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J Thorac Cardiovasc Surg 2006;132:340-346
© 2006 The American Association for Thoracic Surgery
Evolving Technology |
, MD
b
a Department of Biomedical Engineering, Lerner Research Institute, the Cleveland Clinic, Cleveland, Ohio
b Department of Cardiology, the Cleveland Clinic, Cleveland, Ohio
c Department of Thoracic and Cardiovascular Surgery, the Cleveland Clinic, Cleveland, Ohio
Received for publication March 13, 2006; revisions received April 13, 2006; accepted for publication April 18, 2006. * Address for reprints: Kiyotaka Fukamachi, MD, PhD, Department of Biomedical Engineering/ND20, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195 (Email: fukamak{at}ccf.org).
| Abstract |
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METHODS: Ten mongrel dogs (mean weight 28.9 ± 4.6 kg) were used in this study. The atrial exclusion device, constructed from two parallel and rigid titanium tubes and two nitinol springs with a knit-braided polyester fabric, was implanted at the base of the left atrial appendage through a left thoracotomy on a beating heart using a specially designed delivery tool. Dogs were evaluated at 30 days (n = 4) and 90 days (n = 6) by epicardial echocardiography, left atrial and coronary angiography, gross pathology, and histologic inspection.
RESULTS: Device implantation was performed without complications in all dogs. Complete left atrial appendage exclusion without device migration or hemodynamic instability was confirmed, and there was no damage to the left circumflex artery or pulmonary artery. Macroscopic and microscopic assessments revealed favorable biocompatibility during midterm follow-up.
CONCLUSION: The atrial exclusion device enabled rapid, reliable, and safe exclusion of the left atrial appendage. Clinical application may provide a new therapeutic option for reducing the risk of stroke in patients with atrial fibrillation.
| Introduction |
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A novel device, the atrial exclusion device (AED), has been developed for epicardial LAA exclusion on a beating heart. In a previous study,
11
the first-generation AED (first AED) was evaluated, and the validity of the AED concept was confirmed. Subsequently, a second-generation AED was developed with design modifications optimized to ensure uniform compression and occlusion of the anatomically variable human LAA. The purpose of this preclinical study was to determine the safety and effectiveness of the second-generation AED (second AED).
| Material and Methods |
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Animal Study
A total of 10 mongrel dogs, weighing 28.9 ± 4.6 kg, were used in this study. This study was approved by the Cleveland Clinic's Institutional Animal Care and Use Committee, and all animals received humane care in compliance with the "Guide for the Care and Use of Laboratory Animals" prepared by the Institute of Laboratory Animal Resources, National Research Council, and published by the National Academy Press, revised 1996.
Implant and explant studies
The surgical procedures in the implant and explant studies were similar to the previously reported series of animal study with the exception of the device implant technique.11 In brief, the dogs were placed in the right lateral position with electrocardiogram leads attached under general anesthesia. The left carotid artery was cannulated for continuous monitoring of systemic arterial pressure. After a thoracotomy in the left fourth intercostal space, the pericardium was opened to expose the LAA. A 14-gauge angiocatheter was inserted into the left pulmonary vein to monitor the LA pressure and perform LA angiography. A 35-mm AED was chosen for implantation in 8 animals because of the LAA orifice size in those dogs. In the remaining 2 dogs, an oversized device, a 50-mm AED, was intentionally used to assess the impact of implanting an oversized device. The AED was placed over the end of the LAA and aligned with the base of the LAA using the delivery tool (Figure 2, A). Once in the desired position, the AED was released by gently closing the delivery tool.
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On the day of the explant study, the pericardium was reopened to expose the implanted AED. Hemodynamic assessment, LA angiography, 2DEE, and Doppler echocardiography were performed in the same manner as at the implant study. Furthermore, in all 90-day dogs, left coronary angiography was conducted to evaluate LCX blood flow in the left anterior oblique 60° and right anterior oblique 30° planes.
To evaluate electrical isolation between the LAA (distal to the AED) and LA body (proximal to the AED), we applied electrical stimulation to two different locations at a pacing rate greater than the native rate during sinus rhythm in three 30-day and four 90-day dogs. Standard epicardial pacing wires were placed on the LA body and LAA remnant. LA body pacing was performed in asynchronous mode to confirm that the heart could be paced. Electrical stimulation at a maximum current of 20 mA was applied to the LAA in the same manner as during LA body pacing. When the LAA pacing was not accomplished at 20 mA, it was determined that the distal LAA was completely electrically isolated. However, when LAA pacing was accomplished at 20 mA, the pacing threshold of the LAA was measured with a stepwise decrease of the pacing current. If the LA body pacing could be established at less than half of the LAA pacing threshold, it was concluded that the LAA was partially electrically isolated.
Gross necropsy and histologic evaluation
After full heparinization, the dogs were humanely killed by rapid intravenous injection of sodium pentobarbital and potassium chloride. The heart was examined to confirm LAA exclusion and to determine tissue response to the polyester fabrics for gross biocompatibility evaluation.
Tissue specimens of the cross section of the entire LAA, including the polyester fabric and a small part of the LA body (adjacent to the orifice of the LAA), were excised and evaluated. The tissues were fixed in 10% formalin for 48 hours and embedded in paraffin. Sections were cut from each block at 4 µm and collected onto glass slides. All sections were then dried for 60 minutes at 60°C and stained with hematoxylin and eosin.
Data Analysis
All values were expressed as mean ± standard deviation. Repeated-measures analysis of variance was used to assess the differences between data at baseline, pre-implantation, and follow-up.
| Results |
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Explantation
At explantation, the AED remained positioned at the base of the LAA with no evidence of migration. Structures adjacent to the device, such as the LA body, LCX, and PA, were intact without erosion. The LAA in the 30-day dogs was moderately atrophied. All 6 of the 90-day dogs had dense adhesions surrounding the AED with marked atrophy of the LAA. With respect to the 2 dogs with a 50-mm device, there were no adverse effects on the main PA; we observed neither PA erosion nor compression. Before explantation, Doppler echocardiography and LA angiography confirmed lack of communication between the LAA and LA in all dogs. In addition, coronary angiography in all 90-day dogs demonstrated normal LCX anatomy with no apparent obstruction to blood flow (Figure 3,
A and B). Hemodynamic data are summarized in Table 1. There were no statistical changes in hemodynamics throughout the studies. With respect to the LA size, no difference in the LA area (measured in all animals) or LA volume (measured in 6 animals due to unsatisfactory image resolution) was found, which may indicate no device migration. In addition, there were no significant differences in the 2DEE parameters such as EDV, ESV, stroke volume, and ejection fraction. In the three 30-day and four 90-day dogs that were subjected to pacing assessment, either total (n = 4) or partial (n = 3) electrical isolation of the LAA remnant was confirmed.
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| Discussion |
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AF is epidemiologically the most common cardiac arrhythmia, and its prevalence increases in both genders after 40 years and rises rapidly after 65 years.
1,12
Although recent randomized trials have demonstrated that anticoagulation can greatly reduce the stroke rate in patients with AF,
13,14
many physicians remain reluctant to prescribe anticoagulant therapy for elderly AF patients because of an increased risk of anticoagulant-related complications with age, the difficulty of warfarin management, and personal preference.
4,5,15
A potential alternative or adjunctive approach to stroke prevention in AF patients is surgical exclusion of the LAA. Various techniques for LAA exclusion either from the exterior of the heart or from inside the LA during cardiac surgery have been introduced; however, several potential disadvantages such as bleeding and late recanalization exist.
16-19
Although an epicardial approach to LAA exclusion has the potential advantages of simplicity (no transseptal puncture) and low procedural risk of embolism (no left heart endocardial catheters), there is currently no instrumentation available to facilitate rapid, reliable, and safe epicardial exclusion of the LAA.
This novel device, the AED, has application for epicardial LAA exclusion. The benefit of this type of occlusion device is the simplicity of device application on a beating heart. In our previous preclinical study, we confirmed LAA exclusion in a canine model, validating the AED concept.
11
However, we had concluded that refinement of device design would provide improved clinical application. Because there are many anatomic patterns of the LAA (ie, shape, size, and thickness) in humans, a distributed clamping pressure distribution across the width of the device was required so that the device adapts to accommodate the variability of LAA anatomy. Therefore, a design modification of the first AED was made without eliminating the advantages of the AED (namely, the easy device application and reapplication and favorable biocompatibility) resulting in the development of a self-compensating force distribution concept, the second AED. In addition, since a self-compensating force distribution requires physical force to be opened for application, a specially designed delivery tool was also developed to precisely position and apply the second AED on the LAA. This delivery tool permits easy device repositioning and reapplication if initial placement is unsatisfactory.
Thrombus formation on a cul-de-sac or occlusion line formed by the device application at the origin of the LAA is considered one of the most potential and important complications in the chronic phase. In this study, the AED was easily and precisely placed at the base of the LAA, and the resulting occlusion line was smooth and linear without any endocardial furrow or cul-de-sac formation (Figure 5, A). In addition, histologic examination revealed that the endocardial surface of the occlusion site was covered with endothelium-like cells without producing irregularity on the endocardial surface. These findings suggest that the thrombus formation on the occlusion line may be unlikely to occur even in patients with AF. LA and coronary angiography and echocardiography confirmed complete exclusion of the LAA at 30 and 90 days without device migration or damage to the PA, LCX, or other adjacent cardiac structures. As illustrated in Figure 2, B, the cranial end of the second AED was located underneath the main PA without compressing the PA; this lack of compression is attributed to the unique configuration of the 90° nitinol springs at either end of the titanium tubes. The design and physical characteristics of the AED and tissue ingrowth around the polyester covering prevented device migration and damage to adjacent cardiac structures.
Compared with epicardial stapling devices,
18,19
the AED offers two advantages: (1) easy reapplication and (2) elimination of the risk of bleeding that may occur along or beneath the staple line. Other occlusion devices currently available, such as a surgical stapler or clip applier, permanently deform the occlusion apparatus, thereby delivering a permanent implant. The promotion of distal LAA atrophy by the AED may eliminate the possibility of late recanalization of the LAA lumen, one of the potential problems of noncutting stapling devices.
16,17
Although not assessed specifically in this study, the specially designed delivery tool may enable a minimally invasive thoracoscopic approach for LAA exclusion in lone AF patients, providing a possible therapy for stroke prevention. In addition, several reports have indicated that the LAA may be one source of thrombus in patients in sinus rhythm with congestive heart failure.
20,21
The AED and its delivery tool may be beneficial for these high-risk patients in sinus rhythm to prevent embolic events resulting from LAA thrombi. However, it is likely that in patients with LAA thrombi that extend to the orifice of the LAA, epicardial approaches should be avoided.
There are limitations to this preclinical study. The study series was small (n = 10), and the follow-up duration was only a maximum of 90 days. In addition, the application of a normal canine model in this study provided us with idealized implant situations (ie, narrow LAA base, absence of increased LA wall tension or pressure resulting from LA enlargement, absence of LAA fragility caused by advanced age, malnutrition, or other etiology). It is possible that there may be device failures and/or complications of deployment with longer follow-up or with application in patients who do not have tissues as resilient as those of a healthy dog. Furthermore, the possibility of LA thrombus formation after AED application in an AF setting cannot be excluded in this study. Although a very smooth and linear endocardial surface of the occlusion line was found with no cul-de-sac formation in this study, this finding does not alone indicate that the AED can completely eliminate the risk of thrombus formation on the occlusion line in the long-term phase. Therefore, future evaluations using an AF animal model may be required to confirm the long-term stability, durability, and biocompatibility of the device as well as the existence of thrombus formation.
Although LAA exclusion may cause potential adverse effects because of reduced production of serum natriuretic peptide,
22,23
we did not analyze biochemistry levels such as serum natriuretic peptide, troponin, and creatine kinase. In this series, however, no clinical signs of heart failure (general fatigue or significant changes in the weights and heart rates of dogs) were observed. In preparation for clinical AED application, further study will also be required to understand the neurohumoral effects of LAA exclusion.
| Conclusions |
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| Footnotes |
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| References |
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