Design and baseline characteristics of SALT-HF trial: hypertonic saline therapy in ambulatory heart failure.

AIMS: Hypertonic saline solution (HSS) plus intravenous (IV) loop diuretic appears to enhance the diuretic response in patients hospitalized for heart failure (HF). The efficacy and safety of this therapy in the ambulatory setting have not been evaluated. We aimed to describe the design and baseline characteristics of the SALT-HF trial participants. METHODS AND RESULTS: 'Efficacy of Saline Hypertonic Therapy in Ambulatory Patients with HF' (SALT-HF) trial was a multicenter, double-blinded, and randomized study involving ambulatory patients who experienced worsening heart failure (WHF) without criteria for hospitalization. Enrolled patients had to present at least two signs of volume overload, use ≥ 80 mg of oral furosemide daily, and have elevated natriuretic peptides. Patients were randomized 1:1 to treatment with a 1-h infusion of IV furosemide plus HSS (2.6-3.4% NaCl depending on plasmatic sodium levels) versus a 1-h infusion of IV furosemide at the same dose (125-250 mg, depending on basal loop diuretic dose). Clinical, laboratory, and imaging parameters were collected at baseline and after 7 days, and a telephone visit was planned after 30 days. The primary endpoint was 3-h diuresis after treatment started. Secondary endpoints included (a) 7-day changes in congestion data, (b) 7-day changes in kidney function and electrolytes, (c) 30-day clinical events (need of IV diuretic, HF hospitalization, cardiovascular mortality, all-cause mortality or HF-hospitalization). RESULTS: A total of 167 participants [median age, 81 years; interquartile range (IQR), 73-87, 30.5% females] were randomized across 13 sites between December 2020 and March 2023. Half of the participants (n = 82) had an ejection fraction >50%. Most patients showed a high burden of comorbidities, with a median Charlson index of 3 (IQR: 2-4). Common co-morbidities included diabetes mellitus (41%, n = 69), atrial fibrillation (80%, n = 134), and chronic kidney disease (64%, n = 107). Patients exhibited a poor functional NYHA class (69% presenting NYHA III) and several signs of congestion. The mean composite congestion score was 4.3 (standard deviation: 1.7). Ninety per cent of the patients (n = 151) presented oedema and jugular engorgement, and 71% (n = 118) showed lung B lines assessed by ultrasound. Median inferior vena cava diameter was 23 mm, (IQR: 21-25), and plasmatic levels of N-terminal-pro-B-type natriuretic peptide (NTproBNP) and antigen carbohydrate 125 (CA125) were increased (median NT-proBNP 4969 pg/mL, IQR: 2508-9328; median CA125 46 U/L, IQR: 20-114). CONCLUSIONS: SALT-HF trial randomized 167 ambulatory patients with WHF and will determine whether an infusion of hypertonic saline therapy plus furosemide increases diuresis and improves decongestion compared to equivalent furosemide administration alone.

Interplay between psychosocial and heart failure related factors may partially explain limitations in self-efficacy in patients with heart failure: Insights from a real-world cohort of 1,123 patients.

BACKGROUND AND AIMS: Worse self-care is associated with a higher risk of readmission and mortality in patients with heart failure (HF). Little is known about how the interplay between clinical and psycho-social factors may modulate self-care behaviours in these patients. The aim of our study was to identify clinical, and particularly psycho-social factors associated with worse self-care and assess their interaction inpatients with heart failure. METHODS AND RESULTS: We conducted an observational, prospective, cohort study of 1,123 consecutive patients with chronic heart failure. Self-care was assessed with the modified European Heart Failure Self-care Behavior Scale 9-item version (EHFSCBS-9), and both clinical and psycho-social profile of the patients included were also meticulously evaluated. A total of 484 patients (43%) were women, mean age was 72 years, and mean left ventricular ejection fraction was 44.5%. In multivariable analyses combining clinical and psycho-social factors, low social support (OR 3.53, 95% CI [2.13-5.86]; p-value <0.001), absence of caregiver support (OR 2.16, 95% CI [1.34 -3.48]; p-value 0.001) and depressive symptoms (OR 2.40, 95% CI [1.53-3.77]; p-value <0.001) were independent determinants of impaired global self-care. Advanced functional class was associated with better self-care (OR 0.43, 95%CI [0.26-0.70]; p-value 0.001). No other clinical factors remained significantly associated with self-care in these joint models. In discrimination analyses, models containing psycho-social determinants outperformed models only containing heart failure -related (clinical) variables (all p-values<0.001). CONCLUSION: Impairment in self-care behaviour is strongly determined by psycho-social factors. Specifically, low social support, the lack of caregiver support and the presence of depressive symptoms are the main drivers of the risk of impairment of self-care in heart failure patients. Evaluation of self-care and self-care interventions should be complemented by a comprehensive psycho-social assessment in patients with heart failure. ABBREVIATIONS: DAMOCLES, Definition of the neuro-hormonal Activation, Myocardial function, genOmic expressionand CLinical outcomes in hEart failure patients; NYHA, New York Heart Failure Association; GAM, Generalized Additive Model; BMI, Body Mass Index; GDS, GeriatricDepression Scale.

Neurohormonal activation induces intracellular iron deficiency and mitochondrial dysfunction in cardiac cells.

BACKGROUND: Iron deficiency (ID) is common in patients with heart failure (HF) and is associated with poor outcomes, yet its role in the pathophysiology of HF is not well-defined. We sought to determine the consequences of HF neurohormonal activation in iron homeostasis and mitochondrial function in cardiac cells. METHODS: HF was induced in C57BL/6 mice by using isoproterenol osmotic pumps and embryonic rat heart-derived H9c2 cells were subsequently challenged with Angiotensin II and/or Norepinephrine. The expression of several genes and proteins related to intracellular iron metabolism were assessed by Real time-PCR and immunoblotting, respectively. The intracellular iron levels were also determined. Mitochondrial function was analyzed by studying the mitochondrial membrane potential, the accumulation of radical oxygen species (ROS) and the adenosine triphosphate (ATP) production. RESULTS: Hearts from isoproterenol-stimulated mice showed a decreased in both mRNA and protein levels of iron regulatory proteins, transferrin receptor 1, ferroportin 1 and hepcidin compared to control mice. Furthermore, mitoferrin 2 and mitochondrial ferritin were also downregulated in the hearts from HF mice. Similar data regarding these key iron regulatory molecules were found in the H9c2 cells challenged with neurohormonal stimuli. Accordingly, a depletion of intracellular iron levels was found in the stimulated cells compared to non-stimulated cells, as well as in the hearts from the isoproterenol-induced HF mice. Finally, neurohormonal activation impaired mitochondrial function as indicated by the accumulation of ROS, the impaired mitochondrial membrane potential and the decrease in the ATP levels in the cardiac cells. CONCLUSIONS: HF characteristic neurohormonal activation induced changes in the regulation of key molecules involved in iron homeostasis, reduced intracellular iron levels and impaired mitochondrial function. The current results suggest that iron could be involved in the pathophysiology of HF.