Inflammasomes: a novel potential biomarker for chronic heart failure (review)

The objective of this review is to analyze publications about biochemical studies of inflammasome profile proteins in patients with heart failure as diagnostic markers and promising therapeutic targets. Inflammasomes are cytoplasmic high-molecular protein complexes, which activation leads to the development of inflammation through the release of proinflammatory cytokines. The most studied types of inflammasomes are NLRP3 inflammasomes, which contribute to the development of systemic and local inflammation, including in the myocardium. The NLRP3 inflammasome comprises the receptor/sensor protein NLRP3 (nucleotide-binding leucine-rich repeat receptor pyrin domain-containing-3), the adaptor protein ASC (apoptosis-associated speck-like protein containing CARD), and the effector protein caspase-1. The NLRP3 receptor protein, as a structural component of the NLRP3 inflammasome, functions as an intracellular pattern-recognition receptor that detects pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs, molecules from damaged cells). Activation of this receptor triggers the assembly of the NLRP3 inflammasome, leading to the release of interleukin-1β and interleukin-18. The article presents data on studies of inflammasome profile biomarkers and the possibility of their use in order to improve diagnostics, prognosis and personalisation of treatment of heart failure. The accumulated data of clinical and experimental studies convincingly indicate the necessity for further comprehensive analysis of inflammasome profile proteins in patients with heart failure.

1. van Riet EE, Hoes AW, Wagenaar KP, et al. Epidemiology of heart failure: the prevalence of heart failure and ventricular dysfunction in older adults over time. A systematic review. Eur J Heart Fail. 2016;18(3):242-52. DOI: 10.1002/ejhf.483.

2. Polyakov DS, Fomin IV, Belenkov YuN, et al. Chronic heart failure in the Russian Federation: what has changed over 20 years of follow-up? Results of the EPOCH-CHF study. Kardiologiia. 2021;61(4):4-14. (In Russ.) DOI: 10.18087/cardio.2021.4.n1628.

3. Solomon SD, Rizkala AR, Lefkowitz MP, et al. Baseline characteristics of patients with heart failure and preserved ejection fraction in the PARAGON-HF trial. Circ Heart Fail. 2018;11(7):e004962. DOI: 10.1161/CIRCHEARTFAILURE.118.004962.

4. Buckley LF, Canada JM, Del Buono MG, et al. Low NT‐proBNP levels in overweight and obese patients do not rule out a diagnosis of heart failure with preserved ejection fraction. ESC Heart Fail. 2018;5(2):372-8. DOI: 10.1002/ehf2.12235.

5. Dye C, Cruz MD, Larsen T, et al. A review of the impact, pathophysiology, and management of atrial fibrillation in patients with heart failure with preserved ejection fraction. Am Heart J Plus. 2023;33:100309. DOI: 10.1016/j.ahjo.2023.100309.

6. Wu J, Dong E, Zhang Y, Xiao H. The Role of the Inflammasome in Heart Failure. Front Physiol. 2021;12:709703. DOI: 10.3389/fphys.2021.709703.

7. Mathur A, Hayward JA, Man SM. Molecular mechanisms of inflammasome signaling. J Leukoc Biol. 2018;103(2):233-57. DOI: 10.1189/jlb.3MR0617-250R.

8. Próchnicki T, Mangan MS, Latz E. Recent insights into the molecular mechanisms of the NLRP3 inflammasome activation. F1000Res. 2016;5:F1000-Faculty. DOI: 10.12688/f1000research.8614.1.

9. Latz E, Xiao TS, Stutz A. Activation and regulation of the inflammasomes. Nat Rev Immunol. 2013;13(6):397-411. DOI: 10.1038/nri3452.

10. Broz P, Dixit VM. Inflammasomes: mechanism of assembly, regulation and signalling. Nat Rev Immunol. 2016;16(7):407-20. DOI: 10.1038/nri.2016.58.

11. Bauernfeind FG, Horvath G, Stutz A, et al. Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. J Immunol. 2009;183(2):787-91. DOI: 10.4049/jimmunol.0901363.

12. Toldo S, Mauro AG, Cutter Z, et al. The NLRP3 inflammasome inhibitor, OLT1177 (dapansutrile), reduces infarct size and preserves contractile function after ischemia reperfusion injury in the mouse. J Cardiovasc Pharmacol. 2019;73(4):215-22. DOI: 10.1097/FJC.0000000000000658.

13. Walev I, Klein J, Husmann M, et al. Potassium regulates IL-1β processing via calcium-independent phospholipase A2. J Immunol. 2000;164(10):5120-4. DOI: 10.4049/jimmunol.164.10.5120.

14. Schmid‐Burgk JL, Gaidt MM, Schmidt T, et al. Caspase‐4 mediates non‐canonical activation of the NLRP3 inflammasome in human myeloid cells. Eur J Immunol. 2015;45(10):2911-7. DOI: 10.1002/eji.201545523.

15. Brough D, Le Feuvre RA, Wheeler RD, et al. Ca2+ stores and Ca2+ entry differentially contribute to the release of IL-1β and IL-1α from murine macrophages. J Immunol. 2003;170(6):3029-36. DOI: 10.4049/jimmunol.170.6.3029.

16. Lee GS, Subramanian N, Kim AI, et al. The calcium-sensing receptor regulates the NLRP3 inflammasome through Ca2+ and cAMP. Nature. 2012;492(7427):123-27. DOI: 10.1038/nature11588.

17. Zhong Z, Zhai Y, Liang S, et al. TRPM2 links oxidative stress to NLRP3 inflammasome activation. Nat Commun. 2013;4(1):1611. DOI: 10.1038/ncomms2608.

18. Ma MW, Wang J, Dhandapani KM, Brann DW. NADPH oxidase 2 regulates NLRP3 inflammasome activation in the brain after traumatic brain injury. Oxid Med Cell Longev. 2017;2017(1):6057609. DOI: 10.1155/2017/6057609.

19. Bauernfeind F, Bartok E, Rieger A, et al. Cutting edge: reactive oxygen species inhibitors block priming, but not activation, of the NLRP3 inflammasome. J Immunol. 2011;187(2):613-7. DOI: 10.4049/jimmunol.1100613.

20. Zheng Y, Xu L, Dong N, Li F. NLRP3 inflammasome: The rising star in cardiovascular diseases. Front Cardiovasc Med. 2022;9:927061. DOI: 10.3389/fcvm.2022.927061.

21. Nakahira K, Haspel JA, Rathinam VA, et al. Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat Immunol. 2011;12(3):222-30. DOI: 10.1038/ni.1980.

22. Shimada K, Crother TR, Karlin J, et al. Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis. Immunity. 2012;36(3):401-14. DOI: 10.1016/j.immuni.2012.01.009.

23. Zhong Z, Liang S, Sanchez-Lopez E, et al. New mitochondrial DNA synthesis enables NLRP3 inflammasome activation. Nature. 2018;560(7717):198-203. DOI: 10.1038/s41586-018-0372-z.

24. Duewell P, Kono H, Rayner KJ, et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature. 2010;464(7293):1357-61. DOI: 10.1038/nature08938.

25. Orlowski GM, Colbert JD, Sharma S, et al. Correction: Multiple Cathepsins Promote Pro-IL-1β Synthesis and NLRP3-Mediated IL-1β Activation. J Immunol. 2016;196(1):503. DOI: 10.4049/jimmunol.1502363. Erratum for: J Immunol. 2015;195(4):1685-97. DOI: 10.4049/jimmunol.1500509.

26. Miao EA, Rajan JV, Aderem A. Caspase‐1‐induced pyroptotic cell death. Immunol Rev. 2011;243(1):206-14. DOI: 10.1111/j.1600-065X.2011.01044.x.

27. von Haehling S, Schefold JC, Lainscak M, et al. Inflammatory biomarkers in heart failure revisited: much more than innocent bystanders. Heart Fail Clin. 2009;5(4):549-60. DOI: 10.1016/j.hfc.2009.04.001.

28. Deng Y, Xie M, Li Q, et al. Targeting mitochondria-inflammation circuit by β-hydroxybutyrate mitigates HFpEF. Circ Res. 2021;128(2):232-45. DOI: 10.1161/CIRCRESAHA.120.317933.

29. Butts B, Gary RA, Dunbar SB, Butler J. The importance of NLRP3 inflammasome in heart failure. J Card Fail. 2015;21(7):586-93. DOI: 10.1016/j.cardfail.2015.04.014.

30. Bracey NA, Beck PL, Muruve DA, et al. The Nlrp3 inflammasome promotes myocardial dysfunction in structural cardiomyopathy through interleukin-1β. Exp Physiol. 2013;98(2):462-72. DOI: 10.1113/expphysiol.2012.068338.

31. Kawaguchi M, Takahashi M, Hata T, et al. Inflammasome activation of cardiac fibroblasts is essential for myocardial ischemia/reperfusion injury. Circulation. 2011;123(6):594-604. DOI: 10.1161/CIRCULATIONAHA.110.982777.

32. Burkard T, Pfister O, Rickli H, et al.; Time-CHF Investigators. Prognostic impact of systemic inflammatory diseases in elderly patients with congestive heart failure. QJM. 2014;107(2):131-8. DOI: 10.1093/qjmed/hct205.

33. Shen J, Wu JM, Hu GM, et al. Membrane nanotubes facilitate the propagation of inflammatory injury in the heart upon overactivation of the β-adrenergic receptor. Cell Death Dis. 2020;11(11):958. DOI: 10.1038/s41419-020-03157-7.

34. Zafrir B, Lund LH, Laroche C, et al.; ESC-HFA HF Long-Term Registry Investigators. Prognostic implications of atrial fibrillation in heart failure with reduced, mid-range, and preserved ejection fraction: a report from 14 964 patients in the European Society of Cardiology Heart Failure Long-Term Registry. Eur Heart J. 2018;39(48):4277-84. DOI: 10.1093/eurheartj/ehy626.

35. Yeh YH, Kuo CT, Chang GJ, et al. Nicotinamide adenine dinucleotide phosphate oxidase 4 mediates the differential responsiveness of atrial versus ventricular fibroblasts to transforming growth factor-β. Circ Arrhythm Electrophysiol. 2013;6(4):790-8. DOI: 10.1161/CIRCEP.113.000338.

36. Yamashita T, Sekiguchi A, Iwasaki YK, et al. Recruitment of immune cells across atrial endocardium in human atrial fibrillation. Circ J. 2010;74(2):262-70. DOI: 10.1253/circj.cj-09-0644.

37. Smorodinova N, Blaha M, Melenovský V, et al. Analysis of immune cell populations in atrial myocardium of patients with atrial fibrillation or sinus rhythm. PLoS One. 2017;12(2):e0172691. DOI: 10.1371/journal.pone.0172691.

38. Gungor B, Ekmekci A, Arman A, et al. Assessment of interleukin-1 gene cluster polymorphisms in lone atrial fibrillation: new insight into the role of inflammation in atrial fibrillation. Pacing Clin Electrophysiol. 2013;36(10):1220-7. DOI: 10.1111/pace.12182.

39. Nattel S, Sager PT, Hueser J, et al. Why translation from basic discoveries to clinical applications is so difficult for atrial fibrillation and possible approaches to improving it. Cardiovasc Res. 2021;117(7):1616-31. DOI: 10.1093/cvr/cvab093.

40. Ye J, Ji Q, Liu J, et al. Interleukin 22 promotes blood pressure elevation and endothelial dysfunction in angiotensin II–treated mice. J Am Heart Assoc. 2017;6(10):e005875. DOI: 10.1161/JAHA.117.005875.

41. Shirasuna K, Karasawa T, Usui F, et al. NLRP3 deficiency improves angiotensin II-induced hypertension but not fetal growth restriction during pregnancy. Endocrinology. 2015;156(11):4281-92. DOI: 10.1210/en.2015-1408.

42. Gan W, Ren J, Li T, et al. The SGK1 inhibitor EMD638683, prevents Angiotensin II–induced cardiac inflammation and fibrosis by blocking NLRP3 inflammasome activation. Biochim Biophys Acta Mol Basis Dis. 2018;1864(1):1-10. DOI: 10.1016/j.bbadis.2017.10.001.

43. Boonman-de Winter LJM, Rutten FH, Cramer MJM, et al. High prevalence of previously unknown heart failure and left ventricular dysfunction in patients with type 2 diabetes. Diabetologia. 2012;55:2154-62. DOI: 10.1007/s00125-012-2579-0.

44. Bryant C, Fitzgerald KA. Molecular mechanisms involved in inflammasome activation. Trends Cell Biol. 2009;19(9):455-64. DOI: 10.1016/j.tcb.2009.06.002.

45. Minutoli L, Puzzolo D, Rinaldi M, et al. ROS‐mediated NLRP3 inflammasome activation in brain, heart, kidney, and testis ischemia/reperfusion injury. Oxid Med Cell Longev. 2016;2016(1):2183026. DOI: 10.1155/2016/2183026.

46. Xie Y, Huang Y, Ling X, et al. Chemerin/CMKLR1 Axis Promotes Inflammation and Pyroptosis by Activating NLRP3 Inflammasome in Diabetic Cardiomyopathy Rat. Front Physiol. 2020;23;11:381. DOI: 10.3389/fphys.2020.00381.

47. Nalliah CJ, Sanders P, Kottkamp H, Kalman JM. The role of obesity in atrial fibrillation. Eur Heart J. 2016;37(20):1565-72. DOI: 10.1093/eurheartj/ehv486.

48. Aldiss P, Davies G, Woods R, et al. ‘Browning’ the cardiac and peri-vascular adipose tissues to modulate cardiovascular risk. Int J Cardiol. 2017;228:265-74. DOI: 10.1016/j.ijcard.2016.11.074.

49. Timofeev YS, Dzhioeva ON, Drapkina OM. Circulating biological markers of obesity: Towards a systems approach. Cardiovascular Therapy and Prevention. 2023;22(4):3551. (In Russ.) DOI: 10.15829/1728-8800-2023-3551.

50. Mahajan R, Lau DH, Brooks AG, et al. Electrophysiological, electroanatomical, and structural remodeling of the atria as consequences of sustained obesity. J Am Coll Cardiol. 2015;66(1):1-11. DOI: 10.1016/j.jacc.2015.04.058.

51. Scott LJr, Fender AC, Saljic A, et al. NLRP3 inflammasome is a key driver of obesity-induced atrial arrhythmias. Cardiovasc Res. 2021;117(7):1746-59. DOI: 10.1093/cvr/cvab024.

52. Dzhioeva ON, Timofeev YS, Metelskaya VA, et al. Role of epicardial adipose tissue in the pathogenesis of chronic inflammation in heart failure with preserved ejection fraction. Cardiovascular Therapy and Prevention. 2024;23(3):3928. (In Russ.) DOI: 10.15829/1728-8800-2024-3928.