From the original cohort of 110, 101 patients who had previously undergone HIFU AF ablation greater than 4 years ago were screened for inclusion in the study. 17 patients agreed to late electrophysiological study, Electrophysiological data from a further 2 patients who were previously ablated for on-going AF were also included. The studies were conducted at a mean of 65 months post-surgical HIFU isolation procedure. 14 underwent HIFU concomitantly with cardiac surgery, 3 had surgical AF ablation for lone AF and have previously been described in full.⁸

At routine follow up, patients were introduced to the study and invited to participate (EJD). Those who expressed an interest were given a patient information sheet (PIS) and were contacted by telephone to confirm willingness to participate 2-days later. Normal sinus rhythm (NSR) was confirmed by the absence of symptoms, a 7-day full disclosure ambulatory electrocardiogram (ECG) confirming absence of AF and a 12-lead ECG at time of recruitment. The AF group contained those patients having any documented recurrence of AF following a 3-month blanking-period post ablation. Patients with recurrences solely of atrial flutter (AFl) were included in the NSR group but described separately. The patient demographics (as at time of epicardial AF ablation) are shown in Table 1.

A transseptal electrophysiological study was performed in all patients. Patients with a CHA2DS2-VASc of <1 and on-going atrial arrhythmia were anticoagulated with either warfarin (target INR 2.0-3.0) or dabigatran (110mg bd) for a minimum of 3 weeks prior to the study. All diagnostic studies were performed as a day-case using IV sedation (diazemuls and diamorphine titrated to response). Access was gained via the right femoral and subclavian/internal jugular vein. A decapolar catheter was placed in the coronary sinus (CS) and a quadripolar catheter in the right ventricle. Using a standard Brockenbrough needle, a transseptal puncture was performed to allow passage of a steerable sheath - Channel, (BARD Electrophysiology) or Agilis® (St. Jude Medical) into the LA. Puncture was facilitated using a combination of contrast injection and pressure monitoring. IV heparin was administered to maintain the activated clotting time (ACT) at <300s for the duration of LA instrumentation. Pulmonary venography was performed for all PVs. A circular mapping catheter (Expandable Lasso or AFocus II, St. Jude Medical) was sequentially placed in all four PVs and flat on the PW. For patients in sinus rhythm at the time of the study, we tested for exit and entry block and recorded the conduction times between CS and PV. Those in AF at the time of the study were cardioverted (200J biphasic AP pad position) on a maximum of two occasions to allow for conduction to be assessed.

In selected cases of apparent PW isolation (defined as the absence of electrical activity, or evidence of spontaneous isolated atrial complexes), we tested for pace/detect within the PW. We passed a second catheter alongside the steerable sheath and used it alongside the mapping catheter to test for conduction contained within the isolated posterior wall.

In 7 patients with symptomatic drug refractory atrial arrhythmia, further ablation was performed, 5 cases for AF and 2 for AFl. A voltage map was produced using either CARTO (Biosense- Webster) or NavX (St Jude Medical). Using a contact force ablation catheter, additional lesions were delivered either around the pulmonary vein ostia and/or to complete the existing roof and floor lines created by the HIFU procedure. The ablation goal was validated PWI in the cases of AF recurrence.

Of the original 110 patients who underwent surgical AF ablation, 101 were still alive at screening follow-up. Nine had died in the interval: 4 from post-operative complications unrelated to the AF ablation procedure or use of the Epicore device, two died from malignant disease, one suffered an embolic stroke, one a traumatic intracerebral bleed and one from end-stage heart failure.

Of the six patients who had an absence of AF, only 3 were completely free from any atrial arrhythmia recurrence the remaining 3 had experienced episodes of documented atrial flutter. Of the 3 patients where no atrial arrhythmia had occurred since surgical ablation, two had originally experienced PsAF pre-operatively (cases 6&9) and the other infrequent PAF pre-operatively only (case 5).

In cases 6&9, there was no conduction into or out of the PW during capture pacing from the CS together with isolated atrial potentials throughout the pulmonary veins and the posterior wall (Figure 2).

Figure 2. (A) With the circular mapping catheter (PV) placed flat on the posterior wall, an isolated premature atrial beat is seen showing electrical isolation of this region during sinus rhythm. (B) Circular mapping catheter (PV) in the right upper pulmonary vein and capture pacing from the coronary sinus, there is no evidence of conduction into the vein. Also seen is a non-conducted pulmonary vein potential (case 9).

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In the patient with prior pre-operative infrequent PAF (case 5), there was no evidence of either exit or entry block from the posterior region (Figure 3).

Figure 3. In a patient with preoperative paroxysmal AF and freedom from any recurrent atrial arrhythmia. Pacing from CS distal demonstrates intact conduction between the coronary sinus and the posterior wall with a conduction time of 78ms (case 5).

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Of the 6 patients with freedom from AF, 3 have experienced documented recurrences of atypical paroxysmal atrial flutter. In 2 cases, the PW was found to be silent with intact block throughout the veins and posterior LA. The other one case had very delayed conduction between the PW and the CS (case 4). The area of conduction gap is identified near the RUPV (Figure 4)

Figure 4. In a patient with recurrence of paroxysmal left atrial flutter but freedom from atrial fibrillation. (A) Pacing from9-10 has a conduction time to CS of 230ms (B) whereas6-7 to CS is 260ms. (C) Earliest signal from CS pacing is seen in.9-10 (D) Fluoroscopy showing the circular mapping catheter on the posterior wall. The gap is therefore localised to the roof of the LA (case 4).

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In one of the cases of post-operative AFl, the patients remained symptomatic and we proceeded on to ablate a peri-mitral flutter circuit (case 16).

Figure 5. Mitral valve replacement, pre-operative longstanding persistent atrial fibrillation with symptomatic paroxysms of an atypical atrial flutter. (A) NavX voltage map illustrates the border of the scar delivered by the HIFU device and the electrically silent posterior wall. (B) Surface marking show density of recordings over the posterior wall. (C) A peri-mitral flutter was entrainment and ablated back to sinus rhythm by joining the mitral annulus to the adjacent inferior border of the HIFU scar. At 6-month follow-up, the patient has experienced no further arrhythmia (case 16).

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We studied a total of eleven participants with AF following the ablation procedure.

In all instances, persistent atrial electrograms were present throughout the PW and pulmonary veins, ranging from grade 1 to 5 in degree of fractionation.⁹ Cardioversion was performed to restore NSR and allow for the conduction between the CS and the PW/PV to be assessed; rapid reversion back to AF limited assessment in 7 cases.^7,10-¹⁵ Where tested, the conduction times between the PW/PVs and the CS are shown in Table 2. There were no instances of conduction bock in any of the persisting AF cases.

Figure 6. Aortic valve replacement and pre-operative long-standing persistent atrial fibrillation, on-going symptomatic paroxysms of atrial fibrillation. The circular mapping catheter is on the posterior wall. Capture pacing from the coronary sinus shows rapid conduction to the posterior wall around 40ms.

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In summary, of the 11 patients with post-operative AF, none showed any evidence of PW isolation. Conversely, of the 6 patients with absence of post-operative AF, 4 had electrically isolated PW, one had delayed conduction between PW and CS and one (post-operative infrequent PAF only) had intact conduction.

Figure 7. Coronary artery bypass grafting and pre-operative longstanding persistent atrial fibrillation; failed HIFU ablation with persistent atrial fibrillation. NavX voltage map shows minimal evidence of the transmural scar delivered by the HIFU apparatus and an electrically active posterior wall. In this image, the additional endocardial ablation points delivered to complete the box are shown as red dots and the CS catheter is shown in red (case 17).

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All cases who had additional ablation performed for post-operative AF are now in sinus rhythm (one on a class 3 antiarrhythmic) except one (case 17) in whom the posterior wall was not successfully isolated due to poorly tolerating the catheter ablation under sedation.

Possibly the first group to attempt a box pattern using catheters was Ernst et al. in 1999. The limited technology available at that time resulted in failure to achieve PWI in all of their cases.¹⁰ Todd et al. describes the initial 2003 experience following the combined open-chest surgical and catheter cryoablation box pattern for AF.¹¹ At 6-days post procedure, all cases had persistently intact posterior wall isolation, determined through epicardial wires. Late recurrent of atrial arrhythmias in one patient resulted in EP restudy - a gap was found in the posterior wall isolation, closure of which restored sinus rhythm. Todd demonstrated that the isolated PW was able to sustain atrial arrhythmia independent of the remaining atria; this finding has been replicated in our study.

Lim et al. provides a comprehensive assessment of the mechanisms of arrhythmia recurrence following single ring ablation delivered by catheter.¹² In 100 patients with an end-point of validated PWI, 69% experienced recurrence of an atrial arrhythmia (35% AF and 34% flutter). In those patients that underwent a redo procedure for recurrent AF, all had gaps in the ablation ring with conduction in and out of this region. In six of the patients, a flutter circuit was established through two gaps in the ring. Four patients had atrial flutter without evidence of atrial fibrillation and were found to have intact isolation of the posterior wall. The authors conclude that “electrically isolating the posterior LA may thus prevent the initiation and perpetuation of AF”. This agrees with the findings in our patients to mean follow-up of 63-months.

Tamborero et al.¹³ randomised patients undergoing AF ablation to receive PV-encircling lesions and roof-line alone or supplemented with a floor line to complete PWI. A redo procedure was performed in 20% of their patients, and in 67% of initial PWI group, conduction across the roof-line was seen, suggesting that failure of the PWI model was in part due to reconnection. They found no advantage to PWI attempted through the addition of a floor line compared to PV-encircling lesions and roof-line only. Sanders et al. provide a rare example of AF recurrence in one of 27 patients following box isolation in whom the PWI remained intact at restudy.¹⁴ That index patient required additional “substrate modification” to restore sinus rhythm.

Kumagi et al.¹⁵ studied a purely paroxysmal group who, at mean follow-up of 13 months following catheter box-set ablation, showed a 95% rate of freedom from AF. Six of these patients required a redo procedure, three for recurrences of AF and the others from organised/focal arrhythmia. In all cases of recurrence, gaps in the lesions lines were seen. In none of these cases of recurrence was the PW isolated.

A recent resurgence in interest in the box set pattern has come about as a result of the development of hybrid AF ablation techniques, combining epicardial ablation using a variety of platforms with catheter-based endocardial ablation. This has resulted in reported outcomes in the region of 90%. These studies have the potential to offer some further insight into the electrical consequences of a single ring approach.⁵ To date, little has been published on the association between on-going AF prior to the second (catheter) stage of the hybrid pathway and the subsequent EP findings. As technology matures, this is a key opportunity to gaining a greater appreciation into the mechanisms of PsAF.

While it is clear that many features of the posterior LA wall mark it out as a key area of substrate for the propagation and perpetuation of AF, other areas of the atria may also be involved. Such sites as the superior vena cava, LA appendage base, interatrial septum and the anterior LA wall have all been implicated in AF propagation to a lesser extent.¹⁶ In addition, CFAEs,¹⁷ rotors and right atrial autonomic ganglia¹⁸ have also been shown to reside in the non-isolated area.

Oesophageal injury and fistulae formation is a rare but potentially fatal complication arising from ablation delivered onto the posterior wall.¹⁹ There is no instance of oesophageal complication in any of the reported literature on the box-set, but given the relatively low reported numbers, it is difficult to derive many conclusions from this given that the overall rate is estimated at 0.1%.²⁰

Although the EP findings in patients with recurrent atrial arrhythmia following box isolation have previously been described, much less is known about long term invasive findings, especially in the group of patients with no recurrent arrhythmia. The bulk of the previous data comes from reports of patients undergoing transseptal procedures for organised atria arrhythmias. In the six patients free from AF in this present study, 4 had complete isolation of the PW, one had very delayed conduction through one gap near the right upper PV and one (who had experienced very little AF prior to surgery) had a non-isolated PW. The only patient who was AF free and was found to have a non-isolated PW was the only patient in the study with infrequent paroxysmal AF prior to surgery. This is maybe the reason for the clinical success despite the apparent electrophysiological failure. It may be that in such patients it is sufficient to modify the epicardial GP without necessarily achieving complete PWI for successful outcome.

Perhaps more interesting is our observation that in none of the patients with post-operative AF was the posterior wall isolation found to be intact. It can thus be hypothesised that the primary reason for failure to secure sinus rhythm is the failure of the technology used to deliver a complete transmural ablation ring, rather than the inappropriateness of the lesion pattern itself.

The aim of this study was to correlate the late clinical outcome with the electrical properties of the PW. The study achieved this endpoint. However, there are several limitations. Most significant is the low numbers included; a total of 17 patients of which only 6 had freedom from AF. This is in part due to the reluctance of patients with a clinically excellent outcome to undertake a further invasive procedure for no personal gain. The patient information provided was necessarily very comprehensive in describing potential adverse outcomes from what was on their part an entirely altruistic agreement to be studied. We observed a significant attrition rate during the waiting period between agreeing to enter the study and planned study date. All 31 patients who were contactable and eligible for inclusion in the sinus rhythm group were approached. Secondly, we would have hoped to gain an appreciation of the role of the ganglionic plexi (GP) in AF propagation post epicardial HIFU ablation. GP stimulation was excluded from the present study protocol. No initial ‘roadmap’ of their location had been made at time of surgery to guide which sites to address with high frequency stimulation. To attempt to stimulate all potential areas to would have prolonged the procedure beyond what was reasonable for these patients who had agreed to be studied under conscious sedation.