Inflammatory and catabolic activity mediate the association of plasma β-hydroxybutyrate and mortality in heart...

Ketone body levels are elevated in patients with heart failure (HF). Recently, plasma levels of ketone bodies have been associated with mortality in patients with HF. However, little is known about the biological processes active in patients with high levels of ketone bodies. The objective of this study was to investigate the features and prognosis of patients with HF with elevated β-hydroxybutyrate levels. Furthermore, we aimed to determine the specific biological processes that are active in these patients that may result in elevated levels of β-hydroxybutyrate.

β-hydroxybutyrate concentrations were measured by nuclear magnetic resonance spectroscopy in plasma from 478 patients with HF from the BIOSTAT-CHF cohort. In addition, the concentrations of 1057 circulating proteins were measured by liquid chromatography-mass spectrometry. Differential expression and ingenuity pathway analyses were used to investigate which biological processes are associated with high levels of β-hydroxybutyrate. Cox regression was used to investigate the association of β-hydroxybutyrate with mortality and HF hospitalization. Mediation analysis was conducted to determine how much of the association between β-hydroxybutyrate and outcomes is statistically explained by these processes.

The cohort consisted mostly of male patients (64.2%), with equal proportions of HF with reduced ejection fraction and preserved ejection fraction. Elevated β-hydroxybutyrate levels were independently associated with higher heart rate, lower iron levels, and lower body mass index. Moreover, every doubling of β-hydroxybutyrate was associated with a 36.4% increase in mortality (unadjusted hazard ratio 1.364: 95% confidence interval 1.089-1.707). Even after accounting for known risk factors, the relationship remained highly robust (adjusted hazard ratio 1.389; 95% confidence interval 1.150-1.677). Differential expression and ingenuity pathway analyses revealed that higher β-hydroxybutyrate levels were associated with the upregulation of pathways associated with acute inflammation and cachexia, whereas lipogenic and anabolic pathways were down-regulated. Subsequent multiple mediation analysis showed that 76% of the association between β-hydroxybutyrate and mortality was explained by these pathways.

Elevated β-hydroxybutyrate levels predict mortality in chronic HF, independent of established risk factors. Proteomic analysis links elevated β-hydroxybutyrate to heightened inflammation and catabolism, and these pathways largely mediated the association between β-hydroxybutyrate and mortality. These findings suggest that elevated ketone bodies may reflect underlying metabolic stress in patients at risk of adverse outcome.