Introduction

Main Takeaway: In heart failure with preserved ejection fraction (HFpEF), the heart’s ability to burn ketones is significantly impaired—even when ketone supply is boosted—highlighting a critical metabolic bottleneck. This impairment helps explain why ketone-focused therapies show less benefit in HFpEF than in other heart-failure types and underscores the need for multifaceted metabolic interventions.

Heart failure with preserved ejection fraction (HFpEF) represents nearly half of all heart-failure cases, yet it remains therapeutically elusive. Patients with HFpEF experience exercise intolerance, fluid overload, and poor quality of life despite a near-normal pumping capability. Emerging research, including the recent preclinical study by Sun et al. (2025), delves into the heart’s energy metabolism—specifically myocardial ketone metabolism in HFpEF—and reveals why ketone-centered strategies may fall short in this syndrome. This in-depth blog post explores how the HFpEF heart mismanages its fuels, focusing on ketone oxidation, the enzymatic machinery that enables it, and the implications for future therapies and everyday heart-healthy lifestyles.

Why Cardiac Energy Metabolism Matters

The heart is an energy-intensive organ, contracting over 100,000 times per day. To sustain this workload, it flexibly switches among multiple fuel sources:

• Glucose oxidation provides rapid ATP production but is limited by carbohydrate availability.
• Fatty acid oxidation yields abundant ATP but demands more oxygen and can generate harmful byproducts if overly relied upon.
• Ketone oxidation serves as an efficient alternative, producing more ATP per oxygen molecule consumed than fatty acids.

Under stress conditions—such as heart failure with reduced ejection fraction (HFrEF)—the heart shifts toward ketone oxidation as a compensatory mechanism. Clinical trials have demonstrated that exogenous ketone infusion temporarily boosts cardiac output in HFrEF patients, offering a promising metabolic therapy. Given these findings, researchers asked: Can ketone supplementation or SGLT2 inhibitors (which elevate blood ketones) also benefit HFpEF?

The “2-Hit” HFpEF Mouse Model: Mimicking Human Disease

To answer this, Sun et al. used a well-established “2-Hit” HFpEF model combining metabolic and hemodynamic stressors:

1. Obesity stress: Feeding 13-month-old female C57BL/6N mice a 60% high-fat diet.
2. Hypertension stress: Administering L-NAME (an endothelial nitric oxide synthase inhibitor) in drinking water.

This dual approach mirrors two key HFpEF drivers in humans: obesity and hypertension. Female mice were chosen because elderly women are disproportionately affected by HFpEF. Over six weeks, mice were randomized into four groups:

• Control: Standard chow and water.
• HFpEF: High-fat diet + L-NAME.
• HFpEF + EMPA: HFpEF protocol + empagliflozin (SGLT2 inhibitor at 10 mg/kg/day).
• HFpEF + KS: HFpEF protocol + ketone ester supplement (R-1,3-butanediol at 1 g/kg/day).

Researchers tracked body weight, glucose tolerance, blood/tissue ketone levels, cardiac function by echocardiography, and—crucially—metabolic flux in isolated working hearts perfused with radiolabeled substrates.

Baseline Metabolic and Functional Changes in HFpEF

Weight Gain and Glucose Intolerance

All HFpEF groups exhibited accelerated weight gain compared with controls, reflecting diet-induced obesity. Intraperitoneal glucose tolerance tests revealed higher blood glucose excursions in HFpEF mice, indicating systemic insulin resistance and impaired glucose metabolism.

Elevated Blood and Tissue Ketones

Fasting blood ketone levels rose across all HFpEF groups, likely due to increased hepatic ketogenesis in response to high-fat feeding and insulin resistance. Empagliflozin and ketone ester treatments did not further elevate fasting ketones significantly, though both increased cardiac tissue β-hydroxybutyrate (βOHB)—confirming augmented myocardial ketone supply.

Cardiac Dysfunction

Echocardiography showed:

• Isovolumetric relaxation time (IVRT) was prolonged—evidence of diastolic dysfunction common in HFpEF.
• Left ventricular ejection fraction (LVEF) remained near normal, as expected.
• Both EMPA and KS modestly reduced left ventricular mass, hinting at some antihypertrophic effects but without functional improvement in relaxation or contraction parameters.

These findings confirm that the “2-Hit” model successfully induces an HFpEF-like phenotype.

Deciphering Myocardial Fuel Use: The Perfusion Experiments

To evaluate substrate utilization, excised hearts were perfused with a physiological mix of:

• 5 mM glucose (labeled with [U-¹⁴C] glucose).
• 0.8 mM palmitate (labeled with [9,10 ³H] palmitate).
• 100 μU/mL insulin.
• βOHB at either 0.6 mM or 1 mM (labeled with [3 ¹⁴C] βOHB).

Ketone Oxidation Rates

• Control hearts increased ketone oxidation from ~861 to ~1,377 nmol·g⁻¹·min⁻¹ when βOHB rose from 0.6 to 1 mM—a 60% boost.
• HFpEF hearts had a blunted increase (from ~737 to ~897 nmol·g⁻¹·min⁻¹), indicating impaired adaptation to elevated ketones.
• EMPA- and KS-treated HFpEF hearts restored ketone oxidation responses to control levels under high βOHB (to ~1,181 and ~1,240 nmol·g⁻¹·min⁻¹, respectively).

Key insight: Increasing ketone supply can overcome deficient oxidation if enzymatic capacity exists, but raising supply alone does not guarantee functional improvement.

Glucose and Fatty Acid Oxidation

Consistent with prior studies, HFpEF hearts showed:

• Decreased insulin-stimulated glucose oxidation.
• Increased fatty acid oxidation—a hallmark shift from glucose utilization to fats.

Neither acute ketone elevation nor chronic EMPA/KS treatments further altered glucose or fatty acid oxidation appreciably. Glycolytic flux also remained unchanged across groups, suggesting that ketone interventions specifically influenced ketone flux without broader metabolic rewiring.

The Cardiac Energy Budget: ATP Production Analysis

Using known ATP yields—31 ATP per glucose, 104 ATP per palmitate, and 21.25 ATP per βOHB—researchers calculated both absolute and relative ATP contributions.

In control hearts under high ketones:

• Ketone oxidation accounted for 31% of ATP.
• Fatty acids contributed 55%.
• Glucose provided 17%.

In HFpEF hearts:

• Fatty acid oxidation dominated at 70% of ATP.
• Glucose oxidation plummeted to 2%.
• Ketones comprised 13% (low βOHB) to 17% (high βOHB).

Despite the metabolic shift, total ATP production rates were maintained in HFpEF hearts due to compensatory fatty acid oxidation. However, overreliance on fatty acids may exacerbate oxidative stress and diastolic dysfunction.

The Enzymatic Bottleneck: BDH1 and SCOT Downregulation

Efficient ketone oxidation requires two key enzymes:

• BDH1 (β-hydroxybutyrate dehydrogenase 1) converts βOHB to acetoacetate.
• SCOT (succinyl-CoA:3-oxoacid CoA transferase) incorporates ketone-derived carbons into the TCA cycle.

In HFpEF hearts, both BDH1 and SCOT protein levels were significantly reduced. This downregulation:

• Narrows the metabolic gateway, limiting ketone flux even when supply is ample.
• Was not reversed by EMPA or KS treatments—confirming that boosted supply does not upregulate the machinery itself.

Interestingly, HFrEF models often show BDH1 upregulation, highlighting a fundamental metabolic divergence between HFpEF and HFrEF. Whether human HFpEF hearts exhibit similar enzyme deficiencies remains an open question requiring myocardial biopsies or noninvasive tracers in clinical studies.

Why Ketone-Centric Therapies Underperform in HFpEF

1. Enzyme Deficiencies: Reduced BDH1/SCOT expression cripples ketone oxidation capacity, making supply alone insufficient.
2. Fatty-Acid Dominance: Persistent reliance on fatty acids sustains ATP production but perpetuates metabolic stress, inflammation, and diastolic dysfunction.
3. Model Limitations: The “2-Hit” murine model captures obesity-hypertension phenotypes but not all HFpEF subtypes (e.g., aging, inflammation, atrial fibrillation).
4. Species Differences: Murine metabolic rates and substrate preferences differ from humans. Clinical trials of empagliflozin in HFpEF showed benefits—likely via diuresis, improved endothelial function, and anti-inflammatory effects, rather than direct ketone supply augmentation.

Clinical Implications and Future Directions

While this study urges caution in deploying ketone supplements or SGLT2 inhibitors solely for metabolic rescue in HFpEF, it also illuminates therapeutic avenues:

• Enzyme-Targeted Therapies: Strategies to upregulate BDH1 and SCOT—through gene therapy, epigenetic modifiers, or small molecules—could unlock ketone metabolism.
• Combinatorial Metabolic Modulation: Addressing multiple pathways simultaneously (glucose, fatty acids, ketones) may rebalance energy flux more holistically.
• Phenotype-Specific Trials: Recognizing HFpEF as a heterogeneous syndrome, future studies should stratify patients by dominant pathophysiology—obesity, hypertension, aging, or inflammation—to tailor metabolic interventions.
• Noninvasive Metabolic Imaging: Advanced PET tracers capable of quantifying myocardial ketone and fatty-acid uptake in humans will clarify if enzyme downregulation observed in mice translates to patients.

Practical Takeaways for Heart-Healthy Living

For individuals seeking to optimize cardiac metabolism:

• Maintain metabolic flexibility: Incorporate both aerobic exercise (walking, cycling) and resistance training to enhance the heart’s capacity to switch among fuels.
• Balanced nutrition over fads: A diet rich in whole grains, lean proteins, healthy fats (olive oil, nuts), and limited simple sugars supports normal glucose and fatty-acid metabolism.
• Discuss SGLT2 inhibitors with your physician: If you have type 2 diabetes or HFpEF, empagliflozin may confer benefits beyond glycemic control, including reduced hospitalization.
• Be cautious with ketone supplements: While exogenous ketones can raise blood levels, their long-term safety and efficacy in HFpEF remain unproven. Always consult healthcare providers before starting supplements.
• Monitor risk factors: Control blood pressure, weight, and blood sugar to minimize HFpEF progression.

Keyword-Rich Summary for SEO

This comprehensive exploration of HFpEF and ketone metabolism underscores the complexity of myocardial ketone oxidation in heart failure. Key terms include HFpEF, exogenous ketone therapy, SGLT2 inhibitor empagliflozin, ketone ester supplement, βOHB, BDH1, SCOT, fatty acid oxidation, glucose oxidation, cardiac energy metabolism, and metabolic flexibility.

Understanding how the HFpEF heart mismanages its fuels sets the stage for developing targeted therapies. While ketone supplementation strategies may be less effective in HFpEF due to impaired ketone oxidation, multifaceted metabolic approaches and enzyme-targeted treatments hold promise. Continued research in both preclinical models and clinical trials will be crucial to translate these metabolic insights into improved treatments for HFpEF patients.