Calcification of bioprosthetic heart valves treated with ethylene glycol diglycidyl ether

Highlights. The morphology and elemental composition of calcium deposits formed in the tissues of epoxytreated aortic and mitral bioprostheses do not differ from those in the mineralized matrix of stenotic human aortic valve leaflets. Despite similar elemental composition of mineral deposits in the KemCor and UniLine bioprostheses, the morphology of these calcifications differs between bioprosthetic heart valve substitutes and, apparently, is associated with the specific structure of the fibrous matrix of the biological tissues that are used for their manufacturing.

Aim. To analyze the morphology and elemental composition of mineral deposits formed in epoxy-treated aortic and mitral bioprosthetic heart valves made from xenoaortic or xenopericardial material and to compare the obtained findings with the data on calcified human aortic valve.

Methods. Leaflets of the mitral and aortic bioprosthetic heart valves KemCor and UniLine (NeoKor, L Russia, Kemerovo) that were explanted due to their failure, as well as leaflets of the calcified native aortic valve were evaluated. The morphology of calcifications was studied by scanning electron microscopy using an S-3400N microscope (Hitachi, Japan). The elemental composition of calcium deposits was studied by electron probe microanalysis using Hitachi S-3400N microscope with energy dispersive spectrometer Bruker XFlash 4010 (Bruker, Germany).

Results. Large calcifications located at the internal layers of samples were surrounded by collagen fibers commonly with evident signs of the onset of mineralization. Calcium deposits in the native aortic valve and xenoartic bioprostheses KemCor were located mainly at the spongy layer and had a loose structure, while dense lamellar deposits were found at the leaflets of pericardial bioprostheses UniLine. The elemental composition of calcium deposits showed the presence of Ca, P, O, Mg, and Na in the mineralized regions and the presence of S in the regions of low electron density. The calcium to phosphorus ratio (Ca:P) in the calcifications of the aortic valve leaflets was 1.81 (1.79-1.84; min - 1.48; max - 2.05), whereas the Ca:P ratios in the UniLine and KemCor bioprostheses were 1.78 (1.75-1.86; min - 1.52; max - 2.03) and 1.82 (1.81-1.88; min - 1.71; max - 2.06), respectively. There were no significant differences in the Ca:P ratios between calcifications in the study groups (p>0.05).

Conclusion. Calcium deposits detected in epoxy-treated bioprostheses and human aortic valve appeared to be formed under dystrophic calcification. The morphology of calcifications in bioprostheses depended on the type of biological tissue. None correlations between the morphological structure of calcifications and the implantation position were found in bioprosthetic leaflets. The elemental composition of mineral deposits was similar in all study samples.

1. Baumgartner H., Falk V., Bax J.J., De Bonis M., Hamm C., Holm P.J., Iung B., Lancellotti P., Lansac E., Rodriguez Munoz D., Rosenhek R., Sjogren J., Tornos Mas P., Vahanian A., Walther T., Wendler O., Windecker S., Zamorano J.L., ESC Scientific Document Group. 2017 ESC/EACTS Guidelines for the management of valvular heart disease. Eur. Heart J. 2017, 38(36):2739-2791. doi:10.1093/eurheartj/ehx391.

2. Nishimura R.A., Otto C.M., Bonow R.O., Carabello B.A., Erwin J.P. 3rd., Fleisher L.A., Jneid H., Mack M.J., McLeod C.J., O'Gara P.T., Rigolin V.H., Sundt T.M. 3rd., Thompson A. 2017 AHA/ACC focused update of the 2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology American Heart Association task force on clinical practice guidelines. Circulation. 2017, 135(25):e1159-e1195. doi:10.1161/CIR.0000000000000503.

3. Lindman B.R., Clavel M.A., Mathieu P., Iung B., Lancellotti P., Otto C.M., Pibarot P. Calcific aortic stenosis. Nat Rev Dis Primers. 2016; 2:16006. doi:10.1038/nrdp.2016.6.

4. Harb S.C., Griffin B.P. Mitral valve disease: a comprehensive review. Curr Cardiol Rep. 2017; 19(8):73. doi:10.1007/s11886-017-0883-5.

5. Fiedler A.G., Tolis G.Jr. Surgical treatment of valvular heart disease: overview of mechanical and tissue prostheses, advantages, disadvantages, and implications for clinical use. Curr. Treat. Options Cardiovasc. Med. 2018; 20(1):7. doi:10.1007/s11936-018-0601-7.

6. Pibarot P., Dumesnil J.G. Prosthetic heart valves: selection of the optimal prosthesis and long-term management. Circulation. 2009; 119(7):1034-1048. doi:10.1161/CIRCULATIONAHA.108.778886.

7. Li K.Y.C. Bioprosthetic heart valves: upgrading a 50year old technology. Front. Cardiovasc. Med. 2019; 6:47. doi:10.3389/fcvm.2019.00047.

8. Capodanno D., Petronio A.S., Prendergast B., Eltchaninoff H., Vahanian A., Modine T., Lancellotti P., Sondergaard L., Ludman P.F., Tamburino C., Piazza N., Hancock J., Mehilli J., Byrne R.A., Baumbach A., Kappetein A.P., Windecker S., Bax J., Haude M. Standardized definitions of structural deterioration and valve failure in assessing long-term durability of transcatheter and surgical aortic bioprosthetic valves: a consensus statement from the European Association of Percutaneous Cardiovascular Interventions (EAPCI) endorsed by the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS). Eur. Heart J. 2017; 38(45):3382-3390. doi:10.1093/eurheartj/ehx303.

9. Dvir D., Bourguignon T., Otto C.M., Hahn R.T., Rosenhek R., Webb J.G., Treede H., Sarano M.E., Feldman T., Wijeysundera H.C., Topilsky Y., Aupart M., Reardon M.J., Mackensen G.B., Szeto W.Y., Kornowski R., Gammie J.S., Yoganathan A.P., Arbel Y., Borger M.A., Simonato M., Reisman M., Makkar R.R., Abizaid A., McCabe J.M., Dahle G., Aldea G.S., Leipsic J., Pibarot P., Moat N.E., Mack M.J., Kappetein A.P., Leon M.B.; VIVID (Valve in Valve International Data) Investigators. Standardized definition of structural valve degeneration for surgical and transcatheter bioprosthetic aortic valves. Circulation. 2018; 137(4):388-399. doi:10.1161/CIRCULATIONAHA.117.030729.

10. Bonetti A., Marchini M., Ortolani F. Ectopic mineralization in heart valves: new insights from in vivo and in vitro procalcific models and promising perspectives on noncalcifiable bioengineered valves. J. Thorac. Dis. 2019; 11(5):2126-2143. doi:10.21037/jtd.2019.04.78.

11. Schoen F.J., Levy R.J. Calcification of tissue heart valve substitutes: progress toward understanding and prevention. Ann. Thorac. Surg. 2005; 79(3):1072-1080. doi:10.1016/j.athoracsur.2004.06.033.

12. Chen J., Peacock J.R., Branch J., David Merryman W. Biophysical analysis of dystrophic and osteogenic models of valvular calcification. J. Biomech. Eng. 2015; 137(2):020903. doi:10.1115/1.4029115.

13. Delogne C., Lawford P.V., Habesch S.M., Carolan V.A. Characterization of the calcification of cardiac valve bioprostheses by environmental scanning electron microscopy and vibrational spectroscopy. Journal of Microscopy 2007; 228(1):62-77. doi:10.1111/j.1365-2818.2007.01824.x.

14. Chen J., Peacock J.R., Branch J., David Merryman W. Biophysical analysis of dystrophic and osteogenic models of valvular calcification. J. Biomech. Eng. 2015; 137(2):020903. doi:10.1115/1.4029115.

15. Wang Y., Azais T., Robin M., Vallee A., Catania C., Legriel P., Pehau-Arnaudet G., Babonneau F., Giraud-Guille M.M., Nassif N. The predominant role of collagen in the nucleation, growth, structure and orientation of bone apatite. Nat Mater. 2012; 11(8):724-733. doi:10.1038/nmat3362.

16. Aguiari P., Fiorese M., Iop L., Gerosa G., Bagno A. Mechanical testing of pericardium for manufacturing prosthetic heart valves. Interact. Cardiovasc. Thorac. Surg. 2016; 22(1):72-84. doi:10.1093/icvts/ivv282.

17. Soares J.S., Feaver K.R., Zhang W., Kamensky D., Aggarwal A., Sacks M.S. Biomechanical behavior of bioprosthetic heart valve heterograft tissues: characterization, simulation, and performance. Cardiovasc. Eng. Technol. 2016; 7(4):309-351. doi:10.1007/s13239-016-0276-8.

18. Richards J.M., Kunitake J.A.M.R., Hunt H.B., Wnorowski A.N., Lin D.W., Boskey A.L., Donnelly E., Estroff L.A., Butcher J.T. Crystallinity of hydroxyapatite drives myofibroblastic activation and calcification in aortic valves. Acta Biomater. 2018; 71:24-36. doi:10.1016/j.actbio.2018.02.024.

19. Weska R.F., Aimoli C.G., Nogueira G.M., Leirner A.A., Maizato M.J., Higa O.Z., Polakievicz B., Pitombo R.N., Beppu M.M. Natural and prosthetic heart valve calcification: morphology and chemical composition characterization. Artif. Organs. 2010; 34(4):311-318. doi:10.1111/j.1525-1594.2009.00858.x.

20. Cottignoli V., Cavarretta E., Salvador L., Valfre C., Maras A. Morphological and chemical study of pathological deposits in human aortic and mitral valve stenosis: a biomineralogical contribution. Patholog. Res. Int. 2015; 2015:342984. doi:10.1155/2015/342984.

21. Bertazzo S., Gentleman E. Aortic valve calcification: a bone of contention. Eur. Heart J. 2017; 38(16):1189-1193. doi:10.1093/eurheartj/ehw071.

22. Bertazzo S., Gentleman E., Cloyd K.L., Chester A.H., Yacoub M.H., Stevens M.M. Nano-analytical electron microscopy reveals fundamental insights into human cardiovascular tissue calcification. Nat. Mater. 2013; 12(6):576-583. doi:10.1038/nmat3627.

23. Mohler E.R. 3rd., Gannon F., Reynolds C., Zimmerman R., Keane M.G., Kaplan F.S. Bone formation and inflammation in cardiac valves. Circulation. 2001; 103(11):1522-1528. doi:10.1161/01.cir.103.11.1522.

24. Ovcharenko EA, KU Klyshnikov, AE Yuzhalin, GV Savrasov, TV Glushkova, GU Vasukov, DV Nushtaev, YuA Kudryavtsev, LS Barbarash. Comparison of xenopericardial patches of different origin and type of fixation implemented for TAVI. International Journal of Biomedical Engineering and Technology. 2017; 25(1):44-59. doi: 10.1504/IJBET.2017.086551

25. Barbarash L.S., Rogulina N.V., Rutkovskaya N.V., Ovcharenko E.A. Mechanisms underlying bioprosthetic heart valve dysfunctions. Complex Issues of Cardiovascular Diseases. 2018;7(2):10-24. (In Russian) https://doi.org/10.17802/2306-1278-2018-7-2-10-24

26. Lu F., Wu H., Bai Y., Gong D., Xia C., Li Q., Lu F., Xu Z. Evidence of osteogenic regulation in calcific porcine aortic valves. Heart Surg Forum. 2018; 21(5):E375-E381. doi:10.1532/hsf.2033.