Proefschrift Wollersheim by Nicole Nijhuis

UITNODIGING Aortic Valve Replacement and the Stentless Freedom Solo Valve

Aortic Valve Replacement and the Stentless Freedom Solo Valve Laurens W.L.M. Wollersheim

Voor het bijwonen van de openbare verdediging van het proefschrift

Aortic Valve Replacement and the Stentless Freedom Solo Valve door

Laurens Wollersheim op vrijdag 10 juni 2016 om 14:00 uur

Laurens W.L.M. Wollersheim

Agnietenkapel Ouderzijds Voorburgwal 231 te Amsterdam Na afloop bent u van harte uitgenodigd voor de receptie ter plaatse

Laurens Wollersheim laurenswollersheim@gmail.com

2016

Paranimfen: Niels Pijnenburg

n.pijnenburg@outlook.com

Kaj Lambers

ktalambers@gmail.com

Aortic valve replacement and the stentless Freedom SOLO valve

Laurens W.L.M. Wollersheim

Dit proefschrift werd mede mogelijk gemaakt door: LivaNova Nederland NV, Universiteit van Amsterdam, MAQUET Financieel: Netherlands, BISLIFE Foundation, Krijnen Medical Innovations BV, ABN Amro Bank, de Nederlandse Hartstichting Omslag ontwerp: Juul Alewijnse & Johan Manshanden Grafische vormgeving en druk: Gildeprint Enschede ISBN: 978-94-6233-293-5 Het verschijnen van dit proefschrift werd mede mogelijk gemaakt door de steun van de Nederlandse Hartstichting

Aortic valve replacement and the stentless Freedom SOLO valve ACADEMISCH PROEFSCHRIFT ter verkrijging van de graad van doctor aan de Universiteit van Amsterdam op gezag van de Rector Magnificus prof. dr. D.C. van den Boom ten overstaan van een door het College voor Promoties ingestelde commissie, in het openbaar te verdedigen in de Agnietenkapel op vrijdag 10 juni 2016, te 14.00 uur door

Laurens Willem Lodewijk Maria Wollersheim geboren te Nijmegen

PROMOTIECOMMISSIE: Promotor:

prof. mr. dr. B.A.J.M. de Mol

Universiteit van Amsterdam

Copromotores:

dr. W.J.P. van Boven dr. A. Kaya

Universiteit van Amsterdam Universiteit van Amsterdam

Overige leden:

prof. dr. J.J. Piek prof. dr. R.J. de Winter prof. dr. B. Preckel prof. dr. W.J. Morshuis prof. dr. M.G. Hazekamp dr. M.A.A.M. Schepens

Universiteit van Amsterdam Universiteit van Amsterdam Universiteit van Amsterdam Radboud Universiteit Universiteit Leiden Universiteit van Antwerpen

Faculteit der Geneeskunde

CONTENTS Chapter 1

Introduction

Chapter 2

Current status of surgical treatment for aortic valve stenosis Journal of Cardiac Surgery 2014;29:630-7

Chapter 3

Aortic valve replacement with the Freedom SOLO valve â&#x20AC;&#x201C; a systematic review The Annals of Thoracic Surgery 2015;100:1496-504

Chapter 4

Midterm follow-up of the stentless Freedom SOLO bioprosthesis in 350 patients The Annals of Thoracic Surgery 2016: in press

Chapter 5

Stentless versus stented aortic valve bioprostheses in the small aortic root Seminars in Thoracic and Cardiovascular Surgery 2016: in press

Chapter 6

4D flow MRI of stentless and stented aortic valve bioprostheses Manuscript in preparation

Chapter 7

When not to go SOLO? Contraindications based on implant experience Submitted Journal of Cardiac Surgery

Chapter 8

Solutions for a degenerated Freedom SOLO

-Transapical JenaValve in a degenerated Freedom SOLO bioprosthesis The Journal of Thoracic and Cardiovascular Surgery 2014;148:741-2

-A torn Freedom SOLO bioprosthesis (case report) Interactive Cardiovascular and Thoracic Surgery 2014;18:141-2

105

Chapter 9

Discussion

113

Chapter 10

Summary / Samenvatting

127

Acknowledgements / Dankwoord Curriculum Vitae

141 147

CHAPTER 1 Introduction

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8 | Chapter 1

Introduction | 9

Background The two most common indications for aortic valve replacement are aortic valve stenosis and aortic valve insufficiency [1, 2]. Aortic valve stenosis has become the most prevalent valvular heart disease in Europe and North America, and is generally caused by age-related calcification of the aortic valve [3]. Other causes of aortic valve stenosis include congenital and rheumatic valvular disease. Aortic valve stenosis is a progressive disease. The end stage of which is characterized by left ventricular outflow obstruction resulting in inadequate cardiac output, decreased exercise capacity, heart failure, and eventually death [4]. The prevalence of aortic valve stenosis increases with the patientâ&#x20AC;&#x2122;s age from 1.3% in patients aged 60 to 69 years, to 3.9% in the patients aged 70 to 79 years, to 9.8% in the patients aged 80 to 89 years [5]. Survival during the asymptomatic period is comparable to that of the average population. However, once symptoms develop survival declines rapidly (Figure 1) [6]. For most patients, severe symptomatic aortic stenosis needs effective mechanical relief in the form of valve replacement before it becomes a lethal obstruction to outflow [3]. Aortic valve replacement improves survival and quality of life, in patients with aortic valve stenosis [7, 8]. Current European guidelines (class 1B/C) and American guidelines (class 1B) recommend aortic valve replacement for patients with symptomatic and severe aortic valve stenosis, for patients with severe aortic valve stenosis undergoing other cardiac surgery and for asymptomatic patients with severe aortic valve stenosis and impaired left ventricular function [1, 2]. As the age of the worldâ&#x20AC;&#x2122;s population increases, it has been estimated that the annual number of heart valve replacements will triple from approximately 290 000 in 2003, to over 850 000 in 2050 [9].

Figure 1. Survival of patients with aortic stenosis. Reprinted from The Lancet: Carabello BA, Paulus WJ. Aortic stenosis. Lancet 2009;373(9667):956-66, with permission from Elsevier. The original Figure is from: Ross J Jr, Braunwald E. Aortic stenosis. Circulation 1968;38(1 Suppl):61-7; with permission from Wolters Kluwer Health.

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10 | Chapter 1

History Over 100 years ago, in 1912, the French surgeon Theodore Tuffier performed the first successful aortic valve operation. In a 26-year-old male, Tuffier used his finger to push the invaginated anterior aortic wall through the stenotic aortic valve in order to dilate the valve. The patient made a full recovery and was discharged home on postoperative day 12. Eight years after the operation the patient was still alive [10, 11]. In the 1940s Russel Brock used dilators of various sizes to dilate stenotic aortic valves through a number of arterial approaches [12]. The modern balloon valvuloplasty must have been inspired by these techniques. However, mortality rates were high and valve surgery hardly seemed viable until the 1950s [13]. This changed with the development of cardiopulmonary bypass, enabling the repair of intracardiac lesions and heart valves under direct vision. Using cardiopulmonary bypass, Kirklin performed the first direct visual correction of a congenital aortic valve stenosis in 1956 [14]. The first successful aortic valve replacement in the subcoronary position was performed by Harken using a cage-ball mechanical prosthesis in 1960 [15]. From then on, the field of cardiac valve surgery exploded. By 1967 over 2000 patients had been treated with caged ball valves [13]. In the following decades, several types of mechanical valve were developed and durability, hemodynamic characteristics, and biocompatibility improved. The caged-ball valves were followed by tilting disc valves and in the 1970s the bileaflet valves became popular. In the early days of aortic valve replacement, operative mortality was 15% to 20%. Today, with improvements in perioperative care operative mortality has declined to 1% to 3% [16, 17]. Aortic valve bioprosthesis The predominant disadvantage of mechanical valves is the need for lifelong anticoagulation and the related bleeding and thromboembolic complications. Due to the increasing number of elderly patients and the enhanced durability of bioprosthetic valve prostheses, the past two decades have seen a shift from the use of mechanical valves towards bioprostheses. Nowadays, a bioprosthetic valve is used in 79% of patients undergoing aortic valve replacement [16]. The majority of the aortic valve bioprostheses used are stented bioprostheses. Three bovine or porcine pericardial valve leaflets are mounted on a stent to resemble a tri-leaflet valve (Figure 2). Stented aortic valve bioprostheses have proven themselves to be reliable with excellent long-term durability of up to 20 years [18, 19]. Although the stent facilitates easy and fast implantation, it does reduce the effective orifice area and obstructs laminar flow over the prosthesis. This can lead to higher valvular gradients over the stented bioprosthesis, less regression of left ventricular mass and mechanical stress on the bioprosthesis that may lead to structural valve deterioration. To prevent problems that may arise from an obstructing stent, the concept of stentless bioprostheses was introduced in the early 1990s. Actually this was a reintroduction since the first stentless aortic valve bioprostheses used for aortic valve replacement were donor aortic valve homografts in 1962 [20, 21]. At that time the homograft did not replace the popular mechanical prostheses as first choice for aortic valve replacement due to its limited availability and the difficult implantation technique. In the early 1990s some cardiac surgeons believed in the stentless concept of bioprostheses and that these would show a superior hemodynamic performance compared to stented bioprostheses due to the lack of an obstructing stent. Since then, several generations

Introduction | 11

of stentless bioprostheses have been developed and become commercially available. In a randomized controlled trial, the stentless Sorin Pericarbon Freedom (Sorin, Saluggia, Italy) was shown to have lower valvular gradients, a larger effective orifice area and to lead to faster regression of left ventricular mass than stented bioprostheses [22]. Also current best available evidence suggests the hemodynamic performance of stentless valves is superior to that of stented valves [23]. However, since stentless bioprostheses require two suture lines (proximal and distal), implantation was found to be technically more demanding and crossclamp times were longer [24]. Most cardiac surgeons were of the opinion that the implantation technique and prolonged crossclamp time outweighed the hemodynamic advantage and therefore the stentless bioprostheses could not replace the popular stented bioprostheses as the first option for aortic valve replacement. Nevertheless, stentless bioprostheses were found to be advantageous in specific patient groups and were used on special indication. In patients with a small aortic root or impaired left ventricular function, the excellent hemodynamic performance of the stentless bioprosthesis was found to improve perioperative outcomes and even long-term results [25, 26].

Figure 2. Mitroflow with Phospholipid Reduction Treatment, LivaNova

The Freedom SOLO bioprosthesis Although Dunning showed the Pericarbon Freedom stentless bioprosthesis to be hemodynamically superior to a stented bioprosthesis, the traditional proximal and distal suture lines of the stentless bioprostheses were still an obstacle for cardiac surgeons. The introduction of the Freedom SOLO in 2004 (Sorin, Saluggia, Italy, Figure 3), a modification of the Pericarbon Freedom, diminished the technical drawbacks of stentless bioprostheses [27]. The Freedom SOLO is implanted in the supraannular position using a single running suture line in the sinuses of Valsalva. This should make implantation time equal to that of stented bioprostheses. The Freedom SOLO allows the single suture line approach, as all the extra tissue on the inflow side has been trimmed away and the outflow side of the Pericarbon Freedom is scalloped (Figure 4) [27]. Because of supraannular implantation and stentless design, the effective orifice area is maximized which should lead to favorable hemodynamics. The Freedom SOLO consists of two sheets of bovine pericardium. The first sheet consists of three valvular cusps and the second sheet has an outflow edge that is used for the supra annular running suture line. The Freedom SOLO is manufactured by using a process that includes homocysteic acid as an anticalcification treatment to bind and neutralize free glutaraldehyde residues for prolonged durability [28].

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12 | Chapter 1

Figure 3. Freedom SOLO bioprosthesis

Figure 4. Modification from Pericarbon Freedom to Freedom SOLO. Reprinted from: Repossini A, Kotelnikov I, Bouchikhi R, Torre T, Passaretti B, Parodi O, Arena V. Single-suture line placement of a pericardial stentless valve. Journal of Thoracic and Cardiovascular Surgery 2005;130(5):1265-9, with permission from Elsevier.

Introduction | 13

Surgical Technique After institution of cardiopulmonary bypass, application of the aortic crossclamp and administration of cardioplegia, a transverse aortotomy is performed approximately 1 centimeter above the sinotubular junction. The diseased aortic valve is resected and the annulus decalcified if necessary. The aortic annular diameter is measured at the level of the aortic annulus with the manufacturerâ&#x20AC;&#x2122;s sizers. The Freedom SOLO does not have to be rinsed before implantation. Three equidistant 4-0 polypropylene sutures are placed in the nadirs of each of the sinuses of Valsalva, 2 to 3 millimeters above the aortic annulus, and subsequently through the outflow edge of the Freedom SOLO. The running sutures are continued to the top of each of the commissures and tied extra-aortically (Figure 5 and 6). The aortotomy is then closed. Lifelong antiplatelet therapy (acetylsalicylate 100 mg daily) is mandatory.

Figure 5 and 6. Implantation of a Freedom SOLO bioprosthesis

Aim of the thesis This thesis will address four main questions: 1) When should the Freedom SOLO bioprosthesis be the preferred bioprosthesis for aortic valve replacement? 2) What are the advantages and disadvantages of the Freedom SOLO bioprosthesis in certain patient groups? 3) Can the theoretical dynamic and flow advantages of stentless bioprostheses over stented bioprostheses be visualized and quantified? 4) What are the options in the event of a degenerated Freedom SOLO bioprosthesis?

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14 | Chapter 1

Outline of the thesis What influences a surgeon to use a stentless Freedom SOLO valve? This thesis addresses the hemodynamic and clinical performance of a stentless aortic valve bioprosthesis. First, a review of the current status of surgical treatment for aortic valve stenosis is presented (Chapter 2). We examine a number of surgical approaches to the aortic valve and relate these to their clinical outcomes, quality of life, costs and learning curve. In Chapter 3 we systematically review the available evidence on the Freedom SOLO bioprosthesis. The systematic review focuses on the question of whether the Freedom SOLO bioprosthesis offers the best of both worlds: if it does live up to its promise of the superior hemodynamic performance of a stentless valve combined with a simple and fast implantation technique. Subsequently Chapter 4 describes our 9-year experience in 350 consecutive patients with the Freedom SOLO bioprosthesis. Both short- and midterm clinical and echocardiographic results are presented. Extensive follow-up data was collected regarding durability and functional class of the operated patients. In Chapter 5, we investigate if the stentless Freedom SOLO has an advantage when compared with a stented bioprosthesis in patients with a small aortic root. We hypothesize that in patients with a small aortic root the hemodynamic performance of the Freedom SOLO is better than that of a stented bioprosthesis. Additionally, we examine if these differences result in fewer cardiac events. Chapter 6 shows the results of a magnetic resonance imaging study that was conducted in collaboration with our Department of Radiology. We used four-dimensional flow magnetic resonance imaging to visualize the differing flow patterns in stentless and stented aortic valve bioprostheses, and compare these with a native aortic valve in search for the most true-to-life aortic valve bioprosthesis. Chapter 7 describes the contraindications for the Freedom SOLO based on our extensive implant experience. Chapter 8 discusses the options for reintervention for a patient with a degenerated Freedom SOLO prosthesis. Chapter 9 provides a general discussion. The arguments for using, or not using the Freedom SOLO valve are discussed.

Introduction | 15

REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28.

Vahanian A, Alfieri O, Andreotti F, et al. Guidelines on the management of valvular heart disease (version 2012). Eur Heart J. 2012;33:2451-96 Nishimura RA, Otto CM, Bonow RO, et al. 2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;63:e57-185 Carabello BA, Paulus WJ. Aortic stenosis. Lancet. 2009;373:956-66 Otto CM, Prendergast B. Aortic-valve stenosis â&#x20AC;&#x201C; from patients at risk to severe valve obstruction. N Engl J Med. 2014;371:744-56 Eveborn GW, Schirmer H, Heggelund G, et al. The evolving epidemiology of valvular aortic stenosis. The TromsĂ¸ study. Heart. 2013;99:396-400 Ross J Jr, Braunwald E. Aortic stenosis. Circulation. 1968;38(1 Suppl):61-7 Schwarz F, Baumann P, Manthey J, et al. The effect of aortic valve replacement on survival. Circulation. 1982;66:1105-10 Reynolds MR, Magnuson EA, Wang K, et al. Health-related quality of life after transcatheter or surgical aortic valve replacement in high-risk patients with severe aortic stenosis: results from the PARTNER Trial. J Am Coll Cardiol. 2012;60:548-58 Yacoub MH, Takkenberg JJ. Will heart valve tissue engineering change the world? Nat Clin Pract Cardiovasc Med. 2005;2:60-1 Tuffier T. Etat actuel de la chirurgie intrathoracique. Trans Int Congr Med. 1913;2:249 (7 Surgery 1914) Schumacker HB Jr. The evolution of Cardiac Sugery. Indiana University Press, 1992. Brock, Sir Russel. Aortic subvalvular stenosis: Surgical treatment. Guys Hosp Rep 1957;106:221 Cohn LH. Cardiac Surgery in the Adult. 3rd edition. New York, NY:McGraw-Hill, 2007. Ellis FH Jr, Kirklin JW. Congenital valvular aortic stenosis: anatomic findings and surgical techniques. J Thorac Cardiovasc Surg. 1962;43:199 Harken DE, Soroff HS, Taylor WJ, et al. Partial and complete prostheses in aortic insufficiency. J Thorac Cardiovasc Surg 1960;40:744 Thourani VH, Suri RM, Gunter RL, et al. Contemporary real-world outcomes of surgical aortic valve replacement in 141,905 low-risk, intermediate-risk, and high-risk patients. Ann Thorac Surg. 2015;99:55-61 Gott VL, Alejo DE, Cameron DE. Mechanical heart valves: 50 years of evolution. Ann Thorac Surg. 2003;76:S22309 Yankah CA, Pasic M, Musci M, et al. Aortic valve replacement with the Mitroflow pericardial bioprosthesis: durability results up to 21 years. J Thorac Cardiovasc Surg. 2008;136:688-96 Johnston DR, Soltesz EG, Vakil N, et al. Long-term durability of bioprosthetic aortic valves: implications from 12,569 implants. Ann Thorac Surg. 2015;99:1239-47 Barratt-Boyes BG. Homograft aortic valve replacement in aortic incompetence and stenosis. Thorax. 1964;19:13150 Ross DN. Homograft replacement of the aortic valve. Lancet. 1962;2:487 Dunning J, Graham RJ, Thambyrajah J, et al. Stentless vs. stented aortic valve bioprostheses: a prospective randomized controlled trial. Eur Heart J. 2007;28:2369-74 Raja SG, Macarthur KJ, Pollock JC, et al. Impact of stentless aortic valves on left ventricular function and hypertrophy: current best available evidence. J Card Surg. 2006;21:313-9 Funder JA. Current status on stentless aortic bioprosthesis: a clinical and experimental perspective. Eur J Cardiothorac Surg. 2012;41:790-9 Gulbins H, Reichenspurner H. Which patients benefit from stentless aortic valve replacement. Ann Thorac Surg. 2009;88:2061-8 Ennker J, Albert A, Ennker IC. Stentless aortic valves. Current aspects. HSR Proc Intensive Care Cardiovasc Anesth. 2012;4:77-82 Repossini A, Kotelnikov I, Bouchikhi R, et al. Single-suture line placement of a pericardial stentless valve. J Thorac Cardiovasc Surg. 2005;130:1265-9 Stanger O, Bleuel I, Gisler F, et al. The Freedom Solo pericardial stentless valve: Single-center experience, outcomes, and long-term durability. J Thorac Cardiovasc Surg. 2015;150:70-7

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Current status of surgical treatment for aortic valve stenosis | 17

CHAPTER 2 Current status of surgical treatment for aortic valve stenosis

Wollersheim LW, Li WW, de Mol BA Journal of Cardiac Surgery 2014;29:630-7

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18 | Chapter 2

ABSTRACT In this review, we discuss the current surgical treatment for aortic valve stenosis. Surgical strategy for treatment of aortic valve stenosis is based on the risk profile of the patient. We reviewed the existing literature and present the current state-of-the-art of these various approaches, taking into account clinical outcomes, quality of life, costs and learning curve.

Current status of surgical treatment for aortic valve stenosis | 19

INTRODUCTION Aortic valve (AV) stenosis is the most prevalent form of valvular heart disease in developed countries and is mostly caused by age-related calcification [1]. In 1912, Tuffier made the first surgical attempt to dilate a stenotic AV [2]. Almost 50 years later in 1960, Harken et al. carried out the first successful aortic valve replacement (AVR) [3]. Surgical AVR remains the definitive treatment for severe AV stenosis [4, 5], with proven benefits regarding long-term survival and quality of life (QoL), even in patients over 80 years of age [6]. Conventional full median sternotomy has long been the incision of choice to perform an AVR. However, less invasive alternative approaches have become available varying from partial sternotomy to video-assisted and robot-assisted techniques. Additionally, percutaneous catheter-based approaches have recently been developed, enabling transcatheter aortic valve implantation (TAVI). This review will discuss surgical strategies for treatment of AV stenosis, taking into account clinical outcomes, QoL, costs and the learning curve associated with the various approaches.

METHODS Using PubMed a thorough literature search was performed. The search strategy combined ‘Aortic Valve’ [Mesh] OR ‘Aortic valve stenosis’ [Mesh] AND ‘Thoracic Surgery’ [Mesh] OR ‘Cardiac Surgical Procedures’ [Mesh] OR Surgical procedures, minimally invasive [Mesh:noexp] OR Robotics [Mesh] OR Thoracic Surgery, Video-Assisted [Mesh] OR minimal*/hemisternotom*/mini thoracotom* [tiab] OR sutureless [tiab] OR robot* [tiab] OR video-assisted/VATS [tiab] OR transcatheter/percutaneous/transapical/ascending aorta/TAVI [tiab]. The bibliographies of the retrieved manuscripts were searched for relevant papers. In addition, the ‘related articles’ function in PubMed was used. Median sternotomy, the gold standard Median sternotomy has long been the gold standard access approach to most cardiac procedures. It was first described in 1897 by Milton for removal of tuberculous lymph nodes [7]. However, in the early years of cardiac surgery most surgeons preferred the bilateral anterior thoracotomy for exposure. In 1957, Julian successfully reintroduced the median sternotomy into cardiac surgery, showing that cannulation for cardiopulmonary bypass (CPB) was simple and safe, and that this incision was faster to open and close than a bilateral anterior thoracotomy [8]. From 1957 onwards, virtually all cardiac operations were performed through a median sternotomy. The success of laparoscopic surgery in other surgical specialties has encouraged cardiac surgeons to use smaller incisions and explore different approaches. In 1993, Rao used a right thoracotomy approach [9], and in 1996, Cosgrove and Cohn used a right parasternal approach [10, 11] and an upper hemisternotomy [11]. In 1997, Chitwood performed the first video-assisted mitral valve surgery [12], which led to the exploration of video- and robot-assisted AV surgery.

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20 | Chapter 2

In 2002, Cribier introduced TAVI, a totally new clinical treatment option for patients with AV stenosis. He successfully implanted an AV prosthesis through a femoral vein approach into a 57-year old male who had been denied surgical AVR due to severe comorbidities [13]. Several access routes for TAVI are in use today. In 2005, Webb developed the transfemoral arterial method (TF-AVI) [14], and in 2006, the transapical approach for TAVI (TA-AVI) [15]. Another upcoming access route is trough the ascending aorta (TAo-AVI), first described in 2010 by Bapat [16]. Other arterial routes to the AV have also been reported, including the subclavian [17], carotid [18] and brachiocephalic [19]. Despite these innovative developments, median sternotomy continuous to be the most commonly used access route for AVR. In the following sections, we will attempt to determine whether this should be the case in contemporary surgical management of patients with severe AV stenosis, considering clinical outcomes, QoL, costs, and learning curve of the various approaches. Minimal access aortic valve surgery Minimal access aortic valve surgery (MAAVS) offers a wide variety of approaches. Today, the right anterior thoracotomy and upper hemisternotomy are the predominant MAAVS approaches [20]. Twenty years after the introduction of MAAVS by Rao, Cosgrove, and Cohn, there is still an ongoing debate regarding the superiority of this approach when compared to conventional sternotomy. Numerous studies have compared the two techniques (Table 1) [21-33]. Murtuza presented a systematic review and meta-analysis in 2008 [34], which was repeated by Brown in 2009 [35]. Both analyses comprised 26 studies, with 88% similarity, including four randomized controlled trials (RCTs), encompassing over 4500 patients. Murtuza concluded that MAAVS is a safe and noninferior alternative and is associated with fewer blood transfusions (46.6% vs 63.5%), shorter intensive care unit (ICU) stay (1.8 vs 2.4 days), shorter length of hospital stay (LOS) (8.8 vs 10.2 days) and ventilation time (9.4 vs 12.5 hours). The prolonged CPB time (102 vs 90 minutes), cross-clamp time (72 vs 62 minutes) and total operative time (209 vs 192 minutes) in the MAAVS group did not translate into an increased number of adverse effects. They found that MAAVS can be performed safely without a significant increase in postoperative mortality or other major complications. Therefore, it can be offered on the basis of patient choice and cosmesis rather than evident clinical benefit [34]. Neither Mortuza nor Brown found any differences in atrial fibrillation, sternal wound infection, or sternal instability. Brown also showed small significant differences in favor of MAAVS for ventilation time (weighted mean difference (WMD) 2.13 hours), ICU stay (WMD 0.46 days) and LOS (WMD 0.91 days) [35]. However, it should be taken into account that only four out of 22 observational studies were of high quality, as remarked by Murtuza [34]. In addition, Brown commented that in only three out of 22 observational studies an attempt was made to perform patient matched comparison [35]. Thus, in forms of quality the majority of the studies had obvious methodological limitations.

434

200

511

271

466

1042 506

RCT

O O

Bonacchi23

Moustafa25

Calderon26

Dogan24

Stamou29

Vanoverbeke30

Sharony31

Mihaljevic32 Bakir33

2.3 vs 2.7 2.6 vs 4.4

5.6 vs 7.3

2.8 vs 4.1

5.4 vs 5.5

2 vs 1

2.8 vs 9.3 *

0 vs 2.6

0 vs 0

2.5 vs 5

10 vs 10 1.7 vs 0

Mortality (%)

3.4

4.5

6.7

2.5

10 3.3

Conversion (%)

952 vs 1172 *

378 vs 409 *

736 vs 927 *

386 vs 557

233 vs 590 *

240 vs 495 *

183 vs 208 *

479 vs 355 370 vs 520 *

Blood loss (ml)

4.1 u vs 4.2 u

61 % vs 68 %

55 % vs 74% *

2 u vs 3.5 u *

47 % vs 51%

1.77 u vs 3.1 u *

157 ml vs 293 ml *

25 % vs 25%

Transfusions

14 vs 14

6.3 vs 5.8

2 vs 6.4 *

13 vs 13.2

4.4 vs 5.3 *

9.9 vs 9.9 7 vs 10 *

Ventilation (h)

ICU (d)

2.1 vs 2.5

39 h vs 38 h

3.7 vs 4.5 *

2 vs 2

7 h vs 28 h *

1.2 vs 2.1

1.1 vs 1.4 *

1.8 vs 1.9

S* NS

8 vs 18 * 6 vs 6.2

6 vs 7 10.8 vs 12.8 *

6 vs 8 *

8 vs 7.5

10 vs 12 *

S* NS

9.3 vs 9.4

NS S* 7.2 vs 8.2 *

Pain

LOS (d) 6.3 vs 6.3 NS

d = days; h = hour; ICU = intensive care unit; LOS = length of hospital stay; MAAVS = minimal access aortic valve surgery; ml = milliliter; N = number; NS = non-significant; O = observational; RCT = randomized controlled trial; S = significant; u = mean number units of blood; vs = versus; * = significant difference (p = <0.05) in favor of MAAVS.

Masiello

Doll27

RCT RCT

Aris21 Machler22

40 120

Type

Author

Table 1. RCT or observational studies with >200 patients and control group, comparing MAAVS and conventional sternotomy

Current status of surgical treatment for aortic valve stenosis | 21

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22 | Chapter 2

In 2009, Raja published a systematic review on MAAVS including five RCTs and encompassing 340 patients [36]. In the majority of patients, the minimal access approach was an upper hemisternotomy. No significant differences were found between MAAVS and conventional sternotomy concerning perioperative mortality, stroke, renal failure, or respiratory failure. Raja claimed that MAAVS had small but statistically significant benefits in the secondary outcomes of ventilation time, ICU stay, and LOS. However, the actual numbers on these subjects are not presented or provided in a meta-analysis [36]. After this systematic review only one additional RCT was published [26]. Calderon randomly assigned 38 patients to MAAVS (upper hemisternotomy) and 39 to conventional sternotomy. On assessment of respiratory function as the primary endpoint, the minimal access approach was not shown to have any benefits. However, there was a significant reduction in intraoperative blood loss, although no reduction in transfusion rate [26]. Recent, non-randomized studies have suggested that the benefits of MAAVS may be more manifest in patient groups with certain high-risk characteristics, for example, obesity, left ventricular dysfunction, advanced age, and in the setting of reoperative AVR [37, 38]. In a recent study comparing MAAVS with median sternotomy in a group of 160 obese patients (body mass index > 30 kg/m2), Santana showed improved outcomes after MAAVS. The difference was driven by a lower incidence of acute renal failure (0% vs 6%), prolonged intubation (18.7% vs 34%), reintubation (5% vs 16%), deep wound infection (0% vs 4%) and death (0% vs 8%) [37]. In addition, ElBardissi showed excellent outcomes in a cohort of 249 octogenarians with a mean STS score of >10%, who might be considered to be TAVI candidates. Operative mortality after MAAVS was 3%, stroke occurred in 4% of the patients, and long-term survival was no different from that of an age- and gender-matched US population [39]. There are no strict contraindications for MAAVS, however, there are several potential disadvantages. When a hemisternotomy is utilized, the right internal mammary artery may be sacrificed. Regarding CPB cannulation strategy, central arterial cannulation is almost always possible for hemisternotomy. On the other hand, peripheral cannulation is usually necessary for the right anterior thoracotomy approach. Central arterial cannulation is preferred to limit the vascular damage associated with peripheral arterial cannulation, that is local femoral arterial narrowing requiring a surgical patch graft (0.7%), ischemia of the cannulated limb (0.1%), infection (2.7%) and seroma (0.5%) [40]. Also, expertise in transoesophageal echocardiography is essential for accurate positioning of catheters and detection of intracardiac air. Conversion to full sternotomy may be necessary for various reasons, for example, bleeding, ventricular dysfunction, arrhythmia, or poor exposure. The conversion rate for MAAVS in experienced centers is low: 2.6 â&#x20AC;&#x201C; 2.7 % [41, 42]. However, Foghsgaard reported a 14% conversion rate in a small cohort of 98 patients, mostly due to technical problems or bleeding from the aortotomy. Moreover, when conversion to full sternotomy was needed it was associated with longer operating time, longer ICU stay, and LOS [43]. All six available RCTs on MAAVS evaluated postoperative pain. Three found no significant differences [21, 24, 26], while three studies observed less pain in the MAAVS group, but with conflicting results [22, 23, 25]. QoL after MAAVS has never been evaluated in an RCT. The cost evaluation of MAAVS also demonstrates contradictory results in nonrandomized studies. Cohn claimed the overall costs were approximately 20% less for MAAVS [11], in contrast to Szwerc, who concluded there were no differences in all direct and indirect costs [44].

Current status of surgical treatment for aortic valve stenosis | 23

It should be noted that most reports with positive results come from large, high-volume centers. To justify if MAAVS is a good approach for all surgeons its learning curve has to be clarified. A MAAVS Working Group from the United States advised that if surgeons are interested in including MAAVS into their armamentarium, sufficient expertise with conventional AVR should be obtained [20]. Plass noted a reduction in CBP and cross-clamp duration over time in their series of 160 patients [45]. Interestingly, a review by Caffarelli demonstrated that in studies containing over 100 MAAVS patients, CPB time was equal to patients undergoing full sternotomy [46]. On the other hand, smaller studies revealed significantly prolonged CPB and cross-clamp duration in MAAVS patients, indicating the presence of a learning curve in these lower volume studies. Conversely, using a cumulative sum analysis of the first 100 MAAVS cases by a single surgeon, Murzi observed no learning curve effect [47]. These conflicting results show that the learning curve of MAAVS remains poorly defined. In conclusion, MAAVS has proved its equivalence to conventional sternotomy in small RCTs and, at the request of the patient, it can be offered as an alternative to conventional sternotomy. Possible benefits include shorter ventilation time, shorter ICU, and LOS stay. The potential benefits for high-risk patients have to be studied to determine if MAAVS should be the preferred approach in these patients. In addition, higher quality studies are necessary for the evaluation of QoL and costs. However, these potential benefits should be weighed against the possible disadvantages of this approach especially if conversion to full sternotomy is needed. It should also be noted that MAAVS is generally performed by a few experienced cardiac surgeons at high-volume centers. Whether MAAVS can be implemented as a standard technique is in question. For this reason, the issues regarding the learning curve still need to be clarified. Currently, there is not enough evidence to suggest that MAAVS is an appropriate technique for all patients, and for all surgeons. It seems justified that the MAAVS approach is not mentioned in the European and American guidelines [4, 5], and median sternotomy remains the gold standard for surgical AVR for patients with severe AV stenosis. Sutureless valves Sutureless aortic bioprosthesis possess the potential for easy and fast implantation. Clinical reports of these valves showed a short cross-clamp time of 18-39 minutes [48-51] reducing cross-clamp time to 40% compared to the implantation of stented bioprostheses [52]. The hemodynamic performance of sutureless valves is excellent [48-51], and after 4-year follow-up valvular gradients remained stable [49]. The disadvantage of sutureless valves is the higher incidence of paravalvular leakage. With the Perceval S bioprosthesis (Sorin, Saluggia, Italy), perioperative leakage, requiring new aortic cross clamping and valve explantation, occurred in 1.2-1.8% of the patients [50, 52]. Postoperatively, there was no severe paravalvular leakage noted, moderate paravalvular leakage occurred in only one (0.3%) of the in total 396 patients and mild paravalvular leakage occurred in 0-15.6% [48, 50, 52]. Using the 3F Enable (Medtronic, Minneapolis, MN, USA), Aymard reported one patient in a series of 28 patients that required reoperation because of significant paravalvular leakage and two patients with paravalvular leakage who did not require additional treatment [51]. Also with the 3F Enable, Martens showed three patients in a series of 140 patients with major paravalvular leakage that needed reoperation and another three patients with minor paravalvular leakage who did not require additional treatment [53].

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24 | Chapter 2

Because of the shorter cross-clamp and therefore ischemic time, the sutureless valve may offer an advantage in high-risk patients, especially if this is combined with a MAAVS approach. The learning curve is fast, and after about 10 cases, a reduction in deployment time is expected [51]. Video- and robot-assisted aortic valve surgery Currently, there are trials including over 1000 patients who have undergone video-assisted mitral valve surgery [54] and over 100 who have undergone robot-assisted mitral valve surgery [55]. However, the role of video- and robotic-assisted AV surgery is not on the same level as in mitral valve surgery, and only a few cases have been reported. These are often initial experiences. In 1999, Benetti was the first to report AVR with video-assistance through a right anterior thoracotomy in seven patients [56]. The video-assistance resulted in a less traumatic and less painful approach because the removal of ribs and cartilage fragments was not necessary. In 2006, Francesco published a series of 12 patients who underwent video-assisted AVR, without perioperative mortality. However, one patient had to be converted to sternotomy and one patient underwent re-exploration for bleeding [57]. In 2009, Poffo published the results of video-assisted AVR in 14 patients, with no mortality or major postoperative complications, a mean CPB time of 124 minutes, and mean cross-clamp time of 102 minutes [58]. The femoral artery and vein were used for CPB, and there was a groin seroma in one patient. The study population was low-risk and patients undergoing reoperation or with poor ventricular function, obesity, or endocarditis were excluded. Therefore, these results cannot be generalized to the general population. In 2005, Folliquet reported a successful AVR using the Da Vinci robot system in five patients using one or two ports and a 5-cm incision in the right 3rd or 4th intercostal space with a mean procedure time of 231 minutes, CPB time of 122 minutes, and mean cross-clamp time of 98 minutes [59]. Francesco addressed the learning curve associated with video-assisted AVR. Their learning curve was short because they already had experience with video-assisted mitral valve surgery. In their opinion, at least 20-30 cases are needed to acquire confidence in the procedure [57]. Poffo showed CPB and aortic clamping time decreased after 40 cases [58]. In conclusion, AVR with video- and robotic-assistance is possible in low-risk patients. However, videoassistance does not add much to the procedure of AVR and the disadvantages of long operating time, increased costs, and a steep learning curve outweigh the advantages of the smaller incisions. Therefore, video- and robot-assisted AV surgery is still in its infancy, and for now, it only plays a very small role in its field. Transcatheter aortic valve implantation After the introduction of TF-AVI and TA-AVI by Webb in 2005 and 2006, these became the standard approaches for TAVI. There is currently no evidence to favor TF-AVI over TA-AVI [60]. The benefits of TAAVI include more direct access to the stenotic valve and the avoidance of the potential complications of peripheral access. However, the TA-AVI approach does require the use of general anesthesia and it also carries the risk of complications related to the puncture of the left ventricle [61]. Another TAVI-approach is an

Current status of surgical treatment for aortic valve stenosis | 25

access through the ascending aorta. Because of the short distance from the ascending aorta to the aortic annulus, the transcatheter heart valve is easy to position in TAo-AVI. Also, cardiothoracic surgeons are familiar with the central access for TAo-AVI, the cannulation technique of the ascending aorta and conversion to sternotomy could be performed immediately if needed. Clinical outcomes are good in TAo-AVI [62-64] and patients with low ejection fraction and fragile ventricles might benefit from the TAo approach compared to the TA approach [63]. Lardizabal reported the TAo approach is favorable over the TA approach because of lower bleeding rates (28% vs 11%), shorter ICU stay (3 days vs 6 days) and a more favorable learning curve [64]. At our institution, we use a TAo-AVI when problems are expected with the peripheral arteries, for example, small caliber for the sheath or tortuosity. Contraindications for the TAo approach are when the ascending aorta is not accessible, for example, vein grafts with high origin or anatomical deformities of the chest wall, or a heavily calcified ascending aorta. However, the TAo cannulation zone is usually free of calcium [65]. The TF-AVI and TA-AVI approaches have been most extensively studied and have been evaluated in multiple trials. The PARTNER trial investigators performed the first large RCT in TAVI. In 2010, Leon randomized 358 patients with AV stenosis, who were not considered suitable candidates for surgery, into TF-AVI and standard therapy (including balloon aortic valvuloplasty). The TF-AVI was superior at one-year follow-up regarding rate of death from any cause (31% vs 50%), rate of death from cardiovascular cause (20% vs 42%), the rate of repeat hospitalization (22% vs 44%) and a reduction of symptoms. However, the TF-AVI group had more neurological events (11% vs 5%), vascular complications (32% vs 7%), and major bleeding events (22% vs 11%) [66]. This series was updated at a 2-year follow-up by Makkar, who concluded the advantages of TF-AVI over balloon aortic valvuloplasty in nonsurgical patients remained the same, as well as the higher number of patients with neurological events [67]. This RCT was also used to assess QoL after TF-AVI versus standard therapy, showing TF-AVI resulted in significant improvements in health-related QoL for at least one year compared with standard therapy in nonsurgical patients with AV stenosis [68]. As such, TAVI is now considered the gold standard in symptomatic patients with severe AV stenosis who are not suitable for surgical AVR [4]. Much more debate is ongoing concerning high-risk patients with severe AV stenosis who may still be suitable for surgical AVR. Smith, one of the PARTNER trial investigators, randomized 699 high-risk patients with AV stenosis (mean logistic EuroSCORE in both groups was 29) between surgical AVR and TAVI [69]. At one-year follow-up there were no differences in death from any cause (24 vs 27%), death from cardiac cause (14 vs 13%) or repeat hospitalization (18 vs 16%). However, the TAVI group had more stroke or transient ischemic attack (8% vs 4%), vascular complications (18% vs 5%), and more moderate or severe paravalvular regurgitation (7% vs 2%) than the surgical group. The surgical group had more major bleeding events (26% vs 15%) and longer ICU stay (5 vs 3 days) [69]. In 2012, after two-year follow-up this series was updated by Kodali who concluded mortality after TAVI remained similar to that after surgical AVR and the difference in neurological events attenuated over time. However, paravalvular regurgitation remained more common in the TAVI group (6.9% vs 0.9%), and was associated with late mortality (hazard ratio 2.11; 95% CI, 1.43-3.10, p<0.001) [70]. This RCT was also used to assess the QoL in both groups. At one-year followup Reynolds showed health status improved equally in both groups when compared with baseline [71]. In

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26 | Chapter 2

contrast to the results from the PARTNER trial, the STACCATO trial, a multicenter RCT of TA-AVI versus AVR in elderly but operable patients in Denmark, was terminated prematurely due to an excess of events in the TA-AVI group (two deaths, two strokes, one patient requiring hemodialysis in the TA-AVI group versus one stroke in the AVR group) [72]. A comparison of the cost-effectiveness of TAVI and AVR offer conflicting results. Using PARTNER trial data, Reynolds demonstrated no differences between TAVI and AVR in total costs of hospital stay and total 12-month costs [73]. However, Neyt showed TAVI was associated with extra costs of approximately â&#x201A;Ź20 000 per patient in a nonindustry-based study [74]. A few papers have addressed the learning curve of TAVI. Gurvitch compared their first 135 TAVI patients with their second cohort of 135 TAVI patients and, on multivariate analysis, showed that procedural experience (>135 cases) was an independent predictor of 30-day survival. Also, the overall procedural success rate improved significantly from 93% to 98%. These improvements are probably a combination of the learning curve effect, technological advances and patient selection [75]. Nuis, Kempfert and Alli compared their first and second cohorts of TAVI patients and their second cohort had better clinical outcomes [76, 77], decreased procedural times, radiation dose, and volume of contrast used [77, 78]. Despite more experience in TAVI, the rate of acute kidney injury [75, 76], vascular complications [75, 76, 78], and stroke [76] remained high. Considering the above-mentioned results, the clinical judgment of the heart team should be the main factor in choosing between AVR and TAVI in these high-risk patients. Recent literature has tried to give guidance on complex patient selection [79] by taking into account additional clinical risk factors which are not included in the EuroSCORE or STS score. These include previous chest radiation, liver disease, presence of a porcelain aorta, and patent coronary bypass grafts. Additionally, an attempt should be made to quantify the performance status of the patient, by using frailty scores. Based on the combination of these scores and the experience of the heart team, a decision is made between TAVI and AVR. Recently, Adams reported in the CoreValve High Risk study that the one-year survival of 795 randomized high-risk patients treated with the self-expandable CoreValve (Medtronic, Minneapolis, MN, USA) is statistically significant higher compared to conventional AVR (86% vs 81%) [80]. One limitation of the study was that the trial had a lower 30-day mortality rate than the predicted 15%; therefore the trial population may have been at lower risk than intended. Also, 36 patients refused surgical replacement after randomization compared to two patients in the TAVI group. In conclusion, TF-, TA- and TAo-AVI should be standard care for patients who, in the opinion of the heart team, are unsuitable for conventional surgery. In high-risk patients, this decision should be made on an individual patient basis combining the clinical judgment of the heart team with the logistic EuroSCORE and STS scores. The clinical judgment of the heart team should be directive, and the logistic EuroSCORE and STS scores should be supportive. An expected mortality score of >20% on the logistic EuroSCORE and >10% on the STS score could categorize a patient as high-risk [81]. Whether TAVI could be the future standard treatment for intermediate-risk patients with AV stenosis, is currently being investigated in two RCTs (PARTNER 2A and SURTAVI trial).

Current status of surgical treatment for aortic valve stenosis | 27

PRESENT AND FUTURE Currently, clear guidelines are available regarding treatment choice in patients with AV stenosis [4, 5]. However, the optimal surgical access strategy for treatment of a patient with AV stenosis depends on patient profile. The patient profile, from low-risk to unsuitable for surgery, should be the main determinant of the intervention of choice (Table 2). For low- and intermediate-risk patients, surgical AVR with a conventional sternotomy is still the gold standard. MAAVS could be an alternative approach since it has proved its equivalence to conventional sternotomy in small RCTs and it can be offered on patient request or surgeonsâ&#x20AC;&#x2122; preference. It remains to be seen if MAAVS is an appropriate technique, suitable for all patients, and for all surgeons. Currently, video- and robot-assisted AVR is possible in low-risk patients, but is still in its infancy and only plays a very small role in its field. Larger trials are needed to demonstrate the safety and, most of all, feasibility and possible advantages of video- and robot-assisted AV surgery. Also technological improvements are needed to decrease operating time and a reduction in costs is desirable. Although there is currently no indication for TAVI in low- and intermediate risk patients the PARTNER 2A and SURTAVI trial are comparing this option with AVR. TF-, TA- and TAo-AVI should be standard care for patients who are considered unsuitable for conventional AVR. As yet, no RCT has compared these various TAVI approaches. The decision of the heart team is crucial for patients who are at high-risk. Both surgical AVR and TAVI are suitable approaches. The heart teamâ&#x20AC;&#x2122;s decision should be made on an individual basis and based on clinical judgment. It should be directive, and supported by the logistic EuroSCORE and STS score. However, there is room for debate on these high-risk patients. Long-term follow-up of TAVI is not yet available. In addition, the clinical results of the PARTNER trial, the STACCATO trial and the CoreValve High Risk study on TAVI versus surgical AVR differ. The PARTNER trial had strict inclusion criteria; therefore the outcomes may not be generalized to the general population. Furthermore, it would be interesting to see future studies comparing MAAVS with TAVI in these high-risk patients instead of comparing TAVI with a conventional surgical approach. In our opinion, MAAVS could be an attractive surgical alternative in high-risk patients while ensuring a long-term solution with a durable prosthetic valve. To lower cross-clamp and ischemic time, MAAVS in combination with a sutureless valve is an interesting concept. Due to surgical decalcification of the aortic valve, sutureless valves may show less stroke and paravalvular leakage when compared to TAVI [52]. However, improvements are needed to its design to lower the increased incidence of paravalvular leakage. MAAVS will continue to evolve, as there will be an increasing patient demand for reduced surgical trauma involving less discomfort. Randomized trials are needed to evaluate if MAAVS is beneficial in selected high-risk patient groups when compared with a conventional sternotomy or to a TAVI approach. Also, more research is needed to determine if MAAVS provides better QoL and cost reduction. Before MAAVS can be implemented as a standard treatment, the issue of its learning curve must be clarified. TAVI has the potential to play in indispensable role in cardiac surgery. In the future, younger patients might benefit from bioprosthetic prosthesis instead of mechanical prosthesis, because when degenerated, a valvein-valve TAVI is possible. For now, we eagerly await the durability of the TAVI valves.

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>20 %

High-risk

STS

>10 %

<10 %

TAVI

AVR / TAVI

AVR

-TF and TA approach are gold standard, TAo is a good alternative in patients with peripheral artery disease

- Based on clinical judgment of the heart team; considering: frailty / liver disease / patent coronary bypass grafts / porcelain aorta / chest radiation -If a surgical approach is chosen, consider MAAVS instead of median sternotomy for faster recovery and possible lower morbidity in high-risk patients

- Median sternotomy is gold standard - MAAVS is a safe option in experienced and high volume centers and can be opted for based on surgeonâ&#x20AC;&#x2122;s or patientâ&#x20AC;&#x2122;s preference

Present guidelines Recommendations

AVR = aortic valve replacement; log = logistic; MAAVS = minimally access aortic valve surgery; PV = paravalvular; STS = Society of Thoracic Surgeons; TA = trans apical; TAo = trans ascending aorta; TAVI = transcatheter aortic valve implantation; TF = trans femoral

Unsuitable for surgery

<20 %

Log EuroSCORE

Low- / Intermediate-risk

Patient profile

Table 2. Optimal surgical strategy for treatment of severe aortic valve stenosis

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Current status of surgical treatment for aortic valve stenosis | 29

REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26.

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30 | Chapter 2

27. Doll N, Borger MA, Hain J et al. Minimal access aortic valve replacement: effects on morbidity and resource utilization. Ann Thorac Surg 2002;74:S1318-22 28. Masiello P, Coscioni E, Panza A et al. Surgical results of aortic valve replacement via partial upper sternotomy: comparison with median sternotomy. Cardiovasc Surg 2002;10:333-8 29. Stamou SC, Kapetanakis EI, Lowery R et al. Allogenic blood transfusion requirements after minimally invasive versus conventional aortic valve replacement: a risk-adjusted analysis. Ann Thorac Surg 2003;76:1101-6 30. Vanoverbeke H, Van Belleghem Y, Francois K et al. Operative outcome of minimal access aortic valve replacement versus standard procedure. Acta Chir Belg 2004;104:440-4 31. Sharony R, Grossi EA, Saunders PC et al. Propensity score analysis of a six-year experience with minimally invasive isolated aortic valve replacement. J Heart Valve Dis 2004;13:887-93 32. Mihaljevic T, Cohn LH, Unic D et al. One thousand minimally invasive valve operations: early and late results. Ann Surg 2004;240:529-34 33. Bakir I, Casselman FP, Wellens F et al. Minimally invasive versus standard approach aortic valve replacement: a study in 506 patients. Ann Thorac Surg 2006;81:1599-1604 34. Murtuza B, Pepper JR, Stanbridge RD et al. Minimal access aortic valve replacement: is it worth it? Ann Thorac Surg 2008;85:1121-31 35. Brown ML, McKellar SH, Sundt TM et al. Ministernotomy versus conventional sternotomy for aortic valve replacement: a systematic review and meta-analysis. J Thorac Cardiovasc Surg 2009;137:670-9 36. Raja SG, Navaratnarajah M. Impact of minimal access valve surgery on clinical outcomes: current best available evidence. J Card Surg 2009;24:73-9 37. Santana O, Reyna J, Grana R et al. Outcomes of minimally invasive versus standard sternotomy in obese patients undergoing isolated valve surgery. Ann Thorac Surg. 2011;91:406-10. 38. Schmitto JD, Mohr FW, Cohn LH. Minimally invasive aortic valve replacement: how does this perform in high-risk patients? Curr Opin Cardiol 2011;26:118-22. 39. ElBardissi A, Shekar P, Couper GS et al. Minimally invasive aortic valve replacement in octogenarian, high-risk, transcatheter aortic valve implantation candidates. J Thorac Cardiovasc Surg 2011;141:328-35 40. Ayyash B, Tranquilli M, Elefteriades JA. Femoral artery cannulation for thoracic aortic surgery: safe under transesophageal echocardiographic control. J Thorac Cardiovasc Surg 2011;142:1478-81 41. Tabata M, Umakanthan R, Khalpey Z et al. Conversion to full sternotomy during minimal-acces cardiac surgery: reasons and results during a 9.5-year experience. J Thorac Cardiovasc Surg 2007;134:165-9 42. Bang JH, Kim JW, Lee JW et al. Minimally invasive approaches versus conventional sternotomy for aortic valve replacement: a propensity score matching study. Korean J Thorac Cardiovasc Surg 2012;45:80-4 43. Foghsgaard S, Schmidt TA, Kjaergard HK. Minimally invasive aortic valve replacement: late conversion to full sternotomy doubles operative time. Tex Heart Inst J 2009;36:293-7 44. Szwerc MF, Benckart DH, Wiechmann RJ et al. Partial versus full sternotomy for aortic valve replacement. Ann Thorac Surg 1999;68:2209-13 45. Plass A, Scheffel H, Alkadhi H et al. Aortic valve replacement through a minimally invasive approach: preoperative planning, surgical technique, and outcome. Ann Thorac Surg 2009;88:1851-6 46. Caffarelli AD, Robbins RC. Will minimally invasive valve replacement ever really be important? Curr Opin Cardiol 2004;19:123-7 47. Murzi M, Cerillo AG, Bevilacqua S et al. Traversing the learning curve in minimally invasive heart valve surgery: a cumulative analysis of an individual surgeonâ&#x20AC;&#x2122;s experience with a right minithoracotomy approach for aortic valve replacement. Eur J Cardiothorac Surg 2012;41:1242-6 48. Flameng W, Herregods MC, Hermans H et al. Effect of sutureless implantation of the Perceval S aortic valve bioprosthesis on intraoperative and early postoperative outcomes. J Thorac Cardiovasc Surg 2011;142:1453-7 49. Folliquet TA, Laborde F, Zannis K et al. Sutureless perceval aortic valve replacement: results of two European centers. Ann Thorac Surg 2012;93:1483-8 50. Santarpino G, Pfeiffer S, Schmidt J et al. Sutureless aortic valve replacement: first-year single-center experience. Ann Thorac Surg 2012;94:504-8 51. Aymard T, Kadner A, Walpoth N et al. Clinical experience with the second-generation 3f Enable sutureless aortic valve prosthesis. J Thorac Cardiovasc Surg 2010;140:313-6 52. Miceli A, Santarpino G, Pfeiffer S et al. Minimally invasive aortic valve replacement with Perceval S sutureless valve: Early outcomes and one-year survival from two European centers. J Thorac Cardiovasc Surg 2014;148:2838-43

Current status of surgical treatment for aortic valve stenosis | 31

53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77.

Martens S, Sadowski J, Eckstein FS et al. Clinical experience with the ATS 3f Enable© Sutureless Bioprosthesis. Eur J Cardiothorac Surg 2011;40:749-55 Modi P, Rodriquez E, Hargrove WC 3rd et al. Minimally invasive video-assisted mitral valve surgery: a 12-year, 2-center experience in 1178 patients. J Thorac and Cardiovasc Surg 2009;137:1481-7 Gao C, Yang M, Xiao C et al. Robotically assisted mitral valve replacement. J Thorac and Cardiovasc Surg 2012;143:S64-7 Benetti F, Rizzardi JL, Concetti C et al. Minimally aortic valve surgery avoiding sternotomy. Eur J Cardiothorac Surg 1999;16:S84-5 Francesco S, Stefanos D, Romano M et al. Aortic valve replacement through a mini lateral thoracotomy with high thoracic epidural anesthesia. Innovations 2006;1:160-4 Poffo R, Pope RB, Selbach RA et al. Video-assisted cardiac surgery: results from a pioneer project in Brazil. Rev Bras Cir Cardiovasc 2009;24:318-26 Folliquet TA, Vanhuyse F, Konstantinos Z et al. Early experience with robotic aortic valve replacement. Eur J Cardiothorac Surg 2005;28:172-3 Walther T, Blumenstein J, van Linden A et al. Contemporary management of aortic stenosis: surgical aortic valve replacement remains the golden standard. Heart 2012;98 suppl 4:iv23-9 Krishnaswamy A, Tuzcu EM, Kapadia SR. Update on transcatheter aortic valve implantation. Curr Cardiol Rep 2010;12:393-403 Hayashida K, Romano M, Lefèvre T et al. The transaortic approach for transcatheter aortic valve implantation: a valid alternative to the transapical access in patients with no peripheral vascular option. A single center experience. Eur J Cardiothorac Surg 2013;44:692-700 Dahle G, Rein KA. Direct aorta ascending approach in transcatheter aortic valve implantation. Innovations 2014;9:1-9 Lardizabal JA, O’Neill BP, Desai HV et al. The transaortic approach for transcatheter aortic valve replacement: initial clinical experience in the United States. J Am Coll Cardiol 2013;61:2341-5 Bapat VN, Attia RQ, Thomas M. Distribution of calcium in the ascending aorta in patients undergoing transcatheter aortic valve implantation and its relevance to the transaortic approach. JACC Cardiovasc Interv 2012;5:470-6 Leon MB, Smith CR, Mack M et al. Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery. N Engl J Med 2010;363:1597-607 Makkar RR, Fontana GP, Jilaihawi H et al. Transcatheter aortic-valve replacement for inoperable severe aortic stenosis. N Engl J Med 2012;366:1696-704 Reynolds MR, Magnuson EA, Lei Y et al. Health-related quality of life after transcatheter aortic valve replacement in inoperable patients with severe aortic stenosis. Circulation 2011;124:1964-72 Smith CR, Leon MB, Mack MJ et al. Transcatheter versus surgical aortic-valve replacement in high risk patients. N Engl J Med 2011;364:2187-98 Kodali SK, Williams MR, Smith CR et al. Two-year outcomes after transcatheter or surgical aortic-valve replacement. N Engl J Med 2012;366:1686-95 Reynolds MR, Magnuson EA, Wang K et al. Healt-related quality of life after transcatheter or surgical aortic valve replacement in high-risk patients with severe aortic stenosis: results from the PARTNER Trial. J Am Coll Cardiol 2012;6:548-58 Nielsen HH, Klaaborg KE, Nissen H et al. A prospective, randomized trial of transapical transcatheter aortic valve implantation vs. surgical aortic valve replacement in operable elderly patients with aortic stenosis: the STACCATO trial. EuroIntervention 2012;8:383-9 Reynolds MR, Magnuson EA, Lei Y et al. Cost-effectiveness of transcatheter aortic valve replacement compared with surgical aortic valve replacement in high-risk patients with severe aortic stenosis: results of the PARTNER trial. J Am Coll Cardiol 2012;60:2683-92 Neyt M, van Brabandt H, Devriese S et al. A cost-utility analysis of transcatheter aortic valve implantation in Belgium: fosusing on a well-defined and identifiable population. BMJ Open 2012;2 doi: 10.1136/bmjopen-2012-001032 Gurvitch R, Tay EL, Wijesinghe N et al. Transcatheter aortic valve implantation: lessons from the learning curve of the first 270 high-risk patients. Catheter Cardiovasc Interv 2011;78:977-84 Nuis RJ, van Mieghem NM, van der Boon RM et al. Effect of experience on results of transcatheter aortic valve implantation using a Medtronic CoreValve System. Am J Cardiol 2011;107:1824-9 Kempfert J, Rastan A, Holzhey D et al. Transapical aortic valve implantation: analysis of risk factors and learning experience in 299 patients. Circulation 2011;124:S124-9

R1 R2 R3 R4 R5 R6 R7 R8 R9 R10 R11 R12 R13 R14 R15 R16 R17 R18 R19 R20 R21 R22 R23 R24 R25 R26 R27 R28 R29 R30 R31 R32 R33 R34 R35 R36 R37 R38 R39

32 | Chapter 2

78.

Alli OO, Booker JD, Lennon RJ et al. Transcatheter aortic valve implantation: assessing the learning curve. JACC Cardiovasc Interv 2012;5:72-9 79. Van Mieghem NM, Serruys PW. The art of risk stratification in TAVI. Eur Heart J. 2013;34:1859-61 80. Adams DH, Popma JJ, Reardon MJ et al. Transcatheter Aortic-Valve Replacement with a Self-Expanding Prosthesis. N Engl J Med 2014;370:1790-8 81. Vahanian A, Alfieri O, Al-Attar N et al. Transcatheter valve implantation for patients with aortic stenosis: a position statement from the European Association of Cario-Thoracic Sugery (EACTS) and the European Society of Cardiology (ESC), in collaboration with the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J. 2008;29:1463-70

CHAPTER 3 Aortic valve replacement with the stentless Freedom SOLO bioprosthesis: A systematic review

Wollersheim LW, Li WW, Bouma BJ, Repossini A, van der Meulen J, de Mol BA The Annals of Thoracic Surgery 2015;100:1496-504

R1 R2 R3 R4 R5 R6 R7 R8 R9 R10 R11 R12 R13 R14 R15 R16 R17 R18 R19 R20 R21 R22 R23 R24 R25 R26 R27 R28 R29 R30 R31 R32 R33 R34 R35 R36 R37 R38 R39

34 | Chapter 3

ABSTRACT This systematic review examined the clinical and hemodynamic performance of the stentless Freedom SOLO aortic bioprosthesis. The occurrence of postoperative thrombocytopenia was also analyzed. The Freedom SOLO is safe to use in everyday practice with short cross-clamp times, and postoperative pacemaker implantation is notably lower. Valvular gradients are low and remain stable during short-term follow-up. Thrombocytopenia is more severe than in other aortic prostheses; however, this is without clinical consequences. Within a few years, the 15-year follow-up of this bioprosthesis will be known, which will be key to evaluating the long-term durability.

Systematic review Freedom SOLO | 35

INTRODUCTION American and European guidelines recommend aortic valve replacement (AVR) as the treatment of choice in symptomatic patients with severe aortic valve stenosis [1,2]. Today, 80% of valves implanted at AVR are bioprostheses [3]. Various types of bioprostheses are available, including stented and stentless options. The stentless bioprosthesis was designed to improve hemodynamic performance due to the absence of an obstructing stent [4] and to realize a more physiological flow pattern across the prosthesis than in stented valves [5]. However, the implantation of stentless prostheses was found to be technically more demanding and cross-clamp times were longer [6]. With the introduction of the Freedom SOLO (Sorin Group, Milan, Italy), a modification of the Pericarbon Freedom stentless valve (Sorin Group, Milan, Italy), the technical drawbacks of stentless bioprostheses are diminished [7]. The Freedom SOLO is a pericardial bioprosthesis (Figure 1) and implanted in a supraannular position using one running suture line in the sinuses of Valsalva, thus facilitating easy implantation. The Freedom SOLO valve appears to offer the best of both worlds: it promises the superior hemodynamic performance of a stentless valve combined with a simple and fast implantation technique. In this report, we systematically review the available evidence on the performance of this bioprosthesis regarding clinical outcomes and hemodynamic performance.

Figure 1. The stentless Freedom SOLO pericardial bioprosthesis

R1 R2 R3 R4 R5 R6 R7 R8 R9 R10 R11 R12 R13 R14 R15 R16 R17 R18 R19 R20 R21 R22 R23 R24 R25 R26 R27 R28 R29 R30 R31 R32 R33 R34 R35 R36 R37 R38 R39

36 | Chapter 3

MATERIAL AND METHODS A literature search of MEDLINE, EMBASE and The Cochrane library (Figure 2) was done using the search terms ‘’freedom solo’’ or ‘’stentless solo’’. The articles were selected independently by two reviewers (L.W. and W.L.) and are presented in Figure 2. After duplicates were removed, 97 titles were screened. Inclusion criteria for both the title and abstract screening were ‘’everything on the Freedom SOLO bioprosthesis’’. After title screening, 20 titles were excluded (98% agreement). Seventy-seven abstracts were screened and 1 abstract was excluded (99% agreement). Seventy-six full-text articles were assessed for eligibility. There was 96% agreement on full text eligibility, which was resolved after discussion. Four outcome groups were formed – ‘’clinical outcomes,’’ ‘’echocardiography,’’ ‘‘thrombocytopenia,’’ and ‘‘other’’ - and each fulltext was assessed for each outcome group. For ‘‘clinical outcomes,’’ the text had to include number of patients, mortality, and one of the following: reoperation for bleeding, stroke, pacemaker implantation, followup on survival, endocarditis, or reoperations. For ‘’echocardiography’’ the text had to include postoperative echocardiography reporting valvular gradients. For ‘‘thrombocytopenia,’’ the text had to include information on postoperative thrombocytopenia. An addition subgroup was created to examine thrombocytopenia in depth: the text had to include platelet counts both preoperatively and postoperatively and state on which postoperative day. The ‘’other’’ category was created to include new information on the Freedom SOLO that did not qualify for the other groups; for example, case reports of valve failures. A total of 35 full-text articles were included in this systematic review [8-42]. Exclusion criteria for the full text analysis can be found in Figure 2. For details on operative technique and figures of the 3 stay sutures and the continuous suture line, we refer to Glauber and colleagues [8].

Figure 2. Flowchart shows article selection for the review

Systematic review Freedom SOLO | 37

RESULTS Clinical outcomes Table 1 and Table 2 show the clinical outcomes and follow-up of 2185 patients with a Freedom SOLO. In 22 studies, the mean age was 74 years, concomitant procedures were performed in 39% of the patients, and the mean cross-clamp time for isolated AVR with the Freedom SOLO was 66 minutes. Seventy-seven patients (10%) underwent operation for isolated aortic valve insufficiency (AoI). Mean European System for Cardiac Operative Risk Evaluation (EuroSCORE) was 8 and mean logistic EuroSCORE was 12. In all patients, in-hospital and 30-day mortality was 3.5%. The rethoracotomy rate for bleeding was 2.9%, the stroke rate 1.1%, and a permanent pacemaker was implantation in 1.7%. After Freedom SOLO implantation, the reoperation rate was 0.9% (0.5% per patient year), reported over 9 studies (n= 1296) during a mean follow-up of 22 months (maximum 83 months). Five patients underwent reoperation for AoI, 1 patient due to an oversized Freedom SOLO, and 5 patients due to prosthetic valve endocarditis. No patients underwent reoperation due to structural valve deterioration. Overall, prosthetic valve endocarditis was 0.9% (0.5% per patient year), reported over eight studies (n= 1160) during a mean follow-up of 22 months (maximum 83 months). In one study of 13 patients, all of whom were operated on for endocarditis, prosthetic valve endocarditis was absent in 3 to 43 months of follow-up [10]. Overall survival was 91%, 89%, 86%, 78% and 60% at 1, 2, 3, 4 and 5 years, respectively. This was reported in seven, five, five, four and two studies, representing 1147, 818, 818, 690 and 291 patients, respectively. These are the total number of patients in the studies and not the patients at risk at the time of follow-up.

R1 R2 R3 R4 R5 R6 R7 R8 R9 R10 R11 R12 R13 R14 R15 R16 R17 R18 R19 R20 R21 R22 R23 R24 R25 R26 R27 R28 R29 R30 R31 R32 R33 R34 R35 R36 R37 R38 R39

J Cardiovasc Med

J Heart Valve Dis

2010

2011

2012

Piccardo23

Oses22

Reents26

Tarzia33

Miceli31

Pfeiffer10

Tex Heart Inst J

Altintas18

Ann Thorac Surg

Thalmann20 2014 74

2185 74

277

151

128

254

229

13*

116

100

143

256

109

age

111

3.5

4.3

4.6

2.5

4.3

3.1

2.6

3.8

4.9

2.3

1.8

4.4

2.9

1.8

2.3

0.4

3.3

2.8

4.5

1.1

2.2

0.8

1.7

0.7

0.3

1.7

2.7

1.8

concomitant isolated EuroSCORE logistic XCL time isolated AVR mortality bleeding stroke pacemaker procedures (%) AoI (%) EuroSCORE (min) XCL time (min) (%) (%) (%) (%)

AoI = aortic valve insufficiency, AVR = aortic valve replacement, EuroSCORE = European System for Cardiac Operative Risk Evaluation, CXL = cross-clamp time *all endocarditis patients

Total

J Heart Valve Dis

2013

Ustunsoy21

Ann Thorac Surg

2013

Pozzoli24

Heart Surg Forum

2013

Jelenc

Iliopoulos19 2013

J Thorac Cardiovasc Surg

Interact Cardiovasc Thorac Surg

Repossini27 2012

2013

Eur J Cardiothorac Surg

Ann Thorac Surg

J Heart Valve Dis

Eur J Cardiothorac Surg

Scand Cardiovasc J

Innovations

Repossini14 2012

Ravenni

J Heart Valve Dis

2010

Kolseth34

Horst

Ann Thorac Surg

2010

Karimov11

J Heart Valve Dis

2010

Beholz15

J Thorac Cardiovasc Surg

2010

Aymard

Interact Cardiovasc Thorac Surg

Multimed Man Cardiothorac Surg

2007

Yerebakan28 2008

Glauber8

journal

year

author

Table 1 Clinical outcomes

R1 R2 R3 R4 R5 R6 R7 R8 R9 R10 R11 R12 R13 R14 R15 R16 R17 R18 R19 R20 R21 R22 R23 R24 R25 R26 R27 R28 R29 R30 R31 R32 R33 R34 R35 R36 R37 R38 R39 38 | Chapter 3

31 (?-83)

277

0.9

0.4

0.9

1.4

1.6

reoperation on FS valve (%) 1.8

0.9

0.4

0.9

0.7

2.3

endocarditis (%)

*follow-up = mean (range) unless stated otherwise, FS = Freedom SOLO

Total

59 (6-69)

Ustunsoy21

1309

Iliopoulos19

Thalmann

24 (24-24)

128

Altintas18

25 (3-43)

12 (0-39)

100

Oses22

13 (2-20)

143

Horst12

229

22 (?-56)

256

Beholz15

Repossini14

14 (?-52)

109

Aymard9

Pfeiffer10

follow-up* (mon) maximum 48

author

Table 2 Clinical follow-up

1-y survival (%)

2-y survival (%)

3-y survival (%)

82 59 60

82 66 78

5-y survival (%)

4-y survival (%)

Systematic review Freedom SOLO | 39

R1 R2 R3 R4 R5 R6 R7 R8 R9 R10 R11 R12 R13 R14 R15 R16 R17 R18 R19 R20 R21 R22 R23 R24 R25 R26 R27 R28 R29 R30 R31 R32 R33 R34 R35 R36 R37 R38 R39

40 | Chapter 3

Hemodynamic performance Tables 3 and 4 report the hemodynamic performance in 1575 patients in 17 studies on the Freedom SOLO. On average, the preoperative peak gradient was 74 mm Hg which declined to 16.8 mm Hg at discharge. During follow-up of 2 to 60 months, the average peak gradient remained stable at 14.6 mm Hg. The average preoperative mean gradient was 47 mm Hg, which declined to 9.1 mm Hg at discharge. During follow-up of 2 to 60 months, the average mean gradient remained stable at 8.6 mm Hg. Seven studies reported on AoI. At discharge, 0.4% of 779 patients had AoI exceeding grade 1, and during follow-up of 4 to 60 months, 0.7% of 923 patients had AoI exceeding grade 1 (combined valvular and paravalvular). Left ventricular ejection fraction remained stable, at 58% preoperatively, 59% at discharge and 61% during follow-up of 2 to 24 months. In five studies (n=441), measurement with transthoracic echocardiography showed left ventricular (LV) mass decreased 19 to 32% up to 2-year follow-up compared with preoperative measurements (p=<0.05) [13-16, 18]. In six studies (n=745), LV end-diastolic diameters decreased 3 to 10% and LV end-systolic diameters decreased 6 to 12% during 1 to 2 years of follow up [15, 16, 18-21]. Only one study showed a high 5% increase in LV end-diastolic diameters and 4% increase in LV end-systolic during 3 months follow-up [17]. Five studies (n=563) reported posterior wall thickness decreased 5 to 14% during 3 to 12 months follow-up [14-17, 19]. Interventricular septum thickness decreased 7 to 15% during 3 to 24 months follow-up in six studies (n=603) [14-19]. Thrombocytopenia Postoperative platelet counts were extracted from 11 studies (n=1015) and compared with their preoperative value [22-32]. A control group was created using postoperative platelet counts from all other aortic valve prostheses included in these 11 studies (n=1090). This comparison is presented in Figure 3. All 11 studies showed that the thrombocytopenia was significantly lower in the Freedom SOLO. In our study, the degree of thrombocytopenia in the Freedom SOLO group was more severe than in the other aortic prostheses. Platelet count after Freedom SOLO implantation was 81% of the preoperative value after 13 days. On average, in the other aortic prostheses platelet counts were back to their preoperative level on postoperative day 9. Of the 11 articles shown in Figure 3, 10 concluded that thrombocytopenia was a numeric phenomenon with no adverse clinical events [22-31]. However, Hirnle and colleagues reported 1 death in 29 Freedom SOLO patients due to thrombotic thrombocytopenic purpura [32]. Seven studies (n=562) reported postoperative thrombocytopenia without reporting the data required for Figure 3 [18-21, 33-35]. Six studies (n=526) reported low platelet count during the first few postoperative days [18-21, 33, 34]. However, no clinical consequences were reported, and the thrombocytopenia was deemed to be a transient laboratory finding. Ustunsoy and colleagues reported platelet transfusion in 6 of 14 patients (43%) [21]. One study reported no difference in postoperative platelet count between the Freedom SOLO and other bio- and mechanical aortic prostheses [35]. In addition, Tarzia and collegues performed a qualitative assessment of platelet function using rotation thromboelastometry and multiple electrode platelet aggregometry. After implantation of the Freedom SOLO, platelet function and platelet interaction with fibrinogen to form thrombus remained normal [33].

128 11 14 277 1575

2013 J Thorac Cardiovasc Surg

2013 Heart Surg Forum

2013 J Heart Valve Dis

Iliopoulos19

Jelenc13

Ustunsoy21

Thalmann20 2014 Ann Thorac Surg

Total

pre

16.8

17 15

post

Pmax

14.6

13 -

latest

pre

9.1

10 6

post

Pmean

1 AoI

8.6

7 -

0.4

1.2

66 60 38 64

0.8

1.9

60 58

0 0.7

59 66

60 -

latest

1.8

61 46

59 -

post

pre

LVEF

latest post (%) latest (%)

> grade

AoI = aortic insufficiency (AoI >grade 1 is reported), LVEF = left ventricular ejection fraction, post = postoperative, pre = preoperative

2013 Tex Heart Inst J

Altintas18

256

2011 J Heart Valve Dis

Reents26

Repossini27 2012 Interact Cardiovasc Thorac Surg

100

2011 Eur J Cardiothorac Surg

Oses22 104

143

2011 J Heart Valve Dis

Horst12

Repossini14 2012 Eur J Cardiothorac Surg

2010 Scand Cardiovasc J

Kolseth34

256

2010 J Heart Valve Dis

Beholz15

109

Yerebakan28 2008 Interact Cardiovasc Thorac Surg

2010 J Thorac Cardiovasc Surg

2008 Anatol J Clin Investig

Karaca17

2 -

follow-up (mon)

Aymard9

30 87

2007 J Heart Valve Dis 2007 Multimed Man Cardiothorac Surg

Da Col Glauber8

journal

year

author

Table 3 Hemodynamic performance

Systematic review Freedom SOLO | 41

R1 R2 R3 R4 R5 R6 R7 R8 R9 R10 R11 R12 R13 R14 R15 R16 R17 R18 R19 R20 R21 R22 R23 R24 R25 R26 R27 R28 R29 R30 R31 R32 R33 R34 R35 R36 R37 R38 R39

277

178*

258

218

-19

-9

post

LVM (g)

-32

-22

-33

-20

latest

pre

50.9

49.4

44.3

52.1

-3

-2

LVEDD (mm) post

-6

-10

-9

-7

-3

latest

pre

33.7

32.9

32.6

-2

-1

LVESD (mm) post

-7

-12

-8

-10

-11

-6

latest

11.8

12.6

11.9

pre

-8

PWT (mm) post

-14

-13

-8

-7

-5

latest

pre

12.3

13.6

14.1

13.9

13.3

-7

IVS (mm) post

-12

-15

-14

-10

-7

-14

latest

IVS = interventricular septum, LVEDD = left ventricular end diastolic diameter, LVESD = left ventricular end systolic diameter, LVM = left ventricular mass, post = postoperative, pre = preoperative, PWT = posterior wall thickness *indexed left ventricular mass

Thalmann

146*

128

Iliopoulos19

Altintas18

104

Repossini14

Jelenc13

256

Beholz15

Ustunsoy21

Karaca17

pre 274

Da Col16

Follow-up (mon)

author

Table 4 Left ventricular remodeling

R1 R2 R3 R4 R5 R6 R7 R8 R9 R10 R11 R12 R13 R14 R15 R16 R17 R18 R19 R20 R21 R22 R23 R24 R25 R26 R27 R28 R29 R30 R31 R32 R33 R34 R35 R36 R37 R38 R39 42 | Chapter 3

Systematic review Freedom SOLO | 43

Figure 3. Incidence of thrombocytopenia with the Freedom SOLO and other bioprostheses FS = Freedom SOLO, N = number of patients from which the data were extracted, POD = postoperative day

Case reports Six case reports described Freedom SOLO failures that needed reintervention. Three patients underwent reoperation [36-38], and 3 patients underwent transcatheter aortic valve implantation [39-41]. During reoperation, Caprili and colleagues found severe calcifications 18 months after the initial AVR [36]. Giordano and colleagues found regurgitation 6 months after the initial AVR due to a rough outflow surface attached to the aortic wall [37]. The final case involved a sudden tear in an otherwise unimpaired prosthesis, 6 years after initial AVR [38]. Learning curve Two studies suggest that the Freedom SOLO has a short learning curve, which is illustrated by decreasing cross-clamp times. Beholz and colleagues showed that after 10 cases, the mean cross-clamp time decreased from 46 minutes to 36 minutes for the next 38 cases [42]. Thalmann and colleagues showed a decreased cross-clamp time of 17% after the first 10 cases by each of 3 surgeons. Another reduction of 15% was achieved after the next 10 cases [20].

COMMENT This systematic review shows that AVR with the Freedom SOLO is safe and feasible, with good prosthesis performance after a mean follow-up of 22 months (maximum 83 months). Operative mortality of 3.5% and stroke rate of 1.1% in 2185 patients with 39% concomitant procedures is comparable with other studies.

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44 | Chapter 3

Data from the Society of Thoracic Surgeons National Database shows an observed mortality of 3.0% and stroke in 1.5% in 141 905 isolated AVRs [3]. The Freedom SOLO shows excellent outcomes regarding the need for postoperative pacemaker implantation. Seven studies that included 702 patients with 49% concomitant procedures reported a pacemaker implantation rate of only 1.7%. In comparison, the reported incidence of pacemaker implantation after isolated AVR is 3.2% to 4% [3, 43] and in series with concomitant procedures 6.6% to 7.2% [44, 45]. We hypothesize this lower incidence in the Freedom SOLO is due to its supraannular implantation technique. The sutures are further away from the conduction system compared with stented prostheses, which necessitate sutures in the native aortic annulus. The Freedom SOLO prosthesis has a simple and fast implantation technique with a short learning curve. In our review, cross-clamp time for isolated AVR was 66 minutes, approximating cross-clamp times of stented aortic bioprostheses (50 to 67 minutes) [46, 47]. This is shorter than other stentless aortic bioprostheses (72 to 128 minutes) [48, 49]. Long-term durability remains an essential feature for aortic bioprostheses. Our review reports 0.5% reoperation rate per patient-year for the Freedom SOLO measured during a mean follow-up of 22 months. In comparison, the reoperation rate for stented aortic bioprostheses is 1.4-2.2% after 5 years [50, 51] and 10% after 10 years [52]. Although none of the case series report early structural valve deterioration of the Freedom SOLO, this follow-up period is not yet long enough to be able to draw firm conclusions regarding durability. Longer follow-up will reveal if the Freedom SOLO is a durable prosthesis. Six case reports described Freedom SOLO failures requiring high-risk reintervention. In 3 of these patients, a transcatheter approach was used, and the distance between the coronary ostia and the supra-annular Freedom SOLO was emphasized in all cases. Remarkably, a different transcatheter prosthesis was used in all interventions and none were shown of obstruct the coronary ostia. In case of bioprosthesis failure requiring a transcatheter approach, a potential advantage for stentless bioprosthesis could be the larger internal diameter of the stentless bioprosthesis compared to a stented bioprosthesis due to the absence of a stent. Therefore, a larger transcatheter bioprosthesis could be implanted [53]. Prosthetic valve endocarditis occurs in 1% to 6% of patients, with an incidence of 0.3% to 1.2% per patientyear [54]. The incidence of prosthetic valve endocarditis of 0.5% per patient-year in the Freedom SOLO is comparable, also in patients who underwent operation for endocarditis. This could be due to the minimal amount of foreign body material associated with the Freedom SOLO (ie, the lack of a stent and the absence of pledgeted sutures). Overall survival is similar to reports in the literature. In a population of the same mean age of 74 years, survival was 90 to 93% at 1 year, 85% at 3 years, and 77 to 80% at 5 years after AVR with various aortic bioprostheses [50, 51]. The 5-year survival appears to be lower; however, this could be due to the few Freedom SOLO patients at risk at 5 years of follow-up. The effective orifice area of the Freedom SOLO is maximized because of the stentless design. This leads to low peak and mean valvular gradients that remain stable during follow-up. In comparison, stented aortic bioprostheses have higher peak gradients of 20 to 30 mmHg and mean gradients of 10 to 16 mmHg [47]. Owing to the implantation technique, paravalvular leakage also appears to be low. Remodeling of the LV

Systematic review Freedom SOLO | 45

has also been shown, with a reduction of LV mass, LV end-diastolic diameters, LV end-systolic diameters, posterior wall thickness, and interventricular septum thickness. Because of the increased risk of sudden cardiac death associated with LV hypertrophy, a decrease in these parameters is desirable [55]. Postoperative thrombocytopenia has been reported after Freedom SOLO implantation and seems to be more evident than in other prostheses, but appears to be a transient laboratory finding. Only one significant complication was observed in 1577 patients; therefore, the clinical significance of this remarkable laboratory finding remains to be clarified. The Freedom SOLO is detoxified with homocysteic acid and stored in a neutral, aldehyde-free solution. That the homocysteic acid could be responsible for the thrombocytopenia has been suggested [28]; however, this hypothesis was rejected because studies of another bioprosthesis detoxified with the same solution did not reveal comparable thrombocytopenia [56], and rinsing the Freedom SOLO before implantation did not prevent thrombocytopenia [24]. Another hypothesis, that the thrombocytopenia was due to the different implantation technique, was also rejected [27]. Oâ&#x20AC;&#x2122;Brien previously used this technique with another bioprosthesis, and thrombocytopenia did not result [4]. Still, the cause of the transient thrombocytopenia remains to be elucidated. Limitations This systematic review has several limitations. None of the studies was randomized, and only six prospective studies were included [9, 14-18]. The other studies are retrospective and therefore subject to methodological limitations. Seven out of 22 studies [13, 23-26, 28, 31] that reported clinical outcomes had a control group. Selection bias was present in almost all studies because the choice of prosthesis was based on the surgeonâ&#x20AC;&#x2122;s preference. Publication bias could also be present; for example, only seven out of 17 papers that reported hemodynamic data presented their findings on AoI. In addition, the follow-up is too short to draw conclusions on the durability of the Freedom SOLO. Substantial longer follow-up is necessary.

CONCLUSION The Freedom SOLO is a stentless aortic bioprosthesis that is safe to use in everyday practice, with crossclamp times comparable to those of stented bioprostheses. Postoperative pacemaker implantation is notably lower, the learning curve is short, and the incidence of prosthetic valve endocarditis is comparable with other prostheses. Valvular gradients are low and remained stable during short-term follow-up. Postoperative thrombocytopenia appears to be a transient laboratory finding, although the cause of this phenomenon is not known. Within a few years, the 15-year follow-up will be available, which will be key to judging the true durability of this bioprosthesis. Thus far, the stentless Freedom SOLO seems to offer the best of both worlds, with superior hemodynamic performance and short cross-clamp times.

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Nishimura RA, Otto CM, Bonow RO, et al. 2014 AHA/ACC Guideline for the management of patients with valvular heart disease: a report of the American college of Cardiology/American heart association task force on practice guidelines. Circulation 2014;129:e521-643 Vahanian A, Alfieri O, Andreotti F, et al. Guidelines on the management of valvular heart disease (version 2012): 2. the joint task force on the management of valvular heart disease of the European society of Cardiology (ESC) and the European association for Cardiothoracic surgery (EACTS). Eur J Cardiothorac Surg 2012;42:S1-44 3. Thourani VH, Suri RM, Gunter RL, et al. Contemporary real-world outcomes of surgical aortic valve replacement in 141,905 low-risk, intermediate-risk, and high-risk patients. Ann Thorac Surg 2015;99(1):55-61 4. O’Brien MF. The Cryolife-O’Brien composite aortic stentless xenograft: surgical technique of implantation. Ann Thorac Surg 1995;60:S410-3 5. von Knobelsdorff-Brenkenhoff F, Trauzeddel RF, Barker AJ, et al. Blood flow characteristics in the ascending aorta after aortic valve replacement-a pilot study using 4D-flwo MRI. Int J Cardiol 2014;170:426-33 6. Funder JA. Current status on stentless aortic bioprosthesis: a clinical and experimental perspective. Eur J Cariothorac Surg 2012;41:790-9 7. Repossini A, Kotelnikov I, Bouchikhi R, et al. Single-suture line placement of a pericardial stentless valve. J Thorac Cardiovasc Surg 2005;130:1265-9 8. Glauber M, Solinas M, Karimov J. Technique for implant of the stentless aortic valve Freedom Solo. Multimed Man Cardiothorac Surg 2007;1018:mmcts.2007.002618 9. Aymard T, Eckstein F, Englberger L, et al. The Sorin Freedom SOLO stentless aortic valve: technique of implantation and operative results in 109 patients. J Thorac Cardiovasc Surg 2010;139:775-7 10. Pfeiffer S, Santarpino G, Fischlein T. Stentless pericardial valve for acute aortic valve endocarditis with annular destruction. J Cardiovasc Med 2015;16:318-9 11. Karimov JH, Cerillo AG, Gasbarri T, et al. Stentless aortic valve implantation through an upper manubrium-limited V-type ministernotomy. Innovations 2010;5:378-80 12. Horst M, Easo J, Hölzl PP et al. The Freedom SOLO valve: mid-term clinical results with a stentless pericardial valve for aortic valve replacement. J Heart Valve Dis. 2011;20:704-10 13. Jelenc M. Juvan KA, Medvešček NT, et al. Influence of type of aortic valve prosthesis on coronary blood flow velocity. Heart Surg Forum 2013;16:E8-14 14. Repossini A, Rambaldini M, Lucchetti V, et al. Early clinical and haemodynamic results after aortic valve replacement with the Freedom SOLO bioprosthesis (experience of Italian multicenter study). Eur J Cardiothorac Surg 2012;41:1104-10 15. Beholz S, Repossini A, Livi U, et al. The Freedom SOLO valve for aortic valve replacement: clinical and hemodynamic results from a prospective multicenter trial. J Heart Valve Dis 2010;19:115-23 16. Da Col U, Di Bella I, Bardelli G, et al. Short-term hemodynamic performance of the Sorin Freedom SOLO valve. J Heart Valve Dis 2007;16:546-50 17. Karaca M, Demirbaş MI, Biceroğlu S, et al. Short-term outcomes of aortic valve replacement with freedom solo pericarbon stentless aortic valve. Anatol J Clin Investig 2008;2:1-3 18. Altintas G, Dike AI, Hanedan O, et al. The Sorin Freedom SOLO stentless tissue valve: early outcomes after aortic valve replacement. Tex Heart Inst J 2013;40:50-5 19. Iliopoulos DC, Deveja AR, Androutsopoulou V, et al. Single-center experience using the Freedom SOLO aortic bioprosthesis. J Thorac Cardiovasc Surg 2013;146:96-102 20. Thalmann M, Kaiblinger J, Krausler R, et al. Clinical experience with the freedom SOLO stentless aortic valve in 277 consecutive patients. Ann Thorac Surg 2014;98:1301-7 21. Ustunsoy H, Yasmin A, Deniz H, et al. Short-term and mid-term results with the Sorin Freedom Solo aortic valve. J Heart Valve Dis 2013;22:215-21 22. Oses P, Guibaud JP, Elia N, et al. Freedom SOLO valve: early- and intermediate-term results of a single centre’s first 100 cases. Eur J Cardiothorac Surg 2011;39:256-61 23. Piccardo A, Rusinaru D, Petitprez B, et al. Thrombocytopenia after aortic valve replacement with freedom solo bioprosthesis: a propensity study. Ann Thorac Surg 2010;89:1425-30 24. Pozzoli A, de Maat GE, Hillege HL, et al. Severe thrombocytopenia and its clinical impact after implant of the stentless Freedom Solo bioprosthesis. Ann Thorac Surg 2013;96:1581-6

Systematic review Freedom SOLO | 47

25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50.

Ravenni G, Celiento M, Ferrari G, et al. Reduction in platelet count after aortic valve replacement: comparison of three bioprostheses. J Heart Valve Dis 2012;21:655-61 Reents W. Babin-Ebell J, Zacher M, et al. Thrombocytopenia after aortic valve replacement with the Sorin Freedom Solo prosthesis. J Heart Valve Dis 2011;20:313-8 Repossini A, Bloch D, Muneretto C, et al. Platelet reduction after stentless pericardial aortic valve replacement. Interact Cardiovasc Thorac Surg 2012;14:434-8 Yerebakan C, Kaminski A, Westphal B, et al. Thrombocytopenia after aortic valve replacement with the Freedom Solo stentless bioprosthesis. Interact Cardiovasc Thorac Surg 2008;7:616-20 Gersak B, Gartner U, Antonic M. Thrombocytopenia following implantation of the stentless biological sorin freedom SOLO valve. J Heart valve Dis 2011;20:401-6 Hilker L, Wodny M, Ginesta M, et al. Differences in the recovery of platelet counts after biological aortic valve replacement. Interact Cardiovasc Thorac Surg 2009;8:70-3 Miceli A, Gilmanov D, Murzi M, et al. Evaluation of platelet count after isolated biological aortic valve replacement with Freedom Solo bioprosthesis. Eur J Cardiothorac Surg 2012;41:69-73 Hirnle T, Juszcyk G, Tycińska A, et al. Thrombocytopenia and perioperative complications after stentless Freedom Solo valve implantation. Kardiol Pol 2013;71:334-40 Tarzia V, Bottio T, Buratto E, et al. Freedom solo stentless aortic valve: quantitative and qualitative assessment of thrombocytopenia. Ann Thorac Surg 2011;92:1935 Kolseth SM, Nordhaug D, Stenseth R, et al. Initial experience with the Freedom Solo stentless aortic valve in a low volume centre. Scand Cardiovasc J 2010;44:301-6 van Straten HA, Hamad MA, Berreklouw E, et al. Thrombocytopenia after aortic valve replacement: comparison between mechanica land biological valves. J Heart Valve Dis 2010;19:394-9 Caprili L, Fahim AN, Zussa C, et al. Very early malfunction of a large stentless aortic valve. Eur J Cardiothorac Surg 2009;36:417-8 Giordano V, Hermens JA, Wajon WM, et al. Rare prosthesis failure after aortic valve replacement with a Freedom Solo. Interact Cardiovasc Thorac Surg 2011;12:273-5 Wollersheim LW, Li WW, van der Meulen J, et al. A 76-year old man with a torn Freedom SOLO bioprosthesis. Interact Cardiovasc Thorac Surg 2014;18:141-2 Halapas A, Chrissoheris M, Spargias K. Challenging transfemoral valve-in-valve implantation in a degenerated stentless bioprosthetic aortic valve. J Invasive Cardiol 2014;26:E106-8 Matjaž B, Miha S, Igor K, et al. Transfemoral Edwars Sapien XT valve-in-valve implantation for failing Freedom Solo stentless aortic bioprosthesis. Exp Clin Cardiol 2014;20:145-48 Wollersheim LW, Cocchieri R, Symersky P, et al. Transapical JenaValve in a degenerated Freedom SOLO bioprosthesis. J Thorac Cardiovasc Surg 2014;148:741-2 Beholz S, Claus B, Dushe S, et al. Operative technique and early hemodynamic results with the Freedom Solo valve. J Heart Valve Dis 2006;15:429-32 Bagur R, Manazzoni JM, Dumont É, et al. Permanent pacemaker implantation following isolated aortic valve replacement in a large cohort of elderly patients with severe aortic stenosis. Heart 2011;97:1687-94 Schurr UP, Berli J, Berdajs D, et al. Incidence and risk factors for pacemaker implantation following aortic valve replacement. Interact Cardiovasc Thorac Surg 2010;11:556-60 Huynh H, Dalloul G, Ghanbari H, et al. Permanent pacemaker implantation following aortic valve replacement: current prevalence and clinical predictors. Pacing Clin Electrophysiol 2009;32:1520-5 Pollari F, Santarpino G, Dell’Aquila AM, et al. Better short-term outcome by using sutureless valves: a propensitymatched score analysis. Ann Thorac Surg 2014;98:611-6 Dalmau MJ, González-Santos JM, Bláquez JA, et al. Hemodynamic performance of the Medtronic Mosaic and Perimount Magna aortic bioprostheses: five-year results of a prospective randomized study. Eur J Cardiothorac Surg 2011;39:844-52 Nyawo B, Graham R, Hunter S. Aortic valve replacement with the Sorin Pericarbon Freedom stentless valve: five-year follow up. J Heart Valve Dis 2007;16:42-8 Miraldi F, Spagnesi L, Tallarico D, et al. Sorin stentless pericardial valve versus Carpentier-Edwards Perimount pericardial bioprosthesis: is it worthwile to struggle? Int J Cardiol 2007;118:253-5 Asch FM, Heimansohn D, Doyle D, et al. Mitroflow aortic bioprosthesis 5-year follow-up: north American prospective multicenter study. Ann Thorac Surg 2012;4:1198-203

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51.

Glaser N, Franco-Cerededa A, Sartipy U. Late survival after aortic valve replacement with the perimount versus the mosaic bioprosthesis. Ann Thorac Surg 2014;97:1314-20 52. Rahimtoola SH. Choice of prosthetic heart valve in adults an update. J Am Coll Cardiol 2010;55:2413-26 53. Bapat V, Davies W, Attia R, et al. Use of balloon expandable transcatheter valves for valve-in-valve implantations in patients with degenerative stentless aortic bioprostheses: Technical considerations and results. J Thorac Cardiovasc Surg 2014;148:917-22 54. Habib G, Hoen B, Tornos P, et al. Guidelines on the prevention, diagnosis, and treatment of infective endocarditis (new version 2009): the task force on the prevention, diagnosis, and treatment of infective endocarditis of the European society of Cardiology (ESC). Endorsed by the European society of clinical microbiology and infectious diseases (ESCMID) and the international society of chemotherapy (ISC) for infection and cancer. Eur Heart J 2009;30:2369-413 55. Stevens SM, Reinier K, Chugh SS. Increased left ventricular mass as a predictor of sudden cardiac death: is it time to put it to the test? Circ Arrythm Electrophysiol 2013;6:212-7 56. Santarpino G, Pfeiffer S, Fischlein T. Thrombocytopenia after freedom solo: the mystery goes on. Ann Thorac Surg 2011;91:330

CHAPTER 4 Midterm follow-up of the stentless Freedom SOLO bioprosthesis in 350 patients

Wollersheim LW, Li WW, Bouma BJ, Kaya A, van Boven WJ, van der Meulen J, de Mol BA The Annals of Thoracic Surgery 2016: in press

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ABSTRACT Background: The stentless Freedom SOLO aortic bioprosthesis is implanted supraannularly using one running suture line in the sinuses of Valsalva. We report our 9-year experience with this bioprosthesis. Methods: From April 2005 to July 2014, 350 consecutive patients at our institution underwent aortic valve replacement with the Freedom SOLO bioprosthesis. Follow-up and echocardiographic data were collected retrospectively from referring cardiology centers. Results: The mean age was 76 Âą 6 years, 48% were male, and 46% underwent a concomitant procedure. Median EuroSCORE II was 3.0 (interquartile range 1.9 to 4.9). Operative mortality was 5.1% for all procedures and 2.1% for isolated aortic valve replacement. The 1-, 5- and 9-year overall survival was 92%, 74%, and 47%, respectively. At 6 years, freedom from structural valve deterioration and freedom from aortic valve reoperation were 98% and 96%, respectively. Prosthetic valve endocarditis occurred at a rate of 0.8% per patient-year. Permanent pacemaker implantation was necessary in 2.3% (n=8), and moderate and severe prosthesis-patient mismatch occurred in 30 patients overall (9.6%). Postoperative maximum and mean valvular gradients were 17 mmHg and 10 mmHg, respectively, and remained stable during follow-up. Conclusions: Aortic valve replacement with the Freedom SOLO is safe and has a low rate of permanent pacemaker implantations and prosthesis-patient mismatch. Survival is comparable to that with other aortic bioprostheses, and structural valve deterioration and aortic valve reoperation are infrequent during midterm follow-up. Hemodynamic performance is excellent, with low valvular gradients that remain stable during follow-up.

Midterm follow-up of the Freedom SOLO | 51

INTRODUCTION The Freedom SOLO (Sorin, Saluggia, Italy) is a stentless aortic valve bioprosthesis first described in 2005 by Repossini and colleagues after modification of the Pericarbon Freedom stentless valve (Sorin, Saluggia, Italy) [1]. The Freedom SOLO is implanted supraannularly using one running suture line in the sinuses of Valsalva. As a result of the supraannular implantation and its stentless design, effective orifice area is maximized, leading to reduced valvular gradients. Short- and midterm results up to 3 years are excellent, showing low valvular gradients and regression of left ventricular mass [2, 3]. However, Stanger and colleagues recently reported an increased explantation rate of Freedom SOLO bioprostheses after only 6 to 7 years [4]. Therefore, longer follow-up and more data from other institutions are necessary for evaluation of its durability. The purpose of the present study was to report our institution’s 9-year experience in 350 consecutive patients who had an aortic valve replacement (AVR) with the stentless Freedom SOLO bioprosthesis.

MATERIAL AND METHODS Study population Between April 2005 and July 2014, 350 consecutive patients underwent AVR with the Freedom SOLO bioprosthesis at the Academic Medical Center in Amsterdam, The Netherlands. Baseline patient characteristics, operative details, and in-hospital complications were collected from the Academic Medical Center database. On August 1, 2014, information on vital status was obtained from the Dutch national population registry (Statistics Netherlands, Voorburg, The Netherlands). Follow-up data and echocardiographic results were collected retrospectively from referring cardiology centers. Patients were censored at the time of last contact. The Society of Thoracic Surgeons Adult Cardiac Surgery Database Data Specifications, version 2.81, was used for definitions of baseline characteristics and postoperative outcome [5]. Preoperative renal failure was defined as a calculated creatinine clearance of less than 50 mL/min using the Cockcroft-Gault formula [6]. For definitions of structural valve deterioration, nonstructural dysfunction, embolism, bleeding event, endocarditis, and aortic valve reoperation, the guidelines for reporting mortality and morbidity after cardiac valve interventions were used [7]. Moderate and severe prosthesis-patient mismatch (PPM) were defined as an indexed effective orifice area of 0.65 to 0.85 cm2/m2 and less than 0.65 cm2/m2, respectively [8]. This study was approved by the medical ethics committee of the Academic Medical Center in Amsterdam and patient consent was waived. Operative technique and postoperative management Choice of prosthesis was based on surgeon’s preference, and in consultation with the patient. The predominant approach was a median sternotomy (99%). For isolated AVR, routine cannulation of the ascending aorta and right atrium (two-stage cannula) was performed and mild hypothermic (32 to 34°C)

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cardiopulmonary bypass was instituted at the discretion of the surgeon. After aortic cross-clamping and administration of antegrade cardioplegia solution, a transverse aortotomy was performed approximately 1 cm above the sinotubular junction. The diseased aortic valve was resected, and the annulus was decalcified. The aortic annular diameter was measured, and according to the manufacturerâ&#x20AC;&#x2122;s instructions, the Freedom SOLO was not rinsed and implanted supraannularly in the sinuses of Valsalva using three continuous 4-0 polypropylene sutures. After completion, the sutures were tied extra-aortically, and the aortotomy was closed using the Blalock suture technique. Transesophageal echocardiography was used to assess the function of the Freedom SOLO bioprosthesis. Up to 2010, all patients received oral anticoagulation (OAC) therapy for 3 months postoperatively followed by lifelong acetylsalicylate 100 mg daily. From 2010, all patients received only lifelong antiplatelet therapy with acetylsalicylate 100 mg daily unless otherwise indicated by concomitant morbidities. Statistical analysis Data are expressed as mean Âą standard deviations, median with interquartile range or as numbers and percentiles as appropriate. The hazard ratios (HRs) of variables associated with long-term survival were analyzed using Cox regression. First, independent variables were presented to a univariate model. These variables are presented in supplementary Table 1. Variables with a probability value of less than 0.30 were candidates for multivariate Cox regression model. Colinearity was defined as a correlation coefficient of greater than 0.8. If colinearity existed between variables, the variable with the strongest association was selected. Multivariate analysis was continued using backwards selection until all variables reached a probability value of less than 0.05 in the multivariate Cox regression model. The proportional hazard assumptions were tested using the log-minus-log test. Survival, structural valve deterioration, and rate of aortic valve reoperation were analyzed using the Kaplan-Meier method. Statistical analyses were performed using SPSS, version 21 (IBM Corp., Armonk, NY, USA). A probability value of less than 0.05 was considered statistically significant.

RESULTS Baseline patient characteristics are presented in Table 1.

Midterm follow-up of the Freedom SOLO | 53

Table 1. Baseline patient characteristics Characteristic

Freedom SOLO (n=350)

Age (mean±SD) Male (%)

76±6 168 (48)

NYHA functional class I (%)

31 (9)

II (%)

92 (26)

III (%)

178 (51)

IV (%)

49 (14)

BMI (mean±SD)

27±4

Diabetes (%)

88 (25)

Hypertension (%)

235 (67)

Dyslipidemia (%)

192 (55)

COPD (%)

77 (22)

PVD (%)

53 (15)

Previous MI (%) / recent MI (%)

70 (20) / 26 (7)

Previous CVA (%) / previous TIA (%)

14 (4) / 32 (9)

Renal failure (%)

61 (17)

LVEF>50% (%)

270 (78)

LVEF 30-50% (%)

66 (19)

LVEF <30% (%)

11 (3)

Reoperation (%)

10 (3)

Endocarditis (%)

12 (3)

OR indication Aortic stenosis (%)

260 (74)

Aortic insufficiency (%)

13 (4)

Mixed stenosis and insufficiency (%)

77 (22)

EuroSCORE I (mean±SD)

7.6±2.3

EuroSCORE II (median, interquartile)

3.0, 1.9-4.9

Logistic EuroSCORE (median, interquartile) Thrombocytes, x 109/L (mean±SD)

7.7, 5.3-11.6 241±72

BMI = body mass index, COPD = chronic obstructive pulmonary disease, CVA = cerebro-vascular accident, EuroSCORE = European System for Cardiac Operative Risk Evaluation, LVEF = left ventricular ejection fraction, MI = myocardial infarction, NYHA = New York heart association, OR = operation, PVD = peripheral vascular disease, TIA = transientischemic attack

Early clinical outcomes Perioperative data and early clinical outcomes are presented in Table 2. Operative mortality for all procedures was 5.1% (n=18) and for isolated AVR, 2.1% (n=4). Causes of early death were not valve related, being respiratory insufficiency (n=5), low cardiac output (n=4), multi-organ failure (n=3), various cardiac causes (n=3, ventricular fibrillation, sudden cardiac death, and myocardial infarction), and 3 of other noncardiac causes.

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Table 2. Perioperative data and early outcomes Perioperative data and early outcomes

Freedom SOLO (n=350)

Emergency OR (%) Prosthesis size (mm)

9 (3)

19 (%)

7 (2)

21 (%)

69 (20)

23 (%)

117 (33)

25 (%)

106 (30)

27 (%)

51 (15)

Concomitant procedure (%)

162 (46)

CABG

138

MVP

MVR

TVP

Other

Cardiopulmonary bypass time (mean±SD)

131±49

Cross-clamp time (mean±SD)

99±35

Isolated AVR cross-clamp time (mean±SD)

80±19

Mortality (%)

18 (5.1)

CVA (%)

7 (2)

TIA (%)

6 (1.7)

Reoperation for bleeding (%)

25 (7.1)

Renal failure (%)

26 (7.4)

Temporary renal replacement therapy

8 (2.3)

Pacemaker (%)

8 (2.3)

Pneumonia (%)

15 (4.3)

New-onset atrial fibrillation (%)

114 (33)

Sternal wound infection (%)

6 (1.7)

Lowest postoperative thrombocytes (mean±SD)

70±38

On postoperative day (mean ±SD)

2.9±1.5

Reoperation for delayed tamponade (%)

8 (2.3)

Gastrointestinal bleeding event (%)

5 (1.4)

Thrombocyte transfusions after OR, n (%)

35 patients (10)

RBC after OR, n (%)

108 patients (31)

ICU stay (median, interquartile)

2, 1-3

LOS for patients who are discharged home (median, interquartile)

10, 7-14.5

Discharge LVEF >50% (%)

228 (68)

Discharge LVEF 30-50% (%) Discharge LVEF <30% (%)

98 (29) 9 (3)

CABG = coronary artery bypass graft, CVA = cerebro-vascular accident, ICU = intensive care unit, LOS = length of hospital stay, LVEF = left ventricular ejection fraction, MVP = mitral valve repair, MVR = mitral valve replacement, OR = operation, RBC = red blood cell, TIA = transient-ischemic attack, TVP = tricuspid valve repair

Midterm follow-up of the Freedom SOLO | 55

Mean lowest postoperative platelet count was 70 ± 38 109/L which occurred after a mean of 2.9 ± 1.5 days. A postoperative platelet count of less than 50 x 109/L was seen in 106 patients (30%). Postoperatively 108 patients (31%) had a blood transfusion and 35 patients (10%) had a platelet transfusion. Eight patients (2.3%) underwent subxiphoid drainage owing to delayed tamponade, and 5 patients (1.4%) had a gastrointestinal bleeding event. Of these 13 patients, 11 were taking OAC, and one delayed tamponade occurred after removal of the temporary pacemaker wires. Midterm outcomes Mean and median clinical follow-up was 3.4 ± 2.3 (range 0.1 to 9.95 years) and 2.8 years (interquartile range 1.6 to 4.9 years), respectively. Seven patients (2%) were lost to follow-up. Survival Survival is presented in Figure 1. The 1-, 5- and 9-year overall survival was 92%, 74%, and 47%, respectively. During follow-up 71 patients died; the causes of these late deaths were pneumonia (n=10), prosthetic valve endocarditis (n=2), other infection (n=5), heart failure (n=9), myocardial infarction (n=2), stroke (n=3), carcinoma (n=10), euthanasia (n=2), renal failure (n=2), bleeding event (n=1), abdominal aneurysm (n=2), and unknown (n=23). On multivariate analysis, independent risk factors for long-term mortality were recent myocardial infarction (HR 5.1 [95% CI, 2.6-9.9];P=<0.001), pneumonia (HR 3.8 [95% CI, 1.6-9.2];P=0.003), postoperative neurologic event (HR 3.7 [95% CI, 1.5-9.1];P=0.004), PPM (HR 2.1 [95% CI, 1.0-4.2];P=0.04), male (HR 2.0 [95%CI, 1.2-3.3];P=0.01), diabetes mellitus (HR 1.8 [95% CI, 1.1-3.1];P=0.03) and age (HR 1.06 [95% CI, 1.0-1.1]P=0.04). At latest follow-up, 77% of the patients were in New York Heart Association functional class I, 18% were in class II, 4% were in class III, and 1% were in class IV. The latest echocardiogram showed a good left ventricular function in 78% of the patients, a moderate left ventricular function in 20%, and a poor left ventricular function in 2%.

Figure 1. Survival

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Reoperation and prosthetic valve endocarditis At 6 years, freedom from structural valve deterioration is 98% and freedom from aortic valve reoperation is 96% (Figure 2). In total, there were 7 reoperations; the causes of reoperation are presented in Table 3. There was one immediate technical failure in a patient with a calcified aortic annulus and aortic root who underwent reoperation after 12 days. During reoperation, the Freedom SOLO prosthesis showed inadequate coaptation, a fold was seen in the noncoronary cusp, and it was possible to pass a nerve hook through the noncoronary sinus into the left ventricular outflow tract. During early follow-up, 2 patients required reoperation because of aortic valve insufficiency. In 1 patient, a broken polypropylene suture was found to be responsible for the paravalvular leakage and the Freedom SOLO was replaced with a stented bioprosthesis. In the other patient, the right coronary cusp of the Freedom SOLO had become completely attached to the aortic wall, probably because of imperfect symmetric implantation. After careful dissection and two plication sutures, the leaflet was once again functioning normally. The Freedom SOLO was left in place and continued to function well postoperatively, with grade 1 aortic valve insufficiency at 8 years follow-up. However, recently the patient exhibited structural valve deterioration with increased valvular gradients, and is currently under review of the heart team and likely to undergo another reintervention. Two additional patients showed structural valve deterioration after 7 years. One Freedom SOLO was stenotic, and one had a tear. At reoperation, the torn Freedom SOLO was replaced with a stented bioprosthesis [9], and the stenotic Freedom SOLO was replaced with a transapical JenaValve (JenaValve Technology, Munich, Germany) [10]. Nine patients had prosthetic valve endocarditis (0.8% per patient-year, 95% CI, 0.4-1.5). Two patients underwent reoperation at 2 and 3 years postoperatively, during which 1 patient died. The other 7 patients were treated with intravenous antibiotics; 6 treatments were successful, and 1 patient died.

Figure 2. Freedom from aortic valve reoperation and SVD AV = aortic valve, SVD = structural valve deterioration

Midterm follow-up of the Freedom SOLO | 57

Table 3. Freedom SOLO reoperations Follow-up

FS (mm)

Reason

Reoperation

Conclusion

12 days 9 months

23 23

AoI + gradient AoI

AVR AVR

Technical failure Non SVD

2 years

Endocarditis

AVR

Non SVD

2 / 8 years

AoI / stenosis

AVP / HT

Non SVD / SVD

3 years

Endocarditis

AVR

Non SVD

7 years 7 years

25 23

Tear Stenosis

AVR TAVI

SVD SVD

AoI = aortic valve insufficiency, AVP = aortic valve repair, AVR = aortic valve replacement, FS = Freedom SOLO, HT = under consideration of the heart team, SVD = structural valve deterioration, TAVI = transcatheter aortic valve implantation

Thromboembolism and bleeding events During follow-up, 22 patients had an embolic event (1.9% per patient-year, 95% CI, 1.3-3.0). Eleven patients had a stroke: 1 as a results of a septic embolus from endocarditis, 3 caused by atrial fibrillation, 1 patient after carotid endarterectomy, and 2 after reoperation (coronary artery bypass graft and mitral valve replacement). Ten patients had a transient-ischemic attack, 3 of whom were in atrial fibrillation. One patient had a peripheral embolus in her toe. During follow-up, 18 patients had a reported bleeding event (1.6% per patient-year, 95% CI, 1.0-2.5). Eight patients had gastrointestinal bleeding, 6 of whom were using OAC. Two patients had a hemorrhagic cerebrovascular accident; both were taking OAC. One patient had hematuria and was also taking OAC. Seven patients had epistaxis, 3 of whom were taking OAC. Echocardiographic data Echocardiographic data are presented in Table 4. The postoperative maximum and mean valvular gradients were 17 ± 9 mmHg and 10 ± 5 mmHg, respectively, and they remained stable during 9 years of follow-up. Mean aortic valve area was 2.6 ± 0.8 cm2, with a mean implanted valve size of 23.7 mm. Postoperative central aortic valve insufficiency of grade 2 or greater was present in 3% of patients, and postoperative paravalvular leakage of grade 1 or greater was present in 1%. This remained stable during follow-up. Data on PPM were available in 314 patients, either directly postoperatively or on a follow-up transthoracic echocardiography within 2 years. Severe PPM was present in 4 patients (1.3%), and moderate PPM was present in 26 patients (8.3%). Two 21mm, one 23mm, and one 25mm Freedom SOLO bioprostheses were involved in severe PPM, and two 19mm, fifteen 21mm, eight 23mm, and one 25mm bioprostheses were involved in moderate PPM.

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Table 4. Echocardiographic data All (n=350) Pmax Pmean AVA IEOA AoI≥gr II PVL≥gr I 19mm (n=7) Pmax Pmean AVA IEOA AoI≥gr II PVL≥gr I 21mm (n=69) Pmax Pmean AVA IEOA AoI≥gr II PVL≥gr I 23mm (n=117) Pmax Pmean AVA IEOA AoI≥gr II PVL≥gr I 25mm (n=106) Pmax Pmean AVA IEOA AoI≥gr II PVL≥gr I 27mm (n=51) Pmax Pmean AVA IEOA AoI≥gr II PVL≥gr I

Preop n=349 75±24 48±17 0.9±0.2 n=7 66±24 46±12 0.7±0.1 n=69 74±24 47±17 0.8±0.3 n=117 76±23 49±17 0.8±0.2 n=106 78±25 50±18 0.9±0.2 n=50 69±23 44±16 1±0.3 -

Postop n=336 17±9 10±5 2.6±0.8 1.3±0.4 11 (3%) 5 (1%) n=7 28±11 15±6 1.8±0.2 1.0±0.2 1 (14%) 0 n=67 21±8 12±5 2±0.5 1.1±0.3 2 (3%) 0 n=111 18±10 10±5 2.4±0.6 1.3±0.3 2 (2%) 3 (3%) n=102 15±6 9±4 2.8±0.7 1.3±0.4 4 (4%) 1 (1%) n=49 13±8 8±3 3.4±0.7 1.7±0.4 2 (4%) 1 (2%)

3-12 mon n=154 15±7 9±5 2.4±0.7 1.3±0.4 7 (5%) 1 (1%) n=5 17±3 10±2 1.5±0.4 1.0±0.3 1 (20%) 0 n=29 21±9 11±6 1.8±0.4 1.0±0.2 2 (7%) 0 n=50 16±7 9±5 2.4±0.5 1.3±0.3 2 (4%) 0 n=49 14±5 7±3 2.8±0.7 1.4±0.4 2 (4%) 1 (2%) n=21 11±4 6±3 3±0.6 1.5±0.4 0 0

1-2y n=147 17±8 10±5 2.3±0.7 1.2±0.4 8 (5%) 0 n=3 36±8 21±6 1.4±0 0.8 1 (33%) 0 n=38 21±9 12±5 1.8±0.5 1.0±0.3 0 0 n=47 16±6 9±4 2.3±05 1.2±0.3 3 (6%) 0 n=40 16±8 9±5 2.7±0.7 1.4±0.4 2 (5%) 0 n=19 13±5 8±3 3±0.7 1.6±0.3 2 (11%) 0

2-3y n=91 17±8 10±5 2.4±0.8 1.3±0.4 3 (3%) 1 (1%) n=1 20 NA NA NA 0 0 n=15 22±11 15±8 1.5±0.3 0.9±0.2 0 0 n=24 18±7 10±4 2.5±0.6 1.3±0.4 1 (4%) 0 n=37 16±8 9±4 2.7±0.8 1.4±0.5 2 (5%) 0 n=14 14±4 8±2 3±1.1 1.3±0.5 0 1 (7%)

3-5y n=98 19±9 11±5 2.1±0.7 1.1±0.3 1 (1%) 1 (1%) n=4 22±5 12±4 1.5±1 0.9±0.3 0 0 n=26 26±10 17±6 1.8±0.3 1.0±0.3 0 0 n=24 19±7 10±4 2.1±0.5 1.1±0.3 0 0 n=34 17±6 10±3 2.3±0.7 1.1±0.4 1 (3%) 0 n=10 10±6 4±3 3.4±0.8 1.6±0.4 0 1 (10%)

5-7y n=38 22±17 13±13 2±0.7 1.1±0.5 2 (6%) 1 (3%) n=1 28 NA NA NA 0 0 n=7 24±7 13±4 1.6±0.2 0.9±0.3 0 0 n=14 25±25 17±19 1.8±0.8 1.0±0.5 0 0 n=12 20±12 11±8 2.3±0.6 1.2±0.5 2 (17%) 0 n=4 13±2.6 6±1.5 3.4±0 1.8 0 1 (25%)

7-9y n=13 24±18 15±12 1.7±0.6 0.8±0.3 1 (8%) 1 (8%) n=0 n=2 22±1 NA NA NA 0 0 n=6 35±23 22±13 1.6±0.7 0.7±0.3 1 (16%) 0 n=3 11±2 6±0 NA 1.1 0 0 n=2 12±1 6±0 NA NA 0 1 (50%)

AoI = aortic valve insufficiency, AVA = aortic valve area, IEOA = indexed effective orifice area, NA = not available, Pmax = maximum valvular gradient, Pmean = mean valvular gradient, Postop = postoperative, Preop = preoperative, PVL = paravalvular leakage

Midterm follow-up of the Freedom SOLO | 59

COMMENT The current article reviews our 9-year experience with the stentless Freedom SOLO bioprosthesis for AVR in 350 consecutive patients. Midterm results at 6 years showed 98% freedom from structural valve deterioration and 96% freedom from aortic valve reoperation. Early clinical outcomes showed an operative mortality of 5.1%, and 2.3% received a permanent pacemaker. Hemodynamic performance was excellent with low valvular gradients that remained stable during follow-up. Additionally, moderate and severe PPM was present in only 9.6% of patients. Operative mortality was 5.1%, which is in line with the EuroSCORE. Mean age was reasonably high at 76Âą6 years, and concomitant procedures were performed in 46% of patients; both factors increased the operative risks. Operative mortality for isolated AVR was 2.1%, which is comparable to the 3.0% recently reported in The Society of Thoracic Surgeons database [11]. Reoperation for bleeding was necessary in 7% which is comparable to the 6% to 8% reported by both Pozolli and colleagues [12] and Miceli and colleagues [13], but higher compared with other reports on the Freedom SOLO (1.8% to 4.5%) [14, 15]. However, we believe these reoperations for bleeding were not valve related. In our cohort the mean age was 76 years, which makes the 9-year overall survival of 47% satisfactory. This is consistent with data on other aortic bioprostheses with patients of comparable age [16, 17]. Our midterm results at 6 years, show a freedom from structural valve deterioration of 98% and a freedom from aortic valve reoperation of 96%. This is promising; however, the 10-year freedom from structural valve deterioration of aortic bioprostheses is reported to be approximately 90% [18], and all new bioprostheses should be benchmarked against this number. Stanger and colleagues reported the alarming number of 14 Freedom SOLO explantations in 149 patients, and freedom from aortic valve reoperation was 72% at 9 years [4]. In comparison, our series appears to show better durability of the Freedom SOLO. However, after 7 years we have also detected a slight decrease in durability. Whether this is related to the small number of patients at risk in this group (27 patients at 7 years) or because the Freedom SOLO is not durable remains to be clarified. Longer follow-up with more patients is necessary. Reoperations for the Freedom SOLO were technically not more demanding compared to reoperations for stented bioprostheses. At discretion of the surgeon, either the whole prosthesis or only the leaflets were removed. The Freedom SOLO was designed for faster implantation than traditional stentless bioprostheses [1]. In our study, cross-clamp time for isolated AVR was 80 minutes. Other case series with the Freedom SOLO report mean cross-clamp times of 51 to 53 minutes [19, 20]. We believe our longer cross-clamp times are attributable to the proctoring and training of surgeons and residents. Thirteen surgeons in total were involved, only 5 of whom implanted more than 10 Freedom SOLO prostheses. Our data did reveal that a Freedom SOLO can be implanted within 1 hour by experienced surgeons. Permanent pacemaker was implanted in 2.3%, which is lower than the reported 7% in a meta-analysis including 2,557 patients undergoing isolated AVR and receiving stented bioprostheses [21]. This could be related to the supraannular implantation technique of the Freedom SOLO, with suture lines farther away

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60 | Chapter 4

from the conduction system. Of the 8 patients who received a pacemaker, 6 had concomitant procedures (4 coronary artery bypass graft, 1 mitral- and tricuspid valve, and 1 closure of an atrial septal defect), which is an additional risk factor for postoperative pacemaker implantation. The 2 patients who had isolated AVR and received a pacemaker were early in the cohort, owing to third-degree atrioventricular block and brady-tachy syndrome. Possible explanations for the heart block could be extensive decalcification of the aortic annulus or that early in the learning curve the Freedom SOLO is sometimes implanted in the annular position instead of supraannularly. Placing the Freedom SOLO in the annular position is a major flaw, potentially leading to a higher gradient and early structural valve deterioration. In the present study the Freedom SOLO showed excellent valvular gradients, comparable with those of other reports [3, 14], and remained stable during the 9-year follow-up. These valvular gradients are excellent in comparison with other available stented and stentless bioprostheses in which maximal gradients of 20 to 24 mmHg and mean gradients of 10 to 12 mm Hg are reported [22, 23]. The reported incidence of severe PPM is 2% to 11% and of moderate PPM is 20% to 70%, depending on patient population [8]. In another stentless bioprosthesis, PPM was reported to be as high as 36% [24]. Our reported overall 9.6% PPM is therefore acceptable, and in line with other Freedom SOLO reports [14]. This makes the Freedom SOLO an excellent bioprosthesis for patients at risk for PPM, specifically female patients and those with a high body mass index. It would have been interesting to include regression of left ventricular mass in the evaluation of the Freedom SOLO as Altintas and colleagues had shown a significant regression of 32% after 2 years [2]. However, evaluation of left ventricular mass is not included in the standard follow-up echocardiographic investigation in the Netherlands. Postoperative thrombocytopenia was observed, a phenomenon that was previously reported not to have clinical consequences [25, 26]. In our cohort 10% of the patients received at least one platelet transfusion postoperatively, owing to thrombocytopenia or persisted mediastinal chest tube drainage. Thirty-one percent received at least one blood transfusion postoperatively. The threshold for a blood transfusion was a hemoglobin level of 5 mmol/L (8.05 g/dL). The number of patients who received a postoperative blood transfusions appears high; this could be related to the combination of a high number of reoperations for bleeding (7%) and the fairly old population. Also, blood-saving techniques such as mini-sternotomy (only 1%) or minimized extracorporeal circulation were not used. There were 8 (2.3%) reoperations for delayed tamponade and 5 (1.4%) gastrointestinal bleeding events on the ward. Of these 13 patients, 11 were taking OAC. Using linear regression, we found no correlation between thrombocytopenia and these adverse events. It could be argued that as long as the reason for the thrombocytopenia phenomenon is unknown, the implantation of a Freedom SOLO should be avoided in patients with thrombocytopenia preoperatively. This study has several limitations. It is a retrospective study without a comparator group, and the choice to use the Freedom SOLO was made by the surgeon in consultation with the patient. This could induce selection bias. In this retrospective study, 7 patients (2%) were lost to follow-up. There was no standard echocardiographic protocol, and at the referring cardiology centers, follow-up echocardiograms were not scheduled at the same time points. Furthermore, 25% of the patients did not yet have a follow-up echocardiogram.

Midterm follow-up of the Freedom SOLO | 61

Additionally, the follow-up is limited to a maximum of 9 years. Longer follow-up is needed to judge the true durability of the Freedom SOLO.

CONCLUSIONS AVR with the stentless Freedom SOLO is safe and has a low rate of postoperative permanent pacemaker implantations. Survival is comparable to that for other aortic bioprostheses, and freedom from structural valve deterioration and freedom from aortic valve reoperation are infrequent during midterm follow-up. The Freedom SOLO could be very useful in patients at risk for PPM. Its hemodynamic performance is excellent, with low valvular gradients that remain stable during follow-up.

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REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23.

25. 26.

Repossini A, Kotelnikov I, Bouchikhi R, et al. Single-suture line placement of a pericardial stentless valve. J Thorac Cardiovasc Surg. 2005;130:1265-9 Altintas G, Diken AI, Hanedan O, et al. The Sorin Freedom SOLO stentless tissue valve: early outcomes after aortic valve replacement. Tex Heart Inst J 2013;40:50-5 Grubitzsch H, Wang S, Matschke K, et al. Clinical and haemodynamic outcomes in 804 patients receiving the Freedom SOLO stentless aortic valve: results from an international prospective multicentre study. Eur J Cardiothorac Surg 2014;47:e97-104 Stanger O, Bleuel I, Reineke S, et al. Pitfalls and premature failure of the Freedom SOLO stentless valve. Eur J Cardiothorac Surg 2015;48:562-70 STS Adult Cardiac Surgery Database Data Specifications, version 2.81, http://www.sts.org/sts-national-database/ database-managers/adult-cardiac-surgery-database/data-collection Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16:31-41 Akins CW, Miller DC, Turina MI, et al. Guidelines for reporting mortality and morbidity after cardiac valve interventions. J Thorac Cardiovasc Surg 2008;135:732-8 Pibarot P, Dumesnil JG. Prosthesis-patient mismatch: definition, clinical impact, and prevention. Heart 2006;92:1022-9 Wollersheim LW, Li WW, van der Meulen J, et al. A 76-year old man with a torn Freedom SOLO bioprosthesis. Interact Cardiovasc Thorac Surg 2014;18:141-2 Wollersheim LW, Cocchieri R, Symersky P, et al. Transapical JenaValve in a degenerated Freedom SOLO bioprosthesis. J Thorac Cardiovasc Surg 2014;148:741-2 Thourani VH, Suri RM, Gunter RL, et al. Contemporary real-world outcomes of surgical aortic valve replacement in 141,905 low-risk, intermediate-risk, and high-risk patients. Ann Thorac Surg 2015;99:55-61 Pozzoli A, de Maat GE, Hillege HL, et al. Severe thrombocytopenia and its clinical impact after implant of the stentless Freedom Solo bioprosthesis. Ann Thorac Surg 2013;96:1581-6 Miceli A, Gilmanov D, Murzi M, et al. Evaluation of platelet count after isolated biological aortic valve replacement with Freedom Solo bioprosthesis. Eur J Cardiothorac Surg 2012;41:69-73 Thalmann M, Kaiblinger J, Krausler R, et al. Clinical experience with the freedom SOLO stentless aortic valve in 277 consecutive patients. Ann Thorac Surg 2014;98:1301-7 Aymard T, Eckstein F, Englberger L, et al. The Sorin Freedom SOLO stentless aortic valve: technique of implantation and operative results in 109 patients. J Thorac Cardiovasc Surg 2010;139:775-7 Celiento M, Ravenni G, Milano AD, et al. Aortic valve replacement with the Medtronic Mosaic bioprosthesis: a 13-year follow-up. Ann Thorac Surg 2012;93:510-5 Dellgren G, Eriksson MJ, Brodin LA, et al. Eleven years’ experience with the Biocor stentless aortic bioprosthesis: clinical and hemodynamic follow-up with long-term relative survival rate. Eur J Cardiothorac Surg 2002;22:912-21 Rahimtoola SH. Choice of prosthetic heart valve in adults an update. J Am Coll Cardiol 2010;55:2413-26 Oses P, Guibaud JP, Elia N, et al. Freedom SOLO valve: early- and intermediate-term results of a single centre’s first 100 cases. Eur J Cardiothorac Surg 2011;39:256-61 Iliopoulos DC, Deveja AR, Androutsopoulou V, et al. Single-center experience using the Freedom SOLO aortic bioprosthesis. J Thorac Cardiovasc Surg 2013;146:96-102 Matthews IG, Fazal IA, Bates MG, et al. In patients undergoing aortic valve replacement, what factors predict the requirement for permanent pacemaker implantation? Interact Cardiovasc Thorac Surg 2011;12:475-9 Dalmau MJ, González-Santos JM, Bláquez JA, et al. Hemodynamic performance of the Medtronic Mosaic and Perimount Magna aortic bioprostheses: five-year results of a prospective randomized study. Eur J Cardiothorac Surg 2011;39:844-52 Ali A, Halstead JC, Cafferty F, et al. Early clinical and hemodynamic outcomes after stented and stentless aortic valve replacement: results from a randomized controlled trial. Ann Thorac Surg 2007;83:2162-8 24. Mohammadi S, Tchana-Sato V, Kalavrouziotis D, et al. Long-term clinical and echocardiographic follow-up of the Freestyle stentless aortic bioprosthesis. Circulation 2012;126:S198-204 Yerebakan C, Kaminski A, Westphal B, et al. Thrombocytopenia after aortic valve replacement with the Freedom Solo stentless bioprosthesis. Interact Cardiovasc Thorac Surg 2008;7:616-20 Repossini A, Bloch D, Muneretto C, et al. Platelet reduction after stentless pericardial aortic valve replacement. Interact Cardiovasc Thorac Surg 2012;14:434-8

Midterm follow-up of the Freedom SOLO | 63

Supplementary table 1. Risk-factors for long-term mortality Variable Age Male BMI NYHA DM HT Dyslipidemia COPD PVD Previous MI Recent MI Previous CVA Previous TIA Preop renal failure Reoperation Endocarditis OR indication Preop LVF EuroSCORE II Emergerncy OR Concomitant procedure Freedom SOLO valve size CPB time Xcl time Postop Neurologic event Reop bleeding Reop delayed tamponade GI bleeding event Permanent PM Pneumonia New-onset AF Postop renal failure SWI RBC Thrombocyte transfusion Thrombocyte count LVF at discharge AoI at discharge PPM

Univariate P-value 0.24 0.07 0.85 0.07 0.07 0.08 0.15 0.49 0.20 0.01 0.01 0.03 0.54 0.72 0.96 0.69 0.06 0.89 0.02 0.64 0.32 0.20 0.04 0.02 0.01 0.30 0.59 0.73 0.29 0.01 0.63 0.21 0.80 0.04 0.03 0.09 0.50 0.89 0.08

Multivariate P-value 0.04 0.01

Hazard ratio 1.06 2.0

95% CI 1.00 – 1.12 1.16 – 3.32

1.8

1.06 – 3.04

5.1

2.58 – 9.91

0.40 Colinearity Xcl time 0.64 0.01

3.7

1.52 – 9.11

0.96 0.01

3.8

1.60 – 9.22

2.1

1.04 – 4.19

0.28 0.03 0.29 0.85 0.51 0.28 0.01 0.13

0.25 0.64

0.18 0.38 0.79 0.58

0.04

AF = atrial fibrillation, AoI = aortic valve insufficiency, BMI = body mass index, COPD = chronic obstructive pulmonary disease, CPB = cardiopulmonary bypass time, CVA = cerebro-vascular accident, DM = diabetes mellitus, EuroSCORE = European System for Cardiac Operative Risk Evaluation, GI = gastrointestinal, HT = hypertension, LVF = left ventricular function, MI = myocardial infarction, NYHA = New York Heart Association, OR = operation, PM = pacemaker, Postop = postoperative, PPM = prosthesis-patient mismatch, Preop = preoperative, PVD = peripheral vascular disease, RBC = red blood cells, SWI = sternal wound infection, TIA = transient-ischemic attack, Xcl = crossclamp time

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CHAPTER 5 Stentless versus stented aortic valve bioprostheses in the small aortic root

Wollersheim LW, Li WW, Kaya A, Bouma BJ, Driessen AH, van Boven WJ, van der Meulen J, de Mol BA Seminars in Thoracic and Cardiovascular Surgery 2016: in press

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66 | Chapter 5

ABSTRACT Objective: In patients with a small aortic root undergoing aortic valve replacement, the Freedom SOLO bioprosthesis may be the ideal prosthesis due to its stentless design and supraannular implantation. This study investigated if the stentless Freedom SOLO has an advantage when compared with a stented bioprosthesis in patients with a small aortic root. Methods: From April 2005 to July 2014, 269 consecutive patients underwent aortic valve replacement with either a Freedom SOLO (n=76) or Mitroflow (n=193) bioprosthesis size 19mm or 21mm. This retrospective comparison study presents clinical and echocardiographic follow-up data. Results: Operative outcome and survival were similar. At 7 years, cumulative incidence of aortic valve reoperation and structural valve deterioration favor the Freedom SOLO (0% versus 7.1%, P=0.03 and 0% versus 4.5%, P=0.08, respectively). Additionally, the postoperative peak and mean valvular gradients favor the Freedom SOLO (21 ± 9mmHg versus 32 ± 12mmHg and 12 ± 5mmHg versus 19 ± 8mmHg, both P=<0.001, respectively). During midterm follow-up this hemodynamic advantage continued in favor of the Freedom SOLO. Also prosthesis-patient mismatch occurred less frequently in the Freedom SOLO (28% versus 52%, P=0.001). There were no differences in prosthetic valve endocarditis, thromboembolic or bleeding events. Conclusions: The stentless Freedom SOLO has several significant advantages for aortic valve replacement in patients with a small aortic root in comparison with a stented Mitroflow bioprosthesis. The Freedom SOLO shows superior hemodynamic performance with significantly lower valvular gradients that remained stable during midterm follow-up. Additionally significantly fewer prosthesis-patient mismatch occurred and the Freedom SOLO showed superior durability.

Stentless versus stented aortic valve bioprostheses in the small aortic root | 67

INTRODUCTION In patients with a small aortic root undergoing aortic valve replacement (AVR), operative mortality is increased [1]. Additionally, there is an increased risk for prosthesis-patient mismatch which is undesirable as it is associated with decreased hemodynamic function, less regression of left ventricular mass, more cardiac events, and worse survival [2]. Surgical aortic annulus dilatation is an option, but this extends operation time and requires an experienced surgeon [3, 4]. Patients with a small aortic root may profit from the implantation of a stentless bioprostheses since its design provides a larger effective orifice area. This leads to less prosthesis-patient mismatch, lower valvular gradients, and better postoperative outcomes [5]. The Freedom SOLO (Sorin, Saluggia, Italy) is a stentless bioprosthesis with an excellent hemodynamic profile and crossclamp times that are equal to stented bioprostheses [6]. Its stentless design and supraannular implantation technique offers the largest possible effective orifice area. This study investigates if the stentless Freedom SOLO has advantages over a stented bioprosthesis in patients with a small aortic root. We hypothesize that in patients with a small aortic root the hemodynamic performance of the Freedom SOLO is better than that of a stented bioprosthesis.

MATERIAL AND METHODS Study population Between June 2005 and July 2014, 269 consecutive patients underwent AVR with either a stentless Freedom SOLO or a stented Mitroflow (Sorin, Saluggia, Italy) with a size 19mm or 21mm prosthesis. Both manufacturersâ&#x20AC;&#x2122; 19mm and 21mm sizers are comparable in diameter. The Mitroflow prostheses were implanted supraannular. All operations were performed at the Academic Medical Center in Amsterdam, The Netherlands. The choice of prosthesis was based on surgeonâ&#x20AC;&#x2122;s preference and made in consultation with the patient. Baseline patient characteristics, operative details and in-hospital complications were collected from the Academic Medical Center database. On January 6, 2015, information on vital status was obtained from the Dutch national population registry (Statistics Netherlands, Voorburg, The Netherlands). Follow-up data and echocardiographic results were collected retrospectively, during visits to the referring cardiology centers. Patients were censored at time of last contact. The Society of Thoracic Surgeons Adult Cardiac Surgery Database Data Specifications, version 2.81, was used for definitions of baseline characteristics and postoperative outcome [7]. Mortality was defined as 30-day and in-hospital mortality combined. Preoperative renal failure was defined as a calculated creatinine clearance of less than 50 mL/min using the Cockcroft-Gault formula [8]. For definitions of structural valve deterioration, nonstructural dysfunction, embolism, bleeding event, endocarditis, and aortic valve reoperation, the guidelines for reporting mortality and morbidity after cardiac valve interventions were used [9]. Prosthesis-patient mismatch was defined as an indexed effective orifice area of less than 0.85 cm2/m2 [2], measured with transthoracic echocardiography within 2 years postoperatively. Up to 2010, all patients received oral anticoagulation therapy for 3 months

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postoperatively followed by lifelong acetylsalicylate 100 mg daily. From 2010, all patients received only lifelong antiplatelet therapy with acetylsalicylate 100 mg daily unless otherwise indicated by concomitant morbidities. Statistical analysis Data are expressed as mean ± standard deviations, median with interquartile range or as numbers and percentiles as appropriate. Differences in baseline characteristics, operative details, and outcomes were tested for significance by unpaired t-test, Mann-Whitney U test, Fisher’s exact test, and χ2 (for trends) as appropriate. Survival, prosthetic valve endocarditis, thromboembolism, and bleeding events were analyzed using the Kaplan-Meier method. The log-rank test was used to test for differences. Aortic valve reoperation and structural valve deterioration were analyzed using cumulative incidence function using a competing risk analysis [10]. For aortic valve reoperation ‘death’ was considered a competing risk. For structural valve deterioration both ‘death’ and ‘aortic valve reoperation’ were considered a competing risk. Gray’s log-rank test was used to test for differences between the groups in the competing risk analysis. Logistic regression analysis was used to identify if choice of prosthesis was a risk factor for prosthesis-patient mismatch, considering age, gender, and body mass index as variables. The longitudinal follow-up of echocardiographic results were analyzed using a mixed effects model. Statistical analyses were performed using SPSS, version 21 (IBM Corp., Armonk, NY, USA). The cumulative incidence function analysis and the mixed effects model were performed using R (R Foundation for Statistical Computing, Vienna, Austria). A P-value of <0.05 was considered statistically significant.

RESULTS Baseline patient characteristics are presented in Table 1. Seventy-six patients received a Freedom SOLO and 193 patients received a Mitroflow bioprosthesis. Baseline characteristics were similar with the exception of New York Heart Association (NYHA) class and previous cerebro vascular accident. There were more patients in NYHA class III/IV in the Freedom SOLO group than in the Mitroflow group (75% versus 53%, P=0.001), and there were more patients who had a previous cerebro vascular accident in the Mitroflow group than in the Freedom SOLO group (8% versus 1%, P=0.04). The European System for Cardiac Operative Risk Evaluation (EuroSCORE) in both groups was comparable.

Stentless versus stented aortic valve bioprostheses in the small aortic root | 69

Table 1. Baseline patient characteristics Characteristic Age (mean ± SD) Male (%) NYHA functional class I/II (%) III/IV (%) BMI (mean ± SD) BSA (mean ± SD) Diabetes (%) Hypertension (%) Dyslipidemia (%) COPD (%) PVD (%) Previous MI (%) / recent MI (%) Previous CVA (%) / previous TIA (%) Renal failure (%) Reoperation (%) Endocarditis (%) Operation indication Aortic stenosis (%) Aortic insufficiency (%) Mixed stenosis and insufficiency (%) Preoperative LVEF LVEF>50% (%) LVEF 30-50% (%) LVEF <30% (%) Preoperative LVOT (mean ± SD) EuroSCORE I (mean ± SD) EuroSCORE II (median, interquartile) Logistic EuroSCORE (mean ± SD) Emergency operation (%)

Freedom SOLO (n=76) 76±7 7 (9)

Mitroflow (n=193) 75±6 33 (17)

19 (25) 56 (75) 27.4±5.4 1.81 ± 0.2 25 (33) 52 (68) 46 (61) 15 (20) 7 (9) 12 (16) / 5 (7) 1 (1) / 8 (11) 17 (22) 3 (4) 3 (4)

90 (47) 102 (53) 26.7±4 1.82 ± 0.2 54 (28) 127 (66) 106 (55) 32 (17) 28 (15) 33 (17) / 5 (3) 15 (8) / 13 (7) 42 (22) 12 (6) 6 (3)

60 (79) 1 (1) 15 (20)

134 (69) 10 (5) 49 (25)

66 (87) 9 (12) 1 (1) 20.5 ± 1.1 7.7±2.2 3.1, 1.7-5.3 10.5±10.8 1 (1)

156 (81) 32 (17) 3 (2) 20.6 ± 1.2 7.8±2.1 2.8, 1.9-5.1 10.6±10.3 1 (1)

P 0.41 0.10 0.001*

0.27 0.57 0.43 0.68 0.40 0.54 0.25 0.80 / 0.12 0.04* / 0.30 0.93 0.47 0.73 0.18

0.69

0.47 0.79 0.68 0.95 0.49

BMI = body mass index, BSA = body surface area, COPD = chronic obstructive pulmonary disease, CVA = cerebro vascular accident, EuroSCORE = European system for cardiac operative risk evaluation, LVEF = left ventricular ejection fraction, LVOT = left ventricular outflow tract, MI = myocardial infarction, NYHA = New York heart association, PVD = peripheral vascular disease, TIA = transient ischemic attack, * = significantly different

Early clinical outcomes Perioperative data and early clinical outcomes are presented in Table 2. In both groups, 9% of patients received a 19mm prosthesis and the remaining 91% a 21mm prosthesis. In the Mitroflow group there were 6 patients (3%) who underwent an aortic root enlargement resulting in the implantation of five 21mm and one 19mm bioprosthesis. Crossclamp time for isolated AVR was 84 ± 24 minutes for the Freedom SOLO and 82 ± 24 minutes for the Mitroflow (P=0.65). There were no significant differences between the two groups regarding mortality, cerebro vascular accidents, and intensive care unit stay. The majority of patients (79%)

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were discharged to their referring cardiology center. The Freedom SOLO patients who were discharged home had a total length of hospital stay of 10 ± 3 days and the Mitroflow patients of 14 ± 8 days (P=0.12). In the Freedom SOLO group, there were more patients with a postoperative platelet count of less than 50 x 109/L than in the Mitroflow group (39% versus 7%, P=<0.001). This had no clinical consequences since there were no differences in reoperation for delayed tamponade, gastrointestinal bleeding, or platelet transfusions. Table 2. Perioperative data and early outcomes Perioperative data and early outcomes Prosthesis size 19mm (%) 21mm (%) Concomitant procedure (%) CABG MVP MVR Other Cardiopulmonary bypass time (mean ± SD) Crossclamp time (mean ± SD) Crossclamp time isolated AVR (mean ± SD) Mortality (%) Mortality isolated AVR (%) CVA (%) TIA (%) Reoperation for bleeding (%) Renal failure (%) Temporary renal replacement therapy Pacemaker (%) Pneumonia (%) New-onset atrial fibrillation (%) Sternal wound infection (%) Lowest platelet count, x 109/L Reoperation for delayed tamponade (%) Gastrointestinal bleeding event (%) RBC after OR, n (%) Thrombocyte transfusion after OR, n (%) ICU stay (median, interquartile) LOS for patient discharged home (mean ± SD) Prosthesis-patient mismatch Pmax at discharge (mean ± SD) Pmean at discharge (mean ± SD) EOA at discharge (mean ± SD)

Freedom SOLO (n=76)

Mitroflow (n=193)

7 (9) 69 (91) 28 (37) 25 2 1 3 128 ± 48 97 ± 35 84 ± 24 4 (5) 1 (2) 0 (0) 1 (1) 11 (15) 7 (9) 2 (3) 2 (3) 3 (4) 26 (34) 2 (3) 69 ± 35 2 (3) 1 (1) 24 (32) 8 (11) 1, 1-3 10 ± 3 19 (28) 21 ± 9 12 ± 5 1.89 ± 0.49

17 (9) 176 (91) 83 (43) 73 7 1 10 139 ± 58 98 ± 37 82 ± 24 15 (8) 7 (6) 6 (3) 1 (1) 16 (8) 21 (11) 6 (3) 8 (4) 7 (4) 74 (38) 4 (2) 101 ± 39 7 (4) 4 (2) 52 (27) 17 (9) 2, 1-2 14 ± 8 91 (52) 32 ± 12 19 ± 8 1.42 ± 0.46

P 0.92

0.36

0.13 0.78 0.65 0.47 0.26 0.19 0.49 0.13 0.69 0.84 0.56 0.90 0.53 0.78 <0.001* 0.68 0.68 0.45 0.66 0.37 0.12 0.001* <0.001* <0.001* <0.001*

AVR = aortic valve replacement, CABG = coronary artery bypass graft, CVA = cerebro vascular accident, EOA = effective orifice area, ICU = intensive care unit, LOS = length of hospital stay, LVEF = left ventricular ejection fraction, MVP = mitral valve repair, MVR = mitral valve replacement, OR = operation, Pmax = maximum valvular gradient, Pmean = mean valvular gradient, TIA = transient ischemic attack, RBC = red blood cells, * = significantly different

Stentless versus stented aortic valve bioprostheses in the small aortic root | 71

Follow-up and survival The mean and median clinical follow-up for the Freedom SOLO were 4.0 Âą 2.5 (range 0.2 to 9.5 years) and 3.7 years (interquartile range 1.9 to 6.1 years), respectively. The mean and median clinical follow-up for the Mitroflow were 3.6 Âą 2.4 (range 0.1 to 9.1 years) and 3.0 years (interquartile range 1.7 to 5.3 years), respectively. Three patients (1.1%) from the Mitroflow group were lost to follow-up. Survival is presented in Figure 1 and is similar in both groups (P=0.47). The 1-, 5- and 9-year overall survival in the Freedom SOLO group was 95%, 83% and 59%, respectively. The 1-, 5- and 9-year overall survival in the Mitroflow group was 90%, 74% and 51%, respectively.

Figure 1. Survival

Aortic valve reoperation and structural valve deterioration At 7 years, the cumulative incidence function probability for aortic valve reoperation was 0% for the Freedom SOLO and 7.1%for the Mitroflow (95% confidence interval (CI), 1.6-12.6%, P=0.03) (Figure 2A). In the Mitroflow group 10 patients (one 19mm and nine 21mm) underwent reoperation, with a median time of 2.5 years (interquartile range 0.1 to 6.5 years) to reoperation. The reasons for reoperation were: structural valve deterioration in 5 patients, prosthetic valve endocarditis in 3 patients, paravalvular leakage in 1 patient and immediate technical failure with a high valvular gradient and paravalvular leakage in 1 patient. Five patients who underwent reoperation received a new Mitroflow, 3 patients a Freedom SOLO, 1 an Edwards Perimount (Edwards Lifesciences, Irvine, CA, USA), and 1 patient underwent a transcatheter aortic valve implantation with a CoreValve (Medtronic, Minneapolis, MS, USA). Two of the three Freedom SOLO prostheses were 1 size larger than the original Mitroflow and one Freedom SOLO was 1 size smaller than the original Mitroflow. Also at 7 years, the cumulative incidence function probability for structural valve deterioration of the Freedom SOLO was 0% and of the Mitroflow 4.5% (95% CI, 0.5-8.4%, P=0.08) (Figure 2B). In the Mitroflow group there were 7 patients with structural valve deterioration.

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Figure 2. Cumulative incidence function estimates of aortic valve reoperation and structural valve deterioration SVD = structural valve deterioration

Endocarditis, thromboembolism and bleeding events Prosthetic valve endocarditis occurred in 2 patients with a Freedom SOLO (0.7% per patient-year, 95% CI, 0.1-2.3) and both were treated with intravenous antibiotics. Prosthetic valve endocarditis occurred in 10 patients with a Mitroflow (1.6% per patient-year, 95% CI, 0.8-2.8), 3 of whom underwent reoperation, and 7 who were treated with intravenous antibiotics. The difference in prosthetic valve endocarditis was not significant (P=0.27). During follow-up five thromboembolic events occurred in the Freedom SOLO group (1.7% per patient-year, 95% CI, 0.6-3.8). Four patients had a transient ischemic attack, and 1 patient a pulmonary embolus. In the Mitroflow group, 24 patients had a thromboembolic event (3.8% per patient-year, 95% CI, 2.5-5.5). Fifteen patients had a cerebro vascular accident, 7 patients a transient ischemic attack, and 2 a pulmonary embolus. The difference in thromboembolic events was not significant (P=0.10). During follow-up there were two reported bleeding events in the Freedom SOLO group (0.7% per patientyear, 95% CI, 0.1-2.3). One patient had a gastrointestinal bleed, and 1 patient had an episode of epistaxis. Both patients were taking acetylsalicylate only. In the Mitroflow group 15 patients had a reported bleeding event (2.4% per patient-year, 95% CI 1.4-3.8). Eight patients had a gastrointestinal bleed, 4 patients had an episode of epistaxis, 1 patient had a hemorrhagic cerebral accident, 1 patient had hematuria, and 1 patient had bleeding varicose veins. Of the 15 patients with a bleeding event, 7 were taking oral anticoagulants, 7 were taking acetylsalicylate only and one patient was taking dual anti-platelet therapy. The difference in bleeding events was not significant (P=0.08). Echocardiographic data and NYHA Postoperative echocardiographic data are presented in Table 2. The postoperative peak valvular gradient was significantly lower in the Freedom SOLO than in the Mitroflow (21 Âą 9 mmHg versus 32 Âą 12 mmHg, P=<0.001). This difference remains significant during midterm follow-up (P=<0.001) (Figure 3A). The postoperative mean valvular gradient was significantly lower in the Freedom SOLO group than in the

Stentless versus stented aortic valve bioprostheses in the small aortic root | 73

Mitroflow group (12 Âą 5 mmHg versus 19 Âą 8 mmHg, P=<0.001). This difference remains significant during midterm follow-up (P=<0.001) (Figure 3B). In the Freedom SOLO group, overall prosthesis-patient mismatch occurred less frequently than in the Mitroflow group (28% versus 52%, P=0.001, Table 2). On multivariate analysis, the Mitroflow prosthesis was an independent risk factor for prosthesis-patient mismatch, (odds ratio 3.0, 95%CI 1.9-5.6; P=0.001). In the Freedom SOLO group, 73% (n=43) of patients were in NYHA class I, 22% (n=13) of patients were in NYHA class II, and 5% (n=3) of patients were in NYHA class III/IV at most recent follow-up. In the Mitroflow group, 63% (n=76) of patients were in NYHA class I, 18% (n=22) of patients were in NYHA class II, and 19% (n=23) of patients were in NYHA class III/IV at most recent follow-up (P=0.04) (Figure 4).

Figure 3. Mixed effects model of echocardiographic results MF = Mitroflow, Pmax = maximum valvular gradient, Pmean = mean valvular gradient, SOLO = Freedom SOLO

Figure 4. NYHA functional class at most recent follow-up NYHA = New York Heart Association Class

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DISCUSSION This study showed that in patients with a small aortic root requiring AVR the stentless Freedom SOLO has three significant advantages, when compared with the Mitroflow stented bioprosthesis. First, both cumulative incidence function probability of aortic valve reoperation and structural valve deterioration favor the Freedom SOLO at 7-year follow-up (0% versus 7.1%, and 0% versus 4.5%, respectively). Second, prosthesis-patient mismatch is less likely to occur with the Freedom SOLO (28% versus 52%), and the Mitroflow stented bioprosthesis was a significant independent risk factor for prosthesis-patient mismatch (odds ratio 3.0). Third, the postoperative peak and mean valvular gradients were lower in the Freedom SOLO and these differences persisted during midterm follow-up, combined with fewer patients in NYHA class III/IV at most recent follow-up (5% versus 19%). First and second generation stentless bioprostheses require multiple suture lines leading to longer crossclamp times than for stented bioprostheses [11]. The Freedom SOLO was designed as a stentless bioprosthesis for fast implantation in the sinuses of Valsalva with a single suture line. In our study, crossclamp time for isolated AVR was comparable in both groups (84 Âą 24 versus 82 Âą 24 minutes). This shows that the Freedom SOLO can be implanted within the same ischemic time as a stented bioprosthesis. Mortality was 5% for the Freedom SOLO and 8% for the Mitroflow, and in isolated AVR it was 2% for the Freedom SOLO and 6% for the Mitroflow. With regard to the median EuroSCORE II in both groups, this mortality seems quite high. Advanced age and concomitant procedures were factors that increased the EuroSCORE. Additionally, prosthesis implantation in the small aortic root is likely to be more difficult, leading to longer crossclamp times and thus potentially increasing operative risk. A German study by Wilbring et al. reported that the hospital mortality for isolated AVR in a group of 148 patients with a small aortic annulus who received either a 19mm or 21mm Mitroflow was 6.1% [1]. This supports the increased operative risk of AVR in patients with a small aortic annulus. In our study, there were no differences between the two groups regarding early clinical outcomes, implying both bioprostheses are equally safe to implant. One randomized controlled trial showed no survival benefit at 1 year after AVR with a stentless versus a stented bioprosthesis [12]. Our study also showed that the Freedom SOLO had no survival benefit when compared with a stented bioprosthesis over a follow-up period of a maximum of 9.4 years. The 9-year overall survival of the Freedom SOLO (59%) and the Mitroflow (51%) are comparable to the 10-year overall survival of 45% to 54% reported in the literature in patient populations with a comparable mean age [13-15]. The durability of an aortic valve bioprostheses remains an essential feature. At 7 years, the cumulative incidence function probability of valve explant was around 3% to 4% for an aortic-pericardial prosthesis and around 5% for an aortic-porcine prosthesis [10]. The Freedom SOLO showed an excellent 0% of cumulative incidence function probability for reoperation at 7 years in patients with a small aortic root, where the Mitroflow showed a lower cumulative incidence function probability for reoperation of 7.1%. In comparison, other studies on midterm follow-up of the Mitroflow reported conflicting results regarding freedom from reoperation and structural valve deterioration [16, 17]. At 5-year follow-up, Ash and collegues reported 97% freedom from reoperation while SĂŠnage and colleagues reported only 92% freedom from structural valve

Stentless versus stented aortic valve bioprostheses in the small aortic root | 75

deterioration at 3.8 year follow-up, measured using the Kaplan-Meier method [16, 17]. While the durability of the Mitroflow is under debate [18], the results of the Freedom SOLO in the small aortic root are excellent. Therefore, the combination of excellent results and a significant difference found for reoperation in favor of the Freedom SOLO supports its use in AVR in the small aortic root. Another factor that supports the use of the Freedom SOLO is its low valvular gradients. Its supraannular implantation technique and stentless design offer the maximum effective orifice area. In the small aortic root this design has been shown to be effective and to remain effective during follow-up, with valvular gradients statistically significantly lower in the Freedom SOLO than in the Mitroflow. Furthermore, the Freedom SOLO also showed favorable valvular gradients when compared with new generation stented bioprostheses that were implanted supraannularly [19]. The maximum effective orifice area of a Freedom SOLO means a lower risk of prosthesis-patient mismatch. Depending on patient population, severe prosthesis-patient mismatch occurs in 2% to 11% and moderate prosthesis-patient mismatch occurs in 20% to 70% of patients [2]. The prevention of prosthesis-patient mismatch is desirable, since it has been associated with decreased hemodynamic function, less regression of left ventricular mass, more cardiac events and worse survival [2]. In a population at risk for prosthesispatient mismatch, the Freedom SOLO shows a lower rate of 28% prosthesis-patient mismatch compared with 52% in the Mitroflow. In comparison, Jamieson and colleagues showed that prosthesis-patient mismatch occurred in 60% (n=18) in a small group of 30 patients who received either a 19mm or 21mm Mitroflow [20]. Additionally, our study showed that the odds ratio of developing prosthesis-patient mismatch is 3.0 with a stented Mitroflow compared with a stentless Freedom SOLO. Both Jamieson and Wilbring supported the use of the Mitroflow in patients with a small aortic annulus because of good hemodynamic performance and an acceptable incidence of prosthesis-patient mismatch [1, 20]. With regard to valvular gradients and prosthesis-patient mismatch, the results of our study showed that the stentless Freedom SOLO is superior to the stented Mitroflow in patients with a small aortic root. This study has several limitations. One of the limitations of this study is the risk of selection bias. This is a retrospective study and prosthesis choice was made by the surgeon, both of which may induce selection bias. The retrospective nature of this study did not result in equal patient characteristics. The comparison was made with the Mitroflow bioprosthesis only, because of the availability at our center. Also the groups studied were relatively small containing 269 patients in total. Additionally 3 patients (1.1%) were lost to follow-up. There was no standard echocardiographic protocol and follow-up echocardiographs were not scheduled at the same time intervals in the referring cardiology centers. Unfortunately, left ventricular mass is not included in the standard follow-up echocardiographic investigation in the Netherlands and therefore this information is missing.

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CONCLUSION The stentless Freedom SOLO has several significant advantages in AVR in patients with a small aortic root when compared with a stented Mitroflow bioprosthesis. Our hypothesis is confirmed as the Freedom SOLO has shown superior hemodynamic performance with lower valvular gradients that remain stable during midterm follow-up. Additionally, fewer prosthesis-patient mismatches occurred, fewer patients are in NYHA class III/IV, and the Freedom SOLO shows superior durability. This makes the stentless Freedom SOLO the preferred bioprosthesis for patients with a small aortic root at our center. Additional research, preferably prospective, is needed to confirm these results in other stented bioprostheses.

Stentless versus stented aortic valve bioprostheses in the small aortic root | 77

REFERENCES 1.

Wilbring M, Alexiou K, Schumann E, et al. Isolated aortic valve replacement in patients with small aortic annulus-a high-risk group on long-term follow-up. Thorac Cardiovasc Surg 2013;61:379-85 2. Pibarot P, Dumesnil JG. Prosthesis-patient mismatch: definition, clinical impact, and prevention. Heart 2006;92:1022-9 3. Nicks R, Cartmill T, Bernstein L. Hypoplasia of the aortic root. The problem of aortic valve replacement. Thorax 1970;25:339-46 4. Manouguian S, Seybold-Epting W. Patch enlargement of the aortic valve ring by extending the aortic incision into the anterior mitral leaflet. New operative technique. J Thorac Cardiovasc Surg 1979;78:402-12 5. Gulbins H, Reichenspurner H. Which patients benefit from stentless aortic valve replacement? Ann Thorac Surg 2009;88:2061-8 6. Wollersheim LW, Li WW, Bouma BJ, et al. Aortic valve replacement with the stentless Freedom SOLO bioprosthesis: a systematic review. An Thorac Surg 2015;100:1496-504 7. STS Adult Cardiac Surgery Database Data Specifications, version 2.81, http://www.sts.org/sts-national-database/ database-managers/adult-cardiac-surgery-database/data-collection Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16:31-41 8. 9. Akins CW, Miller DC, Turina MI, et al. Guidelines for reporting mortality and morbidity after cardiac valve interventions. J Thorac Cardiovasc Surg 2008;135:732-8 10. Grunkemeier GL, Furnary AP, Wu Y, et al. Durability of pericardial versus porcine bioprosthetis heart valves. J Thorac Cardiovasc Surg 2012;144:1381-6 11. Jin XY, Gibson DG, Yacoub MH, et al. Perioperative assessment of aortic homograft, Toronto stentless valve, and stented valve in the aortic position. Ann Thorac Surg 1995;60(2 Suppl):S395-401 12. Ali A, Halstead JC, Cafferty F, et al. Are stentless valves superior to modern stented valves? A prospective randomized trial. Circulation 2006;114(1 Suppl):I535-40 13. Eichinger WB, Hettich IM, Ruzicka DJ, et al. Twenty-year experience with the St. Jude medical Biocor bioprosthesis in the aortic position. Ann Thorac Surg 2008;86:1204-10 14. Celiento M, Ravenni G, Milano AD, et al. Aortic valve replacement with the Medtronic Mosaic bioprosthesis: a 13-year follow-up. Ann Thorac Surg 2012;93:510-5 15. Lorusso R, Gelsomino S, De Cicco G, et al. The Italian study on the Mitroflow postoperative results (ISTHMUS): a 20-year, multicentre evaluation of Mitroflow pericardial bioprosthesis. Eur J Cardiothorac Surg 2011;39:18-26 16. Ash FM, Heimansohn D, Doyle D, et al. Mitroflow aortic bioprosthesis 5-year follow-up: north American prospective multicenter study. Ann Thorac Surg 2012;94:1198-203 17. SĂŠnage T, Le Tourneau T, Foucher Y, et al. Early structural valve deterioration of Mitroflow aortic bioprosthesis: mode, incidence, and impact on outcome in a large cohort of patients. Circulation 2014;130:2012-20 18. Kaneko T, Gosev I, Leacche M, et al. Early structural valve deterioration of the mitroflow bioprosthesis. Circulation 2014;130:1997-8 19. Modi A, Pousios D, Sadeque S, et al. Early in-vivo hemodynamic comparison of supra-annular aortic bioprostheses: Trifecta versus Perimount Magna Ease. J Heart Valve Dis. 2014;23:325-32 20. Jamieson WR, Forgie WR, Hayden RI, et al. Hemodynamic performance of mitroflow aortic pericardial bioprosthesis â&#x20AC;&#x201C; optimizing management for the small aortic annulus. Thorac Cardiovasc Surg 2010;58:69-75

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CHAPTER 6 4D flow MRI of stented versus stentless aortic valve bioprostheses

Wollersheim LW*, van Kesteren F*, Baan J, Nederveen A, de Mol BA, van Ooij P, Planken RN *Shared first authorship Manuscript in preparation

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ABSTRACT Objectives: The aim of this study was to evaluate the hemodynamic performance of both stented and stentless aortic valve bioprostheses, 1 year after surgical aortic valve replacement using 4D flow magnetic resonance imaging (MRI). Background: Surgical aortic valve replacement is the standard treatment for patients with severe aortic valve disease and bioprosthetic valves are predominantly implanted. Traditional bioprostheses have a stented framework, facilitating easy implantation. However, this framework reduces the effective orifice area and obstructs laminar blood flow; increasing the valvular gradients. As an alternative, stentless bioprostheses have been introduced. We hypothesized that stentless bioprostheses, without a frame, better resemble the native aortic valve than stented prostheses, and would therefore show superior hemodynamic performance. Methods: In this pilot study, 30 patients with either a stented or stentless bioprostheses (Mitroflow or Freedom SOLO), and comparable baseline characteristics underwent non-contrast enhanced 4D flow MRI with 1.5 Tesla, 9 to 15 months after implantation. Pre- and post-processing were performed using commercial and home-built software. Data analysis included quantitative comparison of hemodynamic parameters in the ascending aorta during peak systole. Results: Two patients were excluded due to claustrophobia and atrial fibrillation during scanning. Twentyeight MRI scans (14 Mitroflow, 14 Freedom SOLO) were available for analysis. No statistical differences in hemodynamic parameters were found; peak velocity was 2.45 m/s (2.06-2.73) versus 2.11 m/s (1.84-2.61) (p=0.09), mean velocity was 0.60 m/s (0.53-0.73) versus 0.62 m/s (0.49-0.73) (p=0.89), mean wall shear stress 0.60 Pa (0.50-0.81) versus 0.59 Pa (0.45-0.79) (p=0.55), and viscous energy loss 10.17 mW (6.8613.36) versus 7.82 mW (4.84-10.68) (p=0.10) after Mitroflow and Freedom SOLO implantation, respectively. Conclusion: In this pilot study, we found no statistical differences in the hemodynamic performance of stented and stentless bioprostheses with 4D flow MRI 1 year after implantation.

4D Flow MRI | 81

INTRODUCTION Surgical aortic valve replacement is the standard treatment for operable patients with advanced aortic valve disease including severe aortic valve stenosis and regurgitation [1, 2]. Today, a bioprosthetic heart valve is used in 79% of surgical aortic valve replacements [3]. Traditional bioprosthetic valves have a stented framework, with valve leaflets mounted on the stent to resemble a native tri-leaflet valve (Figure 1A). Although the stented design facilitates easy implantation, it reduces the effective orifice area and obstructs laminar blood flow [4]. As an alternative, stentless bioprostheses have been introduced (Figure 1B). Traditionally, stentless bioprostheses require technically demanding implantation procedures with prolonged crossclamp times. However, this technical drawback has been overcome by the development of the stentless Freedom SOLO (Sorin, Saluggia, Italy, Figure 1B) as its implantation technique requires only a single suture line and facilitates crossclamp times comparable with a stented bioprostheses [5]. Because of the absence of a space-consuming stent, stentless bioprostheses give a better hemodynamic performance than stented bioprostheses, in terms of lower valvular gradients measured with transthoracic echocardiography [6]. Currently, transthoracic echocardiography is used for clinical follow-up of the hemodynamic performance of bioprostheses [1, 2]. However, recently four-dimensional (4D) flow magnetic resonance imaging (MRI), time-resolved 3D-phase contrast MRI, with velocity encoding in all principal velocity directions, has become available. This technique improves the insights into blood flow patterns through the heart and vessels [7, 8]. A diversity of 4D flow MRI measurements can be used for quantification and visualization of blood flow in context of the surrounding tissue and anatomy [9]. The aim of this study was to compare the hemodynamic performance of stented and stentless bioprostheses using 4D flow MRI in comparable patient populations. Because the stentless bioprosthesis resembles the native aortic valve more than the stented bioprosthesis, we hypothesized that the stentless bioprosthesis would show a better, and more true-to-life, hemodynamic performance.

METHODS Study population This pilot study was conducted at the Academic Medical Center in Amsterdam, the Netherlands. With approval from the institutional review board we included 30 patients 9 to 15 months after surgical aortic valve replacement for native aortic valve stenosis with either a stented Mitroflow (Sorin, Saluggia, Italy, Figure 1A), or a stentless Freedom SOLO (Figure 1B) bioprosthesis. In addition to standard MRI exclusion criteria, patients with a history of multiple heart valve replacements or known persistent atrial fibrillation were excluded.

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Figure 1. Stented and stentless bioprosthesis A = Mitroflow with phospholipid reduction treatment, LivaNova; B = Freedom SOLO, LivaNova

MRI All participants underwent a cardiovascular MRI with 1.5 Tesla (Magnetom Avanto, Siemens Medical Systems, Germany). No contrast agent was used. The examination included a standard care electrocardiogram and respiratory-gated short axis time-resolved (CINE) MRI for the evaluation of cardiac dimensions and function. For the assessment of aortic blood flow, time-resolved 3D phasecontrast MRI with three-directional flow encoding (4D flow) was obtained in a sagittal oblique 3D volume covering the aortic valve bioprosthesis and the thoracic aorta using electrocardiogram gating during free breathing with a respiratory navigator placed at the lung-liver interface. Pulse sequence parameters were as follows: echo time/pulse repetition time = 2.451/5.0ms; bandwidth = 440 Hz/pixel; flip angle α = 7 degrees; acceleration mode GRAPPA factor 2 with 24 reference lines; temporal resolution = 40ms; field of view = 320 mm; spatial resolution 2.0 x 1.7 x 2.2 mm3. Velocity sensitivity was adjusted to minimize velocity aliasing (venc = 150-250 m/s). Data analysis Pre-processing included correction for Maxwell phase effects, eddy currents, velocity aliasing, and noise masking using Matlab software (Mathworks, Natick, MA, USA) [10]. The 3D phase contrast data were created by multiplication of the magnitude data with absolute velocities images subsequently averaged over all time frames. A commercial software package (MIMICS, Materialise, Leuven, Belgium) was used to create a 3D mask by segmentation of the data. Matlab Software was used to perform further post-processing. Peak systole was defined as the time frame with the maximum average velocity in the segmentation. In order to reduce the effect of measurement noise, the 3D velocity field at peak systole was filtered with a 3x3x3 median filter. At peak systole, peak and mean velocity, and mean wall shear stress [11] in the ascending aorta were calculated. Additionally, energy loss due to viscous dissipation in the ascending aorta was calculated using the methodology developed by Barker and colleagues [12]. Statistical analysis Results are expressed as means ± standard deviations, medians with interquartiles or as numbers and percentiles as appropriate. The Mann Whitney U, student t, and χ2 test were used to analyze differences

4D Flow MRI | 83

between groups. Statistical analyses were performed using SPSS, version 22 (IBM Corp., Armonk, NY, USA). A P value of <0.05 was considered statistically significant.

RESULTS Of the 30 included patients two patients were excluded, one due to claustrophobia and one because of poor quality of the 4D flow dataset due to paroxysmal atrial fibrillation. Of the 28 remaining patients, 14 had a stented Mitroflow, and 14 a stentless Freedom SOLO. Patient characteristics were comparable (Table 1), except that patients with a Mitroflow had less frequently undergone a concomitant procedure (21% vs 71%, P=<0.01). The mean time to MRI after aortic valve replacement was 12.3 months, and at the time of the MRI all patients were in New York Heart Association class 1. The hemodynamic parameters assessed with 4D flow MRI are presented in Table 2. No statistical differences between the two groups were found. We found consistent hemodynamic performance with satisfactory implant results and no signs of malfunction. Figure 2 shows representative examples of a sagittal maximum intensity projection of velocity in the ascending aorta for patients with a stented Mitroflow or a stentless Freedom Solo. Figure 3 shows a sagittal maximum intensity projection of viscous energy loss in the same subjects. Table 1. Patient characteristics Stented Mitroflow

Stentless Freedom SOLO

N Age

14 74 ± 4

14 74 ± 6

0.89

Male

9 (64)

1.00

Time after operation (months)

12 ± 1

13 ± 2

0.21

21mm

3 (21)

2 (14)

23mm

6 (43)

25mm

4 (29)

27mm

1 (7)

2 (14)

3 (21)

10 (71)

CABG

MVP+TVP

Valve size distribution

Concomitant procedures

0.91

0.01

Baseline MRI measurements LVEF (%)

64 (57-75)

61 (52-69)

0.25

Stroke volume (ml)

89 (75-105)

85 (69-111)

0.75

130 (124-142) 45 (34-57)

149 (122-182) 50 (43-77)

0.18 0.17

LVEDV (ml) LVESV (ml)

CABG = coronary artery bypass graft, LVEDV = left ventricular end diastolic volume, LVEF = left ventricular ejection fraction, LVESV = left ventricular end systolic volume, MVP = mitral valve repair, TVP = tricuspid valve repair

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Figure 2. Peak velocity A = Mitroflow, B = Freedom SOLO

Figure 3. Viscous energy loss A = Mitroflow, B = Freedom SOLO Table 2. 4D Flow MRI parameters in the ascending aorta 1 year after aortic valve replacement Parameter

Stented Mitroflow

Stentless Freedom SOLO

N Peak Velocity (m/s) (median, interquartile)

14 2.45 (2.06-2.73)

14 2.11 (1.84-2.61)

0.09

Mean Velocity (m/s) (median, interquartile)

0.60 (0.53-0.73)

0.62 (0.49-0.72)

0.89

0.60 (0.50-0.81) 10.17 (6.86-13.36)

0.59 (0.45-0.79) 7.82 (4.84-10.68)

0.55 0.10

Mean WSS (Pa) (median, interquartile) Energy loss (mW) (median, interquartile) WSS = wall shear stress

4D Flow MRI | 85

DISCUSSION 4D Flow MRI provides insight into the blood flow through the heart and blood vessels [7, 13]. We used this technique to visualize and quantify the hemodynamic performance of stented and stentless aortic valve bioprostheses 1 year after implantation. The groups were comparable in age, gender, labeled valve size, left ventricular function and time after operation. In this pilot study, 1 year after implantation, we found no significant differences between the two types of prosthesis regarding peak and mean velocity, viscous energy loss and wall shear stress in the ascending aorta during peak systole. Although peak velocity and energy loss over the valve were slightly higher in the stented prosthesis, the differences with the stentless prosthesis were not statistically significant. For the optimal long-term outcome, an aortic valve prosthesis should closely resemble the native aortic valve. Ideally this prosthesis should provide unobstructed central laminar blood flow, with low peak and mean velocity without substantial energy loss. When compared with data available at our center from healthy volunteers (n =2), we found substantially lower peak velocity and viscous energy loss across the native aortic valve (Table 3, Figure 4). This implies that there is still a long way to go in the development of bioprostheses to achieve hemodynamic performance comparable to that of the native aortic valve. Table 3. 4D Flow MRI parameters in the ascending aorta in healthy volunteers with a native aortic valve Parameter

Measurement in native valve (n=2)

Peak Velocity (m/s) (mean) Mean Velocity (m/s) (mean)

1.38 0.69

Mean WSS (Pa) (mean) Energy loss (mW) (mean)

0.79 2.28

WSS = wall shear stress

Figure 4. Peak velocity (a) and energy loss (b) in a native aortic valve

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Optimization of the hemodynamic performance of the prosthesis is important. Increased velocities and obstructed blood flow over the prosthesis may lead to valve leaflet deterioration and potentially the need for reintervention. In addition, optimal performance reduces the left ventricular workload to facilitate left ventricular remodeling, and thereby lowering myocardial mass. Reduction of the left ventricular mass is an indicator of successful aortic valve stenosis treatment as residual hypertrophy, or lack of left ventricular remodeling, is associated with increased mortality [14, 15]. The current standard for evaluation of aortic valve function is echocardiography, which enables assessment of valve leaflet motion and flow velocities. Echocardiography is a cheap, patient-friendly, and widelyavailable imaging technique. However, echocardiography for assessment of flow velocities is limited by acoustic window and the 2D field of view. An alternative imaging modality for assessment of valve function is 4D flow MRI. This technique is not limited by acoustic windows, is not operator- or observer-dependent, and shows good internal consistency of scans, and scan-rescan repeatability [16, 17]. Additionally, it enables visualization and measurement direction of flow and velocity within the scanned field of view. Postprocessing allows for calculation of advanced hemodynamic parameters, including viscous energy loss and wall-shear stress. In this way advanced and comprehensive aortic valve hemodynamic performance can be assessed. This technique potentially allows for better appreciation of potential differences between stentless and stented aortic valve bioprosthesis. Previous studies using echocardiography show higher valvular gradients at discharge, and less regression of left ventricular mass in stented bioprostheses than in stentless bioprostheses, six months after surgery [6]. One year after aortic valve replacement, higher valvular gradients for stented prostheses were still described, however, the difference in left ventricular mass regression between both types of prosthesis diminished [18]. We have described the quantitative hemodynamic effects of stented and stentless prosthesis 1 year after aortic valve replacement in patient groups with similar baseline characteristics. Previously, von KnobelsdorffBrenkenhoff and colleagues used 4D flow MRI to describe qualitative flow characteristics and quantitative wall shear stress in the ascending aorta, years after aortic valve replacement with various types of prostheses [4]. They demonstrated differences in vorticity, helicity, and eccentricity among a heterogeneous group of controls and patients with autografts, mechanical, stentless, and stented aortic valve prostheses. In support of our data, von Knobelsdorff-Brenkenhoff and colleagues showed altered flow in all patients with aortic valve prostheses on comparison with control patients with a native aortic valve. Comparison of eight patients with a stented bioprosthesis with 14 patients with a stentless bioprosthesis, showed that stentless prostheses were associated with lower vorticity and helicity. However, in accordance with our findings, quantitative measurement of wall shear stress between these prostheses types showed no difference [4]. This pilot study has limitations, mainly related to the small sample size as a consequence of the study design. Peak velocity and energy loss require further attention in adequately-powered future studies. In addition, our 4D flow MRI data were acquired without the use of intravenous contrast agent. However, we found the image quality to be sufficient for analysis. Additionally, quantification of 3D wall shear stress and viscous energy loss depend on spatial resolution [11, 19]. Improvements in acquisition technique and scan

4D Flow MRI | 87

protocol potentially allow for more accurate assessment of wall shear stress and viscous energy loss. In general 4D flow MRI has several disadvantages that limit its current clinical applicability. MRI is not yet widely available and associated with higher costs than echocardiography. Furthermore, 4D flow MRI is time consuming and requires a long scan time and pre- and post-processing. Recent technical developments have led to faster acquisition techniques with scan times of 6 to 10 minutes [20, 21]. This makes the technique better applicable in clinical practice because it is more patient friendly and lowers costs. In addition, improvements in software may facilitate faster pre- and post-processing, thus further lowering the threshold for clinical application. The future developments of 4D flow MRI should comprise improvements in the sequence and in particular pre- and post-processing to make the technique more accessible and applicable in a clinical setting. Currently, longitudinal follow-up data of 4D flow MRI parameters are missing. Future studies should acquire comprehensive advanced baseline MRI data with long-term follow-up of the enrolled patients. Ideally, 4D flow MRI will be combined with sequences for tissue characterization and clinical outcome of different aortic valve prostheses and to determine prognostic parameters for individual outcome and patient-specific risk stratification.

CONCLUSION In this pilot study we found no statistical differences in the hemodynamic performance between the stented Mitroflow and the stentless Freedom SOLO bioprostheses with 4D flow MRI 1-year after implantation.

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REFERENCES 1.

Nishimura RA, Otto CM, Bonow RO, et al. 2014 AHA/ACC Guideline for the management of patients with valvular heart disease: a report of the American college of Cardiology/American heart association task force on practice guidelines. J Am Coll Cardiol 2014;63:2489 Vahanian A, Alfieri O, Andreotti F, et al. Guidelines on the management of valvular heart disease (version 2012): 2. the joint task force on the management of valvular heart disease of the European society of Cardiology (ESC) and the European association for Cardiothoracic surgery (EACTS). Eur J Cardiothorac Surg 2012;42:S1.44 3. Thourani VH, Suri RM, Gunter RL, et al. Contemporary real-world outcomes of surgical aortic valve replacement in 141,905 low-risk, intermediate-risk, and high-risk patients. Ann Thorac Surg 2015;99:55-61 4. von Knobelsdorff-Brenkenhoff F, Trauzeddel RF, Barker AJ, et al. Blood flow characteristics in the ascending aorta after aortic valve replacement-a pilot study using 4D-flwo MRI. Int J Cardiol 2014;170:426.33 5. Wollersheim LW, Li WW, Bouma BJ, et al. Aortic valve replacement with the stentless Freedom SOLO bioprosthesis: a systematic review. Ann Thorac Surg 2015;100:1496-5045. 6. Raja SG, Macarthur KJ, Pollock JC. Impact of stentless aortic valves on left ventricular hypertrophy: current best available evidence. J Card Surg 2006;21:313-9 7. Wigström L, Sjöqvist L, Wranne B. Temporally resolved 3D phase-contrast imaging. Magn Reson Med 1996;36:800-3 8. Markl M, Chan FP, Alley MT, et al. Time-resolved three-dimensional phase contrast MRI. J Magn Reson imaging 2003;17:499-506 Dyverfeldt P, Bissell M, Barker AJ, et al. 4D flow cardiovascular magnetic resonance consensus statement. J 9. Cardiovasc Magn Reson 2015;17:72 10. Bock J, Kreher W, Hennig J, et al. Optimized preprocessing of time-resolved 2D and 3D phase contrast MRI data. Proc Intl Soc Mag Reson Med 2007;15:3138 11. Potters WV, van Ooij P, Marquering H, et al. Volumetric arterial wall shear stress calculation based on cine phase contrast MRI. J Magn Reson Imaging 2015;41:505-16 12. Barker AJ, van Ooij P, Bandi K, et al. Viscous energy loss in the presence of abnormal aortic flow. Magn Reson Med 2014;72:620-8 13. Kozerke S, Hasenkamp JM, Pedersen EM, et al. Visualization of flow patterns distal to aortic valve prostheses in humans using a fast approach for cine 3D velocity mapping. J Magn Reson Imaging 2001;13:690-8 14. Stevens SM, Reinier K, Chugh SS. Increased left ventricular mass as a predictor of sudden cardiac death: is it time to put it to the test? Circ Arrythm Electrophysiol 2013;6:212-7 15. Bikkina M, Larson MG, Levy D. Asymptomatic ventricular arrhythmias and mortality risk in subjects with left ventricular hypertrophy. J Am Coll Cardiol 1993;22:1111-6 16. Uribe S, Beerbaum P, Sørensen TS, et al. Four-dimensional (4D) flow of the whole heart and great vessels using real-time respiratory self-gating. Magn Reson Med 2009;62:984-92 17. Wentland AL, Grist TM, Wieben O. Repeatability and internal consistency of abdominal 2D and 4D phase contrast MR flow measurements. Acad Radiol 2013;20:699-704 18. Payne DM, Koka HP, Karanicolas PJ, et al. Hemodynamic performance of stentless versus stented valves: a systematic review and meta-analysis. J Card Surg 2008;23:556-64 19. Casas B, Lantz J, Dyverfeldt P, et al. 4D flow MRI-based pressure loss estimation in stenotic flows: evaluation using numerical simulations. Magn Reson Med 2015. Doi: 10.1002/mrm25772 [Epub ahead of print] 20. Giese D, Wong J, Greil GF, et al. Towards highly accelerated Cartesian time-resolved 3D flow cardiovascular magnetic resonance in the clinical setting. J Cardiovasc Magn Reson 2014;16:42 21. Tariq U, Hsiao A, Alley M, et al. Venous and arterial flow quantification are equally accurate and precise with parallel imaging compressed sensing 4D phase contrast MRI. J Magn Reson Imaging 2013;37:1419-26

CHAPTER 7 When not to go SOLO? Contraindications based on implant experience

Wollersheim LW, Li WW, Kaya A, van Boven WJ, van der Meulen J, de Mol BA Manuscript submitted to the Journal of Cardiac Surgery

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ABSTRACT Background: The Freedom SOLO is a stentless aortic bioprosthesis implanted in the supraannular position. Because of its design and specific implantation technique, patient selection is crucial. In this paper we discuss the contraindications to this prosthesis based on almost 10 years of implant experience. Methods: From April 2005 to February 2015 one surgeon at our center performed 292 aortic valve replacements with a bioprosthesis, with the intention of implanting a Freedom SOLO in every patient. We conducted a search on all these patients and collected data on not using the Freedom SOLO. Results: A Freedom SOLO was implanted in 238 patients (82%) and a stented bioprosthesis was implanted in 54 patients (18%). The predominant reasons not to implant a Freedom SOLO were asymmetrical commissures (26%), large aortic annulus (24%) and calcified aortic sinuses (19%). At 8-year follow-up, the experienced SOLO surgeon had a 96% freedom from aortic valve reoperation rate. Conclusion: In order to maximize the durability of the Freedom SOLO it is imperative to avoid certain pitfalls concerning its implantation. Asymmetrical commissures, large aortic annulus (>27mm), calcified aortic sinuses, dilated sinotubular junction, aberrant location of coronary ostia and whenever the stent of a stented bioprosthesis is useful to cover a defect or hole are surgical-technical indications â&#x20AC;&#x2DC;when not to go SOLOâ&#x20AC;&#x2122;. When these contraindications are taken into account, a very good durability can be achieved with the Freedom SOLO during midterm follow-up.

When not to go SOLO? | 91

INTRODUCTION The Freedom SOLO valve (Sorin, Saluggia, Italy) is a stentless aortic valve bioprosthesis used for aortic valve replacement (AVR). Its stentless design and supraannular implantation offer the maximum effective orifice area. The Freedom SOLO could therefore be the ideal bioprosthesis in specific patient groups at risk for prosthesis-patient mismatch, for example, for patients with a small aortic root [1]. However, due to its specific design and implantation technique, various situations might prohibit the use of the Freedom SOLO. According to the manufacturer no absolute contraindications to the Freedom SOLO exist [2]. Nevertheless, Stanger and colleagues discourage the use of the Freedom SOLO in patients with bicuspid aortic valves and patients with enlarged aortas, because of the asymmetrical distribution of the commissures and the potential for the aorta to dilate in the future and subsequently, cause central aortic insufficiency [3]. If the cardiac surgeon does not conform to the restrictions of the Freedom SOLO there will be premature failures and an increased number of patients with structural valve deterioration [3, 4]. In order to maximize the durability of the Freedom SOLO, patient selection is crucial. In this paper, in a patient series in which the Freedom SOLO was routinely implanted for almost 10 years, we analyze when and why the Freedom SOLO was not used.

MATERIALS AND METHODS From April 2005 to February 2015 one surgeon (JvdM) performed 292 consecutive AVRs with a bioprosthesis at our center. This surgeon aimed to use the Freedom SOLO at every AVR procedure. If the Freedom SOLO was not used, the reason why was stated in the operative report. We conducted a search through all 292 AVR procedures performed by this surgeon and collected data on why the Freedom SOLO was not used. Surgical technique The surgical technique has been described previously [5]. In summary, after institution of cardiopulmonary bypass, application of the aortic crossclamp and administration of cardioplegia solution, a transverse aortotomy is performed approximately 1 centimeter above the sinotubular junction. The diseased aortic valve is resected and the annulus decalcified if necessary. The aortic annular diameter is measured at the level of the aortic annulus with the manufacturerâ&#x20AC;&#x2122;s sizers. The Freedom SOLO does not have to be rinsed before implantation. Three equidistant 4-0 polypropylene sutures are placed in the nadirs of each of the sinuses of Valsalva, 2 to 3 millimeters above the aortic annulus, and subsequently through the outflow edge of the Freedom SOLO. The running sutures are continued to the top of each of the commissures and tied extra-aortically. The aortotomy is then closed.

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RESULTS One surgeon (JvdM) operated on 292 patients who underwent AVR with a bioprostheses. Of these 292 patients, 238 (82%) received a Freedom SOLO. Hence, a Freedom SOLO was not used in 54 (18%) out of 292 possible implantations. Fifty-four stented bioprosthesis were implanted (51 Mitroflow prostheses (Sorin, Saluggia, Italy) and three Perimount prostheses (Edwards Lifesciences, Irvine, CA, USA). The reasons why a Freedom SOLO was not implanted are presented in Table 1. The most common reasons for not using a Freedom SOLO were asymmetrical commissures (26%) and a large annulus of more than 27mm (24%). In 19%, calcified aortic sinuses prohibited the implantation of the Freedom SOLO. Three patients had a bicuspid aortic valve with post-stenotic dilatation of the sinotubular junction, these patients were categorized as bicuspid aortic valves in the asymmetrical commissure group. The three patients in the dilated sinotubular junctions group had sinotubular junctions of 40mm, 45mm and 50mm wide. The patients with the 45mm and 50mm sinotubular junctions did not undergo aortic replacement because the increased operative risks for both patients justified isolated AVR. Of the four patients in whom a stented bioprostheses was preferred to cover annular defects or holes, three were operated on for endocarditis. The fourth patient was undergoing reoperation at which time during explantation of the previously implanted mechanical prosthesis there was damage to the left coronary and non-coronary sinus. The patient with the aberrant location of the coronary ostia had an extremely low origin of the right coronary ostium, this impeded supraannular implantation of a Freedom SOLO. During follow-up of the 238 patients Freedom SOLO patients (mean 3.5 Âą 2.5 years), one patient required aortic valve reintervention due to structural valve deterioration. This patient received a transcatheter aortic valve implantation and this case was published before [6]. After 8 years, there was a 96% freedom from aortic valve reoperation. Table 1. Reasons for not using the Freedom SOLO Reason

N=54

Asymmetrical commissures (bicuspid valve) Large aortic annulus (>27mm)

14 (26%) 13 (24%)

Calcified aortic sinuses

10 (19%)

Dilated sinotubular junction

3 (6%)

Aberrant coronary ostia origin

1 (2%)

Stented bioprosthesis used to cover annular defect

4 (7%)

Other -Resident not familiar with FS -Structural valve deterioration in previous FS -No specific reason reported

9 (17%) 2 1 6

FS = Freedom SOLO

When not to go SOLO? | 93

Figure 1. Kaplan-Meier of the aortic valve reoperations from the experienced SOLO surgeon AV = aortic valve

DISCUSSION The Freedom SOLO is a stentless aortic valve bioprosthesis with excellent clinical and hemodynamic results [7]. Due to its supraannular implantation position and stentless design this bioprosthesis could be very useful in certain patient groups that would profit from its favourable hemodynamic profile. However, in order to maximize the durability of the Freedom SOLO it is imperative to avoid certain pitfalls when implanting this prosthesis. The learning curve is not only a matter of learning the suture technique but also of knowing the limitations of the valve. In this retrospective analysis, in 18% of patients undergoing AVR with a bioprosthesis implanted by an experienced surgeon there were intraoperative reasons for not using the Freedom SOLO. Asymmetrical commissures, large aortic annulus (>27mm), calcified aortic sinuses, dilated sinotubular junction, aberrant location of the coronary ostia are all surgical-technical indications of â&#x20AC;&#x2DC;when not to go SOLOâ&#x20AC;&#x2122;. Also, if annular defects are present after decalcification or in some patients with endocarditis, a stented bioprosthesis is preferable. Sometimes these defects can be closed primarily after which Freedom SOLO implantation is possible. However, primary closure can create an asymmetrical aortic root and crossclamp time can be shortened if it is possible to close the defects with the annular sutures of the stented bioprosthesis. Asymmetrical anatomy prevents the symmetrical distribution of the three commissures of the Freedom SOLO which can lead to excessive mechanical stress on the leaflets. This may lead to early structural valve deterioration with calcified leaflets and should therefore be avoided. In addition to asymmetrical commissures, in some patients oversizing the Freedom SOLO causes iatrogenic asymmetry. If a Freedom SOLO is oversized the valve leaflets become redundant and wrinkled at the level of the suture line. This causes reduced mobility, higher gradients and regurgitation due to irregular coaptation. Thrombosis and early degeneration may be expected [4]. Undersizing the Freedom SOLO should be avoided, and if 27mm is too small (27mm is the largest size available), then another bioprosthesis should be considered. In an undersized Freedom SOLO the leaflets

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do not coapt properly and they are restricted in their movements by an excess of tension on the suture line, aortic tissue and commissures. This may lead to suture dehiscence, early deterioration and commissural tears [4]. Correct suturing is difficult in calcified aortic sinuses and could prevent the perfect alignment of the Freedom SOLO with the aortic wall. Therefore the risk of paravalvular leakage is increased. A dilated sinotubular junction could potentially continue to dilate postoperatively. David and colleagues showed that dilation of the sinotubular junction caused aortic valve insufficiency after AVR with the stentless Toronto SPV (St Jude Medical, St. Paul, MN, USA) [8]. In these patients, the absence of a rigid stent led to coaptation problems of the leaflets and therefore to central aortic regurgitation. Nรถtzold and colleagues showed that an increase of sinotubular junction diameter of more than 32% in the stentless Toronto SPV and 43% in the stentless Medtronic Freestyle (Medtronic, Minneapolis, MS, USA) led to loss of leaflet coaptation resulting in aortic valve insufficiency [9]. Newer generation stentless bioprostheses, the Freedom SOLO and the 3F Aortic (Medtronic, Minneapolis, MS, USA), were developed with redundant leaflet tissue for larger coaptation area. On comparison with older generation stentless bioprostheses both stentless prostheses showed favourable tolerance to sinotubular dilatation, 45% for the Freedom SOLO and 56% for the 3F Aortic [10]. However, restricted use of the Freedom SOLO is still advised in a patient with a dilated sinotubular junction. Freedom from structural valve deterioration and freedom from aortic valve reoperation are essential factors in the evaluation of aortic valve bioprostheses. In the near future the Freedom SOLO will reach a crucial evaluation point. Other bioprostheses have set the benchmark for newer generation bioprostheses [11,12], especially since reoperations for stentless aortic valve bioprostheses can be challenging, frequently require aortic root replacement and are associated with an increased risk of mortality [13]. Stanger and colleagues reported that at their Freedom SOLO reoperations calcification was always strikingly severe and included the entire root. Reoperation in these patients was very difficult and demanding [3]. In our cohort the patient with structural valve deterioration was expected to have a calcified aortic root and she underwent transcatheter aortic valve implantation. Transcatheter options for valve-in-valve implantation are likely to become more popular for the treatment of patients with a degenerated aortic valve bioprosthesis. It is important that at preoperative evaluation of these patients special attention should be paid to the distance between Freedom SOLO and the coronary ostia. Since the Freedom SOLO is implanted supraannularly, the distance from the neo-annulus to the coronary ostia is shorter than in stented bioprostheses and the risk of coronary ostia obstruction is increased. In the patient with structural valve deterioration we implanted a JenaValve (JenaValve Technology, Munich, Germany) into a degenerated Freedom SOLO since its specific design reduced the risk of coronary ostia obstruction [6]. However, the Corevalve (Medtronic, Minneapolis, MS, USA) and the Sapient XT (Edwards Lifesciences, Irvine, CA, USA) have also been implanted successfully into a supraannular Freedom SOLO, although neither report mentioned the coronary height [14,15]. This study has limitations. Since the operative reports were written by a single surgeon, the information derived from these reports is subjective. Although he is a experienced surgeon, the reports are limited to his personal experience and interpretation. There are also few patients at risk in the follow-up period and

When not to go SOLO? | 95

therefore the results at 8 years of follow-up have to be interpreted with caution. In the ‘other’ group (Table 1) there are six patients where no specific reason was reported for the Freedom SOLO not being used. Interestingly, these patients were intermediate to high-risk patients. This could be an example of patient selection bias in retrospective cohort studies.

CONCLUSION In order to maximize the durability of the Freedom SOLO it is imperative to avoid certain pitfalls concerning the implantation of this bioprosthesis. Asymmetrical commissures, large aortic annulus, calcified aortic sinuses, dilated sinotubular junction, aberrant location of coronary ostia, and whenever the stent from a stented prosthesis would be useful to cover a defect or hole are all surgical-technical indications of ‘when not to go SOLO’. When these contraindications are taken into account, a very good durability can be achieved with the Freedom SOLO during midterm follow-up.

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REFERENCES 1.

Gulbins H, Reichenspurner H. Which patients benefit from stentless aortic valve replacement? Ann Thorac Surg 2009;88:2061-8 2. Sorin Freedom SOLO Stentless heart valve; Instructions for use 840-07LS200 Rev C, Sorin Group 3. Stanger O, Bleuel I, Reineke S, et al. Pitfalls and premature failure of the Feedom SOLO stentless valve. Eur J Cardiothorac Surg 2014;48:562-70 4. Repossini A, Bisleri G. Freedom SOLO: avoiding pitfalls to avoid premature failures? Eur j Cardiothorac Surg. 2015 [Epub ahead of print] 5. Glauber M, Solinas M, Karimov J. Technique for implant of the stentless aortic valve Freedom Solo. Multimed Man Cardiothorac Surg 2007;2007(1018):mmcts.2007.002618 6. Wollersheim LW, Cocchieri R, Symersky P, et al. Transapical JenaValve in a degenerated Freedom SOLO bioprosthesis. J Thorac Cardiovasc Surg 2014;148:741-2 7. Wollersheim LW, Li WW, Bouma BJ, et al. Aortic valve replacement with the stentless Freedom SOLO bioprosthesis: a systematic review. Ann Thorac Surg 2015;100:1496-504 8. David TE, Ivanov J, Eriksson MJ, et al. Dilation of the sinotubular junction causes aortic insufficiency after aortic valve replacement with the Toronto SPV bioprosthesis. J Thorac Cardiovasc Surg 2001;122:929-34 9. Nรถtzold A, Schwarfschwerdt M, Thiede L,et al. In-vitro study on the relationship between progressive sinotubular junction dilatation and aortic regurgitation for several stentless aortic valve substitutes. Eur J Cardiothorac Surg 2005;27:90-3 10. Scharfschwerdt M, Sievers HH, Hussein A, et al. Impact of progressive sinotubular junction dilatation on valve competence of the 3F Aortic and Sorin Solo stentless bioprosthetic heart valves. Eur J Cardiothorac Surg 2010;37:631-4 11. Johnston DR, Soltesz EG, Vakil N, et al. Long-term durability of bioprosthetic aortic valves: implications from 12,569 implants. Ann Thorac Surg 2015;99:1239-47 12. Bach DS, Kon ND. Long-term clinical outcomes 15 years after aortic valve replacement with the Freestyle stentless aortic bioprosthesis. Ann Thorac Surg 2014;97:544-51 13. Borger MA, Prasongsukarn K, Armstrong S, et al. Stentless aortic valve reoperations: a surgical challenge. Ann Thorac Surg 2007;84:737-43 14. Halapas A, Chrissoheris M, Spargias K. Challenging transfemoral valve-in-valve implantation in a degenerated stentless bioprosthetic aortic valve. J Invasive Cardiol 2014;26:E106-8 15. Matjaz B, Miha S, Kocijancic I, et al. Transfemoral Edwards Sapien XT valve-in-valve implantation for failing freedom solo stentless aortic bioprosthesis: a case report. Exp Clin Cardiol 2014;20:145-8

CHAPTER 8 Solutions for a degenerated Freedom SOLO

Transapical JenaValve in a degenerated Freedom SOLO bioprosthesis

Wollersheim LW*, Cocchieri R*, Symersky P, de Mol BA * Shared first authorship Journal of Thoracic and Cardiovascular Surgery 2014;148:741-2

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Solutions for a degenerated Freedom SOLO | 101

Degeneration of an aortic bioprosthesis is a complication often requiring high-risk surgical reintervention. Transcatheter aortic valve implantation (TAVI) provides an alternative to high-risk surgery. However, TAVI for a degenerated stentless bioprosthesis becomes more perilous because of the lack of support of a stent and the changed landmarks of the aortic root. Furthermore, the supra-annular implantation technique for the stentless Freedom SOLO (Sorin, Saluggia, Italy) bioprosthesis may increase the risk for coronary occlusion after deployment, because of the reduced distance between the neoannulus and the coronary ostia. In this setting, the use of the JenaValve (JenaValve Technology, MĂźnchen, Germany) could reduce the risk of coronary ostium obstruction because of the specific design of this device. To illustrate this clinical problem, we present the first reported case after successful transcatheter valve-in-vale implantation of a JenaValve in a degenerated Freedom SOLO.

CLINICAL SUMMARY An 86-year-old woman presented with progressive dyspnea on exertion. Her medical history included hypertension, chronic obstructive pulmonary disease and aortic valve replacement (Freedom SOLO 23mm) because of aortic valve stenosis 7 years previously. Transthoracic echocardiography showed severe aortic valve stenosis with a maximum gradient of 103 mmHg and a mean gradient of 65 mmHg over the Freedom SOLO, with an aortic valve area of 0.6 cm2. The logistic European System for Cardiac Operative Risk Evaluation score was 36.5%, and the Society of Thoracic Surgeons score 6.3%. The distance, measured on a computed tomography scan (Figure 1), between the leafletsâ&#x20AC;&#x2122; base and the coronary ostia was 10 mm and 9 mm for the right and left coronary ostia, respectively. Because of the short distance between the coronary ostia and de neoannulus of the Freedom SOLO, the JenaValve was preferred in order to reduce the risk of coronary occlusion.

Figure 1. Reconstruction of the aortic root with measurements of the distance between the coronary ostia and the supraannular Freedom SOLO

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Access to the left ventricular apex was achieved through an anterolateral mini-thoracotomy in the fifth intercostal space. Once the ideal muscular spot was identified, a double Prolene suture with pledgets and an epicardial pacing lead were placed. A 25mm JenaValve was positioned in the Freedom SOLO, the positioning feelers were released and verified for anatomical orientation in the nadirs of each of the 3 leaflets (Figure 2a). Correct positioning was verified under fluoroscopy, and the lower part of the stent was released. The leaflets of the Freedom SOLO were clipped onto the JenaValve while the valve unfolded (Figure 2b). Subsequently, the upper part of the JenaValve was completely deployed (Figure 2c). Transesophageal echocardiography showed a good function of the JenaValve with a Vmax of 3m/s, mean gradient of 16 mmHg and an AVA of 1.2 cm2; and no paravalvular leakage or aortic insufficiency. Postoperative period was uneventful. The patient was discharged in good condition to a cardiology unit in a regional hospital near her home on postoperative day 6.

Figure 2. a: anatomical orientation with the released positioning feelers, positioned in the nadirs of the leaflets b: lower part of the JenaValve released. Leaflets are clipped c: the completely deployed JenaValve without aortic regurgitation

DISCUSSION The Freedom SOLO is a stentless aortic bioprosthesis implanted supra-annularly using only 1 running suture line in the sinuses of Valsalva. Early malfunction of a Freedom SOLO is rare, with only 3 reported cases in known literature [1-3]. This is the first reported case where the risk for surgical reintervention was deemed too high and TAVI was found to be an attractive alternative. However, according to the European guidelines, an elevated risk of coronary artery ostium obstruction, in case of a short distance between the aortic annulus and the coronary ostium, is an absolute contra indication for TAVI [4]. Al-Lamee and colleagues suggest that the height of coronary ostia shorter than 10 mm from the base of the aortic valve leaflets should be an overall contraindication for TAVI, to prevent coronary arterial occlusion [5]. We believe that this risk could be attenuated because of the specific design of the JenaValve. The JenaValve is a self-deploying nitinol prosthesis with an anchoring mechanism that resembles a 3-foil paperclip and grasps each of the leaflets.

Solutions for a degenerated Freedom SOLO | 103

For deployment, 3 feelers are first positioned in each of the 3 nadirs of the leaflets, after which the lower part of the fixation mechanism clasps the internal side of the aortic valve cusps for anchoring. This allows anatomically correct positioning, preventing coronary ostium obstruction. Furthermore, because of the active clip fixation, there could be a lower risk of valve migration towards the coronary ostia during expansion of the JenaValve compared to other transcatheter valves. The minimal coronary height required for placement of the JenaValve is 8 mm. In conclusion, we support the use of the JenaValve when a transcatheter valve-in-valve implantation is required in a degenerated Freedom SOLO in order to reduce the risk of coronary ostium obstruction.

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REFERENCES 1. 2. 3. 4. 5.

Giordano V, Hermens JA, Wajon EM, et al. Rare prosthesis failure after aortic valve replacement with a Freedom SOLO. Interact Cardiovasc Thorac Surg 2011;12:273-5 Wollersheim LW, Li WW, van der Meulen J, et al. A 76-year old man with a torn Freedom SOLO bioprosthesis. Interact Cardiovasc Thorac Surg 2014;18:141-2 Caprili L, Fahim AN, Zussa C, et al. Very early malfunction of a large stentless aortic valve. Eur J Cardiothorac Surg 2009;36:417-8 Vahanian A, Alfieri O, Andreotti F, et al. Guidelines on the management of valvular heart disease (version 2012). European Heart Journal 2012;33:2451-96 Al-Lamee R, Godino C, Colombo A. Transcatheter aortic valve implantation: current principles of patient and technique selection and future perspectives. Circ Cardiovasc Interv 2011;4:387-95

A 76-year old man with a torn Freedom SOLO bioprosthesis

Wollersheim LW, Li WW, van der Meulen J, de Mol BA Interactive Cardiovascular and Thoracic Surgery 2014;18:141-2

Solutions for a degenerated Freedom SOLO | 107

ABSTRACT We describe a case of a 76-year old male who presented with progressive dyspnea. He underwent an aortic valve replacement with a Freedom SOLO bioprosthesis 6 years ago. Transthoracic echocardiography showed a moderate-to-severe leakage of the Freedom SOLO bioprosthesis. During surgical reintervention, a partial tear of the left coronary cusp was seen from the commissure of the right coronary cusp to its base. After radiographic and microscopic examination, no clear cause was found for the failure of this Freedom SOLO bioprosthesis. To our knowledge, this is the third failure of a Freedom SOLO bioprosthesis reported in the literature. When the long-term follow-up of the Freedom SOLO bioprosthesis is available, it has to be compared to other bioprosthesis for long-term durability.

TEXT The Freedom SOLO valve is a stentless aortic bioprosthesis, first described by Repossini in 2005 after modification of the Pericarbon Freedom Stentless valve. Initial short- and mid-term results of the Freedom SOLO bioprosthesis are excellent [1, 2]. However, long-term follow-up is not yet available. Long-term durability remains an essential feature for new bioprostheses, because failure of a bioprosthesis is a serious complication often requiring surgical reintervention. A 76-year old male presented with progressive dyspnea for 4 days. His medical history included hypertension, hypercholesterolemia and paroxysmal atrial fibrillation. Furthermore, he underwent a stentless biologic aortic valve replacement (AVR) (Freedom SOLO 25mm) 6 years before for severe aortic stenosis. During routine outpatient follow-up 2 years before admission, transthoracic echocardiography (TTE) showed a good functioning aortic bioprosthesis. One week prior to presentation, he had complaints of a sore throat and possible fever. On admission, physical examination revealed a new diastolic heart murmur (grade 4/6) and crackles were heard on both sides of his lungs. White blood cell count (WBC) was 9.8 x109/L and C-reactive protein (CRP) was 10.4 mg/L. Chest X-ray showed pulmonary venous congestion with bilateral pleural effusion. TTE was performed which demonstrated a moderate-to-severe leakage of the aortic bioprosthesis, and normal left ventricular dimensions with a normal function. With transesophageal echocardiography a possible tear in the left coronary cusp (LCC) was noticed, suspected to be responsible for the aortic regurgitation. Furthermore, there was some discrete thickening of a leaflet, possibly a vegetation. Intravenous diuretics were started, as well a combination therapy of gentamycine and penicilline, after blood cultures were drawn. The blood cultures came back negative, no fever occurred and WBC and CRP remained low. According to the modified Duke criteria [3], endocarditis seemed unlikely and the antibiotic therapy was stopped. In addition, the patient was scheduled for a surgical reintervention.

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During the reoperation, the Freedom Solo bioprosthesis was attached properly to the aortic wall, with flexible leaflets without any vegetation. However, the LCC showed a tear from the bottom of the left coronary sinus towards the top of the commissure between the LCC and right coronary cusp (RCC) (Figure 1 and 2). The pericardial sewing belt was unaffected. The Freedom Solo bioprosthesis was excised and replaced with a stented aortic bioprosthesis (Sorin, Mitroflow 23mm). The postoperative course was uneventful. TTE showed normal left ventricular function and a well-functioning aortic bioprosthesis with a maximum gradient of 37 mm Hg with trivial central regurgitation. On postoperative day 7, he was discharged to a cardiology unit in a rural hospital near his home. At a routine visit to our outpatient clinic, the patient stated the dyspnea was trivial on exertion.

Figure 1. The left coronary cusp shows a partial tear from the commissure of the right coronary cusp to its base

Figure 2. View from the aortic side. LCC = left coronary cusp, RCC = right coronary cusp, NCC = non coronary cusp

Solutions for a degenerated Freedom SOLO | 109

The torn Freedom Solo bioprosthesis was sent to Sorin, Italy, for further investigation. X-ray analysis showed no calcifications of the leaflets. However, microscopic examination revealed the presence of inflammatory cells and cholesterol clefts, indicative of an atherosclerotic process. Furthermore, Gram-positive bacteria were identified with Gram stain under the mesothelial surface.

COMMENT The Freedom SOLO valve is implanted supra-annular using only one running suture line in the sinuses of Valsalva. Because of the supra-annular position and the stentless design, effective orifice area is maximized. The short-term clinical outcome and hemodynamic results of the Freedom SOLO bioprosthesis are excellent, showing regression of left ventricular hypertrophy and improvement in left ventricular systolic function in a safe and feasible procedure [1]. However, long-term results of the Freedom SOLO valve are not yet available. Structural deterioration of the Freedom SOLO bioprosthesis has been rarely reported. In the largest case series available on the Freedom SOLO bioprosthesis, no graft failures were reported by Beholz and colleagues in 256 patients after 12-month follow-up [1]. To the best of our knowledge, only 2 cases of have been previously reported. The first is a case report by Caprili, where, in a 78-year old woman, the Freedom SOLO bioprosthesis showed severe calcifications, 18 months after the initial AVR, and had to be replaced. Caprili and colleagues suggested that, in this particular case, the positioning and symmetry in a dilated aorta (37.5mm) could not be achieved perfectly. This could lead to increased mechanical stress on the cusps accelerating mineralization [4]. The second case is reported by Giordano and colleagues, describing Freedom SOLO bioprosthesis failure, 6 months after implantation in a 78-year old man. After microscopic and histological analysis Giordano hypothesized the valve failure was caused by a rough outflow surface attaching to the aortic wall with subsequent regurgitation [5]. Both cases have not much in common with our sharp and sudden tear after 6 years, in an otherwise unimpaired prosthesis. In our case, the cause of the tear in the LCC remains uncertain. The suggestion of subclinical endocarditis was not proven by cultures and in our opinion is most likely postexplant contamination. In our experience, the suture line from the bottom of the left coronary sinus towards the commissure between the LCC and the RCC is the most difficult one for a right-handed surgeon. Maybe this was the weak spot of the bioprosthesis caused by the implantation technique and the first part to tear under stress and tearing of the leaflets over time, although the diameter of the aortic root did not dilate over time. Long-term durability continues to be an essential feature when evaluating new aortic bioprostheses. In our own series, which includes just over 300 patients with a follow-up up to 8 years, this is the first tear in a Freedom SOLO valve. In conclusion, a tear in the LCC of a Freedom SOLO valve was found 6 years after implantation. Postoperative examination of the Freedom SOLO valve did not provide a clear diagnosis. The suture line from the bottom

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of the left coronary sinus towards the commissure between the LCC and the RCC is the most difficult one for a right-handed surgeon, indicating the weak spot of the Freedom SOLO valve under stress and tearing of the leaflets over time. If similar events occur in the future, detailed morpho-histological analyses must be performed to find a possible diagnosis.

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REFERENCES 1. 2. 3. 4. 5.

Beholz S, Repossini A, Livi U, et al. The Freedom SOLO valve for aortic valve replacement: clinical and hemodynamic results from a prospective multicenter trial. J Heart Valve Dis 2013;19:115-34 Iliopoulos DC, Deveja AR, Androutsopoulou V, et al. Single-center experience using the Freedom SOLO aortic bioprosthesis. J Thorac Cardiovasc Surg 2013;146:96-102 Li JS, Sexton DJ, Mick N, et al. Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis. Clin Infect Dis. 2000;30:633-8 Caprili L, Fahim AN, Zussa C, et al. Very early malfunction of a large stentless aortic valve. Eur J Cardiothorac Surg 2009;36:417-8 Giordano V, Hermens JA, Wajon EM, et al. Rare prosthesis failure after aortic valve replacement with a Freedom Solo. Interact Cardiovasc Thorac Surg 2011;12:273-5

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CHAPTER 9 Discussion

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Discussion | 115

This dissertation focusses on the evaluation and performance of the stentless Freedom SOLO bioprosthesis (Sorin, Saluggia, Italy) which has been commercially available since 2004. From the studies in this thesis the following conclusions can be drawn. Our systematic review validated the concept of the Freedom SOLO as it seems to offer ‘the best of both worlds’ by combining the superior hemodynamics of stentless valves with a fast implantation technique, equal to the implantation time of stented valves. Our single center Freedom SOLO study results have enabled us to confirm the value of the Freedom SOLO as an option for biological aortic valve replacement, as our short- and midterm results were excellent. In an analysis comparing stentless with stented prostheses in patients with a small aortic root, we found the Freedom SOLO to have significant advantages: superior hemodynamic performance, superior durability, and at follow-up more patients were in New York Heart Association (NYHA) classes 1 and 2. 4D Flow magnetic resonance imaging (MRI) and transthoracic echocardiography were the techniques used for quantification and visualization of valve prosthesis hemodynamic performance. In a pilot study using 4D flow MRI, we were not able to show statistical differences in hemodynamic performance between stentless and stented prostheses. However, on transthoracic echocardiography, the Freedom SOLO showed excellent results at discharge and up to 9 years of follow-up. Additionally, patient selection is crucial in order to experience the maximum durability of the Freedom SOLO. If a Freedom SOLO degenerates, both reoperation and transcatheter aortic valve implantation are possibilities. Best of both worlds The Freedom SOLO was developed in 2004. The underlying idea was to design a hemodynamically superior stentless bioprosthesis with a simplified implantation technique which enables implantation within the same crossclamp time as a stented bioprosthesis. In Chapter 3 we systematically review the available evidence to decide if the Freedom SOLO offers ‘the best of both worlds’, by combining the superior hemodynamic performance of a stentless valve with a simple and fast implantation technique. Mean crossclamp time for isolated aortic valve replacement with the Freedom SOLO was 66 minutes, which is shorter than the crossclamp time of other stentless bioprostheses (72 to 128 minutes), and equal to the crossclamp time of stented bioprostheses (50 to 67 minutes). Chapter 5 also reports the crossclamp times for isolated aortic valve replacement were equal in the Freedom SOLO and the stented Mitroflow (Sorin, Saluggia, Italy). These results indicate that the Freedom SOLO provides equal crossclamp times when compared with stented bioprostheses. In comparison with the mean crossclamp time for isolated aortic valve replacement of 66 minutes (Chapter 3), the crossclamp time of our own case series was 80 minutes (Chapter 4). This prolonged crossclamp time could be the results of rotating OR teams and proctoring and training of surgeons and residents. In total thirteen surgeons were involved in the implantation of 350 Freedom SOLO bioprostheses, only 5 of whom implanted more than 10 Freedom SOLO prostheses. Our data revealed that the Freedom SOLO can be implanted within one hour by experienced surgeons. The systematic review (Chapter 3) also showed that the hemodynamic performance of the Freedom SOLO was excellent. On average, the peak valvular gradient was 17 mmHg at discharge and remained stable at 15 mmHg during follow-up. On average, the mean valvular gradient was 9 mmHg at discharge and remained stable at 9

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mmHg during follow-up. In Chapters 4 and 5 these excellent hemodynamic results are confirmed and we further elaborate on the hemodynamic performance under the subheading â&#x20AC;&#x2DC;hemodynamic performanceâ&#x20AC;&#x2122;. Thus far, the stentless Freedom SOLO seems to offer the best of both worlds, with its superior hemodynamic performance and short crossclamp times. The crossclamp times of stentless prostheses are compared to those of stented prostheses since these are used most often and therefore set the benchmark. The crossclamp times are of interest, especially in highrisk patients. In these high-risk patients a sutureless bioprosthesis is also an option, especially if combined with a minimal access approach (Chapter 2). Sutureless valves showed short crossclamp times of 18 to 39 minutes with good hemodynamic performance. However, initial experiences showed the incidence of paravalvular leakage and pacemaker implantation is a concern in these prostheses. Safe in everyday practice Regarding early outcomes, the Freedom SOLO showed results comparable with benchmark data [1]. Operative mortality was 3.5% to 5.1% for combined procedures (Chapters 3 and 4) and 2.1% for isolated aortic valve replacement (Chapter 4). Stroke occurred in 1.1% to 2% of patients and other postoperative morbidity was also within the acceptable range (Chapters 3 and 4). Therefore, we conclude that the Freedom SOLO is non-inferior to comparable commercially available bioprostheses and safe to use in everyday practice. Additionally we looked at postoperative pacemaker implantations, as we hypothesized that due to the supraannular implantation of the Freedom SOLO, the rate of postoperative pacemaker implantations should be lower since the sutures are further away from the conduction system than in stented bioprostheses in which sutures in the native aortic annulus are necessary. A recent meta-analysis, that included 2557 isolated aortic valve replacements with a stented aortic bioprostheses, showed a pacemaker was necessary in 7% of patients [2]. In our case series of 46% concomitant procedures, only 2.3% of patients received a pacemaker (Chapter 4), and the systematic review showed a pacemaker implantation rate in only 1.7% (Chapter 3). In our opinion, this confirms our hypothesis that because of its implantation technique, the Freedom SOLO is associated with fewer pacemaker implantations. Possible explanations for heart block requiring a pacemaker following Freedom SOLO implantation could be extensive decalcification of the aortic annulus or that early in the learning curve the sutures are placed intraannularly and not supraannularly. Placing the sutures in the annulus is a major flaw that may additionally lead to a high valvular gradient and early structural valve deterioration. Chapter 5 points out that there was no difference in the number of postoperative pacemaker implantations between the Freedom SOLO (3%, N = 2) and the Mitroflow (4%, N = 8). This could be because the groups were relatively too small to show a difference, and that in the Mitroflow group in our study the 4% is lower than the reported 7% in the meta-analysis [2]. Postoperative thrombocytopenia has been reported following Freedom SOLO implantation and this seems to be more evident than in other bioprostheses. Chapters 3 and 5 support this observation. However, the thrombocytopenia appears to be transient. Chapter 4 shows that the mean platelet count after implantation of a Freedom SOLO was 70 x109/L, and this nadir occurred after a mean of 3 postoperative days. A postoperative platelet count of less than 50 x109/L was seen in 106 patients (30%). After 13 days the platelet

Discussion | 117

counts recovered to 81% of the preoperative level (Chapter 3). There were no clinical consequences as postoperative bleeding complications (delayed tamponade and gastrointestinal bleeding events) were within normal ranges, and using linear regression, we found no correlation between thrombocytopenia and adverse bleeding events. Postoperatively 31% of patients received a blood transfusion and 10% received a platelet transfusion. The threshold for a blood transfusion was a hemoglobin level of 5 mmol/L (8.05 g/dl) and the indication for the platelet transfusions was either severe thrombocytopenia or persistent mediastinal chest tube drainage. In total, 7% of the patients required immediate reexploration for early bleeding. This number is high and increases the rate of blood and platelet transfusions. Also blood saving techniques were hardly used and the population was elderly, both factors increase the need for blood transfusions. Additionally, the unfamiliarity of some intensive care doctors with the thrombocytopenia phenomenon may have led to increased platelet transfusion rates. Moreover, in Chapter 5 it is shown that there is no difference in the blood transfusion rate (32% versus 27%) or platelet transfusion rate (11% versus 9%) between the Freedom SOLO and Mitroflow groups. The reason for the thrombocytopenia is currently unknown. Tarzia and colleagues showed platelet function and platelet interaction with fibrinogen to form a thrombus remained normal after implantation of the Freedom SOLO [3]. Additionally, Repossini and colleagues showed platelet activation and consumption should not be considered as the underlying mechanism since von Willebrand factor, P-selectin, prothrombin fragment 1+2 and Î˛-thromboglobulin were equal between the Freedom SOLO and a stented bioprosthesis at 1 hour, 48 hours, and 7 days postoperatively [4]. Furhtermore, Santarpino and colleagues rejected the hypothesis that the solution in which that valve is stored could be the reason, since the predecessor of the Freedom SOLO, the Pericarbon Freedom, is stored in the same solution and does not evidently cause thrombocytopenia [5]. Longitudinal follow-up data are necessary to provide information on survival, functional status, quality of life, and bioprosthetic durability. Chapter 4 shows a 1-, 5- and 9-year overall survival of 92%, 74% and 47%, respectively. In our cohort the mean age was 76 years, and on comparison with patients of the same age with other aortic valve prostheses, the data from our group was satisfactory [6, 7]. At most recent follow-up, functional class was assessed using the NYHA classification. At midterm follow-up, only 5% of patients were in NYHA class 3 or 4 and 77% of the patients were in NYHA class 1. The satisfactory survival after aortic valve replacement with the Freedom SOLO was combined with a good functional class at midterm follow-up. Unfortunately, we have no data on quality of life. We do feel that this is an important feature in the followup after a major cardiovascular operation. Long-term quality of life data is of interest as we want to know if our intervention not only prolongs life, but if it is also a qualitative solution for the patient with the diseased heart valve. Since preoperative baseline quality of life data were not available, no follow-up quality of life data were collected. A preoperative quality of life questionnaire for elective patients should be implemented. Additionally, since minimal access aortic valve replacement and transcatheter aortic valve implantation lead to a shorter recovery period, quality of life in the short-term follow-up is of interest as well. Some skepticism exists about the durability of stentless bioprostheses, because in the past several other stentless bioprosthesis initially showed good clinical results, and at follow-up their durability dropped dramatically. At 10-year follow-up, the stentless Toronto SPV (St. Jude, St. Paul, MN, USA) showed 78%

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freedom from structural valve deterioration [8] and the Cryolife O’Brien (Cryolife International, Atlanta, GA, USA) showed 44% freedom from structural valve deterioration [9]. However, there are some differences between the Toronto SPV, the Cryolife O’Brien and the Freedom SOLO. The Freedom SOLO is made of bovine pericardium where the Toronto SPV and the Cryolife O’Brien are porcine aortic valves. Additionally, the preoperative anticalcification treatments are different. Tissue valves undergo chemical fixation with glutaraldehyde to provide mechanical stability. In addition, the Freedom SOLO is treated with homocysteic acid to remove the free toxic aldehyde residues. Subsequently, the Freedom SOLO is stored in paraben (antimycotic) solution [10]. The durability of bioprosthetic valves is an essential feature and determines the success of a bioprosthetic valve. In order to determine durability, data on structural valve deterioration and aortic valve reoperations from multiple institutions are necessary. Other commercially available stented bioprostheses have set the benchmark regarding long-term durability [11, 12]. The 10-year freedom from structural valve deterioration is expected to be 90% [11, 13], and the predecessor of the Freedom SOLO, the stentless Pericarbon Freedom, showed 94% freedom from structural valve deterioration at 10-year follow-up [14]. Chapter 4 shows a 98% actuarial freedom from structural valve deterioration at 6 years and 88% actuarial freedom from structural valve deterioration at 9.95 years. Our midterm results at 6-year follow-up are promising, and the preliminary results at 9 years are satisfactory. These results are important since there are few data available on longer than 5-year follow-up for the Freedom SOLO. Stanger and colleagues reported the alarming number of 14 Freedom SOLO explantations in 149 patients [15]. Their freedom from structural valve deterioration at 6 and 10 years was 88% and 60%, respectively [16]. They discuss that their Freedom SOLO failures are possibly due to their early use of this prosthesis when the Freedom SOLO first entered the market. Information about design-related limitations was largely unavailable at the outset, and learning curves may have played a role. They concluded that exact sizing, symmetric positioning and observing patient limitations are crucial for optimal outcome [15]. In a letter to the editor on Stanger’s report, Repossini and Bisleri emphasize that avoiding these certain pitfalls during implantation of the Freedom SOLO prevent premature failure [17]. At 6-year follow-up, our series showed a better durability of the Freedom SOLO than Stanger’s series. Whether the Freedom SOLO is a durable bioprosthesis remains to be seen. Longer follow-up with more patients and from different institutions is necessary to determine the durability of the Freedom SOLO. The next 5 years will be a critical observation period for the Freedom SOLO to determine its place among established aortic valve bioprostheses. An improvement could be the merging of data between centers that have long-term follow-up in an international database, to increase the total number of patients at risk at more than10 years of follow-up. Prosthetic valve endocarditis was observed in 9 patients (0.8% per patient-year, Chapter 4), which is within the normal range of 0.5% to 1.2% per patient-year [18]. Additionally, none of the 12 patients operated on for endocarditis had a recurrence. This could be due to the lack of foreign body on the Freedom SOLO. Also the supraannular implantation technique could be helpful in patients in whom the annulus has been destroyed or infected. In these cases the Freedom SOLO does not maintain the infection. Pfeiffer and colleagues also recommend the Freedom SOLO in endocarditis patients in whom the annulus has been destroyed. Thirteen

Discussion | 119

patients with endocarditis received a Freedom SOLO and none of them had a recurrence during follow-up [19]. However, a stent is sometimes useful in endocarditis patients as it can be used to cover annular defects (Chapter 7). Hemodynamic performance Echocardiography The hemodynamic performance of stentless bioprostheses is expected to be excellent. Due to its supraannular implantation and stentless design, the effective orifice area of the Freedom SOLO is as large as possible as the prosthesis aligns with the aortic root. Chapter 4 shows the Freedom SOLO has an effective orifice area of 2.6cm2, which slightly decreased during follow-up. In Chapter 5, the Freedom SOLO was compared with a stented bioprosthesis and it was shown to have a significantly larger effective orifice area. These larger than average effective orifice areas led to excellent valvular gradients. The Freedom SOLO is shown to have excellent maximum and mean valvular gradients in Chapters 2, 3 and 4. When compared with a stented bioprosthesis (Chapter 5), the Freedom SOLO showed superior maximum and mean gradients that remained superior during follow-up. Whether superior valvular gradients enable better durability is an ongoing debate. The lower the valvular gradient, the greater the margin before there is structural valve deterioration. Additionally, with a larger effective orifice area there is faster and more complete regression of left ventricular mass. Magnetic resonance imaging In a pilot study of 28 patients, the hemodynamic performance of the stentless Freedom SOLO was assessed using 4D flow MRI and compared with the stented Mitroflow (Chapter 6). 4D Flow MRI refers to phasecontrast cardio magnetic resonance with flow-encoding in all three spatial directions that is resolved relative to all three dimensions of space and to the dimension of time along the cardiac cycle (3D + time = 4D) [20]. The hemodynamic parameters, peak and mean velocity, viscous energy loss and wall shear stress were calculated during peak systole. Although peak velocity (2.5 m/s versus 2.1 m/s) and viscous energy loss (10.2 mW versus 7.8 mW) were higher for the Mitroflow, no statistically significant differences were found between the two prostheses. Possible explanations for the non-significant difference measured with 4D flow MRI could be that the sample size in this pilot study was small. An obstructing stent leads to altered flow profiles [21], which could lead to viscous energy loss. Therefore, viscous energy loss requires further attention in adequately powered future studies. We foresee a potential role for 4D flow MRI in the evaluation of bioprosthetic heart valves as numerous hemodynamic variables that can be calculated and visualized. Currently, longitudinal follow-up data of 4D flow MRI parameters is missing. Future studies should acquire comprehensive advanced baseline MRI data with long-term follow-up of the enrolled patients. Measuring hemodynamic parameters with 4D flow MRI has several advantages over echocardiography. Postprocessing creates the possibility for retrospective placement of analysis planes at any location within the acquisition volume. This enables measurements in all directions during multiple time frames instead of being dependent on a limited acoustic window. Furthermore, the 4D flow sequence is a protocolled technique,

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which reduces variable velocity assessment due to beam alignment and operator experience. Flow volume measurements with 4D flow MRI have good internal consistency and good scan-rescan repeatability [22, 23]. Controversely, 4D flow MRI technique still has several disadvantages which limits its widespread use in clinical practice. These are predominantly the costs of MRI over echocardiography and the time consuming scan time of the 4D flow MRI, as well as the requirement for data reconstruction and pre-processing before analysis is possible. Which patients could profit from a Freedom SOLO? As the Freedom SOLO has the largest possible effective orifice area, it should be the preferred valve for patients at risk for prosthesis-patient mismatch. Where the indexed effective orifice area is <0.85cm2/m2 there is a prosthesis-patient mismatch [24]. Prosthesis-patient mismatch approximates the native aortic valve stenosis for which the patient most likely underwent the original operation. It should be prevented as prosthesis-patient mismatch is associated with decreased hemodynamic function, less regression of left ventricular mass, more cardiac events, and worse survival [25]. Patients with a small aortic annulus are at risk for prosthesis-patient mismatch. Chapter 5 shows the superior results of the stentless Freedom SOLO compared with the stented Mitroflow in patients with a small aortic root. Prosthesis-patient mismatch occurred more often in the Mitroflow than in the Freedom SOLO (52% versus 28%) and the stented valve was an independent risk factor for prosthesis-patient mismatch (odds ratio 3.0). The Freedom SOLO showed superior hemodynamic performance with significantly lower peak and mean valvular gradients (Pmax: 21mmHg versus 32 mmHg and Pmean: 12 mmHg versus 19 mmHg). During follow-up, these differences remained significantly in favor of the Freedom SOLO. This hemodynamic advantage did not lead to a survival benefit for the Freedom SOLO as the 9-year survival was 59% for the Freedom SOLO and 51% for the Mitroflow. However, the Freedom SOLO did have an advantage regarding the cumulative incidence function for aortic valve reoperation (0% versus 7.1%), and for structural valve deterioration (0% versus 4.5%) at 7-year follow-up. These results support the use of the Freedom SOLO in the small aortic root. An alternative to a stentless prosthesis in a small aortic root is an aortic root enlargement. Possible options are a Nicks [26] or a Manougian [27] technique. More extensive operations are available, only these change the operation and risks for the elective patient considerably and therefore we will not discuss these alternatives. The Nicks procedure is the least invasive where the aortotomy is carried downwards posteriorly through the non-coronary sinus across the aortic ring as far as the origin of the mitral valve [26]. The Nicks procedure increases the aortic annulus by 0.43 millimeters, however, there is debate whether the Nicks procedure leads to implantation of a larger prosthesis [28]. The Manougian procedure is performed by making an incision from the commissure between the left- and non-coronary cusp that extends into the anterior leaflet of the mitral valve [27]. The Manougian increases the aortic annulus by 3.6 millimeters and an increase of 1.3 millimeters in prosthesis size is achieved [28]. As the Manougian is effective in increasing prosthesis size it could be an alternative to the stentless Freedom SOLO in patients with a small aortic root. However, as the Manougian requires an experienced surgeon, longer crossclamp times, and the potential to turn a single heart valve disease into double heart valve disease, we would recommend the Freedom SOLO

Discussion | 121

as the first choice in patients with a small aortic root. If specific contraindications for the Freedom SOLO are present (Chapter 7) a Nicks or Manougian procedure could be an alternative approach in patients at risk for prosthesis-patient mismatch. Patient selection Due to its supraannular position and stentless design the Freedom SOLO may be useful in certain patient groups that would profit from its favourable hemodynamic profile. However, in order to maximize the durability of the Freedom SOLO it is imperative to avoid certain pitfalls when implanting this prosthesis. Its manufacturer - Sorin - does not mention specific contraindications for the use of the Freedom SOLO [29]. However, Chapter 7 shows that if a Freedom SOLO is the first choice when implanting a bioprosthesis, 18% of patients have intraoperative reasons ‘when not to go SOLO’. In order to maximize its durability, the Freedom SOLO has to be implanted symmetrically and if the commissure landmarks are missing or asymmetrical, in bicuspid aortic valves for example, use of the Freedom SOLO should be restricted. Asymmetrical implantation leads to increased mechanical stress on the leaflets and could accelerate structural valve deterioration. Undersizing the Freedom SOLO should also be avoided. If a 27mm sizer is too small for the native aortic annulus, another bioprosthesis should be considered. Furthermore, a heavily calcified aortic root could prevent perfect alignment of the Freedom SOLO to the aortic wall. The risk of paravalvular leakage is increased and these patients should therefore not receive a Freedom SOLO. Additionally, attention should be paid to patients who have a dilated sinotubular junction. When isolated aortic valve replacement is performed the sinotubular junction could further dilate in the future. This could lead to coaptation problems of the Freedom SOLO and subsequently to central aortic valve insufficiency. As the Freedom SOLO is a newer generation stentless valve, there is more redundant leaflet tissue for a larger coaptation area than in earlier generation stentless valves [30]. This will make the Freedom SOLO more tolerant to sinotubular dilatation. However, restricted use of the Freedom SOLO is still advised in a patient with a dilated sinotubular junction. Sometimes anomalies of the coronary ostia can present intraoperatively. If the ostia are located too low in the aortic root they can prevent supraannular implantation of the Freedom SOLO. The pros and cons of the use of the Freedom SOLO in endocarditis are discussed under the subheading ‘safe in everyday practice’. A possible indication for the Freedom SOLO could be in concomitant mitral valve replacement where the stent of the mitral valve could bulk out in the left ventricular outflow tract and aortic annulus. The supraannular implantation of the Freedom SOLO avoids this problem. However, this was not investigated in this thesis. Reoperations and reinterventions Reoperations for the Freedom SOLO are infrequent. Chapter 4 shows a freedom from aortic valve reoperation of 96% at 6 years, and of 92% at 9.95 years. In our cohort of 350 consecutive patients, 7 patients required an aortic valve reintervention. Reoperations for stentless aortic valve bioprostheses are reported to be challenging, frequently requiring aortic root replacement, and the reoperation is associated with increased risk of mortality [31]. Furthermore, Stanger and colleagues reported that during their Freedom SOLO reoperations calcification was always strikingly severe and included the entire root. These patients

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required very difficult and demanding reoperations, however, in patients with tears and cusp ruptures the reoperation was found to be relatively easy [15]. In our cohort, only 1 patient was expected to have a calcified bioprosthesis and that patient received a transcatheter aortic valve implantation instead of an aortic valve re-replacement (Chapter 8). Our other reoperations were technically no more demanding than reoperations for stented aortic bioprostheses. Chapter 8 shows the reinterventions for the 2 patients with structural valve deterioration. The first patient received a stented Mitroflow after a sudden tear 6 years after the implantation of a 25mm Freedom SOLO. The literature reports more tears [15], surprisingly these prostheses are all sizes 25mm or 27mm. We wonder if the larger than average sinuses in these patients put more stress on the leaflets since there is more volume pressing on the leaflets during diastole. This could lead to stress on the leaflets near their anchor points, namely the commissures. This could be an explanation why the tears in the Freedom SOLO valves occur in the larger prostheses near the commissures. At reoperation, we sometimes explanted the whole prosthesis and sometimes only the leaflets. This was done at the discretion of the surgeon. The second patient with structural valve deterioration from Chapter 8 received a transcatheter aortic valve-in-valve implantation. Transcatheter options for valve-in-valve implantation are likely to become more popular for treatment of patients with degenerative aortic valve bioprostheses. In the Introduction (Chapter 1) the increasing use of bioprosthetic valves is described, and, combined with a more active and longer-live population, the odds of structural valve deterioration requiring aortic valve reintervention will increase. Regarding transcatheter aortic valve implantation for degenerated Freedom SOLO valves, special attention should be paid to the distance between the Freedom SOLO and the coronary ostia. As the Freedom SOLO is implanted supraannularly the distance from the neo-annulus to the coronary ostia is shorter than in stented bioprostheses and the risk of coronary ostia obstruction is increased. An advantage of the Freedom SOLO is that when a transcatheter valve-in-valve in necessary, the size of the transcatheter valve can be larger for the Freedom SOLO than in other commercially available bioprostheses [32]. Surgical approach The traditional way to implant an aortic valve prosthesis is through a conventional median sternotomy and this is still the gold standard today. Less invasive alternative approaches have become available, from partial sternotomy to video-assisted and robot-assisted techniques. Additionally catheter-based approaches have been developed enabling transcatheter aortic valve implantation. Minimal access aortic valve replacement has proved its equivalence to conventional sternotomy (Chapter 2). Possible benefits include shorter ventilation time, a shorter stay in an intensive care unit and shorter hospital stay. The implantation of a Freedom SOLO using an upper hemisternotomy has been published before [33] and we have used this approach in a small group of patients. Some surgeons have implemented this approach as their standard access in selected patients, and this approach does not exclude the use of the Freedom SOLO.

Discussion | 123

CONCLUSIONS Based on the information in Chapter 3 we can conclude that at this time, the Freedom SOLO bioprostheses seems to offer the best of both worlds. It combines the hemodynamic advantage of stentless valves with an implantation technique that is equal in terms of speed to conventional stented bioprostheses. As an additional advantage, the rate of postoperative pacemaker implantation is lower than in stented bioprosthesis. Chapter 4 shows that the Freedom SOLO is safe in everyday practice and structural valve deterioration and aortic valve reoperation are infrequently seen at midterm follow-up. In addition, its hemodynamic performance is excellent with low valvular gradients that remain stable during follow-up. Based on these conclusions, the Freedom SOLO bioprosthesis could become the standard for aortic valve replacement in the future for some cardiac surgeons. However, there will be some observations during long-term follow-up, and developments in the future that will decide what the place of the Freedom SOLO will be among its alternatives. First, the Freedom SOLO valve itself has to prove its long-term durability. At this point in time, the midterm results up to 6 years are promising. The longer-term results up to 9 years in our cohort are satisfactory, however, not enough patients are at risk at long-term follow-up. The Freedom SOLO enters a critical point in its observation period, as the upcoming 5 years will determine its 10 to 15 year results regarding durability. If these results are non-inferior to the results of various bioprostheses that have set the benchmark, the Freedom SOLO has a chance of becoming the standard prosthesis for aortic valve replacement. The second development that will decide the place of the Freedom SOLO are upcoming techniques. Chapter 2 shows that minimal access aortic valve replacement has some minor advantages and future research will establish the place of sutureless valves and transcatheter aortic valve implantation. Additionally, the Freedom SOLO could never replace the stented bioprostheses for all patients, as is illustrated in Chapter 7 which considers some situations in which a Freedom SOLO should be avoided. Chapter 5 shows that the Freedom SOLO has an advantage when compared with a stented Mitroflow in patients with a small aortic root. The stentless design and supraannular implantation technique offer the largest possible effective orifice area and this leads to superior hemodynamic performance and less prosthesis-patient mismatch. During follow-up, this resulted in fewer cardiac events. In our opinion the Freedom SOLO should be considered for use in patients with a small aortic root or in patients that in any other way are at risk for prosthesis-patient mismatch, or in patients that could profit from the superior hemodynamic performance. The theoretical hemodynamic advantage of stentless bioprostheses compared with stented bioprostheses is examined in Chapters 5 and 6. Measured with transthoracic echocardiography, the Freedom SOLO showed a larger effective orifice area, less prosthesis-patient mismatch and lower peak and mean valvular gradients that remained stable during follow-up. However, using 4D flow MRI in a pilot study of 28 patients, there were no statistically significant differences between stentless and stented bioprostheses. If a Freedom SOLO degenerates, both aortic valve re-replacement and valve-in-valve transcatheter aortic valve implantation are possibilities. The heart team that handles the case should know that reoperations for degenerated and calcified stentless bioprostheses are challenging and the operative risks are increased.

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In selected cases, valve-in-valve transcatheter aortic valve implantation is an attractive option. However, in the supraannular Freedom SOLO it is important to pay special attention to the coronary ostia and select the appropriate transcatheter device to avoid coronary ostia obstruction.

Discussion | 125

REFERENCES 1.

Thourani VH, Suri RM, Gunter RL, et al. Contemporary real-world outcomes of surgical aortic valve replacement in 141,905 low-risk, intermediate-risk, and high-risk patients. Ann Thorac Surg 2015;99:55-61 2. Matthews IG, Fazal IA, Bates MG, et al. In patients undergoing aortic valve replacement, what factors predict the requirement for permanent pacemaker implantation? Interact Cardiovasc Thorac Surg 2011;12:475-9 3. Tarzia V, Bottio T, Buratto E, et al. Freedom solo stentless aortic valve: quantitative and qualitative assessment of thrombocytopenia. Ann Thorac Surg 2011;92:1935 4. Repossini A, Tononi L, Martinil G, et al. Platelet activation after sorin freedom solo valve implantation: a comparative study with Carpentier-Edwards Perimount Magna. J Heart Valve Dis 2014;23:777-82 5. Santarpino G, Pfeiffer S, Fischlein T. Thrombocytopenia after Freedom Solo: the mystery goes on. Ann Thorac Surg 2011;91:330 6. Celiento M, Ravenni G, Milano AD, et al. Aortic valve replacement with the Medtronic Mosaic bioprosthesis: a 13-year follow-up. Ann Thorac Surg 2012;93:510-5 7. Dellgren G, Eriksson MJ, Brodin LA, et al. Eleven years’ experience with the Biocor stentless aortic bioprosthesis: clinical and hemodynamic follow-up with long-term relative survival rate. Eur J Cardiothorac Surg 2002;22:912-21 8. Desai ND, Merin O, Cohen GN, et al. Long-term results of aortic valve replacement with the St. Jude Toronto stentless porcine valve. Ann Thorac Surg 2004;78:2076-83 9. Pavoni D, Badano LP, Lus F, et al. Limited long-term durability of the Cryolife O’Brien stentless porcine xenograft valve. Circulation 2007;116:I307-13 10. Stanger O, Tevaearai H, Carrel T. The Freedom SOLO bovine pericardial stentless valve. Research reports in Clinical Cardiology 2014;5:349-61 11. Yankah CA, Pasic M, Musci M, et al. Aortic valve replacement with the Mitroflow pericardial bioprosthesis: durability results up to 21 years. J Thorac Cardiovasc Surg. 2008;136:688-96 12. Johnston DR, Soltesz EG, Vakil N, et al. Long-term durability of bioprosthetic aortic valves: implications from 12,569 implants. Ann Thorac Surg. 2015;99:1239-47 13. Kaneko T, Gosev I, Leacche M, et al. Early structural valve deterioration of the mitroflow bioprosthesis. Circulation 2014;130:1997-8 14. Milano AD, Dodonov M, Celiento M, et al. The Sorin freedom stentless pericardial valve: clinical and echocardiographic performance at 10 years. Int J Artif Organs 2012;35:481-8 15. Stanger O, Bleuel I, Reineke S, et al. Pitfalls and premature failure of the Feedom SOLO stentless valve. Eur J Cardiothorac Surg 2014;48:562-70 16. Stanger O, Bleuel I, Gisler F, et al. The Freedom Solo pericardial stentless valve: Single-center experience, outcomes, and long-term durability. J Thorac Cardiovasc Surg. 2015;150:70-7 17. Repossini A, Bisleri G. Freedom SOLO: avoiding pitfalls to avoid premature failures? Eur j Cardiothorac Surg. 2015 [Epub ahead of print] 18. Habib G, Hoen B, Tornos P, et al. Guidelines on the prevention, diagnosis, and treatment of infective endocarditis (new version 2009): the task force on the prevention, diagnosis, and treatment of infective endocarditis of the European society of Cardiology (ESC). Endorsed by the European society of clinical microbiology and infectious diseases (ESCMID) and the international society of chemotherapy (ISC) for infection and cancer. Eur Heart J 2009;30:2369-413 19. Pfeiffer S, Santarpino G, Fischlein T. Stentless pericardial valve for acute aortic valve endocarditis with annular destruction. J Cardiovasc Med 2015;16:318-94. 20. Dyverfeldt P, Bissell M, Barker AJ, et al. 4D flow cardiovascular magnetic resonance consensus statement. J Cardiovasc Magn Reson 2015;17:72 21. von Knobelsdorff-Brenkenhoff F, Trauzeddel RF, Barker AJ, et al. Blood flow characteristics in the ascending aorta after aortic valve replacement-a pilot study using 4D-flwo MRI. Int J Cardiol 2014;170:426-33 22. Uribe S, Beerbaum P, Sørensen TS, et al. Four-dimensional (4D) flow of the whole heart and great vessels using real-time respiratory self-gating. Magn Reson Med 2009;62:984-92 23. Wentland AL, Grist TM, Wieben O. Repeatability and internal consistency of abdominal 2D and 4D phase contrast MR flow measurements. Acad Radiol 2013;20:699-704 24. Rahimtoola SH. The problem of valve prosthesis-patient mismatch. Circulation 1978;58:20-4

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25. 26. 27. 28. 29. 30. 31. 32. 33.

Pibarot P, Dumesnil JG. Prosthesis-patient mismatch: definition, clinical impact, and prevention. Heart 2006;92:1022-9 Nicks R, Cartmill T, Bernstein L. Hypoplasia of the aortic root. The problem of aortic valve replacement. Thorax 1970;25:339-46 Manouguian S, Seybold-Epting W. Patch enlargement of the aortic valve ring by extending the aortic incision into the anterior mitral leaflet. New operative technique. J Thorac Cardiovasc Surg 1979;78:402-12 Losenno KL, Gelinas JJ, Johnson M, et al. Defining the efficiacy of aortic root enlargement procedures: a comparative analysis of surgical techniques. Can J Cardiol 2013;29:434-40 Sorin Freedom SOLO Stentless heart valve; Instructions for use 840-07LS200 Rev C, Sorin Group Scharfschwerdt M, Sievers HH, Hussein A, et al. Impact of progressive sinotubular junction dilatation on valve competence of the 3F Aortic and Sorin Solo stentless bioprosthetic heart valves. Eur J Cardiothorac Surg 2010;37:631-4 Borger MA, Prasongsukarn K, Armstrong S, et al. Stentless aortic valve reoperations: a surgical challenge. Ann Thorac Surg 2007;84:737-43 Bapat V. Valve-in-valve apps: why and how they were developed and how to use them. Eurointervention 2014;10SupplU:U44-51 Karimov JH, Cerillo AG, Gasbarri T, et al. Stentless aortic valve implantation through an upper manubrium-limited V-type ministernotomy. Innovations 2010;5:378-80

CHAPTER 10 Summary Samenvatting

Summary

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Summary | 131

In chapter 1 a general introduction is given. Aortic valve stenosis is a progressive disease and once symptoms develop survival declines rapidly. For most patients, severe symptomatic aortic stenosis needs effective mechanical relief in the form of valve replacement before it becomes a lethal obstruction to outflow. In patients with aortic valve stenosis, aortic valve replacement improves survival and quality of life. Nowadays, a bioprosthetic valve is used in 79% of patients undergoing aortic valve replacement. The majority of the aortic valve bioprostheses used are stented bioprostheses. As an alternative, stentless bioprostheses have been introduced to improve hemodynamic performance. The aim of this thesis is to evaluate the clinical and functional performance of the stentless Freedom SOLO bioprosthesis. Chapter 2 provides a general overview of the current surgical treatment options for aortic valve stenosis. We reviewed the existing literature and present the current state-of-the-art of the various approaches to the aortic valve, taking into account clinical outcomes, quality of life, costs and learning curve. The optimal surgical access strategy for treatment of a patient with aortic valve stenosis depends on patient profile. The patient profile, from low-risk to unsuitable for surgery, should be the main determinant of the intervention of choice. These decisions should be made in a multidisciplinary heart team. Chapter 3 presents a systematic review to examine the clinical and hemodynamic performance of the Freedom SOLO. In total, 35 full-text articles were included. Thus far, the Freedom SOLO combines the best of both worlds: superior hemodynamic performance of a stentless valve, and a simple and fast implantation technique that is equal to stented prostheses. Additionally, because of the implantation technique, the rate of postoperative pacemaker implantation is notably lower than in other aortic bioprostheses (1.7% versus 4% to 7%). However, postoperative thrombocytopenia is more severe than in other aortic bioprostheses, although without clinical consequences. The cause of the thrombocytopenia is currently unknown. In chapter 4 we present the results of 350 consecutive patients who underwent aortic valve replacement with a Freedom SOLO valve. At this point in time, this is the largest single center experience (n=350) and one of the longest follow-ups available (maximum 9.95 years). We showed that the Freedom SOLO is safe to use in everyday practice and has a low rate of pacemaker implantations (2.3%) and prosthesis-patient mismatch (9.6%). Survival is comparable to other bioprostheses, and at most recent follow-up, 95% of patients were in New York Heart Association functional class 1 and 2. Structural valve deterioration and aortic valve reoperations are infrequent during midterm follow-up. Additionally, its hemodynamic performance is excellent with low valvular gradients (Pmax: 17 mmHg, and Pmean: 10 mmHg) that remain stable during follow-up. In the chapter 5 we investigated if the Freedom SOLO valve has an advantage when compared with a stented bioprosthesis in patients with a small aortic root. In total, 269 patients were included in this study with a 19mm or 21mm stented or stentless bioprostheses. Operative outcomes and survival were similar. However, the Freedom SOLO showed several significant advantages for patients with a small aortic root

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132 | Chapter 10

in comparison with a stented bioprosthesis. First, the Freedom SOLO showed a superior durability, using cumulative incidence function probability of aortic valve reoperation and structural valve deterioration. Second, prosthesis-patient mismatch is less likely to occur with the Freedom SOLO (28% versus 52%), and the stented bioprosthesis was a significant independent risk factor for prosthesis-patient mismatch (odds ratio 3.0). Third, the postoperative peak and mean valvular gradients were lower in the Freedom SOLO (Pmax: 21 mmHg versus 32 mmHg, and Pmean: 12 mmHg versus 19 mmHg), and these differences persisted during midterm follow-up. This was combined with more patients in New York Heart Association functional class 1 and 2 at most recent follow-up (95% versus 81%). Chapter 6 evaluates the hemodynamic performance of the Freedom SOLO and a stented bioprosthesis using 4D flow MRI, 1-year after surgical aortic valve replacement. In this pilot study with 28 patients, peak velocity, mean velocity, viscous energy loss, and wall shear stress were calculated during peak systole in the ascending aorta. We were unable to show significant differences between the stentless and stented bioprosthesis. Comparison with a native aortic valve showed that there is still a long way to go in the development of bioprostheses to reach a hemodynamic performance comparable to the native valve. Some 4D flow MRI parameters have the potential to significantly add quality to the field of hemodynamic measurements and the evaluation of commercially available heart valves. 4D Flow MRI follow-up data are necessary to provide insight in the long-term implications of these parameters. In chapter 7 we discuss the relative contraindications for the use of the Freedom SOLO valve based on our extensive implant experience of almost 10 years. Because of the stentless design and supraannular implantation, various situations might prohibit the use of the Freedom SOLO. In order to maximize the durability of the Freedom SOLO, patient selection is crucial. In our opinion, asymmetrical commissures, large aortic annulus (>27mm), calcified aortic sinuses, dilated sinotubular junction, aberrant location of coronary ostia, and whenever the stent of a stented bioprosthesis is appreciated to cover a defect or hole are reasons â&#x20AC;&#x2DC;not to go SOLOâ&#x20AC;&#x2122;. When these contraindications are taken into account, a very good durability can be achieved with the Freedom SOLO during midterm follow-up. Chapter 8 shows the options when a Freedom SOLO degenerates. Both aortic valve re-replacement and transcatheter aortic valve implantation are possibilities. In case of calcified structural valve deterioration with a calcified aortic root, reoperations for stentless aortic valve bioprostheses are challenging. Transcatheter valve-in-valve implantations are likely to become more popular for treatment of patients with degenerative aortic valve bioprostheses. Regarding transcatheter aortic valve implantation for degenerated Freedom SOLO valves, special attention should be paid to the distance between the supraannular Freedom SOLO and the coronary ostia.

Summary | 133

Chapter 9 provides a general discussion. Based on the conclusions, the Freedom SOLO bioprosthesis could become the standard for aortic valve replacement. There will be observations during long-term followup, and developments in the future that will decide what the place of the Freedom SOLO will be. First, the Freedom SOLO valve itself has to prove its long-term durability. And second, the development of upcoming techniques, as sutureless valves and transcatheter valves, will decide the place of the Freedom SOLO among its alternatives. At this moment, the Freedom SOLO should be considered for use in patients with a small aortic root, or in patients that in any other way are at risk for prosthesis-patient mismatch, or in patients that could profit from the superior hemodynamic performance and the large effective orifice area.

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Samenvatting

Samenvatting | 137

Hoofdstuk 1 geeft een algemene inleiding. Aortaklep stenose is een progressieve ziekte en wanneer er symptomen ontstaan, daalt de overleving snel. Voor de meeste symptomatische patiënten moet de aortaklepstenose worden opgeheven door middel van een klepvervanging om de dood te voorkomen. In patiënten met een aortaklep stenose zorgt een aortaklepvervanging voor een verbetering in de overleving en kwaliteit van leven. Op dit moment wordt in 79% van de aortaklepvervangingen een biologische prothese gebruikt. De meerderheid hiervan zijn gestente bioprotheses. Als alternatief werden stentloze bioprotheses ontwikkeld, ter verbetering van de hemodynamiek. Het doel van dit proefschrift is de klinische uitkomsten en functionele prestaties van de stentloze Freedom SOLO bioprothese te evalueren. Hoofdstuk 2 beschrijft de huidige chirurgische behandelopties voor aortaklepstenose. Met behulp van de geraadpleegde literatuur beschrijven wij de huidige stand van zaken met betrekking tot de chirurgische benaderingen in het perspectief van klinische uitkomsten, kwaliteit van leven, de kosten en de leercurve. De optimale chirurgische benadering voor de behandeling van een patiënt met een aortaklepstenose hangt af van het risicoprofiel van de patiënt. Dit risicoprofiel, van laag risico tot niet geschikt voor conventionele chirurgie, moet de belangrijkste factor zijn voor het kiezen van de optimale behandeling. Deze beslissing moet genomen worden in een multidisciplinair hart team. Hoofdstuk 3 bestaat uit een systematische review om de klinische en hemodynamische prestaties van de Freedom SOLO klep te beschrijven. In totaal werden 35 artikelen geïncludeerd. Tot nu toe combineert de Freedom SOLO klep het beste uit twee werelden: de superieure hemodynamische prestatie van een stentloze prothese, samen met een versimpelde en snelle implantatie techniek die even snel is als bij gestente kleppen. Tevens is door de implantatie techniek het aantal pacemaker implantaties lager dan bij andere aortaklep protheses (1.7% versus 4% tot 7%). Echter, de postoperatieve trombocytopenie is meer uitgesproken dan bij andere aortaklep protheses, hoewel dit zonder klinische consequenties blijft. De oorzaak van de trombocytopenie is tot op heden onbekend. In hoofdstuk 4 presenteren wij onze resultaten van 350 opeenvolgende patiënten die een aortaklep vervanging ondergingen met een Freedom SOLO. Op dit moment is dit de grootste serie uit één centrum (n=350), en een van de langste follow-ups die beschikbaar is (maximaal 9.95 jaar). Onze resultaten lieten zien dat de Freedom SOLO veilig is in dagelijks gebruik en dat pacemaker implantaties (2.3%) en prothesepatiënt mismatch (9.6%) weinig voorkomen. De overleving is verglijkbaar met andere bioprotheses, en bij de meest recente follow-up zijn 95% van de patiënten in New York Heart Association klasse 1 en 2. Structurele klepdegeneratie en aortaklep reoperaties komen niet vaak voor op de middellange termijn. Tevens zijn de hemodynamische resultaten uitstekend met lage valvulaire gradiënten (Pmax: 17 mmHg, en Pmean: 10 mmHg), die stabiel blijven gedurende follow-up.

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138 | Chapter 10

In het hoofdstuk 5 onderzoeken wij of de Freedom SOLO een voordeel heeft voor patiënten met een kleine aortawortel, wanneer die vergeleken wordt met een gestente bioprothese. In totaal zijn de resultaten beschreven van 269 patiënten die een 19mm of 21mm, stentloze of gestente, klep hebben gekregen. De operatieve uitkomsten en overleving zijn gelijk voor beide groepen. De Freedom SOLO laat ook significante voordelen zien voor patiënten met een kleine aortawortel, als deze wordt vergleken met een gestente bioprothese. Als eerste laat de Freedom SOLO een betere duurzaamheid zien, waarbij minder aortaklep reoperaties en minder structurele klep degeneratie voorkomen. Ten tweede hebben significant minder patiënten prothese-patiënt mismatch (28% versus 52%), en de gestente bioprothese was een significante risico factor voor prothese-patiënt mismatch (odds ratio 3.0). Als derde voordeel liet de Freedom SOLO superieure hemodynamische resultaten zien met significant lagere valvulaire gradiënten (Pmax: 21 mmHg versus 32 mmHg, en Pmean: 12 mmHg versus 19 mmHg) die stabiel blijven op de middellange termijn. Dit voordeel wordt gecombineerd met meer patiënten in New York Heart Association klasse 1 en 2 (95% versus 81%) bij de meest recente follow-up. Hoofdstuk 6 evalueert de hemodynamische resultaten van de Freedom SOLO en een gestente bioprothese met 4D flow MRI, 1 jaar na chirurgische implantatie. In deze proef studie met 28 patiënten werden peak velocity, mean velocity, viscous energy loss en wall shear stress gemeten gedurende de piek-systole in de aorta ascendens. Wij hebben geen significante verschillen kunnen aantonen tussen de gestente en stentloze klep. De vergelijking met een natieve aortaklep liet zien dat er nog een lange weg te gaan is in de ontwikkeling van bioprotheses, voordat de hemodynamiek vergelijkbaar is met die van een natieve aortaklep. Verschillende 4D flow MRI parameters hebben de potentie om iets toe te voegen aan de evaluatie van de hemodynamiek van hartklep protheses. Om de gevolgen van deze parameters in kaart te brengen is 4D Flow MRI follow-up data nodig op de lange termijn. In hoofdstuk 7 bediscussiëren wij de relatieve contra-indicaties voor het gebruik van een Freedom SOLO klep gebaseerd op onze uitgebreide implantatie ervaring van bijna 10 jaar. Door het stentloze design en de supraannulaire implantatie, is de Freedom SOLO niet geschikt voor iedere patiënt. Om een goede duurzaamheid van de Freedom SOLO te behalen is patiënt selectie cruciaal. Wij vinden asymmetrische commissuren, een grote aortaklep annulus (>27mm), een verkalkte aortawortel, een gedilateerde sinotubulaire junctie, afwijkend gelegen coronair ostia, en wanneer de stent van een gestente bioprothese bruikbaar is voor het dekken van een defect, redenen om geen Freedom SOLO te gebruiken. Als deze contra-indicaties in acht worden genomen kan een zeer goede duurzaamheid bereikt worden met de Freedom SOLO op de middellange termijn. Hoofdstuk 8 beschrijft de mogelijkheden indien een Freedom SOLO gedegenereerd is. Zowel een reoperatie (re-aortaklep vervanging) als een transcatheter klep zijn opties. Indien er sprake is van structurele klep degeneratie met een verkalkte klep en aortawortel, is een reoperatie chirurgisch-technisch uitdagend. Het gebruik van transcatheter klep-in-klep implantaties zal waarschijnlijk toenemen ter behandeling van

Samenvatting | 139

gedegenereerde bioprotheses. Indien er voor een transcatheter klep-in-klep implantatie wordt gekozen bij een Freedom SOLO, moet er aandacht besteed worden aan de hoogte van de coronair ostia ten opzichte van de supraannulaire Freedom SOLO. Hoofdstuk 9 bevat een algemene discussie. Gebaseerd op de conclusies van de voorgaande hoofdstukken, zou de Freedom SOLO in te toekomst de klep van keuze kunnen worden bij een aortaklepvervanging. De aankomende tijd zullen een aantal ontwikkelingen de plek van de Freedom SOLO bepalen. Ten eerste zal de Freedom SOLO zelf zijn duurzaamheid op de lange termijn moeten bewijzen. Ten tweede zullen de ontwikkelingen van nieuwe technieken, zoals kleppen zonder hechtingen en transcatheter kleppen, de plaats gaan bepalen van de Freedom SOLO tussen zijn alternatieven. Op dit moment zou de Freedom SOLO overwogen moeten worden in patiënten met een kleine aortawortel, of in patiënten die het risico lopen op prothese-patiënt mismatch, of in patiënten die kunnen profiteren van de superieure hemodynamiek en het grote effectieve klepoppervlak.

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Acknowledgements / Dankwoord

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142 | Acknowledgements / Dankwoord

Acknowledgements / Dankwoord | 143

ACKNOWLEDGEMENTS / DANKWOORD Hierbij wil ik mijn familie, vrienden en collega’s bedanken. Ook gaat mijn dank uit naar de patiënten en hun familieleden voor de tijd en moeite. Professor de Mol, beste Bas. Hartelijk dank voor uw jarenlange begeleiding. Ik leerde u kennen in 2009 toen ik als student geneeskunde naar Boston wilde. Voor zowel Boston, Houston, mijn oudste co-schap, mijn eerste baan als ANIOS en de begeleiding tijdens dit proefschrift ben ik u dankbaar. U creëerde voor mij een omgeving om mijzelf te ontwikkelen en ik hoefde mij nooit zorgen te maken over randvoorwaarden. Mijn dank hiervoor. Dr van Boven, beste Wim Jan. Dank voor je begeleiding als copromotor. Je heerlijke heldere klinische blik en oplossingsgerichtheid zal ik nooit vergeten. Dank voor al je commentaar op de manuscripten en lessen over hoe wetenschappelijk te schrijven. Hopelijk kijken we nog vaak naar Ajax – Feyenoord. Dr Kaya, beste Abdullah. Dank voor je begeleiding als copromotor. Met je expertise op het gebied van de aortawortel en doelgerichtheid heb je mij ontzettend veel geholpen. Jij hield de vaart erin, dank voor deze focus. Ik ga graag nog een keer tennissen. Graag wil ik ook professor J.J. Piek, professor R.J. de Winter, professor B. Preckel, professor W.J. Morshuis, professor M.G. Hazekamp en dr. M.A.A.M. Schepens bedanken voor hun bereidheid om dit proefschrift op zijn wetenschappelijke waarde te beoordelen. Jan van der Meulen, zonder jou was het SOLO project nooit gestart. Meer dan tien jaar geleden begon jij met het implanteren van SOLOs. Dank voor jouw begeleiding tijdens dit proefschrift en tijdens mijn ANIOS tijd. Ik werk graag met je samen; je enthousiasme en vrolijkheid zijn aanstekelijk. Wilson Li, de afgelopen jaren heb je veel voor mij betekend. Vanaf mijn eerste stappen als ANIOS tot aan de wetenschappelijke begeleiding. Ik kon altijd bij je terecht en samen met jou heb ik het fundament van dit boekje gelegd. Dank voor alles en ik hoop dat we in Nijmegen nog lang zullen samenwerken. Alle co-auteurs: Floortje van Kesteren, het was heel fijn samenwerken met je. Ik ken weinig mensen die zo zorgzaam zijn. De 4D flow MRI was een onbewandeld pad. Samen met Nils Planken hebben we de eerste stappen gezet. Oxford was erg leuk en leerzaam. Pim van Ooij, Aard Nederveen en Jan Baan, dank voor jullie begeleiding en onmisbare inzichten tijdens de 4D flow expeditie. Berto Bouma, dank voor je wetenschappelijke en cardiologische blik op de manuscripten. Je was altijd bereikbaar voor overleg, dat waardeer ik enorm. Antoine Driessen, Riccardo Cocchieri en Petr Symersky, naast dat jullie meegedacht en meegeschreven hebben wil ik jullie ook bedanken voor de klinische begeleiding. Ook op persoonlijk vlak heb ik veel aan jullie adviezen gehad. Alberto Repossini: grazie mille!

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144 | Acknowledgements / Dankwoord

Daphne Lees, dank voor het verbeteren van mijn Engelse teksten. Ik vind je manier van commentaar geven erg leuk. Naast dat ik er ontzettend veel van heb geleerd, heb ik menig maal hardop moeten lachen. Dr L.H. Cohn (†2016), thank you for everything you did for me. I made my first steps in research at the Brigham and you were the best mentor I could have wished for. My time in Boston was unforgettable. March 11 is the best, requiescat in pace. Dr J.M. Duncan, thank you for the incredible experience at the Texas Heart Institute. You allowed me to participate in numerous operations and learned me a great deal about the technical aspects of Cardiac Surgery. It was an honor to be your head student at St. Luke’s. Chirurgen AMC (die nog niet eerder genoemd zijn): Dave Koolbergen, Aria Yazdanbakhsh, Kayan Lam, Albert van den Brink, Jaap Kloek, Toon Winkelman, professor Mark Hazekamp, Vladimir Sojak, Patrique Segers en Winston Lynch: bedankt voor jullie tijd, geduld en begeleiding tijdens mijn ANIOS tijd in het AMC. Ik heb zo ontzettend veel van jullie geleerd. Kayan en Aria, ook duizend maal dank voor Houston! Arts-assistenten AMC: Bram van Wijk, Meike Haverkamp, Henryk Jan te Kolste, Marc Konijnenberg, Robert Dettmers, Eva Diephuis, Art Huzeir, Eric te Gussinklo, Fleur Meijer, Anton Tomsic, Yalda Aziz, Ahmed Aown, Marieke van Paridon, Mathijs van Gool, Hanna Talacua en Esther Wiegerinck, ik wil jullie bedanken omdat jullie fantastische en gezellige collega’s waren of zijn. Ik wens jullie allemaal veel succes. Kamergenoot Johan Manshanden, dank voor alle uren die je me geholpen hebt, zeker als ik weer eens ruzie had met de computer. Dankzij jou zien de figuren en de kaft er in dit proefschrift strak uit. Ik vond het een leuke tijd en ik wens je heel veel succes met het voltooien van jouw project. Paranimfen: Niels Pijnenburg, tijdens de tennisles op de basisschool leerde ik je kennen. Sindsdien delen we lief en leed. We hebben ontzettend veel meegemaakt en je bezit alle kwaliteiten die ik kan wensen als vriend. Ik wens je alle geluk op persoonlijk vlak en heel veel succes met je carrière. Ik ben heel benieuwd wat het leven ons nog gaat brengen en je zusjes zijn fantastisch. Je ouders overigens ook. Kaj Lamers, sinds de eerste dag van onze geneeskunde studie zijn wij vrienden. Aan onze tijd in Boston denk ik vaak en met veel plezier terug. Je bent een geweldige vriend vanwege je vrolijkheid en oprechte interesse. Waar ik ook woon, of ga wonen, je bent altijd meer dan welkom en ik hoop dat je mijn voordeur blijft platlopen totdat we samen in een bejaardentehuis zitten. Gijs Harbers en Teun ter Welle, beste zandbakvrienden van de basisschool. Samen groot geworden en nog steeds evenveel lol. Jullie zijn ontzettend goede vrienden waar ik altijd op kan rekenen. Met de BK hebben we onvergetelijke trips gemaakt, ik hoop dat er nog veel volgen.

Acknowledgements / Dankwoord | 145

Heeren van 2006: Bob van Wijlandt, Rick van Genuchten, Lennart Tonneyck, Charles van der Vlis, Wouter van Dongen, Stefan Kamphuis, Bob Elsenburg en Brian Driessen, beste jaargenoten. Jullie zijn stuk voor stuk echt uniek. Ik wil jullie bedanken voor een ontzettend mooie studententijd en later zijn wij voor elkaar een vriend. Pap en mam, in woorden is moeilijk uit te drukken hoeveel dank ik jullie verschuldigd ben. Ik ga toch een poging wagen. Hub, mijn eerste stappen in het ziekenhuis zette ik aan jouw zijde als klein kind. Na de opmerking “papa is helemaal geen dokter, hij praat alleen maar”, had je al kunnen vermoeden dat ik geen internist wilde worden. De interesse in de geneeskunde en de motivatie om problemen op te lossen heb ik van jou. Ik wil je bedanken voor de onvoorwaardelijke steun die ik altijd heb gevoeld en ik ben heel erg trots op je. Marga, je bent de perfecte moeder en ik ben heel dankbaar voor de manier waarop je ons hebt opgevoed. Jouw nieuwsgierigheid en interesse in reizen heb je aan mij doorgegeven. Ik vond het heel leuk dat je mij in Boston en Houston bent komen opzoeken, en erg dierbaar dat je ons altijd volgt, soms zelfs op de ski’s. Ook dank voor je karakter, dat heeft mij gebracht waar ik nu ben. Pap en mam, ik hou van jullie. Gerlach en Babs, ik ben erg trots op jullie en het is waanzinnig om jullie broer te zijn. Ik vind het mooi om te zien hoe jullie je eigen pad aan het vinden zijn. Hopelijk gaan we nog vaak op vakantie want ik kan mij geen leuker broertje en zusje bedenken. Lieve Juul, je bent de allerliefste schat. Je helpt mij altijd perfect en hebt ook nog eens de prachtige kaft ontworpen. Ik ben super trots, dat je je droom om dokter te worden onlangs hebt binnengekopt. Het was een lange weg, maar je hebt het fantastisch gedaan. We hebben de halve wereld gezien, nu de andere helft nog want ik kan me geen beter maatje wensen. Ik hou ook van jou.

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Curriculum Vitae

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148 | Curriculum Vitae

Curriculum Vitae | 149

CURRICULUM VITAE Laurens Willem Lodewijk Maria Wollersheim was born on March 11, 1987 in Nijmegen, the Netherlands. After graduating from high school ‘Stedelijk Gymnasium Nijmegen’ in 2005 he started Medical School at the University of Amsterdam. In 2007 he started working for BIS (Bio Implant Services), were he quickly became Head Explanter with specialization for Heart valves. He was medically and procedurally responsible for retrieving heart valves in post mortem donors. During this work his interest for Cardiac Surgery developed. In 2010 he went to Boston for his scientific research internship under supervision of Dr. L.H. Cohn. He worked 5 months at Harvard Medical School in the Brigham and Woman’s Hospital with specific interest in minimal access aortic valve surgery. In 2012 he went to the Texas Heart Institute in Houston for his elective clinical rotation under supervision of Dr. Denton A. Cooley and Dr. J.M. Duncan. Subsequently his senior clinical rotation was done at the department of Cardiothoracic Surgery in Amsterdam at the Academic Medical Center under supervision of prof. Dr. B.A.J.M de Mol. In November 2012 he graduated from Medical School and from January 2013 he started working as a resident -not in training- at the department of Cardiothoracic Surgery at the Academic Medical Center. During this work the first steps of this thesis were developed and from June 2014 he could spend the majority of his time on this thesis, sometimes available for clinical work when necessary. In October 2015 he started working as a resident -not in training- at the department of Cardiothoracic Surgery at the Radboud University Nijmegen Medical Center, where he will start his training in July 2016 under supervision of prof. Dr. W.J. Morshuis and Dr. A.F.T.M. Verhagen. Laurens is very keen on sports, especially football and skiing.

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UITNODIGING Aortic Valve Replacement and the Stentless Freedom Solo Valve

Aortic Valve Replacement and the Stentless Freedom Solo Valve Laurens W.L.M. Wollersheim

Voor het bijwonen van de openbare verdediging van het proefschrift

Aortic Valve Replacement and the Stentless Freedom Solo Valve door

Laurens Wollersheim op vrijdag 10 juni 2016 om 14:00 uur

Laurens W.L.M. Wollersheim

Agnietenkapel Ouderzijds Voorburgwal 231 te Amsterdam Na afloop bent u van harte uitgenodigd voor de receptie ter plaatse

Laurens Wollersheim laurenswollersheim@gmail.com

2016

Paranimfen: Niels Pijnenburg

n.pijnenburg@outlook.com

Kaj Lambers

ktalambers@gmail.com

Stellingen

Aortic valve replacement and the stentless Freedom SOLO valve 1) Het gebruik van de Freedom SOLO dient overwogen te worden bij patienten met een kleine aortawortel en bij patienten die een voordeel kunnen hebben van de superieure hemodynamiek of het grote effectieve klepoppervlak. (dit proefschrift) 2) Door de supra annulaire implantatie techniek van de Freedom SOLO, zijn er minder postoperatieve pacemaker implantaties noodzakelijk. (dit proefschrift) 3) De Freedom SOLO is een weinig vergevingsgezinde bioprothese, patient selectie is cruciaal. (dit proefschrift) 4) De Freedom SOLO combineert de superieure hemodynamiek van een stentloze klep, met de implantatie snelheid van een conventioneel gestente klep. (dit proefschrift) 5) Bij retrospectief onderzoek van een nieuw geintroduceerde bioprothese zijn een goede cardioloog, complete echocardiografie en goede verslaglegging zeer belangrijk. (dit proefschrift) 6) 4D Flow MRI heeft potentie bij de hemodynamische beoordeling van hartklepprotheses. De lange termijn implicaties van de verschillende parameters moeten nog worden onderzocht. (dit proefschrift) 7) ‘’Do not tolerate anything less than the highest quality, because that is what wins the game.’’ Dr. L.H. Cohn 8) ‘’What it takes to become a cardiac surgeon? You need the eyes of an eagle, the hands of a woman, and the heart of a lion.’’ Dr. Denton A. Cooley 9) ‘’Als ik zou willen dat je het begreep, had ik het wel beter uitgelegd.’’ Johan Cruijff 10) ‘’The richest man is not he who has the most, but he who needs the least.’’