https://doi.org/10.1007/s00392-025-02625-4
1Federal University of Maranhao, Brazil Maranhão, Brazilien; 2Klinikum Fürth Med. Klinik I - Kardiologie Fürth, Deutschland; 3Federal University of Rio Grande do Norte, Brazil Rio Grande do Norte, Brazilien; 4Federal University of Cuiaba, Brazil Cuiabá, Brazilien; 5Christus University Center, Brazil Fortaleza, Brazilien; 6Mayo Clinic Cardiovascular Medicine Rochester, Minnesota, USA; 7Medical College Thiruvananthapuram Thiruvananthapuram, Indien
Introduction
Patients with heart failure (HF) exhibit a shift in myocardial metabolism, utilizing 3-hydroxybutyrate (3-OHB) as a substrate instead of free fatty acids. It remains unclear whether the implications of this metabolic shift are advantageous, detrimental, or simply incidental.
Objective
To assess the cardiovascular hemodynamic effects of 3-OHB in patients with chronic HF with reduced ejection fraction (HFrEF).
Methods
We conducted a systematic search of Embase, MEDLINE, and Cochrane Central databases for randomized studies comparing the infusion of 3-OHB versus placebo in patients with HFrEF. Pooled analyses were performed to evaluate the effects on heart rate (HR), pulmonary capillary wedge pressure (PCWP), cardiac output (CO), left ventricular ejection fraction (LVEF), stroke volume (SV), and pro-brain natriuretic peptide (BNP). Heterogeneity was examined with I2 statistics. R studio (version 4.4.0) was used for statistical analysis.
Results
We included 112 patients with chronic HFrEF from 3 randomized placebo-controlled trials, 66 of them (50%) receiving 3-OHB infusion. There was no difference between placebo and 3-OHB regarding changes in BNP [Mean difference (MD) -47.81; 95%CI -131.87 to 36.26; p=0.27; I2=63%]. However, when taking into account other hemodynamic parameters, 3-OHB patients presented with an increased HR (MD 5.59; 95%CI 2.96-8.23; p<0.01; I2=0%) as well as SV (MD 13.19; 95%CI 1.03-25.76; p=0.03; I2=95%), leading to improved CO (MD 1.41; 95%CI 0.28-2.54; p=0.01; I2=97%) and LVEF (MD 5.84; 95%CI 2.13-9.54; p<0.01; I2=83%). Furthermore, 3-OHB infusion decreased PCWP (MD -1.50; 95%CI -2.35-0.65; p<0.01; I2=0%), showing that its effects also extend to the pulmonary circulation.
Conclusion
In patients with chronic HFrEF, 3-OHB supplementation increased cardiac performance by increasing ejection fraction and cardiac output and slightly decreasing PCWP compared to placebo, highlighting the promising therapeutic effect of this intervention.
A) Brain-Natriuretic-Peptide
B) Heart Rate
C) Cardiac Output
D) Pulmonary Pressure
E) Left Ventricular Ejection Fraction
F) Stroke Volume
Figure 1. Forrest plot of cardiovascular endpoints with or without 3-OHB in HFrEF.