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
2024
“Cardiomyocyte Ketone Metabolism Regulates Myocardial Hyperemia” https://journals.physiology.org/doi/abs/10.1152/physiol.2024.39.S1.2408
“Unraveling the Mechanism Behind the Ketogenic Diet-Mediated Reversal of Heart Failure in Mice” https://journals.physiology.org/doi/abs/10.1152/physiol.2024.39.S1.1123
“Cardioprotective Role of Beta Hydroxybutyrate in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)” https://journals.physiology.org/doi/abs/10.1152/physiol.2024.39.S1.1092
“Ketone Bodies after Cardiac Arrest: A Narrative Review and the Rationale for Use” https://www.mdpi.com/2073-4409/13/9/784
“Enantiomer‐Specific Cardiovascular Effects of the Ketone Body 3‐Hydroxybutyrate” https://www.ahajournals.org/doi/10.1161/JAHA.123.033628
“Cardiovascular Effects of Oral Ketone Ester Treatment in Patients With Heart Failure With Reduced Ejection Fraction: A Randomized, Controlled, Double-Blind Trial.” https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.123.067971
“Fasting Plasma Ketone Bodies Are Associated with NT-proBNP: A Potential Mechanism to Provide Fuel for the Failing Heart” https://www.mdpi.com/2077-0383/13/6/1541
“Ketones provide an extra source of fuel for the failing heart without impairing glucose oxidation” https://www.metabolismjournal.com/article/S0026-0495(24)00044-1/abstract
Editorial: “Fueling the Failing Heart: The Key May Be Ketones” https://www.sciencedirect.com/science/article/pii/S2452302X23004576
“Effects of ketone body 3-hydroxybutyrate on cardiac and mitochondrial function during donation after circulatory death heart transplantation” https://www.nature.com/articles/s41598-024-51387-y
2023
“Therapeutic Potential of Beta Hydroxybutyrate in Nonalcoholic Fatty Liver Disease (NAFLD)-Induced Cardiovascular Disease” https://www.ahajournals.org/doi/abs/10.1161/circ.148.suppl_1.14039
“Ketone Bodies Rescue Mitochondrial Dysfunction Via Epigenetic Remodeling” https://www.sciencedirect.com/science/article/pii/S2452302X23001201
“Stimulation of the Hydroxycarboxylic Acid Receptor 2 With the Ketone Body 3‐Hydroxybutyrate and Niacin in Patients With Chronic Heart Failure: Hemodynamic and Metabolic Effects” https://www.ahajournals.org/doi/10.1161/JAHA.123.029849
Preprint, thus not peer reviewed yet: “Ketogenic diet regulates cardiac remodeling and calcium homeostasis in diabetic cardiomyopathy” https://www.researchsquare.com/article/rs-3003525/v1
“Ketone ester supplementation suppresses cardiac inflammation and improves cardiac energetics in a swine model of acute myocardial infarction” https://www.metabolismjournal.com/article/S0026-0495(23)00212-3/fulltext
“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
“Ketone body 3-hydroxybutyrate elevates cardiac output through peripheral vasorelaxation and enhanced cardiac contractility.” https://link.springer.com/article/10.1007/s00395-023-01008-y
“Elevated blood acetoacetate levels reduce major adverse cardiac and cerebrovascular events risk in acute myocardial infarction.” https://www.degruyter.com/document/doi/10.1515/med-2023-0793/html
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.
2023
“The Ketogenic Diet Aggravates the Ischemic Response in Mouse Hearts” https://www.ahajournals.org/doi/abs/10.1161/circ.148.suppl_1.19080
The mice were put on 90% calories fat. Usually they still add a few % carbohydrates so we can be fairly certain the mice were undernourished in % protein. Evidence of this is their 2.7 and 1.9 fold increase in adipose tissue and hepatic triglyceride content. This signals lack of carnitine synthesis which impairs fatty acid metabolism. In the following study https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8914108/, reviewing cardiac metabolic substrate shows fatty acids make up around 60%~70% and during the failing heart there is an almost 3-fold increase in ketone utilization.
In order to test the hearts they isolated the hearts and controlled the substrates to a buffer consisting of 0.4mM fatty acids, 5.5mM glucose, 50uU/ml insulin, 1.2mM lactate, and 0.5mM B-OHB thus not allowing the body to self-regulated and creating an artificial static situation.
Thus, the equaled metabolic substrate between all mice while a KD has a vastly different composition from their high carb counterparts.
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
Follow this link for comments on the above study.
“CrossTalk opposing view: Ketone bodies are not an important metabolic fuel for the heart” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8408278/
“A medium-chain triglyceride containing ketogenic diet exacerbates cardiomyopathy in a CRISPR/Cas9 gene-edited rat model with Duchenne muscular dystrophy” https://www.nature.com/articles/s41598-022-15934-9
There is no motivation provided why the DMDKD at the time of weaning were first put on 8% protein for the first 10 days while the normal diet group received 13% protein. The DMDND group received 62% more protein, should we expect this to make no difference?
They did not report on BHB levels but in a previous study, this group used a similar diet and strategy where, under fasted conditions, the animals showed no difference in blood BHB levels versus the normal diet. Only post-prandial was the level slightly raised.
“The ketogenic diet blunts insulin-stimulated glucose oxidation in the failing heart” https://www.sciencedirect.com/science/article/pii/S0022282822003893
Follow this link for comments on the above study.
2021
“β-Hydroxybutyrate Exacerbates Hypoxic Injury by Inhibiting HIF-1α-Dependent Glycolysis in Cardiomyocytes-Adding Fuel to the Fire?” https://link.springer.com/article/10.1007/s10557-021-07267-y
Follow this link for comments on the above study.
“Ketogenic diets inhibit mitochondrial biogenesis and induce cardiac fibrosis” https://www.nature.com/articles/s41392-020-00411-4
Follow this link, this link and this link for comments on the above study.
“Ketogenic Diet Suppressed T-Regulatory Cells and Promoted Cardiac Fibrosis via Reducing Mitochondria-Associated Membranes and Inhibiting Mitochondrial Function” https://www.hindawi.com/journals/omcl/2021/5512322/
Follow this link for comments on the above study.
2020
“Ketogenic diet aggravates cardiac remodeling in adult spontaneously hypertensive rats” https://nutritionandmetabolism.biomedcentral.com/articles/10.1186/s12986-020-00510-7
Follow this link for comments on the above study.
2018
“Cardiac metabolic modulation upon low-carbohydrate low-protein ketogenic diet in diabetic rats studied in vivo using hyperpolarized 13 C pyruvate, butyrate and acetoacetate probes” https://dom-pubs.onlinelibrary.wiley.com/doi/10.1111/dom.13608
These rats were fed a caloric 4.7% protein containing diet. This is undernourishment of protein. In addition, this is an inbred rat model that stays lean and does not represent all features of diabetes. This article warns about the implications when using this model for assessing pre-clinical strategies to treat cardiorenal disease. The study chose this rat model to reduce confounding effects of obesity but diabetes is correlated with obesity so by taking lean animals they are confounding the results for human interpretation.
And finally, the intervention used (dobutamine), generates an effect that is unlike a diabetically stressed heart. It does not augment AMPK activity. It also has an effect on malonyl-coa which influences greatly fatty acid transport.
2006
“Chronic exposure to ketone bodies impairs glucose uptake in adult cardiomyocytes in response to insulin but not vanadate: the role of PI3-K” https://link.springer.com/article/10.1007/s11010-006-9303-7
2003
“Ketone bodies disturb fatty acid handling in isolated cardiomyocytes derived from control and diabetic rats” https://portlandpress.com/biochemj/article-abstract/371/3/753/40692/Ketone-bodies-disturb-fatty-acid-handling-in
2001
“Chronic exposure to beta-hydroxybutyrate impairs insulin action in primary cultures of adult cardiomyocytes” https://journals.physiology.org/doi/full/10.1152/ajpendo.2001.281.6.E1205
Neutral
This is work that generally just shows the correlation between heart failure and increased circulating ketones or just reports on the observation without making a statement whether this is positive or negative.
2024
“The ketogenic diet does not improve cardiac function and blunts glucose oxidation in ischemic heart failure.” https://academic.oup.com/cardiovascres/advance-article-abstract/doi/10.1093/cvr/cvae092/7660967
2023
“Quantification and Proteomic Characterization of β-hydroxybutyrylation Modification in the Hearts of AMPKα2 Knockout Mice.” https://www.mcponline.org/article/S1535-9476(23)00003-8/fulltext
2022
“Differential Effects of Beta-Hydroxybutyrate Enantiomers on Induced Pluripotent Stem Derived Cardiac Myocyte Electrophysiology” https://www.mdpi.com/2218-273X/12/10/1500
2021
“Beta-Hydroxybutyrate, Friend or Foe for Stressed Hearts” https://www.frontiersin.org/articles/10.3389/fragi.2021.681513/full
“Ketone therapy for heart failure: current evidence for clinical use” https://academic.oup.com/cardiovascres/article-abstract/118/4/977/6168424
2020
“Ketones can become the major fuel source for the heart but do not increase cardiac efficiency” https://academic.oup.com/cardiovascres/article/117/4/1178/5836832
“Myocardial ketone body utilization in patients with heart failure: The impact of oral ketone ester” https://www.metabolismjournal.com/article/S0026-0495(20)30316-4/fulltext
“Cardiac ketone body metabolism” https://www.sciencedirect.com/science/article/pii/S0925443920300843
“Association of beta-hydroxybutyrate with development of heart failure: Sex differences in a Dutch population cohort” https://onlinelibrary.wiley.com/doi/10.1111/eci.13468
“Elevated plasma β-hydroxybutyrate predicts adverse outcomes and disease progression in patients with arrhythmogenic cardiomyopathy” https://www.science.org/doi/10.1126/scitranslmed.aay8329
2019
“Increased ketone body oxidation provides additional energy for the failing heart without improving cardiac efficiency” https://academic.oup.com/cardiovascres/article/115/11/1606/5332979
“Ketone body can be a fuel substrate for failing heart” https://academic.oup.com/cardiovascres/article/115/11/1567/5466453
2018
“Increased Cardiac Uptake of Ketone Bodies and Free Fatty Acids in Human Heart Failure and Hypertrophic Left Ventricular Remodeling” https://www.ahajournals.org/doi/10.1161/CIRCHEARTFAILURE.118.004953
“Change of Exhaled Acetone Concentration Levels in Patients with Acute Decompensated Heart Failure” https://www.jstage.jst.go.jp/article/ihj/59/4/59_17-482/_article
2017
“The diabetic heart utilizes ketone bodies as an energy source” https://www.metabolismjournal.com/article/S0026-0495(17)30211-1/fulltext
“Elevated exhaled acetone concentration in stage C heart failure patients with diabetes mellitus” https://bmccardiovascdisord.biomedcentral.com/articles/10.1186/s12872-017-0713-0
2016
“Ketone bodies as fuel in heart failure” https://www.nature.com/articles/nrcardio.2016.22
“Evidence for Intramyocardial Disruption of Lipid Metabolism and Increased Myocardial Ketone Utilization in Advanced Human Heart Failure” https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.115.017545
“Ketones Step to the Plate: A Game Changer for Metabolic Remodeling in Heart Failure?” https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.116.021230
“Exhaled Acetone Concentration Is Related to Hemodynamic Severity in Patients With Non-Ischemic Chronic Heart Failure” https://www.jstage.jst.go.jp/article/circj/80/5/80_CJ-16-0011/_article
2013
“Ketone body metabolism and cardiovascular disease” https://journals.physiology.org/doi/full/10.1152/ajpheart.00646.2012
2012
“Exhaled acetone as a new biomaker of heart failure severity” https://journal.chestnet.org/article/S0012-3692(12)60460-7/fulltext
“Urinary ketone is associated with the heart failure severity” https://www.sciencedirect.com/science/article/abs/pii/S0009912012004936
2011
“Altered systemic ketone body metabolism in advanced heart failure” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3231554/
1997
“Heart failure ketosis” https://onlinelibrary.wiley.com/doi/abs/10.1046/j.1365-2796.1997.00187.x
1996
“Blood ketone bodies in congestive heart failure” https://www.sciencedirect.com/science/article/pii/0735109796002148
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