Diagnostic and prognostic value of cardiospecific integrator protein in patients after myocardial infarction

Introduction. Evaluation of the new biomarker cBIN-1(CS) has advantages; its concentration does not depend on volume status, body weight, CKD, in contrast to natriuretic peptides, which seems valuable in the diagnosis of HF.

Aim. To study the diagnostic and prognostic value of serum cBIN-1(CS) in patients who have suffered myocardial infarction.

Materials and methods. The study analyzed clinical, laboratory and instrumental data of 100 patients on the 7th day after myocardial infarction. Subgroup I included patients with a history of HF, subgroup II included patients with risk factors for developing HF. Studies included echocardiography, TSH, cBIN-1(CS) determination. Over the course of 18 months, clinical outcomes were recorded for participants: a composite endpoint of death due to cardiac causes, incident ADHF, worsening TSH results, and intensification of pharmacotherapy.

Results. In patients with a history of HF, the level of cBIN-1(CS) in the blood was 0.871 ng/ml, in the group with risk factors for HF – 0.690 ng/ml. The results of TSH on day 7 are associated with an increase in cBIN-1(CS) content and a decrease in the result by 80.45 m in the STEMI group and by 177.36 m in the NSTEMI group (p = 0.002). ROC-analysis of the probability of a fatal outcome based on the cBIN-1(CS) level showed the area under the ROC curve in subgroup I with an established diagnosis of HF of 0.743 ± 0.098 (p = 0.023), in subgroup II – 0.746 ± 0.146 (p = 0.103). ROC-analysis of the probability of achieving the composite endpoint for each of the patient subgroups showed AUC of 0.859 ± 0.058 and 0.751 ± 0.063 (p < 0.001), respectively. The cBIN-1(CS) value ≥ 0/826 ng/ml (sensitivity 80.0%, specificity 70.6%) can be considered as a marker of unfavorable outcome after myocardial infarction. According to the Kaplan-Meier survival curve for patients after MI, the cut-off value for cBIN-1(CS) is 0.826 ng/ml (p < 0.0001), which was determined to be the most optimal for separating patients into high and low risk of an adverse outcome.

Conclusion. The cBIN-1(CS) biomarker has high sensitivity and specificity and can be used as a marker for assessing myocardial reserve after myocardial infarction to predict adverse events.

1. Mareev VYu, Fomin IV, Ageev FT, Begrambekova YuL, Vasyuk YuA, Garganeeva AA et al. Russian Heart Failure Society, Russian Society of Cardiology. Russian Scientific Medical Society of Internal Medicine Guidelines for Heart failure: chronic (CHF) and acute decompensated (ADHF). Diagnosis, prevention and treatment. Kardiologiia. 2018;58(6S):8–158. (In Russ.) https://doi.org/10.18087/cardio.2475.

2. Ibrahim N, Januzzi JL. The potential role of natriuretic peptides and other biomarkers in heart failure diagnosis, prognosis and management. Expert Rev Cardiovasc Ther. 2015;13(9):1017–1030. https://doi.org/10.1586/14779072.2015.1071664.

3. Myhre PL, Vaduganathan M, Claggett BL, Anand IS, Sweitzer NK, Fang JC et al. Association of Natriuretic Peptides With Cardiovascular Prognosis in Heart Failure With Preserved Ejection Fraction: Secondary Analysis of the TOPCAT Randomized Clinical Trial. JAMA Cardiol. 2018;3(10):1000–1005. https://doi.org/10.1001/jamacardio.2018.2568.

4. Krauser DG, Lloyd-Jones DM, Chae CU, Cameron R, Anwaruddin S, Baggish AL et al. Effect of body mass index on natriuretic peptide levels in patients with acute congestive heart failure: a ProBNP Investigation of Dyspnea in the Emergency Department (PRIDE) substudy. Am Heart J. 2005;149(4):744–750. https://doi.org/10.1016/j.ahj.2004.07.010.

5. Caldwell JL, Smith CER, Taylor RF, Kitmitto A, Eisner DA, Dibb KM et al. Dependence of cardiac transverse tubules on the BAR domain protein amphiphysin II (BIN-1). Circ Res. 2014;115(12):986–996. https://doi.org/10.1161/CIRCRESAHA.116.303448.

6. Setterberg IE, Le C, Frisk M, Perdreau-Dahl H, Li J, Louch WE. Corrigendum: The Physiology and Pathophysiology of T-Tubules in the Heart. Front Physiol. 2021;12:790227. https://www.frontiersin.org/article/10.3389/fphys.2021.790227.

7. Zhou K, Hong T. Cardiac BIN1 (cBIN1) is a regulator of cardiac contractile function and an emerging biomarker of heart muscle health. Sci China Life Sci. 2017;60(3):257–263. https://doi.org/10.1007/s11427-016-0249-x.

8. Hong TT, Smyth JW, Gao D, Chu KY, Vogan JM, Fong TS et al. BIN1 localizes the L-type calcium channel to cardiac T-tubules. PLoS Biol. 2010;8(2):e1000312. https://doi.org/10.1371/journal.pbio.1000312.

9. Li J, Richmond B, Hong T. Cardiac T-Tubule cBIN1-Microdomain, a Diagnostic Marker and Therapeutic Target of Heart Failure. Int J Mol Sci. 2021;22(5):2299. https://doi.org/10.3390/ijms22052299.

10. Nikolova AP, Hitzeman TC, Baum R, Caldaruse AM, Agvanian S, Xie Y et al. Association of a Novel Diagnostic Biomarker, the Plasma Cardiac Bridging Integrator 1 Score, With Heart Failure With Preserved Ejection Fraction and Cardiovascular Hospitalization. JAMA Cardiol. 2018;3(12):1206–1210. https://doi.org/10.1001/jamacardio.2018.3539.

11. Hitzeman TC, Xie Y, Zadikany RH, Nikolova AP, Baum R, Caldaruse AM et al. cBIN1 Score (CS) Identifies Ambulatory HFrEF Patients and Predicts Cardiovascular Events. Front Physiol. 2020;11:503. https://doi.org/10.3389/fphys.2020.00503.

12. Li J, Richmond B, Hong T. Cardiac T-Tubule cBIN1-Microdomain, a Diagnostic Marker and Therapeutic Target of Heart Failure. Int J Mol Sci. 2021;22(5):2299. https://doi.org/10.3390/ijms22052299.

13. Pinali C, Malik N, Davenport JB, Allan LJ, Murfitt L, Iqbal MM et al. Post-Myocardial Infarction T-tubules Form Enlarged Branched Structures With Dysregulation of Junctophilin-2 and Bridging Integrator 1 (BIN-1). J Am Heart Assoc. 2017;6(5):e004834. https://doi.org/10.1161/JAHA.116.004834.

14. Fu Y, Shaw SA, Naami R, Vuong CL, Basheer WA, Guo X, Hong T. Isoproterenol Promotes Rapid Ryanodine Receptor Movement to Bridging Integrator 1 (BIN1)-Organized Dyads. Circulation. 2016;133(4):388–397. https://doi.org/10.1161/CIRCULATIONAHA.115.018535.

15. Liu Y, Zhou K, Li J, Agvanian S, Caldaruse AM, Shaw S et al. In Mice Subjected to Chronic Stress, Exogenous cBIN1 Preserves Calcium-Handling Machinery and Cardiac Function. JACC Basic Transl Sci. 2020;5(6):561–578. https://doi.org/10.1016/j.jacbts.2020.03.006.

16. Konstam MA, Kramer DG, Patel AR, Maron MS, Udelson JE. Left ventricular remodeling in heart failure: current concepts in clinical significance and assessment. JACC Cardiovasc Imaging. 2011;4(1):98–108. https://doi.org/10.1016/j.jcmg.2010.10.008.

17. Li J, Agvanian S, Zhou K, Shaw RM, Hong T. Exogenous Cardiac Bridging Integrator 1 Benefits Mouse Hearts With Pre-existing Pressure OverloadInduced Heart Failure. Front Physiol. 2020;11:708. https://doi.org/10.3389/fphys.2020.00708.

18. Hong TT, Smyth JW, Chu KY, Vogan JM, Fong TS, Jensen BC et al. BIN1 is reduced and Cav1.2 trafficking is impaired in human failing cardiomyocytes. Heart Rhythm. 2012;9(5):812–820. https://doi.org/10.1016/j.hrthm.2011.11.055.

19. Hong T, Yang H, Zhang SS, Cho HC, Kalashnikova M, Sun B et al. Cardiac BIN1 folds T-tubule membrane, controlling ion flux and limiting arrhythmia. Nat Med. 2014;20(6):624–632. https://doi.org/10.1038/nm.3543.

20. Hong TT, Cogswell R, James CA, Kang G, Pullinger CR, Malloy MJ et al. Plasma BIN1 correlates with heart failure and predicts arrhythmia in patients with arrhythmogenic right ventricular cardiomyopathy. Heart Rhythm. 2012;9(6):961–967. https://doi.org/10.1016/j.hrthm.2012.01.024.

21. Abugov SA, Alekyan BG, Arkhipov MV, Barbarash OL, Boytsov SA, Vasilieva EYu et al. Clinical practice guidelines for Acute ST-segment elevation myocardial infarction. Russian Journal of Cardiology. 2020;25(11):4103. (In Russ.) https://doi.org/10.15829/29/1560-4071-2020-4103.

22. Chaulin AM, Duplyakov DV. Increased natriuretic peptides not associated with heart failure. Russian Journal of Cardiology. 2020;25(4S):4140. (In Russ.) https://doi.org/10.15829/1560-4071-2020-4140.

23. Kalashnikova NM, Zaitsev DN, Govorin AV, Chistyakova MV, Balzhitov BT. Prognostic significance of NT-proBNP and sST2 biomarkers in patients with post-myocardial infarction heart failure after a coronavirus infection. Russian Journal of Cardiology. 2023;28(6):5216. (In Russ.) https://doi.org/10.15829/1560-4071-2023-5216.

24. Fiuzat M, Ezekowitz J, Alemayehu W, Westerhout CM, Sbolli M, Cani D et al. Assessment of Limitations to Optimization of Guideline-Directed Medical Therapy in Heart Failure From the GUIDE-IT Trial: A Secondary Analysis of a Randomized Clinical Trial. JAMA Cardiol. 2020;5(7):757–764. https://doi.org/10.1001/jamacardio.2020.0640.

25. Rohde LE, Zimerman A, Vaduganathan M, Claggett BL, Packer M, Desai AS et al. Associations Between New York Heart Association Classification, Objective Measures, and Long-term Prognosis in Mild Heart Failure: A Secondary Analysis of the PARADIGM-HF Trial. JAMA Cardiol. 2023;8(2):150–158. https://doi.org/10.1001/jamacardio.2022.4427.

26. Aimo A, Vergaro G, Passino C, Ripoli A, Ky B, Miller WL et al. Prognostic Value of Soluble Suppression of Tumorigenicity-2 in Chronic Heart Failure: A Meta-Analysis. JACC Heart Fail. 2017;5(4):280–286. https://doi.org/10.1016/j.jchf.2016.09.010.

27. Kamon D, Sugawara Y, Soeda T, Okamura A, Nakada Y, Hashimoto Y et al. Predominant subtype of heart failure after acute myocardial infarction is heart failure with non-reduced ejection fraction. ESC Heart Fail. 2021;8(1):317–325. https://doi.org/10.1002/ehf2.13070.

28. Khairullin RR, Ruzov VI, Frolova MV, Melnikova MA. Diagnostic informativity of cardiac specific integrator (cbin1(cs)) in postinfarction myocardial remodelling. International Research Journal. 2023;(4):1–6. (In Russ.) https://doi.org/10.23670/IRJ.2023.130.29.

29. Caraballo C, Desai NR, Mulder H, Alhanti B, Wilson FP, Fiuzat M et al. Clinical Implications of the New York Heart Association Classification. J Am Heart Assoc. 2019;8(23):e014240. https://doi.org/10.1161/JAHA.119.014240.

30. Blacher M, Zimerman A, Engster PHB, Grespan E, Polanczyk CA, Rover MM et al. Revisiting heart failure assessment based on objective measures in NYHA functional classes I and II. Heart. 2021;107(18):1487–1492. https://doi.org/10.1136/heartjnl-2020-317984.