Elisabet Zamora

Head-to-head comparison of 2 myocardial fibrosis biomarkers for long-term heart failure risk stratification: ST2 versus galectin-3.

OBJECTIVES ST2 and galectin-3 (Gal-3) were compared head-to-head for long-term risk stratification in an ambulatory heart failure (HF) population on top of other risk factors including N-terminal pro-B-type natriuretic peptide. BACKGROUND ST2 and Gal-3 are promising biomarkers of myocardial fibrosis and remodeling in HF. METHODS This cohort study included 876 patients (median age: 70 years, median left ventricular ejection fraction: 34%). The 2 biomarkers were evaluated relative to conventional assessment (11 risk factors) plus N-terminal pro-B-type natriuretic peptide in terms of discrimination, calibration, and reclassification analysis. Endpoints were 5-year all-cause and cardiovascular mortality, and the combined all-cause death/HF hospitalization. RESULTS During a median follow-up of 4.2 years (5.9 for alive patients), 392 patients died. In bivariate analysis, Gal-3 and ST2 were independent variables for all endpoints. In multivariate analysis, only ST2 remained independently associated with cardiovascular mortality (hazard ratio: 1.27, 95% confidence interval [CI]: 1.05 to 1.53, p = 0.014). Incorporation of ST2 into a full-adjusted model for all-cause mortality (including clinical variables and N-terminal pro-B-type natriuretic peptide) improved discrimination (C-statistic: 0.77, p = 0.004) and calibration, and reclassified significantly better (integrated discrimination improvement: 1.5, 95% CI: 0.5 to 2.5, p = 0.003; net reclassification index: 9.4, 95% CI: 4.8 to 14.1, p < 0.001). Incorporation of Gal-3 showed no significant increase in discrimination or reclassification and worse calibration metrics. On direct model comparison, ST2 was superior to Gal-3. CONCLUSIONS Head-to-head comparison of fibrosis biomarkers ST2 and Gal-3 in chronic HF revealed superiority of ST2 over Gal-3 in risk stratification. The incremental predictive contribution of Gal-3 to existing clinical risk factors was trivial.

Estimated glomerular filtration rate and prognosis in heart failure: value of the Modification of Diet in Renal Disease Study-4, chronic kidney disease epidemiology collaboration, and cockroft-gault formulas.

OBJECTIVES The purpose of this study was to assess the value of estimated glomerular filtration rate (eGFR) calculated by different formulas for predicting the risk of death in heart failure (HF) outpatients. BACKGROUND Patients with both HF and renal insufficiency have a poor prognosis. Three formulas are mostly used to assess renal function: Cockroft-Gault formula, MDRD-4 (Modification of Diet in Renal Disease Study) formula, and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. The prognostic values of these formulas have not been adequately compared in HF patients. METHODS A total of 925 patients (72% men; age 69 years; interquartile range: 59 to 75.5 years) with a left ventricular ejection fraction of 31% (interquartile range: 23.5% to 39%) were studied. Follow-up was 1,202 days (interquartile range: 627.5 to 2,156.5 days). Measures of performance were evaluated using continuous data and by dividing patients into 4 subgroups according to the eGFR: ≥90, 89 to 60, <60 to 30, and <30 ml/min/1.73 m(2). RESULTS The 3 formulas correlated significantly, with the best correlation found between the MDRD-4 and CKD-EPI formulas. The 3 formulas afforded independent prognostic information over long-term follow-up. However, risk prediction was most accurate using the Cockroft-Gault formula as evaluated by Cox proportional hazards models (hazard ratio: 0.75 vs. 0.81 with the MDRD-4 formula and 0.80 with the CKD-EPI equation), area under the curve (0.67 vs. 0.62 and 0.64, respectively), and Bayesian information criterion (both analyzing eGFR as a continuous or categorical variable). Indeed, net reclassification improvement and integrated discrimination improvement using the Cockroft-Gault formula were 21% and 5.04, respectively, versus the MDRD-4 formula (the most used) and 13.1% and 3.77 respectively versus CKD-EPI equation (the more recent) (all p values <0.001). CONCLUSIONS In this ambulatory, real-life cohort of HF patients, the Cockroft-Gault formula was the most accurate of the 3 used eGFR formulas to improve the risk stratification for death.

Development of a Novel Heart Failure Risk Tool: The Barcelona Bio-Heart Failure Risk Calculator (BCN Bio-HF Calculator)

Background A combination of clinical and routine laboratory data with biomarkers reflecting different pathophysiological pathways may help to refine risk stratification in heart failure (HF). A novel calculator (BCN Bio-HF calculator) incorporating N-terminal pro B-type natriuretic peptide (NT-proBNP, a marker of myocardial stretch), high-sensitivity cardiac troponin T (hs-cTnT, a marker of myocyte injury), and high-sensitivity soluble ST2 (ST2), (reflective of myocardial fibrosis and remodeling) was developed. Methods Model performance was evaluated using discrimination, calibration, and reclassification tools for 1-, 2-, and 3-year mortality. Ten-fold cross-validation with 1000 bootstrapping was used. Results The BCN Bio-HF calculator was derived from 864 consecutive outpatients (72% men) with mean age 68.2±12 years (73%/27% New York Heart Association (NYHA) class I-II/III-IV, LVEF 36%, ischemic etiology 52.2%) and followed for a median of 3.4 years (305 deaths). After an initial evaluation of 23 variables, eight independent models were developed. The variables included in these models were age, sex, NYHA functional class, left ventricular ejection fraction, serum sodium, estimated glomerular filtration rate, hemoglobin, loop diuretic dose, β-blocker, Angiotensin converting enzyme inhibitor/Angiotensin-2 receptor blocker and statin treatments, and hs-cTnT, ST2, and NT-proBNP levels. The calculator may run with the availability of none, one, two, or the three biomarkers. The calculated risk of death was significantly changed by additive biomarker data. The average C-statistic in cross-validation analysis was 0.79. Conclusions A new HF risk-calculator that incorporates available biomarkers reflecting different pathophysiological pathways better allowed individual prediction of death at 1, 2, and 3 years.

Combined Use of the Novel Biomarkers High-Sensitivity Troponin T and ST2 for Heart Failure Risk Stratification vs Conventional Assessment

OBJECTIVE To assess an innovative multimarker strategy for risk stratification of death in a real-life ambulatory heart failure (HF) cohort. PATIENTS AND METHODS The study included 876 consecutive outpatients (median age, 70.3 years; left ventricular ejection fraction, 34%) between May 22, 2006, and July 7, 2010, prospectively followed up in a structured HF unit. A combination of biomarkers reflecting myocardial stretch (N-terminal pro-B-type natriuretic peptide [NT-proBNP]), myocyte injury (high-sensitivity cardiac troponin T [hs-cTnT]), and ventricular fibrosis and remodeling (high-sensitivity ST2 [hs-ST2]) were added to an assessment based on established mortality risk factors (age, sex, left ventricular ejection fraction, New York Heart Association functional class, diabetes mellitus, estimated glomerular filtration rate, ischemic etiology, sodium level, hemoglobin level, and pharmacologic treatment). RESULTS During median follow-up of 41.4 months, 311 patients died. The combined addition of hs-cTnT and hs-ST2 to the model yielded good measurements of performance (C statistic, 0.789; Bayesian information criterion, 3611; integrated discrimination improvement, 4.1 [95% CI, 2.5-5.6]; and net reclassification index, 13.9% [95% CI, 6.2-21.6]). Reclassification did not significantly benefit after NT-proBNP addition into the full model; some indices even worsened with all 3 biomarkers. Separate addition of NT-proBNP provided prognostic discrimination only in the subgroup of patients with either hs-cTnT or hs-ST2 levels below the cutoff points (hazard ratio, 2.97; 95% CI, 2.24-9.39; P<.001). CONCLUSION A multimarker strategy seems useful for stratifying risk in chronic HF. However, NT-proBNP in addition to the new-generation biomarkers hs-cTnT and hs-ST2 had a limited effect on risk stratification.

The obesity paradox in heart failure: is etiology a key factor?

BACKGROUND Obesity is paradoxically associated with survival in patients with heart failure (HF). Our objective was to assess whether the relationship between body mass index (BMI) and long-term survival is associated with HF etiology (ischemic vs. non-ischemic) in a cohort of ambulatory HF patients. METHODS BMI and survival status after a median follow-up of 6.1 years (IQR 2.2-7.8) were available for 504 patients (73% men; median age 68 years [IQR 58-74]). Fifty-nine percent of patients had ischemic etiology. Median left ventricular ejection fraction (LVEF) was 30% (IQR 23-39.7%). Most patients were in NYHA functional class II (51%) or III (42%). Patients were divided into four groups according to BMI: low weight (BMI < 20.5 kg/m(2)), normal weight (BMI 20.5 to < 25.5 kg/m(2)), overweight (BMI 25.5 to < 30 kg/m(2)), and obese (BMI ≥ 30 kg/m(2)). RESULTS Mortality differed significantly across the BMI strata in non-ischemic patients (log-rank p < 0.0001) but not in ischemic patients. Using normal weight patients as a reference, hazard ratios for low weight, overweight, and obese patients were 2.08 (1.16-3.75, p = 0.014), 0.88 (0.54-1.43, p = 0.60), and 0.49 (0.28-0.86, p = 0.01), respectively, for non-ischemic patients and 1.19 (0.48-2.97, p = 0.71), 0.88 (0.61-1.27, p = 0.48), and 0.96 (0.66-1.41, p = 0.85), respectively, for ischemic patients. After adjusting for age, sex, NYHA functional class, LVEF, co-morbidities, and treatment, BMI remained an independent predictor of survival in non-ischemic patients. CONCLUSION Over long-term follow-up of ischemic and non-ischemic HF, the obesity paradox was only observed in patients with non-ischemic HF.

Biomarker-assist score for reverse remodeling prediction in heart failure: The ST2-R2 score

BACKGROUND Limited data exists regarding biomarker use to predict left ventricular (LV) reverse remodeling (R2). Our aim was to examine the value of soluble ST2 (ST2), N-terminal-pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin T (hs-cTnT), and galectin-3 relative to LV-R2 in systolic heart failure (HF), and to develop a clinical score for LV-R2 prediction. METHODS R2 was defined as a) LV ejection fraction (LVEF) increase ≥15%, or b) LVEF increase ≥10% plus reduction of LV end-systolic diameter index ≥20% or LV end-systolic volume ≥40%, for 12 months. RESULTS We studied 304 patients (79.6% men, mean age 66.1 ± 12.3 years) with baseline LVEF <40%. R2 was observed in 104 patients (34.2%). In univariable logistic regression, factors associated with R2 were age (p=0.02), non-ischemic etiology of HF (p<0.001), NYHA functional class (p=0.02), baseline LVEF (p=0.005), absence of left bundle branch block (LBBB; p=0.002), ST2 (p=0.004), NT-proBNP (p=0.005), and hs-cTnT (p<0.001); HF duration achieved borderline significance (p=0.08). In multivariable analysis, ST2 remained the only biomarker associated with LV-R2. We developed the ST2-R2 score for use in clinical practice for predicting R2; variables included were ST2 <48 ng/mL, non-ischemic etiology, absence of LBBB, HF duration <12 months, baseline LVEF <24%, and β-blocker treatment. The score had an area under the curve of 0.79 in the derivation cohort and 0.73 in a separate validation cohort. CONCLUSIONS The ST2-R2 score, which includes the novel biomarker ST2 and five clinical variables, reasonably predicts LV-R2 in systolic HF patients. ST2 was the only studied biomarker that was independently associated with R2.

Renal function largely influences Galectin-3 prognostic value in heart failure.

BACKGROUND Galectin-3 (Gal-3) has been associated with cardiac remodeling and heart failure (HF) prognosis. Renal function is also a well known HF prognostic indicator. The link between renal insufficiency, HF, and Gal-3 is not completely elucidated. METHODS AND RESULTS We explored the association between Gal-3 and renal function in a cohort of 876 consecutive ambulatory patients with HF (mean age: 68 years; mean left ventricular ejection fraction [LVEF]: 36%), 52.2% had HF etiology of ischemic heart disease. Circulating Gal-3 was highly correlated with estimated glomerular filtration rate (eGFR), calculated with either the chronic kidney disease-epidemiology (CKD-EPI) equation (r = -0.64) or the CKD-EPI-cystatin-C equation (r = -0.59) and with Cystatin-C levels (r = 0.70), after adjusting for age, sex, New York Heart Association (NYHA) functional class, LVEF, and HF etiology (all p<0.001). Patients were stratified by CKD-EPI-eGFR (ml/min/1.73 m(2)), as follows: ≥ 60 (n = 218), 30 to 59 (n = 434), and <30 (n = 224). In these strata, Gal-3 significantly increased (median [IQR]: 12.3 [10.4-15.6]; 16.1 [13-19.8]; and 24.5 [20-33.8] ng/ml, respectively; trend p < 0.001). This was independent of NYHA functional class (I-II and III-IV) and LVEF (<45% and ≥ 45%). Gal-3 was associated with mortality in univariate analyses, but after adjusting for CKD-EPI-eGFR, the hazard ratios were 1.10 (95% CI: 0.89-1.34, p = 0.39) for all cause death, and 0.90 (95% CI: 0.68-1.21, p = 0.50) for cardiovascular death. Similar results were obtained with eGFRs calculated with the CKD-EPI-cystatin-C equation. CONCLUSION Circulating Gal-3 was highly associated with renal function in outpatients with HF. The value of Gal-3 for HF prognosis declined after adjusting for renal function.

Prognostic Value and Kinetics of Soluble Neprilysin in Acute Heart Failure: A Pilot Study.

OBJECTIVES This study sought to examine the prognostic value of the soluble form of neprilysin (sNEP) in acute heart failure (AHF) and sNEP kinetics during hospital admission. BACKGROUND sNEP was recently identified in chronic heart failure (HF) and was associated with cardiovascular outcomes. METHODS A total of 350 patients (53% women, mean 72.6 ± 10.7 years of age) were included in the study. Primary endpoints were composites of cardiovascular death or HF hospitalizations at short-term (2 months) and long-term (mean: 1.8 ± 1.2 years) follow-up. sNEP was measured using an ad hoc-modified enzyme-linked immunosorbent assay, and its prognostic value was assessed using Cox regression analyses. In a subgroup of patients, sNEP was measured both at admission and at discharge (n = 92). RESULTS Median admission sNEP concentrations were 0.67 ng/ml (Q1 to Q3: 0.37 to 1.29), and sNEP was significantly associated, in age-adjusted Cox regression analyses, with the composite endpoint at short-term (hazard ratio [HR]: 1.29; 95% confidence interval [CI]: 1.04 to 1.61; p = 0.02) and long-term (HR: 1.23; 95% CI: 1.01 to 1.05; p = 0.003) follow-up. In multivariate Cox analyses that included clinical variables and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) concentration, sNEP concentration at admission showed a clear trend toward significance for the composite endpoint at 2 months (HR: 1.22; 95% CI: 0.97 to 1.53; p = 0.09) and remained significant at the end of follow-up (HR: 1.21; 95% CI: 1.04 to 1.40; p = 0.01). At discharge, sNEP levels decreased from 0.70 to 0.52 ng/ml (p = 0.06). CONCLUSIONS Admission sNEP concentration was associated with short- and long-term outcomes in AHF, and dynamic sNEP concentrations were observed during hospital admission. These preliminary data may be hypothesis-generating for the use of NEP inhibitors in AHF.

Recovered heart failure with reduced ejection fraction and outcomes: a prospective study

Significant recovery of left ventricular ejection fraction (LVEF) occurs in a proportion of patients with heart failure (HF) and reduced ejection fraction (HFrEF). We analysed outcomes, including mortality [all‐cause, cardiovascular (CV), HF‐related, and sudden death], and HF‐related hospitalizations in this HF‐recovered group. The primary endpoint was a composite of CV death or HF hospitalization.

Fragility is a key determinant of survival in heart failure patients

BACKGROUND Heart failure (HF) is a chronic condition with poor prognosis, and has a high prevalence among older adults. Due to older age, fragility is often present among HF patients. However, even young HF patients show a high degree of fragility. The effect of fragility on long-term prognosis in HF patients, irrespective of age, remains unexplored. The aim of this study was to assess the influence of fragility on long-term prognosis in outpatients with HF. METHODS AND RESULTS At least one abnormal evaluation among four standardized geriatric scales was used to identify fragility. Predefined criteria for such scales were: Barthel Index, <90; OARS scale, <10 in women and <6 in men; Pfeiffer Test, >3 (± 1, depending on educational grade); and ≥ 1 positive response for depression on the abbreviated Geriatric Depression Scale (GDS). We assessed 1314 consecutive HF outpatients (27.8% women, mean age years 66.7 ± 12.4 years with different etiologies. Fragility was detected in 581 (44.2%) patients. 626 deaths occurred during follow-up; the median follow-up was 3.6 years [P25-P75: 1.8-6.7] for the total cohort, and 4.9 years [P25-P75: 2.5-8.4] for living patients. Fragility and its components were significantly associated with decreased survival by univariate analysis. In a comprehensive multivariable Cox regression analysis, fragility remained independently associated with survival in the entire cohort, and in age and left ventricular ejection fraction subgroups. CONCLUSION Fragility is a key determinant of survival in ambulatory patients with HF across all age strata.