Background: The present cohort study aims to examine the relationship between fibrinogen (Fib) levels and glucose metabolism [fasting blood glucose (FBG) and hemoglobin A1c (HbA1c)] and investigate the impact of high Fib on cardiovascular outcomes in patients with stable CAD and pre-diabetes mellitus (pre-DM) or diabetes mellitus (DM). Methods: This study included 5237 patients from March 2011 to December 2015. Patients were distributed into three groups according to Fib levels (low Fib, median Fib, high Fib) and further categorized by glucose metabolism status [normal glucose regulation (NGR), Pre-DM, DM]. All patients were followed up for the occurrences of major adverse cardiovascular events (MACEs), including cardiovascular mortality, nonfatal MI, stroke, and unplanned coronary revascularization. Results: Linear regression analyses showed that FBG and HbA1c levels were positively associated with Fib in overall CAD participants, either with or without DM (all P < 0.001). During an average of 18,820 patient-years of follow-up, 476 MACEs occurred. High Fib was independently associated with MACEs after adjusting for confounding factors [Hazard Ratio (HR): 1.57, 95% confidence interval (CI) 1.26–1.97, P < 0.001]. Furthermore, DM but not pre-DM was a significant predictor of MACEs (P < 0.001 and P > 0.05, respectively). When patients were stratified by both glucose metabolism status and Fib levels, high Fib was associated with a higher risk of MACEs in pre-DM (HR 1.66, 95% CI 1.02–2.71, P < 0.05). Medium and high Fib levels were associated with an even higher risk of MACEs in DM (HR 1.86, 95% CI 1.14–3.05 and HR 2.28, 95% CI 1.42–3.66, all P < 0.05). After adding the combination of Fib and glucose status to the Cox model, the C-statistic was increased by 0.015 (0.001–0.026). Conclusions: The present study suggested that Fib levels were associated with FBG and HbA1c in stable CAD patients. Moreover, elevated Fib was independently associated with MACEs in CAD patients, especially among those with pre-DM and DM, suggesting that Fib may provide incremental value in the cardiovascular risk stratification of pre-DM and DM patients.

Objective Whether 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). Methods In 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. Results During 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, p<0.001). Kaplan-Meier analysis indicated that Lp(a) tertile 2 (p=0.001) and tertile 3 (p<0.001) groups had significantly lower cumulative event-free survival rates compared with tertile 1 group. Moreover, multivariate Cox regression analysis further revealed that Lp(a) was independently associated with RCVEs risk (HR: 2.01, 95% CI: 1.44 to 2.80, p<0.001). Moreover, adding Lp(a) to the SMART risk score model led to a slight but significant improvement in C-statistic (∆C-statistic: 0.018 (95% CI: 0.011 to 0.034), p=0.002), net reclassification (6.8%, 95% CI: 0.5% to 10.9%, p=0.040) and integrated discrimination (0.3%, 95% CI: 0.1% to 0.7%, p<0.001). Conclusions Circulating 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).

Although there have been many reports in the genetics of familial hypercholesterolemia (FH) worldwide, studies in regard of Chinese population are lacking. In this multi-center study, we aim to characterize the genetic spectrum of FH in Chinese population, and examine the genotype-phenotype correlations in detail. A total of 285 unrelated index cases from China with clinical FH were consecutively recruited. Next-generation sequencing and bioinformatics tools were used for mutation detection of LDLR, APOB and PCSK9 genes and genetic analysis. Overall, the detection rate is 51.9% (148/285) in the unrelated index cases with a total of 119 risk variants identified including 84 in the LDLR gene, 31 in APOB and 4 in PCSK9 gene. Twenty-eight variants were found in more than one individual and LDLR c.1448G > A (p. W483X) was most frequent one detected in 9 patients. Besides, we found 8 (7 LDLR and 1 APOB) novel variants referred as “pathogenic (or likely pathogenic) variants” according to in silico analysis. In the phenotype analysis, patients with LDLR null mutation had significantly higher LDL cholesterol level than LDLR defective and APOB/PCSK9 mutation carriers and those with no mutations (p < 0.001). Furthermore, 13 double heterozygotes, 16 compound heterozygotes and 5 true LDLR homozygotes were identified and the true LDLR homozygotes had the most severe phenotypes. The present study confirmed the heterogeneity of FH genetics in the largest Chinese cohort, which could replenish the knowledge of mutation spectrum and contribute to early screening and disease management.

Ye-Xuan Cao, Hui-Wen Zhang, Jing-Lu Jin, Hui-Hui Liu, Yan Zhang, Rui-Xia Xue, Ying Gao, Yuan-Lin Guo, Cheng-Gang Zhu, Qi Hua, Yan-Fang Li, Raul D. Santos, Na-Qiong Wu, Jian-jun Li

Remnant cholesterol (RC) is increasingly recognized as a key target in the treatment of atherosclerotic cardiovascular disease (ASCVD), addressing much of the residual risk that persists despite standard therapies. However, integrating RC into clinical practice remains challenging. Key issues, such as the development of accessible RC measurement methods, the identification of safe and effective medications, the determination of optimal target levels, and the creation of RC-based risk stratification strategies, require further investigation. This article explores the complex role of RC in ASCVD development, including its definition, metabolic pathways, and its association with both the overall risk and residual risk of ASCVD in primary and secondary prevention. It also examines the effect of current lipid-lowering therapies on RC levels and their influence on cardiovascular outcomes. Recent research has highlighted promising advancements in therapies aimed at lowering RC, which show potential for reducing major adverse cardiovascular events (MACEs). Inhibitors such as angiopoietin-like protein 3 (ANGPTL3), apolipoprotein C-III (apoCIII), and proprotein convertase subtilisin/kexin type 9 (PCSK9) have demonstrated their ability to modulate RC and reduce MACEs by targeting specific proteins involved in RC synthesis and metabolism. There is a pressing need for larger randomized controlled trials to clarify the role of RC in relevant patient populations. The development of targeted RC-lowering therapies holds the promise of significantly reducing the high rates of morbidity and mortality associated with ASCVD.

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. 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. 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). 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.