董倩
中国医学科学院阜外医院
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.
European journal of clinical investigation 2024
Background:Although experimental studies have demonstrated the protective role of total bilirubin (TBil) in cardiovascular diseases, several previous clinical observations are controversial. More importantly, no data are currently available regarding the relation of TBil to major adverse cardiovascular events (MACE) in patients with previous myocardial infarction (MI).Objectives:This study sought to explore the association between TBil and long-term clinical outcomes in patients with previous MI.Methods:A total of 3,809 patients who are post-MI were consecutively enrolled in this prospective study. Cox regression models using HRs and CIs were applied to investigate associations between the TBil concentration category (group 1: bottom to median tertiles within the reference range; group 2: top tertile; group 3: above reference range) and main outcome (recurrent MACE) as well as secondary outcomes (hard endpoints and all-cause mortality).Results:During the 4-year follow-up period, 440 patients (11.6%) suffered from recurrent MACE. Kaplan-Meier survival analysis showed the lowest MACE incidence in group 2 (P < 0.001). When compared with the reference group (group 1) in multivariable analysis, a J-shaped association was apparent for MACE, with decreased risk in group 2 (HR: 0.76; 95% CI: 0.59-0.96) and elevated risk in group 3 (HR: 1.29; 95% CI: 1.03-1.61). Similar associations were identified regarding hard endpoints and all-cause mortality. Moreover, TBil demonstrated incremental discriminatory strength when added to the predictive model.Conclusions:In this prospective cohort study with long-term follow-up, higher TBil levels within the physiological range reduced the incidence of long-term cardiovascular events in patients who are post-MI.
JACC. Asia 2023
BACKGROUND:Low-density lipoprotein-triglyceride (LDL-TG), a novel lipid marker, has been reported to be associated with cardiovascular events (CVEs). However, whether inflammatory status has a combined effect with LDL-TG on CVEs in patients with chronic coronary syndrome (CCS) receiving percutaneous coronary intervention (PCI) remains uncertain.METHODS:A total of 4,415 patient with coronary angiography were primarily enrolled. Among them, 2,215 patients undergoing PCI were finally classified into subgroups according to LDL-TG and high-sensitivity C-reactive protein (hs-CRP) concentrations. Patients were followed up for up to 7 y for CVEs. The associations between LDL-TG, hs-CRP and CVEs were analyzed.RESULTS:Patients with CVEs showed higher concentrations of LDL-TG compared to those without. In Cox regression analysis, LDL-TG was independently associated with CVEs (hazard ratio [HR]: 2.003, 95 % confidence intervals [CI]: 1.365-2.940, p < 0.001). Interestingly, when patients were further categorized into six subgroups according to hs-CRP and LDL-TG concentrations, LDL-TG was correlated with increased events only in patients with high hs-CRP concentrations (HR: 1.726, 95 %CI: 1.055-2.826, p = 0.030). Moreover, the Kaplan-Meier survival curves indicated that patients in the higher plasma concentrations of hs-CRP in combination with the highest LDL-TG concentrations were associated with the highest risk of CVEs.CONCLUSIONS:LDL-TG was associated with increased CVEs among patients receiving PCI with increased hs-CRP concentrations, suggesting that measurement of LDL-TG combined with hs-CRP facilitates prognostic utility for cardiovascular risks.
Clinica chimica acta; international journal of clinical chemistry 2023
[This corrects the article DOI: 10.3389/fendo.2022.1041555.].
Frontiers in endocrinology 2023
Objective:The aim of the present study was to examine the value of high-density lipoprotein (HDL) subfractions for predicting cardiovascular events (CVEs) in untreated type 2 diabetes mellitus (T2DM) patients with stable coronary artery disease (SCAD) using an age- and gender-matched case-control study.Methods:In total, 185 SCAD patients and 185 T2DM patients with SCAD were enrolled and subjected to a clinical follow-up of CVEs. HDL subfractions were analyzed using the Quantimetrix Lipoprint System. The relationship between HDL subfractions and CVEs in T2DM patients with SCAD was evaluated by Kaplan-Meier analysis and Cox proportional hazard models.Results:During a median 37.7-month follow-up, T2DM patients with SCAD had a higher percentage of CVEs compared to SCAD patients (p=0.039). The concentration of the combined intermediate and small HDL-C subfraction (defined as the mixed HDL subfraction) was related to the event incidence in T2DM patients with SCAD (p=0.004), and it was positively associated with increased CVEs even after adjustment in three models. Kaplan-Meier curve analysis indicated that T2DM patients with SCAD in the high mixed HDL subfraction group (>28 mg/dL) had lower event-free survival rates (p=0.008).Conclusions:Elevated concentration of the mixed HDL subfraction concentration predicts events in T2DM patients with SCAD.
Frontiers in endocrinology 2022
Background and Aims:Heterogeneity exists among patients with atherosclerotic cardiovascular disease (ASCVD) with regard to the risk of recurrent events. Current guidelines have definitely refined the disease and we aimed to examine the practicability in Chinese population.Methods:A cohort of 9944 patients with ASCVD was recruited. Recurrent events occurred during an average of 38.5 months' follow-up were collected. The respective and combinative roles of major ASCVD (mASCVD) events and high-risk conditions, being defined by 2018 AHA/ACC guideline, in coronary severity and outcome were studied.Results:The number of high-risk conditions was increased with increasing number of mASCVD events (1.95 ± 1.08 vs. 2.16 ± 1.10 vs. 2.42 ± 1.22). Trends toward the higher to the highest frequency of multi-vessel coronary lesions were found in patients with 1- (71.1%) or ≥2 mASCVD events (82.8%) when compared to those without (67.9%) and in patients with 2- (70.5%) or ≥3 high-risk conditions (77.4%) when compared to those with 0-1 high-risk condition (61.9%). The survival rate was decreased by 6.2% between none- and ≥2 mASCVD events or by 3.5% between 0-1 and ≥3 high-risk conditions. Interestingly, diabetes was independently associated with outcome in patients with 1- [1.54(1.06-2.24)] and ≥2 mASCVD events [1.71(1.03-2.84)]. The positive predictive values were increased among groups with number of mASCVD event increasing (1.10 vs. 1.54 vs. 1.71).Conclusion:Propitious refinement of ASCVD might be reasonable to improve the survival. Concomitant diabetes was differently associated with the incremental risk among different ASCVD categories, suggesting the need of an appropriate estimate rather than a 'blanket' approach in risk stratification.
Frontiers in endocrinology 2022
BACKGROUND: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.METHODS: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.RESULTS: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.CONCLUSIONS: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.
Metabolism: clinical and experimental 2022
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.
Lipids in health and disease 2022
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-1β 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.
Journal of translational medicine 2022
Background:The positive relationship between metabolic healthy obesity (MHO) and cardiovascular risk has been under debate in recent years. Previously, strong evidence supported the causal role of increased plasma lipoprotein(a) [Lp(a)] levels in cardiovascular disease (CVD). The current study aimed to investigate the different associations of Lp(a) and cardiovascular events (CVEs) in patients with coronary artery disease (CAD) and different metabolic phenotypes.Methods:A total of 5,089 patients who were angiography-proven CAD were consecutively included and followed up for CVEs. Obesity was defined as a body mass index (BMI) ≥25 kg/m2 according to Asia-specific BMI criteria. Patients were divided into four groups according to metabolic phenotypes, namely metabolically healthy/unhealthy non-obese and metabolically healthy/unhealthy obese [metabolically healthy non-obese (MHN), MHO, metabolically unhealthy non-obese (MUN), and metabolically unhealthy obesity (MUO)]. Comparisons of CAD severity and outcomes were performed among four groups. Cox regression analyses and cubic spline models were used to examine the relationship between Lp(a) and CVEs in patients with different metabolic phenotypes.Results:During a median of 7.5 years' follow-up, 540 (10.6%) CVEs occurred. MUN and MUO populations had more severe coronary stenosis than MHN ones, while no significant difference in the Gensini score (GS) was observed between MHN and MHO. Patients with MUN and MUO presented a higher risk of CVEs than patients with MHN (hazard ratio [HR]: 1.414, 95% CI: 1.024-1.953-1.556 and HR: 1.747, 95% CI: 1.295-1.363, p < 0.05). In subgroup analysis, restricted cubic spline models showed that there was no association between Lp(a) and CVEs in patients in MHN and MHO, while the MUN and MUO groups presented increasing associations between Lp(a) and CVEs and such association was stronger in the MUO group. In Cox regression analysis, Lp(a) >50 mg/dl was associated with a 2.032- and 2.206-fold higher risk of subsequent CVEs in the MUO and MUN subgroups, respectively.Conclusion:Among patients with angiography-proven stable CAD, Lp(a) had a more significant prognostic value in both MUO and MUN individuals regardless of obesity, suggesting the importance of screening for cardiovascular risk with Lp(a) in metabolically unhealthy patients.
Frontiers in cardiovascular medicine 2022
