Teresa Casas

Soluble ST2, high-sensitivity troponin T- and N-terminal pro-B-type natriuretic peptide: complementary role for risk stratification in acutely decompensated heart failure.

To investigate the use of biomarkers providing independent information regarding physiology in acutely decompensated heart failure (ADHF) for assessment of risk.

Usefulness of clinical and NT-proBNP Monitoring for prognostic guidance in destabilized heart failure outpatients

AIMS To study the relative prognostic value of N-terminal pro-B-type natriuretic peptide (NT-proBNP) monitoring in addition to clinical disease severity scores (CDSSs) in outpatients with destabilized heart failure (HF). METHODS AND RESULTS Seventy-one outpatients with recently destabilized HF were recruited. At baseline, and at all following visits, a CDSS based on Framingham criteria was obtained, and NT-proBNP levels were measured in a blind fashion. CDSS did not correlate with NT-proBNP levels at any time (P > 0.1), although their relative changes correlated during follow-up (P < 0.001). Forty patients (56%) had clinical events (cardiovascular death and/or HF hospitalization) within 1 year of follow-up. Changes in CDSS from baseline were not predictive of subsequent events (P > 0.1 for all visits), whereas changes in NT-proBNP levels were predictive at several time points: week 2 (P = 0.005), week 3 (P = 0.037), week 4 (P = 0.015), and 6 months (P = 0.026). A change in NT-proBNP levels at follow-up week 2 (%) added independent prognostic information (P < 0.001, HR 0.982, 95% CI 0.972-0.992) to baseline CDSS (P = 0.002, HR 2.05, 95% CI 1.290-3.266), age (P = 0.007, HR 1.034, 95% CI 1.009-1.059), and left ventricular ejection fraction (P = 0.013, HR 0.942, 95% CI 0.898-0.987). CONCLUSION Serial monitoring for per cent change in NT-proBNP concentrations offers superior prognostic information to clinical assessment among outpatients with recent destabilized HF.

β-trace protein and cystatin C as predictors of long-term outcomes in patients with acute heart failure.

OBJECTIVES The purpose of this study was to evaluate the prognostic importance of novel markers of renal dysfunction among patients with acutely destabilized heart failure (ADHF). BACKGROUND β-trace protein (BTP) and cystatin C are newer biomarkers for renal dysfunction; the prognostic importance of these tests, particularly BTP, relative to standard measures of renal function remains unclear. METHODS A total of 220 consecutive hospitalized patients with ADHF were prospectively studied. Blood samples were collected on presentation. In-hospital worsening renal function, as well as mortality and/or heart failure (HF) hospitalization, over a median follow-up period of 500 days was examined as a function of BTP or cystatin C concentrations; results were compared with creatinine, estimated glomerular filtration rate, and blood urea nitrogen. RESULTS Neither BTP nor cystatin C was associated with worsening renal function during the index hospitalization. A total of 116 patients (53%) either died or were hospitalized for HF during follow-up. Those with adverse outcomes had higher BTP (1.04 mg/l [range 0.80 to 1.49 mg/l] vs. 0.88 mg/l [range 0.68 to 1.17 mg/l], p = 0.003) and cystatin C (1.29 mg/l [range 1.00 to 1.71 mg/l] vs. 1.03 mg/l [range 0.86 to 1.43 mg/l], p = 0.001). After multivariable adjustment, both BTP (hazard ratio: 1.41, 95% confidence interval: 1.06 to 1.88; p = 0.018) and cystatin C (hazard ratio: 1.50, 95% confidence interval: 1.13 to 2.01; p = 0.006) were significant predictors of death/HF hospitalization, whereas serum creatinine, estimated glomerular filtration rate, and blood urea nitrogen were no longer significant. In patients with an estimated glomerular filtration rate >60 ml/min/1.73 m(2), elevated concentrations of BTP and cystatin C were still associated with significantly higher risk of adverse clinical events (p < 0.05). Net reclassification index analysis suggested cystatin C and BTP deliver comparable information regarding prognosis. CONCLUSIONS Among patients hospitalized with ADHF, BTP and cystatin C predict risk of death and/or HF hospitalization and are superior to standard measures of renal function for this indication.

Highly sensitive troponin T for risk stratification of acutely destabilized heart failure

BACKGROUND A highly sensitive assay for troponin T (hsTnT) has been recently developed, which allows for the detection of even minor myocardial necrosis with high precision. It remains unexplored whether hsTnT provides incremental prognostic accuracy beyond conventional (c)TnT in patients with acutely decompensated heart failure (ADHF). METHODS A total of 202 consecutive patients admitted with ADHF and without criteria for acute myocardial infarction were studied. Troponin T was measured using the highly sensitive assay and compared with the conventional method. Patients were clinically followed up at a median of 406 days, with a primary outcome measure of all-cause mortality. RESULTS The high-sensitive assay detected measurable TnT in 98% of patients vs 56% for cTnT; 81% had an hsTnT above the 99th percentile for a healthy reference population, and it reclassified 60% of those with undetectable cTnT. Both TnT methods predicted the risk of death in adjusted multivariable Cox regression analyses, without a superiority of hsTnT over cTnT in the entire population (area under the curve 0.67 vs 0.71, P = .2). Among patients with a cTnT below 0.03 ng/mL (the lowest cut-point with <10% imprecision; n = 134), solely hsTnT improved the prediction of death over clinical risk factors (relative integrated discrimination improvement +36%, P = .01) and hsTnT above 20 pg/mL identified a significant higher risk of death (hazard ratio 4.7, 95% CI 1.6-13.8, P = .005). CONCLUSION Among patients with ADHF, myocardial necrosis (as detected with the hsTnT assay) was nearly ubiquitous. The highly sensitive assay for TnT provides comparable prognostic information to cTnT overall, but among those in whom the cTnT method was less precise or frankly negative, the hsTnT assay provided prognostic information.

High sensitivity cardiac troponin T and interleukin‐6 predict adverse cardiovascular events and mortality in anticoagulated patients with atrial fibrillation

Summary.  There are limited data on the prognostic role of biomarkers in anticoagulated patients with atrial fibrillation (AF). We evaluated the prognostic value of high sensitivity TnT (hsTnT) and high‐sensitivity interleukin‐6 (hsIL6) in a large cohort of AF patients taking oral anticoagulant therapy (OAC) as both biomarkers have been associated with adverse cardiovascular events. Methods: We studied 930 patients (51% male; median age 76) with permanent/ paroxysmal AF who were stabilized (for at least 6 months) on OAC (INRs 2.0–3.0). Plasma hsTnT and hsIL6 levels were quantified by electrochemiluminescense immunoassay at baseline. Patients were followed‐up for up to 2 years, and adverse events (thrombotic and vascular events, mortality and major bleeding) were recorded. Results: At follow‐up, 96 patients (3.97%/year) died whilst 107 had an adverse cardiovascular event (3.14%/year). On multivariate analysis, high hsTnT and high hsIL6 remained significantly associated with prognosis even after adjusting for CHADS2 score: HR 2.21 (1.46–3.35, P < 0.001) for high hsTnT and 1.97 (1.29–3.02, P = 0.002) for high hsIL6, for adverse cardiovascular events. For all‐cause mortality, the HRs were 1.79 (1.13–2.83, P = 0.013) and 2.48 (1.60–3.85, P < 0.001), respectively. The integrated discrimination index (IDI) values of clinical scores (CHADS2 and CHA2DS2‐VASc) were improved by the addition of hsTnT and/or hsIL6 (all P < 0.05). Conclusion: In a large ‘real world’ cohort of anticoagulated AF patients, both hsTnT and hsIL6 levels provided prognostic information that was complementary to clinical risk scores for prediction of long‐term cardiovascular events and death, suggesting that these biomarkers may potentially be used to refine clinical risk stratification in AF.

La monitorización de ST2 soluble proporciona una estratificación del riesgo adicional en pacientes ambulatorios con insuficiencia cardiaca descompensada

Introduccion y objetivos El ST2 es un nuevo biomarcador que aporta informacion diagnostica en varios contextos clinicos. Nuestro objetivo fue examinar si la monitorizacion de las concentraciones de ST2 soluble (sST2) mejora la estratificacion del riesgo de los pacientes ambulatorios con insuficiencia cardiaca descompensada. Metodos Se determinaron las concentraciones de sST2 y de NT-proBNP, asi como la puntuacion de gravedad de la insuficiencia cardiaca (Heart Failure Severity Score [HFSS]), basada en los criterios de Framingham, en la situacion basal y al cabo de 2 semanas en 48 pacientes ambulatorios con insuficiencia cardiaca descompensada. Para todas las variables, se calcularon los cocientes de los valores determinados a las 2 semanas respecto a los valores basales. Se efectuo un seguimiento durante 1 ano y se registraron los episodios cardiacos (muerte, ingreso por insuficiencia cardiaca, trasplante de corazon). Resultados Al cabo de 1 ano, el 56% de los pacientes habia sufrido un episodio cardiaco. El cociente de sST2 fue significativamente inferior en los pacientes que no habian presentado ningun episodio cardiaco (0,6 ± 0,39 frente a 1,39 ± 0,92; p 0,75 y un valor basal de NT-proBNP > 1.000 ng/l, un 72% sufrio episodios cardiacos (p = 0,018); no hubo ningun episodio en los pacientes con concentraciones de marcadores inferiores a esos valores de referencia. Conclusiones La obtencion de muestras para la determinacion seriada del sST2 proporciona una estratificacion del riesgo adicional en los pacientes ambulatorios con insuficiencia cardiaca descompensada. Las determinaciones repetidas del sST2 podrian ser utiles para la toma de decisiones clinicas.

Soluble ST2 monitoring provides additional risk stratification for outpatients with decompensated heart failure.

INTRODUCTION AND OBJECTIVES The novel biomarker ST2 provides diagnostic information in a variety of clinical settings. The objective was to determine whether measurement of the soluble ST2 (sST2) concentration improves risk stratification in outpatients with decompensated heart failure (HF). METHODS The concentrations of sST2 and N-terminal probrain natriuretic peptide (NT-proBNP) and a heart failure severity score (HFSS), based on Framingham criteria, were determined at baseline and 2 weeks later in 48 outpatients with decompensated hf. The ratio of the value of each variable at week 2 relative to baseline was determined. Patients were followed for 1 year and cardiac events (i.e. death, HF admission and heart transplantation) were recorded. RESULTS By 1 year, 56% of patients had experienced a cardiac event. The sST2 ratio was significantly lower in patients who did not have a cardiac event (0.6 ± 0.39 vs. 1.39 ± 0.92; P< .001). After multivariable adjustment, the sST2 ratio remained an independent predictor of risk (odds ratio=1.054; 95% confidence interval, 1.01-1.09; P=.017). The optimum cut-point for the sST2 ratio determined by receiver operating curve [ROC] analysis was 0.75; this accounted for 25% of the change in sST2 by week 2. Among patients with an sST2 ratio >0.75 and a baseline NT-proBNP level >1000 ng/L, 72% had a cardiac event (P=.018), while no events occurred in patients with marker values below these reference levels. CONCLUSIONS Determination of the sST2 concentration in serial samples provided additional risk stratification in outpatients with decompensated HF. Repeated measurement of sST2 may aid clinical decision-making.

Growth differentiation factor-15, a novel biomarker related with disease severity in patients with hypertrophic cardiomyopathy

BACKGROUND The growth differentiation factor 15 (GDF-15) has been shown up-regulated in stress conditions and to have regulatory actions in myocyte hypertrophy. We hypothesized that GDF-15 could be related to disease severity and functional status in patients with hypertrophic cardiomyopathy (HCM). METHODS AND RESULTS We performed a study which includes 102 consecutive outpatient HCM subjects, 73% males, aged 47.1±14.6 years. A complete history and clinical examination was performed, including 12-lead electrocardiogram, echocardiography, symptom-limited treadmill exercise, 24-hour ECG-Holter monitoring, and magnetic resonance with Gadolinium. Several biomarkers, associated with myocardial remodeling and damage, were compared to GDF-15 levels. The assays were performed with commercial ELISAs or standardized methods when available. There was a significant association between GDF-15 levels and comorbidities, being higher in hypertension (p=0.001), diabetes (p=0.030), atrial fibrillation (p=0.012), dyspnea (p=0.020) and NYHA≥II functional class (p=0.037). GDF-15 levels were positively correlated with clinical variables (age, worse exercise capacity and mild renal dysfunction) and biomarkers of interstitial remodeling, such as metalloproteinase-2 (r: 0.40; p=0.009), N-terminal pro-B-type natriuretic peptide (r: 0.28; p=0.049), high-sensitivity troponin T (r: 0.30; p=0.003) and von Willebrand factor (r: 0.33; p=0.001). Multivariate analysis was assessed to estimate the involvement of these different factors in the GDF-15 levels, confirming the independent implication of severe dyspnea and functional status. CONCLUSIONS The present results show that higher levels of GDF-15 are associated to conditions of severe disease in HCM. Hence, GDF-15 is suggested as a novel marker related to the severity and could represent a further useful tool in monitoring functional capacity of HCM patients.

Utilidad de la prueba de troponina T de alta sensibilidad en la detección de rechazo agudo en trasplante cardiaco

INTRODUCTION AND OBJECTIVES Detection of acute allograft rejection in heart transplant recipients by noninvasive methods is a challenge in the management of these patients. In this study, the usefulness of a new highly sensitive method for the measurement of troponin T is evaluated. METHODS We designed a case-crossover study, in which each patient served as his or her own control, by selecting samples from treated acute rejection episodes (29 cases) and samples obtained immediately before and/or after rejection (38 controls). The highly sensitive troponin T was measured by a new pre-commercial test (Elecsys Troponin T HS). RESULTS In all samples, highly sensitive troponin T was detectable, with a median of 0.068 ng/L (IQR, 0.030-0.300 ng/L). The levels correlated with right atrial pressure (r=0.37; P=.002), N-terminal pro-brain natriuretic peptide concentration (r=0.67; P<.001), and time since transplantation (r=-0.81; P<.001). The highly sensitive troponin T concentrations were higher in patients with rejection (0.155 ng/mL vs 0.047 ng/mL; P=.006). In the receiver operating characteristic analysis, the area under the curve was 0.67 (95% confidence interval, 0.53-0.77) and the best cutoff was 0.035 ng/mL, which was associated with rejection (odds ratio=3.7; 95% confidence interval, 1.2-11.9; P=.02). By restricting the analysis to the first 2 months, the area under the curve increased to 0.86 (95% confidence interval 0.66-0.97), with an optimal cutoff of 1.10 ng/mL (S=58% [28%-85%]; E=100% [74%-100%]). CONCLUSIONS Troponin T was detectable in all samples when a new highly sensitive assay was used, and at higher concentrations in the presence of acute rejection; however, the usefulness of this test in patient management is limited to support for clinical or histological suspicion of rejection, especially in the early post-transplant period.

B-type natriuretic peptide release in the coronary effluent after acute transient ischaemia in humans

Background: The association between B-type natriuretic peptide (BNP) and coronary artery disease is not fully understood. Objective: To assess whether ischaemia per se is a stimulus for BNP secretion. Setting: University tertiary hospital, Spain (Virgen de la Arrixaca). Design: Prospective interventional study. Patients: 11 patients (55 (9) years, left ventricular ejection fraction (LVEF) 45% (7%) with a non-complicated anterior myocardial infarction (MI) and isolated stenosis of the left anterior descending (LAD) coronary artery, successfully treated by primary angioplasty. Interventions: 11.0 (0.9) days after MI, the LAD was occluded (20 min) for intracoronary infusion of progenitor cells. Blood samples were obtained from the femoral artery (peripheral circulation (PC)) and the coronary sinus (coronary circulation (CC)) immediately before and after coronary occlusion. Main outcome measures: BNP (pg/ml) was measured and ischaemia biomarkers were monitored. Results: During coronary occlusion, all patients experienced transitory chest pain and ST-segment dynamic changes. After coronary occlusion, lactic acid levels rose in CC (1.42 (0.63) –1.78 (0.68) ng/ml, p = 0.003). Myoglobin and cardiac troponin T did not differ in CC or PC at 24 h. No differences were found in LVEF (+0.18% (2.4)%, p = 0.86) and motion score index (–0.02 (0.06), p = 0.37). Before occlusion, BNP levels did not differ significantly in CC versus PC (253 (56) vs 179 (34), p = 0.093). After occlusion, BNP showed a significant increase in CC (vs 332 (61), p = 0.004), but no change occurred in PC (vs 177 (23), p = 0.93), and circulating BNP levels were higher in CC versus PC (p = 0.008). Conclusions: In response to acute ischaemia, BNP levels immediately increase in coronary sinus but not at the peripheral level. BNP release in the coronary effluent may exert local beneficial effects.