina-like chest pain and without lipid-lowering drugs treatment were enrolled and followed up for major adverse cardiovascular events (MACEs). Circulating PCSK9 concentration was determined by ELISA. The routine coagulation tests including activated partial thromboplastin time (APTT), prothrombin time (PT) and thrombin time were performed. The associations between PCSK9 concentration, routine coagulation indicators and MACEs were analyzed. RESULTS: Patients with high PCSK9 levels had lower PT and APTT levels (all p <  0.05). However, PCSK9 concentration was only independently and negatively correlated with PT (ß = - 0.115, p <  0.001). During a mean of 38.3 months, 186 (8.1%) MACEs were occurred. Multiple Cox regression analysis indicated high PCSK9 or low PT levels as risk factors related to MACEs. When the prognosis was analyzed by the combination of PCSK9 and PT levels, patients with high PCSK9 and low PT had higher incidence of MACEs compared to those with low PCSK9 and high PT. CONCLUSIONS: Our study firstly suggested that PCSK9 concentration was negatively correlated with plasma levels of PT. Furthermore, high PCSK9 and low PT were associated with MACEs and the combination of PCSK9 with PT had an addictive effect on predicting cardiovascular outcomes in patients with chest pain, which was useful for further subdivision of cardiovascular risks.

Prognostic utility of triglyceride-rich lipoprotein-related markers in patients with coronary artery disease.

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.

Association of circulating PCSK9 concentration with cardiovascular metabolic markers and outcomes in stable coronary artery disease patients with or without diabetes: a prospective, observational cohort study.

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 < 0.05). During a median follow-up of 3.3 years, 103 (8.4%) events occurred. PCSK9 levels were higher in patients with events compared to those without (p < 0.05). The Kaplan-Meier analysis displayed that patients in high PCSK9 group had lower event-free survival than that in low group (p < 0.05). Multivariable Cox regression analysis revealed that PCSK9 levels were independently associated with MACEs in diabetic patients (adjusted hazard ratio [HR]: 1.361, 95% confidence interval [CI]: 1.037-1.785, p < 0.05). When added the combination of PCSK9 levels and diabetic status to stratifying factors, patients in high PCSK9 group appeared to have extremely high risk of subsequent MACEs with diabetes (adjusted HR: 5.233, 95% CI: 2.546-10.757, p < 0.01). 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) predicts recurrent worse outcomes in type 2 diabetes mellitus patients with prior cardiovascular events: a prospective, observational cohort study.

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 (< 7.0%; ≥ 7.0%, both p < 0.05). Furthermore, multivariate Cox regression models indicated that Lp(a) was independently associated with high risk of recurrent CVEs [HR(95% CI): 2.049 (1.308-3.212)], such data remains in different HBA1c status (HR(95% CI): < 7.0%, 2.009 (1.051-3.840); ≥ 7.0%, 2.162 (1.148-4.073)). Moreover, the results of C-statistic were significantly improved by 0.029 when added Lp(a) to the Cox model. 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.

Association of small dense low-density lipoprotein with cardiovascular outcome in patients with coronary artery disease and diabetes: a prospective, observational cohort study.

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 < 0.05). However, no significant association was observed for high sdLDL plus Pre-DM or NGR. 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.

The longitudinal association of remnant cholesterol with cardiovascular outcomes in patients with diabetes and pre-diabetes.

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 < 0.05) and DM (HR: 1.62 and 2.05; both p < 0.05). High RC levels were also positively associated with MACEs in patients with uncontrolled DM. . 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.

Long-term prognostic utility of low-density lipoprotein (LDL) triglyceride in real-world patients with coronary artery disease and diabetes or prediabetes.

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 < 0.05]. Moreover, adding LDL-TG into the original model increased the C-statistic from 0.687 to 0.704 (∆C-statistic = 0.016, p = 0.028) and from 0.734 to 0.749 (∆C-statistic = 0.014, p = 0.002) in Pre-DM and DM, respectively. 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.

Differential leukocyte counts and cardiovascular mortality in very old patients with acute myocardial infarction: a Chinese cohort study.

BACKGROUND: Total leukocyte and differential Leukocyte counts are prognostic indictors in patients with coronary artery disease (CAD). However, there is no data available regarding their prognostic utility in very old patients with acute myocardial infarction (AMI). The aim of this study is to investigate the potential role of different leukocyte parameters in predicting the mortality among very old patients with AMI. METHODS: A total of 523 patients aged over 80 years with AMI were consecutively enrolled into this study. Leukocyte and its subtypes were obtained at admission in each patient. The primary study endpoint was cardiovascular mortality. Patients were followed up for an average of 2.2 years and 153 patients died. The associations of leukocyte parameters with mortality were assessed using Cox regression analyses. The concordance index was calculated to test the model efficiency. RESULTS: In multivariable regression analysis, neutrophils-plus-monocytes-to-lymphocytes ratio (NMLR) and neutrophils-to-lymphocytes ratio (NLR) were two most significant predictors of mortality among all the leukocyte parameters (HR = 3.21, 95% CI 1.75-5.35; HR = 2.79, 95% CI 1.59-4.88, respectively, all p < 0.001, adjusted for age, male gender, body mass index, family history of CAD, smoking, hypertension, diabetes mellitus, high-density lipoprotein cholesterol (HDL-C), non-HDL-C, high sensitivity C-reactive protein, creatinine, left ventricular ejection fraction, troponin I, use of statin, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, and percutaneous coronary intervention). Furthermore, adding NMLR and NLR into the Cox model increased the C-statistic by 0.038 and 0.037 respectively, which were more significant than that of other leukocyte parameters. Besides, addition of NMLR and NLR to the Canada Acute Coronary Syndrome Risk Score model also increased the C-statistic by 0.079 and 0.077 respectively. CONCLUSION: Our data firstly indicated that most leukocyte subtypes were independent markers for the mortality in very old patients with AMI, while NMLR and NLR appeared to be more effective.

Circulating PCSK9 and cardiovascular events in FH patients with standard lipid-lowering therapy.

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.

Impact of free fatty acids on prognosis in coronary artery disease patients under different glucose metabolism status.

BACKGROUND: The 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. METHODS: In 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. RESULTS: During 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, p value = 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 < 0.05] and DM [2.017 (1.164-3.494) and 2.795 (1.619-4.824), all p-value < 0.05]. CONCLUSIONS: The 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.