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Применение экзогенных кетонов для терапии сердечной недостаточности
Применение экзогенных кетонов для терапии сердечной недостаточности
Аксенова Ю.О., Осмоловская Ю.Ф., Жиров И.В., Бениашвили А.Г., Морозова М.А., Терещенко С.Н. Применение экзогенных кетонов для терапии сердечной недостаточности. Consilium Medicum. 2023;25(1):46–51. DOI: 10.26442/20751753.2023.1.202174
© ООО «КОНСИЛИУМ МЕДИКУМ», 2023 г.
DOI: 10.26442/20751753.2023.1.202174
© ООО «КОНСИЛИУМ МЕДИКУМ», 2023 г.
________________________________________________
DOI: 10.26442/20751753.2023.1.202174
Материалы доступны только для специалистов сферы здравоохранения. Авторизуйтесь или зарегистрируйтесь.
Аннотация
Сердечная недостаточность имеет важное клиническое и экономическое значение и остается серьезной проблемой для здравоохранения в мире. Несмотря на существующие подходы к лечению, уровень заболеваемости и смертности у данных пациентов остается высоким. Прогрессирование сердечной недостаточности сопровождается увеличением метаболизма кетоновых тел. Применение экзогенных кетонов может стать новым терапевтическим подходом к повышению эффективности работы сердца, уменьшению дефицита энергии и улучшению сердечной функции у пациентов с сердечной недостаточностью. В обзоре представлены имеющиеся данные о метаболизме кетоновых тел у пациентов с сердечной недостаточностью, доклинические и клинические исследования, демонстрирующие положительные эффекты терапии экзогенными кетонами в исследованиях на животных моделях и людях с сердечной недостаточностью, описаны потенциальные плюсы и минусы использования этого терапевтического подхода.
Ключевые слова: cердечная недостаточность, метаболизм, кетоны, кетоновые тела, β-гидроксибутират
Keywords: heart failure, metabolism, ketones, ketone bodies, β-hydroxybutyrate
Ключевые слова: cердечная недостаточность, метаболизм, кетоны, кетоновые тела, β-гидроксибутират
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Keywords: heart failure, metabolism, ketones, ketone bodies, β-hydroxybutyrate
Полный текст
Список литературы
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27. O’Rourke B, Ashok D, Liu T. Mitochondrial Ca(2+) in heart failure: Not enough or too much? J Mol Cell Cardiol. 2020;151:126-34. DOI:10.1016/j.yjmcc.2020.11.014
28. Sheeran FL, Angerosa J, Liaw NY, et al. Adaptations in Protein Expression and Regulated Activity of Pyruvate Dehydrogenase Multienzyme Complex in Human Systolic Heart Failure. Oxid Med Cell Longev. 2019;2019:4532592. DOI:10.1155/2019/4532592
29. McCommis KS, Kovacs A, Weinheimer CJ, et al. Nutritional Modulation of Heart Failure in Mitochondrial Pyruvate Carrier-Deficient Mice. Nat Metab. 2020;2(11):1232-47. DOI:10.1038/s42255-020-00296-1
30. Bedi KC Jr, Snyder NW, Brandimarto J, et al. Evidence for intramyocardial disruption of lipid metabolism and increased myocardial ketone utilization in advanced human heart failure. Circulation. 2016;133:706-16. DOI:10.1161/CIRCULATIONAHA.115.017545
31. Aubert G, Martin OJ, Horton JL, et al. The failing heart relies on ketone bodies as a fuel. Circulation. 2016;133:698-705. DOI:10.1161/CIRCULATIONAHA.115.017355
32. Cox PJ, Kirk T, Ashmore T, et al. Nutritional ketosis alters fuel preference and thereby endurance performance in athletes. Cell Metab. 2016;24:256-68. DOI:10.1016/j.cmet.2016.07.010
33. Gormsen LC, Svart M, Thomsen HH, et al. 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. 2017;6(3):e005066. DOI:10.1161/JAHA.116.005066
34. Nielsen R, Moller N, Gormsen LC, et al. Cardiovascular effects of treatment with the ketone body 3-hydroxybutyrate in chronic heart failure patients. Circulation. 2019;139:2129-41. DOI:10.1161/CIRCULATIONAHA.118.036459
35. Volek JS, Phinney SD. The Art and Science of Low Carbohydrate Performance: A Revolutionary Program to Extend Your Physical and Mental Performance Envelope. Miami, FL: Beyond Obesity LLC, 2012.
36. Shaw DM, Merien F, Braakhuis A, et al. The effect of 1,3-butanediol on cycling time-trial performance. Int J Sport Nutr Exerc Metab. 2019;29:466-73. DOI:10.1123/ijsnem.2018-0284
37. Scott BE, Laursen PB, James LJ, et al. The effect of 1,3-butanediol and carbohydrate supplementation on running performance. J Sci Med Sport. 2019;22:702-6. DOI:10.1016/j.jsams.2018.11.027
38. Cunnane SC, Courchesne-Loyer A, Vandenberghe C, et al. Can ketones help rescue brain fuel supply in later life? Implications for cognitive health during aging and the treatment of Alzheimer’s disease. Front Mol Neurosci. 2016;9:53. DOI:10.3389/fnmol.2016.00053
39. Harvey CJC, Schofield GM, Williden M, McQuillan JA. The effect of medium chain triglycerides on time to nutritional ketosis and symptoms of keto-induction in healthy adults: a randomised controlled clinical trial. J Nutr Metab. 2018;2018:2630565. DOI:10.1155/2018/2630565
40. Stubbs BJ, Cox PJ, Kirk T, et al. Gastrointestinal effects of exogenous ketone drinks are infrequent, mild, and vary according to ketone compound and dose. Int J Sport Nutr Exerc Metab. 2019;29:596-603. DOI:10.1123/ijsnem.2019-0014
41. Packer M, Anker SD, Butler J, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med. 2020;383:1413-24. DOI:10.1056/NEJMoa2022190
42. Bonner C, Kerr-Conte J, Gmyr V, et al. Inhibition of the glucose transporter SGLT2 with dapagliflozin in pancreatic alpha cells triggers glucagon secretion. Nat Med. 2015;21:512-7. DOI:10.1038/nm.3828
43. Ferrannini E, Baldi S, Frascerra S, et al. Shift to fatty substrate utilization in response to sodium–glucose cotransporter 2 inhibition in subjects without diabetes and patients with type 2 diabetes. Diabetes. 2016;65(5):1190-5. DOI:10.2337/db15-1356
44. Lopaschuk GD, Verma S. Mechanisms of cardiovascular benefits of sodium glucose co-transporter 2 (SGLT2) inhibitors. J Am Coll Cardiol Basic Transl Sci. 2020;5:632-44. DOI:10.1016/j.jacbts.2020.02.004
45. Vishwanath S, Qaderi V, Steves CJ, et al. Cognitive Decline and Risk of Dementia in Individuals With Heart Failure: A Systematic Review and Meta-analysis. J Card Fail. 2022;28(8):1337-48. DOI:10.1016/j.cardfail.2021.12.014
46. Yap NLX, Kor Q, Teo YN, et al. Prevalence and incidence of cognitive impairment and dementia in heart failure – A systematic review, meta-analysis and meta-regression. Hellenic J Cardiol. 2022;67:48-58. DOI:10.1016/j.hjc.2022.07.005
47. Poff AM, Moss S, Soliven M, D'Agostino DP. Ketone Supplementation: Meeting the Needs of the Brain in an Energy Crisis. Front Nutr. 2021;8:783659. DOI:10.3389/fnut.2021.783659
2. Neubauer S. The failing heart – an engine out of fuel. N Engl J Med. 2007;356:1140-151. DOI:10.1056/NEJMra063052
3. Selvaraj S, Kelly DP, Kenneth B. Margulies Implications of Altered Ketone Metabolism and Therapeutic Ketosis in Heart Failure. Circulation. 2020;141(22):1800-12. DOI:10.1161/CIRCULATIONAHA.119.045033
4. Bedi KC Jr, Snyder NW, Brandimarto J, et al. Evidence for intramyocardial disruption of lipid metabolism and increased myocardial ketone utilization in advanced human heart failure. Circulation. 2016;133:706-16. DOI:10.1161/CIRCULATIONAHA.115.017545
5. Lopaschuk GD, Karwi QG, Tian R, et al. Cardiac Energy Metabolism in Heart Failure. Circ Res. 2021;128(10):1487-513. DOI:10.1161/CIRCRESAHA.121.318241
6. Takahara S, Soni S, Maayah ZH, et al. Ketone therapy for heart failure: Current evidence for clinical use. Cardiovasc Res. 2022;118:97-87. DOI:10.1093/cvr/cvab068
7. Puchalska P, Crawford PA. Multi-dimensional roles of ketone bodies in fuel metabolism, signaling, and therapeutics. Cell Metab. 2017;25:262-84. DOI:10.1016/j.cmet.2016.12.022
8. Karwi QG, Uddin GM, Ho KL, Lopaschuk GD. Loss of metabolic flexibility in the failing heart. Front Cardiovasc Med. 2018;5:68. DOI:10.3389/fcvm.2018.00068
9. Nielsen R, Moller N, Gormsen LC, et al. Cardiovascular effects of treatment with the ketone body 3-hydroxybutyrate in chronic heart failure patients. Circulation. 2019;139:2129-41. DOI:10.1161/CIRCULATIONAHA.118.036459
10. Horton JL, Davidson MT, Kurishima C, et al. The failing heart utilizes 3-hydroxybutyrate as a metabolic stress defense. JCI Insight. 2019;4:e124079. DOI:10.1172/jci.insight.124079
11. Pietschner R, Kolwelter J, Bosch A, et al. Effect of empagliflozin on ketone bodies in patients with stable chronic heart failure. Cardiovasc Diabetol. 2021;20:219. DOI:10.1186/s12933-021-01410-7
12. McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019;381:1995-2008. DOI:10.1056/NEJMoa1911303
13. Murthy MS, Pande SV. Malonyl-CoA binding site and the overt carnitine palmitoyltransferase activity reside on the opposite sides of the outer mitochondrial membrane. Proc Natl Acad Sci U S A. 1987;84(2):378-82. DOI:10.1073/pnas.84.2.378
14. Hui S, Ghergurovich JM, Morscher RJ, et al. Glucose feeds the tca cycle via circulating lactate. Nature. 2017;551:115-8. DOI:10.1038/nature24057
15. Ho KL, Karwi QG, Wagg C, et al. Ketones can become the major fuel source for the heart but do not increase cardiac efficiency. Cardiovasc Res. 2020. DOI:10.1093/cvr/cvaa143
16. Evans M, McClure TS, Koutnik AP, Egan B. Exogenous Ketone Supplements in Athletic Contexts: Past, Present, and Future. Sports Med. 2022;52(Suppl. 1):25-67.
DOI:10.1007/s40279-022-01756-2
17. Balasse EO, Féry F. Ketone body production and disposal: effects of fasting, diabetes, and exercise. Diabetes Metab Rev. 1989;5:247-70. DOI:10.1002/dmr.5610050304
18. Laffel L. Ketone bodies: a review of physiology, pathophysiology and application of monitoring to diabetes. Diabetes Metab Res Rev. 1999;15:412-26. DOI:10.1002/(SICI)1520-7560(199911/12)15:6<412::AID-DMRR72>3.0.CO;2-8
19. Fukao T, Lopaschuk GD, Mitchell GA, et al. Pathways and control of ketone body metabolism: on the fringe of lipid biochemistry. Prostaglandins Leukot Essent Fat Acids. 2004;70:243-51. DOI:10.1016/j.plefa.2003.11.001
20. Halestrap AP, Wilson MC. The monocarboxylate transporter family – role and regulation. IUBMB Life. 2012;64(2):109-19. DOI:10.1002/iub.572
21. Fukao T, Song XQ, Mitchell GA, et al. Enzymes of ketone body utilization in human tissues: protein and messenger RNA levels of succinyl-coenzyme A (CoA):3-ketoacid CoA transferase and mitochondrial and cytosolic acetoacetyl-CoA thiolases. Pediatr Res. 1997;42(4):498-502. DOI:10.1203/00006450-199710000-00013
22. Cox PJ, Kirk T, Ashmore T, et al. Nutritional ketosis alters fuel preference and thereby endurance performance in athletes. Cell Metab. 2016;24:256-68. DOI:10.1016/j.cmet.2016.07.010
23. Neubauer S. The failing heart – an engine out of fuel. N Engl J Med. 2007;356(11):1140-51. DOI:10.1056/NEJMra063052
24. Zhou B, Tian R. Mitochondrial dysfunction in pathophysiology of heart failure. J Clin Invest. 2018;128(9):3716-26. DOI:10.1172/JCI120849
25. Shanmugam G, Wang D, Gounder SS, et al. Reductive stress causes pathological cardiac remodeling and diastolic dysfunction. Antioxid Redox Signal. 2020;32:1293-312. DOI:10.1089/ars.2019.7808
26. Tsutsui H, Kinugawa S, Matsushima S. Oxidative stress and heart failure. Am J Physiol Heart Circ Physiol. 2011;301:H2181-90. DOI:10.1152/ajpheart.00554.2011
27. O’Rourke B, Ashok D, Liu T. Mitochondrial Ca(2+) in heart failure: Not enough or too much? J Mol Cell Cardiol. 2020;151:126-34. DOI:10.1016/j.yjmcc.2020.11.014
28. Sheeran FL, Angerosa J, Liaw NY, et al. Adaptations in Protein Expression and Regulated Activity of Pyruvate Dehydrogenase Multienzyme Complex in Human Systolic Heart Failure. Oxid Med Cell Longev. 2019;2019:4532592. DOI:10.1155/2019/4532592
29. McCommis KS, Kovacs A, Weinheimer CJ, et al. Nutritional Modulation of Heart Failure in Mitochondrial Pyruvate Carrier-Deficient Mice. Nat Metab. 2020;2(11):1232-47. DOI:10.1038/s42255-020-00296-1
30. Bedi KC Jr, Snyder NW, Brandimarto J, et al. Evidence for intramyocardial disruption of lipid metabolism and increased myocardial ketone utilization in advanced human heart failure. Circulation. 2016;133:706-16. DOI:10.1161/CIRCULATIONAHA.115.017545
31. Aubert G, Martin OJ, Horton JL, et al. The failing heart relies on ketone bodies as a fuel. Circulation. 2016;133:698-705. DOI:10.1161/CIRCULATIONAHA.115.017355
32. Cox PJ, Kirk T, Ashmore T, et al. Nutritional ketosis alters fuel preference and thereby endurance performance in athletes. Cell Metab. 2016;24:256-68. DOI:10.1016/j.cmet.2016.07.010
33. Gormsen LC, Svart M, Thomsen HH, et al. 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. 2017;6(3):e005066. DOI:10.1161/JAHA.116.005066
34. Nielsen R, Moller N, Gormsen LC, et al. Cardiovascular effects of treatment with the ketone body 3-hydroxybutyrate in chronic heart failure patients. Circulation. 2019;139:2129-41. DOI:10.1161/CIRCULATIONAHA.118.036459
35. Volek JS, Phinney SD. The Art and Science of Low Carbohydrate Performance: A Revolutionary Program to Extend Your Physical and Mental Performance Envelope. Miami, FL: Beyond Obesity LLC, 2012.
36. Shaw DM, Merien F, Braakhuis A, et al. The effect of 1,3-butanediol on cycling time-trial performance. Int J Sport Nutr Exerc Metab. 2019;29:466-73. DOI:10.1123/ijsnem.2018-0284
37. Scott BE, Laursen PB, James LJ, et al. The effect of 1,3-butanediol and carbohydrate supplementation on running performance. J Sci Med Sport. 2019;22:702-6. DOI:10.1016/j.jsams.2018.11.027
38. Cunnane SC, Courchesne-Loyer A, Vandenberghe C, et al. Can ketones help rescue brain fuel supply in later life? Implications for cognitive health during aging and the treatment of Alzheimer’s disease. Front Mol Neurosci. 2016;9:53. DOI:10.3389/fnmol.2016.00053
39. Harvey CJC, Schofield GM, Williden M, McQuillan JA. The effect of medium chain triglycerides on time to nutritional ketosis and symptoms of keto-induction in healthy adults: a randomised controlled clinical trial. J Nutr Metab. 2018;2018:2630565. DOI:10.1155/2018/2630565
40. Stubbs BJ, Cox PJ, Kirk T, et al. Gastrointestinal effects of exogenous ketone drinks are infrequent, mild, and vary according to ketone compound and dose. Int J Sport Nutr Exerc Metab. 2019;29:596-603. DOI:10.1123/ijsnem.2019-0014
41. Packer M, Anker SD, Butler J, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med. 2020;383:1413-24. DOI:10.1056/NEJMoa2022190
42. Bonner C, Kerr-Conte J, Gmyr V, et al. Inhibition of the glucose transporter SGLT2 with dapagliflozin in pancreatic alpha cells triggers glucagon secretion. Nat Med. 2015;21:512-7. DOI:10.1038/nm.3828
43. Ferrannini E, Baldi S, Frascerra S, et al. Shift to fatty substrate utilization in response to sodium–glucose cotransporter 2 inhibition in subjects without diabetes and patients with type 2 diabetes. Diabetes. 2016;65(5):1190-5. DOI:10.2337/db15-1356
44. Lopaschuk GD, Verma S. Mechanisms of cardiovascular benefits of sodium glucose co-transporter 2 (SGLT2) inhibitors. J Am Coll Cardiol Basic Transl Sci. 2020;5:632-44. DOI:10.1016/j.jacbts.2020.02.004
45. Vishwanath S, Qaderi V, Steves CJ, et al. Cognitive Decline and Risk of Dementia in Individuals With Heart Failure: A Systematic Review and Meta-analysis. J Card Fail. 2022;28(8):1337-48. DOI:10.1016/j.cardfail.2021.12.014
46. Yap NLX, Kor Q, Teo YN, et al. Prevalence and incidence of cognitive impairment and dementia in heart failure – A systematic review, meta-analysis and meta-regression. Hellenic J Cardiol. 2022;67:48-58. DOI:10.1016/j.hjc.2022.07.005
47. Poff AM, Moss S, Soliven M, D'Agostino DP. Ketone Supplementation: Meeting the Needs of the Brain in an Energy Crisis. Front Nutr. 2021;8:783659. DOI:10.3389/fnut.2021.783659
2. Neubauer S. The failing heart – an engine out of fuel. N Engl J Med. 2007;356:1140-151. DOI:10.1056/NEJMra063052
3. Selvaraj S, Kelly DP, Kenneth B. Margulies Implications of Altered Ketone Metabolism and Therapeutic Ketosis in Heart Failure. Circulation. 2020;141(22):1800-12. DOI:10.1161/CIRCULATIONAHA.119.045033
4. Bedi KC Jr, Snyder NW, Brandimarto J, et al. Evidence for intramyocardial disruption of lipid metabolism and increased myocardial ketone utilization in advanced human heart failure. Circulation. 2016;133:706-16. DOI:10.1161/CIRCULATIONAHA.115.017545
5. Lopaschuk GD, Karwi QG, Tian R, et al. Cardiac Energy Metabolism in Heart Failure. Circ Res. 2021;128(10):1487-513. DOI:10.1161/CIRCRESAHA.121.318241
6. Takahara S, Soni S, Maayah ZH, et al. Ketone therapy for heart failure: Current evidence for clinical use. Cardiovasc Res. 2022;118:97-87. DOI:10.1093/cvr/cvab068
7. Puchalska P, Crawford PA. Multi-dimensional roles of ketone bodies in fuel metabolism, signaling, and therapeutics. Cell Metab. 2017;25:262-84. DOI:10.1016/j.cmet.2016.12.022
8. Karwi QG, Uddin GM, Ho KL, Lopaschuk GD. Loss of metabolic flexibility in the failing heart. Front Cardiovasc Med. 2018;5:68. DOI:10.3389/fcvm.2018.00068
9. Nielsen R, Moller N, Gormsen LC, et al. Cardiovascular effects of treatment with the ketone body 3-hydroxybutyrate in chronic heart failure patients. Circulation. 2019;139:2129-41. DOI:10.1161/CIRCULATIONAHA.118.036459
10. Horton JL, Davidson MT, Kurishima C, et al. The failing heart utilizes 3-hydroxybutyrate as a metabolic stress defense. JCI Insight. 2019;4:e124079. DOI:10.1172/jci.insight.124079
11. Pietschner R, Kolwelter J, Bosch A, et al. Effect of empagliflozin on ketone bodies in patients with stable chronic heart failure. Cardiovasc Diabetol. 2021;20:219. DOI:10.1186/s12933-021-01410-7
12. McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019;381:1995-2008. DOI:10.1056/NEJMoa1911303
13. Murthy MS, Pande SV. Malonyl-CoA binding site and the overt carnitine palmitoyltransferase activity reside on the opposite sides of the outer mitochondrial membrane. Proc Natl Acad Sci U S A. 1987;84(2):378-82. DOI:10.1073/pnas.84.2.378
14. Hui S, Ghergurovich JM, Morscher RJ, et al. Glucose feeds the tca cycle via circulating lactate. Nature. 2017;551:115-8. DOI:10.1038/nature24057
15. Ho KL, Karwi QG, Wagg C, et al. Ketones can become the major fuel source for the heart but do not increase cardiac efficiency. Cardiovasc Res. 2020. DOI:10.1093/cvr/cvaa143
16. Evans M, McClure TS, Koutnik AP, Egan B. Exogenous Ketone Supplements in Athletic Contexts: Past, Present, and Future. Sports Med. 2022;52(Suppl. 1):25-67.
DOI:10.1007/s40279-022-01756-2
17. Balasse EO, Féry F. Ketone body production and disposal: effects of fasting, diabetes, and exercise. Diabetes Metab Rev. 1989;5:247-70. DOI:10.1002/dmr.5610050304
18. Laffel L. Ketone bodies: a review of physiology, pathophysiology and application of monitoring to diabetes. Diabetes Metab Res Rev. 1999;15:412-26. DOI:10.1002/(SICI)1520-7560(199911/12)15:6<412::AID-DMRR72>3.0.CO;2-8
19. Fukao T, Lopaschuk GD, Mitchell GA, et al. Pathways and control of ketone body metabolism: on the fringe of lipid biochemistry. Prostaglandins Leukot Essent Fat Acids. 2004;70:243-51. DOI:10.1016/j.plefa.2003.11.001
20. Halestrap AP, Wilson MC. The monocarboxylate transporter family – role and regulation. IUBMB Life. 2012;64(2):109-19. DOI:10.1002/iub.572
21. Fukao T, Song XQ, Mitchell GA, et al. Enzymes of ketone body utilization in human tissues: protein and messenger RNA levels of succinyl-coenzyme A (CoA):3-ketoacid CoA transferase and mitochondrial and cytosolic acetoacetyl-CoA thiolases. Pediatr Res. 1997;42(4):498-502. DOI:10.1203/00006450-199710000-00013
22. Cox PJ, Kirk T, Ashmore T, et al. Nutritional ketosis alters fuel preference and thereby endurance performance in athletes. Cell Metab. 2016;24:256-68. DOI:10.1016/j.cmet.2016.07.010
23. Neubauer S. The failing heart – an engine out of fuel. N Engl J Med. 2007;356(11):1140-51. DOI:10.1056/NEJMra063052
24. Zhou B, Tian R. Mitochondrial dysfunction in pathophysiology of heart failure. J Clin Invest. 2018;128(9):3716-26. DOI:10.1172/JCI120849
25. Shanmugam G, Wang D, Gounder SS, et al. Reductive stress causes pathological cardiac remodeling and diastolic dysfunction. Antioxid Redox Signal. 2020;32:1293-312. DOI:10.1089/ars.2019.7808
26. Tsutsui H, Kinugawa S, Matsushima S. Oxidative stress and heart failure. Am J Physiol Heart Circ Physiol. 2011;301:H2181-90. DOI:10.1152/ajpheart.00554.2011
27. O’Rourke B, Ashok D, Liu T. Mitochondrial Ca(2+) in heart failure: Not enough or too much? J Mol Cell Cardiol. 2020;151:126-34. DOI:10.1016/j.yjmcc.2020.11.014
28. Sheeran FL, Angerosa J, Liaw NY, et al. Adaptations in Protein Expression and Regulated Activity of Pyruvate Dehydrogenase Multienzyme Complex in Human Systolic Heart Failure. Oxid Med Cell Longev. 2019;2019:4532592. DOI:10.1155/2019/4532592
29. McCommis KS, Kovacs A, Weinheimer CJ, et al. Nutritional Modulation of Heart Failure in Mitochondrial Pyruvate Carrier-Deficient Mice. Nat Metab. 2020;2(11):1232-47. DOI:10.1038/s42255-020-00296-1
30. Bedi KC Jr, Snyder NW, Brandimarto J, et al. Evidence for intramyocardial disruption of lipid metabolism and increased myocardial ketone utilization in advanced human heart failure. Circulation. 2016;133:706-16. DOI:10.1161/CIRCULATIONAHA.115.017545
31. Aubert G, Martin OJ, Horton JL, et al. The failing heart relies on ketone bodies as a fuel. Circulation. 2016;133:698-705. DOI:10.1161/CIRCULATIONAHA.115.017355
32. Cox PJ, Kirk T, Ashmore T, et al. Nutritional ketosis alters fuel preference and thereby endurance performance in athletes. Cell Metab. 2016;24:256-68. DOI:10.1016/j.cmet.2016.07.010
33. Gormsen LC, Svart M, Thomsen HH, et al. 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. 2017;6(3):e005066. DOI:10.1161/JAHA.116.005066
34. Nielsen R, Moller N, Gormsen LC, et al. Cardiovascular effects of treatment with the ketone body 3-hydroxybutyrate in chronic heart failure patients. Circulation. 2019;139:2129-41. DOI:10.1161/CIRCULATIONAHA.118.036459
35. Volek JS, Phinney SD. The Art and Science of Low Carbohydrate Performance: A Revolutionary Program to Extend Your Physical and Mental Performance Envelope. Miami, FL: Beyond Obesity LLC, 2012.
36. Shaw DM, Merien F, Braakhuis A, et al. The effect of 1,3-butanediol on cycling time-trial performance. Int J Sport Nutr Exerc Metab. 2019;29:466-73. DOI:10.1123/ijsnem.2018-0284
37. Scott BE, Laursen PB, James LJ, et al. The effect of 1,3-butanediol and carbohydrate supplementation on running performance. J Sci Med Sport. 2019;22:702-6. DOI:10.1016/j.jsams.2018.11.027
38. Cunnane SC, Courchesne-Loyer A, Vandenberghe C, et al. Can ketones help rescue brain fuel supply in later life? Implications for cognitive health during aging and the treatment of Alzheimer’s disease. Front Mol Neurosci. 2016;9:53. DOI:10.3389/fnmol.2016.00053
39. Harvey CJC, Schofield GM, Williden M, McQuillan JA. The effect of medium chain triglycerides on time to nutritional ketosis and symptoms of keto-induction in healthy adults: a randomised controlled clinical trial. J Nutr Metab. 2018;2018:2630565. DOI:10.1155/2018/2630565
40. Stubbs BJ, Cox PJ, Kirk T, et al. Gastrointestinal effects of exogenous ketone drinks are infrequent, mild, and vary according to ketone compound and dose. Int J Sport Nutr Exerc Metab. 2019;29:596-603. DOI:10.1123/ijsnem.2019-0014
41. Packer M, Anker SD, Butler J, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med. 2020;383:1413-24. DOI:10.1056/NEJMoa2022190
42. Bonner C, Kerr-Conte J, Gmyr V, et al. Inhibition of the glucose transporter SGLT2 with dapagliflozin in pancreatic alpha cells triggers glucagon secretion. Nat Med. 2015;21:512-7. DOI:10.1038/nm.3828
43. Ferrannini E, Baldi S, Frascerra S, et al. Shift to fatty substrate utilization in response to sodium–glucose cotransporter 2 inhibition in subjects without diabetes and patients with type 2 diabetes. Diabetes. 2016;65(5):1190-5. DOI:10.2337/db15-1356
44. Lopaschuk GD, Verma S. Mechanisms of cardiovascular benefits of sodium glucose co-transporter 2 (SGLT2) inhibitors. J Am Coll Cardiol Basic Transl Sci. 2020;5:632-44. DOI:10.1016/j.jacbts.2020.02.004
45. Vishwanath S, Qaderi V, Steves CJ, et al. Cognitive Decline and Risk of Dementia in Individuals With Heart Failure: A Systematic Review and Meta-analysis. J Card Fail. 2022;28(8):1337-48. DOI:10.1016/j.cardfail.2021.12.014
46. Yap NLX, Kor Q, Teo YN, et al. Prevalence and incidence of cognitive impairment and dementia in heart failure – A systematic review, meta-analysis and meta-regression. Hellenic J Cardiol. 2022;67:48-58. DOI:10.1016/j.hjc.2022.07.005
47. Poff AM, Moss S, Soliven M, D'Agostino DP. Ketone Supplementation: Meeting the Needs of the Brain in an Energy Crisis. Front Nutr. 2021;8:783659. DOI:10.3389/fnut.2021.783659
________________________________________________
2. Neubauer S. The failing heart – an engine out of fuel. N Engl J Med. 2007;356:1140-151. DOI:10.1056/NEJMra063052
3. Selvaraj S, Kelly DP, Kenneth B. Margulies Implications of Altered Ketone Metabolism and Therapeutic Ketosis in Heart Failure. Circulation. 2020;141(22):1800-12. DOI:10.1161/CIRCULATIONAHA.119.045033
4. Bedi KC Jr, Snyder NW, Brandimarto J, et al. Evidence for intramyocardial disruption of lipid metabolism and increased myocardial ketone utilization in advanced human heart failure. Circulation. 2016;133:706-16. DOI:10.1161/CIRCULATIONAHA.115.017545
5. Lopaschuk GD, Karwi QG, Tian R, et al. Cardiac Energy Metabolism in Heart Failure. Circ Res. 2021;128(10):1487-513. DOI:10.1161/CIRCRESAHA.121.318241
6. Takahara S, Soni S, Maayah ZH, et al. Ketone therapy for heart failure: Current evidence for clinical use. Cardiovasc Res. 2022;118:97-87. DOI:10.1093/cvr/cvab068
7. Puchalska P, Crawford PA. Multi-dimensional roles of ketone bodies in fuel metabolism, signaling, and therapeutics. Cell Metab. 2017;25:262-84. DOI:10.1016/j.cmet.2016.12.022
8. Karwi QG, Uddin GM, Ho KL, Lopaschuk GD. Loss of metabolic flexibility in the failing heart. Front Cardiovasc Med. 2018;5:68. DOI:10.3389/fcvm.2018.00068
9. Nielsen R, Moller N, Gormsen LC, et al. Cardiovascular effects of treatment with the ketone body 3-hydroxybutyrate in chronic heart failure patients. Circulation. 2019;139:2129-41. DOI:10.1161/CIRCULATIONAHA.118.036459
10. Horton JL, Davidson MT, Kurishima C, et al. The failing heart utilizes 3-hydroxybutyrate as a metabolic stress defense. JCI Insight. 2019;4:e124079. DOI:10.1172/jci.insight.124079
11. Pietschner R, Kolwelter J, Bosch A, et al. Effect of empagliflozin on ketone bodies in patients with stable chronic heart failure. Cardiovasc Diabetol. 2021;20:219. DOI:10.1186/s12933-021-01410-7
12. McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019;381:1995-2008. DOI:10.1056/NEJMoa1911303
13. Murthy MS, Pande SV. Malonyl-CoA binding site and the overt carnitine palmitoyltransferase activity reside on the opposite sides of the outer mitochondrial membrane. Proc Natl Acad Sci U S A. 1987;84(2):378-82. DOI:10.1073/pnas.84.2.378
14. Hui S, Ghergurovich JM, Morscher RJ, et al. Glucose feeds the tca cycle via circulating lactate. Nature. 2017;551:115-8. DOI:10.1038/nature24057
15. Ho KL, Karwi QG, Wagg C, et al. Ketones can become the major fuel source for the heart but do not increase cardiac efficiency. Cardiovasc Res. 2020. DOI:10.1093/cvr/cvaa143
16. Evans M, McClure TS, Koutnik AP, Egan B. Exogenous Ketone Supplements in Athletic Contexts: Past, Present, and Future. Sports Med. 2022;52(Suppl. 1):25-67.
DOI:10.1007/s40279-022-01756-2
17. Balasse EO, Féry F. Ketone body production and disposal: effects of fasting, diabetes, and exercise. Diabetes Metab Rev. 1989;5:247-70. DOI:10.1002/dmr.5610050304
18. Laffel L. Ketone bodies: a review of physiology, pathophysiology and application of monitoring to diabetes. Diabetes Metab Res Rev. 1999;15:412-26. DOI:10.1002/(SICI)1520-7560(199911/12)15:6<412::AID-DMRR72>3.0.CO;2-8
19. Fukao T, Lopaschuk GD, Mitchell GA, et al. Pathways and control of ketone body metabolism: on the fringe of lipid biochemistry. Prostaglandins Leukot Essent Fat Acids. 2004;70:243-51. DOI:10.1016/j.plefa.2003.11.001
20. Halestrap AP, Wilson MC. The monocarboxylate transporter family – role and regulation. IUBMB Life. 2012;64(2):109-19. DOI:10.1002/iub.572
21. Fukao T, Song XQ, Mitchell GA, et al. Enzymes of ketone body utilization in human tissues: protein and messenger RNA levels of succinyl-coenzyme A (CoA):3-ketoacid CoA transferase and mitochondrial and cytosolic acetoacetyl-CoA thiolases. Pediatr Res. 1997;42(4):498-502. DOI:10.1203/00006450-199710000-00013
22. Cox PJ, Kirk T, Ashmore T, et al. Nutritional ketosis alters fuel preference and thereby endurance performance in athletes. Cell Metab. 2016;24:256-68. DOI:10.1016/j.cmet.2016.07.010
23. Neubauer S. The failing heart – an engine out of fuel. N Engl J Med. 2007;356(11):1140-51. DOI:10.1056/NEJMra063052
24. Zhou B, Tian R. Mitochondrial dysfunction in pathophysiology of heart failure. J Clin Invest. 2018;128(9):3716-26. DOI:10.1172/JCI120849
25. Shanmugam G, Wang D, Gounder SS, et al. Reductive stress causes pathological cardiac remodeling and diastolic dysfunction. Antioxid Redox Signal. 2020;32:1293-312. DOI:10.1089/ars.2019.7808
26. Tsutsui H, Kinugawa S, Matsushima S. Oxidative stress and heart failure. Am J Physiol Heart Circ Physiol. 2011;301:H2181-90. DOI:10.1152/ajpheart.00554.2011
27. O’Rourke B, Ashok D, Liu T. Mitochondrial Ca(2+) in heart failure: Not enough or too much? J Mol Cell Cardiol. 2020;151:126-34. DOI:10.1016/j.yjmcc.2020.11.014
28. Sheeran FL, Angerosa J, Liaw NY, et al. Adaptations in Protein Expression and Regulated Activity of Pyruvate Dehydrogenase Multienzyme Complex in Human Systolic Heart Failure. Oxid Med Cell Longev. 2019;2019:4532592. DOI:10.1155/2019/4532592
29. McCommis KS, Kovacs A, Weinheimer CJ, et al. Nutritional Modulation of Heart Failure in Mitochondrial Pyruvate Carrier-Deficient Mice. Nat Metab. 2020;2(11):1232-47. DOI:10.1038/s42255-020-00296-1
30. Bedi KC Jr, Snyder NW, Brandimarto J, et al. Evidence for intramyocardial disruption of lipid metabolism and increased myocardial ketone utilization in advanced human heart failure. Circulation. 2016;133:706-16. DOI:10.1161/CIRCULATIONAHA.115.017545
31. Aubert G, Martin OJ, Horton JL, et al. The failing heart relies on ketone bodies as a fuel. Circulation. 2016;133:698-705. DOI:10.1161/CIRCULATIONAHA.115.017355
32. Cox PJ, Kirk T, Ashmore T, et al. Nutritional ketosis alters fuel preference and thereby endurance performance in athletes. Cell Metab. 2016;24:256-68. DOI:10.1016/j.cmet.2016.07.010
33. Gormsen LC, Svart M, Thomsen HH, et al. 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. 2017;6(3):e005066. DOI:10.1161/JAHA.116.005066
34. Nielsen R, Moller N, Gormsen LC, et al. Cardiovascular effects of treatment with the ketone body 3-hydroxybutyrate in chronic heart failure patients. Circulation. 2019;139:2129-41. DOI:10.1161/CIRCULATIONAHA.118.036459
35. Volek JS, Phinney SD. The Art and Science of Low Carbohydrate Performance: A Revolutionary Program to Extend Your Physical and Mental Performance Envelope. Miami, FL: Beyond Obesity LLC, 2012.
36. Shaw DM, Merien F, Braakhuis A, et al. The effect of 1,3-butanediol on cycling time-trial performance. Int J Sport Nutr Exerc Metab. 2019;29:466-73. DOI:10.1123/ijsnem.2018-0284
37. Scott BE, Laursen PB, James LJ, et al. The effect of 1,3-butanediol and carbohydrate supplementation on running performance. J Sci Med Sport. 2019;22:702-6. DOI:10.1016/j.jsams.2018.11.027
38. Cunnane SC, Courchesne-Loyer A, Vandenberghe C, et al. Can ketones help rescue brain fuel supply in later life? Implications for cognitive health during aging and the treatment of Alzheimer’s disease. Front Mol Neurosci. 2016;9:53. DOI:10.3389/fnmol.2016.00053
39. Harvey CJC, Schofield GM, Williden M, McQuillan JA. The effect of medium chain triglycerides on time to nutritional ketosis and symptoms of keto-induction in healthy adults: a randomised controlled clinical trial. J Nutr Metab. 2018;2018:2630565. DOI:10.1155/2018/2630565
40. Stubbs BJ, Cox PJ, Kirk T, et al. Gastrointestinal effects of exogenous ketone drinks are infrequent, mild, and vary according to ketone compound and dose. Int J Sport Nutr Exerc Metab. 2019;29:596-603. DOI:10.1123/ijsnem.2019-0014
41. Packer M, Anker SD, Butler J, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med. 2020;383:1413-24. DOI:10.1056/NEJMoa2022190
42. Bonner C, Kerr-Conte J, Gmyr V, et al. Inhibition of the glucose transporter SGLT2 with dapagliflozin in pancreatic alpha cells triggers glucagon secretion. Nat Med. 2015;21:512-7. DOI:10.1038/nm.3828
43. Ferrannini E, Baldi S, Frascerra S, et al. Shift to fatty substrate utilization in response to sodium–glucose cotransporter 2 inhibition in subjects without diabetes and patients with type 2 diabetes. Diabetes. 2016;65(5):1190-5. DOI:10.2337/db15-1356
44. Lopaschuk GD, Verma S. Mechanisms of cardiovascular benefits of sodium glucose co-transporter 2 (SGLT2) inhibitors. J Am Coll Cardiol Basic Transl Sci. 2020;5:632-44. DOI:10.1016/j.jacbts.2020.02.004
45. Vishwanath S, Qaderi V, Steves CJ, et al. Cognitive Decline and Risk of Dementia in Individuals With Heart Failure: A Systematic Review and Meta-analysis. J Card Fail. 2022;28(8):1337-48. DOI:10.1016/j.cardfail.2021.12.014
46. Yap NLX, Kor Q, Teo YN, et al. Prevalence and incidence of cognitive impairment and dementia in heart failure – A systematic review, meta-analysis and meta-regression. Hellenic J Cardiol. 2022;67:48-58. DOI:10.1016/j.hjc.2022.07.005
47. Poff AM, Moss S, Soliven M, D'Agostino DP. Ketone Supplementation: Meeting the Needs of the Brain in an Energy Crisis. Front Nutr. 2021;8:783659. DOI:10.3389/fnut.2021.783659
Авторы
Ю.О. Аксенова1, Ю.Ф. Осмоловская1, И.В. Жиров*1,2, А.Г. Бениашвили3, М.А. Морозова3, С.Н. Терещенко1
1 ФГБУ «Национальный медицинский исследовательский центр кардиологии им. акад. Е.И. Чазова» Минздрава России, Москва, Россия;
2 ФГБОУ ДПО «Российская медицинская академия непрерывного профессионального образования» Минздрава России, Москва, Россия;
3 ФГБНУ «Научный центр психического здоровья», Москва, Россия
*izhirov@mail.ru
1 Chazov National Medical Research Center of Cardiology, Moscow, Russia;
2 Russian Medical Academy of Continuous Professional Education, Moscow, Russia;
3 Mental Health Science Center, Moscow, Russia
*izhirov@mail.ru
1 ФГБУ «Национальный медицинский исследовательский центр кардиологии им. акад. Е.И. Чазова» Минздрава России, Москва, Россия;
2 ФГБОУ ДПО «Российская медицинская академия непрерывного профессионального образования» Минздрава России, Москва, Россия;
3 ФГБНУ «Научный центр психического здоровья», Москва, Россия
*izhirov@mail.ru
________________________________________________
1 Chazov National Medical Research Center of Cardiology, Moscow, Russia;
2 Russian Medical Academy of Continuous Professional Education, Moscow, Russia;
3 Mental Health Science Center, Moscow, Russia
*izhirov@mail.ru
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