Initiation

It is a well-established fact that the electrocardiographic initiation of AF is associated with atrial premature beats (1) (Fig. 1). If they are successful in initiating AF, these

From: Contemporary Cardiology: Management of Cardiac Arrhythmias Edited by: L. I. Ganz © Humana Press Inc., Totowa, NJ

Fig. 1. Electrocardiographic events prior to spontaneously occurring AF. The recording is a modified MCL lead, obtained from a subcutaneously implanted loop recorder. The continuous recording initially demonstrates sinus rhythm. Atrial premature beats intercede in a bigeminal pattern, eventually initiating AF (arrow).

Fig. 1. Electrocardiographic events prior to spontaneously occurring AF. The recording is a modified MCL lead, obtained from a subcutaneously implanted loop recorder. The continuous recording initially demonstrates sinus rhythm. Atrial premature beats intercede in a bigeminal pattern, eventually initiating AF (arrow).

beats likely instigate, either immediately or eventually—multiple wavelet reentry (2). In what appears to be a distinct minority of cases, APDs arise rapidly and persistently, associated with atrial conduction patterns which vary, yielding the electrocardiographic appearance of AF (3a). Regardless, the hypothesis that ablating AF-initiating APDs will eliminate AF makes two assumptions: that their number is limited, and that the sites of origin are constant over time. This hypothesis has yet to be validated, but a remarkable amount of information has recently been accumulated. The "proof of concept" came first from the group in Bordeaux. Haissaguerre et al. described a cohort of patients with a clinical atrial arrhythmia syndrome including AF interspersed with atrial tachycardia and frequent ambient atrial ectopy (4,5). In each of these patients, the entire syndrome was the result of one or more "focal" (capable of being resolved by a single radiofrequency lesion deployed using standard ablation electrode) sites of origin, invariably associated with the myocardium investing the pulmonary veins. Ablation of these sites resulted in a cure, which has largely been maintained in follow-up (5,6). Other atrial areas have been documented to spawn AF-initiating APDs in the context of this syndrome, and these are also amenable to catheter ablation (7,8). Although this syndrome is rare, a growing body of data is addressing the initiation of AF in more common syndromes. The focus remains on the posterior left atrium and the pulmonary veins.

We have systematically catalogued the "sites of origin" (SOO) of AF-initiating APDs utilizing simultaneous multielectrode mapping (9) (Fig. 2). Forty-nine patients with antiarrhythmic drug-refractory AF, including paroxysmal, (including patients with frequent and infrequent ambient atrial ectopy), persistent, and permanent syndromes, have thus far been studied. In 38 of these patients, one or more spontaneous AF initiations were recorded (Fig. 3). In 28 patients, a single SOO was responsible for all observed AF events; in the remaining patients, 2-4 SOO were observed. Among 54 total SOO, 49 (91%) were pulmonary-vein-based. Pulmonary-vein SOO were approximately equally divided between intravenous (iv) (emanating from deep within a vein) and ostial (emanating from at/near a vein ostium) types, emphasizing the potential importance of posterior left atrial myocardium near the vein orifices. The clinical AF syndrome appeared to have little impact on the features of initiation.

Fig. 2. Multielectrode mapping arrangement, designed to "regionalize" the SOO of AF (see text). Catheters were placed simultaneously into right atrial (Halo = multi-electrode catheter sampling areas ranging from septum to free wall; HB = His bundle or high septal region), coronary sinus (CS), and left atrial (multi-electrode catheters placed into each "main" pulmonary vein: RSPV = right superior vein, LSPV = left superior vein, RIPV = right inferior vein, LIPV = left inferior vein).

Fig. 2. Multielectrode mapping arrangement, designed to "regionalize" the SOO of AF (see text). Catheters were placed simultaneously into right atrial (Halo = multi-electrode catheter sampling areas ranging from septum to free wall; HB = His bundle or high septal region), coronary sinus (CS), and left atrial (multi-electrode catheters placed into each "main" pulmonary vein: RSPV = right superior vein, LSPV = left superior vein, RIPV = right inferior vein, LIPV = left inferior vein).

Extensive embryologie and electroanatomic data suggests why the posterior left atrial and pulmonary venous myocardium would be a major seat of AF origin (10-12). More recent clinical data certainly testifies to the unique nature of this tissue (13,14). A particularly intriguing observation has been the frequent observation of left ventricular compliance abnormalities, even in the absence of echocardiography hypertrophy or hypertension history, among patients in whom AF initiated with pulmonary vein-based APDs. It is conceivable that left atrial hypertension resulting from the compliance abnormality causes remodeling of the posterior left atrium/pulmonary venous myocardium in a way which is proarrhythmic. If demonstrable, the details of such remodeling could have important therapeutic implications. However, it is important to recognize that we have barely scratched the surface. Critical issues in relating the current state of knowledge to the majority of patients with AF have yet to be addressed. For example, information regarding AF initiation in patients with significant structural heart disease is almost completely lacking. In addition, AF "onset mapping" is not intrinsically valid. It is possible that SOO which are recorded in the electrophysiology laboratory are irrelevant to the spontaneous ambulatory initiation of AF.

Nevertheless, the results of two relatively large single-center trials of focal ablation targeting SOO to suppress AF initiation have been published. Haissaguerre et al., in their latest report, have gathered 130 patients with paroxysmal AF (15). Among these patients, AF-onset mapping demonstrated 306 pulmonary-vein SOO. Catheter ablation of these foci has resuletd in antiarrhythmic drug-free suppression of AF (8-mo mean

Intracardiac Electrogram
Fig. 3. Intracardiac electrogram recordings bracketing the initiation of AF. The first beat is sinus. The next beat is the AF-initiating APD: the arrow demonstrates its origin, deep and within the right superior pulmonary vein.

follow-up) in 67% of patients. Chen et al., in their latest report, have gathered 167 patients with AF. Among these patients, mapping demonstrated 247 SOO. Catheter ablation of these foci has resulted in antiarrhythmic drug-free suppression (13-mo mean follow-up) in approx 80% of patients. This group has been particularly effective in demonstrating non-pulmonary-vein SOO: in their experience, approx 22% of sites were in other locations, including the superior vena cava (SVC) and the ligament of Marshall, crista terminalis, coronary sinus (CS), and left atrial body (16,16a,16b). This has been corroborated by others (17). Smaller series of focal AF ablation in patients with paroxysmal AF have also been presented, with highly varied results. In our own experience with focal ablation in 33 patients (42 foci), antiarrhythmic drug-free AF suppression (7-mo mean follow-up) has been observed in 55% of patients. Varied outcomes from otherwise experienced operators reflect the nascent state of this art. Difficult-to-communicate issues, such as patient selection biases, electrogram interpretation, ablation-site selection and ablation energy titration habits are some of the likely factors underlying the current variability in procedural success. Some groups have begun to expand the clinical profiles of their ablation cohorts. Haissaguerre et al. recently reported a cohort of 15 patients with persistent AF who underwent focal ablation, resulting in antiarrhythmic drug-free AF suppression (mean follow-up 11 mo) in 60% (18). Chen et al. have not had such a promising experience (19).

It is important to note that focal AF ablation procedures are currently beset by vexing

Carto Biosense Radiofrequency Ablation

Fig. 4. Electroanatomical map (CARTO™), (Biosense/Webster Inc., Diamond Bar, CA, USA) of ablation lesions encircling a right superior pulmonary vein in a patient in whom AF was consistently triggered by atrial premature beats emanating from myocardium deep within this vein. Each circle (A) represents the site of an individual focal radiofrequency energy application. The summed effect of this series of lesions was "electrical isolation" of the vein. (See color plate 2 appearing in the insert following p. 208.)

Fig. 4. Electroanatomical map (CARTO™), (Biosense/Webster Inc., Diamond Bar, CA, USA) of ablation lesions encircling a right superior pulmonary vein in a patient in whom AF was consistently triggered by atrial premature beats emanating from myocardium deep within this vein. Each circle (A) represents the site of an individual focal radiofrequency energy application. The summed effect of this series of lesions was "electrical isolation" of the vein. (See color plate 2 appearing in the insert following p. 208.)

logistical problems. For example, in many patients, once AF is started, it is difficult to resolve. This often leads to multiple cardioversions and limited onset mapping data, particularly when onset occurs within a few beats of cardioversion. Conversely, it is also common to observe patients with no/infrequent AF and sparse atrial ectopy. In many labs, selection of an ablation site is based on activation mapping, necessitating adequate ectopy. Patient behavior in the electrophysiology laboratory is largely unpredictable and ablation procedures are often abandoned. This limitation has led some groups to reduce their dependence on mapping. For example, we have gathered 15 patients in whom activation mapping could not be adequately performed. In each patient, available data suggested that AF initiation was caused by a focus/foci within a single pulmonary vein. This vein was "electrically isolated," utilizing sequential contiguous encircling focal ablation lesion applications at the venoatrial junction (20) (Fig. 4). This "anatomy-guided" procedure has resulted in antiarrhythmic drug-free suppression of AF (mean follow-up 8 mo) in 8 patients. Haissaguerre et al. have evolved to a technique which requires little or no atrial ectopy in designating "arrhythmogenic" pulmonary veins, with ablation performed in sinus rhythm (21). Pappone et al. have

Venoatrial Junction

Fig 5. Three-dimensional CT reconstructions of the left atria and proximal pulmonary veins (poster-oanterior view) from two patients with AF; magnifications are identical. In the left figure, the left superior (LSPV) and inferior (LIPV) pulmonary veins join the body of the left atrium independently. In contrast, in the right figure, the left superior and inferior veins join into a common vein which then joins the left atrial body.

Fig 5. Three-dimensional CT reconstructions of the left atria and proximal pulmonary veins (poster-oanterior view) from two patients with AF; magnifications are identical. In the left figure, the left superior (LSPV) and inferior (LIPV) pulmonary veins join the body of the left atrium independently. In contrast, in the right figure, the left superior and inferior veins join into a common vein which then joins the left atrial body.

taken the most extreme approach, advocating empiric isolation of all four main pulmonary veins (22).

Currently, focal ablation procedures are usually quite time-consuming, even in patients with in whom activation mapping can be adequately performed. This has raised safety concerns and has limited application. It is reasonable to strive for highly abbreviated procedures; this is certainly necessary from an economic perspective. In collaboration with the procedural problems described here, many have envisioned abandoning activation mapping altogether and proceeding with empiric pulmonary-vein ablation, accepting the potential for failure caused by non-pulmonary-vein triggering foci. To this end, an aggressive device development effort is underway by several manufacturers. Each has conceptualized electrical isolation of veins utilizing a catheter designed to create circumferential ablation lesions adjacent to an atriovenous junction. Several prototypes have been tested in animal models (23,24). These studies have emphasized the difficulties of such a venture. For example, Asirvatham et al. utilized intracardiac echocardiography to elucidate that, despite optimal fluoroscopic catheter deployment, contact of the ablation apparatus with the target area was incomplete, resulting in lesion failure (23). Critical considerations for circumferential pulmonary-vein ablation include the marked interindividual variability of human atriovenous anatomy (Fig. 5) and the distensibility of these areas (24a,24b). The first human data summarizing a multicenter experience with a catheter designed specifically to isolate pulmonary veins was recently reported by Natale et al. (25). In contrast to the conceptualized "single pass" efficacy of this device, vein isolation usually necessitated multiple lesion applications, and could not be achieved successfully in all veins (25).

Assuming that AF is not inherently life-threatening, the optimum "value" of catheter ablative cure would be to provide relief from AF-attributable morbidity/symptomatology in a cost-effective manner. This presupposes a low procedural complication rate. Unfortunately, serious complications have been reported in patients undergoing catheter ablation in the left atrium, most importantly cardioembolism and pulmonary-vein steno sis. Cardioembolism is well reported in association with left heart ablation. Although direct data are difficult to find, the incidence is likely to be higher with procedures that require longer dwell times, more hardware, and more extensive ablation (26-28). Cardioembolism has been reported after focal AF ablation (29). One important factor may be ablative energy titration technique (30). Given the variation in technique among investigators, it is difficult to determine the current magnitude of risk. Undoubtedly, this will remain a major obstacle for new catheter technologies. Stenosis has long been recognized as a sequela of operative trauma to the pulmonary veins. In the context of catheter ablation of AF, it was initially observed after deployment of linear lesions. In a study by Robbins et al., multiple vein stenoses had led to a syndrome of pulmonary hypertension (31). Stenosis is now well-described in association with focal ablation (29). Although human pathologic analyses are lacking, most data indicate that the mechanism of stenosis is heat-induced collagen contraction. Even single-vein stenosis can cause severe signs and symptoms. The risk of pulmonary-vein stenosis is currently unclear. Important considerations appear to include the number of lesions, ablative energy titration technique, and baseline vein lumen diameter. Most cases are apparent early after ablation; there seems to be no progressive or late-onset element (31a).

In summary, a reliable ablative cure of AF by targeting initiation should be currently classified as experimental. Although ablation in a small subset of AF patients has provided proof of concept, and has emphasized the importance of the posterior left atrium and pulmonary veins, relevance to "common" AF has yet to be determined. At present, applicability is highly limited. Efficacy rates remain rather low, even in the most experienced hands. Variation in patient selection and mapping/ablation technique inhibit the establishment of core principles. However, despite the problems, there is an astonishing amount of catheter development coalescing around the concept of empiric ablation in the posterior left atrium/pulmonary veins. Ironically, it will be the fruit of this development, by providing anatomical ablation end points reliably achieved and defined, that will permit progress in defining whether initiation ablation works, and for which patients.

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