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Percutaneous left atrial appendage closure with a novel self-modelizing device: A pre-clinical feasibility study
International Journal of Cardiology 177 (2014) 957–963
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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Percutaneous left atrial appendage closure with a novel self-modelizing device: A pre-clinical feasibility study Jai-Wun Park a,⁎,1, Mohammad A. Sherif a,1, Konstantin. Zintl a, Yat-Yin Lam b, Martin Goedde a, Tim Scharnweber c, Friedrich Jung d, Ralf Peter Franke e, Johannes Brachmann a a
Department of Cardiology, Angiology, and Pneumology, Coburg Hospital, 96450 Coburg, Germany Cardiology Department, Chinese University of Hong Kong, China Institute for Biological Interfaces, Karlsruhe Institute of Technology (KIT), Karlsruhe, Germany d Institute of Biomaterial Science, Berlin-Brandenburg Centre for Regenerative Therapies, Helmholtz-Zentrum Geesthacht, Teltow, Germany e University of Ulm, Department of Biomaterials, Ulm, Germany b c
a r t i c l e
i n f o
Article history: Received 19 June 2014 Received in revised form 28 September 2014 Accepted 29 September 2014 Available online 5 October 2014 Keywords: LAA occluder Left atrial appendage Animal study
a b s t r a c t The aim of the study is to evaluate the feasibility and safety of a new left atrial appendage (LAA) occluder. Twelve pigs were included. In 2 pigs the implantation process failed due to pericardial tamponade in 1 pig and device embolization in the other pig. The placement of the devices was controlled via TEE and fluoroscopy. After 6 weeks of implantation the hearts were explanted. The devices were found to be easy to deploy and showed a very good adaptation to the LAA tissue. Eight out of 10 pigs had full closure of the LAA directly after implantation. After six weeks, due to the self-modelizing properties of the device, all pigs had a full closure of the LAA. The macroscopic evaluation of the explanted hearts showed that all devices were securely integrated in LAA tissues. There was one case of mild pericarditis but no macroscopic signs of inflammation on the device surrounding endocardium. The explantation revealed that device loops had penetrated the LAA tissue in three pigs. However, no signs of bleeding, pericardial effusion, or other damage to the LAA wall could be detected and the pigs were in good condition with normal weight gain and no clinical symptoms. The Occlutech® LAA occluder achieved complete closure of the LAA in all pigs, and remained in the LAA, with benign healing and no evidence of new thrombus or damage to surrounding structures. Moreover, the uncompromised survival of all implanted pigs demonstrates the feasibility and safety of the device. © 2014 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Atrial fibrillation (AF) is the most common tachyarrhythmia in clinical practice [1] and can result in thromboembolic events leading to serious illness or even death. Eight to 21% of patients scheduled for a cardioversion attempt present with left atrial thrombi [2,3]. Over 90% of these thrombi are located in the left atrial appendage (LAA) [4]. Emboli originating from the LAA often cause stroke, associated with a mortality of 38% in 12 months and a 12 month recurrence rate of 17% [5]. The risk of embolization of left atrial thrombi depends on the atrial size, sludge formation, and blood flow velocity in the left atrial appendage, patients' age, risk factor profile, and other factors [6]. The main risk of an embolic event in atrial fibrillation, however, is the lack of adequate anticoagulation [7]. Oral anticoagulation (OAC) is very effective and relevantly reduces the stroke risk by 62% [5]. ⁎ Corresponding author at: Department of Cardiology, Coburg Hospital, 96450 Coburg, Germany. E-mail address: [email protected] (J.-W. Park). 1 Drs. Park and Sherif have contributed equally to the work.
http://dx.doi.org/10.1016/j.ijcard.2014.09.194 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
Patients at high risk of embolic stroke, but with contraindications for OAC are in a need of an alternative approach that is not associated with a long-term risk of hemorrhage or other adverse events. This is particularly necessary for those patients who have survived intracranial hemorrhage but remain at high risk for cardiogenic embolism. A reasonable alternative may be the exclusion of the LAA cavity from circulation, using either surgical or percutaneous catheter-based procedures. Currently, the excision of the LAA at the time of mitral valve surgery is recommended for reduction of future stroke risk [8]. The efficacy of LAA exclusion in patients undergoing elective coronary artery bypass graft surgery was shown in the LAA Occlusion Study (LAAOS) [9]. The frequency of thrombus formation in the LAA of patients with AF and its suspected role as a source of embolism led to the hypothesis that resection or obliteration of the LAA might reduce the risk of stroke. Johnson et al. [10] performed atrial appendectomies in 437 patients during cardiac surgery. They found no strokes that were attributed to AF, and no patients were found to have atrial clots on TEE during follow-up [10]. Nevertheless, surgical LAA closure has not been accepted due to its invasive nature. But, based on the surgical experience, the development of a less invasive percutaneous approach to close the LAA by
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implantation of a mechanical device was a logical consequence. Since 2001 clinical studies using different systems (PLAATO®, Amplatzer®, Watchman®) were performed [11–14]. However, these devices have limitations in terms of limited recapture and repositioning capabilities as well as significant leaks after implantation, which increase by time [15]. In the present study the feasibility and safety of the Occlutech® LAA occluder were analyzed in a big animal model study. 2. Methods In accordance with the “Position of the American Heart Association on Research Animal Use,” adopted by the AHA on November 11, 1984 and after approval of the study protocol by the Department of Animal Science University of Kaposvár, Hungary at the Test Facility, twelve young pigs were included in the study. The Test Facility is accredited by the Hungarian Government (9/2001.(III.30.) EüM-FVM) and is registered to conduct research in laboratory animals. All the conditions of testing conform to the national and international Animal Welfare Act. The primary objective of this study was to evaluate the safety of a novel LAA occluder device. Secondarily, to prove the completeness of LAA closure (efficacy). The primary safety endpoint was the absence of device related adverse events. The device is considered safe if: 1 There is no device related disruption of heart function. 2 Device associated thrombus formation is absent after 6 week implantation (evaluated macroscopically and histologically). 3 The device does not embolize or protrude in to the left atrium. 4 The device does not puncture the left atrial appendage (LAA). 5 The device shows good tissue integration and absence of extensive device related inflammation or irritation (evaluated macroscopically and histologically). 2.1. Animal preparation 12 young pigs (species: Sus scrofa, strain: DanBred Hybrid) with a body weight of 40–45 kg were included. A porcine heart model was chosen because of its anatomical similarities to the human heart. The goal was to have 10 animals implanted with the device and followed up over 6 weeks. Animal preparation was in accordance with “Position of the American Heart Association on Research Animal Use,” adopted by the AHA on November 11, 1984. The animals were given ketamine hydrochloride (10 mg/kg) and 0.2 mg/kg xylazine and 0.04 mg atropine i.m. Once sedated, the animals became anesthetized with isoflurane and oxygen, delivered through a facemask. The animals were then intubated and maintained in anesthesia with isoflurane. After the animal was transferred to the procedure table, isoflurane was delivered through a volume-regulated respirator. The ECO2 was maintained within physiological ranges. 2.1.1. Medication To prevent or reduce the occurrence of thrombotic events, animals were treated on Day-1 with aspirin 250 mg, per os (PO) and clopidogrel (300 mg, PO). During the implantation procedure, 5000 IU unfractionated heparin was given through the sheath. The animals were then treated daily with acetylsalicylic acid (500 mg, PO) and clopidogrel (75 mg, PO) until explantation. To prevent infection, animals were given Benzathine-Procaine Penicillin G (40,000 U/kg, IM) and the anti-inflammatory agent Algopyrin (4.3 ml IM) prior to device deployment on Day 0. 2.2. Occluder device The LAA occluder (Occlutech®, Jena, Germany) consists of a self-expanding, flexible nitinol mesh. It has a tapered cylindrical shape that adapts to the shape of the LAA (Fig. 1). The proximal part has a larger diameter to seal the orifice. The loops at the distal rim aid to keep the implanted device in position. The outer surface of the occluder is covered with a non-woven, bio-stable Poly (carbonate) urethane layer. Since all implantations using the soft device passed the tug test, only soft devices were implanted.
Fig. 1. Schematic drawing of the device. The LAA occluder was mounted on the delivery system and advanced through the delivery sheath to the LAA. First a partial deployment was done by pushing half of the occluder into the orifice, so that the distal rim loops could unfold and point backwards. At the final step the occluder was held in position and the delivery catheter was unsheathed. Then a visual inspection of the unfolded device was performed to secure that the loops were folded in the correct position. The device was retracted and repositioned in case positioning and LAA occlusion were not correct. The correct placement of the device and occlusion was confirmed by tug test, TEE and contrast fluoroscopy. The leakage aperture was graded from 0 to 3 where 0 is no leak, 1 is a trivial leak (b3 mm), 2 is a small leak (3–5 mm) and 3 is a significant leak (N5 mm). Once successfully positioned, the LAA device was released. After experiencing a device loss and embolization during release, the procedure was changed so that the tip of the sheath had contact with the proximal end of the device to hold it in place while slowly opening the jaws and pulling back the pusher (Fig. 2). The sheath and pusher were retrieved, the vein was ligated and the skin closed in 2 layers. The animals were then allowed to recover from anesthesia. 2.4. Follow-up To guide the intervention procedure and to evaluate the placement of the device, fluoroscopy was performed at baseline and post-treatment on Day 0. Images were also recorded pre- and post-mortem after 6 weeks. For the 6 week imaging of the device, no contrast media were used. In addition, TEE was used on Day 0 to guide the implantation procedure, to measure the LAA anatomy and to evaluate acute LAA sealing rate. TEE was also used to evaluate the sealing rate after 6 weeks.
3. Results Details of the implanted devices are shown in Table 1. Two procedurerelated complications caused by heart perforations occurred during transseptal puncture due to difficulties in visualizing the atrial septa. One pig died due to tamponade and the other pig had a small pericardial effusion, but recovered fully and had no further complications. These complications depended on difficulties in TEE visualizing the atrial septa due to the anatomy of the pig heart and could not be attributed to the device. In one pig a device embolization to the abdominal aorta occurred during occluder release. This pig had to be euthanized. This explains that 12 pigs were included to enable a complete analysis of 10 pigs.
2.3. Implantation technique
3.1. Gross examination and histological assessment The size of the LAA closure device was chosen according to the LAA landing zone with a device size D2 (diameter of distal part) about 3–5 mm oversized. In a few cases, a deliberate over or under sizing was performed. The implantation was started with the softer occluder design and if the tug test failed, it was planned to use the stiffer design. Since all of the soft devices passed the tug test, no device with a stiffer design was implanted. Through transseptal puncture, a long (280–300 cm) 0.035 guiding wire was placed into the left atrium. Using the angiographic position (RAO 30°/Caudal 20°), the LAA was displayed and measured applying radiographic contrast medium and the delivery catheter was placed into the LAA. The measurement with transesophageal echocardiography (TEE) was used when significant differences between fluoroscopic and echo measurements occurred.
A macroscopical external evaluation of the explanted heart was performed to evaluate the presence of cardiac perforation, inflammation (diffuse or localized pericarditis) and device perforation of the LAA. The heart was then cut open and a macroscopical evaluation of the dissected fresh heart was performed before tissue fixation in respect to thrombus formation, tissue irritation, device placement, device position, device adaptation to the LAA, sealing rate, PU-cover integrity, and device ingrowth.
J.-W. Park et al. / International Journal of Cardiology 177 (2014) 957–963
Step 1
Step 2
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Step 3
Fig. 2. Step by step pictures of new deployment procedure (from pig OCC-10) 1 Advance the delivery sheath to the device to hold it in place. 2 Disconnect the delivery cable from the device, while holding the delivery sheath in place. 3 Carefully remove the delivery catheter from the device. If this is difficult, hold the device in place by pushing the delivery cable to the device.
The explanted tissues were ethanol/methanol fixated. The assessment of endothelialization was performed using immunohistochemistry (staining against CD31). The explants were inspected photo-microscopically and HE stained to evaluate tissue reactions.
3.2. Device embedding in the LAA All devices were securely embedded in the left atrial appendage. The small implants did not protrude into the atrial lumen and were almost completely encapsulated (Fig. 3a). Devices of bigger sizes were more or less prominent into the atrial lumen, always carrying a pseudo-intima, which was more or less thick and showed more or less white color (depending on the thickness of the pseudo-intima, Fig. 3b). In some cases the hubs (see Fig. 3b, arrow) of the devices were not encapsulated.
The non-PU-covered waist (middle part of the device, Fig. 3a) and the umbrella-like lower part of the device were always securely embedded in the LAA-tissue (Figs. 3a and 4). There was also a tight embedding of the PU-covered device shoulder which, however, could be extracted more easily from the surrounding tissues compared to the lower parts of the device (Fig. 4a). There were no signs of inflammation on the surrounding intact endocardium (Fig. 4b) — except one pig which developed a pericarditis. Thrombotic attachments to the luminal device surface were in no case visible. The strength of the embedding in the non-PU layered waist region and downwards was very high as indicated by great amounts of collagen containing tissues crossing from the device interior through the nitinol mesh to the surrounding tissues (Fig. 4a, below left, blue arrow). The PU-covered shoulder region was also tightly embedded, but surrounding tissues were easily separated from the PU-layer with
Table 1 Result summary. Pig
% weight gain in 6 weeks
Device size, D1/D2 (mm)
Leak score Day 0a
Leak score week 6a
Device ingrowth
Other Autopsy findings
Complication
Comments
OCC-1
83
18/15
0
0
50–100%
Device loops visible on the epicardial side of the LAA.
No
OCC-2
79
21/18
2
0
10–50%
OCC-3
75
18/15
0
0
50–100%
Mild pericarditis
Yes (possibly device)
OCC-4
83
18/15 (24/21)
0 [1]
0
50–100%
Device loops penetrating LAA wall
No
A 30 mm orifice, therefore occluder was deeply implanted Small pericardial effusion during transseptal puncture, animal fully recovered without further complications. The cause of pericarditis not known. Device penetration could not be seen during autopsy Two occluders implanted due to double orifice (one in each lobe) 2nd occluder prone in to LA. Both Devices too deeply implanted/ oversized
OCC-5 OCC-6
74 73
21/18 24/21
0 0
0 0
50–100% 50–100%
No No
OCC-7
76
21/18
0
0
50–100%
No
OCC-8
83
21/18
1
0
10–50%
N
OCC-9
n/a
24/21
n/a
n/a
n/a
Yes (device)
OCC-10
71
21/18
0
0
50–100%
OCC-11
n/a
n/a
n/a
n/a
n/a
OCC-12
67
21/18
0
0
50–100%
a
Yes (procedure)
Device loops penetrating LAA wall
Device loops penetrating LAA wall
0 is no leak, 1 is trivial leak (b3 mm), 2 is small leak (3–5 mm) and 3 is significant leak (N5 mm).
No Yes (procedure) No
Loss of appetite and diarrhea at week 2, treated with antibiotics and recovered. Not device or procedure related Small leak that disappeared after tug test (self-modelizing device) Minor gap and compressed loops at implantation, no leak or compressed loops after 6 weeks Pig euthanized. Device embolization during release. Caused by pulling force while the pusher was released from the device. 3 attempts, loops facing the wrong direction each time. Tug test showed stable device Transseptal puncture and tamponade. No device implanted. Device too deeply implanted
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Fig. 3. LAA occluder devices explanted six weeks after implantation. a: Small device thickly encapsulated. b: Large device with a thin pseudo-intimal cover. Hub not encapsulated.
only few and thin tufts of connective tissue sticking to the PU-layer (Fig. 4a, upper left part, black arrows). No evidence of binding between the PU-layer and the nitinol mesh filled with masses of tissues was found after simply peeling off the PU-layer (Fig. 4a, upper right, blue asterisks). The interior of the implants with the exemption of device “OCC 003” was filled with masses of natively mostly white colored tissues (assumed to consist mainly of organized fibrin).
3.3. HE staining On every explant 10 localizations were examined to assess fibrin deposition, adherent platelets, polymorphonuclear granulocytes (PMN), monocytes/macrophages and foreign body giant cells (FBGC). There was no localization on any of the 10 explants where thrombocytes were found. This was equally true for PMN and also for FBGC. Table 2 displays the ratios of the thicknesses of the capsule and the PU-layer (PU). This analysis revealed that in 6 out of 10 animals the ratio of C/PU was smaller than 1 (mean value 0.53) six weeks after the implantation of the occluder system. In the other 4 animals this ratio increased drastically (up to 51-fold) which meant an increase of a factor 96.2. One of these 4 cases was characterized by a mild pericarditis, and another one by an impingement reaction. In both other cases muscle cells could be identified as constituents of the capsule which was also found in case “OCC-010” (impingement), but not in any of the other cases.
3.4. Immunohistology staining Verification of endothelial cells was deduced from the coincidence of the presence of cell nuclei (visualized by DAPI stain in blue, and of positive CD-31 stain in red). In general, the endothelial cells were verified at a primary magnification of 1:20 and a zoom factor 1. Of course, the size of the respective cells had to be appropriate. A certain and differing loss of brilliance of colors over the time of examination was due to bleaching because at least 4 ROI had to be found and focused on each sample. Endothelial cells were found on this occluder system in every case whereupon the numbers of endothelial cells varied considerably (Fig. 5). 4. Discussion Transcatheter LAA occlusion may be considered in non-valvular atrial fibrillation patients with a high stroke risk and contraindications for long-term oral anticoagulation [16]. The number of implantations of LAA occluders already started to grow markedly and is expected to rise further in the near future. At present, 2 different occluder systems are available, the Watchman® and the Amplatzer® Cardiac Plug device. However, both occluders are still having some limitations [17]. The Watchman® device is relatively long and therefore not suitable for patients with shallow LAA. Recapturing the device beyond the level of retention barbs is not recommended, because of the risk of damaging the barbs and this limits its repositioning ability [7]. On the other hand, there is a tendency for the lobe of the Amplatzer Cardiac Plug® to jump forward to the distal part of the LAA after deployment and thereby demanding extra skills from the implanting physicians [18].
Fig. 4. Explanted device after 6 weeks. a: Integration of the device with connective tissue. b: Unblemished endocardium in the vicinity of the device.
J.-W. Park et al. / International Journal of Cardiology 177 (2014) 957–963 Table 2 Ratio of the thicknesses of the capsule (C) resting on the blood facing device surface to the PU-layer (PU). Device
Thicknesses in arbitrary units of the capsule (C)/PU-layer (PU)
Ratio C/PU
OCC 004-1 OCC 008 OCC 003 OCC 010 OCC 007 OCC 006 OCC 002 OCC 005 OCC 004-2 OCC 001 OCC 012
4/7.7 24/43 22/2.3 53/9 37/64 52/130 21/30 19/46 118/43 153/3 46/5
0.52 0.56 9.60 5.90 0.58 0.40 0.70 0.41 2.70 51.00 9.20
Remarks
Pericarditis Impingement
2 devices Muscle cellsa Muscle cells
a Device “OCC 001” exhibited clearly more terminally differentiated muscle cells than device “OCC 012”.
Moreover, both devices need to be delivered via relatively large-sized sheaths (14 Fr. for Watchman and 9–13 Fr. for Amplatzer Cardiac Plug, respectively), which can be associated with more vascular complications and air-embolism. The short device used in this study consists of a self-expanding, self-modelizing, flexible nitinol mesh, which can be placed within 2 cm from LAA ostia. This study demonstrates the feasibility and safety of implanting this novel LAA occluder system (Occlutech® LAA occluder) in young healthy pigs. The device placement (implantation, repositioning and retrieval) and LAA closure were evaluated using TEE and fluoroscopy. The occluder could easily be deployed and showed a very good adjustment to the LAA resulting in a full closure of the LAA in 8 of 10 pigs immediately after implantation and in all pigs after 6 weeks of implantation (Fig. 6). One device embolization occurred during occluder deployment. Thereafter the device release technique was modified to avoid similar adverse events in the future. The small implants did not protrude into the atrial lumen and were completely encapsulated (Fig. 3a). Devices of bigger sizes were more or less prominent into the atrial lumen, always carrying a pseudo-intima, which was more or less thick and showed more or less white color (depending on the thickness of the pseudo-intima). A quantitative analysis of the ratio of the thicknesses of the capsule – resting on the blood facing device surface – to the PU-layer revealed that in 6 out of ten animals the ratio of C/PU was smaller than 1 (mean value 0.53) six weeks after implantation of the occluder system. In the other four animals this ratio increased drastically (up to 51-fold) which meant
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an increase of a factor 96.2. One of these 4 cases had a mild pericarditis, and another one by an impingement reaction. In both other cases muscle cells could be identified as constituents of the capsule. Some muscle cells were also found in the impingement case but not in any of the other cases. Whether this was associated with the implantation technique – a possible myocardial injury could be followed by migration and proliferation of muscle cell precursors – cannot be answered by this study. In some cases the hub (see Fig. 3b arrow) of the devices was not encapsulated. The non-covered waist (middle part of the device) and the expanded umbrella-like lower part of the device were always securely embedded in the LAA-tissue. There was also a tight embedding of the material-covered device shoulder which, however, could be extracted more easily from the surrounding tissues compared to the lower parts of the device. It was remarkable that the implantation depth differed considerably leading to differences in the prominence of the devices into the atrial lumen. The strength of the embedding in the non-PU layered waist region and downwards was very high as indicated by the strength needed to separate this part from surrounding tissue and by great amounts of collagen containing tissues crossing from the device interior through the nitinol mesh to the surrounding tissues (Fig. 4a, below left, blue arrow). Fluoroscopic comparison between the device shapes directly after implantation and after 6 weeks revealed that the loops were straightened pulling the device body into the LAA resulting in complete sealing of the LAA orifice. This is considered as a favorable late remodeling. The explantation revealed that loops had penetrated the LAA tissue in three pigs. However, no signs of bleeding, pericardial effusion, or other damage to the LAA wall could be detected and the pigs were in good condition with normal weight gain and no clinical symptoms. It was therefore considered clinically insignificant. The autopsy allowed concluding that the appearance of loops outside tissues was most probably induced during the explantation procedure. An immuno-histological examination demonstrated that all of the devices were more or less inhabited by endothelial cells, and in some areas a cobblestone like and almost confluent endothelial cell layer was found already. There might be a trend that thinner capsules could coincide with more endothelial cells. That endothelial cells were generally present on these devices is in clear contrast to the findings on the PLAATO system, where nearly no endothelial cells were found even 2.5 years after implantation [19]. There were no signs of inflammation on the device-surrounding endocardium (except one pig with impingement). Also device loops, penetrating the LAA wall – occurring in 3 pigs – did not show inflammation processes. Monocyte/macrophages were sometimes found in small
Fig. 5. View on PU-cover with overlaying pseudo-intimal capsule revealing. a: very low cellularity and only few endothelial cells (OCC006). b: high cellularity and a greater amount of endothelial cells, almost without fibrin.
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Fig. 6. Example of remodeling (pig OCC-002). Device was twisted at implantation (a) but had un-twisted and re-shaped during 6 week implantation (b).
numbers allowing us to conclude that around these implants inflammation did not develop further over the examination period. It can be judged from the absence of foreign body giant cells that no degradation products were released. Also, polymorpho-nuclear granulocytes were not found. Regarding the performance of the Occlutech® LAA occluder in this study in comparison with the performance of the other occluders in animal models, we found that the Occlutech® LAA occluder has achieved complete sealing of the LAA in all animals after 6 weeks. Animal studies for the PLAATO system revealed complete LAA occlusion, no evidence for thrombi on the implant surface, and complete healing 3 months after device implantation [20]. Bass et al. [21] showed that the Amplatzer® LAA occluder achieved complete occlusion of the LAA without thrombi in all animals. In a recent study, Kar et al. [22] showed in a canine model that, there are differences in conformation of LAA surrounding structures with variable healing response between Watchman® and Amplatzer® after LAA closure. Watchman® did not obstruct or impact the LAA adjacent structures, resulting in a favorable surface recovery. In comparison, the disk of Amplatzer® could potentially jeopardize LAA neighboring structures and leads to delayed healing. Moreover, At 28 days, complete neo-endocardial coverage of the Watchman® was observed; however, the Amplatzer® showed an incomplete covering on the disk surface especially at the lower edge and end-screw hub regions [22]. Compared to the two devices that are currently on the market (Amplatzer® and Watchman®), the Occlutech® device has rounded loops at its distal rim to fix the device at the landing zone in the LAA allowing an early reuptake/repositioning of the device, and even an exchange of the device when the device size is not appropriate. In contrast, the other devices have sharp hooks which risk in damaging the soft tissue of the LAA and which complicate retrieval of the device. Furthermore, the nitinol body of the new occluder is soft and has low radial force resulting in a better modeling and adaptation to the LAA wall with complete closure of the LAA. 4.1. Study limitations The number of pigs included in the study is very small, so that one must be cautious to generalize the results. This limitation is partly compensated by the prospective design of the study, the consecutive inclusion and the completion of the follow-up in all of the pigs. Moreover, the study was performed in young animals. In older patients with coronary artery disease and activated platelets the risk of thrombotic events might be higher. No thrombi – neither in vivo nor at the explanted devices – could be found. Obviously, thrombocytes could not adhere to these implant
surfaces due to the applied anticoagulation (heparin 5000 IU) in combination with antiplatelet therapy. Because of the design of the study, it was not possible to rule out completely that transiently, small, mobile device-related thrombi might have formed. It has to be considered, that LAAs in pigs differ from those in humans, as the anatomy is clearly more challenging, with a sharper angulation and more tapering shape compared to humans. In this study, most devices were oversized, therefore they were protruding into the LA, something one would not consider in humans. In 3 cases striated muscle cells or precursors, assumed to originate from the LAA wall, were found in the capsules. Whether this was associated with the implantation technique – a possible LAA wall injury could be followed by migration and proliferation of muscle cell precursors – cannot be answered by this study. 5. Conclusion The study device achieved complete closure of the LAA in all pigs, and remained in the LAA, with benign healing and no evidence of new thrombus or damage to surrounding structures. Moreover, the uncompromised survival of all implanted pigs demonstrates the feasibility and safety of the device. Funding of the study The study was funded by the Occlutech, Jena, Germany. Conflict of interest Dr. Park is a consultant for Occlutech, Jena, Germany. References [1] Falk RH. Atrial fibrillation. N Engl J Med 2001;344:1067–78. [2] Leung DY, Black IW, Cranney GB, Hopkins AP, Walsh WF. Prognostic implications of left atrial spontaneous echo contrast in nonvalvular atrial fibrillation. J Am Coll Cardiol 1994;24:755–62. [3] Manning WJ, Silverman DI, Keighley CS, Oettgen P, Douglas PS. Transesophageal echocardiographically facilitated early cardioversion from atrial fibrillation using short-term anticoagulation: final results of a prospective 4.5-year study. J Am Coll Cardiol 1995;25:1354–61. [4] Blackshear JL, Odell JA. Appendage obliteration to reduce stroke in cardiac surgical patients with atrial fibrillation. Ann Thorac Surg 1996;61:755–9. [5] Forslund T, Wettermark B, Wandell P, von Euler M, Hasselstrom J, Hjemdahl P. Risk scoring and thromboprophylactic treatment of patients with atrial fibrillation with and without access to primary healthcare data: experience from the Stockholm health care system. Int J Cardiol 2013;170:208–14. [6] Guo Y, Wang H, Zhao X, Zhang Y, Zhang D, Ma J, et al. Sequential changes in renal function and the risk of stroke and death in patients with atrial fibrillation. Int J Cardiol 2013;168:4678–84.
J.-W. Park et al. / International Journal of Cardiology 177 (2014) 957–963 [7] Lam YY, Ma TK, Yan BP. Alternatives to chronic warfarin therapy for the prevention of stroke in patients with atrial fibrillation. Int J Cardiol 2011;150:4–11. [8] American College of C, American Heart Association Task Force on Practice G, Society of Cardiovascular A, Bonow RO, Carabello BA, Chatterjee K, de Leon Jr AC, Faxon DP, et al. ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing Committee to Revise the 1998 guidelines for the management of patients with valvular heart disease) developed in collaboration with the Society of Cardiovascular Anesthesiologists endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons. J Am Coll Cardiol 2006;48:e1-148. [9] Healey JS, Crystal E, Lamy A, Teoh K, Semelhago L, Hohnloser SH, et al. Left Atrial Appendage Occlusion Study (LAAOS): results of a randomized controlled pilot study of left atrial appendage occlusion during coronary bypass surgery in patients at risk for stroke. Am Heart J 2005;150:288–93. [10] Johnson WD, Ganjoo AK, Stone CD, Srivyas RC, Howard M. The left atrial appendage: our most lethal human attachment! Surgical implications. Eur J Cardiothorac Surg 2000;17:718–22. [11] Holmes DR, Reddy VY, Turi ZG, Doshi SK, Sievert H, Buchbinder M, et al. Percutaneous closure of the left atrial appendage versus warfarin therapy for prevention of stroke in patients with atrial fibrillation: a randomised non-inferiority trial. Lancet 2009;374:534–42. [12] Ostermayer SH, Reisman M, Kramer PH, Matthews RV, Gray WA, Block PC, et al. Percutaneous left atrial appendage transcatheter occlusion (PLAATO system) to prevent stroke in high-risk patients with non-rheumatic atrial fibrillation: results from the international multi-center feasibility trials. J Am Coll Cardiol 2005;46:9–14. [13] Reddy VY, Mobius-Winkler S, Miller MA, Neuzil P, Schuler G, Wiebe J, et al. Left atrial appendage closure with the Watchman device in patients with a contraindication for oral anticoagulation: the ASAP study (Asa Plavix feasibility Study With Watchman Left Atrial Appendage Closure Technology). J Am Coll Cardiol 2013;61:2551–6.
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[14] Park JW, Bethencourt A, Sievert H, Santoro G, Meier B, Walsh K, et al. Left atrial appendage closure with Amplatzer cardiac plug in atrial fibrillation: initial European experience. Catheter Cardiovasc Interv 2011;77:700–6. [15] Viles-Gonzalez JF, Kar S, Douglas P, Dukkipati S, Feldman T, Horton R, et al. The clinical impact of incomplete left atrial appendage closure with the Watchman Device in patients with atrial fibrillation: a PROTECT AF (Percutaneous Closure of the Left Atrial Appendage Versus Warfarin Therapy for Prevention of Stroke in Patients With Atrial Fibrillation) substudy. J Am Coll Cardiol 2012;59:923–9. [16] Camm AJ, Lip GY, De Caterina R, Savelieva I, Atar D, Hohnloser SH, et al. Guidelines ESCCfP. 2012 focused update of the ESC guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association. Eur Heart J 2012;33:2719–47. [17] Cruz-Gonzalez I, Yan BP, Lam YY. Left atrial appendage exclusion: state-of-the-art. Catheter Cardiovasc Interv 2010;75:806–13. [18] Cruz-Gonzalez I, Cubeddu RJ, Sanchez-Ledesma M, Cury RC, Coggins M, Maree AO, et al. Left atrial appendage exclusion using an Amplatzer device. Int J Cardiol 2009;134:e1–3. [19] Park JW, Gerk U, Franke RP, Jung F. Post-mortem analysis of a left atrial appendage occlusion device (PLAATO) in a patient with permanent atrial fibrillation. Cardiology 2009;112:205–8. [20] Nakai T, Lesh MD, Gerstenfeld EP, Virmani R, Jones R, Lee RJ. Percutaneous left atrial appendage occlusion (PLAATO) for preventing cardioembolism: first experience in canine model. Circulation 2002;105:2217–22. [21] Bass JL. Transcatheter occlusion of the left atrial appendage—experimental testing of a new Amplatzer device. Catheter Cardiovasc Interv 2010;76:181–5. [22] Kar S, Hou D, Jones R, Werner D, Swanson L, Tischler B, et al. Impact of Watchman and Amplatzer devices on left atrial appendage adjacent structures and healing response in a canine model. JACC Cardiovasc Interv 2014;7:801–9.
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Percutaneous left atrial appendage closure with a novel self-modelizing device: A pre-clinical feasibility study Jai-Wun Park a,⁎,1, Mohammad A. Sherif a,1, Konstantin. Zintl a, Yat-Yin Lam b, Martin Goedde a, Tim Scharnweber c, Friedrich Jung d, Ralf Peter Franke e, Johannes Brachmann a a
Department of Cardiology, Angiology, and Pneumology, Coburg Hospital, 96450 Coburg, Germany Cardiology Department, Chinese University of Hong Kong, China Institute for Biological Interfaces, Karlsruhe Institute of Technology (KIT), Karlsruhe, Germany d Institute of Biomaterial Science, Berlin-Brandenburg Centre for Regenerative Therapies, Helmholtz-Zentrum Geesthacht, Teltow, Germany e University of Ulm, Department of Biomaterials, Ulm, Germany b c
a r t i c l e
i n f o
Article history: Received 19 June 2014 Received in revised form 28 September 2014 Accepted 29 September 2014 Available online 5 October 2014 Keywords: LAA occluder Left atrial appendage Animal study
a b s t r a c t The aim of the study is to evaluate the feasibility and safety of a new left atrial appendage (LAA) occluder. Twelve pigs were included. In 2 pigs the implantation process failed due to pericardial tamponade in 1 pig and device embolization in the other pig. The placement of the devices was controlled via TEE and fluoroscopy. After 6 weeks of implantation the hearts were explanted. The devices were found to be easy to deploy and showed a very good adaptation to the LAA tissue. Eight out of 10 pigs had full closure of the LAA directly after implantation. After six weeks, due to the self-modelizing properties of the device, all pigs had a full closure of the LAA. The macroscopic evaluation of the explanted hearts showed that all devices were securely integrated in LAA tissues. There was one case of mild pericarditis but no macroscopic signs of inflammation on the device surrounding endocardium. The explantation revealed that device loops had penetrated the LAA tissue in three pigs. However, no signs of bleeding, pericardial effusion, or other damage to the LAA wall could be detected and the pigs were in good condition with normal weight gain and no clinical symptoms. The Occlutech® LAA occluder achieved complete closure of the LAA in all pigs, and remained in the LAA, with benign healing and no evidence of new thrombus or damage to surrounding structures. Moreover, the uncompromised survival of all implanted pigs demonstrates the feasibility and safety of the device. © 2014 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Atrial fibrillation (AF) is the most common tachyarrhythmia in clinical practice [1] and can result in thromboembolic events leading to serious illness or even death. Eight to 21% of patients scheduled for a cardioversion attempt present with left atrial thrombi [2,3]. Over 90% of these thrombi are located in the left atrial appendage (LAA) [4]. Emboli originating from the LAA often cause stroke, associated with a mortality of 38% in 12 months and a 12 month recurrence rate of 17% [5]. The risk of embolization of left atrial thrombi depends on the atrial size, sludge formation, and blood flow velocity in the left atrial appendage, patients' age, risk factor profile, and other factors [6]. The main risk of an embolic event in atrial fibrillation, however, is the lack of adequate anticoagulation [7]. Oral anticoagulation (OAC) is very effective and relevantly reduces the stroke risk by 62% [5]. ⁎ Corresponding author at: Department of Cardiology, Coburg Hospital, 96450 Coburg, Germany. E-mail address: [email protected] (J.-W. Park). 1 Drs. Park and Sherif have contributed equally to the work.
http://dx.doi.org/10.1016/j.ijcard.2014.09.194 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
Patients at high risk of embolic stroke, but with contraindications for OAC are in a need of an alternative approach that is not associated with a long-term risk of hemorrhage or other adverse events. This is particularly necessary for those patients who have survived intracranial hemorrhage but remain at high risk for cardiogenic embolism. A reasonable alternative may be the exclusion of the LAA cavity from circulation, using either surgical or percutaneous catheter-based procedures. Currently, the excision of the LAA at the time of mitral valve surgery is recommended for reduction of future stroke risk [8]. The efficacy of LAA exclusion in patients undergoing elective coronary artery bypass graft surgery was shown in the LAA Occlusion Study (LAAOS) [9]. The frequency of thrombus formation in the LAA of patients with AF and its suspected role as a source of embolism led to the hypothesis that resection or obliteration of the LAA might reduce the risk of stroke. Johnson et al. [10] performed atrial appendectomies in 437 patients during cardiac surgery. They found no strokes that were attributed to AF, and no patients were found to have atrial clots on TEE during follow-up [10]. Nevertheless, surgical LAA closure has not been accepted due to its invasive nature. But, based on the surgical experience, the development of a less invasive percutaneous approach to close the LAA by
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implantation of a mechanical device was a logical consequence. Since 2001 clinical studies using different systems (PLAATO®, Amplatzer®, Watchman®) were performed [11–14]. However, these devices have limitations in terms of limited recapture and repositioning capabilities as well as significant leaks after implantation, which increase by time [15]. In the present study the feasibility and safety of the Occlutech® LAA occluder were analyzed in a big animal model study. 2. Methods In accordance with the “Position of the American Heart Association on Research Animal Use,” adopted by the AHA on November 11, 1984 and after approval of the study protocol by the Department of Animal Science University of Kaposvár, Hungary at the Test Facility, twelve young pigs were included in the study. The Test Facility is accredited by the Hungarian Government (9/2001.(III.30.) EüM-FVM) and is registered to conduct research in laboratory animals. All the conditions of testing conform to the national and international Animal Welfare Act. The primary objective of this study was to evaluate the safety of a novel LAA occluder device. Secondarily, to prove the completeness of LAA closure (efficacy). The primary safety endpoint was the absence of device related adverse events. The device is considered safe if: 1 There is no device related disruption of heart function. 2 Device associated thrombus formation is absent after 6 week implantation (evaluated macroscopically and histologically). 3 The device does not embolize or protrude in to the left atrium. 4 The device does not puncture the left atrial appendage (LAA). 5 The device shows good tissue integration and absence of extensive device related inflammation or irritation (evaluated macroscopically and histologically). 2.1. Animal preparation 12 young pigs (species: Sus scrofa, strain: DanBred Hybrid) with a body weight of 40–45 kg were included. A porcine heart model was chosen because of its anatomical similarities to the human heart. The goal was to have 10 animals implanted with the device and followed up over 6 weeks. Animal preparation was in accordance with “Position of the American Heart Association on Research Animal Use,” adopted by the AHA on November 11, 1984. The animals were given ketamine hydrochloride (10 mg/kg) and 0.2 mg/kg xylazine and 0.04 mg atropine i.m. Once sedated, the animals became anesthetized with isoflurane and oxygen, delivered through a facemask. The animals were then intubated and maintained in anesthesia with isoflurane. After the animal was transferred to the procedure table, isoflurane was delivered through a volume-regulated respirator. The ECO2 was maintained within physiological ranges. 2.1.1. Medication To prevent or reduce the occurrence of thrombotic events, animals were treated on Day-1 with aspirin 250 mg, per os (PO) and clopidogrel (300 mg, PO). During the implantation procedure, 5000 IU unfractionated heparin was given through the sheath. The animals were then treated daily with acetylsalicylic acid (500 mg, PO) and clopidogrel (75 mg, PO) until explantation. To prevent infection, animals were given Benzathine-Procaine Penicillin G (40,000 U/kg, IM) and the anti-inflammatory agent Algopyrin (4.3 ml IM) prior to device deployment on Day 0. 2.2. Occluder device The LAA occluder (Occlutech®, Jena, Germany) consists of a self-expanding, flexible nitinol mesh. It has a tapered cylindrical shape that adapts to the shape of the LAA (Fig. 1). The proximal part has a larger diameter to seal the orifice. The loops at the distal rim aid to keep the implanted device in position. The outer surface of the occluder is covered with a non-woven, bio-stable Poly (carbonate) urethane layer. Since all implantations using the soft device passed the tug test, only soft devices were implanted.
Fig. 1. Schematic drawing of the device. The LAA occluder was mounted on the delivery system and advanced through the delivery sheath to the LAA. First a partial deployment was done by pushing half of the occluder into the orifice, so that the distal rim loops could unfold and point backwards. At the final step the occluder was held in position and the delivery catheter was unsheathed. Then a visual inspection of the unfolded device was performed to secure that the loops were folded in the correct position. The device was retracted and repositioned in case positioning and LAA occlusion were not correct. The correct placement of the device and occlusion was confirmed by tug test, TEE and contrast fluoroscopy. The leakage aperture was graded from 0 to 3 where 0 is no leak, 1 is a trivial leak (b3 mm), 2 is a small leak (3–5 mm) and 3 is a significant leak (N5 mm). Once successfully positioned, the LAA device was released. After experiencing a device loss and embolization during release, the procedure was changed so that the tip of the sheath had contact with the proximal end of the device to hold it in place while slowly opening the jaws and pulling back the pusher (Fig. 2). The sheath and pusher were retrieved, the vein was ligated and the skin closed in 2 layers. The animals were then allowed to recover from anesthesia. 2.4. Follow-up To guide the intervention procedure and to evaluate the placement of the device, fluoroscopy was performed at baseline and post-treatment on Day 0. Images were also recorded pre- and post-mortem after 6 weeks. For the 6 week imaging of the device, no contrast media were used. In addition, TEE was used on Day 0 to guide the implantation procedure, to measure the LAA anatomy and to evaluate acute LAA sealing rate. TEE was also used to evaluate the sealing rate after 6 weeks.
3. Results Details of the implanted devices are shown in Table 1. Two procedurerelated complications caused by heart perforations occurred during transseptal puncture due to difficulties in visualizing the atrial septa. One pig died due to tamponade and the other pig had a small pericardial effusion, but recovered fully and had no further complications. These complications depended on difficulties in TEE visualizing the atrial septa due to the anatomy of the pig heart and could not be attributed to the device. In one pig a device embolization to the abdominal aorta occurred during occluder release. This pig had to be euthanized. This explains that 12 pigs were included to enable a complete analysis of 10 pigs.
2.3. Implantation technique
3.1. Gross examination and histological assessment The size of the LAA closure device was chosen according to the LAA landing zone with a device size D2 (diameter of distal part) about 3–5 mm oversized. In a few cases, a deliberate over or under sizing was performed. The implantation was started with the softer occluder design and if the tug test failed, it was planned to use the stiffer design. Since all of the soft devices passed the tug test, no device with a stiffer design was implanted. Through transseptal puncture, a long (280–300 cm) 0.035 guiding wire was placed into the left atrium. Using the angiographic position (RAO 30°/Caudal 20°), the LAA was displayed and measured applying radiographic contrast medium and the delivery catheter was placed into the LAA. The measurement with transesophageal echocardiography (TEE) was used when significant differences between fluoroscopic and echo measurements occurred.
A macroscopical external evaluation of the explanted heart was performed to evaluate the presence of cardiac perforation, inflammation (diffuse or localized pericarditis) and device perforation of the LAA. The heart was then cut open and a macroscopical evaluation of the dissected fresh heart was performed before tissue fixation in respect to thrombus formation, tissue irritation, device placement, device position, device adaptation to the LAA, sealing rate, PU-cover integrity, and device ingrowth.
J.-W. Park et al. / International Journal of Cardiology 177 (2014) 957–963
Step 1
Step 2
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Step 3
Fig. 2. Step by step pictures of new deployment procedure (from pig OCC-10) 1 Advance the delivery sheath to the device to hold it in place. 2 Disconnect the delivery cable from the device, while holding the delivery sheath in place. 3 Carefully remove the delivery catheter from the device. If this is difficult, hold the device in place by pushing the delivery cable to the device.
The explanted tissues were ethanol/methanol fixated. The assessment of endothelialization was performed using immunohistochemistry (staining against CD31). The explants were inspected photo-microscopically and HE stained to evaluate tissue reactions.
3.2. Device embedding in the LAA All devices were securely embedded in the left atrial appendage. The small implants did not protrude into the atrial lumen and were almost completely encapsulated (Fig. 3a). Devices of bigger sizes were more or less prominent into the atrial lumen, always carrying a pseudo-intima, which was more or less thick and showed more or less white color (depending on the thickness of the pseudo-intima, Fig. 3b). In some cases the hubs (see Fig. 3b, arrow) of the devices were not encapsulated.
The non-PU-covered waist (middle part of the device, Fig. 3a) and the umbrella-like lower part of the device were always securely embedded in the LAA-tissue (Figs. 3a and 4). There was also a tight embedding of the PU-covered device shoulder which, however, could be extracted more easily from the surrounding tissues compared to the lower parts of the device (Fig. 4a). There were no signs of inflammation on the surrounding intact endocardium (Fig. 4b) — except one pig which developed a pericarditis. Thrombotic attachments to the luminal device surface were in no case visible. The strength of the embedding in the non-PU layered waist region and downwards was very high as indicated by great amounts of collagen containing tissues crossing from the device interior through the nitinol mesh to the surrounding tissues (Fig. 4a, below left, blue arrow). The PU-covered shoulder region was also tightly embedded, but surrounding tissues were easily separated from the PU-layer with
Table 1 Result summary. Pig
% weight gain in 6 weeks
Device size, D1/D2 (mm)
Leak score Day 0a
Leak score week 6a
Device ingrowth
Other Autopsy findings
Complication
Comments
OCC-1
83
18/15
0
0
50–100%
Device loops visible on the epicardial side of the LAA.
No
OCC-2
79
21/18
2
0
10–50%
OCC-3
75
18/15
0
0
50–100%
Mild pericarditis
Yes (possibly device)
OCC-4
83
18/15 (24/21)
0 [1]
0
50–100%
Device loops penetrating LAA wall
No
A 30 mm orifice, therefore occluder was deeply implanted Small pericardial effusion during transseptal puncture, animal fully recovered without further complications. The cause of pericarditis not known. Device penetration could not be seen during autopsy Two occluders implanted due to double orifice (one in each lobe) 2nd occluder prone in to LA. Both Devices too deeply implanted/ oversized
OCC-5 OCC-6
74 73
21/18 24/21
0 0
0 0
50–100% 50–100%
No No
OCC-7
76
21/18
0
0
50–100%
No
OCC-8
83
21/18
1
0
10–50%
N
OCC-9
n/a
24/21
n/a
n/a
n/a
Yes (device)
OCC-10
71
21/18
0
0
50–100%
OCC-11
n/a
n/a
n/a
n/a
n/a
OCC-12
67
21/18
0
0
50–100%
a
Yes (procedure)
Device loops penetrating LAA wall
Device loops penetrating LAA wall
0 is no leak, 1 is trivial leak (b3 mm), 2 is small leak (3–5 mm) and 3 is significant leak (N5 mm).
No Yes (procedure) No
Loss of appetite and diarrhea at week 2, treated with antibiotics and recovered. Not device or procedure related Small leak that disappeared after tug test (self-modelizing device) Minor gap and compressed loops at implantation, no leak or compressed loops after 6 weeks Pig euthanized. Device embolization during release. Caused by pulling force while the pusher was released from the device. 3 attempts, loops facing the wrong direction each time. Tug test showed stable device Transseptal puncture and tamponade. No device implanted. Device too deeply implanted
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Fig. 3. LAA occluder devices explanted six weeks after implantation. a: Small device thickly encapsulated. b: Large device with a thin pseudo-intimal cover. Hub not encapsulated.
only few and thin tufts of connective tissue sticking to the PU-layer (Fig. 4a, upper left part, black arrows). No evidence of binding between the PU-layer and the nitinol mesh filled with masses of tissues was found after simply peeling off the PU-layer (Fig. 4a, upper right, blue asterisks). The interior of the implants with the exemption of device “OCC 003” was filled with masses of natively mostly white colored tissues (assumed to consist mainly of organized fibrin).
3.3. HE staining On every explant 10 localizations were examined to assess fibrin deposition, adherent platelets, polymorphonuclear granulocytes (PMN), monocytes/macrophages and foreign body giant cells (FBGC). There was no localization on any of the 10 explants where thrombocytes were found. This was equally true for PMN and also for FBGC. Table 2 displays the ratios of the thicknesses of the capsule and the PU-layer (PU). This analysis revealed that in 6 out of 10 animals the ratio of C/PU was smaller than 1 (mean value 0.53) six weeks after the implantation of the occluder system. In the other 4 animals this ratio increased drastically (up to 51-fold) which meant an increase of a factor 96.2. One of these 4 cases was characterized by a mild pericarditis, and another one by an impingement reaction. In both other cases muscle cells could be identified as constituents of the capsule which was also found in case “OCC-010” (impingement), but not in any of the other cases.
3.4. Immunohistology staining Verification of endothelial cells was deduced from the coincidence of the presence of cell nuclei (visualized by DAPI stain in blue, and of positive CD-31 stain in red). In general, the endothelial cells were verified at a primary magnification of 1:20 and a zoom factor 1. Of course, the size of the respective cells had to be appropriate. A certain and differing loss of brilliance of colors over the time of examination was due to bleaching because at least 4 ROI had to be found and focused on each sample. Endothelial cells were found on this occluder system in every case whereupon the numbers of endothelial cells varied considerably (Fig. 5). 4. Discussion Transcatheter LAA occlusion may be considered in non-valvular atrial fibrillation patients with a high stroke risk and contraindications for long-term oral anticoagulation [16]. The number of implantations of LAA occluders already started to grow markedly and is expected to rise further in the near future. At present, 2 different occluder systems are available, the Watchman® and the Amplatzer® Cardiac Plug device. However, both occluders are still having some limitations [17]. The Watchman® device is relatively long and therefore not suitable for patients with shallow LAA. Recapturing the device beyond the level of retention barbs is not recommended, because of the risk of damaging the barbs and this limits its repositioning ability [7]. On the other hand, there is a tendency for the lobe of the Amplatzer Cardiac Plug® to jump forward to the distal part of the LAA after deployment and thereby demanding extra skills from the implanting physicians [18].
Fig. 4. Explanted device after 6 weeks. a: Integration of the device with connective tissue. b: Unblemished endocardium in the vicinity of the device.
J.-W. Park et al. / International Journal of Cardiology 177 (2014) 957–963 Table 2 Ratio of the thicknesses of the capsule (C) resting on the blood facing device surface to the PU-layer (PU). Device
Thicknesses in arbitrary units of the capsule (C)/PU-layer (PU)
Ratio C/PU
OCC 004-1 OCC 008 OCC 003 OCC 010 OCC 007 OCC 006 OCC 002 OCC 005 OCC 004-2 OCC 001 OCC 012
4/7.7 24/43 22/2.3 53/9 37/64 52/130 21/30 19/46 118/43 153/3 46/5
0.52 0.56 9.60 5.90 0.58 0.40 0.70 0.41 2.70 51.00 9.20
Remarks
Pericarditis Impingement
2 devices Muscle cellsa Muscle cells
a Device “OCC 001” exhibited clearly more terminally differentiated muscle cells than device “OCC 012”.
Moreover, both devices need to be delivered via relatively large-sized sheaths (14 Fr. for Watchman and 9–13 Fr. for Amplatzer Cardiac Plug, respectively), which can be associated with more vascular complications and air-embolism. The short device used in this study consists of a self-expanding, self-modelizing, flexible nitinol mesh, which can be placed within 2 cm from LAA ostia. This study demonstrates the feasibility and safety of implanting this novel LAA occluder system (Occlutech® LAA occluder) in young healthy pigs. The device placement (implantation, repositioning and retrieval) and LAA closure were evaluated using TEE and fluoroscopy. The occluder could easily be deployed and showed a very good adjustment to the LAA resulting in a full closure of the LAA in 8 of 10 pigs immediately after implantation and in all pigs after 6 weeks of implantation (Fig. 6). One device embolization occurred during occluder deployment. Thereafter the device release technique was modified to avoid similar adverse events in the future. The small implants did not protrude into the atrial lumen and were completely encapsulated (Fig. 3a). Devices of bigger sizes were more or less prominent into the atrial lumen, always carrying a pseudo-intima, which was more or less thick and showed more or less white color (depending on the thickness of the pseudo-intima). A quantitative analysis of the ratio of the thicknesses of the capsule – resting on the blood facing device surface – to the PU-layer revealed that in 6 out of ten animals the ratio of C/PU was smaller than 1 (mean value 0.53) six weeks after implantation of the occluder system. In the other four animals this ratio increased drastically (up to 51-fold) which meant
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an increase of a factor 96.2. One of these 4 cases had a mild pericarditis, and another one by an impingement reaction. In both other cases muscle cells could be identified as constituents of the capsule. Some muscle cells were also found in the impingement case but not in any of the other cases. Whether this was associated with the implantation technique – a possible myocardial injury could be followed by migration and proliferation of muscle cell precursors – cannot be answered by this study. In some cases the hub (see Fig. 3b arrow) of the devices was not encapsulated. The non-covered waist (middle part of the device) and the expanded umbrella-like lower part of the device were always securely embedded in the LAA-tissue. There was also a tight embedding of the material-covered device shoulder which, however, could be extracted more easily from the surrounding tissues compared to the lower parts of the device. It was remarkable that the implantation depth differed considerably leading to differences in the prominence of the devices into the atrial lumen. The strength of the embedding in the non-PU layered waist region and downwards was very high as indicated by the strength needed to separate this part from surrounding tissue and by great amounts of collagen containing tissues crossing from the device interior through the nitinol mesh to the surrounding tissues (Fig. 4a, below left, blue arrow). Fluoroscopic comparison between the device shapes directly after implantation and after 6 weeks revealed that the loops were straightened pulling the device body into the LAA resulting in complete sealing of the LAA orifice. This is considered as a favorable late remodeling. The explantation revealed that loops had penetrated the LAA tissue in three pigs. However, no signs of bleeding, pericardial effusion, or other damage to the LAA wall could be detected and the pigs were in good condition with normal weight gain and no clinical symptoms. It was therefore considered clinically insignificant. The autopsy allowed concluding that the appearance of loops outside tissues was most probably induced during the explantation procedure. An immuno-histological examination demonstrated that all of the devices were more or less inhabited by endothelial cells, and in some areas a cobblestone like and almost confluent endothelial cell layer was found already. There might be a trend that thinner capsules could coincide with more endothelial cells. That endothelial cells were generally present on these devices is in clear contrast to the findings on the PLAATO system, where nearly no endothelial cells were found even 2.5 years after implantation [19]. There were no signs of inflammation on the device-surrounding endocardium (except one pig with impingement). Also device loops, penetrating the LAA wall – occurring in 3 pigs – did not show inflammation processes. Monocyte/macrophages were sometimes found in small
Fig. 5. View on PU-cover with overlaying pseudo-intimal capsule revealing. a: very low cellularity and only few endothelial cells (OCC006). b: high cellularity and a greater amount of endothelial cells, almost without fibrin.
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Fig. 6. Example of remodeling (pig OCC-002). Device was twisted at implantation (a) but had un-twisted and re-shaped during 6 week implantation (b).
numbers allowing us to conclude that around these implants inflammation did not develop further over the examination period. It can be judged from the absence of foreign body giant cells that no degradation products were released. Also, polymorpho-nuclear granulocytes were not found. Regarding the performance of the Occlutech® LAA occluder in this study in comparison with the performance of the other occluders in animal models, we found that the Occlutech® LAA occluder has achieved complete sealing of the LAA in all animals after 6 weeks. Animal studies for the PLAATO system revealed complete LAA occlusion, no evidence for thrombi on the implant surface, and complete healing 3 months after device implantation [20]. Bass et al. [21] showed that the Amplatzer® LAA occluder achieved complete occlusion of the LAA without thrombi in all animals. In a recent study, Kar et al. [22] showed in a canine model that, there are differences in conformation of LAA surrounding structures with variable healing response between Watchman® and Amplatzer® after LAA closure. Watchman® did not obstruct or impact the LAA adjacent structures, resulting in a favorable surface recovery. In comparison, the disk of Amplatzer® could potentially jeopardize LAA neighboring structures and leads to delayed healing. Moreover, At 28 days, complete neo-endocardial coverage of the Watchman® was observed; however, the Amplatzer® showed an incomplete covering on the disk surface especially at the lower edge and end-screw hub regions [22]. Compared to the two devices that are currently on the market (Amplatzer® and Watchman®), the Occlutech® device has rounded loops at its distal rim to fix the device at the landing zone in the LAA allowing an early reuptake/repositioning of the device, and even an exchange of the device when the device size is not appropriate. In contrast, the other devices have sharp hooks which risk in damaging the soft tissue of the LAA and which complicate retrieval of the device. Furthermore, the nitinol body of the new occluder is soft and has low radial force resulting in a better modeling and adaptation to the LAA wall with complete closure of the LAA. 4.1. Study limitations The number of pigs included in the study is very small, so that one must be cautious to generalize the results. This limitation is partly compensated by the prospective design of the study, the consecutive inclusion and the completion of the follow-up in all of the pigs. Moreover, the study was performed in young animals. In older patients with coronary artery disease and activated platelets the risk of thrombotic events might be higher. No thrombi – neither in vivo nor at the explanted devices – could be found. Obviously, thrombocytes could not adhere to these implant
surfaces due to the applied anticoagulation (heparin 5000 IU) in combination with antiplatelet therapy. Because of the design of the study, it was not possible to rule out completely that transiently, small, mobile device-related thrombi might have formed. It has to be considered, that LAAs in pigs differ from those in humans, as the anatomy is clearly more challenging, with a sharper angulation and more tapering shape compared to humans. In this study, most devices were oversized, therefore they were protruding into the LA, something one would not consider in humans. In 3 cases striated muscle cells or precursors, assumed to originate from the LAA wall, were found in the capsules. Whether this was associated with the implantation technique – a possible LAA wall injury could be followed by migration and proliferation of muscle cell precursors – cannot be answered by this study. 5. Conclusion The study device achieved complete closure of the LAA in all pigs, and remained in the LAA, with benign healing and no evidence of new thrombus or damage to surrounding structures. Moreover, the uncompromised survival of all implanted pigs demonstrates the feasibility and safety of the device. Funding of the study The study was funded by the Occlutech, Jena, Germany. Conflict of interest Dr. Park is a consultant for Occlutech, Jena, Germany. References [1] Falk RH. Atrial fibrillation. N Engl J Med 2001;344:1067–78. [2] Leung DY, Black IW, Cranney GB, Hopkins AP, Walsh WF. Prognostic implications of left atrial spontaneous echo contrast in nonvalvular atrial fibrillation. J Am Coll Cardiol 1994;24:755–62. [3] Manning WJ, Silverman DI, Keighley CS, Oettgen P, Douglas PS. Transesophageal echocardiographically facilitated early cardioversion from atrial fibrillation using short-term anticoagulation: final results of a prospective 4.5-year study. J Am Coll Cardiol 1995;25:1354–61. [4] Blackshear JL, Odell JA. Appendage obliteration to reduce stroke in cardiac surgical patients with atrial fibrillation. Ann Thorac Surg 1996;61:755–9. [5] Forslund T, Wettermark B, Wandell P, von Euler M, Hasselstrom J, Hjemdahl P. Risk scoring and thromboprophylactic treatment of patients with atrial fibrillation with and without access to primary healthcare data: experience from the Stockholm health care system. Int J Cardiol 2013;170:208–14. [6] Guo Y, Wang H, Zhao X, Zhang Y, Zhang D, Ma J, et al. Sequential changes in renal function and the risk of stroke and death in patients with atrial fibrillation. Int J Cardiol 2013;168:4678–84.
J.-W. Park et al. / International Journal of Cardiology 177 (2014) 957–963 [7] Lam YY, Ma TK, Yan BP. Alternatives to chronic warfarin therapy for the prevention of stroke in patients with atrial fibrillation. Int J Cardiol 2011;150:4–11. [8] American College of C, American Heart Association Task Force on Practice G, Society of Cardiovascular A, Bonow RO, Carabello BA, Chatterjee K, de Leon Jr AC, Faxon DP, et al. ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing Committee to Revise the 1998 guidelines for the management of patients with valvular heart disease) developed in collaboration with the Society of Cardiovascular Anesthesiologists endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons. J Am Coll Cardiol 2006;48:e1-148. [9] Healey JS, Crystal E, Lamy A, Teoh K, Semelhago L, Hohnloser SH, et al. Left Atrial Appendage Occlusion Study (LAAOS): results of a randomized controlled pilot study of left atrial appendage occlusion during coronary bypass surgery in patients at risk for stroke. Am Heart J 2005;150:288–93. [10] Johnson WD, Ganjoo AK, Stone CD, Srivyas RC, Howard M. The left atrial appendage: our most lethal human attachment! Surgical implications. Eur J Cardiothorac Surg 2000;17:718–22. [11] Holmes DR, Reddy VY, Turi ZG, Doshi SK, Sievert H, Buchbinder M, et al. Percutaneous closure of the left atrial appendage versus warfarin therapy for prevention of stroke in patients with atrial fibrillation: a randomised non-inferiority trial. Lancet 2009;374:534–42. [12] Ostermayer SH, Reisman M, Kramer PH, Matthews RV, Gray WA, Block PC, et al. Percutaneous left atrial appendage transcatheter occlusion (PLAATO system) to prevent stroke in high-risk patients with non-rheumatic atrial fibrillation: results from the international multi-center feasibility trials. J Am Coll Cardiol 2005;46:9–14. [13] Reddy VY, Mobius-Winkler S, Miller MA, Neuzil P, Schuler G, Wiebe J, et al. Left atrial appendage closure with the Watchman device in patients with a contraindication for oral anticoagulation: the ASAP study (Asa Plavix feasibility Study With Watchman Left Atrial Appendage Closure Technology). J Am Coll Cardiol 2013;61:2551–6.
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[14] Park JW, Bethencourt A, Sievert H, Santoro G, Meier B, Walsh K, et al. Left atrial appendage closure with Amplatzer cardiac plug in atrial fibrillation: initial European experience. Catheter Cardiovasc Interv 2011;77:700–6. [15] Viles-Gonzalez JF, Kar S, Douglas P, Dukkipati S, Feldman T, Horton R, et al. The clinical impact of incomplete left atrial appendage closure with the Watchman Device in patients with atrial fibrillation: a PROTECT AF (Percutaneous Closure of the Left Atrial Appendage Versus Warfarin Therapy for Prevention of Stroke in Patients With Atrial Fibrillation) substudy. J Am Coll Cardiol 2012;59:923–9. [16] Camm AJ, Lip GY, De Caterina R, Savelieva I, Atar D, Hohnloser SH, et al. Guidelines ESCCfP. 2012 focused update of the ESC guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association. Eur Heart J 2012;33:2719–47. [17] Cruz-Gonzalez I, Yan BP, Lam YY. Left atrial appendage exclusion: state-of-the-art. Catheter Cardiovasc Interv 2010;75:806–13. [18] Cruz-Gonzalez I, Cubeddu RJ, Sanchez-Ledesma M, Cury RC, Coggins M, Maree AO, et al. Left atrial appendage exclusion using an Amplatzer device. Int J Cardiol 2009;134:e1–3. [19] Park JW, Gerk U, Franke RP, Jung F. Post-mortem analysis of a left atrial appendage occlusion device (PLAATO) in a patient with permanent atrial fibrillation. Cardiology 2009;112:205–8. [20] Nakai T, Lesh MD, Gerstenfeld EP, Virmani R, Jones R, Lee RJ. Percutaneous left atrial appendage occlusion (PLAATO) for preventing cardioembolism: first experience in canine model. Circulation 2002;105:2217–22. [21] Bass JL. Transcatheter occlusion of the left atrial appendage—experimental testing of a new Amplatzer device. Catheter Cardiovasc Interv 2010;76:181–5. [22] Kar S, Hou D, Jones R, Werner D, Swanson L, Tischler B, et al. Impact of Watchman and Amplatzer devices on left atrial appendage adjacent structures and healing response in a canine model. JACC Cardiovasc Interv 2014;7:801–9.