تاثیر دوکوزاهگزانوئیک اسید همراه با تمرینات ورزشی بر روی بافت قلب بیماران دیابتی: (مقاله مروری)

نوع مقاله : مقاله مروری

نویسندگان

1 دکتری فیزیولوژی ورزشی دانشگاه محقق اردبیلی، اردبیل، ایران

2 کارشناس علوم ورزشی، گروه فیزیولوژی ورزشی، دانشگاه شهید مدنی آذربایجان، تبریز، ایران

3 دانشجوی کارشناس ارشد فیزیولوژی ورزشی، دانشکده علوم ورزشی، دانشگاه گیلان، گیلان، ایران

10.22038/mjms.2025.88895.5047

چکیده

مقدمه
امروزه دوکوزاهگزانوئیک اسید به عنوان یک ماده موثره در پیشگیری و بهبود وضعیت دیابت مورد توجه قرار گرفته است. لذا هدف ما بررسی برخی از کارآزمایی‌های قبلی مربوط به استفاده از دوکوزاهگزانوئیک اسید همراه با ورزش بر بافت قلب بیماران دیابتی بود.
روش کار
تحقیق حاضر یک مطالعه مروری توصیفی است و با استفاده از چندین پایگاه اطلاعاتی مشتمل Google Scholar، Web of Science، Science Direct، Pupmed، Scopus و با استفاده از عناوین دیابت و نام انواع آنها و اسامی مرتبط برای کلید واژه های قلب دیابت و نیز دوکوزاهگزانوئیک اسید و فعالیت های ورزشی تا پایان سال 2024 جستجو صورت گرفت.
نتایج
با تمرکز بر روی تاثیرات دوکوزاهگزانوئیک اسید که در مطالعات مختلف مورد استفاده قرار گرفته است می توان گفت که بسیاری از مطالعات در مورد نقش مثبت دوکوزاهگزانوئیک اسید در بافت قلب بیماران دیابتی شامل روش‌ها و معیارهای پیامد متفاوتی است، اکثریت قریب به اتفاق مطالعات ظرفیت مثبت این مکمل را برای افراد دیابتیک نشان می‌دهد. چندین مکانیسم پاتوفیزیولوژیک پیشنهادی وجود دارد که مسئول اثرات کاهش فعالیت بر روی عملکرد بافت های مختلف در بیماران دیابتیک با ضایعات مختلف است.
نتیجه‌گیری
براساس بررسی مطالعات مختلف در این پژوهش می توان به نقش مهم و اساسی دوکوزاهگزانوئیک اسید در ضایعات دیابتیک در بافت قلب تاکید کرد که باید مورد توجه قرار گیرد.

کلیدواژه‌ها

موضوعات


عنوان مقاله [English]

The effect of docosahexaenoic acid combined with exercise on cardiac tissue in diabetic patients: (Review article)

نویسندگان [English]

  • Afshin Rahbarghazi 1
  • Omid Moghaddami 2
  • Ebrahim Esfandar 3
1 Ph.D Exercise Physiology, Faculty of Education and Psychology, University of Mohaghegh Ardabili, Ardabil, Iran
2 BSc Student of Sports Science, Department of Sport Sciences, Faculty of Education and Psychology, Azarbaijan Shahid Madani University, Tabriz. Iran.
3 Master Student of Exercise Physiology, Faculty of Sport Sciences, University of Guilan, Rasht, Iran
چکیده [English]

Abstract
Introduction: Nowadays, docosahexaenoic acid is considered an effective substance for preventing and improving diabetes. Therefore, our goal was to review some previous trials related to the use of docosahexaenoic acid along with exercise on the heart tissue of diabetic patients.
Subjects & Methods: The present study is a descriptive review study that was conducted using several databases, including Google Scholar, Web of Science, Science Direct, PubMed, and Scopus. It used the titles of diabetes and its types and related names for the keywords of diabetes heart, docosahexaenoic acid, and sports activities until the end of 2024.
Results: Focusing on the effects of DHA, which has been used in various studies, it can be said that many studies on the positive role of DHA in the heart tissue of diabetic patients include different methods and outcome measures, the vast majority of studies show the positive capacity of this supplement for diabetics. There are several proposed pathophysiological mechanisms responsible for the effects of reduced activity on the function of various tissues in diabetic patients with different lesions.
Conclusion: Based on a review of various studies, this research can emphasize the fundamental role of docosahexaenoic acid in diabetic lesions in heart tissue, which should be considered.

کلیدواژه‌ها [English]

  • Docosahexaenoic acid
  • cardiomyopathy
  • diabetes
  • exercise
  1. Rahbarghazi A, Alamdari KA, Rahbarghazi R, Salehi-Pourmehr H. Co-administration of exercise training and melatonin on the function of diabetic heart tissue: a systematic review and meta-analysis of rodent models. Diabetology & Metabolic Syndrome. 2023;15(1):67.
  2. Adarme-Vega TC, Thomas-Hall SR, Schenk PM. Towards sustainable sources for omega-3 fatty acids production. Current opinion in biotechnology. 2014;26:14-8.
  3. Siriwardhana N, Kalupahana NS, Moustaid-Moussa N. Health benefits of n-3 polyunsaturated fatty acids: eicosapentaenoic acid and docosahexaenoic acid. Advances in food and nutrition research. 2012;65:211-22.
  4. Horrocks LA, Yeo YK. Health benefits of docosahexaenoic acid (DHA). Pharmacological research. 1999;40(3):211-25.
  5. Kromhout D, Giltay EJ, Geleijnse JM. n–3 Fatty acids and cardiovascular events after myocardial infarction. New England Journal of Medicine. 2010;363(21):2015-26.
  6. Tortosa-Caparrós E, Navas-Carrillo D, Marín F, Orenes-Piñero E. Anti-inflammatory effects of omega 3 and omega 6 polyunsaturated fatty acids in cardiovascular disease and metabolic syndrome. Critical reviews in food science and nutrition. 2017;57(16):3421-9.
  7. Marklund M, Wu JH, Imamura F, Del Gobbo LC, Fretts A, De Goede J, et al. Biomarkers of dietary omega-6 fatty acids and incident cardiovascular disease and mortality: an individual-level pooled analysis of 30 cohort studies. Circulation. 2019;139(21):2422-36.
  8. Chareonrungrueangchai K, Wongkawinwoot K, Anothaisintawee T, Reutrakul S. Dietary factors and risks of cardiovascular diseases: an umbrella review. Nutrients. 2020;12(4):1088.
  9. Gui T, Li Y, Zhang S, Zhang N, Sun Y, Liu F, et al. Docosahexaenoic acid protects against palmitate-induced mitochondrial dysfunction in diabetic cardiomyopathy. Biomedicine & Pharmacotherapy. 2020;128:110306.
  10. Habicht I, Mohsen G, Eichhorn L, Frede S, Weisheit C, Hilbert T, et al. DHA Supplementation Attenuates MI‐Induced LV Matrix Remodeling and Dysfunction in Mice. Oxidative Medicine and Cellular Longevity. 2020;2020(1):7606938.
  11. Huang N, Wang F, Li S, Zhai X, Ma W, Liu K, et al. Associations of eicosapentaenoic acid and docosahexaenoic acid intakes with cardiovascular and all-cause mortality in patients with diabetes: result from national health and nutrition examination survey 1999–2008. Frontiers in Cardiovascular Medicine. 2023;9:1031168.
  12. Lindgren M, Börjesson M. The importance of physical activity and cardiorespiratory fitness for patients with heart failure. Diabetes research and clinical practice. 2021;176:108833.
  13. Patel P, Zwibel H. Physiology, Exercise. StatPearls. Treasure Island (FL). StatPearls Publishing Copyright; 2021.
  14. Pechlivani N, Ajjan RA. Thrombosis and vascular inflammation in diabetes: mechanisms and potential therapeutic targets. Frontiers in cardiovascular medicine. 2018;5:1.
  15. Wang B, Gan L, Deng Y, Zhu S, Li G, Nasser MI, et al. RETRACTED: Cardiovascular Disease and Exercise: From Molecular Mechanisms to Clinical Applications. Journal of Clinical Medicine. 2022;11(24):7511.
  16. Colberg SR, Sigal RJ. Prescribing exercise for individuals with type 2 diabetes: recommendations and precautions. The Physician and Sportsmedicine. 2011;39(2):13-26.
  17. De Geest B, Mishra M. Role of oxidative stress in diabetic cardiomyopathy. Antioxidants. 2022;11(4):784.
  18. Sowers JR, Epstein M, Frohlich ED. Diabetes, hypertension, and cardiovascular disease: an update. Hypertension. 2001;37(4):1053-9.
  19. Rubler S, Dlugash J, Yuceoglu YZ, Kumral T, Branwood AW, Grishman A. New type of cardiomyopathy associated with diabetic glomerulosclerosis. The American journal of cardiology. 1972;30(6):595-602.
  20. Bugger H, Abel ED. Molecular mechanisms of diabetic cardiomyopathy. Diabetologia. 2014;57:660-71.
  21. DiMeglio LA, Evans-Molina C, Oram RA. Type 1 diabetes. The Lancet. 2018;391(10138):2449-62.
  22. Katsarou A, Gudbjörnsdottir S, Rawshani A, Dabelea D, Bonifacio E, Anderson BJ, et al. Type 1 diabetes mellitus. Nature reviews Disease primers. 2017;3(1):1-17.
  23. Maruyama T, Nakagawa T, Kasuga A, Murata M. Heterogeneity among patients with latent autoimmune diabetes in adults. Diabetes/metabolism research and reviews. 2011;27(8):971-4.
  24. Svensson J, Carstensen B, Mortensen HB, Borch-Johnsen K, Diabetes DSGoC. Early childhood risk factors associated with type 1 diabetes–is gender important? European journal of epidemiology. 2005;20:429-34.
  25. Patterson CC, Gyürüs E, Rosenbauer J, Cinek O, Neu A, Schober E, et al. Trends in childhood type 1 diabetes incidence in Europe during 1989–2008: evidence of non-uniformity over time in rates of increase. Diabetologia. 2012;55:2142-7.
  26. Gillespie KM. Type 1 diabetes: pathogenesis and prevention. Cmaj. 2006;175(2):165-70.
  27. Care D. Classification and diagnosis of diabetes. Diabetes Care. 2015;38(Suppl 1):S8-S16.
  28. Nerup J, Platz P, Andersen OO, Christy M, Lyngsøe J, Poulsen J, et al. HL-A antigens and diabetes mellitus. The Lancet. 1974;304(7885):864-6.
  29. Roep BO, Thomaidou S, Van Tienhoven R, Zaldumbide A. Type 1 diabetes mellitus as a disease of the β-cell (do not blame the immune system?). Nature Reviews Endocrinology. 2021;17(3):150-61.
  30. Cho YK, Jung CH. Immune-checkpoint inhibitors-induced type 1 diabetes mellitus: from its molecular mechanisms to clinical practice. Diabetes & Metabolism Journal. 2023;47(6):757-66.
  31. Erlich HA, Valdes AM, McDevitt SL, Simen BB, Blake LA, McGowan KR, et al. Next generation sequencing reveals the association of DRB3* 02: 02 with type 1 diabetes. Diabetes. 2013;62(7):2618-22.
  32. Askar M, Daghstani J, Thomas D, Leahy N, Dunn P, Claas F, et al. 16th IHIW: global distribution of extended HLA haplotypes. Wiley Online Library; 2013.
  33. Delli AJ, Lindblad B, Carlsson A, Forsander G, Ivarsson SA, Ludvigsson J, et al. Type 1 diabetes patients born to immigrants to Sweden increase their native diabetes risk and differ from Swedish patients in HLA types and islet autoantibodies. Pediatric diabetes. 2010;11(8):513-20.
  34. Serrano‐Rìos M, Goday A, Martìnez Larrad T. Migrant populations and the incidence of Type 1 diabetes mellitus: an overview of the literature with a focus on the Spanish‐heritage countries in Latin America. Diabetes/metabolism research and reviews. 1999;15(2):113-32.
  35. Devendra D, Eisenbarth GS. 17. Immunologic endocrine disorders. Journal of Allergy and Clinical Immunology. 2003;111(2):S624-S36.
  36. Caillat-Zucman S, Garchon H-J, Timsit J, Assan R, Boitard C, Djilali-Saiah I, et al. Age-dependent HLA genetic heterogeneity of type 1 insulin-dependent diabetes mellitus. The Journal of clinical investigation. 1992;90(6):2242-50.
  37. Garvey WT, Ryan DH, Henry R, Bohannon NJ, Toplak H, Schwiers M, et al. Prevention of type 2 diabetes in subjects with prediabetes and metabolic syndrome treated with phentermine and topiramate extended release. Diabetes care. 2014;37(4):912-21.
  38. DeFronzo RA, Abdul-Ghani MA. Preservation of β-cell function: the key to diabetes prevention. The Journal of Clinical Endocrinology & Metabolism. 2011;96(8):2354-66.
  39. Wang X, Bao W, Liu J, OuYang Y-Y, Wang D, Rong S, et al. Inflammatory markers and risk of type 2 diabetes: a systematic review and meta-analysis. Diabetes care. 2013;36(1):166-75.
  40. DeFronzo R. Insulin resistance, lipotoxicity, type 2 diabetes and atherosclerosis: the missing links. The Claude Bernard Lecture 2009. Diabetologia. 2010;53(7):1270-87.
  41. Bunney P, Zink A, Holm A, Billington C, Kotz C. Orexin activation counteracts decreases in nonexercise activity thermogenesis (NEAT) caused by high-fat diet. Physiology & behavior. 2017;176:139-48.
  42. Fu Z, R. Gilbert E, Liu D. Regulation of insulin synthesis and secretion and pancreatic Beta-cell dysfunction in diabetes. Current diabetes reviews. 2013;9(1):25-53.
  43. Boland BB, Rhodes CJ, Grimsby JS. The dynamic plasticity of insulin production in β-cells. Molecular metabolism. 2017;6(9):958-73.
  44. Rorsman P, Ashcroft FM. Pancreatic β-cell electrical activity and insulin secretion: of mice and men. Physiological reviews. 2018;98(1):117-214.
  45. Islam MS. The ryanodine receptor calcium channel of β-cells: molecular regulation and physiological significance. Diabetes. 2002;51(5):1299-309.
  46. Dali-Youcef N, Mecili M, Ricci R, Andrès E. Metabolic inflammation: connecting obesity and insulin resistance. Annals of medicine. 2013;45(3):242-53.
  47. Roca-Rivada A, Castelao C, Senin LL, Landrove MO, Baltar J, Crujeiras AB, et al. FNDC5/irisin is not only a myokine but also an adipokine. PloS one. 2013;8(4):e60563.
  48. Graciano MF, Valle M, Kowluru A, Curi R, Carpinelli A. Regulation of insulin secretion and reactive oxygen species production by free fatty acids in pancreatic islets. Islets. 2011;3(5):213-23.
  49. Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. jama. 2001;286(3):327-34.
  50. Venkatasamy VV, Pericherla S, Manthuruthil S, Mishra S, Hanno R. Effect of physical activity on insulin resistance, inflammation and oxidative stress in diabetes mellitus. Journal of clinical and diagnostic research: JCDR. 2013;7(8):1764.
  51. Association AD. 3. Prevention or delay of type 2 diabetes: standards of medical care in diabetes—2019. Diabetes Care. 2019;42(Supplement_1):S29-S33.
  52. Vandanmagsar B, Youm Y-H, Ravussin A, Galgani JE, Stadler K, Mynatt RL, et al. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nature medicine. 2011;17(2):179-88.
  53. Shamsuzzaman AS, Winnicki M, Wolk R, Svatikova A, Phillips BG, Davison DE, et al. Independent association between plasma leptin and C-reactive protein in healthy humans. Circulation. 2004;109(18):2181-5.
  54. Leeuwenburgh C, Fiebig R, Chandwaney R, Ji LL. Aging and exercise training in skeletal muscle: responses of glutathione and antioxidant enzyme systems. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology. 1994;267(2):R439-R45.
  55. Huo J-L, Feng Q, Pan S, Fu W-J, Liu Z, Liu Z. Diabetic cardiomyopathy: Early diagnostic biomarkers, pathogenetic mechanisms, and therapeutic interventions. Cell death discovery. 2023;9(1):256.
  56. De Geest B, Mishra M. Role of oxidative stress in heart failure: insights from gene transfer studies. Biomedicines. 2021;9(11):1645.
  57. Wilson AJ, Gill EK, Abudalo RA, Edgar KS, Watson CJ, Grieve DJ. Reactive oxygen species signalling in the diabetic heart: emerging prospect for therapeutic targeting. Heart. 2018;104(4):293-9.
  58. Liu Q, Wang S, Cai L. Diabetic cardiomyopathy and its mechanisms: role of oxidative stress and damage. Journal of diabetes investigation. 2014;5(6):623-34.
  59. Faria A, Persaud SJ. Cardiac oxidative stress in diabetes: mechanisms and therapeutic potential. Pharmacology & therapeutics. 2017;172:50-62.
  60. Ritchie R, Love JE, Huynh K, Bernardo B, Henstridge D, Kiriazis H, et al. Enhanced phosphoinositide 3-kinase (p110α) activity prevents diabetes-induced cardiomyopathy and superoxide generation in a mouse model of diabetes. Diabetologia. 2012;55:3369-81.
  61. Tan Y, Zhang Z, Zheng C, Wintergerst KA, Keller BB, Cai L. Mechanisms of diabetic cardiomyopathy and potential therapeutic strategies: preclinical and clinical evidence. Nature Reviews Cardiology. 2020;17(9):585-607.
  62. Rendra E, Riabov V, Mossel DM, Sevastyanova T, Harmsen MC, Kzhyshkowska J. Reactive oxygen species (ROS) in macrophage activation and function in diabetes. Immunobiology. 2019;224(2):242-53.
  63. Sharma A, Tate M, Mathew G, Vince JE, Ritchie RH, De Haan JB. Oxidative stress and NLRP3-inflammasome activity as significant drivers of diabetic cardiovascular complications: therapeutic implications. Frontiers in physiology. 2018;9:114.
  64. Chrysohoou C, Pitsavos C, Barbetseas J, Kotroyiannis I, Brili S, Vasiliadou K, et al. Chronic systemic inflammation accompanies impaired ventricular diastolic function, detected by Doppler imaging, in patients with newly diagnosed systolic heart failure (Hellenic Heart Failure Study). Heart and vessels. 2009;24:22-6.
  65. Kobayashi S, Liang Q. Autophagy and mitophagy in diabetic cardiomyopathy. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease. 2015;1852(2):252-61.
  66. Paulus WJ, Tschöpe C. A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation. Journal of the American college of cardiology. 2013;62(4):263-71.
  67. Luo B, Huang F, Liu Y, Liang Y, Wei Z, Ke H, et al. NLRP3 inflammasome as a molecular marker in diabetic cardiomyopathy. Frontiers in physiology. 2017;8:519.
  68. Wang S, Ding L, Ji H, Xu Z, Liu Q, Zheng Y. The role of p38 MAPK in the development of diabetic cardiomyopathy. International journal of molecular sciences. 2016;17(7):1037.
  69. Huynh K, Kiriazis H, Du X-J, Love JE, Gray SP, Jandeleit-Dahm KA, et al. Targeting the upregulation of reactive oxygen species subsequent to hyperglycemia prevents type 1 diabetic cardiomyopathy in mice. Free Radical Biology and Medicine. 2013;60:307-17.
  70. Cai L, Li W, Wang G, Guo L, Jiang Y, Kang YJ. Hyperglycemia-induced apoptosis in mouse myocardium: mitochondrial cytochrome C–mediated caspase-3 activation pathway. Diabetes. 2002;51(6):1938-48.
  71. Varma A, Das A, Hoke NN, Durrant DE, Salloum FN, Kukreja RC. Anti-inflammatory and cardioprotective effects of tadalafil in diabetic mice. 2012.
  72. Sari FR, Watanabe K, Thandavarayan RA, Harima M, Zhang S, Muslin AJ, et al. 14-3-3 protein protects against cardiac endoplasmic reticulum stress (ERS) and ERS-initiated apoptosis in experimental diabetes. Journal of pharmacological sciences. 2010;113(4):325-34.
  73. Riehle C, Bauersachs J. Of mice and men: models and mechanisms of diabetic cardiomyopathy. Basic research in cardiology. 2019;114(1):2.
  74. Levine B, Klionsky DJ. Development by self-digestion: molecular mechanisms and biological functions of autophagy. Developmental cell. 2004;6(4):463-77.
  75. Nakai A, Yamaguchi O, Takeda T, Higuchi Y, Hikoso S, Taniike M, et al. The role of autophagy in cardiomyocytes in the basal state and in response to hemodynamic stress. Nature medicine. 2007;13(5):619-24.
  76. Matsui Y, Takagi H, Qu X, Abdellatif M, Sakoda H, Asano T, et al. Distinct roles of autophagy in the heart during ischemia and reperfusion: roles of AMP-activated protein kinase and Beclin 1 in mediating autophagy. Circulation research. 2007;100(6):914-22.
  77. Ceylan-Isik AF, Kandadi MR, Xu X, Hua Y, Chicco AJ, Ren J, Nair S. Apelin administration ameliorates high fat diet-induced cardiac hypertrophy and contractile dysfunction. Journal of molecular and cellular cardiology. 2013;63:4-13.
  78. Desrois M, Sidell RJ, Gauguier D, Davey CL, Radda GK, Clarke K. Gender differences in hypertrophy, insulin resistance and ischemic injury in the aging type 2 diabetic rat heart. Journal of molecular and cellular cardiology. 2004;37(2):547-55.
  79. Feng B, Chen S, Chiu J, George B, Chakrabarti S. Regulation of cardiomyocyte hypertrophy in diabetes at the transcriptional level. American Journal of Physiology-Endocrinology and Metabolism. 2008;294(6):E1119-E26.
  80. Lorenzo-Almorós A, Cepeda-Rodrigo J, Lorenzo Ó. Diabetic cardiomyopathy. Revista Clínica Española (English Edition). 2022;222(2):100-11.
  81. Zhang H, Dhalla NS. The role of pro-inflammatory cytokines in the pathogenesis of cardiovascular disease. International Journal of Molecular Sciences. 2024;25(2):1082.
  82. Ramesh P, Yeo JL, Brady EM, McCann GP. Role of inflammation in diabetic cardiomyopathy. Therapeutic Advances in Endocrinology and Metabolism. 2022;13:20420188221083530.
  83. Baldasseroni S, Antenore A, Di Serio C, Orso F, Lonetto G, Bartoli N, et al. Adiponectin, diabetes and ischemic heart failure: a challenging relationship. Cardiovascular diabetology. 2012;11:1-8.
  84. Chakraborty S, Verma A, Garg R, Singh J, Verma H. Cardiometabolic risk factors associated with type 2 diabetes mellitus: a mechanistic insight. Clinical Medicine Insights: Endocrinology and Diabetes. 2023;16:11795514231220780.
  85. Leyva F, Godsland IF, Ghatei M, Proudler AJ, Aldis S, Walton C, et al. Hyperleptinemia as a component of a metabolic syndrome of cardiovascular risk. Arteriosclerosis, thrombosis, and vascular biology. 1998;18(6):928-33.
  86. Barouch LA, Berkowitz DE, Harrison RW, O’Donnell CP, Hare JM. Disruption of leptin signaling contributes to cardiac hypertrophy independently of body weight in mice. Circulation. 2003;108(6):754-9.
  87. Huss JM, Kelly DP. Mitochondrial energy metabolism in heart failure: a question of balance. The Journal of clinical investigation. 2005;115(3):547-55.
  88. Russell LK, Finck BN, Kelly DP. Mouse models of mitochondrial dysfunction and heart failure. Journal of molecular and cellular cardiology. 2005;38(1):81-91.
  89. Braczko A, Kutryb-Zajac B, Jedrzejewska A, Krol O, Mierzejewska P, Zabielska-Kaczorowska M, et al. Cardiac mitochondria dysfunction in dyslipidemic mice. International Journal of Molecular Sciences. 2022;23(19):11488.
  90. Li H, Wang J, Wilhelmsson H, Hansson A, Thorén P, Duffy J, et al. Genetic modification of survival in tissue-specific knockout mice with mitochondrial cardiomyopathy. Proceedings of the National Academy of Sciences. 2000;97(7):3467-72.
  91. Graham BH, Waymire KG, Cottrell B, Trounce IA, MacGregor GR, Wallace DC. A mouse model for mitochondrial myopathy and cardiomyopathy resulting from a deficiency in the heart/muscle isoform of the adenine nucleotide translocator. Nature genetics. 1997;16(3):226-34.
  92. Exil VJ, Roberts RL, Sims H, McLaughlin JE, Malkin RA, Gardner CD, et al. Very-long-chain acyl-coenzyme a dehydrogenase deficiency in mice. Circulation research. 2003;93(5):448-55.
  93. Finck BN, Lehman JJ, Leone TC, Welch MJ, Bennett MJ, Kovacs A, et al. The cardiac phenotype induced by PPARα overexpression mimics that caused by diabetes mellitus. The Journal of clinical investigation. 2002;109(1):121-30.
  94. Kurtz DM, Rinaldo P, Rhead WJ, Tian L, Millington DS, Vockley J, et al. Targeted disruption of mouse long-chain acyl-CoA dehydrogenase gene reveals crucial roles for fatty acid oxidation. Proceedings of the National Academy of Sciences. 1998;95(26):15592-7.
  95. Lehman JJ, Barger PM, Kovacs A, Saffitz JE, Medeiros DM, Kelly DP. Peroxisome proliferator–activated receptor γ coactivator-1 promotes cardiac mitochondrial biogenesis. The Journal of clinical investigation. 2000;106(7):847-56.
  96. WU P, Sato J, Zhao Y, JASKIEWICZ J, POPOV MK, HARRIS AR. Starvation and diabetes increase the amount of pyruvate dehydrogenase kinase isoenzyme 4 in rat heart. Biochemical Journal. 1998;329(1):197-201.
  97. Shen X, Zheng S, Metreveli NS, Epstein PN. Protection of cardiac mitochondria by overexpression of MnSOD reduces diabetic cardiomyopathy. Diabetes. 2006;55(3):798-805.
  98. Ye G, Metreveli NS, Donthi RV, Xia S, Xu M, Carlson EC, Epstein PN. Catalase protects cardiomyocyte function in models of type 1 and type 2 diabetes. Diabetes. 2004;53(5):1336-43.
  99. Ye G, Metreveli NS, Ren J, Epstein PN. Metallothionein prevents diabetes-induced deficits in cardiomyocytes by inhibiting reactive oxygen species production. Diabetes. 2003;52(3):777-83.
  100. Ramaccini D, Montoya-Uribe V, Aan FJ, Modesti L, Potes Y, Wieckowski MR, et al. Mitochondrial function and dysfunction in dilated cardiomyopathy. Frontiers in cell and developmental biology. 2021;8:624216.
  101. Jiang T, Peng D, Shi W, Guo J, Huo S, Men L, et al. IL-6/STAT3 signaling promotes cardiac dysfunction by upregulating FUNDC1-dependent mitochondria-associated endoplasmic reticulum membranes formation in sepsis mice. Frontiers in cardiovascular medicine. 2022;8:790612.
  102. Merlo M, Daneluzzi C, Mestroni L, Cannatà A, Sinagra G. Historical terminology, classifications, and present definition of DCM. Dilated Cardiomyopathy: From Genetics to Clinical Management. 2019:1-9.
  103. Urtz N, Gaertner F, von Bruehl M-L, Chandraratne S, Rahimi F, Zhang L, et al. Sphingosine 1-phosphate produced by sphingosine kinase 2 intrinsically controls platelet aggregation in vitro and in vivo. Circulation research. 2015;117(4):376-87.
  104. Jiang X, Liu W, Deng J, Lan L, Xue X, Zhang C, et al. Polydatin protects cardiac function against burn injury by inhibiting sarcoplasmic reticulum Ca2+ leak by reducing oxidative modification of ryanodine receptors. Free Radical Biology and Medicine. 2013;60:292-9.
  105. Makino N, Dhalla K, Elimban V, Dhalla NS. Sarcolemmal Ca2+ transport in streptozotocin-induced diabetic cardiomyopathy in rats. American Journal of Physiology-Endocrinology and Metabolism. 1987;253(2):E202-E7.
  106. Xu J, Wang G, Wang Y, Liu Q, Xu W, Tan Y, Cai L. Diabetes‐and angiotensin II‐induced cardiac endoplasmic reticulum stress and cell death: metallothionein protection. Journal of cellular and molecular medicine. 2009;13(8a):1499-512.
  107. Liu Z-W, Zhu H-T, Chen K-L, Dong X, Wei J, Qiu C, Xue J-H. Protein kinase RNA-like endoplasmic reticulum kinase (PERK) signaling pathway plays a major role in reactive oxygen species (ROS)-mediated endoplasmic reticulum stress-induced apoptosis in diabetic cardiomyopathy. Cardiovascular diabetology. 2013;12:1-16.
  108. Mustroph J, Wagemann O, Lücht CM, Trum M, Hammer KP, Sag CM, et al. Empagliflozin reduces Ca/calmodulin‐dependent kinase II activity in isolated ventricular cardiomyocytes. ESC heart failure. 2018;5(4):642-8.
  109. Pereira L, Ruiz-Hurtado G, Rueda A, Mercadier J-J, Benitah J-P, Gómez AM. Calcium signaling in diabetic cardiomyocytes. Cell calcium. 2014;56(5):372-80.
  110. Lambert R, Srodulski S, Peng X, Margulies KB, Despa F, Despa S. Intracellular Na+ concentration ([Na+] i) is elevated in diabetic hearts due to enhanced Na+–glucose cotransport. Journal of the American Heart Association. 2015;4(9):e002183.
  111. Karmazyn M, Liu Q, Gan XT, Brix BJ, Fliegel L. Aldosterone increases NHE-1 expression and induces NHE-1-dependent hypertrophy in neonatal rat ventricular myocytes. Hypertension. 2003;42(6):1171-6.
  112. Galicia-Garcia U, Benito-Vicente A, Jebari S, Larrea-Sebal A, Siddiqi H, Uribe KB, et al. Pathophysiology of type 2 diabetes mellitus. International journal of molecular sciences. 2020;21(17):6275.
  113. Ferrannini E, Mark M, Mayoux E. CV protection in the EMPA-REG OUTCOME trial: a “thrifty substrate” hypothesis. Diabetes care. 2016;39(7):1108-14.
  114. Petersen MC, Shulman GI. Mechanisms of insulin action and insulin resistance. Physiological reviews. 2018.
  115. Neubauer S. The failing heart—an engine out of fuel. New England Journal of Medicine. 2007;356(11):1140-51.
  116. Lorenzo-Almorós A, Tuñón J, Orejas M, Cortés M, Egido J, Lorenzo Ó. Diagnostic approaches for diabetic cardiomyopathy. Cardiovascular diabetology. 2017;16:1-14.
  117. Krüger M, Babicz K, von Frieling-Salewsky M, Linke WA. Insulin signaling regulates cardiac titin properties in heart development and diabetic cardiomyopathy. Journal of molecular and cellular cardiology. 2010;48(5):910-6.
  118. Eriksson L, Nyström T. Antidiabetic agents and endothelial dysfunction–beyond glucose control. Basic & clinical pharmacology & toxicology. 2015;117(1):15-25.
  119. Maack C, Lehrke M, Backs J, Heinzel FR, Hulot J-S, Marx N, et al. Heart failure and diabetes: metabolic alterations and therapeutic interventions: a state-of-the-art review from the Translational Research Committee of the Heart Failure Association–European Society of Cardiology. European heart journal. 2018;39(48):4243-54.
  120. Van Heerebeek L, Hamdani N, Handoko ML, Falcao-Pires I, Musters RJ, Kupreishvili K, et al. Diastolic stiffness of the failing diabetic heart: importance of fibrosis, advanced glycation end products, and myocyte resting tension. Circulation. 2008;117(1):43-51.
  121. Gherasim L, Taşcă C, Havriliuc C, Vasilescu C. A morphological quantitative study of small vessels in diabetic cardiomyopathy. Morphologie et embryologie. 1985;31(3):191-5.
  122. Ritchie RH, Abel ED. Basic mechanisms of diabetic heart disease. Circulation research. 2020;126(11):1501-25.
  123. Vancheri F, Longo G, Vancheri S, Henein M. Coronary microvascular dysfunction. Journal of Clinical Medicine. 2020;9(9):2880.
  124. Mohammed SF, Hussain S, Mirzoyev SA, Edwards WD, Maleszewski JJ, Redfield MM. Coronary microvascular rarefaction and myocardial fibrosis in heart failure with preserved ejection fraction. Circulation. 2015;131(6):550-9.
  125. Yu Y, Ohmori K, Kondo I, Yao L, Noma T, Tsuji T, et al. Correlation of functional and structural alterations of the coronary arterioles during development of type II diabetes mellitus in rats. Cardiovascular research. 2002;56(2):303-11.
  126. Hayashi T, Sohmiya K, Ukimura A, Endoh S, Mori T, Shimomura H, et al. Angiotensin II receptor blockade prevents microangiopathy and preserves diastolic function in the diabetic rat heart. Heart. 2003;89(10):1236-42.
  127. Joshi MS, Berger PJ, Kaye DM, Pearson JT, Bauer JA, Ritchie RH. Functional relevance of genetic variations of endothelial nitric oxide synthase and vascular endothelial growth factor in diabetic coronary microvessel dysfunction. Clinical and Experimental Pharmacology and Physiology. 2013;40(4):253-61.
  128. Chou E, Suzuma I, Way KJ, Opland D, Clermont AC, Naruse K, et al. Decreased cardiac expression of vascular endothelial growth factor and its receptors in insulin-resistant and diabetic States: a possible explanation for impaired collateral formation in cardiac tissue. Circulation. 2002;105(3):373-9.
  129. Oltman CL, Richou LL, Davidson EP, Coppey LJ, Lund DD, Yorek MA. Progression of coronary and mesenteric vascular dysfunction in Zucker obese and Zucker diabetic fatty rats. American Journal of Physiology-Heart and Circulatory Physiology. 2006;291(4):H1780-H7.
  130. Sharma A, Rizky L, Stefanovic N, Tate M, Ritchie RH, Ward KW, de Haan JB. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) activator dh404 protects against diabetes-induced endothelial dysfunction. Cardiovascular Diabetology. 2017;16:1-13.
  131. Steadman CD, Jerosch-Herold M, Grundy B, Rafelt S, Ng LL, Squire IB, et al. Determinants and functional significance of myocardial perfusion reserve in severe aortic stenosis. JACC: Cardiovascular Imaging. 2012;5(2):182-9.
  132. Gulsin GS, Henson J, Brady EM, Sargeant JA, Wilmot EG, Athithan L, et al. Cardiovascular determinants of aerobic exercise capacity in adults with type 2 diabetes. Diabetes Care. 2020;43(9):2248-56.
  133. Zanatta E, Colombo C, D’amico G, d’Humières T, Dal Lin C, Tona F. Inflammation and coronary microvascular dysfunction in autoimmune rheumatic diseases. International journal of molecular sciences. 2019;20(22):5563.
  134. Goldin A, Beckman JA, Schmidt AM, Creager MA. Advanced glycation end products: sparking the development of diabetic vascular injury. Circulation. 2006;114(6):597-605.
  135. Aragno M, Mastrocola R, Medana C, Catalano MG, Vercellinatto I, Danni O, Boccuzzi G. Oxidative stress-dependent impairment of cardiac-specific transcription factors in experimental diabetes. Endocrinology. 2006;147(12):5967-74.
  136. Ma H, Li SY, Xu P, Babcock SA, Dolence EK, Brownlee M, et al. Retracted: Advanced glycation endproduct (AGE) accumulation and AGE receptor (RAGE) up‐regulation contribute to the onset of diabetic cardiomyopathy. Journal of cellular and molecular medicine. 2009;13(8b):1751-64.
  137. Salvatore T, Pafundi PC, Galiero R, Albanese G, Di Martino A, Caturano A, et al. The diabetic cardiomyopathy: the contributing pathophysiological mechanisms. Frontiers in Medicine. 2021;8:695792.
  138. Kass DA. Getting better without AGE: new insights into the diabetic heart. Lippincott Williams & Wilkins; 2003. p. 704-6.
  139. Huynh K, Bernardo BC, McMullen JR, Ritchie RH. Diabetic cardiomyopathy: mechanisms and new treatment strategies targeting antioxidant signaling pathways. Pharmacology & therapeutics. 2014;142(3):375-415.
  140. Tate M, Grieve DJ, Ritchie RH. Are targeted therapies for diabetic cardiomyopathy on the horizon? Clinical Science. 2017;131(10):897-915.
  141. Yusuf S, Dagenais G, Pogue J, Bosch J, Sleight P. Vitamin E supplementation and cardiovascular events in high-risk patients. The New England journal of medicine. 2000;342(3):154-60.
  142. Ede K, Hwang K-K, Wu C-C, Wu M, Yang Y-H, Lin W-S, et al. Plasmin immunization preferentially induces IgG-anticardiolipin antibodies that are potentially prothrombotic in MRL/MpJ mice. Arthritis and rheumatism. 2009;60(10):3108.
  143. Xu Y-Z, Zhang X, Wang L, Zhang F, Qiu Q, Liu M-L, et al. An increased circulating angiotensin II concentration is associated with hypoadiponectinemia and postprandial hyperglycemia in men with nonalcoholic fatty liver disease. Internal medicine. 2013;52(8):855-61.
  144. Widyantoro B, Emoto N, Nakayama K, Anggrahini DW, Adiarto S, Iwasa N, et al. Endothelial cell–derived endothelin-1 promotes cardiac fibrosis in diabetic hearts through stimulation of endothelial-to-mesenchymal transition. Circulation. 2010;121(22):2407-18.
  145. Tezze C, Romanello V, Sandri M. FGF21 as modulator of metabolism in health and disease. Frontiers in physiology. 2019;10:440125.
  146. Mraz M, Bartlova M, Lacinova Z, Michalsky D, Kasalicky M, Haluzikova D, et al. Serum concentrations and tissue expression of a novel endocrine regulator fibroblast growth factor‐21 in patients with type 2 diabetes and obesity. Clinical endocrinology. 2009;71(3):369-75.
  147. Chavez AO, Molina-Carrion M, Abdul-Ghani MA, Folli F, DeFronzo RA, Tripathy D. Circulating fibroblast growth factor-21 is elevated in impaired glucose tolerance and type 2 diabetes and correlates with muscle and hepatic insulin resistance. Diabetes care. 2009;32(8):1542-6.
  148. Zhang X, Yang L, Xu X, Tang F, Yi P, Qiu B, Hao Y. A review of fibroblast growth factor 21 in diabetic cardiomyopathy. Heart Failure Reviews. 2019;24:1005-17.
  149. Wang R, Zhang X, Ye H, Yang X, Zhao Y, Wu L, et al. Fibroblast growth factor 21 improves diabetic cardiomyopathy by inhibiting ferroptosis via ferritin pathway. Cardiovascular Diabetology. 2024;23(1):394.
  150. Jia G, Hill MA, Sowers JR. Diabetic cardiomyopathy: an update of mechanisms contributing to this clinical entity. Circulation research. 2018;122(4):624-38.
  151. León LE, Rani S, Fernandez M, Larico M, Calligaris SD. Subclinical detection of diabetic cardiomyopathy with microRNAs: challenges and perspectives. Journal of diabetes research. 2016;2016(1):6143129.
  152. Feng B, Chen S, George B, Feng Q, Chakrabarti S. miR133a regulates cardiomyocyte hypertrophy in diabetes. Diabetes/metabolism research and reviews. 2010;26(1):40-9.
  153. Greco S, Fasanaro P, Castelvecchio S, D’Alessandra Y, Arcelli D, Di Donato M, et al. MicroRNA dysregulation in diabetic ischemic heart failure patients. Diabetes. 2012;61(6):1633-41.
  154. Lee J, Harris AN, Holley CL, Mahadevan J, Pyles KD, Lavagnino Z, et al. Rpl13a small nucleolar RNAs regulate systemic glucose metabolism. The Journal of clinical investigation. 2016;126(12):4616-25.
  155. Guo R, Nair S. Role of microRNA in diabetic cardiomyopathy: from mechanism to intervention. Biochimica et biophysica acta (BBA)-molecular basis of disease. 2017;1863(8):2070-7.
  156. Zhou B, Li C, Qi W, Zhang Y, Zhang F, Wu J, et al. Downregulation of miR-181a upregulates sirtuin-1 (SIRT1) and improves hepatic insulin sensitivity. Diabetologia. 2012;55:2032-43.
  157. Trajkovski M, Hausser J, Soutschek J, Bhat B, Akin A, Zavolan M, et al. MicroRNAs 103 and 107 regulate insulin sensitivity. Nature. 2011;474(7353):649-53.
  158. Katare R, Caporali A, Zentilin L, Avolio E, Sala-Newby G, Oikawa A, et al. Intravenous gene therapy with PIM-1 via a cardiotropic viral vector halts the progression of diabetic cardiomyopathy through promotion of prosurvival signaling. Circulation research. 2011;108(10):1238-51.
  159. Xiao J, Luo X, Lin H, Zhang Y, Lu Y, Wang N, et al. MicroRNA miR-133 represses HERG K+ channel expression contributing to QT prolongation in diabetic hearts. Journal of Biological Chemistry. 2007;282(17):12363-7.
  160. Duisters RF, Tijsen AJ, Schroen B, Leenders JJ, Lentink V, van der Made I, et al. miR-133 and miR-30 regulate connective tissue growth factor: implications for a role of microRNAs in myocardial matrix remodeling. Circulation research. 2009;104(2):170-8.
  161. Bentwich I, Avniel A, Karov Y, Aharonov R, Gilad S, Barad O, et al. Identification of hundreds of conserved and nonconserved human microRNAs. Nature genetics. 2005;37(7):766-70.
  162. Li J, Pora BL, Dong K, Hasjim J. Health benefits of docosahexaenoic acid and its bioavailability: A review. Food science & nutrition. 2021;9(9):5229-43.
  163. Calder PC. Docosahexaenoic acid. Annals of Nutrition and Metabolism. 2016;69(Suppl. 1):8-21.
  164. Newman M. A new picture of life's history on Earth. Proceedings of the National Academy of Sciences. 2001;98(11):5955-6.
  165. Richards MP, Pettitt PB, Stiner MC, Trinkaus E. Stable isotope evidence for increasing dietary breadth in the European mid-Upper Paleolithic. Proceedings of the National Academy of Sciences. 2001;98(11):6528-32.
  166. Nakamura MT, Nara TY. Structure, function, and dietary regulation of Δ6, Δ5, and Δ9 desaturases. Annu Rev Nutr. 2004;24(1):345-76.
  167. Cho HP, Nakamura MT, Clarke SD. Cloning, expression, and nutritional regulation of the mammalian Δ-6 desaturase. Journal of Biological Chemistry. 1999;274(1):471-7.
  168. de Lorgeril M, Salen P, Defaye P. Importance of nutrition in chronic heart failure patients. Oxford University Press; 2005. p. 2215-7.
  169. Xiang M, Rahman M, Ai H, Li X, Harbige L. Diet and gene expression: delta-5 and delta-6 desaturases in healthy Chinese and European subjects. Annals of nutrition and metabolism. 2007;50(6):492-8.
  170. Plourde M, Cunnane SC. Extremely limited synthesis of long chain polyunsaturates in adults: implications for their dietary essentiality and use as supplements. Applied physiology, nutrition, and metabolism. 2007;32(4):619-34.
  171. Kornsteiner M, Singer I, Elmadfa I. Very low n–3 long-chain polyunsaturated fatty acid status in Austrian vegetarians and vegans. Annals of Nutrition and Metabolism. 2008;52(1):37-47.
  172. Skrzypski J, Bellenger S, Bellenger J, Sinclair A, Poisson J-P, Tessier C, et al. Revisiting delta-6 desaturase regulation by C18 unsaturated fatty acids, depending on the nutritional status. Biochimie. 2009;91(11-12):1443-9.
  173. Liou YA, Innis SM. Dietary linoleic acid has no effect on arachidonic acid, but increases n-6 eicosadienoic acid, and lowers dihomo-γ-linolenic and eicosapentaenoic acid in plasma of adult men. Prostaglandins, leukotrienes and essential fatty acids. 2009;80(4):201-6.
  174. Harris WS, Mozaffarian D, Lefevre M, Toner CD, Colombo J, Cunnane SC, et al. Towards establishing dietary reference intakes for eicosapentaenoic and docosahexaenoic acids. The Journal of nutrition. 2009;139(4):804S-19S.
  175. Zhu H, Fan C, Xu F, Tian C, Zhang F, Qi K. Dietary fish oil n-3 polyunsaturated fatty acids and alpha-linolenic acid differently affect brain accretion of docosahexaenoic acid and expression of desaturases and sterol regulatory element-binding protein 1 in mice. The Journal of nutritional biochemistry. 2010;21(10):954-60.
  176. Decsi T, Kennedy K. Sex-specific differences in essential fatty acid metabolism12345. The American journal of clinical nutrition. 2011;94:S1914-S9.
  177. Lv W, Xu D. Docosahexaenoic acid delivery systems, bioavailability, functionality, and applications: A review. Foods. 2022;11(17):2685.
  178. Yamagata K. Docosahexaenoic acid regulates vascular endothelial cell function and prevents cardiovascular disease. Lipids in health and disease. 2017;16:1-13.
  179. Ravet JL, Brett MT, Arhonditsis GB. The effects of seston lipids on zooplankton fatty acid composition in Lake Washington, Washington, USA. Ecology. 2010;91(1):180-90.
  180. Miles EA, Calder PC. Modulation of immune function by dietary fatty acids. Proceedings of the Nutrition Society. 1998;57(2):277-92.
  181. Zapata-Gonzalez F, Rueda F, Petriz J, Domingo P, Villarroya F, Diaz-Delfin J, et al. Human dendritic cell activities are modulated by the omega-3 fatty acid, docosahexaenoic acid, mainly through PPARγ: RXR heterodimers: comparison with other polyunsaturated fatty acids. Journal of Leucocyte Biology. 2008;84(4):1172-82.
  182. Colson C. Effets des métabolites d’acides gras sur la formation et la fonction des adipocytes thermogéniques: Université Côte d'Azur; 2020.
  183. Woodman RJ, Mori TA, Burke V, Puddey IB, Watts GF, Beilin LJ. Effects of purified eicosapentaenoic and docosahexaenoic acids on glycemic control, blood pressure, and serum lipids in type 2 diabetic patients with treated hypertension1, 2, 3. The American journal of clinical nutrition. 2002;76(5):1007-15.
  184. Bhaswant M, Poudyal H, Brown L. Mechanisms of enhanced insulin secretion and sensitivity with n-3 unsaturated fatty acids. The Journal of nutritional biochemistry. 2015;26(6):571-84.
  185. Calder PC. Marine omega-3 fatty acids and inflammatory processes: Effects, mechanisms and clinical relevance. Biochimica et Biophysica Acta (BBA)-Molecular and Cell Biology of Lipids. 2015;1851(4):469-84.
  186. Talukdar S, Bae EJ, Imamura T, Morinaga H, Fan W, Li P, et al. GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects. Cell. 2010;142(5):687-98.
  187. Bannenberg G, Serhan CN. Specialized pro-resolving lipid mediators in the inflammatory response: An update. Biochimica et Biophysica Acta (BBA)-Molecular and Cell Biology of Lipids. 2010;1801(12):1260-73.
  188. Serhan CN, Yacoubian S, Yang R. Anti-inflammatory and proresolving lipid mediators. Annu Rev Pathol Mech Dis. 2008;3(1):279-312.
  189. Komprda T. Eicosapentaenoic and docosahexaenoic acids as inflammation-modulating and lipid homeostasis influencing nutraceuticals: A review. Journal of Functional Foods. 2012;4(1):25-38.
  190. Calder PC. n–3 Fatty acids and cardiovascular disease: evidence explained and mechanisms explored. Clinical science. 2004;107(1):1-11.
  191. SE N. Fish consumption and mortality from coronary heart disease. Br Med J (Clin Res Ed). 1986;293:426.
  192. Daviglus ML, Stamler J, Orencia AJ, Dyer AR, Liu K, Greenland P, et al. Fish consumption and the 30-year risk of fatal myocardial infarction. New England Journal of Medicine. 1997;336(15):1046-53.
  193. Calder PC. Functional roles of fatty acids and their effects on human health. Journal of parenteral and enteral nutrition. 2015;39:18S-32S.
  194. Mori TA, Bao DQ, Burke V, Puddey IB, Beilin LJ. Docosahexaenoic acid but not eicosapentaenoic acid lowers ambulatory blood pressure and heart rate in humans. Hypertension. 1999;34(2):253-60.
  195. Simopoulos AP. The importance of the omega-6/omega-3 fatty acid ratio in cardiovascular disease and other chronic diseases. Experimental biology and medicine. 2008;233(6):674-88.
  196. Singhal A, Lanigan J, Storry C, Low S, Birbara T, Lucas A, Deanfield J. Docosahexaenoic acid supplementation, vascular function and risk factors for cardiovascular disease: a randomized controlled trial in young adults. Journal of the American Heart Association. 2013;2(4):e000283.
  197. Pawlosky RJ, Hibbeln JR, Novotny JA, Salem Jr N. Physiological compartmental analysis of α-linolenic acid metabolism in adult humans. Journal of lipid research. 2001;42(8):1257-65.
  198. Burdge GC, Calder PC. Dietary α-linolenic acid and health-related outcomes: a metabolic perspective. Nutrition research reviews. 2006;19(1):26-52.
  199. Wall R, Ross RP, Fitzgerald GF, Stanton C. Fatty acids from fish: the anti-inflammatory potential of long-chain omega-3 fatty acids. Nutrition reviews. 2010;68(5):280-9.
  200. Russo GL. Dietary n− 6 and n− 3 polyunsaturated fatty acids: From biochemistry to clinical implications in cardiovascular prevention. Biochemical pharmacology. 2009;77(6):937-46.
  201. Baum SJ, Kris-Etherton PM, Willett WC, Lichtenstein AH, Rudel LL, Maki KC, et al. Fatty acids in cardiovascular health and disease: a comprehensive update. Journal of clinical lipidology. 2012;6(3):216-34.
  202. Willett WC. Dietary fats and coronary heart disease. Journal of internal medicine. 2012;272(1):13-24.
  203. Asztalos IB, Gleason JA, Sever S, Gedik R, Asztalos BF, Horvath KV, et al. Effects of eicosapentaenoic acid and docosahexaenoic acid on cardiovascular disease risk factors: a randomized clinical trial. Metabolism. 2016;65(11):1636-45.
  204. Gillies PJ, Bhatia SK, Belcher LA, Hannon DB, Thompson JT, Vanden Heuvel JP. Regulation of inflammatory and lipid metabolism genes by eicosapentaenoic acid-rich oil [S]. Journal of lipid research. 2012;53(8):1679-89.
  205. Kris-Etherton PM, Harris WS, Appel LJ. Omega-3 fatty acids and cardiovascular disease: new recommendations from the American Heart Association. Arteriosclerosis, thrombosis, and vascular biology. 2003;23(2):151-2.
  206. Kris-Etherton PM, Harris WS, Appel LJ, Committee N. Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Arterioscler Thromb Vasc Biol. 2003;23(2):e20-30.
  207. Nodari S, Triggiani M, Campia U, Manerba A, Milesi G, Cesana BM, et al. Effects of n-3 polyunsaturated fatty acids on left ventricular function and functional capacity in patients with dilated cardiomyopathy. Journal of the American College of Cardiology. 2011;57(7):870-9.
  208. Chrysohoou C, Metallinos G, Georgiopoulos G, Mendrinos D, Papanikolaou A, Magkas N, et al. Short term omega-3 polyunsaturated fatty acid supplementation induces favorable changes in right ventricle function and diastolic filling pressure in patients with chronic heart failure; A randomized clinical trial. Vascular pharmacology. 2016;79:43-50.
  209. Kohashi K, Nakagomi A, Saiki Y, Morisawa T, Kosugi M, Kusama Y, et al. Effects of eicosapentaenoic acid on the levels of inflammatory markers, cardiac function and long-term prognosis in chronic heart failure patients with dyslipidemia. Journal of Atherosclerosis and Thrombosis. 2014;21(7):712-29.
  210. Moertl D, Hammer A, Steiner S, Hutuleac R, Vonbank K, Berger R. Dose-dependent effects of omega-3-polyunsaturated fatty acids on systolic left ventricular function, endothelial function, and markers of inflammation in chronic heart failure of nonischemic origin: a double-blind, placebo-controlled, 3-arm study. American heart journal. 2011;161(5):915. e1-. e9.
  211. Mozaffarian D, Lemaitre RN, King IB, Song X, Spiegelman D, Sacks FM, et al. Circulating long-chain ω-3 fatty acids and incidence of congestive heart failure in older adults: the cardiovascular health study: a cohort study. Annals of internal medicine. 2011;155(3):160-70.
  212. Ouchi S, Miyazaki T, Shimada K, Sugita Y, Shimizu M, Murata A, et al. Low docosahexaenoic acid, dihomo-gamma-linolenic acid, and arachidonic acid levels associated with long-term mortality in patients with acute decompensated heart failure in different nutritional statuses. Nutrients. 2017;9(9):956.
  213. J. Romero-Bermejo F, Ruiz-Bailen M, Gil-Cebrian J, J. Huertos-Ranchal M. Sepsis-induced cardiomyopathy. Current cardiology reviews. 2011;7(3):163-83.
  214. Martin JM, Stapleton RD. Omega-3 fatty acids in critical illness. Nutrition reviews. 2010;68(9):531-41.
  215. Welty FK. Omega-3 fatty acids and cognitive function. Current opinion in lipidology. 2023;34(1):12-21.
  216. Welty FK, Hariri E, Asbeutah AA, Daher R, Amangurbanova M, Chedid G, et al. Regression of coronary fatty plaque and risk of cardiac events according to blood pressure status: data From a randomized trial of eicosapentaenoic acid and docosahexaenoic acid in patients with coronary artery disease. Journal of the American Heart Association. 2023;12(18):e030071.
  217. Casagrande BP, Sherrard G, Fowler MS, Estadella D, Bueno AA. Capillary Blood Docosahexaenoic Acid Levels Predict Electrocardiographic Markers in a Sample Population of Premenopausal Women. Journal of Clinical Medicine. 2024;13(19):5957.
  218. Duda MK, O'Shea KM, Stanley WC. ω-3 polyunsaturated fatty acid supplementation for the treatment of heart failure: mechanisms and clinical potential. Cardiovascular research. 2009;84(1):33-41.
  219. Goel A, Pothineni NV, Singhal M, Paydak H, Saldeen T, Mehta JL. Fish, fish oils and cardioprotection: promise or fish tale? International journal of molecular sciences. 2018;19(12):3703.
  220. McMillin JB, Bick RJ, Benedict CR. Influence of dietary fish oil on mitochondrial function and response to ischemia. American Journal of Physiology-Heart and Circulatory Physiology. 1992;263(5):H1479-H85.
  221. Pepe S, Tsuchiya N, Lakatta EG, Hansford RG. PUFA and aging modulate cardiac mitochondrial membrane lipid composition and Ca2+ activation of PDH. American Journal of Physiology-Heart and Circulatory Physiology. 1999;276(1):H149-H58.
  222. Park T-S, Hu Y, Noh H-L, Drosatos K, Okajima K, Buchanan J, et al. Ceramide is a cardiotoxin in lipotoxic cardiomyopathy* s⃞. Journal of lipid research. 2008;49(10):2101-12.
  223. Wang X, McLennan SV, Allen TJ, Tsoutsman T, Semsarian C, Twigg SM. Adverse effects of high glucose and free fatty acid on cardiomyocytes are mediated by connective tissue growth factor. American Journal of Physiology-Cell Physiology. 2009;297(6):C1490-C500.
  224. Novinbahador T, Nourazarian A, Asgharzadeh M, Rahbarghazi R, Avci ÇB, Bagca BG, et al. Docosahexaenoic acid attenuates the detrimental effect of palmitic acid on human endothelial cells by modulating genes from the atherosclerosis signaling pathway. Journal of Cellular Biochemistry. 2018;119(12):9752-63.
  225. Karbasforush S, Nourazarian A, Darabi M, Rahbarghazi R, Khaki‐Khatibi F, Biray Avci Ç, et al. Docosahexaenoic acid reversed atherosclerotic changes in human endothelial cells induced by palmitic acid in vitro. Cell Biochemistry and Function. 2018;36(4):203-11.
  226. Jimenéz‐Aranda A, Fernández‐Vázquez G, Mohammad A‐Serrano M, Reiter RJ, Agil A. Melatonin improves mitochondrial function in inguinal white adipose tissue of Zücker diabetic fatty rats. Journal of pineal research. 2014;57(1):103-9.
  227. Siracuse JJ, Chaikof EL. The pathogenesis of diabetic atherosclerosis. Diabetes and Peripheral Vascular Disease: Diagnosis and Management: Springer; 2012. p. 13-26.
  228. Aronson D, Rayfield EJ. How hyperglycemia promotes atherosclerosis: molecular mechanisms. Cardiovascular diabetology. 2002;1:1-10.
  229. Fadaei R, Parvaz E, Emamgholipour S, Moradi N, Vatannejad A, Najafi M, Doosti M. The mRNA expression and circulating levels of visfatin and their correlation with coronary artery disease severity and 25-hydroxyvitamin D. Hormone and metabolic research. 2016;48(04):269-74.
  230. Teimouri M, Shabani P, Zali F, Najafi M, Shateri H, Asadnia M, et al. Circulating levels of LAMP2 in coronary artery disease: Association with serum lipid profile. Hormone and Metabolic Research. 2017;49(02):109-14.
  231. Hamburg NM, Creager MA. Pathophysiology of Peripheral Artery Disease. Vascular Medicine: A Companion to Braunwald's Heart Disease E-Book. 2019:231.
  232. Mukohda M, Lu K-T, Guo D-F, Wu J, Keen HL, Liu X, et al. Hypertension-causing mutation in peroxisome proliferator–activated receptor γ impairs nuclear export of nuclear factor-κb p65 in vascular smooth muscle. Hypertension. 2017;70(1):174-82.
  233. Mansoori A, Sotoudeh G, Djalali M, Eshraghian M-R, Keramatipour M, Nasli-Esfahani E, et al. Effect of DHA-rich fish oil on PPARγ target genes related to lipid metabolism in type 2 diabetes: A randomized, double-blind, placebo-controlled clinical trial. Journal of clinical lipidology. 2015;9(6):770-7.
  234. van de Weijer T, Schrauwen-Hinderling VB, Schrauwen P. Lipotoxicity in type 2 diabetic cardiomyopathy. Cardiovascular research. 2011;92(1):10-8.
  235. Carley AN, Severson DL. Fatty acid metabolism is enhanced in type 2 diabetic hearts. Biochimica et Biophysica Acta (BBA)-Molecular and Cell Biology of Lipids. 2005;1734(2):112-26.
  236. Ding W, Zhang X, Xiao D, Chang W. Decreased in n‐3 DHA enriched triacylglycerol in small extracellular vesicles of diabetic patients with cardiac dysfunction. Journal of Diabetes. 2023;15(12):1070-80.
  237. Wang Z-Q, Chen M-T, Zhang R, Zhang Y, Li W, Li Y-G. Docosahexaenoic acid attenuates doxorubicin-induced cytotoxicity and inflammation by suppressing NF-κB/iNOS/NO signaling pathway activation in H9C2 cardiac cells. Journal of Cardiovascular Pharmacology. 2016;67(4):283-9.
  238. Cottin S, Sanders T, Hall W. The differential effects of EPA and DHA on cardiovascular risk factors. Proceedings of the Nutrition Society. 2011;70(2):215-31.
  239. Hafstad AD, Boardman N, Aasum E. How exercise may amend metabolic disturbances in diabetic cardiomyopathy. Antioxidants & redox signaling. 2015;22(17):1587-605.
  240. Sivitz WI, Yorek MA. Mitochondrial dysfunction in diabetes: from molecular mechanisms to functional significance and therapeutic opportunities. Antioxidants & redox signaling. 2010;12(4):537-77.
  241. Jin L, Geng L, Ying L, Shu L, Ye K, Yang R, et al. FGF21–Sirtuin 3 Axis confers the protective effects of exercise against diabetic cardiomyopathy by governing mitochondrial integrity. Circulation. 2022;146(20):1537-57.
  242. Fontana F, Limonta P. The multifaceted roles of mitochondria at the crossroads of cell life and death in cancer. Free Radical Biology and Medicine. 2021;176:203-21.
  243. Dabkowski ER, Baseler WA, Williamson CL, Powell M, Razunguzwa TT, Frisbee JC, Hollander JM. Mitochondrial dysfunction in the type 2 diabetic heart is associated with alterations in spatially distinct mitochondrial proteomes. American Journal of Physiology-Heart and Circulatory Physiology. 2010;299(2):H529-H40.
  244. Kuznetsov AV, Javadov S, Margreiter R, Grimm M, Hagenbuchner J, Ausserlechner MJ. The role of mitochondria in the mechanisms of cardiac ischemia-reperfusion injury. Antioxidants. 2019;8(10):454.
  245. Pizzino G, Irrera N, Cucinotta M, Pallio G, Mannino F, Arcoraci V, et al. Oxidative stress: harms and benefits for human health. Oxidative medicine and cellular longevity. 2017;2017(1):8416763.
  246. Paulson DJ, Mathews R, Bowman J, Zhao J. Metabolic effects of treadmill exercise training on the diabetic heart. Journal of applied physiology. 1992;73(1):265-71.
  247. Ko TH, Marquez JC, Kim HK, Jeong SH, Lee S, Youm JB, et al. Resistance exercise improves cardiac function and mitochondrial efficiency in diabetic rat hearts. Pflügers Archiv-European Journal of Physiology. 2018;470:263-75.
  248. Nazir A, Heryaman H, Juli C, Ugusman A, Martha JW, Moeliono MA, Atik N. Resistance Training in Cardiovascular diseases: a review on its effectiveness in Controlling Risk factors. Integrated Blood Pressure Control. 2024:21-37.
  249. Jagsz S, Sikora M. The Effectiveness of High-Intensity Interval Training vs. Cardio Training for Weight Loss in Patients with Obesity: A Systematic Review. Journal of Clinical Medicine. 2025;14(4):1282.
  250. Yoo J, Hwang J, Choi J, Ramalingam M, Jeong H, Jang S, et al. The effects of resistance training on cardiovascular factors and anti-inflammation in diabetic rats. Heliyon. 2024;10(17).
  251. Hua L, Lei M, Xue S, Li X, Li S, Xie Q. Effect of fish oil supplementation combined with high-intensity interval training in newly diagnosed non-obese type 2 diabetes: a randomized controlled trial. Journal of Clinical Biochemistry and Nutrition. 2020;66(2):146-51.
  252. Rontoyanni VG, Hall WL, Pombo-Rodrigues S, Appleton A, Chung R, Sanders TA. A comparison of the changes in cardiac output and systemic vascular resistance during exercise following high-fat meals containing DHA or EPA. British Journal of Nutrition. 2012;108(3):492-9.
  253. Capó X, Martorell M, Sureda A, Tur JA, Pons A. Effects of dietary Docosahexaenoic, training and acute exercise on lipid mediators. Journal of the International Society of Sports Nutrition. 2016;13(1):16.
  254. Martínez-Gayo A, Félix-Soriano E, Sáinz N, González-Muniesa P, Moreno-Aliaga MJ. Changes induced by aging and long-term exercise and/or DHA supplementation in muscle of obese female mice. Nutrients. 2022;14(20):4240.
  255. Félix-Soriano E, Martínez-Gayo A, Cobo MJ, Pérez-Chávez A, Ibáñez-Santos J, Palacios Samper N, et al. Effects of DHA-rich n-3 fatty acid supplementation and/or resistance training on body composition and cardiometabolic biomarkers in overweight and obese post-menopausal women. Nutrients. 2021;13(7):2465.
  256. Hashemzadeh AA, Nasoohi N, Raygan F, Aghadavod E, Akbari E, Taghizadeh M, et al. Flaxseed oil supplementation improve gene expression levels of PPAR-γ, LP (a), IL-1 and TNF-α in type 2 diabetic patients with coronary heart disease. Lipids. 2017;52(11):907-15.
  257. Štěpán M, Daďová K, Matouš M, Krauzová E, Sontáková L, Koc M, et al. Exercise training combined with Calanus oil supplementation improves the central cardiodynamic function in older women. Nutrients. 2021;14(1):149.
  258. Shah IA, Ishaq S, Lee S-D, Wu B-T. Effects of Exercise Training on Cardiac Mitochondrial Functions in Diabetic Heart: A Systematic Review. International Journal of Molecular Sciences. 2024;26(1):8.
  259. Hashimoto M, Hossain S, Al Mamun A, Matsuzaki K, Arai H. Docosahexaenoic acid: one molecule diverse functions. Critical reviews in biotechnology. 2017;37(5):579-97.
  260. Choi GY, Calder PC. The differential effects of eicosapentaenoic acid and docosahexaenoic acid on cardiovascular risk factors: an updated systematic review of randomized controlled trials. Frontiers in Nutrition. 2024;11:1423228.
  261. Matsuo N, Miyoshi T, Takaishi A, Kishinoue T, Yasuhara K, Tanimoto M, et al. High plasma docosahexaenoic acid associated to better prognoses of patients with acute decompensated heart failure with preserved ejection fraction. Nutrients. 2021;13(2):371.
  262. Wang C, Han D, Feng X, Hu L, Wu J. Docosahexaenoic acid alleviates LPS-induced cytotoxicity in HL-1 cardiac cells via improving stress-induced mitochondrial fragmentation. Heliyon. 2023;9(12).
  263. Holub BJ. Docosahexaenoic acid (DHA) and cardiovascular disease risk factors. Prostaglandins, Leukotrienes and Essential Fatty Acids. 2009;81(2-3):199-204.
  264. Naeini Z, Toupchian O, Vatannejad A, Sotoudeh G, Teimouri M, Ghorbani M, et al. Effects of DHA-enriched fish oil on gene expression levels of p53 and NF-κB and PPAR-γ activity in PBMCs of patients with T2DM: A randomized, double-blind, clinical trial. Nutrition, Metabolism and Cardiovascular Diseases. 2020;30(3):441-7.