Research Progress on the Application and Mechanisms of β-Hydroxybutyrate Supplementation in Cardiovascular Diseases

Authors

    Tingting Li, Hui Zhang, Mingchen Zhang, Xiaowen Wang, Zhongguang Sun Department of Rehabilitation Medicine, The Fourth Affiliated Hospital of Soochow University, Suzhou 215000, China Department of Rehabilitation Medicine, Shandong Public Health Clinical Center, Jinan 250132, China School of Rehabilitation Medicine, Shandong Second Medical University, Weifang 261053, China School of Rehabilitation Medicine, Shandong Second Medical University, Weifang 261053, China School of Rehabilitation Medicine, Shandong Second Medical University, Weifang 261053, China

Keywords:

β-Hydroxybutyrate, Ketogenic diet, Cardiovascular diseases, Nutritional ketosis

Abstract

The prevention and treatment of cardiovascular diseases have always been a focal point in related fields. This paper explores the application and underlying mechanisms of exogenous and endogenous β-hydroxybutyrate supplementation in addressing cardiovascular diseases, including myocardial ischemia, myocardial infarction, diabetic cardiomyopathy, hypertension, myocardial inflammation, hypertrophic cardiomyopathy, and heart failure. Exogenous β-hydroxybutyrate supplementation offers a rapid and direct energy source for the heart, thereby aiding in the prevention and management of cardiac injury. Notably, the overall efficacy of exogenous β-hydroxybutyrate is markedly superior to that of endogenous β-hydroxybutyrate. Endogenous fatty acids, derived from a ketogenic diet, undergo oxidation to form β-hydroxybutyrate in the body for energy production. However, this process is significantly influenced by glucose and lipid metabolism, particularly in the context of underlying health conditions. Currently, the use of a ketogenic diet is not advocated for the prevention or treatment of myocardial ischemia, myocardial infarction, diabetic cardiomyopathy, or hypertension.

References

Stubbs BJ, Cox PJ, Evans RD, et al., 2017, On the Metabolism of Exogenous Ketones in Humans. Front Physiol, 8: 848.

Ma LY, Wang ZW, Fan J, et al., 2022, Interpretation of China Cardiovascular Health and Disease Report 2021. Chin Gen Pract, 25(27): 3331–3346.

Wang XF, Lu YL, Sun XC, et al., 2023, Cardiovascular Death Trend and Prediction Analysis of the Elderly in China from 2009 to 2019. Mod Prev Med, 50(1): 39–45.

Abdul KA, Clarke K, Evans RD, 2020, Cardiac Ketone Body Metabolism. Biochim Biophys Acta Mol Basis Dis, 1866(6): 165739.

Falkenhain K, Daraei A, Forbes SC, et al., 2022, Effects of Exogenous Ketone Supplementation on Blood Glucose: A Systematic Review and Meta-Analysis. Adv Nutr, 13(5): 1697–1714.

Gormsen LC, Svart M, Thomsen HH, et al., 2017, Ketone Body Infusion with 3-Hydroxybutyrate Reduces Myocardial Glucose Uptake and Increases Blood Flow in Humans: A Positron Emission Tomography Study. J Am Heart Assoc, 6(3): e005066.

Ho KL, Karwi QG, Wagg C, et al., 2021, Ketones Can Become the Major Fuel Source for the Heart But Do Not Increase Cardiac Efficiency. Cardiovasc Res, 117(4): 1178–1187.

Leone A, De AR, Lessa C, et al., 2019, Food and Food Products on the Italian Market for Ketogenic Dietary Treatment of Neurological Diseases. Nutrients, 11(5): 1104.

Williams KA, 2019, Nutrition, Risk Factors, Prevention, and Imaging: The 2018 Mario Verani Lecture. J Nucl Cardiol, 26(1): 86–91.

Yu Y, Wang F, Wang J, et al., 2020, Ketogenic Diet Attenuates Aging-Associated Myocardial Remodeling and Dysfunction in Mice. Exp Gerontol, 140: 111058.

Lindsay RT, Dieckmann S, Krzyzanska D, et al., 2021, β-Hydroxybutyrate Accumulates in the Rat Heart During Low-Flow Ischaemia with Implications for Functional Recovery. Elife, 10: e71270.

Dong AQ, Zhang XL, Lin SP, et al., 2022, β-Hydroxybutyric Acid Inhibits Cell Death and Reduces Myocardial Ischemia-Reperfusion Injury. Chin Heart J, 34(01): 12–17.

Yu Y, Yu Y, Zhang Y, et al., 2018, Treatment with D-β-Hydroxybutyrate Protects Heart from Ischemia/Reperfusion Injury in Mice. Eur J Pharmacol, 829: 121–128.

Liu W, Jiang Z, Yao YT, et al., 2022, Effect of Plasma β-Hydroxybutyric Acid on Cardiac Death in Patients with ST-Segment Elevation Myocardial Infarction. J Guizhou Med Univ, 47(12): 1448–1452.

Zou Z, Sasaguri S, Rajesh KG, et al., 2002, Dl-3-Hydroxybutyrate Administration Prevents Myocardial Damage After Coronary Occlusion in Rat Hearts. Am J Physiol Heart Circ Physiol, 283(5): H1968–H1974.

Liu TT, Dong HY, Ma YL, et al., 2022, D-β-Hydroxybutyric Acid Improves Acute Myocardial Infarction in Rats by Activating Notch1/Hes1 Pathway and Inhibiting Endoplasmic Reticulum Stress. Med J West Chin, 34(12): 1736–1742.

Dai B, Li H, Fan J, et al., 2018, MiR-21 Protected Against Diabetic Cardiomyopathy Induced Diastolic Dysfunction by Targeting Gelsolin. Cardiovasc Diabetol, 17(1): 123.

Thai PN, Miller CV, King MT, et al., 2021, Ketone Ester D-β-Hydroxybutyrate-(R)-1,3 Butanediol Prevents Decline in Cardiac Function in Type 2 Diabetic Mice. J Am Heart Assoc, 10(19): e020729.

Qi H, Gu L, Xu D, et al., 2021, β-Hydroxybutyrate Inhibits Cardiac Microvascular Collagen 4 Accumulation by Attenuating Oxidative Stress in Streptozotocin-Induced Diabetic Rats and High Glucose Treated Cells. Eur J Pharmacol, 899: 174012.

Oka SI, Tang F, Chin A, et al., 2021, β-Hydroxybutyrate, a Ketone Body, Potentiates the Antioxidant Defense via Thioredoxin 1 Upregulation in Cardiomyocytes. Antioxidants (Basel), 10(7): 1153.

Zhao J, Peng HL, Han JL, et al., 2023, Relationship between Serum β-Hydroxybutyric Acid Concentration and Left Ventricular Hypertrophy in Patients with Diabetic Kidney Disease. J Clin Nephrol, 23(01): 24–30.

Walsh JJ, Neudorf H, Little JP, et al., 2021, 14-Day Ketone Supplementation Lowers Glucose and Improves Vascular Function in Obesity: A Randomized Crossover Trial. J Clin Endocrinol Metab, 106(4): e1738–e1754.

McCarthy CG, Waigi EW, Yeoh BS, et al., 2022, Low-Dose 1,3-Butanediol Reverses Age-Associated Vascular Dysfunction Independent of Ketone Body β-Hydroxybutyrate. Am J Physiol Heart Circ Physiol, 322(3): H466–H473.

Qian LW, Deng Y, Li T, et al., 2021, Study on the Mechanism of Keto-β-Hydroxybutyric Acid in Alleviating Oxidative Stress in Mitochondria of Vascular Endothelial Cells in Inflammatory State. J Sichuan Univ (Med Sci), 52(6): 954–959.

Ji L, He Q, Liu Y, et al., 2022, Ketone Body Β-Hydroxybutyrate Prevents Myocardial Oxidative Stress in Septic Cardiomyopathy. Oxid Med Cell Longev, 2022: 2513837.

Liu Y, Wei X, Wu M, et al., 2020, Cardioprotective Roles of β-Hydroxybutyrate Against Doxorubicin Induced Cardiotoxicity. Front Pharmacol, 11: 603596.

Takahara S, Soni S, Phaterpekar K, et al., 2021, Chronic Exogenous Ketone Supplementation Blunts the Decline of Cardiac Function in the Failing Heart. ESC Heart Fail, 8(6): 5606–5612.

Nagao M, Toh R, Irino Y, et al., 2016, β-Hydroxybutyrate Elevation as a Compensatory Response Against Oxidative Stress in Cardiomyocytes. Biochem Biophys Res Commun, 475(4): 322–328.

Murashige D, Jang C, Neinast M, et al., 2020, Comprehensive Quantification of Fuel Use by the Failing and Nonfailing Human Heart. Science, 370(6514): 364–368.

Monzo L, Sedlacek K, Hromanikova K, et al., 2021, Myocardial Ketone Body Utilization in Patients with Heart Failure: The Impact of Oral Ketone Ester. Metabolism, 115: 154452.

White H, Heffernan AJ, Worrall S, et al., 2021, A Systematic Review of Intravenous β-Hydroxybutyrate Use in Humans - A Promising Future Therapy? Front Med (Lausanne), 8: 740374.

Nielsen R, Møller N, Gormsen LC, et al., 2019, Cardiovascular Effects of Treatment with the Ketone Body 3-Hydroxybutyrate in Chronic Heart Failure Patients. Circulation, 139(18): 2129–2141.

Thai PN, Seidlmayer LK, Miller C, et al., 2019, Mitochondrial Quality Control in Aging and Heart Failure: Influence of Ketone Bodies and Mitofusin-Stabilizing Peptides. Front Physiol, 10: 382.

Yurista SR, Matsuura TR, Silljé HHW, et al., 2021, Ketone Ester Treatment Improves Cardiac Function and Reduces Pathologic Remodeling in Preclinical Models of Heart Failure. Circ Heart Fail, 14(1): e007684.

Liao S, Tang Y, Yue X, et al., 2021, β-Hydroxybutyrate Mitigated Heart Failure with Preserved Ejection Fraction by Increasing Treg Cells via Nox2/GSK-3β. J Inflamm Res, 14: 4697–4706.

Liu J, Lloyd SG, 2013, High-Fat, Low-Carbohydrate Diet Alters Myocardial Oxidative Stress and Impairs Recovery of Cardiac Function After Ischemia and Reperfusion in Obese Rats. Nutr Res, 33(4): 311–321.

Taha A, Ahmed S, Ahmed MR, et al., 2022, Type 2 Myocardial Infarction Related to Very Low Carbohydrate Ketogenic Diet. J Investig Med High Impact Case Rep, 10: 23247096221074879.

Guo Y, Zhang C, Shang FF, et al., 2020, Ketogenic Diet Ameliorates Cardiac Dysfunction via Balancing Mitochondrial Dynamics and Inhibiting Apoptosis in Type 2 Diabetic Mice. Aging Dis, 11(2): 229–240.

Brahma MK, Ha CM, Pepin ME, et al., 2020, Increased Glucose Availability Attenuates Myocardial Ketone Body Utilization. J Am Heart Assoc, 9(15): e013039.

Tao J, Chen H, Wang YJ, et al., 2021, Ketogenic Diet Suppressed T-Regulatory Cells and Promoted Cardiac Fibrosis via Reducing Mitochondria-Associated Membranes and Inhibiting Mitochondrial Function. Oxid Med Cell Longev, 2021: 5512322.

You Y, Guo Y, Jia P, et al., 2020, Ketogenic Diet Aggravates Cardiac Remodeling in Adult Spontaneously Hypertensive Rats. Nutr Metab (Lond), 17: 91.

Guo Y, Wang X, Jia P, et al., 2020, Ketogenic Diet Aggravates Hypertension via NF-κB-Mediated Endothelial Dysfunction in Spontaneously Hypertensive Rats. Life Sci, 258: 118124.

Clément A, Boutley H, Poussier S, et al., 2020, A 1-Week Extension of a Ketogenic Diet Provides a Further Decrease in Myocardial (18)F-FDG Uptake and a High Detectability of Myocarditis with FDG-PET. J Nucl Cardiol, 27(2): 612-618.

Aubert G, Martin OJ, Horton JL, et al., 2016, The Failing Heart Relies on Ketone Bodies as a Fuel. Circulation, 133(8): 698–705.

Nakamura M, Odanovic N, Nakada Y, et al., 2021, Dietary Carbohydrates Restriction Inhibits the Development of Cardiac Hypertrophy and Heart Failure. Cardiovasc Res, 117(11): 2365–2376.

Uchihashi M, Hoshino A, Okawa Y, et al., 2017, Cardiac-Specific Bdh1 Overexpression Ameliorates Oxidative Stress and Cardiac Remodeling in Pressure Overload-Induced Heart Failure. Circ Heart Fail, 10(12): e004417.

Horton JL, Davidson MT, Kurishima C, et al., 2019, The Failing Heart Utilizes 3-Hydroxybutyrate as a Metabolic Stress Defense. JCI Insight, 4(4): 124079.

Murano C, Binda A, Palestini P, et al., 2021, Effect of the Ketogenic Diet in Excitable Tissues. Am J Physiol Cell Physiol, 320(4): C547–C553.

Byrne NJ, Soni S, Takahara S, et al., 2020, Chronically Elevating Circulating Ketones can Reduce Cardiac Inflammation and Blunt the Development of Heart Failure. Circ Heart Fail, 13(6): e006573.

Guo Y, Liu X, Li T, et al., 2022, Alternate-Day Ketogenic Diet Feeding Protects Against Heart Failure through Preservation of Ketogenesis in the Liver. Oxid Med Cell Longev, 2022: 4253651.

Meroni E, Papini N, Criscuoli F, et al., 2018, Metabolic Responses in Endothelial Cells Following Exposure to Ketone Bodies. Nutrients, 10(2): 250.

Challa AA, Lewandowski ED, 2022, Short-Chain Carbon Sources: Exploiting Pleiotropic Effects for Heart Failure Therapy. JACC Basic Transl Sci, 7(7): 730–742.

Liu SH, Nan WW, Li XL, et al., 2021, Clinical Application and Research Progress of Ketogenic Diet. Progress in Physiological Sciences, 52(6): 445–450.

Luong TV, Nielsen EN, Falborg L, et al., 2023, Intravenous and Oral Whole Body Ketone Dosimetry, Biodistribution, Metabolite Correction, and Kinetics Studied by (R)-[1-11C]β-Hydroxybutyrate ([11C]OHB) PET in Healthy Humans. EJNMMI Radiopharm Chem, 8(1): 12.

Willeford A, Suetomi T, Nickle A, et al., 2018, CaMKIIδ-Mediated Inflammatory Gene Expression and Inflammasome Activation in Cardiomyocytes Initiate Inflammation and Induce Fibrosis. JCI Insight, 3(12): e97054.

Xu S, Tao H, Cao W, et al., 2021, Ketogenic Diets Inhibit Mitochondrial Biogenesis and Induce Cardiac Fibrosis. Signal Transduct Target Ther, 6(1): 54.

Buga A, Kackley ML, Crabtree CD, et al., 2021, The Effects of a 6-Week Controlled, Hypocaloric Ketogenic Diet, with and without Exogenous Ketone Salts, on Body Composition Responses. Front Nutr, 8: 618520.

Zhang Q, Xu L, Xia J, et al., 2018, Treatment of Diabetic Mice with a Combination of Ketogenic Diet and Aerobic Exercise via Modulations of PPARs Gene Programs. PPAR Res, 2018: 4827643.

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Published

2024-12-27