Cardiac bridging integrator 1 (cBIN1) score (CS), has recently been introduce as a diagnostic and prognostic biomarker of heart failure (HF), in patients with HF with preserved ejection fraction (HFpEF)1 and HF with reduced EF (HFrEF)2. cBIN1 is a cardiac-specific transverse tubule (t-tubule) membrane scaffolding protein, which functions to organize microdomains responsible for calcium release and excitation-contraction (EC) coupling3,4. cBIN1 transcription is decreased in failing human hearts5,6, impairing EC coupling and myocardial function. Furthermore, cBIN1 is released from cardiomyocytes into circulation7 and the resultant cBIN1 blood level7-9 correlates with its content in myocardium. CS is a biomarker derived from the inverse of plasma cBIN1 level1, which rises with worsening HF and prognosticates in stable, ambulatory HF patients, independent of volume overload1,2.

The cBIN1 Score (CS) assay

The Sarcotein cBIN1 Score (CS) Quantitative ELISA is a sandwich ELISA assay for detection and quantitation of levels of cBIN1 in plasma. The assay is performed on an ELISA platform which uses commercially available mouse monoclonal anti-BIN1 exon 17 capture antibody coated onto the wells of microwell plates. Upon addition of a diluted test specimen containing cBIN1, immune complexes are formed through the interaction between cBIN1 antigen in the specimen and anti-BIN1 antibodies coated on the microwells7.The specimen is aspirated following incubation, and microwells are washed with the buffer. Next, conjugate containing horseradish peroxidase (HRP)-labeled Sarcotein recombinant anti-BIN1 exon 13 detector antibody, is added to all microwells. HRP-labeled anti-BIN1 antibodies bind to any BIN1 antigen captured on the solid phase. A blue color is produced after an aspiration and wash to remove excess conjugate and incubation with TMB (Tetramethylbenzidine) substrate. With the addition of a phosphoric acid solution, the enzyme reaction is stopped and changes the substrate color to yellow. The amount of cBIN1 antigen present in specimens is quantitatively proportional to color intensity, which can be read on any ELISA reader. A recombinant cBIN1 standard is used to generate a standard curve for cBIN1 antigen. Results of the ELISA will be used to quantitate the cBIN1 antigen in EDTA plasma specimens.

Referenced Publications:

  1. Nikolova AP, Hitzeman TC, Baum R, Caldaruse AM, Agvanian S, Xie Y, Geft DR, Chang DH, Moriguchi JD, Hage A, Azarbal B, Czer LS, Kittleson MM, Patel JK, Wu AHB, Kobashigawa JA, Hamilton M, Hong T and Shaw RM. 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. https://www.ncbi.nlm.nih.gov/pubmed/30383171
  2. Xie, Y.; Hitzeman, T.C.; Zadikany, R.H.; Nikolova, A.P.; Baum, R.; Xu, B.; Agvanian, S.; Melmed, G.Y.; McGovern, D.T.; Geft, D.R.; Chang, D.H.; Moriguchi, J.D.; Hage, A.; Azarbal, B.; Czer, L.S.; Kittleson, M.M.; Patel, J.K.; Wu, A.H.B.; Kobashigawa, J.A.; Hamilton, M.; Hong, T.; Shaw, R.M. Plasma cBIN1 Score (CS) Identifies HFrEF and Can Predict Cardiac Hospitalization in Stable Ambulatory Patients. Preprints 2018, 2018010040 (doi: 10.20944/preprints201801.0040.v1). https://www.preprints.org/manuscript/201801.0040/v1
  3. Hong T, Yang H, Zhang SS, Cho HC, Kalashnikova M, Sun B, Zhang H, Bhargava A, Grabe M, Olgin J, Gorelik J, Marban E, Jan LY and Shaw RM. Cardiac BIN1 folds T-tubule membrane, controlling ion flux and limiting arrhythmia. Nat Med. 2014;20:624-32. https://www.ncbi.nlm.nih.gov/pubmed/24836577
  4. Hong TT, Smyth JW, Gao D, Chu KY, Vogan JM, Fong TS, Jensen BC, Colecraft HM and Shaw RM. BIN1 localizes the L-type calcium channel to cardiac T-tubules. PLoS biology. 2010;8:e1000312. https://www.ncbi.nlm.nih.gov/pubmed/20169111
  5. Hong TT, Smyth JW, Chu KY, Vogan JM, Fong TS, Jensen BC, Fang K, Halushka MK, Russell SD, Colecraft H, Hoopes CW, Ocorr K, Chi NC and Shaw RM. BIN1 is reduced and Cav1.2 trafficking is impaired in human failing cardiomyocytes. Heart Rhythm. 2012;9:812-20.https://www.ncbi.nlm.nih.gov/pubmed/22138472
  6. Fu Y, Shaw SA, Naami R, Vuong CL, Basheer WA, Guo X and Hong T. Isoproterenol Promotes Rapid Ryanodine Receptor Movement to Bridging Integrator 1 (BIN1)-Organized Dyads. Circulation. 2016;133:388-97.
  7. Xu B, Fu Y, Liu Y, Agvanian S, Wirka RC, Baum R, Zhou K, Shaw RM and Hong T. The ESCRT-III pathway facilitates cardiomyocyte release of cBIN1-containing microparticles. PLoS biology. 2017;15:e2002354.
  8. Hong T and Shaw RM. Cardiac T-Tubule Microanatomy and Function. Physiol Rev. 2017;97:227-252.
  9. Hong TT, Cogswell R, James CA, Kang G, Pullinger CR, Malloy MJ, Kane JP, Wojciak J, Calkins H, Scheinman MM, Tseng ZH, Ganz P, De Marco T, Judge DP and Shaw RM. Plasma BIN1 correlates with heart failure and predicts arrhythmia in patients with arrhythmogenic right ventricular cardiomyopathy. Heart Rhythm. 2012;9:961-7. https://www.ncbi.nlm.nih.gov/pubmed/22300662

Additional Publications:

  1. Caldwell JL, Smith CE, Taylor RF, Kitmitto A, Eisner DA, Dibb KM, Trafford AW. Dependence of cardiac transverse tubules on the BAR domain protein amphiphysin II (BIN-1). Circ Res. 2014 Dec 5;115(12):986-96. https://www.ncbi.nlm.nih.gov/pubmed/25332206
  2. Laury-Kleintop LD, Mulgrew JR, Heletz I, Nedelcoviciu RA, Chang MY, Harris DM, Koch WJ, Schneider MD, Muller AJ, Prendergast GC. Cardiac-specific disruption of Bin1 in mice enables a model of stress- and age-associated dilated cardiomyopathy. J Cell Biochem. 2015 Nov;116(11):2541-51. https://www.ncbi.nlm.nih.gov/pubmed/25939245
  3. Fu Y, Hong T. BIN1 regulates dynamic t-tubule membrane. Biochim Biophys Acta. 2016 Jul;1863(7 Pt):1839-47. https://www.ncbi.nlm.nih.gov/pubmed/26578114
  4. De La Mata A, Tajada S, O’Dwyer S, Matsumoto C, Dixon RE, Hariharan N, Moreno CM, Santana LF. BIN1 Induces the Formation of T-Tubules and Adult-Like Ca2+ Release Units in Developing Cardiomyocytes. Stem Cells. 2019 Jan;37(1):54-64. https://www.ncbi.nlm.nih.gov/pubmed/30353632
  5. Lawless M, Caldwell JL, Radcliffe EJ, Smith CER, Madders GWP, Hutchings DC, Woods LS, Church SJ, Unwin RD, Kirkwood GJ, Becker LK, Pearman CM, Taylor RF, Eisner DA, Dibb KM, Trafford AW. Phosphodiesterase 5
    nhibition improves contractile function and restores transverse tubule loss and catecholamine responsiveness in heart failure. Sci Rep. 2019 May 1;9(1):6801. https://www.ncbi.nlm.nih.gov/pubmed/31043634
  6. An S, Gilani N, Huang Y, Muncan A, Zhang Y, Tang YD, Gerdes AM, Ojamaa K. Adverse transverse-tubule remodeling in a rat model of heart failure is attenuated with low-dose triiodothyronine treatment. Mol Med. 2019 Dec 6;25(1):53. https://www.ncbi.nlm.nih.gov/pubmed/31810440
  7. Jiang XX, Zhu YR, Liu HM, Chen SL, Zhang DM. Effect of BIN1 on cardiac dysfunction and malignant arrhythmias. Acta Physiol (Oxf). 2020 Mar;228(3):e13429. https://www.ncbi.nlm.nih.gov/pubmed/31837094
  8. Hong T, Shaw RM. Editorial commentary: Extracellular vesicles in cardiovascular diagnosis and therapy. Trends Cardiovasc Med. 2019 Aug;29(6):324-325. https://www.ncbi.nlm.nih.gov/pubmed/30471985
  9. Zadikany RH, Hong T, Shaw RM. Heart failure: distinguishing failing myocardium from volume overload. Biomark Med. 2019 Jun;13(9):697-700. https://www.ncbi.nlm.nih.gov/pubmed/31172804