Global longitudinal strain assessment of cardiac function and extravascular lung water formation after diving using semi-closed circuit rebreather.

PURPOSE: The aim of the present investigation is to study the relationship of ventricular global longitudinal strain (GLS) and ultrasound lung comets (ULC) formation to establish a link between extravascular pulmonary water formation and cardiac contractile dysfunction. METHODS: This is a prospective observational study including 14 active military divers. The subjects performed two sea dives of 120 min each with a semi-closed SCUBA circuit at 10 m depth. Divers were examined at baseline, 15 min (D1) and 60 min (D2) after diving. The evaluation included pulmonary and cardiac echography (including speckle tracking techniques). Blood samples were drawn at baseline and after diving, assessing hs-TnT and Endothelin-1. RESULTS: ULC were detected in 9 (64.2%) and 8 (57.1%) of the subjects after D1 and D2 respectively. No differences were found in right and left ventricular GLS after both immersions (RV: Baseline: - 17.9 4.9 vs. D1: - 17.2 6.5 and D2: - 16.7 5.8 s-1; p = 0.757 and p = 0.529; LV: Baseline: - 17.0 2.3 vs. D1: - 17.4 2.1 and D2: - 16.9 2.2 s-1; p = 0.546 and p = 0.783). However, a decrease in atrial longitudinal strain parameters have been detected after diving (RA: Baseline: 35.5 9.2 vs. D1: 30.3 12.8 and D2: 30.7 13.0 s-1; p = 0.088 and p = 0.063; LA: Baseline: 39.0 10.0 vs. D1: 31.6 6.1 and D2: 32.4 10.6 s-1; p = 0.019 and p = 0.054). CONCLUSION: In the present study, no ventricular contractile dysfunction was observed. However, increase pulmonary vasoconstriction markers were present after diving.

Influence of the matrix type over the concentration of GDF-15.

Growth differentiation factor 15 (GDF-15) has been suggested as a prognostic biomarker for bleeding and mortality in atrial fibrillation (AF). To date, serum and EDTA matrices are standardized for the GDF-15 assay but it is unclear if it can be measured also in citrate. In this study, we aim to investigate if the Elecsys GDF-15 assay (Roche Diagnostics, Mannheim, Germany) can be determined accurately in citrate samples in a cohort of 10 patients with AF and 10 healthy controls. From January 2018 to March 2018, we included healthy controls and patients with AF under vitamin K antagonists in a tertiary hospital. Blood samples were drawn in both groups. We included 10 controls (50% males, mean age 36.4±8.9 years) and 10 patients with AF (80% males, mean age 76.5±16.6 years). The mean GDF-15 levels were increased in patients with AF in comparison to healthy controls, as expected by the presence of a heart-related condition and the higher age of this population. In healthy controls, GDF-15 levels showed an optimal correlation between EDTA-serum (r=0.975; p<0.001), EDTA-citrate (r=0.972; p<0.001), and serum-citrate (r=0.997; p<0.001) samples. This was also observed in patients with AF: EDTA-serum (r=0.975; p<0.001), serum-citrate (r=0.835; p=0.003), and EDTA-citrate (r=0.768; p=0.009). Our results demonstrate that citrate samples may be used for the determination of GDF-15 in AF given the positive and good correlation with EDTA and serum matrices. Further studies should validate these observations.

Refining Stroke and Bleeding Prediction in Atrial Fibrillation by Adding Consecutive Biomarkers to Clinical Risk Scores.

Background and Purpose- Current European guidelines for the management of atrial fibrillation suggest using biomarkers to refine the risk stratification process. However, it is unclear whether ≥2 biomarkers incrementally improve risk prediction beyond 1 biomarker alone. We investigated whether the predictive performance of CHA2DS2-VASc and HAS-BLED scores could be enhanced by incrementally adding consecutive different biomarkers in real-world atrial fibrillation patients taking vitamin K antagonists therapy. Methods- We included 940 atrial fibrillation patients stable on vitamin K antagonists (international normalized ratio, 2.0-3.0) for at least the previous 6 months. At inclusion, VWF (von Willebrand factor), high-sensitivity troponin T, NT-proBNP (N-terminal pro-B-type natriuretic peptide), high-sensitivity IL (interleukin)-6, fibrin monomers, and BTP (ß-trace protein) concentrations were quantified. During follow-up, all adverse events were recorded, and biomarkers were added to CHA2DS2-VASc and HAS-BLED scores depending on the C index. Results- During 6.5 (4.3-7.9) years, there were 98 ischemic strokes (1.60% per year) and 172 major bleeds (1.60% per year). After the addition of biomarkers, the predictive performance of CHA2DS2-VASc was not significantly increased, although the model with 3 biomarkers (ie, NT-proBNP+BTP+VWF) showed a low gain in sensitivity (integrated discrimination improvement, 2.70%; P<0.001). The predictive performance of HAS-BLED was enhanced in all biomarker-based models, with the best prediction shown by the model with 3 biomarkers (ie, VWF+NT-proBNP+high-sensitivity IL-6; C index, 0.600 [95% CI, 0.561-0.625] versus 0.639 [95% CI, 0.607-0.669]; P=0.025). This model also confirmed an increased sensitivity (integrated discrimination improvement, 5.20%; P<0.001) and positive reclassification (net reclassification improvement, 19.20%; P=0.020). Conclusions- By adding consecutive biomarkers, the predictive ability of CHA2DS2-VASc for ischemic stroke was not increased, whereas the predictive ability of HAS-BLED for major bleeding was only slightly enhanced. The net benefit and clinical usefulness of the biomarker-based models were marginal in comparison to the original scores based on clinical factors.

Galectin-3 and ß-trace protein concentrations are higher in clinically unaffected patients with Fabry disease.

Current therapies have not shown benefit in organ damage reversal in Fabry disease (FD), but biomarkers could help risk stratification and prognosis. We investigated if several biomarkers of cardiac fibrosis, cardiac wall stress, myocardial injury, renal function and inflammation, are associated with early cardiac affectation in FD patients. We included FD patients from four cardiology outpatient clinics of southeastern Spain. At inclusion, Galectin-3 (Gal-3), N-terminal proB-type natriuretic peptide, high sensitivity troponin T (hsTnT), ß-trace protein (BTP) and interleukin-6 concentrations were measured. The relation of biomarkers concentrations with clinical features, cardiac involvement and organ affectation according to the Mainz Severity Score Index (MSSI) was investigated. 44 FD patients (n = 21 affected and n = 23 unaffected) were compared to age and sex-respectively matched healthy controls. Significant differences in biomarkers' concentration between FD groups were observed. Importantly, Gal-3 and BTP levels were higher in unaffected patients when compared with age and sex-matched healthy controls (both p < 0.05). All the biomarkers correlated with clinical features. When cut-off values for clinical affectation (measured as MSSI ≥ 20) were established, only hsTnT (OR 30.69, 95% CI 2.70-348.42) and male sex (OR 8.17, 95% CI 1.16-57.75) were independently associated with cardiac damage by multivariate regression analysis. Gal-3 and BTP levels are increased in unaffected FD patients compared to healthy controls. This suggests that these biomarkers could be useful for the early detection of cardiac affectation in FD patients. On the other hand, hsTnT and male sex are independent risk factors for established clinical cardiac damage in FD.

A FCGR3A Polymorphism Predicts Anti-drug Antibodies in Chronic Inflammatory Bowel Disease Patients Treated With Anti-TNF.

BACKGROUND: The production of anti-drug antibodies (ADAs) against IgG monoclonal antibodies (mAbs) targeting tumour necrosis factor (TNF) is an important cause of loss of response to anti-TNF mAbs in patients with inflammatory bowel diseases (IBD) such as Crohn's disease (CD) and ulcerative colitis (UC). Since receptors for the Fc portion of IgG (FCGRs) are involved in the degradation of IgG complexes, we hypothesised that a polymorphism in FCGR3A (V158F; rs396991) gene could be involved in anti-TNF ADA generation and treatment resistance. MATERIAL AND METHODS: A cohort of 103 IBD patients (80 CD, 23 UC) were genotyped and serum level of both anti-TNFs (infliximab or adalimumab) and ADA against them were measured. RESULTS: No significant differences were observed between ADA occurrence or V158F genotype and type of disease or the kind of anti-TNF administrated. Interestingly, VV genotype correlated with patients producing ADA (VV: 37.5% vs. FV: 10.6% or FF: 5%; p=0.004) and was an independent predictor of this event after multivariate analysis. Moreover, VV genotype also correlated with those patients receiving anti-TNF dose intensification (p=0.03). CONCLUSION: FCGR3A V158F polymorphism seems to be associated with ADA production against mAbs and it could be taken into account when considering the dose and type of anti-TNF in IBD patients.

Enhancing the 'real world' prediction of cardiovascular events and major bleeding with the CHA2DS2-VASc and HAS-BLED scores using multiple biomarkers.

BACKGROUND: Atrial fibrillation (AF)-European guidelines suggest the use of biomarkers to stratify patients for stroke and bleeding risks. We investigated if a multibiomarker strategy improved the predictive performance of CHA2DS2-VASc and HAS-BLED in anticoagulated AF patients. METHODS: We included consecutive patients stabilized for six months on vitamin K antagonists (INRs 2.0-3.0). High sensitivity troponin T, NT-proBNP, interleukin-6, von Willebrand factor concentrations and glomerular filtration rate (eGFR; using MDRD-4 formula) were quantified at baseline. Time in therapeutic range (TTR) was recorded at six months after inclusion. Patients were follow-up during a median of 2375 (IQR 1564-2887) days and all adverse events were recorded. RESULTS: In 1361 patients, adding four blood biomarkers, TTR and MDRD-eGFR, the predictive value of CHA2DS2-VASc increased significantly by c-index (0.63 vs. 0.65; p = .030) and IDI (0.85%; p < .001), but not by NRI (-2.82%; p < .001). The predictive value of HAS-BLED increased up to 1.34% by IDI (p < .001). Nevertheless, the overall predictive value remains modest (c-indexes approximately 0.65) and decision curve analyses found lower net benefit compared with the originals scores. CONCLUSIONS: Addition of biomarkers enhanced the predictive value of CHA2DS2-VASc and HAS-BLED, although the overall improvement was modest and the added predictive advantage over original scores was marginal. Key Messages Recent atrial fibrillation (AF)-European guidelines for the first time suggest the use of biomarkers to stratify patients for stroke and bleeding risks, but their usefulness in real world for risk stratification is still questionable. In this cohort study involving 1361 AF patients optimally anticoagulated with vitamin K antagonists, adding high sensitivity troponin T, N-terminal pro-B-type natriuretic peptide, interleukin 6, von Willebrand factor, glomerular filtration rate (by the MDRD-4 formula) and time in therapeutic range, increased the predictive value of CHA2DS2-VASc for cardiovascular events, but not the predictive value of HAS-BLED for major bleeding. Reclassification analyses did not show improvement adding multiple biomarkers. Despite the improvement observed, the added predictive advantage is marginal and the clinical usefulness and net benefit over current clinical scores is lower.

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.

The Effects of One-Anastomosis Gastric Bypass on Glucose Metabolism in Goto-Kakizaki Rats.

BACKGROUND: The improvement in glucose metabolism after bariatric surgery is well established. The aim of this study was to investigate the hormones and glycemic control in diabetes after a one-anastomosis gastric bypass (OAGB) variant in an animal model of non-obese type 2 diabetes mellitus. METHODS: Thirty-six Goto-Kakizaki rats were randomly assigned to undergo one of the following procedures: OAGB (18 rats) or sham intervention (18 rats). Each group was subdivided into three additional groups according to the time of surgery (early-12 weeks; intermediate-16 weeks; and late-20 weeks). Weight, fasting glycemia, glucose tolerance test (OGTT), and hormone levels (glucagon, insulin, glucagon-like peptide-1 [GLP-1], and glucose-dependent insulinotropic peptide [GIP]) were measured. RESULTS: All rats maintained their weight. The OGTT showed a significant improvement in glycemic levels in rats with OAGB in all time groups (p < 0.002, for all groups at 60 min). Insulin levels decreased significantly in all animals with OAGB, but glucagon levels increased (glucagon paradoxical response). GLP-1 and GIP increased in rats with OAGB at all times, but was only statistically significant in the early surgery group of GLP-1 (p < 0.005). CONCLUSION: OAGB in a non-obese diabetic rat model improves glycemic control, with a significant decrease in glucose and insulin levels. This reduction without weight loss suggests a surgically induced enhancement of pancreatic function. It appears that this improvement occurs, although the GLP-1 levels were significantly increased only in the early stages. The paradoxical response of glucagon should be further evaluated.

Second trimester angiotensing-converting enzyme and uterine artery Doppler as predictors of preeclampsia in a high-risk population.

OBJECTIVE: To investigate whether serum angiotensing-converting enzyme (ACE) and uterine artery Doppler (UAD) are useful markers as predictors of preeclampsia (PE) in a high-risk population. METHODS: Patients at risk of PE (n = 68) were subclassified as having PE (n = 8) or no PE (n = 60). Blood samples were obtained between 19 and 22 weeks of gestation. Doppler ultrasound of the uterine arteries was done at the time of blood sampling. Maternal serum ACE was determined through spectrophotometry assay (A15 Biosystem, ATOM, Barcelona, Spain). RESULTS: Comparing the group who presented PE with the one who was not developed it, we found significant differences for ACE (54.2 ± 21.2, 38.1 ± 12.3 U/L; p = 0.003); the pulsatility index (PI) (1.2 ± 0, 3.1 ± 0.3; p = 0.032) and resistance index (RI) (0.7 ± 0.1, 0.5 ± 0.1; p = 0.004). The AUC for ACE was 0.724, so we selected the cutoff of 36.5 U/L (sensitivity: 62.5% and specificity: 86.7%). The AUC for PI was 0.652 choosing a cutoff of 1.4 (sensitivity: 57.1% and specificity: 93.1%). The AUC for RI was 0.712 and the cutoff of 0.7 (sensitivity of 71.4% and specificity: 89.6%). The combination that allowed us to increase the diagnostic performance was the ACE+RI with Doppler study, increasing the AUC to 0.872. CONCLUSIONS: ACE, PI and RI as parameters of Doppler study were useful predictors of PE in the second trimester of gestation. The best combination to increase the diagnostic performance was ACE with the RI.

Safety of new oral anticoagulant drugs: a perspective.

The recent development of new oral anticoagulants (NOACs) offers the possibility of efficacy, relative safety and convenience compared with warfarin. This could lead to greater patient compliance, with easier management and improved provision of thromboprophylaxis. Safety whilst using NOACs should be focused on bleeding cases, surgery or on the management of patients receiving anticoagulant therapy with concomitant impairment of renal function, especially since many NOACs are dependent on renal excretion. Thus, if the clearance creatinine indicates severe renal impairment, NOACS will be contraindicated or their dose needs to be changed. In patients who need surgery, there are published protocols of management, depending on the severity of the intervention and renal function. In the case of severe hemorrhage, requiring rapid reversal of the anticoagulant effect and in the absence of specific antidotes, alternatives such as one of the nonspecific haemostatic agents must be considered. Clinical evaluation in bleeding situations and a meticulous risk-benefit appraisal for NOACs is needed, and these procoagulant agents and patients must be monitored closely. This article provides an overview of the pharmacology and potential risks, as well as the efficacy and safety of NOACs.

Placental growth factor, soluble fms-like tyrosine kinase 1 and progesterone as diagnostic biomarkers for ectopic pregnancy and missed abortion.

OBJECTIVE: The aim of this study is to investigate if progesterone, placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt1) serum levels are useful markers to differentiate between ectopic pregnancy (EP), missed abortion (MA) and viable intrauterine implantation pregnancy (IUP). METHODS: We designed a retrospective case-control study which included 100 pregnant women (50 EP and 50 MA) at 6-8 weeks of gestation with ßhCG serum levels between 800 and 3500 UI/L and a viable IUP group. Progesterone, PlGF and sFlt-1 levels were measured with an electrochemiluminescence assay (Roche Diagnostics, Manheim, Alemania). A non parametric test was used to compare the markers in the different groups and we used receiver operating characteristic (ROC) curve analysis to calculate the area under the curve (AUC). RESULTS: When we compared the EP group with the MA group, we didn't find significant differences for PlGF (15.1[13.2-17.4]/16.7[12.8-18.7] pg/mL) (p=0.275). We only obtained significant differences for progesterone (9.1[3.1-16.8]/2.6[1.3-6.1] ng/mL) (p<0.001) and sFlt-1 (84[65-96]/126[94-256] pg/mL) (p<0.001). The AUC for progesterone was 0.756 and the cutoff point with better sensitivity and lower false positive rate was 6 ng/mL (sensitivity=60%, specificity=72.7%). The AUC for sFlt-1 was 0.842 and the cutoff point was 93 pg/mL (sensitivity=84.5%, specificity=86.3%). The combination of both markers allowed us to increase the AUC to 0.910. CONCLUSIONS: In conclusion, the present study suggests that sFlt-1 could be a useful marker to differentiate between an EP or a MA when ßhCG levels are similar in both groups. The combination of sFlt-1 with progesterone helps to increase the diagnostic performance.

Usefulness of N-terminal pro-B-type natriuretic Peptide levels for stroke risk prediction in anticoagulated patients with atrial fibrillation.

BACKGROUND AND PURPOSE: Oral anticoagulation is highly effective in reducing stroke and mortality in atrial fibrillation (AF). Several risk stratification schemes have been developed using clinical characteristics. Elevated levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP) are important markers of increased mortality and morbidity in congestive heart failure and general community population. The aim of our study was to assess the predictive value of NT-proBNP levels in an unselected real-world cohort of anticoagulated patients with AF. METHODS: We studied 1172 patients (49% male; median age, 76 years) with permanent AF who were well stabilized on oral anticoagulation (international normalized ratio, 2.0-3.0). Plasma NT-proBNP levels were quantified at baseline. We recorded thrombotic and vascular events, mortality, and major bleeding. The best cutoff points were assessed by receiver-operating characteristic curves. RESULTS: Median levels (interquartile range) of NT-proBNP were 610 (318-1037) pg/mL. Median follow-up was 1007 (806-1279) days. On multivariate analysis, high NT-proBNP was significantly associated with the risk of stroke (hazards ratio, 2.71; P=0.001) and composite vascular events (acute coronary syndrome or acute heart failure; hazards ratio, 1.85; P=0.016), as well as a significant association with mortality (adjusted hazards ratio, 1.66; P=0.006). No association with bleeding was found (P=0.637). The integrated discrimination improvement (IDI) analysis demonstrated that NT-proBNP improved the Congestive heart failure, Hypertension, Age≥75 (doubled), Diabetes mellitus, Stroke (doubled)-Vascular disease and Sex category (female); CHA2DS2-VASc score for predicting embolic events (relative IDI, 2.8%; P=0.001) and all-cause death (relative IDI, 1.8%; P=0.001). CONCLUSIONS: In real-world cohort of anticoagulated patients with AF, NT-proBNP provided complementary prognostic information to an established clinical risk score (CHA2DS2-VASc) for the prediction of stroke/systemic embolism. NT-proBNP was also predictive of all-cause mortality, suggesting that this biomarker may potentially be used to refine clinical risk stratification in anticoagulated patients with AF.

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.

The HAS-BLED score has better prediction accuracy for major bleeding than CHADS2 or CHA2DS2-VASc scores in anticoagulated patients with atrial fibrillation.

OBJECTIVES: The aim of this study was to test the hypothesis that a specific bleeding risk score, HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol concomitantly), was better at predicting major bleeding compared with CHADS2 (congestive heart failure, hypertension, 75 years of age or older, diabetes mellitus, and previous stroke or transient ischemic attack) and CHA2DS2-VASc (congestive heart failure, hypertension, 75 years of age and older, diabetes mellitus, previous stroke or transient ischemic attack, vascular disease, 65 to 74 years of age, female) in anticoagulated atrial fibrillation (AF) patients. BACKGROUND: The CHADS2 and CHA2DS2-VASc scores are well-validated stroke risk prediction scores for AF, but are also associated with increased bleeding and mortality. METHODS: We recruited 1,370 consecutive AF patients (49% male; median age, 76 years) receiving oral anticoagulation therapy from our outpatient anticoagulation clinic, all of whom were receiving acenocoumarol and had an international normalized ratio between 2.0 and 3.0 during the preceding 6 months. During follow-up, major bleeding events were identified by the 2005 International Society on Thrombosis and Haemostasis criteria. Model performance was evaluated by calculating the C-statistic, and the improvement in predictive accuracy was evaluated by calculating the net reclassification improvement and integrated discrimination improvement. RESULTS: After a median follow-up of 996 (range, 802 to 1,254) days, 114 patients (3.0%/year) presented with a major bleeding event; 31 of these events were intracranial hemorrhages (0.8%/year). Based on the C-statistic, HAS-BLED had a model performance superior to that of both CHADS2 and CHA2DS2-VASc (both p < 0.001). Both net reclassification improvement and integrated discrimination improvement analyses also show that HAS-BLED was more accurately associated with major bleeding compared with CHADS2 and CHA2DS2-VASc scores. CONCLUSIONS: In anticoagulated AF patients, a validated specific bleeding risk score, HAS-BLED, should be used for assessing major bleeding. The practice of using CHADS2 and CHA2DS2-VASc as a measure of high bleeding risk should be discouraged, given its inferior predictive performance compared with the HAS-BLED score.

ß-Trace protein and prognosis in patients with atrial fibrillation receiving anticoagulation treatment.

BACKGROUND: Atrial fibrillation (AF) is associated with a high risk of mortality and morbidity and it commonly coexists with chronic kidney disease. A biomarker of renal function, ß-trace protein (BTP), has been implicated in the progression of cardiovascular disease. The aim of our study was to evaluate the association of BTP with adverse cardiovascular events, bleeding, and mortality in patients with AF. METHODS: In a consecutive cohort of patients with nonvalvular AF receiving anticoagulation treatment, plasma BTP was determined using an automated nephelometer BN ProSpec System (Siemens) and related to estimated glomerular filtration rate (eGFR). We recorded adverse cardiovascular events (stroke, acute coronary syndrome, and acute pulmonary edema), major bleeding, and mortality. RESULTS: We included 1,279 patients (48.6% men), aged 76 years (IQR, 71-81 years), who were followed up for 996 days (IQR, 802-1,254 days). During the follow-up, there were 150 cardiovascular events (annual rate, 3.99%), 57 embolisms (annual rate, 1.54%), and 114 major bleeding events (annual rate, 3.04%), and 161 patients died (annual rate, 4.32%). BTP levels were inversely associated with eGFR (P < .001). High BTP concentrations were significantly associated with embolic events (hazard ratio [HR], 4.64 [1.98-10.86]; P < .001), composite adverse cardiovascular events (HR, 1.93 [1.31-2.85]; P = .001), and mortality (HR, 2.08 [1.49-2.90]; P < .001), even after adjusting for CHAD2DS2-VASc (congestive heart failure, hypertension, age ≥ 75 years [doubled], diabetes mellitus, stroke [doubled], vascular disease, age 65 to 74 years, sex category) score and renal function. High BTP was associated with major bleeding events (HR, 1.88 [1.18-3.00]; P = .008), even after adjusting for the HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or redisposition, labile international normalized ratio, elderly [> 65 years], drugs/alcohol concomitantly) score. CONCLUSIONS: We suggest that BTP, a proposed renal damage biomarker, may be a novel predictor of adverse cardiovascular events, major bleeding, and mortality in patients with AF. BTP may help refine clinical risk stratification in these patients.

Identification and confirmation of haptoglobin as a potential serum biomarker in hypertrophic cardiomyopathy using proteomic approaches.

INTRODUCTION: Aiming at identifying biomarkers for hypertrophic cardiomyopathy (HCM), the serum proteome was explored through a two-dimensional gel-based proteomic approach (2D-DIGE) coupled with mass spectrometry and database interrogation. METHODS: Serum samples from 20 male HCM patients and their sex- and age-matched controls were cleaned from interfering components. Patients and controls were pooled in five matched groups with the same age, and proteins extracts from each pool were labelled with cyanine dyes. Then, gel images were analysed using a fluorescence scanner and proteins were identified. Tryptic peptides were analysed by capillary reversed-phase liquid chromatography coupled online with tandem mass spectrometry (MS/MS). RESULTS: Four different proteins were observed to be differentially expressed between HCM patients and their matched controls. Of them, decreases in haptoglobin levels were confirmed to be associated with HCM in an independent set of 181 consecutive HCM patients from our monographic clinic and 114 controls with similar age and sex using a nephelometer-based technique. Moreover, a significant negative correlation was observed between haptoglobin and subaortic gradient, thus highlighting the role of haptoglobin in HCM. CONCLUSION: All these observations point out the utility of the 2D-DIGE proteomic strategy for the identification of serum proteins indicative of the presence of cardiac injury.

Performance evaluation of biochemical and ultrasound markers for the screening of chromosomal numerical abnormalities in the first trimester of pregnancy.

BACKGROUND: To estimate the effectiveness of the first-trimester combined screening test in our population, departing from the results of diagnostic sensitivity and false positive rate (FPR), and checking some important parameters in prenatal screening. METHODS: The test was evaluated on 14250 pregnant women. The following variables were studied: the number of invasive techniques and the reasons for using such techniques, newborns with chromosomal abnormalities, total number of births, variation of biochemical markers throughout the gestational weeks, and MoM (multiple of the median) for biochemical and ultrasound markers. RESULTS: An important coverage and a decreased number of invasive techniques were obtained. For our population of pregnant women, the best gestational week to determine free beta-hCG and PAPP-A would be week 11 in which the best discrimination was found between affected and non affected fetuses for the three trisomies researched. We propose the cut-off 1/350, because it is the best one to increase sensitivity without exceeding the 5% FPR. CONCLUSIONS: Combined screening should be offered to pregnant woman, preferentially at week 11. Although different cut-offs for this prenatal test have been recommended by scientific societies, biochemical laboratories should set their own cut-off for getting the best sensitivity and FPR results. There should be a good level of collaboration between the laboratory and each participating ultrasound unit in order to ensure an optimal use of the first-trimester combined screening test.

Comparative determination and monitoring of biomarkers of necrosis and myocardial remodeling between radiofrequency ablation and cryoablation.

BACKGROUND: Biomarkers of necrosis and inflammation have been found raised after radiofrequency ablation (RF). There is scarce information on biomarkers' behavior after cryoablation. Our aim was to study biomarkers of necrosis, inflammation, and interstitial remodeling after two different approaches: RF versus cryoablation. METHODS: We studied 22 consecutive patients with atrial flutter who underwent RF (10) or cryoablation (12). All patients underwent electrophysiological study and subsequent ablation. Peripheral samples were collected before the procedure, immediately after, the following day, 3 days, 1 week, 1 month, and 2 months after ablation. Samples were assayed for biomarkers of inflammation (high sensitive C-reactive protein [hs-CRP]) and tissue remodeling (C-propeptide of type I procollagen [CICP], matrix metalloproteinase 2 [MMP-2], matrix metalloproteinase 9 [MMP-9], and metallopeptidase inhibitor 1 [TIMP-1]). We also determined biomarkers of tissue necrosis (creatine kinase [CK], its MB isoenzyme, cardiac troponin I [TnI], and troponin T (TnT)] in samples obtained immediately after ablation, 6 hours postablation, and 12 hours postablation. RESULTS: Bidirectional isthmus block was achieved in all patients. We found significantly higher levels of CK, CK-MB, and TnI after cryoablation compared to RF ablation for all timing samples. These necrosis biomarkers showed significant differences depending on the time (all P < 0.001), and the interaction between the time and the used ablation approach (P = 0.005, P < 0.001, and P < 0.001, respectively). For patients who undergoing RF ablation, MMP-2 showed the greatest changes depending on the interaction between time and number of applications (P = 0.041), whereas for patients who undergoing cryoablation, CK was the most relevant biomarker depending on the interaction between time and number of applications (P = 0.006). CONCLUSIONS: We show higher levels of necrosis and myocardial injury biomarker after cryoablation versus RF. However, we found higher remodeling processes after RF. Our data support previous publications showing different lesion formation in cryoablation and RF.

Serum levels of high-sensitivity troponin T: a novel marker for cardiac remodeling in hypertrophic cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is characterized by inappropriate hypertrophy, small-vessel coronary artery disease, myocyte disarray, and increased interstitial fibrosis. High-sensitivity troponin T (hs-TnT) could be a reliable indicator of myocardial remodeling, a proposed prognostic marker in HCM. Therefore we hypothesized that increased hs-TnT levels are related to different variables associated with myocardial remodeling, such as the presence of fibrosis assessed with cardiac magnetic resonance imaging (MRI). METHODS AND RESULTS: We included 95 hemodynamically stable HCM patients, 72 male, aged 45.7 ± 14.2 years, and 45 healthy control subjects with similar age and gender. A complete history and clinical examination was performed, including 12-lead electrocardiogram (ECG), echocardiography, 24-hour ECG-Holter monitoring, symptom-limited treadmill exercise test, and late gadolinium enhancement in cardiac MRI. Risk factors for sudden death were evaluated. A blinded cardiac MRI was performed with late gadolinium enhancement study. Serum hs-TnT levels were assayed. A high proportion (42%) of hemodynamically stable patients studied showed increased levels of hs-TnT. The hs-TnT levels were raised in patients with severe dyspnea: New York Heart Association (NYHA) functional class ≥3 (P = .020), outflow obstruction (P = .013), systolic dysfunction (P = .037), abnormal blood pressure response (P = .036), and presence of gadolinium enhancement (P = .021). The hs-TnT levels correlated positively with the maximum left ventricular wall thickness (r = 0.47; P < .001), left atrial diameter (r = 0.36, P = .014), and outflow gradient (r = 0.28; P = .008). CONCLUSIONS: A high proportion of hemodynamically stable patients show increased levels of hs-TnT. We observed that raised hs-TnT serum levels are associated with different conditions related to the severity of the disease.