Ketones like 3-betahydroxybutyrate (BHB) are best known as an alternative fuel source, supplying energy to the brain and muscles during fasting, ketogenic diets, or supplementation. But ketones are more than fuel. They also function as signaling molecules that can influence vascular health, inflammation, and even gene expression. A groundbreaking study recently published in the Journal of the American Heart Association sheds new light on how different forms of BHB can uniquely impact the cardiovascular system, opening new possibilities for therapeutic applications and supplement design.
In chemistry, molecules sometimes exist as “mirror images” of one another, known as enantiomers. In the case of BHB, there are two: the D-form, which is the biologically familiar energy carrier, and the L-form, which has long been considered less important. The new study challenged this assumption by investigating how each enantiomer affects heart function and blood vessels. Researchers used a randomized crossover design in pigs, infusing either pure D-BHB, pure L-BHB, or a racemic mixture containing both forms, and then compared the results with control infusions. Using advanced tools such as pressure-volume catheterization, PET imaging, and mitochondrial assays, they measured cardiac output, vascular tone, and metabolic processing of each enantiomer.
The findings were striking. Both the racemic mixture and L-BHB infusion significantly increased cardiac output by nearly three liters per minute, while D-BHB alone produced only a modest and statistically non-significant effect. This enhancement in cardiac performance was not due to increased contractility or higher blood volume, but rather to a reduction in afterload—the resistance the heart must pump against. In other words, ketones, and particularly the L-form, helped the heart work more efficiently by easing the pressure in the arteries.
Interestingly, both enantiomers were equally effective at relaxing coronary arteries in isolated tissue experiments, but their behavior in the body was quite different. D-BHB was rapidly taken up and metabolized by the heart, disappearing quickly from circulation. L-BHB, in contrast, lingered longer in the bloodstream, leading to higher and more sustained circulating levels. This slower clearance appears to be the reason why L-BHB produced more pronounced cardiovascular effects despite not being used as a direct energy source to the same extent as D-BHB. PET imaging confirmed this, showing that D-BHB had greater cardiac tissue uptake, whereas L-BHB remained primarily in the circulation.
The implications are profound. For decades, research and supplement development have focused on D-BHB, the “classic” energy ketone. This new evidence suggests that L-BHB may be an underappreciated partner, particularly when it comes to cardiovascular health. Its ability to enhance cardiac output through afterload reduction points to potential therapeutic applications in conditions such as heart failure, where the heart struggles to pump efficiently against vascular resistance. It also raises exciting possibilities: could formulations enriched in L-BHB offer unique cardiovascular benefits that traditional ketone products containing only D-BHB do not?
Of course, this research was conducted in pigs, whose cardiovascular physiology closely resembles that of humans, but is not identical. Clinical trials in people will be needed to confirm whether L-BHB exerts similar effects in patients with heart disease or in healthy individuals using ketone supplements for performance or wellness. Still, the study adds to a growing body of evidence that ketones are far more than simple metabolic fuel. Their structure, form, and kinetics all matter in determining how they influence the body.
For athletes, biohackers, and health-conscious individuals, these findings reinforce an important principle: ketones are a diverse class of molecules with multiple mechanisms of action. The specific forms and ratios of ketones consumed may shape outcomes in ways we are only beginning to appreciate. At Audacious Nutrition, we follow these developments closely, as they highlight the importance of science-driven innovation in creating next-generation metabolic products. To provide the most health benefits, all Audacious Nutrition products contain both enantiomers, D-BHB and L-BHB. By tailoring ketone formulations to harness the unique benefits of different enantiomers, our mission is to design supplements that not only fuel the body, but also support cardiovascular resilience and long-term health.
This study is a reminder that nutrition science is constantly evolving. Ketones are not a one-size-fits-all solution. Their stereochemistry—the precise three-dimensional orientation of their molecules—can dramatically influence their biological effects. In the years ahead, as research continues to uncover these nuances, with the proper ketone supplementation we could move beyond general energy support into targeted applications for heart health, athletic performance, and longevity.
SUMMARY:
Introduction: Ketone Bodies Beyond Metabolism
Ketones like 3‑betahydroxybutyrate (BHB)—popular in low‑carb and ketogenic wellness circles—aren’t just fuel for the brain and muscles. Emerging science reveals they may also influence heart function. A striking study by Gopalasingam et al. sets out to understand how the two mirror-image forms of BHB—D‑BHB and L‑BHB—affect cardiac dynamics differently.
Study Design: Pig Hearts Under the Microscope
In a rigorous randomized crossover study involving three groups of eight pigs, researchers tested infusions of:
- A racemic mix (D/L‑BHB),
- Pure L‑BHB, or
-
Pure D‑BHB,
followed by comparisons with a control infusion.
They measured:
- Cardiac output (CO) using pressure‑volume catheterization,
- Myocardial metabolism via PET scanning with radiolabeled ketones,
- Coronary artery tone ex vivo using myography, and
- Mitochondrial function via high-resolution respiratory assays.
Key Findings: A Tale of Two Enantiomers
1. Boosted Cardiac Output—But Which Enantiomer Wins?
Infusions of the racemic mix and L‑BHB both significantly raised CO by ~2.7 L/min (p < 0.003). In contrast, D‑BHB alone produced only a non-significant uptick (p = 0.2).
2. Circulating Levels Correlate With Heart Output
CO closely tracked circulating BHB levels for both enantiomers (p < 0.001), suggesting that L‑BHB’s stronger hemodynamic impact likely stems from its higher and more sustained blood levels—due to slower metabolism compared to D‑BHB.
3. Afterload Not Preload: The Mechanism Behind the Magic
Rather than ramping up heart muscle contractility or increasing volume load, the increase in CO was mediated by reducing arterial elastance—i.e., lowering afterload. Preload and contractility remained unchanged.
4. Equal Coronary Dilation—Metabolic Impact Dissent
Both enantiomers equally relaxed coronary arteries in ex vivo assays. Yet, when it came to mitochondrial function—measured in myocardial biopsies—no sustained differences emerged between the ketone treatments and control.
5. Divergent Myocardial Uptake & Processing
PET imaging revealed major differences:
- D‑[11C]BHB showed rapid uptake and metabolism in cardiac tissue.
- L‑[11C]BHB had slower pharmacokinetics and lower tissue retention (volume of distribution ~1.46 vs 3.77 for D‑form).
In essence: D-BHB is rapidly consumed, while L-BHB stays longer in circulation, producing more pronounced cardiovascular effects despite lower myocardial uptake.
Why It Matters: Ketone Navigation for the Heart
This study debunks the assumption that only D-BHB is biologically active. Instead, L-BHB emerges as a potent agent, boosting cardiac output through sustained circulation and afterload reduction—even without directly fueling heart cell mitochondria.
For Athletes, Biohackers:
- L-BHB might offer unique cardiovascular benefits beyond standard ketone supplements, which are typically D-BHB. All Audacious Nutrition supplements contain both D and L form!
- Heart failure and cardiovascular therapeutics could potentially leverage this enantiomer-specific action for safer, more targeted interventions.
Considerations
- Human implications: These findings are based on porcine models, and translation to human physiology requires further studies.
- Mechanistic fluency needed: Why L-BHB circulates longer, and how ketones reduce afterload without shifting metabolism, remain open questions.
- Therapeutic formulation: supplements containing L-Form (such as all Audacious Nutrition products) could redefine how ketones serve as both fuel and cardiovascular modulators.
Conclusion: Rethinking Ketones in Cardiometabolic Health
Gopalasingam et al. illuminate a groundbreaking insight: Different forms of the same ketone act differently in the heart. L-BHB, though slower to metabolize, may be the more powerful modulator of cardiac output, primarily by easing vascular resistance. This invites a paradigm shift: not only D-BHB is biologically active, but L-BHB is too and L-BHB is more potent to improve cardiac function.
Listen to a short, podcast style discussion explaining this study: CLICK HERE
A couple interesting notes and studies:
........."heart homogenate contained an enriched amount of L-3HB (37.67 microM/mg protein) generated a significant ratio of 66/34 (D/L)"
Stereoselective effects of 3-hydroxybutyrate on glucose utilization of rat cardiomyocytes - PubMed
......."L‐3‐OHB infusion causes a greater increase in cardiac output (CO) of 2.7 L/min, whereas D‐3‐OHB infusion was only minor rise in CO of 0.6 L/min. This difference was explained by higher circulating 3‐OHB levels during L‐3‐OHB due to its slower metabolization at whole body level".
........."we observed similar vasorelaxant effects of the 2 enantiomers on isolated coronary arteries under closely controlled D‐ and L‐3‐OHB concentrations. Our findings challenge the concept that D‐3‐OHB is the only enantiomer with cardiovascular effects."
Enantiomer-Specific Cardiovascular Effects of the Ketone Body 3-Hydroxybutyrate - PubMed
.........."Clinical studies have shown that D/L‐3‐OHB infusion increases CO by 33% in healthy participants"