The purpose of the study was to evaluate the effect of L-arginine on the general condition of patients with coronary artery disease and anemia, on the dynamics of laboratory parameters of iron metabolism, glucose, high-sensitivity C-reactive protein, lipid metabolism and the functional state of the kidneys in particular category of patients. Materials and methods. The study involved 53 patients with coronary heart disease and anemia, aged from 56 to 85 years. The patients were randomized into two groups. The control group included 24 patients who received standard therapy for coronary heart disease and anemia. The main group included 29 patients who, in addition to standard therapy, received L-arginine intravenously and orally according to the scheme. Results and discussion. As a result of treatment, red blood counts and iron metabolism in the main and control groups normalized. A comparative analysis of iron metabolism indicators showed that during treatment, patients who received L-arginine had a more active metabolism and accumulation of iron in the body. Restoration of hemoglobin levels in patients with coronary heart disease and anemia contributed to the improvement of the general condition and well-being in both groups. But general weakness (p<0.001) and palpitations (p<0.05) after treatment were less pronounced in the main group. Observations showed the dynamics of high-sensitivity C-reactive protein, indicators of lipid metabolism and the functional state of the kidneys in the main and control groups. A significant decrease in lipidogram parameters after treatment was noted both in patients of the control and the main group; but due to the addition of L-arginine, changes in total cholesterol, high density lipoprotein and atherogenic index in the main group compared with the control group were more pronounced (from p<0.01 to p<0.001). The inclusion of statins in the standard therapy contributed to a significant decrease in the levels of high-sensitivity C-reactive protein in patients in the main group – 17.8% (p<0.001) and 11.4% (p<0.05) in the control group. Conclusion. According to the results of the study, it was found that nitric oxide donors have a beneficial effect on iron metabolism, lipid profile, high-sensitivity C-reactive protein level, the functional state of the kidneys, and, probably, on the degree of heart failure. It has been established that against the background of treatment with L-arginine, the bioavailability of orally incoming iron increases; the supply of iron in the body increases significantly; there was a trend towards normalization of lipid profile and functional state of the kidneys with significant changes in creatinine and glomerular filtration rate levels; decrease in signs of heart failure (general weakness, palpitations)

Keywords: coronary heart disease, anemia, comorbid conditions, cardiovascular risk, nitric oxide donors

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1. WHO reveals leading causes of death and disability worldwide: 2000-2019. Available from: https://www.who.int/news/item/09-12-2020-who-reveals-leading-causes-of-death-and-disability-worldwide-2000-2019
2. WHO. World health statistics 2021: a visual summary. Available from: https://www.who.int/data/gho/publications/world-health-statistics
3. WHO/Health topics/Cardiovascular diseases. Available from: https://www.who.int/news-room/fact-sheets/detail/cardiovascular-diseases-(cvds)
4. Tanaka N, Inoue K, Okada M, Sakata Y, Akao M, Yamashita T, et al; J-ELD AF investigators. Impact of anemia on the clinical outcomes in elderly patients with atrial fibrillation receiving apixaban: J-ELD AF registry subanalysis. Int J Cardiol Heart Vasc. 2022 Mar 21;40:100994. PMID: 35342786. PMCID: PMC8943397. https://doi.org/10.1016/j.ijcha.2022.100994
5. Spazzafumo L, Olivieri F, Sabbatinelli J, Galeazzi R, Recchioni R, Marcheselli F, et al. Prognostic relevance of normocytic anemia in elderly patients affected by cardiovascular disease. J Geriatr Cardiol. 2021 Aug 28;18(8):654-662. PMID: 34527031. PMCID: PMC8390933. https://doi.org/10.11909/j.issn.1671-5411.2021.08.008
6. Ambrosy AP, Gurwitz JH, Tabada GH, Artz A, Schrier S, Rao SV, et al; RBC HEART Investigators. Incident anaemia in older adults with heart failure: rate, aetiology, and association with outcomes. Eur Heart J Qual Care Clin Outcomes. 2019 Oct 1;5(4):361-369. PMID: 30847487. PMCID: PMC6775859. https://doi.org/10.1093/ehjqcco/qcz010
7. Stahl-Gugger A, de Godoi Rezende Costa Molino C, Wieczorek M, Chocano-Bedoya PO, Abderhalden LA, et al; DO-HEALTH Research Group. Prevalence and incidence of iron deficiency in European community-dwelling older adults: an observational analysis of the DO-HEALTH trial. Aging Clin Exp Res. 2022 Mar 18. PMID: 35304704. https://doi.org/10.1007/s40520-022-02093-0
8. Matsue Y, Kamiya K, Saito H, Saito K, Ogasahara Y, Maekawa E, et al. Prevalence and prognostic impact of the coexistence of multiple frailty domains in elderly patients with heart failure: the FRAGILE-HF cohort study. Eur J Heart Fail. 2020 Nov;22(11):2112-2119. PMID: 32500539. https://doi.org/10.1002/ejhf.1926
9. Krittayaphong R, Pumprueg S, Thongsri T, Wiwatworapan W, Choochunklin T, Kaewkumdee P, et al; COOL-AF Investigators. Impact of anemia on clinical outcomes of patients with atrial fibrillation: The COOL-AF registry. Clin Cardiol. 2021 Mar;44(3):415-423. PMID: 33538035. PMCID: PMC7943899. https://doi.org/10.1002/clc.23559
10. Rodgers JL, Jones J, Bolleddu SI, Vanthenapalli S, Rodgers LE, Shah K, et al. Cardiovascular Risks Associated with Gender and Aging. J Cardiovasc Dev Dis. 2019;6(2):19. PMID: 31035613. PMCID: PMC6616540. https://doi.org/10.3390/jcdd6020019
11. Martín-Ontiyuelo C, Rodó-Pin A, Sancho-Muñoz A, Martinez-Llorens JM, Admetlló M, Molina L, et al. Is iron deficiency modulating physical activity in COPD? Int J Chron Obstruct Pulmon Dis. 2019 Jan 11;14:211-214. PMID: 30666101. PMCID: PMC6333152. https://doi.org/10.2147/COPD.S182700
12. van Haalen H, Jackson J, Spinowitz B, Milligan G, Moon R. Impact of chronic kidney disease and anemia on health-related quality of life and work productivity: analysis of multinational real-world data. BMC Nephrol. 2020 Mar 7;21(1):88. PMID: 32143582. PMCID: PMC7060645. https://doi.org/10.1186/s12882-020-01746-4
13. Mathias SD, Blum SI, Sikirica V, Johansen KL, Colwell HH, Okoro T. Symptoms and impacts in anemia of chronic kidney disease. J Patient Rep Outcomes. 2020 Jul 29;4(1):64. PMID: 32728779. PMCID: PMC7391458. https://doi.org/10.1186/s41687-020-00215-8
14. Dinatolo E, Dasseni N, Metra M, Lombardi C, von Haehling S. Iron deficiency in heart failure. J Cardiovasc Med (Hagerstown). 2018 Dec;19(12):706-716. PMID: 30222663. https://doi.org/10.2459/JCM.0000000000000686
15. Salman B, Hussain M, Shafique K, Imtiaz S, Dhrolia MF. Risk factors of hospitalization among chronic kidney disease patients in tertiary care hospitals - A single-center experience. Saudi J Kidney Dis Transpl. 2018 Sep-Oct;29(5):1150-1158. PMID: 30381512. https://doi.org/10.4103/1319-2442.243973
16. Hindricks G, Potpara T, Dagres N, Arbelo E, Bax JJ, Blomström-Lundqvist C, et al; ESC Scientific Document Group. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J. 2021 Feb 1;42(5):373-498. PMID: 32860505. https://doi.org/10.1093/eurheartj/ehaa612
17. Hanyukov AA, Pesockaya LA, Sapozhnichenko LV, Pampuha AA. Rasprostranennost i patogenez anemii u pacientov s hronicheskoj serdechnoj nedostatochnostyu [Prevalence and pathogenesis of anemia in patients with chronic heart failure]. Gematologiya. Transfuziologiya. Vostochnaya Evropa. 2021;7(2):219-228. [Russian]
18. Paolillo S, Scardovi AB, Campodonico J. Role of comorbidities in heart failure prognosis Part I: Anaemia, iron deficiency, diabetes, atrial fibrillation. Eur J Prev Cardiol. 2020 Dec;27(2_suppl):27-34. PMID: 33238738. PMCID: PMC7691628. https://doi.org/10.1177/2047487320960288
19. Tanaka S, Kamiya K, Saito H, Saito K, Ogasahara Y, Maekawa E, et al. Prevalence and prognostic value of the coexistence of anaemia and frailty in older patients with heart failure. ESC Heart Fail. 2021 Feb;8(1):625-633. PMID: 33295134. PMCID: PMC7835564. https://doi.org/10.1002/ehf2.13140
20. Pizzini A, Aichner M, Sonnweber T, Tancevski I, Weiss G, Löffler-Ragg J. The Significance of iron deficiency and anemia in a real-life COPD cohort. Int J Med Sci. 2020 Aug 19;17(14):2232-2239. PMID: 32922186. PMCID: PMC7484656. https://doi.org/10.7150/ijms.46163
21. Goh VJ, Tromp J, Teng TK, Tay WT, Van Der Meer P, Ling LH, et al; ASIAN-HF investigators. Prevalence, clinical correlates, and outcomes of anaemia in multi-ethnic Asian patients with heart failure with reduced ejection fraction. ESC Heart Fail. 2018 Aug;5(4):570-578. PMID: 29604185. PMCID: PMC6073031. https://doi.org/10.1002/ehf2.12279
22. Anand IS, Gupta P. Anemia and Iron Deficiency in Heart Failure: Current Concepts and Emerging Therapies. Circulation. 2018 Jul 3;138(1):80-98. PMID: 29967232. https://doi.org/10.1161/CIRCULATIONAHA.118.030099
23. Kiani FZ, Ahmadi A. Prevalence of different comorbidities in chronic obstructive pulmonary disease among Shahrekord PERSIAN cohort study in southwest Iran. Sci Rep. 2021 Jan 15;11(1):1548. PMID: 33452286; PMCID: PMC7810834. https://doi.org/10.1038/s41598-020-79707-y
24. Batchelor EK, Kapitsinou P, Pergola PE, Kovesdy CP, Jalal DI. Iron Deficiency in Chronic Kidney Disease: Updates on Pathophysiology, Diagnosis, and Treatment. J Am Soc Nephrol. 2020 Mar;31(3):456-468. PMID: 32041774. PMCID: PMC7062209. https://doi.org/10.1681/ASN.2019020213
25. Nowakowska M, Zghebi SS, Ashcroft DM, Buchan I, Chew-Graham C, Holt T, et al. The comorbidity burden of type 2 diabetes mellitus: patterns, clusters and predictions from a large English primary care cohort. BMC Med. 2019 Jul 25;17(1):145. PMID: 31345214; PMCID: PMC6659216. https://doi.org/10.1186/s12916-019-1373-y
26. Alemu B, Techane T, Dinegde NG, Tsige Y. Prevalence of Anemia and Its Associated Factors Among Chronic Kidney Disease Patients Attending Selected Public Hospitals of Addis Ababa, Ethiopia: Institutional-Based Cross-Sectional Study. Int J Nephrol Renovasc Dis. 2021 Mar 5;14:67-75. PMID: 33707966. PMCID: PMC7943544. https://doi.org/10.2147/IJNRD.S296995
27. Sathyan S, George S, Vijayan P. Prevalence of anemia and cardiovascular diseases in chronic kidney disease patients: a single tertiary care centre study. Int J Adv Med. 2017;4(1):247-251. https://doi.org/10.18203/2349-3933.ijam20170120
28. Zakharova NO, Bulgakova SV, Treneva EV, Guseva VM. [Specificity of anemic syndrome in geriatric patients with chronic kidney disease.]. Klin Lab Diagn. 2020;65(5):275-280. [Russian]. PMID: 32298542. https://doi.org/10.18821/0869-2084-2020-65-5-275-280
29. Stucchi M, Cantoni S, Piccinelli E, Savonitto S, Morici N. Anemia and acute coronary syndrome: current perspectives. Vasc Health Risk Manag. 2018 May 30;14:109-118. PMID: 29881284. PMCID: PMC5985790. https://doi.org/10.2147/VHRM.S140951
30. WHO /Home/Newsroom/Fact sheets/Detail/Cardiovascular diseases (CVDs). Available from: https://www.who.int/news-room/fact-sheets/detail/cardiovascular-diseases-(cvds)
31. Schrage B, Rübsamen N, Ojeda FM, Thorand B, Peters A, Koenig W, et al. Association of iron deficiency with incident cardiovascular diseases and mortality in the general population. ESC Heart Fail. 2021 Dec;8(6):4584-4592. PMID: 34610649. PMCID: PMC8712835. https://doi.org/10.1002/ehf2.13589
32. Lanser L, Fuchs D, Scharnagl H, Grammer T, Kleber ME, März W, et al. Anemia of Chronic Disease in Patients With Cardiovascular Disease. Front Cardiovasc Med. 2021 Aug 12;8:666638. PMID: 34458328. PMCID: PMC8387678. https://doi.org/10.3389/fcvm.2021.666638
33. Al-Shamsi S, Al-Bluwi GSM, Al Shamsi M, Al Kaabi N, Al Khemeiri S, Baniyas N. Prognostic impact of anemia on the mortality of United Arab Emirates nationals with cardiovascular disease. Qatar Med J. 2022 Mar 12;2022(1):3. PMID: 35321122. PMCID: PMC8928605. https://doi.org/10.5339/qmj.2022.3
34. Kaiafa G, Kanellos I, Savopoulos C, Kakaletsis N, Giannakoulas G, Hatzitolios AI. Is anemia a new cardiovascular risk factor? Int J Cardiol. 2015;186:117-24. PMID: 25814357. https://doi.org/10.1016/j.ijcard.2015.03.159
35. Ge Z, Baber U, Claessen BE, Farhan S, Chandrasekhar J, Li SX, et al. The prevalence, predictors and outcomes of guideline-directed medical therapy in patients with acute myocardial infarction undergoing PCI, an analysis from the PROMETHEUS registry. Catheter Cardiovasc Interv. 2019 Feb 15;93(3):E112-E119. PMID: 30351514. https://doi.org/10.1002/ccd.27860
36. Mahendiran T, Nanchen D, Gencer B, Meier D, Klingenberg R, Räber L, et al. Prognosis of Patients with Chronic and Hospital-Acquired Anaemia After Acute Coronary Syndromes. J Cardiovasc Transl Res. 2020 Aug;13(4):618-628. PMID: 31768948. https://doi.org/10.1007/s12265-019-09934-w
37. Li X, Lin Y, Zhang R. Associations between endothelial nitric oxide synthase gene polymorphisms and the risk of coronary artery disease: A systematic review and meta-analysis of 132 case-control studies. Eur J Prev Cardiol. 2019 Jan;26(2):160-170. PMID: 30789045. https://doi.org/10.1177/2047487318780748
38. Ahmad A, Dempsey SK, Daneva Z, Azam M, Li N, Li PL, et al. Role of Nitric Oxide in the Cardiovascular and Renal Systems. Int J Mol Sci. 2018 Sep 3;19(9):2605. PMID: 30177600. PMCID: PMC6164974. https://doi.org/10.3390/ijms19092605.
39. Farah C, Michel LYM, Balligand JL. Nitric oxide signalling in cardiovascular health and disease. Nat Rev Cardiol. 2018 May;15(5):292-316. PMID: 29388567. https://doi.org/10.1038/nrcardio.2017.224
40. Tejero J, Shiva S, Gladwin MT. Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation. Physiol Rev. 2019 Jan 1;99(1):311-379. PMID: 30379623. PMCID: PMC6442925. https://doi.org/10.1152/physrev.00036.2017
41. Kuhn V, Diederich L, Keller TCS 4th, Kramer CM, Lückstädt W, Panknin C, et al. Red Blood Cell Function and Dysfunction: Redox Regulation, Nitric Oxide Metabolism, Anemia. Antioxid Redox Signal. 2017 May 1;26(13):718-742. PMID: 27889956. PMCID: PMC5421513. https://doi.org/10.1089/ars.2016.6954
42. Münzel T, Daiber A. Inorganic nitrite and nitrate in cardiovascular therapy: A better alternative to organic nitrates as nitric oxide donors? Vascul Pharmacol. 2018 Mar;102:1-10. PMID: 29174923. https://doi.org/10.1016/j.vph.2017.11.003
43. Rashid J, Kumar SS, Job KM, Liu X, Fike CD, Sherwin CMT. Therapeutic Potential of Citrulline as an Arginine Supplement: A Clinical Pharmacology Review. Paediatr Drugs. 2020 Jun;22(3):279-293. PMID: 32140997. PMCID: PMC7274894. https://doi.org/10.1007/s40272-020-00384-5
44. Radzyshevsky N. Violation of homeostasis and oxidative carbohydrate metabolism and their effects on the heart and blood vessels in patients with comorbid diseases. Ther Ukrainian J. 2016;1:30–35.
45. Stepanov YuM, Kononov YN, Zhurbyna AY, Fylyppova AYu. Arginin v medytsynskoy praktyke [Arginine in medical practice]. Zhurn AMN Ukrayiny. 2004;10(1):340–352. [Russian]
46. Martynyuk LP, Vons LZ, Ruzhytska OO. The effect of L-arginine on oxidative stress and microalbuminuria in patients with type 2 diabetes mellitus and chronic kidney disease. Int J Med Medical Res. 2017;3(1):22–25. https://doi.org/10.11603/ijmmr.2413-6077.2017.1.7867
47. Loboda OM, Krasyuk ІV, Alexeeva VV, Korol LV, Drіyanska VY, Dudar ІO. The relationship of lipid peroxidation and chronic inflammation of atherosclerotic changes in vessels and poeaznykamy endothelial dysfunction in patients with CKD stages II–IV. Ukr J Nephrolog Dialysis. 2015;1(45):13–20. https://doi.org/10.31450/ukrjnd.1(45).2015.03
48. Senbel AM, Omar AG, Abdel-Moneim LM, Mohamed HF, Daabees TT. Evaluation of l-arginine on kidney function and vascular reactivity following ischemic injury in rats: protective effects and potential interactions. Pharmacol Rep. 2014 Dec;66(6):976-83. PMID: 25443724. https://doi.org/10.1016/j.pharep.2014.06.013
49. Mengal V, Silva PH, Tiradentes RV, Santuzzi CH, de Almeida SA, Sena GC, et al. Aliskiren and l-arginine treatments restore depressed baroreflex sensitivity and decrease oxidative stress in renovascular hypertension rats. Hypertens Res. 2016 Nov;39(11):769-776. PMID: 27383506. https://doi.org/10.1038/hr.2016.61
50. Santuzzi CH, Tiradentes RV, Mengal V, Claudio ER, Mauad H, Gouvea SA, et al. Combined aliskiren and L-arginine treatment has antihypertensive effects and prevents vascular endothelial dysfunction in a model of renovascular hypertension. Braz J Med Biol Res. 2015 Jan;48(1):65-76. PMID: 25493385. PMCID: PMC4288495. https://doi.org/10.1590/1414-431x20144191
51. Dudar I, Loboda O, Korol L, Alieksieieva V. Progression of chronic kidney disease and the role of oxidative stress in different stages of CKD. Ukr J Nephrolog Dialysis. 2012;2(34):18–24.