Xylitol is prothrombotic and associated with cardiovascular risk (2024)

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Marco Witkowski

Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic

9500 Euclid Avenue, Cleveland, OH 44195

USA

Present address: Department of Cardiology, Angiology and Intensive Care, German Heart Center of Charité, Campus Benjamin Franklin, Berlin, Germany and Friede Springer Cardiovascular Prevention Center at Charité, Berlin, Germany and German Center for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin, Germany.

https://orcid.org/0000-0002-6952-5038

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Ina Nemet

Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic

9500 Euclid Avenue, Cleveland, OH 44195

USA

https://orcid.org/0000-0002-0657-7121

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Xinmin S Li

Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic

9500 Euclid Avenue, Cleveland, OH 44195

USA

https://orcid.org/0000-0003-4946-4271

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Jennifer Wilcox

Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic

9500 Euclid Avenue, Cleveland, OH 44195

USA

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Marc Ferrell

Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic

9500 Euclid Avenue, Cleveland, OH 44195

USA

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Hassan Alamri

Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic

9500 Euclid Avenue, Cleveland, OH 44195

USA

Present address: Department of Clinical Laboratory Sciences, College of Applied Medical Sciences\King Abdullah International Medical Research Centre, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.

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Abstract

Background and Aims

The pathways and metabolites that contribute to residual cardiovascular disease risks are unclear. Low-calorie sweeteners are widely used sugar substitutes in processed foods with presumed health benefits. Many low-calorie sweeteners are sugar alcohols that also are produced endogenously, albeit at levels over 1000-fold lower than observed following consumption as a sugar substitute.

Methods

Untargeted metabolomics studies were performed on overnight fasting plasma samples in a discovery cohort (n = 1157) of sequential stable subjects undergoing elective diagnostic cardiac evaluations; subsequent stable isotope dilution liquid chromatography tandem mass spectrometry (LC-MS/MS) analyses were performed on an independent, non-overlapping validation cohort (n = 2149). Complementary isolated human platelet, platelet-rich plasma, whole blood, and animal model studies examined the effect of xylitol on platelet responsiveness and thrombus formation in vivo. Finally, an intervention study was performed to assess the effects of xylitol consumption on platelet function in healthy volunteers (n = 10).

Results

In initial untargeted metabolomics studies (discovery cohort), circulating levels of a polyol tentatively assigned as xylitol were associated with incident (3-year) major adverse cardiovascular event (MACE) risk. Subsequent stable isotope dilution LC-MS/MS analyses (validation cohort) specific for xylitol (and not its structural isomers) confirmed its association with incident MACE risk [third vs. first tertile adjusted hazard ratio (95% confidence interval), 1.57 (1.12–2.21), P < .01]. Complementary mechanistic studies showed xylitol-enhanced multiple indices of platelet reactivity and in vivo thrombosis formation at levels observed in fasting plasma. In interventional studies, consumption of a xylitol-sweetened drink markedly raised plasma levels and enhanced multiple functional measures of platelet responsiveness in all subjects.

Conclusions

Xylitol is associated with incident MACE risk. Moreover, xylitol both enhanced platelet reactivity and thrombosis potential in vivo. Further studies examining the cardiovascular safety of xylitol are warranted.

Structured Graphical Abstract

Role of the artificial sweetener xylitol in cardiovascular event risk. In initial untargeted metabolomics studies (discovery cohort) and subsequent stable isotope dilution liquid chromatography tandem mass spectrometry (LC-MS/MS) studies (validation cohort), fasting levels of xylitol are associated with incident major adverse cardiovascular events (MACE). Using human whole blood, platelet-rich plasma, and washed platelets, xylitol enhances multiple indices of platelet reactivity in vitro. Xylitol also was shown to enhance thrombosis formation in a murine arterial injury model in vivo. In human intervention studies, when subjects ingested a typical dietary amount of xylitol in an artificially sweetened food, multiple functional measures of platelet responsiveness were significantly increased. Xylitol is both clinically associated with cardiovascular event risks and mechanistically linked to enhanced platelet responsiveness and thrombosis potential in vivo. ADP, adenosine diphosphate; MI, myocardial infarction.

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Artificial sweetener, Low-calorie sweetener, Cardiovascular disease, Platelet, Thrombosis, Heart attack, Stroke, Sugar alcohol, Polyol, Nutrition

© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.

This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/pages/standard-publication-reuse-rights)

Topic:

cardiovascular diseases
thrombosis
blood platelets
calories
plasma
sugar alcohols
sweetening agents
xylitol
whole blood

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