Changes in natriuretic peptide and cytokine plasma levels in patients with heart failure, after treatment with high dose of furosemide plus hypertonic saline solution (HSS) and after a saline loading,☆☆

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Abstract

Background and Aims

Neurohormonal activation and inflammation characterizes heart failure, relates to outcome, and is a therapeutic target.

The aim of this study was to evaluate the effects of high-dose furosemide plus small-volume hypertonic saline solutions (HSS) on natriuretic peptides and immuno-inflammatory marker levels and to analyze, after treatment, the response to acute saline loading.

Methods and Results

120 patients with heart failure treated with high-dose furosemide + HSS (Furosemide/HSS group) were matched with: 30 subjects with heart failure treated with high-dose furosemide (furosemide group), 30 controls with asymptomatic left-ventricular dysfunction (ALVD) (asymptomatic group) and 30 controls without heart failure or ALVD (Healthy group). We evaluated plasma levels of natriuretic peptides and cytokine levels in baseline, after treatment and after acute saline load.

After treatment with high-dose furosemide + HSS compared to treatment with furosemide alone we observed a significant lowering of ANP [96 (46.5–159.5) pg/ml vs 64 (21–150) pg/ml], BNP [215.5 (80.5–487) pg/ml vs 87 (66–141.5) pg/ml], TNF-α [389.5 (265–615.5) pg/ml vs 231.5 (156–373.5) pg/ml], IL-1β [8 (7–9) pg/ml vs 4 (3–7) pg/ml], IL-6 [5 (3–7.5) pg/ml vs 3 (2–4) pg/ml], plasma values and after an acute saline load, a lower percentage change of ANP (+18.6% vs +28.03% vs +25% vs +29%), BNP (+14.5% vs +29.2% vs +30% vs +29.6%) TNF-α (+10.8% vs +15.8% vs +17.8% vs +11.3%), IL-1β (+20% vs 34.4% vs 40% vs 34.4%) compared to control groups.

Conclusions

Treatment with HSS could be responsible for a stretching relief that could influence natriuretic and immuno-inflammatory markers.

Introduction

In recent years, it has been acknowledged that neuroendocrine activation is of pathophysiological and prognostic importance in patients with heart failure (HF) [1], [2].

Some authors hypothesized that neuroendocrine profile might be valuable to obtain a more specific diagnosis and classification of HF and that neuroendocrine activation may also predict the response to medical treatment [3], [4], [5]. Moreover, Recent studies have determined that expression of inflammatory mediators, such as cytokines and chemokines, is an important factor in the development and progression of heart failure (HF). These inflammatory mediators are expressed in response to various myocardial insults, including myocardial ischemia, viral infection, and toxins, and appear to have a detrimental effect on cardiac function and prognosis in HF patients [6].

Natriuretic peptide levels are higher in heart failure in proportion to the atrial pressure [7]. BNP levels also increase in heart failure and are diagnostically superior to ANP [8].

Our group previously showed that the combination of high-dose furosemide associated with small-volume hypertonic saline solution (HSS) infusion is safe and tolerable [9], [10] and that this combination in patients with severe HF determined a significant reduction of hospitalization time, the maintenance of the achieved New York Heart Association (NYHA) class at discharge, the reduction of readmissions to hospital for HF worsening and a significant mortality rate reduction [11]. More recently we also reported that HSS group reached a significantly faster reduction in BNP levels in the 30 day study period [12].

Nevertheless, to our knowledge, no study has attempted to evaluate both natriuretic peptides and markers of immuno-inflammatory activation such as cytokines, selectins and adhesion molecules in patients with heart failure, through the analysis of the effects of diuretic therapy on these neurohormonal and inflammatory pathways. Moreover, no study, to our knowledge, evaluated the effects of an acute saline loading after intravenous diuretic treatment on cytokines and natriuretic peptide blood levels in order to test a possible treatment-related relief of inflammatory and neuroendocrine pathways.

On this basis, the aim of this study was to evaluate the effects of high-dose furosemide treatment plus HSS on natriuretic peptides and immuno-inflammatory marker plasma levels in patients with heart failure and to analyze, at the end of a treatment period with high-dose furosemide plus HSS, the effects of an acute saline loading on natriuretic peptides and inflammatory marker plasma levels.

Section snippets

Patient population

Inclusion criteria: all consecutive patients admitted to our hospital from 2005 to 2009 with heart failure (furosemide/HSS group).

Exclusion criteria were: acute myocarditis, active pulmonary and liver disease, autoimmune disorders, infection, malignant disease, muscle disorder [creatine kinase (CK)  200 IU/L] and renal insufficiency (serum creatinine  2.5 mg/dl), inflammatory or infectious diseases, cancer, hematological diseases and severe renal or liver failure, as well as those who were under

Statistical analysis

Data are reported as median (lower quartile  upper quartile). Comparisons between groups changes were performed by Mann–Whitney U test. The Wilcoxon signed ranks test was performed to investigate in-group statistical differences in baseline and after-treatment variables. The Kruskal–Wallis test was performed as non-parametric analysis of variance for multiple comparisons, and/the Conover–Inman procedure was used as post hoc test to make all possible pairwise comparisons between groups. Pearson

Results

We enrolled in the Furosemide/HSS group 120 subjects (female/male 55/65) with heart failure of different etiologies (see Table 1).

We enrolled as controls 30 subjects in the Furosemide group, 30 subjects in the Asymptomatic group and 30 subjects in the Healthy group.

Clinical, laboratory, neurohormonal and immuno-inflammatory variables of the Furosemide/HSS group, Furosemide group, asymptomatic and healthy groups are shown in Table 1. NYHA class distribution is shown in Table 1.

After treatment

Discussion

In the present study we report that high-dose i.v. furosemide plus HSS treatment is associated with a significant lowering of ANP, BNP and of some immuno-inflammatory marker plasma levels. After this treatment, an acute saline load was associated with a slight increase of natriuretic peptides and TNF-α, IL-1β plasma levels that did not reach the pre-treatment plasma levels and that showed, compared to control subjects, a significantly lower percent change in comparison with the values observed

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      In contrast, NGAL is a very early marker of tubular damage that increases in patients with acute and chronic renal injury [36,37], and in patients with heart failure [7] and its levels did not significantly differ between groups, a finding possibly related to the limited number of patients studied; otherwise, it should be noticed that NGAL has been more closely associated with pathophysiological conditions of tissue damage and inflammation; [38,39] however, the effects of HSS over renal function are probably related to modulation of renal hemodynamics as well as mechanisms of water and electrolyte homeostasis. We found no effect of HSS over humoral and inflammatory markers, an aspect that has been scarcely studied in patients with heart failure [40]. Immune-modulator effects of HSS have been described in other scenarios [41,42] and include modulation of neutrophils, macrophages, T-cells' activation, reduction of TNF-alpha production, increase in anti-inflammatory cytokines, modulation of apoptosis, and influence on the transcriptional, functional and protein expression of genes related to matrix metalloproteinases.

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