Device-less patent foramen ovale closure by radiofrequency thermal energy

The goal of this study was to assess the feasibility, safety and success of a system which uses radiofrequency energy (RFE) rather than a device for percutaneous closure of patent foramen ovale (PFO). Methods: Sixteen patients (10 men, 6 women, mean age 50 years) were included in the study. All of them had a proven PFO with documented right-to-left shunt (RLS) after Valsalva manoeuvre (VM) during transoesophageal echocardio graphy (TEE). The patients had an average PFO diameter of 6 ± 2 mm at TEE and an average of 23 ± 4 microembolic signals (MES) in power M-mode transcranial Doppler sonography (pmTCD), measured over the middle cerebral artery. An atrial septal aneurysm (ASA) was present in 7 patients (44%). Balloon measurement, performed in all patients, revealed a stretched PFO diameter of 8 ± 3 mm. In 2 patients (stretched diameter 11 and 14 mm respectively, both with ASA >10 mm), radiofrequency was not applied (PFO too large) and the PFO was closed with an Amplatzer PFO occluder instead. A 6-month follow-up TEE was performed in all patients. Results: There were no serious adverse events during the procedure or at follow-up (12 months average). TEE 6 months after the first RFE procedure showed complete closure of the PFO in 50% of the patients (7/14). Closure appeared to be influenced by PFO diameter, complete closure being achieved in 89% (7/8) with a balloon-stretched diameter ≤7 mm but in none of the patients >7 mm. Only one of the complete closure patients had an ASA. Of the remainder, 4 (29%) had an ASA. Although the PFO was not completely closed in this group, some reduction in the diameter of the PFO and in MES was documented by TEE and pm-TCD with VM. Five of the 7 residual shunt patients received an Amplatzer PFO occluder. Except for one patient with a minimal residual shunt, all showed complete closure of PFO at 6-month follow-up TEE and pm-TCD with VM. The other two refused a closure device. Conclusions: The results confirm that radio frequency closure of the PFO is safe albeit less efficacious and more complex than device closure. The technique in its current state should not be attempted in patients with a balloon-stretched PFO diameter >7 mm and an ASA.

The diagnosis, evaluation, and treatment of PFO have attracted increasing interest as the importance and frequency of its implication in several pathologic processes has been recognised.
Pre-clinical animal studies have been performed to demonstrate the safety and feasibility of the PFx closure system using radiofrequency energy (RFE) in 29 pigs.A native PFO was present in 17 of the 29.RFE was successfully applied in all cases and 6 of the 7 PFO were closed.First degree atrioventricular (AV) block occurred in 2 of the 17 animals but there were no other complications [34,35].Histology was evaluated in 19 pigs at 6 weeks.All animals had healing fibrosis and inflammation with complete endothelialisation of both right and left atrial surfaces without thrombus.
The first human study to demonstrate the safety and feasibility of the PFx closure system for the treatment of PFO was the Paradigm I study.Thirty patients were enrolled (15 females, 15 males, mean age 48 years).Mean PFO size was 8.5 ± 2.7 mm (stretched diameter).RFE application was achieved in 27 patients.The remaining 3 patients received an implantable closure device.Patients were free from serious adverse events.Thirteen of the 30 patients (43%) had complete PFO closure following the first procedure.Nine of the patients underwent a second procedure using RFE.Five of the 7 were closed following the second procedure, resulting in a secondary closure rate of 60% [36].
The purpose of the current study was to further assess the safety, feasibility, and technical success of the new system.

Patients
Inclusion criteria were age 18-65 years, PFO grade 02 (more than 6 crossed bubbles visible on a still frame of the left atrium), cryptogenic stroke (11 patients), divers with a history of diving incidents (1), or debilitating migraine (3).
Exclusion criteria were active infection, atrial thrombus, pregnancy, atrioventricular block, or atrial septal defect with left to right shunt.The study was approved by the Bern Ethics Committee, and all patients gave informed consent.

PFO closure technique
The PFx™-PFO closure system (CIERRA Inc.Redwood City, CA, USA) produces monopolar RF energy, which denatures the tissue to the end of fusing the tunnel between the atrial septum secundum and septum primum at the level of the fossa ovalis, thereby closing the PFO.The procedure is carried out from the groin through the inferior vena cava and the right atrium.The metal electrode, which is connected to the RF generator, has a diameter of 15 or 19 mm.It has an elastomeric distal housing which covers the electrode.
An external generator produces the ablation energy.It monitors impedances and has an automatic shut down feature, germane to standard electrophysiology ablation equipment.As the energy is monopolar, a defibrillator pad is used as the return electrode.The procedure was carried out under TEE (Acuson Sequoia, Siemens, Erlangen, Germany) and fluoroscopic guidance.All patients    were intubated under general anaesthesia during the procedure.
Prior to the PFO closure, the diagnosis of PFO was confirmed by contrast TEE.A multipurpose catheter was then inserted into the right femoral vein, and a guidewire passed through the PFO.A measuring balloon was passed over the guidewire and expanded with contrast media within the PFO to assess the PFO's stretched diameter to determine suitability for the procedure per protocol.Another TEE examination of the PFO without VM was repeated after the balloon measurement to exclude balloon induced anatomical changes.
A 16 French (5.5 mm) sheath was inserted into the patient's femoral vein to accommodate the PFx-15 closure system.The system was passed over the guidewire until it reached the PFO.Its position was monitored by TEE and fluoroscopy (fig. 1 and 2

left).
Once the position of the distal catheter was confirmed, suction was applied at the bell-shaped end of the catheter to hold the septum primum and secundum in place and united.In this stable position RFE was delivered via the catheter to close the PFO (fig. 1 and 2 right).RFE causes the tissue temperature to rise to about 40-60 °C which induces denaturation of collagens and proteins to weld the tissues of the septum primum and septum secundum together at the level of the fossa ovalis.
After completion of RFE application a TEE bubble study without VM was performed.The PFx closure system and the vascular access sheath were then removed, haemostasis was achieved using manual compression and the patients were extubated.

Follow-up
On the day following the intervention, a transthoracic echocardiography, a pm-TCD, and a 12-lead ECG were performed before discharge.All patients were instructed to take acetylsalicylic acid 100 mg daily for 1 month and clopidogrel 75 mg daily for 6 months.Follow-up examinations included a 12-lead ECG at 1, 3, 9, and 12 months after the intervention.Six months after the intervention TEE and pm-TCD were repeated to screen for a residual shunt.

Patients
Between May and November 2006, 16 patients (mean ag 50, range 21-75 years, 6 females) were enrolled in the study.All of them had a proven PFO grade >2 with documented RLS during VM.The patients had an average PFO diameter of 6 ± 2 mm at TEE with VM and an average of 23 ± 4 microembolic signals (MES) in pm-TCD measured over the middle cerebral artery (Terumo Cardiovascular Systems Corporation, Ann Arbor, MI 48103, USA).Seven of the 16 patients (44%) had an atrial septal aneurysm (ASA) associated with PFO.The indications for PFO closure were secondary prevention of cryptogenic stroke (n = 11), diving incident (n = 1), or migraine headaches refractory to medical treatment (n = 3).

Intervention
Balloon measurement, performed in all patients, revealed a stretched PFO diameter of 8 ± 3 mm.Overall, the agreement between PFO diameters measured at TEE and during balloon sizing was 1:1.3.
Two of the 16 patients had to be excluded because their stretched PFO diameter measured by balloon sizing was >10 mm (11 and 14 mm) and the PFx catheter was unable to seal successfully for suction.Both had an ASA.Their PFO were closed during the same procedure with a 25 mm and 35 mm Amplatzer PFO occluder respectively, with complete closure in 1 and 1 minimal residual shunt in the other at 6 months in TEE and pm-TCD during VM.

PFO closure rate
The definition of the PFO closure rate was based on TEE 50% (7/14) rather than on pm-TCD 36% (5/14) in the 6-month follow-up examination.No differences of persistence of a right-to-left shunt were recorded early after the intervention and at the 1, 3, 6, and 12-month follow-up examinations (TTE with pm-TCD at 1, 3 and 12 months and TEE with pm-TCD at 6 months).
The PFO closure rate was 89% (7/8) in patients with a balloon stretched diameter 97 mm, while closure was not achieved in any of the 6 patients with a diameter >7 mm.The mean PFO diameter of the 7 patients with successful closure by TEE had been 4 ± 1 mm with a balloon stretched diameter of 6 ± 2 mm.The mean MES had been 20 ± 3 signals in pm-TCD.Only 1 of these 7 patients had an associated ASA.The 7 patients with residual shunt at the 6-month TEE with pm-TCD evaluation had had a larger mean PFO diameter of 7 ± 2 mm (balloon stretched diameter of 9 ± 2 mm prior to the intervention) and 4 of them had an ASA.In pm-TCD an average of 24 ± 3 MES had been recorded in these patients before RF application.However, 6 months after RF application PFO diameter was reduced in these unsuccessful cases to 6 ± 2 mm, and only an average of 17 ± 2 MES were still recorded in pm-TCD.PFO closure with a 25 mm Amplatzer PFO occluder was performed in 5 of the 7 patients with residual shunt at TEE 6 months after the RF therapy.Except for one patient with a minimal residual shunt (grade 1), all of them showed complete closure at 6 months after the second procedure with TEE and pm-TCD.The two remaining patients refused device closure.

Clinical follow-up
During a follow-up of 12 ± 2 months there were no serious adverse events or recurrent embolic events.Two patients (14%) presented with transient atrial arrhythmia, 3 patients (21%) had a new first degree atrioventricular block and 2 patients (14%) a new partial right bundle branch block.

Discussion
This study confirms that PFO closure without device implantation by use of radiofrequency energy [34][35][36] is acceptably safe.There were no major procedural or follow-up complications.In general the reported events were comparable to those identified in the Paradigm 1 study using the same technique in larger studies evaluating implant devices [36].
However, despite the exclusion of patients deemed unsuitable for RFE closure and counting only residual shunts documented by TEE, the closure rate of PFO at the 6-month TEE was only 50% (in balloon-stretched diameter <7 mm 89%).The current maximum RFE application electrode size is 19 mm, which is apparently not suitable for larger PFO >7 mm (balloon-stretched diameter).Larger catheters are under development and could improve inclusion range and success.Notwithstanding, it will probably be more difficult to produce a tight seal for suction with them.The primary closure rates with current doubleumbrella devices are as high as 90% [2].Of the 7 RFE failures in the study who received an Amplatzer PFO occluder only 1 had a minimal residual shunt at follow-up compared with 9/14 with at least a minimal shunt in the RFE patients.Compared with device closure, RFE closure is of lower efficacy and more complex.Thus, despite the advantage of avoiding an implant, RFE closure is not competitive for PFO (balloonstretched diameter) >7 mm pending refinement of the technique.PFO ≤7 mm (balloon-stretched diameter) involve little likelihood of paradoxical embolism.

Figure 1 Left:
Figure 1 Left: Balloon measurement of a PFO in a 37-year-old woman representing a case for the technique.The marker distance of 15 mm is indicated.The tunnel measures 8 mm both in length and diameter.Right: TEE aspect of the measuring balloon; LA = left atrium; RA = right atrium; B = balloon.

Figure 3
Figure 3PFO diameters before (pre) the intervention and at 6 months (Fu).

Figure 4
Figure 4Power M-mode transcranial Doppler device microemboli signals before (pre) the intervention and at 6 months (Fu).

Figure 2
Figure 2 Left: Devices under suction during heat application adhering to both the septum secundum (SS) and septum primum (SP).C = RF catheter.Right: TEE aspect during heat application.SS = septum secundum; SP = septum primum; LA = left atrium; RA = right atrium; C = RF catheter.