The keto cure? Exploring ketogenic diet in heart failure with preserved ejection fraction

The ketogenic diet (KD), introduced in 1921 by Dr. Russell Wilder to mimic fasting and treat epilepsy, gained early interest for its anti‐convulsant effects through ketosis. Though it declined with the rise of anti‐epileptic drugs, KD saw a revival in the 1990s due to interest in treating drug‐resistant epilepsy. Recently, KD has expanded beyond epilepsy treatment to include potential applications in metabolic, oncologic and cardiovascular conditions. The KD induces a profound metabolic shift from glucose dependence to fat metabolism, resulting in the hepatic production of ketone bodies. Ketone bodies (Table 1), primarily β‐hydroxybutyrate (BHB) and acetoacetate (AcAc), are not only alternative energy substrates but also act as powerful metabolic regulators that influence numerous cellular signalling pathways. These ketone bodies are produced in the liver during periods of low‐carbohydrate availability (e.g. fasting or adherence to a KD) and have far‐reaching effects on cellular homeostasis, mitochondrial efficiency, inflammation, oxidative stress and gene expression. One of the most significant pathways influenced by ketone bodies is the inhibition of class I histone deacetylases (HDACs), particularly by BHB. HDACs normally suppress gene expression by modifying chromatin structure; thus, their inhibition by BHB leads to increased expression of genes involved in oxidative stress resistance, including forkhead box O3 (FOXO3A) and manganese superoxide dismutase (MnSOD). This epigenetic modulation enhances antioxidant defence and promotes cellular resilience against metabolic stress. This HDAC inhibition is also implicated in cardio protection, as it helps maintain mitochondrial integrity and reduces cardiomyocyte apoptosis. Ketone bodies also play a crucial role in regulating inflammation through suppression of the NOD‐, LRR‐ and pyrin domain‐containing protein 3 (NLRP3) inflammasome, a key component in innate immune activation. BHB inhibits NLRP3 activation via reduced potassium (K⁺) efflux and by blocking apoptosis‐associated speck‐like protein (ASC) oligomerization, thereby decreasing interleukin (IL)‐1β and IL‐18 secretion. This anti‐inflammatory action is particularly relevant in cardiometabolic diseases, where low‐grade chronic inflammation contributes to endothelial dysfunction and myocardial fibrosis (Murakami & Tognini, 2022).

Table 1.

Ketone bodies and their physiological roles in cardiometabolic health and heart failure with preserved ejection fraction (HFpEF)

Attribute	β‐Hydroxybutyrate (BHB)	Acetoacetate (AcAc)	Acetone
Biochemical structure	4‐Carbon hydroxyacid (C₄H₇O₃⁻)	4‐Carbon ketoacid (C₄H₅O₃⁻)	Volatile, 3‐carbon molecule (C₃H₆O)
Primary role	Main circulating and most bioactive ketone body	Precursor to BHB and acetone	Byproduct of AcAc; minor ketone body
Mechanisms of action	‐Oxidized for ATP production ‐Inhibits HDACs ‐Suppresses NLRP3 inflammasome ‐Activates GPR109A ‐Epigenetic β‐hydroxybutyrylation	‐Oxidized for energy ‐Interconverts with BHB ‐Supports redox balance	‐Spontaneously generated from AcAc ‐Excreted via breath and urine
Cardiometabolic effects	‐Enhances mitochondrial efficiency ‐Reduces inflammation and ROS ‐Improves insulin sensitivity ‐Promotes cardiac stress resilience	‐Provides ATP under stress ‐Supports systemic ketone levels ‐May help buffer redox state	‐Minimal metabolic effect ‐Useful as a non‐invasive biomarker of ketosis (e.g. breath testing)
Implications in HFpEF	‐Improves cardiac output and stroke volume ‐Decreases ventricular stiffness and filling pressure ‐Supports failing myocardial energetics	‐Supplementary cardiac fuel in HFpEF ‐Helps restore energetic balance during metabolic stress	‐No direct therapeutic role ‐May be used to monitor depth of ketosis in HFpEF patients

Abbreviations: HDACs, histone deacetylases; ROS, reactive oxygen species.

Another important signalling pathway influenced by ketone bodies is the activation of peroxisome proliferator‐activated receptors (PPARs), especially PPARα. This nuclear receptor is involved in lipid metabolism, mitochondrial fatty acid oxidation and anti‐inflammatory responses. When activated by fatty acids and ketone derivatives, PPARα enhances transcription of genes encoding enzymes critical for β‐oxidation, thereby improving cardiac energy efficiency, particularly under metabolic stress as seen in heart failure with preserved ejection fraction (HFpEF). This activation also suppresses pro‐inflammatory gene expression, contributing further to cardioprotection. In mitochondrial regulation, ketone bodies improve bioenergetics by increasing NAD⁺/NADH ratios, which enhances oxidative phosphorylation (OXPHOS) and reduces the production of reactive oxygen species (ROS). This metabolic optimization also influences the activity of sirtuins, especially SIRT1 and SIRT3, which are NAD⁺‐dependent deacetylases involved in mitochondrial function, longevity and resistance to oxidative stress. Activation of these sirtuins further promotes fatty acid oxidation and mitochondrial biogenesis, which are crucial for maintaining myocardial energy demands under pressure‐overload conditions typical of HFpEF. Ketone bodies also interact with G‐protein–coupled receptors (GPCRs), such as GPR109A (also known as HCAR2), which is activated by BHB. Activation of this receptor has anti‐lipolytic and anti‐inflammatory effects, including the suppression of nuclear factor kappa B (NF‐κB) signalling and the reduction of pro‐inflammatory cytokine release in macrophages. These actions may reduce systemic inflammation and atherosclerotic progression, which are often comorbid with HFpEF. Additionally, the mammalian target of rapamycin (mTOR) signalling pathway is inhibited under ketogenic conditions due to reduced insulin and glucose levels. Inhibition of mTOR promotes autophagy, a process critical for removing damaged organelles and proteins, thereby supporting cellular health and metabolic flexibility. This process is particularly important in cardiac tissue, where impaired autophagy is linked to HF and metabolic syndrome (Murakami & Tognini, 2022).

In this comprehensive experimental study using lean and obese male ZSF1 rats, Dr. Gonçalves and colleagues remarkably demonstrated that a KD led to weight gain on obese rats (used as a model of HFpEF), primarily due to increased perirenal fat. These rats also had elevated blood glucose levels, which were normalized by KD. Consistently they showed greater glucose intolerance, which was modestly improved by KD. However, KD did not correct the marked insulin resistance observed in obese rats. Similarly, elevated serum triglycerides and total cholesterol levels in obese rats were reduced by KD. KD also increased circulating BHB levels in both lean and obese rats. Gene expression analysis revealed higher GLUT1 levels in obese rats, whereas GLUT4 expression was comparable between groups; KD did not alter the expression of either transporter. Echocardiography showed that obese rats had increased left ventricular (LV) mass and elevated E/e′, with other cardiac parameters remaining unchanged. KD significantly reduced LV mass to levels comparable with lean animals. Histological analysis showed increased cardiomyocyte area and fibrosis in obese rats, both of which were attenuated by KD. Further investigation of cardiomyocyte calcium (Ca²⁺) handling revealed that obese phenotype impaired Ca²⁺ dynamics – evidenced by delayed Ca²⁺ peak, prolonged relaxation and reduced contraction amplitude and sarcomere shortening. KD partially or fully reversed these abnormalities by enhancing Ca²⁺ amplitude and peak, as well as improving contraction performance. Finally, plasma biomarker analysis showed that KD reduced NT‐proBNP levels in obese rats. Overall, this study highlights the potential of a KD as a therapeutic strategy for HFpEF. In a rat model of HFpEF, KD was shown to improve multiple aspects of metabolic health, including reduction of blood glucose, serum triglycerides and cholesterol and modest improvement in glucose tolerance. Importantly, KD also attenuated cardiac remodelling by reducing LV mass, cardiomyocyte hypertrophy and myocardial fibrosis. At the cellular level, KD enhanced cardiomyocyte excitation–contraction coupling by improving Ca²⁺ handling and contractile performance, which are typically impaired in HFpEF. Additionally, KD reduced circulating levels of NT‐proBNP, a biomarker of cardiac stress (Gonçalves et al., 2026).

Indeed, recent preliminary studies have increasingly highlighted the benefits of KD and ketone metabolism in HFpEF. In a mouse model, elevated ketone supply enhanced cardiac ATP production by increasing both ketone and glucose oxidation, without impairing fatty acid metabolism – promoting more efficient energy use (Sun et al., 2024). Animal models have also shown that the absence of ketone production worsens cardiac hypertrophy and mitochondrial dysfunction, underscoring ketones’ role in preserving myocardial energetics (Yamada et al., 2021). Clinically, a retrospective study of 125 HF patients (66 with HFpEF) found that adherence to a low‐carbohydrate KD led to significant weight loss, improved insulin sensitivity, stable lipid profiles and a 50% reduction in HFpEF‐related hospitalizations (Moseley et al., 2024). Furthermore, a double‐blind crossover trial demonstrated that 2 weeks of oral ketone ester supplementation in HFpEF patients with type 2 diabetes significantly increased BHB levels, improved cardiac output, reduced filling pressures and enhanced ventricular compliance, both at rest and during exercise (Gopalasingam et al., 2024).

Although preclinical and early clinical studies suggest that ketone‐based metabolism may improve cardiac energetics and haemodynamics in HFpEF, translating these findings into long‐term therapies remains challenging. One of the foremost challenges is the heterogeneity of HFpEF. HFpEF is not a singular disease but rather a syndrome with multiple phenotypes, including obesity‐related, hypertensive, diabetic and inflammatory subtypes. This diversity complicates the identification of which patient populations might benefit most from KD interventions. For example, although obese or diabetic HFpEF patients may exhibit significant metabolic flexibility and responsiveness to ketone modulation, lean HFpEF patients with preserved metabolic profiles may derive limited benefit or even experience adverse effects. Adherence and sustainability of KDs also pose practical limitations. Strict carbohydrate restriction required to maintain nutritional ketosis can be difficult to maintain, particularly in elderly patients or those with comorbidities affecting appetite or gastrointestinal function. Furthermore, long‐term safety data on KD in cardiovascular populations remain limited. Although a retrospective review found that a low‐carbohydrate KD was safe and effective for weight loss and reduced hospitalization in HFpEF patients, these results were obtained in a controlled setting with clinical supervision and may not generalize to real‐world practice (Moseley et al., 2024). Mechanistically, ketones like BHB appear to support cardiac energetics and reduce inflammation, but the underlying pathways – such as post‐translational modifications like β‐hydroxybutyrylation – are still not fully understood (Wang et al., 2024). Future translational potential lies in more targeted and flexible approaches to ketosis induction. This may include the use of exogenous ketone esters or salts, which can elevate circulating ketone levels without the need for strict dietary restriction. A recent randomized trial using oral ketone esters in HFpEF patients with type 2 diabetes demonstrated improved cardiac output, reduced filling pressures, and enhanced ventricular compliance within just 2 weeks, illustrating the rapid functional benefits of controlled ketone elevation (Gopalasingam et al., 2024). Another promising direction is personalized metabolic phenotyping to identify patients who may respond best to ketone therapy. Biomarkers of mitochondrial function, ketone utilization capacity or inflammation may help stratify patients and tailor interventions more precisely. Moreover, combining KDs or ketone therapies with other established treatments such as SGLT2 inhibitors – which themselves promote mild ketosis – may yield synergistic effects, although this requires further clinical testing (Gonçalves et al., 2026). Overall, although ketone‐based therapies show promise, further research is needed to overcome clinical, mechanistic and implementation challenges.

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