Ketone-Based Therapies in Adults with Heart Failure: A Systematic Review and Quantitative Analysis

Background Ketone bodies may improve cardiac metabolism and function in patients with heart failure (HF). We evaluated the effects of exogenous ketone-based interventions on cardiac function in patients with HF or related cardiometabolic risk factors. Methods We conducted a systematic review based on a search of MEDLINE, EMBASE, CINAHL, Cochrane Library, and Scopus through January 2025 for randomized controlled trials (RCTs) comparing exogenous ketone bodies (oral or infusion) to placebo in adults with HF and other cardiometabolic conditions.. Paired reviewers independently screened and identified hits at title-and-abstract and full-text levels to determine eligibility and extracted data from eligible studies. Random-effects meta-analysis was performed. Effects of interventions were summarized as mean differences (MD). Risk of bias was assessed via Cochrane RoB 2.0, and certainty of evidence via the GRADE (grading of recommendations assessment, development and evaluation) approach. Results From 565 unique records, 8 RCTs met inclusion criteria. Exogenous ketone administration increased left ventricular ejection fraction (LVEF) (MD=3.94, 95% CI 2.18-5.70, P =0.001), cardiac output (CO) (MD=1.11 L/min, 95% CI 0.55-1.67, P =0.002), heart rate (4.85 BPM, 95% CI 2.24-7.46, P =0.003), and stroke volume (SV) (MD=10.21 mL, 95% CI 4.06-16.35, P =0.005). Pulmonary capillary wedge pressure (PCWP) decreased (MD=-0.93 mmHg, 95% CI -1.44 to -0.43, P =0.003), while mean arterial pressure showed no change (MD=-1.37 mmHg, 95% CI -3.53-0.79, P =0.18). Conclusions Exogenous ketone-based therapies are associated with improved hemodynamic measures in patients with HF and associated cardiometabolic conditions, including increased LVEF, CO, and SV, and reduced PCWP. However, these findings reflect acute physiological effects observed across heterogeneous intervention protocols, and the clinical significance of these changes remains uncertain in the absence of data on patient-important outcomes such as mortality, hospitalization, or quality of life.