Neutrophil-activating Peptide 2 as a Novel Modulator of Fibrin Clot Properties in Patients with Atrial Fibrillation.

Neutrophil-activating peptide 2 (NAP-2, CXCL7), a platelet-derived neutrophil chemoattractant, is involved in inflammation. We investigated associations between NAP-2 levels, neutrophil extracellular traps (NETs) formation, and fibrin clot properties in atrial fibrillation (AF). We recruited 237 consecutive patients with AF (mean age, 68 ± 11 years; median CHA2DS2VASc score of 3 [2-4]) and 30 apparently healthy controls. Plasma NAP-2 concentrations were measured, along with plasma fibrin clot permeability (Ks) and clot lysis time (CLT), thrombin generation, citrullinated histone H3 (citH3), as a marker of NETs formation, and 3-nitrotyrosine reflecting oxidative stress. NAP-2 levels were 89% higher in AF patients than in controls (626 [448-796] vs. 331 [226-430] ng/ml; p < 0.0001). NAP-2 levels were not associated with demographics, CHA2DS2-VASc score, or the AF manifestation. Patients with NAP-2 in the top quartile (> 796 ng/ml) were characterized by higher neutrophil count (+ 31.7%), fibrinogen (+ 20.8%), citH3 (+ 86%), and 3-nitrotyrosine (+ 111%) levels, along with 20.2% reduced Ks and 8.4% prolonged CLT as compared to the remaining subjects (all p < 0.05). NAP-2 levels were positively associated with fibrinogen in AF patients (r = 0.41, p = 0.0006) and controls (r = 0.65, p < 0.01), along with citH3 (r = 0.36, p < 0.0001) and 3-nitrotyrosine (r = 0.51, p < 0.0001) in the former group. After adjustment for fibrinogen, higher citH3 (per 1 ng/ml ß = -0.046, 95% CI -0.029; -0.064) and NAP-2 (per 100 ng/ml ß = -0.21, 95% CI -0.14; -0.28) levels were independently associated with reduced Ks. Elevated NAP-2, associated with increased oxidative stress, has been identified as a novel modulator of prothrombotic plasma fibrin clot properties in patients with AF.

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.

Thin-cap fibroatheroma and increased coronary intima-media thickness are associated with an altered balance of arginine metabolites.

INTRODUCTION: Arginase inhibition increases plasma citrulline and citrulline / ornithine (C/O) ratio, and reduces plasma ornithine and ornithine / arginine (O/A) ratio in an animal model of myocardial infarction (MI). OBJECTIVES: We hypothesized that the presence of thin­cap fibroatheroma (TCFA) in the culprit lesion and increased non­culprit intima­media thickness of an infarct­related artery (IRA) are associated with an altered balance of arginine metabolites. PATIENTS AND METHODS: Arginine and its metabolites were measured using liquid chromatography and tandem mass spectrometry in 100 consecutive MI patients upon admission and at 6­month follow­up. TCFA and adjacent to culprit lesion proximal and distal 10­mm segments were assessed with optical coherence tomography in the acute phase. Twenty five patients without coronary lesions on angiography served as controls. RESULTS: The C/O ratio increased 5.33 times (P <0.001), while the O/A ratio decreased 2.53 times (P <0.001) at the 6­month follow­up, as compared with the acute phase of MI. The patients with (n = 75) vs without (n = 25) TCFA had lower C/O ratio by 29% (P = 0.003), while the mean intima­media diameter of adjacent non­culprit region correlated with the follow­up O/A ratio (R = 0.337; P = 0.003). In a multivariable analysis, a higher acute phase C/O ratio was associated with a lower risk of TCFA presence (odds ratio, 0.978; 95% CI, 0.962-0.994; P = 0.006), whereas a higher follow­up O/A ratio correlated with larger intima­media diameter of the adjacent segments (ß coefficient, 0.227; 95% CI for ß coefficient, 0.045-0.409; P = 0.018). CONCLUSIONS: Enhanced arginase activity over nitric oxide synthase following ischemia was associated with the presence of TCFA in the culprit lesion, while a similar metabolic shift in the chronic phase correlated with a greater thickness of the intima­media in the adjacent non­culprit IRA segments.

Elevated 8-isoprostane concentration is associated with thromboembolic events in patients with atrial fibrillation.

BACKGROUND: Enhanced oxidative stress occurs in atrial fibrillation (AF), however its impact on the efficacy and safety of anticoagulation is unknown. We sought to evaluate whether 8-isoprostaglandin F2 (8-isoprostane) levels are associated with clinical outcomes in anticoagulated AF patients. METHODS: In a study involving 243 AF patients (median age 69 years), we measured serum 8-isoprostane, along with prothrombotic markers, including plasma fibrin clot permeability, clot lysis time (CLT), endogenous thrombin potential (ETP), von Willebrand factor (VWF), and fibrinolytic proteins. Ischemic cerebrovascular events, major bleeding, and death were recorded during a median follow-up of 53 months while on anticoagulation, largely on non-vitamin K antagonist oral anticoagulants (NOACs). RESULTS: Increased 8-isoprostane levels were observed in women, in patients with arterial hypertension, and those with paroxysmal or persistent AF. Patients with 8-isoprostane levels ≥559 pg/mL (the top quartile) compared with those with 8-isoprostane <250 pg/mL (the bottom quartile) had higher fibrinogen, lower VWF, higher plasminogen activator inhibitor 1, along with lower fibrin clot permeability with no difference in CHA2DS2-VASc score, CLT or ETP. Patients who experienced thromboembolic events (n = 20, 1.9%/year) had 48.6% higher 8-isoprostane concentrations compared to the remainder (P <0.01). Levels of 8-isoprostane >459 pg/mL based on the optimal cut-off value were associated with thromboembolic events during follow-up (hazard ratio 2.87, 95% confidence interval 1.17-7.03, P = 0.02). There were no associations between 8-isoprostane and major bleeding (2.0%/year) or all-cause mortality (1.9%/year). CONCLUSIONS: Increased 8-isoprostane levels partly through altered fibrin clot structure are associated with thromboembolic events despite anticoagulant therapy in AF patients.

Machine Learning Analyzed Weather Conditions as an Effective Means in the Predicting of Acute Coronary Syndrome Prevalence.

Background: The prediction of the number of acute coronary syndromes (ACSs) based on the weather conditions in the individual climate zones is not effective. We sought to investigate whether an artificial intelligence system might be useful in this prediction. Methods: Between 2008 and 2018, a total of 105,934 patients with ACS were hospitalized in Lesser Poland Province, one covered by two meteorological stations. The predicted daily number of ACS has been estimated with the Random Forest machine learning system based on air temperature (°C), air pressure (hPa), dew point temperature (Td) (°C), relative humidity (RH) (%), wind speed (m/s), and precipitation (mm) and their daily extremes and ranges derived from the day of ACS and from 6 days before ACS. Results: Of 840 pairwise comparisons between individual weather parameters and the number of ACS, 128 (15.2%) were significant but weak with the correlation coefficients ranged from -0.16 to 0.16. None of weather parameters correlated with the number of ACS in all the seasons and stations. The number of ACS was higher in warm front days vs. days without any front [40 (29-50) vs. 38 (27-48), respectively, P < 0.05]. The correlation between the predicted and observed daily number of ACS derived from machine learning was 0.82 with 95% CI of 0.80-0.84 (P < 0.001). The greatest importance for machine learning (range 0-1.0) among the parameters reached Td daily range with 1.00, pressure daily range with 0.875, pressure maximum daily range with 0.864, and RH maximum daily range with 0.853, whereas among the clinical parameters reached hypertension daily range with 1.00 and diabetes mellitus daily range with 0.28. For individual seasons and meteorological stations, the correlations between the predicted and observed number of ACS have ranged for spring from 0.73 to 0.77 (95% CI 0.68-0.82), for summer from 0.72 to 0.76 (95% CI 0.66-0.81), for autumn from 0.72 to 0.83 (95% CI 0.67-0.87), and for winter from 0.76 to 0.79 (95% CI 0.71-0.83) (P < 0.001 for each). Conclusion: The weather parameters have proven useful in predicting the prevalence of ACS in a temperate climate zone for all the seasons, if analyzed with an artificial intelligence system. Simultaneously, the analysis of individual weather parameters or frontal scenarios has provided only weak univariate relationships. These findings will require validation in other climatic zones.

Markers of NET formation and stroke risk in patients with atrial fibrillation: association with a prothrombotic state.

INTRODUCTION: Neutrophil extracellular traps (NETs) formation contributes to thrombosis but its role in atrial fibrillation (AF) is poorly explored. We investigated whether increased circulating NETs markers in relation to a hypercoagulable state can predispose to ischemic stroke in anticoagulated AF patients during long-term follow-up. MATERIALS AND METHODS: In this cohort study 243 AF patients (median age 69 years) were assessed. Serum levels of citrullinated histone H3 (H3cit), myeloperoxidase (MPO), and peptidylarginine deiminase 4 (PAD4), along with plasma fibrin clot permeability (Ks), clot lysis time (CLT), endogenous thrombin potential (ETP), von Willebrand factor (VWF), and fibrinolysis proteins were measured. Stroke/transient ischemic attacks (TIA), major bleeding, and mortality were recorded during a median follow-up of 53 months while on anticoagulation. RESULTS: Ischemic cerebrovascular events were observed in 20 patients (1.9%/year) who had at baseline higher H3cit, MPO, and PAD4 levels, all positively associated with CLT. Increased thrombin generation correlated positively with H3cit and PAD4, while Ks was inversely associated with H3cit levels. The independent predictors of ischemic stroke/TIA were H3cit (hazard ratio [HR] 9.48, 95% confidence interval [CI] 3.88-22.41, p < 0.0001) and VWF (HR 1.20, 95% CI 1.11-1.49, p = 0.001). Major bleeding (2.0%/year) and all-cause mortality (1.9%/year) were not related to NETs markers. CONCLUSIONS: Enhanced NETs formation related to prothrombotic markers is associated with increased risk of stroke/TIA in AF patients, suggesting a prognostic value of NETosis in AF.

The shifted balance of arginine metabolites in acute myocardial infarction patients and its clinical relevance.

The arginine metabolism as a target for cardioprotection in patients with ST-segment elevation myocardial infarction (STEMI) remains insufficiently understood. Arginine, ornithine, citrulline, asymmetric dimethylarginine (ADMA) and proline plasma levels were measured using liquid chromatography and tandem mass spectrometry in 70 consecutive STEMI patients upon admission and at 6-month follow-up and were compared with left ventricular function, volumes, and infarct characteristics determined by cardiac magnetic resonance imaging, and with 5-year clinical outcomes. Baseline median concentration of arginine was higher by 49% (P = 0.002) when compared to 6-month measurements and was correlated with an ischemia risk area (R = 0.34, P = 0.004) and infarct size (R = 0.33, P = 0.006). Following ischemia median citrulline/arginine index decreased when compared with 6-month result (P = 0.002), while citrulline/ornithine and arginine/ADMA ratios maintained unchanged indicating a shift of arginine metabolism from nitric oxide synthase (NOS) towards arginase. The 6-month arginine concentration reached the area under the ROC curve of 0.67 (95% confidence interval 0.54-0.81) for prediction of death, myocardial infarction or heart failure hospitalization and its value of < 29 µM was associated with lower event free survival (P = 0.02). In STEMI patients, during ischemia conversion of elevated plasma arginine was shifted from NOS towards arginase. Decreased 6-month arginine concentrations were associated with worse long-term outcomes.

Use of dietary and herbal supplements in adult patients with epilepsy.

PURPOSE: To study the extent and characteristics of dietary and herbal supplements use in a large cohort of adult patients with epilepsy. METHODS: This prospective study included 490 patients receiving care at a university epilepsy clinic. A number of variables, including demographics, characteristics of epilepsy and its treatment, comedication as well as data related to supplements intake were collected from medical records and a dedicated questionnaire. RESULTS: Overall 247 patients (50.4%) took at least one dietary supplement; nearly half (111, 44.9%) of this group took >1 products. Multivitamins and magnesium were the most prevalent supplements. Most of the patients used supplements for general health rather than their epilepsy condition. The average number of supplements and prescription medications used per person was 5.4. Ten percent (25 of 247) of subjects used dietary supplements which could have proconvulsive effect or potential for interaction with prescription medications. Multivariate analysis revealed two independent variables associated with supplements intake, younger age and female sex. CONCLUSION: Dietary and herbal supplements use is common in patients with epilepsy, adding to the burden of overmedication. Concurrent use of supplements may potentially lead to interactions with prescription medications or loss of seizure control. Health care providers should routinely check for dietary supplements use to limit potential harm related to their intake.

Somatic comorbidity in Polish patients with epilepsy.

INTRODUCTION A wide spectrum of somatic and psychiatric disorders occurs frequently in patients with epilepsy, which adds to the burden of this disease. OBJECTIVES The aim of the study was to estimate the prevalence and risk factors of somatic comorbidities and analyze somatic comedication in adult patients with epilepsy. PATIENTS AND METHODS This study involved patients with epilepsy treated in university epilepsy clinic. Data on epilepsy, antiepileptic drugs (AEDs), somatic comorbidities, and their treatment were collected from a structured interview and from medical records. RESULTS The sample population consisted of 636 patients (mean age, 35.3 years); 380 (59.7%) were female and 241 (37.9%) had well­controlled epilepsy. At least 1 comorbid somatic condition was found in 216 patients (34%). The most prevalent somatic comorbidities were cardiovascular diseases, allergies, migraine, hyperlipidemia, thyroid disorders, and chronic lower respiratory diseases. Furthermore, 200 patients (31.4%) were prescribed at least 1 medication for somatic disorders. Logistic regression analysis revealed several independent risk factors for the occurrence of somatic comorbidities: older age, shorter duration of epilepsy, lower seizure frequency, and lower number of AEDs. CONCLUSIONS Somatic comorbidities and comedication with non­AEDs were found in one­third of the relatively young cohort of adult patients with epilepsy. Patients with pharmacoresistant epilepsy may be at risk of underdiagnosis and undertreatment of somatic comorbidities. The presence of comorbidities may have implications for the diagnosis and treatment of seizure disorder and coexisting condition.

Polyhedral erythrocytes in intracoronary thrombus and their association with reperfusion in myocardial infarction.

OBJECTIVE: The tightly packed arrays of polyhedral erythrocytes, polyhedrocytes, formed during thrombus contraction, have been detected in some intracoronary thrombi (ICT) obtained from patients with ST-segment elevation myocardial infarction (STEMI). We sought to investigate determinants of polyhedrocyte content in ICT and its association with reperfusion in STEMI. METHODS: We assessed the composition of ICT obtained during thrombectomy within 12 h since the symptom onset in 110 STEMI patients, following 300 mg of aspirin (n = 110) and 600 mg of clopidogrel (n = 75). The predominance of fibrin, erythrocytes, polyhedrocytes or platelets was evaluated using scanning electron microscopy. RESULTS: Polyhedrocytes were found in 34 (30.9%) ICT, in which they covered 20-50% (median 38.8%) fields of view. Patients with polyhedrocytes in ICT had lower median minimal reference infarct-related artery (IRA) diameter by 20% (p < 0.0001) and area by 31% (p < 0.0001) versus those without polyhedrocytes. Time of ischemia showed association with the polyhedrocyte content (r = 0.26, p = 0.007). By multivariate analysis, minimal IRA diameter (ß = - 0.50, p < 0.0001) and ischemia time (ß = 0.20, p = 0.035) independently affected polyhedrocyte content in ICT (R2 = 0.45, p < 0.0001). Patients with ischemia time of > 3 h and polyhedrocytes present in ICT had more frequently TIMI-2/3 flow after thrombus aspiration (96% vs. 67%, p = 0.02) and final TIMI-2/3 myocardial perfusion grade (92% vs. 57%, p = 0.044) versus those without polyhedrocytes. CONCLUSIONS: Our findings indicate that the presence of polyhedrocytes in ICT, observed in one-third of STEMI patients, is associated with smaller minimal IRA diameter, prolonged ischemia and their formation in late presenters is associated with more effective thrombus aspiration and better myocardial reperfusion.

Coronary artery dissection following aortic valve replacement. How can one deal with this rare yet life-threatening complication?

Coronary artery dissection following its cannulation for cardioplegia administration as a result of aortic valve replacement (AVR) is a rare but nevertheless life-threatening complication. The three cases of a patient suffering from aortic stenosis illustrated below focus on the issue of how to identify and treat the dissected artery. In all of the patients who had undergone AVR diagnosed was a periprocedural myocardial infarction. Angiography revealed the dissection of the left main in two of the patients, while in the third one that of the right coronary artery. In the case of local dissection, angiography was sufficient to identify the true lumen, whereas in a dissection encompassing the whole of the coronary tree it was necessary to either find the coronary artery not involved in the dissection or to perform intravascular ultrasound imaging. After true lumen identification, the entry of dissection was stented with the optimal angiographic result.

Psychiatric comedication in patients with epilepsy.

Psychiatric disorders are more common in patients with epilepsy than in the general population. The aims of the study were to assess the frequency and type of psychotropic drug usage in patients with epilepsy, to assess the risk factors for their use, and to assess their proconvulsive potential and the risk of interactions with antiepileptic drugs. This 20-month prospective study included patients treated at the university hospital outpatient clinic. Psychotropic drugs have been classified according to the Anatomical Therapeutic Chemical Classification System. Of the 621 patients (with a mean age of 35.4years), 60% were women, and 37.5% were in remission; 54.8% of the patients used antiepileptic drug monotherapy. The most commonly used antiepileptic drugs were valproate, levetiracetam, lamotrigine, and carbamazepine. Eighty-nine (14.3%) patients received psychiatric comedication. Sertraline, perazine, and hydroxyzine were the predominantly used psychotropic drugs. Independent variables associated with psychotropic drug usage in the logistic regression model included age, active epilepsy, combined focal and generalized epilepsy type, use of somatic comedication, and phenobarbital. Over one-third of the patients simultaneously received antiepileptic drugs and psychotropic drugs, between which clinically significant interactions may occur, 10% of patients used psychotropic drugs to lower the seizure threshold. The results of the study indicate the need for closer cooperation between doctors of various specialties when caring for patients with epilepsy.