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Ketogenic diet and ketone salts differentially improve cardiometabolic complications in an HFpEF rat model.

The Journal of physiology
April 3, 2025
Alexandre Gonçalves et al. (18 authors)
Journal ArticleAnimal Study
Study Details

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.

Extracted Claims (43)
InterventionDirectionEndpointPopulationDosageImpactClaim #
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
Abstract

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.

Study Links
Quality Scores
SafetyNot Assessed
Efficacy85/10
Quality80/10
Citation Metrics
Total Citations1
Citations/Year1.0
Research Impact Scores
APT Score0.05
Weight Score1.39
Normalized Score0.70
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