CASE REPORT Is Moderate/Large Residual Shunt After PFO Closure Justifiable for a Patient with a Prior History of Cryptogenic Stroke and Transient Ischemic Attack? Francesco Melillo,1 MD, Gregory Popusoi,3 MD, Francesca Frecentese,1 MD, Vittoria Miano,1 MD, Alessandro Santoro,2 MD, Tullio Tesorio,3 MD and Eustaquio Maria Onorato,4 MD Summary A 36-year-old woman suffered from an embolic stroke of an undetermined source documented by magnetic resonance imaging with residual right arm weakness. She underwent percutaneous patent foramen ovale (PFO) closure with an 18/25 mm device in another center. One year later, the patient suffered from a transient ischemic attack with dysarthria. She asked for a second opinion at our institution and a contrast-transthoracic (cTTE)/transesophageal echocardiography showed a large residual right-to-left shunt (RLS) through a still patent tunnel after PFO closure. Written informed consent for a redo procedure was obtained from the patient. A catheter-based closure of the residual shunt was therefore planned under local anesthesia and rotational intracardiac echo monitoring. A second equally sized disc (18/18 mm) device was successfully implanted without complications. The patient was discharged home the following day in good clinical condition. Dual antiplatelet therapy was recommended for the first 2 months and then single antiplatelet therapy up to 6 months. At the 6month follow-up, the cTTE color Doppler showed the stable position of the two nitinol double-disc devices and the c-transcranial Doppler confirmed the abolition of the residual RLS. (Int Heart J 2024; 65: 146-151) Key words: Paradoxical embolism, Patent foramen ovale associated with atrial septal aneurysm, Recurrent embolic events, Residual right-to-left shunt, Transcatheter PFO closure, Transcranial Doppler andomized clinical trials and systematic reviews have provided consistent clinical efficacy and safety data supporting patent foramen ovale (PFO) closure compared with medical treatment for preventing recurrent cerebrovascular events.1-6) Complications related to the procedure and the device have been very low and generally transient.7) Furthermore, the selection of the appropriate patients and devices suitable for the corresponding PFO anatomical features is essential for effective closure.8) Although percutaneous PFO closure has an extremely high success rate, a moderate-to-large residual right-to-left shunt (RLS) after PFO closure is seen in nearly 10% of the patients9,10) and has been associated with an increased risk of recurrent stroke or transient ischemic attack (TIA) in the long-term follow-up. Until now, no agreement has been reached regarding the best management of significant residual shunt. Several reports of second device closure achieving complete closure are described in the literature.11-13) We report a case of a significant residual shunt after initial PFO closure with an Amplatzer 18/25 mm device (Abbott Medical, St. Paul, MN, USA) that was success- R fully treated with a second 18/18 mm MemoPart PFO Occluder (Lepu Medical Technology, Beijing). Case Report A 36-year-old woman suffered in September 2021 from an embolic stroke (left capsular lesion) of an undetermined source presenting with right arm paresthesia and homolateral hand weakness. The patient was treated with intravenous fibrinolytic therapy, complicated by hemorrhagic transformation that resolved at pre-discharge computed tomography scan. Her medical history was unremarkable, with no history of either or both chest pain and palpitations. The 24-hour Holter monitor was normal. Two-dimensional (2D) transthoracic and transesophageal echocardiography (TTE/TEE) color Doppler showed normal biventricular systolic and diastolic function, normal atrial volumes, and no valvular abnormalities. Bubble saline contrast-TTE/TEE demonstrated the presence of a permanent significant RLS via a PFO associated with atrial septal aneurysm (ASA). In October 2021, catheter PFO closure with an 18/25 mm Amplatzer device was performed in another center. From the 1Echo Laboratory, Clinica Montevergine di Mercogliano, Avellino, Italy, 2Intensive Care Unit, Clinica Montevergine di Mercogliano, Avellino, Italy, 3Invasive Cardiology Unit, Clinica Montevergine di Mercogliano, Avellino, Italy and 4University Cardiology Department, IRCCS GaleazziSant’Ambrogio Hospital, Milan, Italy. Address for correspondence: Eustaquio Maria Onorato, MD, University Cardiology Department, IRCCS Galeazzi-Sant’Ambrogio Hospital, Via Cristina Belgioioso 173, 20157 Milan, Italy. E-mail: eustaquio.onorato@gmail.com Received for publication July 23, 2023. Revised and accepted November 6, 2023. doi: 10.1536/ihj.23-375 All rights reserved by the International Heart Journal Association. 146 Int Heart J January 2024 RESIDUAL SHUNT AFTER PATENT FORAMEN OVALE CLOSURE 147 Figure 1. A: 2D TEE X-plane color Doppler in bicaval view showing residual color flow in between the discs (left side); after infusion of agitated saline contrast, RLS is seen (yellow arrow) through a persistent tunnel in between the discs (right side). B: cTCD showing high-intensity transient signals in the spectral curve of the middle cerebral artery suggesting persistent RLS after the first device implant. Figure 2. Preprocedure 2D TEE color Doppler bicaval view (108°) showing a 10-mm hypertrophic septum secundum (S2). The device discs were not able to correctly catch the septum secundum, probably leading to residual RLS through the tunnel. One year later, the patient suffered from a transient ischemic attack (TIA) with dysarthria while receiving therapy with a single antiplatelet agent (acetylsalicylic acid 100 mg die). c-2D TTE color Doppler and contrast-enhanced transcranial Doppler (cTCD) (Figure 1) showed a persistent significant residual RLS. The patient asked for a second opinion at our institution. Septum secundum hypertrophy (10 mm) was noted and was hypothesized to contribute to the incomplete capture of the hypertrophied muscular rims by the closure device (Figure 2). During her hospital stay, she was monitored for vital parameters without any abnormalities. The electrocardiogram (ECG) showed an incomplete right bundle branch block. Chest X-ray revealed no signs of increased pulmonary flow. Continuous ECG ruled out atrial fibrillation. After the heart team discussion, written informed consent for a redo procedure was obtained from the patient. A catheter-based closure procedure was planned under local anesthesia and rotational intracardiac echo monitoring (Ultra ICE, Boston Scientific Corporation, San Jose, CA, United States). Right and left femoral vein accesses were obtained using 8-Fr short introducer sheaths. An intravenous bolus of 5,000 U of heparin and an oral dose of cephalosporin were given. The residual tunnel-like space in-between the discs of the previously implanted device was visible by Ultra ICE and then crossed by a 6-Fr multipurpose catheter in the left anterior oblique view showing the device in profile. After the successful placement of the guidewire in the left atrium, the dedicated 9Fr delivery sheath was advanced over the stiff exchange wire into the left atrium. In the absence of a purposespecific occluder for the residual shunt after PFO closure and according to the local availability of devices, we selected the smallest regular and flexible PFO device with two equally sized discs (18/18 mm). Under fluoroscopic 148 MELILLO, ET AL Int Heart J January 2024 Figure 3. A: Intra-procedure fluoroscopic guidance on the left anterior oblique view showing the 6-Fr multipurpose catheter crossing the residual tunnel-like space in between the discs of the previously implanted device. B: After the successful placement of the guidewire in the left atrium, the dedicated 9-Fr delivery sheath was advanced over the guidewire into the left atrium. C, D: The left disc of the 18/18 mm MemoPart PFO device was deployed and pulled back against the atrial septum and the 18/25 mm Amplatzer device. E, F: Final result. Figure 4. Intra-procedure rotational intracardiac echocardiography (Ultra ICE) guidance. The residual defect (yellow arrow, left side) was correctly closed by the positioning of the second device (truncated yellow arrow, right side). *First device. RA indicates right atrium; LA, left atrium; and TV, tricuspid valve. guidance, the left disc of the 18/18 mm MemoPart PFO device was deployed and pulled back against the atrial septum and the 18/25 mm Amplatzer device. To correctly deploy the right atrial disc, we kept tension on the delivery cable, further withdrawing the delivery sheath. Finally, the second device was successfully implanted under fluoroscopic and rotational intracardiac ultrasound guid- ance (Figures 3, 4) showing the two devices in profile, without interferences or malapposition/dislocations between them. The patient was discharged home the following day in good clinical condition. Dual antiplatelet therapy (aspirin 100 mg/daily and clopidogrel 75 mg/daily) was recommended for the first 2 months and then single antiplatelet Int Heart J January 2024 RESIDUAL SHUNT AFTER PATENT FORAMEN OVALE CLOSURE 149 Figure 5. 2D TTE color Doppler in subcostal view (A, B) at 6-month follow-up showing the 18/18 mm MemoPart PFO device correctly implanted and cTTE in apical four-chamber view (C) confirming the absence of residual shunt; cTCD in basal conditions (D) and post Valsalva maneuver (E) showing the abolition of any residual shunt. *Devices. RA indicates right atrium; RV, right ventricle; LA, left atrium; and LV, left ventricle. therapy (aspirin 100 mg/daily) up to 6 months. At the 6-month follow-up, the cTTE color Doppler confirmed the stable position of the two nitinol doubledisc devices and cTCD in the absence of any residual shunt (Figure 5). Currently, right arm weakness has improved, reducing stress and anxiety and providing a better quality of life. Discussion Many types of residual shunts can be distinguished according to the underlying pathophysiological mechanisms. The most frequent type is the shunt through the PFO channel in between the discs (“tunnel-like”), often present when larger devices are used. Another type of shunt may occur when the device is too small and not covering the tunnel width or when there is a partial dislocation of the right disc into the tunnel. The remaining types of residual shunts can be due to accessory undetected small septum primum defects (fenestrated septum primum aneurysm) or iatrogenic erosions induced at the level of the occluder rims resulting in small atrial septal defect with left-to-right shunt and long hemodynamic impairment.14,15) Furthermore, some anatomical variants are proven independent predictors for residual shunting after PFO closure. ASA is considered one of the most frequent among the complex PFO anatomies. Wider ASA and greater ex- cursions of the septum primum may relate to the development of a residual shunt.16) Wider PFOs (> 5 mm) are also associated with persistent RLS through the junction between the discs.17) A stiff PFO tunnel can affect the device deployment causing therefore residual shunt. A tunnel with a large overlap (> 10 mm) with the septum secundum can lead to an inappropriate spreading force between the discs of the occluder giving rise to a distorted device shape with residual shunt. Septum primum fenestrations are another important but avoidable cause of significant residual shunt after PFO closure. This anatomic feature should be ruled out at the baseline echocardiographic evaluation or at the time of the procedure. Hypertrophy or lipomatous hypertrophy of the septum secundum, the last defined when the thickness is !15 mm, is associated with a high risk of procedural failure, and residual RLSs are due to difficulty in catching up of the hypertrophied septum secundum rims by currently available devices. As previously mentioned, the use of large devices (> 30 mm) is considered a procedural challenge related to residual shunt. Moderate-to-large residual RLS after transcatheter PFO closure represents a procedure-related failure, certainly not justified and acceptable by the patients. Without a doubt, this complication should not only be monitored over time but also deserves to be further treated due to the high risk of recurrent embolic events. Wahl A et al. re- 150 Int Heart J January 2024 MELILLO, ET AL ported that patients with residual shunt showed a more than twofold increased annual risk of recurrent cerebrovascular events when compared with a similar cohort of 620 patients followed for one year (2.9% versus 1.3%).18) Furthermore, in the prospective cohort study of 1078 consecutive patients undergoing percutaneous PFO closure for secondary stroke prevention, Deng W et al. found residual shunt, particularly of moderate or large size, to be a novel risk factor independently associated with long-term stroke or TIA recurrence, most of them occurring within the first few years (26.2% in < 1 year and 78% in < 6 years). After adjustment for potential confounders, large and moderate shunts were associated with a greater than four times higher rate of recurrent stroke/ TIA (aHR, 4.28; 95% CI, 2.07-8.88) in comparison to no shunt.19) Unfortunately, the optimal management of a residual moderate or large residual shunt after PFO closure is based on low-quality data,20) and the literature on longterm results after second device implantation is scarce, but retrospective evaluations are encouraging.9-12,21) Although some recommendations can be proposed given the important clinical implications of residual shunt: first, long-term (!5 years) clinical follow-up with regular c-TTE or c-transcranial Doppler evaluations and, second, optimal management of the inherent PFO-related risk factors (thrombophilic disorders, prophylaxis of deep venous thrombosis, and atrial fibrillation). We strongly believe that a second percutaneous closure procedure, less invasive than surgery, to avoid further complications is mandatory for patients with moderate-tolarge residual shunts and appears to be technically feasible, effective, and safe. To improve procedural success, a better understanding of the anatomic and device-related factors associated with closure efficacy is needed. Conclusion In summary, moderate-to-large residual shunts after a PFO closure device constitute a technical- or procedurerelated failure that in the majority of cases may be due to inaccurate selection of PFO anatomies and devices. Undoubtedly, this complication needs further treatment, percutaneously or by surgery, due to the high risk of recurrent embolic events. The present case demonstrates, in line with the published work, that a second transcatheter closure of residual RLS may be technically feasible, effective, safe, and less invasive than a surgical approach. Disclosure Conflicts of interest: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Data availability: The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding author. Ethics: The studies involving human participants were ap- proved by the Ethics Committee of Clinica Montevergine di Mercogliano (Av), Italy. The patient provided written informed consent to participate in this study. Written informed consent was obtained from the patient for the publication of any potentially identifiable images or data included in this article. Author contributions: Conceptualization: GP and EMO; methodology: FM, VM, and FF; investigation: FF, VM, and FM; writing-original draft preparation: EMO; writingreview and editing: EMO; visualization: FM, GP, and AS; data curation: GP, FM, and EMO. All authors contributed to the article and approved the submitted version. References 1. Saver JL, Carroll JD, Thaler DE, et al. Long-term outcomes of patent foramen ovale closure or medical therapy after stroke. N Engl J Med 2017; 377: 1022-32. 2. Mas JL, Derumeaux G, Guillon B, et al. Patent foramen ovale closure or anticoagulation vs. antiplatelets after stroke. N Engl J Med 2017; 377: 1011-21. 3. Søndergaard L, Kasner SE, Rhodes JF, et al. Patent foramen ovale closure or antiplatelet therapy for cryptogenic stroke. N Engl J Med 2017; 377: 1033-42. 4. Shah R, Nayyar M, Jovin IS, et al. Device closure versus medical therapy alone for patent foramen ovale in patients with cryptogenic stroke: a systematic review and meta-analysis. 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