Rationale and study design of intravenous loop diuretic administration in acute heart failure. DIUR-AHF

Aims: Although loop diuretics are the most commonly used drugs in acute heart failure (AHF) treatment, their short-term and long-term effects are relatively unknown. The significance of worsening renal function occurrence during intravenous treatment is not clear enough. This trial aims to clarify all these features and contemplate whether continuous infusion is better than an intermittent strategy in terms of decongestion efficacy, diuretic efficiency, renal function, and long-term prognosis. Methods and results: This is a prospective, multicentre, randomized study that compares continuous infusion to intermittent infusion and a low vs. high diuretic dose of furosemide in patients with a diagnosis of acute heart failure, BNP ≥ 100 pg/mL, and specific chest X-ray signs. Randomization criteria have been established at a 1:1 ratio using a computer-generated scheme of either twice-daily bolus injection or continuous infusion for a time period ranging from 72 to 120 h. The initial dose will be 80 mg/day of intravenous furosemide and, in the case of poor response, will be doubled using an escalation algorithm. A high diuretic dose is defined as a furosemide daily amount >120 mg/day respectively. Conclusions: Continuous and high dose groups could reveal a more intensive diuresis and a greater decongestion with respect to intermittent and low dose groups; high dose and poor loop diuretic efficiency should be related to increased diuretic resistance, renal dysfunction occurrence, and greater congestion status. Poor diuretic response will be associated with less decongestion and an adverse prognosis

The role of the kidney in acute and chronic heart failure

Renal dysfunction affects approximately 30 to 50% of heart failure (HF) patients. The unfavourable relationship between heart and kidney dysfunction contributes to worse outcomes through several mechanisms such as inflammation, oxidative stress, impaired hydrosaline homeostasis, and diuretic resistance. Renal dysfunction not only carries important prognostic value both in acute and in chronic HF, but also is a potential precipitating factor after the first diagnosis. Because renal dysfunction encompasses different etiologies, a better understanding of its definition, incidence, and pathophysiology provides additional information. Although old and novel available biomarkers for the detection of renal dysfunction have been recently proposed, there is no general consensus regarding the terminology and definition of renal dysfunction in HF. Due to some specific pathophysiological mechanisms, renal impairment seems to be different on an individual patient level and, recognizing it in acute and chronic settings, could be useful to optimize decongestive treatment. For these reasons, in this review, we aim to describe and evaluate different phenotypes of renal dysfunction in acute and chronic HF and the possible management in these settings. Key messages center dot Chronic kidney dysfunction and worsening renal function are highly prevalent in acute heart failure and chronic heart failure and associated with poor outcomes. center dot This association is modified by the context in which it occurs, i.e. worsening renal function in the context of adequate decongestion in acute heart failure, or worsening renal function after initiation of neurohormonal blockers in chronic heart failure. center dot Future research should be aimed at elucidating the mechanisms involved in these differenct contexts, as well as alternative treatment approaches in the case of true worsening renal function

The role of natriuretic peptides for the diagnosis of left ventricular dysfunction

Natriuretic peptides (NPs) are entered in current guidelines for heart failure (HF) diagnosis and management because of their high specificity and sensibility in screening patients with acute dyspnea. Due to their availability and relatively low cost, they became the first step examinations in HF patients evaluation at hospital admission together with clinical and chest radiography examination. NPs are released following any cardiac haemodynamic stress due to volume or pressure overload and should be considered as a mirror of cardiac condition helping in recognizing patients with poor outcome. Moreover, the exact role of NPs in early HF stages, in isolated diastolic dysfunction, and in general population is questioned. Several promising reports described their potential role; however, the wide cut-off definition, inclusion criteria, and intrinsic measurement biases do not actually consent to their clinical application in these settings. A multimodality strategy including both NPs and imaging studies appears to be the best strategy to define the cardiac dysfunction etiology and its severity as well as to identify patients with higher risk. In this review, we describe the current and potential role of NPs in patients with asymptomatic cardiac insufficiency, evaluating the requirement to obtain a better standardization for imaging as for laboratory criteria

Combined use of lung ultrasound, B-type natriuretic peptide, and echocardiography for outcome prediction in patients with acute HFrEF and HFpEF

Background: Lung ultrasound (LUS) can be used to assess pulmonary congestion by imaging B-lines (‘comets’) for patients with acute heart failure (AHF). Objectives: Investigate relationship of B-lines, plasma concentrations of B-type natriuretic peptide (BNP), and echocardiographic left ventricular (LV) function measured at admission and discharge and their relationship to prognosis for AHF with preserved (HFpEF) or reduced (HFrEF) LV ejection fraction. Methods: Patients with AHF had the above tests done at admission and discharge. The primary outcome was re-hospitalization for heart failure or death at 6 months. Results: Of 162 patients enrolled, 95 had HFrEF and 67 had HFpEF, median age was 80 [77–85] years, and 85 (52%) were women. The number of B-lines at admission (median 31 [27–36]) correlated with respiratory rate (r = 0.75; p < 0.001), BNP (r = 0.43; p < 0.001), clinical congestion score (r = 0.25; p = 0.001), and systolic pulmonary artery pressure (r = 0.42; p < 0.001). At discharge, B-lines were also correlated with BNP (r = 0.69; p < 0.001) and congestion score (r = 0.57; p < 0.001). B-line count at discharge predicted outcome (AUC 0.83 [0.77–0.90]; univariate HR 1.12 [1.09–1.16]; p < 0.001; multivariable HR 1.16 [1.11–1.21]; p < 0.001). Results were similar for HFpEF and HFrEF. Conclusions: LUS appears a useful method to assess severity and monitor the resolution of lung congestion. At hospital admission, B-lines are strongly related to respiratory rate, which may be a key component of the sensation of dyspnea. Measurement of lung congestion at discharge provides prognostic information for patients with either HFpEF or HFrEF

Short and long-term effects of continuous versus intermittent loop diuretics treatment in acute heart failure with renal dysfunction

Intravenous loop diuretics are still the cornerstone of therapy in acute decompensated heart failure, however, the optimal dosage and administration strategies remain poorly defined particularly in patients with an associated renal dysfunction. This is a single-center, pilot, randomized trial involving patients with acute HF and renal dysfunction. Patients were assigned to receive continuous furosemide infusion (cIV) or bolus injections of furosemide (iIV). Primary end points were the evaluation of urine output volumes, renal function, and b-type natriuretic peptide (BNP) levels during treatment time. Secondary end point included: weight loss, length of hospitalization, differences in plasma electrolytes, need for additional treatment, and evaluation of cardiac events during follow-up period. 57 patients were included in the study. The cIV group showed an increase in urine output (2,505 ± 796 vs 2140 ± 468 ml/day, p < 0.04) and a more significant decrease of BNP levels in respect to the iIV group (679.6 ± 397 vs 949 ± 548 pg/ml, p < 0.04). We observed a significant increase in creatinine levels (1.78 ± 0.5 vs 1.41 ± 0.3 mg/dl, p < 0.01), and a reduction of the estimated glomerular filtration rate in cIV (44.8 ± 6.1 vs 46.7 ± 6.1 ml/min, p < 0.05). We observed a significant difference in eGFR (p = 0.01), creatinine (p = 0.02) and BNP levels (p = 0.03) from baseline to the end of treatment in both groups. A significant increase of in-hospital additional treatment as well as length of hospitalization was observed in cIV. Finally, cIV revealed a higher rate of adverse events during the follow-up period (p < 0.03). cIV appears to provide a more efficient diuresis and BNP level reduction during hospitalization, however, it was associated with increased rate of worsening renal function during hospitalization. cIV also appears related to a longer hospitalization and an increased number of adverse events during follow-up. For all of these reasons, a larger multi-center study is required to determine whether high-dose diuretics are responsible for worsening renal function and to define the best modality of administratio

The prognostic role of different renal function phenotypes in patients with acute heart failure

Objective: Worsening renal function (WRF) is common in patients treated for acute heart failure (AHF) and might be associated with a significant increase in blood nitrogen urea (BUN). Although many patients develop WRF during hospitalisation, its prognostic role is still unclear. Thus, we aimed to evaluate the prognostic relevance of WRF according to BUN changes during hospitalization. Methods: We studied patients with AHF screened for Diur-HF Trial (NCT01441245). WRF was defined as an in-hospital rise in serum creatinine ≥0.3 mg/dl or estimated glomerular filtration rate (GFR) reduction ≥20%. BUN increase was defined as a rise in BUN ≥20% during admission. Effective decongestion was defined as complete resolution of two, or more, signs of HF, or absence of clinical signs of congestion at discharge. Results: Of 247 patients enrolled, 59 (23%) patients experienced WRF, 107 (43%) had a BUN increase ≥20%, and 111 (45%) were effectively decongested during hospitalization. During 180 days of follow-up, 136 patients died or were re-hospitalised for AHF. An increase in BUN was an independent predictor of adverse outcome, regardless of WRF (HR = 2.19 [1.35–3.54], p = 0.002 and 1.71 [1.14–2.59], p = 0.010; with and without WRF, respectively) or congestion at discharge. WRF was not an independent predictor of outcome if BUN did not increase or when congestion was effectively relieved. Conclusions: an increase in BUN≥20% during hospitalization for AHF predicts a poor outcome independently from renal function deterioration and decongestion. WRF predicts adverse outcome only if BUN increases substantially or clinical congestion persists

Generation of spheroids from human primary myofibroblasts: an experimental system to study myofibroblasts deactivation

Fibroblasts represent a heterogeneous cell population, that in adult body maintains the homeostasis of the extracellular matrix (ECM) and can acquire an immunoregulatory phenotype. Indeed, activated fibroblasts produce large amounts of cyclooxygenase-2 (COX-2) and proinflammatory cytokines (1). The activation of fibroblasts is represented by their differentiation into myofibroblasts. This process, either in wound healing or cancer tissue, is associated with the expression of alpha-smooth muscle actin (alpha-SMA), increased levels of growth factors and ECM-degrading proteases (2). Moreover, myofibroblasts form clusters in wound healing process and hypertrophic scars. In particular, cell clusters of hypertrophic scars are represented by nodules of myofibroblasts (3). It is known that human dermal fibroblasts established from neonatal foreskin, and forced in vitro to form clusters named spheroids, are activated to produce massive amounts of COX-2, prostaglandins and proinflammatory cytokines: this process leads to a programmed necrosis, designated “nemosis” (1). In the present study we generated spheroids from human primary myofibroblasts of skin, to evaluate necrotic, inflammation and activation markers during myofibroblasts clustering. Western blotting analysis, showing low levels of COX-2 and a significant decrease of alpha-SMA in protein extracts of spheroids, led to hypothesize that myofibroblasts have undergone a deactivation process within spheroids. This hypothesis is confirmed by cytostatic effect exerted by spheroids conditioned medium on both normal and cancer cell lines, by confocal immunofluorescence analysis of connexin 43 and immunohistochemical evaluation of proliferation marker Ki-67. This work could represent an experimental model to study myofibroblasts deactivation and highlights an alternative process regulating the turnover of myofibroblasts

Ultrasound indices of congestion in patients with acute heart failure according to body mass index

Background: The inverse relationship between body mass index (BMI) and natriuretic peptide levels complicates the diagnosis of heart failure (HF) in obese patients. Assessment of congestion with ultrasound could facilitate HF diagnosis but it is unclear if any relationship exists amongst BMI, inferior vena cava (IVC) diameter and the number of B-lines. Methods: We performed a comprehensive echocardiographic evaluation within 24 h from hospital admission in patients with HF, including lung B-lines and IVC diameter, and studied their relationship with BMI and outcome. Results: 216 patients (median age 81 (77–86) years) were enrolled. Median number of B-lines was 31 (IQR 26–38), median IVC diameter was 23 (22–25) mm and median BNP 991 (727–1601) pg/mL. BMI was inversely correlated with B-lines (r = − 0.50, p &lt; 0.001), but not with IVC diameter (r = − 0.04, p = 0.58). Compared to overweight patients (BMI 25–29.9 kg/m2; n = 100) or with a normal BMI (BMI &lt; 25 kg/m2; n = 59), obese patients (BMI ≥ 30 kg/m2; n = 57) had lower B-lines [28 (24–33) vs 30 (26–35), and vs 38 (32–42), respectively; p &lt; 0.001] but similar IVC diameter. During the first 60 days of follow-up, there were 53 primary events: 29 patients died and 24 had a HF-related hospitalisation. B-lines and IVC diameter were independently associated with an increased risk. However, B-lines were less likely to predict outcome in the subgroup of patients with a BMI ≥ 30 kg/m2. Conclusions: Assessment of IVC diameter or B-lines in patients admitted with AHF identifies those at greater risk of death or HF readmission. However, assessment of B-lines might be influenced by BMI