Cardiovascular Effects of Oral Ketone Ester Treatment in Patients With Heart Failure With Reduced Ejection Fraction : A Randomized, Controlled, Double-Blind Trial
BACKGROUND: Heart failure triggers a shift in myocardial metabolic substrate utilization, favoring the ketone body 3-hydroxybutyrate as energy source. We hypothesized that 14-day treatment with ketone ester (KE) would improve resting and exercise hemodynamics and exercise capacity in patients with heart failure with reduced ejection fraction.
METHODS: In a randomized, double-blind cross-over study, nondiabetic patients with heart failure with reduced ejection fraction received 14-day KE and 14-day isocaloric non-KE comparator regimens of 4 daily doses separated by a 14-day washout period. After each treatment period, participants underwent right-sided heart catheterization, echocardiography, and blood sampling at plasma trough levels and after dosing. Participants underwent an exercise hemodynamic assessment after a second dosing. The primary end point was resting cardiac output (CO). Secondary end points included resting and exercise pulmonary capillary wedge pressure and peak exercise CO and metabolic equivalents.
RESULTS: We included 24 patients with heart failure with reduced ejection fraction (17 men; 65±9 years of age; all White). Resting CO at trough levels was higher after KE compared with isocaloric comparator (5.2±1.1 L/min versus 5.0±1.1 L/min; difference, 0.3 L/min [95% CI, 0.1-0.5), and pulmonary capillary wedge pressure was lower (8±3 mm Hg versus 11±3 mm Hg; difference, -2 mm Hg [95% CI, -4 to -1]). These changes were amplified after KE dosing. Across all exercise intensities, KE treatment was associated with lower mean exercise pulmonary capillary wedge pressure (-3 mm Hg [95% CI, -5 to -1] ) and higher mean CO (0.5 L/min [95% CI, 0.1-0.8]), significantly different at low to moderate steady-state exercise but not at peak. Metabolic equivalents remained similar between treatments. In exploratory analyses, KE treatment was associated with 18% lower NT-proBNP (N-terminal pro-B-type natriuretic peptide; difference, -98 ng/L [95% CI, -185 to -23]), higher left ventricular ejection fraction (37±5 versus 34±5%; P=0.01), and lower left atrial and ventricular volumes.
CONCLUSIONS: KE treatment for 14 days was associated with higher CO at rest and lower filling pressures, cardiac volumes, and NT-proBNP levels compared with isocaloric comparator. These changes persisted during exercise and were achieved on top of optimal medical therapy. Sustained modulation of circulating ketone bodies is a potential treatment principle in patients with heart failure with reduced ejection fraction.
REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05161650.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - year:2024 |
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| Enthalten in: |
Circulation - (2024) vom: 27. März |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Berg-Hansen, Kristoffer [VerfasserIn] |
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| Links: |
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| Themen: |
Cardiac output |
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| Anmerkungen: |
Date Revised 27.03.2024 published: Print-Electronic ClinicalTrials.gov: NCT05161650 Citation Status Publisher |
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| doi: |
10.1161/CIRCULATIONAHA.123.067971 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM370231988 |
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| 100 | 1 | |a Berg-Hansen, Kristoffer |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Cardiovascular Effects of Oral Ketone Ester Treatment in Patients With Heart Failure With Reduced Ejection Fraction |b A Randomized, Controlled, Double-Blind Trial |
| 264 | 1 | |c 2024 | |
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| 500 | |a Date Revised 27.03.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a ClinicalTrials.gov: NCT05161650 | ||
| 500 | |a Citation Status Publisher | ||
| 520 | |a BACKGROUND: Heart failure triggers a shift in myocardial metabolic substrate utilization, favoring the ketone body 3-hydroxybutyrate as energy source. We hypothesized that 14-day treatment with ketone ester (KE) would improve resting and exercise hemodynamics and exercise capacity in patients with heart failure with reduced ejection fraction | ||
| 520 | |a METHODS: In a randomized, double-blind cross-over study, nondiabetic patients with heart failure with reduced ejection fraction received 14-day KE and 14-day isocaloric non-KE comparator regimens of 4 daily doses separated by a 14-day washout period. After each treatment period, participants underwent right-sided heart catheterization, echocardiography, and blood sampling at plasma trough levels and after dosing. Participants underwent an exercise hemodynamic assessment after a second dosing. The primary end point was resting cardiac output (CO). Secondary end points included resting and exercise pulmonary capillary wedge pressure and peak exercise CO and metabolic equivalents | ||
| 520 | |a RESULTS: We included 24 patients with heart failure with reduced ejection fraction (17 men; 65±9 years of age; all White). Resting CO at trough levels was higher after KE compared with isocaloric comparator (5.2±1.1 L/min versus 5.0±1.1 L/min; difference, 0.3 L/min [95% CI, 0.1-0.5), and pulmonary capillary wedge pressure was lower (8±3 mm Hg versus 11±3 mm Hg; difference, -2 mm Hg [95% CI, -4 to -1]). These changes were amplified after KE dosing. Across all exercise intensities, KE treatment was associated with lower mean exercise pulmonary capillary wedge pressure (-3 mm Hg [95% CI, -5 to -1] ) and higher mean CO (0.5 L/min [95% CI, 0.1-0.8]), significantly different at low to moderate steady-state exercise but not at peak. Metabolic equivalents remained similar between treatments. In exploratory analyses, KE treatment was associated with 18% lower NT-proBNP (N-terminal pro-B-type natriuretic peptide; difference, -98 ng/L [95% CI, -185 to -23]), higher left ventricular ejection fraction (37±5 versus 34±5%; P=0.01), and lower left atrial and ventricular volumes | ||
| 520 | |a CONCLUSIONS: KE treatment for 14 days was associated with higher CO at rest and lower filling pressures, cardiac volumes, and NT-proBNP levels compared with isocaloric comparator. These changes persisted during exercise and were achieved on top of optimal medical therapy. Sustained modulation of circulating ketone bodies is a potential treatment principle in patients with heart failure with reduced ejection fraction | ||
| 520 | |a REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05161650 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a cardiac output | |
| 650 | 4 | |a esters | |
| 650 | 4 | |a exercise | |
| 650 | 4 | |a heart failure | |
| 650 | 4 | |a hemodynamics | |
| 650 | 4 | |a hydroxybutyrate dehydrogenase | |
| 650 | 4 | |a metabolism | |
| 700 | 1 | |a Gopalasingam, Nigopan |e verfasserin |4 aut | |
| 700 | 1 | |a Christensen, Kristian Hylleberg |e verfasserin |4 aut | |
| 700 | 1 | |a Ladefoged, Bertil |e verfasserin |4 aut | |
| 700 | 1 | |a Andersen, Mads Jønsson |e verfasserin |4 aut | |
| 700 | 1 | |a Poulsen, Steen Hvitfeldt |e verfasserin |4 aut | |
| 700 | 1 | |a Borlaug, Barry A |e verfasserin |4 aut | |
| 700 | 1 | |a Nielsen, Roni |e verfasserin |4 aut | |
| 700 | 1 | |a Møller, Niels |e verfasserin |4 aut | |
| 700 | 1 | |a Wiggers, Henrik |e verfasserin |4 aut | |
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