Cardiovascular Pathology 23 (2014) 65–70
Contents lists available at ScienceDirect
Cardiovascular Pathology
Innovative Cardiovascular Pathology, Pathobiology, Interventions, and Technologies
Transcatheter aortic valve implantation: status and challenges Gregory A. Fishbein a,⁎, Frederick J. Schoen b, Michael C. Fishbein a a b
Department of Pathology and Laboratory Medicine David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, CHS 13–145, Los Angeles, CA 90095–1732 Department of Pathology Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115
a r t i c l e
i n f o
Article history: Received 28 May 2013 Received in revised form 19 August 2013 Accepted 1 October 2013 Keywords: Aortic valve Transcatheter valve implantation Prosthetic valve Aortic stenosis Valvular disease
a b s t r a c t Calcific aortic valve disease of the elderly is the most prevalent hemodynamically-significant valvular disease, and the most common lesion requiring valve replacement in industrialized countries. Transcatheter aortic valve implantation is a less invasive alternative to classical aortic valve replacement that can provide a therapeutic option for high-risk or inoperable patients with aortic stenosis. These devices must be biocompatible, have excellent hemodynamic performance, be easy to insert, be securely anchored without sutures, and be durable, without increased risk of thrombosis or infection. To date, complications are related to the site of entry for insertion, the site of implantation (aorta, coronary ostia, base of left ventricle), and to the structure and design of the inserted device. However, as with any novel technology unanticipated complications will develop. Goals for future development will be to make the devices more effective, more durable, safer, and easier to implant, so as to further improve outcome for patients with severe aortic stenosis. The pathologist participating in research and development, and examination of excised devices will have a critical role in improving outcome for these patients. © 2014 Elsevier Inc. All rights reserved.
1. Summary Transcatheter aortic valve implantation (TAVI) is a less invasive alternative to classical aortic valve replacement that can provide a therapeutic option for high-risk or inoperable patients with aortic stenosis. The pathologist participating in research and development and the examination of excised devices will have a critical role in improving outcome for these patients. 2. The problem Calcific aortic valve disease, exemplified by its advanced clinical manifestation, calcific aortic stenosis (AS) (a.k.a. aortic stenosis of the elderly) is the most prevalent hemodynamically-significant valvular disease in the industrialized world. Calcific AS is also the most common lesion requiring valve replacement in industrialized countries. Calcification of the aortic valve is present in more than 50% of people over 85 years old [1]. Among octogenarians, AS has been reported in as many as 8.1% of individuals [2]. The aortic valve undergoes fibrosis and calcification due to a complex interplay of shear stress, inflammatory processes, altered lipid metabolism, and abnormalities in endothelial cell structure and function [3,4]. Calcification of the aortic valve and aortic stenosis are associated with risk factors for atherosclerosis, including aging, hypertension, diabetes mellitus, elevated low-density lipoprotein, and smoking. Recent genome-wide association studies have impli⁎ Corresponding author. Tel.: +1 310 825 5719; fax: +1 310 267 2058. E-mail address: gfi[email protected] (G.A. Fishbein). 1054-8807/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.carpath.2013.10.001
cated genetic polymorphisms associated with aortic valve calcification [5]. While these findings elucidate potential therapeutic targets, currently there is no effective medical therapy for calcific AS. Once patients become symptomatic with chest pain, syncope, or evidence of congestive heart failure, short-term mortality rates are extremely high [2]. Once diagnosed with AS, there is an 80% risk of congestive heart failure, aortic valve replacement, or death over five years [6]. Fortunately, overall, surgical outcome is excellent, even among octogenarians. Accordingly, the teaching has been that there is virtually no contraindication to valve replacement for AS in a patient expected to survive the surgery, as valve replacement surgery outcomes are generally very good and un-operated patient mortality is unacceptably high. However, as the population is aging and patients have more and more comorbidity, there are patients who are unlikely to survive open-heart surgery. In fact, Iung et al. [7] have shown that, in practice, surgery is denied in as many as 33% of elderly candidates. Older age and left ventricular dysfunction were the dominant features causing patients to be denied surgery. In Iung's cohort, 73% of patients age 75–80 were offered surgery. In contrast, surgery was offered to only 55% of patients age 85–90, and 0% of patients over 90. Indeed, a less invasive treatment of aortic stenosis in such patients would be of great utility. 3. The solution: transcatheter aortic valve replacement TAVI is a relatively new, less invasive alternative to classical aortic valve replacement. The rationale is to provide a therapeutic option for high-risk or inoperable patients with AS. There have already been
66
G.A. Fishbein et al. / Cardiovascular Pathology 23 (2014) 65–70
over 50,000 implants in over 40 countries [8]. A variety of prostheses are currently in use, under clinical evaluation, or in development. The devices must be capable of percutaneous or minimallyinvasive transcatheter implantation, be securely anchored within the valve orifice without sutures, and must provide acceptable biocompatibility, hemodynamic performance, and durability comparable to conventional bioprosthetic devices, without increased risk of thrombosis or infection. Two models of prosthetic devices comprise the first generation of implantable valves: the Edwards SAPIEN prosthesis (Edwards Lifescience, Irvine, CA, USA) and the Medtronic CoreValve ReValving system (Medtronic Inc, Minneapolis, MN, USA). Both employ trileaflet tissue valves mounted on a compressible metallic stent. Both are designed to function similarly, though notable differences in construction and delivery mechanisms exist. The Edwards SAPIEN valve is constructed from bovine pericardium, preserved in gluteraldehyde, affixed to a stainless steel stent frame. The valve is compressed onto a balloon catheter which is rapidly inflated and then deflated, expanding and releasing the device. This serves to passively secure the prosthesis to the underlying native valve leaflets. In contrast, the CoreValve is composed of bovine, and later porcine, pericardium tissue valve, mounted in a self-expanding Nitinol stent. The switch from bovine to porcine tissue was motivated by decreased thickness of porcine pericardium, allowing for a lower profile compressed device [9]. Valves may be introduced via catheter antegrade, through a transseptal or left ventricular apical approach, or retrograde, from a peripheral artery or the ascending aorta. These procedures are minimally invasive and do not typically require extracorporal circulation or cardioplegia. The transapical and transaortic approaches are more invasive, requiring a left minithoracotomy. These approaches are usually reserved for patients with severe peripheral vascular disease [10]. The transvenous, antegrade transseptal approach was primarily employed in early experiences with TAVI [11] and has fallen out of favor due to its complexity and associated complications; its contemporary use has been suggested in patients with no other access [12]. When the prosthetic valve is implanted through a catheter, the patient's native aortic valve must be pushed aside, compressed against the aortic root (Fig. 1A & B). Delivery and positioning may be challenging, and are not without complications (to be discussed). Accurate assessment of aortic valvular size must be done by transesophageal echocardiography, computed tomography, and/or magnetic resonance imaging [8]. The evaluation, treatment and long-term care of the candidate for TAVI is complex and best performed by a multidisciplinary team with specialized procedural rooms in centers of expertise [8]. In spite of the presence of the heavily calcified native valve, hemodynamic performance after TAVI is excellent with low transaortic systolic gradients of ≤10 mm Hg and valve orifice areas between 1.2 and 1.9 cm 2 [13]. Aortic insufficiency (AI), while uncommon after classical aortic valve replacement, is common after TAVI and is an accepted complication [14,15]. This AI is usually due to paravalvular leaks, as it is usually not possible to have a complete annular seal due to the nodules of calcium present in the native valve leaflets. Leaks, even moderate in sizes, are usually well-tolerated, but the greater the leak the worse the outcome. Many skeptics cite the propensity for paravalvular leak as one of the main weaknesses of TAVI [15]. Unbehaun et al. have adopted an aggressive strategy using redilation or immediate implantation of a second valve (valve-in-valve [16]) to lower the incidence of significant valvular leaks [14]. Over a one year period, the valve-in-valve technique has been shown to be comparable to a single valve implantation in safety and efficacy [15]. Repositionable valves may be beneficial in lowering procedural complications due to severe paravalvular leaks [17]. Furthermore, newer devices designed to minimize paravalvular leaks are emerging rapidly. Complications associated directly with the tissue leaflets
would be expected to be similar to those in bioprosthetic valves implanted surgically (Fig. 1C–E). There have been a number of clinical trials from different countries, including randomized trials comparing TAVI to classical aortic valve replacement [18–22]. The consensus of these studies is that TAVI is not inferior to classical aortic valve replacement in terms of procedure “success” and short-term morbidity and mortality. Longterm survival is primarily limited by comorbidities in this elderly group of patients–death is often due to severe renal, pulmonary, or non-valvular heart disease.
4. Complications As with any new procedure, TAVI will be associated with predictable as well as unanticipated complications. Safety and efficacy are best evaluated through large clinical trials with standardized reporting of outcomes and complications to large registries [23,24]. Vascular complications: vascular events are the most common complications of the procedure and contribute to procedural mortality. This is particularly true of the transfemoral approach [25]; the risk is greatest in patients with significant peripheral vascular disease [26]. Vascular injury is related to the large-caliber sheaths used for device deployment. The resulting vascular injury may lead to significant bleeding at the insertion site, sometimes requiring transfusion, and even death. Embolic risk to the brain or other organs is present in patients with extensive peripheral vessel or aortic atherosclerosis (see stroke below). As smaller, lower-profile systems are developed, serious vascular injuries are expected to occur less frequently. Vascular complications can be avoided in high-risk patients by an antegrade transapical approach. This is a more invasive procedure, requiring a left anterolateral minithoracotomy. Bleeding at the apical puncture site, pseudoaneurysm, aneurysm, and new apical hypo-/akinesia are potential complications of this approach. Reexploration due to postoperative thoracic bleeding has been reported in up to 14% of transapical implantations [27]. Renal complications: a rise in creatinine following TAVI has been reported in 5–28% of cases [28]. However, renal function often improves with the increase in cardiac output. Coronary artery complications (Fig. 1F and G): The elderly patients that are candidates for TAVI generally have some degree of atherosclerotic coronary artery disease (CAD). The presence of severe CAD increases procedural risks and must be dealt with before the procedure. Calcific fragments of the native valve may break off and embolize, causing coronary occlusion. The coronary ostia can be blocked by the device. The risk is dependent on anatomic factors, such as unusually heavy calcification of the aortic valve or aortic root, or low coronary ostia, as well as the design and placement of the device. Coronary obstruction is a complication of high implantation [29]. In addition, it is more frequently associated with balloonexpandable devices [30]. Conduction system complications (Fig. 2A–C): The conduction system passes through the interventricular septum immediately below the aortic valve. Hence, injury to this region during valve placement may cause or worsen conduction disorders. New-onset bundle branch block following TAVI has been reported in up to 45% of patients, according to early reports [23]. Conduction system complications are more frequently associated with self-expandable devices. Fraccaro et al. reported an extraordinary 77% of patients receiving third generation self-expandable devices developed new or worsening conduction abnormalities; 39% of these patients required inhospital permanent pacemaker implantation [31]. The most common new conduction disorders were left bundle branch block and firstdegree AV (atrioventricular) block. Predictors of permanent pacemaker implantation included pre-existing right bundle branch block and increased depth of prosthesis implantation.
G.A. Fishbein et al. / Cardiovascular Pathology 23 (2014) 65–70
67
Fig. 1. (A) Valve in situ. Note that the heavily calcified native aortic valve has been pushed aside, but there were no paravalvular leaks. (B) Heavily calcified native aortic valve that has been pressed against the aortic root. Compression of the native valve can cause embolization of calcific debris or blockage of coronary ostia if the valve is positioned low in the sinuses of Valsalva (AV=aortic valve, and MV=mitral valve). (C) Inflow surface of valve with granular deposits on the bioprosthetic leaflets. (D) Trichrome stain showing mural thrombus (T) on the valve leaflet (VL) (original magnification ×40). (E) Hematoxylin and eosin stain showing host mononuclear and multinucleated (arrow) cells on surface of leaflet (original magnification ×400). (F) Probe from proximal right coronary artery (RCA) into aorta showing no obstruction; however, Panel G shows that the probe is going through the struts of the stent, rather than above the stent. This is not an optimal placement since fibrosis and/or thrombosis of the stent could obstruct the coronary ostium.
Myocardial injury: TAVI is commonly associated with some myocardial injury, as assessed by CK-MB and cTnT release. RodésCabau et al. found some myocardial injury in 97% of patients in whom a transfemoral approach was utilized [32]. Myocardial injury, judged by elevated cardiac biomarkers, was inversely correlated to improvement in ejection fraction and directly proportional to post-procedural cardiac mortality. In that study, the pathogenesis of the myocardial injury was not clarified. Stroke: stroke during or after TAVI may occur from thromboemboli, aortic injury (e.g. dissection or atheroemboli), hypotension, hemorrhage, or dislodgement of calcific fragments during valvuloplasty. Given that TAVI is intended for individuals who are poor surgical candidates, it is not surprising that many have comorbidities that increase the risk of thrombosis and stroke. In recent investiga-
tions, 11% patients in this high-risk population had pre-existing intracardiac thrombi [33]. An additional 24% had high-grade left atrial spontaneous echo contrast (SEC) detected by transesophageal echo. SEC is an indicator of blood stasis and a well-established predictor of cardioembolic stroke [34–36]. Not surprisingly, individuals most at risk included those with a history of atrial fibrillation, severe diastolic dysfunction, and/or left atrial or ventricular hypertrophy. Mitral valve complications: mitral valve complications were first reported in early experiences with the antegrade transseptal approach [11]. Injury may occur as the device passes by the anterior leaflet during delivery. The catheter may be passed under the mitral chordae if the transapical approach is employed. Regardless of the approach, the ventricular end of the prosthesis may contact the anterior curtain of the mitral valve [37]. Placement of the device too
68
G.A. Fishbein et al. / Cardiovascular Pathology 23 (2014) 65–70
Fig. 2. (A) View of left ventricular outflow tract (LVOT) after valve has been removed. Note erosion of the endocardial surface from the inferior portion of the metallic stent (arrow). Injury in and around this region has the potential to cause complete or bundle branch heart block. (B) The bundle of His (BH) is intact. There is calcification in the base of the septum (C), and there is fibrous thickening (F) of the endocardium of the left ventricular outflow tract and myocardium (hematoxylin and eosin stain; original magnification ×40). (C) Symmetric valve with proper coaptation of the leaflets. (D) Distortion of valve resulting in loss of complete coaptation with resulting regurgitation.
far into the left ventricle may interfere with movement of the anterior mitral leaflet [38]. Risk factors related to aortic valve pathology: The underlying aortic valve pathology is an important determinant of potential complications. Eccentric valvular calcification, heavy annular calcification, and a high degree of left ventricular outflow tract angulation predispose to paravalvular leaks [39]. Patients with bulky valvular calcification, small sinotubular junction, small aortic annulus, and “porcelain” aorta are at increased risk of annular rupture. Severe LV hypertrophy, subaortic stenosis, and combined AS/AI are risk factors for acute hemodynamic compromise and shock.
5. Outcome The safety and efficacy of TAVI in high-risk patients have been established in single-arm and randomized controlled studies. Gilard et al. reported on 3195 patients from 34 centers in the French national transcatheter aortic valve implantation registry, FRANCE 2 [22]. The mean age of patients was 82.7 years; half were women. Overall procedural success rate was 96.9%. Death rates at 30 days were 9.7%, and at one year 24.0%. The incidence of stroke at one year was 4.1%. The incidence of paravalvular leak was 64.5%. The use of a transapical approach and a greater degree of regurgitation were associated with reduced survival. Smith et al. performed a randomized control study assigning 699 high-risk patients to either TAVI or surgical replacement [20]. Death rates from any cause in the TAVI group were 3.4% and 24.2% at 30 days and one year respectively, while in the surgical group, death rates were 6.5% and 26.8% at 30 days and one year respectively. More patients in the TAVI group had an improvement in symptoms at 30 days, but there was no difference at 1 year.
More recently, Kodali et al. reported on the two year outcome of the same cohort of 699 patients [21]. At 2 years, TAVI and surgical treatment were similar in mortality, improved symptomatology, and improved hemodynamics. Paravalvular regurgitation was more common after TAVI, and associated with an increase in late mortality. 6. Pathologic evaluation of TAVI patients As with any new procedure, pathologic evaluation is the ultimate quality assurance tool to assess efficacy and complications in patients who die either early or late after TAVI, or in those whose valves are revised surgically. The knowledge ascertained by pathologic evaluation is critical for optimal design of future procedures and equipment. Furthermore, such knowledge helps clinicians anticipate and recognize complications in current patients. At autopsy, in patients who had undergone TAVI through an arterial approach, the access site should be carefully examined for vascular injury and hemorrhage. If bleeding occurs from a femoral artery site, blood will track into the retroperitoneal tissues. This bleeding can be missed if the prosector is merely looking in the peritoneal cavity or lower extremity. Also, considerable bleeding may occur in muscle or adipose tissue; thus, measurement of liquid blood alone will underestimate the blood loss. If a transapical approach has been used, there is the potential for damage to the distal left anterior descending (LAD) artery. Therefore, it is important to document the status of the LAD and myocardium it supplies. Since a device will be present in the aortic position, opening the heart according to flow through that area is not possible. So the outflow surface of the valve can be visualized, the aorta should be transected about one centimeter above the palpable distal end of the prosthesis. This may be 1–3 cm above the sino-tubular junction. The
G.A. Fishbein et al. / Cardiovascular Pathology 23 (2014) 65–70
aorta itself should be carefully inspected for evidence of dissection or disruption of atherosclerotic plaques that could be the source of athero- or thromboemboli. Evaluation of the status of the coronary ostia is critical, as there can be blockage of the ostia by the device, embolic material, or the compressed, heavily calcified native aortic valve. Prior to any significant manipulation, the heart and device should be evaluated by X-ray in two planes, so as to document the location and status of the prosthesis and to evaluate for any wire fractures. The ventricles should be sliced transversely, again as close to the aortic valve as possible, to view the inflow surface of the implanted device. The myocardium should be inspected for recent and/or old ischemic injury. The degree of hypertrophy and dilation (wall thickness, heart weight) may shed some insight into the degree of valvular stenosis and/or regurgitation that might exist. The valve should first be examined in situ. The position should be noted with attention to whether there may be contact with the aorta and/or myocardium of the left ventricular outflow tract that could impact the conduction system. Often the valve can be seen and felt through the right atrial wall where it is adjacent to the aortic root. The valve leaflets should be examined for thrombi and/or vegetations in the early post-procedural period. After longer implant periods, host connective tissue overgrowth (pannus), calcification, fibrosis, and degeneration (tears, perforations) may be noted. A probe should be used to look for space between the device and aorta, indicative of paravalvular regurgitation. The shape of the device should be noted– round versus oval–as distortion of the device associated with inadequate coaptation of the leaflets has been reported [40] (Fig. 2C & D). Once the device is removed, the leaflets may be sampled for microscopic examination. Histologic examination is crucial in evaluation of possible traumatic leaflet injury, as collagen fiber fragmentation and disruption may be present even in the absence of macroscopic findings [41]. This is particularly true of balloonexpandable devices. The implantation site can then be examined for thrombi and vegetations. It is fascinating to see how the heavily calcified native aortic valve can be compressed against the aortic wall. The conduction system can then be dissected and submitted for histologic examination; the conduction tissue may be of interest in patients who have developed conduction block. Liberal use of photographs to document findings is encouraged. A complete autopsy is indicated so other organs can be assessed for emboli and resulting ischemic lesions, especially the brain. 7. Challenges 7.1. Long term durability As TAVI is a relatively new therapy, long-term data regarding prosthesis durability are currently unavailable. At the time of the first human implantation, the original bovine pericardial valve withstood ex-vivo durability testing of 100 million cycles (2.5 years) [11]. Reports of mid-term evaluation (2–3 years following implantation) show no significant structural degradation, leaflet thickening, calcification, thrombus formation, or change in transvalvular pressure gradient from baseline [19,21,42]. While long-term TAVI data are still being collected, studies of surgically implanted bioprosthetic aortic valves demonstrate that primary valve failure begins at 7–8 years [43]. Whether these data are predictive of long-term TAVI prostheses durability remains to be seen. 7.2. New developments New devices are in development to address the specific complications of TAVI. Second generation prostheses are made to be repositionable and retrievable or to provide better sealing without the potential for migration to allow optimal deployment, reducing paravalvular leak, valve migration, and conduction disturbance [44].
69
Cerebral protection devices, similar to those utilized in carotid procedures, are being evaluated to reduce the risk of stroke [45]. Valves are being miniaturized, reducing the rate of vascular complications, particularly from a peripheral approach. Smaller, lower profile valves minimize contact with surrounding tissue, reducing the risk of conduction disturbance and coronary ostial occlusion. Schmidt et al. have demonstrated the minimally-invasive implantation of autologous tissue engineered heart valves in vivo [46]. These living tissue valves may have regenerative properties protective of calcification and progressive degeneration, as seen in conventional bioprosthetic valves. 7.3. Other percutaneous valves Currently, the greatest need, in terms of numbers of patients, and the greatest experience, in terms of number of valves implanted, is for aortic valve devices. However, need and experience exist for replacement of other valves. Indeed, for pulmonary valve replacement two systems exist, the Medtronic Melody (Medtronic Inc. Minneapolis, MN) and the Edwards SAPIEN (Edwards LifeSciences, Irvine, CA). Both systems have been tested in humans and have been demonstrated efficacious in reducing right ventricular outflow tract pressure gradient without significant regurgitation [47]. The majority of data come from short term studies, so longer term studies are needed to determine durability, and preserved hemodynamic efficacy. Mitral regurgitation is another common valvular abnormality that would be best approached by minimally-invasive procedures. Indeed, repairs, while often imperfect, can be accomplished by transcatheter closed-chest placement of an annuloplasty ring or by partial closure of the mitral valve with a suture or clip. However, recurrence of mitral regurgitation after such repair is not uncommon. The feasibility of transcatheter mitral valve replacement has been demonstrated in a large animal model [48]. In addition, in patients with a failed bioprosthetic valve in the mitral position, a valve-in-valve transcatheter approach has been reported with encouraging results [49]. There is no question that there will continue to be efforts to develop and implement transcatheter approaches for a variety of valvular disorders. 7.4. Future directions TAVI is a relatively new procedure, with implantation techniques and devices under evaluation and development. Yet, one could argue that TAVI is already the established therapy for high-risk patients with aortic stenosis. It is expected that future developments in minimallyinvasive and percutaneous therapy may deprecate surgical valve replacement altogether. References [1] O'Brien KD. Epidemiology and genetics of calcific aortic valve disease. J Invest Med 2007;55:284–91. [2] Likosky DS, Sorensen MJ, Dacey LJ, Baribeau YR, Leavitt BJ, DiScipio AW, et al. Longterm survival of the very elderly undergoing aortic valve surgery. Circulation 2009;120:S127–33. [3] Goldbarg SH, Elmariah S, Miller MA, Fuster V. Insights into degenerative aortic valve disease. J Am Coll Cardiol 2007;50:1205–13. [4] Rajamannan NM, Evans FJ, Aikawa E, Grande-Allen KJ, Demer LL, Heistad DD, et al. 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;124:1783–91. [5] Thanassoulis G, Campbell CY, Owens DS, Smith JG, Smith AV, Peloso GM, et al. Genetic associations with valvular calcification and aortic stenosis. N Engl J Med 2013;368:503–12. [6] Otto CM, Burwash IG, Legget ME, Munt BI, Fujioka M, Healy NL, et al. Prospective study of asymptomatic valvular aortic stenosis: clinical, echocardiographic, and exercise predictors of outcome. Circulation 1997;95:2262–70. [7] Iung B, Cachier A, Baron G, Messika-Zeitoun D, Delahaye F, Tornos P, et al. Decision-making in elderly patients with severe aortic stenosis: why are so many denied surgery? Eur Heart J 2005;26:2714–20.
70
G.A. Fishbein et al. / Cardiovascular Pathology 23 (2014) 65–70
[8] Webb JG, Wood DA. Current status of transcatheter aortic valve replacement. J Am Coll Cardiol 2012;60:483–92. [9] Chiam PTL, Ruiz CE. Percutaneous transcatheter aortic valve implantation: evolution of the technology. Am Heart J 2009;157:229–42. [10] Zajarias A, Cribier AG. Outcomes and safety of percutaneous aortic valve replacement. J Am Coll Cardiol 2009;53:1829–36. [11] Cribier A, Eltchaninoff H, Bash A, Borenstein N, Tron C, Bauer F, et al. Percutaneous transcatheter implantation of an aortic valve prosthesis for calcific aortic stenosis: first human case description. Circulation 2002;106:3006–8. [12] Cohen MG, Singh V, Martinez CA, O'Neill BP, Alfonso CE, Martinezclark PO, et al. Transseptal antegrade transcatheter aortic valve replacement for patients with no other access approach — a contemporary experience. Catheter Cardiovasc Interv. 2013;In press. [13] Webb J, Cribier A. Percutaneous transarterial aortic valve implantation: what do we know? Eur Heart J 2011;32:140–7. [14] Unbehaun A, Pasic M, Dreysse S, Drews T, Kukucka M, Mladenow A, et al. Transapical aortic valve implantation: incidence and predictors of paravalvular leakage and transvalvular regurgitation in a series of 358 patients. J Am Coll Cardiol 2012;59:211–21. [15] Généreux P, Head SJ, Hahn R, Daneault B, Kodali S, Williams MR, et al. Paravalvular leak after transcatheter aortic valve replacement: the new achilles' heel? A comprehensive review of the literature. J Am Coll Cardiol 2013;61. [16] Ussia GP, Mulè M, Tamburino C. The valve-in-valve technique: transcatheter treatment of aortic bioprothesis malposition. Catheter Cardio Inte 2009;73:713–6. [17] Willson AB, Rodès-Cabau J, Wood DA, Leipsic J, Cheung A, Toggweiler S, et al. Transcatheter aortic valve replacement with the St. Jude Medical Portico valve: first-in-human experience. J Am Coll Cardiol 2012;60:581–6. [18] Pasic M, Unbehaun A, Dreysse S, Drews T, Buz S, Kukucka M, et al. Transapical aortic valve implantation in 175 consecutive patients: excellent outcome in very high-risk patients. J Am Coll Cardiol 2010;56:813–20. [19] Buellesfeld L, Gerckens U, Schuler G, Bonan R, Kovac J, Serruys PW, et al. 2-year follow-up of patients undergoing transcatheter aortic valve implantation using a self-expanding valve prosthesis. J Am Coll Cardiol 2011;57:1650–7. [20] Smith C, Leon M, Mack M. Transcatheter versus surgical aortic-valve replacement in high-risk patients. N Engl J Med 2011;364:2187–98. [21] Kodali SK, Williams MR, Smith CR, Svensson LG, Webb JG, Makkar RR, et al. Twoyear outcomes after transcatheter or surgical aortic-valve replacement. N Engl J Med 2012;366:1686–95. [22] Gilard M, Eltchaninoff H, Iung B, Donzeau-Gouge P, Chevreul K, Fajadet J, et al. Registry of transcatheter aortic-valve implantation in high-risk patients. N Engl J Med 2012;366:1705–15. [23] Leon MB, Piazza N, Nikolsky E, Blackstone EH, Cutlip DE, Kappetein AP, et al. Standardized endpoint definitions for transcatheter aortic valve implantation clinical trials: a consensus report from the valve academic research consortium. J Am Coll Cardiol 2011;57:253–69. [24] Rosengart TK, Feldman T, Borger MA, Vassiliades TA, Gillinov AM, Hoercher KJ, et al. Percutaneous and minimally invasive valve procedures: a scientific statement from the American Heart Association Council on Cardiovascular Surgery and Anesthesia, Council on Clinical Cardiology, Functional Genomics and Translational Biology Interdisciplin. Circulation 2008;117:1750–67. [25] Wenaweser P, Pilgrim T, Roth N, Kadner A, Stortecky S, Kalesan B, et al. Clinical outcome and predictors for adverse events after transcatheter aortic valve implantation with the use of different devices and access routes. Am Heart J 2011;161:1114–24. [26] Kahlert P, Al-Rashid F, Weber M, Wendt D, Heine T, Kottenberg E, et al. Vascular access site complications after percutaneous transfemoral aortic valve implantation. Herz 2009;34:398–408. [27] Bleiziffer S, Ruge H, Mazzitelli D, Hutter A, Opitz A, Bauernschmitt R, et al. Survival after transapical and transfemoral aortic valve implantation: talking about two different patient populations. J Thorac Cardiovasc Surg 2009;138:1073–80. [28] Bagur R, Webb JG, Nietlispach F, Dumont E, De Larochellière R, Doyle D, et al. Acute kidney injury following transcatheter aortic valve implantation: predictive factors, prognostic value, and comparison with surgical aortic valve replacement. Eur Heart J 2010;31:865–74. [29] Laborde J-C, Brecker SJD, Roy D, Jahangiri M. Complications at the time of transcatheter aortic valve implantation. Methodist Debakey Cardiovasc J 2012;8:38–41.
[30] Ribeiro HB, Nombela-Franco L, Urena M, Mok M, Pasian S, Doyle D, et al. Coronary obstruction following transcatheter aortic valve implantation: a systematic review. J Am Coll Cardiol Intv 2013;6:452–61. [31] Fraccaro C, Buja G, Tarantini G, Gasparetto V, Leoni L, Razzolini R, et al. Incidence, predictors, and outcome of conduction disorders after transcatheter selfexpandable aortic valve implantation. Am J Cardiol 2011;107:747–54. [32] Rodés-Cabau J, Gutiérrez M, Bagur R, De Larochellière R, Doyle D, Côté M, et al. Incidence, predictive factors, and prognostic value of myocardial injury following uncomplicated transcatheter aortic valve implantation. J Am Coll Cardiol 2011;57: 1988–99. [33] Lenders GD, Paelinck BP, Wouters K, Claeys MJ, Rodrigus IE, Van Herck PL, et al. Transesophageal echocardiography for cardiac thromboembolic risk assessment in patients with severe, symptomatic aortic valve stenosis referred for potential transcatheter aortic valve implantation. J Am Coll Cardiol. 2013; In Press. [34] Lee RJ, Bartzokis T, Yeoh TK, Grogin HR, Choi D, Schnittger I. Enhanced detection of intracardiac sources of cerebral emboli by transesophageal echocardiography. Stroke 1991;22:734–9. [35] Fatkin D, Kelly RP, Feneley MP. Relations between left atrial appendage blood flow velocity, spontaneous echocardiographic contrast and thromboembolic risk in vivo. J Am Coll Cardiol 1994;23:961–9. [36] Erbel R, Stern H, Ehrenthal W, Schreiner G, Treese N, Meyer J, et al. Detection of spontaneous echocardiographic contrast within the left atrium by transesophageal echocardiography: spontaneous echocardiographic contrast. Clin Cardiol 1986;9:245–52. [37] Masson J-B, Kovac J, Schuler G, Ye J, Cheung A, Kapadia S, et al. Transcatheter aortic valve implantationreview of the nature, management, and avoidance of procedural complications. JACC Cardiovasc Interv 2009;2:811–20. [38] Wong DR, Boone RH, Thompson CR, Allard MF, Altwegg L, Carere RG, et al. Mitral valve injury late after transcatheter aortic valve implantation. J Thorac Cardiovasc Surg 2009;137:1547–9. [39] Holmes David RJ, Mack MJ, Kaul S, Agnihotri A, Alexander KP, Bailey SR, et al. ACCF/AATS/SCAI/STS expert consensus document on transcatheter aortic valve replacement. J Am Coll Cardiol 2012;59:1200–54. [40] Zegdi R, Ciobotaru V, Noghin M, Sleilaty G, Lafont A, Latrémouille C, et al. Is it reasonable to treat all calcified stenotic aortic valves with a valved stent? Results from a human anatomic study in adults. J Am Coll Cardiol 2008;51:579–84. [41] Zegdi R, Bruneval P, Blanchard D, Fabiani J-N. Evidence of leaflet injury during percutaneous aortic valve deployment. Eur J Cardiothorac Surg 2011;40:257–9. [42] Gurvitch R, Wood DA, Tay EL, Leipsic J, Ye J, Lichtenstein SV, et al. Transcatheter aortic valve implantation: durability of clinical and hemodynamic outcomes beyond 3 years in a large patient cohort. Circulation 2010;122:1319–27. [43] Hammermeister K, Sethi GK, Henderson WG, Grover FL, Oprian C, Rahimtoola SH. Outcomes 15 years after valve replacement with a mechanical versus a bioprosthetic valve: final report of the Veterans Affairs randomized trial. J Am Coll Cardiol 2000;36:1152–8. [44] Van der Boon RM, Nuis R-J, Van Mieghem NM, Jordaens L, Rodés-Cabau J, van Domburg RT, et al. New conduction abnormalities after TAVI — frequency and causes. Nat Rev Cardiol 2012;9:454–63. [45] Bourantas C V, van Mieghem NM, Farooq V, Soliman OI, Windecker S, Piazza N, et al. Future perspectives in transcatheter aortic valve implantation. Int J Cardiol. 2013;In press. [46] Schmidt D, Dijkman PE, Driessen-Mol A, Stenger R, Mariani C, Puolakka A, et al. Minimally-invasive implantation of living tissue engineered heart valvesa comprehensive approach from autologous vascular cells to stem cells. J Am Coll Cardiol 2010;56:510–20. [47] Faza N, Kenny D, Kavinsky C, Amin Z, Heitschmidt M, Hijazi ZM. Singlecenter comparative outcomes of the edwards SAPIEN and medtronic melody transcatheter heart valves in the pulmonary position. Catheter Cardiovasc Interv. 2013;In Press. [48] Shuto T, Kondo N, Dori Y, Koomalsingh KJ, Glatz AC, Rome JJ, et al. Percutaneous transvenous melody valve-in-ring procedure for mitral valve replacement. J Am Coll Cardiol 2011;58:2475–80. [49] Cheung AW, Gurvitch R, Ye J, Wood D, Lichtenstein SV, Thompson C, et al. Transcatheter transapical mitral valve-in-valve implantations for a failed bioprosthesis: a case series. J Thorac Cardiovasc Surg 2011;141:711–5.
Contents lists available at ScienceDirect
Cardiovascular Pathology
Innovative Cardiovascular Pathology, Pathobiology, Interventions, and Technologies
Transcatheter aortic valve implantation: status and challenges Gregory A. Fishbein a,⁎, Frederick J. Schoen b, Michael C. Fishbein a a b
Department of Pathology and Laboratory Medicine David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, CHS 13–145, Los Angeles, CA 90095–1732 Department of Pathology Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115
a r t i c l e
i n f o
Article history: Received 28 May 2013 Received in revised form 19 August 2013 Accepted 1 October 2013 Keywords: Aortic valve Transcatheter valve implantation Prosthetic valve Aortic stenosis Valvular disease
a b s t r a c t Calcific aortic valve disease of the elderly is the most prevalent hemodynamically-significant valvular disease, and the most common lesion requiring valve replacement in industrialized countries. Transcatheter aortic valve implantation is a less invasive alternative to classical aortic valve replacement that can provide a therapeutic option for high-risk or inoperable patients with aortic stenosis. These devices must be biocompatible, have excellent hemodynamic performance, be easy to insert, be securely anchored without sutures, and be durable, without increased risk of thrombosis or infection. To date, complications are related to the site of entry for insertion, the site of implantation (aorta, coronary ostia, base of left ventricle), and to the structure and design of the inserted device. However, as with any novel technology unanticipated complications will develop. Goals for future development will be to make the devices more effective, more durable, safer, and easier to implant, so as to further improve outcome for patients with severe aortic stenosis. The pathologist participating in research and development, and examination of excised devices will have a critical role in improving outcome for these patients. © 2014 Elsevier Inc. All rights reserved.
1. Summary Transcatheter aortic valve implantation (TAVI) is a less invasive alternative to classical aortic valve replacement that can provide a therapeutic option for high-risk or inoperable patients with aortic stenosis. The pathologist participating in research and development and the examination of excised devices will have a critical role in improving outcome for these patients. 2. The problem Calcific aortic valve disease, exemplified by its advanced clinical manifestation, calcific aortic stenosis (AS) (a.k.a. aortic stenosis of the elderly) is the most prevalent hemodynamically-significant valvular disease in the industrialized world. Calcific AS is also the most common lesion requiring valve replacement in industrialized countries. Calcification of the aortic valve is present in more than 50% of people over 85 years old [1]. Among octogenarians, AS has been reported in as many as 8.1% of individuals [2]. The aortic valve undergoes fibrosis and calcification due to a complex interplay of shear stress, inflammatory processes, altered lipid metabolism, and abnormalities in endothelial cell structure and function [3,4]. Calcification of the aortic valve and aortic stenosis are associated with risk factors for atherosclerosis, including aging, hypertension, diabetes mellitus, elevated low-density lipoprotein, and smoking. Recent genome-wide association studies have impli⁎ Corresponding author. Tel.: +1 310 825 5719; fax: +1 310 267 2058. E-mail address: gfi[email protected] (G.A. Fishbein). 1054-8807/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.carpath.2013.10.001
cated genetic polymorphisms associated with aortic valve calcification [5]. While these findings elucidate potential therapeutic targets, currently there is no effective medical therapy for calcific AS. Once patients become symptomatic with chest pain, syncope, or evidence of congestive heart failure, short-term mortality rates are extremely high [2]. Once diagnosed with AS, there is an 80% risk of congestive heart failure, aortic valve replacement, or death over five years [6]. Fortunately, overall, surgical outcome is excellent, even among octogenarians. Accordingly, the teaching has been that there is virtually no contraindication to valve replacement for AS in a patient expected to survive the surgery, as valve replacement surgery outcomes are generally very good and un-operated patient mortality is unacceptably high. However, as the population is aging and patients have more and more comorbidity, there are patients who are unlikely to survive open-heart surgery. In fact, Iung et al. [7] have shown that, in practice, surgery is denied in as many as 33% of elderly candidates. Older age and left ventricular dysfunction were the dominant features causing patients to be denied surgery. In Iung's cohort, 73% of patients age 75–80 were offered surgery. In contrast, surgery was offered to only 55% of patients age 85–90, and 0% of patients over 90. Indeed, a less invasive treatment of aortic stenosis in such patients would be of great utility. 3. The solution: transcatheter aortic valve replacement TAVI is a relatively new, less invasive alternative to classical aortic valve replacement. The rationale is to provide a therapeutic option for high-risk or inoperable patients with AS. There have already been
66
G.A. Fishbein et al. / Cardiovascular Pathology 23 (2014) 65–70
over 50,000 implants in over 40 countries [8]. A variety of prostheses are currently in use, under clinical evaluation, or in development. The devices must be capable of percutaneous or minimallyinvasive transcatheter implantation, be securely anchored within the valve orifice without sutures, and must provide acceptable biocompatibility, hemodynamic performance, and durability comparable to conventional bioprosthetic devices, without increased risk of thrombosis or infection. Two models of prosthetic devices comprise the first generation of implantable valves: the Edwards SAPIEN prosthesis (Edwards Lifescience, Irvine, CA, USA) and the Medtronic CoreValve ReValving system (Medtronic Inc, Minneapolis, MN, USA). Both employ trileaflet tissue valves mounted on a compressible metallic stent. Both are designed to function similarly, though notable differences in construction and delivery mechanisms exist. The Edwards SAPIEN valve is constructed from bovine pericardium, preserved in gluteraldehyde, affixed to a stainless steel stent frame. The valve is compressed onto a balloon catheter which is rapidly inflated and then deflated, expanding and releasing the device. This serves to passively secure the prosthesis to the underlying native valve leaflets. In contrast, the CoreValve is composed of bovine, and later porcine, pericardium tissue valve, mounted in a self-expanding Nitinol stent. The switch from bovine to porcine tissue was motivated by decreased thickness of porcine pericardium, allowing for a lower profile compressed device [9]. Valves may be introduced via catheter antegrade, through a transseptal or left ventricular apical approach, or retrograde, from a peripheral artery or the ascending aorta. These procedures are minimally invasive and do not typically require extracorporal circulation or cardioplegia. The transapical and transaortic approaches are more invasive, requiring a left minithoracotomy. These approaches are usually reserved for patients with severe peripheral vascular disease [10]. The transvenous, antegrade transseptal approach was primarily employed in early experiences with TAVI [11] and has fallen out of favor due to its complexity and associated complications; its contemporary use has been suggested in patients with no other access [12]. When the prosthetic valve is implanted through a catheter, the patient's native aortic valve must be pushed aside, compressed against the aortic root (Fig. 1A & B). Delivery and positioning may be challenging, and are not without complications (to be discussed). Accurate assessment of aortic valvular size must be done by transesophageal echocardiography, computed tomography, and/or magnetic resonance imaging [8]. The evaluation, treatment and long-term care of the candidate for TAVI is complex and best performed by a multidisciplinary team with specialized procedural rooms in centers of expertise [8]. In spite of the presence of the heavily calcified native valve, hemodynamic performance after TAVI is excellent with low transaortic systolic gradients of ≤10 mm Hg and valve orifice areas between 1.2 and 1.9 cm 2 [13]. Aortic insufficiency (AI), while uncommon after classical aortic valve replacement, is common after TAVI and is an accepted complication [14,15]. This AI is usually due to paravalvular leaks, as it is usually not possible to have a complete annular seal due to the nodules of calcium present in the native valve leaflets. Leaks, even moderate in sizes, are usually well-tolerated, but the greater the leak the worse the outcome. Many skeptics cite the propensity for paravalvular leak as one of the main weaknesses of TAVI [15]. Unbehaun et al. have adopted an aggressive strategy using redilation or immediate implantation of a second valve (valve-in-valve [16]) to lower the incidence of significant valvular leaks [14]. Over a one year period, the valve-in-valve technique has been shown to be comparable to a single valve implantation in safety and efficacy [15]. Repositionable valves may be beneficial in lowering procedural complications due to severe paravalvular leaks [17]. Furthermore, newer devices designed to minimize paravalvular leaks are emerging rapidly. Complications associated directly with the tissue leaflets
would be expected to be similar to those in bioprosthetic valves implanted surgically (Fig. 1C–E). There have been a number of clinical trials from different countries, including randomized trials comparing TAVI to classical aortic valve replacement [18–22]. The consensus of these studies is that TAVI is not inferior to classical aortic valve replacement in terms of procedure “success” and short-term morbidity and mortality. Longterm survival is primarily limited by comorbidities in this elderly group of patients–death is often due to severe renal, pulmonary, or non-valvular heart disease.
4. Complications As with any new procedure, TAVI will be associated with predictable as well as unanticipated complications. Safety and efficacy are best evaluated through large clinical trials with standardized reporting of outcomes and complications to large registries [23,24]. Vascular complications: vascular events are the most common complications of the procedure and contribute to procedural mortality. This is particularly true of the transfemoral approach [25]; the risk is greatest in patients with significant peripheral vascular disease [26]. Vascular injury is related to the large-caliber sheaths used for device deployment. The resulting vascular injury may lead to significant bleeding at the insertion site, sometimes requiring transfusion, and even death. Embolic risk to the brain or other organs is present in patients with extensive peripheral vessel or aortic atherosclerosis (see stroke below). As smaller, lower-profile systems are developed, serious vascular injuries are expected to occur less frequently. Vascular complications can be avoided in high-risk patients by an antegrade transapical approach. This is a more invasive procedure, requiring a left anterolateral minithoracotomy. Bleeding at the apical puncture site, pseudoaneurysm, aneurysm, and new apical hypo-/akinesia are potential complications of this approach. Reexploration due to postoperative thoracic bleeding has been reported in up to 14% of transapical implantations [27]. Renal complications: a rise in creatinine following TAVI has been reported in 5–28% of cases [28]. However, renal function often improves with the increase in cardiac output. Coronary artery complications (Fig. 1F and G): The elderly patients that are candidates for TAVI generally have some degree of atherosclerotic coronary artery disease (CAD). The presence of severe CAD increases procedural risks and must be dealt with before the procedure. Calcific fragments of the native valve may break off and embolize, causing coronary occlusion. The coronary ostia can be blocked by the device. The risk is dependent on anatomic factors, such as unusually heavy calcification of the aortic valve or aortic root, or low coronary ostia, as well as the design and placement of the device. Coronary obstruction is a complication of high implantation [29]. In addition, it is more frequently associated with balloonexpandable devices [30]. Conduction system complications (Fig. 2A–C): The conduction system passes through the interventricular septum immediately below the aortic valve. Hence, injury to this region during valve placement may cause or worsen conduction disorders. New-onset bundle branch block following TAVI has been reported in up to 45% of patients, according to early reports [23]. Conduction system complications are more frequently associated with self-expandable devices. Fraccaro et al. reported an extraordinary 77% of patients receiving third generation self-expandable devices developed new or worsening conduction abnormalities; 39% of these patients required inhospital permanent pacemaker implantation [31]. The most common new conduction disorders were left bundle branch block and firstdegree AV (atrioventricular) block. Predictors of permanent pacemaker implantation included pre-existing right bundle branch block and increased depth of prosthesis implantation.
G.A. Fishbein et al. / Cardiovascular Pathology 23 (2014) 65–70
67
Fig. 1. (A) Valve in situ. Note that the heavily calcified native aortic valve has been pushed aside, but there were no paravalvular leaks. (B) Heavily calcified native aortic valve that has been pressed against the aortic root. Compression of the native valve can cause embolization of calcific debris or blockage of coronary ostia if the valve is positioned low in the sinuses of Valsalva (AV=aortic valve, and MV=mitral valve). (C) Inflow surface of valve with granular deposits on the bioprosthetic leaflets. (D) Trichrome stain showing mural thrombus (T) on the valve leaflet (VL) (original magnification ×40). (E) Hematoxylin and eosin stain showing host mononuclear and multinucleated (arrow) cells on surface of leaflet (original magnification ×400). (F) Probe from proximal right coronary artery (RCA) into aorta showing no obstruction; however, Panel G shows that the probe is going through the struts of the stent, rather than above the stent. This is not an optimal placement since fibrosis and/or thrombosis of the stent could obstruct the coronary ostium.
Myocardial injury: TAVI is commonly associated with some myocardial injury, as assessed by CK-MB and cTnT release. RodésCabau et al. found some myocardial injury in 97% of patients in whom a transfemoral approach was utilized [32]. Myocardial injury, judged by elevated cardiac biomarkers, was inversely correlated to improvement in ejection fraction and directly proportional to post-procedural cardiac mortality. In that study, the pathogenesis of the myocardial injury was not clarified. Stroke: stroke during or after TAVI may occur from thromboemboli, aortic injury (e.g. dissection or atheroemboli), hypotension, hemorrhage, or dislodgement of calcific fragments during valvuloplasty. Given that TAVI is intended for individuals who are poor surgical candidates, it is not surprising that many have comorbidities that increase the risk of thrombosis and stroke. In recent investiga-
tions, 11% patients in this high-risk population had pre-existing intracardiac thrombi [33]. An additional 24% had high-grade left atrial spontaneous echo contrast (SEC) detected by transesophageal echo. SEC is an indicator of blood stasis and a well-established predictor of cardioembolic stroke [34–36]. Not surprisingly, individuals most at risk included those with a history of atrial fibrillation, severe diastolic dysfunction, and/or left atrial or ventricular hypertrophy. Mitral valve complications: mitral valve complications were first reported in early experiences with the antegrade transseptal approach [11]. Injury may occur as the device passes by the anterior leaflet during delivery. The catheter may be passed under the mitral chordae if the transapical approach is employed. Regardless of the approach, the ventricular end of the prosthesis may contact the anterior curtain of the mitral valve [37]. Placement of the device too
68
G.A. Fishbein et al. / Cardiovascular Pathology 23 (2014) 65–70
Fig. 2. (A) View of left ventricular outflow tract (LVOT) after valve has been removed. Note erosion of the endocardial surface from the inferior portion of the metallic stent (arrow). Injury in and around this region has the potential to cause complete or bundle branch heart block. (B) The bundle of His (BH) is intact. There is calcification in the base of the septum (C), and there is fibrous thickening (F) of the endocardium of the left ventricular outflow tract and myocardium (hematoxylin and eosin stain; original magnification ×40). (C) Symmetric valve with proper coaptation of the leaflets. (D) Distortion of valve resulting in loss of complete coaptation with resulting regurgitation.
far into the left ventricle may interfere with movement of the anterior mitral leaflet [38]. Risk factors related to aortic valve pathology: The underlying aortic valve pathology is an important determinant of potential complications. Eccentric valvular calcification, heavy annular calcification, and a high degree of left ventricular outflow tract angulation predispose to paravalvular leaks [39]. Patients with bulky valvular calcification, small sinotubular junction, small aortic annulus, and “porcelain” aorta are at increased risk of annular rupture. Severe LV hypertrophy, subaortic stenosis, and combined AS/AI are risk factors for acute hemodynamic compromise and shock.
5. Outcome The safety and efficacy of TAVI in high-risk patients have been established in single-arm and randomized controlled studies. Gilard et al. reported on 3195 patients from 34 centers in the French national transcatheter aortic valve implantation registry, FRANCE 2 [22]. The mean age of patients was 82.7 years; half were women. Overall procedural success rate was 96.9%. Death rates at 30 days were 9.7%, and at one year 24.0%. The incidence of stroke at one year was 4.1%. The incidence of paravalvular leak was 64.5%. The use of a transapical approach and a greater degree of regurgitation were associated with reduced survival. Smith et al. performed a randomized control study assigning 699 high-risk patients to either TAVI or surgical replacement [20]. Death rates from any cause in the TAVI group were 3.4% and 24.2% at 30 days and one year respectively, while in the surgical group, death rates were 6.5% and 26.8% at 30 days and one year respectively. More patients in the TAVI group had an improvement in symptoms at 30 days, but there was no difference at 1 year.
More recently, Kodali et al. reported on the two year outcome of the same cohort of 699 patients [21]. At 2 years, TAVI and surgical treatment were similar in mortality, improved symptomatology, and improved hemodynamics. Paravalvular regurgitation was more common after TAVI, and associated with an increase in late mortality. 6. Pathologic evaluation of TAVI patients As with any new procedure, pathologic evaluation is the ultimate quality assurance tool to assess efficacy and complications in patients who die either early or late after TAVI, or in those whose valves are revised surgically. The knowledge ascertained by pathologic evaluation is critical for optimal design of future procedures and equipment. Furthermore, such knowledge helps clinicians anticipate and recognize complications in current patients. At autopsy, in patients who had undergone TAVI through an arterial approach, the access site should be carefully examined for vascular injury and hemorrhage. If bleeding occurs from a femoral artery site, blood will track into the retroperitoneal tissues. This bleeding can be missed if the prosector is merely looking in the peritoneal cavity or lower extremity. Also, considerable bleeding may occur in muscle or adipose tissue; thus, measurement of liquid blood alone will underestimate the blood loss. If a transapical approach has been used, there is the potential for damage to the distal left anterior descending (LAD) artery. Therefore, it is important to document the status of the LAD and myocardium it supplies. Since a device will be present in the aortic position, opening the heart according to flow through that area is not possible. So the outflow surface of the valve can be visualized, the aorta should be transected about one centimeter above the palpable distal end of the prosthesis. This may be 1–3 cm above the sino-tubular junction. The
G.A. Fishbein et al. / Cardiovascular Pathology 23 (2014) 65–70
aorta itself should be carefully inspected for evidence of dissection or disruption of atherosclerotic plaques that could be the source of athero- or thromboemboli. Evaluation of the status of the coronary ostia is critical, as there can be blockage of the ostia by the device, embolic material, or the compressed, heavily calcified native aortic valve. Prior to any significant manipulation, the heart and device should be evaluated by X-ray in two planes, so as to document the location and status of the prosthesis and to evaluate for any wire fractures. The ventricles should be sliced transversely, again as close to the aortic valve as possible, to view the inflow surface of the implanted device. The myocardium should be inspected for recent and/or old ischemic injury. The degree of hypertrophy and dilation (wall thickness, heart weight) may shed some insight into the degree of valvular stenosis and/or regurgitation that might exist. The valve should first be examined in situ. The position should be noted with attention to whether there may be contact with the aorta and/or myocardium of the left ventricular outflow tract that could impact the conduction system. Often the valve can be seen and felt through the right atrial wall where it is adjacent to the aortic root. The valve leaflets should be examined for thrombi and/or vegetations in the early post-procedural period. After longer implant periods, host connective tissue overgrowth (pannus), calcification, fibrosis, and degeneration (tears, perforations) may be noted. A probe should be used to look for space between the device and aorta, indicative of paravalvular regurgitation. The shape of the device should be noted– round versus oval–as distortion of the device associated with inadequate coaptation of the leaflets has been reported [40] (Fig. 2C & D). Once the device is removed, the leaflets may be sampled for microscopic examination. Histologic examination is crucial in evaluation of possible traumatic leaflet injury, as collagen fiber fragmentation and disruption may be present even in the absence of macroscopic findings [41]. This is particularly true of balloonexpandable devices. The implantation site can then be examined for thrombi and vegetations. It is fascinating to see how the heavily calcified native aortic valve can be compressed against the aortic wall. The conduction system can then be dissected and submitted for histologic examination; the conduction tissue may be of interest in patients who have developed conduction block. Liberal use of photographs to document findings is encouraged. A complete autopsy is indicated so other organs can be assessed for emboli and resulting ischemic lesions, especially the brain. 7. Challenges 7.1. Long term durability As TAVI is a relatively new therapy, long-term data regarding prosthesis durability are currently unavailable. At the time of the first human implantation, the original bovine pericardial valve withstood ex-vivo durability testing of 100 million cycles (2.5 years) [11]. Reports of mid-term evaluation (2–3 years following implantation) show no significant structural degradation, leaflet thickening, calcification, thrombus formation, or change in transvalvular pressure gradient from baseline [19,21,42]. While long-term TAVI data are still being collected, studies of surgically implanted bioprosthetic aortic valves demonstrate that primary valve failure begins at 7–8 years [43]. Whether these data are predictive of long-term TAVI prostheses durability remains to be seen. 7.2. New developments New devices are in development to address the specific complications of TAVI. Second generation prostheses are made to be repositionable and retrievable or to provide better sealing without the potential for migration to allow optimal deployment, reducing paravalvular leak, valve migration, and conduction disturbance [44].
69
Cerebral protection devices, similar to those utilized in carotid procedures, are being evaluated to reduce the risk of stroke [45]. Valves are being miniaturized, reducing the rate of vascular complications, particularly from a peripheral approach. Smaller, lower profile valves minimize contact with surrounding tissue, reducing the risk of conduction disturbance and coronary ostial occlusion. Schmidt et al. have demonstrated the minimally-invasive implantation of autologous tissue engineered heart valves in vivo [46]. These living tissue valves may have regenerative properties protective of calcification and progressive degeneration, as seen in conventional bioprosthetic valves. 7.3. Other percutaneous valves Currently, the greatest need, in terms of numbers of patients, and the greatest experience, in terms of number of valves implanted, is for aortic valve devices. However, need and experience exist for replacement of other valves. Indeed, for pulmonary valve replacement two systems exist, the Medtronic Melody (Medtronic Inc. Minneapolis, MN) and the Edwards SAPIEN (Edwards LifeSciences, Irvine, CA). Both systems have been tested in humans and have been demonstrated efficacious in reducing right ventricular outflow tract pressure gradient without significant regurgitation [47]. The majority of data come from short term studies, so longer term studies are needed to determine durability, and preserved hemodynamic efficacy. Mitral regurgitation is another common valvular abnormality that would be best approached by minimally-invasive procedures. Indeed, repairs, while often imperfect, can be accomplished by transcatheter closed-chest placement of an annuloplasty ring or by partial closure of the mitral valve with a suture or clip. However, recurrence of mitral regurgitation after such repair is not uncommon. The feasibility of transcatheter mitral valve replacement has been demonstrated in a large animal model [48]. In addition, in patients with a failed bioprosthetic valve in the mitral position, a valve-in-valve transcatheter approach has been reported with encouraging results [49]. There is no question that there will continue to be efforts to develop and implement transcatheter approaches for a variety of valvular disorders. 7.4. Future directions TAVI is a relatively new procedure, with implantation techniques and devices under evaluation and development. Yet, one could argue that TAVI is already the established therapy for high-risk patients with aortic stenosis. It is expected that future developments in minimallyinvasive and percutaneous therapy may deprecate surgical valve replacement altogether. References [1] O'Brien KD. Epidemiology and genetics of calcific aortic valve disease. J Invest Med 2007;55:284–91. [2] Likosky DS, Sorensen MJ, Dacey LJ, Baribeau YR, Leavitt BJ, DiScipio AW, et al. Longterm survival of the very elderly undergoing aortic valve surgery. Circulation 2009;120:S127–33. [3] Goldbarg SH, Elmariah S, Miller MA, Fuster V. Insights into degenerative aortic valve disease. J Am Coll Cardiol 2007;50:1205–13. [4] Rajamannan NM, Evans FJ, Aikawa E, Grande-Allen KJ, Demer LL, Heistad DD, et al. 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;124:1783–91. [5] Thanassoulis G, Campbell CY, Owens DS, Smith JG, Smith AV, Peloso GM, et al. Genetic associations with valvular calcification and aortic stenosis. N Engl J Med 2013;368:503–12. [6] Otto CM, Burwash IG, Legget ME, Munt BI, Fujioka M, Healy NL, et al. Prospective study of asymptomatic valvular aortic stenosis: clinical, echocardiographic, and exercise predictors of outcome. Circulation 1997;95:2262–70. [7] Iung B, Cachier A, Baron G, Messika-Zeitoun D, Delahaye F, Tornos P, et al. Decision-making in elderly patients with severe aortic stenosis: why are so many denied surgery? Eur Heart J 2005;26:2714–20.
70
G.A. Fishbein et al. / Cardiovascular Pathology 23 (2014) 65–70
[8] Webb JG, Wood DA. Current status of transcatheter aortic valve replacement. J Am Coll Cardiol 2012;60:483–92. [9] Chiam PTL, Ruiz CE. Percutaneous transcatheter aortic valve implantation: evolution of the technology. Am Heart J 2009;157:229–42. [10] Zajarias A, Cribier AG. Outcomes and safety of percutaneous aortic valve replacement. J Am Coll Cardiol 2009;53:1829–36. [11] Cribier A, Eltchaninoff H, Bash A, Borenstein N, Tron C, Bauer F, et al. Percutaneous transcatheter implantation of an aortic valve prosthesis for calcific aortic stenosis: first human case description. Circulation 2002;106:3006–8. [12] Cohen MG, Singh V, Martinez CA, O'Neill BP, Alfonso CE, Martinezclark PO, et al. Transseptal antegrade transcatheter aortic valve replacement for patients with no other access approach — a contemporary experience. Catheter Cardiovasc Interv. 2013;In press. [13] Webb J, Cribier A. Percutaneous transarterial aortic valve implantation: what do we know? Eur Heart J 2011;32:140–7. [14] Unbehaun A, Pasic M, Dreysse S, Drews T, Kukucka M, Mladenow A, et al. Transapical aortic valve implantation: incidence and predictors of paravalvular leakage and transvalvular regurgitation in a series of 358 patients. J Am Coll Cardiol 2012;59:211–21. [15] Généreux P, Head SJ, Hahn R, Daneault B, Kodali S, Williams MR, et al. Paravalvular leak after transcatheter aortic valve replacement: the new achilles' heel? A comprehensive review of the literature. J Am Coll Cardiol 2013;61. [16] Ussia GP, Mulè M, Tamburino C. The valve-in-valve technique: transcatheter treatment of aortic bioprothesis malposition. Catheter Cardio Inte 2009;73:713–6. [17] Willson AB, Rodès-Cabau J, Wood DA, Leipsic J, Cheung A, Toggweiler S, et al. Transcatheter aortic valve replacement with the St. Jude Medical Portico valve: first-in-human experience. J Am Coll Cardiol 2012;60:581–6. [18] Pasic M, Unbehaun A, Dreysse S, Drews T, Buz S, Kukucka M, et al. Transapical aortic valve implantation in 175 consecutive patients: excellent outcome in very high-risk patients. J Am Coll Cardiol 2010;56:813–20. [19] Buellesfeld L, Gerckens U, Schuler G, Bonan R, Kovac J, Serruys PW, et al. 2-year follow-up of patients undergoing transcatheter aortic valve implantation using a self-expanding valve prosthesis. J Am Coll Cardiol 2011;57:1650–7. [20] Smith C, Leon M, Mack M. Transcatheter versus surgical aortic-valve replacement in high-risk patients. N Engl J Med 2011;364:2187–98. [21] Kodali SK, Williams MR, Smith CR, Svensson LG, Webb JG, Makkar RR, et al. Twoyear outcomes after transcatheter or surgical aortic-valve replacement. N Engl J Med 2012;366:1686–95. [22] Gilard M, Eltchaninoff H, Iung B, Donzeau-Gouge P, Chevreul K, Fajadet J, et al. Registry of transcatheter aortic-valve implantation in high-risk patients. N Engl J Med 2012;366:1705–15. [23] Leon MB, Piazza N, Nikolsky E, Blackstone EH, Cutlip DE, Kappetein AP, et al. Standardized endpoint definitions for transcatheter aortic valve implantation clinical trials: a consensus report from the valve academic research consortium. J Am Coll Cardiol 2011;57:253–69. [24] Rosengart TK, Feldman T, Borger MA, Vassiliades TA, Gillinov AM, Hoercher KJ, et al. Percutaneous and minimally invasive valve procedures: a scientific statement from the American Heart Association Council on Cardiovascular Surgery and Anesthesia, Council on Clinical Cardiology, Functional Genomics and Translational Biology Interdisciplin. Circulation 2008;117:1750–67. [25] Wenaweser P, Pilgrim T, Roth N, Kadner A, Stortecky S, Kalesan B, et al. Clinical outcome and predictors for adverse events after transcatheter aortic valve implantation with the use of different devices and access routes. Am Heart J 2011;161:1114–24. [26] Kahlert P, Al-Rashid F, Weber M, Wendt D, Heine T, Kottenberg E, et al. Vascular access site complications after percutaneous transfemoral aortic valve implantation. Herz 2009;34:398–408. [27] Bleiziffer S, Ruge H, Mazzitelli D, Hutter A, Opitz A, Bauernschmitt R, et al. Survival after transapical and transfemoral aortic valve implantation: talking about two different patient populations. J Thorac Cardiovasc Surg 2009;138:1073–80. [28] Bagur R, Webb JG, Nietlispach F, Dumont E, De Larochellière R, Doyle D, et al. Acute kidney injury following transcatheter aortic valve implantation: predictive factors, prognostic value, and comparison with surgical aortic valve replacement. Eur Heart J 2010;31:865–74. [29] Laborde J-C, Brecker SJD, Roy D, Jahangiri M. Complications at the time of transcatheter aortic valve implantation. Methodist Debakey Cardiovasc J 2012;8:38–41.
[30] Ribeiro HB, Nombela-Franco L, Urena M, Mok M, Pasian S, Doyle D, et al. Coronary obstruction following transcatheter aortic valve implantation: a systematic review. J Am Coll Cardiol Intv 2013;6:452–61. [31] Fraccaro C, Buja G, Tarantini G, Gasparetto V, Leoni L, Razzolini R, et al. Incidence, predictors, and outcome of conduction disorders after transcatheter selfexpandable aortic valve implantation. Am J Cardiol 2011;107:747–54. [32] Rodés-Cabau J, Gutiérrez M, Bagur R, De Larochellière R, Doyle D, Côté M, et al. Incidence, predictive factors, and prognostic value of myocardial injury following uncomplicated transcatheter aortic valve implantation. J Am Coll Cardiol 2011;57: 1988–99. [33] Lenders GD, Paelinck BP, Wouters K, Claeys MJ, Rodrigus IE, Van Herck PL, et al. Transesophageal echocardiography for cardiac thromboembolic risk assessment in patients with severe, symptomatic aortic valve stenosis referred for potential transcatheter aortic valve implantation. J Am Coll Cardiol. 2013; In Press. [34] Lee RJ, Bartzokis T, Yeoh TK, Grogin HR, Choi D, Schnittger I. Enhanced detection of intracardiac sources of cerebral emboli by transesophageal echocardiography. Stroke 1991;22:734–9. [35] Fatkin D, Kelly RP, Feneley MP. Relations between left atrial appendage blood flow velocity, spontaneous echocardiographic contrast and thromboembolic risk in vivo. J Am Coll Cardiol 1994;23:961–9. [36] Erbel R, Stern H, Ehrenthal W, Schreiner G, Treese N, Meyer J, et al. Detection of spontaneous echocardiographic contrast within the left atrium by transesophageal echocardiography: spontaneous echocardiographic contrast. Clin Cardiol 1986;9:245–52. [37] Masson J-B, Kovac J, Schuler G, Ye J, Cheung A, Kapadia S, et al. Transcatheter aortic valve implantationreview of the nature, management, and avoidance of procedural complications. JACC Cardiovasc Interv 2009;2:811–20. [38] Wong DR, Boone RH, Thompson CR, Allard MF, Altwegg L, Carere RG, et al. Mitral valve injury late after transcatheter aortic valve implantation. J Thorac Cardiovasc Surg 2009;137:1547–9. [39] Holmes David RJ, Mack MJ, Kaul S, Agnihotri A, Alexander KP, Bailey SR, et al. ACCF/AATS/SCAI/STS expert consensus document on transcatheter aortic valve replacement. J Am Coll Cardiol 2012;59:1200–54. [40] Zegdi R, Ciobotaru V, Noghin M, Sleilaty G, Lafont A, Latrémouille C, et al. Is it reasonable to treat all calcified stenotic aortic valves with a valved stent? Results from a human anatomic study in adults. J Am Coll Cardiol 2008;51:579–84. [41] Zegdi R, Bruneval P, Blanchard D, Fabiani J-N. Evidence of leaflet injury during percutaneous aortic valve deployment. Eur J Cardiothorac Surg 2011;40:257–9. [42] Gurvitch R, Wood DA, Tay EL, Leipsic J, Ye J, Lichtenstein SV, et al. Transcatheter aortic valve implantation: durability of clinical and hemodynamic outcomes beyond 3 years in a large patient cohort. Circulation 2010;122:1319–27. [43] Hammermeister K, Sethi GK, Henderson WG, Grover FL, Oprian C, Rahimtoola SH. Outcomes 15 years after valve replacement with a mechanical versus a bioprosthetic valve: final report of the Veterans Affairs randomized trial. J Am Coll Cardiol 2000;36:1152–8. [44] Van der Boon RM, Nuis R-J, Van Mieghem NM, Jordaens L, Rodés-Cabau J, van Domburg RT, et al. New conduction abnormalities after TAVI — frequency and causes. Nat Rev Cardiol 2012;9:454–63. [45] Bourantas C V, van Mieghem NM, Farooq V, Soliman OI, Windecker S, Piazza N, et al. Future perspectives in transcatheter aortic valve implantation. Int J Cardiol. 2013;In press. [46] Schmidt D, Dijkman PE, Driessen-Mol A, Stenger R, Mariani C, Puolakka A, et al. Minimally-invasive implantation of living tissue engineered heart valvesa comprehensive approach from autologous vascular cells to stem cells. J Am Coll Cardiol 2010;56:510–20. [47] Faza N, Kenny D, Kavinsky C, Amin Z, Heitschmidt M, Hijazi ZM. Singlecenter comparative outcomes of the edwards SAPIEN and medtronic melody transcatheter heart valves in the pulmonary position. Catheter Cardiovasc Interv. 2013;In Press. [48] Shuto T, Kondo N, Dori Y, Koomalsingh KJ, Glatz AC, Rome JJ, et al. Percutaneous transvenous melody valve-in-ring procedure for mitral valve replacement. J Am Coll Cardiol 2011;58:2475–80. [49] Cheung AW, Gurvitch R, Ye J, Wood D, Lichtenstein SV, Thompson C, et al. Transcatheter transapical mitral valve-in-valve implantations for a failed bioprosthesis: a case series. J Thorac Cardiovasc Surg 2011;141:711–5.
