铁代谢在心力衰竭中的研究进展
Research Progress in Iron Metabolism in Heart Failure
DOI: 10.12677/ACM.2023.133663, PDF,    科研立项经费支持
作者: 赵 航:大理大学临床医学院,云南 大理;吕晋琳:大理大学第一附属医院,云南 大理
关键词: 铁代谢铁调素心力衰竭Iron Metabolism Hepcidin Heart Failure
摘要: 铁是人体必要的微量元素,它对生命体中几乎所有类型的细胞都是必不可少的;铁稳态对人体至关重要,铁的缺乏和过量对人体是有害的,可导致患者发生心力衰竭。因此,必须严格控制铁稳态,以防止缺铁导致贫血以及铁过量使游离铁的产生和活性氧的增加,致组织损伤和器官衰竭。铁调素在调节铁代谢中起着重要的作用,是脊椎动物全身性铁稳态的关键调节剂,当铁调素水平升高时,铁被困在十二指肠肠细胞、肝细胞、脾巨噬细胞及胎盘合胞滋养细胞内,导致血浆铁水平下降。心肌细胞铁调素是自主细胞铁稳态所必需的,心脏铁调素的功能不仅限于调控铁水平,同时也具有抗心肌细胞凋亡、抗心肌肥大和抗心肌纤维化作用。HF患者ID发生率较高,有研究表明对HF患者静脉补充铁剂治疗ID可改善其运动能力和生活质量,连续静脉补铁12周后可减少HF的住院率,口服铁补充剂不能提高运动能力和生活质量,但它们可以减少全因死亡和心力衰竭住院率,但口服铁制剂的胃肠道副作用发生率很高,可能导致胃肠道吸收不良、胃肠道溃疡穿孔、饮食不良或乳糜泻等,此外,铁调素的上调也会减少膳食铁的吸收,因此,目前推荐静脉补充铁剂来治疗HF。
Abstract: Iron is an essential trace element for the human body, it is essential for almost all types of cells in the living body. Iron homeostasis is essential for the human body. Iron deficiency and excess are harmful to the human body and can lead to heart failure in patients. Therefore, iron homeostasis must be strictly controlled to prevent anemia due to iron deficiency and the increase of free iron production and reactive oxygen species due to iron overdose, leading to tissue damage and organ failure. Hepcidin plays an important role in regulating iron metabolism and is a key regulator of systemic iron homeostasis in vertebrates. When hepcidin levels are elevated, iron is trapped in duodenal cells, hepatocytes, splenic macrophages, and placental syncytial trophoblasts, resulting in a decrease in plasma iron levels. Cardiomyocyte hepcidin is required for iron homeostasis in autonomous cells, and the function of cardiac hepcidin is not limited to regulating iron levels, but also has the effects of anti-cardiomyocyte apoptosis, anti-myocardial hypertrophy, and anti-myocardial fibrosis. Patients with HF have a higher incidence of ID, studies have shown that intravenous iron treatment with ID improves exercise capacity and quality of life in patients with HF, reduces hospitalization of HF after 12 weeks, oral iron supplementation does not improve exercise capacity and quality of life, but they can reduce all-cause mortality and heart failure hospitalization. However, oral iron preparations have a high incidence of gastrointestinal side effects that may lead to gastrointestinal malabsorption, perforation of gastrointestinal ulcers, poor diet, or celiac disease. In addition, the upregulation of hepcidin also reduces the absorption of dietary iron. Therefore, intravenous iron is currently recommended for HF.
文章引用:赵航, 吕晋琳. 铁代谢在心力衰竭中的研究进展[J]. 临床医学进展, 2023, 13(3): 4616-4622. https://doi.org/10.12677/ACM.2023.133663

参考文献

[1] Liu, H.D., Li, W., Chen, Z.R., et al. (2013) Increased Expression of Ferritin in Cerebral Cortex after Human Traumatic Brain Injury. Neurological Sciences, 34, 1173-1180. [Google Scholar] [CrossRef] [PubMed]
[2] Dutt, S., Hamza, I. and Bartnikas, T.B. (2022) Molecular Mechanisms of Iron and Heme Metabolism. Annual Review of Nutrition, 42, 311-335. [Google Scholar] [CrossRef] [PubMed]
[3] Wen, Z., Zhao, Y., Gong, Z., et al. (2022) The Mechanism of Action of Ginkgolic Acid (15:1) against Gram-Positive Bacteria Involves Cross Talk with Iron Ho-meostasis. Microbiology Spectrum, 10, e0099121. [Google Scholar] [CrossRef] [PubMed]
[4] Gulec, S. anderson, G.J. and Collins, J.F. (2014) Mechanistic and Regulatory Aspects of intestinal Iron Absorption. The American Journal of Physiology-Gastrointestinal and Liver Phys-iology, 307, G397-G409. [Google Scholar] [CrossRef] [PubMed]
[5] Chifman, J., Laubenbacher, R. and Torti, S.V. (2014) A Systems Biology Approach to Iron Metabolism. Advances in Experimental Medicine and Biology, 844, 201-225. [Google Scholar] [CrossRef] [PubMed]
[6] Wang, J. and Pantopoulos, K. (2011) Regulation of Cellular Iron Metabolism. Biochemical Journal, 434, 365-381. [Google Scholar] [CrossRef
[7] Prajapati, M., Conboy, H.L., Hojyo, S., et al. (2021) Biliary Excretion of Excess Iron in Mice Requires Hepatocyte Iron Import by Slc39a14. Journal of Biological Chemistry, 297, Article ID: 100835. [Google Scholar] [CrossRef] [PubMed]
[8] Katsarou, A. and Pantopoulos, K. (2020) Basics and Principles of Cellular and Systemic Iron Homeostasis. Molecular Aspects of Medicine, 75, Article ID: 100866. [Google Scholar] [CrossRef] [PubMed]
[9] Drakesmith, H., Nemeth, E. and Ganz, T. (2015) Ironing out Fer-roportin. Cell Metabolism, 22, 777-787. [Google Scholar] [CrossRef] [PubMed]
[10] Balusikova, K., Dostalikova-Cimburova, M., Tacheci, I., et al. (2022) Expression Profiles of Iron Transport Molecules along the Duodenum. Journal of Cellular and Molecular Medi-cine, 26, 2995-3004. [Google Scholar] [CrossRef] [PubMed]
[11] Cegarra, L., Colins, A., Gerdtzen, Z.P., et al. (2019) Mathematical Mod-eling of the Relocation of the Divalent Metal Transporter DMT1 in the Intestinal Iron Absorption Process. PLOS ONE, 14, e0218123. [Google Scholar] [CrossRef] [PubMed]
[12] Lane, D.J., Merlot, A.M., Huang, M.L., et al. (2015) Cellular Iron Uptake, Trafficking and Metabolism: Key Molecules and Mechanisms and Their Roles in Disease. Biochimica et Biophysica Acta, 1853, 1130-1144. [Google Scholar] [CrossRef] [PubMed]
[13] Peng, Y., Chang, X. and Lang, M. (2021) Iron Homeostasis Disorder and Alzheimer’s Disease. International Journal of Molecular Sciences, 22, 12442. [Google Scholar] [CrossRef] [PubMed]
[14] Krause, A., Neitz, S., Magert, H.J., et al. (2000) LEAP-1, a Novel Highly Disulfide-Bonded Human Peptide, Exhibits Antimicrobial Activity. FEBS Letters, 480, 147-150. [Google Scholar] [CrossRef
[15] Park, C.H., Valore, E.V., Waring, A.J., et al. (2001) Hep-cidin, a Urinary Antimicrobial Peptide Synthesized in the Liver. Journal of Biological Chemistry, 276, 7806-7810. [Google Scholar] [CrossRef
[16] Wojciechowska, M., Wisniewski, O.W., Kolodziejski, P., et al. (2021) Role of Hepcidin in Physiology and Pathophysiology. Emerging Experimental and Clinical Evidence. Journal of Physiology and Pharmacology, 72, 23-33.
[17] Jordan, J.B., Poppe, L., Haniu, M., et al. (2009) Hepcidin Revisited, Disulfide Connectivity, Dynamics, and Structure. Journal of Biological Chemistry, 284, 24155-24167. [Google Scholar] [CrossRef
[18] Rishi, G. and Subramaniam, V.N. (2017) The Liver in Regulation of Iron Homeostasis. The American Journal of Physiology-Gastrointestinal and Liver Physiology, 313, G157-G165. [Google Scholar] [CrossRef] [PubMed]
[19] Merle, U., Fein, E., Gehrke, S.G., et al. (2007) The Iron Regulatory Peptide Hepcidin Is Expressed in the Heart and Regulated by Hypoxia and Inflammation. Endocrinology, 148, 2663-2668. [Google Scholar] [CrossRef] [PubMed]
[20] Nguyen, N.B., Callaghan, K.D., Ghio, A.J., et al. (2006) Hepcidin Expression and Iron Transport in Alveolar Macrophages. American Journal of Physiology—Lung Cellular and Molecular Physiology, 291, L417-L425. [Google Scholar] [CrossRef] [PubMed]
[21] Liu, X.B., Nguyen, N.B., Marquess, K.D., et al. (2005) Regula-tion of Hepcidin and Ferroportin Expression by Lipopolysaccharide in Splenic Macrophages. Blood Cells, Molecules, and Diseases, 35, 47-56. [Google Scholar] [CrossRef] [PubMed]
[22] Crielaard, B.J., Lammers, T. and Rivella, S. (2017) Targeting Iron Metabolism in Drug Discovery and Delivery. Nature Reviews Drug Discovery, 16, 400-423. [Google Scholar] [CrossRef] [PubMed]
[23] Liu, J., Sun, B., Yin, H., et al. (2016) Hepcidin: A Promising Therapeu-tic Target for Iron Disorders: A Systematic Review. Medicine (Baltimore), 95, e3150. [Google Scholar] [CrossRef
[24] Ginzburg, Y.Z. (2019) Hepcidin-Ferroportin Axis in Health and Disease. Vitamins and Hormones, 110, 17-45. [Google Scholar] [CrossRef] [PubMed]
[25] Ganz, T. and Nemeth, E. (2011) Hepcidin and Disorders of Iron Metabolism. Annual Review of Medicine, 62, 347-360. [Google Scholar] [CrossRef] [PubMed]
[26] Donovan, A., Lima, C.A., Pinkus, J.L., et al. (2005) The Iron Exporter Ferroportin/Slc40a1 Is Essential for Iron Homeostasis. Cell Metabolism, 1, 191-200. [Google Scholar] [CrossRef] [PubMed]
[27] Ganz, T. and Nemeth, E. (2016) Iron Balance and the Role of Hep-cidin in Chronic Kidney Disease. Seminars in Nephrology, 36, 87-93. [Google Scholar] [CrossRef] [PubMed]
[28] Kim, G.H. (2020) Hepcidin as a Biomarker of Cardiorenal Syndrome. Journal of Korean Medical Science, 35, e20. [Google Scholar] [CrossRef] [PubMed]
[29] Malhotra, R., Wunderer, F., Barnes, H.J., et al. (2019) Hepcidin Deficiency Protects against Atherosclerosis. Arteriosclerosis, Thrombosis, and Vascular Biology, 39, 178-187. [Google Scholar] [CrossRef
[30] Ganz, T. (2003) Hepcidin, a Key Regulator of Iron Metabo-lism and Mediator of Anemia of Inflammation. Blood, 102, 783-788. [Google Scholar] [CrossRef] [PubMed]
[31] Heidenreich, P.A., Bozkurt, B., Aguilar, D., et al. (2022) 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: Executive Summary: A Report of the American Col-lege of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation, 145, e876-e894. [Google Scholar] [CrossRef
[32] Virani, S.S., Alonso, A., Benjamin, E.J., et al. (2020) Heart Disease and Stroke Statistics-2020 Update: A Report from the American Heart Association. Circulation, 141, e139-e596.
[33] Roger, V.L. (2021) Epidemiology of Heart Failure: A Contemporary Perspective. Circulation Research, 128, 1421-1434. [Google Scholar] [CrossRef
[34] Bozkurt, B. and Khalaf, S. (2017) Heart Failure in Women. Methodist DeBakey Cardiovascular Journal, 13, 216-223. [Google Scholar] [CrossRef] [PubMed]
[35] Wenzel, J.P., Nikorowitsch, J., Bei der Kellen, R., et al. (2022) Heart Failure in the General Population and Impact of the 2021 European Society of Cardiology Heart Failure Guidelines. ESC Heart Failure Journal, 9, 2157-2169. [Google Scholar] [CrossRef] [PubMed]
[36] Ambrosy, A.P., Fonarow, G.C., Butler, J., et al. (2014) The Global Health and Economic Burden of Hospitalizations for Heart Failure: Lessons Learned from Hospitalized Heart Failure Registries. Journal of the American College of Cardiology, 63, 1123-1133. [Google Scholar] [CrossRef] [PubMed]
[37] Wang, H., Chai, K., Du, M., et al. (2021) Prevalence and Incidence of Heart Failure among Urban Patients in China: A National Population-Based Analysis. Circulation: Heart Failure, 14, e008406. [Google Scholar] [CrossRef
[38] Mclean, E., Cogswell, M., Egli, I., et al. (2009) Worldwide Prevalence of Anaemia, WHO Vitamin and Mineral Nutrition Information System, 1993-2005. Public Health Nutrition, 12, 444-454. [Google Scholar] [CrossRef
[39] Loncar, G., Obradovic, D., Thiele, H., et al. (2021) Iron Defi-ciency in Heart Failure. ESC Heart Failure Journal, 8, 2368-2379. [Google Scholar] [CrossRef] [PubMed]
[40] Cohen-Solal, A., Damy, T., Terbah, M., et al. (2014) High Prevalence of Iron Deficiency in Patients with Acute Decompensated Heart Failure. European Journal of Heart Failure, 16, 984-991. [Google Scholar] [CrossRef] [PubMed]
[41] Kobak, K.A., Radwanska, M., Dziegala, M., et al. (2019) Structural and Functional Abnormalities in Iron-Depleted Heart. Heart Failure Reviews, 24, 269-277. [Google Scholar] [CrossRef] [PubMed]
[42] Alnuwaysir, R.I.S., Hoes, M.F., Van Veldhuisen, D.J., et al. (2021) Iron Deficiency in Heart Failure: Mechanisms and Pathophysiology. Journal of Clinical Medicine, 11, 125. [Google Scholar] [CrossRef] [PubMed]
[43] Von Haehling, S., Ebner, N., Evertz, R., et al. (2019) Iron Deficiency in Heart Failure: An Overview. JACC: Heart Failure, 7, 36-46. [Google Scholar] [CrossRef] [PubMed]
[44] Ponikowska, B., Iwanek, G., Zdanowicz, A., et al. (2022) Bi-omarkers of Myocardial Injury and Remodeling in Heart Failure. Journal of Personalized Medicine, 12, 799. [Google Scholar] [CrossRef] [PubMed]
[45] Kremastinos, D.T. and Farmakis, D. (2011) Iron Overload Cardiomyo-pathy in Clinical Practice. Circulation, 124, 2253-2263. [Google Scholar] [CrossRef
[46] Hider, R.C. and Kong, X. (2013) Iron: Effect of Overload and Deficiency. Metal Ions in Life Sciences, 13, 229-294. [Google Scholar] [CrossRef] [PubMed]
[47] Das, S., Misra, A., Kashyap, A., et al. (2021) Study of Trans-fusion-Related Iron Overload (Trio) in Pediatric Patients with Hematological Malignancy and Bone Marrow Failure Syn-dromes. American Journal of Blood Research, 11, 384-390.
[48] Gujja, P., Rosing, D.R., Tripodi, D.J., et al. (2010) Iron Overload Cardiomyopathy: Better Understanding of an Increasing Disorder. Journal of the American College of Cardiology, 56, 1001-1012. [Google Scholar] [CrossRef] [PubMed]
[49] Kane, S.F., Roberts, C. and Paulus, R. (2021) Hereditary Hemochromatosis: Rapid Evidence Review. American Family Physician, 104, 263-270.
[50] Lakhal-Littleton, S., Wolna, M., Chung, Y.J., et al. (2016) An Essential Cell-Autonomous Role for Hep-cidin in Cardiac Iron Homeostasis. Elife, 5, e19804. [Google Scholar] [CrossRef
[51] Island, M.L., Fatih, N., Leroyer, P., et al. (2011) GATA-4 Transcription Factor Regulates Hepatic Hepcidin Expression. Biochemical Journal, 437, 477-482. [Google Scholar] [CrossRef
[52] Naito, Y., Hosokawa, M., Sawada, H., Oboshi, M., et al. (2014) Hepcidin Is Increased in the Hypertrophied Heart of Dahl Salt-Sensitive Rats. International Journal of Cardiolo-gy, 172, e45-e47. [Google Scholar] [CrossRef] [PubMed]
[53] Hsieh, Y.P., Huang, C.H., Lee, C.Y., et al. (2014) Silencing of Hepcidin Enforces the Apoptosis in Iron-Induced Human Cardiomyocytes. Journal of Occupational Medicine and Toxi-cology, 9, 11. [Google Scholar] [CrossRef] [PubMed]
[54] Mei, Z., Chen, J., Luo, S., et al. (2022) Comparative Efficacy of In-travenous and Oral Iron Supplements for the Treatment of Iron Deficiency in Patients with Heart Failure: A Network Meta-Analysis of Randomized Controlled Trials. Pharmacological Research, 182, Article ID: 106345. [Google Scholar] [CrossRef] [PubMed]
[55] Lopez-Vilella, R., Lozano-Edo, S., Arenas Martin, P., et al. (2022) Impact of Intravenous Ferric Carboxymaltose on Heart Failure with Preserved and Reduced Ejection Fraction. ESC Heart Failure Journal, 9, 133-145. [Google Scholar] [CrossRef] [PubMed]
[56] Ismahel, H. and Ismahel, N. (2021) Iron Replacement Therapy in Heart Failure: A Literature Review. The Egyptian Heart Journal, 73, 85. [Google Scholar] [CrossRef] [PubMed]