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The Ketone Bridge Between the Heart and the Bladder: How Fast Should We Go?

Ana Charrua|Gabriel Faria-Costa|João Oliveira|Inês Vilas-Boas|Inês Campelo|Elisa Azeredo Silva|Carmen Brás-Silva|Susana Maria Silva|Tiago Antunes-Lopes
대한배뇨장애요실금학회 (Korean Continence Society)|2024.11|International Neurourology Journal|제28권 제1호|pp. 2-11|DOI 10.5213/inj.2346250.125

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키워드

Metabolic syndromeKetogenic dietIntermittent fastingKetone bodiesSGLT2 inhibitors

초록

Metabolic syndrome (MS) is associated with both cardiovascular and bladder dysfunction. Insulin resistance (IR) and central obesity, in particular, are the main risk factors. In these patients, vicious pathological cycles exacerbate abnormal carbohydrate metabolism and sustain an inflammatory state, with serious implications for both the heart and bladder. Ketone bodies serve as an alternative energy source in this context. They are considered a “super-fuel” because they generate adenosine triphosphate with less oxygen consumption per molecule, thus enhancing metabolic efficiency. Ketone bodies have a positive impact on all components of MS. They aid in weight loss and glycemic control, lower blood pressure, improve lipid profiles, and enhance endothelial function. Additionally, they possess direct anti-inflammatory, antioxidant, and vasodilatory properties. A shared key player in dysfunction of both the heart and bladder dysfunction is the formation of the NLRP3 inflammasome, which ketone bodies inhibit. Interventions that elevate ketone body levels—such as fasting, a ketogenic diet, ketone supplements, and sodium-glucose cotransporter 2 inhibitors—have been shown to directly affect cardiovascular outcomes and improve lower urinary tract symptoms derived from MS. This review explores the pathophysiological basis of the benefits of ketone bodies in cardiac and bladder dysfunction.

Abstract

Metabolic syndrome (MS) is associated with both cardiovascular and bladder dysfunction. Insulin resistance (IR) and central obesity, in particular, are the main risk factors. In these patients, vicious pathological cycles exacerbate abnormal carbohydrate metabolism and sustain an inflammatory state, with serious implications for both the heart and bladder. Ketone bodies serve as an alternative energy source in this context. They are considered a “super-fuel” because they generate adenosine triphosphate with less oxygen consumption per molecule, thus enhancing metabolic efficiency. Ketone bodies have a positive impact on all components of MS. They aid in weight loss and glycemic control, lower blood pressure, improve lipid profiles, and enhance endothelial function. Additionally, they possess direct anti-inflammatory, antioxidant, and vasodilatory properties. A shared key player in dysfunction of both the heart and bladder dysfunction is the formation of the NLRP3 inflammasome, which ketone bodies inhibit. Interventions that elevate ketone body levels—such as fasting, a ketogenic diet, ketone supplements, and sodium-glucose cotransporter 2 inhibitors—have been shown to directly affect cardiovascular outcomes and improve lower urinary tract symptoms derived from MS. This review explores the pathophysiological basis of the benefits of ketone bodies in cardiac and bladder dysfunction.

참고문헌 (89)

  1. Efeyan A, "Nutrient-sensing mechanisms and pathways", Nature, 517, pp.302~310 (2015)
  2. Fahed G, "Metabolic syndrome : updates on pathophysiology and management in 2021", Int J Mol Sci, 23, pp.786~ (2022)
  3. Saklayen MG, "The global epidemic of the metabolic syndrome", Curr Hypertens Rep, 20, pp.12~ (2018)
  4. Alberti KG, "Harmonizing the metabolic syndrome : a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation;International Atherosclerosis Society; and International Association for the Study of Obesity", Circulation, 120, pp.1640~1645 (2009)
  5. Pashootan P, "Association between metabolic syndrome and severity of lower urinary tract symptoms(LUTS) : an observational study in a 4666 European men cohort", BJU Int, 116, pp.124~130 (2015)
  6. Li X, "Impact of metabolic syndrome and it’s components on prognosis in patients with cardiovascular diseases : a meta-analysis", Front Cardiovasc Med, 8, pp.704145~ (2021)
  7. Huang PL, "A comprehensive definition for metabolic syndrome", Dis Model Mech, 2, pp.231~237 (2009)
  8. Antunes-Lopes T, "The impact of chronic pelvic ischemia on LUTS and urinary levels of neuroinflammatory, inflammatory, and oxidative stress markers in elderly men : a case-control study", Urology, 123, pp.230~234 (2019)
  9. Rochlani Y, "Metabolic syndrome : pathophysiology, management, and modulation by natural compounds", Ther Adv Cardiovasc Dis, 11, pp.215~225 (2017)
  10. Russo GI, "Emerging links between non-neurogenic lower urinary tract symptoms secondary to benign prostatic obstruction, metabolic syndrome and its components : a systematic review", Int J Urol, 22, pp.982~990 (2015)
  11. Wallner LP, "Hyperglycemia, hyperinsulinemia, insulin resistance, and the risk of BPH", LUTS severity and progression over time in community dwelling black men : the Flint Men’s Health Study, 2013, pp.82, 881~886
  12. Seim A, "The prevalence and correlates of urinary tract symptoms in Norwegian men : the HUNT study", BJU Int, 96, pp.88~92 (2005)
  13. Penson DF, "Obesity, physical activity and lower urinary tract symptoms : results from the Southern Community Cohort Study", J Urol, 186, pp.2316~2322 (2011)
  14. Park HJ, "Sitting time, physical activity and the risk of lower urinary tract symptoms : a cohort study", BJU Int, 122, pp.293~299 (2018)
  15. Morelli A, "Testosterone and farnesoid X receptor agonist INT-747 counteract high fat diet-induced bladder alterations in a rabbit model of metabolic syndrome", J Steroid Biochem Mol Biol, 132, pp.80~92 (2012)
  16. Russo GI, "Insulin resistance is an independent predictor of severe lower urinary tract symptoms and of erectile dysfunction : results from a cross-sectional study", J Sex Med, 11, pp.2074~2082 (2014)
  17. Morelli A, "Acute vardenafil administration improves bladder oxygenation in spontaneously hypertensive rats", J Sex Med, 7, pp.107~120 (2010)
  18. Kim JK, "Obesity, metabolic health, and urological disorders in adults : a nationwide population-based study", Sci Rep, 11, pp.8687~ (2021)
  19. Yoshida M, "The effects of chronic hyperlipidemia on bladder function in myocardial infarction-prone Watanabe heritable hyperlipidemic(WHHLMI)rabbits", Neurourol Urodyn, 29, pp.1350~1354 (2010)
  20. He Q, "Obesity-initiated metabolic syndrome promotes urinary voiding dysfunction in a mouse model", Prostate, 76, pp.964~976 (2016)
  21. Vignozzi L, "Testosterone protects from metabolic syndrome-associated prostate inflammation : an experimental study in rabbit", J Endocrinol, 212, pp.71~84 (2012)
  22. Chavalmane AK, "Sex steroid receptors in male human bladder : expression and biological function", J Sex Med, 7, pp.2698~2713 (2010)
  23. Vignozzi L, "Tadalafil effect on metabolic syndrome-associated bladder alterations : an experimental study in a rabbit model", J Sex Med, 11, pp.1159~1172 (2014)
  24. Blaha I, "Impaired excitatory neurotransmission in the urinary bladder from the obese zucker rat : role of cannabinoid receptors", PLoS One, 11, pp.e0157424~ (2016)
  25. Kolb H, "Ketone bodies : from enemy to friend and guardian angel", BMC Med, 19, pp.313~ (2021)
  26. Dhillon KK, "StatPearls" (2024), StatPearls Publishing
  27. Mohammadifard N, "The effect of ketogenic diet on shared risk factors of cardiovascular disease and cancer", Nutrients, 14, pp.3499~ (2022)
  28. Lopaschuk GD, "Myocardial fatty acid metabolism in health and disease", Physiol Rev, 90, pp.207~258 (2010)
  29. Mizuno Y, "The diabetic heart utilizes ketone bodies as an energy source", Metabolism, 77, pp.65~72 (2017)
  30. Yurista SR, "Therapeutic potential of ketone bodies for patients with cardiovascular disease : JACC state-of-the-art review", J Am Coll Cardiol, 77, pp.1660~1669 (2021)
  31. Gormsen LC, "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, pp.e005066~ (2017)
  32. Yu Y, "Treatment with Dbeta-hydroxybutyrate protects heart from ischemia", reperfusion injury in mice, 2018, pp.829, 121~128
  33. Bae HR, "beta-Hydroxybutyrate suppresses inflammasome formation by ameliorating endoplasmic reticulum stress via AMPK activation", Oncotarget, 7, pp.66444~66454 (2016)
  34. Zheng Y, "NLRP3 inflammasome : the rising star in cardiovascular diseases", Front Cardiovasc Med, 9, pp.927061~ (2022)
  35. Stubbs BJ, "On the metabolism of exogenous ketones in humans", Front Physiol, 8, pp.848~ (2017)
  36. Otsubo A, "Excessive accumulation of visceral fat is associated with lower urinary symptoms including overactive bladder in female patients", Int J Urol, 28, pp.397~403 (2021)
  37. Cao M, "NMR-based metabolomic analysis of human bladder cancer", Anal Sci, 28, pp.451~456 (2012)
  38. Akanksha M, "Role of FGFR3 in urothelial carcinoma", Iran J Pathol, 14, pp.148~155 (2019)
  39. Qi J, "Beta-hydroxybutyrate : a dual function molecular and immunological barrier function regulator", Front Immunol, 13, pp.805881~ (2022)
  40. Cosin-Roger J, "Metabolite sensing GPCRs : promising therapeutic targets for cancer treatment?", Cells, 9, pp.2345~ (2020)
  41. Chen L, "NLRP3", IL1beta inflammasome associated with the aging bladder triggers bladder dysfunction in female rats, 2019, pp.19, 2960~2968
  42. Hughes FM Jr, "Inflammation triggered by the NLRP3 inflammasome is a critical driver of diabetic bladder dysfunction", Front Physiol, 13, pp.920487~ (2022)
  43. Hughes FM Jr, "Bladder fibrosis during outlet obstruction is triggered through the NLRP3 inflammasome and the production of IL-1beta", Am J Physiol Renal Physiol, 313, pp.F603~F610 (2017)
  44. Butler DSC, "Neuroepithelial control of mucosal inflammation in acute cystitis", Sci Rep, 8, pp.11015~ (2018)
  45. Qian J, "D-beta-hydroxybutyrate promotes functional recovery and relieves pain hypersensitivity in mice with spinal cord injury", Br J Pharmacol, 174, pp.1961~1971 (2017)
  46. Patterson RE, "Metabolic effects of intermittent fasting", Annu Rev Nutr, 37, pp.371~393 (2017)
  47. Varady KA, "Cardiometabolic benefits of intermittent fasting", Annu Rev Nutr, 41, pp.333~361 (2021)
  48. Dong TA, "Intermittent fasting : a heart healthy dietary pattern?", Am J Med, 133, pp.901~907 (2020)
  49. Kamarul Zaman M, "Effects of time-restricted eating with different eating duration on anthropometrics and cardiometabolic health : a systematic review and meta-analysis", World J Cardiol, 15, pp.354~374 (2023)
  50. Povoa R, "Intermittent fasting and blood pressure reduction : related mechanisms", Arq Bras Cardiol, 120, pp.e20230265~ (2023)
  51. Nesci A, "Gut microbiota and cardiovascular disease : evidence on the metabolic and inflammatory background of a complex relationship", Int J Mol Sci, 24, pp.9087~ (2023)
  52. Hu X, "Intermittent fasting modulates the intestinal microbiota and improves obesity and host energy metabolism", NPJ Biofilms Microbiomes, 9, pp.19~ (2023)
  53. Singh Y, "Embarking effect of ACE2-angiotensin 1-7", Mas receptor axis in benign prostate hyperplasia, 2018, pp.28, 115~124
  54. Breyer BN, "Hyperglycemia and insulin resistance and the risk of BPH", LUTS : an update of recent literature, 2014, pp.15, 462~
  55. Stekovic S, "Alternate day fasting improves physiological and molecular markers of aging in healthy, non-obese humans", Cell Metab, 30, pp.462~476 (2019)
  56. Meydani SN, "Long-term moderate calorie restriction inhibits inflammation without impairing cell-mediated immunity : a randomized controlled trial in non-obese humans", Aging(Albany NY), 8, pp.1416~1431 (2016)
  57. Wang C, "The regulatory effect of intermittent fasting on inflammasome activation in health and disease", Nutr Rev (2023)[DOI]
  58. Roco-Videla A, "Intermittent fasting and reduction of inflammatory response in a patient with ulcerative colitis", Medicina(Kaunas), 59, pp.1453~ (2023)
  59. Uzun H, "Association of insulin resistance with overactive bladder in female patients", Int Neurourol J, 16, pp.181~186 (2012)
  60. Luda KM, "Ketolysis drives CD8(+)T cell effector function through effects on histone acetylation", Immunity, 56, pp.2021~2035 (2023)
  61. van Dorp J, "The bladder cancer immune micro-environment in the context of response to immune checkpoint inhibition", Front Immunol, 14, pp.1235884~ (2023)
  62. Lin F, "A novel CD8(+)T cell-related gene signature for predicting the prognosis and immunotherapy efficacy in bladder cancer", Inflamm Res, 72, pp.1665~1687 (2023)
  65. Serger E, "The gut metabolite indole-3 propionate promotes nerve regeneration and repair", Nature, 607, pp.585~592 (2022)
  66. Dynka D, "The ketogenic diet and cardiovascular diseases", Nutrients, 15, pp.3368~ (2023)
  67. Bueno NB, "Verylow-carbohydrate ketogenic diet v. low-fat diet for long-term weight loss : a meta-analysis of randomised controlled trials", Br J Nutr, 110, pp.1178~1187 (2013)
  68. Ebbeling CB, "Effects of dietary composition on energy expenditure during weight-loss maintenance", JAMA, 307, pp.2627~2634 (2012)
  69. Jornayvaz FR, "A high-fat, ketogenic diet causes hepatic insulin resistance in mice, despite increasing energy expenditure and preventing weight gain", Am J Physiol Endocrinol Metab, 299, pp.E808~E815 (2010)
  70. Choi YJ, "Impact of a ketogenic diet on metabolic parameters in patients with obesity or overweight and with or without type 2 diabetes : a meta-analysis of randomized controlled trials", Nutrients, 12, pp.2005~ (2020)
  71. Kosinski C, "Effects of ketogenic diets on cardiovascular risk factors : evidence from animal and human studies", Nutrients, 9, pp.517~ (2017)
  72. Castellana M, "Efficacy and safety of very low calorie ketogenic diet(VLCKD)in patients with overweight and obesity : a systematic review and meta-analysis", Rev Endocr Metab Disord, 21, pp.5~16 (2020)
  73. Nielsen R, "Cardiovascular effects of treatment with the ketone body 3-hydroxybutyrate in chronic heart failure patients", Circulation, 139, pp.2129~2141 (2019)
  74. Fuller A, "The ketogenic diet. Nature of the bactericidal agent", Lancet, 224, pp.855~856 (1933)
  75. Sun Y, "Ketogenic diet may be a new approach to treatment stress urinary incontinence in obese elderly women : report of five cases", BMC Womens Health, 22, pp.402~ (2022)
  76. Kayode OT, "Biochemical and histomorphological changes in testosterone propionate-induced benign prostatic hyperplasia in male Wistar rats treated with ketogenic diet", Biomed Pharmacother, 132, pp.110863~ (2020)
  77. Condorelli RA, "Beneficial effects of the very-low-calorie ketogenic diet on the symptoms of male accessory gland inflammation", Nutrients, 14, pp.1081~ (2022)
  78. Saucedo-Orozco H, "SGLT2 Inhibitors and Ketone Metabolism in Heart Failure", J Lipid Atheroscler, 11, pp.1~19 (2022)
  79. Kaplan A, "Direct cardiovascular impact of SGLT2 inhibitors : mechanisms and effects", Heart Fail Rev, 23, pp.419~437 (2018)
  80. Ferrannini E, "CV protection in the EMPAREG OUTCOME Trial : a"thrifty substrate"hypothesis", Diabetes Care, 39, pp.1108~1114 (2016)
  81. Chilelli NC, "Lower urinary tract symptoms (LUTS) in males with type 2 diabetes recently treated with SGLT2 inhibitors-overlooked and overwhelming? A retrospective case series", Endocrine, 59, pp.690~693 (2018)
  82. Shikuma J, "Changes in overactive bladder symptoms after sodium glucose cotransporter-2 inhibitor administration to patients with type 2 diabetes", Practical Diabetes, 35, pp.47~50 (2018)
  83. Ansary TM, "Diuretic effects of sodium glucose cotransporter 2 inhibitors and their influence on the reninangiotensin system", Int J Mol Sci, 20, pp.629~ (2019)
  84. Peters AL, "Euglycemic diabetic ketoacidosis : a potential complication of treatment with sodium-glucose cotransporter 2 inhibition", Diabetes Care, 38, pp.1687~1693 (2015)
  85. Faria-Costa G, "Myogenic underactive bladder and heart failure resemblance : a novel role for SGLT2 Inhibition?", Eur Urol Focus, 8, pp.1783~1786 (2022)
  86. Fernández-Cardona A, "Intermittent fasting as a trigger of ketoacidosis in a patient with stable, longterm type 1 diabetes", J Endocr Soc, 4, pp.bvaa126~ (2020)
  87. Blanco JC, "Starvation ketoacidosis due to the ketogenic diet and prolonged fasting-a possibly dangerous diet trend", Am J Case Rep, 20, pp.1728~1731 (2019)
  88. Bashir B, "Non-diabetic ketoacidosis : a case series and literature review", Postgrad Med J, 97, pp.667~671 (2021)
  89. Rosenstock J, "Euglycemic diabetic ketoacidosis : a predictable, detectable, and preventable safety concern with SGLT2 inhibitors", Diabetes Care, 38, pp.1638~1642 (2015)

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