Quantification and impact of circulating cardiotonic steroids in the RATE-AF randomised trial of patients with atrial fibrillation and heart failure
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Background
The presence and role of endogenous digoxin-like cardiotonic steroids (CTS) in humans is controversial. This study utilises a novel pipeline to quantify CTS and examines their interaction with digoxin within a randomised trial.
Methods
The RAte control Therapy Evaluation in permanent Atrial Fibrillation (RATE-AF) trial randomised patients with permanent AF and symptoms of heart failure to low-dose digoxin or beta-blocker therapy; clinicaltrials.gov NCT02391337. Circulating CTS were detected and quantified using a new ultra-high-performance liquid chromatography tandem mass spectrometry (LC–MS/MS) pipeline.
Results
All 160 participants of the RATE-AF trial were included, with mean age 76 years (SD 8) and 46% women. Endogenous CTS detected and quantified in baseline samples included digoxigenin and digitoxigenin, plus low or unquantifiable levels of ouabain, telocinobufagin, cinobufagin, marinobufagenin, bufalin, cinobufotalin, dihydroouabain, and ouabagenin. Compared to beta-blockers, patients randomised to digoxin had better functional outcomes at 12 months for heart failure (− 0.57 New York Heart Association class, 95% CI − 0.82 to − 0.32; p < 0.001) and atrial fibrillation (odds ratio 2.24 for a two-class improvement in modified European Heart Rhythm Association class, 95% CI 1.43–3.84; p < 0.001), with lower NT-pro-B-type natriuretic peptide (geometric mean ratio 0.78, 95% CI 0.61 to 0.99; p = 0.006). No interactions were observed for any baseline CTS with each outcome. Digoxin was associated with fewer adverse events (odds ratio 0.16, 95% CI 0.07–0.34; p < 0.001), again without any interaction from circulating CTS. Digoxin levels by LC–MS/MS were strongly correlated with measurement by a clinical immunoassay (r = 0.87; p < 0.001), and treatment with digoxin did not affect CTS concentrations at 6-month follow-up.
Conclusions
A range of CTS are detected in the circulation of patients with atrial fibrillation and heart failure. Within this randomised trial but limited by low circulating levels, CTS do not appear to interact with the ability of digoxin to improve wellbeing compared to conventional first-line treatment with beta-blockers.
The presence and role of endogenous digoxin-like cardiotonic steroids (CTS) in humans is controversial. This study utilises a novel pipeline to quantify CTS and examines their interaction with digoxin within a randomised trial.
Methods
The RAte control Therapy Evaluation in permanent Atrial Fibrillation (RATE-AF) trial randomised patients with permanent AF and symptoms of heart failure to low-dose digoxin or beta-blocker therapy; clinicaltrials.gov NCT02391337. Circulating CTS were detected and quantified using a new ultra-high-performance liquid chromatography tandem mass spectrometry (LC–MS/MS) pipeline.
Results
All 160 participants of the RATE-AF trial were included, with mean age 76 years (SD 8) and 46% women. Endogenous CTS detected and quantified in baseline samples included digoxigenin and digitoxigenin, plus low or unquantifiable levels of ouabain, telocinobufagin, cinobufagin, marinobufagenin, bufalin, cinobufotalin, dihydroouabain, and ouabagenin. Compared to beta-blockers, patients randomised to digoxin had better functional outcomes at 12 months for heart failure (− 0.57 New York Heart Association class, 95% CI − 0.82 to − 0.32; p < 0.001) and atrial fibrillation (odds ratio 2.24 for a two-class improvement in modified European Heart Rhythm Association class, 95% CI 1.43–3.84; p < 0.001), with lower NT-pro-B-type natriuretic peptide (geometric mean ratio 0.78, 95% CI 0.61 to 0.99; p = 0.006). No interactions were observed for any baseline CTS with each outcome. Digoxin was associated with fewer adverse events (odds ratio 0.16, 95% CI 0.07–0.34; p < 0.001), again without any interaction from circulating CTS. Digoxin levels by LC–MS/MS were strongly correlated with measurement by a clinical immunoassay (r = 0.87; p < 0.001), and treatment with digoxin did not affect CTS concentrations at 6-month follow-up.
Conclusions
A range of CTS are detected in the circulation of patients with atrial fibrillation and heart failure. Within this randomised trial but limited by low circulating levels, CTS do not appear to interact with the ability of digoxin to improve wellbeing compared to conventional first-line treatment with beta-blockers.
Date Issued
2025-12-29
Date Acceptance
2025-10-23
Citation
BMC Medicine, 2025, 23
ISSN
1741-7015
Publisher
BMC
Journal / Book Title
BMC Medicine
Volume
23
Issue
1
Copyright Statement
© The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/41462450
PII: 10.1186/s12916-025-04476-2
Subjects
Atrial fibrillation
CTS
Cardiotonic steroids
Digitoxigenin
Digoxigenin
Digoxin
Ouabain
Humans
Atrial Fibrillation
Female
Aged
Male
Heart Failure
Digoxin
Adrenergic beta-Antagonists
Aged, 80 and over
Cardiotonic Agents
Cardiac Glycosides
Tandem Mass Spectrometry
Publication Status
Published
Coverage Spatial
England
Article Number
694
Date Publish Online
2025-12-29