“Our findings revealed that in subjects with ADHF, treatment with i.v. furosemide plus HSS significantly decreased the serum levels of IL-6, sST2, hsTnT, galectin-3, and NT-proBNP and modulated some miRNA expression.”
Heart failure remains one of the leading causes of hospitalization among older adults worldwide. During episodes of acute decompensated heart failure (ADHF), excess fluid builds up in the lungs and body, making breathing difficult and increasing the risk of serious complications. Although intravenous loop diuretics such as furosemide are the standard treatment for relieving congestion, many patients continue to experience persistent inflammation, ongoing cardiac remodeling, and worsening heart function despite therapy.
A research paper published in Volume 18 of Aging titled “Effects of intravenous furosemide plus small-volume hypertonic saline solutions on inflammatory, remodelling markers and epigenetics signatures of patients with congestive acute decompensated heart failure (ADHF),” investigated whether combining intravenous furosemide with small volumes of hypertonic saline solution (HSS) could improve biological markers associated with heart failure compared with furosemide alone.
The study was led by first author Mario Daidone from University Hospital, Policlinico, Paolo Giaccone, and the University of Palermo, with corresponding author Antonino Tuttolomondo from the same institutions.
Why Add Salt to a Diuretic?
At first glance, combining a salt solution with a diuretic may seem counterintuitive because heart failure treatment typically focuses on removing excess fluid and limiting sodium intake.
However, previous studies have suggested that administering a small volume of hypertonic saline together with high-dose furosemide may temporarily improve intravascular volume and kidney perfusion during aggressive diuresis. This could enhance the effectiveness of the diuretic while helping maintain circulation, potentially leading to better fluid removal and improved clinical outcomes. The current study was designed to examine not only these clinical effects but also whether the combination therapy influenced inflammation, cardiac remodeling, and circulating microRNAs linked to heart failure.
Testing a New Treatment Strategy
The investigators conducted a randomized controlled trial involving 200 patients hospitalized with acute decompensated heart failure caused by heart failure with reduced ejection fraction (HFrEF).
Participants were randomly assigned to receive either:
- intravenous furosemide plus small-volume hypertonic saline solution, or
- intravenous furosemide alone.
Patients were evaluated at hospital admission, after six days of treatment, and again after undergoing a standardized saline challenge designed to assess how well the heart responded after treatment. At each time point, the researchers measured several biomarkers associated with heart failure, including:
- NT-proBNP, a marker of cardiac wall stress,
- high-sensitivity troponin T (hsTnT), a marker of myocardial injury,
- soluble ST2 (sST2) and galectin-3, which are associated with cardiac remodeling and fibrosis,
- interleukin-6 (IL-6) and C-reactive protein (CRP), markers of inflammation,
- and several circulating microRNAs involved in heart failure biology.
Greater Improvements in Selected Heart Failure Biomarkers
After six days of treatment, several biomarkers declined in both groups. When the researchers compared the magnitude of these changes, patients receiving furosemide plus hypertonic saline showed significantly greater reductions in IL-6, sST2, and NT-proBNP than those receiving furosemide alone. Although hsTnT and galectin-3 also decreased during treatment, the magnitude of their reduction did not differ significantly between the two groups in the absolute change analysis. CRP likewise did not show a significant treatment-related difference between groups.
The researchers also observed that patients treated with hypertonic saline produced more urine and experienced greater weight loss during hospitalization, findings consistent with more effective decongestion. In addition, symptoms such as exertional shortness of breath and peripheral edema improved in a greater proportion of patients receiving the combination therapy.
The Heart Responded Differently to a Saline Challenge
One distinctive feature of the study was that, after completing treatment, all participants underwent an acute saline challenge.
Patients treated with furosemide alone experienced larger increases in biomarkers such as IL-6, sST2, hsTnT, galectin-3, and NT-proBNP following the saline infusion.
In contrast, patients who had received furosemide plus hypertonic saline showed smaller increases in these biomarkers after the saline load. The authors interpreted this pattern as suggesting a more favorable response to acute volume loading after decongestive treatment.
Changes Extended to Epigenetic Markers
Beyond conventional biomarkers, the investigators also examined several circulating microRNAs, small regulatory RNA molecules that influence gene expression and have been implicated in inflammation, fibrosis, and cardiac remodeling.
The treatment groups also differed in the expression patterns of several microRNAs, particularly miR-214, miR-365, and miR-181b. The direction and timing of these changes varied across the treatment and saline-challenge phases, indicating that the combination regimen altered selected circulating microRNA profiles rather than producing a uniform effect across all markers.
Although the biological significance of these changes remains uncertain, the authors propose that circulating microRNAs may eventually serve as biomarkers for monitoring treatment response in patients with heart failure. However, they emphasize that additional research is needed before these markers can be incorporated into routine clinical practice.
Why These Findings Matter
Heart failure is driven by more than excess fluid alone. Persistent inflammation, myocardial injury, neurohormonal activation, and structural remodeling all contribute to disease progression and worsening outcomes.
This study suggests that combining small-volume hypertonic saline with intravenous furosemide may improve multiple biological processes associated with heart failure rather than simply increasing urine output. Improvements in selected biomarkers related to inflammation, cardiac stress, and remodeling raise the possibility that this approach could provide broader benefits during treatment of acute decompensated heart failure.
However, improvements in biomarkers do not necessarily translate into better long-term clinical outcomes, and further studies are needed to determine whether these biological effects lead to sustained reductions in hospitalization or mortality.
Looking Ahead
The authors conclude that, in patients with acute decompensated heart failure and reduced ejection fraction, intravenous furosemide plus small-volume hypertonic saline reduced several biomarkers associated with inflammation, myocardial injury, cardiac remodeling, and ventricular wall stress more effectively than furosemide alone. The combination therapy also altered circulating microRNA profiles linked to heart failure biology, suggesting potential effects on molecular pathways involved in disease progression.
While these findings are encouraging, the study was conducted at a single center, and larger multicenter randomized trials will be needed to determine whether these improvements in biomarkers translate into better long-term patient outcomes. Future research will also help clarify whether circulating microRNAs can become reliable tools for monitoring treatment response and guiding personalized therapy in heart failure.
Click here to read the full research paper published in Aging.
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