Ketone-Based Therapies in Adults Heart Failure: A Systematic Review and Quantitative Analysis

This systematic review and meta-analysis of eight randomized controlled trials demonstrates that exogenous ketone-based therapies significantly improve key hemodynamic markers of cardiac function, including increased left ventricular ejection fraction, cardiac output, and stroke volume, alongside reduced pulmonary capillary wedge pressure, in adults with heart failure or related cardiometabolic risk factors.

The Gist

Imagine your heart as a hardworking engine in a car that's been running for too long. Over time, this engine (the heart) starts to struggle. It gets tired, burns fuel inefficiently, and can't pump enough gas (blood) to keep the car moving smoothly. This condition is called Heart Failure.

Doctors have standard tools to fix this engine—medications that help it run better. But sometimes, even with the best tools, the engine still sputters, and the driver (the patient) still feels tired and short of breath.

This new study asks a question: What if we could give the heart a different kind of fuel?

The "Special Fuel" Idea: Ketones

Normally, our hearts run on a mix of fats and sugars. But when the heart is sick, it gets confused and can't process these fuels well. Enter Ketones. Think of ketones as a "premium, high-octane fuel" that the failing heart can actually use more easily. It's like swapping out old, clogged spark plugs for a brand-new, high-performance set.

The researchers wanted to know: If we give this special fuel to people with heart failure, does the engine run better?

How They Tested It

The authors didn't just guess; they acted like detectives. They gathered 8 different scientific studies (like collecting 8 different test drives) involving hundreds of patients. In these tests, some people got the "special fuel" (ketones) and others got a "fake fuel" (placebo), and the researchers measured how the engines performed.

What They Found: The Engine Revs Up!

The results were surprisingly positive. When the heart got the ketone fuel, here's what happened:

1. The Pump Got Stronger: The heart's main pumping power (called Ejection Fraction) went up. Imagine a water pump that was only pushing 40% of its water out suddenly pushing 44%. It's a small number, but for a struggling heart, that's a big deal.
2. More Blood Flow: The amount of blood the heart pushed out every minute (Cardiac Output) increased significantly. It's like the engine suddenly found enough power to drive up a steep hill it couldn't climb before.
3. Less Backlog: The pressure in the lungs (Pulmonary Capillary Wedge Pressure) went down. Think of this like unclogging a drain. When the heart pumps better, water doesn't back up into the lungs, so the patient can breathe easier.
4. The Heartbeat Sped Up: Interestingly, the heart rate went up a little bit. This is a bit like a runner who suddenly starts running faster because they have more energy. While a faster heart rate can sometimes be bad, in this short-term test, it seemed to be part of the heart working harder to do its job.

The One Thing That Didn't Change: The blood pressure stayed the same. This is actually good news! Many heart drugs that make the heart pump harder also squeeze the blood vessels, raising blood pressure. Ketones seemed to boost the engine without squeezing the pipes.

The Catch: It's a Short-Term Boost

Here is the most important part to understand: These tests were very short.

Most of the studies only looked at what happened minutes or days after giving the ketones. It's like testing a new battery in a flashlight for 10 minutes. The light is bright! But we don't know yet if that battery will last for a whole week, or if it will eventually overheat.

• The Good News: The heart can use this fuel and get stronger immediately.
• The Unknown: We don't know if taking ketones every day for a year will keep the heart healthy, or if it will cause other problems. We also don't know yet if this actually saves lives or keeps people out of the hospital.

The Bottom Line

Think of this study as a promising test drive. The car (the heart) ran smoother, faster, and more efficiently with the new fuel (ketones) than with the old one.

However, before we tell everyone to fill up their tanks with ketones, we need to drive the car for a much longer distance to make sure it doesn't break down later. The researchers are now calling for bigger, longer studies to see if this "special fuel" can truly become a standard part of heart failure treatment.

In short: Ketones look like a very exciting new tool for heart failure, but we need more time to see if it's a permanent solution or just a temporary boost.

Technical Summary

1. Problem Statement

Heart failure (HF) remains a leading cause of global morbidity and mortality, with prevalence rising significantly despite the availability of guideline-directed medical therapy (GDMT). A substantial proportion of patients remain symptomatic or at high risk of hospitalization due to limitations in current treatments, including cost, adherence issues, and specific contraindications.

There is growing interest in exogenous ketone bodies (ketone esters, salts, or infusions) as an adjunctive therapy. Theoretically, ketones offer a dual mechanism of action for the failing heart:

• Metabolic: Serving as an alternative, efficient fuel substrate for cardiac myocytes.
• Non-metabolic: Inducing vasodilation and reducing inflammation.

However, existing clinical evidence regarding the efficacy of exogenous ketones on cardiac function and hemodynamics is fragmented, heterogeneous, and lacks a comprehensive quantitative synthesis. This review aims to fill that gap by evaluating the effects of exogenous ketone interventions on cardiac function in adults with HF or cardiometabolic risk factors.

2. Methodology

The study followed a rigorous systematic review and meta-analysis protocol registered with PROSPERO (CRD420261289091).

• Search Strategy: A comprehensive search was conducted across MEDLINE, EMBASE, CINAHL, Cochrane Library, and Scopus from inception to January 2025.
• Inclusion Criteria:
  • Study Design: Randomized Controlled Trials (RCTs), including crossover trials.
  • Intervention: Exogenous ketones (oral or infusion) vs. placebo.
  • Population: Adults (>18 years) with HF or risk factors (Type 2 Diabetes, Hypertension, CAD).
  • Exclusions: Healthy populations, ketogenic diets, specific non-ketone supplements (e.g., raspberry ketones), and studies lacking cardiac/hemodynamic outcomes.
• Data Extraction & Analysis:
  • Two independent reviewers screened studies and extracted data.
  • Primary Outcomes: Cardiac Output (CO) and Left Ventricular Ejection Fraction (LVEF).
  • Secondary Outcomes: Stroke Volume (SV), Heart Rate (HR), Pulmonary Capillary Wedge Pressure (PCWP), and Mean Arterial Pressure (MAP).
  • Statistical Approach: Random-effects meta-analysis was used to calculate Mean Differences (MD) with 95% Confidence Intervals (CI). Heterogeneity was assessed via $I^2$ statistics.
  • Quality Assessment: Risk of bias was evaluated using the Cochrane RoB 2.0 tool, and the certainty of evidence was graded using the GRADE framework.

3. Key Contributions

• First Quantitative Synthesis: This is the first meta-analysis to quantitatively pool data on the acute hemodynamic effects of exogenous ketones specifically in HF and cardiometabolic populations.
• Differentiation from Traditional Therapies: The analysis highlights a unique hemodynamic profile of ketones (increased CO without increased afterload) compared to traditional inotropes.
• Evidence Grading: The study provides a structured assessment of evidence certainty, identifying where data is robust (e.g., PCWP) versus where heterogeneity limits conclusions (e.g., LVEF, CO).
• Identification of Gaps: The review explicitly identifies the lack of long-term data and patient-important outcomes (mortality, hospitalization) in current literature, guiding future research directions.

4. Key Results

Out of 565 records, 8 studies (involving 152 patients in the primary analysis) met inclusion criteria. All were crossover RCTs with short-term follow-up (acute to 14 days).

Hemodynamic Improvements:

• Left Ventricular Ejection Fraction (LVEF): Significant increase of 3.94% (MD 3.94, 95% CI 2.18–5.70, $p=0.001$).
  • Note: High heterogeneity ($I^2 = 77\%$); Certainty of evidence: Moderate.
• Cardiac Output (CO): Significant increase of 1.11 L/min (MD 1.11, 95% CI 0.55–1.67, $p=0.002$).
  • Note: Very high heterogeneity ($I^2 = 97\%$); Certainty of evidence: Moderate.
• Stroke Volume (SV): Significant increase of 10.21 mL (MD 10.21, 95% CI 4.06–16.35, $p=0.005$).
  • Note: High heterogeneity ($I^2 = 94\%$); Certainty of evidence: Moderate.
• Heart Rate (HR): Significant increase of 4.85 bpm (MD 4.85, 95% CI 2.24–7.46, $p=0.003$).
  • Note: High heterogeneity ($I^2 = 87\%$); Certainty of evidence: Moderate.
• Pulmonary Capillary Wedge Pressure (PCWP): Significant decrease of 0.93 mmHg (MD -0.93, 95% CI -1.44 to -0.43, $p=0.003$).
  • Note: Low heterogeneity ($I^2 = 0\%$); Certainty of evidence: High.
• Mean Arterial Pressure (MAP): No significant change (MD -1.37 mmHg, $p=0.18$).

Risk of Bias:
Most studies showed low risk of bias or "some concerns." Specific concerns were noted regarding allocation concealment and blinding of outcome assessors in a few studies (e.g., Nielsen 2019, Gulbrandsen 2023, Solis-Herrera 2025).

5. Significance and Clinical Implications

• Mechanistic Insight: The findings suggest that exogenous ketones improve cardiac performance by increasing contractility (higher CO and SV) and reducing preload (lower PCWP) without increasing systemic vascular resistance (unchanged MAP). This distinguishes them from traditional inotropes, which often increase myocardial oxygen demand and afterload.
• Clinical Relevance: While the improvements in LVEF (4%) and SV (10 mL) approach thresholds often considered clinically meaningful in other contexts, the short duration of current trials prevents definitive conclusions on long-term patient outcomes (mortality, hospitalization).
• Future Directions: The authors emphasize the need for larger, longer-duration trials (e.g., ongoing studies in Denmark and the US) to assess:
  • Durability of the hemodynamic effects.
  • Safety profiles in acute vs. chronic settings.
  • Impact on patient-reported outcomes and quality of life.
  • Efficacy in specific phenotypes like HF with preserved ejection fraction (HFpEF).

Conclusion: Exogenous ketone-based therapies demonstrate favorable short-term hemodynamic effects in adults with heart failure, characterized by improved cardiac output and reduced filling pressures. However, due to the short follow-up periods and lack of hard clinical endpoints in current literature, these therapies remain investigational and require further validation before routine clinical adoption.