Ketogenic diet and ketone salts differentially improve cardiometabolic complications in an HFpEF rat model.
Study Goal
The researchers aimed to determine whether increasing ketones through a ketogenic diet or exogenous ketone salts could help manage heart failure with preserved ejection fraction (HFpEF) in a rat model.
Results Summary
Both the ketogenic diet and ketone salts improved structural echocardiographic parameters, reduced fibrosis and hypertrophy, and enhanced metabolic profiles, though diastolic function in vivo was unaffected. Ex vivo cardiomyocyte preparations showed improved calcium handling and relaxation, with ketone salts particularly reversing stiffness and improving force development.
Population
ZSF1 obese rats with HFpEF.
Effective Dosage
Not specified for the ketogenic diet; ketone salts were added to drinking water (exact dosage not provided).
Duration
10 weeks.
Interactions
None mentioned.
| Intervention | Direction | Endpoint | Population | Dosage | Impact | Claim # |
|---|---|---|---|---|---|---|
ketogenic diet (KD) | decrease | HFpEF phenotype | ZSF1 rat model of HFpEF | - | ameliorated | #1 |
ketogenic diet (KD) | increase | structural echocardiographic parameters | ZSF1 rat model of HFpEF | - | improving | #2 |
ketogenic diet (KD) | decrease | glycaemia | ZSF1 rat model of HFpEF | - | lowering | #3 |
ketogenic diet (KD) | decrease | lipid profiles | ZSF1 rat model of HFpEF | - | lowering | #4 |
ketogenic diet (KD) | decrease | HFpEF-related fibrosis | ZSF1 rat model of HFpEF | - | reducing | #5 |
ketogenic diet (KD) | decrease | hypertrophy | ZSF1 rat model of HFpEF | - | reducing | #6 |
ketogenic diet (KD) | increase | calcium handling | ex vivo cardiomyocyte preparations | - | improved | #7 |
ketogenic diet (KD) | increase | myofilament relaxation | ex vivo cardiomyocyte preparations | - | improved | #8 |
ketogenic diet (KD) | increase | fat mass | ZSF1 rat model of HFpEF | - | increased | #9 |
ketogenic diet (KD) | decrease | myofilament Ca2+ sensitivity | ZSF1 rat model of HFpEF | - | decreased | #10 |
ketogenic diet (KD) | no change | active and passive tension | ZSF1 rat model of HFpEF | - | normalized | #11 |
ketogenic diet (KD) | decrease | cardiac structural impairments | ZSF1 Obese heart failure with preserved ejection fraction (HFpEF) phenotype | - | reversed | #12 |
ketogenic diet (KD) | decrease | left ventricular mass | ZSF1 Obese heart failure with preserved ejection fraction (HFpEF) phenotype | - | ameliorating | #13 |
ketogenic diet (KD) | decrease | fibrosis | ZSF1 Obese heart failure with preserved ejection fraction (HFpEF) phenotype | - | reduced | #14 |
ketogenic diet (KD) | decrease | hypertrophy | ZSF1 Obese heart failure with preserved ejection fraction (HFpEF) phenotype | - | reduced | #15 |
ketogenic diet (KD) | increase | cardiomyocyte contractile and relaxation performance | ZSF1 Obese heart failure with preserved ejection fraction (HFpEF) phenotype | - | improved | #16 |
ketogenic diet (KD) | increase | myofilament Ca2+ sensitivity | ZSF1 Obese heart failure with preserved ejection fraction (HFpEF) phenotype | - | improved | #17 |
ketogenic diet (KD) | increase | metabolic profile | ZSF1 Obese heart failure with preserved ejection fraction (HFpEF) phenotype | - | improved | #18 |
ketogenic diet (KD) | decrease | hyperglycaemia | ZSF1 Obese heart failure with preserved ejection fraction (HFpEF) phenotype | - | reducing | #19 |
ketogenic diet (KD) | decrease | blood triglycerides | ZSF1 Obese heart failure with preserved ejection fraction (HFpEF) phenotype | - | reducing | #20 |
ketogenic diet (KD) | decrease | levels of NT-proBNP | ZSF1 Obese heart failure with preserved ejection fraction (HFpEF) phenotype | - | reducing | #21 |
ketone salts (KS) | decrease | HFpEF phenotype | ZSF1 rat model of HFpEF | - | ameliorated | #22 |
ketone salts (KS) | increase | structural echocardiographic parameters | ZSF1 rat model of HFpEF | - | improving | #23 |
ketone salts (KS) | decrease | glycaemia | ZSF1 rat model of HFpEF | - | lowering | #24 |
ketone salts (KS) | decrease | lipid profiles | ZSF1 rat model of HFpEF | - | lowering | #25 |
ketone salts (KS) | decrease | HFpEF-related fibrosis | ZSF1 rat model of HFpEF | - | reducing | #26 |
ketone salts (KS) | decrease | hypertrophy | ZSF1 rat model of HFpEF | - | reducing | #27 |
ketone salts (KS) | increase | calcium handling | ex vivo cardiomyocyte preparations | - | improved | #28 |
ketone salts (KS) | increase | myofilament relaxation | ex vivo cardiomyocyte preparations | - | improved | #29 |
ketone salts (KS) | decrease | myofilament Ca2+ sensitivity | ZSF1 rat model of HFpEF | - | decreased | #30 |
ketone salts (KS) | no change | active and passive tension | ZSF1 rat model of HFpEF | - | normalized | #31 |
ketone salts (KS) | decrease | cardiac structural impairments | ZSF1 Obese heart failure with preserved ejection fraction (HFpEF) phenotype | - | reversed | #32 |
ketone salts (KS) | decrease | left ventricular mass | ZSF1 Obese heart failure with preserved ejection fraction (HFpEF) phenotype | - | ameliorating | #33 |
ketone salts (KS) | decrease | fibrosis | ZSF1 Obese heart failure with preserved ejection fraction (HFpEF) phenotype | - | reduced | #34 |
ketone salts (KS) | decrease | hypertrophy | ZSF1 Obese heart failure with preserved ejection fraction (HFpEF) phenotype | - | reduced | #35 |
ketone salts (KS) | increase | cardiomyocyte contractile and relaxation performance | ZSF1 Obese heart failure with preserved ejection fraction (HFpEF) phenotype | - | reversed | #36 |
ketone salts (KS) | decrease | HFpEF-related cardiomyocyte stiffness | ZSF1 Obese heart failure with preserved ejection fraction (HFpEF) phenotype | - | reversed | #37 |
ketone salts (KS) | no change | development of maximum force | ZSF1 Obese heart failure with preserved ejection fraction (HFpEF) phenotype | - | prevented a reduction in | #38 |
ketone salts (KS) | increase | myofilament Ca2+ sensitivity | ZSF1 Obese heart failure with preserved ejection fraction (HFpEF) phenotype | - | improved | #39 |
ketone salts (KS) | increase | metabolic profile | ZSF1 Obese heart failure with preserved ejection fraction (HFpEF) phenotype | - | improved | #40 |
ketone salts (KS) | decrease | hyperglycaemia | ZSF1 Obese heart failure with preserved ejection fraction (HFpEF) phenotype | - | reducing | #41 |
ketone salts (KS) | decrease | blood triglycerides | ZSF1 Obese heart failure with preserved ejection fraction (HFpEF) phenotype | - | reducing | #42 |
ketone salts (KS) | decrease | levels of NT-proBNP | ZSF1 Obese heart failure with preserved ejection fraction (HFpEF) phenotype | - | reducing | #43 |
Heart failure with preserved ejection fraction (HFpEF) remains a major health concern with limited therapeutic options. Growing evidence supports the multiple benefits of ketones in heart disease, but their impact on HFpEF remains unknown. We investigated whether increasing ketones can help to manage HFpEF. Using the ZSF1 rat model of HFpEF, 16-week-old rats were randomly assigned to one of three subgroups: (i) control diet; (ii) ketogenic diet (KD); or (iii) control diet with added exogenous ketone salts (KS) in their drinking water for 10 weeks. We found that both KD and KS ameliorated the HFpEF phenotype by improving structural echocardiographic parameters, lowering glycaemia and lipid profiles, and reducing HFpEF-related fibrosis and hypertrophy without impacting in vivo diastolic function. Nevertheless, ex vivo cardiomyocyte preparations showed improved calcium handling and myofilament relaxation, suggesting benefits at the cellular level. Interestingly, KD still proved effective, despite the potentially adverse increase in fat mass. There was decreased myofilament Ca2+ sensitivity and normalized active and passive tension in both groups, especially KS. These results suggest that providing ketone through the diet or supplements could be a valuable strategy to complement HFpEF treatment. Given the well-known challenges of implementing dietary changes, exogenous KS offer a more practical and effective option to achieve these benefits. KEY POINTS: Ketogenic diet and ketone salts effectively reversed the cardiac structural impairments associated with the ZSF1 Obese heart failure with preserved ejection fraction (HFpEF) phenotype by ameliorating left ventricular mass. Both treatments reduced fibrosis and hypertrophy, leading to improved or, in the case of ketone salts, even reversed cardiomyocyte contractile and relaxation performance. Ketone salts also reversed HFpEF-related cardiomyocyte stiffness and prevented a reduction in the development of maximum force. Both treatments improved myofilament Ca2+ sensitivity. Both treatments also improved the metabolic profile, reducing hyperglycaemia, blood triglycerides and levels of NT-proBNP, a well-known biomarker of worsening heart failure.