Low bleeding acceptance is associated with increased death risk in patients with atrial fibrillation on oral anticoagulation.

Bleeding is the most feared complication of anticoagulation. We sought to investigate whether the bleeding risk acceptance has a prognostic value during long-term follow-up in the era of direct oral anticoagulants (DOACs) among patients with atrial fibrillation (AF). We studied 167 consecutive AF outpatients [aged 68.8 SD 10.6 years; 141 (84.4%) on DOACs]. The bleeding acceptance was assessed based on the Bleeding Ratio defined as the declared maximum number of major bleedings that a patient would be willing to accept to prevent one major stroke. We recorded cerebrovascular ischemic events, major or clinically relevant non-major bleeds (CRNMB), and mortality. A median Bleeding Ratio was 4 (IQR 2-5). During follow-up of 946 patient-years, cerebrovascular ischemic events and/or death were observed in 28 patients (3.3%/ year) and major bleeding or CRNMB in 33 (4.6%/ year). The Bleeding Ratio was lower in patients who experienced cerebrovascular events or death (p = 0.004), but not bleeding. Patients with the Bleeding Ratio 0-3 were more often non-persistent to the OAC therapy, and more likely to have cerebrovascular event or die than those with higher bleeding acceptance (odds ratio 2.55; 0.95% CI 1.08-6.02) which was driven by the impact on mortality. The multiple Cox proportional hazards model showed that lower Bleeding Ratio, higher CHA2DS2-VASc score, and older age predicted cerebrovascular events or death during follow-up. AF patients who are willing to accept fewer serious bleedings to avoid major stroke during anticoagulation are more likely to experience death and/or cerebrovascular ischemic events, but not bleeding, what might be related to non-persistence.

In-Hospital Levels of Circulating MicroRNAs as Potential Predictors of Left Ventricular Remodeling Post-Myocardial Infarction.

Background and Objectives: Biochemical and molecular regulation of both adaptive and pathological responses of heart tissue to ischemic injury is widely investigated. However, it is still not fully understood. Several biomarkers are tested as predictors of left ventricle (LV) remodeling after myocardial infarction (MI). The aim of this study was to assess the relationship between selected microRNAs (miRNAs) and LV function and morphology in patients after MI. Materials and Methods: Selected miRNAs related to heart failure were assessed in the acute phase of MI: miR-150-3p, miR-21-5p, miR-19b-3p, miR-155-5p, miR-22-5p. Echocardiography with 3D imaging was performed at baseline and after 6 months. Remodeling was defined as >20% increase in LV end-diastolic volume, whereas reverse remodeling was defined as >10% reduction in LV end-systolic volume. Results: Eighty patients entered the registry. Remodeling occurred in 26% and reverse remodeling was reported in 51% of patients. In the presented study, none of the analyzed miRNAs were found to be a significant LV remodeling predictor. The observed correlations between miRNAs and other circulating biomarkers of myocardial remodeling were relatively weak. Conclusions: Our analysis does not demonstrate an association between the analyzed miRNAs and LV remodeling in patients with MI.

Enhanced neutrophil extracellular traps formation in AF patients with dilated left atrium.

BACKGROUND: Atrial fibrillation (AF) is associated with cardiac remodelling and prothrombotic state. Enhanced neutrophil extracellular traps (NETs) formation has been reported in AF, contributing to thromboembolism. PURPOSE: We investigated whether increased left atrium (LA) diameter and reduced left ventricular ejection fraction (LVEF) affect NETs formation and prothrombotic state in AF patients. METHODS: In 243 AF patients (median CHA2 DS2 -VASc = 4) we measured LA diameter and LVEF, 123 of them with LVEF<50%. Moreover, we determined 3 markers of NETosis: circulating citrullinated histone H3 (H3cit), myeloperoxidase (MPO) and peptidylarginine deiminase 4 (PAD4), along with prothrombotic markers, including endogenous thrombin potential, plasma fibrin clot permeability (Ks ) and clot lysis time (CLT). Ischaemic cerebrovascular events, major bleeding and death were recorded during a median follow-up of 53 months, on anticoagulation. RESULTS: LA diameter correlated positively with H3cit, MPO and PAD4, while LVEF was inversely associated with the same NETosis markers. After adjustment for age and body mass index, concentrations of MPO (per 10 units; ß = -1.9, 95%CI -3.40;-0.42) and H3cit (per 10 units; ß = 2.02, 95%CI 0.61-3.42) were independently associated with LVEF and LA diameter. LA diameter, but not LVEF, correlated inversely with Ks and positively with CLT. The Cox regression analysis revealed that H3cit >6.16 ng/mL (HR = 21.76, 95%CI 2.85-166.28, p = .003) and LA diameter > 46 mm (HR = 2.89, 95%CI 1.04-8.03, p = .043) independently predicted cerebrovascular ischaemic events (1.9%/year). CONCLUSIONS: This hypothesis-generating study suggests that in AF enlarged LA diameter and reduced LVEF are associated with enhanced NETs formation, which might have clinical importance and contribute to thromboembolic events despite anticoagulation.

Elevated factor XIa as a modulator of plasma fibrin clot properties in coronary artery disease.

INTRODUCTION: Patients with coronary artery disease (CAD) display a prothrombotic fibrin clot phenotype, involving low permeability and resistance to lysis. The determinants of this phenotype remain elusive. Circulating tissue factor (TF) and activated factor XI (FXIa) are linked to arterial thromboembolism. We investigated whether detectable active TF and FXIa influence fibrin clot properties in CAD. METHODS: In 118 CAD patients (median age 65 years, 78% men), we assessed Ks, an indicator of clot permeability, and clot lysis time (CLT) in plasma-based assays, along with the presence of active TF and FXIa. We also analysed proteins involved in clotting and thrombolysis, including fibrinogen, plasminogen activator inhibitor-1 (PAI-1) and thrombin activatable thrombolysis inhibitor (TAFI). During a median 106 month (interquartile range 95-119) follow-up, myocardial infarction (MI), stroke, systemic thromboembolism (SE) and cardiovascular (CV) death were recorded. RESULTS: Circulating TF and FXIa, detected in 20.3% and 39.8% of patients, respectively, were associated with low Ks and prolonged CLT. Solely FXIa remained an independent predictor of low Ks and high CLT on multivariable analysis. Additionally, fibrinogen and PAI-1 were associated with low Ks, while PAI-1 and TAFI-with prolonged CLT. During follow-up low Ks and prolonged CLT increased the risk of MI and the latter also a composite endpoint of MI, stroke/SE or CV death. CONCLUSIONS: To our knowledge, this study is the first to show that circulating FXIa is associated with prothrombotic fibrin clot properties in CAD, suggesting additional mechanisms through which FXIa inhibitors could act as novel antithrombotic agents in CAD.

Thrombus containing lesions strategies during primary percutaneous coronary interventions in ST-segment elevation myocardial infarction: insights from ORPKI National Registry.

In the era of potent P2Y12 inhibitors, according to current guidelines, treatment with glycoprotein IIb/IIIa inhibitors (GPIs) should be limited to bail-out and/or highly thrombotic situations. Similarly, the recommendation for aspiration thrombectomy (AT) is downgraded to very selective use. We examine the prevalence, and predictors of GPI and AT use in STEMI patients referred to primary percutaneous coronary intervention (PCI). Data on 116,873 consecutive STEMI patients referred to primary PCI in Poland between 2015 and 2020 were analyzed. GPIs were administered in 29.3%, AT was used in 11.6%, and combined treatment with both in 6.1%. There was a mild trend toward a decrease in GPI and AT usage during the analyzed years. On the contrary, there was a rapid growth of the ticagrelor/prasugrel usage rate from 6.5 to 48.1%. Occluded infarct-related artery at baseline and no-reflow during PCI were the strongest predictors of GPI administration (OR 2.3; 95% CI 2.22-2.38 and OR 3.47; 95% CI 3.13-3.84, respectively) and combined usage of GPI and AT (OR 4.4; 95% CI 4.08-4.8 and OR 3.49; 95% CI 3.08-3.95 respectively) in a multivariate logistic regression model. Similarly, the administration of ticagrelor/prasugrel was an independent predictor of both adjunctive treatment strategies. In STEMI patients in Poland, GPIs are selectively used in one in four patients during primary PCI, and the combined usage of GPI and AT is marginal. Despite the rapid growth in potent P2Y12 inhibitors usage in recent years, GPIs are selectively used at a stable rate during PCI in highly thrombotic lesions.

Factors affecting self-reported bleeding acceptance in acute ischemic stroke survivors on various types of antithrombotic therapy.

OBJECTIVES: Prior ischemic cerebrovascular event and younger age have been shown to increase bleeding acceptance among anticoagulated outpatients with atrial fibrillation (AF). We sought to determine factors affecting bleeding acceptance in acute ischemic stroke (AIS) survivors on various types of antithrombotic therapy. MATERIALS AND METHODS: We enrolled 173 consecutive patients hospitalized for AIS (aged 68.2±11.7 years, 54.9% male), including 54 (31.2%) with AF, who had favorable functional outcome. On discharge, the Bleeding ratio, defined as the declared maximum number of major bleedings that a patient is willing to accept to prevent one major stroke, was evaluated. We assessed the predicted bleeding risk in non-cardioembolic and cardioembolic stroke survivors using S2TOP-BLEED and HAS-BLED scores, respectively. RESULTS: Patients with the low Bleeding ratio, defined as 5 (median) or less accepted bleeds (n=92; 53.2%), were older and more likely to receive thrombolysis and/or thrombectomy, with no impact of previous stroke. Prior major bleed (odds ratio [OR] 4.67; 95% confidence interval [CI] 0.92-23.72), AF with use of oral anticoagulants (OR 2.35, 95% CI 1.12-4.93), reperfusion treatment (OR 1.95, 95% CI 1.02-3.76), and hospitalization ≤10 days (OR 4.56; 95% CI 1.50-13.87) were associated with the low Bleeding Ratio. Prior use of anticoagulants or aspirin as well as HAS-BLED and S2TOP-BLEED scores did not affect the bleeding acceptance. CONCLUSIONS: Lower bleeding acceptance declared on discharge by AIS survivors is determined by prior bleeding, anticoagulation in AF, reperfusion treatment, and duration of hospitalization, which might affect medication adherence. The results might help optimize post-discharge management and educational efforts in patients on antithrombotic therapy.

Effect of series of periodic limb movements in sleep on blood pressure, heart rate and high frequency heart rate variability.

INTRODUCTION: The phenomenon known as periodic limb movements in sleep (PLMS) has been linked to a change in autonomic nervous system (ANS) activity and its effect on circulatory regulation. Autonomic dysfunction or dysregulation in patients with PLMS has been described in some domains; however, any relationship between heart rate variability (HRV) and PLMS has not been clearly established. HRV analysis is a recognised, non-invasive research method that describes the influence of the ANS on heart rate (HR). The aim of our study was to further investigate the dysregulation of autonomic HR control in patients with PLMS. MATERIAL AND METHODS: We undertook a retrospective analysis of the polysomnographic (PSG), demographic and medical data of five patients with a total number of 1,348 PLMS. We analysed HR, HRV HF, systolic blood pressure (SBP), and diastolic blood pressure (DBP) for 10 heartbeats before the series of PLMS and 10 consecutive heartbeats as beat-to-beat measurements. The presented method of using successive, short, 10 RR interval segments refers to the time-frequency measurement, which is very clear and useful for presenting changes in the calculated parameters over time and thereby illustrating their dynamics. This method allowed us to assess dynamic changes in HRV HF during successive PLMS series. Statistical analysis was performed using IBM SPSS Statistics (v. 28.0.0.0). The Kruskal-Wallis test was performed to find statistically significant changes from baseline. RESULTS: No statistically significant changes in HR, SBP, or DBP were found in our group, although an increase in the value of the HRV HF was noted, suggesting an increase in intracardiac parasympathetic activity during the subsequent series of PLMS. CONCLUSIONS: Our study indicates an increase in parasympathetic activity during the appearance of successive PLMS, which, with the simultaneous lack of changes in HR, may suggest an increase in sympathetic activity, and therefore the appearance of so-called 'autonomic co-activation' resulting in the possibility of life-threatening cardiac events. CLINICAL IMPLICATIONS: Our findings add to the literature information regarding HRV in PLMS, and highlight the need for further studies to elucidate the effects of these conditions on the ANS, and on cardiovascular health.

Fibrinogen ß chain and FXIII polymorphisms affect fibrin clot properties in acute pulmonary embolism.

BACKGROUND: Prothrombotic fibrin clot properties, including increased clot density, are in part genetically determined. We investigated whether fibrinogen alpha-chain gene (FGA) c.991A>G (rs6050), fibrinogen beta chain gene (FGB) -455G>A (rs1800790) and factor XIII gene (F13) c.103G>T (rs5985) polymorphisms affect plasma fibrin clot properties in patients with acute pulmonary embolism (PE). METHODS: As many as 126 normotensive patients with PE, free of cancer, were genotyped by TaqMan assay. Fibrin clot permeability (Ks ), clot lysis time (CLT) and endogenous thrombin potential (ETP) were assessed on admission. RESULTS: The minor allele frequencies were as follows: FGA rs6050 (n = 62, 0.31), FGB rs1800790 (n = 40, 0.17) and F13 rs5985 (n = 49, 0.23). There were no differences related to any of the polymorphisms with regard to demographic, clinical and laboratory data, except for fibrinogen concentration, which was higher in carriers of F13 rs5985 polymorphism (p = .024), and PE combined with deep-vein thrombosis, which was less prevalent in FGB rs1800790 polymorphism carriers (p = .004). Carriers of FGB rs1800790 A allele and F13 rs5985 T allele had lower Ks , prolonged CLT and higher ETP compared with major homozygotes (all p < .05). After adjustment for fibrinogen, all differences remained significant (all p < .01). There were no associations between the FGA rs6050 polymorphism and Ks , CLT or ETP. CONCLUSION: Our study showed that FGB rs1800790 and F13 rs5985 polymorphisms contribute to the prothrombotic fibrin clot phenotype and these effects are strong enough to be observed in the acute phase of PE.

Annual operator volume among patients treated using percutaneous coronary interventions with rotational atherectomy and procedural outcomes: Analysis based on a large national registry.

BACKGROUND: Low operator and institutional volume are associated with poorer procedural and long-term clinical outcomes in the general population of patients treated with percutaneous coronary interventions (PCI). AIM: To assess the relationship between operator experience and procedural outcomes of patients treated with PCI and rotational atherectomy (RA). METHODS: Data for conducting the current analysis were obtained from the national registry of percutaneous coronary interventions (ORPKI) maintained in cooperation with the Association of Cardiovascular Interventions (AISN) of the Polish Cardiac Society. The study covers data from January 2014 to December 2020. RESULTS: During the investigated period, there were 162 active CathLabs, at which 747,033 PCI procedures were performed by 851 operators (377 RA operators [44.3%]). Of those, 5188 were PCI with RA procedures; average 30 ± 61 per site/7 years (Me: 3; Q1-Q3: 0-31); 6 ± 18 per operator/7 years (Me: 0; Q1-Q3: 0-3). Considering the number of RA procedures annually performed by individual operators during the analyzed 7 years, the first quartile totaled (Q1: < =2.57), the second (Q2: < =5.57), and the third (Q3: < =11.57), while the fourth quartile was (Q4: > 11.57). The maximum number of procedures was 39.86 annually per operator. We demonstrated, through a nonlinear relationship with annualized operator volume and risk-adjusted, that operators performing more PCI with RA per year (fourth quartile) have a lower number of the overall periprocedural complications (p = 0.019). CONCLUSIONS: High-volume RA operators are related to lower overall periprocedural complication occurrence in patients treated with RA in comparison to low-volume operators.

Thin-cap fibroatheroma predicts clinical events in diabetic patients with normal fractional flow reserve: the COMBINE OCT-FFR trial.

AIMS: The aim of this study was to understand the impact of optical coherence tomography (OCT)-detected thin-cap fibroatheroma (TCFA) on clinical outcomes of diabetes mellitus (DM) patients with fractional flow reserve (FFR)-negative lesions. METHODS AND RESULTS: COMBINE OCT-FFR study was a prospective, double-blind, international, natural history study. After FFR assessment, and revascularization of FFR-positive lesions, patients with ≥1 FFR-negative lesions (target lesions) were classified in two groups based on the presence or absence of ≥1 TCFA lesion. The primary endpoint compared FFR-negative TCFA-positive patients with FFR-negative TCFA-negative patients for a composite of cardiac mortality, target vessel myocardial infarction, clinically driven target lesion revascularization or unstable angina requiring hospitalization at 18 months. Among 550 patients enrolled, 390 (81%) patients had ≥1 FFR-negative lesions. Among FFR-negative patients, 98 (25%) were TCFA positive and 292 (75%) were TCFA negative. The incidence of the primary endpoint was 13.3% and 3.1% in TCFA-positive vs. TCFA-negative groups, respectively (hazard ratio 4.65; 95% confidence interval, 1.99-10.89; P < 0.001). The Cox regression multivariable analysis identified TCFA as the strongest predictor of major adverse clinical events (MACE) (hazard ratio 5.12; 95% confidence interval 2.12-12.34; P < 0.001). CONCLUSIONS: Among DM patients with ≥1 FFR-negative lesions, TCFA-positive patients represented 25% of this population and were associated with a five-fold higher rate of MACE despite the absence of ischaemia. This discrepancy between the impact of vulnerable plaque and ischaemia on future adverse events may represent a paradigm shift for coronary artery disease risk stratification in DM patients.

Experience with Optical Coherence Tomography Enhanced by a Novel Software (Ultreon™ 1.0 Software)-The First One Hundred Cases.

Introduction: Optical coherence tomography (OCT) intravascular imaging including the latest version Ultreon™ 1.0 Software (Abbott Vascular, Santa Clara, CA, USA), not only improve patients prognosis, but also facilitates improved percutaneous coronary intervention (PCI). Objectives: The aim of the study was to compare procedure related decision making, procedural indices, clinical outcomes according to the extent of stent expansion and assess risk factors of underexpansion in patients treated with PCI using OCT. Methods: The study comprised 100 patients, which were divided in groups according to the extent of stent expansion: <90 (29 patients) and ≥90% (71 patients). Comparison of OCT parameters, selected clinical and procedural characteristics was performed between groups. We assessed clinical outcomes during the follow-up: major adverse cardiovascular events and risk factors of stent underexpansion. Results: Patients from the stent underexpansion group were treated more often in the past with percutaneous peripheral interventions (p=0.02), no other significant differences being noted in general characteristics, procedural characteristics or clinical outcomes comparing both groups. Significant predictors of stent underexpansion assessed by simple linear univariable analysis included: hypercholesterolemia, obstructive bronchial diseases and treatment with inhalators, family history of cardiovascular disease, PCI of other than the left main coronary artery, stent and drug-eluting stent implantation, PCI without drug-eluting balloon, paclitaxel antimitotic agent, greater maximal stent diameter and lower mean Euroscore II value. Univariable logistic regression analysis revealed a correlation between stent underexpansion and greater creatinine serum concentration before [OR: 0.97, 95%CI: 0.95-0.99, p=0.01] and after PCI [OR: 0.98, 95%CI: 0.96-0.99, p=0.02]. Conclusions: Based on the presented analysis, the degree of stent expansion is not related to the selected procedural, OCT imaging indices and clinical outcomes. Logistic regression analysis confirmed such a relationship for creatinine level.

Clinical and procedural characteristics of COVID-19 patients treated with percutaneous coronary interventions.

BACKGROUND: COVID-19 pandemic has affected healthcare systems worldwide. Resources are being shifted and potentially jeopardize safety of non-COVID-19 patients with comorbidities. Our aim was to investigate the impact of national lockdown and SARS-CoV-2 pandemic on percutaneous treatment of coronary artery disease in Poland. METHODS: Data on patients who underwent percutaneous coronary procedures (angiography and/or percutaneous coronary intervention [PCI]) were extracted for March 13-May 13, 2020 from a national PCI database (ORPKI Registry) during the first month of national lockdown and compared with analogous time period in 2019. RESULTS: Of 163 cardiac catheterization centers in Poland, 15 (9.2%) were indefinitely or temporarily closed down due to SARS-CoV-2 pandemic. There were nine physicians (9 of 544; 1.7%) who were infected with SARS-CoV-2. There were 13,750 interventional cardiology procedures performed in Poland in the analyzed time period. In 66% of cases an acute coronary syndrome was diagnosed, and in the remaining 34% it was an elective procedure for the chronic coronary syndrome in comparison to 50% in 2019 (p < .001). There were 362 patients (2.6% of all) with COVID-19 confirmed/suspected who were treated in interventional cardiology centers and 145 with ST-Elevation Myocardial Infarction (STEMI) diagnosis (6% of all STEMIs). CONCLUSIONS: Due to SARS-CoV-2 pandemic there was an absolute reduction in the number of interventional procedures both acute and elective in comparison to 2019 and a significant shift into acute procedures. COVID-19 confirmed/suspected patients do not differ in terms of procedural and baseline characteristics and reveal similar outcomes when treated with percutaneous coronary interventions.

DOAC-Remove abolishes the effect of direct oral anticoagulants on activated protein C resistance testing in real-life venous thromboembolism patients.

Background Direct oral anticoagulants (DOACs) may cause false results of activated protein C resistance (APC-R) ratio. DOAC-Remove, a new reagent based on activated carbon, has been designed to eliminate the interference of DOACs on coagulation assays. The aim of the study was to investigate whether the use of DOAC-Remove enables to determine APC-R in patients treated with DOACs. Methods We assessed 74 venous thromboembolism (VTE) patients, including 25 on rivaroxaban, 25 on apixaban and 24 taking dabigatran. APC-R was determined using the Russell Viper Venom Time (RVVT)-based clotting test. APC-R and DOAC concentrations were tested at baseline and following DOAC-Remove. Thrombophilia, including factor V Leiden (FVL) mutation was tested. Results FVL mutation was found in 20 (27%) patients. The APC-R ratio at baseline was measurable in 43 patients (58.1%), including 20 (80%) on rivaroxaban, 19 (76%) on apixaban and four (16.7%) on dabigatran. In patients with measurable APC-R at baseline, the ratio >2.9 was found in 23 patients (53.5%). In 16 (37.2%) subjects APC-R ratio <1.8 suggested FVL mutation which was genetically confirmed. Four (9.3%) FVL carriers on dabigatran showed negative/equivocal APC-R results. In 11 (14.9%) patients taking rivaroxaban or apixaban, in whom blood was collected 2-5 h since the last dose, we observed unmeasurable APC-R. DOAC-Remove almost completely eliminated all plasma DOACs. After addition of DOAC-Remove all APC-R ratios were measurable. In four FVL carriers on dabigatran with false negative APC-R, DOAC-Remove resulted in APC-R ratios <1.8. Conclusions DOAC-Remove effectively reduces DOACs concentration in plasma, which enables FVL testing using APC-R.

Long-Term Prognostic Significance of High-Sensitive Troponin I Increase during Hospital Stay in Patients with Acute Myocardial Infarction and Non-Obstructive Coronary Arteries.

Background and Objectives: A topic already widely investigated is the negative prognostic value regarding the extent of high sensitive troponin I (hs-TnI) increases among patients with myocardial infarction (MI) and obstructive coronary atherosclerosis compared to a group of patients with MI and non-obstructive coronary atherosclerosis (MINOCA). Thus, the aim of this study was to evaluate the prognostic value concerning the extent of hs-TnI increase on clinical outcomes among patients with a MINOCA working diagnosis. Materials and Methods: We selected 337 consecutive patients admitted to hospital with a working diagnosis of MINOCA. The patients were divided in three groups according to the extent of hs-TnI increase during hospitalization (increase ≤5-times above the limit of the upper norm, >5 and ≤20-times, and >20-times). The study endpoints included all-cause mortality and major adverse cardiac and cerebrovascular events (MACCE; cerebral stroke and transient ischemic attacks, MI, coronary artery revascularization, either percutaneous coronary intervention or coronary artery bypass grafting and all-cause mortality). Results: During the mean follow-up period of 516.1 ± 239.8 days, using Kaplan-Meier survival curve analysis, significantly higher mortality rates were demonstrated among patients from the group with the greatest hs-TnI increase compared to the remaining groups (p = 0.01) and borderline values for MACCE (p = 0.053). Multivariable cox regression analysis did not confirm hs-TnI among factors related to increased MACCE or all-cause mortality rates. Conclusion: While a relationship between clinical outcomes and the extent of the hs-TnI increase among patients with a MINOCA working diagnosis remains, it does not seem to be not as strong as it is in patients with obstructive coronary atherosclerosis.

Serum cytokine profile as a potential prognostic tool in colorectal cancer patients - one center study.

AIM: Comparison of 14 cytokines levels between a control group and prospectively enrolled CRC patients to confirm their significance in CRC development. We tested if a model based on 14 cytokines levels could predict prognosis in Caucasian CRC patients treated with 5-FU based chemotherapy. BACKGROUND: Novel prognostic tools in colorectal cancer (CRC) are necessary to optimize treatment, reduce toxicity and chemotherapy (CHT) costs. MATERIALS AND METHODS: We assessed prognostic significance of 14 cytokines: IL-1 beta, IL-1RA, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL12p70, IL-13, IL-17A in 75 prospectively enrolled CRC patients before initiation of palliative or adjuvant CHT and in 22 control subjects. Readings were taken using the Bio-Plex 200 System. Response to treatment was assessed after 6 months from initiation of CHT. The treated group was divided depending on the response into a progressors (death, progression of disease) and non-progressors group (stable disease, partial response, complete response). RESULTS: We found that increased concentration of IL-8 was a negative prognostic factor in the whole group and palliative subgroup, whereas increased level of IL-10, IL-7, and IL-12p70 was a negative predictor in the adjuvant group CHT. CONCLUSIONS: We proposed a statistical model based on circulating cytokine levels, showing a good prognostic value in prediction of the response to CHT (AUC = 0.956). The model, including combined IL-2, IL-8, IL-10 and IL-13 levels, established in the whole treated group, should be validated in larger trials.

Highly-calcific carotid lesions endovascular management in symptomatic and increased-stroke-risk asymptomatic patients using the CGuard™ dual-layer carotid stent system: Analysis from the PARADIGM study.

OBJECTIVES: To assess feasibility, safety, angiographic, and clinical outcome of highly-calcific carotid stenosis (HCCS) endovascular management using CGuard™ dual-layer carotid stents. BACKGROUND: HCCS has been a challenge to carotid artery stenting (CAS) using conventional stents. CGuard combines a high-radial-force open-cell frame conformability with MicroNet sealing properties. METHODS: The PARADIGM study is prospectively assessing routine CGuard use in all-comer carotid revascularization patients; the focus of the present analysis is HCCS versus non-HCCS lesions. Angiographic HCCS (core laboratory evaluation) required calcific segment length to lesion length ≥2/3, minimal calcification thickness ≥3 mm, circularity (≥3 quadrants), and calcification severity grade ≥3 (carotid calcification severity scoring system [CCSS]; G0-G4). RESULTS: One hundred and one consecutive patients (51-86 years, 54.4% symptomatic; 106 lesions) received CAS (16 HCCS and 90 non-HCCS); eight others (two HCCS) were treated surgically. CCSS evaluation was reproducible, with weighted kappa (95% CI) of 0.73 (0.58-0.88) and 0.83 (0.71-0.94) for inter- and intra-observer reproducibility respectively. HCCS postdilatation pressures were higher than those in non-HCCS; 22 (20-24) versus 20 (18-24) atm, p = .028; median (Q1-Q3). Angiography-optimized HCCS-CAS was feasible and free of contrast extravasation or clinical complications. Overall residual diameter stenosis was single-digit but it was higher in HCCS; 9 (4-17) versus 3 (1-7) %, p = .002. At 30 days and 12 months HCCS in-stent velocities were normal and there were no adverse clinical events. CONCLUSION: CGuard HCCS endovascular management was feasible and safe. A novel algorithm to grade carotid artery calcification severity was reproducible and applicable in clinical study setting. Larger HCCS series and longer-term follow-up are warranted.

Restenosis is associated with prothrombotic plasma fibrin clot characteristics in endovascularly treated patients with critical limb ischemia.

INTRODUCTION: Hypolysible fibrin clots composed of tightly packed fibers characterize patients with peripheral artery disease (PAD) especially those with critical limb ischemia (CLI). Little is known about the impact of a prothrombotic clot phenotype on restenosis following endovascular revascularization in CLI. The goal of this study was to compare fibrin clot properties and their determinants in CLI patients with restenosis after endovascular treatment (ET) and those free of this complication. METHODS: 85 patients with CLI and restenosis within 1 year after ET on optimal pharmacotherapy and 47 PAD control patients without restenosis were included into the study. Plasma fibrin clot permeability (Ks, a measure of the average pore size in the fibrin network) and clot lysis time (CLT) with its potential determinants were determined. During follow-up, the composite endpoint including re-intervention, amputation and death was assessed. RESULTS: Compared with the control group, patients with restenosis had reduced Ks (- 9.5%, p < 0.001), prolonged CLT (+ 12.4%, p = 0.003), higher thrombin generation (+ 7.9%, p < 0.001) and elevated von Willebrand factor (vWF) antigen (+ 14.2%, p < 0.001). During a 24 months follow-up the composite endpoint occurred in 54 CLI patients with restenosis (63.5%) and nine control patients (19.1%, p < 0.001) with no association with baseline Ks and CLT. CONCLUSION: The increased thrombin formation and unfavorable fibrin clot properties occur in patients with CLI who experienced restenosis despite optimal endovascular and pharmacological therapy.

Unfavourably altered plasma clot properties in patients with primary Raynaud's phenomenon: association with venous thromboembolism.

Associations of Raynaud's phenomenon (RP) with venous thromboembolism (VTE) are unclear. We investigated the occurrence of RP together with prothrombotic state markers and fibrin clot properties in VTE patients. In this prospective cohort study we enrolled 360 patients free of known autoimmune disease. D-dimer, von Willebrand factor (vWF), plasma clot permeability (Ks), clot lysis time (CLT) along with fibrinolysis activators and inhibitors were determined at least 3 months since the VTE event. The presence/absence of RP was diagnosed at least 6 months before VTE. Primary RP occurred in 57 subjects (17%) with a 3.6-fold higher prevalence among women. Patients with RP had 11% higher fibrinogen, 16% higher vWF, 5% lower Ks, and 10% longer CLT (all p < 0.05). Females with RP (21%) had 6.6% lower Ks, 11.2% longer CLT, and 18.5% higher vWF (all p < 0.05) compared with men. CLT was predicted by PAI-1 and vWF levels. Regression analysis showed that RP was a predictor of prolonged CLT in the whole patient group (OR 3.46, 95% CI 1.92-6.24) and in women following VTE (OR 2.75, 95% CI 1.31-5.78). Primary RP patients tend to form denser plasma fibrin clots displaying impaired lysability and increased endothelial damage. RP might be a novel risk factor for VTE, especially in women.

Involvement of CD8+ T cell subsets in early response to vascular injury in patients with peripheral artery disease in vivo.

AIMS: Adaptive immunity is critical in vascular remodelling following arterial injury. We hypothesized that acute changes in T cells at a percutaneous transluminal angioplasty (PTA) site could serve as an index of their potential interaction with the injured vascular wall. METHODS AND RESULTS: T cell subsets were characterised in 45 patients with Rutherford 3-4 peripheral artery disease (PAD) undergoing PTA. Direct angioplasty catheter blood sampling was performed before and immediately after the procedure. PTA was associated with an acute reduction of α/ß-TcR CD8+ T cells. Further characterisation revealed significant reduction in pro-atherosclerotic CD28nullCD57+ T cells, effector (CD45RA+CCR7-) and effector memory (CD45RA-CCR7-) cells, in addition to cells bearing activation (CD69, CD38) and tissue homing/adhesion markers (CD38, CCR5). CONCLUSIONS: The acute reduction observed here is likely due to the adhesion of cells to the injured vascular wall, suggesting that immunosenescent, activated effector CD8+ cells have a role in the early vascular injury immune response following PTA in PAD patients.

Polyhedrocytes in blood clots of type 2 diabetic patients with high cardiovascular risk: association with glycemia, oxidative stress and platelet activation.

BACKGROUND: Little is known about factors that affect the composition of contracted blood clots in specific diseases. We investigated the content of polyhedral erythrocytes (polyhedrocytes) formed in blood clots and its determinants in type 2 diabetes (T2D) patients. METHODS: In 97 patients with long-standing T2D [median HbA1c, 6.4% (interquartile range 5.9-7.8)], we measured in vitro the composition of blood clots, including a clot area covered by polyhedrocytes using scanning electron microscopy and the erythrocyte compression index (ECI), defined as a ratio of the mean polyhedrocyte area to the mean native erythrocyte area. Moreover, plasma fibrin clot permeability (Ks), clot lysis time (CLT), thrombin generation, oxidative stress [total protein carbonyl (total PC), total antioxidant capacity and thiobarbituric acid reactive substances (TBARS)], and platelet activation markers were determined. The impact of glucose concentration on polyhedrocytes formation was assessed in vitro. RESULTS: Polyhedrocytes content in contracted clots was positively correlated with glucose (r = 0.24, p = 0.028), glycated hemoglobin (r = 0.40, p = 0.024), total cholesterol (r = 0.22, p = 0.044), TBARS (r = 0.60, p = 0.0027), P-selectin (r = 0.54, p = 0.0078) and platelet factor-4, PF4 (r = 0.59, p = 0.0032), but not with thrombin generation, platelet count, Ks or CLT. Patients who formed more polyhedrocytes (≥ 10th percentile) (n = 83, 85.6%) had higher glucose (+ 15.7%, p = 0.018), fibrinogen (+ 16.6%, p = 0.004), lower red blood cell distribution width (RDW, - 8.8%, p = 0.034), reduced plasma clot density (- 21.8% Ks, p = 0.011) and impaired fibrinolysis (+ 6.5% CLT, p = 0.037) when compared to patients with lesser amount of polyhedrocytes (< 10th percentile). ECI and the content of polyhedrocytes were strongly associated with total PC (r = 0.79, p = 0.036 and r = 0.67, p = 0.0004, respectively). In vitro an increase of glucose concentration by 10 mmol/L was associated with 94% higher polyhedrocytes content (p = 0.033) when compared to the baseline (7.1 mM). After adjustment for age, sex and fibrinogen, multiple regression analysis showed that RDW was the only independent predictor of polyhedrocytes content in T2D (OR = 0.61, 95% CI 0.39-0.92). CONCLUSIONS: Poor glycemic control, together with enhanced platelet activation and oxidative stress, increase the content of polyhedrocytes in blood clots generated in T2D patients.