Could Low-Voltage Areas Identified on Voltage Mapping Be Ablation Targets for Catheter Ablation of Atrial Fibrillation?

Following the seminal identification that the pulmonary veins (PVs) and their antra are the major trigger and substrate of atrial fibrillation (AF), catheter ablation of AF has become an established treatment strategy, and PV isolation (PVI) is the cornerstone strategy irrespective of AF type. However, in a subset of the population (patients with advanced atrial remodeling and those with underlying atrial diseases), the AF freedom after ablation is suboptimal. Although several substrate-based ablation strategies have been proposed, to date there has been no uniformly accepted and successful technique showing additional benefit after PVI.

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It is well recognized that atrial remodeling involving atrial fibrosis and scarring is a factor of AF pathogenesis due to several mechanisms, including conduction slowing predisposing to reentry. Scar can be detected by late gadolinium enhancement magnetic resonance imaging,¹ but the evaluation of atrial scar is challenging in thin-walled atria, and dense scar correlates to a certain extent with low-voltage areas (LVAs) identified on the endocardial voltage map. Several studies have demonstrated that the presence of LVAs are a strong predictor of AF recurrence after catheter ablation irrespective of AF type.² Against that background, LVA-guided ablation was initially proposed by Rolf et al in 2014 as a tailored atrial substrate modification method.³ They reported that LVAs were detected in 35% and 10% of patients with persistent and paroxysmal AF, respectively, and additional LVA-based substrate modification improved the AF freedom in patients with LVAs, which was similar to the AF freedom in patients without LVAs. Subsequently, several groups investigated the feasibility of the LVA-guided substrate modification in AF ablation presumably because of the theoretical rationality and technical easiness (Table).^4–10 Most of the published studies have shown a favorable effect on AF freedom of additional LVA-guided ablation following PVI; however, they have been single-center observational studies, which included potential patient selection biases.^3–5,7,10 In addition, the randomized studies did not set the PVI alone as the control group.^6,8,9 Importantly, there are no published studies that have evaluated the additional effect of LVA-guided ablation after PVI on clinical outcomes in a prospective randomized fashion.

Table. Published Literature on LVA-Guided Ablation

Year	Authors	Study design	Group	n	LVA	Ablation strategy	Follow-up	AF freedom
2014	Rolf et al3	Retrospective	Study	47	LVA+	PVI+LVA	12 months	70%
				131	LVA−	PVI		62%
			Control	26	LVA+	PVI		27%
2016	Jadidi et al4	Retrospective	Study	62	LVA+	PVI+limited LVA	13 months	69%
				23	LVA−	PVI
			Control	66	Unknown	PVI		47%
2016	Yamguchi et al5	Retrospective	Study	39	LVA+	PVI+LVA	18 months	72%
				62	LVA−	PVI		79%
			Control	16	LVA+	PVI	32 months	38%
2017	Yang et al6	Prospective randomized	Group-1	52	LVA+	PVI+LVA	18 months	74%
				62	LVA−	PVI
			Group-2	115	Unknown	Stepwise		71%
2017	Yagishita et al7	Retrospective		42	LVA−	PVI	12 months	71%
				159	LVA+	PVI+LVA		72%
2018	Kircher et al8	Prospective randomized	Group-1	19	LVA+	PVI±linear ablation	12 months	42%
				41	LVA−
			Group-2	16	LVA+	PVI+LVA		68%
				46	LVA−	PVI
2019	Kumagai et al9	Prospective randomized	Group-1	21	LVA+	PWI	24 months	62%
			Group-2	33	LVA+	PWI+LVA		67%
				61	LVA−	PWI		82%
2020	Nery et al10	Retrospective	Study	95	LVA+	PVI+LVA	18 months	72%
			Control	50	LVA−	PVI		58%
2021	Masuda et al11	Prospective randomized		336	LVA−	PVI	25 months	81%
			Group-1	30	LVA+	PVI+LVA		43%
			Group-2	32	LVA+	PVI		41%

AF, atrial fibrillation; LVA, low-voltage area; PVI, pulmonary vein isolation: PWI, posterior wall isolation.

In this issue of the Journal, Masuda et al¹¹ report extended follow-up (median 25 months) data of the VOLCANO trial, which demonstrated comparable 1-year rhythm outcomes between patients with and without ablation targeting LVAs in addition to PVI among paroxysmal AF patients with LVAs. Among 402 paroxysmal AF patients, LVAs were present in 60 patients randomly allocated to 2 groups with (group B) and without LVA ablation (group C). The AF/atrial tachycardia (AT) freedom was higher in the patients without (group A) than in those with LVAs (group B+C), and was comparable between groups B and C after single and multiple procedures. During the repeat procedures, a total of 31 ATs, including 6 bi-atrial ATs, were mapped, and the incidence of regular ATs was higher in group B than in group C. The most interesting findings were that (1) LVA-guided substrate modification had no beneficial effect on the clinical outcomes, and (2) LVA ablation increased iatrogenic AT development during repeat ablation, especially bi-atrial tachycardia after an anterior-septal LVA ablation. The results seem to be reasonable because LVAs are most frequently observed on the LA anteroseptal wall,¹² and an LA anterior linear lesion often predisposes to the occurrence of bi-atrial ATs.¹³ The most likely explanation is that the LVAs are the result of underlying atrial myopathy and that LVA ablation newly creates a critical isthmus for iatrogenic ATs in the LVAs. Naturally progressing atrial fibrosis and ablation-related fibrosis may have a different effect on the rhythm status. The limitations of the study were (1) voltage mapping with a circular mapping catheter (no use of high-density mapping catheter), (2) relatively short follow-up period to evaluate recurrent spontaneous clinical ATs, and (3) the endpoint of the LVA ablation was not clear as in the other studies. Nevertheless, the study results suggest consideration of the optimal ablation strategy for AF patients, and I congratulate the authors on this excellent study.

Although atrial fibrosis plays an important role in the perpetuation of AF, we need to recognize that while the terms “LVA” and “scar/fibrosis” are often used interchangeably, there is a fundamental difference between them and the voltage amplitude should not be used as a reference to quantify myocardial tissue fibrosis. In general, atrial LVAs are defined as areas with bipolar amplitude <0.5 mV during sinus rhythm or atrial pacing. However, the bipolar voltage amplitude is influenced by multiple factors, including the conduction velocity, fiber orientation and curvature, activation vector, characteristics of the recording catheter (electrode size, interelectrode spacing, and orientation relative to the tissue), tissue contact, filtering, mapping density, and mapping resolution, and this has been shown in both animal and human studies.¹⁴ Thus, voltage mapping alone is neither sensitive nor specific enough to assess tissue fibrosis. We should also recognize that the relationship between fibrosis and AF is unclear and that the sole presence of fibrosis does not imply increased arrhythmogenicity. Indeed, AF mechanisms cannot be simply explained by localized mechanisms and both atria contribute to the maintenance.¹⁵ In addition, although “homogenization” is a well-used ambiguous term as an endpoint of ablation, this does not imply the creation of a transmural lesion. A half-baked radiofrequency lesion may further promote the occurrence of iatrogenic ATs. So far, we have no universally effective ablation strategy beyond PVI for this patient population to improve their clinical outcomes. We need to wait for the results of ongoing multicenter prospective randomized studies to answer the question of “whether LVAs could be an ablation target in AF ablation”.

Conflict of Interest

The author belongs or has belonged to endowed departments of Medtronic, Boston Scientific, Abbott, DVx, Japan Lifeline, APEX, WIN INTERNATIONAL, and received lecture fees from Boehringer Ingelheim, Medtronic, Boston Scientific, Bristol Myers Squibb, Daiichi Sankyo, and received research funding from Johnson & Johnson for the past 3 years.

References

• 1.   Oakes RS, Badger TJ, Kholmovski EG, Akoum N, Burgon NS, Fish EN, et al. Detection and quantification of left atrial structural remodeling with delayed-enhancement magnetic resonance imaging in patients with atrial fibrillation. Circulation 2009; 119: 1758–1767.
• 2.   Verma A, Wazni OM, Marrouche NF, Martin DO, Kilicaslan F, Minor S, et al. Pre-existent left atrial scarring in patients undergoing pulmonary vein antrum isolation: An independent predictor of procedural failure. J Am Coll Cardiol 2005; 45: 285–292.
• 3.   Rolf S, Kircher S, Arya A, Eitel C, Sommer P, Richter S, et al. Tailored atrial substrate modification based on low-voltage areas in catheter ablation of atrial fibrillation. Circ Arrhythm Electrophysiol 2014; 7: 825–833.
• 4.   Jadidi AS, Lehrmann H, Keyl C, Sorrel J, Markstein V, Minners J, et al. Ablation of persistent atrial fibrillation targeting low-voltage areas with selective activation characteristics. Circ Arrhythm Electrophysiol 2016; 9: e002962.
• 5.   Yamaguchi T, Tsuchiya T, Nakahara S, Fukui A, Nagamoto Y, Murotani K, et al. Efficacy of left atrial voltage-based catheter ablation of persistent atrial fibrillation. J Cardiovasc Electrophysiol 2016; 27: 1055–1063.
• 6.   Yang B, Jiang C, Lin Y, Yang G, Chu H, Cai H, et al. STABLE-SR (Electrophysiological Substrate Ablation in the Left Atrium During Sinus Rhythm) for the treatment of nonparoxysmal atrial fibrillation: A prospective, multicenter randomized clinical trial. Circ Arrhythm Electrophysiol 2017; 10: e005405.
• 7.   Yagishita A, Gimbel JR, DE Oliveira S, Manyam H, Sparano D, Cakulev I, et al. Long-term outcome of left atrial voltage-guided substrate ablation during atrial fibrillation: A novel adjunctive ablation strategy. J Cardiovasc Electrophysiol 2017; 28: 147–155.
• 8.   Kircher S, Arya A, Altmann D, Rolf S, Bollmann A, Sommer P, et al. Individually tailored vs. standardized substrate modification during radiofrequency catheter ablation for atrial fibrillation: A randomized study. Europace 2018; 20: 1766–1775.
• 9.   Kumagai K, Toyama H, Zhang B. Effects of additional ablation of low-voltage areas after Box isolation for persistent atrial fibrillation. J Arrhythm 2019; 35: 197–204.
• 10.   Nery PB, Alqarawi W, Nair GM, Sadek MM, Redpath CJ, Golian M, et al. Catheter ablation of low-voltage areas for persistent atrial fibrillation: Procedural outcomes using high-density voltage mapping. Can J Cardiol 2020; 36: 1956–1964.
• 11.   Masuda M, Asai M, Iida O, Okamoto S, Ishihara T, Nanto K, et al. Low-voltage-area ablation in paroxysmal atrial fibrillation: Extended follow-up results of the VOLCANO Trial. Circ J 2022; 86: 245–252.
• 12.   Marcus GM, Yang Y, Varosy PD, Ordovas K, Tseng ZH, Badhwar N, et al. Regional left atrial voltage in patients with atrial fibrillation. Heart Rhythm 2007; 4: 138–144.
• 13.   Mikhaylov EN, Mitrofanova LB, Vander MA, Tatarskiy RB, Kamenev AV, Abramov ML, et al. Biatrial tachycardia following linear anterior wall ablation for the perimitral reentry: Incidence and electrophysiological evaluations. J Cardiovasc Electrophysiol 2015; 26: 28–35.
• 14.   Josephson ME, Anter E. Substrate mapping for ventricular tachycardia: Assumptions and misconceptions. JACC Clin Electrophysiol 2015; 1: 341–352.
• 15.   Haissaguerre M, Hocini M, Denis A, Shah AJ, Komatsu Y, Yamashita S, et al. Driver domains in persistent atrial fibrillation. Circulation 2014; 130: 530–538.