刘明名
中国医学科学院阜外医院 血脂中心
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:Hypertension is a known risk factor for cardiovascular disease; however, its impact on clinical outcomes in patients with heterozygous familial hypercholesterolemia (HeFH) is unclear. Hence, we aimed to investigate the effects of hypertension on severity of coronary artery atherosclerosis and cardiovascular outcomes in patients with HeFH.METHODS:A total of 480 patients with clinical or molecular diagnosis of definite or probable familial hypercholesterolemia according to Dutch Lipid Clinic Network criteria (DLCN score ≥6) were included in the study. They were divided into the two groups according to their blood pressure status: hypertension group and normotension group. The severity of coronary stenosis was assessed by a number of diseased vessels, Gensini, Syntax, and Jeopardy scores. All individuals were followed up for cardiovascular events (CVEs) and cox proportion hazard models were used to evaluate the association of hypertension with cardiovascular outcomes.RESULTS:Patients with hypertension had more severe coronary stenosis and a higher incidence of CVEs compared with the ones with normotension (log-rank P < 0.001). After multivariable adjustment, there was a 2.1-fold increased risk of CVEs among patients with hypertension compared with patients with normotension (adjusted hazard ratio 2.06, 95% confidential interval 1.17-3.65, P < 0.01). Hypertension control status was also associated with CVEs even after adjustment of multiple variables. However, no combined effect on increased cardiovascular risks was detected in this HeFH cohort.CONCLUSION:In patients with HeFH, hypertension is an independent risk factor for cardiovascular events. Moreover, blood pressure control status in patients with hypertension is associated with the worse outcomes.
Journal of hypertension 2022
AIMS:Type 2 diabetes mellitus (T2DM) is an independent risk factor for cardiovascular disease. However, the association between T2DM and coronary artery disease (CAD) in patients with heterozygous familial hypercholesterolaemia (HeFH) has not been thoroughly evaluated. Our study aimed to assess the effect of T2DM on CAD severity and hard cardiovascular endpoints in a HeFH cohort.METHODS AND RESULTS:A total of 432 patients with HeFH with a molecular and/or clinical Dutch Lipid Clinic Network score ≥6 (definite and probable) were enrolled. Patients were divided into a T2DM group (n = 99) and a non-T2DM group (n = 333). The severity of coronary stenosis was assessed by the number of diseased vessels and Gensini, SYNTAX, and Jeopardy scores. Hard endpoints included a composite of non-fatal myocardial infarction, non-fatal stroke, and cardiac death. Cox regression and Kaplan-Meier analyses were used to evaluate the effect of T2DM on hard cardiovascular endpoints. The prevalence of CAD was higher in patients with T2DM compared with those without (96.0% vs. 77.5%, respectively; P < 0.001). Patients with T2DM demonstrated a greater number of diseased vessels (P = 0.029) and more severe coronary lesions with high Gensini, SYNTAX, and Jeopardy score tertiles (P = 0.031, P = 0.001, and P = 0.024, respectively). During a median of 3.75 years up to a maximum of 9 years of follow-up, hard endpoints occurred in 13 of 99 patients with T2DM and 16 of 333 without T2DM at baseline. Compared with patients without T2DM, patients with T2DM were at a significantly greater risk of hard endpoints [multivariate adjusted hazard ratio (HR) 2.32, 95% confidence interval (CI) 1.02-4.84; P = 0.025]. Additionally, patients with T2DM and good glucose control (HbA1c < 7.0%) were at a lower risk of hard endpoints compared with those with poor glucose control (HbA1c ≥ 7.0%, HR 0.08, 95% CI 0.01-0.56; P = 0.011).CONCLUSION:We conclude that T2DM is an independent predictor of CAD severity when assessed by number of diseased vessels, Gensini, SYNTAX, Jeopardy scores, and hard cardiovascular endpoints, suggesting that T2DM could be further used for risk stratification of patients with HeFH.
European journal of preventive cardiology 2022
BACKGROUND:Non-fasting blood samples are routinely used to assess plasma lipid profiles except in patients with severe hypertriglyceridemia according to the previous consensus. However, the impact of statin use on non-fasting plasma lipid measurements has not been thoroughly evaluated.METHODS:In this cross-sectional study, 686 patients with normal triglyceride (TG) levels, who were hospitalized due to chest pain, were enrolled. Fasting (8-12 h) and non-fasting (2-4 h after breakfast) lipid profiles were measured on the second day of admission. Patients were divided into the non-statin (n=499) group and statin treatment (n=187) group. Differences in fasting and non-fasting lipid profiles between the statin and non-statin groups were compared.RESULTS:The mean age of participants was 57±13 years, and 54.4% were male. A linear correlation was observed between fasting and non-fasting lipid profiles. Although a postprandial impact on lipid parameters was observed, the general pattern of differences between fasting and non-fasting lipids was similar in both groups. Additionally, the diff(%) [(non-fasting-fasting)/fasting ×100%] of lipid panels did not vary by statin treatment. Moreover, no effects of statin types or duration of use on non-fasting lipid profiles were identified.CONCLUSIONS:The current study found fasting and non-fasting lipid panels were similar in individuals with or without statin treatment. Non-fasting lipid panels were not significantly affected by statin types or duration of use, suggesting that non-fasting lipid measurement is an acceptable test for patients receiving statin treatment.
Annals of translational medicine 2021
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 (β = - 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.
Thrombosis journal 2021
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.
Journal of translational medicine 2021
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.
Cardiovascular diabetology 2020
BACKGROUND:Data are limited with regard to the relationship of albuminuria and major adverse cardiovascular events (MACE) in Chinese elder patients with high cardiovascular risk.METHODS:We did a retrospective cohort study using Chinese elder patients with high cardiovascular risks (n = 1474) to identify the association of albumin-to-creatinine ratio (ACR) and the incidence of MACE and all-cause mortality. Individuals were followed up from January, 2002 to November, 2007. The all-cause mortality and MACE, composite outcome of cardiovascular death, myocardial infarction, stroke and hospitalization of congestive heart failure were defined as primary endpoint.RESULTS:During the median following up of 56 months, 213 patients developed primary endpoint and 117 patients died. Patients with higher baseline urinary ACR (> 30 mg/g) experienced a nearly 2-fold of all-cause mortality and a 3-fold of heart failure hospitalization than those with lower baseline urinary ACR (≤10 mg/g).MACE, cardiovascular death, stoke and myocardial infarction showed no difference in three grades of urinary ACR (> 30 mg/g, 10 mg/g-30 mg/g, ≤10 mg/g) in this cohort. Patients above 65 years with increased ACR tended to experience higher mortality risks, and the association of increased ACR with higher hospitalization of congestive heart failure seemed to be more prominent in patients below 65 years than above 65 years.CONCLUSIONS:In this post hoc analysis of Chinese individuals with high cardiovascular risks, higher urinary ACR was associated with higher all-cause mortality and heart failure hospitalization. Further studies are needed to find out whether there is age-specific ACR cutoff point.
Clinical hypertension 2018
