CURRENT ISSUES OF MODELING HEART FAILURE AND MYOCARDIAL FIBROSIS IN RATS

Highlights

• Methods for modeling heart failure in rats are classified into models requiring surgical intervention, toxic, genetic and autoimmune models, models based on the effects of physical factors, the use of special dietary regimens.
• It is impossible to single out a single ideal model, since the development of heart failure is a multifactorial process, it is preferable to use a combination of several methods.
• The correctness of the choice of the model and its compliance with the tasks of future research must be confirmed by combining several diagnostic methods for verifying myocardial fibrosis - laboratory, histological, instrumental.

Annotation

Detailed study of the mechanisms of heart failure and its main pathogenetic factor, myocardial fibrosis, is required for developing new effective treatment strategies. The choice of an appropriate model is key for a reliable experimental study. The aim of the review is to systematize current data on methods for modeling heart failure in rats. The main advantages of these animals are high genetic, biochemical and physiological similarity with humans, ease of breeding, availability of maintenance, small size, while allowing for surgery. This article classifies the currently available rat models of heart failure, discusses their pathophysiological basis, timing of the formation of heart failure, clinical features, advantages and disadvantages of each experimental model. The authors have paid particular attention to methods developed by domestic scientists. Methods for assessing the developed myocardial fibrosis and the influence of drugs on its formation are considered. The study of heart failure requires reliable animal models to assess biochemical, functional, morphological changes in damaged myocardium, and controlled testing of new drugs. Should the necessity arise, specialists should use several methods simultaneously, whereas the choice of treatment strategy depends on the aim of the study.

1. Roger V.L. Epidemiology of Heart Failure: A Contemporary Perspective. Circ Res. 2021;128(10):1421-1434. doi: 10.1161/CIRCRESAHA.121.318172.

2. Boytsov SA. Chronic heart failure: evolution of etiology, prevalence and mortality over the past 20 years. Terapevticheskii arkhiv. 2022;94(1):5-8. doi: 10.26442/00403660.2022.01.201317 (In Russian)

3. Ponzoni M., Coles J.G., Maynes J.T. Rodent Models of Dilated Cardiomyopathy and Heart Failure for Translational Investigations and Therapeutic Discovery. Int J Mol Sci. 2023;24(4):3162. doi: 10.3390/ijms24043162

4. Wang Y., Wang M., Samuel C.S., Widdop R.E. Preclinical rodent models of cardiac fibrosis. Br J Pharmacol. 2022;179(5):882-899. doi: 10.1111/bph.15450.

5. Farag A., Mandour A.S., Hendawy H., Elhaieg A., Elfadadny A., Tanaka R. A review on experimental surgical models and anesthetic protocols of heart failure in rats. Front Vet Sci. 2023;10:1103229. doi: 10.3389/fvets.2023.1103229.

6. Katz M.G., Fargnoli A.S., Gubara S.M., Chepurko E., Bridges C.R., Hajjar R.J. Surgical and physiological challenges in the development of left and right heart failure in rat models. Heart Fail Rev. 2019;24(5):759-777. doi: 10.1007/s10741-019-09783-4

7. Cops J., Haesen S., De Moor B., Mullens W., Hansen D.. Current animal models for the study of congestion in heart failure: an overview. Heart Fail Rev. 2019;24(3):387-397. doi: 10.1007/s10741-018-9762-4.

8. Abramov A.A., Lakomkin V.L., Prosvirnin A.V., Kapelko V.I. Pressure and Volume Characteristics of the Left Ventriclе in Its Diastolic and Systolic Dysfunction. Kardiologiia. 2019;59(4):45-51. doi: 10.18087/ cardio.2019.4.2647 (In Russian)

9. Abbasnezhad A., Salami F., Mohebbati R. A review: Systematic research approach on toxicity model of liver and kidney in laboratory animals Animal Model Exp Med. 2022;5(5):436-444. doi: 10.1002/ame2.12230

10. Song J., Xie Q., Wang L., Lu Y., Liu P., Yang P., Chen R., Shao C., Qiao C., Wang Z., Yan J. The TIR/BB-loop mimetic AS-1 prevents Ang II-induced hypertensive cardiac hypertrophy via NF-κB dependent downregulation of miRNA-143. Sci Rep. 2019;9(1):6354. doi: 10.1038/s41598-019-42936-x.

11. Droogmans S., Franken P.R., Garbar C., Weytjens C., Cosyns B., Lahoutte T., Caveliers V., Pipeleers-Marichal M., Bossuyt A., Schoors D., Van Camp G. In vivo model of drug-induced valvular heart disease in rats: pergolide-induced valvular heart disease demonstrated with echocardiography and correlation with pathology. Eur Heart J. 2007;28(17):2156-62. doi: 10.1093/eurheartj/ehm263.

12. Andersen A., van der Feen D.E., Andersen S., Schultz J.G., Hansmann G., Bogaard H.J. Animal models of right heart failure. Cardiovasc Diagn Ther. 2020;10(5):1561-1579. doi: 10.21037/cdt-20-400.

13. Guo W., Zhu C., Yin Z., Zhang Y., Wang C., Walk A.S., Lin Y.H., McKinsey T.A., Woulfe K.C., Ren J., Chew H.G.Jr. The ryanodine receptor stabilizer S107 ameliorates contractility of adult Rbm20 knockout rat cardiomyocytes. Physiol Rep. 2021;9(17):e15011. doi: 10.14814/phy2.15011.

14. Saryeva O.P., Kulida L.V., Protsenko E.V., Malysheva M.V. Cardiomyopathy in children – clinical, genetic and morphological aspects. I.P. Pavlov Russian Medical Biological Herald. 2020;28(1):99-110. doi: 10.23888/PAVLOVJ202028199-110 (In Russian)

15. Sugihara H., Kimura K., Yamanouchi K., Teramoto N., Okano T., Daimon M., Morita H., Takenaka K., Shiga T., Tanihata J., Aoki Y., Inoue-Nagamura T., Yotsuyanagi H., Komuro I. Age-Dependent Echocardiographic and Pathologic Findings in a Rat Model with Duchenne Muscular Dystrophy Generated by CRISPR/Cas9 Genome Editing. Int Heart J. 2020;61(6):1279-1284. doi: 10.1536/ihj.20-372.

16. Cherdantseva T.M., Bakovetskaya O.V., Nikiforov A.A., Nekrasova M.S. Morphological and laboratory genetic studies of muscular dystrophies. Science of the young (Eruditio Juvenium). 2021;9(3):481–491. doi:10.23888/HMJ202193481-491 (In Russian)

17. Symbol report for ISCA1. HUGO Gene Nomenclature Committee (HGNC). Available at: https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/28660. (Accessed: 31.07.2023)

18. Proshina L.G., Zhmajlova S.V., Shevcova L.M., Proshin A.V., Bykova O.S., Fedorova N.P., Grigorieva M.V. Study of myocardial cell under experimental heart failure in rats. Vestnik Nov SU. 2019;115(3):24-27. doi:10.34680/2076-8052.2019.3(115).24-27 (In Russian)

19. Inchina V.I., Stoljarova V.V., Gar'kin G.G. et al. Sostojanie miokarda v model'noj situacii aktivacii gipertenzivnyh mehanizmov. Tezisy Vtorogo congressa popatofiziologii. Moscow; 2000. P. 68. (In Russian)

20. Rumjanceva T.A., Fateev M.M., Fedorov V.N., Salnikov E.V., Sidorov A.V. Morphological evidence of chronic heart failure induced by fractional dosed oleothorax in rats. Vestnik Nizhegorodskogo universitetaim. N. I. Lobachevskogo. 2009;5:123-127. (In Russian)

21. Wang Y., Han L., Shen M., Jones E.S., Spizzo I., Walton S.L., Denton K.M., Gaspari T.A., Samuel C.S., Widdop R.E. Serelaxin and the AT2 Receptor Agonist CGP42112 Evoked a Similar, Nonadditive, Cardiac Antifibrotic Effect in High Salt-Fed Mice That Were Refractory to Candesartan Cilexetil. ACS Pharmacol Transl Sci. 2020;3(1):76-87. doi: 10.1021/acsptsci.9b00095.

22. Withaar C., Lam C.S.P., Schiattarella G.G., de Boer R.A., Meems L.M.G. Heart failure with preserved ejection fraction in humans and mice: embracing clinical complexity in mouse models. Eur Heart J. 2021;42(43):4420-4430. doi: 10.1093/eurheartj/ehab389

23. Gyöngyösi M., Winkler J., Ramos I., Do Q.T., Firat H., McDonald K., González A., Thum T., Díez J., Jaisser F., Pizard A., Zannad F. Myocardial fibrosis: biomedical research from bench to bedside. Eur J Heart Fail. 2017;19(2):177-191. doi: 10.1002/ejhf.696.

24. Tao W., Yang X., Zhang Q., Bi S., Yao Z. Optimal treatment for post-MI heart failure in rats: dapagliflozin first, adding sacubitril-valsartan 2 weeks later. Front Cardiovasc Med. 2023;10:1181473. doi: 10.3389/fcvm.2023.1181473

25. Song R., Wang P., Yang L., Liu J., Chen Z., Ding Y. Association of FOXO3A with right ventricular myocardial fibrosis and its detection by speckle-tracking echocardiography in pulmonary hypertension. Echocardiography. 2023;40(9):958-968. doi: 10.1111/echo.15663.

26. JawharMamand S., Mustafa Z.A. The Impact of Dapagliflozin on Aldosterone Hormone in Rats with Heart Failure. Polytechnic Journal. 2023;12 (2):53-60. doi:10.25156/ptj.v12n2y2022.pp53-60

27. Berdibekov B.Sh., Aleksandrova S.A., Golukhova E.Z. Quantification of myocardial fibrosis in patients with a nonischemic ventricular arrhythmias by late gadolinium-enhanced magnetic resonance. Creative Cardiology. 2021; 15 (3): 342–53. doi: 10.24022/1997-3187-2021-15-3-342-353 (In Rusian.)

28. Zhu J., Chen Y., Xu Z., Wang S., Wang L., Liu X., Gao F. Non-invasive assessment of early and acute myocarditis in a rat model using cardiac magnetic resonance tissue tracking analysis of myocardial strain. Quant Imaging Med Surg. 2020;10(11):2157-2167. doi: 10.21037/qims-20-122.

29. Schneider J.E., Lanz T., Barnes H., Medway D., Stork L.A., Lygate C.A., Smart S., Griswold M.A., Neubauer S. Ultra-fast and accurate assessment of cardiac function in rats using accelerated MRI at 9.4 Tesla. Magn Reson Med. 2008;59(3):636-41. doi: 10.1002/mrm.21491.

30. Qi Y., Chen Z., Guo B., Liu Z., Wang L., Liu S., Xue L., Ma M., Yin Y., Li Y., Liu G. Speckle-tracking echocardiography provides sensitive measurements of subtle early alterations associated with cardiac dysfunction in T2DM rats. BMC Cardiovasc Disord. 2023;23(1):266. doi: 10.1186/s12872-023-03239-2.

31. Sabatino J., De Rosa S., Tammè L., Iaconetti C., Sorrentino S., Polimeni A., Mignogna C., Amorosi A., Spaccarotella C., Yasuda M., Indolfi C. Empagliflozin prevents doxorubicin-induced myocardial dysfunction. Cardiovasc Diabetol. 2020;19(1):66. doi: 10.1186/s12933-020-01040-5.

32. Ulusan S., Gülle K., Peynirci A., Sevimli M., Karaibrahimoglu A., Kuyumcu M.S. Dapagliflozin May Protect Against Doxorubicin-Induced Cardiotoxicity. Anatol J Cardiol. 2023 ;27(6):339-347. doi: 10.14744/AnatolJCardiol.2023.2825.