Bioprosthetic Valve Dysfunction: A Complex Biological Process

Life is a perpetual instruction in cause and effect.—Ralph Waldo Emerson Valvular heart disease remains a significant economic and societal health issue.1.Moore M Chen J Mallow PJ Rizzo JA The direct health-care burden of valvular heart disease: evidence from US national survey data.Clinicoecon Outcomes Res. 2016; 8 (doi: 10.2147/CEOR.S112691): 613-627Google Scholar Fortunately, the advent of bioprosthetic heart valves (BPHVs) has served as a revolutionary treatment option first with surgical valve replacement and then with the advent of transcatheter valve replacement, which continues to evolve. Despite the general success of BPHVs, valve dysfunction and deterioration remain key problems to address that are often complicated by determining cause and effect in a complex biological system.2.Rodriguez-Gabella T Voisine P Puri R Pibarot P Rodes-Cabau J Aortic bioprosthetic valve durability: incidence, mechanisms, predictors, and management of surgical and transcatheter valve degeneration.J Am Coll Cardiol. 2017; 70 (doi: 10.1016/j.jacc.2017.07.715): 1013-1028Google Scholar, 3.Del Trigo M Munoz-Garcia AJ Wijeysundera HC et al.Incidence, timing, and predictors of valve hemodynamic deterioration after transcatheter aortic valve replacement: multicenter registry.J Am Coll Cardiol. 2016; 67 (doi: 10.1016/j.jacc.2015.10.097): 644-655Google Scholar, 4.Salaun E Mahjoub H Dahou A et al.Hemodynamic deterioration of surgically implanted bioprosthetic aortic valves.J Am Coll Cardiol. 2018; 72 (doi: 10.1016/j.jacc.2018.04.064): 241-251Google Scholar In this issue of Structural Heart, Ramana and colleagues5.Ramana R, Morreale C, Burke M, Rajamannan N. Calcification and thrombosis as mediators of bioprosthetic valve deterioration. Struct Heart. 2018;3: this issue. doi: 10.1080/24748706.2018.1562265.Google Scholar propose thrombus and calcification as the primary mediators in the dysfunction of BPHV. The role of calcium and thrombus causing dysfunction as the authors propose is highly supported by both clinical imaging studies and analysis of explanted valves; thrombus and calcium are noted on dysfunctional and failed BPHVs and in the setting of increased trans-valvular gradients.2.Rodriguez-Gabella T Voisine P Puri R Pibarot P Rodes-Cabau J Aortic bioprosthetic valve durability: incidence, mechanisms, predictors, and management of surgical and transcatheter valve degeneration.J Am Coll Cardiol. 2017; 70 (doi: 10.1016/j.jacc.2017.07.715): 1013-1028Google Scholar How the pathways associated with thrombus formation and calcification play out in BPHVs and potentially interact still requires further study; while calcification has been proposed as a platform for thrombus in other settings including the coronary arteries and on mitral annular calcification,6.Sia YT Dulay D Burwash IG Beauchesne LM Ascah K Chan KL Mobile ventricular thrombus arising from the mitral annulus in patients with dense mitral annular calcification.Eur J Echocardiogr. 2010; 11 (doi: 10.1093/ejechocard/jep181): 198-201Google Scholar,7.Karanasos A Ligthart JM Witberg KT Regar E Calcified nodules: an underrated mechanism of coronary thrombosis?.JACC Cardiovasc Imaging. 2012; 5 (doi: 10.1016/j.jcmg.2012.04.010): 1071-1072Google Scholar thrombus prior to calcification seems consistent with many imaging studies of BPHVs. Early valve thrombosis in the absence of calcification is detectable by current clinical imaging and is also a feature of valves studied on explant; thrombus has been incidentally noted on routine post procedural CT imaging within 30 days of SAVR and TAVR, well before calcification is evident on imaging. Calcification is also a histopathological feature of valves implanted for longer durations than those with thrombus alone with recent analysis of explanted TAVR valves showing calcification in TAVR explants after 4 years.8.Leetmaa T, Hansson NC, Leipsic J, et al. Early aortic transcatheter heart valve thrombosis: diagnostic value of contrast-enhanced multidetector computed tomography. Circ Cardiovasc Interv. 2015;8(4). doi: 10.1161/CIRCINTERVENTIONS.114.001596.Google Scholar, 9.Pache G Blanke P Zeh W Jander N Cusp thrombosis after transcatheter aortic valve replacement detected by computed tomography and echocardiography.Eur Heart J. 2013; 34 (doi: 10.1093/eurheartj/eht316): 3546Google Scholar, 10.Chakravarty T Sondergaard L Friedman J et al.Subclinical leaflet thrombosis in surgical and transcatheter bioprosthetic aortic valves: an observational study.Lancet. 2017; 389 (doi: 10.1016/S0140-6736(17)30757-2): 2383-2392Google Scholar, 11.Yahagi K Ladich E Kutys R et al.Pathology of balloon-expandable transcatheter aortic valves.Catheter Cardiovasc Interv. 2017; 90 (doi: 10.1002/ccd.v90.6): 1048-1057Google Scholar, 12.Yahagi K Torii S Ladich E et al.Pathology of self-expanding transcatheter aortic valves: findings from the CoreValve US pivotal trials.Catheter Cardiovasc Interv. 2018; 91 (doi: 10.1002/ccd.27314): 947-955Google Scholar, 13.Dangas GD Weitz JI Giustino G Makkar R Mehran R Prosthetic heart valve thrombosis.J Am Coll Cardiol. 2016; 68 (doi: 10.1016/j.jacc.2016.09.958): 2670-2689Google Scholar On a cellular basis, thrombus as a mediator of calcium also seems more likely. Calcification following thrombosis is a well-documented entity and calcific processes can be a long-term outcome associated with inflammation which has been shown at early time-points following BPHV implantation.11.Yahagi K Ladich E Kutys R et al.Pathology of balloon-expandable transcatheter aortic valves.Catheter Cardiovasc Interv. 2017; 90 (doi: 10.1002/ccd.v90.6): 1048-1057Google Scholar,14.Demer LL Tintut Y Inflammatory, metabolic, and genetic mechanisms of vascular calcification.Arterioscler Thromb Vasc Biol. 2014; 34 (doi: 10.1161/ATVBAHA.113.302070): 715-723Google Scholar Overall, calcification and thrombus are undoubtedly a part of BPHV dysfunction but perhaps our focus should not be solely on two entities, but take a wider view of the complex system that leads to valve dysfunction within a diverse patient population. BPHV deterioration is complicated by the fact that SAVR and TAVR valves are not homogeneous in design or tissue composition.2.Rodriguez-Gabella T Voisine P Puri R Pibarot P Rodes-Cabau J Aortic bioprosthetic valve durability: incidence, mechanisms, predictors, and management of surgical and transcatheter valve degeneration.J Am Coll Cardiol. 2017; 70 (doi: 10.1016/j.jacc.2017.07.715): 1013-1028Google Scholar,15.Vesely I The evolution of bioprosthetic heart valve design and its impact on durability.Cardiovasc Pathol. 2003; 12: 277-286Google Scholar Moreover, BPHV implanted in different anatomical locations (e.g. mitral versus aortic position) may be subject to very different variables including flow patterns and sheer stresses. By design, implant position, or make, valves may have a varying extent of washout as well as proprietary fixation and pre-implant treatment regimens that can potentially affect leaflet degeneration.13.Dangas GD Weitz JI Giustino G Makkar R Mehran R Prosthetic heart valve thrombosis.J Am Coll Cardiol. 2016; 68 (doi: 10.1016/j.jacc.2016.09.958): 2670-2689Google Scholar,16.Schoen FJ Levy RJ Calcification of tissue heart valve substitutes: progress toward understanding and prevention.Ann Thorac Surg. 2005; 79 (doi: 10.1016/j.athoracsur.2004.06.033): 1072-1080Google Scholar,17.Simionescu DT Prevention of calcification in bioprosthetic heart valves: challenges and perspectives.Expert Opin Biol Ther. 2004; 4 (doi: 10.1517/14712598.4.12.1971): 1971-1985Google Scholar Awareness and transparency regarding these differences is essential in designing the necessary experiments and studies to help advance our understanding of the mechanisms of structural valve degeneration and ultimately to advance the science in a meaningful way so as to prevent its occurrence. Understanding BPHV degeneration is also complicated by the complex cellular nature of the process. We commend Ramana and colleagues for bringing forth these important questions as they relate to calcification and thrombus as well as highlighting the interplay of dyslipidemic, metabolic, and cardiovascular risk factors. How do we now build on this to fill in the many blanks in the wider view of the complex system that leads to valve dysfunction? There is much to be done to advance our understanding as to how to prevent early valve thrombus. Can we intercede on the pro-thrombotic flow dynamics and binding affinity of fibrinogen for the collagen that composes the majority BPHV leaflets? Although glutaraldehyde fixation of BPHVs is to improve valve durability, can we build on this pre-implant treatment to provide more protection against thrombosis?16.Schoen FJ Levy RJ Calcification of tissue heart valve substitutes: progress toward understanding and prevention.Ann Thorac Surg. 2005; 79 (doi: 10.1016/j.athoracsur.2004.06.033): 1072-1080Google Scholar,18.Manji RA Ekser B Menkis AH Cooper DK Bioprosthetic heart valves of the future.Xenotransplantation. 2014; 21 (doi: 10.1111/xen.12080): 1-10Google Scholar,19.Schoen FJ Tsao JW Levy RJ Calcification of bovine pericardium used in cardiac valve bioprostheses. Implications for the mechanisms of bioprosthetic tissue mineralization.Am J Pathol. 1986; 123: 134-145Google Scholar In doing so, this may aid in endothelialization of BPHVs and prevent thrombus. To this end, determining the role of dysfunction of endothelial cells (ECs) on BPHVS has potential; peripheral endothelial dysfunction has been associated with BPHV thrombosis, but little is known of the state of ECs that populate implanted valves.20.Kaya H Ozkan M Yildiz M Relationship between endothelial dysfunction and prosthetic heart valve thrombosis: a preliminary investigation.Eur Rev Med Pharmacol Sci. 2013; 17: 1594-1598Google Scholar EC dysfunction, through factors such as reduced nitric oxide production and generation of reactive oxygen species and inflammatory cytokines would inevitably contribute to valve fibrosis and inflammation.21.Forstermann U Sessa WC Nitric oxide synthases: regulation and function.Eur Heart J. 2012; 33 (837a–837d. doi: 10.1093/eurheartj/ehr304): 829-837Google Scholar,22.Li H Forstermann U Nitric oxide in the pathogenesis of vascular disease.J Pathol. 2000; 190 (doi: 10.1002/(SICI)1096-9896(200002)190: 3<244::AID-PATH575>3.0.CO;2-8): 244-254Google Scholar Thus, would improving endothelial function, potentially through addressing cardiovascular risk factors as the authors suggest, help? Reduction of inflammation would certainly be helpful. Inflammatory cells are a source of chemokines and cytokines that can be pro-fibrotic. Fibrosis/pannus remains a problem with BPHV and can be an outcome of organizing thrombus. Moreover, inflammatory and fibroblast signalling may drive a pro-osteogenic environment and remodelling process prone to the development of dystrophic calcification. This may also relate to the deposition of oxidized low-density lipoprotein and glycosaminoglycans as well as expression of proteinases with the potential to degrade BPHV leaflets.14.Demer LL Tintut Y Inflammatory, metabolic, and genetic mechanisms of vascular calcification.Arterioscler Thromb Vasc Biol. 2014; 34 (doi: 10.1161/ATVBAHA.113.302070): 715-723Google Scholar,23.Mahmut A Mahjoub H Boulanger MC et al.Lp-PLA2 is associated with structural valve degeneration of bioprostheses.Eur J Clin Invest. 2014; 44 (doi: 10.1111/eci.12199): 136-145Google Scholar, 24.Vattikuti R Towler DA Osteogenic regulation of vascular calcification: an early perspective.Am J Physiol Endocrinol Metab. 2004; 286 (doi: 10.1152/ajpendo.00552.2003): E686-E696Google Scholar, 25.Nissinen L Kahari VM Matrix metalloproteinases in inflammation.Biochim Biophys Acta. 2014; 1840 (doi: 10.1016/j.bbagen.2014.03.007): 2571-2580Google Scholar Collectively, the underlying composition of BPHV would seem to have potential to serve as a biological scaffold for factors that contribute to SVD. As Ramana and colleagues detail, thrombus and calcification are major components of this SVD process. Clinically, we evaluate the outcomes of these processes through imaging and evaluation of pressures and patient symptoms. On the bench, we have made strides to understand the more granular cellular aspects. Creating links between these two views of BPHV degeneration and understanding more about valve thrombosis and calcification as Ramana and colleagues encourage us to do seems a timely goal (Figure 1). Dr. Leipsic is a consultant for and receives research support from Edwards Lifescience and provides CT core lab services for Edwards Lifesciences, Medtronic, Neovasc, GDS, and Tendyne Holdings, for which there is no direct compensation. Dr. Leipsic also has stock options in, is a consultant to, and receives institutional research support from HeartFlow. The other author reports no conflict of interest.

Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.