Vol. 25 No. 3 (2021)
CONGENITAL HEART DISEASES

Role of toll-like receptors in complications of cardiac surgery for congenital heart defects in children

A.V. Tsepokina
Research Institute for Complex Issues of Cardiovascular Diseases, Kemerovo
Bio
A.A. Anikeenko
Research Institute for Complex Issues of Cardiovascular Diseases, Kemerovo
S.A. Shmulevich
Research Institute for Complex Issues of Cardiovascular Diseases, Kemerovo
A.V. Ponasenko
Research Institute for Complex Issues of Cardiovascular Diseases, Kemerovo
A.V. Shabaldin
Research Institute for Complex Issues of Cardiovascular Diseases, Kemerovo

Published 2021-09-28

Keywords

  • congenital heart disease,
  • postoperative complication,
  • toll-like receptor

How to Cite

Tsepokina, A., Anikeenko, A., Shmulevich, S., Ponasenko, A., & Shabaldin, A. (2021). Role of toll-like receptors in complications of cardiac surgery for congenital heart defects in children. Patologiya Krovoobrashcheniya I Kardiokhirurgiya, 25(3), 34–42. https://doi.org/10.21688/1681-3472-2021-3-34-42

Abstract

Background. Cardiac surgery in combination with hypothermia, ischaemia and reperfusion leads to an inflammatory response causing postoperative complications. Toll-like receptors are signalling molecules through which some functions of innate immunity can be activated, and polymorphic variants in the TLR-family genes can be predictors of complications after cardiac surgery.
Aim. To study the associations of TLR-family genes with infectious and non-infectious complications of cardiac surgery for congenital heart defects.
Methods. The study included 89 children (44 girls and 45 boys) with congenital heart defects who underwent cardiac surgery. Complications occurred in 47 children 47 days after cardiac surgery. There were no complications in 42 children. Genotyping was performed by real-time PCR using TaqMan probes.
Results. A two-locus model of gene-gene interaction between TLR1 rs5743551 and TLR2 rs3804099 was the best fit, accounting for 4.01% of phenotypic entropy. The TLR2 gene polymorphic variant rs5743708 had the highest predictive potential (2.59%).
Conclusion. The development of postoperative complications of cardiac surgical treatment for congenital heart defects can be due to the synergistic effect of the polymorphic variants rs5743551 in the TLR1 gene and rs3804099 in the TLR2 gene. This effect occurs through the features of TLR1 and TLR2 transcription, the subsequent expression of receptors on cells and signalling which activates the synthesis of proinflammatory cytokines and chemokines.

Received 25 February 2021. Revised 11 May 2021. Accepted 12 May 2021.

Funding: The work is supported by the complex program of fundamental research of the Siberian Branch of the Russian Academy of Sciences (No. 0554-2019-0002).

Conflict of interest: The authors declare no conflicts of interests.

Contribution of the authors
Conception and study design: A.V. Shabaldin, A.V. Ponasenko, A.V. Tsepokina
Data collection and analysis: A.A. Anikeenko, A.V. Tsepokina, S.A. Shmulevich
Statistical analysis: A.V. Shabaldin, A.V. Tsepokina
Drafting the article: A.V. Shabaldin, A.V. Tsepokina, A.V. Ponasenko
Critical revision of the article: A.V. Tsepokina
Final approval of the version to be published: A.V. Tsepokina, A.A. Anikeenko, S.A. Shmulevich, A.V. Ponasenko, A.V. Shabaldin

References

  1. Васильева М.А. Анализ динамики врожденных пороков сердца у новорожденных на территории Новосибирской области за 2015–2019 гг. Медицинская генетика. 2020;19(7):36-37. [Vasilyeva M.A. Analysis of the dynamics of congenital heart defects in newborns in the territory of the Novosibirsk region for 2015–2019. Medical Genetics. 2020;19(7):36-37. (In Russ.)] https://doi.org/10.25557/2073-7998.2020.07.36-37
  2. Попов Д.А., Хрусталев А.А. Прогностическая ценность новых биомаркеров у детей первого года жизни с врожденными пороками сердца в периоперационном периоде. Лабораторная служба. 2019;8(4):13-21. [Popov D.A., Khrustalev А.А. Prognostic value of new biomarkers in newborns and children with congenital heart disease. Laboratory Service. 2019;8(4):13-21. (In Russ.)] https://doi.org/10.17116/labs2019804113
  3. Boehne M., Sasse M., Karch A., Dziuba F., Horke A., Kaussen T., Mikolajczyk R., Beerbaum P., Jack T. Systemic inflammatory response syndrome after pediatric congenital heart surgery: Incidence, risk factors, and clinical outcome. J Card Surg. 2017;32(2):116-125. PMID: 27928843. https://doi.org/10.1111/jocs.12879
  4. Justus G., Walker C., Rosenthal L.-M., Berger F., Miera O., Schmitt K.R.L. Immunodepression after CPB: Cytokine dynamics and clinics after pediatric cardiac surgery – A prospective trial. Cytokine. 2019;122:154018. PMID: 28411047. https://doi.org/10.1016/j.cyto.2017.03.017
  5. West A.P., Koblansky A.A., Ghosh S. Recognition and signaling by toll‐like receptors. Annu Rev Cell Dev Biol. 2006;22:409-437. PMID: 16822173. https://doi.org/10.1146/annurev.cellbio.21.122303.115827
  6. Akira S. Toll receptor families: structure and function. Semin Immunol. 2004;16(1):1-2. PMID: 14751756. https://doi.org/10.1016/j.smim.2003.10.001
  7. Sharma S., Garg I., Ashraf M.Z. TLR signalling and association of TLR polymorphism with cardiovascular diseases. Vascul Pharmacol. 2016;87:30-37. PMID: 27826031. https://doi.org/10.1016/j.vph.2016.10.008
  8. Suluba E., Shuwei L., Xia Q., Mwanga A. Congenital heart diseases: genetics, non-inherited risk factors, and signaling pathways. Egypt J Med Hum Genet. 2020;21:11. https://doi.org/10.1186/s43042-020-0050-1
  9. Хуторная М.В., Понасенко А.В., Радивилко А.С., Кутихин А.Г., Жидкова И.И., Крутицкий С.С., Салахов Р.Р., Григорьев Е.В., Головкин А.С. Значение генов врожденного иммунитета в развитии критических послеоперационных осложнений коронарного шунтирования. Трансляционная медицина. 2017;4(5):15-27. [Khutornaya M.V., Ponasenko A.V., Radivilko A.S., Kutikhin A.G., Zhidkova I.I., Krutitskiy S.S., Salakhov R.R., Grigoryev E.V., Golovkin A.S. Impact of innate immunity genes in development of critical postoperative complications after coronary artery bypasses grafting. Translational Medicine. 2017;4(5):15-27. (In Russ.)] https://doi.org/10.18705/2311-4495-2017-4-5-15-27
  10. Merbecks M.B., Ziesenitz V.C., Rubner T., Meier N., Klein B., Rauch H., Saur P., Ritz N., Loukanov T., Schmitt S., Gorenflo M. Intermediate monocytes exhibit higher levels of TLR2, TLR4 and CD64 early after congenital heart surgery. Cytokine. 2020;133:155153. PMID: 32554157. https://doi.org/10.1016/j.cyto.2020.155153
  11. Neamatallah M., El-Bendary M., Elalfy H., Besheer T., El-Maksoud M.A., Elhammady D., Abed S., Elegezy M., Kandeel L., Eldeib D., Mousa N., Abd El-Hafeez M., El-Gilany A.-H., Esmat G. Impact of Toll-like receptors 2(TLR2) and TLR 4 gene variations on HCV susceptibility, response to treatment and development of hepatocellular carcinoma in cirrhotic HCV patients. Immunol Invest. 2020;49(4):462-476. PMID: 31615295. https://doi.org/10.1080/08820139.2019.1673772
  12. Tongtawee T., Simawaranon T., Wattanawongdon W., Dechsukhum C., Leeanansaksiri W. Toll-like receptor 2 and 4 polymorphisms associated with Helicobacter pylori susceptibility and gastric cancer. Turk J Gastroenterol. 2019;30(1):15-20. PMID: 30301709; PMCID: PMC6389301. https://doi.org/10.5152/tjg.2018.17461
  13. Gao Sh.-L., Chen Y.-D., Yue Ch., Chen J., Zhang L.-F., Wang S.-M., Zuo L. -196 to -174del, rs4696480, rs3804099 polymorphisms of Toll-like receptor 2 gene impact the susceptibility of cancers: evidence from 37053 subjects. Biosci Rep. 2019;39(12):BSR20191698. PMID: 31710083; PMCID: PMC6900473. https://doi.org/10.1042/BSR20191698
  14. Gomes Torres A.C.M.B., Leite N., Tureck L.V., de Souza R.L.R., Titski A.C.K., Milano-Gai G.E., Lazarotto L., da Silva L.R., Furtado-Alle L. Association between Toll-like receptors (TLR) and NOD-like receptor (NLR) polymorphisms and lipid and glucose metabolism. Gene. 2019;685:211-221. https://doi.org/10.1016/j.gene.2018.11.065
  15. Salvador-Martín S., López-Cauce B., Nuñez O., Laserna-Mendieta E.J., García M.I., Lobato E., Abarca-Zabalía J., Sanjurjo-Saez M., Lucendo A.J., Marín-Jiménez I., Menchén L.A., López-Fernández L.A. Genetic predictors of long-term response and trough levels of infliximab in Crohn's disease. Pharmacol Res. 2019;149:104478. PMID: 31605784. https://doi.org/10.1016/j.phrs.2019.104478
  16. Xie X., Shi X., Liu M. The roles of TLR gene polymorphisms in atherosclerosis: A systematic review and meta-analysis of 35,317 subjects. Scand J Immunol. 2017;86(1):50-58. PMID: 28474755. https://doi.org/10.1111/sji.12560
  17. Santana N.de L., Rêgo J.L., Oliveira J.M., de Almeida L.F., Braz M., Machado L.M.M., Machado P.R.L., Castellucci L.C. Polymorphisms in genes TLR1, 2 and 4 are associated with differential cytokine and chemokine serum production in patients with leprosy. Mem Inst Oswaldo Cruz. 2017;112(4):260-268. PMID: 28327786; PMCID: PMC5354609. https://doi.org/10.1590/0074-02760160366