Allele-selective lowering of mutant HTT protein by HTT-LC3 linker compounds.

Accumulation of mutant proteins is a major cause of many diseases (collectively called proteopathies), and lowering the level of these proteins can be useful for treatment of these diseases. We hypothesized that compounds that interact with both the autophagosome protein microtubule-associated protein 1A/1B light chain 3 (LC3)1 and the disease-causing protein may target the latter for autophagic clearance. Mutant huntingtin protein (mHTT) contains an expanded polyglutamine (polyQ) tract and causes Huntington's disease, an incurable neurodegenerative disorder2. Here, using small-molecule-microarray-based screening, we identified four compounds that interact with both LC3 and mHTT, but not with the wild-type HTT protein. Some of these compounds targeted mHTT to autophagosomes, reduced mHTT levels in an allele-selective manner, and rescued disease-relevant phenotypes in cells and in vivo in fly and mouse models of Huntington's disease. We further show that these compounds interact with the expanded polyQ stretch and could lower the level of mutant ataxin-3 (ATXN3), another disease-causing protein with an expanded polyQ tract3. This study presents candidate compounds for lowering mHTT and potentially other disease-causing proteins with polyQ expansions, demonstrating the concept of lowering levels of disease-causing proteins using autophagosome-tethering compounds.

Suppression of toxicity of the mutant huntingtin protein by its interacting compound, desonide.

Identifying inhibitors of pathogenic proteins is the major strategy of targeted drug discoveries. This strategy meets challenges in targeting neurodegenerative disorders such as Huntington's disease (HD), which is mainly caused by the mutant huntingtin protein (mHTT), an "undruggable" pathogenic protein with unknown functions. We hypothesized that some of the chemical binders of mHTT may change its conformation and/or stability to suppress its downstream toxicity, functioning similarly to an "inhibitor" under a broader definition. We identified 21 potential mHTT selective binders through a small-molecule microarray­based screening. We further tested these compounds using secondary phenotypic screens for their effects on mHTT-induced toxicity and revealed four potential mHTT-binding compounds that may rescue HD-relevant phenotypes. Among them, a Food and Drug Administration­approved drug, desonide, was capable of suppressing mHTT toxicity in HD cellular and animal models by destabilizing mHTT through enhancing its polyubiquitination at the K6 site. Our study reveals the therapeutic potential of desonide for HD treatment and provides the proof of principle for a drug discovery pipeline: target-binder screens followed by phenotypic validation and mechanistic studies.

High stress hyperglycemia ratio predicts adverse clinical outcome in patients with coronary three-vessel disease: a large-scale cohort study.

BACKGROUND: Coronary three-vessel disease (CTVD) accounts for one-third of the overall incidence of coronary artery disease, with heightened mortality rates compared to single-vessel lesions, including common trunk lesions. Dysregulated glucose metabolism exacerbates atherosclerosis and increases cardiovascular risk. The stress hyperglycemia ratio (SHR) is proposed as an indicator of glucose metabolism status but its association with cardiovascular outcomes in CTVD patients undergoing percutaneous coronary intervention (PCI) remains unclear. METHODS: 10,532 CTVD patients undergoing PCI were consecutively enrolled. SHR was calculated using the formula: admission blood glucose (mmol/L)/[1.59×HbA1c (%)-2.59]. Patients were divided into two groups (SHR Low and SHR High) according to the optimal cutoff value of SHR. Multivariable Cox regression models were used to assess the relationship between SHR and long-term prognosis. The primary endpoint was cardiovascular (CV) events, composing of cardiac death and non-fatal myocardial infarction (MI). RESULTS: During the median follow-up time of 3 years, a total of 279 cases (2.6%) of CV events were recorded. Multivariable Cox analyses showed that high SHR was associated with a significantly higher risk of CV events [Hazard Ratio (HR) 1.99, 95% Confidence interval (CI) 1.58-2.52, P < 0.001). This association remained consistent in patients with (HR 1.50, 95% CI 1.08-2.10, P = 0.016) and without diabetes (HR 1.97, 95% CI 1.42-2.72, P < 0.001). Additionally, adding SHR to the base model of traditional risk factors led to a significant improvement in the C-index, net reclassification and integrated discrimination. CONCLUSIONS: SHR was a significant predictor for adverse CV outcomes in CTVD patients with or without diabetes, which suggested that it could aid in the risk stratification in this particular population regardless of glucose metabolism status.

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.

Nuclear cGAS suppresses DNA repair and promotes tumorigenesis.

Accurate repair of DNA double-stranded breaks by homologous recombination preserves genome integrity and inhibits tumorigenesis. Cyclic GMP-AMP synthase (cGAS) is a cytosolic DNA sensor that activates innate immunity by initiating the STING-IRF3-type I IFN signalling cascade1,2. Recognition of ruptured micronuclei by cGAS links genome instability to the innate immune response3,4, but the potential involvement of cGAS in DNA repair remains unknown. Here we demonstrate that cGAS inhibits homologous recombination in mouse and human models. DNA damage induces nuclear translocation of cGAS in a manner that is dependent on importin-α, and the phosphorylation of cGAS at tyrosine 215-mediated by B-lymphoid tyrosine kinase-facilitates the cytosolic retention of cGAS. In the nucleus, cGAS is recruited to double-stranded breaks and interacts with PARP1 via poly(ADP-ribose). The cGAS-PARP1 interaction impedes the formation of the PARP1-Timeless complex, and thereby suppresses homologous recombination. We show that knockdown of cGAS suppresses DNA damage and inhibits tumour growth both in vitro and in vivo. We conclude that nuclear cGAS suppresses homologous-recombination-mediated repair and promotes tumour growth, and that cGAS therefore represents a potential target for cancer prevention and therapy.

The impact of fasting stress hyperglycemia ratio, fasting plasma glucose and hemoglobin A1c on in-hospital mortality in patients with and without diabetes: findings from the China acute myocardial infarction registry.

BACKGROUND: Stress hyperglycemia was positively associated with poor prognosis in individuals with acute myocardial infarction (AMI). However, admission glucose and stress hyperglycemia ratio (SHR) may not be the best indicator of stress hyperglycemia. We performed this study to evaluate the comparative prognostic value of different measures of hyperglycemia (fasting SHR, fasting plasma glucose [FPG], and hemoglobin A1c [HbA1c]) for in-hospital mortality in AMI patients with or without diabetes. METHODS: In this prospective, nationwide, multicenter China Acute Myocardial Infarction (CAMI) registry, 5,308 AMI patients including 2081 with diabetes and 3227 without diabetes were evaluated. Fasting SHR was calculated using the formula [(first FPG (mmol/l))/(1.59×HbA1c (%)-2.59)]. According to the quartiles of fasting SHR, FPG and HbA1c, diabetic and non-diabetic patients were divided into four groups, respectively. The primary endpoint was in-hospital mortality. RESULTS: Overall, 225 (4.2%) patients died during hospitalization. Individuals in quartile 4 had a significantly higher rate of in-hospital mortality compared with those in quartile 1 in diabetic cohort (9.7% vs. 2.0%; adjusted odds ratio [OR] 4.070, 95% CI 2.014-8.228) and nondiabetic cohort (8.8% vs. 2.2%; adjusted OR 2.976, 95% CI 1.695-5.224). Fasting SHR was also correlated with higher in-hospital mortality when treated as a continuous variable in diabetic and nondiabetic patients. Similar results were observed for FPG either as a continuous variable or a categorical variable. In addition, fasting SHR and FPG, rather than HbA1c, had a moderate predictive value for in-hospital mortality in patients with diabetes (areas under the curve [AUC] for fasting SHR: 0.702; FPG: 0.689) and without diabetes (AUC for fasting SHR: 0.690; FPG: 0.693). The AUC for fasting SHR was not significantly different from that of FPG in diabetic and nondiabetic patients. Moreover, adding fasting SHR or FPG to the original model led to a significant improvement in C-statistic regardless of diabetic status. CONCLUSIONS: This study indicated that, in individuals with AMI, fasting SHR as well as FPG was strongly associated with in-hospital mortality regardless of glucose metabolism status. Fasting SHR and FPG might be considered as a useful marker for risk stratification in this population. TRIAL REGISTRATION: ClinicalTrials.gov NCT01874691.

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.

Stress hyperglycemia ratio and long-term mortality after acute myocardial infarction in patients with and without diabetes: A prospective, nationwide, and multicentre registry.

AIMS: To assess the predictive value of stress hyperglycemia ratio (SHR) for long-term mortality after acute myocardial infarction (AMI) in patients with and without diabetes. MATERIALS AND METHODS: We evaluated 6892 patients with AMI from the prospective, nationwide, multicentre China Acute Myocardial Infarction registry, of which 2820 had diabetes, and the remaining 4072 were nondiabetic patients. Patients were divided into high SHR and low SHR groups according to the optimal cutoff values of SHR to predict long-term mortality for diabetic and nondiabetic patients, respectively. The primary endpoint was all-cause mortality at 2 years. RESULTS: The optimal cutoff values of SHR for predicting 2-year mortality were 1.20 and 1.08 for the diabetic and nondiabetic population, respectively. Overall, patients with high SHR were significantly associated with higher all-cause mortality compared with those with low SHR, in both diabetic patients (18.5% vs. 9.7%; hazard ratio [HR] 2.01, 95% confidence interval 1.63-2.49) and nondiabetic patients (12.0% vs. 6.4%; HR 1.95, 95%CI 1.57-2.41). After the potential confounders were adjusted, high SHR was significantly associated with higher risks of long-term mortality in both diabetic (adjusted HR 1.73, 95%CI 1.39-2.15) and nondiabetic (adjusted HR 1.63, 95%CI 1.30-2.03) patients. Moreover, adding SHR to the original model led to a slight albeit significant improvement in C-statistic, net reclassification, and integrated discrimination regardless of diabetic status. CONCLUSIONS: This study demonstrated a strong positive association between SHR and long-term mortality in patients with AMI with and without diabetes, suggesting that SHR should be considered a useful marker for risk stratification in these patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT01874691.

Impact of Lipoprotein(a) concentrations on long-term cardiovascular outcomes in patients undergoing percutaneous coronary intervention: A large cohort study.

BACKGROUND AND AIMS: Till now, the prognostic value of lipoprotein(a) [Lp(a)] in patients with coronary artery disease (CAD) who underwent percutaneous coronary intervention (PCI) remains controversial. We therefore conducted this study to evaluate the effect of Lp(a) levels on clinical outcomes in this population. METHODS AND RESULTS: A total of 10,059 CAD patients who underwent PCI were prospectively enrolled in this cohort study, of which 6564 patients had Lp(a) ≤30 mg/dl and 3495 patients had Lp(a) > 30 mg/dl. The primary endpoint was major adverse cardiovascular and cerebrovascular event (MACCE), defined as a composite of all-cause death, myocardial infarction, stroke or unplanned revascularization. Multivariate Cox regression analysis and propensity-score matching analysis were performed. After propensity-score matching, 3449 pairs of patients were identified, and post-matching absolute standardized differences were <10% for all the covariates. At 2.4 years, the risk of MACCE was significantly higher in patients with elevated Lp(a) levels than those with normal Lp(a) levels in both overall population (13.0% vs. 11.4%; adjusted hazard ratio [HR] 1.142, 95% confidence interval [CI] 1.009-1.293; P = 0.040) and propensity-matched cohorts (13.0% vs. 11.2%; HR 1.167, 95%CI 1.019-1.337; P = 0.026). Of note, the predictive value of Lp(a) levels on MACCE tended to be more evident in individuals >65 years or those with left main and/or three-vessel disease. On the contrary, elevated Lp(a) levels had almost no effect on clinical outcomes in patients ≤65 years (P interaction = 0.021) as well as those who had one- or two-vessel coronary artery disease (P interaction = 0.086). CONCLUSION: In CAD patients who underwent PCI, elevated Lp(a) levels were positively related to higher risk of MACCE at 2.4-year follow-up, especially in patients >65 years and those with left main and/or three-vessel disease. REGISTRATION NUMBER: not applicable.

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.

cGAS facilitates sensing of extracellular cyclic dinucleotides to activate innate immunity.

Cyclic dinucleotides (CDNs) are important second messenger molecules in prokaryotes and eukaryotes. Within host cells, cytosolic CDNs are detected by STING and alert the host by activating innate immunity characterized by type I interferon (IFN) responses. Extracellular bacteria and dying cells can release CDNs, but sensing of extracellular CDNs (eCDNs) by mammalian cells remains elusive. Here, we report that endocytosis facilitates internalization of eCDNs. The DNA sensor cGAS facilitates sensing of endocytosed CDNs, their perinuclear accumulation, and subsequent STING-dependent release of type I IFN Internalized CDNs bind cGAS directly, leading to its dimerization, and the formation of a cGAS/STING complex, which may activate downstream signaling. Thus, eCDNs comprise microbe- and danger-associated molecular patterns that contribute to host-microbe crosstalk during health and disease.

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.

Validation of the DAPT score in large-scale consecutive and contemporary patients population in the real world.

Dual antiplatelet therapy (DAPT) score emerged as a tool for quantification of ischemia and bleeding risks. However, there was discrepancy of the prediction ability of DAPT score in previous studies. We aimed to assess the utility of DAPT score in a large-scale cohort of consecutive percutaneous coronary intervention (PCI) patients. This study enrolled 9,114 patients who had undergone PCI at Fuwai Hospital in 2013, adhered to DAPT and were event-free within the first 12 months following PCI. The endpoints included primary ischemic endpoints (major adverse cardiovascular and cerebrovascular events, and myocardial infarction and/or stent thrombosis), and bleeding endpoint from 12 through 24 months after PCI. Patients were classified into low (score <2, n = 3,989) and high (score ≥2, n = 5,125) DAPT score groups. The incidence rates of primary ischemic endpoints and bleeding endpoint were similar between the two groups. Multivariable analysis demonstrated DAPT score not to be an independent predictor of primary ischemic endpoints or bleeding endpoint. Based on receiver operating characteristic curves analysis, the C-statistic of DAPT score for primary ischemic endpoints or bleeding endpoint did not achieve a significant extent. In this large-scale cohort of PCI patients, DAPT score did not discriminate the risks of ischemic and bleeding events.