JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. -, NO.

-, 2021
ª 2021 THE AUTHORS. PUBLISHED BY ELSEVIER ON BEHALF OF THE AMERICAN

COLLEGE OF CARDIOLOGY FOUNDATION. THIS IS AN OPEN ACCESS ARTICLE UNDER

THE CC BY-NC-ND LICENSE (http://creativecommons.org/licenses/by-nc-nd/4.0/).

JACC FOCUS SEMINAR

Therapeutic Potential of Ketone Bodies

for Patients With Cardiovascular Disease
JACC Focus Seminar

Salva R. Yurista, MD, PHD,a Cher-Rin Chong, PHD,b,c Juan J. Badimon, PHD,d Daniel P. Kelly, MD,e
Rudolf A. de Boer, MD, PHD,a B. Daan Westenbrink, MD, PHDa

ABSTRACT

Metabolic perturbations underlie a variety of cardiovascular disease states; yet, metabolic interventions to prevent or
treat these disorders are sparse. Ketones carry a negative clinical stigma as they are involved in diabetic ketoacidosis.
However, evidence from both experimental and clinical research has uncovered a protective role for ketones in cardio-
vascular disease. Although ketones may provide supplemental fuel for the energy-starved heart, their cardiovascular
effects appear to extend far beyond cardiac energetics. Indeed, ketone bodies have been shown to influence a variety of
cellular processes including gene transcription, inflammation and oxidative stress, endothelial function, cardiac remod-
eling, and cardiovascular risk factors. This paper reviews the bioenergetic and pleiotropic effects of ketone bodies that
could potentially contribute to its cardiovascular benefits based on evidence from animal and human studies.
(J Am Coll Cardiol 2021;-:-–-) © 2021 The Authors. Published by Elsevier on behalf of the American College of
Cardiology Foundation. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/
licenses/by-nc-nd/4.0/).

K etone bodies are endogenous metabolites

produced by the liver, in particular under
conditions of prolonged fasting, insulin
deprivation, and extreme exercise (1). Growing evi-
have also recently been identified. More importantly,
regardless of the method used to increase ketone de-
livery to the heart, a general favorable effect has been
observed in CVD (6,7). The scope of this paper is to re-
dence suggests that ketones may be beneficial for pa- view the evidence and discuss the pleiotropic effects
tients with cardiovascular disease (CVD) (2–4). of ketone bodies beyond bioenergetics.
Interventions that enhance circulating ketone levels
result in increased myocardial ketone oxidation and KETONE METABOLISM:
improved cardiac function (2–5). In addition to the ex- KETOGENESIS AND KETOLYSIS
pected role of ketones as an efficient substrate for
(cardiac) metabolism, as they require less oxygen Systemic ketone metabolism has been reviewed in
per molecule of ATP generated, ancillary cardiopro- detail previously (1,8). In this section, we provide a
tective effects of ketone bodies beyond energetics brief overview of ketone body metabolism (Figure 1).

From the aUniversity Medical Center Groningen, University of Groningen, Department of Cardiology, Groningen, the Netherlands;
b
Basil Hetzel Institute for Translational Research, The Queen Elizabeth Hospital, Australia; cAdelaide Medical School, University of
Adelaide, Adelaide, Australia; dAtheroThrombosis Research Unit, Cardiovascular Institute, Icahn School of Medicine at Mount
Sinai, New York, New York, USA; and the eCardiovascular Institute, Department of Medicine, Perelman School of Medicine at the
University of Pennsylvania, Philadelphia, Pennsylvania, USA. Subodh Verma, MD, PhD, served as Guest Associate Editor for this
paper. Javed Butler, MD, MPH, MBA, served as Guest Editor-in-Chief for this paper.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’
institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information,
visit the Author Center.

Manuscript received December 1, 2020; accepted December 14, 2020.

ISSN 0735-1097 https://doi.org/10.1016/j.jacc.2020.12.065

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Ketones and Cardiovascular Disease -, 2021:-–-

ABBREVIATIONS Under the influence of a reduced insulin to

AND ACRONYMS HIGHLIGHTS
glucagon ratio, such as occurs with fasting,
fatty acids are mobilized and converted into
Data from experimental and human
BDH = beta-hydroxybutyrate
dehydrogenases
ketone bodies by the liver. Ketones are then studies suggest that ketone bodies exert
transferred from the liver, which cannot protective effects in patients with CVD.
CVD = cardiovascular disease
oxidize ketones by itself, to peripheral tis-
HF = heart failure
Administration of exogenous ketones
sues where they undergo terminal oxidation
KD = ketogenic diet may become an alternative to a ketogenic
donating reducing equivalents to the elec-
KE = ketone ester diet as a means of elevating ketone
tron transport chain. Ketones provide ancil-
KS = ketone salts bodies.
lary fuels for multiple organs during
MCT = medium-chain prolonged fasting, during severe carbohy-
Future studies should assess the clinical
triglycerides
drate restriction, or after periods of very impact of increasing ketone utilization in
bOHB = beta-hydroxybutyrate
intense exercise. Under these extreme con- patients with or at risk of developing
ditions, up to 300 g of ketone bodies are produced in CVD.
the liver per day, which constitutes approximately 5%
to 20% of the total energy expenditure (9). Ketogen- metabolism to increased reliance on ketone bodies as
esis includes a series of reactions that leads to the a fuel source (2,16,17).
formation of the ketone bodies acetoacetate (AcAc),
EVIDENCE FOR INCREASED KETONE OXIDATION IN
beta-hydroxybutyrate (b OHB), and acetone. Keto-
HEART FAILURE. Although metabolic perturbations
genesis primarily occurs in hepatocytes, and to a
in HF have been studied since the 1930s, it took
lesser extent in kidney epithelia, astrocytes, and
more than 80 years before the metabolic switch to-
enterocytes. The process of ketone body oxidation, or
ward increased ketone metabolism was discovered
ketolysis, can occur in almost every cell (1,9).
by 2 independent research groups in 2016 (16,17). In

CARDIAC METABOLISM IN NORMAL HEART a critical follow-up study, Horton et al. (2) provided

AND HEART DISEASE compelling evidence that the shift toward increased
ketone utilization is adaptive. Separate studies
Cardiac metabolism has been discussed in detail demonstrated that circulating ketone concentrations
elsewhere (10,11). Here, we provide a brief review of and cardiac ketone utilization are increased in a
cardiac fuel utilization in the healthy and diseased variety of clinical conditions, including heart failure
heart. with reduced ejection fraction (HFrEF) and HF with
Under normal conditions, fatty acyl-CoA, primary preserved ejection fraction (16–19). Increased
metabolites of fatty acid, is the preferred substrate in acetone levels have been detected in the breath of
the adult heart to produce ATP (w40% to 60%), and HFrEF patients, and were inversely related to car-
interestingly, the heart consumed only little glucose diac function and prognosis (20). Moreover, plasma
(12). Lactate, ketone bodies, and amino acids can also b OHB and cardiac utilization thereof are also
contribute to oxidative cardiac metabolism, but their increased in patients with diabetes and arrhythmo-
relative contribution is limited by low availability. Of genic cardiomyopathy, suggesting that the ketogenic
note, myocardial ketone oxidation is known to be shift is a universal cardiac response to stress (21,22).
proportional to its arterial concentrations, indicating In a murine model of HFrEF, ketone body oxida-
that circulating ketone levels are a major determinant tion accounts for approximately 20% of cardiac en-
of myocardial ketone body oxidation rates (13). ergy production (23). This is roughly similar to what
Cardiac diseases are associated with loss of meta- has been observed in clinical studies using coronary
bolic flexibility. Even in early stages of structural sinus sampling, where the contribution of ketone
heart diseases, substrate utilization switches from oxidation to myocardial ATP production increases
fatty acids to glucose utilization, and oxidative from 6.4% in control subjects to 16.4% in patients
metabolism is reduced (14). This metabolic reprog- with HFrEF (12). Importantly, there is a strong corre-
ramming results in a fuel preference pattern that is lation between circulating KB concentrations and
similar to the fetal state. The majority of evidence cardiac ketone oxidation in patients with or without
indicates that the reduced capacity to utilize fatty HF, indicating that circulating ketone concentrations
acids sets the stage for myocardial energy starvation, determine the contribution of ketones to the cardiac
contributing to the pathogenesis of heart failure (HF) diet (12).
(15). Intriguingly, in the context of reduced fatty acid STRATEGIES TO INDUCE KETOSIS RELEVANT TO
oxidation, the failing heart appears to reprogram HEART FAILURE. In general, a BHB level $0.5 mmol/l
JACC VOL. -, NO. -, 2021 Yurista et al. 3
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F I G U R E 1 Metabolic Pathways of Ketone Bodies in Liver and Extrahepatic Organs

Fatty acids are transported to mitochondria by carnitine palmitoyltransferase 1 (CPT1) and subsequently, ketone bodies acetoacetate (AcAc), beta-hydroxybutyrate
(bOHB) and acetone are synthesized from acetyl-CoA that is derived from b-oxidation. AcAc and bOHB are released into the circulation by monocarboxylate trans-
porters (MCTs). After internalization in extra-hepatic tissues, AcAc and bOHB are converted back to acetyl-CoA, which is subsequently metabolized in the TCA cycle to
generate ATP. Acetone is not metabolically active and is either excreted through urine or exhaled. Part of illustration elements courtesy of Servier Medical Art.
ACAT ¼ acetoacetyl-CoA thiolase; ATP ¼ adenosine triphosphate; BDH ¼ beta-hydroxybutyrate dehydrogenases; HMG-CoA ¼ hydroxymethylglutaryl-CoA;
HMGCS ¼ HMG-CoA lyase HMGCL ¼ HMG-CoA synthase; SCOT ¼ succinyl-CoA:3-ketoacid-CoA transferase; TCA cycle ¼ tricarboxylic acid cycle.

has been considered as a cut-off point for entry into Ketosis can also be achieved through ketone sup-
ketosis (24). Circulating ketone body concentrations plementation; in this review we will focus on the 4
range between 0.1 to 0.25 mmol/l in healthy subjects. principal methods (Figure 2).
Prolonged exercise or >24 h of fasting can increase The bOHB precursor 1,3-butanediol is widely
ketone levels above 1 mmol/l. Ketosis can also be available nontoxic alcohol and has been shown to
achieved by a ketogenic diet (KD) or by ingesting increase blood bOHB concentrations by 0.3 to
ketone precursors, such as 1,3-butanediol or medium- 0.8 mmol/l in healthy individuals (26,27). Side effects
chain triglyceride (MCT). Alternatively, exogenous include an unpleasant taste, nausea, and GI distress.
sources of ketones, such as ketone salts (KS) or ketone In addition, 1,3-butanediol has been reported to
esters (KE), can be ingested. The KD has become induce euphoria and dizziness, which could be
extremely popular, both within and outside of the related to alcohol intoxication (26). MCT are also
medical arena. KD consists of a very low- considered to be precursors of ketones, as MCT sup-
carbohydrate and high-fat diet that forces the body plementation increases blood ketone levels to 0.3 to
into endogenous ketosis (25). Although sustained KD 1.0 mmol/l and the side effects are generally limited
can raise blood bOHB to 2 to 4 mmol/l (10), long-term to mild GI distress at high doses (28,29). Of the
compliance is low, often due to gastrointestinal exogenous ketones, both KS and KE have been tested
(GI) distress. in clinical trials and cause sustained increases in
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F I G U R E 2 Different Methods to Induce Nutritional Ketosis

Several ketone supplementation approaches including 1,3-butanediol, medium-chain triglyceride (MCT), ketone salts (KS), and
ketone ester (KE) have been explored for their ability to raise circulating ketone levels in various preclinical and clinical scenarios.
bOHB ¼ beta-hydroxybutyrate.

circulating bOHB concentrations, although the keto- with a substantial sodium load, which may limit their
genic effects of KE are more pronounced than for KS chronic use in patients with CVD. However, KE are
(1 to 3 mmol/l vs. 2 to 6 mmol/l, respectively) more expensive and bitter-tasting than KS. GI distress
(10,30,31). Although KS are more palatable than KE, after ingestion of KE or KS is generally mild, infre-
the doses required to achieve ketosis are associated quent, and dose-related (30).
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T A B L E 1 Clinical Trials Utilizing Nutritional Ketones for CVD or CVD-Related Conditions

Clinical Trial Identifier First Author (Ref.), Year Intervention, Condition/Disease N, Participants Major Outcomes

— Cox et al. (31), 2016 Ketone ester with carbohydrate N ¼ 35 high-performance athletes KE decreased glycolysis and plasma
(KE (CHO) vs. control. lactate, increased intramuscular
triacylglycerol oxidation during
exercise.
— Stubbs et al. (81), 2017 KE vs. KS in health. N ¼ 15 healthy adults KE and KS lowered blood glucose, free
fatty acids, and triglyceride
concentrations.
— Holdsworth et al. (86), 2017 KE vs. placebo in health. N ¼ 12 well-trained male athletes KE increased insulin levels and glucose
uptake during 2-h glucose clamps, as
well as muscle glycogen.
— Gormsen et al. (4), 2017 KS infusion vs. placebo; to N ¼ 8, age 50 to 68 yrs healthy KS infusion reduced MGU and increased
investigate effects of ketones adults myocardial blood flow.
on MGU and myocardial blood
flow.
— Stubbs et al. (67), 2018 KE vs. isocaloric dextrose drink in N ¼ 15 healthy adults KE reduced plasma insulin, ghrelin,
health. glucagon-like peptide-1, and peptide
tyrosine levels.
— Myett-Cote et al. (76), 2018 KE vs. placebo in health. N ¼ 10, age 18–35 yrs healthy KE reduced the glycemic response and
volunteers markers of insulin sensitivity without
affecting insulin secretion.
NCT03461068 Myett-Cote et al. (75), 2019 KE vs. taste-matched placebo; N ¼ 15, age 30–65 yrs KE lowered glucose and NEFA AUC with
cross-over trial; to investigate individuals with obesity no increase in circulating insulin.
effects if ingestion before oral
glucose tolerance test could
reduce blood glucose.
— Soto-Mota et al. (87), 2019 KE for 28 days to investigate N ¼ 24; age 19–70 yrs healthy No effect on body weight or
safety profile. adults composition, fasting blood glucose,
cholesterol, triglyceride or
electrolyte concentrations, nor blood
gases or renal function.
NCT03073356 Nielsen et al. (3), 2019 KS infusion vs. placebo; to N ¼ 24 HFrEF patients and 10 age- KS infusion in patients with HFrEF
investigate effects of ketones matched healthy volunteers improved CO and reduced SVR in a
on cardiac efficiency. dose-dependent manner without
impairing MEE.
NCT03603782 Cuenoud et al. (88), 2020 DL-BHB; to evaluate metabolism N ¼ 15 healthy adults Tracer study showed that ketones are
of ketones in whole body using rapidly absorbed by heart and kidney.
ketone tracer 11C-acetoacetate.
NCT03531554 Bleeker et al. (89), 2020 KEþCHO vs. CHO alone; to N ¼ 5; age 17–45 yrs confirmed VLCADD-specific plasma acylcarnitine
investigate if KE ingestion VLCADD by genetic profiling levels, quadriceps glycolytic
prior to exercise could boost intermediate levels and in vivo Pi/PCr
muscular ATP homeostasis. ratio were all improved by KE þ CHO
compared with CHO.
NCT03889210 — KE vs. placebo, in the pre-diabetic N ¼ 18; age >18 yrs pre-diabetic Awaiting study outcome.
patients. patients with at least 1 episode
of acute pancreatitis
NCT03817749 — KE vs. placebo; in the pre-diabetic N ¼ 15; age 30–69 yrs pre-diabetic Awaiting study outcome.
patients. patients
NCT03226197 — KE drink, open-label; to assess the N ¼ 10, age >18 yrs, comatose Awaiting study outcome.
feasibility and safety of survivor out-of-hospital
delivering a ketone drink via cardiac arrest patients
nasogastric tube.

BMI ¼ body mass index; CHO ¼ carbohydrate; CVD ¼ cardiovascular disease; DL-BHB ¼ DL-beta-hydroxybutyrate; EPO ¼ erythropoietin; HFrEF ¼ heart failure with reduced ejection fraction; KE ¼ ketone
esters; KS ¼ ketone salts; MGU ¼ myocardial glucose uptake; NEFA ¼ nonesterified fatty acids; VLCADD ¼ very long-chain acyl-CoA dehydrogenase deficiency.

Sodium-glucose cotransporter inhibitors (SGLT2i) SGLT2i are mediated by the increases in circulating
are drugs that stimulate urinary glucose excretion ketone bodies (34,35), but a causal link remains
and have recently received considerable interest controversial. We and others have shown that
because of their cardiovascular benefits in HF pa- SGLT2i increased ketone levels in nondiabetic small
tients with and without diabetes (32). SGLT2i and large animal models of HF, accompanied by
reduce insulin levels and stimulate lipolysis, which increased myocardial markers of ketone oxidation
in turn drives ketone production in the liver (33). and normalization of cardiac ATP (5,36). A recent
Accordingly, SGLT2i induce mild ketosis in both study showed that SGLT2i attenuated the Nod-like
diabetic and nondiabetic subjects (34). Some au- receptor protein 3 (NLRP3) inflammasome activity
thors have suggested that CV benefits during in patients with diabetes and that this was
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Ketones and Cardiovascular Disease -, 2021:-–-

C E N T R A L IL L U ST R A T I O N Bioenergetic and Pleiotropic Effects of Ketone Bodies

Yurista, S.R. et al. J Am Coll Cardiol. 2021;-(-):-–-.

Beyond their contribution to energy generation, ketone bodies may exert salutary effects on endothelial function, oxidative stress, mito-
chondrial function, inflammation, cardiac remodeling, and other systemic extracardiac effects on body weight, blood pressure, glycemia, and
lipid profile. HDACs ¼ histone deacytelases.

explained by enhanced bOHB concentrations and identified that may provide additional CV benefit
decreased serum levels of insulin (37). In addition, (Central Illustration).
previous studies demonstrated that ketone bodies ENDOTHELIAL FUNCTION. Treatment with 1,3-
possess antioxidative activity and other pleiotropic butanediol increased nitric oxide synthase activity
effects beyond cardiac energetics (38,39). Thus, in resistance arteries from Dahl salt-sensitive rats
mild ketosis induced by SGLT2i might benefit pa- (40). In the clinical setting, bHOB infusion increased
tients with HF through multiple mechanism. myocardial blood flow by about 75% and induced
Further mechanistic studies are required to define vasodilatation (3,4). bHOB infusion also increased
the mechanisms underlying the cardiovascular local cerebral and renal blood flow in humans (41,42).
benefits of SGLT2i that may be related to substrate In addition, KD-fed animals had increased endothe-
metabolism or a signaling role of ketone bodies. lial nitric oxide synthase protein expressions (43).
Table 1 lists clinical trials utilizing nutritional ke- These findings suggest that bOHB is a potent
tones for CVD or CVD-related conditions. endothelium-dependent vasodilator that may be
beneficial for patients with CVD.
KETONE BODIES: PLEIOTROPIC EFFECTS OXIDATIVE STRESS AND MITOCHONDRIAL FUNCTION.
BEYOND CARDIAC ENERGETICS Cardiac overexpression of beta-hydroxybutyrate de-
hydrogenases 1 (BDH1) in mice resulted in 1.7-fold
Besides the effects of ketones on (cardiac) energetics, increase in cardiac ketone body oxidation, increased
several pleiotropic effects of ketones have been expression of antioxidant superoxide dismutase,
JACC VOL. -, NO. -, 2021 Yurista et al. 7
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and suppressed oxidative stress after transaortic overload was also more pronounced in mice with
constriction (TAC) (44). Histone deacetylases cardiomyocyte-specific knockout of succinyl-CoA:3-
(HDACs) serve critical roles in transcriptional regula- ketoacid-CoA transferase (54). Our group has
tion, and bOHB can inhibit class I HDACs. This demonstrated that KE improves cardiac function
resulted in the suppression of mitochondrial oxida- with reduction in pathological cardiac remodeling in
tive stress via activation of Foxo3a and Mt2 promoter animal models of HF, associated with increased
genes (38). In animals, bOHB infusion reduced mito- markers myocardial uptake and oxidation of ke-
chondrial stress in the myocardium after ischemia/ tones (55).
reperfusion injury (45). In isolated mitochondria, KD reduced cardiac remodeling after TAC and was
bOHB provided an alternate fuel in the context of associated with lower circulating leptin and insulin
limited substrate availability, thereby improving concentrations, consistent with the concept that
redox state and mitochondrial membrane potential these hormones directly stimulate cardiac growth
(2). KD was reported to mitigate lethal mitochondrial (52). In isolated cardiomyocytes, ketone bodies
cardiomyopathy and increase the number of cardiac exerted antiapoptotic effects via activating the PI3K-
mitochondria (46,47). Together, these data suggest Akt pathway, thus increasing Bcl2/Bax ratio and
that ketone bodies have the potential to mitigate decreasing caspase-3 activity (56). In addition, sub-
salutary effects on oxidative stress and mitochondrial stantial evidence demonstrated class I and II HDAC
function in CVD. involvement in the pathogenesis of HF and its
INFLAMMATION. NLRP3 inflammasome plays an antecedent conditions, such as cardiac hypertrophy
important role in the heart, as its activation has a and adverse remodeling (57). Interestingly, HDAC
detrimental effect on loss of functional myocardium inhibitors reduced stress-induced cardiomyocyte
(48). bOHB also has a direct anti-inflammatory action death, hypertrophy, and ventricular fibrosis, and
as it specifically inhibits NLRP3 inflammasome in thus blunted pathological cardiac remodeling in
LPS-stimulated human monocytes. b OHB reduced the small and large animal models of HF (57–59). A
expression of the NLRP3 inflammasome pathway previous observation that b OHB specifically inhibits
components, such as NLRP3 and caspase-1, and also class I HDACs (38) raises the possibility that cardiac
limits the release of proinflammatory cytokines remodeling might also be reduced upon elevating
IL-1b and IL-18 (38,49). In the clinical setting, KD bOHB.
resulted in reduced circulating inflammation markers EFFECT OF KETONES ON CARDIOVASCULAR RISK
compared with a low-fat diet (50). Although limited, FACTORS. B l o o d p r e s s u r e . In a study in high salt-
these findings provide the evidence that ketone sensitive hypertensive rats, mild ketosis induced by
bodies can directly target inflammation in a way that 1,3-butanediol reduced blood pressure, possibly
may be beneficial for CVD. mediated by reduced NLRP3 inflammasome activity
CARDIAC REMODELING. Cardiac remodeling refers (60). Although the effects of exogenous ketones on
to alterations in molecular, cellular and interstitial blood pressure are not well described, it has been
myocardium, which lead to changes in heart size, reported that a KD results in a slight but temporary
shape, structure, and function as the result of reduction in systolic blood pressure (61,62). Further
myocardial injury, and it has been recognized as an studies are warranted to elucidate the effects of
important determinant of the clinical course of HF ketosis on blood pressure.
(51). Increasing circulating ketone concentrations via B o d y w e i g h t . In animals, administration of KE R,S-
KD or infusion of bOHB ameliorated pathological 1,3-butanediol acetoacetate diester (BD-AcAc2)
cardiac remodeling and improved cardiac function reduced body weight (63,64), whereas another type of
in small and large animal models of HF (2,45,52,53). KE D-b -hydroxybutyrate-(R)-1,3-butanediol mono-
In addition, mice with cardiac-specific over- ester (BD-BHB) did not. BD-BHB and BD-AcAc2 did,
expression of BDH1 are more resistant to maladap- however, lower plasma leptin levels and decrease
tive cardiac remodeling after TAC (44). Conversely, food intake in rodents (65,66). In healthy volunteers,
a combination of pressure overload/ischemic insult BD-BHB lowered plasma ghrelin levels and reduced
resulted in more severe cardiac dysfunction and hunger. It thus appears that KE reduces appetite,
exaggerated pathological cardiac remodeling in mice while the effects on body weight are not consistent
with cardiac-specific knockout of BDH1 (2). Patho- (67). KS reduced visceral adipocyte volume in rats,
logical cardiac remodeling in response to pressure- but the effects on body weight are limited (68).
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Ketones and Cardiovascular Disease -, 2021:-–-

The effect of a KD on body weight in animals is cholesterol biosynthesis pathways (85). In summary,
inconsistent and appears to be short lived (69–71). In the impact of exogenous ketones and KD on lipid
humans, however, there is strong evidence that a KD profile differs, and long-term studies are needed to
is a very effective method to induce weight loss fully define the effect of ketone bodies in serum lipid
(61,72,73). The mechanisms responsible for reduction concentrations.
in body weight include reduced caloric intake,
SUMMARY AND PERSPECTIVES
increased satiety, increased energy expenditure,
decreased appetite, and reduced ghrelin and leptin
Evidence for benefits of ketone bodies in subjects
levels (65–67).
with cardiovascular disease is rapidly emerging. In
B l o o d g l u c o s e . Administration of exogenous ke-
addition to the role of ketones in provision of an
tones in animals reduced blood glucose within a few
ancillary fuel for the failing heart, ketone bodies may
minutes (74). In obese and nonobese subjects,
also exert a myriad of pleiotropic effects. Ketone
ingestion of BD-BHB reduced blood glucose without
bodies may improve endothelial function, ameliorate
affecting insulin secretion (75,76). The hypoglycemic
oxidative stress, improve mitochondrial function,
potential of a KD is, however, a more controversial
exert anti-inflammatory actions, and mitigate cardiac
issue. In animals, some authors have reported that KD
remodeling. Other systemic extracardiac effects on
caused insulin resistance (77,78), whereas others
body weight, blood pressure, glycemia, and lipid
showed that KD improved glycemic control (56,70). In
profile may also benefit patients with CVD. Regard-
humans, KD has been reported to lower fasting
less of the pathway to achieve ketosis, ketone bodies
glucose and improve insulin sensitivity (61,73).
have potential clinical applications that require
Conversely, a large dietary analysis study demon-
further exploration, including new therapeutic ap-
strated that KD was associated with higher HbA1c and
proaches to harness the beneficial effect of ketosis. In
a higher likelihood of having diabetes (79). Further
the coming years, we will learn whether ketone
studies are warranted to ascertain any potential role
bodies can be beneficial and optimized to be used in
for ketone bodies in monitoring blood glucose, and
treatment and prevention of CVD.
whether exogenous ketones and KD have different
outcomes. FUNDING SUPPORT AND AUTHOR DISCLOSURES
L i p i d p r o fi l e . Dyslipidemia is a well-known risk
The UMCG, which employs Drs. Yurista, de Boer, and Westenbrink,
factor for CVD. In animals, KS has been shown to in-
has received research grants and/or fees from Abbott, AstraZeneca,
crease HDL cholesterol and decrease the LDL/HDL Bristol Myers Squibb, Novartis, Novo Nordisk, and Roche. Dr.
ratio (68), whereas KE BD-AcAc2 and BD-BHB did not Chong is supported by a fellowship jointly awarded by the National

alter total cholesterol and triglycerides levels (80). Health & Medical Research Council (GNT1162356) and National
Heart Foundation of Australia (102126). Dr. Kelly is supported by
Reduced plasma free fatty acid and triglycerides have
NIH R01 HL058493, HL128349, and HL151345; and has served as a
also been observed in healthy volunteers consuming scientific consultant for Pfizer, Amgen, and Janssen. Dr. de Boer is
exogenous ketone drinks containing either KE BD- supported by the Netherlands Heart Foundation (CVON DOUBLE
DOSE, grant 2020-8005, CVON SHE-PREDICTS-HF, grant 2017-21,
BHB or KS (81).
and CVON RED-CVD, grant 2017-11) and the European Research
Long-term KD increased total cholesterol and tri- Council (ERC CoG 818715, SECRETE-HF); and has received personal
glyceride levels in animals (70,82). In humans, the fees from Abbott, AstraZeneca, Novartis, and Roche. Dr. West-
effect of KD on the lipid profile is more controversial. enbrink is supported by the Netherlands Organisation for Scientific
Research (NWO VENI, grant 016.176.147) and the Netherlands Heart
Some authors reported that KD increased atherogenic
Foundation Senior Clinical Scientist Grant (2019T064) and CVON
apoB–containing lipoproteins and decreased HDL DOUBLE DOSE (grant 2020-8005). All other authors have reported
(25), whereas others demonstrated that KD increased that they have no relationships relevant to the contents of this
HDL and reduced total cholesterol, LDL, and triglyc- paper to disclose.

eride levels (61,73,83). KD was reported to reduce

insulin levels and further suppress both transcription ADDRESS FOR CORRESPONDENCE: Dr. B. Daan
factors and enzymes fatty acid synthase, stearoyl-CoA Westenbrink, Department of Cardiology, University
desaturase-1, and sterol regulatory element-binding Medical Center Groningen, P.O. Box 30.001, Groningen
protein-1c, which are involved in lipid synthesis 9700RB, the Netherlands. E-mail: b.d.westenbrink@
(84). Because ingestion of KE reduces insulin levels, it umcg.nl. Twitter: @salvareverentia, @Rudolf_deboer,
would be expected that KE would also decrease @WestenbrinkDaan, @CardiologyUMCG.
JACC VOL. -, NO. -, 2021 Yurista et al. 9
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HDAC inhibition improves cardiopulmonary exercised rodent models. Nutrients 2019;11:2330. failure, ketones, pleiotropic effects