Kalp ve Aortta Ketojenik Diyetin Yapısal Etkileri: Sıçanlarda Işık ve Elektron Mikroskobik Bir Çalışma

Öz

Bu çalışmada, sıçanlarda ketojenik diyetin kalp kası ve aort dokusu üzerindeki etkilerinin incelenmesi amaçlanmıştır. Ketojenik diyet, kilo kaybı ve glisemik kontrolün iyileştirilmesi gibi metabolik avantajlarıyla iyi bilinmektedir. Ancak özellikle mikroskobik düzeyde kalp ve damar dokuları üzerindeki doğrudan etkileri yeterince aydınlatılmamıştır. Yetişkin erkek Sprague Dawley sıçanlar rastgele iki gruba ayrıldı ve iki ay boyunca standart diyet veya %78,8 yağ içeren ketojenik diyet ile beslendi. Vücut ağırlığı ve besin alımı düzenli olarak izlendi. İki aylık sürenin sonunda, kalp ve aort dokuları ışık mikroskobik ve transmisyon elektron mikroskobik incelemeler için tespit edildi. Çalışma süresi boyunca her iki grupta da vücut ağırlığı artış gösterdi. Ketojenik diyet alan sıçanlarda, kontrol grubuyla karşılaştırıldığında hem kardiyak hem de aort dokularında belirgin ışık ve elektron mikroskobik düzeyde yapısal değişiklikler saptandı. Miyokardiyumda kapiller dilatasyon, eritrosit stazı, endotelyal şişme, sitoplazmik vakuolizasyon ve fokal miyofibriller dejenerasyon izlendi. Aort incelemesinde histolojik olarak erken dönem vasküler yeniden yapılanma ile uyumlu olan fokal intimal kalınlaşma, elastik lamel fragmentasyonu, endotel ve düz kas hücrelerinde yapısal değişiklikler saptandı. Ketojenik diyet, belirgin bir metabolik hastalık yokluğunda dahi sıçanlarda kalp kası ve aort dokusunda yapısal değişikliklere yol açmaktadır. Bu bulgular, ketojenik beslenmenin subklinik kardiyovasküler doku stresi ya da adaptif yeniden yapılanmayı tetikleyebileceğini düşündürmektedir. Bu nedenle ketojenik diyetlerin değerlendirilmesinde, özellikle uzun süreli yüksek yağ maruziyetinde, yalnızca sistemik metabolik sonuçlar değil aynı zamanda organ-özgü yapısal etkiler de göz önünde bulundurulmalıdır.

Anahtar Kelimeler

• Ketojenik Diyet
• Kalp Kası
• Aort
• Işık Mikroskop
• Geçirimli Elektron Mikroskop

Destekleyen Kurum

Başkent Üniversitesi Araştırma Fonunca desteklenmiştir.

Proje Numarası

DA24/06

Etik Beyan

Başkent Üniversitesi Hayvan Deneyleri Yerel Etik Kurulu tarafından onaylanmıştır.

Teşekkür

Deneysel sürecin yürütülmesine sağladığı katkılar nedeniyle Prof. Dr. Ayşe Arzu Yiğit’e teşekkür ederiz.

Structural Effects of the Ketogenic Diet on the Heart and Aorta: A Light and Electron Microscopic Study in Rats

Öz

The purpose of this study was to investigate the effects of a ketogenic diet on heart muscle and aortic tissue in rats. The ketogenic diet is well known for its metabolic advantages, including weight loss and improved glycemic control. However, what it does to the heart and blood vessel tissues directly, particularly from a microscopic perspective, is not well understood. Adult male Sprague Dawley rats were randomly divided into two groups and were maintained on standard diet or ketogenic diet containing 78.8% fat for two months. Regular monitoring was done for body weight and food intake. At the end of two months, heart and aorta tissues were fixed for light microscopic and transmission electron microscopic studies. Body weight increased in both groups over the study period. Rats receiving the ketogenic diet exhibited distinct structural and ultrastructural alterations in both cardiac and aortic tissues compared with controls. In the myocardium, capillary dilation, erythrocyte stasis, endothelial swelling, cytoplasmic vacuolization, and focal myofibrillar degeneration were observed. Aortic examination revealed focal intimal thickening, fragmentation of elastic lamellae, endothelial alterations, and structural changes in smooth muscle cells, histologically consistent with early vascular remodeling. A ketogenic diet induces structural alterations in cardiac muscle and aortic tissue in rats, even in the absence of overt metabolic disease. These findings suggest that ketogenic feeding may elicit subclinical cardiovascular tissue stress or adaptive remodeling. Evaluation of ketogenic diets should therefore consider not only systemic metabolic outcomes but also organ-specific structural effects, particularly with prolonged high-fat exposure.

Anahtar Kelimeler

• Ketogenic Diet
• Cardiac Muscle
• Aorta
• Light Microscopy
• Transmission Electron Microscopy

Destekleyen Kurum

This Study supported by Baskent University Research Fund.

Proje Numarası

DA24/06

Etik Beyan

This study was approved by Baskent University Ethical Committee for Experimental Resarch on Animals.

Teşekkür

The authors would like to thank Prof. Dr. Ayşe Arzu Yiğit for her valuable contributions to the experimental procedures.

Kaynakça

1. 1. Available online: https://www.who.int/health-topics/cardiovascular-diseases#tab=tab_1.
2. 2. Dong T, Guo M, Zhang P, Sun G, Chen B. The effects of low-carbohydrate diets on cardiovascular risk factors: A meta-analysis. PLoS One. Public Library of Science; 2020;15. https://doi.org/10.1371/journal.pone.0225348.
3. 3. Abdurrachim D, Teo XQ, Woo CC et al. Cardiac metabolic modulation upon low-carbohydrate low-protein ketogenic diet in diabetic rats studied in vivo using hyperpolarized 13C pyruvate, butyrate and acetoacetate probes. Diabetes Obes Metab. 2019;21:949–60. https://doi.org/10.1111/dom.13608
4. 4. Zhou C, Wang M, Liang J, He G, Chen N. Ketogenic Diet Benefits to Weight Loss, Glycemic Control, and Lipid Profiles in Overweight Patients with Type 2 Diabetes Mellitus: A Meta-Analysis of Randomized Controlled Trails. Int J Environ Res Public Health. 2022;19:10429. https://doi.org/10.3390/ijerph191610429
5. 5. Lyngstad A, Nymo S, Coutinho SR, et al. Investigating the effect of sex and ketosis on weight-loss-induced changes in appetite. Am J Clin Nutr. 2019;109:1511–8. https://doi.org/10.1093/ajcn/nqz002
6. 6. Dyńka D, Kowalcze K, Charuta A, Paziewska A. The Ketogenic Diet and Cardiovascular Diseases. Nutrients. 2023;15(15):3368. https://doi.org/10.3390/nu15153368
7. 7. Roberts MN, Wallace MA, Tomilov AA, et al. A Ketogenic Diet Extends Longevity and Healthspan in Adult Mice. Cell Metab. 2017;26:539-546.e5. https://doi.org/10.1016/j.cmet.2017.08.005
8. 8. Pinto A, Bonucci A, Maggi E, Corsi M, Businaro R. Anti-oxidant and anti-inflammatory activity of ketogenic diet: New perspectives for neuroprotection in Alzheimer’s disease. Antioxidants.2018. https://doi.org/10.3390/antiox7050063

9. 9. Dupuis N, Curatolo N, Benoist JF, Auvin S. Ketogenic diet exhibits anti-inflammatory properties. Epilepsia. 2015;56:e95–e98. https://doi.org/10.1111/epi.13038
10. 10. Dyńka D, Kowalcze K, Paziewska A. The Role of Ketogenic Diet in the Treatment of Neurological Diseases. Nutrients. 2022;14(23):5003. https://doi.org/10.3390/nu14235003
11. 11. Mu J, Wang T, Li M, Guan T, Guo Y, Zhang X, et al. Ketogenic diet protects myelin and axons in diffuse axonal injury. Nutr Neurosci. 2022;25:1534–47. https://doi.org/10.1080/1028415X.2021.18753
12. 12. Hirschberger S, Effinger D, Yoncheva P, et al. The impact of a ketogenic diet on weight loss, metabolism, body composition and quality of life. iScience. 2024;27:111291. https://doi.org/10.1016/j.isci.2024.111291
13. 13. Jia P, Huang B, You Y, Su H, Gao L. Ketogenic diet aggravates kidney dysfunction by exacerbating metabolic disorders and inhibiting autophagy in spontaneously hypertensive rats. Biochem Biophys Res Commun. 2021;573:13–8. https://doi.org/10.1016/j.bbrc.2021.08.003
14. 14. Arsyad A, Idris I, Rasyid AA, et al. Long-Term Ketogenic Diet Induces Metabolic Acidosis, Anemia, and Oxidative Stress in Healthy Wistar Rats. J Nutr Metab. 2020;2020:3642035. https://doi.org/10.1155/2020/3642035
15. 15. Noeman SA, Hamooda HE, Baalash AA. Biochemical Study of Oxidative Stress Markers in the Liver, Kidney and Heart of High Fat Diet Induced Obesity in Rats. Diabetol Metab Syndr. 2011;3:17. https://doi.org/10.1186/1758-5996-3-17
16. 16. Kodur N, Yurista S, Province V, et al. Ketogenic Diet in Heart Failure. JACC Heart Fail. 2023;11:838–44. https://doi.org/10.1016/j.jchf.2023.05.009
17. 17. Kosinski C, Jornayvaz FR. Effects of Ketogenic Diets on Cardiovascular Risk Factors: Evidence from Animal and Human Studies. Nutrients. 2017;9(5):517. https://doi.org/10.3390/nu9050517
18. 18. Ellenbroek JH, Van Dijck L, Töns HA, et al. Long-term ketogenic diet causes glucose intolerance and reduced-and-cell mass but no weight loss in mice. Am J Physiol Endocrinol Metab. 2014;306:552–8. https://doi.org/10.1152/ajpendo.00453.2013.-High-fat
19. 19. Trang NN, Lee TW, Kao YH, Chao TF, Lee TI, Chen YJ. Ketogenic diet modulates cardiac metabolic dysregulation in streptozocin-induced diabetic rats. J Nutr Biochem. 2023;111:109161.https://doi.org/10.1016/j.jnutbio.2022.109161
20. 20. Luong TV, Abild CB, Bangshaab M, Gormsen LC, Søndergaard E. Ketogenic Diet and Cardiac Substrate Metabolism. Nutrients. 2022;14(7):1322.
21. 21. Liu J, Wang P, Zou L, et al. High-fat, low-carbohydrate diet promotes arrhythmic death and increases myocardial ischemia-reperfusion injury in rats. American Journal of Physiology-Heart and Circulatory Physiology. 2014;307:H598–608.
22. 22. Yurista SR, Nguyen CT, Rosenzweig A, de Boer RA, Westenbrink BD. Ketone bodies for the failing heart: fuels that can fix the engine? Trends in Endocrinology and Metabolism. 2021. p. 814–26. https://doi.org/10.1016/j.tem.2021.07.006
23. 23. Powell-Wiley TM, Poirier P, Burke LE, et al. Obesity and Cardiovascular Disease: A Scientific Statement From the American Heart Association. Circulation. 2021;143(21):e984-e1010. https://doi.org/10.1161/CIR.0000000000000973
24. 24. Zhao Q, Stafstrom CE, Fu DD, Hu Y, Holmes GL. Detrimental Effects of the Ketogenic Diet on Cognitive Function in Rats. Pediatr Res. 2004;55:498–506. https://doi.org/10.1203/01.PDR.0000112032.47575.D1
25. 25. Manohar MS, Ramamoorthy B, Latiff AA, Subramanian S. Histomorphometric Study of the Tunics of Ductus Arteriosus in Human Fetal Cadavers Using the ImageJ Software. Cureus. 2024;16(7):e64148. doi:10.7759/cureus.64148
26. 26. Burén J, Ericsson M, Damasceno NRT, Sjödin A. A ketogenic low‐carbohydrate high‐fat diet increases LDL cholesterol in healthy, young, normal‐weight women: A randomized controlled feeding trial. Nutrients. 2021;13:1–12. https://doi.org/10.3390/nu13030814
27. 27. Bielohuby M, Sisley S, Sandoval D, et al. Impaired glucose tolerance in rats fed low-carbohydrate, high-fat diets. Am J Physiol Endocrinol Metab. 2013;305:1059–70. https://doi.org/10.1152/ajpendo.00208.2013.-Moderate
28. 28. Chevli PA, Selvaraj S, Jaeger BC, et al. Integrating ketone bodies in multi-marker risk prediction of incident heart failure in the multi-ethnic study of atherosclerosis. Eur J Prev Cardiol. 2026;33(2):189-198. https://doi.org/10.1093/eurjpc/zwaf168
29. 29. Newman JC, Verdin E. β-hydroxybutyrate: Much more than a metabolite. Diabetes Res Clin Pract. 2014;106:173–81. https://doi.org/10.1016/j.diabres.2014.08.009
30. 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 HeartFailure.Circulation.2016;133(8):706-716. https://doi.org/10.1161/CIRCULATIONAHA.115.017545
31. 31. Ravnskov U. Is High Cholesterol Deleterious? An Alternative Point of View. Comment on Burén et al. A Ketogenic Low-Carbohydrate High-Fat Diet Increases LDL Cholesterol in Healthy, Young, Normal-Weight Women: A Randomized Controlled Feeding Trial. Nutrients 2021, 13, 814. Nutrients. 2021;13:2119. https://doi.org/10.3390/nu1306.2119
32. 32. Kolb H, Kempf K, Röhling M, et al. Ketone bodies: from enemy to friend and guardian angel. 2021;19:313. https://doi.org/10.1186/s12916-021-02185-0
33. 33. Lu Y, Yang Y-Y, Zhou M-W, et al. Ketogenic diet attenuates oxidative stress and inflammation after spinal cord injury by activating Nrf2 and suppressing the NF-κB signaling pathways. Neurosci Lett. 2018;683:13–8 https://doi.org/10.1016/j.neulet.2018.06.016