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Clinical Benefit of Ablating Localized Sources for Human Atrial Fibrillation
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
VOL. 69, NO. 10, 2017
ª 2017 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
ISSN 0735-1097/$36.00
PUBLISHED BY ELSEVIER
http://dx.doi.org/10.1016/j.jacc.2016.11.079
Clinical Benefit of Ablating Localized Sources for Human Atrial Fibrillation The Indiana University FIRM Registry John M. Miller, MD, Vikas Kalra, MD, Mithilesh K. Das, MD, Rahul Jain, MD, MPH, Jason B. Garlie, MD, Jordan A. Brewster, MD, Gopi Dandamudi, MD
ABSTRACT BACKGROUND Mounting evidence shows that localized sources maintain atrial fibrillation (AF). However, it is unclear in unselected “real-world” patients if sources drive persistent atrial fibrillation (PeAF), long-standing persistent atrial fibrillation (LPeAF), or paroxysmal atrial fibrillation (PAF); if right atrial sites are important; and what the long-term success of source ablation is. OBJECTIVES The aim of this study was to analyze the role of rotors and focal sources in a large academic registry of consecutive patients undergoing source mapping for AF. METHODS One hundred seventy consecutive patients (mean age 59 12 years, 79% men) with PAF (37%), PeAF (31%), or LPeAF (32%). Of these, 73 (43%) had undergone at least 1 prior ablation attempt (mean 1.9 0.8; range: 1 to 4). Focal impulse and rotor modulation (FIRM) with an endocardial basket catheter was used in all cases. RESULTS FIRM analysis revealed sources in the right atrium in 85% of patients (1.8 1.3) and in the left atrium in 90% of patients (2.0 1.3). FIRM ablation terminated AF to sinus rhythm or atrial flutter or tachycardia in 59% (PAF), 37% (PeAF), and 19% (LPeAF) of patients, with 15 of 67 terminations due to right atrial ablation. On follow-up, freedom from AF after a single FIRM procedure for the entire series was 95% (PAF), 83% (PeAF), and 82% (LPeAF) at 1 year and freedom from all atrial arrhythmias was 77% (PAF), 75% (PeAF), and 57% (LPeAF). CONCLUSIONS In the Indiana University FIRM registry, FIRM-guided ablation produced high single-procedure success, mostly in patients with nonparoxysmal AF. Data from mapping, acute terminations, and outcomes strongly support the mechanistic role of biatrial rotors and focal sources in maintaining AF in diverse populations. Randomized trials of FIRM-guided ablation and mechanistic studies to determine how rotors form, progress, and regress are needed. (J Am Coll Cardiol 2017;69:1247–56) © 2017 by the American College of Cardiology Foundation.
A
trial fibrillation (AF) is the most common sus-
lower for persistent AF (PeAF) (6), results that are
uncertainty
not improved by the ablation of complex fractionated
continues.
Although
the
pandemic of AF is likely related to obesity and other
Listen to this manuscript’s
AF (PAF) is approximately 60% (4,5), and this rate is
tained arrhythmia (1), for which mechanistic
electrograms or empirical linear ablation (6,7).
comorbidities (1,2), it is unclear how they contribute
Mounting evidence suggests that localized rota-
to AF or how to reverse their effects (1). Because
tional circuits (rotors) or focal sources comprise the
drug therapy for rate or rhythm control has modest
electric substrate for AF; 1 strategy of identifying and
success, ablation is increasingly used for symptom re-
treating these is focal impulse and rotor modulation
lief (3). However, even with current technology, the
(FIRM). Optical mapping, the gold standard for map-
single-procedure success rate at 1 year for paroxysmal
ping AF (8), has recently been applied to atria from
audio summary by JACC Editor-in-Chief Dr. Valentin Fuster.
From the Krannert Institute of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana. This work was supported by institutional funds. Dr. Miller has received honoraria from Medtronic, St. Jude Medical, Biotronik, Biosense Webster, and Boston Scientific; and has been a scientific advisor to Abbott/Topera (modest, <$10,000). Dr. Dandamudi has received honoraria from Medtronic and Biosense Webster. Dr. Jain has received honoraria from Biosense Webster. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Manuscript received June 6, 2016; revised manuscript received November 28, 2016, accepted November 29, 2016.
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Outcomes With FIRM Ablation in AF
ABBREVIATIONS
patients with clinical AF (9). This has shown
medications for 5 half-lives (2 to 6 weeks in patients
AND ACRONYMS
that AF is driven by stable endocardial micro–
on amiodarone). Electrode catheters were advanced
re-entrant sources where targeted ablation
to the coronary sinus and right atrium and then trans-
terminated AF (9), with transient epicardial
septally to the left atrium. A 64-pole basket catheter
AF = atrial fibrillation FIRM = focal impulse and rotor modulation
IQR = interquartile range LA = left atrial LPeAF = long-standing persistent atrial fibrillation
PAF = paroxysmal atrial fibrillation
breakthroughs or partial re-entry. These re-
(Constellation, Boston Scientific, Natick, Massachu-
sults are similar to recent clinical reports of
setts [n ¼ 44]; or FIRMap, Abbott Electrophysiology,
AF sources (10) and also reconcile less stable
Menlo Park, California [n ¼ 126]) was advanced
sources seen by epicardial mapping (11).
through an 8.5-F sheath to map AF in both atria in
However, rotors (12) and sources (13) are not
sequence. Basket sizes were selected to approximate
found by classical mapping, possibly because
the left atrial (LA) size on pre-procedural computed
of limitations of marking electrograms in AF
tomography or acquired electroanatomic mapping
(14) and/or other technical limitations (15).
PeAF = persistent atrial
The aim of the IU-FIRM (Indiana Univer-
fibrillation
atrial “shell,” then positioned to optimize fluoroscopic coverage and electrogram signals (Figure 1).
PVI = pulmonary vein isolation
sity FIRM) registry was to: 1) determine if
Generally, baskets sized to fit the left atrium tended
RA = right atrial
rotors and focal sources are common in a
to map the right atrium well.
RF = radiofrequency
large real-world population of unselected
Digital electroanatomic atrial shells were created
patients with PeAF, long-standing PeAF
using Carto (Biosense Webster, Diamond Bar, Califor-
(LPeAF), or PAF; 2) discover whether intervention at
nia). Intravenous heparin was administered as a bolus
sources supports their mechanistic role across AF
after femoral access, followed by infusion to achieve
phenotypes; and 3) establish the “real-world” clinical
activated clotting times >350 s. Unipolar atrial elec-
outcomes of rotor- and source-based ablation.
trograms from the basket catheter were filtered at 0.05
SEE PAGE 1270
METHODS
to 500 Hz and recorded at a 1-kHz sampling frequency for export from the electrophysiological recording system (Bard/Boston Scientific, Lowell, Massachusetts). AF was the presenting rhythm in 96 patients (57%),
STUDY DESIGN. We studied 170 consecutive patients
atrial flutter in 11 (6%), and sinus rhythm in 63 (37%).
referred to Indiana University/Methodist Hospital
In patients presenting in sinus rhythm or in whom
from January 2012 to October 2015 for ablation of
presenting AF or atrial flutter was terminated by
symptomatic AF for standard indications (3). Subjects
ablation, AF induction was attempted using rapid
were $18 years of age, with AF despite $1 antiarrhythmic drug. Patients were excluded if they were
pacing with or without isoproterenol (5 to 15 m g/min) or epinephrine (0.05 to 0.2 m g/kg/min) as needed.
unable or refused to provide written informed consent
MAPPING AF SOURCES. FIRM mapping has been
or did not have sustained AF (>5 min) during the pro-
described elsewhere (10). Briefly, unipolar AF elec-
cedure. The population included patients with PAF,
trograms recorded using basket catheters are pro-
PeAF, or LPeAF by standard definitions (3). This was
cessed using algorithms to determine propagation
the first ablation procedure for most patients, although
sequences. When deflections are monophasic or
73 (43%) had undergone at least 1 prior ablation pro-
noncomplex, mapping can identify rotational or focal
cedure. Table 1 summarizes patient characteristics.
activations as previously illustrated (10). In cases in
Each patient underwent AF mapping using a
which AF deflections are multiphasic, the use of
multipolar catheter inserted sequentially into both
classical rules such as dV/dt may mark deflections
atria as previously described, followed by computa-
within repolarization (far-field) (14). In such cases,
tional methods to interpret electrograms using repo-
FIRM assigns local activation on the basis of physio-
larization and conduction dynamics to reveal sources
logical information, such as action potential duration
(16). Ablation targeted the identified sources in each
restitution (17) to account for changes in refractori-
patient. One hundred sixty-one patients (95%) also
ness with changes in cycle length during AF, and then
underwent pulmonary vein isolation (PVI); the
applies phase analysis to identify rotors. The system
remaining 9 patients prospectively declined this.
(RhythmView, Abbott Electrophysiology, Menlo Park,
Follow-up with event and/or ambulatory monitoring
California) then generates AF propagation maps,
or implantable device interrogation in 151 patients
which are subsequently correlated to corresponding
(89%) was used to determine clinical efficacy and
basket electrode locations within the chamber.
establish the mechanistic impact of interventions targeting these defined mechanisms.
AF propagation (FIRM) maps were analyzed in near real time for FIRM-guided ablation at sources. Electric
ELECTROPHYSIOLOGIC STUDY. Electrophysiologic study
rotors (Figure 2D) were defined as rotational activa-
was performed after discontinuing antiarrhythmic
tion
around
a
phase-mapped
singularity
that
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Outcomes With FIRM Ablation in AF
generated peripheral disorganization, while focal impulses showed centrifugal spread of activation
T A B L E 1 Characteristics of Population
from an origin. Rotors and focal impulses were considered AF sources if they existed in consistent
Overall (n ¼ 170)
Paroxysmal AF (n ¼ 64)
Persistent AF (n ¼ 52)
Long-Standing Persistent AF (n ¼ 54)
p Value
59 12
57 12
61 11
59 12
NS
spatial regions of 2 to 8 cm 2 (with some precession
Age, yrs
[18]) on repeated maps.
Male/female
135/35
52/12
36/16
47/7
NS
ABLATION APPROACH. Radiofrequency (RF) energy
Prior ablations
73 (43)
31 (48)
23 (19)
19 (35)
0.34
Presented in AF
96 (56)
4 (6)
44 (85)
48 (89)
<0.001
(ThermoCool or SmartTouch, Biosense Webster) at
Left atrial diameter, cm
5.2 1.0
4.9 1.0
5.4 0.9
5.3 1.1
NS
20 to 35 W. Ablation commenced guided by FIRM data
Ejection fraction, %
47 10
50 7
46 10
46 11
NS
was delivered with a 3.5-mm tip irrigated catheter
in 131 patients (77%). FIRM-guided ablation followed PVI in 39 patients (23%). RF energy was delivered for
Values are mean SD, n, or n (%). AF ¼ atrial fibrillation; NS ¼ not significant.
approximately 30 s at any 1 location to cover the 2- to 8-cm2 area of AF sources with closely spaced RF applications (Figures 2 and 3), to achieve an electrogram amplitude
decrease
of
>70%.
The
The secondary outcome was freedom from all atrial
procedural
arrhythmias after blanking. Subjects were followed for
endpoint was rotor elimination on repeat mapping or
at least 6 months (mean 15 10 months) post-
noninducibility of AF, if ablation terminated the
procedure. In patients with arrhythmia recurrence af-
arrhythmia to sinus rhythm. When AF terminated
ter the blanking period, continued observation, anti-
during ablation, RF application was continued to
arrhythmic drug therapy or repeat ablation was offered
eliminate electrograms in the region designated by
(3). If ablation was performed, detailed mapping was
mapping (Figures 2 and 3). Thereafter, attempts were
repeated. Results presented hereafter are those of the
made to reinitiate AF as noted previously, and repeat mapping and ablation were performed if AF, atrial flutter, or tachycardia was induced. The duration of FIRM mapping and ablation, from initial basket deployment to the end of final ablation of FIRMdesignated sources, was 94 54 min. Conventional ablation (PVI [3]) was performed in all patients but those in whom FIRM-only therapy was used or patients in whom PVI was present from prior procedures. Ablation comprised widearea circumferential ablation of left and right pulmonary vein pairs, verifying pulmonary vein entrance and exit block using a circular mapping catheter (Lasso, Biosense Webster). Adenosine challenge or pacing along the ablation line was used to confirm isolation at procedure’s end. If atrial tachycardia or flutter was diagnosed, mapping and ablation were performed as feasible; when linear right atrial (RA) or LA ablation was used for this, confirmation of bidirectional con-
index FIRM procedure only. STATISTICAL ANALYSIS. Continuous variables are
summarized as mean SD and were compared using analysis of variance, after being verified as normally distributed by the Kolmogorov-Smirnov test. Nominal variables were compared between patient groups using chi-square tests or Fisher exact tests if expected cell frequencies were <5. Long-term outcomes were assessed, and survival analyses were conducted using the Cox proportional hazards model, censoring patients after events. Survival curves were generated using the Kaplan-Meier method and compared using log-rank tests. The proportionality assumption was deemed satisfied upon inspection of log-log plots. A p value of <0.05 was considered to indicate statistical significance.
RESULTS
duction block along such lines was used. AF persisting
STABLE SOURCES OBSERVED ACROSS AF CLASSES. All
after the completion of ablation was cardioverted.
patients had intraprocedural AF, of whom 96 (57%)
POST-PROCEDURAL
presented in AF (Table 1). FIRM mapping revealed
CARE. During
a 3-month post-
ablation “blanking period,” antiarrhythmic medica-
stable AF rotors or focal sources in all cases. Of 3.5
tions were continued in 8% of patients, then
2.1 sources per patient (median 4; interquartile range
discontinued in all but 2 patients (by patient prefer-
[IQR]: 3), 54% were in the left atrium (2.3 1.3 per
ence). No repeat ablation procedures were performed
patient; median 2; IQR: 2) and 46% in the right atrium
in the blanking period. The primary endpoint was
(2.1 1.3 per patient; median 2; IQR: 2) (Table 2). Per
freedom from AF after a single procedure, defined as
patient, 85% had at least 1 RA source; 90% had LA
AF >30 s on ambulatory electrocardiography and/or
sources. Of the 17 patients without LA sources, 5 had
event monitors (3) or implanted device interrogation
AF termination during RA ablation without subse-
(n ¼ 24) following the 3-month blanking period.
quent AF inducibility, precluding LA source mapping.
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Outcomes With FIRM Ablation in AF
F I G U R E 1 Patient-Tailored Atrial Fibrillation Mapping
(A) 50-mm basket (FIRMap) placed in the right atrium through a long sheath, then trans-septally into the left atrium. Red arrows denote boundaries of basket splines. Note that in the left atrium, the basket is posterior to the coronary sinus (right anterior oblique) and covers most of the left atrium (left anterior oblique). (B) Raw atrial fibrillation (AF) unipolar electrograms from basket catheter in the left atrium; 12 electrocardiographic leads (top) and red signals (center, from coronary sinus) show clear AF. Recordings from each basket spline are grouped by color (8 recordings/spline). Abl ¼ ablation catheter; Eso ¼ esophageal temperature probe; His ¼ His bundle recording.
Most sources were rotors, with 24 (14%) being foci (16
recurrent AF, atrial flutter, or atrial tachycardia versus
RA, 8 LA). Mean procedure duration was 356 60
27 of 103 (26%) without termination (p ¼ 0.12).
min; mean fluoroscopy time was 25 13 min.
AF TERMINATION BY ABLATING RA ROTORS. A
Figure 2 shows AF in a 51-year-old man with PeAF
specific goal of the IU-FIRM registry was to define the
and no prior ablation (Figure 2A). RA FIRM mapping
role of RA rotors and focal sources. Figure 3 shows
showed a posterior septal rotor where ablation had no
termination of PeAF to sinus rhythm by RA rotor
effect on the rhythm. LA FIRM mapping revealed a
ablation alone in a 55-year-old man. The patient was
rotor on the anteromedial wall (Figure 2D) where
free of AF at 1.5-year follow-up.
ablation slowed and organized the rhythm to a rapid
Overall, RA FIRM ablation alone terminated AF in 9
flutter (Figure 2B) that then terminated to sinus
patients. Sources were located in several areas of the
rhythm (Figure 2C) after a total of 3.1 min. AF was then
right atrium, with no single characteristic site.
noninducible, and per patient request, ablation concluded using FIRM-only guidance (Figure 2E)
LONG-TERM EFFICACY FROM FIRM-GUIDED ABLATION.
without PVI. The patient remained free of AF after 16
Freedom from AF after a single-FIRM procedure at
months following FIRM-only ablation.
1 year (IQR: 222 to 629 days) off medications in all but
AF TERMINATION WITH FIRM-GUIDED ABLATION. Table 3
2 patients (as noted earlier) in the IU-FIRM registry
summarizes rates of AF termination from FIRM abla-
was 87% (Central Illustration). Freedom from AF was
tion alone. Most of these terminated to sinus rhythm
higher for PAF than for PeAF or LPeAF (95% vs. 83%
(n ¼ 38 [57%]) (Figure 2C) rather than typical RA flutter
vs. 82%, respectively, p < 0.01). Freedom from all
(n ¼ 8; all were ablated successfully) or nonflutter atrial
atrial tachyarrhythmias after a single FIRM procedure
tachycardia (n ¼ 21; 12 were ablated, 9 terminated with
at 1 year (IQR: 179 to 570 days) off medications in the
pacing or catheter manipulation and were not seen
IU-FIRM registry was 70%. The Central Illustration
again). AF terminations by FIRM-guided ablation were
shows that freedom from all atrial tachyarrhythmias
more common in patients with PAF than in those with
was higher for PAF and PeAF than for LPeAF (77% vs.
PeAF or LPeAF (59% vs. 37% vs. 19%, respectively,
75% vs. 57%, respectively, p <0.02).
p < 0.001). Of note, there was no relationship between
COMPLICATIONS. The
acute termination of AF (to sinus or organized atrial
overall serious complication rate of 3.5%, including 3
tachyarrhythmia)
arrhythmia
cases of cardiac tamponade requiring drainage,
recurrence: 10 of 67 (15%) with terminations had
1 pericardial effusion, 1 case of heart block, and
and
freedom
from
IU-FIRM
registry
had
an
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Outcomes With FIRM Ablation in AF
F I G U R E 2 Left Atrial Rotor Sustains Persistent Atrial Fibrillation Present for >8 Months in a 51-Year-Old Man With
3 Transiently Successful Past Cardioversions
(A) Atrial fibrillation (AF) at baseline. (B) After 1.3 min of ablation at focal impulse and rotor modulation (FIRM) site, AF organized to atypical flutter. (C) After 3.1 min of radiofrequency ablation, the rhythm terminated to sinus rhythm. (D) Anteroseptal left atrial (LA) rotor on FIRM mapping. (E) Anterior view of electroanatomic shells (right atrium, green; left atrium, gray); successful septal LA FIRM site (red dots; total ablated area w8 cm2). This patient declined pulmonary vein isolation and remained free of AF or atrial tachycardia off antiarrhythmic medications at >16 months. IVC ¼ inferior vena cava; LIPV ¼ left inferior pulmonary vein; LSPV ¼ left superior pulmonary vein; SVC ¼ superior vena cava.
1 spontaneous epidural hematoma. None were related
medications). In an important subset of patients
to the basket catheter. Other complications included
who declined PVI, the ability of FIRM-only ablation
mild hematuria (2 cases) and 2 moderate femoral
to eliminate AF on long-term follow-up strongly sup-
hematomas that did not require intervention. No
ports the mechanistic role of rotors and sources. Thus,
strokes, peripheral emboli, phrenic nerve injuries, or
the IU-FIRM registry shows that clinical and mecha-
atrioesophageal fistulae were noted. There were no
nistic conclusions from the CONFIRM (Conventional
procedural deaths.
Ablation With or Without Focal Impulse and Rotor
DISCUSSION
Modulation) trial and optical mapping of human atria apply broadly to patients referred for AF ablation and that FIRM-guided ablation may improve success rates
The IU-FIRM registry supports the mechanistic role
above those expected from PVI alone.
of localized rotors and focal sources in sustaining PeAF, LPeAF, and PAF. Ablation at FIRM-mapped
MECHANISTIC IMPLICATIONS. Our data support re-
sources in the left or right atrium was able to termi-
sults from optical mapping of AF in human atria (9)
nate AF in patients across disease classes. In combi-
and clinical studies (10) that human AF is sustained
nation with PVI, ablation produced 87% freedom
by localized sources. The ability of FIRM-guided
from AF after a single FIRM procedure at 1 year in
ablation to terminate AF often to sinus rhythm in
patients, mostly those with nonparoxysmal AF
patients with all AF phenotypes strongly supports a
(almost none of whom were taking antiarrhythmic
mechanistic role for rotors and focal sources, as do
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Outcomes With FIRM Ablation in AF
F I G U R E 3 Right Atrial Rotor Sustains Persistent Atrial Fibrillation for >3 Months in a 55-Year-Old Man
(A) Atrial fibrillation (AF) at baseline. (B) AF terminated while ablating at right atrial (RA) rotor. (C) Electroanatomic map of RA rotors; the pink dot at the center of the yellow dots is the site of termination to sinus (total ablated area w2.5 cm2). The patient remained free of AF or atrial tachycardia off antiarrhythmic medications at >18 months.
results of FIRM-guided ablation alone, albeit in a
limit multiple wavelets does not improve success (6,7).
small subset of patients.
Of note, in preliminary studies, AF rotational sources
Debate continues on AF mechanisms, yet it is
identified by high-resolution optical mapping in
increasingly clear that this may in part reflect the
explanted human hearts are also identified by basket
choice of mapping tools. Classical electrogram map-
electrodes and FIRM methods (21).
ping nicely indicates the complexity of AF substrates
Although termination of fibrillation (especially
(13), yet electrograms in AF often show far-field
when persistent) to an organized atrial tachyar-
mixed with local activity (14,19). This may explain
rhythmia or sinus rhythm is proof of concept and
why classical electrogram mapping of AF rarely shows
validates the mechanistic nature of rotors and focal
rotors, whereas optical mapping studies, including in
sources in AF maintenance, the poor correlation of
explanted human atria (9), show AF maintained by
termination with long-term freedom from recurrent
rotational drivers or focal sources.
arrhythmia is perplexing. This may reflect incomplete
Localized AF sources may explain observations that
eradication of the entire rotor substrate in cases in
AF can be terminated by focused interventions (10,20),
which ablation terminates AF, similar to the poor
and why extensive ablation that would be expected to
correlation of long-term freedom from recurrent typical RA flutter when arrhythmia termination rather than demonstration of bidirectional cavotricuspid
T A B L E 2 Procedural Data
isthmus block is the procedural endpoint. Currently, the only means of determining that the rotor sub-
Type of AF
strate has been eliminated is remapping during
Overall (n ¼ 170)
Paroxysmal (n ¼ 64)
Persistent (n ¼ 52)
Long-Standing Persistent (n ¼ 54)
Patients (% of total)
144 (85)
49 (77)
44 (85)
51 (94)
0.03
possible if fibrillation terminates and cannot be
Total (per patient)
297 (2.1)
95 (1.9)
90 (2.0)
112 (2.2)
NS
reinitiated. Future technical advances may help
Patients (% of total)
153 (90)
55 (86)
47 (90)
51 (94)
NS
Total (per patient)
352 (2.3)
113 (2.1)
108 (2.3)
131 (2.6)
NS
FIRM RF area, cm2
15 9
12 8
15 8
20 10
<0.001*
RF time for FIRM, min
24 12
23 14
24 12
28 12
NS
ported experience of FIRM-guided ablation to date and
p Value
resolve when the substrate has been fully treated.
Left atrial sources
Total RF time, min Procedure time, min Fluoroscopy time, min
ongoing fibrillation and observing that the previously targeted rotor or focus has been eradicated; this is not
Right atrial sources
COMPARISON WITH OTHER STUDIES OF FIRM-GUIDED ABLATION. The IU-FIRM registry is the largest re-
56 14
51 18
60 9
59 15
NS
validates the original CONFIRM trial (10) and smaller
356 60
358 59
342 46
372 56
NS
reports that FIRM-guided ablation can produce favor-
25 13
29 14
21 10
27 12
NS
able results in unselected patients with all types of AF.
Values are n (%), n (n per patient), or mean SD. *Paroxysmal AF versus long-standing persistent AF. FIRM ¼ focal impulse and rotor modulation; RF ¼ radiofrequency; other abbreviations as in Table 1.
Single-procedure freedom from AF of 87% at 1 year in our study supports the 80.5% freedom from AF in the 10-center registry of FIRM-guided ablation in
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Outcomes With FIRM Ablation in AF
78 patients (22) and the 82.4% success in the CONFIRM trial (10). These results are substantially
T A B L E 3 Termination Rates, Focal Impulse and Rotor Modulation–Guided Ablation
Type of AF
better than the 38% freedom from AF and 21% freedom from all arrhythmias reported by Buch et al. (23) in 43 patients (one-half with PAF). This might be
Termination
Overall (n ¼ 170)
Paroxysmal (n ¼ 64)
Persistent (n ¼ 52)
Long-Standing Persistent (n ¼ 54)
p Value
explained by technical factors applying FIRM or PVI
To sinus rhythm
38 (22)
25 (39)
8 (15)
5 (9)
0.002
(15) or challenging patients and must be reconciled.
To atrial flutter/tachycardia
29 (17)
13 (20)
11 (21)
5 (9)
<0.001
Gianni et al. (24) reported single-procedure freedom
Total
67 (39)
38 (59)
19 (37)
10 (19)
<0.001
from AF or atrial tachycardia off drugs in PeAF and LPeAF of only 17% at 6 months by FIRM-guided
Values are n (%). AF ¼ atrial fibrillation.
ablation alone (i.e., without PVI). It is unclear if those results are worse than in our series because of relatively early experience with FIRM mapping and ablation by these seasoned investigators, with 29
(Sustained Treatment of Paroxysmal Atrial Fibrilla-
procedures among several operators. Differences may
tion) (30), and other trials. Because PVI was also used
also reflect study design, as in that trial, when FIRM
in most of our patients, the effect of FIRM on subse-
organized AF to atrial tachycardias, they were not
quent atrial tachycardias is not clear. Further study is
ablated
needed to clarify these results.
but
cardioverted.
Conversely,
in
the
CONFIRM trial and in this study, atrial tachycardias
FUTURE DIRECTIONS. Additional clinical studies are
were targeted for ablation, which may reduce their
required to determine if the results of FIRM-guided
recurrence. FIRM-guided ablation has been success-
ablation in the IU-FIRM and other recent indepen-
ful in challenging patients in other studies; Sommer
dent studies are maintained on long-term follow-up
et al. (25) reported 80% freedom from atrial ar-
(2 to 5 years), as in the CONFIRM trial (29). It is
rhythmias in patients with mostly LPeAF, and 70% to
important to determine why the results of the IU-FIRM
80% success was reported by Tomassoni et al. (26)
registry are better than those of FIRM with PVI in 2
and Rashid and Sweeney (27).
recent studies by Buch et al. (23) in 43 patients. If dif-
FIRM-GUIDED VERSUS OTHER FORMS OF ABLATION
ferences in outcomes with our 170 patient series reflect
ACROSS
relatively large
more extensive experience in the FIRM technique,
population of the IU-FIRM registry provides the first
then efforts must be made to reduce the learning
opportunity to dissect FIRM-guided ablation results
curve. If differences reflect study design, then treat-
across types of AF, showing favorable success across
ment should be standardized to include such ele-
all AF subgroups (Central Illustration).
ments. Finally, if variations in outcome reflect
AF
POPULATIONS. The
In patients with nonparoxysmal AF (n ¼ 106), the single-procedure success rate was higher than the
different patient cohorts, then both ideal and less ideal populations must also be defined and studied.
approximate 55% freedom from AF on or off medi-
STUDY LIMITATIONS. Although IU-FIRM was not
cations or approximate 40% freedom from all ar-
randomized, it is a relatively large registry of
rhythmias
STAR-AF2
consecutive patients at a large academic medical
(Substrate and Trigger Ablation for Reduction of
off
medications
in
the
center. A strength of this study is that our experience
Atrial Fibrillation Part 2) trial (6). For patients with
may have circumvented limitations encountered by
PAF (n ¼ 64), single-procedure success in the IU-
otherwise seasoned investigators with less experi-
FIRM registry (95% freedom from AF, 77% freedom
ence in FIRM mapping or FIRM-guided rotor elimi-
from all atrial arrhythmias) was higher than the
nation. The number of cases needed to achieve
60% to 65% freedom from AF in recent trials of
success with FIRM-guided ablation will vary with
contact force catheters (4,5) or the FIRE AND ICE
patient selection, operator skill, and other factors.
study (comparing cryoballoon or RF ablation), in
Because this was a registry study, it is difficult to
which repeat ablation was permitted in the blanking
exclude case-related differences in PVI or other
period (28).
ablation in contributing to outcomes in some cases.
The IU-FIRM registry also provides the first series
However, many PVI trials included additional abla-
able to detect whether FIRM-guided ablation pro-
tion even for PAF (4,31), such as RAAFT-2 (Radio-
duces a substantial rate of atrial tachycardias. The
frequency Ablation Versus Antiarrhythmic Drugs as
16.5% rate of atrial tachycardias in IU-FIRM and rates
First-Line
found in other studies (22,25,29) are comparable to
which included 20% to 40% use of additional targets,
those from PVI alone in the STAR-AF2 (6), STOP-AF
including linear ablation and ablation of complex
Therapy
of
Atrial
Fibrillation-2)
(31),
Miller et al.
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JACC VOL. 69, NO. 10, 2017 MARCH 14, 2017:1247–56
Outcomes With FIRM Ablation in AF
C E NT R AL IL L U STR AT IO N Ablating Localized Sources for Atrial Fibrillation: Clinical Benefit
B
1-Year Freedom from Recurrent AF
1-Year Freedom from Recurrent AT/AF
100
100
80
80 Arrhythmia-Free Survival (%)
Arrhythmia-Free Survival (%)
A
60
40
60
40
20
20
0
0 0
100
200
300
400
0
100
200
Days Number at risk
64 52 54
55 37 46
62 49 54
All Patients
300
400
38 20 31
34 14 25
Days 45 22 35
43 16 31
Paroxysmal AF
Number at risk
64 52 54
Persistent AF
62 49 54
50 34 37
Long-Standing Persistent AF
Miller, J.M. et al. J Am Coll Cardiol. 2017;69(10):1247–56.
(A) Freedom from recurrent atrial fibrillation (AF) after focal impulse and rotor modulation (FIRM) ablation. Kaplan-Meier curves are displayed for freedom from recurrent AF in each group as well as aggregate (legend at bottom), with number at risk at each 100 days of follow-up shown at bar at bottom. (B) Freedom from recurrence of any atrial arrhythmia after FIRM ablation. Kaplan-Meier curves are displayed for freedom from any recurrent atrial arrhythmia in each group as well as aggregate (legend at bottom), with number at risk at each 100 days of follow-up shown at bar at bottom. AT ¼ atrial tachycardia including flutter.
of
substrate ablation. Mechanistically, the ability of
follow-up electrocardiographic monitoring was not
targeted ablation at localized rotors and focal sources
possible because of the wide area of patient referrals,
to terminate AF and eliminate AF on long-term
and thus some asymptomatic episodes of AF or other
follow-up supports the role of sources in the left
arrhythmias may have escaped detection; however,
and right atrium in maintaining AF. These data
only 5 patients without known arrhythmia recurrence
strongly motivate randomized controlled trials of
had no long-term monitoring. Finally, these results
FIRM-guided ablation.
fractionated
electrograms.
Complete
control
must be compared with those of PVI alone in a randomized clinical trial; such trials are under way.
CONCLUSIONS
ACKNOWLEDGMENTS The
Straka,
RN,
for
authors
coordinator
thank
support
and
Susan Tina
Baykaner, MD, MPH, for statistical support.
The IU-FIRM registry is the largest reported series of FIRM-guided ablation for unselected patients with a
ADDRESS FOR CORRESPONDENCE: Dr. John M.
range of AF presentations, mostly nonparoxysmal AF.
Miller, Krannert Institute of Cardiology, Department
We found that FIRM-guided ablation at AF substrates
of Medicine, Indiana University, 1800 North Capitol
produced single-procedure success rates higher than
Avenue, E-488, Indianapolis, Indiana 46202. E-mail:
those from PVI alone or with traditional forms of
[email protected].
Miller et al.
JACC VOL. 69, NO. 10, 2017 MARCH 14, 2017:1247–56
Outcomes With FIRM Ablation in AF
PERSPECTIVES COMPETENCY IN PATIENT CARE AND
TRANSLATIONAL OUTLOOK: Further studies are
PROCEDURAL SKILLS: Use of FIRM technology to
needed to more clearly define the role of FIRM-guided AF
localize areas of atrial myocardium responsible for
ablation and to identify characteristics of patients most
maintenance of AF results in greater freedom from
likely to gain incremental benefit from this approach.
recurrent AF than PVI alone.
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10. Narayan SM, Krummen DE, Shivkumar K, Clopton P, Rappel W-J, Miller J. Treatment of atrial fibrillation by the ablation of localized
American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014; 64:2246–80.
sources: CONFIRM (Conventional Ablation for Atrial Fibrillation With or Without Focal Impulse and Rotor Modulation) trial. J Am Coll Cardiol 2012;60:628–36.
2. Abed HS, Wittert GA, Leong DP, et al. Effect of weight reduction and cardiometabolic risk factor management on symptom burden
11. Haïssaguerre M, Hocini M, Denis A, et al. Driver domains in persistent atrial fibrillation. Circulation 2014;130:530–8.
and severity in patients with atrial fibrillation: a randomized clinical trial. JAMA 2013;310: 2050–60. 3. Calkins H, Kuck KH, Cappato R, et al. 2012 HRS/EHRA/ECAS expert consensus statement on catheter and surgical ablation of atrial fibrillation: recommendations for patient selection, procedural techniques, patient management and follow-up, definitions, endpoints, and research trial design. Heart Rhythm 2012;9:632–96. 4. Natale A, Reddy VY, Monir, et al. Paroxysmal AF catheter ablation with a contact force sensing catheter: results of the prospective, multicenter SMART-AF trial. J Am Coll Cardiol 2014;64: 647–56. 5. Reddy VY, Dukkipati SR, Neuzil P, et al. Randomized, controlled trial of the safety and effectiveness of a contact force-sensing irrigated catheter for ablation of paroxysmal atrial fibrillation: results of the Tacticath Contact Force Ablation Catheter Study for Atrial Fibrillation (TOCCASTAR) study. Circulation 2015;132: 907–15. 6. Verma A, Jiang CY, Betts TR, et al. Approaches to catheter ablation for persistent atrial fibrillation. N Engl J Med 2015;372:1812–22. 7. Wong KC, Paisey JR, Sopher M, et al. No benefit of complex fractionated atrial electrogram ablation in addition to circumferential pulmonary vein ablation and linear ablation: Benefits of Complex Ablation study. Circ Arrhythm Electrophysiol 2015; 8:1316–24.
12. Lee S, Sahadevan J, Khrestian CM, Cakulev I, Markowitz A, Waldo AL. Simultaneous biatrial high-density (510-512 electrodes) epicardial mapping of persistent and long-standing persistent atrial fibrillation in patients: new insights into the mechanism of its maintenance. Circulation 2015;132:2108–17. 13. Allessie MA, de Groot NM, Houben RP, et al. Electropathological substrate of long-standing persistent atrial fibrillation in patients with structural heart disease: longitudinal dissociation. Circ 606–15.
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14. Narayan SM, Wright M, Derval N, et al. Classifying fractionated electrograms in human atrial fibrillation using monophasic action potentials and activation mapping: evidence for localized drivers, rate acceleration and non-local signal etiologies. Heart Rhythm 2011;8:244–53. 15. Jalife J, Filgueiras Rama D, Berenfeld O. Letter by Jalife et al regarding article, “Quantitative analysis of localized sources identified by focal impulse and rotor modulation mapping in atrial fibrillation.” Circ Arrhythm Electrophysiol 2015;8: 1296–8. 16. Narayan SM, Krummen DE, Rappel W-J. Clinical mapping approach to diagnose electrical rotors and focal impulse sources in human atrial fibrillation. J Cardiovasc Electrophysiol 2012;23: 447–54.
8. Efimov IR, Nikolski VP, Salama G. Optical imaging of the heart. Circ Res 2004;95:21–33.
17. Narayan SM, Franz MR, Clopton P, Pruvot EJ, Krummen DE. Repolarization alternans reveals vulnerability to human atrial fibrillation. Circulation 2011;123:2922–30.
9. Hansen BJ, Zhao J, Csepe TA, et al. Atrial fibrillation driven by micro-anatomic intramural re-entry revealed by simultaneous sub-epicardial
18. Narayan SM, Shivkumar K, Krummen DE, Miller JM, Rappel WJ. Panoramic electrophysiological mapping but not electrogram morphology
and sub-endocardial optical mapping in explanted human hearts. Eur Heart J 2015;36:2390–401.
identifies sustaining sites for human atrial fibrillation: stable atrial fibrillation rotors and focal
sources relate poorly to fractionated electrograms). Circ Arrhythm Electrophysiol 2013;6: 58–67. 19. Narayan SM, Zaman JA. Mechanistically based mapping of human cardiac fibrillation. J Physiol 2015;594:2399–415. 20. Shivkumar K, Ellenbogen KA, Hummel JD, Miller JM, Steinberg JS. Acute termination of human atrial fibrillation by identification and catheter ablation of localized rotors and sources: first multicenter experience of focal impulse and rotor modulation (FIRM) ablation. J Cardiovasc Electrophysiol 2012;23: 1277–85. 21. Hansen BJ, Briggs C, Moore BT. Abstract 18402: human atrial fibrillation drivers seen simultaneously by focal impulse and rotor mapping and high-resolution optical imaging (abstr). Circulation 2015;132 Suppl 3:A18402. 22. Miller JM, Kowal RC, Swarup V, et al. Initial independent outcomes from focal impulse and rotor modulation ablation for atrial fibrillation: multicenter FIRM registry. J Cardiovasc Electrophysiol 2014;25:921–9. 23. Buch E, Share M, Tung R, et al. Long-term clinical outcomes of focal impulse and rotor modulation for treatment of atrial fibrillation: a multicenter experience. Heart Rhythm 2016;13: 636–41. 24. Gianni C, Mohanty S, Di Biase L, et al. Acute and early outcomes of focal impulse and rotor modulation (FIRM)-guided rotorsonly ablation in patients with nonparoxysmal atrial fibrillation. Heart Rhythm 2016;13: 830–5. 25. Sommer P, Kircher S, Rolf S, et al. Successful repeat catheter ablation of recurrent longstanding persistent atrial fibrillation with rotor elimination as the procedural endpoint: a case series. J Cardiovasc Electrophysiol 2016;27: 274–80. 26. Tomassoni G, Duggal S, Muir M, et al. Longterm follow-up of FIRM-guided ablation of atrial fibrillation: a single-center experience. J Innov Card Rhythm Mgmnt 2015;6:2145–51. 27. Rashid H, Sweeney A. Approaches for focal impulse and rotor mapping in complex patients: a US private practice perspective. J Innov Card Rhythm Mgmnt 2015;6:2193–8.
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Outcomes With FIRM Ablation in AF
28. Kuck KH, Brugada J, Furnkranz A, et al. Cryoballoon or radiofrequency ablation for paroxysmal atrial fibrillation. N Engl J Med 2016;374: 2235–45. 29. Narayan SM, Baykaner T, Clopton P, et al. Ablation of rotor and focal sources reduces late recurrence of atrial fibrillation compared with trigger ablation alone: extended follow-up of the CONFIRM trial (Conventional Ablation for Atrial
Fibrillation With or Without Focal Impulse and Rotor Modulation). J Am Coll Cardiol 2014;63: 1761–8. 30. Packer DL, Kowal RC, Wheelan KR, et al. Cryoballoon ablation of pulmonary veins for paroxysmal atrial fibrillation: first results of the North American Arctic Front (STOP AF) pivotal trial. J Am Coll Cardiol 2013;61: 1713–23.
31. Morillo CA, Verma A, Connolly SJ, et al. Radiofrequency Ablation vs Antiarrhythmic Drugs as First-Line Treatment of Paroxysmal Atrial Fibrillation (RAAFT-2): a randomized trial. JAMA 2014; 311:692–700.
KEY WORDS ablation, AF termination, atrial fibrillation, clinical trial, electrical rotors, FIRM
VOL. 69, NO. 10, 2017
ª 2017 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
ISSN 0735-1097/$36.00
PUBLISHED BY ELSEVIER
http://dx.doi.org/10.1016/j.jacc.2016.11.079
Clinical Benefit of Ablating Localized Sources for Human Atrial Fibrillation The Indiana University FIRM Registry John M. Miller, MD, Vikas Kalra, MD, Mithilesh K. Das, MD, Rahul Jain, MD, MPH, Jason B. Garlie, MD, Jordan A. Brewster, MD, Gopi Dandamudi, MD
ABSTRACT BACKGROUND Mounting evidence shows that localized sources maintain atrial fibrillation (AF). However, it is unclear in unselected “real-world” patients if sources drive persistent atrial fibrillation (PeAF), long-standing persistent atrial fibrillation (LPeAF), or paroxysmal atrial fibrillation (PAF); if right atrial sites are important; and what the long-term success of source ablation is. OBJECTIVES The aim of this study was to analyze the role of rotors and focal sources in a large academic registry of consecutive patients undergoing source mapping for AF. METHODS One hundred seventy consecutive patients (mean age 59 12 years, 79% men) with PAF (37%), PeAF (31%), or LPeAF (32%). Of these, 73 (43%) had undergone at least 1 prior ablation attempt (mean 1.9 0.8; range: 1 to 4). Focal impulse and rotor modulation (FIRM) with an endocardial basket catheter was used in all cases. RESULTS FIRM analysis revealed sources in the right atrium in 85% of patients (1.8 1.3) and in the left atrium in 90% of patients (2.0 1.3). FIRM ablation terminated AF to sinus rhythm or atrial flutter or tachycardia in 59% (PAF), 37% (PeAF), and 19% (LPeAF) of patients, with 15 of 67 terminations due to right atrial ablation. On follow-up, freedom from AF after a single FIRM procedure for the entire series was 95% (PAF), 83% (PeAF), and 82% (LPeAF) at 1 year and freedom from all atrial arrhythmias was 77% (PAF), 75% (PeAF), and 57% (LPeAF). CONCLUSIONS In the Indiana University FIRM registry, FIRM-guided ablation produced high single-procedure success, mostly in patients with nonparoxysmal AF. Data from mapping, acute terminations, and outcomes strongly support the mechanistic role of biatrial rotors and focal sources in maintaining AF in diverse populations. Randomized trials of FIRM-guided ablation and mechanistic studies to determine how rotors form, progress, and regress are needed. (J Am Coll Cardiol 2017;69:1247–56) © 2017 by the American College of Cardiology Foundation.
A
trial fibrillation (AF) is the most common sus-
lower for persistent AF (PeAF) (6), results that are
uncertainty
not improved by the ablation of complex fractionated
continues.
Although
the
pandemic of AF is likely related to obesity and other
Listen to this manuscript’s
AF (PAF) is approximately 60% (4,5), and this rate is
tained arrhythmia (1), for which mechanistic
electrograms or empirical linear ablation (6,7).
comorbidities (1,2), it is unclear how they contribute
Mounting evidence suggests that localized rota-
to AF or how to reverse their effects (1). Because
tional circuits (rotors) or focal sources comprise the
drug therapy for rate or rhythm control has modest
electric substrate for AF; 1 strategy of identifying and
success, ablation is increasingly used for symptom re-
treating these is focal impulse and rotor modulation
lief (3). However, even with current technology, the
(FIRM). Optical mapping, the gold standard for map-
single-procedure success rate at 1 year for paroxysmal
ping AF (8), has recently been applied to atria from
audio summary by JACC Editor-in-Chief Dr. Valentin Fuster.
From the Krannert Institute of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana. This work was supported by institutional funds. Dr. Miller has received honoraria from Medtronic, St. Jude Medical, Biotronik, Biosense Webster, and Boston Scientific; and has been a scientific advisor to Abbott/Topera (modest, <$10,000). Dr. Dandamudi has received honoraria from Medtronic and Biosense Webster. Dr. Jain has received honoraria from Biosense Webster. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Manuscript received June 6, 2016; revised manuscript received November 28, 2016, accepted November 29, 2016.
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Outcomes With FIRM Ablation in AF
ABBREVIATIONS
patients with clinical AF (9). This has shown
medications for 5 half-lives (2 to 6 weeks in patients
AND ACRONYMS
that AF is driven by stable endocardial micro–
on amiodarone). Electrode catheters were advanced
re-entrant sources where targeted ablation
to the coronary sinus and right atrium and then trans-
terminated AF (9), with transient epicardial
septally to the left atrium. A 64-pole basket catheter
AF = atrial fibrillation FIRM = focal impulse and rotor modulation
IQR = interquartile range LA = left atrial LPeAF = long-standing persistent atrial fibrillation
PAF = paroxysmal atrial fibrillation
breakthroughs or partial re-entry. These re-
(Constellation, Boston Scientific, Natick, Massachu-
sults are similar to recent clinical reports of
setts [n ¼ 44]; or FIRMap, Abbott Electrophysiology,
AF sources (10) and also reconcile less stable
Menlo Park, California [n ¼ 126]) was advanced
sources seen by epicardial mapping (11).
through an 8.5-F sheath to map AF in both atria in
However, rotors (12) and sources (13) are not
sequence. Basket sizes were selected to approximate
found by classical mapping, possibly because
the left atrial (LA) size on pre-procedural computed
of limitations of marking electrograms in AF
tomography or acquired electroanatomic mapping
(14) and/or other technical limitations (15).
PeAF = persistent atrial
The aim of the IU-FIRM (Indiana Univer-
fibrillation
atrial “shell,” then positioned to optimize fluoroscopic coverage and electrogram signals (Figure 1).
PVI = pulmonary vein isolation
sity FIRM) registry was to: 1) determine if
Generally, baskets sized to fit the left atrium tended
RA = right atrial
rotors and focal sources are common in a
to map the right atrium well.
RF = radiofrequency
large real-world population of unselected
Digital electroanatomic atrial shells were created
patients with PeAF, long-standing PeAF
using Carto (Biosense Webster, Diamond Bar, Califor-
(LPeAF), or PAF; 2) discover whether intervention at
nia). Intravenous heparin was administered as a bolus
sources supports their mechanistic role across AF
after femoral access, followed by infusion to achieve
phenotypes; and 3) establish the “real-world” clinical
activated clotting times >350 s. Unipolar atrial elec-
outcomes of rotor- and source-based ablation.
trograms from the basket catheter were filtered at 0.05
SEE PAGE 1270
METHODS
to 500 Hz and recorded at a 1-kHz sampling frequency for export from the electrophysiological recording system (Bard/Boston Scientific, Lowell, Massachusetts). AF was the presenting rhythm in 96 patients (57%),
STUDY DESIGN. We studied 170 consecutive patients
atrial flutter in 11 (6%), and sinus rhythm in 63 (37%).
referred to Indiana University/Methodist Hospital
In patients presenting in sinus rhythm or in whom
from January 2012 to October 2015 for ablation of
presenting AF or atrial flutter was terminated by
symptomatic AF for standard indications (3). Subjects
ablation, AF induction was attempted using rapid
were $18 years of age, with AF despite $1 antiarrhythmic drug. Patients were excluded if they were
pacing with or without isoproterenol (5 to 15 m g/min) or epinephrine (0.05 to 0.2 m g/kg/min) as needed.
unable or refused to provide written informed consent
MAPPING AF SOURCES. FIRM mapping has been
or did not have sustained AF (>5 min) during the pro-
described elsewhere (10). Briefly, unipolar AF elec-
cedure. The population included patients with PAF,
trograms recorded using basket catheters are pro-
PeAF, or LPeAF by standard definitions (3). This was
cessed using algorithms to determine propagation
the first ablation procedure for most patients, although
sequences. When deflections are monophasic or
73 (43%) had undergone at least 1 prior ablation pro-
noncomplex, mapping can identify rotational or focal
cedure. Table 1 summarizes patient characteristics.
activations as previously illustrated (10). In cases in
Each patient underwent AF mapping using a
which AF deflections are multiphasic, the use of
multipolar catheter inserted sequentially into both
classical rules such as dV/dt may mark deflections
atria as previously described, followed by computa-
within repolarization (far-field) (14). In such cases,
tional methods to interpret electrograms using repo-
FIRM assigns local activation on the basis of physio-
larization and conduction dynamics to reveal sources
logical information, such as action potential duration
(16). Ablation targeted the identified sources in each
restitution (17) to account for changes in refractori-
patient. One hundred sixty-one patients (95%) also
ness with changes in cycle length during AF, and then
underwent pulmonary vein isolation (PVI); the
applies phase analysis to identify rotors. The system
remaining 9 patients prospectively declined this.
(RhythmView, Abbott Electrophysiology, Menlo Park,
Follow-up with event and/or ambulatory monitoring
California) then generates AF propagation maps,
or implantable device interrogation in 151 patients
which are subsequently correlated to corresponding
(89%) was used to determine clinical efficacy and
basket electrode locations within the chamber.
establish the mechanistic impact of interventions targeting these defined mechanisms.
AF propagation (FIRM) maps were analyzed in near real time for FIRM-guided ablation at sources. Electric
ELECTROPHYSIOLOGIC STUDY. Electrophysiologic study
rotors (Figure 2D) were defined as rotational activa-
was performed after discontinuing antiarrhythmic
tion
around
a
phase-mapped
singularity
that
Miller et al.
JACC VOL. 69, NO. 10, 2017 MARCH 14, 2017:1247–56
1249
Outcomes With FIRM Ablation in AF
generated peripheral disorganization, while focal impulses showed centrifugal spread of activation
T A B L E 1 Characteristics of Population
from an origin. Rotors and focal impulses were considered AF sources if they existed in consistent
Overall (n ¼ 170)
Paroxysmal AF (n ¼ 64)
Persistent AF (n ¼ 52)
Long-Standing Persistent AF (n ¼ 54)
p Value
59 12
57 12
61 11
59 12
NS
spatial regions of 2 to 8 cm 2 (with some precession
Age, yrs
[18]) on repeated maps.
Male/female
135/35
52/12
36/16
47/7
NS
ABLATION APPROACH. Radiofrequency (RF) energy
Prior ablations
73 (43)
31 (48)
23 (19)
19 (35)
0.34
Presented in AF
96 (56)
4 (6)
44 (85)
48 (89)
<0.001
(ThermoCool or SmartTouch, Biosense Webster) at
Left atrial diameter, cm
5.2 1.0
4.9 1.0
5.4 0.9
5.3 1.1
NS
20 to 35 W. Ablation commenced guided by FIRM data
Ejection fraction, %
47 10
50 7
46 10
46 11
NS
was delivered with a 3.5-mm tip irrigated catheter
in 131 patients (77%). FIRM-guided ablation followed PVI in 39 patients (23%). RF energy was delivered for
Values are mean SD, n, or n (%). AF ¼ atrial fibrillation; NS ¼ not significant.
approximately 30 s at any 1 location to cover the 2- to 8-cm2 area of AF sources with closely spaced RF applications (Figures 2 and 3), to achieve an electrogram amplitude
decrease
of
>70%.
The
The secondary outcome was freedom from all atrial
procedural
arrhythmias after blanking. Subjects were followed for
endpoint was rotor elimination on repeat mapping or
at least 6 months (mean 15 10 months) post-
noninducibility of AF, if ablation terminated the
procedure. In patients with arrhythmia recurrence af-
arrhythmia to sinus rhythm. When AF terminated
ter the blanking period, continued observation, anti-
during ablation, RF application was continued to
arrhythmic drug therapy or repeat ablation was offered
eliminate electrograms in the region designated by
(3). If ablation was performed, detailed mapping was
mapping (Figures 2 and 3). Thereafter, attempts were
repeated. Results presented hereafter are those of the
made to reinitiate AF as noted previously, and repeat mapping and ablation were performed if AF, atrial flutter, or tachycardia was induced. The duration of FIRM mapping and ablation, from initial basket deployment to the end of final ablation of FIRMdesignated sources, was 94 54 min. Conventional ablation (PVI [3]) was performed in all patients but those in whom FIRM-only therapy was used or patients in whom PVI was present from prior procedures. Ablation comprised widearea circumferential ablation of left and right pulmonary vein pairs, verifying pulmonary vein entrance and exit block using a circular mapping catheter (Lasso, Biosense Webster). Adenosine challenge or pacing along the ablation line was used to confirm isolation at procedure’s end. If atrial tachycardia or flutter was diagnosed, mapping and ablation were performed as feasible; when linear right atrial (RA) or LA ablation was used for this, confirmation of bidirectional con-
index FIRM procedure only. STATISTICAL ANALYSIS. Continuous variables are
summarized as mean SD and were compared using analysis of variance, after being verified as normally distributed by the Kolmogorov-Smirnov test. Nominal variables were compared between patient groups using chi-square tests or Fisher exact tests if expected cell frequencies were <5. Long-term outcomes were assessed, and survival analyses were conducted using the Cox proportional hazards model, censoring patients after events. Survival curves were generated using the Kaplan-Meier method and compared using log-rank tests. The proportionality assumption was deemed satisfied upon inspection of log-log plots. A p value of <0.05 was considered to indicate statistical significance.
RESULTS
duction block along such lines was used. AF persisting
STABLE SOURCES OBSERVED ACROSS AF CLASSES. All
after the completion of ablation was cardioverted.
patients had intraprocedural AF, of whom 96 (57%)
POST-PROCEDURAL
presented in AF (Table 1). FIRM mapping revealed
CARE. During
a 3-month post-
ablation “blanking period,” antiarrhythmic medica-
stable AF rotors or focal sources in all cases. Of 3.5
tions were continued in 8% of patients, then
2.1 sources per patient (median 4; interquartile range
discontinued in all but 2 patients (by patient prefer-
[IQR]: 3), 54% were in the left atrium (2.3 1.3 per
ence). No repeat ablation procedures were performed
patient; median 2; IQR: 2) and 46% in the right atrium
in the blanking period. The primary endpoint was
(2.1 1.3 per patient; median 2; IQR: 2) (Table 2). Per
freedom from AF after a single procedure, defined as
patient, 85% had at least 1 RA source; 90% had LA
AF >30 s on ambulatory electrocardiography and/or
sources. Of the 17 patients without LA sources, 5 had
event monitors (3) or implanted device interrogation
AF termination during RA ablation without subse-
(n ¼ 24) following the 3-month blanking period.
quent AF inducibility, precluding LA source mapping.
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Outcomes With FIRM Ablation in AF
F I G U R E 1 Patient-Tailored Atrial Fibrillation Mapping
(A) 50-mm basket (FIRMap) placed in the right atrium through a long sheath, then trans-septally into the left atrium. Red arrows denote boundaries of basket splines. Note that in the left atrium, the basket is posterior to the coronary sinus (right anterior oblique) and covers most of the left atrium (left anterior oblique). (B) Raw atrial fibrillation (AF) unipolar electrograms from basket catheter in the left atrium; 12 electrocardiographic leads (top) and red signals (center, from coronary sinus) show clear AF. Recordings from each basket spline are grouped by color (8 recordings/spline). Abl ¼ ablation catheter; Eso ¼ esophageal temperature probe; His ¼ His bundle recording.
Most sources were rotors, with 24 (14%) being foci (16
recurrent AF, atrial flutter, or atrial tachycardia versus
RA, 8 LA). Mean procedure duration was 356 60
27 of 103 (26%) without termination (p ¼ 0.12).
min; mean fluoroscopy time was 25 13 min.
AF TERMINATION BY ABLATING RA ROTORS. A
Figure 2 shows AF in a 51-year-old man with PeAF
specific goal of the IU-FIRM registry was to define the
and no prior ablation (Figure 2A). RA FIRM mapping
role of RA rotors and focal sources. Figure 3 shows
showed a posterior septal rotor where ablation had no
termination of PeAF to sinus rhythm by RA rotor
effect on the rhythm. LA FIRM mapping revealed a
ablation alone in a 55-year-old man. The patient was
rotor on the anteromedial wall (Figure 2D) where
free of AF at 1.5-year follow-up.
ablation slowed and organized the rhythm to a rapid
Overall, RA FIRM ablation alone terminated AF in 9
flutter (Figure 2B) that then terminated to sinus
patients. Sources were located in several areas of the
rhythm (Figure 2C) after a total of 3.1 min. AF was then
right atrium, with no single characteristic site.
noninducible, and per patient request, ablation concluded using FIRM-only guidance (Figure 2E)
LONG-TERM EFFICACY FROM FIRM-GUIDED ABLATION.
without PVI. The patient remained free of AF after 16
Freedom from AF after a single-FIRM procedure at
months following FIRM-only ablation.
1 year (IQR: 222 to 629 days) off medications in all but
AF TERMINATION WITH FIRM-GUIDED ABLATION. Table 3
2 patients (as noted earlier) in the IU-FIRM registry
summarizes rates of AF termination from FIRM abla-
was 87% (Central Illustration). Freedom from AF was
tion alone. Most of these terminated to sinus rhythm
higher for PAF than for PeAF or LPeAF (95% vs. 83%
(n ¼ 38 [57%]) (Figure 2C) rather than typical RA flutter
vs. 82%, respectively, p < 0.01). Freedom from all
(n ¼ 8; all were ablated successfully) or nonflutter atrial
atrial tachyarrhythmias after a single FIRM procedure
tachycardia (n ¼ 21; 12 were ablated, 9 terminated with
at 1 year (IQR: 179 to 570 days) off medications in the
pacing or catheter manipulation and were not seen
IU-FIRM registry was 70%. The Central Illustration
again). AF terminations by FIRM-guided ablation were
shows that freedom from all atrial tachyarrhythmias
more common in patients with PAF than in those with
was higher for PAF and PeAF than for LPeAF (77% vs.
PeAF or LPeAF (59% vs. 37% vs. 19%, respectively,
75% vs. 57%, respectively, p <0.02).
p < 0.001). Of note, there was no relationship between
COMPLICATIONS. The
acute termination of AF (to sinus or organized atrial
overall serious complication rate of 3.5%, including 3
tachyarrhythmia)
arrhythmia
cases of cardiac tamponade requiring drainage,
recurrence: 10 of 67 (15%) with terminations had
1 pericardial effusion, 1 case of heart block, and
and
freedom
from
IU-FIRM
registry
had
an
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Outcomes With FIRM Ablation in AF
F I G U R E 2 Left Atrial Rotor Sustains Persistent Atrial Fibrillation Present for >8 Months in a 51-Year-Old Man With
3 Transiently Successful Past Cardioversions
(A) Atrial fibrillation (AF) at baseline. (B) After 1.3 min of ablation at focal impulse and rotor modulation (FIRM) site, AF organized to atypical flutter. (C) After 3.1 min of radiofrequency ablation, the rhythm terminated to sinus rhythm. (D) Anteroseptal left atrial (LA) rotor on FIRM mapping. (E) Anterior view of electroanatomic shells (right atrium, green; left atrium, gray); successful septal LA FIRM site (red dots; total ablated area w8 cm2). This patient declined pulmonary vein isolation and remained free of AF or atrial tachycardia off antiarrhythmic medications at >16 months. IVC ¼ inferior vena cava; LIPV ¼ left inferior pulmonary vein; LSPV ¼ left superior pulmonary vein; SVC ¼ superior vena cava.
1 spontaneous epidural hematoma. None were related
medications). In an important subset of patients
to the basket catheter. Other complications included
who declined PVI, the ability of FIRM-only ablation
mild hematuria (2 cases) and 2 moderate femoral
to eliminate AF on long-term follow-up strongly sup-
hematomas that did not require intervention. No
ports the mechanistic role of rotors and sources. Thus,
strokes, peripheral emboli, phrenic nerve injuries, or
the IU-FIRM registry shows that clinical and mecha-
atrioesophageal fistulae were noted. There were no
nistic conclusions from the CONFIRM (Conventional
procedural deaths.
Ablation With or Without Focal Impulse and Rotor
DISCUSSION
Modulation) trial and optical mapping of human atria apply broadly to patients referred for AF ablation and that FIRM-guided ablation may improve success rates
The IU-FIRM registry supports the mechanistic role
above those expected from PVI alone.
of localized rotors and focal sources in sustaining PeAF, LPeAF, and PAF. Ablation at FIRM-mapped
MECHANISTIC IMPLICATIONS. Our data support re-
sources in the left or right atrium was able to termi-
sults from optical mapping of AF in human atria (9)
nate AF in patients across disease classes. In combi-
and clinical studies (10) that human AF is sustained
nation with PVI, ablation produced 87% freedom
by localized sources. The ability of FIRM-guided
from AF after a single FIRM procedure at 1 year in
ablation to terminate AF often to sinus rhythm in
patients, mostly those with nonparoxysmal AF
patients with all AF phenotypes strongly supports a
(almost none of whom were taking antiarrhythmic
mechanistic role for rotors and focal sources, as do
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Outcomes With FIRM Ablation in AF
F I G U R E 3 Right Atrial Rotor Sustains Persistent Atrial Fibrillation for >3 Months in a 55-Year-Old Man
(A) Atrial fibrillation (AF) at baseline. (B) AF terminated while ablating at right atrial (RA) rotor. (C) Electroanatomic map of RA rotors; the pink dot at the center of the yellow dots is the site of termination to sinus (total ablated area w2.5 cm2). The patient remained free of AF or atrial tachycardia off antiarrhythmic medications at >18 months.
results of FIRM-guided ablation alone, albeit in a
limit multiple wavelets does not improve success (6,7).
small subset of patients.
Of note, in preliminary studies, AF rotational sources
Debate continues on AF mechanisms, yet it is
identified by high-resolution optical mapping in
increasingly clear that this may in part reflect the
explanted human hearts are also identified by basket
choice of mapping tools. Classical electrogram map-
electrodes and FIRM methods (21).
ping nicely indicates the complexity of AF substrates
Although termination of fibrillation (especially
(13), yet electrograms in AF often show far-field
when persistent) to an organized atrial tachyar-
mixed with local activity (14,19). This may explain
rhythmia or sinus rhythm is proof of concept and
why classical electrogram mapping of AF rarely shows
validates the mechanistic nature of rotors and focal
rotors, whereas optical mapping studies, including in
sources in AF maintenance, the poor correlation of
explanted human atria (9), show AF maintained by
termination with long-term freedom from recurrent
rotational drivers or focal sources.
arrhythmia is perplexing. This may reflect incomplete
Localized AF sources may explain observations that
eradication of the entire rotor substrate in cases in
AF can be terminated by focused interventions (10,20),
which ablation terminates AF, similar to the poor
and why extensive ablation that would be expected to
correlation of long-term freedom from recurrent typical RA flutter when arrhythmia termination rather than demonstration of bidirectional cavotricuspid
T A B L E 2 Procedural Data
isthmus block is the procedural endpoint. Currently, the only means of determining that the rotor sub-
Type of AF
strate has been eliminated is remapping during
Overall (n ¼ 170)
Paroxysmal (n ¼ 64)
Persistent (n ¼ 52)
Long-Standing Persistent (n ¼ 54)
Patients (% of total)
144 (85)
49 (77)
44 (85)
51 (94)
0.03
possible if fibrillation terminates and cannot be
Total (per patient)
297 (2.1)
95 (1.9)
90 (2.0)
112 (2.2)
NS
reinitiated. Future technical advances may help
Patients (% of total)
153 (90)
55 (86)
47 (90)
51 (94)
NS
Total (per patient)
352 (2.3)
113 (2.1)
108 (2.3)
131 (2.6)
NS
FIRM RF area, cm2
15 9
12 8
15 8
20 10
<0.001*
RF time for FIRM, min
24 12
23 14
24 12
28 12
NS
ported experience of FIRM-guided ablation to date and
p Value
resolve when the substrate has been fully treated.
Left atrial sources
Total RF time, min Procedure time, min Fluoroscopy time, min
ongoing fibrillation and observing that the previously targeted rotor or focus has been eradicated; this is not
Right atrial sources
COMPARISON WITH OTHER STUDIES OF FIRM-GUIDED ABLATION. The IU-FIRM registry is the largest re-
56 14
51 18
60 9
59 15
NS
validates the original CONFIRM trial (10) and smaller
356 60
358 59
342 46
372 56
NS
reports that FIRM-guided ablation can produce favor-
25 13
29 14
21 10
27 12
NS
able results in unselected patients with all types of AF.
Values are n (%), n (n per patient), or mean SD. *Paroxysmal AF versus long-standing persistent AF. FIRM ¼ focal impulse and rotor modulation; RF ¼ radiofrequency; other abbreviations as in Table 1.
Single-procedure freedom from AF of 87% at 1 year in our study supports the 80.5% freedom from AF in the 10-center registry of FIRM-guided ablation in
Miller et al.
JACC VOL. 69, NO. 10, 2017 MARCH 14, 2017:1247–56
1253
Outcomes With FIRM Ablation in AF
78 patients (22) and the 82.4% success in the CONFIRM trial (10). These results are substantially
T A B L E 3 Termination Rates, Focal Impulse and Rotor Modulation–Guided Ablation
Type of AF
better than the 38% freedom from AF and 21% freedom from all arrhythmias reported by Buch et al. (23) in 43 patients (one-half with PAF). This might be
Termination
Overall (n ¼ 170)
Paroxysmal (n ¼ 64)
Persistent (n ¼ 52)
Long-Standing Persistent (n ¼ 54)
p Value
explained by technical factors applying FIRM or PVI
To sinus rhythm
38 (22)
25 (39)
8 (15)
5 (9)
0.002
(15) or challenging patients and must be reconciled.
To atrial flutter/tachycardia
29 (17)
13 (20)
11 (21)
5 (9)
<0.001
Gianni et al. (24) reported single-procedure freedom
Total
67 (39)
38 (59)
19 (37)
10 (19)
<0.001
from AF or atrial tachycardia off drugs in PeAF and LPeAF of only 17% at 6 months by FIRM-guided
Values are n (%). AF ¼ atrial fibrillation.
ablation alone (i.e., without PVI). It is unclear if those results are worse than in our series because of relatively early experience with FIRM mapping and ablation by these seasoned investigators, with 29
(Sustained Treatment of Paroxysmal Atrial Fibrilla-
procedures among several operators. Differences may
tion) (30), and other trials. Because PVI was also used
also reflect study design, as in that trial, when FIRM
in most of our patients, the effect of FIRM on subse-
organized AF to atrial tachycardias, they were not
quent atrial tachycardias is not clear. Further study is
ablated
needed to clarify these results.
but
cardioverted.
Conversely,
in
the
CONFIRM trial and in this study, atrial tachycardias
FUTURE DIRECTIONS. Additional clinical studies are
were targeted for ablation, which may reduce their
required to determine if the results of FIRM-guided
recurrence. FIRM-guided ablation has been success-
ablation in the IU-FIRM and other recent indepen-
ful in challenging patients in other studies; Sommer
dent studies are maintained on long-term follow-up
et al. (25) reported 80% freedom from atrial ar-
(2 to 5 years), as in the CONFIRM trial (29). It is
rhythmias in patients with mostly LPeAF, and 70% to
important to determine why the results of the IU-FIRM
80% success was reported by Tomassoni et al. (26)
registry are better than those of FIRM with PVI in 2
and Rashid and Sweeney (27).
recent studies by Buch et al. (23) in 43 patients. If dif-
FIRM-GUIDED VERSUS OTHER FORMS OF ABLATION
ferences in outcomes with our 170 patient series reflect
ACROSS
relatively large
more extensive experience in the FIRM technique,
population of the IU-FIRM registry provides the first
then efforts must be made to reduce the learning
opportunity to dissect FIRM-guided ablation results
curve. If differences reflect study design, then treat-
across types of AF, showing favorable success across
ment should be standardized to include such ele-
all AF subgroups (Central Illustration).
ments. Finally, if variations in outcome reflect
AF
POPULATIONS. The
In patients with nonparoxysmal AF (n ¼ 106), the single-procedure success rate was higher than the
different patient cohorts, then both ideal and less ideal populations must also be defined and studied.
approximate 55% freedom from AF on or off medi-
STUDY LIMITATIONS. Although IU-FIRM was not
cations or approximate 40% freedom from all ar-
randomized, it is a relatively large registry of
rhythmias
STAR-AF2
consecutive patients at a large academic medical
(Substrate and Trigger Ablation for Reduction of
off
medications
in
the
center. A strength of this study is that our experience
Atrial Fibrillation Part 2) trial (6). For patients with
may have circumvented limitations encountered by
PAF (n ¼ 64), single-procedure success in the IU-
otherwise seasoned investigators with less experi-
FIRM registry (95% freedom from AF, 77% freedom
ence in FIRM mapping or FIRM-guided rotor elimi-
from all atrial arrhythmias) was higher than the
nation. The number of cases needed to achieve
60% to 65% freedom from AF in recent trials of
success with FIRM-guided ablation will vary with
contact force catheters (4,5) or the FIRE AND ICE
patient selection, operator skill, and other factors.
study (comparing cryoballoon or RF ablation), in
Because this was a registry study, it is difficult to
which repeat ablation was permitted in the blanking
exclude case-related differences in PVI or other
period (28).
ablation in contributing to outcomes in some cases.
The IU-FIRM registry also provides the first series
However, many PVI trials included additional abla-
able to detect whether FIRM-guided ablation pro-
tion even for PAF (4,31), such as RAAFT-2 (Radio-
duces a substantial rate of atrial tachycardias. The
frequency Ablation Versus Antiarrhythmic Drugs as
16.5% rate of atrial tachycardias in IU-FIRM and rates
First-Line
found in other studies (22,25,29) are comparable to
which included 20% to 40% use of additional targets,
those from PVI alone in the STAR-AF2 (6), STOP-AF
including linear ablation and ablation of complex
Therapy
of
Atrial
Fibrillation-2)
(31),
Miller et al.
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Outcomes With FIRM Ablation in AF
C E NT R AL IL L U STR AT IO N Ablating Localized Sources for Atrial Fibrillation: Clinical Benefit
B
1-Year Freedom from Recurrent AF
1-Year Freedom from Recurrent AT/AF
100
100
80
80 Arrhythmia-Free Survival (%)
Arrhythmia-Free Survival (%)
A
60
40
60
40
20
20
0
0 0
100
200
300
400
0
100
200
Days Number at risk
64 52 54
55 37 46
62 49 54
All Patients
300
400
38 20 31
34 14 25
Days 45 22 35
43 16 31
Paroxysmal AF
Number at risk
64 52 54
Persistent AF
62 49 54
50 34 37
Long-Standing Persistent AF
Miller, J.M. et al. J Am Coll Cardiol. 2017;69(10):1247–56.
(A) Freedom from recurrent atrial fibrillation (AF) after focal impulse and rotor modulation (FIRM) ablation. Kaplan-Meier curves are displayed for freedom from recurrent AF in each group as well as aggregate (legend at bottom), with number at risk at each 100 days of follow-up shown at bar at bottom. (B) Freedom from recurrence of any atrial arrhythmia after FIRM ablation. Kaplan-Meier curves are displayed for freedom from any recurrent atrial arrhythmia in each group as well as aggregate (legend at bottom), with number at risk at each 100 days of follow-up shown at bar at bottom. AT ¼ atrial tachycardia including flutter.
of
substrate ablation. Mechanistically, the ability of
follow-up electrocardiographic monitoring was not
targeted ablation at localized rotors and focal sources
possible because of the wide area of patient referrals,
to terminate AF and eliminate AF on long-term
and thus some asymptomatic episodes of AF or other
follow-up supports the role of sources in the left
arrhythmias may have escaped detection; however,
and right atrium in maintaining AF. These data
only 5 patients without known arrhythmia recurrence
strongly motivate randomized controlled trials of
had no long-term monitoring. Finally, these results
FIRM-guided ablation.
fractionated
electrograms.
Complete
control
must be compared with those of PVI alone in a randomized clinical trial; such trials are under way.
CONCLUSIONS
ACKNOWLEDGMENTS The
Straka,
RN,
for
authors
coordinator
thank
support
and
Susan Tina
Baykaner, MD, MPH, for statistical support.
The IU-FIRM registry is the largest reported series of FIRM-guided ablation for unselected patients with a
ADDRESS FOR CORRESPONDENCE: Dr. John M.
range of AF presentations, mostly nonparoxysmal AF.
Miller, Krannert Institute of Cardiology, Department
We found that FIRM-guided ablation at AF substrates
of Medicine, Indiana University, 1800 North Capitol
produced single-procedure success rates higher than
Avenue, E-488, Indianapolis, Indiana 46202. E-mail:
those from PVI alone or with traditional forms of
[email protected].
Miller et al.
JACC VOL. 69, NO. 10, 2017 MARCH 14, 2017:1247–56
Outcomes With FIRM Ablation in AF
PERSPECTIVES COMPETENCY IN PATIENT CARE AND
TRANSLATIONAL OUTLOOK: Further studies are
PROCEDURAL SKILLS: Use of FIRM technology to
needed to more clearly define the role of FIRM-guided AF
localize areas of atrial myocardium responsible for
ablation and to identify characteristics of patients most
maintenance of AF results in greater freedom from
likely to gain incremental benefit from this approach.
recurrent AF than PVI alone.
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KEY WORDS ablation, AF termination, atrial fibrillation, clinical trial, electrical rotors, FIRM