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Longitudinal Changes in Circulating Ketone Body Levels in Patients With Acute Heart Failure: A Post Hoc Analysis of the EMPA-Response-AHF Trial

Open AccessPublished:October 13, 2022DOI:https://doi.org/10.1016/j.cardfail.2022.09.009

      Abstract

      Background

      Ketone bodies are endogenous fuels produced by the liver under conditions of metabolic or neurohormonal stress. Circulating ketone bodies are increased in patients with chronic heart failure (HF), yet little is known about the effect of acute HF on ketosis. We tested the hypothesis that ketogenesis is increased in patients with acute decompensated HF.

      Methods and results

      This was a post hoc analysis of 79 patients with acute HF included in the EMPA-RESPONSE-AHF trial, which compared sodium-dependent glucose-cotransporter protein 2 inhibitor treatment with empagliflozin for 30 days with placebo in patients with acute HF [NCT03200860]. Plasma concentrations of ketone bodies acetone, β-hydroxybutyrate, and acetoacetate were measured at baseline and 5 different timepoints. Changes in ketone bodies over time were monitored using repeated measures analysis of variance. In the total cohort, median total ketone body concentration was 251 µmol/L (interquartile range, 178–377 µmol/L) at baseline, which gradually decreased to 202 µmol/L (interquartile range, 156–240 µmol/L) at day 30 (P = .041). Acetone decreased from 60 µmol/L (interquartile range, 34–94 µmol/L) at baseline to 30 µmol/L (interquartile range, 21–42 µmol/L) ( P < .001), whereas β-hydroxybutyrate and acetoacetate remained stable over time. Higher acetone concentrations were correlated with higher N-terminal pro brain natriuretic peptide levels (r = 0.234; P = .039). Circulating ketone bodies did not differ between patients treated with empagliflozin or placebo throughout the study period. A higher acetone concentration at baseline was univariately associated with a greater risk of the composite end point, including in-hospital worsening HF, HF rehospitalizations, and all-cause mortality after 30 days. However, after adjustment for age and sex, acetone did not remain an independent predictor for the combined end point.

      Conclusions

      Circulating ketone body concentrations, and acetone in particular, were significantly higher during an episode of acute decompensated HF compared with after stabilization. Treatment with empagliflozin did not affect ketone body concentrations in patients with acute HF.

      Graphical Abstract

      Key Words

      Heart failure (HF) is the leading cause of hospitalizations in individuals ages more than 60 years, and mortality rates are very high.
      • Alla F
      • Zannad F
      • Filippatos G.
      Epidemiology of acute heart failure syndromes.
      A central mechanism underlying HF is that cardiac uptake and use of fatty acids and carbohydrates is perturbed, leading to cardiac energy depletion.
      • Murashige D
      • Jang C
      • Neinast M
      • et al.
      Comprehensive quantification of fuel use by the failing and nonfailing human heart.
      ,
      • Schulze PC
      • Biolo A
      • Gopal D
      • et al.
      Dynamics in insulin resistance and plasma levels of adipokines in patients with acute decompensated and chronic stable heart failure.
      Despite intense efforts, effective treatments to restore cardiac energy in HF remain limited.
      Ketone bodies are endogenous fuels produced by the liver under conditions of metabolic or neurohormonal stress, a process called ketogenesis. Accordingly, circulating concentrations of ketone bodies are increased in patients with chronic HF, accompanied by an increase in the cardiac oxidation of these metabolites.
      • Murashige D
      • Jang C
      • Neinast M
      • et al.
      Comprehensive quantification of fuel use by the failing and nonfailing human heart.
      ,
      • Bedi KC
      • Snyder NW
      • Brandimarto J
      • et al.
      Evidence for intramyocardial disruption of lipid metabolism and increased myocardial ketone utilization in advanced human heart failure.
      ,
      • Voros G
      • Ector J
      • Garweg C
      • et al.
      Increased cardiac uptake of ketone bodies and free fatty acids in human heart failure and hypertrophic left ventricular remodeling.
      Studies in model organisms indicate that this increase in cardiac ketone oxidation is adaptive and that increasing ketone delivery to the heart can restore cardiac energy.
      • Yurista SR
      • Matsuura TR
      • Silljé HHW
      • et al.
      Ketone ester treatment improves cardiac function and reduces pathologic remodeling in preclinical models of heart failure.
      ,
      • Horton JL
      • Davidson MT
      • Kurishima C
      • et al.
      The failing heart utilizes 3-hydroxybutyrate as a metabolic stress defense.
      Surprisingly, relatively little is known about the mechanisms of HF-induced ketosis or changes in ketone concentrations in clinical HF. Ketone bodies are synthesized by the liver from free fatty acids through a process called ketogenesis. The two main ketone bodies, β-hydroxybutyrate and acetoacetate, are easily taken up by the heart and their oxidation occurs in a concentration-dependent manner.
      • Stanley WC
      • Recchia FA
      • Lopaschuk GD.
      Myocardial substrate metabolism in the normal and failing heart.
      The third ketone body, acetone, is a breakdown product of acetoacetate and is metabolically inert.,
      • Abdul Kadir A
      • Clarke K
      • Evans RD.
      Cardiac ketone body metabolism.
      Acetone concentrations may, therefore, provide the best reflection of ketogenesis, because the levels of the other ketone bodies are also subject to changes in their metabolization rates.
      • Marcondes-Braga FG
      • Gutz IGR
      • Batista GL
      • et al.
      Exhaled acetone as a new biomarker of heart failure severity.
      ,
      • Ruzsányi V
      • Kalapos MP.
      Breath acetone as a potential marker in clinical practice.
      Although ketogenesis is primarily regulated by changes in the insulin-to-glucagon ratio, catecholamines and natriuretic peptides have also been shown to induce ketosis in an insulin-independent manner.
      • Yurista SR
      • Nguyen CT
      • Rosenzweig A
      • de Boer RA
      • Westenbrink BD.
      Ketone bodies for the failing heart: fuels that can fix the engine?.
      Furthermore, in animal models of HF,
      • Yurista SR
      • Silljé HHW
      • Oberdorf-Maass SU
      • et al.
      Sodium–glucose co-transporter 2 inhibition with empagliflozin improves cardiac function in non-diabetic rats with left ventricular dysfunction after myocardial infarction.
      ,
      • Santos-Gallego CG
      • Requena-Ibanez JA
      • San Antonio R
      • et al.
      Empagliflozin ameliorates adverse left ventricular remodeling in nondiabetic heart failure by enhancing myocardial energetics.
      and in patients at increased cardiovascular risk,
      • Al Jobori H
      • Daniele G
      • Adams J
      • et al.
      Determinants of the increase in ketone concentration during SGLT2 inhibition in NGT, IFG and T2DM patients.
      ,
      • Polidori D
      • Iijima H
      • Goda M
      • Maruyama N
      • Inagaki N
      • Crawford PA.
      Intra- and inter-subject variability for increases in serum ketone bodies in patients with type 2 diabetes treated with the sodium glucose co-transporter 2 inhibitor canagliflozin.
      it has been shown that sodium-dependent glucose-cotransporter protein 2 (SGLT2) inhibitors induce ketosis through decreases in the insulin-to-glucagon ratio. Whether these drugs also induce ketosis in patients with HF is not well-described.
      We hypothesized that ketogenesis is activated during an episode of acute decompensated HF and that circulating ketone body concentrations will, therefore, be higher during acute cardiac decompensation than after stabilization. We additionally hypothesized that SGLT2 inhibitors would further increase circulating ketone body concentrations in this setting. To test these hypotheses, we determined longitudinal changes in circulating ketone body concentrations over the course of 30 days in patients admitted for acute HF who were randomized to the SGLT2 inhibitor empagliflozin or placebo.

      Methods

      Study Design EMPA RESPONSE AHF Trial

      This study is a post hoc analysis of the EMPA-RESPONSE-AHF trial (clinical trial registration number: NCT03200860), the design of which has been described in more detail elsewhere.
      • Damman K
      • Beusekamp JC
      • Boorsma EM
      • et al.
      Randomized, double-blind, placebo-controlled, multicentre pilot study on the effects of empagliflozin on clinical outcomes in patients with acute decompensated heart failure (EMPA-RESPONSE-AHF).
      In brief, the EMPA-RESPONSE-AHF was a randomized, double-blind, placebo-controlled, multicenter pilot study in which patients with acute decompensated HF were randomized to empagliflozin or placebo treatment on top of standard of care within 24 hours after hospital admission and were treated for 30 days. The standard-of-care regimen was provided according to the applicable guidelines for treatment of acute HF. Clinical disease parameters, vital signs, demographic variables, medical history, medical therapy and laboratory assessments including N-terminal pro brain natriuretic peptide (NT-pro BNP), estimated glomerular filtration rate (eGFR), creatinine, and glucose were collected at baseline. The combined clinical end point included in-hospital worsening HF, rehospitalization for HF, and mortality after 30 and 60 days. The study was conducted according to the Declaration of Helsinki and the International Conference on Harmonization Guidelines for Good Clinical Practice, and all participants provided written informed consent (METc 2017/411).

      Study Population

      The study included patients 18 years or older, who were hospitalized with acute HF, which was defined as presentation with typical signs and symptoms of congestion, increased NT-pro BNP levels, and treatment with loop diuretics at screening.
      • Damman K
      • Beusekamp JC
      • Boorsma EM
      • et al.
      Randomized, double-blind, placebo-controlled, multicentre pilot study on the effects of empagliflozin on clinical outcomes in patients with acute decompensated heart failure (EMPA-RESPONSE-AHF).
      Patients with type 1 diabetes, with an eGFR of less than 30 mL/min/1.73 m2 or a noncardiac cause of dyspnea were excluded. A detailed overview of the inclusion and exclusion criteria can be found in the original publication.
      • Damman K
      • Beusekamp JC
      • Boorsma EM
      • et al.
      Randomized, double-blind, placebo-controlled, multicentre pilot study on the effects of empagliflozin on clinical outcomes in patients with acute decompensated heart failure (EMPA-RESPONSE-AHF).
      Patients were included and randomized to study treatment within 24 hours after initial presentation in the hospital.

      Plasma Ketone Body Measurements

      In the present study, 3 ketone bodies (acetone, β-hydroxybutyrate, and acetoacetate) were measured in nonfasting plasma samples, which were drawn at 6 timepoints during the treatment phase: at baseline, after 24 hours, after 48 hours, after 72 hours, after 96 hours, and after 30 days of treatment. Samples were collected in ethylenediamine tetra-acetic acid tubes, centrifuged and stored at –80˚ C within 2 hours of collection and thawed before analysis. Measurements were performed using 400 MHz proton (1 H) nuclear magnetic resonance spectroscopy in the use of the Vantera Clinical Analyzer (LabCorp, Morrisville, NC).
      • Garcia E
      • Shalaurova I
      • Matyus SP
      • et al.
      Ketone bodies are mildly elevated in subjects with type 2 diabetes mellitus and are inversely associated with insulin resistance as measured by the lipoprotein insulin resistance index.
      The coefficients of variation ranged from 3.8% to 9.1% for acetone, 1.3%–9.3% for β-hydroxybutyrate, and 3.1%–7.7% for acetoacetate.
      • Garcia E
      • Shalaurova I
      • Matyus SP
      • et al.
      Ketone bodies are mildly elevated in subjects with type 2 diabetes mellitus and are inversely associated with insulin resistance as measured by the lipoprotein insulin resistance index.

      Statistical Analyses

      All statistical analyses were performed using the statistical package for social science (SPSS 23 for Windows+ SPSS Inc., Chicago, IL(. Baseline characteristics were presented as means ± standard deviations or medians (interquartile range [IQR]) for continuous variables or as percentages for categorical variables. Cross-sectional differences between tertiles of ketone body concentrations were evaluated using the Kruskal–Wallis test for nonparametric continuous variables, 1-way analysis of variance (ANOVA) for parametric continuous variables or the χ2 test for categorical variables. The cohort was stratified in tertiles of baseline ketone body concentrations. Spearman's rho correlation coefficients were calculated 2 sided between ketone bodies and continuous clinical baseline parameters which were considered to be relevant based on clinical judgment. Changes in ketone body concentrations over time were determined using repeated measures ANOVA with within-patient analysis and the effect of empagliflozin on ketone body concentrations over time was determined using a repeated measures ANOVA with within- and between- patient comparisons. To explore relations between ketone body concentrations and clinical outcome, univariate and multivariate logistic regression analysis was performed using the backward likelihood ratio method. All baseline characteristics with a P of less than .01 or that were judged to be clinically relevant were included in the multivariate analysis. Impaired clinical outcome was defined as the composite of in-hospital worsening HF, rehospitalization for HF, and mortality after 30 days. Outcomes were reported as odds ratio with corresponding 95% confidence intervals. A P value of less than .05 was considered statistically significant for all analyses.

      Results

      Baseline Characteristics

      A total of 79 patients randomized in the EMPA-RESPONSE-AHF between 2017 and 2019 were included in the analysis. Baseline characteristics were stratified for tertiles of TKB in Table 1. The median age among patients was 76 years (IQR 68–83), 34% were female, and the mean body weight was 85.1 ± 21.6 kg. In the total cohort, 47% of patients presented with HF de novo, median NT-pro BNP was 5236 pg/L (IQR 3416–8371 pg/L) and the median eGFR was 48 mL/min/1.73 m2 (IQR 41–63 mL/min/1.73 m2). The median baseline TKB concentrations were 251 µmol/L (IQR 178–377 µmol/L), compounded of acetone (60 µmol/L, IQR 23–93 µmol/L), β-hydroxybutyrate (126 µmol/L, IQR 91–179 µmol/L) and acetoacetate (60 µmol/L, IQR 40–92 µmol/L).
      Table 1Baseline Characteristics Stratified by Tertiles of Total Ketone Body Concentration at Baseline
      Total Ketone Body Concentration at Baseline
      Total (N = 79)Tertile 1 (n = 27)Tertile 2 (n = 26)Tertile 3 (n = 26)P Value
      Baseline characteristics
      Female sex26 (33)10 (37)11 (42)5 (19).178
      Age (years)76 [68–83]74 [61–81]78 [72–84]79 [70–84].429
      Caucasian race77 (97)27 (100)26 (92)26 (100).124
      Body weight (kg)85.1 ± 21.682.8 ± 17.781.9 ± 24.590.6 ± 20.3.281
      Systolic BP (mm Hg)124 ± 24129 ±28126 ± 23118 ± 19.247
      Diastolic BP (mm Hg)74 ± 1575 ± 1874 ± 1573 ± 12.932
      Heart rate (bpm)78 [67–93]72 [61–86]77 [67–94]86 [73–103].050
      Resp. rate (breaths/min)20 [16–22]20 [16–23]20 [15–21]19 [16–22].421
      NYHA functional class III/IV73 (95)27 (100)21 (88)25 (96).124
      Medical history
      LVEF; if known (n = 46)36 [25–50]25 [15–43]35 [25–51]50 [30–55].042
      Heart failure de novo37 (47)11 (41)15 (58)11 (42).295
      Ischemic etiology22 (28)5 (19)8 (31)9 (36).352
      Atrial fibrillation/flutter56 (71)17 (63)15 (58)24 (92).012
      Myocardial infarction27 (34)7 (26)7 (27)13 (50).115
      Hypertension49 (62)18 (67)16 (62)15 (58).796
      Type 2 DM26 (33)11 (41)9 (35)6 (23).382
      COPD21 (27)9 (33)4 (15)8 (31).282
      CVA4 (5)1 (4)1 (4)2 (8).757
      Medical therapy
      ACEi34 (44)11 (42)10 (38)13 (50).694
      ARB15 (19)9 (35)3 (12)3 (12).051
      ARNI3 (4)0 (0)1 (4)2 (8).353
      Beta-blocker53 (68)15 (58)17 (65)21 (81).192
      MRA36 (46)14 (54)12 (46)10 (38).538
      Loop diuretic79 (100)27 (100)26 (100)26 (100)
      ICD12 (15)5 (19)3 (12)4 (15).778
      CRT11 (14)3 (11)4 (15)4 (15).873
      Laboratory values
      NT-pro BNP (pg/mL)5236 [3416–8371]4559 [2924–5630]6803[3810–11684]5666 [3863–9393].036
      eGFR (mL/min/1.73 m2)48 [41–63]52 [41–63]46 [41–62]51 [42–73].838
      Creatinine (µmol/L)108 [86–139]109 [86–136]107 [85–143]111 [85–142].986
      Glucose (mmol/L)7.7 ± 2.07.9 ± 2.07.8 ± 2.07.6 ± 1.9.825
      Ketone bodies
      TKB (µmol/L)251 [178–377]170 [152–181]252 [222–266]516 [376–691]
      Acetone (µmol/L)60 [34–94]31 [26–42]59 [39–80]114 [74–173]
      βhb (µmol/L)126 [91–179]86 [78–103]123 [103–157]229 [178–409]
      AcAc (µmol/L)60 [40–92]39 [33–54]60 [45–73]118 [91–197]
      AcAc, acetoacetate; ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; ARNI, angiotensin II receptor–neprilysin inhibitor; βhb, β-hydroxybutyrate; BP, blood pressure; COPD, chronic obstructive pulmonary disease; CRT, Cardiac resynchronization therapy; CVA, Cerebrovascular accident; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; ICD, Implantable cardioverter defibrillator; LVEF, left ventricular ejection fraction; MRA, Mineralocorticoid receptor antagonist; NT-pro BNP, N-terminal pro brain natriuretic peptide; NYHA, New York Heart Association; Resp., respiratory; TKB, total ketone bodies.
      Data are shown as number (%), mean ± standard deviation, or median [interquartile range] and for tertiles of total ketone body concentration at baseline (tertile 1: ≤196 µmol/L; tertile 2: 197–321 µmol/L; tertile 3: ≥322 µmol/L).
      Demographic characteristics, New York Heart Association functional class, and vital clinical signs at baseline were similar among groups, although patients with higher baseline TKB concentrations tended to have higher heart rates (P = .050). Patients with higher baseline TKB concentrations had a higher left ventricular ejection fraction (LVEF) (P = .042), a higher prevalence of atrium fibrillation or flutter (P = .012), and higher NT-pro BNP concentrations (P = .036). Glucose, eGFR, and medical treatment did not differ between tertiles of TKB at the time of admission.

      Longitudinal Changes in Circulating Ketone Body Concentrations

      Longitudinal changes in circulating ketone body concentrations are depicted in Fig. 1 in relative changes from baseline values. TKB concentrations at baseline were 251 µmol/L (IQR 178-377 µmol/L), which gradually decreased to 202 µmol/L (IQR 156–240 µmol/L) at day 30 (P = .041). Similarly, acetone concentration was 60 µmol/L (IQR 34–94 µmol/L) at baseline and decreased to 30 µmol/L (IQR 21–42 µmol/L) at 30 days (P < .001). No significant changes in β-hydroxybutyrate or acetoacetate were observed over the time course of the study.
      Fig 1
      Fig. 1Longitudinal changes in plasma ketone body concentrations in acute heart failure. Plasma ketone concentrations for the total cohort (N = 79), measured in µmol/L at 6 timepoints: baseline, after 24 hours, 48 hours, 72 hours, 96 hours, and 30 days. Data are displayed as median (interquartile range) relative delta change from baseline. Changes in concentration over time were measured using repeated measures analysis of variance. *P < .05; **P < .001.

      Associations Between Ketone Bodies and Clinical Parameters

      Correlations between ketone bodies and continuous clinical parameters are depicted in supplementary Tables 1A–1D. Higher NT-pro BNP concentrations were significantly correlated with higher acetone levels (r = 0.234; P = .02) (Fig. 2). No significant correlations were found between NT-pro BNP and TKB, β-hydroxybutyrate, or acetoacetate. Furthermore, higher heart rate correlated with higher TKB (r = 0.237; P = .035) and with higher β-hydroxybutyrate concentrations (r = 0.243; P = .031). Other correlations were found between LVEF and both TKB (r = 0.361; P = .014) and β-hydroxybutyrate (r = .426; P = .003) at baseline.
      Fig 2
      Fig. 2Correlations between baseline ketone body concentrations and NT-pro BNP. Higher NT-pro BNP concentrations were correlated with higher acetone concentrations (r = 0.234; P = .039). Correlations between NT-pro BNP and total ketone bodies were nonsignificant (r = 0.206; P = .070). NT-pro BNP, N-terminal pro brain natriuretic peptide.

      Effect of Empagliflozin on Ketone Body Concentrations in Acute HF

      Baseline total ketone body concentrations were similar between patients randomized to empagliflozin and placebo treatment (252 µmol/L [IQR 161–457 µmol/L] vs 249 µmol/L [IQR 196-345 µmol/L], respectively). After randomization and over the course of treatment, no significant changes between treatment groups were found in circulating TKB (P value for ANOVA between groups = 0.389) or acetone concentration (P value for ANOVA between groups = 0.381) (Fig. 3).
      Fig 3
      Fig. 3Effect of empagliflozin on ketone body concentrations in acute heart failure. Plasma concentrations of ketone bodies were measured in µmol/L at 6 timepoints: baseline, 24 hours, 48 hours, 72 hours, 96 hours and 30 days. Data are displayed as median (in interquartile range) relative delta change from baseline. Changes in concentration over time were measured using repeated measures analysis of variance. TKB, total ketone bodies.

      Association Between Ketone Bodies and Clinical Outcome at 30 Days

      In univariate logistic regression analyses, the baseline acetone concentration was associated with the incidence of the combined end point of in-hospital worsening of HF, all-cause mortality, and HF hospitalizations at 30 days after randomization (odds ratio 1.007 per µmol/L increase; 95% confidence interval 1.000–1.014, P = .043). Baseline concentrations of β-hydroxybutyrate, acetoacetate or TKB concentrations were not significantly associated with the combined end point. After adjustment for age and sex in a multivariate model, acetone did not remain an independent predictor for the combined end point.

      Discussion

      This study presents the first analysis of longitudinal changes in circulating ketone body concentrations in patients who were hospitalized for acute HF. We found that circulating TKB concentrations were significantly higher during the initial stages of acute HF as compared with the concentrations after stabilization. A longitudinal analysis of all separate ketone bodies showed that the increase in circulating ketone body concentrations was primarily driven by acetone. Moreover, higher acetone concentrations at baseline were correlated with higher NT-pro BNP values. Surprisingly, treatment with the SGLT2 inhibitor empagliflozin did not influence circulating ketone body concentrations in acute HF. Furthermore, baseline acetone concentration was univariately associated with impaired clinical outcome after 30 days.
      Enhanced knowledge on the mechanism of ketosis in HF could lead to better understanding of the mechanisms of current treatment options and could potentially lead to exploration of new therapies in the future.

      Treatment With the Ketone Body 3-hydroxybutyrate in Patients With Acute Heart Failure (KETO-AHF1). Available from: https://clinicaltrials.gov/ct2/show/NCT04442555

      Although chronic HF is associated with an increase in circulating ketone bodies compared with individuals without HF, data on the effect of acute HF on ketosis are sparse.
      • Murashige D
      • Jang C
      • Neinast M
      • et al.
      Comprehensive quantification of fuel use by the failing and nonfailing human heart.
      ,
      • Bedi KC
      • Snyder NW
      • Brandimarto J
      • et al.
      Evidence for intramyocardial disruption of lipid metabolism and increased myocardial ketone utilization in advanced human heart failure.
      In the healthy population, TKB concentrations remain at less than 100 µmol/L in the postprandial state.
      • Bedi KC
      • Snyder NW
      • Brandimarto J
      • et al.
      Evidence for intramyocardial disruption of lipid metabolism and increased myocardial ketone utilization in advanced human heart failure.
      ,
      • Owen OE
      • Felig P
      • Morgan AP
      • Wahren J
      • Cahill GF.
      Liver and kidney metabolism during prolonged starvation.
      However, absolute cut-off values for abnormal concentrations of ketone body concentrations have not been established, at least in part because ketone body concentrations are highly dependent on prandial status, diagnostic method, and assay. The limited number of studies that have measured circulating ketone body concentrations in patients with acute HF used a cross-sectional design, which does not inform on changes within an individual patient.
      • Stryeck S
      • Gastrager M
      • Degoricija V
      • et al.
      Serum concentrations of citrate, tyrosine, 2- and 3- hydroxybutyrate are associated with increased 3-month mortality in acute heart failure patients.
      ,
      • Yokokawa T
      • Sato T
      • Suzuki S
      • et al.
      Change of exhaled acetone concentration levels in patients with acute decompensated heart failure.
      The only other article reporting longitudinal changes in ketone concentrations was performed using breath analysis assays, which is a suboptimal method lacking specificity.
      • Yokokawa T
      • Sato T
      • Suzuki S
      • et al.
      Change of exhaled acetone concentration levels in patients with acute decompensated heart failure.
      Interestingly, these authors also reported increases in the concentration of the metabolically inert ketone body acetone, which also declined with the stabilization of HF.
      • Yokokawa T
      • Sato T
      • Suzuki S
      • et al.
      Change of exhaled acetone concentration levels in patients with acute decompensated heart failure.
      Our study shows that both TKB and acetone concentrations are significantly elevated during an episode of acute decompensated HF compared with the stabilized situation. Furthermore, the ketone concentrations observed at 30 days after randomization were comparable with other studies in the chronic setting.
      • Janardhan A
      • Chen J
      • Crawford PA.
      Altered systemic ketone body metabolism in advanced heart failure.
      ,
      • Lommi J
      • Kupari M
      • Koskinen P
      • et al.
      Blood ketone bodies in congestive heart failure.
      The associations between circulating acetone concentrations and NT-pro BNP are in line with other studies and support the hypothesis that ketogenesis in HF could partly be driven by an increased hemodynamic load.
      • Yurista SR
      • Nguyen CT
      • Rosenzweig A
      • de Boer RA
      • Westenbrink BD.
      Ketone bodies for the failing heart: fuels that can fix the engine?.
      ,
      • Flores-Guerrero JL
      • Daan Westenbrink B
      • Connelly MA
      • et al.
      Association of beta-hydroxybutyrate with development of heart failure: sex differences in a Dutch population cohort.
      The rate of ketogenesis is, among other things, controlled by changes in the ratio between insulin and glucagon. Decrease in this ratio, which for example occur during fasting, promote lipolysis and the subsequent release of free fatty acids that are transformed into ketone bodies by the liver.
      • Abdul Kadir A
      • Clarke K
      • Evans RD.
      Cardiac ketone body metabolism.
      ,
      • Capozzi ME
      • Coch RW
      • Koech J
      • et al.
      The limited role of glucagon for ketogenesis during fasting or in response to SGLT2 inhibition.
      Moreover, catecholamines, natriuretic peptides and proinflammatory cytokines have also been shown to stimulate ketogenesis through multiple complementary mechanisms.
      • Yurista SR
      • Nguyen CT
      • Rosenzweig A
      • de Boer RA
      • Westenbrink BD.
      Ketone bodies for the failing heart: fuels that can fix the engine?.
      To this day, the mechanisms responsible for the increased ketogenesis in HF are not completely understood. Based on our findings that circulating ketone bodies are higher during an acute cardiac decompensation than after stabilization, it could be hypothesized that an increase in neurohormones and natriuretic peptides could influence ketone body concentrations in acute HF.
      • Yurista SR
      • Nguyen CT
      • Rosenzweig A
      • de Boer RA
      • Westenbrink BD.
      Ketone bodies for the failing heart: fuels that can fix the engine?.
      In line with this finding, we found a correlation between heart rate and higher levels of TKB and β-hydroxybutyrate. The association between higher total ketone bodies at baseline and higher LVEF corresponds with the results from previous experimental and clinical studies showing that an increase in ketone body concentrations was associated with an increase in the LVEF or cardiac output.
      • Yurista SR
      • Matsuura TR
      • Silljé HHW
      • et al.
      Ketone ester treatment improves cardiac function and reduces pathologic remodeling in preclinical models of heart failure.
      ,
      • Nielsen R
      • Møller N
      • Gormsen LC
      • et al.
      Cardiovascular effects of treatment with the ketone body 3-hydroxybutyrate in chronic heart failure patients.
      This finding is supported by the fact that this association is also existing for higher β-hydroxybutyrate, which is the ketone body that can be used by the heart, but not for the metabolically inactive acetone. However, whether there is a causal relationship between these variables cannot be concluded from this study.
      Recently, SGLT2 inhibitors have emerged as novel treatment options for HF. The DAPA-HF and EMPEROR-Reduced trials showed that SGLT2 inhibition on top of standard of care led to a significant decrease in cardiovascular death or HF rehospitalizations in patients with chronic HF with reduced ejection fraction,
      • McMurray JJV
      • DeMets DL
      • Inzucchi SE
      • et al.
      The Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure (DAPA-HF) trial: baseline characteristics.
      ,
      • Packer M
      • Anker SD
      • Butler J
      • et al.
      Cardiovascular and renal outcomes with empagliflozin in heart failure.
      whereas EMPEROR-Preserved demonstrated this in patients with an LVEF of greater than 40% (HF with midrange ejection fraction and HF with preserved ejection fraction ),
      • Anker SD
      • Butler J
      • Filippatos G
      • et al.
      Empagliflozin in heart failure with a preserved ejection fraction.
      and SOLOIST and EMPULSE in diabetic and nondiabetic patients with acutely decompensated HF.
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      • et al.
      Sotagliflozin in patients with diabetes and recent worsening heart failure.
      ,
      • Voors AA
      • Fonarow GC
      • Adamo M
      • et al.
      Renal effects of empagliflozin in patients hospitalized for acute heart failure: from the EMPULSE trial.
      Despite the consistency of this beneficial effect, the mechanisms underpinning the effects of SGLT2 inhibition remain incompletely understood. In nondiabetic animals with HF, treatment with SGLT2 inhibition increased both circulating ketone body levels and myocardial expression of multiple ketogenic enzymes.
      • Yurista SR
      • Silljé HHW
      • Oberdorf-Maass SU
      • et al.
      Sodium–glucose co-transporter 2 inhibition with empagliflozin improves cardiac function in non-diabetic rats with left ventricular dysfunction after myocardial infarction.
      ,
      • Santos-Gallego CG
      • Requena-Ibanez JA
      • San Antonio R
      • et al.
      Empagliflozin ameliorates adverse left ventricular remodeling in nondiabetic heart failure by enhancing myocardial energetics.
      In stable diabetic patients, there is robust evidence that SGLT2 inhibitors induce a longstanding, persistent increase in fasting ketone body levels.
      • Polidori D
      • Iijima H
      • Goda M
      • Maruyama N
      • Inagaki N
      • Crawford PA.
      Intra- and inter-subject variability for increases in serum ketone bodies in patients with type 2 diabetes treated with the sodium glucose co-transporter 2 inhibitor canagliflozin.
      However, it seems that the ketogenic effects of SGLT2 inhibitors are less evident in patients with normal glucose tolerance,
      • Al Jobori H
      • Daniele G
      • Adams J
      • et al.
      Determinants of the increase in ketone concentration during SGLT2 inhibition in NGT, IFG and T2DM patients.
      particularly when measured in nonfasting patients.
      • Ferrannini E
      • Baldi S
      • Frascerra S
      • et al.
      Shift to fatty substrate utilization in response to sodium-glucose cotransporter 2 inhibition in subjects without diabetes and patients with type 2 diabetes.
      In the current study, treatment with empagliflozin on top of standard-of-care HF therapy did not lead to an increase in ketone body concentration in nonfasted patients. This finding is slightly contradictory to a recent study in which empagliflozin did increase fasting ketone concentrations in patients with chronic HF.
      • Pietschner R
      • Kolwelter J
      • Bosch A
      • et al.
      Effect of empagliflozin on ketone bodies in patients with stable chronic heart failure.
      Whether the lack of ketogenesis observed in our study reflects the acute setting or the fasting state is currently unknown. More research is required to determine the true contribution of ketogenesis to the effects of SGLT2 inhibition in HF. It should be stressed, however, that the analysis of ketone body concentrations in a fed state is more representative. Furthermore, it can also be concluded from our data that treatment with SGLT2 inhibitors in the setting of acute HF did not increase the risk for diabetic ketoacidosis. These data also align with other recent reports which suggest that the risk of ketoacidosis in patients with HF treated with SGLT2 inhibitors is generally low.
      • Selvaraj S
      • Fu Z
      • Jones P
      • et al.
      Metabolomic profiling of the effects of dapagliflozin in heart failure with reduced ejection fraction: DEFINE-HF.
      In this pilot study, a univariate association was found between acetone concentration and impaired clinical outcome after 30 days. This finding is in accordance with a different study in 130 patients with acute HF, which showed that acetone levels at time of hospitalization were associated with increased 3-month mortality rates.
      • Stryeck S
      • Gastrager M
      • Degoricija V
      • et al.
      Serum concentrations of citrate, tyrosine, 2- and 3- hydroxybutyrate are associated with increased 3-month mortality in acute heart failure patients.
      It should be noted that both studies were not powered to detect a difference in clinical outcomes and that these results should be interpreted with caution. Nevertheless, ketone body concentrations have also been linked to adverse outcome in other clinical scenario's. Circulating ketone body levels were markedly increased in patients presenting with ST-elevation myocardial infarction and the degree of increase in ketone body levels was associated with the severity of cardiac dysfunction.
      • de Koning MSLY
      • Westenbrink BD
      • Assa S
      • et al.
      Association of circulating ketone bodies with functional outcomes after ST-segment elevation myocardial infarction.
      Furthermore, circulating ketone body levels predicted the incidence of new onset HF in a large, prospective cohort.
      • Flores-Guerrero JL
      • Daan Westenbrink B
      • Connelly MA
      • et al.
      Association of beta-hydroxybutyrate with development of heart failure: sex differences in a Dutch population cohort.
      Together, these data conceivably indicate that ketogenesis is activated in patients with acute HF, suggesting that it may be a universal metabolic response to hemodynamic stress.

      Limitations

      The following limitations of this study should be noted. Previous elevations of ketone body concentrations after SGLT2 inhibition in both diabetic and nondiabetic patients have mostly been discovered under fasting conditions.
      • Ferrannini E
      • Baldi S
      • Frascerra S
      • et al.
      Shift to fatty substrate utilization in response to sodium-glucose cotransporter 2 inhibition in subjects without diabetes and patients with type 2 diabetes.
      Nonfasting blood sampling could potentially mask the ketolytic effect of empagliflozin treatment to some extent. The fact that our analysis was performed in a fed state may, therefore, be interpreted as a limitation of our study. However, the fed state is more representative for the general hospitalized acute HF patient and fasting regimens are not recommended during the initiation of SGLT2 inhibitors.
      • Hassanein M
      • Bashier A
      • Randeree H
      • et al.
      Use of SGLT2 inhibitors during Ramadan: an expert panel statement.
      We, therefore, consider the metabolic state of patients in this study to be a good reflection of the clinical syndrome of acute HF. Second, this cohort had a relatively small size and consisted of a mixed population of patients with HF with both preserved and reduced ejection fraction. Research on ketone body metabolism in larger and more homogenous cohorts of patients with acute HF could provide more insights into ketone body metabolism in acute HF. Nonetheless, this is the first study to provide a detailed longitudinal follow-up of all circulating ketone body levels in a population of patients with acute HF, making it unique in its kind. Previous reports in this setting employed breath analysis rather than quantitative biochemistry. Future studies are required to determine the mechanism responsible and to explore to which extent ketone bodies could serve as biomarkers for metabolic stress in acute HF.

      Conclusions

      Circulating ketone body concentrations, and acetone in particular, were significantly higher during an episode of acute decompensated HF compared with after stabilization. Empagliflozin did not affect ketone body concentrations in our study.

      Lay Summary

      Ketone bodies are endogenous metabolites that can fuel the heart and circulating ketone bodies are increased in patients with chronic heart failure (HF). Little is known about ketone body concentrations in the setting of acute HF. We performed longitudinal analysis of ketone body concentrations in the EMPA-response-AHF which randomized patients with acute HF to empagliflozin or placebo. A significant rise and fall in circulating ketone bodies was discovered in patients with acute decompensated HF. Treatment with empagliflozin did not affect ketone body concentrations in this setting. These data suggest that ketone body metabolism is activated during episodes of acute HF.
      Three brief bullet points about how our work applies to patients:
      • -
        Circulating ketone bodies are increased in patients with chronic HF, yet little is known about the effect of acute HF on ketosis.
      • -
        Circulating ketone body concentrations, and acetone in particular, were significantly higher during an episode of acute decompensated HF compared with after stabilization.
      • -
        Improved understanding of ketone body metabolism in HF could provide mechanistic insights into the pathophysiology of HF and lead to novel treatments.

      Proposed tweet

      In this first longitudinal analysis of ketone body metabolism in patients with acute HF, circulating ketone bodies were significantly higher during decompensation than after stabilization. This suggests that ketone body metabolism is activated during episodes of acute HF.

      Disclosures

      The UMCG, which employs several of the authors, received research grants and/or fees from AstraZeneca, Abbott, Boehringer Ingelheim, Cardior Pharmaceuticals Gmbh, Ionis Pharmaceuticals, Inc., Novo Nordisk, and Roche. Dr. Voorrips. has received speaker fees from Astra Zeneca. Dr. de Boer has received grants from the Netherlands Heart Foundation (DOUBLE DOSE 2020) and the European Research Council (ERC CoG 818715, SECRETE-HF) and received speaker fees from Abbott, AstraZeneca, Bayer, Novartis, and Roche. Dr. Connelly is an employee of LabCorp. Dr. van Veldhuisen received consultancy fees and/or grants from Novartis, Novo Nordisk, Vifor Pharma, Astra Zeneca, Pfizer, Pharmacosmos, Pharma Nord and Ionis. Dr. Voors has received research support and/or has been a consultant for Amgen, AstraZeneca, Bayer AG, Boehringer Ingelheim, Cytokinetics, Merck, Myokardia, Novo Nordisk, Novartis, and Roche Diagnostics. Dr. Damman received speaker fees Abbott, Boehringer Ingelheim, Astra Zeneca. BDW has received consulting fees from Boehringer Ingelheim, Novartis, Astra Zeneca and received research grants from Siemens, Bristol-Myers Squibb, Dutch Heart foundation. All other authors have nothing to disclose.

      Appendix. Supplementary materials

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      Linked Article

      • Ketone bodies in acute heart failure: fuel for thought
        Journal of Cardiac Failure
        • Preview
          Ketone bodies (KB) might increase in response to physiological situations, usually after glycogen stores have been exhausted (fasting, prolonged exercise) or due to pathological causes (cardiac dysfunction and development of congestion); in patients with acute heart failure, diuresis might reduce KB. Therefore, KB might be a marker of cardiac and hemodynamic stress in heart failure (left panel). Preliminary experimental and human studies suggest that augmentation of KB might have beneficial effects on cardiac hemodynamics and function; for instance, KB might increase heart rate (HR), left ventricular ejection fraction (LVEF), and stroke volume (SV), and atrial contraction, and cause a fall in systemic (SVR) and pulmonary (PVR) vascular resistance (right panel).
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