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.

Concordance of PGT for aneuploidies between blastocyst biopsies and spent blastocyst culture medium.

RESEARCH QUESTION: Non-invasive preimplantation genetic testing for aneuploidies (niPGT-A) avoids the possible detrimental impact of invasive PGT-A on embryo development and clinical outcomes. Does cell-free DNA (cfDNA) from spent blastocyst culture medium (BCM) reflect embryonic chromosome status better than trophectoderm (TE) biopsy? DESIGN: In this study, 35 donated embryos were used for research and the BCM, TE biopsy, inner cell mass (ICM) and residual blastocyst (RB) were individually picked up from these embryos. Whole genome amplification (WGA) was performed and amplified DNA was subject to next-generation sequencing. Chromosome status concordance was compared among the groups of samples. RESULTS: The WGA success rates were 97.0% (TE biopsy), 100% (ICM), 97.0% (RB) and 88.6% (BCM). Using ICM as the gold standard, the chromosomal ploidy concordance rates for BCM, TE biopsy and RB were 58.33% (14/24), 68.75% (22/32) and 78.57% (22/28); the diagnostic concordance rates were 83.33% (20/24), 87.50% (28/32) and 92.86% (26/28); and the sex concordance rates were 92.31% (24/26), 100% (32/32) and 100% (28/28), respectively. Considering RB the gold standard, the chromosome ploidy concordance rates for BCM and TE biopsy were 61.90% (13/21) and 81.48% (22/27); the diagnostic concordance rates were 71.43% (15/21) and 88.89% (24/27); and the sex concordance rates were 91.30% (21/23) and 100% (27/27), respectively. CONCLUSIONS: The results of niPGT-A of cfDNA of spent BCM are comparable to those of invasive PGT-A of TE biopsies. Modifications of embryo culture conditions and testing methods will help reduce maternal DNA contamination and improve the reliability of niPGT-A.

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.

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.

Sodium Ferulate Inhibits Rat Cardiomyocyte Hypertrophy Induced by Angiotensin II Through Enhancement of Endothelial Nitric Oxide Synthase/Nitric Oxide/Cyclic Guanosine Monophosphate Signaling Pathway.

ABSTRACT: Sodium ferulate (SF) is the sodium salt of ferulic acid, which is one of the effective components of Angelica sinensis and Lignsticum chuanxiong , and plays an important role in protecting the cardiovascular system. In this study, myocardial hypertrophy was induced by angiotensin II 0.1 µmol/L in neonatal Sprague-Dawley rat ventricular myocytes. Nine groups were designed, that is, normal, normal administration, model, L-arginine (L-arg 1000 µmol/L), SF (50, 100, 200 µmol/L) group, and N G -nitro-L-arg-methyl ester 1500 µmol/L combined with SF 200 µmol/L or L-arg 1000 µmol/L group, respectively. Cardiomyocyte hypertrophy was confirmed by observing histological changes and measurements of cell diameter, protein content and atrial natriuretic factor, and ß-myosin heavy chain levels of the cells. Notably, SF could inhibit significantly myocardial hypertrophy of neonatal rat cardiomyocytes in a concentration-dependent manner without producing cytotoxicity, and the levels of nitric oxide, NO synthase (NOS), endothelial NOS, and cyclic guanosine monophosphate were increased, but the level of cyclic adenosine monophosphate was decreased in cardiomyocytes. Simultaneously, levels of protein kinase C beta, Raf-1, and extracellular regulated protein kinase 1/2 (ERK1/2) were downregulated, whereas levels of mitogen-activated protein kinase phosphatase-1 were significantly upregulated. All the beneficial effects of SF were blunted by N G -nitro-L-arg-methyl ester. Overall, these findings reveal that SF can inhibit angiotensin II-induced myocardial hypertrophy of neonatal rat cardiomyocytes, which is closely related to activation of endothelial NOS/NO/cyclic guanosine monophosphate, and inhibition of protein kinase C and mitogen-activated protein kinase signaling pathways.

Association between remnant cholesterol and verbal learning and memory function in the elderly in the US.

BACKGROUND: The relationship between remnant cholesterol (RC) and atherosclerotic cardiovascular risk has been given increasing attention in recent years. However, its association with verbal learning and memory performance has not been reported. METHODS: Data were extracted from the National Health and Nutrition Examination Survey (NHANES) 2011-2014 database. Participants aged ≥60 years with available fasting lipid data were included. Verbal learning and memory performance were evaluated using the Consortium to Establish a Registry for Alzheimer's Disease Word List Memory Task (CERAD-WL) subtest. The CERAD total score was calculated as the mean of three immediate recalls and a delayed recall. RC was calculated as total cholesterol (TC) minus the sum of low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C). Multivariate ordinal logistic regression was performed to evaluate the association between RC, as well as its derived marker, the TC/RC ratio, and age-stratified quartiles of the CERAD total score. RESULTS: A total of 1377 participants were analysed. On a continuous scale, per 1 mmol/L increase in RC and per 1 unit increase in the TC/RC ratio were associated with multivariable adjusted odds ratios (95% CI) of 0.74 (0.58-0.94) and 1.45 (1.13-1.87), respectively, for having a CERAD total score in a higher quartile. On a categorical scale, higher RC quartiles were associated with a CERAD total score in a lower quartile; in contrast, the higher TC/RC quartile was associated with a CERAD total score in a higher quartile (all P for trend < 0.05). CONCLUSIONS: The current study suggests that lower RC levels and a higher TC/RC ratio are associated with better verbal learning and memory function, which indicates that lowering RC levels could be beneficial for preventing cognitive impairment in elderly individuals. Further research is needed to validate the causal roles of RC and the TC/RC ratio in cognition.

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.

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.

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.

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.

Diallyl disulfide improves lipid metabolism by inhibiting PCSK9 expression and increasing LDL uptake via PI3K/Akt-SREBP2 pathway in HepG2 cells.

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

Allelopathy of Alexandrium pacificum on Thalassiosira pseudonana in laboratory cultures.

Alexandrium pacificum is a toxin-producing dinoflagellate with allelopathic effects. The elucidation of allelopathic mechanism of A. pacificum is of great significance for understanding A. pacificum blooms. To this end, using the model diatom Thalassiosira pseudonana as a target species, we observed changes in physiological, biochemical and gene transcription of T. pseudonana upon being co-cultured with A. pacificum. We found reciprocal effects between A. pacificum and T. pseudonana, and corroborated A. pacificum's allelopathy on T. pseudonana by observing inhibitory effects of filtrate from A. pacificum culture on the growth of T. pseudonana. We also found that co-culturing with A. pacificum, the expression of T. pseudonana genes related to photosynthesis, oxidative phosphorylation, antioxidant system, nutrient absorption and energy metabolism were drastically influenced. Coupled with the alterations in Fv/Fm (the variable/maximum fluorescence ratio), activity of superoxide dismutase, contents of malondialdehyde, neutral lipid and total protein in T. pseudonana co-cultured with A. pacificum, we propose that A. pacificum allelopathy could reduce the efficiency of photosynthesis and energy metabolism of T. pseudonana and caused the oxidative stress, while the nutrient absorption was also affected by allelopathic effects. The resultant data potentially uncovered the allelopathic molecular mechanism of A. pacificum to model alga T. pseudonana. The changes in nutrient uptake and even energy metabolism in T. pseudonana, as an adaptation to environmental conditions, may prevent it from stress-related injuries. Our finding might advance the understanding of allelopathic mechanism of A. pacificum.

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.

Prognostic utility of lipoprotein(a) combined with fibrinogen in patients with stable coronary artery disease: a prospective, large cohort study.

BACKGROUND: Elevated lipoprotein(a) [Lp(a)] and fibrinogen (Fib) are both associated with coronary artery disease (CAD). The atherogenicity of Lp(a) can be partly due to the potentially antifibrinolytic categories. We hypothesize that patients with higher Lp(a) and Fib may have worse outcomes. METHODS: In this prospective study, we consecutively enrolled 8,417 Chinese patients with stable CAD from March 2011 to March 2017. All subjects were divided into 9 groups according to Lp(a) (Lp(a)-Low, Lp(a)-Medium, Lp(a)-High) and Fib levels (Fib-Low, Fib-Medium, Fib-High) and followed up for CVEs, including nonfatal acute myocardial infarction, stroke, and cardiovascular mortality. Kaplan-Meier, Cox regression and C-statistic analyses were performed. RESULTS: During a median of 37.1 months' follow-up, 395 (4.7%) CVEs occurred. The occurrence of CVEs increased by Lp(a) (3.5 vs. 5.3 vs. 5.6%, p = 0.001) and Fib (4.0 vs. 4.4 vs. 6.1%, p < 0.001) categories. When further classified into 9 groups by Lp(a) and Fib levels, the CVEs were highest in the 9th (Lp(a)-High and Fib-High) compared with the 1st (Lp(a)-Low and Fib-Low) group (7.2 vs. 3.3%, p < 0.001). The highest risk of subsequent CVEs was found in the 9th group (HRadjusted 2.656, 95% CI 1.628-4.333, p < 0.001), which was more significant than Lp(a)-High (HRadjusted 1.786, 95% CI 1.315-2.426, p < 0.001) or Fib-High (HRadjusted 1.558, 95% CI 1.162-2.089, p = 0.003) group. Moreover, adding the combined Lp(a) and Fib increased the C-statistic by 0.013. CONCLUSION: Combining Fib and Lp(a) enhance the prognostic value for incident CVEs beyond Lp(a) or Fib alone.

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.

Prognostic utility of heart-type fatty acid-binding protein in patients with stable coronary artery disease and impaired glucose metabolism: a cohort study.

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 < 0.001). Interestingly, H-FABP levels were also elevated in DM and pre-DM groups compared with NGR group (p < 0.001), when combined glucose metabolism status with H-FABP stratification, patients in the highest tertile of H-FABP appeared to have higher risk of CVEs with pre-DM (adjusted hazard ratio [HR]: 1.855, 95% confidential intervals [CIs] 1.076-3.214; p = 0.033) and DM (adjusted HR: 2.560, 95% CIs 1.409-4.650; p = 0.002). The Kaplan-Meier curve indicated that DM patients with the highest H-FABP levels were associated with the greatest risk of CVEs (p < 0.05). 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.

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.

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.

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.