Metabolomics and a Breath Sensor Identify Acetone as a Biomarker for Heart Failure

Gladding, Patrick; Cooper, M.; Young, Renée; Loader, S.; Smith, Kevin; Zarate, Erica; Green, Saras; Villas‐Bôas, Silas G.; Shepherd, Phillip; Kakadiya, Purvi; Thorstensen, Eric B.; Keven, Christine; Coe, Margaret; Jüllig, Mia; Zhang, Edmond; Schlegel, Todd T.

doi:10.3390/biom13010013

Cited by 9 publications

(6 citation statements)

References 40 publications

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“…Indeed, in a study of non-ischemic HF patients, exhaled acetone levels, which were correlated with blood KB levels, were associated with higher NYHA class and higher BNP ( 26 ). In a study of 45 patients with HF, higher KB levels were correlated with a lower EF ( 2 ), while another study of 46 patients with HF with reduced EF found higher levels of acetone among HF patients compared with controls ( 27 ). However, we observed no cross-sectional association between KB and EF categories after controlling for several potential confounding factors, indicating that our findings surrounding KB correlates apply to the entire spectrum of the HF syndrome.…”

Section: Discussionmentioning

confidence: 97%

“…A study of 615 HF patients found that patients with high AcAc concentrations (≥ 35 μM) were at a small but detectable increased risk of all-cause mortality ( 36 ). Several studies have found an association between higher breath acetone levels and HF ( 26 , 27 , 33 , 37 ). Elevated levels of exhaled breath acetone have been reported to be an independent predictor of mortality in HF with reduced EF ( 25 , 38 ).…”

Section: Discussionmentioning

confidence: 99%

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Circulating ketone bodies and mortality in heart failure: a community cohort study

Oyetoro,

Conners,

Joo

et al. 2024

Front. Cardiovasc. Med.

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BackgroundThe relationship between ketone bodies (KB) and mortality in patients with heart failure (HF) syndrome has not been well established.ObjectivesThe aim of this study is to assess the distribution of KB in HF, identify clinical correlates, and examine the associations between plasma KB and all-cause mortality in a population-based HF cohort.MethodsThe plasma KB levels were measured by nuclear magnetic resonance spectroscopy. Multivariable linear regression was used to examine associations between clinical correlates and KB levels. Proportional hazard regression was employed to examine associations between KB (represented as both continuous and categorical variables) and mortality, with adjustment for several clinical covariates.ResultsAmong the 1,382 HF patients with KB measurements, the median (IQR) age was 78 (68, 84) and 52% were men. The median (IQR) KB was found to be 180 (134, 308) μM. Higher KB levels were associated with advanced HF (NYHA class III–IV) and higher NT-proBNP levels (both P < 0.001). The median follow-up was 13.9 years, and the 5-year mortality rate was 51.8% [95% confidence interval (CI): 49.1%–54.4%]. The risk of death increased when KB levels were higher (HRhigh vs. low group 1.23; 95% CI: 1.05–1.44), independently of a validated clinical risk score. The association between higher KB and mortality differed by ejection fraction (EF) and was noticeably stronger among patients with preserved EF.ConclusionsMost patients with HF exhibited KB levels that were consistent with those found in healthy adults. Elevated levels of KB were observed in patients with advanced HF. Higher KB levels were found to be associated with an increased risk of death, particularly in patients with preserved EF.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Circulating ketone bodies and mortality in heart failure: a community cohort study

Oyetoro,

Conners,

Joo

et al. 2024

Front. Cardiovasc. Med.

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“…4 ). Acetone is a ketone body that is produced primarily in the liver during fasting and which has been associated with several cardiometabolic conditions including heart failure 55 and diabetes 56 in biochemical and epidemiological studies. In the GWAS, we identified associations for acetone at ten loci (only one associated locus— APOA5 —was identified in the previous NMR GWAS meta-analysis 4 ), and Mendelian randomization yielded 20 robust associations (Fig.…”

Section: Mendelian Randomizationmentioning

confidence: 99%

Genome-wide characterization of circulating metabolic biomarkers

Karjalainen,

Karthikeyan,

Oliver-Williams

et al. 2024

Nature

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Genome-wide association analyses using high-throughput metabolomics platforms have led to novel insights into the biology of human metabolism1–7. This detailed knowledge of the genetic determinants of systemic metabolism has been pivotal for uncovering how genetic pathways influence biological mechanisms and complex diseases8–11. Here we present a genome-wide association study for 233 circulating metabolic traits quantified by nuclear magnetic resonance spectroscopy in up to 136,016 participants from 33 cohorts. We identify more than 400 independent loci and assign probable causal genes at two-thirds of these using manual curation of plausible biological candidates. We highlight the importance of sample and participant characteristics that can have significant effects on genetic associations. We use detailed metabolic profiling of lipoprotein- and lipid-associated variants to better characterize how known lipid loci and novel loci affect lipoprotein metabolism at a granular level. We demonstrate the translational utility of comprehensively phenotyped molecular data, characterizing the metabolic associations of intrahepatic cholestasis of pregnancy. Finally, we observe substantial genetic pleiotropy for multiple metabolic pathways and illustrate the importance of careful instrument selection in Mendelian randomization analysis, revealing a putative causal relationship between acetone and hypertension. Our publicly available results provide a foundational resource for the community to examine the role of metabolism across diverse diseases.

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“…25,49 HF is a modestly ketotic state recognized by an increase in exhaled acetone and circulating ßOHB in human patients. [49][50][51][52][53][54] Given that cardiac uptake of ketone bodies is proportional to circulating concentrations, augmented hepatic ketogenesis is a likely contributor to increased cardiac utilization in HF via increased supply (Figure 2). 25,27 Extraction of ßOHB proportional to supply is increased in patients with reduced LVEF.…”

Section: Ketone Metabolism In the Hypertrophied And Failing Heart Car...mentioning

confidence: 99%

Ketones and the Heart: Metabolic Principles and Therapeutic Implications

Matsuura

Puchalska

Crawford

et al. 2023

Circulation Research

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The ketone bodies beta-hydroxybutyrate and acetoacetate are hepatically produced metabolites catabolized in extrahepatic organs. Ketone bodies are a critical cardiac fuel and have diverse roles in the regulation of cellular processes such as metabolism, inflammation, and cellular crosstalk in multiple organs that mediate disease. This review focuses on the role of cardiac ketone metabolism in health and disease with an emphasis on the therapeutic potential of ketosis as a treatment for heart failure (HF). Cardiac metabolic reprogramming, characterized by diminished mitochondrial oxidative metabolism, contributes to cardiac dysfunction and pathologic remodeling during the development of HF. Growing evidence supports an adaptive role for ketone metabolism in HF to promote normal cardiac function and attenuate disease progression. Enhanced cardiac ketone utilization during HF is mediated by increased availability due to systemic ketosis and a cardiac autonomous upregulation of ketolytic enzymes. Therapeutic strategies designed to restore high-capacity fuel metabolism in the heart show promise to address fuel metabolic deficits that underpin the progression of HF. However, the mechanisms involved in the beneficial effects of ketone bodies in HF have yet to be defined and represent important future lines of inquiry. In addition to use as an energy substrate for cardiac mitochondrial oxidation, ketone bodies modulate myocardial utilization of glucose and fatty acids, two vital energy substrates that regulate cardiac function and hypertrophy. The salutary effects of ketone bodies during HF may also include extra-cardiac roles in modulating immune responses, reducing fibrosis, and promoting angiogenesis and vasodilation. Additional pleotropic signaling properties of beta-hydroxybutyrate and AcAc are discussed including epigenetic regulation and protection against oxidative stress. Evidence for the benefit and feasibility of therapeutic ketosis is examined in preclinical and clinical studies. Finally, ongoing clinical trials are reviewed for perspective on translation of ketone therapeutics for the treatment of HF.

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Metabolomics and a Breath Sensor Identify Acetone as a Biomarker for Heart Failure

Cited by 9 publications

References 40 publications

Circulating ketone bodies and mortality in heart failure: a community cohort study

Circulating ketone bodies and mortality in heart failure: a community cohort study

Genome-wide characterization of circulating metabolic biomarkers

Ketones and the Heart: Metabolic Principles and Therapeutic Implications

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