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Fasting ketonuria is inversely associated with coronary artery calcification in non-diabetic individuals

  • In Young Cho
    Affiliations
    Department of Family Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea
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  • Yoosoo Chang
    Correspondence
    Corresponding author. Department of Occupational and Environmental Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Samsung Main Building B2, 250 Taepyung-ro 2ga, Jung-gu, Seoul, 04514, Republic of Korea.
    Affiliations
    Center for Cohort Studies, Total Healthcare Center, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea

    Department of Occupational and Environmental Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea

    Department of Clinical Research Design and Evaluation, SAIHST, Sungkyunkwan University, Seoul, South Korea
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  • Eunju Sung
    Affiliations
    Department of Family Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea

    Center for Cohort Studies, Total Healthcare Center, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea
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  • Yejin Kim
    Affiliations
    Center for Cohort Studies, Total Healthcare Center, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea
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  • Jae-Heon Kang
    Affiliations
    Department of Family Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea
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  • Hocheol Shin
    Affiliations
    Department of Family Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea

    Center for Cohort Studies, Total Healthcare Center, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea
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  • Sarah H. Wild
    Affiliations
    Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK
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  • Christopher D. Byrne
    Affiliations
    Nutrition and Metabolism, Faculty of Medicine, University of Southampton, Southampton, UK

    National Institute for Health Research Southampton Biomedical Research Centre, University Hospital Southampton, Southampton, UK
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  • Seungho Ryu
    Correspondence
    Corresponding author. Department of Occupational and Environmental Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Samsung Main Building B2, 250 Taepyung-ro 2ga, Jung-gu, Seoul, 04514, Republic of Korea.
    Affiliations
    Center for Cohort Studies, Total Healthcare Center, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea

    Department of Occupational and Environmental Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea

    Department of Clinical Research Design and Evaluation, SAIHST, Sungkyunkwan University, Seoul, South Korea
    Search for articles by this author

      Highlights

      • The association between ketone bodies and coronary artery calcium remains unknown.
      • Fasting ketonuria was inversely associated with prevalent coronary calcification.
      • Fasting ketonuria was associated with lower progression of coronary calcification.

      Abstract

      Background and aims

      Increased levels of ketone bodies, an alternative fuel when glucose availability is low, may exert beneficial effects on cardiovascular disease (CVD) risk factors. Whether increased ketone bodies are associated with coronary artery calcium (CAC), a recognized and strong cardiovascular risk factor, remains unknown. We investigated the association of fasting ketonuria with CAC and its progression.

      Methods

      Cross-sectional and longitudinal studies were conducted in adults without diabetes or CVD. Subjects underwent routine health examinations including cardiac computed tomography estimations of CAC scores. Logistic regression models were performed to compute the odds ratios (ORs), 95% confidence intervals (CIs), for prevalent CAC scores >0 according to fasting ketonuria categories (0, 1, and ≥2). Linear mixed models with random intercepts and random slopes were used to estimate CAC progression.

      Results

      Of 144,346 subjects, 12.3% had CAC scores >0 at baseline. Overall, higher fasting ketonuria was associated with decreased prevalence of coronary calcification than no ketonuria. Multivariable-adjusted ORs (95% CIs) for prevalent CAC by comparing ketonuria categories 1 and ≥2 with no ketonuria, were 0.94 (0.84–1.06) and 0.82 (0.71–0.95), respectively. The associations did not differ according to clinically relevant subgroups. Ketonuria was associated with lower CAC progression over time; the multivariable adjusted ratio of progression rates comparing ketonuria ≥2 versus no ketonuria was 0.976 (0.965–0.995).

      Conclusions

      We found an inverse association between fasting ketonuria and subclinical coronary atherosclerosis, in both prevalence and progression. The potentially protective role of increased ketone body formation in CVD requires further investigation.

      Graphical abstract

      Keywords

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      References

        • Roth G.A.
        • Mensah G.A.
        • Johnson C.O.
        • et al.
        Global burden of cardiovascular diseases and risk factors, 1990-2019: update from the GBD 2019 study.
        J. Am. Coll. Cardiol. 2020; 76: 2982-3021
        • Timmis A.
        • Townsend N.
        • Gale C.P.
        • et al.
        European society of cardiology: cardiovascular disease statistics 2019.
        Eur. Heart J. 2020; 41: 12-85
        • Sampson U.K.
        • Fazio S.
        • Linton M.F.
        Residual cardiovascular risk despite optimal LDL cholesterol reduction with statins: the evidence, etiology, and therapeutic challenges.
        Curr. Atherosclerosis Rep. 2012; 14: 1-10
        • Mach F.
        • Baigent C.
        • Catapano A.L.
        • et al.
        2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk.
        Eur. Heart J. 2020; 41: 111-188
        • Wong N.D.
        • Zhao Y.
        • Quek R.G.W.
        • et al.
        Residual atherosclerotic cardiovascular disease risk in statin-treated adults: the Multi-Ethnic Study of Atherosclerosis.
        J Clin Lipidol. 2017; 11: 1223-1233
        • Khot U.N.
        • Khot M.B.
        • Bajzer C.T.
        • et al.
        Prevalence of conventional risk factors in patients with coronary heart disease.
        JAMA. 2003; 290: 898-904
        • Yurista S.R.
        • Chong C.R.
        • Badimon J.J.
        • et al.
        Therapeutic potential of ketone bodies for patients with cardiovascular disease: JACC focus seminar.
        J. Am. Coll. Cardiol. 2021; 177: 1660-1669
        • Cotter D.G.
        • Schugar R.C.
        • Crawford P.A.
        Ketone body metabolism and cardiovascular disease.
        Am. J. Physiol. Heart Circ. Physiol. 2013; 304: H1060-H1076
        • Puchalska P.
        • Crawford P.A.
        Multi-dimensional roles of ketone bodies in fuel metabolism, signaling, and therapeutics.
        Cell Metabol. 2017; 25: 262-284
        • Miller V.J.
        • Villamena F.A.
        • Volek J.S.
        Nutritional ketosis and mitohormesis: potential implications for mitochondrial function and human health.
        J Nutr Metab. 2018; 2018: 5157645
        • Newman J.C.
        • Verdin E.
        Ketone bodies as signaling metabolites.
        Trends Endocrinol. Metabol. 2014; 25: 42-52
        • Nasser S.
        • Vialichka V.
        • Biesiekierska M.
        • et al.
        Effects of ketogenic diet and ketone bodies on the cardiovascular system: concentration matters.
        World J. Diabetes. 2020; 11: 584-595
        • Gershuni V.M.
        • Yan S.L.
        • Medici V.
        Nutritional ketosis for weight management and reversal of metabolic syndrome.
        Curr Nutr Rep. 2018; 7: 97-106
        • Hartman A.L.
        • Vining E.P.
        Clinical aspects of the ketogenic diet.
        Epilepsia. 2007; 48: 31-42
        • Coleman M.D.
        • Nickols-Richardson S.M.
        Urinary ketones reflect serum ketone concentration but do not relate to weight loss in overweight premenopausal women following a low-carbohydrate/high-protein diet.
        J. Am. Diet Assoc. 2005; 105: 608-611
        • Laffel L.
        Ketone bodies: a review of physiology, pathophysiology and application of monitoring to diabetes.
        Diabetes Metab Res Rev. 1999; 15: 412-426
        • Joo N.S.
        • Lee D.J.
        • Kim K.M.
        • et al.
        Ketonuria after fasting may be related to the metabolic superiority.
        J. Kor. Med. Sci. 2010; 25: 1771-1776
        • Kim G.
        • Lee S.G.
        • Lee B.W.
        • et al.
        Spontaneous ketonuria and risk of incident diabetes: a 12 year prospective study.
        Diabetologia. 2019; 62: 779-788
        • Budoff M.J.
        • Achenbach S.
        • Blumenthal R.S.
        • et al.
        Assessment of coronary artery disease by cardiac computed tomography: a scientific statement from the American heart association committee on cardiovascular imaging and intervention, council on cardiovascular radiology and intervention, and committee on cardiac imaging, council on clinical cardiology.
        Circulation. 2006; 114: 1761-1791
        • Pletcher M.J.
        • Tice J.A.
        • Pignone M.
        • et al.
        Using the coronary artery calcium score to predict coronary heart disease events: a systematic review and meta-analysis.
        Arch. Intern. Med. 2004; 164: 1285-1292
        • Budoff M.J.
        • Young R.
        • Burke G.
        • et al.
        Ten-year association of coronary artery calcium with atherosclerotic cardiovascular disease (ASCVD) events: the multi-ethnic study of atherosclerosis (MESA).
        Eur. Heart J. 2018; 39: 2401-2408
        • Chang Y.
        • Kim B.K.
        • Yun K.E.
        • et al.
        Metabolically-healthy obesity and coronary artery calcification.
        J. Am. Coll. Cardiol. 2014; 63: 2679-2686
        • Chang Y.
        • Ryu S.
        • Sung K.C.
        • et al.
        Alcoholic and non-alcoholic fatty liver disease and associations with coronary artery calcification: evidence from the Kangbuk Samsung Health Study.
        Gut. 2019; 68: 1667-1675
        • Craig C.L.
        • Marshall A.L.
        • Sjostrom M.
        • et al.
        International physical activity questionnaire: 12-country reliability and validity.
        Med. Sci. Sports Exerc. 2003; 35: 1381-1395
        • Mathiesen U.L.
        • Franzen L.E.
        • Aselius H.
        • et al.
        Increased liver echogenicity at ultrasound examination reflects degree of steatosis but not of fibrosis in asymptomatic patients with mild/moderate abnormalities of liver transaminases.
        Dig. Liver Dis. 2002; 34: 516-522
        • Agatston A.S.
        • Janowitz W.R.
        • Hildner F.J.
        • et al.
        Quantification of coronary artery calcium using ultrafast computed tomography.
        J. Am. Coll. Cardiol. 1990; 15: 827-832
        • Reilly M.P.
        • Wolfe M.L.
        • Localio A.R.
        • et al.
        Coronary artery calcification and cardiovascular risk factors: impact of the analytic approach.
        Atherosclerosis. 2004; 173: 69-78
        • Qasim A.
        • Mehta N.N.
        • Tadesse M.G.
        • et al.
        Adipokines, insulin resistance, and coronary artery calcification.
        J. Am. Coll. Cardiol. 2008; 52: 231-236
        • Szklo M.
        • Nieto J.
        Epidemiology: beyond the Basics.
        Jones & Bartlett Learning, 2007
        • World Health Organization and Regional Office for the Western Pacific
        The Asia-Pacific Perspective: Redefining Obesity and its Treatment.
        Health Communications Australia, Sydney2000
        • Gassett A.J.
        • Sheppard L.
        • McClelland R.L.
        • et al.
        Risk factors for long-term coronary artery calcium progression in the multi-ethnic study of atherosclerosis.
        J. Am. Heart Assoc. 2015; 4e001726
        • Yancy Jr., W.S.
        • Olsen M.K.
        • Guyton J.R.
        • et al.
        A low-carbohydrate, ketogenic diet versus a low-fat diet to treat obesity and hyperlipidemia: a randomized, controlled trial.
        Ann. Intern. Med. 2004; 140: 769-777
        • Tendler D.
        • Lin S.
        • Yancy Jr., W.S.
        • et al.
        The effect of a low-carbohydrate, ketogenic diet on nonalcoholic fatty liver disease: a pilot study.
        Dig. Dis. Sci. 2007; 52: 589-593
        • Kosinski C.
        • Jornayvaz F.R.
        Effects of ketogenic diets on cardiovascular risk factors: evidence from animal and human studies.
        Nutrients. 2017; 9
        • Bhanpuri N.H.
        • Hallberg S.J.
        • Williams P.T.
        • et al.
        Cardiovascular disease risk factor responses to a type 2 diabetes care model including nutritional ketosis induced by sustained carbohydrate restriction at 1 year: an open label, non-randomized, controlled study.
        Cardiovasc. Diabetol. 2018; 17: 56
        • Athinarayanan S.J.
        • Hallberg S.J.
        • McKenzie A.L.
        • et al.
        Impact of a 2-year trial of nutritional ketosis on indices of cardiovascular disease risk in patients with type 2 diabetes.
        Cardiovasc. Diabetol. 2020; 19: 208
        • Kim B.R.
        • Seo J.W.
        • Kim S.M.
        • et al.
        The presence of urinary ketones according to metabolic status and obesity.
        J. Kor. Med. Sci. 2020; 35 (e273-e273)
        • Mohammadiha H.
        Resistance to ketonuria and ketosis in obese subjects.
        Am. J. Clin. Nutr. 1974; 27: 1212-1213
        • Kekwick A.
        • Pawan G.L.
        • Chalmers T.M.
        Resistance to ketosis in obese subjects.
        Lancet. 1959; 2: 1157-1159
        • Caprio M.
        • Infante M.
        • Moriconi E.
        • et al.
        Very-low-calorie ketogenic diet (VLCKD) in the management of metabolic diseases: systematic review and consensus statement from the Italian Society of Endocrinology (SIE).
        J. Endocrinol. Invest. 2019; 42: 1365-1386
        • Anton S.D.
        • Moehl K.
        • Donahoo W.T.
        • et al.
        Flipping the metabolic switch: understanding and applying the health benefits of fasting.
        Obesity. 2018; 26: 254-268
        • Mattson M.P.
        • Longo V.D.
        • Harvie M.
        Impact of intermittent fasting on health and disease processes.
        Ageing Res. Rev. 2017; 39: 46-58
        • O'Neill B.
        • Raggi P.
        The ketogenic diet: pros and cons.
        Atherosclerosis. 2020; 292: 119-126
        • Goldberg I.J.
        • Ibrahim N.
        • Bredefeld C.
        • et al.
        Ketogenic diets, not for everyone.
        J Clin Lipidol. 2021; 15: 61-67
        • Ahn Y.
        • Kwon E.
        • Shim J.E.
        • et al.
        Validation and reproducibility of food frequency questionnaire for Korean genome epidemiologic study.
        Eur. J. Clin. Nutr. 2007; 61: 1435-1441