Ketones support the failing heart and may help repair it

I noticed that in the past few years there is quite a bit of research coming out investigating the effect of beta-hydroxybutyrate on a failing heart. It seems that a failing heart somehow increases the production of ketones which it then consumes to support its function.

As this is picking up attention in the scientific community, I also noticed a few papers trying to prove detrimental effect but these papers clearly make either an interpretation that doesn’t correspond with the situation observed or they create artificial situations in which nothing can help and then state that as a negative for ketones.

So what I want to do here is collect all heart related papers. I’ll be updating this page regularly. The idea is to show the volume and the findings so that if you see a paper appearing claiming negative properties, it has to be weighted against all the positive ones that are listed here.

As I don’t want to create bias, I’ll also list the negative ones and where possible, I’ll point out the issues in those studies if there are any.

Positive

2023

“Ketones and the cardiovascular system” https://www.nature.com/articles/s44161-023-00259-1

“β-Hydroxybutyrate Administered at Reperfusion Reduces Infarct Size and Preserves Cardiac Function by Improving Mitochondrial Function Through Autophagy” https://papers.ssrn.com/sol3/papers.cfm?abstract_id=4395350

“D-beta-hydroxybutyrate reduced the enhanced cardiac microvascular endothelial FoxO1 to play protective roles in diabetic rats and high glucose-stimulated human cardiac microvascular endothelial cells” https://www.sciencedirect.com/science/article/abs/pii/S0040816623000198

“Ketone Bodies and Cardiovascular Disease: An Alternate Fuel Source to the Rescue” https://www.mdpi.com/1422-0067/24/4/3534

“A ketogenic diet improves vascular hyperpermeability in type 2 diabetic mice by downregulating vascular pescadillo1 expression” https://onlinelibrary.wiley.com/doi/10.1111/jcmm.17744

2022

“Ketone body oxidation increases cardiac endothelial cell proliferation” https://www.embopress.org/doi/full/10.15252/emmm.202114753

“Ketone Bodies as Metabolites and Signalling Molecules at the Crossroad between Inflammation and Epigenetic Control of Cardiometabolic Disorders” https://www.mdpi.com/1422-0067/23/23/14564

“Ketogenic diet modulates cardiac metabolic dysregulation in streptozocin-induced diabetic rats” https://www.sciencedirect.com/science/article/abs/pii/S0955286322002297

“HMGCS2 silencing attenuates high glucose-induced in vitro diabetic cardiomyopathy by increasing cell viability, and inhibiting apoptosis, inflammation, and oxidative stress” https://www.tandfonline.com/doi/full/10.1080/21655979.2022.2063222

“β-Hydroxybutyrate in Cardiovascular Diseases : A Minor Metabolite of Great Expectations” https://www.frontiersin.org/articles/10.3389/fmolb.2022.823602/full

“Neonatal ketone body elevation regulates postnatal heart development by promoting cardiomyocyte mitochondrial maturation and metabolic reprogramming” https://www.nature.com/articles/s41421-022-00447-6

“Ketone Body β-Hydroxybutyrate Prevents Myocardial Oxidative Stress in Septic Cardiomyopathy” https://www.hindawi.com/journals/omcl/2022/2513837/

“Alternate-Day Ketogenic Diet Feeding Protects against Heart Failure through Preservation of Ketogenesis in the Liver” https://www.hindawi.com/journals/omcl/2022/4253651/

“Metabolic Changes Associated With Cardiomyocyte Dedifferentiation Enable Adult Mammalian Cardiac Regeneration” https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.122.061960

“Fasting confers stress resistance to skeletal muscle stem cells through non-metabolic actions of β-hydroxybutyrate: implications in cardioprotection and aging” https://cardiovascularaging.com/article/view/5012

“Low Carbohydrate Diets for Diabetic Cardiomyopathy: A Hypothesis” https://www.frontiersin.org/articles/10.3389/fnut.2022.865489/full

“Exercise Ameliorates Atherosclerosis via Up-Regulating Serum β-Hydroxybutyrate Levels” https://www.mdpi.com/1422-0067/23/7/3788/htm

2021

“Chronic exogenous ketone supplementation blunts the decline of cardiac function in the failing heart” https://onlinelibrary.wiley.com/doi/10.1002/ehf2.13634

“Ketone bodies for the failing heart: fuels that can fix the engine?” https://www.cell.com/trends/endocrinology-metabolism/fulltext/S1043-2760(21)00172-7

“Ketogenic Diets and Cardio-Metabolic Diseases” https://www.frontiersin.org/articles/10.3389/fendo.2021.753039/full

“CrossTalk proposal: Ketone bodies are an important metabolic fuel for the heart” https://physoc.onlinelibrary.wiley.com/doi/10.1113/JP281004

2020

“Effects of ketogenic diet and ketone bodies on the cardiovascular system: Concentration matters” https://www.wjgnet.com/1948-9358/full/v11/i12/584.htm

“Ketone metabolism in the failing heart” https://www.sciencedirect.com/science/article/abs/pii/S1388198120302055

“Implications of Altered Ketone Metabolism and Therapeutic Ketosis in Heart Failure” https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.119.045033

“Ketone Ester Treatment Improves Cardiac Function and Reduces Pathologic Remodeling in Preclinical Models of Heart Failure” https://www.ahajournals.org/doi/10.1161/CIRCHEARTFAILURE.120.007684

“Chronically Elevating Circulating Ketones Can Reduce Cardiac Inflammation and Blunt the Development of Heart Failure” https://www.ahajournals.org/doi/10.1161/CIRCHEARTFAILURE.119.006573

“Dietary carbohydrates restriction inhibits the development of cardiac hypertrophy and heart failure” https://academic.oup.com/cardiovascres/article/117/11/2365/5929700

“Ketogenic Diet Ameliorates Cardiac Dysfunction via Balancing Mitochondrial Dynamics and Inhibiting Apoptosis in Type 2 Diabetic Mice” http://www.aginganddisease.org/EN/10.14336/AD.2019.0510

“Ketogenic diet attenuates aging-associated myocardial remodeling and dysfunction in mice” https://www.sciencedirect.com/science/article/abs/pii/S053155652030406X

“Myocardial Ketones Metabolism in Heart Failure” https://www.onlinejcf.com/article/S1071-9164(20)30033-6/fulltext

2019

“The failing heart utilizes 3-hydroxybutyrate as a metabolic stress defense” https://insight.jci.org/articles/view/124079

“Cardiovascular Effects of Treatment With the Ketone Body 3-Hydroxybutyrate in Chronic Heart Failure Patients” https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.118.036459

2017

“Cardiac-Specific Bdh1 Overexpression Ameliorates Oxidative Stress and Cardiac Remodeling in Pressure Overload-Induced Heart Failure” https://www.ahajournals.org/doi/10.1161/CIRCHEARTFAILURE.117.004417

2016

“The Failing Heart Relies on Ketone Bodies as a Fuel” https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.115.017355

“β-Hydroxybutyrate elevation as a compensatory response against oxidative stress in cardiomyocytes” https://www.sciencedirect.com/science/article/abs/pii/S0006291X16308051

“Failing Heart and Starving Brain: Ketone Bodies to the Rescue” https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.116.022141

2014

“Cardiomyocyte-specific deficiency of ketone body metabolism promotes accelerated pathological remodeling” https://www.sciencedirect.com/science/article/pii/S2212877814001367

2007

“Low carbohydrate ketogenic diet enhances cardiac tolerance to global ischaemia” https://poj.peeters-leuven.be/content.php?url=article&id=2022282&journal_code=AC

Negative

In general, what you can see is that they sometimes severely restrict the protein content in rodents. This leads to a reduction in protein synthesis in these animals. For example, this leads to a reduced level of carnitine (CPT1 protein) because casein, the main protein source, is a poor є-N-trimethyllysine donor on which carnitine biosynthesis depends. CPT1 is required to metabolize long chain fatty acids in the liver. As a result they end up with a fatty liver and also with a slightly more increase in lipid droplet size in the heart (likely as a way to buffer against lipotoxicity). It will affect the pathological situation in the heart. This leads to results that cannot be translated to normal human conditions.

There are also papers that state negative effects of low carb. However, the distinction should be made with a low carb ketogenic diet. Because of the distinct effect that ketones have, if a low carb diet is not low enough to elicit a substantial increase in ketones then it is also not listed. This selection is primarily done by checking if the paper explicitly mentions something about ketones or not. I did not arbitrate on the level of blood BHB itself.

There are in vitro papers that perform incubation with BHB for a while. This however does not represent a normal blood flow. The likely result is that the cells will start to accumulate lipid droplets due to underutilization of the excessive acetyl-coa being generated. This goes in hand with the formation of diacylglycerol (DAG) which affects the insulin receptors of the cell, causing insulin resistance. It is also unclear if the incubation is done in serum that represents the state in which endogenous ketogenesis occurs. For example such incubation may be done including higher insulin levels than one could reasonably expect on a ketogenic diet, thus another example of an artificial and likely irrelevant situation.

One other point which I want to question is research that injures the heart and then shows adaptations noted by the KD. These adaptations may for example show enlargement of the heart or increased fibrosis. Those are generally seen as negative facts when evaluating a healthy heart. But these adaptations should be seen in light of the injured heart. For example, fibrosis may protect the heart from rupture when cardiac muscle cells are failing such as with Duchene muscle dystrophy. Without careful analysis, chronic fibrosis progression is considered detrimental. Finding more fibrosis is not necessarily detrimental when it is stable. I have not seen this analysis done in those that point out the higher fibrosis levels. Ideally they would also run longevity tests but to date these have not been done to my knowledge.

That said, there may be real cases where ketones are not desired or where the combination with other drugs creates negative effects. These are the cases that we want to identify and avoid. This can be the case especially when introducing exogenous ketones.

2022

“Ketone Body Exposure of Cardiomyocytes Impairs Insulin Sensitivity and Contractile Function through Vacuolar-Type H+-ATPase Disassembly-Rescue by Specific Amino Acid Supplementation” https://www.mdpi.com/1422-0067/23/21/12909