Von Willebrand factor is associated with atrial fibrillation development in ischaemic patients after cardiac surgery.

AIMS: Atrial fibrillation (AF) is associated with an increased morbidity and mortality after cardiac surgery. Von Willebrand factor (vWF) has been proposed as a biomarker of endothelial damage/dysfunction. We hypothesized that vWF levels could be used as valuable biomarker for AF occurrence after cardiac surgery. Moreover, we explored the potential association between vWF and tissue remodelling as possible implication in post-surgical AF. METHODS AND RESULTS: We prospectively recruited 100 consecutive patients who undergoing programmed cardiac surgery with cardiopulmonary bypass and with no previous history of AF. Plasma vWF levels were determined from citrated plasma samples. Right atrial appendage tissue was obtained during cardiac surgery, and vWF expression as well as interstitial fibrosis was analysed by immunostaining and Masson's trichrome, respectively. We found raised vWF plasma levels in ischaemic vs. valvular patients (200.2 ± 66.3 vs. 157.2 ± 84.3 IU/dL; P = 0.015). Fibrosis degree was associated with plasma vWF levels. Plasma vWF was an independent prognostic marker for AF development in ischaemic patients [odds ratio, OR 6.44 (95% confidence interval, CI 1.40-36.57), P = 0.035]. CONCLUSION: Plasma vWF levels are associated with tissue fibrosis in patients undergoing cardiac surgery and with post-surgical AF development in ischaemic patients. These findings suggest an association among vWF levels, atrial remodelling, and AF development. It is supported by higher vWF expression in right atrial tissue in ischaemic patients, who developed post-surgical AF.

TWEAK and NT-proBNP levels predict exercise capacity in hypertrophic cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is characterized by inappropriate hypertrophy, myocyte disarray and increased interstitial fibrosis. The tumour necrosis factor-like weak inducer of apoptosis (TWEAK) is a cell surface cytokine with biological activities including stimulation of cell growth, induction of inflammatory cytokines and stimulation of apoptosis. There are controversial data about the potential role of TWEAK in different cardiovascular pathologies. NT-proBNP is an established biomarker of myocardial wall stress, associated with poor functional class in HCM. We hypothesized that effort capacity in patients with HCM could be related to serum levels of these biomarkers. MATERIALS AND METHODS: We included 40 haemodynamic stable HCM patients and 53 healthy controls with similar sex and age. We studied exercise capacity by maximal oxygen consumption in a limited treadmill exercise test. TWEAK and NT-proBNP were assayed by ELISA method and automated Elecsys® platform, respectively. We obtained 46 samples of myocardial tissues by septal myectomy in patients with HCM and evaluated myocardial fibrosis, immunoreaction with TWEAK antibody and apoptosis with TUNEL assay. RESULTS: We found raised TWEAK and NT-proBNP serum levels in patients when compared with control levels (both P < 0.001). In a multivariate analysis, TWEAK and NT-proBNP levels, as well as sex, remained independently associated with the effort capacity (all P < 0.05). We found an association between immunoreaction degree and the degree of myocardial fibrosis (P = 0.021), as well as apoptosis (P = 0.002) in the tissue samples from patients undergoing septal myectomy. CONCLUSIONS: TWEAK and NT-proBNP levels are biomarkers of disease severity independently associated with the effort capacity in patients with HCM.

Major bleeding risk prediction using Chronic Kidney Disease Epidemiology Collaboration and Modification of Diet in Renal Disease equations in acute coronary syndrome.

BACKGROUND: Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations estimate glomerular filtration rate more accurately than the Modification of Diet in Renal Disease (MDRD) Study equation. Our aim was to evaluate whether CKD-EPI equations based on serum creatinine and/or cystatin C (CysC) predict risk for major bleeding (MB) more accurately than the MDRD Study equation in patients with non-ST-segment elevation acute coronary syndromes (ACS). MATERIALS AND METHODS: Three hundred and fifty consecutive subjects with non-ST-segment elevation ACS (68 ± 12 years, 70% male) were studied. Glomerular filtration rate was estimated using the CKD-EPI and MDRD Study equations. The primary endpoint was the occurrence of MB during the follow-up, which was defined according to the Bleeding Academic Research Consortium Definition criteria as bleeding types 3-5. RESULTS: During the median follow-up of 589 days (interquartile range, 390-986), 27 patients had MB (0.04% events per person year). Patients with MB had worse kidney function parameters, regardless of the estimating equation used (P < 0.001). After multivariate Cox regression adjustment, both CysC-based CKD-EPI equations were independent predictors of MB (CKD-EPI(creatinine-cystatin) C per mL/min/1.73 m(2), HR = 0.973 (95%CI 0.955-0.991; P = 0.003) and CKD-EPI(cystatin) C per mL/min/1.73 m(2), HR = 0.976 (95%CI 0.976-0.992; P = 0.003), while the CKD-EPI(creatinine) and MDRD equations did not achieve statistical significance. Both CKD-EPI(creatine-cystatin) C and CKD-EPI(cystatin) C were associated with a significant improvement in MB risk reclassification. CONCLUSIONS: In this cohort of non-ST-segment elevation ACS patients with relatively preserved renal function, both CysC-based CKD-EPI equations improved ability to predict risk for MB and were superior to other equations for this application.

Beta-trace protein and cystatin c as predictors of major bleeding in non-ST-segment elevation acute coronary syndrome.

BACKGROUND: Beta-trace protein (BTP) and cystatin C (CysC) are novel biomarkers of renal function. We assessed the ability of both to predict major bleeding (MB) in patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS), compared to other renal function parameters and clinical risk scores. METHODS AND RESULTS: We included 273 patients. Blood samples were obtained within 24h of admission. The endpoint was MB. During a follow-up of 760 days (411-1,098 days), 25 patients (9.2%) had MB. Patients with MB had higher concentrations of BTP (0.98 mg/L; 0.71-1.16 mg/L vs. 0.72 mg/L, 0.60-0.91 mg/L, P=0.002), CysC (1.05 mg/L; 0.91-1.30 mg/L vs. 0.90 mg/L, 0.75-1.08 mg/L, P=0.003), higher CRUSADE score (39 ± 16 points vs. 29 ± 15 points, P=0.002) and lower estimated glomerular filtration rate (eGFR; 66 ± 27 vs. 80 ± 30 ml·min(-1)·1.73 m(-2), P=0.02) than patients without MB; there was no difference in creatinine level between the groups (P=0.14). After multivariable adjustment, both were predictors of MB, while eGFR and creatinine did not achieve statistical significance. Among subjects with eGFR >60 ml·min(-1)·1.73 m(-2), those with elevated concentrations of both biomarkers had a significantly higher risk for MB. Net reclassification indexes from the addition of BTP and CysC to CRUSADE risk score were 38% and 21% respectively, while the relative integrated discrimination indexes were 12.5% and 3.8%. CONCLUSIONS: Among NSTE-ACS patients, BTP and CysC were superior to conventional renal parameters for predicting MB, and improved clinical stratification for hemorrhagic risk.

Galectin-3 as a marker of interstitial atrial remodelling involved in atrial fibrillation.

Remodelling in the atria could appear as a result of hypertension, diabetes or ischaemic heart disease. Galectin-3 (Gal-3) is a mediator of profibrotic pathways and a potential biomarker of cardiac remodelling. We prospectively recruited consecutive patients undergoing elective cardiac surgery. Preoperative Gal-3 levels were determined from serum samples, and the presence of fibrosis was assessed from atrial appendage tissue samples obtained during cardiac surgery. We included 100 patients with aortic valve or ischaemic heart diseases and 15 controls with permanent AF. Gal-3 levels were associated with sex, left atrial volume, previous cardiac disease, diabetes mellitus, hypertension, NYHA and NT-proBNP. We observed differences in serum Gal-3 concentrations between patients and controls with permanent AF (p = 0.020). We performed ROC curves related to fibrosis and established a cutoff point for Gal-3 >13.65 ng/ml. Multivariate analyses showed previous cardiac disease, NYHA scale and high Gal-3 to be independent predictors of fibrosis. After adjustment for confounding factors, atrial fibrosis remained the only independent factor for the development of AF (p = 0.022). High Gal-3 serum levels predict fibrosis of the atrial appendage. NYHA scale and previous cardiac disease were also associated with tissue fibrosis in patients undergoing surgery. Atrial fibrosis was the only independent predictor for post-operative AF occurrence in our model after correcting for confounding factors.

Comparison of Risk Prediction With the CKD-EPI and MDRD Equations in Non-ST-Segment Elevation Acute Coronary Syndrome.

BACKGROUND: Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations estimate glomerular filtration rate (GFR) more accurately than the Modification of Diet in Renal Disease (MDRD) equation. HYPOTHESIS: New CKD-EPI equations improve risk stratification in patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS) and provide complementary information to the Global Registry of Acute Coronary Events (GRACE) risk score. METHODS: We studied 350 subjects (mean age, 68 ± 12 years; 70% male) with NSTE-ACS. Estimated GFR was calculated using the MDRD and new CKD-EPI equations based on serum creatinine (SCr) and/or cystatin C (CysC) concentrations obtained within 48 hours of hospital admission. The primary endpoint was all-cause death during follow-up. RESULTS: Over the study period (median, 648 days [interquartile range, 236-1042 days]), 31 patients died (0.05% events per person-year). Decedents had poorer renal-function parameters (P < 0.001). Both CysC-based CKD-EPI equations had the highest areas under the receiver operating characteristic curve for the prediction of all-cause mortality. After multivariate adjustment, only CysC-based CKD-EPI equations were independent predictors of all-cause mortality (CKD-EPISCr - CysC , per mL/min/1.73 m(2) : hazard ratio: 0.975, 95% confidence interval: 0.956-0.994, P = 0.009; CKD-EPICysC , per mL/min/1.73 m(2) : hazard ratio: 0.976, 95% confidence interval: 0.959-0.993, P = 0.005). Reclassification analyses showed that only CysC-based CKD-EPI equations improved predictive accuracy of the GRACE risk score. CONCLUSIONS: In patients with NSTE-ACS, CysC-based CKD-EPI equations improved clinical risk stratification for mortality and added complementary prognostic information to the GRACE risk score.

Novel biomarkers in cardiology: MicroRNAs in atrial fibrillation.

Atrial fibrillation (AF) is the most common sustained chronic cardiac arrhythmia in clinical practice, which increases the risk of stroke and thromboembolism and is an independent predictor of mortality. The underlying mechanisms involved in the development of AF have yet to be fully elucidated. However, once initiated, AF tends to self-perpetuate, owing to structural and electrical remodeling in the atria. MicroRNAs (miRNAs) represent a sizable sub-group of small non-coding RNAs, which degrades or inhibits the translation of their target mRNAs, thus regulating gene expression and playing an important role in a wide range of biologic processes. Clinically, there is increasing evidence of the potential diagnostic role of miRNAs as biomarkers, representing a novel therapeutic target in AF. The aim of this review is to provide an exhaustive overview of the role of miRNAs in AF and to discuss the diagnostic and therapeutic potential of miRNAs in this arrhythmia.

[HDL cholesterol and high-sensitive troponin T as predictive biomarkers of atrial fibrillation after heart surgery]. / Colesterol HDL y troponina T ultrasensible como biomarcadores predictivos de fibrilación auricular postoperatoria.

INTRODUCTION: Atrial fibrillation (AF) has an incidence rate of approximately 30% and is the most frequent arrhythmia following heart surgery. Factors such as inflammation, the presence of heart fibrosis, stress and cardiomyocyte apoptosis, have all been associated with AF. OBJECTIVES: We believe that atrial remodelling is a pre-existent process in patients with post-surgical AF. We have analyzed the factors related to the incidence of atrial fibrillation in the period after heart surgery. METHODS: We included consecutive, hemodynamically stable patients with a sinusal rhythm who were subjected to programmed heart surgery with extracorporeal circulation. An assessment was made of the fall in atrial fibrillation after surgery using prolonged electrocardiographic monitoring. RESULTS: A total of 100 patients were included in the study and were subjected to either coronary revascularisation surgery (59) or aortic valve substitution due to severe aortic stenosis (41). Postoperative AF occurred in 29 patients who received predominantly more valve surgery than coronary surgery. The following factors were predictive of postoperative AF in the multivariate analysis: Male sex; beta-blocker therapy for chronic disease; the use of intraoperative; fibrinogen perfusion; low HDL cholesterol values; and high sensitive troponin T values, in the preoperative period. CONCLUSIONS: HDL cholesterol and high sensitive troponin T can be useful biomarkers to predict the occurrence of AF after surgery. The early identification of these patients who develop of FA allows us to take preventive measures to minimize the negative effects.

High-sensitivity troponin T as a biomarker for the development of atrial fibrillation after cardiac surgery.

OBJECTIVES: Atrial fibrillation (AF) occurs in ∼ 30% of patients undergoing coronary artery bypass grafting (CABG) and in 40% of patients after valve surgery. High-sensitivity cardiac troponin T (hsTnT) is a specific and high-sensitivity marker of myocardial injury, while N-terminal proB-type natriuretic peptide (NT-proBNP) is an established biomarker for wall remodelling. We investigated whether hsTnT and NT-proBNP levels could be used as valuable biomarkers for AF occurrence after cardiac surgery. METHODS: We included consecutive haemodynamically stable patients undergoing programmed cardiac surgery with cardiopulmonary bypass pump. We determined hsTnT and NT-proBNP levels before and after cardiac surgery and recorded AF development by prolonged electrocardiogram monitoring. RESULTS: We included 100 patients with predominantly aortic valve (n = 42) or ischaemic heart (n = 58) diseases. Twenty-nine patients (29%) developed post-surgical AF. Patients developing AF had a longer hospital stay (P = 0.005). hsTnT levels increased after surgery [P < 0.001], indicating perioperative myocardial injury, with higher presurgery levels in patients who developed AF [P = 0.015]. Body mass index and EuroSCORE risk scale were independently associated with higher hsTnT levels presurgery. On univariate analysis, age (P = 0.048), male sex (P = 0.031), indexed left atrial volume (P = 0.042), ß-blockers treatment (P = 0.024), type of surgery (valve surgery vs CABG; P = 0.034), EuroSCORE risk scale (P = 0.025) and higher preoperative hsTnT levels (P = 0.009) were predictors of AF development, but NT-proBNP did not reach statistical significance (P = 0.060). hsTnT levels in blood samples obtained the day after surgery were not associated with post-surgical AF development (P = 0.165). In a multivariate model, only higher hsTnT levels before cardiac surgery (>11.87 ng/l) [Odds Ratio, OR; (95% Confidence interval, CI) 4.27 (1.43-12.77), P = 0.009] and male sex [OR 5.10 (1.72-15.13), P = 0.003)] were independently associated with the occurrence of post-surgical AF. CONCLUSION: High presurgical hsTnT levels were independently predictive of patients developing AF after cardiac surgery. hsTnT levels determined post-surgery suggest that cardiac perioperative myocardial injury is not associated with postoperative AF development. NT-proBNP did not reach statistical significance as a biomarker for AF prediction.

Interleukin-6 and high-sensitivity C-reactive protein for the prediction of outcomes in non-ST-segment elevation acute coronary syndromes.

INTRODUCTION AND OBJECTIVES: High baseline levels of interleukin-6 and C-reactive protein confer an increased risk of mortality in non-ST-segment elevation acute coronary syndrome. The aim of the study was to determine whether serial measurements of interleukin-6 and high-sensitivity C-reactive protein provide additional information to baseline measurements for risk stratification of non-ST-segment elevation acute coronary syndrome. METHODS: Two hundred and sixteen consecutive patients with non-ST-segment elevation acute coronary syndrome were prospectively included. Blood samples were obtained within 24 h of hospital admission and at 30 days of follow-up. The endpoint was a composite of all-cause death, nonfatal myocardial infarction, or acute decompensated heart failure. RESULTS: Both interleukin-6 and high-sensitivity C-reactive protein levels decreased from day 1 to day 30, regardless of adverse events (both P<.001). Interleukin-6 levels at 2 time points (interleukin-6 day 1, per pg/mL; hazard ratio=1.006, 95% confidence interval, 1.002-1.010; P=.002 and interleukin-6 day 30, per pg/mL, hazard ratio=1.047, 95% confidence interval, 1.021-1.075, P<.001) were independent predictors of adverse events, whereas high-sensitivity C-reactive protein day 1 and high-sensitivity C-reactive protein day 30 levels were not. Patients with interleukin-6 day 1≤8.24 pg/mL and interleukin-6 day 30≤4.45 pg/mL had the lowest event rates (4.7%), whereas those with both above the median values had the highest event rates (35%). After addition of interleukin-6 day 30 to the multivariate model, C-index increased from 0.71 (95% confidence interval, 0.63-0.78) to 0.80 (95% confidence interval, 0.72-0.86), P=.042, and net reclassification improvement was 0.39 (95% confidence interval, 0.14-0.64; P=.002). CONCLUSIONS: In this population, both interleukin-6 and high-sensitivity C-reactive protein concentrations decreased after the acute phase. Serial samples of interleukin-6 concentrations improved the prognostic risk stratification of these patients.

Usefulness of ß-trace protein and cystatin C for the prediction of mortality in non ST segment elevation acute coronary syndromes.

Beta-trace protein (BTP) is a low-molecular mass protein belonging to the lipocalin protein family, which is more sensitive than serum creatinine for detecting impaired renal function. The aims of the present study were to evaluate whether plasma BTP improves the risk stratification of patients with non-ST-segment elevation acute coronary syndromes and to compare it to cystatin C (CysC), serum creatinine, and estimated glomerular filtration rate. Two hundred twenty-six consecutive patients with non-ST-segment elevation acute coronary syndromes were prospectively included. Blood samples were obtained within 24 hours of hospital admission to measure BTP, CysC, and creatinine. The study end point was all-cause death. Over a median follow-up period of 859 days (interquartile range [IQR] 524 to 1,164), 24 patients (10.6%) died. Decedents had higher concentrations of BTP (1.03 mg/L [IQR 0.89 to 1.43] vs 0.74 mg/L [IQR 0.61 to 0.92], p <0.001), CysC (1.16 mg/L [IQR 0.91 to 1.59] vs 0.90 mg/L [IQR 0.76 to 1.08], p = 0.001), and serum creatinine (1.10 mg/L [IQR 0.87 to 1.46] vs 0.94 mg/L [IQR 0.80 to 1.10], p = 0.004) and a lower mean estimated glomerular filtration rate (60 ± 20 vs 80 ± 24 ml/min/1.73 m(2), p <0.001). After multivariate adjustment, BTP and CysC were predictors of all-cause death, while estimated glomerular filtration rate and serum creatinine concentrations did not achieve statistical significance. In stratified analyses according to kidney function, elevated BTP and CysC were associated with a higher risk for all-cause death. Reclassification analyses showed that BTP and CysC added complementary information to Global Registry for Acute Coronary Events (GRACE) risk score. In conclusion, BTP and CysC levels were associated with all-cause death risk and modestly improved prognostic discrimination beyond the GRACE risk score in patients with non-ST segment elevation acute coronary syndromes.

Novel biomarkers in cardiology: MicroRNAs in atrial fibrillation / Nuevos biomarcadores en cardiología: microARN en fibrilación auricular

Atrial fibrillation (AF) is the most common sustained chronic cardiac arrhythmia in clinical practice, which increases the risk of stroke and thromboembolism and is an independent predictor of mortality. The underlying mechanisms involved in the development of AF have yet to be fully elucidated. However, once initiated, AF tends to self-perpetuate, owing to structural and electrical remodeling in the atria. MicroRNAs (miRNAs) represent a sizable sub-group of small non-coding RNAs, which degrades or inhibits the translation of their target mRNAs, thus regulating gene expression and playing an important role in a wide range of biologic processes. Clinically, there is increasing evidence of the potential diagnostic role of miRNAs as biomarkers, representing a novel therapeutic target in AF. The aim of this review is to provide an exhaustive overview of the role of miRNAs in AF and to discuss the diagnostic and therapeutic potential of miRNAs in this arrhythmia.

La fibrilación auricular (FA) es la arritmia cardíaca sostenida crónica más común en la práctica clínica, lo que aumenta el riesgo de accidente cerebrovascular y tromboembolismo, y es un predictor independiente de mortalidad. Los mecanismos subyacentes implicados en el desarrollo de la FA todavía no se han aclarado completamente. Sin embargo, una vez iniciada, la FA tiende a perpetuarse, debido al remodelado estructural y eléctrico en la aurícula. Los microARN (miARN) representan un subgrupo importante de pequeños ARN no codificantes, que degradan o inhiben la traducción de sus ARN mensajeros diana, regulando así la expresión génica y que desempeñan un papel importante en una amplia gama de procesos biológicos. Clínicamente, se ha observado con creciente interés el posible papel diagnóstico de los miARN como biomarcadores, representando una nueva diana terapéutica en la FA. El objetivo de esta revisión es proporcionar una visión exhaustiva de la función de los miARN en la FA y discutir el posible papel diagnóstico y terapéutico de los miARN en esta arritmia.

Colesterol HDL y troponina T ultrasensible como biomarcadores predictivos de fibrilación auricular postoperatoria / HDL cholesterol and high-sensitive troponin T as predictives biomarkers of atrial fibrillation after heart surgery

Introducción: La fibrilación auricular (FA), con una incidencia aproximada del 30%, es la arritmia más frecuente tras cirugía cardiaca. Se han asociado a la FA factores como la inflamación, la presencia de fibrosis cardiaca, el estrés y la apoptosis de cardiomiocitos. Objetivos: Consideramos que el remodelado auricular es un proceso preexistente en los pacientes con FA posquirúrgica. Analizamos los factores relacionados con la incidencia de FA en el postoperatorio de cirugía cardiaca. Métodos: Incluimos a pacientes consecutivos, estables hemodinámicamente y en ritmo sinusal, sometidos a cirugía cardiaca programada con circulación extracorpórea. Se valora la caída en FA posquirúrgica. Resultados: Se incluyeron un total de 100 pacientes sometidos a cirugía de revascularización coronaria (59) o sustitución valvular aórtica (41) por estenosis aórtica grave. La FA postoperatoria se produjo en 29 pacientes con predominio de la cirugía valvular respecto a la cirugía coronaria. Los factores predictivos de la aparición de FA postoperatoria en el análisis multivariable fueron el sexo masculino, la ausencia de terapia crónica con betabloqueadores, la perfusión de fibrinógeno intraoperatorio, valores bajos de colesterol HDL y valores elevados de troponina T ultrasensible en el preoperatorio. Conclusiones: El colesterol HDL y la troponina T ultrasensible pueden ser biomarcadores útiles para predecir la aparición de FA postoperatoria. La identificación precoz de estos pacientes nos permite adoptar medidas preventivas para minimizar sus efectos negativos.

Introduction: Atrial fibrillation (AF) has an incidence rate of approximately 30% and is the most frequent arrhythmia following heart surgery. Factors such as inflammation, the presence of heart fibrosis, stress and cardiomyocyte apoptosis, have all been associated with AF. Objectives: We believe that atrial remodelling is a pre-existent process in patients with post-surgical AF. We have analyzed the factors related to the incidence of atrial fibrillation in the period after heart surgery. Methods: We included consecutive, hemodynamically stable patients with a sinusal rhythm who were subjected to programmed heart surgery with extracorporeal circulation. An assessment was made of the fall in atrial fibrillation after surgery using prolonged electrocardiographic monitoring. Results: A total of 100 patients were included in the study and were subjected to either coronary revascularisation surgery (59) or aortic valve substitution due to severe aortic stenosis (41). Postoperative AF occurred in 29 patients who received predominantly more valve surgery than coronary surgery. The following factors were predictive of postoperative AF in the multivariate analysis: Male sex; beta-blocker therapy for chronic disease; the use of intraoperative; fibrinogen perfusion; low HDL cholesterol values; and high sensitive troponin T values, in the preoperative period. Conclusions: HDL cholesterol and high sensitive troponin T can be useful biomarkers to predict the occurrence of AF after surgery. The early identification of these patients who develop of FA allows us to take preventive measures to minimize the negative effects.