Serum secreted phosphoprotein 1 level is associated with plaque vulnerability in patients with coronary artery disease.

Background: Vulnerable plaque was associated with recurrent cardiovascular events. This study was designed to explore predictive biomarkers of vulnerable plaque in patients with coronary artery disease. Methods: To reveal the phenotype-associated cell type in the development of vulnerable plaque and to identify hub gene for pathological process, we combined single-cell RNA and bulk RNA sequencing datasets of human atherosclerotic plaques using Single-Cell Identification of Subpopulations with Bulk Sample Phenotype Correlation (Scissor) and Weighted gene co-expression network analysis (WGCNA). We also validated our results in an independent cohort of patients by using intravascular ultrasound during coronary angiography. Results: Macrophages were found to be strongly correlated with plaque vulnerability while vascular smooth muscle cell (VSMC), fibrochondrocyte (FC) and intermediate cell state (ICS) clusters were negatively associated with unstable plaque. Weighted gene co-expression network analysis showed that Secreted Phosphoprotein 1 (SPP1) in the turquoise module was highly correlated with both the gene module and the clinical traits. In a total of 593 patients, serum levels of SPP1 were significantly higher in patients with vulnerable plaques than those with stable plaque (113.21 [73.65 - 147.70] ng/ml versus 71.08 [20.64 - 135.68] ng/ml; P < 0.001). Adjusted multivariate regression analysis revealed that serum SPP1 was an independent determinant of the presence of vulnerable plaque. Receiver operating characteristic curve analysis indicated that the area under the curve was 0.737 (95% CI 0.697 - 0.773; P < 0.001) for adding serum SPP1 in predicting of vulnerable plaques. Conclusion: Elevated serum SPP1 levels confer an increased risk for plaque vulnerability in patients with coronary artery disease.

Circulating secretoneurin level reflects angiographic coronary collateralization in stable angina patients with chronic total occlusion.

OBJECTIVE: To investigate the association between circulating secretoneurin (SN) and angiographic coronary collateralization in stable angina patients with chronic coronary total occlusion (CTO). METHODS: SN concentrations in serum were measured in 641 stable angina patients with CTO by radioimmunoassay. The status of coronary collaterals from the contra-lateral vessel was visually estimated using the Rentrop grading system, and was categorized into poor (grade 0 or 1) or good (grade 2 or 3) collateralization. RESULTS: Serum SN levels were significantly higher in patients with good coronary collaterals compared to those with poor collaterals (175.23 ± 52.09 pmol/L vs. 143.29 ± 42.01 pmol/L, P < 0.001). Serum SN increased stepwise across Rentrop score 0 to 3 (P < 0.001), and increasing SN tertiles were associated with higher proportion of good coronary collateralization (OR, 1.907; 95% CI, 1.558 ~ 2.335, P < 0.001). After adjustment for confounding variables, serum SN (per tertile) remained an independent factor for predicting good coronary collaterals (OR, 1.870; 95% CI, 1.515 ~ 2.309; P < 0.001). Moreover, the diagnostic value of serum SN (per tertile) was consistent after stratifying patients based on gender, age, body mass index, hypertension, diabetes, history of smoking, severity of coronary artery disease and kidney function (OR: 1.511 ~ 2.680, P interaction ≥ 0.327). CONCLUSION: Elevated circulating SN reflects good angiographic coronary collaterals in stable angina patients with CTO. The findings may provide insight into decision-making for these patients.

Long-term glycemic variability predicts compromised development of heart failure with improved ejection fraction: a cohort study.

Background: A substantial portion of heart failure (HF) patients adherent to guideline-directed medical therapies have experienced improved ejection fraction (EF), termed HFimpEF. Glycemic variability (GV) has emerged as a critical cardiometabolic factor. However, the relation between long-term GV and the incidence of HFimpEF is still unclear. Methods: A total of 591 hospitalized HF patients with reduced EF (HFrEF, EF≤ 40%) admitted from January 2013 to December 2020 were consecutively enrolled. Repeat echocardiograms were performed at baseline and after around 12 months. The incidence of HFimpEF, defined as (1) an absolute EF improvement ≥10% and (2) a second EF > 40% and its association with long-term fasting plasma glucose (FPG) variability were analyzed. Results: During a mean follow-up of 12.2 ± 0.6 months, 218 (42.0%) patients developed HFimpEF. Multivariate analysis showed FPG variability was independently associated with the incidence of HFimpEF after adjustment for baseline HbA1c, mean FPG during follow-up and other traditional risk factors (odds ratio [OR] for highest vs. lowest quartile of CV of FPG: 0.487 [95% CI 0.257~0.910]). Evaluation of GV by alternative measures yielded similar results. Subgroup analysis revealed that long-term GV was associated with HFimpEF irrespective of glycemic levels and diabetic conditions. Conclusions: This study reveals that greater FPG variability is associated with compromised development of HFimpEF. A more stable control of glycemic levels might provide favorable effects on myocardial functional recovery in HF patients even without diabetes.

Brachial and central hypertension in relation to coronary stenosis in patients with coronary angiography.

The clinical significance of central beyond brachial blood pressure (BP) remains unclear. In patients who underwent coronary angiography, the authors explored whether elevated central BP would be associated with coronary arterial disease (CAD) irrespective of the status of brachial hypertension. From March 2021 to April 2022, 335 patients (mean age 64.9 years, 69.9% men) hospitalized for suspected CAD or unstable angina were screened in an ongoing trial. CAD was defined if a coronary stenosis of ≥50%. According to the presence of brachial (non-invasive cuff systolic BP ≥140 mmHg or diastolic BP ≥90 mmHg) and central (invasive systolic BP ≥130 mmHg) hypertension, patients were cross-classified as isolated brachial hypertension (n = 23), isolated central hypertension (n = 93), and concordant normotension (n = 100) or hypertension (n = 119). In continuous analyses, both brachial and central systolic BPs were significantly related to CAD with similar standardized odds ratios (OR, 1.47 and 1.45, p < .05). While categorical analyses showed that patients with isolated central hypertension or concordant hypertension had a significantly higher prevalence of CAD and the Gensini score than those with concordant normotension. Multivariate-adjusted OR (95% confidence interval [CI]) for CAD was 2.24 (1.16 to 4.33, p = .009) for isolated central hypertension and 3.02 (1.58 to 5.78, p < .001) for concordant hypertension relative to concordant normotension. The corresponding OR (95% CI) of a high Gensini score was 2.40 (1.26-4.58) and 2.17 (1.19-3.96), respectively. In conclusion, regardless of the presence of brachial hypertension, elevated central BP was associated with the presence and severity of CAD, indicating that central hypertension is an important risk factor for coronary atherosclerosis.

Vasostatin-2 associates with coronary collateral vessel formation in diabetic patients and promotes angiogenesis via angiotensin-converting enzyme 2.

AIMS: Members of the chromogranin family play a role in angiogenesis. One such biologically active peptide, generated through the processing of chromogranin A, is vasostatin-2. This study aimed at assessing the association of serum vasostatin-2 levels with coronary collateral vessels (CCV) in diabetic patients with chronic total occlusions (CTO) and the effects of vasostatin-2 on angiogenesis in diabetic mice with hindlimb or myocardial ischemia. METHODS AND RESULTS: Serum levels of vasostatin-2 in 452 diabetic CTO patients were evaluated. The status of CCV was categorized according to the Rentrop score. Vasostatin-2 recombinant protein or phosphate-buffered saline were then injected intraperitoneally in diabetic mouse models of hindlimb or myocardial ischemia, followed by laser Doppler imaging and molecular biology examinations. The effects of vasostatin-2 were also ascertained in endothelial cells and macrophages, with mechanisms clarified using ribonucleic acid (RNA) sequencing. Serum levels of vasostatin-2 were significantly different and progressively higher across Rentrop score 0, 1, 2, and 3 groups (P < .001), with significantly lower levels in patients with poor CCV (Rentrop score 0 and 1) than in those with good CCV (Rentrop score 2 and 3) (P < .05). Vasostatin-2 significantly promoted angiogenesis in diabetic mice with hindlimb or myocardial ischemia. RNA-seq analyzes verified an angiotensin-converting enzyme 2 (ACE2)-mediated vasostatin-2-induction of angiogenesis in ischemic tissues. CONCLUSION: Lower serum levels of vasostatin-2 are associated with poor CCV in diabetic CTO patients compared with patients with good CCV. Vasostatin-2 significantly promotes angiogenesis in diabetic mice with hindlimb or myocardial ischemia. Such effects are mediated by ACE2.

HbA1c level is associated with the development of heart failure with recovered ejection fraction in hospitalized heart failure patients with type 2 diabetes.

BACKGROUND: Due to advances in medical treatments, a substantial proportion of heart failure (HF) patients with reduced left ventricular ejection fraction (EF, HFrEF) have experienced partial or complete recovery of EF, termed HFrecEF, and markedly improved clinical outcomes. In the present study, we sought to investigate the relationship between glycemic control and the incidence of HFrecEF in hospitalized HFrEF patients with type 2 diabetes mellitus (T2DM). METHODS: A total of 463 hospitalized T2DM patients with HFrEF were consecutively enrolled. Follow-up echocardiogram was performed after around 12 months. Patients who had an absolute EF improvement ≥10% and a second EF > 40% were classified into HFrecEF, and those who did not meet these criteria were defined as persistent HFrEF. RESULTS: During the 12-month follow-up, 44.5% of T2DM patients developed HFrecEF. Patients with HFrecEF had significantly lower HbA1c level than those with persistent HFrEF (6.5% [IQR 5.8% âˆ¼ 7.2%] vs. 6.7% [IQR 6.1% âˆ¼ 7.8%], P = 0.003), especially in HF of an ischemic etiology. HbA1c levels were inversely correlated with changes in EF during follow-up. After multivariate adjustment, every 1% increase in HbA1c conferred a 17.4% (OR: 0.826 [95% CI 0.701-0.968]) lower likelihood of HFrecEF. Compared to patients with good glycemic control (HbA1c ≤ 6.2%), those with poor glycemic control (HbA1c > 7.1%) had a 52.0% (OR: 0.480 [95% CI 0.281-0.811] decreased likelihood of HFrecEF. CONCLUSIONS: This study demonstrates that uncontrolled HbA1c level is associated with compromised development of HFrecEF in T2DM patients with HF, especially in those with an ischemic etiology.

SerpinG1: A Novel Biomarker Associated With Poor Coronary Collateral in Patients With Stable Coronary Disease and Chronic Total Occlusion.

Background This study aimed to explore predictive biomarkers of coronary collateralization in patients with chronic total occlusion. Methods and Results By using a microarray expression profiling program downloaded from the Gene Expression Omnibus database, weighted gene coexpression network analysis was constructed to analyze the relationship between potential modules and coronary collateralization and screen out the hub genes. Then, the hub gene was identified and validated in an independent cohort of patients (including 299 patients with good arteriogenic responders and 223 patients with poor arteriogenic responders). Weighted gene coexpression network analysis showed that SERPING1 in the light-cyan module was the only gene that was highly correlated with both the gene module and the clinical traits. Serum levels of serpinG1 were significantly higher in patients with bad arteriogenic responders than in patients with good arteriogenic responders (472.53±197.16 versus 314.80±208.92 µg/mL; P<0.001) and were negatively associated with the Rentrop score (Spearman r=-0.50; P<0.001). Receiver operating characteristic curve analysis indicated that the area under the curve was 0.77 (95% CI, 0.72-0.81; P<0.001) for serum serpinG1 in prediction of bad arteriogenic responders. After adjusting for traditional cardiovascular risk factors, serum serpinG1 levels (per SD) remained an independent risk factor for bad arteriogenic responders (odds ratio, 2.20 [95% CI, 1.76-2.74]; P<0.001). Conclusions Our findings illustrate that SERPING1 screened by weighted gene coexpression network analysis was associated with poor collateralization in patients with chronic total occlusion.

Serum apolipoprotein A-IV levels are associated with flow-mediated dilation in patients with type 2 diabetes mellitus.

BACKGROUND: Endothelial dysfunction is common in diabetes. Apolipoprotein (apo) A-IV functions to antagonize inflammation and oxidative stress. The present study aimed to investigate the relationship between flow-mediated dilation (FMD) and serum apoA-IV level in type 2 diabetes mellitus (T2DM) patients.  METHODS: A total of 84 T2DM patients with chest discomfort were enrolled in this study. Their baseline characteristics and clinical parameters were documented. Endothelial function of the participants was evaluated by examining FMD of brachial artery. The severity of coronary atherosclerosis was determined by quantitative coronary angiography. Serum apoA-IV levels were measured by ELISA. RESULTS: These diabetic patients were dichotomized into low FMD (n = 42) and high FMD (n = 42) groups. Serum apoA-IV levels were significantly higher in high FMD group than in low FMD group (29.96 ± 13.17 vs 17.69 ± 9.16 mg/dL, P < 0.001). Moreover, the patients were also categorized into three apoA-IV tertile groups. FMD was significantly different across three apoA-IV tertiles (P < 0.001). Serum apoA-IV levels were positively correlated to FMD (r = 0.469, P < 0.001). Logistic regression analysis was performed to determine risk factors for low FMD. apoA-IV levels together with the risk factor hsCRP remained significantly to be independent determinants of low FMD (P < 0.01). Linear regression analysis was performed, and apoA-IV levels together with total-to-HDL cholesterol ratio were independently correlated with FMD (P < 0.01). CONCLUSIONS: Serum apoA-IV levels are associated with FMD, suggesting that apoA-IV protects endothelial function in patients with T2DM.

Serum Uric Acid Is Associated with the Progression of Left Ventricular Diastolic Dysfunction in Apparently Healthy Subjects.

Background: Left ventricular (LV) diastolic dysfunction (LVDD) is the defining feature of heart failure with preserved ejection fraction (HFpEF) and predicts subsequent incident heart failure (HF) and all-cause mortality. Mounting evidence reveals that cardiometabolic risk factors play critical roles in the development of LVDD. In this study, we sought to investigate the relation between serum uric acid (SUA) level and the progression of LVDD in apparently healthy patients. Methods: A total of 1082 apparently healthy subjects without diagnosed cardiovascular disease and LVDD were consecutively enrolled. SUA levels were measured, and repeat echocardiography and tissue Doppler imaging (TDI) were performed at baseline and during 1-year follow-up. Results: By dividing the study population based on quartiles of SUA, we found subjects in higher quartiles had greater increases in TDI-derived early diastolic velocity (e') and E (peak LV filling velocity)/e' ratios during 1-year follow-up. After multivariate adjustment, high SUA persisted to be an independent predictor for the subsequent worsening of LVDD (odds ratio: 1.351 [95% CI 1.125~1.625], per 100 µmol/L SUA). Subgroup analysis suggested that the association between SUA and LVDD development was more pronounced in subjects without other cardiometabolic risk factors involved. Factor analysis demonstrated that high SUA was the major cardiometabolic attribute in patients with LVDD progression. Conclusion: Our findings suggest that high SUA is an independent cardiometabolic risk factor for the progression of LVDD in apparently healthy subjects.

Insulin Resistance Is Associated With Heart Failure With Recovered Ejection Fraction in Patients Without Diabetes.

Background Because of advances in medical treatments, a substantial proportion of patients with heart failure (HF) have experienced recovery of ejection fraction (EF), termed HF with recovered EF (HFrecEF). Insulin resistance (IR) is prevalent in HF and tightly related with prognosis. This study investigates the relationship between IR and the incidence of HFrecEF in patients who are nondiabetic. Methods and Results A total of 262 patients with HF with reduced EF (HFrEF) who were nondiabetic were consecutively enrolled. Patients were classified into HFrecEF (follow-up EF>40% and ≥10% absolute increase) or otherwise persistent HFrEF based on repeat echocardiograms after 12 months. IR was estimated by an updated homeostasis model assessment for IR (HOMA2-IR). The median HOMA2-IR level was 1.05 (interquartile range [IQR], 0.67-1.63) in our cohort of patients with HF who were nondiabetic. During follow-up, 121 (odds ratio [OR], 46.2% [95% CI 40.2-52.2]) patients developed HFrecEF. Compared with patients with HFrEF, patients with HFrecEF had significantly lower HOMA2-IR levels (0.92 [IQR, 0.61-1.37] versus 1.14 [IQR, 0.75-1.78], P=0.007), especially in nonischemic HF. Log2-transformed HOMA2-IR was inversely correlated to improvements in EF (Pearson's r=-0.25, P<0.001). After multivariable adjustment, a doubling of HOMA2-IR was associated with a 42.8% decreased likelihood of HFrecEF (OR, 0.572 [95% CI, 0.385-0.827]). Conclusions This study reveals that IR is independently associated with compromised development of HFrecEF in patients who are nondiabetic.

Diabetic dyslipidemia impairs coronary collateral formation: An update.

Coronary collateralization is substantially impaired in patients with type 2 diabetes and occlusive coronary artery disease, which leads to aggravated myocardial ischemia and a more dismal prognosis. In a diabetic setting, altered serum lipid profiles and profound glycoxidative modification of lipoprotein particles induce endothelial dysfunction, blunt endothelial progenitor cell response, and severely hamper growth and maturation of collateral vessels. The impact of dyslipidemia and lipid-lowering treatments on coronary collateral formation has become a topic of heightened interest. In this review, we summarized the association of triglyceride-based integrative indexes, hypercholesterolemia, increased Lp(a) with its glycoxidative modification, as well as quantity and quality abnormalities of high-density lipoprotein with impaired collateral formation. We also analyzed the influence of innovative lipid-modifying strategies on coronary collateral development. Therefore, clinical management of diabetic dyslipidemia should take into account of its effect on coronary collateralization in patients with occlusive coronary artery disease.

High serum levels of N-epsilon-carboxymethyllysine are associated with poor coronary collateralization in type 2 diabetic patients with chronic total occlusion of coronary artery.

BACKGROUND: The formation of advanced glycation end-products (AGEs) is a crucial risk factor for the pathogenesis of cardiovascular diseases in diabetes. We investigated whether N-epsilon-carboxymethyllysine (CML), a major form of AGEs in vivo, was associated with poor coronary collateral vessel (CCV) formation in patients with type 2 diabetes mellitus (T2DM) and chronic total occlusion (CTO) of coronary artery. METHODS: This study consisted of 242 T2DM patients with coronary angiographically documented CTO. Blood samples were obtained and demographic/clinical characteristics were documented. The coronary collateralization of these patients was defined according to Rentrop or Werner classification. Serum CML levels were evaluated using ELISA assay. Receiver operating characteristic curve and multivariable regression analysis were performed. RESULTS: 242 patients were categorized into poor CCV group or good CCV group (107 vs. 135 by the Rentrop classification or 193 vs. 49 by the Werner classification, respectively). Serum CML levels were significantly higher in poor CCV group than in good CCV group (110.0 ± 83.35 vs. 62.95 ± 58.83 ng/ml by the Rentrop classification and 94.75 ± 78.29 ng/ml vs. 40.37 ± 28.69 ng/ml by Werner classification, both P < 0.001). Moreover, these CML levels were also significantly different across the Rentrop and Werner classification subgroups (P < 0.001). In multivariable logistic regression, CML levels (P < 0.001) remained independent determinants of poor CCV according to the Rentrop or Werner classification after adjustment of traditional risk factors. CONCLUSIONS: This study suggests that higher serum CML level is associated with poor collateralization in T2DM patients with CTO.

One-year outcome of single-stent crossover versus accurate ostial stenting for isolated left anterior descending ostial stenosis.

BACKGROUND: The optimal strategy of percutaneous coronary intervention (PCI) for isolated left anterior descending (LAD) ostial lesions remains debatable. This study aimed to compare clinical outcomes of patients with isolated LAD ostial stenosis treated by single-stent crossover versus accurate ostial stenting. METHODS: A total of 216 eligible consecutive patients with isolated de novo LAD ostial stenosis were enrolled, and were stratified according to the stenting techniques. Clinical follow-up was performed by review of medical charts or telephone contact with the patients, and repeat angiography was made at 9-12 months after the procedure. Major adverse cardiovascular events (MACE) including cardiac death, myocardial infarction, non-fatal stroke and target vessel revascularization (TVR) were recorded. RESULTS: Single-stent crossover and accurate ostial stenting were applied to 78 (36%) and 138 (64%) patients, respectively. During a mean of 13 ± 4.1 months of follow-up, the rate of composite MACE (19.6 vs. 8.9%; P = 0.040) was higher in LAD ostial stenosis patients treated with accurate ostial stenting than those treated with single-stent crossover technique, mainly driven by more frequent TVR (17.4 vs. 7.7%; P = 0.048). PCI strategy was an independent predictor of MACE (hazard ratio 2.561; 95% CI, 1.041-6.299; P = 0.021) in the multivariable Cox regression analysis. CONCLUSIONS: Our retrospective study suggests that the single-stent crossover technique is associated with a better 1-year clinical outcome compared with accurate ostial stenting in patients with isolated LAD ostial stenosis.

Analysis of risk factors for early stent thrombosis in the Chinese population: A multicenter restrospective study.

BACKGROUND: The predictive scoring systems for early stent thrombosis (EST) remains blank in China. The study aims to evaluate the risk factors and conduct a prediction model of EST in the Chinese population. METHODS: EST was defined as thrombosis that occurs within the first 30 days after primary percutaneous coronary intervention (PCI). Patients from ten Chinese hospitals diagnosed as stent thrombosis (ST) from January 2010 to December 2016 were retrospectively included as the study group. A control group (1 case:2 controls) was created by including patients without ST, major adverse cardiovascular events, or cerebrovascular events during follow-up. The present study evaluated 426 patients with single-vessel lesions and ultimately included 40 patients with EST and 80 control patients, who were included to identify factors that predicted EST and to develop a prediction scoring system. The other 171 patients without integrated 1:2 pair were used for external validation. RESULTS: EST was independently associated with a low hemoglobin concentration (adjusted odds ratio [OR] 0.946, 95% confidence interval [95% CI] 0.901-0.993, P=0.026), a high pre-PCI Synergy between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery (SYNTAX) score (OR 1.166, 95% CI 1.049-1.297, P=0.004), and a DAPT (DAPT) duration of <30 days (OR 28.033, 95% CI 5.302-272.834, P<0.001). The simple EST prediction score provided an area under the curve (AUC) of 0.854 (95% CI 0.777-0.932, P<0.001) with 70.0% sensitivity and 90.0% specificity, and 0.742 (95% CI 0.649-0.835, P<0.001) with 54.5% sensitivity and 81.0% specificity for external validation dataset. CONCLUSIONS: EST may be independently associated with DAPT discontinuation within 30 days, a low hemoglobin concentration, and a high SYNTAX score. The scoring system also has a good ability to predict the risk of EST and may be useful in the clinical setting.

Impact of glycemic control on the association of endothelial dysfunction and coronary artery disease in patients with type 2 diabetes mellitus.

BACKGROUND: We investigated whether glycemic control affects the relation between endothelial dysfunction and coronary artery disease in patients with type 2 diabetes mellitus (T2DM). METHODS: In 102 type 2 diabetic patients with stable angina, endothelial function was evaluated using brachial artery flow-mediated dilation (FMD) with high-resolution ultrasound, and significant stenosis of major epicardial coronary arteries (≥ 50% diameter narrowing) and degree of coronary atherosclerosis (Gensini score and SYNTAX score) were determined. The status of glycemic control was assessed by blood concentration of glycated hemoglobin (HbA1c). RESULTS: The prevalence of significant coronary artery stenosis (67.9% vs. 37.0%, P = 0.002) and degree of coronary atherosclerosis (Gensini score: 48.99 ± 48.88 vs. 15.07 ± 21.03, P < 0.001; SYNTAX score: 15.88 ± 16.36 vs. 7.28 ± 10.54, P = 0.003) were higher and FMD was lower (6.03 ± 2.08% vs. 6.94 ± 2.20%, P = 0.036) in diabetic patients with poor glycemic control (HbA1c ≥ 7.0%; n = 56) compared to those with good glycemic control (HbA1c < 7.0%; n = 46). Multivariate regression analysis revealed that tertile of FMD was an independent determinant of presence of significant coronary artery stenosis (OR = 0.227 95% CI 0.056-0.915, P = 0.037), Gensini score (ß = - 0.470, P < 0.001) and SYNTAX score (ß = - 0.349, P = 0.004) in diabetic patients with poor glycemic control but not for those with good glycemic control (P > 0.05). CONCLUSION: Poor glycemic control negatively influences the association of endothelial dysfunction and coronary artery disease in T2DM patients.

Using circulating O-sulfotyrosine in the differential diagnosis of acute kidney injury and chronic kidney disease.

BACKGROUND: Sulfation of tyrosine, yielding O-sulfotyrosine, is a common but fixed post-translational modification in eukaryotes. Patients with increased circulating O-sulfotyrosine levels experience a faster decline in renal function with progression to end-stage renal disease (ESRD). In the present study, we measured serum O-sulfotyrosine levels in individuals with chronic kidney disease (CKD) and acute kidney injury (AKI) to explore its ability to differentiate AKI from CKD. METHODS: A total of 135 patients (20 with AKI and 115 with CKD) were recruited prospectively for liquid chromatography-mass spectrometry assessment of circulating O-sulfotyrosine. We also studied C57BL/6 mice with CKD after 5/6 nephrectomy (Nx). Blood samples were drawn from the tail vein on Day 1, 3, 5, 7, 14, 30, 60, and 90 after CKD. Serum separation and characterization of creatinine, blood urea nitrogen (BUN), and O-sulfotyrosine was performed. Thus, the time-concentration curves of the O-sulfotyrosine level demonstrate the variation of kidney dysfunction. RESULTS: The serum levels of O-sulfotyrosine were markedly increased in patients with CKD compared with AKI. Median O-sulfotyrosine levels in CKD patients versus AKI, respectively, were as follows:243.61 ng/mL(interquartile range [IQR] = 171.90-553.86) versus 126.55 ng/mL (IQR = 48.19-185.03, P = 0.004). In patients with CKD, O-sulfotyrosine levels were positively correlated with creatinine, BUN, and Cystatin C (r = 0.63, P < 0.001; r = 0.49, P < 0.001; r = 0.61, P < 0.001, respectively) by the multivariate linear regression analysis (ß = 0.71, P < 0.001; ß = 0.40, P = 0.002; ß = 0.73, P < 0.001, respectively). However, this association was not statistically significant in patients with AKI (r = - 0.17, P = 0.472; r = 0.11, P = 0.655; r = 0.09, P = 0.716, respectively). The receiver operating characteristic (ROC) analysis illustrated that the area under the curve was 0.80 (95% confidence interval [CI] 0.71-0.89; P < 0.001) and the optimal cut-off value of serum O-sulfotyrosine suggesting AKI was < 147.40 ng/mL with a sensitivity and specificity of 80.90 and 70.00% respectively. In animal experiments, serum levels of O-sulfotyrosine in mice were elevated on Day 7 after 5/6 nephrectomy (14.89 ± 1.05 vs. 8.88 ± 2.62 ng/mL, P < 0.001) until Day 90 (32.65 ± 5.59 vs. 8.88 ± 2.62 ng/mL, P < 0.001). CONCLUSION: Serum O-sulfotyrosine levels were observed correlated with degrading renal function and in CKD patients substantially higher than those in AKI patients. Thus serum O-sulfotyrosine facilitated the differential diagnosis of AKI from CKD.

Circulating Chromogranin B Is Associated With Left Ventricular Functional Recovery After Successful Recanalization of Chronic Total Occlusion.

Background: Chromogranin B (CgB) is increased in heart failure and proportionate to disease severity. We investigated whether circulating CgB level is associated with left ventricular (LV) functional recovery potential after successful recanalization of chronic total occlusion (CTO). Methods: Serum levels of CgB were assayed in 53 patients with stable angina with LV functional recovery [an absolute increase in LV ejection fraction (EF) of ≥5%] and 53 age- and sex-matched non-recovery controls after successful recanalization of CTO during 12-month follow-up. Results: We found that CgB level was significantly lower in the recovery group than in the non-recovery group (593 [IQR 454-934] vs. 1,108 [IQR 696-2020] pg/ml, P < 0.001), and that it was inversely correlated with changes in LVEF (Spearman's r = -0.31, P = 0.001). Receiver operating characteristic (ROC) analysis showed that the area under the curve of CgB for predicting LVEF improvement was 0.76 (95% CI 0.664-0.856), and that the optimal cutoff value was 972.5 pg/ml. In multivariate analyses, after adjusting for confounding factors, high CgB level remained an independent determinant of impaired LV functional recovery after CTO recanalization. LV functional improvement appeared to be more responsive to CgB in patients with poor than with good coronary collaterals. Conclusions: Elevated circulating CgB level confers an increased risk of impaired LV functional recovery after successful recanalization of CTO in patients with stable coronary artery disease.

Visit-to-visit HbA1c variability is associated with in-stent restenosis in patients with type 2 diabetes after percutaneous coronary intervention.

BACKGROUND: Patients with type 2 diabetes are under substantially higher risk of in-stent restenosis (ISR) after coronary stent implantation. We sought to investigate whether visit-to-visit HbA1c variability is a potential predictor of ISR in diabetic patients after stent implantation. METHODS: We consecutively enrolled type 2 diabetic patients who underwent successful elective percutaneous coronary intervention and performed follow-up coronary angiography after around 12 months. The incidence of ISR and its relationship with visit-to-visit HbA1c variability, expressed as coefficient of variation (CV), standard deviation (SD) and variability independent of the mean (VIM), were studied. Multivariable Cox proportional hazards models were constructed to analyze the predictive value of HbA1c variability for ISR. RESULTS: From September 2014 to July 2018 in Ruijin Hospital, a total of 420 diabetic patients (688 lesions) after stent implantation were included in the final analysis. During a mean follow-up of 12.8 ± 1.3 months, the incidence of ISR was 8.6%, which was significantly increased in patients with higher CV of HbA1c (P = 0.001). The mean diameter stenosis (DS), net luminal loss and net luminal gain were 22.9 ± 16.8%, 0.42 ± 0.88 mm and 1.66 ± 0.83 mm, respectively. Greater DS was observed in subjects with higher tertiles of CV of HbA1c (P < 0.001), and this trend was more prominent in patients with optimal glycemic control (HbA1c ≤ 7%) in the baseline. In multivariate analysis, HbA1c variability was independently associated with incidence of ISR after adjustment for traditional risk factors and mean HbA1c (HR: 3.00 [95% CI 1.14-7.92] for highest vs. lowest tertile). Inclusion of CV of HbA1c led to a better risk stratification accuracy. Assessing HbA1c variability by SD or VIM yielded similar findings. CONCLUSIONS: This study suggests that visit-to-visit HbA1c variability is an independent predictor of incidence of ISR in patients with type 2 diabetes after stent implantation. Trial registration NCT02089360: NCT.

Visit-to-visit fasting plasma glucose variability is associated with left ventricular adverse remodeling in diabetic patients with STEMI.

BACKGROUND: Patients with type 2 diabetes mellitus (T2DM) are predisposed to poor cardiovascular outcomes after ST-segment elevation myocardial infarction (STEMI). Left ventricular adverse remodeling (LVAR) triggered upon myocardial infarction is recognized as the predominant pathological process in the development of heart failure. In the present study, we sought to investigate whether visit-to-visit fasting plasma glucose (FPG) variability is a potential predictor of LVAR in T2DM patients after STEMI. METHODS: From January 2014 to December 2018 in Ruijin Hospital, T2DM patients with STEMI who underwent primary percutaneous coronary intervention were consecutively enrolled and followed up for ~ 12 months. The changes in left ventricular geometric and functional parameters between baseline and 12-month follow-up were assessed by echocardiography. The incidence of LVAR, defined as 20% increase in indexed left ventricular end-diastolic volume (LVEDV), and its relationship with visit-to-visit FPG variability were analyzed. Multivariate regression models were constructed to test the predictive value of FPG variability for post-infarction LVAR. RESULTS: A total of 437 patients with type 2 diabetes and STEMI were included in the final analysis. During a mean follow-up of 12.4 ± 1.1 months, the incidence of LVAR was 20.6% and mean enlargement of indexed LVEDV was 3.31 ± 14.4 mL/m2, which was significantly increased in patients with higher coefficient variance (CV) of FPG (P = 0.002) irrespective of baseline glycemic levels. In multivariate analysis, FPG variability was independently associated with incidence of post-infarction LVAR after adjustment for traditional risk factors, baseline HbA1c as well as mean FPG during follow-up (OR: 3.021 [95% CI 1.081-8.764] for highest vs. lowest tertile of CV of FPG). Assessing FPG variability by other two measures, including standard deviation (SD) and variability independent of the mean (VIM), yielded similar findings. CONCLUSIONS: This study suggests that visit-to-visit FPG variability is an independent predictor of incidence of LVAR in T2DM patients with STEMI. Trial registration Trials number, NCT02089360; registered on March 17,2014.

Impact of coronary collateralization on long-term clinical outcomes in type 2 diabetic patients after successful recanalization of chronic total occlusion.

BACKGROUND: To assess the prognostic role of coronary collaterals in patients with type 2 diabetes mellitus (T2DM) after successful percutaneous coronary intervention (PCI) for chronic total occlusion (CTO). METHODS: Coronary collateralization was graded according to Rentrop scoring system in 198 type 2 diabetic patients and 335 non-diabetics with stable angina undergoing PCI for at least one CTO lesion. Left ventricular ejection fraction (LVEF) was determined and major adverse cardio-cerebral events (MACCE) were recorded during follow-up. RESULTS: Poor collateralization was more common in patients with T2DM than in non-diabetics (40% vs 29%, p = 0.008). At 13.5 ± 4.1 months, the rate of composite MACCE (17.3% vs 27.6%, p = 0.034) and repeat revascularization (15.2% vs 25.5%, p = 0.026) was lower and the increase in LVEF (3.10% vs 1.80%, p = 0.024) was greater in patients with good collaterals than in those with poor collaterals for non-diabetic group. The associations were in the same direction for T2DM group (35% vs 44%; 30% vs 36%; 2.14% vs 1.65%, respectively) with a higher all-cause mortality in diabetic patients with poor collaterals (p = 0.034). Multivariable Cox proportional hazards analysis showed that coronary collateralization was an independent factor for time to MACCE (HR 2.155,95% CI 1.290-3.599, p = 0.003) and repeat revascularization (HR 2.326, 95% CI 1.357-3.986, p = 0.002) in non-diabetic patients, but did not enter the model in those with T2DM. CONCLUSIONS: T2DM is associated with reduced coronary collateralization. The effects of the status of coronary collateralization on long-term clinical outcomes and left ventricular function appear to be similar in size in type 2 diabetic patients and non-diabetics after successful recanalization of CTO.