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
Graphical Abstract
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to AtherosclerosisAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Global burden of cardiovascular diseases and risk factors, 1990-2019: update from the GBD 2019 study.J. Am. Coll. Cardiol. 2020; 76: 2982-3021
- European society of cardiology: cardiovascular disease statistics 2019.Eur. Heart J. 2020; 41: 12-85
- Residual cardiovascular risk despite optimal LDL cholesterol reduction with statins: the evidence, etiology, and therapeutic challenges.Curr. Atherosclerosis Rep. 2012; 14: 1-10
- 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk.Eur. Heart J. 2020; 41: 111-188
- Residual atherosclerotic cardiovascular disease risk in statin-treated adults: the Multi-Ethnic Study of Atherosclerosis.J Clin Lipidol. 2017; 11: 1223-1233
- Prevalence of conventional risk factors in patients with coronary heart disease.JAMA. 2003; 290: 898-904
- Therapeutic potential of ketone bodies for patients with cardiovascular disease: JACC focus seminar.J. Am. Coll. Cardiol. 2021; 177: 1660-1669
- Ketone body metabolism and cardiovascular disease.Am. J. Physiol. Heart Circ. Physiol. 2013; 304: H1060-H1076
- Multi-dimensional roles of ketone bodies in fuel metabolism, signaling, and therapeutics.Cell Metabol. 2017; 25: 262-284
- Nutritional ketosis and mitohormesis: potential implications for mitochondrial function and human health.J Nutr Metab. 2018; 2018: 5157645
- Ketone bodies as signaling metabolites.Trends Endocrinol. Metabol. 2014; 25: 42-52
- Effects of ketogenic diet and ketone bodies on the cardiovascular system: concentration matters.World J. Diabetes. 2020; 11: 584-595
- Nutritional ketosis for weight management and reversal of metabolic syndrome.Curr Nutr Rep. 2018; 7: 97-106
- Clinical aspects of the ketogenic diet.Epilepsia. 2007; 48: 31-42
- 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
- Ketone bodies: a review of physiology, pathophysiology and application of monitoring to diabetes.Diabetes Metab Res Rev. 1999; 15: 412-426
- Ketonuria after fasting may be related to the metabolic superiority.J. Kor. Med. Sci. 2010; 25: 1771-1776
- Spontaneous ketonuria and risk of incident diabetes: a 12 year prospective study.Diabetologia. 2019; 62: 779-788
- 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
- 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
- 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
- Metabolically-healthy obesity and coronary artery calcification.J. Am. Coll. Cardiol. 2014; 63: 2679-2686
- 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
- International physical activity questionnaire: 12-country reliability and validity.Med. Sci. Sports Exerc. 2003; 35: 1381-1395
- 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
- Quantification of coronary artery calcium using ultrafast computed tomography.J. Am. Coll. Cardiol. 1990; 15: 827-832
- Coronary artery calcification and cardiovascular risk factors: impact of the analytic approach.Atherosclerosis. 2004; 173: 69-78
- Adipokines, insulin resistance, and coronary artery calcification.J. Am. Coll. Cardiol. 2008; 52: 231-236
- Epidemiology: beyond the Basics.Jones & Bartlett Learning, 2007
- The Asia-Pacific Perspective: Redefining Obesity and its Treatment.Health Communications Australia, Sydney2000
- Risk factors for long-term coronary artery calcium progression in the multi-ethnic study of atherosclerosis.J. Am. Heart Assoc. 2015; 4e001726
- 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
- The effect of a low-carbohydrate, ketogenic diet on nonalcoholic fatty liver disease: a pilot study.Dig. Dis. Sci. 2007; 52: 589-593
- Effects of ketogenic diets on cardiovascular risk factors: evidence from animal and human studies.Nutrients. 2017; 9
- 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
- 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
- The presence of urinary ketones according to metabolic status and obesity.J. Kor. Med. Sci. 2020; 35 (e273-e273)
- Resistance to ketonuria and ketosis in obese subjects.Am. J. Clin. Nutr. 1974; 27: 1212-1213
- Resistance to ketosis in obese subjects.Lancet. 1959; 2: 1157-1159
- 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
- Flipping the metabolic switch: understanding and applying the health benefits of fasting.Obesity. 2018; 26: 254-268
- Impact of intermittent fasting on health and disease processes.Ageing Res. Rev. 2017; 39: 46-58
- The ketogenic diet: pros and cons.Atherosclerosis. 2020; 292: 119-126
- Ketogenic diets, not for everyone.J Clin Lipidol. 2021; 15: 61-67
- Validation and reproducibility of food frequency questionnaire for Korean genome epidemiologic study.Eur. J. Clin. Nutr. 2007; 61: 1435-1441
Article info
Publication history
Published online: March 29, 2022
Accepted:
March 15,
2022
Received in revised form:
February 25,
2022
Received:
November 1,
2021
Identification
Copyright
© 2022 Elsevier B.V. All rights reserved.
