Elevated β-hydroxybutyrate levels predict mortality in chronic heart failure independent of established risk factors, with 76% of this association mediated by heightened inflammation and catabolism pathways identified through proteomic analysis.
Every doubling of plasma β-hydroxybutyrate was associated with a 36.4% increase in mortality in heart failure patients.
Elevated β-hydroxybutyrate levels were independently associated with higher heart rate, lower iron levels, and lower body mass index.
Higher β-hydroxybutyrate levels were associated with upregulation of pathways related to acute inflammation and cachexia, and downregulation of lipogenic and anabolic pathways.
Inflammatory and catabolic pathways statistically mediated 76% of the association between β-hydroxybutyrate and mortality.
Elevated ketone body levels may reflect underlying metabolic stress in heart failure patients at risk of adverse outcomes rather than serving a purely compensatory role.
This research suggests that in patients with heart failure, higher blood levels of a molecule called β-hydroxybutyrate — a type of ketone body produced when the body burns fat for fuel — are linked to a significantly greater risk of death. Using data from 478 heart failure patients, the researchers found that each time β-hydroxybutyrate levels doubled, the risk of dying increased by about 36%, even after adjusting for other known risk factors. Patients with elevated ketone levels also tended to have faster heart rates, lower iron levels, and lower body weight. To understand why elevated ketones might be dangerous, the researchers analyzed over 1,000 proteins circulating in patients' blood. They found that patients with high ketone levels showed biological signs of increased inflammation and muscle/tissue breakdown (cachexia), while processes that build and store energy (lipogenic and anabolic pathways) were turned down. Importantly, these inflammatory and catabolic processes accounted for 76% of the statistical link between ketone levels and mortality, suggesting they are a key part of the mechanism. This research suggests that elevated ketone bodies in heart failure patients are not simply a helpful adaptation but may instead be a signal of serious underlying metabolic stress. Rather than ketones being beneficial on their own, their elevation may mark a state in which the body is inflamed and breaking down — a combination associated with worse outcomes. These findings could have implications for how clinicians interpret ketone levels in heart failure and for the design of future treatments targeting metabolism in this disease.
Palm C, van Essen B, Baumhove L, Alnuwaysir R, Connelly M, Petersmann A, et al.. (2026). Inflammatory and catabolic activity mediate the association of plasma β-hydroxybutyrate and mortality in heart failure.. ESC heart failure. https://doi.org/10.1093/eschf/xvag193