The Anatomical Basis of Pulmonary Vein Reconnection After Ablation for Atrial Fibrillation

Abstract

Atrial fibrillation (AF), the most common cardiac arrhythmia, is a major cause of strokes, hospitalizations, and mortality in the United States. The toll of AF is expected to worsen in coming decades as the number of elderly Americans increases (1). This harsh demographic reality has provided an impetus to seek new strategies to prevent, control, and eliminate the arrhythmia. About a decade ago, it was discovered that AF is frequently triggered by ectopy or bursts of tachycardia that originate in muscle bundles that extend from the atrium to the pulmonary veins (PVs) (2) and that electrical pulmonary vein isolation (PVI) by transcatheter ablation can maintain sinus rhythm. The past decade has witnessed great enthusiasm for PVI. With current techniques, 50% to 60% of patients remain in sinus rhythm 1 year after a single procedure (3), but the remainder show early or late recurrence of AF (4).

In almost all cases in which AF recurs after PVI, 1 or more of the PVs is found to have re-established electrical connection to the atria (5–9). Although the pathological basis of PV reconnection is not known, it is suspected to be caused by gaps in the line of ablations (10) or failure to produce completely transmural lesions (11), both undetected at the initial procedure. However, reconnection could also theoretically result from tissue remodeling or via additional conduits such as the ligament of Marshall (12). A better understanding of the mechanism of electrical reconnection may allow modification of current procedural techniques or development of new tools to achieve more durable PVI.

In this issue of the Journal, Kowalski et al. (13) provide unique human data on the histopathology of the PV–left atrial junction after PVI. To test whether PV reconnection is associated with failure to produce a transmural scar, the investigators took a simple yet ingenious approach. They studied patients who were undergoing a surgical Cox maze III procedure for recurrent AF after an initially successful PVI procedure. All patients (N = 12) were reported to have had complete electrical isolation of all 4 PVs at the time of the index procedure. Epicardial mapping revealed that 34 of 48 (71%) PVs had re-established electrical connection to the atria. As in previous studies (5–9), most patients (10 of 12 [83%]) had at least 1 reconnected PV. After atriotomy, the authors examined the endocardial surface for scars and obtained 22 full-thickness biopsy specimens of the atrium at points where the atriotomy line crossed previous ablation lesions. Thus, although sampling was limited to the prescribed surgical incisions, biopsy specimens that were taken passed through visually confirmed prior ablation lesions. Biopsy specimens were classified as showing a transmural scar, a partial-thickness scar with viable myocardium, or entirely viable myocardium.

The authors’ results are summarized in Table 1. Biopsy results from PVs that maintained electrical isolation were more likely to show transmural scar (5 of 7 [71%]) than PVs that had reconnected (6 of 15 [40%]; p = 0.36, Fisher exact test). The results fall short of statistical significance, probably because of the small number of samples. Of note, although one may expect that reconnected veins would show gaps in the ablation line, actual biopsies showed an equal distribution of histological types. Interestingly, biopsy results from reconnected veins showed an even distribution across histological types even though one may expect a preponderance of biopsy specimens showing gaps in the ablation line. In these cases, gaps sufficient for PV reconnection may have been missed because it was not technically feasible to take biopsy specimens along the entire circumference of the PV. The authors concluded that electrical PV reconnection was frequently seen in patients with recurrent AF after initially successful PVI, and that the return of PV conduction was associated with histopathologic evidence of nontransmural lesions along the ablation line.

Table 1.

Summary of Study Results

Finding	Transmural Scar	Partial Scar	Viable Myocardium
Nonconducting PV	5	1	1
Conducting PV	6	6	3

Numbers of specimens in each category shown.

PV = pulmonary vein.

The authors should be commended for obtaining unique human atrial biopsy data after transcatheter PVI and correlating them with the presence or absence of electrical PV connection. The results of this pilot series are consistent with the hypothesis that PV reconnection is caused by an anatomic gap in the ablation line or by failure to produce a transmural scar. Just as importantly, the findings raise several intriguing questions. Two PVs in the series showed complete electrical isolation even though corresponding biopsy results contained viable (i.e., nontransmurally scarred) myocardium. This counterintuitive finding may be explained by conduction block from scar proximal to the biopsy site or potentially from source-sink effects. Furthermore, previous work from the authors’ laboratory has shown that tissue geometry may enable conduction block despite discontinuous ablation lines (14). A recent computer modeling study revealed that the size of the maximum permissible interlesion gap varies with tissue conductivity (10), such that in a canine model with reduced conductivity (e.g., from ablation-related heating or inflammation), conduction was blocked despite 3- to 5-mm gaps in ablation lines. Thus, despite acute PVI at the index procedure in the series by Kowalski et al. (13), PVs could theoretically have reconnected with recovery of inflamed tissue without postulating healing of ablation lesions. Conductivity could also recover with reversal of electrical remodeling from reduced AF burden (15,16).

Recovery of PV conduction over longer time periods may have a different mechanism. The median time to AF recurrence in this study was 3.5 months (range 1 to 20 months), and others have reported recurrence as late as 5 years after ablation (17). Surprisingly, Kowalski et al. (13) also report that tissue within PVI scar exhibited nuclear pyknosis and myocytolysis months and even years after the index ablation, suggesting that tissue can remain viable and capable of recovery over a prolonged period of time. Late reconnection may also occur through tissue remodeling or through conduction across PV-atrial conduits (e.g., the ligament of Marshall) that were undetected or nonfunctional at the time of ablation (12).

Finally, durable PVI is not invariably associated with the absence of AF. As stated in the present study (13), 2 patients had recurrent AF despite electrical isolation of all 4 PVs. It is possible that recurrent AF in these patients was triggered and maintained by tissue outside the PVs (8,9). Extra-PV mechanisms are more likely to cause persistent AF than paroxysmal AF, and future studies should relate recurrence to PV reconnection in patients with both types of AF. Interestingly, it has been shown that PVs may reconnect even in patients without recurrent AF (18). Whether this finding reflects insensitivity of clinical detection for AF, reconnection of only “nonculprit” PVs, or other mechanisms remains uncertain.

How should these results affect clinical practice? Clearly, PVI is more likely to be successful if lesions are transmural and contiguous. However, better indicators of transmural damage are required than acute loss of conduction. Administration of adenosine or adenosine triphosphate (with or without isoproterenol) may unmask dormant PV conduction (19–21), although the relevance of this finding has recently been questioned (22). PV conduction may also be transiently unmasked after cardioversion (23). Late gadolinium enhancement on magnetic resonance imaging immediately after ablation can identify nonenhancing lesions that may form scar (11) and distinguish scar from pathologies such as edema (24). Such imaging may enable improved techniques to ensure more durable PVI.

In summary, Kowalski et al. (13) should be commended for an elegant and highly relevant clinical study. They have provided objective pathological evidence in humans supporting the hypothesis that PV reconnection is caused by a failure to form a permanent uninterrupted surrounding electrical barrier despite acute evidence for isolation. They also show, counterintuitively, that PVs may remain electrically isolated despite clear gaps in ablation lesions and provide tissue data that may refine our concepts on ablation lesion recovery. Future studies should extend this work to test whether improvements in imaging, PVI, or other techniques will provide more robust success from AF ablation.