Effects of ketone bodies supplementation in patients with heart failure: A systematic review and meta-analysis

Abstract

BACKGROUND

Ketone bodies, especially β-hydroxybutyrate, have shown the potential to improve hemodynamic outcomes such as cardiac output (CO) and left ventricular ejection fraction (LVEF) in patients with heart failure (HF). However, the overall effectiveness of ketone body supplementation in this population remains uncertain. Therefore, we conducted this systematic review and meta-analysis to evaluate the impact of ketone body supplementation on cardiac and hemodynamic parameters in patients with HF while accounting for the limited and emerging nature of the available randomized evidence.

AIM

To evaluate the impact of ketone body supplementation on cardiac and hemodynamic parameters in patients with HF while accounting for the limited and emerging nature of the available randomized evidence.

METHODS

A systematic search of PubMed, Scopus, EMBASE, and the Cochrane Central Register of Controlled Trials was conducted from inception to March 2025, with additional screening of ClinicalTrials.gov for unpublished or ongoing trials. Randomized controlled trials (RCTs) comparing ketone body supplementation with placebo in patients with HF were included. Statistical analyses were performed using a random-effects model in RevMan 5.4 to calculate weighted mean differences (MDs) with 95% confidence intervals (CIs). Outcomes assessed included CO, systemic vascular resistance, LVEF, heart rate, venous oxygen saturation, pulmonary capillary wedge pressure, and other cardiac functional indices. Given the small number of included studies, subgroup analyses were considered exploratory.

RESULTS

Four randomized controlled trials involving a total of 94 patients were included. Compared with placebo, ketone supplementation was associated with a significant increase in CO (MD = 1.11, 95%CI: 0.13-2.09, P = 0.03) and a reduction in systemic vascular resistance (MD = -252.61, 95%CI: -475.72 to -29.50, P = 0.03). Improvements were also observed in LVEF (MD = 3.31, 95%CI: 0.39-6.22, P = 0.03), venous oxygen saturation (MD = 3.33, 95%CI: -0.01 to 6.68, P = 0.05), and pulmonary capillary wedge pressure (MD = -1.09, 95%CI: -1.60 to -0.59, P < 0.0001), along with an increase in heart rate (MD = 4.08, 95%CI: 3.00-5.17, P < 0.0001). Subgroup analyses by HF phenotype (HF with reduced ejection fraction vs HF with preserved ejection fraction) suggested differential effects; however, several subgroups included only one study and should be interpreted as hypothesis-generating only. No statistically significant changes were observed in global longitudinal strain, left ventricular end-diastolic volume, or tricuspid annular plane systolic excursion, and substantial heterogeneity and potential small-study effects limit the robustness of pooled estimates.

CONCLUSION

Ketone body supplementation was associated with short-term improvements in selected hemodynamic and cardiac functional parameters in patients with HF. However, these findings are based on a small number of short-duration trials with limited sample sizes and crossover designs, precluding firm clinical conclusions. Larger, well-powered randomized trials with longer follow-up are required to confirm the therapeutic role, optimal dosing, and clinical impact of ketone supplementation in HF.

Key Words: Ketone bodies; Heart failure; Cardiac output; Left ventricular ejection fraction; 3-β-hydroxybutyrate

Core Tip: Metabolic modulation has emerged as a novel therapeutic strategy in heart failure (HF). This systematic review and meta-analysis of randomized controlled trials demonstrates that ketone body supplementation, particularly β-hydroxybutyrate, significantly improves cardiac output, left ventricular ejection fraction, and key hemodynamic parameters while reducing systemic vascular resistance and pulmonary capillary wedge pressure in patients with HF. These findings highlight the potential role of ketone bodies as an adjunctive metabolic therapy to enhance myocardial efficiency and hemodynamic performance, especially in HF with reduced ejection fraction.

INTRODUCTION

Introduction heart failure (HF) is a growing global health concern, affecting over 64 million individuals worldwide, and is associated with high rates of morbidity, mortality, and rehospitalization[1-3]. Current treatment strategies primarily focus on improving hemodynamics through modulation of the renin-angiotensin-aldosterone system and the sympathetic nervous system[4,5]. While these approaches improve symptoms and clinical outcomes, they do not fully reverse disease progression or address underlying metabolic alterations in HF, highlighting the need for novel therapeutic targets[6].

Recently, ketone body metabolism has emerged as a potential metabolic target in HF[7]. Among ketone bodies, β-hydroxybutyrate (β-OHB) has garnered particular interest due to its role as an efficient energy substrate for the failing heart[8]. In patients with advanced HF with reduced ejection fraction (HFrEF), myocardial expression of ketolytic enzymes and utilization of 3-hydroxybutyrate (3-OHB) are up regulated, suggesting a metabolic shift toward ketone use under conditions of impaired myocardial energetics[9]. Experimental studies further support this hypothesis, demonstrating that overexpression of key genes involved in 3-OHB metabolism may protect against contractile dysfunction[10]. However, the translational relevance of these findings to clinical HF populations remains incompletely understood.

Clinical investigations have shown that acute infusion of 3-OHB can improve hemodynamic parameters in patients with HFrEF, including increases in cardiac output (CO) and reductions in cardiac filling pressures[11-14]. These studies, however, are largely short-term, involve small sample sizes, and vary in intervention protocols, limiting the generalizability of their findings. In parallel, sodium-glucose cotransporter 2 inhibitors have been shown to increase circulating 3-OHB levels, raising the possibility that some of their benefits in HF may be mediated, at least in part, through ketone-related metabolic pathways[14].

Consequently, several endogenous and exogenous strategies to increase circulating ketone levels have been explored, including ketogenic diets, fasting, ketone ester supplementation, and direct 3-OHB administration[7,14-18]. While preclinical and early clinical studies suggest potential improvements in cardiac function and hemodynamics, the magnitude and consistency of these effects across different HF phenotypes and study designs remain variable[19-23]. Moreover, no consensus has been established regarding optimal dosing, formulation, or long-term clinical benefit.

Therefore, we conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to synthesize the available evidence on ketone body supplementation and its effects on cardiac and hemodynamic parameters in patients with HF. Given the limited number of trials and small sample sizes, this analysis was designed to provide an exploratory, hypothesis-generating assessment rather than definitive clinical conclusions.

MATERIALS AND METHODS

Methods

This study adheres to the reporting guidelines set by the PRISMA and the Cochrane Handbook for Systematic Reviews of Interventions[24]. Permission from an ethical review board was not required because the data were publicly available.

Data sources and search strategy

Two independent reviewers (Kumar A and Kumar S) conducted a comprehensive literature search of PubMed and Scopus, covering studies published from inception through March 2025. To reduce the risk of publication bias and enhance search completeness, additional searches were conducted in EMBASE and the Cochrane Central Register of Controlled Trials. The specific search strategies used for each database are outlined in Supplementary Table 1.

We also searched ClinicalTrials.gov to identify unpublished or ongoing RCTs. All identified articles were imported into EndNote X7 (Clarivate Analytics, Philadelphia, PA, United States) to remove duplicates. Two reviewers (Ahmad M and Akhtar S) independently screened titles and abstracts, followed by full-text assessment based on predefined inclusion and exclusion criteria. Reference lists of eligible studies were manually screened to identify additional relevant articles.

Any disagreements between reviewers were resolved through discussion or, when necessary, by consultation with a third reviewer (Siddiqi AK). No additional eligible trials were identified through database expansion, registry searches, or manual screening.

Study selection and eligibility criteria

Studies were eligible for inclusion if they met the following criteria: (1) Adult participants (≥ 18 years) with HF; (2) RCT design; (3) Ketone body supplementation (3-OHB) compared with placebo; and (4) Patients receiving guideline-directed medical therapy for HF.

Exclusion criteria included: (1) Commentaries, editorials, or narrative reviews without original patient data; (2) Preclinical or animal studies; and (3) Non-English language publications.

After screening and eligibility assessment, four RCTs met the inclusion criteria and were included in the final analysis. Given the small number of eligible studies, all analyses were interpreted with caution.

Data extraction and quality assessment

Two independent reviewers (Kumar A and Ahmad M) extracted data using a standardized data extraction form. Extracted baseline characteristics included first author, country, HF phenotype, intervention type, sample size, sex distribution, mean age, body mass index, heart rate (HR), systolic and diastolic blood pressure, left ventricular ejection fraction (LVEF), N-terminal pro-B-type natriuretic peptide, and baseline medical therapy.

The following outcomes were extracted: CO, systemic vascular resistance (SVR), LVEF, mixed venous oxygen saturation (SVO₂), pulmonary capillary wedge pressure (PCWP), HR, left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV), global longitudinal strain (GLS), systolic mitral annular peak velocity (S’max), and tricuspid annular plane systolic excursion (TAPSE). Risk of bias was assessed using the Cochrane Risk of Bias 2 tool for randomized trials[25].

Statistical analysis

All statistical analyses were performed using RevMan, version 5.4 (Nordic Cochrane Centre, Copenhagen, Denmark)[26]. A random-effects model was applied to account for between-study variability. For continuous outcomes, mean differences (MDs) with corresponding 95% confidence intervals (CIs) were calculated, and forest plots were generated.

Statistical heterogeneity was assessed using the I² statistic, with values of 25%-49%, 50%-74%, and ≥ 75% representing low, moderate, and high heterogeneity, respectively[27]. Due to the limited number of included studies, formal meta-regression and funnel plot-based publication bias assessment were not feasible.

Subgroup analyses were conducted according to HF phenotype [HFrEF vs HF with preserved ejection fraction (HFpEF)]. These subgroup analyses were predefined but considered exploratory and hypothesis-generating, particularly when based on a single study. In cases of substantial heterogeneity (I² > 50%), sensitivity analyses using a leave-one-out approach were performed to assess the influence of individual studies on pooled estimates.

A two-sided P value < 0.05 was considered statistically significant. All findings were interpreted in the context of limited sample size and potential small-study effects.

RESULTS

Search and study characteristics

The initial database search yielded 3782 articles. After screening and applying the inclusion criteria, four RCTs were included in this meta-analysis. These trials collectively enrolled 94 patients, the majority of whom were men (85%). All included studies were randomized crossover trials conducted in Denmark. Figure 1 illustrates the study selection process using a PRISMA flowchart, and Table 1 provides an overview of the key characteristics of the included studies.

Figure 1  PRISMA flow chart summarizing the study selection process.

Table 1 Baseline Characteristics of included studies, n (%).

Trials	Country	Patient population	Intervention	Sample size (n)	Gender (M/F)	Age, years	BMI, kg/m2	HR, bpm	SBP, mmHg	DBP, mmHg	LVEF, %	NT-proBNP, ng/L	HbA1c, mmol/mol	eGFR, mL	Medications
Nielsen et al[14], 2019	Denmark	Patients with HFrEF (LVEF ≤ 40%), NYHA class II-III, and on stable guideline-directed therapy	3-hydroxybutyrate infusion	34	31/3	60	26	65	130	77	36	617	39	77	ACE inhibitor/ARB/ARNI: 15 (94)
															Platelet inhibitors: 12 (75)
															Beta Blockers: 16 (100)
															Diuretics: 8 (50)
															MRA: 10 (63)
Berg-Hansen et al[12], 2024	Denmark	Stable HFrEF patients (LVEF ≤ 40%), NYHA class II-III, receiving optimal medical therapy at an outpatient HF clinic	Oral ketone ester drink	24	17/7	65	30	63	124	75	33	609	5.8	50	ACE inhibitor/ARB/ARNI: 24 (100). MRA: 19 (79)
Gopalasingam et al[11], 2023	Denmark	HFrEF patients (LVEF ≤ 40%), NYHA class II-III, and no recent history of MI	3-hydroxybutyrate infusion	12	11/1	64	N/A	72	120	76	33	360	41	85	ACE inhibitor/ARB/ARNI: 24 (100)
															Platelet inhibitors: 14 (58)
															Beta blockers: 16 (100)
															Diuretics: 21 (88)
															MRA: 19 (79)
Gopalasingam et al[22], 2024	Denmark	Patients with HFpEF (LVEF > 40%), T2D, and diastolic dysfunction, with either LV hypertrophy (≥ 12 mm) or a history of MI	Oral ketone ester drink	24	22/2	64	30	76	135	81	52	100	51	77	ACE inhibitor/ARB/ARNI: 8 (67)
															Platelet inhibitors: 4 (33)
															Beta blockers: 7 (58)
															Diuretics: 11 (92)
															MRA: 10 (63)

Data are reported as mean ± SD or median (interquartile range). M: Male; F: Female; eGFR: Estimated glomerular filtration rate; BMI: Body mass index; HR: Heart rate; SBP: Systolic blood pressure; DBP: Diastolic blood pressure; NT-proBNP: N-terminal pro brain-natriuretic-peptide; HbA1c: Hemoglobin A1c; HFrEF: Heart failure with reduced ejection fraction; LVEF: Left ventricular ejection fraction; NYHA: New York Heart Association; ACE: Angiotensin-converting enzyme; ARB: Angiotensin-2 receptor blockers; ARNI: Angiotensin receptor-neprilysin inhibitor; MRA: Mineralocorticoid receptor antagonists; LV: Left ventricular; MI: Myocardial infarction; N/A: Not applicable; T2D: Type-2 diabetes.

Results of quality assessment

The risk of bias in the four included RCTs was evaluated using the Cochrane Risk of Bias tool. Two trials were judged to have a low risk of bias, while the other two were assessed as having a moderate risk. An overview of the quality assessment is presented in Supplementary Figure 1.

Results of meta-analysis

CO: All four included studies reported data on CO, and the pooled analysis demonstrated that ketone supplementation was associated with a significant increase in CO compared to placebo (MD = 1.11, 95%CI: 0.13-2.09; P = 0.03; Figure 2A). Subgroup analysis based on the phenotype of HF supported these findings, with a significant increase observed in both patients with HFrEF (MD = 1.49, 95%CI: 0.22-2.76; P = 0.02; I² = 88%) and those with HFpEF (MD = 0.20, 95%CI: 0.09-0.31; P = 0.0005; Figure 2A). Sensitivity analysis conducted within the HFrEF subgroup showed that removing the study by Berg-Hansen et al[12] reduced heterogeneity to 0%, while the effect size remained significant (MD = 2.04, 95%CI: 1.51-2.57; P < 0.0001), indicating the robustness of the findings (Supplementary Figure 2).

Figure 2 Effect of ketone supplementation vs placebo on cardiac function and hemodynamic parameters in patients with heart failure. A: Cardiac output; B: Systemic vascular resistance; C: Left ventricular ejection fraction; D: Venous oxygen saturation; E: Pulmonary capillary wedge pressure; F: Heart rate; G: Left ventricular end-diastolic volume; H: Left ventricular end-systolic volume; I: Global longitudinal strain; J: Systolic mitral annular peak velocity; K: Tricuspid annular plane systolic excursion. HFrEF: Heart failure with reduced ejection fraction; HFpEF: Heart failure with preserved ejection fraction; CI: Confidence interval.

SVR: Pooled analysis of four studies demonstrated that ketone supplementation was associated with a significant reduction in SVR compared to placebo (MD = -252.61, 95%CI: -475.72 to -29.50; P = 0.03; Figure 2B). Subgroup analysis based on HF phenotype revealed consistent findings, with significant reductions observed in both patients with HFrEF (MD = -325.19, 95%CI: -529.93 to -120.45; P = 0.002) and those with HFpEF (MD = -64.00, 95%CI: -82.11 to -45.89; P < 0.00001). Due to the high heterogeneity observed in the HFrEF subgroup, a leave-one-out sensitivity analysis was performed. Omitting the study by Berg-Hansen et al[12] lowered heterogeneity to 0%, while the results remained consistent and statistically significant (MD = -433.67, 95%CI: -533.11 to -334.22; P < 0.0001) (Supplementary Figure 3).

LVEF: Pooled analysis of four studies demonstrated that ketone supplementation was associated with a significant improvement in LVEF compared to placebo (MD = 3.31, 95%CI: 0.39-6.22; P = 0.03; Figure 2C). Subgroup analysis based on HF phenotype showed that this improvement was more pronounced in patients with HFrEF (MD = 4.62, 95%CI: 1.71-7.52; P = 0.002), while a modest, non-significant increase was observed in patients with HFpEF (MD = 1.00, 95%CI: -0.13 to 2.13; P = 0.08).

SVO₂%: Pooled analysis of four studies revealed that ketone supplementation led to a marginally significant increase in SVO₂% compared to placebo (MD = 3.33, 95%CI: -0.01 to 6.68; P = 0.05; Figure 2D). Subgroup analysis revealed significant improvements in SVO₂ in both patients with HFrEF (MD = 4.36, 95%CI: 0.31-8.41; P = 0.03; Figure 2D) and those with HFpEF (MD = 1.00, 95%CI: 0.43-1.57; P = 0.0005). Furthermore, a leave-one-out sensitivity analysis in the HFrEF subgroup showed that removing the study by Berg-Hansen et al[12] reduced heterogeneity to 0% without significantly altering the results (MD = 6.60, 95%CI: 4.41-8.78; P < 0.0001) (Supplementary Figure 4).

PCWP: All four studies reported data on PCWP, and pooled analysis showed that ketone supplementation resulted in a significant overall reduction in PCWP compared to placebo (MD = -1.09, 95%CI: -1.60 to -0.59; P < 0.0001; Figure 2E). When analyzing subgroups, ketone supplementation led to a significant reduction in PCWP in patients with HFrEF (MD = -1.44, 95%CI: -2.53 to -0.34; P = 0.010; Figure 2E) and HFpEF (MD = -1.00, 95%CI: -1.57 to -0.43; P = 0.0005).

HR: Pooled analysis of all four studies demonstrated a significant increase in HR in the ketone supplementation group compared to placebo (MD = 4.08, 95%CI: 3.00-5.17; P < 0.0001; Figure 2F). Subgroup analysis showed similar findings, with ketone supplementation significantly increasing HR in patients with HFrEF (MD = 5.34, 95%CI: 1.05-9.63; P = 0.01; Figure 2F) and in those with HFpEF (MD = 4.00, 95%CI: 2.87-5.13; P < 0.00001).

LVEDV: Three studies reported data on LVEDV, all of which included patients with HFrEF. The pooled analysis found no significant difference in LVEDV between the ketone supplementation and placebo groups (MD = -11.99, 95%CI: -32.36 to 8.39; P = 0.25; Figure 2G).

LVESV: Three studies reported on LVESV, all of which included patients with HFrEF. Our pooled analysis demonstrated a significant reduction in LVESV with ketone supplementation compared to placebo (MD = -18.35, 95%CI: -35.71 to -0.99; P = 0.04; Figure 2H).

GLS: This outcome was reported in four studies. The pooled analysis showed no significant overall difference in GLS with ketone supplementation compared to placebo (MD = 0.45; 95%CI: -0.61 to 1.50; P = 0.41; Figure 2I). Subgroup analysis similarly revealed no significant effect on patients with HFrEF (MD = 1.02; 95%CI: -0.10 to 2.13; P = 0.07) or those with HFpEF (MD = -0.30; 95%CI: -0.70 to 0.10; P = 0.14).

S’max: Our pooled analysis of four studies reporting on this outcome demonstrated a significant overall improvement in S’max with ketone supplementation compared to placebo (MD = 1.98; 95%CI: 0.45-3.51; P = 0.01; I² = 94%; Figure 2J). In subgroup analysis, patients with HFrEF showed a trend toward improved S’max, although this did not reach statistical significance (MD = 3.03; 95%CI: -0.30 to 6.36; P = 0.07). In contrast, patients with HFpEF experienced a significant increase in S’max with ketone supplementation (MD = 0.30; 95%CI: 0.13-0.47; P = 0.0005). Given the high heterogeneity observed in the HFrEF subgroup, a leave-one-out sensitivity analysis was conducted, which showed that excluding the study by Nielsen et al[13] reduced heterogeneity to 20% (Supplementary Figure 5).

TAPSE: This outcome was documented in three studies, all of which involved patients with HFrEF. Our pooled analysis indicated no significant difference between the ketone supplementation and placebo groups (MD = 0.21, 95%CI: -0.04 to 0.46; P = 0.10; Figure 2K).

DISCUSSION

In this systematic review and meta-analysis of four RCTs involving 94 patients with HF, ketone body supplementation was associated with improvements in several cardiac and hemodynamic parameters. Specifically, increases in CO and LVEF, along with reductions in SVR and PCWP, were observed. However, these findings should be interpreted cautiously given the small number of included studies, limited sample size, and substantial heterogeneity observed for certain outcomes. HR and S′max increased, while LVESV decreased, suggesting enhanced systolic performance. In contrast, no statistically significant changes were observed in LVEDV, GLS, or TAPSE, indicating that the effects of ketone supplementation may be parameter-specific rather than universal across all aspects of cardiac function.

The improvement in CO observed in our analysis is consistent with prior experimental and clinical studies reporting favorable hemodynamic effects of ketone bodies in HF. Nielsen et al[14] demonstrated that β-OHB infusion increased CO in patients with chronic HF, potentially by improving myocardial energetic efficiency and reducing reliance on glucose and fatty acid oxidation. Notably, these studies were short-term and involved small cohorts, which limits direct comparison and generalizability. The hypothesis that ketone bodies serve as a more efficient myocardial fuel is biologically plausible, particularly in the setting of impaired oxidative phosphorylation characteristic of the failing heart[28]. β-OHB has also been shown to influence key signaling pathways involved in cardiac stress responses and post-myocardial infarction remodeling[29]. Experimental evidence suggests that β-OHB may enhance mitochondrial function and reduce oxidative stress, partly through histone deacetylase inhibition and activation of antioxidant pathways[30]. While these mechanistic insights are compelling, their translation to sustained clinical benefit in diverse HF populations remains uncertain.

The observed reduction in SVR aligns with prior evidence suggesting vasodilatory effects of ketone bodies. β-OHB has been shown to relax arterial and venous smooth muscle, potentially reducing vascular tone and afterload[30]. Ketones may also enhance endothelial function by promoting angiogenesis and vascular repair mechanisms[31]. However, the degree to which these vascular effects contribute to long-term clinical outcomes such as symptom improvement or reduced hospitalization remains unclear.

LVEF, a key marker of systolic function, was modestly but significantly improved with ketone supplementation. This finding is in agreement with prior studies indicating a positive inotropic effect of 3-OHB, potentially mediated through enhanced oxidative metabolism and ATP generation within cardiomyocytes[32]. Additionally, ketone bodies may mitigate oxidative stress and inflammation - key drivers of myocardial dysfunction in HF - by reducing reactive oxygen species and activating antioxidant pathways involving forkhead box protein O3, catalase, and superoxide dismutase[7,33-36]. Nevertheless, given the short duration of interventions in the included trials, it remains unknown whether these effects translate into sustained improvements in myocardial remodeling or long-term ventricular function.

PCWP, an indicator of left ventricular filling pressures and pulmonary congestion, was reduced following ketone supplementation. This finding may reflect improved ventricular efficiency and reduced vascular resistance, which together could alleviate cardiac workload[12,36]. The observed increase in HR may represent a compensatory response associated with enhanced myocardial energetics and increased CO. However, the clinical significance of this HR increase is uncertain and warrants further investigation, particularly in patients at risk for tachyarrhythmias.

An increase in S’max was also noted, suggesting improved longitudinal systolic function. This effect may be linked to metabolic adaptations, including altered substrate utilization and improved myocardial efficiency[13]. Importantly, these findings were accompanied by substantial heterogeneity and should be considered exploratory.

Despite these promising observations, several important limitations must be acknowledged. The total sample size was small, and all included studies were conducted in a single country (Denmark), limiting external validity. The crossover design and short-term nature of the included trials further restrict inference regarding long-term efficacy and safety. Formal assessment of publication bias was not feasible due to the limited number of studies, raising concern for potential small-study effects. Subgroup analyses by HF phenotype - particularly HFpEF - were based on one study and should therefore be regarded as hypothesis-generating only. Additionally, heterogeneity in intervention protocols, dosing regimens, follow-up duration, and outcome assessment methods may have influenced pooled estimates.

CONCLUSION

In conclusion, this meta-analysis indicates that ketone body supplementation, particularly β-OHB, is associated with modest short-term improvements in selected hemodynamic measures, including CO, SVR, and LVEF, in patients with HF. However, no significant effects were observed on key structural and functional echocardiographic parameters such as GLS, LVEDV, and TAPSE, highlighting important gaps in the current evidence base. The overall findings are constrained by small sample sizes, crossover designs, short intervention durations, and substantial heterogeneity across trials. Consequently, these results should be viewed as hypothesis-generating rather than definitive. Larger, well-powered, multicenter randomized trials with standardized ketone formulations, longer follow-up, and clinically meaningful endpoints including HF hospitalization and mortality are required to clarify the therapeutic role of ketone supplementation in HF management.