Calcification and Thrombosis as Mediators of Bioprosthetic Valve Deterioration

Abstract

Calcific aortic valve disease is the most common indication for surgical aortic valve replacement (SAVR) and transcatheter aortic valve replacement (TAVR) of diseased valves worldwide.1.Salaun E Mahjoub H Dahou A Mathieu P Larose E Despres JP Rodes-Cabau J Arsenault BJ Puri R Clavel MA Pibarot P 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 For years, the mechanisms of bioprosthetic valve deterioration were thought to be due to passive degeneration of the valve leading to structural valve failure. However, in the last decade, studies have emerged which have demonstrated the phenotypic characteristics of bioprosthetic valve calcification, identification of risk factors for valve deterioration including risk of thrombosis, and the possibility of medical therapies to slow the progression of disease. With the advent of TAVR, possible mechanisms of bioprosthetic heart valve deterioration in patients with calcific aortic valve disease have been rapidly emerging in the field. Risk factors, ex vivo studies, and retrospective databases have provided clues to the mechanistic causes of bioprosthetic valve deterioration.2.Salaun E Clavel MA Rodes-Cabau J Pibarot P Bioprosthetic aortic valve durability in the era of transcatheter aortic valve implantation.Heart. 2018; 104 (doi: 10.1136/heartjnl-2017-311582): 1323-1332Google Scholar The role of lipids in the development of calcification and the timing of thrombosis have been the leading discoveries in the field of bioprosthetic valve calcification. This opinion paper will discuss the role of risk factors in the initiation of calcification, and eventual discovery of thrombosis in the progression of valve deterioration, and the potential role of therapeutic agents to slow progression, preserve, and maintain bioprosthetic valve function long term. Calcific aortic stenosis is the most common indication for surgical valve replacement in the United States and Europe.3.Rajamannan NM Evans FJ Aikawa E Grande-Allen KJ Demer LL Heistad DD Simmons CA Masters KS Mathieu P O’Brien KD Schoen FJ Towler DA Yoganathan AP Otto CM Calcific aortic valve disease: not simply a degenerative process: a review and agenda for research from the National heart and lung and blood institute aortic stenosis working group. Executive summary: calcific aortic valve disease-2011 update.Circulation. 2011; 124 (doi: 10.1161/CIRCULATIONAHA.110.006767): 1783-1791Google Scholar Currently, mechanical and bioprosthetic heart valves (SAVR and TAVR) are the two options for valve replacement.2.Salaun E Clavel MA Rodes-Cabau J Pibarot P Bioprosthetic aortic valve durability in the era of transcatheter aortic valve implantation.Heart. 2018; 104 (doi: 10.1136/heartjnl-2017-311582): 1323-1332Google Scholar The choice of valve depends on patient characteristics and preference at the time of surgery.4.Bonow RO Carabello BA Kanu C de Leon Jr., AC Faxon DP Freed MD Gaasch WH Lytle BW Nishimura RA O’Gara PT O’Rourke RA Otto CM Shah PM Shanewise JS Smith Jr., SC Jacobs AK Adams CD Anderson JL Antman EM Fuster V Halperin JL Hiratzka LF Hunt SA Nishimura R Page RL Riegel B ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association task force on practice guidelines (writing committee to revise the 1998 guidelines for the management of patients with Valvular Heart disease): developed in collaboration with the society of cardiovascular anesthesiologists: endorsed by the society for cardiovascular angiography and interventions and the society of thoracic surgeons.Circulation. 2006; 114 (doi: 10.1161/CIRCULATIONAHA.106.176857): e84-e231Google Scholar In the past, bioprosthetic heart valves have been thought to have a decreased risk of thrombosis leading to a decreased need for anticoagulation. Therefore, despite their limited long-term durability,2.Salaun E Clavel MA Rodes-Cabau J Pibarot P Bioprosthetic aortic valve durability in the era of transcatheter aortic valve implantation.Heart. 2018; 104 (doi: 10.1136/heartjnl-2017-311582): 1323-1332Google Scholar bioprosthetic valves have remained the treatment of choice in patients who are older than 75 years of age or who have contraindications to long-term anticoagulation.5.Schoen FJ Pathologic considerations in replacement heart valves and other cardiovascular prosthetic devices.Monogr Pathol. 1995; 37: 194-222Google Scholar,6.Vesey JM Otto CM Complications of prosthetic heart valves.Curr Cardiol Rep. 2004; 6: 106-111Google Scholar It is estimated that 20–30% of implanted bioprosthetic heart valves will have some degree of hemodynamic dysfunction at 10 years, but more recent studies indicate improved outcomes for this patient population.2.Salaun E Clavel MA Rodes-Cabau J Pibarot P Bioprosthetic aortic valve durability in the era of transcatheter aortic valve implantation.Heart. 2018; 104 (doi: 10.1136/heartjnl-2017-311582): 1323-1332Google Scholar,7.Johnston DR Soltesz EG Vakil N Rajeswaran J Roselli EE Sabik 3rd, JF Smedira NG Svensson LG Lytle BW Blackstone EH Long-term durability of bioprosthetic aortic valves: implications from 12, 569 implants.Ann Thorac Surg. 2015; 99 (doi: 10.1016/j.athoracsur.2014.10.070): 1239-1247Google Scholar For decades, the mechanism of native valvular calcification was thought to be due to a passive degeneration. However, in 2009, the National Heart, Lung, and Blood Institute established the first working group in biology to study heart valves, confirming the established hypothesis from scientists across North America that calcification in the heart valve is an osteogenic process.3.Rajamannan NM Evans FJ Aikawa E Grande-Allen KJ Demer LL Heistad DD Simmons CA Masters KS Mathieu P O’Brien KD Schoen FJ Towler DA Yoganathan AP Otto CM Calcific aortic valve disease: not simply a degenerative process: a review and agenda for research from the National heart and lung and blood institute aortic stenosis working group. Executive summary: calcific aortic valve disease-2011 update.Circulation. 2011; 124 (doi: 10.1161/CIRCULATIONAHA.110.006767): 1783-1791Google Scholar,8.Mohler 3rd, ER Adam LP McClelland P Graham L Hathaway DR Detection of osteopontin in calcified human aortic valves.Arterioscler Thromb Vasc Biol. 1997; 17 (doi: 10.1161/01.ATV.17.3.547): 547-552Google Scholar, 9.Mohler 3rd, ER Gannon F Reynolds C Zimmerman R Keane MG Kaplan FS Bone formation and inflammation in cardiac valves.Circulation. 2001; 103: 1522-1528Google Scholar, 10.Rajamannan NM Subramaniam M Rickard D Stock SR Donovan J Springett M Orszulak T Fullerton DA Tajik AJ Bonow RO Spelsberg T Human aortic valve calcification is associated with an osteoblast phenotype.Circulation. 2003; 107 (doi: 10.1161/01.CIR.0000070591.21548.69): 2181-2184Google Scholar Additionally, recent studies have demonstrated risk factors for bioprosthetic valve calcification similar to those of vascular atherosclerosis.11.Farivar RS Cohn LH Hypercholesterolemia is a risk factor for bioprosthetic valve calcification and explantation.J Thorac Cardiovasc Surg. 2003; 126 (doi: 10.1016/S0022): 969-975Google Scholar, 12.Nollert G Miksch J Kreuzer E Reichart B Risk factors for atherosclerosis and the degeneration of pericardial valves after aortic valve replacement.J Thorac Cardiovasc Surg. 2003; 126 (doi: 10.1016/S0022): 965-968Google Scholar, 13.Antonini-Canterin F, Zuppiroli A, Popescu BA, Granata G, Cervesato E, Piazza R, Pavan D, Nicolosi GL. Effect of statins on the progression of bioprosthetic aortic valve degeneration. Am J Cardiol. 2003 Dec 15;1479–1482.Google Scholar, 14.Briand M Pibarot P Despres JP Voisine P Dumesnil JG Dagenais F Mathieu P Metabolic syndrome is associated with faster degeneration of bioprosthetic valves.Circulation. 2006; 114 (doi: 10.1161/CIRCULATIONAHA.105.000422): I512-I517Google Scholar An inflammatory reaction involving lipid deposition, inflammatory cell infiltration, and bone matrix protein expression in calcifying bioprosthesis have been clearly shown in pathology studies.15.Shetty R Pepin A Charest A Perron J Doyle D Voisine P Dagenais F Pibarot P Mathieu P Expression of bone-regulatory proteins in human valve allografts.Heart. 2006; 92 (doi: 10.1136/hrt.2005.075903): 1303-1308Google Scholar, 16.Wilhelmi MH Bara C Kofidis T Wilhelmi M Pichlmaier M Haverich A Long-term cardiac allograft valves after heart transplant are functionally and structurally preserved, in contrast to homografts and bioprostheses.J Heart Valve Dis. 2006; 15: 777-782Google Scholar, 17.Wilhelmi MH Mertsching H Wilhelmi M Leyh R Haverich A Role of inflammation in allogeneic and xenogeneic heart valve degeneration: immunohistochemical evaluation of inflammatory endothelial cell activation.J Heart Valve Dis. 2003; 12: 520-526Google Scholar, 18.Skowasch D Steinmetz M Nickenig G Bauriedel G Is the degeneration of aortic valve bioprostheses similar to that of native aortic valves? Insights into valvular pathology.Expert Rev Med Devices. 2006; 3 (doi: 10.1586/17434440.3.4.453): 453-462Google Scholar, 19.Bottio T Thiene G Pettenazzo E Perron J Doyle D Voisine P Dagenais F Pibarot P Mathieu P Hancock II bioprosthesis: a glance at the microscope in mid-long-term explants.J Thorac Cardiovasc Surg. 2003; 126: 99-105Google Scholar These findings parallel the histopathology3.Rajamannan NM Evans FJ Aikawa E Grande-Allen KJ Demer LL Heistad DD Simmons CA Masters KS Mathieu P O’Brien KD Schoen FJ Towler DA Yoganathan AP Otto CM Calcific aortic valve disease: not simply a degenerative process: a review and agenda for research from the National heart and lung and blood institute aortic stenosis working group. Executive summary: calcific aortic valve disease-2011 update.Circulation. 2011; 124 (doi: 10.1161/CIRCULATIONAHA.110.006767): 1783-1791Google Scholar found in native calcific aortic valve disease.8.Mohler 3rd, ER Adam LP McClelland P Graham L Hathaway DR Detection of osteopontin in calcified human aortic valves.Arterioscler Thromb Vasc Biol. 1997; 17 (doi: 10.1161/01.ATV.17.3.547): 547-552Google Scholar, 9.Mohler 3rd, ER Gannon F Reynolds C Zimmerman R Keane MG Kaplan FS Bone formation and inflammation in cardiac valves.Circulation. 2001; 103: 1522-1528Google Scholar, 10.Rajamannan NM Subramaniam M Rickard D Stock SR Donovan J Springett M Orszulak T Fullerton DA Tajik AJ Bonow RO Spelsberg T Human aortic valve calcification is associated with an osteoblast phenotype.Circulation. 2003; 107 (doi: 10.1161/01.CIR.0000070591.21548.69): 2181-2184Google Scholar,20.Rajamannan NM Nealis TB Subramaniam M Pandya S Stock SR Ignatiev CI Sebo TJ Rosengart TK Edwards WD McCarthy PM Bonow RO Spelsberg TC Calcified rheumatic valve neoangiogenesis is associated with vascular endothelial growth factor expression and osteoblast-like bone formation.Circulation. 2005; 111 (doi: 10.1161/CIRCULATIONAHA.104.473165): 3296-3301Google Scholar, 21.Caira FC Stock SR Gleason TG McGee EC Huang J Bonow RO Spelsberg TC McCarthy PM Rahimtoola SH Rajamannan NM Human degenerative valve disease is associated with up-regulation of low-density lipoprotein receptor-related protein 5 receptor-mediated bone formation.J Am Coll Cardiol. 2006; 47 (doi: 10.1016/j.jacc.2006.02.040): 1707-1712Google Scholar, 22.O’Brien KD Shavelle DM Caulfield MT McDonald TO Olin-Lewis K Otto CM Probstfield JL Association of angiotensin-converting enzyme with low-density lipoprotein in aortic valvular lesions and in human plasma.Circulation. 2002; 106: 2224-2230Google Scholar, 23.O’Brien KD Kuusisto J Reichenbach DD Ferguson M Giachelli C Alpers CE Otto CM Osteopontin is expressed in human aortic valvular lesions.Circulation. 1995; 92: 2163-2168Google Scholar, 24.Kaden JJ Dempfle CE Grobholz R Fischer CS Vocke DC Kilic R Sarikoc A Pinol R Hagl S Lang S Brueckmann M Borggrefe M Inflammatory regulation of extracellular matrix remodeling in calcific aortic valve stenosis.Cardiovasc Pathol. 2005; 14 (doi: 10.1016/j.carpath.2005.01.002): 80-87Google Scholar, 25.Olsson M Thyberg J Nilsson J Presence of oxidized low density lipoprotein in nonrheumatic stenotic aortic valves.Arterioscler Thromb Vasc Biol. 1999; 19: 1218-1222Google Scholar The role of calcification in the heart-osteocardiology26.Rajamannan NM Osteocardiology: defining the Go/No-Go time point for therapy.Cardiology. 2018; 139 (doi: 10.1159/000485074): 175-183Google Scholar may reveal a parallel mechanism of calcification in the bioprosthesis as more animal models emerge to define the cellular mechanisms. Already established in the literature are parallel risk factors for native valve calcification as well as bioprosthetic calcification including hyperlipidemia, smoking, hypertension, and male gender.3.Rajamannan NM Evans FJ Aikawa E Grande-Allen KJ Demer LL Heistad DD Simmons CA Masters KS Mathieu P O’Brien KD Schoen FJ Towler DA Yoganathan AP Otto CM Calcific aortic valve disease: not simply a degenerative process: a review and agenda for research from the National heart and lung and blood institute aortic stenosis working group. Executive summary: calcific aortic valve disease-2011 update.Circulation. 2011; 124 (doi: 10.1161/CIRCULATIONAHA.110.006767): 1783-1791Google Scholar Recently, a seminal discovery in the field of bioprosthetic valve calcification determined that hemodynamic deterioration of bioprosthetic heart valves is secondary to specific lipid risk factors including elevated plasma Lp-PLA2, PCSK9, and HOMA index.1.Salaun E Mahjoub H Dahou A Mathieu P Larose E Despres JP Rodes-Cabau J Arsenault BJ Puri R Clavel MA Pibarot P 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 The authors concluded that hemodynamic valve deterioration is associated with adverse outcomes and the presence of leaflet calcification on computed tomography (CT) is strongly associated with hemodynamic valve deterioration (HVD) and subsequent adverse clinical outcomes including re-intervention and death.1.Salaun E Mahjoub H Dahou A Mathieu P Larose E Despres JP Rodes-Cabau J Arsenault BJ Puri R Clavel MA Pibarot P 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 2015, during an ongoing clinical trial, the discovery of reduced aortic valve leaflet motion was noted on computed tomography angiography (CTA) in a patient who had suffered a cerebrovascular event following TAVR. This finding raised concern of the possibility of subclinical leaflet thrombosis in this patient population.25.Olsson M Thyberg J Nilsson J Presence of oxidized low density lipoprotein in nonrheumatic stenotic aortic valves.Arterioscler Thromb Vasc Biol. 1999; 19: 1218-1222Google Scholar The investigators discovered reduced leaflet motion which was noted on CTA in 22 of 55 patients (40%) in the clinical trial and in 17 of 132 patients (13%) in the two registries; the SAVORY registry, NCT02426307; and RESOLVE registry, NCT02318342. Notably, reduced leaflet motion was detected among two different patient populations with multiple bioprosthesis types, including transcatheter and surgical bioprosthesis. Finally, the investigators discovered in these databases, that therapeutic anticoagulation with warfarin, as compared with dual antiplatelet therapy, was associated with a decreased incidence of reduced leaflet motion (0% and 55%, respectively, p = 0.01 in the clinical trial; and 0% and 29%, respectively, p = 0.04 in the pooled registries). In patients who were re-evaluated with follow-up CTA, restoration of leaflet motion was noted in all 11 patients who were receiving anticoagulation and in 1 of 10 patients who were not receiving anticoagulation (p < 0.001). The mechanisms of bioprosthetic heart valve dysfunction are secondary to complex mechanisms derived from the multiple risk events involved in the degeneration process. Canadian investigators, describe the role of lipids in bioprosthetic heart valves removed from patients for valve degeneration and oxidized lipoproteins and inflammatory cells in the commissural areas of macroscopic calcification and pannus formation.27.Karakoyun S Ozan Gursoy M Yesin M Kalcik M Astarcioglu MA Gunduz S Emrah Oguz A Coban Kokten S Nimet Karadayi A Tuncer A Koksal C Gokdeniz T Ozkan M Histopathological and immunohistochemical evaluation of pannus tissue in patients with prosthetic valve dysfunction.J Heart Valve Dis. 2016; 25: 104-111Google Scholar Pannus tissue appears to be formed as the result of a neointimal response in periannular regions of prosthetic valves that consist of periannular cellular migration, myofibroblast and extracellular matrix proliferation with vascular components. This process is similar to the calcification and nodules which develop along the surface of a calcified valve leaflet. It is a chronic active process in which mediators such as TGF-β, VEGF and MMP-2 play roles in both matrix formation, atherosclerosis and future calcification mechanisms.27.Karakoyun S Ozan Gursoy M Yesin M Kalcik M Astarcioglu MA Gunduz S Emrah Oguz A Coban Kokten S Nimet Karadayi A Tuncer A Koksal C Gokdeniz T Ozkan M Histopathological and immunohistochemical evaluation of pannus tissue in patients with prosthetic valve dysfunction.J Heart Valve Dis. 2016; 25: 104-111Google Scholar The data from the large multi-center registries are critical evidence as to the timing and potential approach towards slowing the development of bioprosthetic valve calcification. A recent analysis of explanted TAVR valves28.Yahagi K Ladich E Kutys R Mori H Svensson LG Mack MJ Herrmann HC Smith CR Leon MB Virmani R Finn AV Pathology of balloon-expandable transcatheter aortic valves.Catheter Cardiovasc Interv. 2017; 90 (doi: 10.1002/ccd.27160): 1048-1057Google Scholar demonstrates calcium in TAVR explants after 4 years, but findings of thrombus at earlier time points. Del Trigo et al.,29.Del Trigo M Munoz-Garcia AJ Wijeysundera HC Nombela-Franco L Cheema AN Gutierrez E Serra V Kefer J Amat-Santos IJ Benitez LM Mewa J Jimenez-Quevedo P Alnasser S Garcia Del Blanco B Dager A Abdul-Jawad Altisent O Puri R Campelo-Parada F Dahou A Paradis JM Dumont E Pibarot P Rodes-Cabau J 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 has published in a large multicenter registry that elucidates key predicators and timing of TAVR valve degeneration. These predicators include: (1) absence of anticoagulation therapy at discharge; (2) valve-in-valve procedure (TAVR in a surgical valve); (3) ≤23 mm transcatheter heart valve; and (4) greater body mass index. Dvir et al., have also proposed a novel classification system for valve degeneration. Hemodynamic valve deterioration (HVD) as identified by Doppler echocardiography occurred in one third of patients and was associated with a 2.2-fold higher adjusted mortality. Diabetes mellitus and renal insufficiency were associated with early HVD, whereas female sex, warfarin use, and stented BPs (versus stentless) were associated with late HVD.29.Del Trigo M Munoz-Garcia AJ Wijeysundera HC Nombela-Franco L Cheema AN Gutierrez E Serra V Kefer J Amat-Santos IJ Benitez LM Mewa J Jimenez-Quevedo P Alnasser S Garcia Del Blanco B Dager A Abdul-Jawad Altisent O Puri R Campelo-Parada F Dahou A Paradis JM Dumont E Pibarot P Rodes-Cabau J 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 Another high risk patient population are patients with renal failure on hemodialysis who receive anticoagulation, Vitamin K inhibitors may be at risk for accelerated calcification a well-known complication in this patient population in their native aortic valves, as defined by Holden et al.30.Dvir D Bourguignon T Otto CM Hahn RT Rosenhek R Webb JG Treede H Sarano ME Feldman T Wijeysundera HC Topilsky Y Aupart M Reardon MJ Mackensen GB Szeto WY Kornowski R Gammie JS Yoganathan AP Arbel Y Borger MA Simonato M Reisman M Makkar RR Abizaid A McCabe JM Dahle G Aldea GS Leipsic J Pibarot P Moat NE Mack MJ Kappetein AP Leon MB Investigators V Standardized definition of structural valve degeneration for surgical and transcatheter bioprosthetic aortic valves.Circulation. 2018; 137: 388-399Google Scholar Renal failure may pose a serious risk for bioprosthetic valve calcification and place them at higher risk for anticoagulation. Finally, the role of osteocardiology in the native mitral valve versus the aortic valve is well defined.31.Holden RM Sanfilippo AS Hopman WM Zimmerman D Garland JS Morton AR Warfarin and aortic valve calcification in hemodialysis patients.J Nephrol. 2007; 20: 417-422Google Scholar The native valve mechanisms important foundation for studying HVD as defined by anatomic location and hemodynamics for the mitral versus aortic valves and the role of pressure differentials across these two different valves.26.Rajamannan NM Osteocardiology: defining the Go/No-Go time point for therapy.Cardiology. 2018; 139 (doi: 10.1159/000485074): 175-183Google Scholar Further prospective studies are required to determine whether a specific antithrombotic versus aggressive risk factor reduction post-TAVR will help to reduce the risk of VHD. In conclusion, the role of traditional cardiovascular risk factors in the development of calcification is a critical discovery towards understanding that valve deterioration is not a passive phenomenon. Instead, this calcification process and the discovery of subclinical thrombosis leads to the understanding of a possible dual mechanism of hemodynamic valve deterioration: (1) the development of calcification along the surface of the aortic valve leaflets as defined in parallel mechanisms of osteocardiology;24.Kaden JJ Dempfle CE Grobholz R Fischer CS Vocke DC Kilic R Sarikoc A Pinol R Hagl S Lang S Brueckmann M Borggrefe M Inflammatory regulation of extracellular matrix remodeling in calcific aortic valve stenosis.Cardiovasc Pathol. 2005; 14 (doi: 10.1016/j.carpath.2005.01.002): 80-87Google Scholar and (2) the development of subclinical valve thrombosis with subsequent hemodynamic valve deterioration (Figure 1).