Assessment of platelet functional activity in healthy individuals and patients receiving antiplatelet therapy. Possible inconsistencies between aggregation and flow cytometry tests.

Platelet functional activity was assessed in healthy volunteers (HV, n=92), patients with stable angina pectoris (SA, n=42) and acute coronary syndrome (ACS, n=73), treated with acetylsalicylic acid (ASA) + clopidogrel and ASA + ticagrelor, respectively. In all HV and patients we have compared parameters of platelet aggregation (maximum light transmission and velocity, Tmax and Vmax) and parameters, characterizing exposure of platelet activation markers, evaluated by flow cytometry. HV platelets were activated by 10 µM, 1 µM TRAP, and 20 µM, 5 µM, 2.5 µM ADP; patient platelets were activated by 10 µM TRAP and by 20 µM and 5 µM ADP. Strong and significant correlations between the aggregation and flow cytometry parameters (the r correlation coefficient from 0.4 up to >0.6) most frequently were registered in HV platelet during activation by 1 µM TRAP and in SA patients during platelet activation by 20 µM and 5 µM ADP. However, in many other cases these correlations were rather weak (r < 0.3) and sometimes statistically insignificant. In HV the differences in PAC-1 binding parameters between platelets activated by 10 µM TRAP (the strongest agonist) and all ADP concentrations were negligible (≤ 10%), while CD62P binding (at all ADP concentrations) and LTA parameters for (5 µM and 2.5 µM ADP) were significantly lower (by 40-60%). Antiplatelet therapy in patients decreased all parameters as compared to HV, but to varying extents. For 10 µM TRAP the MFI index for PAC-1 binding (40-50% decrease) and for both ADP concentrations the Tmax values (60-85% decrease) appeared to be the most sensitive in comparison with the other parameters that decreased to a lesser extent. The data obtained indicate a possibility of inconsistency between different LTA and flow cytometry parameters in assessing platelet activity and efficacy of antiplatelet drugs.

The impact of statins treatments for plaque characteristics in stable angina pectoris patients with very low and high low-density lipoprotein cholesterol levels: an intracoronary optical coherence tomography study.

Low-density lipoprotein cholesterol (LDL-C) levels are recommended according to the patient's risk factors based on guidelines. In patients achieving low LDL-C levels, the need for statins is uncertain, and the plaque characteristics of patients not treated with statins are unclear. In addition, the difference in plaque characteristics with and without statins is unclear in similarly high LDL levels. We evaluate the impact of statins on plaque characteristics on optical coherence tomography (OCT) in patients with very low LDL-C levels and high LDL-C levels. A total of 173 stable angina pectoris patients with 173 lesions undergoing OCT before percutaneous coronary intervention were evaluated. We divided the LDL-C levels into three groups: < 70 mg/dL (n = 48), 70 mg/dL ≤ LDL-C < 100 mg/dL (n = 71), and ≥ 100 mg/dL (n = 54). Among patients with LDL-C < 70 mg/dL, patients not treated with statins showed a significantly higher C-reactive protein level (0.27 ± 0.22 mg/dL vs. 0.15 ± 0.19 mg/dL, p = 0.049), and higher incidence of thin-cap fibroatheromas (TCFAs; 44% [7/16] vs. 13% [4/32], p = 0.021) than those treated with statins. Among patients with LDL-C level ≥ 100 mg/dL, patients treated with statins showed a significantly higher prevalence of familial hypercholesterolemia (FH) (38% [6/16] vs. 5% [2/38], p = 0.004), lower incidence of TCFAs (6% [1/16] vs. 39% [15/38], p = 0.013), healed plaques (13% [2/16] vs. 47% [18/38], p = 0.015), and higher incidence of fibrous plaques (75% [12/16] vs. 42% [16/38], p = 0.027) than patients not treated with statins. While patients achieved a low LDL-C, patients not treated with statins had high plaque vulnerability and high systemic inflammation. While patients had a high LDL-C level with a high prevalence of FH, patients treated with statins had stable plaque characteristics.

Association between dietary macronutrient composition and plasma one-carbon metabolites and B-vitamin cofactors in patients with stable angina pectoris.

Elevated plasma concentrations of several one-carbon metabolites are associated with increased CVD risk. Both diet-induced regulation and dietary content of one-carbon metabolites can influence circulating concentrations of these markers. We cross-sectionally analysed 1928 patients with suspected stable angina pectoris (geometric mean age 61), representing elevated CVD risk, to assess associations between dietary macronutrient composition (FFQ) and plasma one-carbon metabolites and related B-vitamin status markers (GC-MS/MS, LC-MS/MS or microbiological assay). Diet-metabolite associations were modelled on the continuous scale, adjusted for age, sex, BMI, smoking, alcohol and total energy intake. Average (geometric mean (95 % prediction interval)) intake was forty-nine (38, 63) energy percent (E%) from carbohydrate, thirty-one (22, 45) E% from fat and seventeen (12, 22) E% from protein. The strongest associations were seen for higher protein intake, i.e. with higher plasma pyridoxal 5'-phosphate (PLP) (% change (95 % CI) 3·1 (2·1, 4·1)), cobalamin (2·9 (2·1, 3·7)), riboflavin (2·4 (1·1, 3·7)) and folate (2·1 (1·2, 3·1)) and lower total homocysteine (tHcy) (-1·4 (-1·9, -0·9)) and methylmalonic acid (MMA) (-1·4 (-2·0, -0·8)). Substitution analyses replacing MUFA or PUFA with SFA demonstrated higher plasma concentrations of riboflavin (5·0 (0·9, 9·3) and 3·3 (1·1, 5·6)), tHcy (2·3 (0·7, 3·8) and 1·3 (0·5, 2·2)) and MMA (2·0 (0·2, 3·9) and 1·7 (0·7, 2·7)) and lower PLP (-2·5 (-5·3, 0·3) and -2·7 (-4·2, -1·2)). In conclusion, a higher protein intake and replacing saturated with MUFA and PUFA were associated with a more favourable metabolic phenotype regarding metabolites associated with CVD risk.

Decreased serum SIRT6 as a novel predictor of coronary artery disease.

OBJECTIVE: SIRT6 is an NAD-dependent histone deacetylase known to regulate aging, inflammation and energy metabolism, and might play an important role in atherosclerosis. However, whether it also plays a role in coronary artery disease (CAD) remains unclear. PATIENTS AND METHODS: In this study, we detected the expression of SIRT6 in serum by Western blotting. The concentrations of SIRT6 in serum specimens from 69 patients with CAD [30 with stable angina (SA) and 39 with acute coronary syndrome (ACS)] and 16 controls were analysed using the enzyme-linked immunosorbent assay (ELISA) method. RESULTS: Western blotting analysis of the serum samples found that SIRT6 expression was decreased in the SA group (p=0.000) and ACS group (p=0.000) compared with the control group. Significantly lower levels of serum SIRT6 were observed in SA patients (18.80±9.14 ng/mL) and ACS patients (16.85±9.66 ng/mL) than in healthy controls (25.79±14.23 ng/mL). SIRT6 concentrations were positively correlated with other markers of CAD, such as high-density lipoprotein cholesterol (r=0.362, p<0.01) and age (r=0.265, p<0.05), and negatively correlated with blood glucose (r=-0.284, p<0.05). Multivariate logistic regression analysis demonstrated that lower SIRT6 levels were independently associated with the presence of CAD in men (OR=0.817, 95% CI 0.694-0.962, p=0.015). Receiver operating characteristic (ROC) curve analysis showed that lower serum SIRT6 could distinguish CAD patients (AUC, 0.726; 95% CI, 0.508-0.943; p=0.041) from controls. SIRT6 is found downregulated in blood vessels of atherosclerotic APOE-/- mice and human aorta arteries. CONCLUSIONS: We demonstrated that SA and ACS patients had lower serum concentrations of SIRT6. The decreased serum SIRT6 level was independently associated with the diagnosis of CAD. SIRT6 may play a cardioprotective role in CAD patients, and future research is required to address this issue.

Triglycerides and low HDL cholesterol predict coronary heart disease risk in patients with stable angina.

We assessed whether high triglycerides (TG) and low high-density lipoprotein cholesterol (HDL-C) levels, expressed by an increased TG/HDL-C ratio, predict coronary atherosclerotic disease (CAD) outcomes in patients with stable angina. We studied 355 patients (60 ± 9 years, 211 males) with stable angina who underwent coronary computed tomography angiography (CTA), were managed clinically and followed for 4.5 ± 0.9 years. The primary composite outcome was all-cause mortality and non-fatal myocardial infarction. At baseline, the proportion of males, patients with metabolic syndrome, diabetes and obstructive CAD increased across TG/HDL-C ratio quartiles, together with markers of insulin resistance, hepatic and adipose tissue dysfunction and myocardial damage, with no difference in total cholesterol or LDL-C. At follow-up, the global CTA risk score (HR 1.06, 95% confidence interval (CI) 1.03-1.09, P = 0.001) and the IV quartile of the TG/HDL-C ratio (HR 2.85, 95% CI 1.30-6.26, P < 0.01) were the only independent predictors of the primary outcome. The TG/HDL-C ratio and the CTA risk score progressed over time despite increased use of lipid-lowering drugs and reduction in LDL-C. In patients with stable angina, high TG and low HDL-C levels are associated with CAD related outcomes independently of LDL-C and treatments.Trial registration. EVINCI study: ClinicalTrials.gov NCT00979199, registered September 17, 2009; SMARTool study: ClinicalTrials.gov NCT04448691, registered June 26, 2020.

Relation of renal function to mid-term prognosis of stable angina patients with high- or low-dose pitavastatin treatment: REAL-CAD substudy.

BACKGROUND: It has not yet been established whether higher-dose statins have beneficial effects on cardiovascular events in patients with stable coronary artery disease (CAD) and renal dysfunction. METHODS: The REAL-CAD study is a prospective, multicenter, open-label trial. As a substudy, we categorized patients by an estimated glomerular filtration rate (eGFR) as follows: eGFR ≥60 (n = 7,768); eGFR ≥45 and <60 (n = 3,176); and eGFR <45 mL/Min/1.73 m2 (n = 1,164), who were randomized to pitavastatin 4mg or 1mg therapy. The primary endpoint was a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal ischemic stroke, or unstable angina, and was assessed by the log-rank test and Cox proportional hazards model. RESULTS: The baseline characteristics and medications were largely well-balanced between two groups. The magnitude of low-density lipoprotein cholesterol (LDL-C) reduction at 6 months in high- and low-dose pitavastatin groups was comparable among all eGFR categories. During a median follow-up of 3.9 years, high- compared with low-dose pitavastatin significantly reduced cardiovascular events in patients with eGFR ≥60 (hazard ratio (HR) 0.73; 95% confidence interval (CI) 0.58-0.91; P = .006), and reduced but not significant for patients with eGFR ≥45 and <60 (HR 0.85; 95% CI, 0.63-1.14; P = .27) or eGFR <45 mL/Min/1.73 m2 (HR 0.90; 95% CI 0.62-1.33; P = .61). An interaction test of treatment by eGFR category was not significant (P value for interaction = .30). CONCLUSION: Higher-dose pitavastatin therapy reduced LDL levels and cardiovascular events in stable CAD patients irrespective of eGFR level, although the effect on events appeared to be numerically lower in patients with lower eGFR.

Machine Learning Identifies Metabolic Signatures that Predict the Risk of Recurrent Angina in Remitted Patients after Percutaneous Coronary Intervention: A Multicenter Prospective Cohort Study.

Recurrent angina (RA) after percutaneous coronary intervention (PCI) has few known risk factors, hampering the identification of high-risk populations. In this multicenter study, plasma samples are collected from patients with stable angina after PCI, and these patients are followed-up for 9 months for angina recurrence. Broad-spectrum metabolomic profiling with LC-MS/MS followed by multiple machine learning algorithms is conducted to identify the metabolic signatures associated with future risk of angina recurrence in two large cohorts (n = 750 for discovery set, and n = 775 for additional independent discovery cohort). The metabolic predictors are further validated in a third cohort from another center (n = 130) using a clinically-sound quantitative approach. Compared to angina-free patients, the remitted patients with future RA demonstrates a unique chemical endophenotype dominated by abnormalities in chemical communication across lipid membranes and mitochondrial function. A novel multi-metabolite predictive model constructed from these latent signatures can stratify remitted patients at high-risk for angina recurrence with over 89% accuracy, sensitivity, and specificity across three independent cohorts. Our findings revealed reproducible plasma metabolic signatures to predict patients with a latent future risk of RA during post-PCI remission, allowing them to be treated in advance before an event.

Elevated plasma fatty acid-binding protein 3 is related to prolonged corrected QT interval and reduced ejection fraction in patients with stable angina.

Background: Higher concentrations of plasma fatty acid-binding protein 3 (FABP3) play a role in the development of cardiovascular events, cerebrovascular deaths, and acute heart failure. However, little is known about the relationship between plasma FABP3 level and prolonged QT interval and reduced ejection fraction (EF). This study aimed to investigate the relationship between plasma FABP3 level and prolonged corrected QT (QTc) interval and reduced EF in patients with stable angina. Inflammatory cytokine and adipocytokine levels were also measured to investigate their associations with plasma FABP3. Methods: We evaluated 249 consecutive patients with stable angina. Circulating levels of FABP3 were measured by ELISA. In addition, 12-lead ECG and echocardiography recordings were obtained from each patient. Results: Multiple regression analysis showed that high-density lipoprotein cholesterol, high sensitivity C-reactive protein (hs-CRP), white blood cell (WBC) count, visfatin, adiponectin, FABP4, heart rate, QTc interval, left atrial diameter, left ventricular mass index, end-systolic volume, end-systolic volume index, fractional shortening, and EF were independently associated with FABP3 (all p<0.05). Patients with an abnormal QTc interval had a higher median plasma FABP3 level than those with a borderline and normal QTc interval. With increasing FABP3 tertiles, the patients had higher frequencies of abnormal QTc interval, left ventricular systolic dysfunction, and all-cause mortality, incrementally lower EF, higher WBC count, and higher levels of hs-CRP, visfatin, adiponectin, and FABP4. Conclusion: This study indicates that plasma FABP3 may act as a surrogate parameter of prolonged QTc interval and reduced EF in patients with stable angina, partially through the effects of inflammation or cardiomyocyte injury. Further studies are required to elucidate whether plasma FABP3 plays a role in the pathogenesis of QTc prolongation and reduced EF.

Relationship Between Systemic Immune-Inflammation Index (SII) and the Severity of Stable Coronary Artery Disease.

Systemic immune-inflammation index (SII; platelet count × neutrophil-to-lymphocyte ratio), a novel marker, predicts adverse clinical outcomes in coronary artery diseases (CAD). We hypothesized that SII could provide more valuable information in assessing the severity of CAD than ratios obtained from other white blood cell subtypes. Patients (n = 669) who underwent coronary angiography were analyzed in this retrospective study. We analyzed the relation between the SII and the angiographic severity of CAD. The severity of coronary atherosclerosis was determined by the SYNTAX score (SxS). Patients with CAD were divided into 3 groups according to the SxS. Multivariate logistic analysis was used to assess risk factors of CAD. In multivariate logistic regression analysis, the SII (odds ratio: 1.004; 95% CI: 1.001-1.007; P = .015) was an independent predictor of high SxS. Additionally, there was a positive correlation between SII and SxS (Rho: 0.630, P ≤ .001). In the receiver-operating characteristic curve analysis, SII with an optimal cutoff value of 750 × 103 predicted the severe coronary lesion with a sensitivity of 86.2% and specificity of 87.3%. The SII, an inexpensive and easily measurable laboratory variable, was significantly associated with the severity of CAD and high SxS in patients with stable angina pectoris.

Effect of DLT-SML on Chronic Stable Angina Through Ameliorating Inflammation, Correcting Dyslipidemia, and Regulating Gut Microbiota.

ABSTRACT: Chronic stable angina (CSA) is caused by coronary atherosclerosis. The gut microbiota (GM) and their metabolite trimethylamine-N-oxide (TMAO) levels are associated with atherosclerosis. Danlou tablet (DLT) combined with Salvia miltiorrhiza ligustrazine (SML) injection has been used to treat CSA. This study aims to investigate how DLT combined with SML (DLT-SML) regulates serum lipids, inflammatory cytokines, GM community, and microbial metabolite in patients with CSA. In this study, 30 patients with CSA were enrolled in the DLT-SML group, and 10 healthy volunteers were included in the healthy control group. The patients in the DLT-SML group were subdivided as the normal total cholesterol (TC) group and high-TC group according to their serum TC level before treatment. Blood samples were collected to investigate the (1) lipid content, including triglyceride (TG), TC, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol, (2) fasting blood glucose (Glu), (3) inflammatory cytokines, including interleukin-1 beta (IL-1ß), interleukin-6 (IL-6), interleukin-10 (IL-10), and tumor necrosis factor-α (TNF-α), and (4) gut-derived metabolite, including lipopolysaccharides and TMAO level. GM composition was analyzed by sequencing 16S rRNA of fecal samples. Results showed that DLT-SML significantly decreased serum TG, TC, low-density lipoprotein cholesterol, IL-1ß, TNF-α, and TMAO levels of patients with CSA. DLT-SML increased the abundance of Firmicutes and decreased Proteobacteria, which were significantly lower or higher in patients with CSA, respectively, compared with the healthy control group. In particular, DLT-SML increased the microbial diversity and decreased Firmicutes/Bacteroidetes ratio of patients with high-TC. The abundance of Sarcina, Anaerostipes, Streptococcus, Weissella, and Erysipelatoclostridium was decreased, whereas Romboutsia, Faecalibacterium, and Subdoligranulum were increased by DLT-SML treatment in patients with CSA. These findings indicated that DLT-SML improved patients with CSA by ameliorating dyslipidemia profile, decreasing the circulating inflammatory cytokines, and regulating the GM composition and their metabolites.

Increased Circulating Cathepsin L in Patients with Coronary Artery Disease.

Cathepsin L (CatL) is a potent collagenase involved in atherosclerotic vascular remodeling and dysfunction in animals and humans. This study investigated the hypothesis that plasma CatL is associated with the prevalence of coronary artery disease (CAD). Between February May 2011 and January 2013, 206 consecutive subjects were enrolled from among patients who underwent coronary angiography and percutaneous coronary intervention treatment. Age-matched subjects (n = 215) served as controls. Plasma CatL and high-sensitive C-reactive protein (hs-CRP) and high-density lipoprotein cholesterol were measured. The patients with CAD had significantly higher plasma CatL levels compared to the controls (1.4 ± 0.4 versus 0.4 ± 0.2 ng/mL, P < 0.001), and the patients with acute coronary syndrome had significantly higher plasma CatL levels compared to those with stable angina pectoris (1.7 ± 0.7 versus 0.8 ± 0.4 ng/mL, P < 0.01). Linear regression analysis showed that overall, the plasma CatL levels were inversely correlated with the high-density lipoprotein levels (r = -0.32, P < 0.01) and positively with hs-CRP levels (r = 0.35, P < 0.01). Multiple logistic regression analyses shows that cathepsin L levels were independent predictors of CAD (add ratio, 1.8; 95% CI, 1.2 to 2.1; P < 0.01). These data demonstrated that increased levels of plasma CatL are closely associated with the presence of CAD and that circulating CatL serves as a useful biomarker for CAD.

Circulating hepassocin level in patients with stable angina is associated with fatty liver and renal function.

Background: Chronic kidney disease (CKD) is a major risk factor for coronary artery disease and it is often associated with hepatic steatosis. Hepassocin (also known as hepatocyte-derived fibrinogen related protein or fibrinogen-like 1) is a novel hepatokine that causes hepatic steatosis and induces insulin resistance. However, the role of hepassocin in renal function status remains unclear. Our objective was to investigate the association of plasma hepassocin level with fatty liver and renal function status in patients with stable angina. Methods: Plasma hepassocin levels were determined by enzyme-linked immunosorbent assays in 395 consecutive patients with stable angina. Renal function was defined as an estimated glomerular filtration rate (eGFR). Fatty liver was defined by ultrasonography and fibrosis-4 (FIB-4) index. Results: With increasing hepassocin tertiles, patients had higher prevalence of fatty live, an increased waist-to-hip ratio, and neutrophil count, monocyte count, and FIB-4 index, higher levels of uric acid, blood urine nitrogen and higher sensitivity C-reactive protein. They also had incrementally lower eGFR, serum hemoglobin and albumin levels. In multiple linear stepwise regression analysis, only eGFR was significantly independent negatively associated with plasma hepassocin levels. Conclusion: Our results indicate that circulating hepassocin in patients with stable angina is associated with fatty liver and renal function, which suggests that increased plasma hepassocin may be involved in the pathogenesis of fatty liver and CKD.

Association of lower vitamin D levels with inflammation and leucocytes parameters in patients with and without diabetes mellitus undergoing coronary angiography.

BACKGROUND: Diabetes mellitus has been associated with a chronic low-grade inflammation and a higher risk of cardiovascular and infectious disease, that could be prevented by the effects of vitamin D. We aimed at evaluating the impact of vitamin D levels on the biomarkers of acute-phase response, inflammation and glucose metabolism in a large cohort of diabetic patients with cardiovascular disease. MATERIALS AND METHODS: Consecutive patients undergoing coronary angiography were included. Diabetes mellitus was defined as previous diagnosis, specific treatment administration (oral drug or insulin), fasting glycaemia >6.99 mmol/L or HbA1c >48 mmol/L. Glucose parameters, white blood cells, Neutrophil-to-Lymphocyte Ratio (NLR), Monocyte-to-Lymphocyte Ratio (MLR), C-reactive protein (CRP) and vitamin D were measured at admission. Vitamin D levels were measured by chemiluminescence immunoassay kit LIAISON® Vitamin D assay (Diasorin Inc). RESULTS: We included 1472 diabetic patients and 2499 non-diabetic patients that were divided according to vitamin D tertiles. Among diabetic patients, lower levels of vitamin D were associated with female gender (P = .02), obesity (P = .004), active smoking and acute presentation (P < .001) and with a more atherogenic metabolic profile. The levels of white blood cells, leucocytes subfamilies, and inflammatory parameters significantly correlated with vitamin D levels in both patients with and without diabetes (diabetic: P = .012 for WBC, P = .004 for NLR and P < .001 for MLR and C-reactive protein, non-diabetic: P < .001 for WBC; NLR, MLR and C-reactive protein, respectively). Among diabetic patients, results were confirmed at multivariate analysis with no significant interaction according to glycaemic control. CONCLUSION: The present study demonstrates that, among patients with cardiovascular disease, vitamin D deficiency is associated with metabolic dysregulation and with an elevation of cellular and humoural inflammatory parameters, especially among diabetics, although not being dependent from glycaemic control.

Correlation of Serum Adipolin with Epicardial Fat Thickness and Severity of Coronary Artery Diseases in Acute Myocardial Infarction and Stable Angina Pectoris Patients.

OBJECTIVE: Adipolin/C1q/TNF-related protein-12 is a family of CTRPs highly expressed in adipose tissue with glucose-lowering and anti-inflammatory effects. Various risk factors have been suggested in the incidence of cardiovascular diseases, such as a decrease in anti-inflammatory or an increase in inflammatory factors. The purpose of the present study was to investigate the correlation of adipolin with anthropometric, angiographic, echocardiographic, and biochemical parameters. SUBJECT AND METHODS: A total of 90 patients who were candidates for angiography were included in the study and divided into 3 groups: 30 patients with acute myocardial infarction (AMI), 30 patients with stable angina pectoris (SAP), and 30 subjects as a control group with a history of chest pain but normal angiography. Anthropometric, angiographic, echocardiographic, and biochemical parameters were measured in all subjects. RESULTS: Serum adipolin levels were significantly decreased in patients with AMI compared with the SAP and control groups (p < 0.001 for both). In addition, there was a negative association between serum levels of adipolin and epicardial fat thickness (EFT) and Gensini score in CAD patients. The results of multivariate linear regression analysis revealed that EFT values were independently associated with serum adipolin levels. CONCLUSION: The current study showed an independent association of adipolin with EFT for the first time in patients with AMI. Decreased adipolin levels in patients with AMI may be involved in the process of atherosclerosis, which requires further study.

Postexercise troponin I levels in patients with suspected stable ischemic heart disease.

BACKGROUND AND AIMS: Previous studies showed that troponin blood levels may increase after exercise. In this study, we assessed whether, among patients with suspected of having stable angina, the increase in troponin I (TnI) levels after exercise stress test (EST) might help identify those with obstructive coronary artery disease (CAD) and myocardial ischemia. METHODS: We performed maximal treadmill EST in 50 patients (age 64 ±â€Š9 years; 38 men) admitted to our Cardiology Department to undergo elective coronary angiography because of a suspicion of stable angina. TnI was measured before and 12 h after EST. RESULTS: TnI increased after EST compared with baseline in the whole population (from 0.44 ±â€Š0.76 to 0.84 ±â€Š1.12 ng/dl, P < 0.001). No difference in TnI increase was observed between patients with obstructive CAD (n = 29; 0.61 ±â€Š0.90-1.13 ±â€Š1.33 ng/dl) and no obstructive CAD (NO-CAD; n = 21; 0.21 ±â€Š0.46-0.44 ±â€Š0.54 ng/dl; P = 0.51). There was also no significant difference in post-EST TnI increase between patients with positive EST (n = 34; 0.56 ±â€Š0.89-1.05 ±â€Š1.28 ng/dl) or negative EST (n = 16; 0.19 ±â€Š0.26-0.39 ±â€Š0.43 ng/dl; P = 0.16). Moreover, no significant difference was observed in the post-EST TnI increase among groups of patients with positive EST and obstructive CAD, positive EST and NO-CAD, negative EST and obstructive CAD and negative EST and NO-CAD (P = 0.12). No clinical or EST variable was associated with post-EST TnI increase, although there was a tendency for a greater increase in those achieving a heart rate more than 85 vs. less than 85% of maximal predicted heart rate during EST (P = 0.075). CONCLUSION: TnI increase after EST in patients with suspected stable angina is largely independent of the results of coronary angiography and EST.

Colchicine Inhibits Neutrophil Extracellular Trap Formation in Patients With Acute Coronary Syndrome After Percutaneous Coronary Intervention.

Background Release of neutrophil extracellular traps (NETs) after percutaneous coronary intervention (PCI) in acute coronary syndrome (ACS) is associated with periprocedural myocardial infarction, as a result of microvascular obstruction via pro-inflammatory and prothrombotic pathways. Colchicine is a well-established anti-inflammatory agent with growing evidence to support use in patients with coronary disease. However, its effects on post-PCI NET formation in ACS have not been explored. Methods and Results Sixty patients (40 ACS; 20 stable angina pectoris) were prospectively recruited and allocated to colchicine or no treatment. Within 24 hours of treatment, serial coronary sinus blood samples were collected during PCI. Isolated neutrophils from 10 patients with ACS post-PCI and 4 healthy controls were treated in vitro with colchicine (25 nmol/L) and stimulated with either ionomycin (5 µmol/L) or phorbol 12-myristate 13-acetate (50 nmol/L). Extracellular DNA was quantified using Sytox Green and fixed cells were stained with Hoechst 3342 and anti-alpha tubulin. Baseline characteristics were similar across both treatment and control arms. Patients with ACS had higher NET release versus patients with stable angina pectoris (P<0.001), which was reduced with colchicine treatment (area under the curve: 0.58 versus 4.29; P<0.001). In vitro, colchicine suppressed unstimulated (P<0.001), phorbol 12-myristate 13-acetate-induced (P=0.009) and ionomycin-induced (P=0.002) NET formation in neutrophils isolated from patients with ACS post-PCI, but not healthy controls. Tubulin organization was impaired in neutrophils from patients with ACS but was restored by colchicine treatment. Conclusions Colchicine suppresses NET formation in patients with ACS post-PCI by restoring cytoskeletal dynamics. These findings warrant further investigation in randomized trials powered for clinical end points. Registration URL: https://anzctr.org.au; Unique identifier: ACTRN12619001231134.

Association Between Plasma ADAMTS-9 Levels and Severity of Coronary Artery Disease.

Genome-wide association studies have shown that a disintegrin and metalloproteinase with thrombospondin motifs 9 (ADAMTS-9) is associated with the development of atherosclerosis. We assessed the level of ADAMTS-9 in patients with coronary artery disease (CAD) and its severity and prognosis. We selected 666 participants who underwent coronary angiography in our hospital and met the inclusion and exclusion criteria; participants included non-CAD patients, patients with stable angina pectoris (SAP), unstable angina, non-ST-segment elevation myocardial infarction, or ST-segment elevation myocardial infarction. The serum level of ADAMTS-9 was higher in patients with CAD than in non-CAD patients (37.53 ± 8.55 ng/mL vs 12.04 ± 7.02 ng/mL, P < .001) and was an independent predictor for CAD (odds ratio = 1.871, 95% CI: 1.533-2.283, P < .001). Subgroup analysis showed that compared with the SAP group, the acute coronary syndrome groups had higher serum levels of ADAMTS-9. In addition, the level of ADAMTS-9 was related to the SYNTAX score (r = 0.523, P < .001). Patients with acute myocardial infarction (AMI) with elevated levels of ADAMTS-9 had a higher risk of major adverse cardiovascular events (MACE) within 12 months than those with lower levels (log-rank = 4.490, P = .034). Plasma ADAMTS-9 levels may be useful for the diagnosis of CAD and as predictors of MACE in AMI patients.

Usefulness of Lipoprotein (a) for Predicting Outcomes After Percutaneous Coronary Intervention for Stable Angina Pectoris in Patients on Hemodialysis.

Serum lipoprotein (a) level is genetically determined and remains consistent during a person's life. Previous studies have reported that people with high lipoprotein (a) level are at a high risk of cardiac events. We investigated the association between lipoprotein (a) levels and clinical outcomes after percutaneous coronary intervention (PCI) for stable angina pectoris (SAP) in hemodialysis (HD) patients. Serum lipoprotein (a) levels were measured on admission in 410 consecutive HD patients who underwent successful PCI for SAP. Patients were divided into 2 groups: low and high group having lipoprotein (a) level <40 mg/dL (n = 297) and ≧40 mg/dL (n = 113) respectively. After PCI, the incidence of major adverse cardiac event (MACE) including cardiac death, nonfatal myocardial infarction, necessity of a new coronary revascularization procedure (coronary bypass surgery, repeat target lesion PCI, PCI for a new non-target lesion) was analyzed. At a median follow-up of 24 months (12 to 37 months), MACE occurred in 188 patients (45.6%). The rate of MACE rate was significantly higher in the high lipoprotein (a) group than in the low lipoprotein (a) group (59.2% vs 40.7%, long-rank test chi-square = 12.3; p < 0.001). Cox analysis showed that high lipoprotein (a) level (Hazard Ratio, 1.62; 95% Confidence Interval, 1.19 to 2.20; p = 0.002) was an independent predictor for MACE after PCI. In conclusion, high lipoprotein (a) level was associated with a higher incidence of MACE after PCI for SAP in HD patients.

An extracellular vesicle epitope profile is associated with acute myocardial infarction.

The current standard biomarker for myocardial infarction (MI) is high-sensitive troponin. Although powerful in clinical setting, search for new markers is warranted as early diagnosis of MI is associated with improved outcomes. Extracellular vesicles (EVs) attracted considerable interest as new blood biomarkers. A training cohort used for diagnostic modelling included 30 patients with STEMI, 38 with stable angina (SA) and 30 matched-controls. Extracellular vesicle concentration was assessed by nanoparticle tracking analysis. Extracellular vesicle surface-epitopes were measured by flow cytometry. Diagnostic models were developed using machine learning algorithms and validated on an independent cohort of 80 patients. Serum EV concentration from STEMI patients was increased as compared to controls and SA. EV levels of CD62P, CD42a, CD41b, CD31 and CD40 increased in STEMI, and to a lesser extent in SA patients. An aggregate marker including EV concentration and CD62P/CD42a levels achieved non-inferiority to troponin, discriminating STEMI from controls (AUC = 0.969). A random forest model based on EV biomarkers discriminated the two groups with 100% accuracy. EV markers and RF model confirmed high diagnostic performance at validation. In conclusion, patients with acute MI or SA exhibit characteristic EV biomarker profiles. EV biomarkers hold great potential as early markers for the management of patients with MI.

Randomized controlled trial of landiolol, a short-acting beta-1 adrenergic receptor blocker, illustrating changes in high-molecular weight adiponectin levels after elective percutaneous coronary intervention.

Adiponectin (APN) has cardioprotective properties and bisoprolol has been reported to increase myocardial APN expression and reduce myocardial damage. Administration of landiolol, which has a higher cardio-selectivity and shorter half-life than bisoprolol, during the percutaneous coronary intervention (PCI) may increase serum APN and high-molecular weight (HMW)-APN, an active form of APN, in patients with stable angina pectoris (SAP). We recruited 70 patients with SAP and randomized them to intravenous landiolol during PCI (N = 35) or control group (N = 35). The primary endpoint was serum APN and HMW-APN level 3 days after PCI. There was no difference in the primary endpoint between the landiolol and control groups (8.93 ± 5.24 vs. 10.18 ± 5.81 µg/mL, p = 0.35 and 3.36 ± 2.75 vs. 4.28 ± 3.13 µg/mL, p = 0.20) for APN and HMW-APN levels, respectively. APN and HMW-APN level were significantly decreased 1 day after PCI [-0.55 ± 0.92 µg/mL (9.87-9.32 µg/mL), p < 0.001 and -0.20 ± 0.45 µg/mL (3.89-3.69 µg/mL), p < 0.001, respectively]. Additionally, the absolute change in HMW-APN was significantly smaller in the landiolol group compared to the control group (-0.08 ± 0.27 vs. -0.31 ± 0.55 µg/mL, p = 0.031). Multiple linear regression analysis showed that use of landiolol was an independent predictor of change in HMW-APN (ß = 0.276, p = 0.014). Serum APN and HMW-APN level 3 days after PCI were similar between patients treated with and without landiolol. APN and HMW-APN decreased 1 day after PCI in the SAP and landiolol mitigated decrease in HMW-APN.