Ana I. Romero-Aniorte

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), β-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.

Usefulness of β-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.

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

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.

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.

Involvement of the -420C>G RETN polymorphism in myocardial fibrosis in patients with hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is characterized by left ventricular hypertrophy and fibrosis. HCM is an autosomal‐dominant disease caused by more than 400 mutations in sarcomeric genes. Changes in nonsarcomeric genes contribute to its phenotypic heterogeneity. Cardiac fibrosis can be studied using late gadolinium enhancement (LGE) cardiac magnetic resonance imaging. We evaluated the potential role of two polymorphisms in nonsarcomeric genes on interstitial fibrosis in HCM.

La concentración sérica de adiponectina como biomarcador de calcificación arterial coronaria y lesiones coronarias graves

Coronary artery calcification (CAC) is an independent risk factor for coronary atherosclerosis and belongs to the type VII category on Stary’s classification. Because CAC strongly predicts adverse cardiovascular events, and coronary disease is a major cause of death, the problem is of obvious clinical importance. Despite the heterogeneous extent of calcification among atherosclerotic patients, CAC can be easily and noninvasively quantified by cardiac computed tomography (CCT). Little information is available, however, on the underlying mechanisms of plaque calcification. Plasma adiponectin appears to exert cardioprotective effects, showing differences in both genders–probably influenced by testosterone levels–and distinct pathological conditions. Low adiponectin levels seem to be associated with CAC progression and susceptibility to plaque rupture, although the paradoxical role of adiponectin depending on the type of patients is increasingly debated. To highlight the role of adiponectin and testosterone in CAC and coronary lesions, we recruited stable ambulatory patients undergoing CCT for chest pain of possible coronary origin. Blood samples were obtained (immediately before performing CCT) by venepuncture in overnight fasting conditions. The samples underwent standard processing and researchers performed a blind analysis. Serum testosterone (detection limit 0.025 ng/mL, 8.4% interassay variation) and adiponectin (detection limit 0.195 ng/mL, 8.6% interassay variation) levels were respectively determined by electrochemiluminescence (Roche) and by enzymelinked immunosorbent assay (R&D Systems). Calcium score was determined using 64-slice CT (General Electric Healthcare). The total calcium content was quantified by a standardized protocol based on the Agatston score ( 400 Hounsfield units indicated a high calcification score). Severe lesions (stenosis 70% in 1 of the main coronary arteries) were assessed by coronary angiography. The statistical analysis was performed using SPSS 15.0 for Windows. We prospectively included 139 patients, aged 58.5 (11.4) years; 46.8% were males. A total of 17.3% of the patients had a high calcification score and 18.7% had severe coronary lesions (Table 1). A receiver operating characteristic (ROC) curve was calculated and a higher calcium score was associated with lower adiponectin levels but the predictive value for adiponectin was modest (cstatistic=0.65; 95% confidence interval [95%CI], 0.53-0.77; P=.021), the optimal cut-off being 8418 mg/mL, with a positive predictive value of 31% and a negative predictive value of 93%. Univariate analysis also showed that age and diabetes mellitus were associated with calcium score. After adjustment for confounding factors in the multivariate analysis (those presenting P-values<.15 in the univariate analysis), age, low adiponectin levels and high testosterone levels were independently associated with the calcification score. Additionally, adiponectin levels modestly predicted the presence of severe coronary lesion (c-statistic=0.68; 95%CI, 0.57-0.79, P=.004) in the ROC curve with an optimal cut-off of 8005 mg/mL, a positive predictive value of 32% and a negative predictive value of 90%. In addition to well-recognized atherosclerosis risk factors such as smoking and diabetes mellitus, high testosterone levels, male gender and high CAC were also significantly associated with severe coronary lesions in the univariate analysis. Only low adiponectin levels, high CAC and high testosterone concentrations remained as independent variables predicting severe coronary lesions after the multivariate analysis was performed (including variables with P-values of<.15 in the univariate analysis) (Table 2). Notably, high testosterone levels were independently associated with severe coronary lesions, even after adjusting for clinical and demographic features, including the category of gender. In addition, adiponectin levels were negatively correlated with serum testosterone levels. However, the inclusion of adiponectin to the integrated discrimination improvement (IDI) index and ROC curve calculations failed to produce statistical improvement within the model for the calcium score P=.061 or for severe angiographic lesions (P=.056). Our data are in agreement with previous reports performed in asymptomatic patients with subclinical coronary artery disease in whom CAC progression was associated with low circulating adiponectin levels. We established a cut-off point for serum adiponectin levels, with concentrations below this cut-off may indicate both CAC (<8418 mg/mL) and severe coronary lesions (<8005 mg/mL). Importantly, we found a strong association between among high CAC score and the presence of severe coronary lesions, supporting previous data on calcification in the atherosclerotic process. Moreover, the data on the protective or deleterious role of testosterone in coronary disease are conflicting and strong evidence indicates that testosterone suppresses adiponectin production. The association data also suggest that testosterone may increase coronary lesion severity, probably by reducing circulating adiponectin levels. Thus, testosteronereduced adiponectin levels may lead to CAC development and subsequently increase coronary lesion severity. Serum adiponectin level determination in patients at low cardiovascular risk could help their management as biomarker of

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.

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

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).

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

Abstract 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.

Disparities in the Estimation of Glomerular Filtration Rate According to Cockcroft‐Gault, Modification of Diet in Renal Disease‐4, and Chronic Kidney Disease Epidemiology Collaboration Equations and Relation With Outcomes in Patients With Acute Coronary Syndrome

Background A simple method to assess renal function is the estimated glomerular filtration rate, and it shows prognostic implications. However, it remains unknown which equation should be used in patients with acute coronary syndrome. We compared the ability and correlation of the Cockcroft‐Gault, Modification of Diet in Renal Disease‐4 (MDRD‐4), and Chronic Kidney Disease Epidemiology Collaboration (CKD‐EPI) equations and their predictive performance for major adverse cardiovascular events, all‐cause mortality, and major bleeding in a cohort of patients with acute coronary syndrome. Methods and Results Multicenter prospective registry involving 1699 consecutive patients with acute coronary syndrome from 3 tertiary institutions. At entry, renal function was assessed using the Cockcroft‐Gault, MDRD‐4, and CKD‐EPI‐creatinine equations. During 12 months of follow‐up, we recorded all major adverse cardiovascular events (composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal ischemic stroke), bleeding events (Bleeding Academic Research Consortium classification), and all‐cause mortality. Receiver operating characteristic curve comparisons demonstrated that Cockcroft‐Gault equation had higher predictive ability compared with MDRD‐4 equation for major adverse cardiovascular events (0.651 versus 0.616; P=0.023), major bleeding (0.600 versus 0.551; P=0.005), and all‐cause mortality (0.754 versus 0.717; P=0.033), as well as higher predictive ability compared with CKD‐EPI equation for major bleeding (0.600 versus 0.564; P=0.018). Integrated discrimination improvement and net reclassification improvement analyses showed superior discrimination and reclassification of Cockcroft‐Gault equation. Decision curve analyses graphically demonstrated higher net benefit and clinical usefulness of the Cockcroft‐Gault equation in comparison with MDRD‐4 and CKD‐EPI equations. Conclusions In patients with acute coronary syndrome, the Cockcroft‐Gault equation presented superior predictive ability for major adverse cardiovascular events, major bleeding, and all‐cause mortality compared with MDRD‐4 equation, and superior predictive ability for major bleeding compared with CKD‐EPI equation. The Cockcroft‐Gault equation also showed higher net benefit and clinical usefulness.