Atrial fibrillation (AF) is the most common cardiac arrhythmia and is associated with an increased risk of morbidity and mortality.1 Despite important advances in its treatment, AF remains an independent predictor of both morbidity and mortality. Morbidity is related to frequent hospitalisations due to debilitating symptoms, heart failure (HF), stroke and systemic thromboembolism. The rise in hospital admission rates for AF among elderly patients worldwide is striking, and its cost to society is exponentially increasing in line with the ageing of the population and the rising prevalence of risk factors.
Natural History of Atrial Fibrillation in the Era of Catheter Ablation
At present, there are no prospective studies on AF progression and associated risks that allow us to evaluate the potential benefits of catheter ablation on the progression and clinical course of the arrhythmia. In an ongoing long-term prospective study conducted from 2002 to 2007 in our centre, we have observed that:
- about half of consecutive patients with first paroxysmal AF not due to potentially reversible causes had no further recurrences during a five-year follow-up in the absence of antiarrhythmic therapy;
- compared with patients with lone AF, those with associated diseases are more likely to rapidly progress to permanent AF despite conventional antiarrhythmic drug therapy (ADT);
- age, HF and diabetes are independent predictors of progression to permanent AF; and
- catheter ablation may be of benefit in delaying progression to permanent AF over a follow-up of five years.2,3
We also demonstrated that progression from persistent to permanent AF is faster than progression from recurrent paroxysmal to persistent AF despite conventional ADT.2 As a result, early ablation of subjects with AF at high risk of progression to permanent AF may be of benefit to avoid a late procedure when AF becomes permanent. Indeed, ablation targets for permanent AF are multiple: pulmonary vein (PV) isolation, vagal denervation, coronary sinus disconnection, roof and mitral lines and bi-atrial linear lesions. In patients with long-lasting or permanent AF, achievement of stable sinus rhythm directly or by intermediate atrial tachycardia (AT) and AF/AT non-inducibility may be time-consuming, with multiple sequential lesions and repeated procedures after the index procedure, which ultimately may be associated with a higher risk of complications. Taken together, these findings emphasise the need for early ablation, possibly at the time of paroxysmal recurrent AF, to avoid rapid progression to the permanent form, which in patients with concomitant diseases is associated with the highest risk of morbidity and mortality.
At present, limited long-term data detailing the impact of catheter ablation of AF on morbidity are available, but there are no randomised comparative studies on mortality in patients with AF undergoing AF ablation and ADT. One landmark non-randomised study by our group4 reported that AF ablation may reduce mortality compared with ADT in a large cohort of patients with paroxysmal (69%) or chronic (31%) AF followed up for about three years. No cardiovascular disease was found in about one-third of patients, and hypertension was the most commonly associated disease. In this study, survival for ablated patients was longer than that for the ADT group, and not different from that expected for healthy persons of the same age and gender.4 These results are important and indicate for the first time that an ablation strategy may indeed result in a mortality benefit, thus achieving one of the most important end-points. In fact, it is likely that long-term maintenance of sinus rhythm after ablation in the absence of currently available ADT may result in a mortality benefit; this needs to be confirmed in larger multicentre, randomised trials with a much longer follow-up period.
The possibility of performing catheter ablation safely in patients with HF is an important finding. Recently, Hsu et al.5 reported an improvement in cardiac function among patients who had no AF recurrences after AF ablation. If catheter ablation is safe and results in haemodynamic improvement, it will constitute a novel strategy for the management of patients with both AF and HF, in whom morbidity and mortality are highest.
Catheter Ablation for Atrial Fibrillation versus Antiarrhythmic Drug Therapy
Fuelled by dissatisfaction with ADT and following the development of catheter-based technologies over the last decade, catheter AF ablation has matured from an investigational technique to an effective alternative to ADT. The impressive improvement in the results of catheter ablation in all forms of AF compared with ADT over the last decade indicates that this approach can be considered early in the management of patients with AF, regardless of their baseline left ventricular function. Randomised studies have shown that catheter ablation is also superior to ADT in patients with ‘chronic’ AF,6–9 but whether this superiority translates into morbidity and mortality benefits remains to be demonstrated in future multicentre trials.
The first trial, by our group,4 was a long-term (median follow-up: 900 days), non-randomised study that demonstrated the striking superiority of AF ablation strategy over ADT in 1,171 patients with paroxysmal and chronic AF. The patients in the ablation group had longer arrhythmia duration (5.5 versus 3.6 years). Freedom from AF was significantly higher (78 and 37% in the ablated and medical groups, respectively). In addition, ablated patients had fewer hospitalisations than patients treated medically.
The second trial, by Wazni et al.,6 was a randomised study that compared AF ablation as a first-line strategy with long-term ADT among 70 patients with initial episodes of paroxysmal AF. PV isolation was superior to initial ADT at one-year follow-up (87 and 37%, respectively).
The third trial7 was a randomised study that confirmed the superiority of AF ablation strategy when combined with ADT over ADT alone (56 and 9%, respectively) in preventing AF recurrences among 137 patients with paroxysmal or persistent AF in whom ADT had already failed.
The fourth trial, by our group and the Michigan University Hospital,9 was the first multicentre, randomised study among 146 patients with chronic AF; it demonstrated that sinus rhythm was maintained long-term in the majority of ablated patients independently of the effects of ADT, cardioversion or both. The maintenance of sinus rhythm was associated with a significant decrease in both the severity of symptoms and the left atrial diameter, while no left atrial remodelling was observed in the group of patients assigned to ADT.
The last trial, by our group,8 was a randomised study among 198 patients with paroxysmal AF, and also demonstrated a striking superiority of ablation over long-term ADT with three widely used antiarrhythmic drugs – amiodarone, flecainide and sotalol – at maximum tolerable doses. Ablation was much more effective than amiodarone (86 and 35%, respectively) in preventing AF recurrences in the absence of serious complications. Asymptomatic post-ablation AF recurrences were recorded in about 3% of patients who also experienced symptomatic recurrences and in 27% of the ADT group.
Current Scenario of Catheter Ablation for Atrial Fibrillation
At present, catheter ablation represents a realistic and safe therapeutic option in almost all patients with AF, including those with long-lasting persistent AF.10 From 1999 to 2008 we performed more than 20,000 AF ablation procedures with an overall success of >90% in paroxysmal/persistent AF and 80% in permanent AF, with an acceptably low incidence of major complications.
As catheter ablation has progressed from treating patients with ectopic paroxysmal AF by eliminating PV potentials (PV isolation alone, whether ostial or antral, without additional substrate modification) to treating recurrent paroxysmal, long-lasting, persistent and permanent AF, the crucial role of treating the left atrial substrate has become evident (circumferential pulmonary vein ablation [CPVA] stepwise approach).
Recently, we demonstrated the benefit of vagal denervation in patients with paroxysmal AF undergoing AF ablation, and these findings remain a cornerstone in our understanding of AF pathophysiology and treatment.11 In the last few years, catheter ablation has allowed us to better understand AF mechanisms, but despite the development of newer technologies and tools most of them still remain unknown. Currently, we need more information on the pathophysiology of persistent/permanent AF to tailor or limit ablation targets to active substrates only, since patients with long-lasting or permanent AF now require an extensive ablation of both active and passive substrates with repeat procedures.
Targets of Catheter Ablation
In the majority of laboratories, procedural targets of catheter ablation for AF include PV electrical disconnection and additional lesion lines (mitral and roof lines, the endocardial/pericardial coronary sinus [CS] disconnection).10–16 The sequence of multiple targets essentially depends on the clinical form of AF (paroxysmal, persistent or permanent AF) and the patient’s clinical characteristics. Since it is difficult during the index procedure to determine which patients need substrate modification by linear lesions in addition to PV isolation, standard CPVA as performed in our centre also includes substrate modification in all patients with AF to improve the outcome.11–16
Pulmonary Vein Disconnection
PV isolation is the first step in all AF patients undergoing catheter ablation, and is performed by eliminating PV potentials as guided by the Lasso catheter or by encircling point by point the left and right PVs individually or in pairs. Validation of electrical isolation with a circular mapping catheter is not routinely performed in our laboratory since we perform a true distal electrical isolation, as confirmed by Lasso catheter, by potential abatement (>90% reduction of electrogram amplitude) even within the encircled areas (electrogram amplitude <0.1mV).
PV disconnection is obtained by optimal catheter stability and wall contact, which results in rapid attenuation of atrial electrograms during each radiofrequency (RF) energy application, up to complete elimination for up to 50 seconds. This usually takes a few seconds depending on the local effect. Partially ablated signals require further RF applications before moving on to the next ablation site.
Autonomic Targets with Vagal Denervation
Where possible, in our experience elimination of vagal reflexes at innervation sites during the procedure represents one of the most important targets, since vagal denervation is a strong predictor for long-term success. We first demonstrated that CPVA induces a long-term but transient vagal denervation that enhances the efficacy of the procedure in terms of long-term outcome.11 These results have been confirmed by many other authors using various AF ablation approaches, and vagal denervation now constitutes a fascinating new AF ablation strategy.
Our results on the modification of heart-rate variability (HRV) parameters after ablation provide new insights into the mechanisms of AF and its treatment. While performing the standard CPVA lesion set, RF applications evoke vagal reflexes in up to 30% of patients. Vagal reflexes are considered to include sinus bradycardia (<40 beats per minute), asystole, AV block and hypotension that occurs within a few seconds after the onset of RF application. If a reflex is elicited, RF energy is delivered until such reflexes are abolished, or for up to 30 seconds. The end-point of ablation at these sites is termination of the reflex, followed by sinus tachycardia or AF. Failure to reproduce the reflexes with repeated RF applications is considered as confirmation of denervation. Complete local vagal denervation is defined by the abolition of all vagal reflexes. Based on our experience, we always attempt to elicit and then ablate potential sites of reflexes for vagal denervation. We reported a detailed ‘autonomic map’ of the left atrium as a target for ablation, showing that, like the left superior PV, the septal region is richly innervated.11
Linear Lesions
Additional ablation lines alter the AF substrate by eliminating large macro-re-entrant circuits able to sustain AF and/or AT.10–16 Standard CPVA linear lesions include the mitral isthmus line, the roof line and the posterior wall line.11–16 Multiple additional linear lesions in the left atrium or right atrium (bi-atrial lesions) are required in patients with permanent AF to obtain stable sinus rhythm or AF/AT non-inducibility at the end of the index procedure (CPVA stepwise approach).
Each ablation target is performed sequentially based on the cumulative increase of AF cycle length until conversion to sinus rhythm or an AT, which is then mapped conventionally and ablated.10 In our experience, completeness of lesion lines is important, but in many cases achievement of complete block is unnecessary – particularly in the mitral isthmus line, where a delay of about 100ms is sufficient to prevent post-ablation macro-re-entrant left AT. If necessary, adjunctive linear ablation (usually the septum or the base of the left anterior ascending [LAA]) is performed before CS isolation, which is the last target.
Coronary Sinus Disconnection
If AF/AT inducibility persists even after cardioversion, we accurately revisit lesion lines and encircled areas to check for residual potentials, and apply RF where needed. Conduction block is assessed by the presence of a corridor of double potentials and demonstration of activation moving towards the line of block on both sides. Rapid atrial activity from the musculature of the CS may be a driver for long-lasting or permanent AF. Electrical disconnection of the coronary sinus from the atrium is performed by endocardial or epicardial ablation, or both. Total elimination of CS activity is the ideal end-point, but organisation of CS activity and/or slowing of local rate with dissociation between CS and left atrium potential activity is also considered proof of CS isolation. Endocardial and/or epicardial CS sites are frequent ablation targets in patients with permanent AF and enlarged atria.
Post-ablation Artrial Fibrillation
If targets are successfully achieved in the index procedure, post-ablation ATs may develop in fewer than 5% of patients, and usually are macro- or microre- entrant gap-related rather than focal tachycardias.13 In our extensive experience, these ATs should initially be treated conservatively, with medical therapy and cardioversion.13–16 Only incessant ATs in symptomatic patients require a repeat procedure with accurate mapping to optimise ablation therapy, which will lead to a cure in most cases.13–16
Technical Improvement
Currently, most catheter ablation procedures in patients with AF are performed with manual catheters, which requires advanced operator skills and experience with catheter manipulation and ablation. The feasibility of the remote system, which is not operator-dependent, may represent an attractive alternative approach in many laboratories worldwide to reproduce the success rates of the pioneering groups while minimising risks.16–18 Currently, two main systems for magnetic and robotic navigation are available for clinical use (Stereotaxis and Hansen systems, respectively). The recent availability of remote tip-irrigated magnetic catheters will enhance the benefits of the remote magnetic system (Stereotaxis), making deeper lesions than with manual catheters regardless of the operator’s experience. At present, limited data are available on the efficacy and safety profile of balloon technology. Balloon technology for PV isolation is not frequently used, as in most patients with AF catheter ablation is not limited to PV disconnection alone, and the achievement of additional multiple targets precludes its use. In addition, PVs have largely variable anatomies from patient to patient, with a wide range of diameters, and the frequent presence of common ostia in up to 30% of patients makes the use of balloon-based catheters challenging.
Conclusions
Catheter ablation of AF may provide a true cure rather than only palliative therapy, as provided by ADT, in most patients with AF. The first randomised trials comparing catheter ablation with long-term ADT in patients with AF demonstrated a striking superiority of ablation with higher efficacy, lower morbidity and improved quality of life. In patients with long-lasting or permanent AF, multiple sequential lesions and repeat procedures are still required to achieve a stable sinus rhythm, which emphasises the need for a tailored approach to limit extensive unnecessary bi-atrial lesions.