The Neutrophil to Lymphocyte Ratio Modifies Lipoprotein (a)-Related Poor Prognosis in Patients After Percutaneous Coronary Intervention.

Lipoprotein (a) [Lp(a)] could contribute to coronary artery disease (CAD) through proinflammatory effects. The neutrophil to lymphocyte ratio (NLR) is an inflammatory biomarker. We consecutively enrolled 7,922 CAD patients to investigate the synergistic association of Lp(a) and NLR with prognosis in patients undergoing percutaneous coronary intervention (PCI). NLR was calculated as the neutrophil count divided by the lymphocyte count. Cutoff for NLR was a median of 2.07. The threshold value was set at 30 mg/dL for Lp(a). The primary endpoint was major adverse cardiac events (MACEs), including all-cause mortality and myocardial infarction. During 2 years follow-up, 111 (1.40%) MACEs occurred. Lp(a) > 30 mg/dL was associated with an increased MACE risk in participants with NLR ≥2.07 [adjusted hazard ratio (HR), 1.84; 95% CI, 1.12-3.03], but not in participants with NLR <2.07 (adjusted HR, 0.74; 95% CI, 0.38-1.45) (Pinteraction = 0.021). Subgroup analysis demonstrated that the synergistic association of Lp(a) and NLR with prognosis was more pronounced in female patients (Pinteraction = 0.028). This study suggested that combining Lp(a) and NLR may be useful for risk stratification in CAD population.

Association of triglyceride-glucose index with adverse cardiovascular events in patients with established coronary artery disease according to different inflammatory status.

BACKGROUND AND AIMS: This study aimed to investigate the association of the triglyceride-glucose (TyG) index, a simple-but-reliable indicator of insulin resistance, with risk of cardiovascular (CV) events in coronary artery disease (CAD) patients with different inflammation status. METHODS AND RESULTS: We consecutively recruited 20,518 patients with angiograph-proven-CAD from 2017 to 2018 at Fuwai Hospital. Patients were categorized according to baseline TyG index tertiles (T) (tertile 1: ≤8.624; T2: 8.624-9.902 and T3: >9.902) and further assigned into 6 groups by high-sensitivity C-reactive protein (hsCRP) medians. The primary endpoint was CV events including CV death, nonfatal myocardial infarction and nonfatal stroke. During the 3.1-year-follow-up, 618 (3.0%) CV events were recorded. Overall, patients with high TyG index levels (T2 or T3) showed significantly increased risk of CV events (hazard ratio [HR]: 1.24; 95% confidence interval [CI]: 1.01-1.53; HR: 1.33; 95%CI: 1.05-1.68, respectively) compared with those with lowest Tyg index (T1) after adjusting for confounding factors. Upon stratification by hsCRP levels, elevated TyG index was associated with increased risk of CV events only in patients with hsCRP levels > median (per-1-unit-increase HR: 1.39; 95%CI: 1.11-1.74), rather than in those with hsCRP levels ≤ median. Furthermore, adding the TyG index to the predicting model led to a significant improvement in patients with hsCRP > median rather than in those with hsCRP ≤ median. CONCLUSIONS: We firstly found that elevated TyG index levels were associated with increased risk of CV events in CAD patients, especially in those with increased inflammatory status, suggesting that it could help in risk stratification and prognosis in this population.

Triglyceride-glucose index as a suitable non-insulin-based insulin resistance marker to predict cardiovascular events in patients undergoing complex coronary artery intervention: a large-scale cohort study.

BACKGROUND: Insulin resistance (IR), a hallmark of proceeding diabetes and cardiovascular (CV) disease, has been shown to predict prognosis in patients undergoing percutaneous coronary intervention (PCI). The triglyceride-glucose (TyG) index, triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio and metabolic score for insulin resistance (METS-IR) have been shown to be simple and reliable non-insulin-based surrogates for IR. However, limited studies have determined the associations between distinct non-insulin-based IR markers and CV outcomes in patients undergoing complex PCI who are at higher risk of CV events after PCI. Therefore, this study aimed to investigate and compare the prognostic value of these markers in patients undergoing complex PCI. METHODS: This was a descriptive cohort study. From January 2017 to December 2018, a total of 9514 patients undergoing complex PCI at Fuwai Hospital were consecutively enrolled in this study. The 3 IR indices were estimated from the included patients. The primary study endpoint was CV events, defined as a composite of CV death, nonfatal myocardial infarction and nonfatal stroke. RESULTS: During a median follow-up of 3.1 years, 324 (3.5%) CV events occurred. Multivariable Cox regression models showed per-unit increase in the TyG index (hazard ratio [HR], 1.42; 95% confidence interval [CI] 1.13-1.77), rather than per-unit elevation in either Ln(TG/HDL-C ratio) (HR, 1.18; 95%CI 0.96-1.45) or METS-IR (HR, 1.00; 95%CI 0.98-1.02), was associated with increased risk of CV events. Meanwhile, adding the TyG index to the original model led to a significant improvement in C-statistics (0.618 vs. 0.627, P < 0.001), NRI (0.12, P = 0.031) and IDI (0.14%, P = 0.003), whereas no significant improvements were observed when adding Ln (TG/HDL-C ratio) or METS-IR (both P > 0.05) to the original model. CONCLUSIONS: The TyG index, not TG/HDL-C ratio and METS-IR, was positively associated with worse CV outcomes in patients undergoing complex PCI. Our study, for the first time, demonstrated that the TyG index can serve as the suitable non-insulin-based IR marker to help in risk stratification and prognosis in this population.

Glycemic control and cardiovascular outcomes in patients with diabetes and coronary artery disease according to triglyceride-glucose index: a large-scale cohort study.

BACKGROUND: The role of triglyceride-glucose (TyG) index, an insulin resistance indicator, in glycemic management for diabetic patients with coronary artery disease (CAD) was still unknown. Therefore, we aimed to explore the association between glycemic control and cardiovascular (CV) outcomes in patients with diabetes and CAD according to different TyG index levels. METHODS: A total of 9996 diabetic patients with angiograph-proven CAD were consecutively recruited from 2017 to 2018 at Fuwai Hospital. Patients were assigned into 3 groups according to TyG index tertiles (T) (T1: <8.895; T2: 8.895-9.400; T3: ≥9.400). According to American Diabetes Association guidelines, controlled glycemia was defined as targeting glycosylated hemoglobin Alc (HbA1c) < 7%. The primary endpoint was CV events including CV death, nonfatal myocardial infarction, and nonfatal stroke. RESULTS: During a median 3-year follow-up, 381 (3.8%) CV events occurred. Overall, high TyG index (T3) was associated with increased risk of CV events (hazard ratio [HR]: 1.40; 95% confidence interval [CI]: 1.02-1.94) compared with the lowest TyG index (T1) after multivariable adjustment. Upon stratification by the TyG index, in fully adjusted models, controlled glycemia was associated with reduced risk of CV events in the high TyG index (T3) subgroup (HR: 0.64; 95%CI: 0.42-0.96) but not in the low (T1; HR: 0.79; 95%CI: 0.53-1.16) and moderate (T2; HR: 0.84; 95%CI: 0.56-1.25) TyG index subgroups. CONCLUSIONS: Controlled glycemia was associated with improved CV outcomes in patients with diabetes and established CAD, especially in those with high TyG index levels. Our study, for the first time, provided valuable information that TyG index could help making risk stratification on the glycemic management in diabetic patients with CAD.

Impact of Relative Improvement in Quantitative Flow Ratio on Clinical Outcomes After Percutaneous Coronary Intervention　- A Subanalysis of the PANDA III Trial.

BACKGROUND: The clinical impact of relative improvements in coronary physiology in patients receiving percutaneous coronary intervention (PCI) for coronary artery disease (CAD) remains undetermined.Methods and Results: The quantitative flow ratio (QFR) recovery ratio (QRR) was calculated in 1,424 vessels in the PANDA III trial as (post-PCI QFR-pre-PCI QFR)/(1-pre-PCI QFR). The primary endpoint was the 2-year vessel-oriented composite endpoint (VOCE; a composite of vessel-related cardiac death, vessel-related non-procedural myocardial infarction, and ischemia-driven target vessel revascularization). Study vessels were dichotomously stratified according to the optimal QRR cut-off value. During the 2-year follow-up, 41 (2.9%) VOCEs occurred. Low (<0.86) QRR was associated with significantly higher rates of 2-year VOCEs than high (≥0.86) QRR (6.6% vs. 1.4%; adjusted hazard ratio [aHR] 5.05; 95% confidence interval [CI] 2.53-10.08; P<0.001). Notably, among vessels with satisfactory post-procedural physiological results (post-PCI QFR >0.89), low QRR also conferred an increased risk of 2-year VOCEs (3.7% vs. 1.4%; aHR 3.01; 95% CI 1.30-6.94; P=0.010). Significantly better discriminant and reclassification performance was observed after integrating risk stratification by QRR and post-PCI QFR to clinical risk factors (area under the curve 0.80 vs. 0.71 [P=0.010]; integrated discrimination improvement 0.05 [P<0.001]; net reclassification index 0.64 [P<0.001]). CONCLUSIONS: Relative improvement of coronary physiology assessed by QRR showed applicability in prognostication. Categorical classification of coronary physiology could provide information for risk stratification of CAD patients.

High triglyceride-glucose index predicts cardiovascular events in patients with coronary bifurcation lesions: a large-scale cohort study.

BACKGROUND: Coronary bifurcation lesion, as a complex coronary lesion, is associated with higher risk of long-term poor prognosis than non-bifurcation lesions. The triglyceride-glucose (TyG) index has been shown to predict cardiovascular (CV) events in patients with coronary artery disease (CAD). However, the prognostic value of the TyG index in patients with bifurcation lesions who are at high risk of CV events remains undetermined. Therefore, this study aimed to investigate the association between the TyG index and CV events in patients with bifurcation lesions. METHODS: A total of 4530 consecutive patients with angiography-proven CAD and bifurcation lesions were included in this study from January 2017 to December 2018. The TyG index was calculated as Ln [fasting triglyceride (mg/dL) × fasting plasma glucose (mg/dL)/2]. Patients were assigned into 3 groups according to TyG tertiles (T) (T1: <8.633; T2: 8.633-9.096 and T3: ≥9.096). The primary endpoint was CV events, including CV death, nonfatal myocardial infarction and nonfatal stroke at 3-year follow-up. Restricted cubic spline (RCS) analysis, Kaplan-Meier curves and Cox proportional hazard models were used to investigate the associations between the TyG index and study endpoints. RESULTS: During a median follow-up of 3.1 years, 141 (3.1%) CV events occurred. RCS analysis demonstrated a linear relationship between the TyG index and events after adjusting for age and male sex (non-linear P = 0.262). After multivariable adjustments, elevated TyG index (both T2 and T3) was significantly associated with the risk of CV events (hazard ratio [HR], 1.68; 95% confidence interval [CI],1.06-2.65; HR, 2.10; 95%CI, 1.28-3.47, respectively). When study patients were further stratified according to glycemic status, higher TyG index was associated with significantly higher risk of CV events in diabetic patients after adjusting for confounding factors (T3 vs. T1; HR, 2.68; 95%CI, 1.17-6.11). In addition, subgroup analysis revealed consistent associations of the TyG index with 3-year CV events across various subgroups. Furthermore, adding the TyG index to the original model significantly improved the predictive performance. CONCLUSIONS: High TyG index was associated with CV events in patients with bifurcation lesions, suggesting the TyG index could help in risk stratification and prognosis in this population.

Prevalence and prognostic impact of stress-induced hyperglycemia in patients with acute type A aortic dissection.

AIMS: To explore the prevalence of stress-induced hyperglycemia (SIH) in acute type A aortic dissection (ATAAD) patients without diabetes, and its impact on short-term and long-term clinical outcomes. METHODS: A total of 1098 patients with confirmed diagnosis of ATAAD were consecutively enrolled. According to the admission blood glucose (BG), patients were divided into the normoglycemia group (BG < 7.8 mmol/L), mild to moderate SIH group (7.8 ≤ BG < 11.1 mmol/L) and severe SIH group (BG ≥ 11.1 mmol/L). Multivariate regression analysis were used to explore the association between SIH and mortality risk. RESULTS: There were 421 ATAAD patients (38.3%) with SIH, including 361 cases (32.9%) in the mild to moderate group and 60 cases (5.46%) in the severe group. The proportion of high-risk clinical manifestations and conservative treatment was greater in the SIH group than the normoglycemia group. Severe SIH was associated with high risk of 30-day (OR: 3.773, 95%CI: 1.004-14.189, P = 0.0494) and 1-year mortality risk (OR: 3.522 95%CI: 1.018-12.189, P = 0.0469). CONCLUSIONS: Approximately 40% of the patients with ATAAD had SIH, and were more likely to present with high-risk clinical features and receive non-surgical treatment. Severe SIH could be used as an independent predictor of increased short-term and long-term mortality risk and reflect the disease severity of ATAAD.

Association of sleep quality, its change and sleep duration with the risk of type 2 diabetes mellitus: Findings from the English longitudinal study of ageing.

AIMS: This study aimed to evaluate the association of sleep quality and its long-term change with the risk of type 2 diabetes mellitus (T2DM) and to assess the relationship between sleep duration and the risk of T2DM according to categories of sleep quality. MATERIALS AND METHODS: 5728 participants free of T2DM at wave 4 from the English Longitudinal Study of Ageing were included and received a follow-up with a median time of 8 years. We created a sleep quality score to evaluate sleep quality, which was based on three Jenkins Sleep Problems Scale questions (the frequency of feeling hard to fall asleep, waking up at night, and feeling tired in the morning) and one question for rating overall sleep quality. Participants were allocated into three groups according to their baseline sleep quality scores (groups of good [4-8], intermediate [8-12], and poor quality [12-16]). Sleep duration was assessed by a self-reporting sleep hours from each participant. RESULTS: 411 (7.2%) T2DM cases were documented during the follow-up. Compared with the good quality group, subjects with poor sleep quality showed a significantly higher risk of T2DM (hazard ratio (HR) 1.45, confidence interval (CI) 1.09, 1.92). In participants with good baseline sleep quality, those who experienced worsened sleep quality showed a significantly increased T2DM risk (HR 1.77, 95% CI 1.26, 2.49). Type 2 diabetes mellitus risk was not changed regardless of sleep duration in subjects with good quality. Short sleep duration (≤4h) was associated with an elevated T2DM risk in participants with intermediate sleep quality, and both short (≤4h) and prolonged sleep time (≥9h) were associated with an increased T2DM risk in the poor sleep quality group. CONCLUSIONS: Poor sleep quality is correlated with an increase in T2DM risk, and regulating sleep quality to a good range could potentially be an effective approach for preventing T2DM.

Single-Cell Profiling Reveals Sustained Immune Infiltration, Surveillance, and Tumor Heterogeneity in Infiltrative Basal Cell Carcinoma.

Infiltrative basal cell carcinoma (iBCC) is a particularly aggressive subtype of basal cell carcinoma that tends to progress and recur after surgery, and its malignancy is closely related to the tumor microenvironment. In this study, we performed a comprehensive single-cell RNA analysis to profile 29,334 cells from iBCC and adjacent normal skin. We found active immune collaborations enriched in iBCC. Specifically, SPP1+CXCL9/10high macrophage 1 had strong BAFF signaling with plasma cells, and T follicular helper-like cells highly expressed the B-cell chemokine CXCL13. Heterogeneous proinflammatory SPP1+CXCL9/10high macrophage 1 and angiogenesis-related SPP1+CCL2high macrophage 1 were identified within the tumor microenvironment. Interestingly, we found an upregulation of major histocompatibility complex I molecules in fibroblasts in iBCC compared with those in adjacent normal skin. Moreover, MDK signals derived from malignant basal cells were markedly increased, and their expression was an independent factor in predicting the infiltration depth of iBCC, emphasizing its role in driving malignancy and remodeling the tumor microenvironment. In addition, we identified differentiation-associated SOSTDC1+IGFBP5+CTSV+ malignant basal subtype 1 and epithelial-mesenchymal transition-associated TNC+SFRP1+CHGA+ malignant basal subtype 2 cells. The high expression of malignant basal 2 cell markers was associated with the invasion and recurrence of iBCC. Altogether, our study helps to elucidate the cellular heterogeneity in iBCC and provides potential therapeutic targets for clinical research.

Trends in dietary patterns over the last decade and their association with long-term mortality in general US populations with undiagnosed and diagnosed diabetes.

BACKGROUND: Dietary management plays an important role in diabetes care, while the trends in dietary patterns over the last decade in US adults with diagnosed and undiagnosed diabetes remain unknown. This study aims to estimate the dietary patterns over the last decade by baseline diabetes diagnoses and explore their association with long-term prognosis. METHODS: Participants' data were extracted from the National Health and Nutrition Examination Survey (NHANES) 2007-2018, which were divided into three groups according to the diabetes diagnosis: without diabetes, undiagnosed diabetes, and diagnosed diabetes. Healthy eating index (HEI) and dietary inflammatory index (DII) were used to evaluate dietary patterns. Survival analyses were adopted to estimate the association between HEI/DII scores and long-term all-cause mortality and cause-specific mortality. RESULTS: The prevalence of diabetes was increasing among US adults over the last decade. HEI scores of all three groups presented a downward trend in recent years. Participants with undiagnosed diabetes (weighted mean: 50.58, 95% CI: 49.79, 51.36) got significantly lower HEI score in comparison to participants with diagnosed diabetes (weighted mean: 51.59, 95% CI: 50.93, 52.25). Compared with participants without diabetes, participants in the undiagnosed or diagnosed diabetes group had higher DII scores, indicating a higher dietary inflammatory potential. Survival analysis found a significant association between HEI scores and all-cause mortality and death of heart diseases. Similar correlation was observed in DII scores. CONCLUSIONS: Along with the growth in diabetes prevalence in the US, dietary management of people with diabetes is decreasing. The management of US adults' diets needs special attention, and dietary inflammatory potential may be considered in the dietary intervention.

High absolute neutrophil count with type 2 diabetes is associated with adverse outcome in patients with coronary artery disease: A large-scale cohort study.

Background: Inflammatory processes crucially modulate the development, progression, and outcomes of coronary artery disease (CAD). Since hyperglycemia could alter inflammatory responses, this study aimed to investigate the effect of ANC, a novel and rapidly available inflammatory biomarker, on the prognosis of patients undergoing PCI with or without type 2 diabetes (T2D). Methods: A total of 7,826 patients with CAD hospitalized for PCI at Fuwai Hospital were consecutively recruited. According to the median ANC value, patients were stratified as having high ANC (ANC-H) or low ANC (ANC-L) and were further classified into four groups by T2D. The primary endpoint was major adverse cardiovascular and cerebrovascular events (MACCEs), including all-cause mortality, myocardial infarction, stroke, and target vessel revascularization. Results: During a median follow-up of 2.4 years, 509 (6.5%) MACCEs were documented. Diabetic patients with increased ANC were at significantly higher risk of MACCEs (aHR, 1.55; 95% CI, 1.21-1.99; P = 0.001) compared to those in the ANC-L/non-T2D group (P for interaction between T2D and ANC categories = 0.044). Meanwhile, multivariable regression analysis demonstrated the highest MACCE risk in diabetic patients with a higher level of ANC than others (P for trend <0.001). Conclusion: This study suggests that stratification of patients with elevated ANC and T2D could provide prognostic information for CAD patients undergoing PCI.

LIM and Cysteine-Rich Domains 1 Promotes Transforming Growth Factor ß1-Induced Epithelial-Mesenchymal Transition in Human Kidney 2 Cells.

Renal fibrosis is the major pathologic manifestation of chronic kidney disease (CKD). LIM and cysteine-rich domains 1 (LMCD1) is upregulated in the kidney tissue from patients with CKD and the transforming growth factor ß1 (TGF-ß1)-treated human renal tubular epithelial cell line human kidney 2 (HK-2) (Gene Expression Omnibus: GSE66494 and GSE23338). Previously, we have demonstrated that the knockdown of LMCD1 ameliorated renal fibrosis in mice by blocking the activation of the extracellular signal-regulated kinase pathway. In this study, we sought to further investigate whether LMCD1 affects TGF-ß1-induced epithelial-mesenchymal transition (EMT) of kidney tubular epithelial cells and its potential role in the TGF-ß1/Smad signaling pathway. First, we confirmed that LMCD1 expression was increased in the fibrotic kidneys of patients with CKD compared with that in normal kidneys and that LMCD1 was predominantly localized in the renal tubules. LMCD1 and mesenchymal markers were upregulated in obstructed kidney tissues of mice at 21 days after unilateral ureteral obstruction surgery compared with the tissues in sham mice. Next, we demonstrated that TGF-ß1 significantly increased LMCD1 expression through Smad-mediated transcription in HK-2 cells in vitro. In turn, LMCD1 acted as a transcriptional coactivator of E2F transcription factor 1 to promote the transcription of TGF-ß1. Moreover, TGF-ß1 increased the interaction between LMCD1 and Smad ubiquitination regulatory factor 2 (Smurf2) and accelerated Smurf2-mediated LMCD1 degradation via the ubiquitination system. The knockdown of LMCD1 inhibited TGF-ß1-induced EMT in both HK-2 cells and unilateral ureteral obstruction mice. Our results indicate a positive feedback loop between TGF-ß1 and LMCD1 for EMT induction in HK-2 cells and that Smurf2 acts as a negative regulator in this process by accelerating LMCD1 degradation.

HbA1c-based rather than fasting plasma glucose-based definitions of prediabetes identifies high-risk patients with angiographic coronary intermediate lesions: a prospective cohort study.

BACKGROUND: Prediabetes is common and associated with poor prognosis in patients with acute coronary syndrome and those undergoing revascularization. However, the impact of prediabetes on prognosis in patients with coronary intermediate lesions remains unclear. The objective of the current study is to explore the impact of prediabetes and compare the prognostic value of the different definitions of prediabetes in patients with coronary intermediate lesions. METHODS: A total of 1532 patients attending Fuwai hospital (Beijing, China), with intermediate angiographic coronary lesions, not undergoing revascularization, were followed-up from 2013 to 2021. Patients were classified as normal glucose tolerance (NGT), prediabetes and diabetes according to various definitions based on HbA1c or admission fasting plasma glucose (FPG). The primary endpoint was defined as major adverse cardiovascular events (MACE), the composite endpoint of all-cause death, non-fatal myocardial infarction and repeated revascularization therapy. Multivariate cox regression model was used to explore the association between categories of abnormal glucose category and MACE risk. RESULTS: The proportion of patients defined as prediabetes ranged from 3.92% to 47.06% depending on the definition used. A total of 197 MACE occurred during a median follow-up time of 6.1 years. Multivariate cox analysis showed that prediabetes according to the International Expert Committee (IEC) guideline (6.0 ≤ HbA1c < 6.5%) was associated with increased risk of MACE compared with NGT (hazard ratio [HR]: 1.705, 95% confidence interval [CI] 1.143-2.543) and after confounding adjustment (HR: 1.513, 95%CI 1.005-2.277). Consistently, the best cut-off point of glycated haemoglobin (HbA1c) identified based on the Youden's index was also 6%. Restricted cubic spline analysis delineated a linear positive relationship between baseline HbA1c and MACE risk. Globally, FPG or FPG-based definition of prediabetes was not associated with patients' outcome. CONCLUSIONS: In this cohort of patients with intermediate coronary lesions not undergoing revascularization therapy, prediabetes based on the IEC-HbA1c definition was associated with increased MACE risk compared with NGT, and may assist in identifying high-risk patients who can benefit from early lifestyle intervention.

Trends in cardiovascular risk factors control among US adults by glycemic statuses, 2007-2018.

AIMS: Understanding the national trends in cardiovascular risk factors control of individuals with prediabetes and diabetes is critical for diabetes prevention and management. Our study aims to estimate how cardiovascular risk factors changed in US adults with different glycemic statuses between 2007-2008 and 2017-2018. METHODS AND RESULTS: This was a serial cross-sectional study based on the National Health and Nutrition Examination Surveys (between 2007-2008 and 2017-2018 cycle). Non-pregnant American participants aged 20 years or older were included. Cardiovascular risk factors including weight, blood pressure, plasma cholesterol, and smoking by glycemic statuses were estimated. A total of 33 040 American adults were included. From 2007-2008 to 2017-2018, the age-adjusted proportions of individuals who reached weight control (body mass index <30 kg/m2) of both normoglycemia group and prediabetes group had a significant decrease over the study period, while the trend in participants with diabetes was not significant (mean difference: -5.34%, 95% confidence interval: -15.28%, 4.59%; P for trend = 0.298). The age-adjusted means of total cholesterol of all three groups decreased during the study decade (P for trend < 0.010), with participants with diabetes maintaining the lowest level. Individuals with high total cholesterol were more likely to receive statin therapy in the diabetes group. Notably, prediabetes participants had the highest level of total cholesterol and low-density lipoprotein cholesterol and were less likely to achieve lipid control with statin therapy. Sensitivity analysis with the second definition of prediabetes and diabetes resulted in a consistent trend. CONCLUSIONS: In this nationally representative cross-sectional study, we systematically estimated the cardiovascular risk factors control in American adults and found poor weight control in the normoglycemia and prediabetes group. Despite the significant decrease trend of plasma total cholesterol in all groups, the high cholesterol level in the prediabetes group deserves special concern.

This work mapped the changes in key cardiovascular risk factors control of the general US adults with different glycemic statuses from 2007 to 2018. Weight, blood pressure, and smoking control had not significantly improved in American adults with different glycemic statuses. Plasma cholesterol levels had decreased over the study period, but the poor lipid control in the prediabetes group deserves special attention.

Diabetic kidney disease induces transcriptome alterations associated with angiogenesis activity in human mesenchymal stromal cells.

BACKGROUND: Therapeutic interventions that optimize angiogenic activities may reduce rates of end-stage kidney disease, critical limb ischemia, and lower extremity amputations in individuals with diabetic kidney disease (DKD). Infusion of autologous mesenchymal stromal cells (MSC) is a promising novel therapy to rejuvenate vascular integrity. However, DKD-related factors, including hyperglycemia and uremia, might alter MSC angiogenic repair capacity in an autologous treatment approach. METHODS: To explore the angiogenic activity of MSC in DKD, the transcriptome of adipose tissue-derived MSC obtained from DKD subjects was compared to age-matched controls without diabetes or kidney impairment. Next-generation RNA sequencing (RNA-seq) was performed on MSC (DKD n = 29; Controls n = 9) to identify differentially expressed (DE; adjusted p < 0.05, |log2fold change|> 1) messenger RNA (mRNA) and microRNA (miRNA) involved in angiogenesis (GeneCards). Paracrine-mediated angiogenic repair capacity of MSC conditioned medium (MSCcm) was assessed in vitro using human umbilical vein endothelial cells incubated in high glucose and indoxyl sulfate for a hyperglycemic, uremic state. RESULTS: RNA-seq analyses revealed 133 DE mRNAs (77 upregulated and 56 down-regulated) and 208 DE miRNAs (119 up- and 89 down-regulated) in DKD-MSC versus Control-MSC. Interestingly, miRNA let-7a-5p, which regulates angiogenesis and participates in DKD pathogenesis, interacted with 5 angiogenesis-associated mRNAs (transgelin/TAGLN, thrombospondin 1/THBS1, lysyl oxidase-like 4/LOXL4, collagen 4A1/COL4A1 and collagen 8A1/COL8A1). DKD-MSCcm incubation with injured endothelial cells improved tube formation capacity, enhanced migration, reduced adhesion molecules E-selectin, vascular cell adhesion molecule 1 and intercellular adhesion molecule 1 mRNA expression in endothelial cells. Moreover, angiogenic repair effects did not differ between treatment groups (DKD-MSCcm vs. Control-MSCcm). CONCLUSIONS: MSC from individuals with DKD show angiogenic transcriptome alterations compared to age-matched controls. However, angiogenic repair potential may be preserved, supporting autologous MSC interventions to treat conditions requiring enhanced angiogenic activities such as DKD, diabetic foot ulcers, and critical limb ischemia.

The Combined Effect of Systemic Immune-Inflammation Index and Type 2 Diabetes Mellitus on the Prognosis of Patients Undergoing Percutaneous Coronary Intervention: A Large-Scale Cohort Study.

Background: Chronic low-grade inflammation is the common mechanism of both atherosclerosis and type 2 diabetes mellitus (T2DM), and systemic immune-inflammation index (SII) has been emerged as a novel and simple inflammatory biomarker. However, the association between SII and glycemic metabolism and their synergetic effect on the prognosis of coronary artery disease (CAD) patients remains unclear. Methods: A total of 8602 patients hospitalized for percutaneous coronary intervention (PCI) were included. The primary endpoint was major adverse cardiovascular events (MACE), including all-cause death, myocardial infarction (MI), and target vessel revascularization. According to the optimal cut-off value of SII for MACEs, patients were grouped into higher levels of SII (SII-H) and lower levels of SII (SII-L) and further divided by the concomitance of T2DM into four groups: SII-H/T2DM, SII-H/Non-T2DM, SII-L/T2DM, SII-L/Non-T2DM. Results: During a median 2.4-year follow-up, 522 MACEs occurred. The optimal cut-off value of SII for MACEs was 502.5. A 1-unit increase of SII (transformed by natural logarithm) was associated with a 29% increase of MACE risks in the T2DM cohort [adjusted hazard ratio (HR): 1.29, 95% confidence interval (CI): 1.03 to 1.61, P = 0.024], while had no effect in the non-T2DM cohort (HR: 1.03, 95% CI: 0.80 to 1.34, P = 0.800). Compared to those in SII-H/T2DM group, patients in SII-H/Non-T2DM, SII-L/T2DM, SII-L/Non-T2DM had significantly decreased risk of MACEs [adjusted HR: 0.77, 95% CI: 0.61 to 0.98, P = 0.036; adjusted HR: 0.66, 95% CI: 0.50 to 0.87, P = 0.003; adjusted HR: 0.58, 95% CI: 0.45 to 0.74, P < 0.001; respectively]. Multivariable Cox regression analysis also indicated the highest risk in T2DM patients with higher levels of SII than others (P for trend < 0.001). Conclusion: In this large-scale real-world study, diabetic patients with elevated SII levels were associated with worse clinical outcomes after PCI.

Signatures of EMT, immunosuppression, and inflammation in primary and recurrent human cutaneous squamous cell carcinoma at single-cell resolution.

Rationale: The recurrence of cutaneous squamous cell carcinoma (cSCC) after surgery is associated with the reprogramming of the tumor microenvironment (TME), and remains a key factor affecting its outcomes. Methods: We employed single-cell RNA sequencing (scRNA-seq) to examine the dynamic changes in epithelial cells, T cells, myeloid cells, and fibroblasts between primary and recurrent cSCC. Cell clustering, cell trajectory, cell-cell communication, and gene set enrichment analysis were used to investigate the TME heterogeneity between primary and recurrent cSCC. Gene expression differences were monitored by IHC staining. Results: We examined the immunosuppressed microenvironment in recurrent cSCC, which exhibited a T cell-excluded and SPP1+ tumor-associated macrophages (TAMs)-enriched status. In recurrent cSCC, CD8+ T cells showed high exhaustion and low inflammatory features, while SPP1+ TAMs displayed global pro-tumor characteristics, including decreased phagocytosis and inflammation and increased angiogenesis. Furthermore, the subgroups of SPP1+ TAMs harbored distinct functions. SPP1+ CD209high TAMs showed features of phagocytosis, while SPP1+ CD209low TAMs tended to have a high angiogenic ability. A subpopulation of tumor-specific keratinocytes (TSKs) showed significant epithelial-mesenchymal transition (EMT) features in recurrent cSCC, probably due to their active communication with IL7R + cancer-associated fibroblasts (CAFs). Moreover, we found that the pleiotropic growth factor/cytokine Midkine (MDK) could provoke different cell-cell interactions in cSCC with distinctive staging. In primary cSCC, MDK was highly expressed in fibroblasts and could promote their proliferation and block the migration of tumor cells, while in recurrent cSCC, the high expression of MDK in TSKs promoted their proliferation and metastasis. Conclusion: Our study provides insights into the critical mechanisms of cSCC progression, which might facilitate the development of a powerful approach for the prevention and treatment of cSCC recurrence.

Prognostic value of N-terminal Pro-B-Type natriuretic peptide in patients with intermediate coronary lesions.

Background: The optimal treatment strategy for patients with coronary intermediate lesions, defined as diameter stenosis of 50-70%, remains a great challenge for cardiologists. Identification of potential biomarkers predictive of major adverse cardiovascular events (MACEs) risk may assist in risk stratification and clinical decision. Methods: A total of 1,187 patients with intermediate coronary lesions and available N-terminal pro-brain natriuretic peptide (NT-proBNP) levels were enrolled in the current study. A baseline NT-proBNP level was obtained. The primary endpoint was defined as MACEs, the composite endpoint of all-cause death and non-fatal myocardial infarction. A multivariate Cox regression model was used to explore the association between NT-proBNP level and MACE risk. Results: The mean age of the study cohort was 59.2 years. A total of 68 patients experienced MACE during a median follow-up of 6.1 years. Restricted cubic spline analysis delineated a linear relationship between the baseline NT-proBNP level and MACE risk. Both univariate and multivariate analyses demonstrated that an increased NT-proBNP level was associated with an increased risk of MACE [adjusted hazard ratio (HR) per doubling: 1.412, 95% confidence interval (CI): 1.022-1.952, p = 0.0365]. This association remains consistent in clinical meaningful subgroups according to age, sex, body mass index (BMI), and diabetes. Conclusion: An increased NT-proBNP level is associated with an increased risk of MACE in patients with intermediate coronary lesions and may serve as the potential biomarker for risk stratification and treatment decision guidance.

High neutrophil to lymphocyte ratio with type 2 diabetes mellitus predicts poor prognosis in patients undergoing percutaneous coronary intervention: a large-scale cohort study.

BACKGROUND: Inflammation plays a crucial role in the pathogenesis and progression of coronary artery disease (CAD). The neutrophil to lymphocyte ratio (NLR) is a novel inflammatory biomarker and its association with clinical outcomes in CAD patients with different glycemic metabolism after percutaneous coronary intervention (PCI) remains undetermined. Therefore, this study aimed to investigate the effect of NLR on the prognosis of patients undergoing PCI with or without type 2 diabetes mellitus (T2DM). METHODS: We consecutively enrolled 8,835 patients with CAD hospitalized for PCI at Fuwai hospital. NLR was calculated using the following formula: neutrophil (*109/L)/lymphocyte (*109/L). According to optimal cut-off value, study patients were categorized as higher level of NLR (NLR-H) and lower level of NLR (NLR-L) and were further stratified as NLR-H with T2DM and non-T2DM, and NLR-L with T2DM and non-T2DM. The primary endpoint was major adverse cardiovascular and cerebrovascular events (MACCEs), defined as all-cause mortality, myocardial infarction (MI), stroke and target vessel revascularization. RESULTS: A total of 674 (7.6%) MACCEs were recorded during a median follow-up of 2.4 years. The optimal cut-off value of NLR was 2.85 determined by the surv_cutpoint function. Compared to those in the NLR-H/T2DM groups, patients in the NLR-L/non-T2DM, NLR-H/non-T2DM and NLR-L/T2DM groups were at significantly lower risk of 2-year MACCEs [adjusted hazard ratio (HR): 0.67, 95% confidence interval (CI): 0.52 to 0.87, P = 0.003; adjusted HR: 0.62, 95%CI: 0.45 to 0.85, P = 0.003; adjusted HR: 0.77, 95%CI: 0.61 to 0.97, P = 0.025; respectively]. Remarkably, patients in the NLR-L/non-T2DM group also had significantly lower risk of a composite of all-cause mortality and MI than those in the NLR-H/T2DM group (adjusted HR: 0.57, 95%CI: 0.35 to 0.93, P = 0.024). Multivariable Cox proportional hazards model also indicated the highest risk of MACCEs in diabetic patients with higher level of NLR than others (P for trend = 0.009). Additionally, subgroup analysis indicated consistent impact of NLR on MACCEs across different subgroups. CONCLUSIONS: Presence of T2DM with elevated NLR is associated with worse clinical outcomes in CAD patients undergoing PCI. Categorization of patients with elevated NLR and T2DM could provide valuable information for risk stratification of CAD patients.

Elevated cardiac troponin I and short-term mortality in patients with acute type A aortic dissection.

AIMS: To explore the association between elevated cardiac troponin I (cTnI) on 30-day mortality in patients with acute type A aortic dissection (ATAAD). METHODS AND RESULTS: A total of 1321 consecutive patients who were admitted to the emergency department of Fuwai Hospital from January 2016 to December 2020 were enrolled. Patients had computed tomography-confirmed ATAAD and were measured serum cTnI on admission. Patients were divided into the troponin-positive (cTnI > 0.02 ng/mL) or the troponin-negative group (cTnI ≤ 0.02 ng/mL). Troponin was detected by PATHFAST instrument produced by Medins Co., Ltd., and the reference range of normal value is 0-0.02 ng/mL. A total of 522 out of 1321 patients (39.5%) in our study had elevated cTnI, who had higher 30-day mortality rate compared with the troponin-negative group (44.4% vs. 19.4% P < 0.0001). Multivariate logistic regression results showed that elevated cTnI was an independent risk indicator for 30-day mortality (odds ratio: 2.582; 95% confidence interval: 1.357-4.914; P = 0.0039). The addition of elevated cTnI level to a clinical-based risk prediction model resulted in significant incremental prognostic value (AUC difference: 0.0261). CONCLUSION: Elevated cTnI is common in patients with ATAAD, and is associated with increased 30-day mortality risk.