Luca Bettari

Is Worsening Renal Function an Ominous Prognostic Sign in Patients with Acute Heart Failure? The Role of Congestion and Its Interaction with Renal Function

Background— Worsening renal function (WRF), traditionally defined as an increase in serum creatinine levels ≥0.3 mg/dL, is a frequent finding in patients with acute heart failure (AHF) and has been associated with poorer outcomes in some but not all studies. We hypothesized that these discrepancies may be caused by the interaction between WRF and congestion in AHF patients. Methods and Results— We measured serum creatinine levels on a daily basis during the hospitalization and assessed the persistence of signs of congestion at discharge in 599 consecutive patients admitted at our institute for AHF. They had a postdischarge mortality and mortality or AHF readmission rates of 13% and 43%, respectively, after 1 year. Patients were subdivided into 4 groups according to the development or not of WRF and the persistence of ≥1 sign of congestion at discharge. Patients with WRF and no congestion had similar outcomes compared with those with no WRF and no congestion, whereas the risk of death or of death or AHF readmission was increased in the patients with persistent congestion alone and in those with both WRF and congestion (hazard ratio, 5.35; 95% confidence interval, 3.0–9.55 at univariable analysis; hazard ratio, 2.44; 95% confidence interval, 1.24–4.18 at multivariable analysis for mortality; hazard ratio, 2.14; 95% confidence interval, 1.39–3.3 at univariable analysis; and hazard ratio, 1.39; 95% confidence interval, 0.88–2.2 at multivariable analysis for mortality and rehospitalizations). Conclusions— WRF alone, when detected using serial serum creatinine measurements, is not an independent determinant of outcomes in patients with AHF. It has an additive prognostic value when it occurs in patients with persistent signs of congestion.Background— Worsening renal function (WRF), traditionally defined as an increase in serum creatinine levels ≥0.3 mg/dL, is a frequent finding in patients with acute heart failure (AHF) and has been associated with poorer outcomes in some but not all studies. We hypothesized that these discrepancies may be caused by the interaction between WRF and congestion in AHF patients. Methods and Results— We measured serum creatinine levels on a daily basis during the hospitalization and assessed the persistence of signs of congestion at discharge in 599 consecutive patients admitted at our institute for AHF. They had a postdischarge mortality and mortality or AHF readmission rates of 13% and 43%, respectively, after 1 year. Patients were subdivided into 4 groups according to the development or not of WRF and the persistence of ≥1 sign of congestion at discharge. Patients with WRF and no congestion had similar outcomes compared with those with no WRF and no congestion, whereas the risk of death or of death or AHF readmission was increased in the patients with persistent congestion alone and in those with both WRF and congestion (hazard ratio, 5.35; 95% confidence interval, 3.0–9.55 at univariable analysis; hazard ratio, 2.44; 95% confidence interval, 1.24–4.18 at multivariable analysis for mortality; hazard ratio, 2.14; 95% confidence interval, 1.39–3.3 at univariable analysis; and hazard ratio, 1.39; 95% confidence interval, 0.88–2.2 at multivariable analysis for mortality and rehospitalizations). Conclusions— WRF alone, when detected using serial serum creatinine measurements, is not an independent determinant of outcomes in patients with AHF. It has an additive prognostic value when it occurs in patients with persistent signs of congestion.

Galectin-3 in Ambulatory Patients with Heart Failure: Results from the HF-ACTION Study

Background— Galectin-3 is a soluble s-galactoside–binding lectin released by activated cardiac macrophages. Elevated levels of galectin-3 have been found to be associated with adverse outcomes in patients with heart failure. We evaluated the association between galectin-3 and long-term clinical outcomes in ambulatory heart failure patients enrolled in the HF-ACTION study. Methods and Results— HF-ACTION was a randomized, controlled trial of exercise training in patients with chronic heart failure caused by left ventricular systolic dysfunction. Galectin-3 was assessed at baseline in a cohort of 895 HF-ACTION subjects with stored plasma samples available. The association between galectin-3 and clinical outcomes was assessed using a series of Cox proportional hazards models. Higher galectin-3 levels were associated with other measures of heart failure severity, including higher New York Heart Association class, lower systolic blood pressure, higher creatinine, higher amino-terminal proB-type natriuretic peptide (NTproBNP), and lower maximal oxygen consumption. In unadjusted analysis, there was a significant association between elevated galectin-3 levels and hospitalization-free survival (unadjusted hazard ratio, 1.14 per 3-ng/mL increase in galectin-3; P <0.0001). In multivariable modeling, the prognostic impact of galectin-3 was significantly attenuated by the inclusion of other known predictors, and galectin-3 was no longer a significant predictor after the inclusion of NTproBNP. Conclusions— Galectin-3 is elevated in ambulatory heart failure patients and is associated with poor functional capacity and other known measures of heart failure severity. In univariate analysis, galectin-3 was significantly predictive of long-term outcomes, but this association did not persist after adjustment for other predictors, especially NTproBNP. Clinical Trial Registration— URL: . Unique identifier: [NCT00047437][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00047437&atom=%2Fcirchf%2F5%2F1%2F72.atomBackground— Galectin-3 is a soluble ß-galactoside–binding lectin released by activated cardiac macrophages. Elevated levels of galectin-3 have been found to be associated with adverse outcomes in patients with heart failure. We evaluated the association between galectin-3 and long-term clinical outcomes in ambulatory heart failure patients enrolled in the HF-ACTION study. Methods and Results— HF-ACTION was a randomized, controlled trial of exercise training in patients with chronic heart failure caused by left ventricular systolic dysfunction. Galectin-3 was assessed at baseline in a cohort of 895 HF-ACTION subjects with stored plasma samples available. The association between galectin-3 and clinical outcomes was assessed using a series of Cox proportional hazards models. Higher galectin-3 levels were associated with other measures of heart failure severity, including higher New York Heart Association class, lower systolic blood pressure, higher creatinine, higher amino-terminal proB-type natriuretic peptide (NTproBNP), and lower maximal oxygen consumption. In unadjusted analysis, there was a significant association between elevated galectin-3 levels and hospitalization-free survival (unadjusted hazard ratio, 1.14 per 3-ng/mL increase in galectin-3; P<0.0001). In multivariable modeling, the prognostic impact of galectin-3 was significantly attenuated by the inclusion of other known predictors, and galectin-3 was no longer a significant predictor after the inclusion of NTproBNP. Conclusions— Galectin-3 is elevated in ambulatory heart failure patients and is associated with poor functional capacity and other known measures of heart failure severity. In univariate analysis, galectin-3 was significantly predictive of long-term outcomes, but this association did not persist after adjustment for other predictors, especially NTproBNP. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00047437.

Is Worsening Renal Function an Ominous Prognostic Sign in Patients With Acute Heart Failure?Clinical Perspective

Background— Worsening renal function (WRF), traditionally defined as an increase in serum creatinine levels ≥0.3 mg/dL, is a frequent finding in patients with acute heart failure (AHF) and has been associated with poorer outcomes in some but not all studies. We hypothesized that these discrepancies may be caused by the interaction between WRF and congestion in AHF patients. Methods and Results— We measured serum creatinine levels on a daily basis during the hospitalization and assessed the persistence of signs of congestion at discharge in 599 consecutive patients admitted at our institute for AHF. They had a postdischarge mortality and mortality or AHF readmission rates of 13% and 43%, respectively, after 1 year. Patients were subdivided into 4 groups according to the development or not of WRF and the persistence of ≥1 sign of congestion at discharge. Patients with WRF and no congestion had similar outcomes compared with those with no WRF and no congestion, whereas the risk of death or of death or AHF readmission was increased in the patients with persistent congestion alone and in those with both WRF and congestion (hazard ratio, 5.35; 95% confidence interval, 3.0–9.55 at univariable analysis; hazard ratio, 2.44; 95% confidence interval, 1.24–4.18 at multivariable analysis for mortality; hazard ratio, 2.14; 95% confidence interval, 1.39–3.3 at univariable analysis; and hazard ratio, 1.39; 95% confidence interval, 0.88–2.2 at multivariable analysis for mortality and rehospitalizations). Conclusions— WRF alone, when detected using serial serum creatinine measurements, is not an independent determinant of outcomes in patients with AHF. It has an additive prognostic value when it occurs in patients with persistent signs of congestion.Background— Worsening renal function (WRF), traditionally defined as an increase in serum creatinine levels ≥0.3 mg/dL, is a frequent finding in patients with acute heart failure (AHF) and has been associated with poorer outcomes in some but not all studies. We hypothesized that these discrepancies may be caused by the interaction between WRF and congestion in AHF patients. Methods and Results— We measured serum creatinine levels on a daily basis during the hospitalization and assessed the persistence of signs of congestion at discharge in 599 consecutive patients admitted at our institute for AHF. They had a postdischarge mortality and mortality or AHF readmission rates of 13% and 43%, respectively, after 1 year. Patients were subdivided into 4 groups according to the development or not of WRF and the persistence of ≥1 sign of congestion at discharge. Patients with WRF and no congestion had similar outcomes compared with those with no WRF and no congestion, whereas the risk of death or of death or AHF readmission was increased in the patients with persistent congestion alone and in those with both WRF and congestion (hazard ratio, 5.35; 95% confidence interval, 3.0–9.55 at univariable analysis; hazard ratio, 2.44; 95% confidence interval, 1.24–4.18 at multivariable analysis for mortality; hazard ratio, 2.14; 95% confidence interval, 1.39–3.3 at univariable analysis; and hazard ratio, 1.39; 95% confidence interval, 0.88–2.2 at multivariable analysis for mortality and rehospitalizations). Conclusions— WRF alone, when detected using serial serum creatinine measurements, is not an independent determinant of outcomes in patients with AHF. It has an additive prognostic value when it occurs in patients with persistent signs of congestion.

Galectin-3 in Ambulatory Patients With Heart FailureClinical Perspective

Background— Galectin-3 is a soluble s-galactoside–binding lectin released by activated cardiac macrophages. Elevated levels of galectin-3 have been found to be associated with adverse outcomes in patients with heart failure. We evaluated the association between galectin-3 and long-term clinical outcomes in ambulatory heart failure patients enrolled in the HF-ACTION study. Methods and Results— HF-ACTION was a randomized, controlled trial of exercise training in patients with chronic heart failure caused by left ventricular systolic dysfunction. Galectin-3 was assessed at baseline in a cohort of 895 HF-ACTION subjects with stored plasma samples available. The association between galectin-3 and clinical outcomes was assessed using a series of Cox proportional hazards models. Higher galectin-3 levels were associated with other measures of heart failure severity, including higher New York Heart Association class, lower systolic blood pressure, higher creatinine, higher amino-terminal proB-type natriuretic peptide (NTproBNP), and lower maximal oxygen consumption. In unadjusted analysis, there was a significant association between elevated galectin-3 levels and hospitalization-free survival (unadjusted hazard ratio, 1.14 per 3-ng/mL increase in galectin-3; P <0.0001). In multivariable modeling, the prognostic impact of galectin-3 was significantly attenuated by the inclusion of other known predictors, and galectin-3 was no longer a significant predictor after the inclusion of NTproBNP. Conclusions— Galectin-3 is elevated in ambulatory heart failure patients and is associated with poor functional capacity and other known measures of heart failure severity. In univariate analysis, galectin-3 was significantly predictive of long-term outcomes, but this association did not persist after adjustment for other predictors, especially NTproBNP. Clinical Trial Registration— URL: . Unique identifier: [NCT00047437][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00047437&atom=%2Fcirchf%2F5%2F1%2F72.atomBackground— Galectin-3 is a soluble ß-galactoside–binding lectin released by activated cardiac macrophages. Elevated levels of galectin-3 have been found to be associated with adverse outcomes in patients with heart failure. We evaluated the association between galectin-3 and long-term clinical outcomes in ambulatory heart failure patients enrolled in the HF-ACTION study. Methods and Results— HF-ACTION was a randomized, controlled trial of exercise training in patients with chronic heart failure caused by left ventricular systolic dysfunction. Galectin-3 was assessed at baseline in a cohort of 895 HF-ACTION subjects with stored plasma samples available. The association between galectin-3 and clinical outcomes was assessed using a series of Cox proportional hazards models. Higher galectin-3 levels were associated with other measures of heart failure severity, including higher New York Heart Association class, lower systolic blood pressure, higher creatinine, higher amino-terminal proB-type natriuretic peptide (NTproBNP), and lower maximal oxygen consumption. In unadjusted analysis, there was a significant association between elevated galectin-3 levels and hospitalization-free survival (unadjusted hazard ratio, 1.14 per 3-ng/mL increase in galectin-3; P<0.0001). In multivariable modeling, the prognostic impact of galectin-3 was significantly attenuated by the inclusion of other known predictors, and galectin-3 was no longer a significant predictor after the inclusion of NTproBNP. Conclusions— Galectin-3 is elevated in ambulatory heart failure patients and is associated with poor functional capacity and other known measures of heart failure severity. In univariate analysis, galectin-3 was significantly predictive of long-term outcomes, but this association did not persist after adjustment for other predictors, especially NTproBNP. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00047437.

Metabolic exercise test data combined with cardiac and kidney indexes, the MECKI score: A multiparametric approach to heart failure prognosis

OBJECTIVES We built and validated a new heart failure (HF) prognostic model which integrates cardiopulmonary exercise test (CPET) parameters with easy-to-obtain clinical, laboratory, and echocardiographic variables. BACKGROUND HF prognostication is a challenging medical judgment, constrained by a magnitude of uncertainty. METHODS Our risk model was derived from a cohort of 2716 systolic HF patients followed in 13 Italian centers. Median follow up was 1041days (range 4-5185). Cox proportional hazard regression analysis with stepwise selection of variables was used, followed by cross-validation procedure. The study end-point was a composite of cardiovascular death and urgent heart transplant. RESULTS Six variables (hemoglobin, Na(+), kidney function by means of MDRD, left ventricle ejection fraction [echocardiography], peak oxygen consumption [% pred] and VE/VCO2 slope) out of the several evaluated resulted independently related to prognosis. A score was built from Metabolic Exercise Cardiac Kidney Indexes, the MECKI score, which identified the risk of study end-point with AUC values of 0.804 (0.754-0.852) at 1year, 0.789 (0.750-0.828) at 2years, 0.762 (0.726-0.799) at 3years and 0.760 (0.724-0.796) at 4years. CONCLUSIONS This is the first large-scale multicenter study where a prognostic score, the MECKI score, has been built for systolic HF patients considering CPET data combined with clinical, laboratory and echocardiographic measurements. In the present population, the MECKI score has been successfully validated, performing very high AUC.

A prospective comparison of alginate-hydrogel with standard medical therapy to determine impact on functional capacity and clinical outcomes in patients with advanced heart failure (AUGMENT-HF trial)

Aims AUGMENT-HF was an international, multi-centre, prospective, randomized, controlled trial to evaluate the benefits and safety of a novel method of left ventricular (LV) modification with alginate-hydrogel. Methods Alginate-hydrogel is an inert permanent implant that is directly injected into LV heart muscle and serves as a prosthetic scaffold to modify the shape and size of the dilated LV. Patients with advanced chronic heart failure (HF) were randomized (1 : 1) to alginate-hydrogel (n = 40) in combination with standard medical therapy or standard medical therapy alone (Control, n = 38). The primary endpoint of AUGMENT-HF was the change in peak VO2 from baseline to 6 months. Secondary endpoints included changes in 6-min walk test (6MWT) distance and New York Heart Association (NYHA) functional class, as well as assessments of procedural safety. Results Enrolled patients were 63 ± 10 years old, 74% in NYHA functional class III, had a LV ejection fraction of 26 ± 5% and a mean peak VO2 of 12.2 ± 1.8 mL/kg/min. Thirty-five patients were successfully treated with alginate-hydrogel injections through a limited left thoracotomy approach without device-related complications; the 30-day surgical mortality was 8.6% (3 deaths). Alginate-hydrogel treatment was associated with improved peak VO2 at 6 months—treatment effect vs. Control: +1.24 mL/kg/min (95% confidence interval 0.26–2.23, P = 0.014). Also 6MWT distance and NYHA functional class improved in alginate-hydrogel-treated patients vs. Control (both P < 0.001). Conclusion Alginate-hydrogel in addition to standard medical therapy for patients with advanced chronic HF was more effective than standard medical therapy alone for improving exercise capacity and symptoms. The results of AUGMENT-HF provide proof of concept for a pivotal trial. Trial Registration Number NCT01311791.

One-year follow-up results from AUGMENT-HF: a multicentre randomized controlled clinical trial of the efficacy of left ventricular augmentation with Algisyl in the treatment of heart failure

AUGMENT‐HF was an international, multicentre, prospective, open‐label, randomized, controlled evaluation testing the hypothesis that Algisyl (injectable calcium alginate hydrogel) is superior to standard medical therapy (SMT) for improving functional capacity and clinical outcomes in patients with advanced heart failure (HF). We previously reported results following 6 months of follow‐up. This report presents the results from 1 year of extended follow up for this clinical trial.

A novel discharge risk model for patients hospitalised for acute decompensated heart failure incorporating N-terminal pro-B-type natriuretic peptide levels: a European coLlaboration on Acute decompeNsated Heart Failure: ÉLAN-HF Score

Background Models to stratify risk for patients hospitalised for acute decompensated heart failure (ADHF) do not include the change in N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels during hospitalisation. Objective The aim of our study was to develop a simple yet robust discharge prognostication score including NT-proBNP for this notorious high-risk population. Design Individual patient data meta-analyses of prospective cohort studies. Setting Seven prospective cohorts with in total 1301 patients. Patients Our study population was assembled from the seven studies by selecting those patients admitted because of clinically validated ADHF, discharged alive, and NT-proBNP measurements available at admission and at discharge. Main outcome measures The endpoints studied were all-cause mortality and a composite of all-cause mortality and/or first readmission for cardiovascular reason within 180 days after discharge. Results The model that incorporated NT-proBNP levels at discharge as well as the changes in NT-proBNP during hospitalisation in addition to age ≥75 years, peripheral oedema, systolic blood pressure ≤115 mm Hg, hyponatremia at admission, serum urea of ≥15 mmol/L and New York Heart Association (NYHA) class at discharge, yielded the best C-statistic (area under the curve, 0.78, 95% CI 0.74 to 0.82). The addition of NT-proBNP to a reference model significantly improved prediction of mortality as shown by the net reclassification improvement (62%, p<0.001). A simplified model was obtained from the final Cox regression model by assigning weights to individual risk markers proportional to their relative risks. The risk score we designed identified four clinically significant subgroups. The pattern of increasing event rates with increasing score was confirmed in the validation group (BOT-AcuteHF, n=325, p<0.001). Conclusions In patients hospitalised for ADHF, the addition of the discharge NT-proBNP values as well as the change in NT-proBNP to known risk markers, generates a relatively simple yet robust discharge risk score that importantly improves the prediction of adverse events.

Acute heart failure: Multiple clinical profiles and mechanisms require tailored therapy

Acute heart failure (HF) is the most common diagnosis at discharge in patients aged >65years. It carries a dismal prognosis with a high in-hospital mortality and very high post-discharge mortality and re-hospitalization rates. It is a complex clinical syndrome that cannot be described as a single entity as it varies widely with respect to underlying pathophysiologic mechanisms, clinical presentations and, likely, treatments. It is the aim of this paper to describe some of the main clinical presentations of acute HF. Amongst them, we will consider de novo HF versus acutely decompensated chronic HF, HF caused, and/or worsened, by myocardial ischemia, acute HF with low, normal, or high systolic blood pressure, acute HF caused by lung congestion or fluid retention or fluid redistribution to the lungs, and acute HF with comorbidities (diabetes, anemia, renal insufficiency, etc.). Different pathophysiologic mechanisms and clinical presentations may coexist in the same patient. Identification and, whenever possible, treatment of underlying pathophysiologic mechanisms may become important for acute HF management.

Nebivolol: Haemodynamic Effects and Clinical Significance of Combined β-Blockade and Nitric Oxide Release

Nebivolol is a third-generation beta-adrenergic receptor antagonist (beta-blocker) with high selectivity for beta(1)-adrenergic receptors. In addition, it causes vasodilatation via interaction with the endothelial L-arginine/nitric oxide (NO) pathway. This dual mechanism of action underlies many of the haemodynamic properties of nebivolol, which include reductions in heart rate and blood pressure (BP), and improvements in systolic and diastolic function. With respect to BP lowering, the NO-mediated effects cause a reduction in peripheral vascular resistance and an increase in stroke volume with preservation of cardiac output. Flow-mediated dilatation and coronary flow reserve are also increased during nebivolol administration. Other haemodynamic effects include beneficial effects on pulmonary artery pressure, pulmonary wedge pressure, exercise capacity and left ventricular ejection fraction. In addition, nebivolol does not appear to have adverse effects on lipid metabolism and insulin sensitivity like traditional beta-blockers. The documented beneficial haemodynamic effects of nebivolol are translated into improved clinical outcomes in patients with hypertension or heart failure. In patients with hypertension, the incidence of bradycardia with nebivolol is often lower than that with other currently available beta-blockers. This, along with peripheral vasodilatation and NO-induced benefits such as antioxidant activity and reversal of endothelial dysfunction, should facilitate better protection from cardiovascular events. In addition, nebivolol has shown an improved tolerability profile, particularly with respect to events commonly associated with beta-blockers, such as fatigue and sexual dysfunction. Data from SENIORS (Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors with Heart Failure) showed that significantly fewer nebivolol versus placebo recipients experienced the primary endpoint of all-cause mortality or cardiovascular hospitalization. The benefits of nebivolol therapy were shown to be cost effective. Thus, nebivolol is an effective and well tolerated agent with benefits over and above those of traditional beta-blockade because of its effects on NO release, which give it unique haemodynamic effects, cardioprotective activity and a good tolerability profile.