Percutaneous Closure of Patent Foramen Ovale and Valvular Function — Effect of the Amplatzer Occluder

Abstract: Background. Percutaneous closure of the patent foramen ovale (PFO) is a widely used procedure in patients with paradoxical embolism. Whether or not implantation of a PFO closure device alters cardiac chamber anatomy and in turn affects valvular function is unclear. Methods. Out of 334 patients who underwent PFO closure between 2002 and 2010, a total of 196 received an Amplatzer septal occluder and were retrospectively analyzed. Nineteen patients (9.7%) were excluded due to an incomplete follow-up. Thus, 177 patients with a mean age of 51 ± 13 years remained for analysis. Clinical and echocardiographic examinations were performed before and 6 month after PFO closure. Results. At follow-up, significant residual shunt (>20 microbubbles) was present in only 11 patients (6.2%). Newly developed or worsened aortic regurgitation (AR) was noted in 16 patients (9%), whereas in 2 patients (1%) a previously documented AR had disappeared. In 33 patients (19%), mitral valve regurgitation (MR) developed or worsened, while in 10 patients (5.6%) a previously documented MR was no longer present at follow-up. In 44 patients (25%), tricuspid regurgitation (TR) had developed at follow-up, while in 5 patients (3%) a previously documented TR was no longer visible echocardiographically. Conclusion. Implantation of an Amplatzer septal occluder is a safe and effective procedure. However, it can induce or worsen valvular regurgitation in almost half of the patients. Although the degree of regurgitation was generally mild, it is likely that implanted devices alter cardiac chamber structure.

J INVASIVE CARDIOL 2012;24(6):274-277

Key words: PFO closure, paradoxical embolism, Amplatzer septal occluder, valvular function

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With an incidence of up to 29% at autopsy, the patent foramen ovale (PFO) of the interatrial septum is the most common congenital defect in adults.¹ Of note, the true incidence might have been underestimated in such studies, as the presence of a PFO declines with age, suggesting that anatomic closure may occur even in adulthood or that patients with PFO have a shorter life expectancy.² Indeed, several studies have found an association between PFO and cryptogenic stroke.^3-7 PFOs that are associated with an atrial septum aneurysm (ASA) or a large right-to-left shunt are associated with an even higher risk of stroke.^8-16 In a recent review of non-randomized trials, a lower rate of recurrent stroke after device closure of PFO has been reported, suggesting a causal link between this congenital defect and cerebral emboli.¹⁷ As a consequence, transcatheter PFO closure became a widely used procedure in patients with suspected paradoxical embolism. Although the procedure is technically simple and generally safe with the use of current closure devices, several complications such as cardiac perforation, air or device embolization during implantation, atrial fibrillation, non-specific malaise attributed to nickel allergy, thrombus formation on the device, and puncture site problems may occur.¹⁸ Only recently, another safety aspect was described by echocardiographic follow-up studies, ie, newly developing or worsened aortic regurgitation in up to 10% of patients undergoing the procedure.¹⁹ However, a subsequently conducted study using cardiac magnetic resonance imaging could not confirm an impact of percutaneous closure device implantation on valvular function.²⁰

The present study aimed to further elucidate the effect of Amplatzer septal occluder on heart valve function in a larger series of patients. Particularly since no specific PFO closure device has been approved by the Food and Drug Administration so far,^21-23 assessment of long-term outcome and safety of transcatheter PFO closure remains crucial.

Methods

Patients. Out of 334 patients who underwent PFO closure between May 2002 and July 2010,  a total of 196 (59%) received an Amplatzer septal occluder. Nineteen out of 196 patients (9.7%) were excluded due to an incomplete follow-up. Thus, a total of 177/196 (90.3%) patients remained for the current analysis. Patient characteristics are summarized in Table 1. Transcatheter PFO closure was performed after a cryptogenic ischemic event as previously defined²⁴ following echocardiographic documentation of an interatrial shunt. The present study was approved by the institutional review board (Cantonal Ethics Committee) of Zurich, Switzerland.

Echocardiography. Echocardiographic examinations were performed using an Acuson Sequoia C512 (Siemens) or an iE33 (Philips Medical Systems) ultrasound system. Retrospective work-up included analysis of two-dimensional transthoracic echocardiography and transesophageal echocardiography before and 6 months after defect closure, with particular focus on valve function in a standardized manner. Furthermore, possible residual shunts, thrombus formation, and device dislocation were assessed. Semiquantitative assessment of valve regurgitation was performed according to jet length, jet width, and (in the case of aortic regurgitation [AR]) based on the ratio of the jet to ventricular outflow tract width as well as pressure half-time. Severity of regurgitation was classified into four grades (minimal, mild, moderate, and severe), according to the recommendations of the American Society of Echocardiography.²⁵

Interatrial defect closure. Two different closure device sizes were used at the discretion of the operator: the 25-mm or 35-mm diameter Amplatzer Septal Occluder (AGA Corporation). The procedure has been described elsewhere.²⁶

Statistical analysis. Continuous variables were reported as mean values ± standard deviation. Categorical variables were reported as numbers and percentages. The McNemar test was applied to compare the incidence of regurgitation at baseline and follow-up. Comparison of baseline and follow-up regurgitation rate including newly developed and worsened regurgitation was performed using the Wilcoxon Signed Rank test.

Results

Devices and implantation. A sole PFO was diagnosed in 76/177 patients (43%), and a PFO combined with an ASA in 92/177 (52%). Four patients had either an ASD or an ASD in combination with an ASA. One patient presented with a combination of PFO and ASD. A total of 153/177 patients (86.4%) received a 25 mm Amplatzer Septal Occluder. A 35 mm Amplatzer Septal Occluder was implanted in 24 patients (13.6%).

Procedural success. Implantation was successful in all patients; however, 3 patients required a second intervention. In 1 patient, device embolization occurred during the implantation procedure. The lost device was successfully removed from the descending aorta by transfemoral snaring and a larger device was subsequently implanted. Two patients underwent a second intervention due to marked residual shunt.

Findings at follow-up. At 6-month follow-up, significant residual shunt (>20 microbubbles) was found in 11 patients (6.2%). Transient atrial fibrillation occurred in 6 patients (3%), while 1 patient (0.6%) developed persistent atrial fibrillation requiring oral anticoagulation. Thrombus formation on the implanted device requiring oral anticoagulation at follow-up was noted in 3 patients (1.5%).

At baseline, aortic regurgitation (AR) was documented in 28 patients (16%), minimal in 22 (12%), mild in 5 (3%), and moderate in 1 (0.6%). None of the patients had severe AR.

At follow-up 6 months after PFO closure, AR was noted in 39 patients (22%). Newly developed AR was documented in 13 patients (7%), whereas in 3 patients (1.6%) a pre-existing AR had worsened. Conversely, in 2 patients a previously documented minimal AR had disappeared (Figures 1 and 2).

At baseline, mitral regurgitation (MR) was present in 78 patients (44%). Of those, 75 were of minimal degree, 2 were classified as mild, 1 as moderate, and 0 as severe MR. At follow-up, MR was observed in 97 patients (55%). Newly developed MR was documented in 29 patients (16%), whereas in 4 patients (<1%) MR had worsened. In 10 patients, a previously documented MR had disappeared (Figures 1 and 2).

Tricuspid regurgitation (TR) was found in 104 patients (59%) at baseline. No data were available as to the degree of TR. However, 6 months after device implantation, TR was observed in 143 patients (81%). TR newly occurred in 44 patients (25%), while it had disappeared in 5 patients (3%; Figures 1 and 2).

Regurgitation of all valves was independent of baseline characteristics such as age, gender, medical therapy, and risk factors for an emerging valve regurgitation (chamber dimensions, hypertension, bicuspid aortic valves, or enlarged aortic root). Furthermore, there was no difference in sizes of the devices used in patients with newly developed or worsened valve regurgitation compared to the group without disturbance of valve function. Table 2 shows valve function at baseline and follow-up.

Discussion

The present study confirms the high primary success and low complication rate of percutaneous PFO closure. While major complications causing functional damage or requiring surgery did not occur, the incidence of a significant residual shunt of 6.2% at 6-month follow-up is in line with previously published data.^27,28 It is also known that residual shunts continue to disappear even after 6 months by sustained endothelialization of the device.²⁹ The major finding of this study, however, is an increased incidence of aortic, mitral, and tricuspid valve regurgitation, mainly of trivial and mild degree, 6 months after device implantation.

Several factors might account for the increased incidence of valvular regurgitation after PFO closure device implantation: (1) the natural course of preexisting valvular incompetence; (2) day-to-day variation of mild valvular regurgitation (depending on actual volume status, heart rate, and blood pressure levels); and (3) alteration of cardiac chamber structure due to the implantation of a stiff device within the atrial septum.

The natural course of valvular regurgitation is an unlikely explanation of the observed findings, since the increased incidence of regurgitant valves was observed already after 6 months of device implantation and because regurgitation of valves was independent of baseline characteristics such as age, gender, medical therapy, and risk factors for an emerging valve regurgitation (chamber dimensions, hypertension, bicuspid aortic valves, or enlarged aortic root). A day-to-day variation is also an unlikely cause of the increased frequency of regurgitant valves in patients who received a PFO occluder, since the number of patients with more pronounced or newly developed regurgitation was too big and patients are asked to attend the follow-up visits in a fasting state as they are when invited for the procedure itself. Thus, the implantation of a PFO occluder must alter cardiac chamber structure slightly and in turn cause or worsen valvular regurgitaton. Surprisingly, there was no difference in size of the devices used in patients with newly developed or worsened valve regurgitation compared to the group without disturbance of valve function. This may be due to the fact that the operators selected smaller and larger devices based on the individual anatomy of the patients. Further, this suggests that the intrinsic anatomy of the PFO, ie, tubular, flat open, size, and rim of the defect among others, and in turn the position of the device might be more importantly involved in the remodelling of atrial and valvular structures after device implantation. Whether the stiffness of PFO occluders plays an important role in altering cardiac chamber structure, this warrants further studies with other PFO occluders, which are slightly stiffer.

In summary, the results of this study suggest that device implantation in the atrial position to occlude a PFO with or without aneurysm is associated with subtle changes in cardiac chamber anatomy leading to worsening of existing and the development of new valvular regurgitation in the aortic, mitral, and/or tricuspid position. At follow-up 6 months after PFO closure, there were no clinical manifestations of the valvular insufficiency. The long-term effects of these changes on echocardiographic findings and clinical outcomes in these patients warrant further studies. Further, more flexible devices adapting better to the prevailing cardiac anatomy of an individual patient may be a medical need in the management of patients with cryptogenic stroke and PFO.

Acknowledgment. The authors are grateful to Vreni Widmer and Jana Kunst for their assistance in obtaining echo data for the patients in this study.

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*Joint first authors.
From the Department of Cardiology, Cardiovascular Center, University Hospital Zurich, Switzerland.
Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. Krasniqi was supported by unrestricted grants from Biotronik, Boston Scientific, Medtronic, and St. Jude. The other authors report no disclosures.
Manuscript submitted November 21, 2011, provisional acceptance given December 20, 2011, final version accepted February 28, 2012.
Address for correspondence: Roberto Corti, MD, Cardiology, Andreas Gruentzig Catheterization Laboratory, University Hospital Zurich, Raemistrasse 100, CH-8091 Zurich, Switzerland. Email: roberto.corti@usz.ch