127: Ketones and Your Heart - How Ketones Protect the Cardiovascular System | Dr. Ben Bikman

Ketones don't just give you energy, they actually help your heart work easier. Your heart is an energy machine, and when it's under stress, ketones become one of the preferred fuels. And here's the surprising part. When ketones rise, your heart can pump more blood with less effort. That's because ketones help relax your blood vessels, lowering the pressure your heart has to push against what we call afterload. And they also turn down inflammation. In fact, BHB specifically shuts off a major inflammatory pathway tied to heart failure. And ketones activate protective genes that help your heart handle oxidative stress, giving it a kind of cellular shield. So yes, ketones provide energy, but they also widen blood vessels, reduce inflammation, protect your heart cells and help a struggling heart do its job better. This is lecture 127 of the Metabolic Classroom. Looking to improve your own metabolic health? Visit insuliniq.com for courses, coaching, consultations and a 10 day free community membership trial. To dive deep into the science behind metabolic health, become an insider@Benbickman.com where you'll enjoy my exclusive content ad free podcasts, live stream Q and A access and and more. Welcome to the Metabolic Classroom. I'm Professor Benjamin Bickman, a biomedical scientist and professor of cell biology. Today we're examining how ketones, specifically beta hydroxybutyrate or what I will just call bhb, interact with the cardiovascular system. This topic is particularly relevant given the growing interest in not only ketogenic diets, but also the fact that heart disease continues to be the number one killer. Also, the rise and adoration, for lack of a better term, for some of these medications that are generally considered anti diabetic but are increasingly used for heart health, namely SGLT2 inhibitors. What I want to show you today is that ketones are far more than just a fuel for the heart. They're metabolically active molecules that reduce cardiac workload, relax blood vessels, dampen inflammation and modulate gene expression in ways that promote cardiovascular resilience. We'll start with the fundamental energetics, how the heart uses ketones as fuel and what this means for oxygen efficiency. Then we'll move into hemodynamic effects, specifically how the heart uses ketones in a beneficial way to lower afterload, or how the blood vessels use ketones to reduce this load, or the resistance, and then how that then helps the heart pump out its blood, a phenomenon called cardiac output, the amount of blood coming out of the heart with every pump. From there we'll examine the direct vascular effects, the anti inflammatory signaling pathways and finally, the practical implications for heart health. I should note that while ketogenic diets and ketone supplementation are sometimes framed through ideological lenses, whether someone's pro carbohydrate or prolo carbohydrate, my intention in the lecture today is really just purely on the biochemistry and physiology. We're examining what actually happens when ketones interact with the cardiovascular system. Let me start with a fundamental point. Your heart is a metabolic powerhouse. It has high demands for ATP, the main molecule of cellular work, and it makes a lot. It produces roughly 6kg of ATP every single day. That means it's. It produces more mass of ATP than the heart weighs itself its own mass. This enormous demand is met almost entirely through oxidative phosphorylation. So that is to say, the mitochondria using up fats and glucose for fuel. Now, under normal conditions, fatty acids are in fact the predominant fuel. Somewhere between about 40 to 70% of the amount of ATP the heart makes, followed by glucose, which is about 20 to 30%. And then all the rest of it is met with lactate and ketones, mostly because those are just at such lower levels. But here's where it gets interesting. Ketones are not the backup fuel you may think they are. They are an adaptive fuel that the heart will use as they are available, especially when the heart is under stress, as we'll get to. And the benefits go well beyond just the heart itself. All right, to get things started, let's start with the bioenergetics of it all. And we'll do so by starting with a hypothesis when it comes to the heart, called the thrifty fuel hypothesis. This is the idea that ketones are more oxygen efficient than, say, fats are. And remember, that matters, because fats are in fact the primary fuel for the heart. And there is some truth to this idea. There is support for this hypothesis when we look at the P O ratio, the PO ratio, that is the amount of ATP produced per oxygen atom consumed, ketones come in at approximately 2.5 compared to 2.33 for fatty acids. That is a meaningful advantage when oxygen delivery may be compromised, as it is in heart failure. So, if every unit of oxygen is precious, if you can produce more ATP for every unit of oxygen, then you have an advantage. Ketones do that. Furthermore, when we calculate ATP yield per gram of substrate, or how much ATP can you get with any given amount of ketone? In this case, 100 grams of BHB generates about 10,500 grams of ATP, whereas 100 grams of glucose yields significantly less, about 8, 500 grams of ATP. So, on a weight for weight basis, BHB is remarkably energy dense. It not only requires less oxygen, but over that same demand, it actually is able to produce more ATP. That's a pretty good exchange. What all of this suggests is that ketones serve the failing heart by providing an additional source of ATP. When the capacity to utilize fatty acids and glucose is impaired, and the failing heart is indeed energy impaired, it is starving. But the benefit goes beyond just oxygen efficiency. And in fact, it touches at the very heart of the bioenergetics of the of the heart itself. And so that brings us to what happens in heart failure. The pioneering work of Daniel Kelly and his group demonstrated something remarkable. The failing heart upregulates its capacity to oxidize ketones using a technique called quantitative mitochondrial proteomics. In a preclinical animal model, they induced heart failure through a method called pressure overload hypertrophy. So this is just an experimental model of heart failure. They found increased expression of beta hydroxybutyrate dehydrogenase 1, BDH1. That matters because that is the rate limiting enzyme for ketone oxidation in the heart. And what's remarkable is that human studies confirmed this. When researchers measured metabolites in failing human hearts, they found elevated levels of a marker of increased ketone oxidation. The heart is essentially reprogramming its fuel preference, shifting toward ketone utilization as its ability to rely on other fuels like fats, diminishes. And work at the University of Alberta, specifically Gary Lopachuk's lab, showed that this shift is not detrimental. In a very recent paper, using another model of heart failure, they demonstrated that increasing ketone supply to the failing heart increases the reliance on ketones and improved heart contractility. Now let's turn to what I consider one of the most clinically relevant aspects, with namely the hemodynamic effect of ketones. So we're going a little outside the heart now, and this is where the research really becomes fascinating. In 2019, Nielsen and colleagues published what we could call a landmark study in the journal Circulation, examining what happens when you infuse BHB into patients with heart failure, who also with the heart failure, are manifesting with something called reduced ejection fraction. So this is the amount of blood, just another marker of how much blood the heart is ejecting whenever it is pumping. What they found was remarkable. Cardiac output, or the amount of blood that the heart is pumping out every time it beats, increased by 2 liters per minute, which was about a 40% improvement. And left ventricular ejection fraction improved by 8 percentage points. The effect was dose dependent and detectable even with physiological concentration ranges. So just a normal amount of BHB was resulting in significant improvements. But to add to this, the cardiac output was accompanied by vasodilation, so reduced systemic and pulmonary vascular resistance. But that didn't mean it didn't actually lead to an overall reduction in blood pressure systemically. But what they found was that the heart was pumping more blood, not because it had to work harder, but because the afterload, or the pressure against which the heart has to pump the blood. So when the heart is pumping and it's pushing the blood out, there's a resistance to that blood coming out. That resistance went down, so the heart was able to more easily eject its blood. A more recent study in the Journal of the American Heart association took this further by examining the specific enantiomers of bhb. So you'll know that there's two forms of bhb, D and L. And they found that the L form of bhb, which is at generally lower levels, in fact, much lower when you're just relying on your own production, but you can, of course, supplement with it. So when they increased lbhb, they found a particularly potent effect. And they found that the LBHB increased cardiac output by 2.7 liters per minute, primarily once again, through a reduced aft. So it wasn't making the heart beat harder, it was simply reducing the pressure against which the heart has to beat, making it easier for the heart to get that blood out. What this means clinically, is remarkable. Ketones make the heart's job easier. They reduce the resistance the heart pumps against, allowing it to generate more output with less strain. For a failing heart, this is exactly what you want. Improved function without increasing mechanical stress. So the heart doesn't have to work harder. You're, in fact, allowing it to work easier. Now, how do ketones reduce the afterload? This brings us to their direct effects on blood vessels. Work from the University of Aras and other labs has demonstrated that BHB acts directly on vascular smooth muscle and endothelial cells to cause vasorelaxation. So if you're looking down the length of a blood vessel, you have the endothelial cells lining the innermost part, and then the smooth muscle, which can contract or constrict or relax, is outside of that. And again, BHB affects both in preclinical studies at very physiological levels of ketones. So in the 2 to 4 millimolar range. That's higher, but very achievable just through normal long term fasting or of course, through exogenous ketones. But they found that BHB increased arterial diameter by 30, by about 32%. And of course, the bigger that gets, the lower the vascular resistance is. If it's, if it's a bigger tube than the liquid, in this case the blood, the fluid can move through it much more, more easily. The mechanism that explains that relaxation or the expansion of the arteries appears to involve both ion channels, specifically potassium, as I'll note, as well as a production of nitric oxide. Changes in potassium levels will alter the ability of the smooth muscle to relax. It actually just changes the polarization or how inclined the muscle would be to contract. And of course, the increased nitric oxide is then having in effect, albeit much more modestly, like a medication like Cialis. Some of these drugs that are taken in order to induce vasodilation, BHB has a similar effect again, albeit more modestly. In a 2023 review paper recently published in Nature Cardiovascular Research this the authors emphasize that the vascular effects extend even to the endothelial cells. So everything I just got done describing is a mechanism of whereby BHB affects the muscle surrounding the endothelial cells. But there's evidence to show that it also affects the endothelium itself in heart failure. So when the heart is suffering, there's a phenomenon called microvascular rarefication. In other words, the small blood vessels are getting increasingly rare or you're losing them naturally. That is going to impair the degree to which blood can perfuse through the heart muscle itself. Remember, heart has a very high metabolic demand. With that high demand comes a high requirement for blood flow. So the heart needs to be able to pump blood into its own muscle tissue. But with heart failure, those small little blood vessels are starting to go away. Well, ketone oxidation in endothelial cells appear to enhance endothelial cell proliferation, which can then act to prevent this blood vessel loss, thereby maintaining that microvascular network that is so important for the very busy and very hungry myocardium, or heart muscle to continue to function. Now we need to shift from thinking about ketones purely as metabolic substrates to understanding them more as signaling molecules. And this is where things get even another layer of fascinating science. BHB functions as an endogenous histone deacetylase inhibitor, particularly targeting Class 1 HDACs. HDACs. By inhibiting these enzymes, BHB can actually promote histone hyperacetylation. This has a phenomenon within the cell of opening up the chromatin structure and thereby enhancing the transcription of specific genes along chromosomes or along the DNA. And among these genes that are now able to be transcribed more readily, we get more of it. We have some that encode for antioxidant proteins like FoxO3a or metallothionine 2 or thioredoxin, a very important one. The practical implication of this is enhanced resistance to oxidative stress. The heart, with its very massive oxygen consumption is particularly vulnerable to oxidative damage by promoting antioxidant gene expression. Ketones provide a form of molecular armor or just a better defense. But it doesn't end there. Perhaps even more fascinating is the discovery that beta hydroxybutyrate can directly modify proteins through a process called lysine beta hydroxybutylation. This is once again a histone modification similar to what I just mentioned with acetylation or even methylation. If you've heard of DNA methylation. And in this case it appears that with the beta hydroxybutylation we activate transcription of genes in starvation response metabolic pathways or those that are activated with autophagy in the heart. This post translational modification may regulate gene networks involved in metabolism, stress response and just adaptation to cellular stress. But it's another layer of how ketones communicate information to cells simply, well beyond simply just being burned for energy. Now, the signaling effects do not stop even there. One of the most important signaling effects of BHB relates to inflammation. A seminal paper published 10 years ago, 2015 demonstrated that BHB specifically inhibits the NLRP3 inflammasome. Something you've probably heard me discuss. AB the NLRP3 inflammaSome is a molecular complex that when activated triggers not only proteins involved in apoptosis or cell death, but also the release of many pro inflammatory cytokines. This inflammasome is implicated in numerous cardiovascular pathologies including heart failure and atherosclerosis and cardiomyopathy. But this team in the 2015 paper found that BHB suppressed the NLRP3 inflammasome in respons response to myriad pro inflammatory stimuli. So even when you tried to induce inflammation, if BHB is up, it keeps things turned down. And this was a specific effect to bhb. Other ketones like acetoacetate or acetone did not have this effect for the heart. This is very clinically meaningful because part of heart failure with NLRP3 activation is this inflammation driven cardiac Remodeling, So the actual substance of the heart muscle itself becomes kind of broken or compromised because of the inflammation. By inhibiting this pathway, ketones now have an entirely new way of protecting the heart. Because if you can tamp down the inflammation, you increase the potential of the heart maintaining its normal structure. And a lot of what I've said actually connects back to SGLT2 inhibitors. Now again, SGLT2 inhibitors were first used for their antidiabetic effects. You're forcing the glucose out of the kidneys, which helps blood glucose levels come down. But an off target effect is the stimulation of ketone production. And indeed people who take SGLT2 inhibitors will consistently have higher levels of ketones. You are just driving or activating greater ketogenesis. Multiple studies have demonstrated that these drugs, SGLT2 inhibitors, blunt the NLRP3 inflammasome from activating, which could be through the ketone mechanism. So even these anti inflammatory effects of the SGLT2 inhibitors could be a result of the increased BHB. Now a topic that I've alluded to throughout this mini lecture has been the oxidative stress. Now I mentioned a moment ago that BHB upregulates antioxidant gene expression like genes like Foxo3a which then encode proteins that help neutralize oxidative stress molecules. But second, ketone oxidation itself appears to produce fewer reactive oxygen species than when other fuels are metabolized. For example, the most common fuel, fatty acids. When fatty acids undergo beta oxidation, they can generate significantly more oxidative stress byproducts than ketones are. So when ketones are being used for fuel, as I alluded to earlier, they're producing more ATP with less oxidative stress produced. But third, studies have shown that BHB can directly upregulate thioredoxin 1, a key antioxidant protein in heart muscle cells. So this provides another level of protection. Now I'd mentioned this one and let's revisit the idea of cardiac remodeling. This is the process by which the heart changes its size, shape and function in response to injury or hemodynamic stress like chronic hypertension. But it is a hallmark of heart failure progression. While ketones appear to beneficially modulate this process. One study model here is something called the canine pacing model of heart failure. And I mentioned earlier a study that shook found that chronic BHB infusion completely prevented rises in left ventricular and diastolic pressure and it preserved heart rate. And this was a study I alluded to, although I didn't give this level of detail, but it also reduced the pacing, induced diminution of cardiac output in ejection fraction. All of this to say simply that every measured marker of heart failure was improved with bhb. And it also the BHP helped the left ventricle, which is the main ventricle of the heart that does all the work. When you think of the heart pumping blood out, it helped prevent this. Not only it restored the ability to dilate or expand, but it also prevented the heart muscle from getting too thick. That's something called cardiac hypertrophy. So one of the versions of heart failure is when the heart muscle is getting thicker and thicker and making the chamber get smaller and smaller where it can't hold as much blood. BHB prevented all of this. In heart failure with compromised ejection fraction, BHB just kept everything working totally normally. Again, a pretty remarkable finding. Now, with all of these mechanisms and energetics in mind, how can we translate some of this into practice? I think there are are several approaches worth investigating. So firstly, ketogenic diets. Studies have shown that ketogenic diets can reverse some of the compromised enzymes involved in energy, like succinate dehydrogenase activity in cardiomyocytes. However, the effects are nuanced and prolonged. Ketogenic diets may have other off target effects that someone doesn't want. Like for example, increased uric acid. Although again, if the problem with uric acid is inflammation, BHB reduces that inflammation. A paper my lab published. But with exogenous ketones we have another opportunity where if someone is interested in bumping up ketones without perhaps the rigor of a ketogenic diet, then you have a very viable way of doing that. In heavy or hearty defense of exogenous ketones. One of the most powerful studies I mentioned was one that used lbhb. If you're interested in lbhb, you've really got to focus on exogenous ketones. Your own production of LBHB is very modest. The human body does not make a lot. Now that does not mean it's irrelevant because as one of the studies I alluded to showing profound improvements in cardiac output, only saw that that was happening with lbhb. To wrap up, let me synthesize what we've covered. Ketones, most especially bhb, serve the heart in multifaceted ways that extend far beyond simple fuel provision. As an alternative fuel, I wouldn't say backup. They provide ATP when fatty acid and glucose oxidation are impaired in the failing heart with better oxygen efficiency, so producing more ATP per unit oxygen consumed. Beyond that, as hemodynamic modulators, they reduce afterload through direct vasodilation, making the heart's job easier and increasing cardiac output without increasing the strain of the heart. As anti inflammatory agents, they specifically inhibit the inflammasome, reducing inflammation that can drive adverse cardiac remodeling, not to mention atherosclerosis. As antioxidant promoters, they upregulate myriad antioxidant genes, which just helps control or reduce oxidative stress. And then there are further effects as you have BHB acting as a signaling molecule and even helping reduce the loss of the small blood vessels that feed through the myocardium. So when it comes to the heart, in my view, the evidence is unambiguous. Ketones are cardiovascular allies that extend far beyond their role as just a fuel, which is how they're so commonly viewed. They represent what we might call a metabolic signal of fasting, a signal that paradoxically can improve cardiovascular resilience. The fact that the failing heart actively upregulates its ketone oxidation machinery tells us something important about the adaptive value of these molecules. In fact, I cannot help but be struck by how analogous that is to the failing brain, that when the brain is experiencing its decline in function, it also starts increasing its reliance on ketones as a fuel. Unfortunately, you utter the word ketone around many people, even those who should know better, and it just erodes into an ideological debate about macronutrients, which can really just obscure a lot of these findings. People's general wariness of ketones, I would say born primarily from ignorance, causes them to just be totally unaware or force them to overlook many of the benefits from these very well conducted studies that I've outlined. As an aside, if you're interested in trying exogenous ketones, I strongly recommend cleanformnutrition.com that's where I go to get mine. In fact, so much so that they've given me a discount code that I can share it. Use the code BEN10 for 10% off. Class dismissed. Until next time. More knowledge, Better Health. Looking to improve your own metabolic health? Visit insuliniq.com for courses, coaching, consultations and a 10 day free community membership trial to dive deep into the science behind metabolic health. Become an insider@Benbickman.com where you'll enjoy my exclusive content ad, free podcasts, livestream, Q and A access and more.