Association of beta‐hydroxybutyrate with development of heart failure: Sex differences in a Dutch population cohort

Flores‐Guerrero, Jose L.; Westenbrink, B. Daan; Connelly, Margery A.; Otvos, James D.; Groothof, Dion; Shalaurova, Irina; Garcia, Erwin; Navis, Gerjan; Boer, Rudolf A. de; Bakker, Stephan J. L.; Dullaart, Robin P. F.

doi:10.1111/eci.13468

Cited by 33 publications

(34 citation statements)

References 38 publications

(72 reference statements)

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“…Circulating ketone body concentrations were increased in patients with heart failure, in correlation with cardiac use. The concentrations of βOHB in circulation were also increased in persons with incident heart failure [115]. Circulating levels of ketone bodies and their myocardial use were also found increased in persons with type 2 diabetes [14].…”

Section: (Pre)clinical Experience With Supplementation Of Ketone Bodiesmentioning

confidence: 93%

Ketone bodies: from enemy to friend and guardian angel

Kolb

Kempf

Röhling

et al. 2021

BMC Med

190

119

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During starvation, fasting, or a diet containing little digestible carbohydrates, the circulating insulin levels are decreased. This promotes lipolysis, and the breakdown of fat becomes the major source of energy. The hepatic energy metabolism is regulated so that under these circumstances, ketone bodies are generated from β-oxidation of fatty acids and secreted as ancillary fuel, in addition to gluconeogenesis. Increased plasma levels of ketone bodies thus indicate a dietary shortage of carbohydrates. Ketone bodies not only serve as fuel but also promote resistance to oxidative and inflammatory stress, and there is a decrease in anabolic insulin-dependent energy expenditure. It has been suggested that the beneficial non-metabolic actions of ketone bodies on organ functions are mediated by them acting as a ligand to specific cellular targets. We propose here a major role of a different pathway initiated by the induction of oxidative stress in the mitochondria during increased ketolysis. Oxidative stress induced by ketone body metabolism is beneficial in the long term because it initiates an adaptive (hormetic) response characterized by the activation of the master regulators of cell-protective mechanism, nuclear factor erythroid 2-related factor 2 (Nrf2), sirtuins, and AMP-activated kinase. This results in resolving oxidative stress, by the upregulation of anti-oxidative and anti-inflammatory activities, improved mitochondrial function and growth, DNA repair, and autophagy. In the heart, the adaptive response to enhanced ketolysis improves resistance to damage after ischemic insults or to cardiotoxic actions of doxorubicin. Sodium-dependent glucose co-transporter 2 (SGLT2) inhibitors may also exert their cardioprotective action via increasing ketone body levels and ketolysis. We conclude that the increased synthesis and use of ketone bodies as ancillary fuel during periods of deficient food supply and low insulin levels causes oxidative stress in the mitochondria and that the latter initiates a protective (hormetic) response which allows cells to cope with increased oxidative stress and lower energy availability. Keywords Ketogenic diet, Ketone bodies, Beta hydroxybutyrate, Insulin, Obesity, Type 2 diabetes, Inflammation, Oxidative stress, Cardiovascular disease, SGLT2, Hormesis

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Section: (Pre)clinical Experience With Supplementation Of Ketone Bodiesmentioning

confidence: 93%

Ketone bodies: from enemy to friend and guardian angel

Kolb

Kempf

Röhling

et al. 2021

BMC Med

190

119

View full text Add to dashboard Cite

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“…One showed similar levels of N-terminal pro-BNP [ 6 ] between men and women, whilst another study showed women tended to have a higher BNP [ 26 ]. Although the implications are unknown currently, one paper discovered that high plasma concentrations of beta hydroxybuturate were associated with increased risk of HFrEF particularly in women [ 27 ].…”

Section: Biomarkersmentioning

confidence: 99%

Heart Failure with Reduced Ejection Fraction—Does Sex Matter?

Swaraj

Kozor

Arnott

et al. 2021

Curr Heart Fail Rep

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Purpose of Review There is an increasing recognition of the importance of sex in susceptibility, clinical presentation, and outcomes for heart failure. This review focusses on heart failure with reduced ejection fraction (HFrEF), unravelling differences in biology, clinical and demographic features and evidence for diagnostic and therapeutic strategies. This is intended to inform clinicians and researchers regarding state-of-the-art evidence relevant to women, as well as areas of unmet need. Recent Findings Females are well recognised to be under-represented in clinical trials, but there have been some improvements in recent years. Data from the last 5 years reaffirms that women presenting with HFrEF women are older and have more comorbidities like hypertension, diabetes and obesity compared with men and are less likely to have ischaemic heart disease. Non-ischaemic aetiologies are more likely to be the cause of HFrEF in women, and women are more often symptomatic. Whilst mortality is less than in their male counterparts, HFrEF is associated with a bigger impact on quality of life in females. The implications of this for improved prevention, treatment and outcomes are discussed. Summary This review reveals distinct sex differences in HFrEF pathophysiology, types of presentation, morbidity and mortality. In light of this, in order for future research and clinical medicine to be able to manage HFrEF adequately, there must be more representation of women in clinical trials as well as collaboration for the development of sex-specific management guidelines. Future research might also elucidate the biochemical foundation of the sex discrepancy in HFrEF.

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“…We found values higher than normal for nine TTS patients, reaching a maximum of almost 3 mM in 3HB and 1 mM in AcAc. In contrast, healthy subjects show concentrations of KB as low as 19 μM, which can increase to approximately 120 μM after an overnight fast [ 38 ]. Our TTS patients were studied in the nonfasting state upon admission, thereby enhancing the significance of the high KB levels observed.…”

Section: Discussionmentioning

confidence: 99%

A Pilot Study on the 1H-NMR Serum Metabolic Profile of Takotsubo Patients Reveals Systemic Response to Oxidative Stress

et al. 2021

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Takotsubo syndrome (TTS) presents as an acute coronary syndrome characterized by severe left ventricular (LV) dysfunction and non-obstructive coronary artery disease that typically shows spontaneous recovery within days or weeks. The mechanisms behind TTS are mainly related to beta-adrenergic overstimulation and acute endogenous catecholamine surge, both of which could increase oxidative status that may induce further deterioration of cardiac function. Although several studies reported evidence of inflammation and oxidative stress overload in myocardial tissue of TTS models, systemic biochemical evidence of augmented oxidant activity in patients with TTS is lacking. In this study, serum samples of ten TTS patients and ten controls have been analyzed using 1H-NMR spectroscopy. The results of this pilot study show a marked alteration in the systemic metabolic profile of TTS patients, mainly characterized by significant elevation of ketone bodies, 2-hydroxybutyrate, acetyl-L-carnitine, and glutamate levels, in contrast with a decrease of several amino acid levels. The overall metabolic fingerprint reflects a systemic response to oxidative stress caused by the stressor that triggered the syndrome’s onset.

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Association of beta‐hydroxybutyrate with development of heart failure: Sex differences in a Dutch population cohort

Cited by 33 publications

References 38 publications

Ketone bodies: from enemy to friend and guardian angel

Ketone bodies: from enemy to friend and guardian angel

Heart Failure with Reduced Ejection Fraction—Does Sex Matter?

A Pilot Study on the 1H-NMR Serum Metabolic Profile of Takotsubo Patients Reveals Systemic Response to Oxidative Stress

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