Cardiovascular Effects of Oral Ketone Ester Treatment in Patients With Heart Failure With Reduced Ejection Fraction: A Randomized, Controlled, Double-Blind Trial

Abstract

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.

High-resolution respirometry reveals altered mammalian tissue ketone body oxidation in different cardiometabolic diseases

“…Whether this is the result of the compromised activity of enzymes involved in the FNS pathways induced by HF or relates to a different metabolic landscape resulting in greater circulating KBs in HF, remains to be determined. Taken together, our findings lend further support to approaches of KB supplementation in humans with HF 63 .…”

“…Previous research reported alterations of KB metabolism in humans with and animal models of HF 6,8,22,62 . Although accumulating evidence indicates a therapeutic role for KBs in cardiovascular diseases, HF, and even cardiogenic shock [6][7][8][9]63 , there remains uncertainty as to whether the KBs' cardioprotective effects can be attributed to their role as mitochondrial substrates or should be ascribed to other KBs' functions, such as their role as signaling molecules 64,65 . Our data demonstrated that in the failing heart myocardial mitochondria maintain their capacity to utilize KBs for ATP generation despite a compromised ability to generate energy via other pathways, such as the degradation of fatty acids ([F]P), or that of substrates of the N ([FN]P) and S ([FNS]P) pathway.…”

The Impact of Malnutrition on COPD Outcomes: Role of Mini-Nutritional Assessment (Mna) in Predicting Acute Exacerbations in Patients with Highly Complex COPD and Its Clinical and Prognostic Implications

“…As recommended by the latest GOLD report [1], a combination of exercise, specific interventions to control respiratory and systemic inflammation, and targeted nutritional support may be used to prevent all the negative effects of the development of pulmonary cachexia. Future development may consider the use of nutritional supplements for this category of subjects, such as oral supplementation with ketone bodies, as already proposed for subjects with heart failure [35]. Over dietary intervention, exercise, especially in comorbid patients where cardiovascular, metabolic and respiratory disorders coexist, is recognized as the be er intervention strategy to reverse some of the skeletal muscle abnormalities typical of COPD patients [36,37], being the most effective nonpharmacological intervention to improve exercise capacity and dyspnea.…”

Unlocking Pathways That Improve Cardiac Function in Chronic Heart Failure: Are Ketones the Key?

“…In advanced HF, the myocardium is a ready consumer of ketones and can do so in a dose-dependent manner. 4 In this issue of Circulation, Berg-Hansen and colleagues 5 report findings from patients with stable HFrEF, New York Heart Association class 2 to 3, who were randomized to 14 days of an oral ketone ester (KE) that consisted of a ketone monoester that included (R)-βhydroxybutyrate-(R)-1,3 butanediol (25 g, Ketone Aid Inc, Falls Church, VA) or isocaloric placebo taken 4 times per day in a randomized, double-blind crossover study with a 2-week washout period. Primary outcomes were changes in resting cardiac output (Qc) and ejection fraction.…”