Predictors and Clinical Outcomes of Residual Shunt in Patients undergoing Percutaneous Transcatheter Closure of Patent Foramen O

A patent foramen ovale (PFO) can be identified in as many as 25% of the adult population.¹ Though in the vast majority of cases the PFO is clinically silent, its presence is associated with serious and well-recognized complications. The association between a PFO and paradoxical embolization resulting in cerebrovascular and other systemic events has been recognized for many years. The combination of a PFO and atrial septal aneurysm (ASA) has been shown to increase the risk for cryptogenic stroke nearly five-fold in patients younger than 55 years of age.⁴ Furthermore, the presence of a PFO has been associated with platypnea orthodeoxia syndrome, and lately has been implicated in migraine headaches as well.^2,3 Patients with recurrent cryptogenic strokes and other systemic paradoxical embolic events who have failed or are unable to take conventional anticoagulation therapy, may benefit from PFO closure. An increasing number of such patients with suspected paradoxical embolization are being referred for percutaneous closure of the PFO. Recently, this technique has been shown to be as effective as medical treatment for the prevention of recurrent cerebrovascular events in patients with cryptogenic strokes and PFO.⁵ Residual shunt may be seen in a limited number of patients after percutaneous closure of the PFO, but its clinical implications are unclear. Anatomic characteristics of the atria or the PFO may influence the persistence of right-to-left shunt and may help to tailor appropriate management. Thus, we evaluated echocardiographic characteristics of the atria, atrial septum and foramen ovale, in addition to clinical characteristics that may identify patients who are likely to have residual shunt following percutaneous closure. Methods Patients. The study included 101 consecutive patients with a PFO who were referred to our institution for percutaneous closure of the PFO between July 2002 and June 2004. After excluding those with incomplete procedural or echocardiographic data, 76 patients (42 women and 34 men) with a mean age of 51 ± 15 years were included in the study. Systematic review of their records was performed. The indication for percutaneous PFO closure included platypnea/orthodeoxia syndrome (n = 4) and recurrent paradoxical embolization in patients who failed or had a contraindication for systemic anticoagulation (n = 72). Six of these patients had peripheral embolic events, 45 had documented cerebrovascular events and 21 had transient ischemic attacks. All patients provided informed consent after a thorough explanation of the risks, benefits and alternatives for the procedure. Percutaneous closure of the PFO was performed under transesophageal echocardiographic (TEE) and fluoroscopic guidance. Demographic, procedural and echocardiographic data were analyzed. Percutaneous closure. The technique for percutaneous PFO closure with an Amplatzer septal occluder has been previously described.⁶ Briefly, an 8 Fr sheath was inserted in the femoral vein using the modified Seldinger technique under sterile conditions. Patients were systemically anticoagulated with intravenous unfractionated heparin and were given prophylactic intravenous antibiotics. The PFO was crossed using a 1.5 mm J-tipped Amplatzer wire guided over a 7 Fr Multipurpose A-2 catheter. The Multipurpose catheter was exchanged for a 9 Fr delivery sheath. Right and left atrial pressures were recorded. Under TEE and fluoroscopic guidance, an AGA Amplatzer PFO septal occluder (AGA Medical Corp., Golden Valley, Minnesota) was deployed after ascertaining that there was no impingement of the surrounding structures. Following device deployment, a saline contrast study was performed to document PFO closure. Three hundred milligrams of clopidogrel were given immediately after the procedure. A postero-anterior and lateral chest X-ray was obtained following the procedure to document device position. Transesophageal echocardiography. Patients underwent a TEE study utilizing a Sequoia multiplanar transducer (Acuson Corp., Mountain View, California) with fundamental imaging modality and a transmitting frequency of 7.0 MHz. A full echocardiographic study was performed with careful evaluation of the atria, interatrial septum, aorta and atrioventricular valves. The interatrial septum was evaluated for the presence of lipomatous hypertrophy, atrial septal aneurysm and long PFO tunnels. Measurements of the PFO length and diameter, redundant septum primum length and excursion diameter in either atria were obtained. Once the device was placed, its relationship with the atrioventricular valves, pulmonary veins and vena cava were observed. A saline contrast bubble study was performed immediately after device deployment. Transthoracic echocardiography. Within 24 hours of device implantation and at 6 months, a limited transthoracic echocardiogram (TTE) was performed employing second harmonic imaging, using a transmitting frequency of 1.8–2 MHz and a receiving frequency of 3.6–4 MHz. Studies were performed with the Sonos 5500 (Phillips, Andover, Massachusetts), Sequoia C256 (Siemens Medical Solutions, Malvern, Pennsylvania), or the Vivid 7 (General Electric, Milwaukee, Wisconsin) imaging system. The apical 4-chamber view was performed with the administration of saline contrast. Gain settings were adjusted individually to optimize the visualization of the saline bubbles and the interatrial septum. Saline contrast study. Saline contrast was prepared by agitating 1 cc of air with 9 cc of sterile saline solution using two 10 cc syringes and a 3-way stopcock. Saline contrast was administered from a peripheral intravenous line in all patients. Approximately 8 milliliters of saline contrast were administered rapidly, avoiding injection of the visible air at rest and during the release phase of the Valsalva maneuver. The presence of an interatrial right-to-left shunt was confirmed when 5 or more bubbles were seen in the left atrium within the first 5 cardiac cycles following contrast appearance in the right atrium. Bubbles visualized after this time were classified as intrapulmonary shunts. Shunt severity was quantified by the number of bubbles visualized in the left atrium in one frame as: mild (5–10 bubbles); moderate (10–20 bubbles); and severe (> 20 bubbles). Image acquisition involved the capture of 10 continuous beats on videotape and digital storage media prior to and immediately following the release phase of the Valsalva maneuver. All studies were analyzed by expert echocardiographers blinded to the clinical history, the result of the implantation procedure and other echocardiograms. Follow up. Patients were prescribed 75 mg of clopidogrel and 81 mg of aspirin daily for the first month following device placement. The aspirin dose was increased to 325 mg daily for the following 5 months. The decision to continue warfarin therapy was left to the discretion of the referring physician or neurologist. In all cases, warfarin was discontinued after 1 month. Antibiotic prophylaxis was recommended for 6 months. At 6 months, patients underwent a complete medical interview with special emphasis on symptom recurrence and a repeat TTE with bubble study. Definitions. For the purpose of this study we defined the following: 1) Atrial septal aneurysm: Redundancy of the atrial septum with excursion of greater than or equal to 10 mm into either atrial chamber, and a base measuring at least 15 mm.⁷ 2) Redundant atrial septum: Protuberance of the atrial septum more than 5 mm but less than10 mm into either atrial cavity. 3) Lipomatous hypertrophy of the atrial septum: Benign infiltration of the atrial septum with lipomatous tissue that gives it a characteristic echocardiographic appearance. Statistical analysis. The data were expressed as absolutes and analyzed with descriptive statistics (mean, standard deviation, percentages). The following statistical tests were applied: Chi-squared for dichotomous variables and the paired Student’s T-test for paired variables. Statistical significance was defined a priori as a p-value (SPSS, Inc., Chicago, Illinois). Results Patient characteristics. Seventy-six patients were included in our study with mean age of 51 ± 15 years. 55% were females and 45% were males. The primary indications for closure were: strokes (59%), transient ischemic attacks (28%), peripheral embolism (8%), and hypoxemia (5%). Their comorbidities included hypertension (6%), migraine headaches (15%), deep venous thrombosis (7%), coronary artery disease (4%), diabetes mellitus (3%), and hypercoagulable state (3%). Of the 2 patients who were found to have a hypercoagulable state, 1 had primary antiphospholipid syndrome and the other had Factor V Leiden mutation. Five patients had a concurrent deep venous thrombosis, and 10 patients were incidentally noted to suffer from migraine headaches. Procedure-related characteristics. All patients underwent successful deployment of the AGA Amplatzer PFO septal occluder. No major procedural complications were encountered. The majority of the devices placed were 25 mm (n = 54) or 35 mm (n = 9) in size. Thirteen patients treated during the last 6 months of the year 2002 received an AGA Amplatzer ASD septal occluder due to lack of clinical availability of the PFO septal occluding devices. One patient required 2 PFO occluders (25 mm and 8 mm) to effectively stop the interatrial shunting. Forty-eight patients (63%) had total elimination of the interatrial shunt within the first 24 hours after device deployment as evidenced by a normal saline contrast echocardiogram (Figure 1). The remaining 28 patients (37%) had persistent shunt (p Echocardiographic predictors. All patients who had an atrial septal aneurysm (n = 7) had evidence of residual shunt at 24 hours (p p n = 2), but this did not reach statistical significance due to its low frequency of occurrence (Figure 4). There were no other unifying variables that identified the remaining 13 patients with early persistent shunts (Table 1). Patients’ age, device size, the use of ASD occluding devices, PFO length or diameter were not statistically significant in the prediction of procedural success. Follow up. At 6 months, 73 patients (96%) who underwent PFO closure have had complete elimination of the shunt as demonstrated by the saline contrast TTE. Of the 3 patients with a persistent shunt at 6 months, 2 had an atrial septal aneurysm. One of these 3 patients had a recurrent nonfatal transient ischemic attack. The rest of the patient population was free of any recurrent paradoxical embolic event or symptoms suggestive of such events. Discussion The number of patients undergoing percutaneous PFO closure has significantly increased in the recent years. The availability of effective percutaneous closure devices and their ease of use have contributed to this trend. Earlier studies have reported a success rate of 80–95% at 6 to 12 months for these closure devices,⁸ as determined by the presence and severity of right-to-left shunt. In our study, the successful closure was achieved in 96% of patients by 6 months following initial closure. However, nearly one third of the patients had early residual shunt during the initial 24 hours following percutaneous PFO closure. Residual shunt may depend on the type of septal occluder and the intrinsic anatomic characteristics of the heart, since shunt immediately post-procedure ranges from 13–40%.^9,10 The CardioSeal device (NMT Medical, Inc., Boston, Massachusetts) has a reported residual shunt of 15–30%.^10,11 Initial shunt may be seen through the middle of the Amplatzer septal occluders since the nitinol mesh requires time to acquire its final conformation. Both devices require endothelialization to achieve elimination of the residual shunt. Identifying factors that predispose patients to persistent or residual shunt and understanding the natural history of such residual shunts are crucial for tailoring further treatment. In particular, this may help to guide the need and the duration of additional anticoagulation in high-risk patients prone to recurrent paradoxical embolic events. As seen from our data, the Amplatzer PFO septal occluder provides successful closure immediately in the majority of the population, and almost totally at 6 months. Atrial septal aneurysm, redundant atrial septum and lipomatous hypertrophy of the atrial septum are easily recognized by echocardiography, and are associated with early persistence of atrial shunting. An atrial septal aneurysm or a redundant atrial septum is characterized by a hypermobile interatrial septum. This phenomenon has been associated with an increasing risk of recurrent stroke.^12,13 For appropriate closure, the PFO occluder device must flatten and stabilize the interatrial septum aiding in the process of endothelialization by approximation of both septal edges. The Amplatzer occluding device is known to fully re-expand and acquire its original conformation up to 6 months after deployment, and thus closure may not be complete until this time. During the initial 6-month period, it is possible for bubbles to pass along the edge of the device contributing to a positive bubble study. The clinical significance of such shunt is negligible in our observation. The deployment of larger devices in patients with ASA did not influence the shunt of persistence in our study. The presence of lipomatous hypertrophy of the atrial septum was associated with persistent early shunting as well. An excessively thick septum will limit the ability of the closure device to straddle the interatrial septum and will predispose it to inappropriate seating and residual shunting. In our study, only 2 patients were found with this phenomenon. It is likely that this did not reach statistical significance due to its low frequency of occurrence. Large studies are needed to further address the significance of these characteristics. The combined event recurrence rate of transient ischemic attacks, cerebrovascular accidents or peripheral embolism is estimated at 3.4%.¹⁴ In our series, only 1 of the 76 patients (0.8%) who underwent PFO closure suffered a recurrent paradoxical embolic event at 6 months. The antiplatelet regimen used in our study consisted of 81 mg of aspirin and 75 mg of clopidogrel daily for the first month, and 325 mg of aspirin thereafter. Several patients received warfarin at the recommendation of their neurologist or primary physicians for the first month, but none after this time. Although up to one-third of our patients had an early residual shunt, their risk of recurrent event was considerably lower. It is likely that the closure device impedes the direct and uninterrupted flow of particulate material across the PFO that causes embolic events. We suggest that the presence of the shunt identified by bubble study is most likely due to small channels that exist along the device edges. These channels are large enough to permit the passage of bubbles, but not large enough for the particulate material that can contribute to an embolic event. In those with residual shunts, the fact that the severity of the shunt had significantly decreased compared to baseline supports this hypothesis. Atrial volume and spatial relationships with the mitral and tricuspid valve and the pulmonary venous inflow also plays an important role in device selection and complete closure of the PFO. A large device may impinge on the surrounding structures and generate further complications. In our experience, one can safely use a smaller device in such instances, as long as the shunt is diminished considerably. The residual shunt will likely be eliminated slowly over time with complete endothelialization. Also, the option to deploy an additional smaller device exists, especially if the shunt persists long after the initial 6 months. Conclusions Percutaneous closure of a PFO is safe and effective. The percutaneous approach confers early closure of a PFO and elimination of shunt in the majority of patients. Residual shunts are seen in patients with atrial septal aneurysms, redundant atrial septum and lipomatous hypertrophy of the atrial septum, but resolve by 6 months without any major clinical sequelae. Large studies may help to identify other factors associated with residual shunts.

References 1. Hagen PT, Scholz DG, Edwards WD. Incidence and size of patent foramen ovale during the first 10 decades of life: An autopsy study of 965 normal hearts. Mayo Clin Proc 1984;59:17–20. 2. Holmes DR, Cohen H, Katz WE, Reeder GS. Patent foramen ovale, systemic embolization and closure. Curr Probl Cardiol 2004;29:60–94. 3. Scwerzmann, M, Wiher S, Nedeltchev K, et al. Percutaneous closure of patent foramen ovale reduces the frequency of migraine attacks. Neurology 2004;62:1399–1401. 4. Overell JR, Bone I, Lees KR. Interatrial septal abnormalities and stroke: A meta-analysis of case-control studies. Neurology 2000;55:1172–1179. 5. Windecker W, Wahl A, Nedeltchev K, et al. Comparison of medical treatment with percutaneous closure of patent foramen ovale in patients with cryptogenic stroke. J Am Coll Cardiol 2004;44:750–758. 6. Waigth DJ, Cao QL, Hijazi ZM. Closure of patent foramen ovale in patients with orthodeoxia-platypnea using Amplatzer devices. Catheter Cardiovasc Interv 2000;50:195–198. 7. Mugge A, Daniel WG, Angermann C, et al. Atrial septal aneurysm in adult patients: A multicenter study using transthoracic and transesophageal echocardiography. Circulation 1995;91:2785–2792. 8. Hong TE, Thaler D, Brorson J, et al. Transcatheter closure of patent foramen ovale associated with paradoxical embolism using the Amplatzer PFO Occluder: Initial and intermediate-term results of the U.S. multicenter clinical trial. Catheter Cardiovasc Interv 2003;60:524–528. 9. Alameddine F, Block P. Transcatheter patent foramen ovale closure for secondary prevention of paradoxical embolic events: Acute results form the FORECAST registry. Catheter Cardiovasc Interv 2004;62:512–516. 10. Hung J, Landzberg M, Jenkins K, et al. Closure of patent foramen ovale for paradoxical emboli: intermediate term risk of recurrent neurological events following transcatheter device placement. J Am Coll Cardiol 2000;35:1311–1316. 11. Braun M, Gliech V, Boscheri A, et al. Transcatheter closure of patent foramen ovale (PFO) in patients with paradoxical embolism. Periprocedural safety and mid-term follow-up results of three different device occluder systems. Eur Heart J 2004;25:424–430. 12. Mas JL, Arquizan C, Lamy C, et al. Recurrent cerebrovascular events associated with patent foramen ovale, atrial septal aneurysm or both. N Engl J Med 2001;345:1740–1746. 13. Mas JL, Zuber M, et al. Recurrent cerebrovascular events in patients with patent foramen ovale, atrial septal aneurysm, or both and cryptogenic stroke or transient ischemic attack. Am Heart J 1995;130:1083–1088. 14. Windecker S, Wahl A, Chatterjee T, et al. Percutaneous closure of patent foramen ovale in patients with paradoxical embolism. Long term risk of recurrent thromboembolic events. Circulation 2000;101:893–898.