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29 Treatment of Cardiac Septal Defects

The Evolution of the Amplatzer ® Family of Devices

JOHN L. BASS, MD

C O N T E N T S

ATRIAL SEPTAL DEFECT

THE AMPLATZER ® FAMILY OF DEVICES SAFETY

PATENT DUCTUS ARTERIOSUS AND MUSCULAR VENTRICULAR SEPTAL DEFECT ECCENTRIC DEVICE DESIGN

DEVICES WITHOUT FABRIC SUMMARY

REFERENCES

1. ATRIAL SEPTAL DEFECT 1.1. History

Atrial septal defects are congenital deficiencies in the wall separating systemic and pulmonary venous returns as they enter the heart. This allows blood from the lungs to flow through the defect and increase the volume of blood passing through the pulmonary arteries. In individuals in their 20s, living with such a defect can eventually cause permanent damage to the pulmonary vasculature. To prevent this and other problems associated with these malformations (i.e., cardiac arrhythmias), closure of atrial septal defects is recommended during the first few years of life (1).

The first successful surgical closure of an atrial septal defect was performed on a patient at the University of Minnesota Hospital in 1952 (2). Such an operative approach for correction of a congenital intracardiac defect is considered one of the safest open heart operations performed today, with a mortality rate under 0.5% (3). Nevertheless, such surgical closures are not without potential complications, including: (1) morbidity from the required sternotomy or right thoracotomy, (2) the chance of exposure to blood products, (3) utilization of a chest tube, (4) a 3- to 5-d hospitalization, (5) 4-6 weeks of convales- cence, and (6) the possibility of postpericardiotomy syndrome.

The opportunity to minimize or eliminate such problems has spurred attempts to develop a method of transcatheter closure.

From: Handbook of Cardiac Anatomy, Physiology, and Devices Edited by: P. A. Iaizzo © Humana Press Inc., Totowa, NJ

Specifically, it is generally considered that secundum atrial septal defects are ideal for transcatheter closure. These defects are typically surrounded by rims of tissue that a device could clasp; they do not have borders formed by valves or the walls of the heart. King and Mills reported the first attempted transcatheter closure of a secundum atrial septal defect in 1976 (4). This was followed by development of the Clamshell/

CardioSEAL (5), Sideris Button (6), ASDOS (7), and Angel Wings (8) devices (Table 1). These developments were clinically exciting for they provided an alternative to surgical closure.

Initially, their use also presented a number of challenges, including: (1) large devices were required with the central post design; (2) these devices were not self-centering; (3) their center posts could move within the defect; and (4) each device required large delivery systems. Furthermore, in some cases, their use was plagued by embolization (e.g., unbuttoning) (9). Unfortu- nately, frame fatigue and arm fracture occurred in up to 10% of some early designs, with asymptomatic wire embolization in some patients. In general, each of these designs was considered difficult to use clinically, or it was often impossible to recap- ture or retrieve after deployment. It was reported that surgical removal was required if they were deployed in an improper position, and residual shunt rates were significant (10).

1.2. Device Design

The ideal septal occluder device would have the following features: (1) easy delivery and implantation; (2) ability to self-

413

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414 PART IV: DEVICES AND THERAPIES/BASS

Table 1

History of Transcatheter Closure of Atrial Septal Defects

Device Year

King and Mills 1974

Rashkind 1987

Clamshell a 1989

Sideris Button 1990

ASDOS 1991

Angel Wings 1993

CardioSEAL a 1996

Amplatzer ® 1998

STARFlex a 1999

Helex 1999

Clamshell, CardioSEAL, and STARflex devices represent progres-sive modifications of a design.

Table 2

Frequent Complications in Phase II FDA Trial of Amplatzer Septal Occluder Major complications Minor complications

• Pericardial effusion with tamponade

• Repeat surgery

• Cardiac arrhythmias requir- ing permanent pacemaker placement or long-term antiarrhythmic medication

• Device embolizations requir- ing immediate surgical removal

• Device embolization with percutaneous retrieval

• Cardiac arrhythmia with treatment

• Pericardial effusion requir- ing medical management

• Surgical wound complications

center; (3) ability to pass easily through a small delivery system; (4) recapturability and redeployability; (5) high resiliency without fracturing; and (6) high effectiveness in avoiding significant residual shunts. Furthermore, the materials it is constructed from should be biocompatible and nontoxic. Nev- ertheless, durability is important when the majority of patients are children, and there is a long "lifetime" after implantation.

All Amplatzel ~ atrial septal defect devices have been designed to fulfill the aforementioned requirements. For example, the Amplatzer Septal Occluder is a woven mesh of 72 Nitinol (see Section 3) wires 0.003- to 0.008-in diameter with shape memory. There are two retention disks with a central waist that sits within the defect (Fig. 1); the left atrial disk is 12-14 m m larger than the waist. The stenting action of the waist and the clasping of the atrial septum by the retention disks hold it in place. Fabric baffles, sewn inside the disks and waist, promote thrombosis and occlusion of the defect. The delivery system is relatively small (6- to 12-French delivery sheaths). Further, the device is recapturable and redeployable with a microscrew/

cable attachment. To date, available waist diameters range from 4 to 40 mm, allowing closure of even large defects (11).

As with all implantable devices, animal trials have been performed and have demonstrated the effectiveness of the Amplatzer Septal Occluder approach. In one trial, dilating the foramen ovale in dogs created an atrial septal defect, and a 10-

m m device was placed; there was complete occlusion with no residual shunt. Furthermore, the devices were completely covered by a neoendothelium at sacrifice 3 mo after implantation, and no thrombus formed on the device (12). Subsequent patient trials confirmed that no retroaortic rim was required for stable device position and complete closure. Importantly, and even amazingly, patients could be discharged the morning after device placement and remained on low-dose aspirin and endocarditis prophylaxis for 6 mo after closure.

1.3. Food and Drug Administration Testing

A Food and Drug Administration (FDA) clinical trial to determine the effectiveness of the Amplatzer Septal Occluder technology was begun based on the success of animal studies and European trials in humans. Nevertheless, the optimal study design was difficult to determine. Many patients and their families wanted to avoid any such surgery despite the long history of safe surgical closure; in addition, they were concerned about the lack of long-term follow-up of this new device. Thus, randomization was extremely difficult and unsuccessful because many patients and families originally chosen for the surgical group simply opted out of the trial, preferring to wait for final FDA approval. Subsequently, the study design was changed to allow device closure at some institutions with patients recruited

t o designated surgical centers. Hence, we are left with a trial without true randomization; this illustrates how difficult it is to employ such a study design in the real world.

Importantly, the results of phase II of this FDA trial have shown that an Amplatzer Septal Occluder is more effective and safe compared with the surgical group. At the end of 12 mo, there was complete closure, or a <2-mm residual shunt, in 98.5% of device patients compared to 100% of surgically closed patients. Major and minor complications most fre- quently observed in either group are listed in Table 2; there was no difference between groups in the incidence of major complications. Minor complications were more common in surgical patients (27/442, 6.1% in the Amplatzer group vs 29/

154, 18.8% in the surgery group).

However, recall that these patients were not randomized;

there were differences between groups, with the surgical patients younger (18.1 _+ 19.3 yr in the Amplatzer group vs 5.9 +- 6.2 yr in the surgery group, p < 0.001) and smaller (42.3 _+

27.3 kg in the Amplatzer group vs 20.6 _+ 15.2 kg in the surgery group, p < 0.001) (11). Nevertheless, based on this positive outcome, the FDA granted premarket approval of the Amplatzer Septal Occluders in December 2001, and to date it remains the only atrial septal defect closure device with FDA approval.

2. THE A M P L A T Z E R ® F A M I L Y OF DEVICES

Amplatzer devices are designed for occlusion of abnormal congenital cardiovascular communications. The devices are based on the model of a self-expanding stent with the ends of the wires bound together forming a closed frame. The shape of the wire frame is tailored to fit the abnormal vascular or intracardiac communication. Retention disks fix the device against vascular or cardiac walls. A central waist further holds the device in place with radial force against the margins of the communication. This provides stable fixation of the device.

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CHAPTER 29 ! CARDIAC SEPTAL DEFECTS 415

Fig. 1. Amplatzer Septal Occluder device. (A) Right atrial anglogram performed after deployment of the device in a secundum atrial septal defect, but before release. The right atrial disk is obscured by contrast with the waist within the atrial septal defect. (B) Levophase of the right atrial angiogram opacifying the left atrium. Contrast outlines the left atrial disk completely within the left atrium.

Initially, occlusion occurs through thrombosis within the polyester baffles or the stuffing sutured inside the wire frame. Furthermore, over 3 mo, the device is covered with a protein and cellular layer, reducing the potential for forming a surface thrombus and eliminating the risk of bacterial endocarditis (12).

The development of Amplatzer devices began when thin- wire technology reached a developmental point that allowed the construction of a frame of nontoxic Nitinol wires. Like all stents, the collapsed device is long and narrow to fit through the delivery sheath. It is important to note that Nitinol metal has shape memory. Thus, as it exits the sheath, the device expands and assumes its original shape at body temperature. Each current device also has a microscrew fixed to the proximal end that allows attachment to a delivery cable. This then enables the device to reconnect with the cable after deployment to allow it to be either removed or repositioned. The device is detached by unscrewing once secure, and the effective position is confirmed (e.g., by fluoroscopy).

3 . S A F E T Y

Nickel-containing alloys, such as stainless steel, have been used in human medicine for over 100 yr. Uses include surgical instruments as well as implants such as pacemaker wires, vascular clips, mechanical cardiac valves, orthopedic prostheses, Harrington rods, and inferior vena caval filters. These successful applications have demonstrated the lack of toxicity of nickel-containing metallic implants; no systemic effects were observed or reported. However, a local fibrotic reaction surrounding stainless steel implants was thought to be caused by local passivation of nickel ions into surrounding tissue despite the absence of microscopically visible corrosion. Subsequently,

the US Navy developed a new nickel-containing metal, Niti- nol, in the 1960s that is an alloy of nickel and titanium and displays superior corrosion resistance. This alloy still carries the name of its heritage: Nickel Titanium-Naval Ordnance Laboratory (Nitinol).

Nitinol has numerous other physical properties besides corrosion resistance that make it attractive to use in biomedical devices, such as superelasticity (pseudoelasticity), thermal shape memory, high resiliency, and fatigue resistance. Origi- nally, thin-wire technology, the development of the "diamond- drawn" wire, provided a shape that could be used in endodontal appliances. The tendency for Nitinol to return to its nominal shape when it is deformed was especially useful in this application. This property has also made Nitinol a valuable material in the production of endoluminal devices; a Nitinol device stretched for introduction through a small delivery catheter would expand to its original shape when deployed. This new alloy has replaced many stainless steel devices, especially self- expanding stents. Fatigue resistance prevents wire fractures and makes Nitinol devices very durable. Its lack of ferromagnetic properties allows magnetic resonance imaging of implanted devices.

To date, Amplatzer devices have proven nontoxic (13). Fur- ther, devices that have been immersed in a saline bath while fatigue tested did not corrode. In addition, devices examined after 18 mo of implantation in humans and animals did not reveal surface corrosion. Importantly, nickel levels in patients before and after insertion of an Amplatzer device did not increase. The incidence of nickel allergy is estimated to be around 10% in humans. Nevertheless, with over 60,000 current implants of Amplatzer devices worldwide over the past 8 yr, no case of a reaction has been detected.

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416 PART IV: DEVICES AND THERAPIES/BASS

A

Fig. 2. Amplatzer Ductal Occluder Device. (A) Photograph of the device with clearly visible suturing of the baffle and stuffing to the ductal plug. (B) Aortogram immediately after device placement. The aortic disk is flat against the aortic wall with the plug within the ductal lumen.

There is no flow through the ductus and no obstruction of the aorta or left pulmonary artery.

Thermal shape memory provides great flexibility to devices constructed of Nitinol. The nominal shape is determined by heating a formed wire frame. When cooled, the device retains the memory of its configuration.

4. PATENT DUCTUS

ARTERIOSUS A N D MUSCULAR VENTRICULAR SEPTAL DEFECT

Patent ductus arteriosus and muscular ventricular septal defects are similar communications to secundum atrial defects in that they are surrounded by normal vessel or muscular ventricular septum. More recent concentric devices, modified from the design of the Amplatzer Septal Occluder device, have now provided the clinical opportunity for transcatheter closure in patients with such defects.

Patent ductus arteriosus is a failure of closure of a vascular channel present before birth; it normally closes in the first 2 d of life. Overcirculation of the lungs results when this vessel remains open, and this can cause damage to the pulmonary vasculature, overwork the heart, or predispose the patient to bacterial endocarditis. Closure is primarily recommended to reduce the workload of the heart, specifically when spontane- ous closure is considered no longer likely (beyond 1-2 yr of age) (14). Like operative closure of a secundum atrial septal defect, surgical closure of a patent ductus arteriosus is a low- risk procedure that has been performed for decades (15).

Transcatheter closure of such defects is considered to carry a risk at least as low as the major invasive approach.

Successful transcatheter closure of a small patent ductus arteriosus was performed before the design of successful com- mercially available devices. Specifically, a coil occlusion of a patent ductus arteriosus was first performed at the University of

Minnesota in 1972. Filling the aortic ampulla with stainless steel coils and their attached Dacron fibers or "hanging" a coil across the narrowest part of a patent ductus arteriosus produced reliable closure. However, the first embolization coils were not attached to a delivery wire, and the coil sometimes embolized into the pulmonary circulation. This technique was most effective when the narrowest diameter of the patent ductus was <3 mm (16). At that time, a retrievable device that would occlude larger ductus was considered highly desirable.

The Amplatzer Ductal Occluder is shaped and plug sized to the aortic ampulla, with an aortic retention disk designed to prevent embolization through the ductus (Fig. 2). The device is delivered by the venous route; delivery catheters can be small (5-8 French) because of the small collapsed device diameter. This simple modification of a self-expanding stent was extremely successful in producing complete occlusion of even a large patent ductus arteriosus. In the phase II FDA trial, there was over 97% complete closure at 6 and 12 mo. Further- more, there was only a 2.3% incidence of serious and major adverse events (including one embolization that required surgical removal and one death of a child, not device related, with a chromosomal trisomy) (17). Premarket FDA approval of the Amplatzer Ductal Occluder device was granted in January 2003.

Muscular ventricular septal defects typically occur in the lower, thicker ventricular septum. Procedural closure is recommended for the same indications as both atrial septal defects and patent ductus arteriosus, that is, eliminating overwork of the heart and overcirculation to the lungs. However, unlike the other two defects, it is generally considered that surgery to close muscular ventricular septal defects is not a nontrivial or low- risk option.

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CHAPTER 29 / CARDIAC SEPTAL DEFECTS 417 I

A B

Fig. 3. Amplatzer Muscular Ventricular Septal Occluder. (A) Photograph of the device; the waist is wider than that of the Amplatzer Septal Occluder to allow for the thicker muscular ventricular septum. (B) Left ventricular angiogram 3 mo after device placement showing complete occlusion of a midmuscular ventricular septal defect.

Surgical closure of muscular ventricular septal defects is often difficult because the right ventricular aspect of the defect can be hidden from the surgeon' s eyes by trabeculations within the right ventricular cavity. This results in a high incidence of residual leaks with a right ventricular approach. Directly incis- ing the left ventricle allows clearer visualization of the defect margins, but left ventricular aneurysms or diminished left ventricular function sometimes result (18). The potential for such complications has made transcatheter closure an attractive alternative.

The Amplatzer Muscular Ventricular Septal Occluder is very similar to the Amplatzer Septal Occluder. Fortunately, like a secundum atrial septal defect, muscular ventricular septal defects are separated from cardiac valves by myocardium.

Yet, the obvious difference between the two malformations is the thickness of the ventricular myocardium. Hence, these devices were designed with a greater distance between the disks to accommodate such differences in myocardial thicknesses (Fig. 3). In addition, greater stability can be produced by radial force applied against the thicker muscular ventricular septum, and thus the retention disk diameters were decreased to 6-8 mm larger than the waist.

Attempts at transcatheter closure of muscular ventricular septal defects using the Clamshell/CardioSEAL device were reported to produce a 40% incidence of residual leaks (19). It should be noted that these devices have a central post instead of a waist that is the size of the defect. Thus, the "retention" disks designed had to be at least twice the diameter of the defect;

residual leaks likely result from migration of the central post within the defect. In contrast, the self-centering Amplatzer Muscular Ventricular Septal Occluder is fixed within the defect by its waist. Another advantage of the Amplatzer device is the

smaller maximum device diameter required to close a muscular ventricular septal defect compared with central post devices.

Successful animal trials to close surgically created muscular ventricular septal defects have supported application for human use (20). To date, the Amplatzer Muscular Ventricular Septal Occluder has been deployed in eight patients at the University of Minnesota; it should be noted that three devices were implanted in the operating room directly through the right ventricular wall without cardiopulmonary bypass. Com- plete defect closure was detected in all eight study subjects, and there were no serious or major adverse events. FDA trials are in progress. This device should significantly improve the care of children who need closure of a muscular ventricular septal defect.

5. ECCENTRIC DEVICE DESIGN

Amplatzer devices designed for closing secundum atrial septal defects, patent ductus arteriosus, and muscular ventricular septal defects are concentrically symmetrical because there are no valves near the edges of the defects they are designed to close. It is noteworthy that perimembranous ventricular septal defects are different in an important way: the aortic and tricuspid valves are close to the defect margins. Previous attempts to close perimembranous ventricular septal defects with the Clamshell and Sideris button devices have been less than optimal. For example, distortion of the aortic valve resulted in aortic insufficiency, and in some cases, the devices embolized (21).

With these challenges in mind, it was considered that the flexibility of shaping the Amplatzer device frame could produce an eccentric, asymmetric device. Subsequently, an Amplatzer Perimembranous Ventricular Septal Occluder (Fig. 4) was designed with a minimal rim of the left ventricular

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418 PART IV: DEVICES AND THERAPIES / BASS

,a,

I:I

Fig. 4. Amplatzer Perimembranous Ventricular Septal Occluder device. (A) Photograph of the perimembranous device showing the delivery cable attached to the right ventricular disk. The asymmetric left ventricular disk is positioned with the minimal rim of the subaortic portion at the top of the device, thus preventing interfer- ence with the aortic valve. (B) Left ventriculogram after device placement. The asymmetric left ventricular disk avoids distortion of the aortic valve. There is no flow through the device immediately after deployment.

disk (0.5 mm) to sit beneath the aortic valve, whereas a longer (5.5 mm) inferior left ventricular disk with a short waist (1.5 mm) was designed to keep the right ventricular disk away from the tricuspid valve. Recent animal trials have shown that an eccentric design protected the aortic and tricuspid valves, but at the same time allowed closure of perimembranous ventricular septal defects.

It is noteworthy that an initial difficulty in deploying these eccentric devices was in the reliability of delivering the device in the proper (optimal) orientation. For example, advancing a pigtail catheter from the pulmonary artery through a patent ductus often resulted in the curl of the catheter oriented along the lesser curvature of the aorta. Subsequently, a sharply curved delivery sheath was designed to deliver the device to the left ventricular apex, mimicking this property. Yet, simply advancing the asymmetric device through this sheath did not always result in proper device orientation.

Hence, a sharply curved delivery catheter was designed that forced attachment of the device with the longer left ventricular disk along the lesser curvature of the catheter (Fig. 5).

When this catheter design was used in combination with the sharply curved delivery sheath positioned in the left ventricular apex, the device was easily advanced to the tip of the delivery sheath to assume proper orientation (22). This was confirmed in human trials; complete closure occurred in 96%

of patients, and there were no serious complications, although the numbers were small (23).

The aortic disk of the concentric Amplatzer Ductal Occluder sometimes protrudes into the aortic lumen. This is because the ductus arteriosus forms a 65 ° angle with the descending aorta, and the concentric device has a 90 ° angle. An eccentric device was designed to allow the aortic disk to hug the aortic wall (Fig. 6), and a similar combination of a sharply curved delivery catheter and sheath resulted in proper orientation of the device (24).

6. DEVICES W I T H O U T FABRIC

The polyester baffles and stuffing of Amplatzer devices sewn within the Nitinol wire frame are considered important for reliably producing thrombosis within the fabric spacing and occlusion of defects. However, sewing the material into the frames is time consuming and costly and limits automation of production. Thus, eliminating fabric could greatly simplify production and might even reduce the size of delivery systems.

The initial attempt at a fabric-free device was simply to increase the wire count. Standard Amplatzer devices have a 72-wire Nitinol frame. An angled Ductal Occluder Device was developed with 144 wires. In an animal model, this resulted in complete occlusion of an artificially created patent ductus arteri osus (25). This simple design modification also allowed placement through a 6-French guiding catheter. Yet, human use has revealed the potential for recanalization with this design (26).

Hence, it was considered that a more effective solution would be to place wire mesh inserts within the frame of the device (Fig. 6). Initial experimental trials with the newest design placed in both a patent ductus arteriosus and atrial septal defect suggested that this may again reliably produce occlusion of such defects, but could greatly simplify device production. It remains to be determined how much this will reduce delivery system size.

7. SUMMARY

The Amplatzer family of devices is an interesting case study in the development of minimally invasive cardiac devices. They provide a successful means for transcatheter closures of congenital cardiovascular abnormalities. The simple design of such devices has allowed easy modification for numerous different types of abnormal communications. Unique characteristics of this family of devices include ease of delivery, small delivery systems, retrievability, safety, and effectiveness. To the credit of their inventor (Kurt Amplatz, MD), these devices were initially designed for use in children despite a larger adult market.

Over the past 25 yr, there have been several changes in the therapy of children with congenital heart disease. Noninvasive echocardiographic diagnosis of congenital heart disease was the first significant change to reduce the number of cardiac catheterizations. Balloon dilation of congenital narrowing of valves and arteries was the next big change in management.

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CHAPTER 29 / CARDIAC SEPTAL DEFECTS 419

A

Fig. 5. Delivery system for an asymmetric device. (A) Photograph of the slot in the delivery catheter, flat at the upper margin; this matches a flattened area at the upper surface of the microscrew. The microscrew will only fit into the slot in the correct orientation. (B) The asymmetric Perimembranous Ventricular Septal Occluder is attached to the curved delivery catheter. The longer rim of the left ventricular disk is oriented along the lesser curvature of the delivery catheter.

t.

Fig. 6. Angled ductal occluder device without fabric. (A) Photograph of the device showing the external frame, which is composed of 144 wires.

Arrows indicate a wire insert shaped like the external frame. (B) Aortogram performed immediately after device placement in a surgically created "ductus arteriosus" in a canine model. The angled aortic disk lies snuggly along the aortic wall. There is immediate complete occlusion of the ductus.

This caused a return to the cardiac catheterization laboratory for interventional procedures.

The Amplatzer family of devices has further changed the face of treatment of congenital heart disease in children. Yet, transcatheter therapy is not limited to simpler lesions that often precede

surgical repair, decreasing the complexity of surgical interven- tion. Amplatzer devices can also be delivered in the operating room directly through the surface of the heart without cardiopulmonary bypass. This has brought a new era of cooperation between pediatric cardiologists and cardiovascular surgeons.

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420 PART IV: DEVICES A N D THERAPIES / BASS

REFERENCES

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7. Hausdorf, G., Schneider, M., Granzbach, B., Kampmann, C., Kargus, K., and Goeldner, B. (1996) Transcatheter closure of secundum atrial septal defects with the atrial septal defect occlusion system: initial experience in children. Heart. 75, 83-88.

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9. Rao, P.S., Berger, F., Rey, C., et al. (2000) Results of transvenous occlusion of secundum atrial septal defects with the fourth genera- tion buttoned device: comparison with first, second and third genera- tion devices. International Buttoned Device Trial Group. J Am Coll Cardiol. 36, 583-592.

10. Agarwal, S.K., Ghosh, P.K., and Mittal, P.K. (1996) Failure of devices used for closure of atrial septal defects: mechanisms and management. J Thorac Cardiovasc Surg. 112, 21-26.

11. Du, Z.D., Hijazi, Z.M., Kleinman, C.S., Silverman, N.H., Larntz, K., and Amplatzer Investigators. (2002) Comparison between transcatheter and surgical closure of secundum atrial septal defect in children and adults: results of a multicenter nonrandomized trial. J Am Coll Cardiol. 39, 1836-1844.

12, Sharafuddin, M.J.A., Gu, X., Titus, J.L., Urness, M.C., Cervera- Ceballos, J.J., and Amplatz, K. (1997) Transvenous closure of secundum atrial septal defects: preliminary results with a new self-expanding Nitinol prosthesis in a swine model. Circulation. 95, 2162-2168.

13. Kong, H., Wilkinson, J.L., Coe, J.Y., et al. (2002) Corrosive behav- ior of Amplatzer devices in experimental and biological environ- ments. Cardiol Young. 12, 260-265.

14. Gersony, W.M. and Apfel, H.D. (2000) Patent ductus arteriosus and other aortopulmonary anomalies, In Pediatric CardiovascularMedi- cine (Moiler, J.H. and Hoffman, J.I.E., eds.), Churchill Livingstone, New York, NY, pp. 323-330.

15. Kirklin, J.W. and Barratt-Boyes, B.G. (1993). Patent ductus arterio- sus, In Cardiac Surgery, 2nd Ed. (Kirklin, J.W. and Barratt-Boyes, B.G., eds.), Churchill Livingstone, New York, NY, p. 854.

16. Nykanen, D.G., Hayes A.M., Benson, L.N., and Freedom, R.M.

(1994) Transcatheter patent ductus arteriosus occlusion: application in the small child. J Am Coll Cardiol. 23, 1666-1670.

17. Pass, R.H., Hijazi, Z., Hsu, D.T., Lewis, V., and Hellenbrand, W.E.

(2004) Multicenter USA Amplatzer PDA occlusion device trial: ini- tial and mid-term results. J Am Coll Cardiol. 44:513-5 19..

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23. Bass, J.L., Kalra, G.S., Arora, R., et al. (2003) Initial human experience with the Amplatzer perimembranous ventricular septal occluder device. Catheter Cardiovasc lnterv. 53,238-245.

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(2002) Experimental evaluation of a new angled Amplatzer duct occluder. Paper presented at 37th Annual General Meeting of the AEPC, Porto, Portugal, May 15-18.

26. Bass, J.L. (2003) Amplatzer devices without fabric. Sixth Interna- tional Workshop Catheter Interventions in Congenital Heart Dis- ease, Frankfurt, Germany, June 21.