Heart failure triggers a shift in the utilization of metabolic substrates in the myocardium, allowing the ketone body 3-hydroxybutyrate to be a source of energy. Recently, the journal Circulation published a study hypothetizing that 14 days of ketone ester (KE) therapy in patients with heart failure with reduced ejection fraction can improve hemodynamics and exercise capacity at rest and during exercise.
Source: Heart Online
Background:
A healthy heart seamlessly transitions between various metabolic substrates to maintain energy production and contractile function. However, a characteristic of heart failure (HF) is marked metabolic remodeling and increased dependence on alternative substrates such as ketone bodies. Recent evidence suggests that the ketone body 3-hydroxybutyrate (3-OHB) plays a key role as an alternative metabolic substrate in failing hearts. In patients with HF with reduced ejection fraction (HFrEF), utilization of both cardiac enzymes and 3-OHB is increased. Conversely, inducing overexpression of genes that utilize 3-OHB in the myocardium can resist myocardial contractility dysfunction.
In fact, ketone bodies are easily absorbed by the heart muscle and oxidized proportionally according to the circulating level. Given the favorable energy properties of 3-OHB and the adaptive response of failing hearts to increased ketone utilization, increasing circulating 3-OHB with continuous dosing may confer cardiovascular benefits and improve cardiac oxidative metabolism, potentially enhancing cardiac function.
Urgent infusion of 3-OHB significantly increases cardiac output (CO) and left ventricular ejection fraction (LVEF) in patients with HF. In addition, a single dose of oral ketone ester (KE) induces favorable hemodynamic changes in HF patients with cardiogenic shock. To date, no studies have evaluated the effects of 3-OHB on hemodynamics after short-term treatment. This study speculates that if treatment with KE is continued for 14 days, the acute effects may persist during exercise stress, even at pharmacological trough levels. Therefore, this study aims to investigate the effects of a 14-day KE treatment regimen on resting hemodynamics, exercise hemodynamics and exercise capacity, clinical symptoms, and safety parameters before and after short-term administration of KE.
Research Methods:
In this randomized, double-blind crossover study, patients with non-diabetic HFrEF were treated with a 14-day KE and a 14-day isocaloric non-KE comparator, which were taken four times a day with a 14-day washout period in between. At the end of each session, participants undergo right heart catheterization, echocardiography, and blood samples at the trough of blood medication and after medication. After the second dose, participants underwent exercise hemodynamic assessment.
- Primary outcome: Resting cardiac output (CO).
- Secondary outcomes included resting and exercise pulmonary capillary wedge pressure, peak exercise CO and metabolic equivalents.
Findings:
Twenty-four patients with HFrEF (17 males; 65±9 years old; all white) were included in this study.
Compared with the isocaloric non-KE group, the KE group after taking the drug:
- Higher levels of resting CO2 at trough: 5.2±1.1 L/min vs. 5.0±1.1 L/min; difference: 0.3 L/min [95% CI: 0.1-0.5];
- 肺毛细血管楔压更低：8±3mmHg vs.11±3mmHg；差异：-2mmHg[95%CI：-4至-1]；
- These changes were amplified after taking KE.
KE treatment was associated with lower mean exercise pulmonary capillary wedge pressure (-3 mmHg [95% CI: -5 to -1]) and higher mean carbon dioxide emissions (0.5 L/min [95% CI: 0.1 to 0.8]) at all exercise intensities, with significant differences during low- to moderate-steady state exercise, but not during peak exercise.
Metabolic equivalents remained similar between the different therapies. In the exploratory analysis, patients in the KE treatment group:
- NT-proBNP（N-末端前B型脑钠肽；差异：-98ng/L[95%CI：-185至-23]）降低18%；
- 左室射血分数提高（37±5 vs.34±5%； P=0.01）；
- Decreased left atrial and left ventricular volumes
Figure 1: Hemodynamic parameters during treatment in both groups
Findings:
Compared with the isothermic non-KE group, treatment with KE for 14 days increased CO values at rest, decreased filling pressure, cardiac volume, and NT-proBNP levels. These changes persist during exercise and are achieved on the basis of optimal drug therapy. Continuous modulation of circulating ketones is a potential therapeutic principle for patients with HFrEF.
Key points to review
The study found that:
- In patients with heart failure with reduced ejection fraction, haemodynamics at rest and exercise are more desirable after 14 days of KE treatment.
- At pre-3-OHB levels, there was a marked improvement in hemodynamic parameters in some resting states, manifested by increased cardiac output and increased left ventricular ejection fraction.
- At the same time, congestion markers such as pulmonary capillary wedge pressure, left atrial and left ventricular volumes, and brain natriuretic peptide also decreased.
- After taking ketone esters at rest, the cardiovascular effects were further enhanced and persisted during incremental exercise.
Research Applications:
- The results of this study suggest that 14 days of KE treatment in patients with HFrEF can produce a favorable cardiovascular effect on the basis of optimal medical treatment for heart failure. It emphasizes that the continuous regulation of circulating ketones is a new therapeutic principle.
- These results suggest that larger, long-term trials are warranted to evaluate the clinical benefits of ketone esters in patients with HFrEF.
来源：Cardiovascular Effects of Oral Ketone Ester Treatment in Patients With Heart Failure With Reduced Ejection Fraction: A Randomized, Controlled, Double-Blind Trial. Circulation. 2024 Mar 27. doi: 10.1161/CIRCULATIONAHA.123.067971. Epub ahead of print.
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